SECTION 9 Sexually transmitted diseases

9.1 Epidemiology of sexually transmitted infection

9.1 Epidemiology of sexually transmitted infections 1589

ESSENTIALS Although accurate incidence figures are not available in most coun- tries, sexually transmitted infections are a large cause of morbidity worldwide. The burden falls especially heavily on women and in- fants, with up to half a million perinatal deaths attributable to syph- ilis annually. Mobile populations, those with many sexual partners, and those whose partners have many partners are at increased risk, and the prevalence of treatable sexually transmitted infections is many times higher in poor populations, who often lack access to effective treatment. Other sexually transmitted infections, especially those that cause genital ulceration, increase the risk of human im- munodeficiency virus transmission. Incidence In Western countries, the reported incidence of many sexually transmitted infections fell during the 1980s and 1990s, probably as a result of changes in sexual behaviour resulting from the human immunodeficiency virus epidemic, but has increased subsequently. The reported incidence of Chlamydia trachomatis infection has increased in the general population, especially in teenagers and young adults, and the incidence of syphilis and gonorrhoea has increased in high-​risk groups, particularly men who have sex with men. Although accurate data are not available from most low-​ and middle-​income countries, there is no doubt that sexually trans- mitted infections are more prevalent in the developing world. Strategies to control sexually transmitted infections These include health education and the promotion of condoms; the provision of accessible, acceptable, and affordable clinical ser- vices to provide effective treatment and hence prevent complica- tions and further transmission; and partner notification to reach infected people who may not present to a health facility. Since many sexually transmitted infections are asymptomatic, screening programmes may also play an important role. Screening of preg- nant women for syphilis is recommended policy in most countries, and has been shown to be cost-​effective even where the prevalence is low. Screening programmes for C. trachomatis infection have re- cently been implemented in some Western countries, and there is some evidence that they have reduced the incidence of complica- tions such as pelvic inflammatory disease. Introduction Few countries outside Western Europe and North America have accurate reporting systems for sexually transmitted infections (STIs). As a result, in most of the world’s population, the in- cidence of these infections is unknown. Knowledge of their epidemiology is based on the results of improvised prevalence surveys undertaken in convenient populations (e.g. antenatal clinic attenders), but these might not be representative of the population as a whole. In an attempt to calculate the worldwide incidence of the four most common curable STIs—​syphilis, gonorrhoea, trichomon- iasis, and chlamydial infection—​the World Health Organization (WHO) estimated the prevalence of each infection by region, on the basis of published surveys, and divided this figure by the esti- mated duration of the infection. They concluded that, each year, an estimated 357 million cases of curable STIs (excluding chancroid) occur worldwide (Fig. 9.1.1). The most common (curable) is tricho- moniasis (143  million cases), followed by chlamydial infection (131 million), gonorrhoea (78 million), and syphilis (5.6 million). In view of the uncertainty surrounding the prevalence estimates, the duration of untreated STIs, and the mean duration before ef- fective treatment is received, these figures cannot be considered definitive. Transmission of STIs The rate at which an STI spreads in a population depends on the average quantity of new cases of infection generated by an infected individual, that is, the basic reproductive number (R0). This in turn depends on the mean rate of sexual partner change (c), the average duration of the infection (D), and its infectiousness (i.e. the likeli- hood of it being transmitted per sexual act, β). This relationship has been described by the simple formula R0 = βcD. When R0 falls below 1 in a given population, the infection will eventually disappear. However, even when R0 is less than 1 in the general population, infections can be maintained in core groups with a high rate of change of sexual partners, and might continue to occur in the general population as a result of sexual contact with members of high-​risk groups. 9.1 Epidemiology of sexually transmitted infections David Mabey and Anita Vas-​Falcao

Section 9   Sexually transmitted diseases 1590 The duration of a curable infection depends on the time that elapses before effective treatment is given, which is largely deter- mined by the healthcare-​seeking behaviour of the population and their access to healthcare. A disease such as chancroid, which al- most always causes painful symptoms, is likely to be treated rapidly in populations with access to effective treatment. For this reason, it has almost disappeared in most industrialized countries, but re- mains endemic in core groups in some developing countries. In contrast, chlamydial infection, which is often asymptomatic in both sexes, is likely to be of longer duration and thus to persist even in affluent populations. Risk factors for STIs By definition, STIs are usually transmitted by sexual intercourse, although mother-​to-​child transmission is also of great public health importance in the case of syphilis and gonorrhoea. Those at highest risk are therefore those with many sexual partners, frequent change of partner, or those whose partners have many partners; in other words, those who belong to high-​risk sexual networks. These include sex workers and their clients, and mobile populations such as migrant labourers, truck drivers, fishermen, and soldiers. The youngest sexually active age groups are at particularly high risk, with 15-​ to 24-​year-​olds accounting for nearly half of all newly diagnosed STIs in the United Kingdom, despite representing only 25% of the sexually active population (Fig. 9.1.2). In Western coun- tries, the incidence of lymphogranuloma venereum (LGV) and syphilis is high among men who have sex with men (MSM), many of whom are also HIV positive. STIs are more common in poor populations. The incidence of gonorrhoea in black communities in the United States is 12 times than that of white communities, and similar to that in many developing countries. Poor people are at increased risk of STIs for several reasons. They might have to travel long distances away from their families in search of work. Many poor rural villagers have migrated into cities in low-​ and middle-​income countries (LMICs) in the last few decades, and many more have been dis- placed by wars and famines. Poverty and lack of education drive many women into sex work. Health education messages warning of the dangers of HIV/​AIDS might be lost on those whose most pressing need is the cost of their next meal. But perhaps most im- portantly, poor people often lack access to effective treatment for curable STIs. However, the control of STIs in resource-​limited 18 million 31 million 63 million 64 million WHO Region of the Americas WHO Eastern Mediterranean Region WHO Euopean Region WHO South-East Asia Region WHO Western pacific Region WHO African Region The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. 39 million 142 million Fig. 9.1.1  The global distribution of four curable STIs (syphilis, gonorrhoea, chlamydial infection, and trichomoniasis), 2015 data. Reprinted from WHO Factsheet: Sexually transmitted infections (STIs). © World Health Organization 2015. http://​www.who.int/​mediacentre/​factsheets/​fs110/​en/​

9.1  Epidemiology of STIs 1591 settings is achievable, with countries including Thailand and Cuba reporting sustained reductions comparable to the countries of North America and Europe. In China, paradoxically, rapid economic development has co- incided with a dramatic increase in the incidence of reported STIs. Rates of syphilis, which were bordering on elimination in the 1960s following a massive public health campaign including compulsory screening and treatment for those at risk, increased by more than 20-​fold between 1990 and 2005. This reflected the loss of free healthcare, which made screening and treatment in- accessible, particularly to the many migrant workers from rural areas seeking work in the cities. Since 2008, however, the Chinese government has invested heavily in surveillance and early treat- ment of STIs, and introduced point-​of-​care syphilis screening for pregnant women. Between 2008 and 2012, the number of re- ported cases of syphilis fell by 17%, and primary and secondary syphilis by 46%. STIs in developed countries In the United Kingdom, a free and confidential service for people with STIs was established in 1916. Details of patients seen at genito- urinary medicine (GUM) clinics are reported to the public health agency for that country and, since few patients are treated for STIs outside these clinics, the data are believed to be fairly complete and comprehensive. Since the epidemiology of STIs is similar in most countries in Western Europe, the figures for the United Kingdom will be cited as an example. Gonorrhoea The number of reported cases of both gonorrhoea and syphilis de- clined steadily from a peak in the early 1980s to the late 1990s, pre- sumably as a result of changes in sexual behaviour following the HIV epidemic (Fig. 9.1.3). Following this, the number of cases of 6000 4000 2000 0 2000 4000 6000 15–19 20–24 25–29 30–34 35–39 40–44 45–49 50–54 55–59 Rate per 100 000 Age group (years) Women Men Fig. 9.1.2  Rates of newa STI diagnoses in England 2016 by age and gender. a New STIs include chlamydia, anogenital warts (first episode), non​specific genital infection, anogenital herpes (first episode), gonorrhoea, syphilis (primary, secondary, and early latent), new HIV diagnoses (acute infection and AIDS-​defining illness), as well as chancroid/​LGV/​donovanosis, molluscum contagiosum, pelvic inflammatory disease (PID) and epididymitis, scabies/​pediculosis pubis, and trichomoniasis). © Crown copyright. Reproduced with permission of Public Health England. 1925 – 10 000 20 000 30 000 40 000 50 000 60 000 Male Female Total

Section 9   Sexually transmitted diseases 1592 gonorrhoea increased in the late 1990s, and has increased further since 2008, particularly in males (Fig. 9.1.4). In England, reported cases increased by 15% between 2012–​2014, and by 26% in MSM. The incidence in London was more than twice the national average and, as in the United States of America, was highest in ethnic minorities of African and Caribbean origin. Efforts to reverse the resurgence of gonorrhoea are hindered by increasing antimicrobial resist- ance. Resistance to third-​generation cephalosporins, the last class of antibiotics to which Neisseria gonorrhoeae is susceptible, is be- coming more prevalent. In the last 15 years, more than 10 countries have confirmed isolates with full resistance to extended spectrum cephalosporins, and a further 42 have noted strains with reduced susceptibility. Syphilis In England, the number of reported cases of primary and secondary syphilis increased by 35% between 2005 and 2014 (Fig. 9.1.5). This increase is largely due to cases among MSM in whom HIV was a common co​infection. In Eastern Europe, an epidemic of syphilis in the newly inde- pendent states of the former Soviet Union was reported in the 1990s. This was linked to changes in health infrastructure, sexual behaviour, and the emergence of the HIV/​AIDS pandemic. In 1999, the annual incidence of reported syphilis in these countries ranged from 55 to 180 per 100 000, with increases particularly evident in older adolescents. There was a 20-​fold increase in the reported in- cidence of syphilis in Russia between 1992 and 1996. Incidence peaked in 2007 before falling by fourfold to 59.9 per 100 000 popu- lation; however, accurate current data for these areas are not easily obtained. Chlamydial infection In Western countries, reported case numbers have increased dramatically since 2005. It is not clear to what extent this in- crease is due to an increase in the number of people tested, with some countries having started national screening programmes, or to the use of the more sensitive nucleic acid amplification tests, which became widely used in the late 1990s. Data from the latest national survey of sexual attitudes and lifestyles study (NATSAL) suggests that the increased reported incidence is largely due to increased testing, as most that tested positive for chlamydia had not been previously tested or attended a sexual health clinic in the last year, and the reported incidence in- creased considerably after the screening programme was intro- duced. Encouragingly, the reported incidence of complications of chlamydial infection, such as pelvic inflammatory disease (PID), epididymitis, and ectopic pregnancy, declined over the same period, presumably due to earlier identification and treat- ment of infections (Fig. 9.1.6). Reported incidence rates vary across the United Kingdom, ran- ging from 93/​100 000 (total male and female Northern Ireland) to 384/​100 000 (total England). As part of the NATSAL, there was a population-​based prevalence survey for C. trachomatis in- fection in men and women aged 16–​44 in the United Kingdom. 20 000 18 000 16 000 14 000 12 000 10 000 8000 Number of diagnoses reported Number of diagnoses of gonorrhoea reported by gender and sexual risk, England, 2010–2014 6000 4000 2000 0 2010 2011 2012 2013 2014 WSW Heterosexual men MSM Heterosexual women Fig. 9.1.4  Number of diagnoses of gonorrhoea by sex and by sexual risk. population, particularly MSMs. Data from Public Health England. © Crown copyright. Reproduced with permission of Public Health England.

9.1  Epidemiology of STIs 1593 4000 3500 3000 2500 2000 1500 1000 500 0 Number of diagnoses reported Number of diagnoses of syphilis reported by gender and sexual risk, England, 2010–2014 2010 2011 2012 Year 2013 2014 WSW Heterosexual men MSM Heterosexual women Fig. 9.1.5  Number of reported cases of syphilis by sex and sexual risk. Data from Public Health England. © Crown copyright. Reproduced with permission of Public Health England. 500 25 20 15 10 5 0 450 400 350 300 250 Diagnosis of chlamydia per 100 000 population Diagnosis of chlamydia per 100 000 population 200 150 100 50 0 2005 2006 2007 2008 2009 Year 2010 2005 2012 2013 2014 Diagnosis rate of chlamydia and chlamydial PID/epididymitis in the United Kingdom Chlamydia - male Chlamydia - total Chlamydial PID/Epipdidimytis - total Chlamydial epipdidimytis Chlamydial PID Chlamydia-female Fig. 9.1.6  Incidence of Chlamydia trachomatis infection, PID, and epididymitis in the United Kingdom.

Section 9   Sexually transmitted diseases 1594 Infection was found in 1.1% of men, and 1.5% of women, with the highest prevalence in men aged 20–​24 (3.4%) and women aged 18–​19 years (4.7%). Lymphogranuloma venereum (LGV), caused by the more inva- sive L1, L2, and L3 strains of C. trachomatis, had been a rare disease in industrialized countries since the 1960s, and was generally con- sidered a ‘tropical’ STI until 2003, when there was an outbreak of LGV proctitis due to the L2 serovar among homosexual men in the Netherlands. The disease has subsequently spread in the MSM com- munity across Western Europe, the United States, and Australasia, resulting in recommended screening in some countries including the United Kingdom and United States. The majority in whom the diagnosis is made are HIV positive. Rates of LGV rose steeply since 2003, peaking in 2010, and it is now considered to be endemic in the United Kingdom. Genital herpes The incidence of reported genital herpes in women in England was 73/​100 000 and 45/​100 000 in men in 2014, both these fig- ures increasing by at least two-​thirds since 2005. The worldwide prevalence of genital herpes simplex virus (HSV) infection is over 500 million. Classically, genital herpes is due to herpes simplex virus type 2 (HSV2), while herpes simplex type 1 (HSV1) causes oral lesions and is a common childhood infection. Once acquired, these infections persist for life, causing recurrent vesicular and ul- cerative lesions. In the United Kingdom, the proportion of genital ulcers due to HSV1 is increasing, presumably because of changing sexual practices. Human papillomavirus (HPV) HPV affects more than 290 million women worldwide, making it one of the most common STIs. Certain types of HPV (predomin- antly 6 and 11) cause genital warts, while others (predominantly 16 and 18) cause cervical carcinoma, the second most common cancer worldwide in women. Genital warts are the most frequently reported viral STI in GUM clinics in the United Kingdom, most commonly affecting those aged 18–​28. In England there were more than 70 000 reported cases in 2014, increasing slightly from 2005 but showing a downward trend from 2008. To reduce and ultimately prevent HPV-​associated cervical cancer, programmes administering HPV vaccines to young adolescent girls are being implemented in many countries. In the United Kingdom, HPV vaccination of girls was introduced in 2008, but adolescent boys are not vaccinated as they are in the United States and Australia. In 2014 vaccination coverage in the United Kingdom was approxi- mately 80% of the targeted population, and NATSAL 3 reported lower rates of HPV types 16 and 18 in 18-​ to 20-​year-​olds than NATSAL 2. In the future, using HPV tests for cervical screening rather than cytology could greatly improve the identification of women at risk of cervical cancer. STIs in developing countries Few reliable data are available on the incidence of STIs in developing countries, although the latest global burden of disease study con- firmed that the impact in terms of healthy life years lost was greatest in sub-​Saharan Africa. Based on numbers of cases seen at health facilities, it has been suggested that the incidence of gonorrhoea is at least 50 times higher in sub-​Saharan Africa than in the United Kingdom. Several large population-​based surveys have confirmed that the prevalence of STIs is high in sub-​Saharan Africa, even in rural populations. For example, 5–​10% of adults have been found to be infected with syphilis, 20–​30% of women, and 10% of men with Trichomonas vaginalis, and up to 50% of women were found to have bacterial vaginosis. Between 2.5% and 17% of pregnant women in Africa are infected with syphilis. A population-​based serological study in rural Tanzania found that 50% of women and 25% of men were infected with HSV2 by the age of 20 years. Seropositivity was rare before the age of 16 in both sexes, confirming that HSV2 is mainly transmitted sexually in this population. The proportion of genital ulcers caused by HSV2 has in- creased in Africa as a result of the HIV epidemic, as recurrences be- come more frequent and prolonged in the immunocompromized. At the same time, chancroid has apparently become less common in high-​risk populations in Africa, perhaps as a result of behav- ioural change resulting from the HIV epidemic. HPV causes 266 000 cervical cancer deaths per year, 88% of which occur in low-​income countries, and it is easily the most common malignancy in women in much of the developing world. This is secondary to the high incidence of sexually transmitted HPV infection. Despite this, few LMICs include HPV vaccination into their national immunization programmes. If 70% coverage can be achieved in these countries, then more than four million female deaths could be prevented. Interactions between HIV and other STIs Diseases such as chancroid, syphilis, and herpes, which cause genital ulceration, facilitate sexual transmission of HIV by increasing infectivity and susceptibility. A prospective study of STI clinic attenders in Nairobi, Kenya showed that the likelihood of a man who had acquired a genital ulcer from an HIV-​positive sex worker also acquiring HIV was about 1 in 6 after a single sexual ex- posure. This suggests that the presence of a genital ulcer increases the risk of transmission 50–​100-​fold. STIs such as gonorrhoea that cause genital discharge increase shedding of HIV in both seminal and cervicovaginal secretions. A  community-​randomized trial in Mwanza, Tanzania, found that improved STI services in rural health centres and dispens- aries, using the syndromic approach, reduced the incidence of HIV infection by 40% over a two-​year period. In Uganda, a community-​ randomized study found that periodic mass treatment for STIs had no impact on the incidence of HIV. In this trial, the HIV epidemic was more advanced, and a high proportion of genital ulcers were caused by HSV2, which was not treated. HIV and HSV2 appear to facilitate transmission of one another, leading to a vicious circle (Fig. 9.1.7). Control of HSV2, perhaps by vaccination, could greatly reduce transmission of HIV in the developing world, although clinical trials of suppressive treatment for herpes failed to show an impact on HIV incidence. Control of STIs Strategies for the control of STIs aim to reduce β (transmissibility), c (rate of partner change), or D, the duration of infection.

9.1  Epidemiology of STIs 1595 Primary prevention Transmissibility can be reduced by the use of condoms. Health pro- motion and health education aim to encourage the use of condoms, and to persuade people to have fewer sexual partners. This is some- times referred to as primary prevention, since these measures can prevent people from ever becoming infected. There have been few formal trials of health education in the primary prevention of STIs; but the example of health education in schools suggests that, al- though education often improves knowledge, it seldom influences behaviour. Education programmes were most effective when given by health workers, over a prolonged time, and with community involvement rather than just in school. It was also more effective when comprehensive rather than promoting abstinence only. In Thailand, legislation to close down brothels where condom use was not mandatory was successful in reducing the incidence and preva- lence of HIV infection in the general population. Transmissibility can also be reduced by biomedical means, such as HPV vaccination, microbicidal gels, and male circumcision, which has been shown to reduce the risk of heterosexual transmission of HIV by 60% as well as offering some protection against other STIs. Secondary prevention: case management The duration of treatable STIs can be reduced by the provision of accessible, acceptable, and affordable clinical services, combined with partner notification. Prompt treatment of STIs should be seen as a ‘public good’, equivalent to the treatment of pulmonary tuber- culosis, since it prevents transmission to others, as well as bene- fiting the person treated. The aims of patient care are: • to detect or rule out infection • to give treatment if necessary • to educate and counsel on treatment compliance, STI/​HIV pre- vention, and condom use • to ensure that sexual partner(s) are evaluated and managed (con- tact tracing) • to test for other STIs, including HIV In most developing countries, case management of STIs must be syndromic, because laboratory diagnosis is not available outside a few specialist centres. Syndromic management of genital ulcers and genital discharge in men is straightforward and cost-​effective, but syndromic management of vaginal discharge in women is not, because symptoms are poor predictors of the presence of an STI. A cheap, simple, point-​of-​care (POC) test for gonorrhoea and chla- mydial infection in women would be valuable in the control of these infections. To provide an adequate clinical service, the following compo- nents are needed: • Training should be given to health workers, for instance in the use of flowcharts to simplify the management of sexually trans- mitted infection (STI) patients, or to strengthen their health edu- cation and counselling skills. • Laboratory services need to be expanded, depending on the level of healthcare provided. A reference laboratory should be developed in each country to provide quality control, monitor the antimicrobial susceptibility of N. gonorrhoeae, and support operational research, for example, on the aetiology of common syndromes. • Information systems or surveillance are needed to gather epi- demiological data, to assess trends, and to provide data for programme planning and monitoring. Various surveillance methods can be used—​clinician notification, laboratory notifi- cation, sentinel site surveillance (either of syndromes or of aetio- logical diagnoses), or prevalence studies in specific population groups. Screening programmes Many people with STIs have no symptoms, and so do not seek ­medical care. While effective programmes for partner notifica- tion may identify some of these, screening programmes have been advocated to identify and treat these people. Because of the se- vere adverse effects of syphilis on the fetus, screening of pregnant women for syphilis is recommended policy in most countries, and remains a highly cost-​effective intervention even when the preva- lence of syphilis in pregnant women is less than 0.01%, as in the United Kingdom. POC tests are now available which can be per- formed anywhere, since they do not require laboratory equipment or electricity, and a combined POC test for HIV and syphilis offers an important opportunity to increase the coverage of antenatal screening for the prevention of mother-​to-​child transmission of both infections. Screening of other groups is more controversial. In some coun- tries where sex work is legal or tolerated, screening programmes for sex workers are routinely implemented. A study in the United States found that population-​based screening for chlamydial infec- tion reduced the incidence of pelvic inflammatory disease (PID). Conclusion A successful STI control programme, by reducing both the inci- dence and prevalence of STIs, will reduce the morbidity, suffering, and economic cost associated with these infections. By eliminating STIs as a facilitating factor for HIV transmission, and by con- tributing to behavioural changes towards safer sex, it will play an Altered frequency, natural history and response to Rx UNPROTECTED SEXUAL INTERCOURSE HIV Herpes Cofactor effect? IMPAIRED IMMUNITY Transmission, and progression to clinical disease? Fig. 9.1.7  Interactions between HIV infections and genital herpes.

Section 9   Sexually transmitted diseases 1596 important role in the prevention and control of HIV/​AIDS. In the longer term, control of STIs will depend on targeting and modi- fying high-​risk behaviour in key populations, and improved access to services for poor people, particularly women. FURTHER READING Chen X-​S, et al. (2011). The epidemic of sexually transmitted infec- tions in China: implications for control and future perspectives. BMC Medicine, 9, 111. Chico R, et al. (2012). Prevalence of malaria and sexually transmitted and reproductive tract infections in pregnancy in sub-​Saharan Africa: a systematic review. JAMA, 307, 2079–​86. Fleming DT, Wasserheit JN (1999). From epidemiological synergy to public health policy and practice: the contribution of other sexu- ally transmitted diseases to sexual transmission of HIV infection. Sex Transm Infect, 75, 3–​17. Fonner V, et al. (2014). School-​based sex education and HIV preven- tion in low-​ and middle-​income countries: a systematic review and meta-​analysis. PLoS Med, 9, e89692. Hawkes S, et al. (2013). Early antenatal care: does it make a difference to outcomes of pregnancy associated with syphilis? A systematic review and meta-​analysis. PLoS Med, 8, e56713. Health Protection Agency (2009). Syphilis and Lymphogranuloma Venereum: Resurgent Sexually Transmitted Infections in the UK. https://​www.gov.uk/​government/​uploads/​system/​uploads/​ attachment_​data/​file/​396987/​Syphilis_​and_​Lymphogranuloma_​ Venereum_​-​_​Resurgent_​Sexually_​Transmitted_​Infections_​in_​ the_​UK.pdf Kuznik A, et al. (2013). Antenatal syphilis screening using point-​of-​ care testing in sub-​Saharan African countries: a cost-​efffectiveness analysis. PLoS Med, 10, e1001545. Newman L, et al. (2013). Global estimates of syphilis in pregnancy and associated adverse outcomes: analysis of multinational ante- natal surveillance data. PLoS Med, 10, e1001396. Obasi A, et al. (1999). Antibodies to herpes simplex virus type 2 as a marker of sexual risk behaviour in rural Tanzania. J Infect Dis, 179, 16–​24. Schmid G (2004). Economic and programmatic aspects of congenital syphilis prevention. Bull WHO, 82, 402–​9. Sexually transmitted infections and chlamydia screening in England 2014. Public Health England Infection Report, Vol. 9, Issue 22, 23 June 2015. https://​www.gov.uk/​government/​uploads/​system/​uploads/​ attachment_​data/​file/​437433/​hpr2215_​STI_​NCSP_​v6.pdf Sonnenberg P, et al. (2014). Prevalance, risk factors, and uptake of interventions for sexually transmitted infections in Britain: find- ings from the National Surveys or Sexual Attitudes and Lifestyles (Natsal). Lancet, 382, 1795–​806. Tucker JD, et al. (2010). Scaling up syphilis testing in China: imple- mentation beyond the clinic. Bull WHO, 88, 452–​7. World Health Organization (WHO) (2013). Report on Global Sexually Transmitted Infection Surveillance. http://​who.int/​ reproductivehealth/​publications/​rtis/​stis-​surveillance-​2013/​en/

9.2 Sexual behaviour 1597

9.2 Sexual behaviour 1597

ESSENTIALS Discussion of sexual lifestyle and the ability to take a sexual history are relevant to many types of clinical practice. Most of the popula- tion is attracted to, and has sex, exclusively with people of the op- posite sex. The age at which people first have sex has decreased and the age at which people start cohabiting has become later in recent decades, increasing the time available to accumulate sexual part- ners and thus be at risk of sexually transmitted infections, including human immunodeficiency virus. While many people have few part- ners, a small proportion of the population has many. People with many partners are most at risk of sexually transmitted infections, but there are many other influences including the gender, age, and ethnicity of their partners and the type of sexual practice. Strategies to reduce the adverse consequences of sexual behaviour (including sexually transmitted infections and unintended preg- nancy) encourage reducing partner numbers, using condoms and effective contraception, and engaging in less risky practices. Issues with sexual function are relatively common and need to be considered in a range of clinical consultations. Introduction Most men and women are sexually active for a large part of their adult life and sexual fulfilment is important in enhancing the quality of many people’s lives. Patterns of sexual behaviour in populations are a key determinant of fertility and transmission of sexually transmitted infections (STIs). Discussion of sexual lifestyle and ability to take a sexual his- tory are relevant to many types of clinical consultations. Common topics include management of genitourinary symptoms, contra- ceptive advice, sexual dysfunction, and resumption of sexual ac- tivity following childbirth, major illnesses, or surgery. Sexual orientation Surveys of sexual behaviour in representative population samples show that most men and women are predominantly attracted to, and have experience with, members of the opposite sex throughout their lives. However, sexual orientation is not a simple dichotomy between ‘homosexual’ and ‘heterosexual’, but varies from ex- perience exclusively with people of the opposite-sex experience through various shades of attraction to, and experience with, both genders, to having exclusively same-​sex experience. Indeed, gender is increasingly recognized as being a more fluid concept, as more and more people identify as neither nor male nor female. In a large British study of adults aged 16–​74 years undertaken 2010–2012, 8.0% of men and 11.5% of women reported having sexual experience with someone of the same sex at some time. For some, this was a fleeting adolescent experience, followed in many cases by partnerships exclusively with people of the opposite-sex. A smaller proportion of the British population report same-sex partnerships involving some form of genital contact (5.5% of men and 6.1% of women). Similar findings are reported from France and the United States of America. Most of those with same-​sex partners have had experience of intercourse with someone of the opposite- sex at some time. Exclusively same-sex experience throughout life is thus relatively unusual. Age of first intercourse with someone of the opposite-sex The age of first intercourse with someone of the opposite-sex has been gradually decreasing over recent decades. The proportion of people having sexual intercourse before marriage has rapidly in- creased, so that sex before marriage has become almost universal in Britain. For men born in the years between 1935 and 1945, the median age of first intercourse was 18, and for women 19. For men and women born between 1985 and 1995, the median age at first intercourse is 16. Similar trends have been observed in other European countries and in the United States of America. English law gives the age of consent for intercourse with someone of the opposite-sex as 16, and it is illegal for a man to have sex with a woman under 16 in England (and other parts of the United Kingdom). The proportion of men and women in Britain reporting first intercourse before the age of 16 has risen rapidly over recent decades to 34.1% of men and 30.9% of women aged 16–​19 in 2010–​ 12. This has important implications for the provision of sex educa- tion and the timing of human papilloma virus (HPV) vaccination programmes. Those just embarking on their sexual careers may 9.2 Sexual behaviour Catherine H. Mercer and Anne M. Johnson

Section 9   Sexually transmitted diseases 1598 be most vulnerable to the unwanted consequences of unprotected sexual intercourse: STIs and termination of pregnancy are more common in 16-​ to 24-​year-​olds than in older men and women. Numbers of sexual partners The number of opposite-sex partners is highly variable. While many people have few partners, a small proportion has many. Among men aged 16–​74 in Britain, 67.0% reported zero or one opposite-sex partners in the last five years; 5.6% reported at least 10; and a small proportion reported hundreds or even thousands of partners during their lives. The risk of acquiring or transmitting an STI increases with the number of sexual partners. For example, in the British survey, 1.1% of men and women reporting one partner in the five years prior to the survey reported STI diagnoses, compared to 23.8% of those with at least 10 partners. Those with high numbers of part- ners may account for a relatively high proportion of STI transmis- sion in a community and for sustaining endemic STI transmission. The choice of partner also influences STI transmission in popu- lations. Age, gender, and ethnic mixing are important, as well as the extent to which people choose partners with lifestyles similar to their own (assortative mixing) or different (disassortative mixing), and whether they have serially monogamous or concur- rent partnerships. Commercial sex workers and their clients remain at high risk of HIV and STIs in some parts of the developing world where condom use is infrequent. In some countries, such as Thailand, public health campaigns have succeeded in increasing the use of condoms in commercial sex contacts. In many developed countries, although sex workers are at increased risk of STIs, there is evidence that high levels of condom use may protect both them and their clients. The proportion of men who have commercial sex contacts varies widely between countries. In the British survey, 11.0% of men aged 16–​74 years reported paying money for sex at some time in their lives, but considerably more frequent exposure is reported in other countries. Multiple partnerships with people of the opposite-sex are most common among young people, and among those who are not mar- ried or cohabiting. More than 1 in 10 men aged 16–​24 in Britain re- ported more than 10 partners during the previous five years, even though this group included many individuals who had not yet be- come sexually active. Age is not the only influence on sexual be- haviour. Whatever their age, those who are separated, divorced, or widowed are more likely than married people of a similar age to have multiple partners, illustrating the effects of the life course on pat- terns of partnership. Since the HIV epidemic emerged, public health campaigns have emphasized behaviour change for sexual health promotion. Some evidence suggests that, in the developed world in the late 1980s, there was a reduction in numbers of partners and in- creased use of condoms resulting in declining rates of STIs. However, since the late 1990s, these trends have been reversed with a return to risky sexual behaviour. In some parts of the developing world, such as Uganda and Thailand, the incidence of HIV has decreased, mainly due to changes in behaviour but also the epidemic stage. Sexual practices with people of the opposite-sex The repertoire and frequency of sexual practices varies between individuals. Vaginal intercourse is the most common practice in opposite-sex partnerships, but most couples include other prac- tices, particularly mutual masturbation and orogenital contact, in their repertoire. The frequency of sexual contact varies with age, life stage, and availability of a sexual partner. Among sexually active people, the median frequency of sexual intercourse is about three times per month, but this is highly variable. Frequency declines with age, depending partly on the duration of the relationship, but also the tendency for people to experience greater poor health as they age. Among men and women aged 16–​74 in Britain, around two-​ thirds reported orogenital contact during the previous year, both cunnilingus and fellatio. In contrast, anal intercourse is a relatively infrequent activity in opposite-sex partnerships. In the British survey, 34.9% of men and 28.3% of women reported having experienced anal intercourse with a partner of the op- posite sex at some time, but only around 11.9% had experienced it in the previous year. Anal intercourse was more commonly re- ported by younger people with 17.8% of 16-​ to 24-​year-​olds doing so, although these data provide no indication of the frequency with which people engage in this sexual practice; some people may experiment with anal sex, while others may make it part of their regular sexual repertoire. Engaging in sexual practices with a partner increases the risk of the transmission of STIs. Anal intercourse, in addition to vaginal intercourse, may increase the risk of transmission of HIV between people of opposite-sex, but since anal intercourse is practised relatively infrequently world- wide, most HIV transmission people of the opposite-sex is attrib- utable to vaginal intercourse. Same-sex behaviour The lifestyles of gay, bisexual and other men who have sex with men have been more intensively studied than those of lesbian and bisexual women. Studies of volunteer samples of men who have sex with men (MSM) in the United States of America in the 1970s identified a distinctive lifestyle characterized by multiple casual sexual partners, often encountered at gay meeting places such as bars, clubs, and ‘bathhouses’. These men were at high risk of STIs and were among the first to experience high rates of HIV infection. Research in Britain identified a group of MSM with similar life- styles. However, studies of MSM recruited from places other than sexual health clinics and gay-​orientated venues show smaller num- bers of sexual partners, less frequent changes of partner, and lower prevalence of sexually acquired pathogens. MSM are at increased risk of HIV infection and other STIs, including hepatitis B and syphilis. The sexual practices engaged in by women who have sex with women (WSW) carry a low risk of STI transmission. However, WSW may be at risk of STIs and HIV as a result of their partnerships with men, since a high proportion of these women also have male partners.

9.2  Sexual behaviour 1599 Many same-sex partnerships are restricted to mutual mastur- bation or orogenital contact and do not involve penetrative anal intercourse. It is anal intercourse that carries the highest risk of transmission of sexually acquired organisms between MSM. Many MSM practise both receptive and insertive anal intercourse. Receptive anal intercourse carries the highest risk of HIV trans- mission. After the HIV epidemic emerged, there was evidence of a reduction in high-​risk behaviour among gay men. Increased use of condoms and reduced partner numbers reduced exposure to unprotected anal intercourse. However, since the late 1990s, risky behaviour has increased and new HIV infections continue to be a significant public health challenge. Data from surveys of MSM in London have shown that over the last decade the proportion re- porting unprotected anal intercourse has increased, although a higher proportion also report ‘serosorting’ (i.e. choosing partners with the same reported HIV status). While uptake of HIV testing has increased greatly, as has the number of men in treatment, overall this has not reduced the incidence of HIV infection due to continuing high-​risk behaviours. Risk reduction strategies and sexual health Increasing attention is being paid to promoting sexual health and reducing the adverse consequences of sexual behaviour. Extensive discussion of population strategies is outside the scope of this chapter. However, individuals can reduce their risk of STIs and unintended pregnancy by reducing the numbers of partners with whom they have unprotected intercourse, using condoms, using ef- fective contraception, and enjoying sexual practices with less risk of transmission. Negotiating sexual fulfilment is a more difficult matter, but a greater focus on communication between partners, and on sexual technique, is important. Difficulties with sexual function are relatively common. Around 40% of the men and 50% of the women in the British survey reported some kind of issue with sexual function lasting at least three months during the previous year. The most common difficulty experienced by both sexes is a lack of interest in having sex. Although issues with sexual function are common, few people report being dissatisfied or distressed with their sex lives, and few avoid sex because of their own or their partner’s sexual dif- ficulties. However, among those who believe that their health af- fects their sex life, only a minority—​23.5% of men and 18.4% of women—​had sought clinical help. Most who do consult their gen- eral practitioner. Health professionals can help by being capable of taking a tactful sexual history, having the necessary clinical skills, and being informed about sexual health and the need for health promotion. FURTHER READING Field N, et al. (2013). Associations between health and sexual life- styles in Britain: findings from the third National Survey of Sexual Attitudes and Lifestyles (Natsal-​3). Lancet, 382, 1830–​44. Johnson AM, et al. (1992). Sexual behaviour and HIV risk. Nature, 360, 410–​12. Johnson AM, et al. (1993). Sexual attitudes and lifestyles. Blackwell Scientific, Oxford. Mercer CH, et al. (2013). Changes in sexual attitudes and lifestyles in Britain through the life course and over time: findings from the National Surveys of Sexual Attitudes and Lifestyles (Natsal). Lancet, 382, 1780–​94. Mitchell K, et al. (2013). Sexual function in Britain: findings from the third National Survey of Sexual Attitudes and Lifestyles (Natsal). Lancet, 382, 1817–​29. Sonnenberg P, et al. (2013). Prevalence, risk factors, and uptake of interventions for sexually transmitted infections in Britain: find- ings from the National Surveys of Sexual Attitudes and Lifestyles (Natsal). Lancet, 382, 1795–​806. Wellings K, et al. (2006). Sexual behaviour in context: a global per- spective. Lancet, 368, 1706–​28.

9.3 Sexual history and examination 1600

9.3 Sexual history and examination 1600

ESSENTIALS Sexually transmitted infections are common, especially in young people, and it is important that doctors recognize both the need to obtain a sexual history and when to perform genital examination. Sexually transmitted infections can present with generalized or extragenital symptoms, the significance of which might be missed. This chapter gives advice on how to take a sexual history and per- form genital examination in both sexes. It also summarizes the common symptoms and syndromes associated with sexually trans- mitted infections and their causative pathogens, cross-​referring to other chapters in the textbook. Introduction Sexually transmitted infections (STIs) are a common cause of mor- bidity, especially in young people. Although many STIs are asymp- tomatic, important symptoms may be missed because patients are not questioned directly about genital symptoms (Table 9.3.1). If a sexual history is not taken, the risk of an STI might not be appre- ciated. In general medical practice, it is important that doctors are aware that STIs can present with extragenital symptoms (Table 9.3.2). Examples include secondary syphilis, primary HIV infection, disseminated gonococcal infection, and herpes simplex meningitis. Failure to consider a sexually acquired infection in the differential diagnosis might delay diagnosis and treatment. Sexual history A sexual history is essential to establish the patient’s risk of an STI, to elicit symptoms that might guide diagnostic tests, and to facili- tate treatment of sexual partners who might be at risk (partner notification). If an STI is diagnosed, the discussion is extended to provide relevant information about the condition and to educate on reducing future risk. The clinician must ask questions that are extremely personal. Initially this can be mutually embarrassing for the doctor and pa- tient. The clinician should endeavour to see the patient alone as they might be reluctant to reveal personal information, especially about previous sexual activity, if their current partner is in the room. It can be difficult for a young person to talk about sexual ac- tivity if a parent is present. Sexual history taking is facilitated by • being explicit about confidentiality • asking permission, explaining what to expect, and why you are asking the questions • asking only what is relevant and necessary • starting with the less intrusive questions, such as symptoms, be- fore asking the ones that are more personal • using appropriate language and tact • not making assumptions about sexual orientation or practices Asking questions Use open questions such as: • ‘Are you sexually active?’ • ‘Are you in a relationship?’ • ‘Have you changed partners recently?’ • ‘Do you have sex with men, women, or both?’ • ‘When was the last time you had any kind of sex?’ The key features of a sexual history are: • symptoms • details of sexual partner(s): gender, timing of last sexual activity, use of condoms or contraception, whether partner is contactable or not, whether partner reported any symptoms • concurrent illness • previous STI • current medication • in women, assessment of pregnancy risk However, many STIs may present with extragenital symptoms or signs (Table 9.3.2). Examination In symptomatic patients, examination is necessary because a visual diagnosis might be possible, examination might suggest the need 9.3 Sexual history and examination Gary Brook, Jackie Sherrard, and Graz A. Luzzi

9.3  Sexual history and examination 1601 for further tests, and might also identify complications that need longer or altered treatment regimens (e.g. pelvic examination might suggest pelvic infection requiring a specific treatment regimen). In asymptomatic patients, genital examination is also recommended because patients are often surprisingly unaware of the presence of infection. Although symptoms may be denied, important abnor- malities might be found on examination. The increased availability of nucleic acid tests allows non​invasive sampling for many STIs; however, genital examination should always be considered. Examination involves full inspection of the genito-​anal area in both sexes, including palpation of the inguinal nodes and examination of the pubic area. Good lighting is essential. In patients with syphilis, late HIV disease, sexually acquired reactive arthritis (SARA), and disseminated gonococcal infec- tion, a full examination is necessary. Some non-​STIs can present with genital signs (e.g. lichen sclerosus, lichen planus, psoriasis, eczema, Crohn’s disease); in these cases, a full examination can be helpful in making the diagnosis. In men, examination of the genital area includes palpation of the scrotal contents to detect epididymal or testicular swelling or tenderness. This is best carried out while the patient is standing up. Epididymal cysts are relatively common, especially with increasing age. Acute epididymitis causes tender swelling of the epididymis, usually unilaterally, sometimes with involvement of the testis (epididymo-​orchitis) causing generalized testicular swelling and hydrocele. In uncircumcized men, the foreskin should be fully retracted and the subpreputial area inspected for rashes, ulcer, and lumps. The urethral meatus should be everted slightly and inspected for discharge, and lumps such as genital warts. In men who have sex with men (MSM) who report practising anal sex, the anal/​perianal region should be examined; the rectum inspected by proctoscopy if there are rectal symptoms; and, if they report orogenital sex, the oropharyngeal mucosae should be inspected for ulcers and other abnormalities. In women, examination includes careful inspection of the vulva, which is best performed in the lithotomy position. The vagina and cervix should be inspected by speculum examination and a bi- manual examination performed to check for cervical or adnexal tenderness and pelvic masses. Table 9.3.1  Common presentations of STIs Symptoms Common causes (see Section 8 and Chapters 9.4 and 9.5) In women Change in vaginal discharge Candida, TV, BV, less commonly GC, CT Anogenital sores/​ulcers Herpes simplex, trauma, syphilis Anogenital lumps Genital warts, molluscum contagiosum, normal anatomical variants Pelvic pain/​dypareunia and/​or irregular menses Pelvic inflammatory disease: CT, GC, MG In men Urethritis: urethral irritation/​discomfort and/​or discharge Chlamydia, gonorrhoea, MG nonspecific urethritis Anogenital sores/​ulcers Herpes simplex, trauma, syphilis Anogenital lumps Genital warts, molluscum contagiosum, normal anatomical variants Scrotal pain/​swelling Chlamydia, gonorrhoea Additionally in men who have sex with men (MSM) Rectal pain/​discharge/​tenesmus GC, CT, LGV, HSV, Syphilis BV, bacterial vaginosis; CT, chlamydia; GC, gonorrhoea; HSV, herpes simplex virus; LGV, lymphogranuloma venereum; MG, Mycoplasma genitalium; TV, Trichomonas vaginalis. Table 9.3.2  Some extragenital symptoms or signs of STIs System/​category Syndrome/​site Causes (see Sections 7 and 25, and Chapter 19.8) Eyes Uveitis, conjunctivitis, optic neuritis, retinitis Syphilis/​HIV/​GC/​CT/​SARA Joints Tenosynovitis/​septic arthritis especially of small-​ and medium-​sized joints Septic arthritis Syphilis/​GC/​SARA (CT associated)/​HIV GC Skin SARA, GC, HIV, syphilis, scabies, molluscum contagiosum,
pubic lice Cardiac Syphilis, GC, HIV Malignancy Carcinomas: cervix, vulva, penis, anus, lymphoma, Kaposi’s sarcoma HPV, HIV Gastrointestinal system Hepatitis, perihepatitis diarrhoea Hepatitis B and C, CT HIV, LGV CT, chlamydia; GC, gonorrhoea; LGV, lymphogranuloma venereum; SARA, sexually acquired reactive arthritis.

Section 9   Sexually transmitted diseases 1602 Role of chaperones In the United Kingdom, the General Medical Council has pro- duced guidance on intimate examinations, which includes: • the routine offer of a chaperone • giving the patient privacy to undress and dress • explaining to the patient why examination is necessary and what it will involve • obtaining the patient’s permission before the examination and discontinuing it if the patient asks you to Before performing an intimate examination (examination of the genitalia, rectum, or breast), a chaperone should always be offered and the offer recorded in the notes along with a note indicating who the chaperone was. If the offer is declined, this should be re- corded, and it might be necessary to reschedule the examination if the doctor does not feel comfortable about proceeding without a chaperone. During general examination, especially when male doctors examine the heart and lungs of female patients, misunderstandings can arise about perceived inappropriate touching of the breasts. The manner in which the examination is conducted is therefore clearly very important, with appropriate explanation and profession- alism. The general examination is often conducted in the absence of a chaperone, but there are circumstances in which a chaperone should be sought, including when this is requested by the patient, or if the doctor feels that it is appropriate. A chaperone is present as a safeguard for all parties (patient and practitioner) and is a witness to continuing consent of the pro- cedure. However, a chaperone is not a guarantee of protection for either the patient or the practitioner, and for most patients, explan- ation, consent, privacy, and a respectful and professional attitude take precedence over the need for a chaperone. When issues arise about individual clinical practice, good record-​keeping is very helpful. FURTHER READING Clinical Effectiveness Group: British Association for Sexual Health and HIV (2014). 2013 UK National Guideline for Consultations Requiring Sexual History Taking. https://​www.bashh.org/​docu- ments/​Sexual%20History%20Guidelines%202013%20final.pdf. Int J STD & AIDS, 25, 391–​404.

9.4 Vaginal discharge 1603

9.4 Vaginal discharge 1603

ESSENTIALS Vaginal symptoms are a frequent source of discomfort and distress for many women. Bacterial vaginosis, vulvovaginal candidiasis, and trichomoniasis are considered the most common causes in pre- menopausal women, but atrophic vaginitis and non​infectious dis- orders seem to occur more often in menopausal women. Self-​diagnosis and syndromic management, although increas- ingly encouraged in many parts of the world, are fraught with in- accuracy. A  proper diagnosis depends on a thorough history, examination, and readily available tests in the clinic. Ancillary tests to be considered in selective circumstances include culture for yeast, culture, or nucleic acid amplification testing for Trichomonas vaginalis, Neisseria gonorrhoeae, or Chlamydia trachomatis, and Gram stain or (rarely) maturation index. Once a proper diagnosis is obtained, appropriate treatment can be selected. Introduction Vaginal discharge, itching, burning, irritation, and odour are common causes of distress in women, yet they are frequently ig- nored or trivialized by healthcare providers. With the availability of over-​the-​counter antifungals, self-​diagnosis and self-​treatment of vaginal symptoms have become routine, but questions remain about their accuracy. Appropriate tests in the clinic and laboratory are the only reliable basis for treatment. The normal vaginal environment An understanding of the normal vaginal environment is crucial to accurate clinical assessment and interpretation of test results. The normal vaginal environment is controlled by a woman’s oes- trogen status. By increasing the glycogen content of vaginal epithe- lial cells, oestrogen fosters the growth of lactobacilli, which in turn seem to inhibit the growth of other organisms. Thus, a Gram stain of vaginal secretions from a healthy woman in her reproductive years should be dominated by lactobacilli and gram-​positive rods. However, vaginal cultures will yield a broad range of organisms, including skin and faecal flora (e.g. Staphylococcus epidermidis, Staph. aureus, Escherichia coli, anaerobes) and organisms, which in some situations, are considered pathogenic (e.g. Streptococcus aga- lactiae (group B streptococci), Mycoplasma hominis, Ureaplasma urealyticum, Gardnerella vaginalis, and Candida albicans). In women who are either prepubertal or postmenopausal, lactobacilli are less numerous, and other bacteria will frequently predominate. Differential diagnosis and clinical investigation Most studies suggest that infections such as bacterial vaginosis (BV) (30–​35% of cases), vulvovaginal candidiasis (20–​25%), and trichomoniasis (15–​20%) are the most common causes of vaginal symptoms, but many miscellaneous conditions, including atrophic vaginitis, vulvar conditions (e.g. vulvodynia, lichen sclerosus, li- chen simplex), or even a physiological discharge can cause symp- toms that require assessment. A thorough evaluation will usually allow correct diagnosis. An accurate diagnosis relies on both patient history and exam- ination. Symptoms can range from discharge alone to itching, burning, irritation, dyspareunia, or malodour. Since patients may be too embarrassed to mention some of these, it is helpful to in- quire about each of them in turn. Other pertinent information is location (vulvar, introital, or vaginal), duration, variation with menstrual cycle, association with sexual activity, and response to previous therapy. A sexual history might identify women at in- creased risk of a sexually transmitted infection. Pelvic examination should include inspection of the vulva and vestibule; touching the vulva and vestibule with a swab (the ‘Q-​tip test’) may elicit areas of tenderness. Samples should be obtained for further evaluation. Vaginal pH testing, an amine (‘whiff’) test, and saline and 10% po- tassium hydroxide microscopy should be practised routinely. If the source of discharge is primarily the cervix, culture or nucleic acid amplification tests (NAATs) for N. gonorrhoeae and C. trachomatis should be obtained. Suspected vulvar diseases might require a bi- opsy for diagnosis. Finally, in situations where the diagnosis is not clear, definitive tests can assist in the diagnosis of bacterial vagin- osis, trichomoniasis, and vulvovaginal candidiasis (Table 9.4.1). With bacterial vaginosis and vulvovaginal candidasis specifically, 9.4 Vaginal discharge Paul Nyirjesy

Section 9   Sexually transmitted diseases 1604 NAAT is available in many settings; however, it offers no clear benefit over other tests and is frequently much more expensive. Trichomoniasis Trichomonas vaginalis is a common sexually transmitted proto- zoan, causing an estimated 180 million infections per year world- wide. Traditionally, it has been considered a minor nuisance, but it is associated statistically with an increased risk of low birth weight or preterm delivery in pregnant women and of HIV transmission in non​pregnant women. Asymptomatic men and women are the primary reservoir for infection. Affected women will complain of an abnormal purulent, frothy, or bloody discharge, itching, mal- odour, dysuria, urinary frequency, dyspareunia, and post-​coital bleeding. Examination might reveal erythema and excoriations of the vulva or vagina, an abnormal discharge, and punctate haem- orrhages of the cervix (the ‘strawberry cervix’). Saline microscopy might reveal motile trichomonads, but it has limited sensitivity (22–​75%). Finding many white blood cells on microscopy, a posi- tive amine test, or an elevated pH might suggest the presence of trichomoniasis, but do not prove the diagnosis. The current gold standard is culture or NAAT. Where available, antigen-​based tests at the point of care are much more sensitive than microscopy and provide a more rapid answer than culture. Treatment is with nitroimidazoles, either metronidazole or tinidazole. A single dose of 2 g of either will cure more than 90% of affected cases. Alternatively, a seven-​day course of 500 mg twice daily is recommended, and is recommended as initial therapy for HIV-​positive women. As with other sexually transmitted infec- tions (STIs), treatment of the partner is crucial to prevent reinfec- tion. Patients who are allergic to metronidazole should be referred for desensitization and then treated with metronidazole. In cases of treatment failure, patient compliance must first be confirmed and reinfection by her partner excluded. Since tinidazole seems to be more effective than metronidazole, higher doses of tinidazole, such as 2 g daily for seven days, can be considered. Pregnant women with trichomoniasis should receive metronidazole, as there are no data on tinidazole use in pregnancy. Bacterial vaginosis This is considered the most common cause of vaginitis, with a prevalence of 5–​25%. It represents a polymicrobial infection of the vagina. The vaginal flora is markedly altered. Hydrogen peroxide-​ producing lactobacilli are absent, and there is an overgrowth of a wide variety of organisms, including G. vaginalis, M. hominis, Bacteroides spp., Prevotella spp., Mobiluncus spp., and many other fastidious bacteria. Bacterial vaginosis is associated with a variety of risk factors, including multiple partners, more frequent sexual intercourse, smoking, and douching. Although BV-​associated bacteria can be found in male or female partners, there is no evi- dence that treating partners will decrease the risk of recurrence. In non​pregnant women, it has been associated with many conditions including pelvic inflammatory disease, infection after abortion or hysterectomy, cervicitis, urinary tract infection, and HIV and herpes simplex virus-​2 transmission. In pregnant women, studies have linked bacterial vaginosis to prematurity, preterm premature rupture of membranes, and post-​partum endometritis. Although up to 50% of women are asymptomatic, affected women will note an abnormal discharge or a fishy odour, which is often worse during menses or after intercourse. Itching and ir- ritation are considered rare. The clinical criteria (Amsel’s criteria) which are used to diagnose infection consist of the following: • a homogeneous grey or white discharge • a vaginal pH exceeding 4.5 • a positive amine test • more than 20% clue cells (vaginal epithelial cells stippled with bacteria) on saline microscopy Three out of the four criteria are adequate for a diagnosis. Alternatively, a Gram stain (Nugent) score, which evaluates the presence or absence of various bacterial morphotypes, can be used. Because the Nugent score is a permanent record which can be read by personnel who are blinded to patient information, it is the pre- ferred method of diagnosis in research studies. Oral or topical treatments seem equally effective. • Oral regimens, including metronidazole 500 mg twice a day for seven days, tinidazole 1 g daily for five days, or 2 g daily for two days, or clindamycin 300 mg twice daily for seven days, tend to be less expensive but might cause gastrointestinal adverse effects; metronidazole and tinidazole are incompatible with drinking alcohol. • Topical regimens, such as 0.75% metronidazole gel (one 5 g ap- plication daily for five days), 2% clindamycin standard (one 5 g application daily for seven days), or single-​dose creams (one 5 g application), and 100 mg clindamycin ovules (one ovule nightly, for three doses) tend to be more expensive. In high-​risk pregnant women, particularly those with prior pre- term birth, as well as non​pregnant women undergoing either hysterectomy or abortion, screening and treating for bacterial vaginosis might decrease associated morbidities. To date, low-​risk pregnant women do not seem to benefit from screening and treat- ment for asymptomatic bacterial vaginosis. Apart from tinidazole, Table 9.4.1  Testing for vaginal infections Vaginal pH Amine test Microscopy Gold standard Normal ≤4.5 − Normal Bacterial vaginosis

4.5

Clue cells Gram stain Trichomoniasis

4.5 ± Trichomonads Trichomonas culture or NAAT Vulvovaginal candidiasis ≤4.5 − Pseudohyphae, blastospores Yeast culture Atrophy 4.5 − Immature epithelial cells Maturation index

9.4  Vaginal discharge 1605 pregnant women can be treated with similar bacterial vaginosis re- gimens as non​pregnant women. Recurrence after treatment seems to occur commonly, up to 50% within six months. For patients with frequent recurrences (three or more per year), a prolonged four-​month course of suppressive antibiotic therapy, such as metronidazole 0.75% gel, one 5 g appli- cator twice weekly, was associated with much lower rates of bac- terial vaginosis than a placebo group. Although probiotics have been proposed as a way to repopulate the vagina with lactobacilli, there are no conclusive data to support their use or efficacy, even in women with recurrent bacterial vaginosis. Vulvovaginal candidiasis About 75% of women will, at some time in their lives, develop vulvovaginal candidiasis or ‘yeast infections’. C. albicans causes 90–​95% of vulvovaginal candidiasis; of the many other species of yeast that are sometimes implicated, C. glabrata is thought to be the second most common. Commonly recognized risk factors for candidiasis include the use of oral contraceptives, recent use of broad-​spectrum antimicrobials, pregnancy, diabetes mellitus, and immunosuppression. Being sexually active and practising oral receptive sex are associated with vulvovaginal candidiasis, but there are no data to support partner treatment. Patients with vulvovaginal candidiasis complain primarily of vulvar or vaginal pruritus, irritation, burning, dyspareunia, or abnormal discharge. The symptom of discharge is quite unreliable in predicting which women with vaginitis actually have vulvovaginal candidiasis. Examination of affected women might reveal vulvar erythema, oe- dema, excoriations, or fissures. Vaginal thrush might be present. The vaginal pH is normal. On microscopy, hyphae or blastospores may be seen, but the sensitivity is fairly low (c. 50%); thus, a simple yeast culture is recommended in women who are symptomatic but with negative microscopy. For most women with vulvovaginal candidiasis, the infection will be uncomplicated: it is sporadic, associated with relatively mild symptoms, caused by C. albicans, and is occurring in an otherwise normal host. Uncomplicated vulvovaginal candidiasis generally responds readily to any available antimycotic treatment. Topical therapies consist primarily of imidazoles, including miconazole, clotrimazole, butoconazole, and terconazole, which are available as creams or suppositories applied for 1–​7 days. A single 150 mg dose of oral fluconazole seems equivalent to topical treatments. An estimated 5% will suffer complicated vulvovaginal candid- iasis, marked by either an underlying medical problem such as diabetes mellitus or HIV infection, severe symptoms, recurrent disease (four or more episodes per year), or an infection caused by a yeast other than C. albicans. Most of these women will not have any of the commonly recognized risk factors for infection. Complicated vulvovaginal candidiasis will recur within a month in at least 50% of cases, and is best managed by first obtaining a positive yeast culture to obtain information about the species of the isolate, then by more aggressive therapy and follow-​up. In patients with severe vulvovaginal candidiasis, a second dose of fluconazole three days after the first, or a second week of topical therapy, im- proves the chance of complete resolution. Women with recurrent vulvovaginal candidiasis caused by C. albicans benefit from pro- longed suppressive therapy with weekly oral fluconazole (100–​ 200 mg) after an initial induction phase of three doses given three days apart. Finally, for C. glabrata infections, boric acid capsules (600 mg vaginally), nightly for 14 days, are often curative. Atrophic vaginitis Since women are living longer in many countries, larger propor- tions of their lives are postmenopausal. As a consequence, atro- phic vaginitis, which is caused by a lack of oestrogen, is likely to become increasingly common. Women with atrophy may present with a spectrum of complaints, including an abnormal discharge, dryness, itching, and dyspareunia. Signs of labial atrophy, vaginal pallor, or loss of rugal folds can be easily missed. The vaginal pH will usually be elevated above 4.5. On wet mount, immature epithe- lial cells, either parabasals or intermediate cells, which are rounder, smaller, and have a greater nuclear:cytoplasmic ratio can be seen. Because of its effects on vaginal flora, there might be a decreased normal flora or even a shift to cocci instead of bacilli. In the absence of contraindications, oestrogen remains the medication of choice. Topical therapy, in the form of cream, tablets, or an oestrogen ring, will give the highest local levels of oestrogen, while minimizing systemic absorption but not eliminating it. Since oestrogen tends to cause slow improvement, patients should be in- structed to adhere to treatment for at least six weeks before con- cluding that it will be ineffective. Conclusions Vaginitis is a common problem in women of all ages. Effective therapy is available for the many causes of vulvovaginal symptoms, but will depend on an accurate diagnosis. FURTHER READING Anderson MR, Klink K, Cohrssen A (2004). Evaluation of vaginal complaints. JAMA, 291, 1368–​79. Centers for Disease Control and Prevention (2015). Sexually trans- mitted diseases treatment guidelines, 2015. MMWR, 64, 69–​78.

9.5 Urethritis 1606

9.5 Urethritis 1606

ESSENTIALS Urethritis is defined as detectable urethral inflammation in the pres- ence of symptoms or an observable urethral discharge. It is con- ventionally classified into gonococcal urethritis (caused by Neisseria gonorrhoeae) and non​gonococcal urethritis (caused by Chlamydia trachomatis, Mycoplasma genitalium, and other causes, but with no known pathogen detected in over 30% of cases). Diagnosis is by urethral smear and microbiological investigations. Treatment with appropriate antibiotics should be given only to those with proven urethritis, and the diagnosis and its implications should be dis- cussed with the patient. Partner notification is essential, not only to prevent re-​infection but also to prevent onward transmission from partner(s) and the development of complications if left untreated. Introduction Urethritis, as defined in clinical practice, is detectable urethral inflammation in the presence of symptoms (discharge, dysuria, and/​or penile irritation) or an observable urethral discharge (acute urethritis). Detectable urethral inflammation in the ab- sence of symptoms or signs may not be uncommon in high-​risk individuals (>1 sexual partner in the previous three months) and may resolve spontaneously. The detection of sexually transmitted organisms is much more common in men with acute urethritis who are clinically symptomatic. Our understanding of this con- dition is further complicated by the fact that some men with a discharge on examination do not report a urethral discharge (i.e. without an examination they would be classified as clinically asymptomatic). Historically urethritis was divided into gonococcal (GU) and non​gonococcal (NGU) because they could be differentiated by microscopic examination of a urethral smear. Neisseria gonor- rhoeae could be confirmed by culture and specific treatment for gonorrhoea was effective in GU but not NGU. It was unclear why placebo treatments resulted in resolution of symptoms in 30% of symptomatic patients without GU and why some men had symp- toms in the absence of detectable inflammation, which could have a significant psychological morbidity. It was only in the 1970s that definitive diagnostic criteria for non​gonococcal urethritis (NGU) were agreed, Chlamydia trachomatis identified as an important pathogen, and effective treatment regimens identified. Since then, Mycoplasma gentialium has also been identified as an important cause and the search is on to identify other causes. Aetiology of acute urethritis Urethritis is defined as either GU or NGU. This section will deal with acute (clinically symptomatic) urethritis (Table 9.5.1). GU is caused by Neisseria gonorrhoeae. The proportion of ureth- ritis cases attributable to gonorrhoea will depend on the popula- tion under investigation (e.g. geographical location and ethnicity) and the background asymptomatic carriage in high risk groups such as men who have sex with men. Chlamydia trachomatis is identified in 30–​40% of cases. It is de- tected more often in younger men. Mycoplasma genitalium is identified in 10–​25% of men. There is evidence of increasing macrolide antimicrobial resistance world- wide since 2009, probably as a result of azithromycin use to treat chlamydia and NGU. Quinolone resistance is also on the increase. Ureaplasma urealyticum probably accounts for c.5% of cases. U. parvum is not associated with urethritis. Only recently have studies differentiated between U. urealyticum and U. parvum using nucleic acid amplification tests (NAAT), both of which are detected by culture. Nevertheless, asymptomatic carriage of U. urealyticum also occurs in men with urethritis, so even detection by NAAT does not indicate causality (see chapter on Mycoplasmas). Trichomonas vaginalis is an uncommon cause of urethritis in Western Europe. In countries or populations, such as the Afro-​ Caribbean community in the United Kingdom, where trichomonas is more common its importance as a cause of urethritis probably increases. Herpes virus and adenovirus account for less than 5% of cases. Bacterial urinary tract infection can occasionally present atypically as NGU. In over 30% of cases, none of these infections are identified. This has been termed idiopathic urethritis. N. meningitidis, Haemophilus sp., Candida sp., urethral stricture, and foreign bodies have all been 9.5 Urethritis Patrick Horner

9.5  Urethritis 1607 reported in a few cases. There is increasing evidence that bacterial vaginosis-​associated bacteria, such as anaerobic peptococci or Leptotrichia/Sneathia spp. may potentially cause NGU in some men. It has also been postulated that a persistent immune response fol- lowing resolution of infection may account for some cases. Clinically asymptomatic urethritis often resolves spontaneously if left untreated, suggesting that in some men it may be a transient phenomenon. Although sexually transmitted infections (STIs) are isolated much less frequently from men with clinically asymptomatic ur- ethritis compared to those with symptoms or signs, the detection of STIs is more common than from men with no urethritis. Epidemiology Clinically symptomatic urethritis typically only occurs in men who are sexually active. It is associated with multiple sexual part- ners or recent change in sexual partner and unprotected sexual intercourse. Asymptomatic urethritis is also associated with high-​ risk behaviour. Although urethritis is commoner in younger men, it can also occur in older men (>35 years), which is consistent with the 2010 NATSAL survey indicating that more than 10% of men aged 35–​ 64 years had a new sexual partner in the previous year. Urethral infection with gonorrhoea usually results in symp- toms within 2–​8 days, which is in general shorter than for micro-​ organisms that cause NGU (7–​21 days). Pathology/​Pathogenesis Urethritis is an inflammatory response to an infection which predominantly consists of polymorphonuclear leucocytes, al- though lymphocytes and macrophages are also present. This inflammatory response is, in general, greatest in men with gon- orrhoea, chlamydia, and M. genitalium. The greater the inflam- matory response, the greater the likelihood of symptoms, which probably explains the association of symptoms and/​or signs with an STI in men with urethritis. Inflammation can persist even after eradication of the infection. In urethritis with a viral aeti- ology, mononuclear leucocytes predominate. Whether there are non​infective causes of urethritis following sexual intercourse is unknown. Clinical features The predominant symptoms are discharge and/​or dysuria and/​or penile/​urethral irritation. Patients with gonorrhoea have a greater likelihood of a mucopurulent or purulent discharge than men without gonorrhoea (Figs. 9.5.1a and 9.5.1b). In men with ureth- ritis both a urethral discharge and/​or dysuria are associated with detection of chlamydia and M. genitalium, but not in men solely with penile irritation. Men with symptoms of dysuria and/​or penile irritation, with no observable discharge, and who do not have urethritis on micros- copy are not at increased risk of an STI. Differential diagnosis The differential diagnosis of urethritis is physiological urethral dis- charge, urinary tract infection, and acute pelvic pain of unknown aetiology. Clinical investigations Only clinically symptomatic patients should be examined for the presence of urethritis, and they are best managed in departments with access to microscopy to detect urethritis. Men should be examined for presence of a urethral discharge and to check for other pathology such as ulceration (Figs. 9.5.1a and 9.5.1b). Ideally, examination and tests should be delayed for at least one hour after patients last voided urine. Urethral smear A urethral smear should be taken and used to prepare a Gram-​ stained slide for microscopic examination. More than four poly- morphonuclear cells per high power field (×1000) (pmns/​hpf) in five or more fields is diagnostic of urethritis. The presence of intra- cellular Gram-​negative diplococci has a more than 95% predictive value for N. gonorrhoeae. Low grade inflammation (5–​15 pmns/​ hpf) can be missed, particularly if the person taking the smear and/​ or the microscopist is inexperienced. The patient should be reassured if their urethral smear is nega- tive. If their symptoms persist and microbiological tests are nega- tive, they should be advised to re-​attend for an early morning urethral smear (EMS) having held their urine overnight (>8 hours) If microscopy is not possible, the following can be considered supportive of a diagnosis of urethritis, although their positive pre- dictive values are poor: (1) the presence of a mucopurulent/​puru- lent urethral discharge (Figs. 9.5.1a and 9.5.1b); (2) a positive (>1+) leucocyte esterase test on a first voided urine (FVU) specimen; (3) the presence of urinary threads in the FVU specimen (Fig. 9.5.2). Microbiological investigations The following microbiological investigations should be under- taken: (1) urethral culture for N. gonorrhoeae; (2) NAAT of a FVU specimen for chlamydia and gonorrhoea; (3) FVU NAAT test for Table 9.5.1  Infections known to cause urethritis Causes of acute, clinically symptomatic urethritis Prevalence N. gonorrhoeae <1–​30% C. trachomatis 25–​40% M. genitalium 10–​25% U. urealyticum (causal in <50%) 5–​20% T. vaginalis <1–​20% Adenoviruses, herpes simplex virus, urinary tract infection <5% None of these infections detected 30–​40%

Section 9   Sexually transmitted diseases 1608 M. genitalium, which is highly likely to improve clinical outcomes. Ideally, if positive, these tests should also include macrolide and quinolone antimicrobial resistance genotyping; (4) dipstick urin- alysis of a mid-​stream urine specimen if a urinary tract infection (UTI) is suspected. Treatment If urethritis is not identified, the UK and European guidelines recommend reassurance and awaiting results of microbiological investigations. An EMS is then indicated if symptoms persist, as discussed previously. Gonorrhoea Ceftriaxone intramuscularly as a single dose, with azithromycin (see Chapter 8.6.6). Non​gonococcal urethritis The standard treatment is doxycycline 100  mg twice daily for seven days, which is recommended by the 2016 European treat- ment guideline. Although less effective against M.  genitalium than azithromycin 1 g, it is not associated with the development of macrolide resistance. Azithromycin 1 g is no longer the recom- mended first-​line treatment. If the patient is allergic to doxycycline, then azithromycin 500 mg as a single dose followed by 250 mg daily for four days is preferred. Discussion with the patient The diagnosis and its implications should be discussed with the patient. A patient information leaflet is available at: https://www. bashhguidelines.org/media/1040/ngu_pil_digital_2015.pdf Patients should be advised to abstain from sexual intercourse (even with a condom) for at least seven days or until symptoms have resolved, whichever is the longer. Partner notification is essential, not only to prevent re-​infection but also to prevent onward transmission from partner(s) and the development of complications if left untreated (see Chapters 8.6.6 and 8.6.45). All sexual partners within the previous four weeks should be advised to be tested for chlamydia. Currently it is considered good practice to treat partners epidemiologically with doxycycline 100 mg twice daily for seven days before the results of tests are avail- able. Guidance may change when point-​of-​care NAAT testing for gonorrhoea, chlamydia, and M. genitalium becomes routinely avail- able, with treatment recommended only for those who are NAAT-​ positive, given the concerns about antimicrobial stewardship. Prognosis/​outcome Ten to twenty per cent (10–​20%) of patients with NGU will have recurrent or persistent symptoms following initial treatment. For those with persistent symptoms, management is best undertaken in a specialist setting or in consultation with a specialist. Re-​infection or persistent infection are the most likely causes, but symptoms (a) (b) Fig. 9.5.1  (a) Purulent gonococcal discharge. (b) Meatal inflammation in association with a mucopurulent discharge. A urethral discharge is sometimes only visible after urethral massage. Courtesy of Dr Colm O’Mahony. Fig. 9.5.2  Urinary threads in a first voided urine specimen. Courtesy of Mr Peter Greenhouse.

9.5  Urethritis 1609 can persist in the absence of inflammation and may resolve with reassurance. Further treatment should only be offered to men with confirmed urethritis on microscopy. The recommended second-​line therapy is azithromycin 500 mg as a single dose, followed by 250 mg daily for four days, plus metronidazole 400 mg twice daily for five days. The optimal extended azithromycin regimen is not known and readers should refer to the European (IUSTI) or UK (BASHH) NGU guideline for up-​to-​date guidance. If macrolide-​resistant M. genitalium is detected, treatment should be with moxifloxacin 400 mg once daily for 7–​14 days, which should be used with caution because of rare but serious adverse hepatic reactions. Special circumstances/​complications Men with urethritis may develop epididymo-​orchitis or sexually acquired reactive arthritis, although these are uncommon compli- cations. Despite effective antimicrobial therapy, the symptoms may become chronic in some men, developing into chronic pelvic pain syndrome (CPPS). The aetiology of this condition is complex, with increased pelvic floor muscle tone probably playing an important role. A biopsychosocial pharmacotherapeutic approach for man- aging such patients has been demonstrated to be effective. Areas of uncertainty, controversy, and future developments With recent developments in bacterial genomics technology, re- search is beginning to focus on the male urethral microbiome with the prospect of other micro-​organisms which can cause urethritis being elucidated. It is very likely that NAAT point-​of-​care testing for STIs will improve the management of men with symptoms of urethritis, enabling administration of infection specific treatment of index cases and their partner(s), resulting in better outcomes including possibly reducing costs and a reduction in use of antimicrobials. This will require evaluation through randomized controlled trials. Studies of the effect of the psyche on pelvic floor muscle tone and its role in the development and persistence of urogenital symptoms may lead to interventions that can help patients with distressing chronic pelvic pain. FURTHER READING BASHH (2014). UK Guidelines on the Management of Non-​gonococcal Urethritis. https://www.bashh.org/guidelines Crofts M, et al. (2014). How to manage the chronic pelvic pain syn- drome in men presenting to sexual health services. Sex Transm Infect, 90, 370–​3. Csonka GW (1965). Non-​gonococcal urethritis. Br J Vener Dis, 41, 1–​8. IUSTI (2012, 2016). European Guidelines on the Management of a) Gonorrhoea and b) Non-​gonococcal Urethritis. https://www.iusti. org/regions/europe/euroguidelines.htm Moi H, Blee K, Horner PJ (2015). Management of non-​gonococcal urethritis. BMC Infect Dis, 15, 294. Swartz SL, Kraus SJ (1979). Persistent urethral leukocytosis and asymptomatic chlamydial urethritis. J Infect Dis, 140, 614–​7.

9.6 Genital ulceration 1610

9.6 Genital ulceration 1610

ESSENTIALS Genital ulceration can be caused by many common and rare sexu- ally transmitted infections, dermatological conditions, and trauma. Key to making a specific diagnosis that will direct treatment is a standard sexual and travel history followed by appropriate diag- nostic tests. Genital ulcer disease is a major risk factor for the acqui- sition and transmission of human immunodeficiency virus. Introduction Genital ulceration can represent one of the more complex pres- entations in genito-​urinary medicine. The differential diagnosis is wide and encompasses a range of common and rare sexually transmitted infections (STIs), dermatological conditions, and trauma. The list of possible aetiologies can be bewildering (Table 9.6.1), but a standard sexual and travel history will narrow the range of possibilities. Trauma, when acute, is usually easy to recognize, ranging from superficial abrasions to cleanly incised areas. The presence of extragenital lesions, the involvement of other mucous membranes, and a relapsing course might direct attention to dermatological causes. However, breaks in the skin can act as a portal for infection and careful review and further testing might be required if the individual is also at risk of STIs. Various classifications and algorithms are proposed to help iden- tify pathogens and guide immediate management but care must be taken when working through these. Infectious agents can often be present together and the variety of presentations makes classical disease the exception. In recent years, the importance of genital ulcer disease as a major risk factor for the acquisition and transmission of HIV has been recognized. Many of the rarer pathogens such as the L serovars of Chlamydia trachomatis (the cause of lymphogranuloma venereum) and Treponema pallidum (the causative agent of syphilis) circulate at much higher levels in those communities with HIV and their presence should always trigger concerns around risk-​taking behaviours. Both initial ex- clusion and carefully timed follow-​up are required to exclude HIV in those at risk. Herpes simplex virus infection Herpes simplex infection causes acute and chronic recurrent mucocutaneous ulceration. Both herpes simplex virus type 1 (HSV1) and herpes simplex virus type 2 (HSV2) can cause genital ulceration. Genital acquisition requires direct inoculation into the local epithelium. The usual route for HSV1 is orogenital contact and for HSV2 is genital-​to-​genital contact. Only one-​third of ini- tial acquisitions are symptomatic and these tend to be worse in those that have not been previously infected with the other virus type. It also tends to be worse in females, patients with diabetes, and those with immunocompromized states. Incubation tends to be one to three weeks. Classical presentations with bilateral mul- tiple superficial lesions, lymphadenopathy, and systemic features of myalgia and headache make up the minority of cases. Left un- treated, the episode peaks in severity at 11 days and typically lasts three weeks. Particularly severe episodes with urinary retention and a variety of local neurological complications including auto- nomic dysfunction, radiculitis, and meningeal inflammation can occur. Disseminated infection is rare. Oral antiviral therapy with aciclovir or valaciclovir is recommended immediately on suspicion of infection. The diagnosis can have significant ad- verse psychosexual impact and it is advisable to confirm all clin- ical diagnoses with a sensitive laboratory method (polymerase chain reaction (PCR) being 30–​50% more sensitive then culture). Laboratory viral typing of HSV1 or HSV2 will provide useful in- formation for both prognostication and counselling. Most pa- tients with symptomatic acquisition of HSV will have recurrences with HSV1 recurring less than once a year and HSV2 recurring 4–​6 times on average. Up to 10% of patients will have more than 10 episodes per year. Many patients with genital HSV will only present at the time of a recurrence (having had an unnoticed acquisition episode) and care must be taken in declaring any first episode as being re- cently acquired. Recurrences are typically unilateral, sort lived (five days) and milder than first episodes. Many recurrent epi- sodes will be mild and unnoticed by the patient; asymptomatic, subclinical infectious viral shedding can occur and accounts for most transmissions of the virus. Troublesome recurrent disease 9.6 Genital ulceration Patrick French and Raj Patel

9.6  Genital ulceration 1611 (both physical and psychological) responds well to continuous suppressive antiviral medication. This can also be used to modify transmission risk. Syphilis Syphilis is caused by the spirochaete bacterium Treponema pal- lidum subsp pallidum and the early stages of infection are char- acterized by genital ulceration. Ulceration occurs at the site of inoculation with the usual transmission route being orogenital or genital–​genital contact. The period between the acquisition of infection and the development of ulceration is between 9 and 90 days, however most individuals develop ulcers two to three weeks after exposure. The initial lesion is a papule or papules, which then ulcerate. Typically the ulcers are indurated and painless and are often single, however they can be multiple and painful. The ulcers are associated with local lymphadenopathy. This stage of syphilis is called primary syphilis with the ulcera- tive lesion called a syphilitic chancre. This ulcer heals spontan- eously after three to four weeks and might then be followed, three to six weeks later, by the more generalized symptoms and signs of secondary syphilis. Secondary syphilis is characterized by a rash and constitutional symptoms such as fever and malaise, but might also be accompanied by mucosal ulceration affecting both the mouth and anogenital area. These ulcers also heal spon- taneously without treatment, but in some cases can be followed by relapsing episodes of secondary syphilis over the following months. The diagnosis of syphilis-​associated genital ulceration is made by undertaking a careful clinical assessment and by performing appropriate diagnostic tests. In specialist services, tests to dir- ectly identify T.  pallidum in material from the ulcer might be available but, in most settings, clinical assessment followed by serological tests for syphilis remain the cornerstones of diag- nosis. Dark ground microscopy is a point-​of-​care test in which a sample of fluid from the base of an ulcer is placed on a saline drop and examined using a phase contrast microscope. T. pall- idum is a motile organism and can be identified by its charac- teristic morphology and movement. However, this technique is highly observer-​dependant and is only used in specialist centres. Increasingly, Treponema pallidum PCR tests are being em- ployed to diagnose early syphilis when it presents as genital ul- ceration and is highly sensitive and specific. This PCR test can be combined in multiplex tests with herpes simplex type 1 and 2 and, if appropriate, Haemophilus ducreyi PCR tests allowing a single swab to be taken to diagnose all four major causes of STI-​ associated ulceration. These tests are not available in most set- tings and the mainstay of diagnosis is clinical serological testing for syphilis. The screening test of choice for syphilis in the United Kingdom and the first serological test to become positive after acquiring syphilis is the Treponema pallidum EIA IgM/​IgG test, which becomes positive two to three weeks after acquiring syph- ilis. In early primary syphilis, this test can be negative. If syphilis is suspected, a syphilis PCR test is not available and empirical treatment for syphilis is not being given, an initial negative sero- logical test for syphilis should be repeated two to three weeks later to exclude infection. The diagnosis of secondary syphilis is much more straightforward, as serological tests are invariably strongly positive (see Chapter 8.6.37). Chancroid This bacterial STI caused by Haemophilus ducreyi is predom- inantly seen in the tropical countries of Africa, Asia, South America, and the Caribbean. Outbreaks in closed, relatively iso- lated, European and North American communities have also been reported. Lesions develop within 3–​10 days. Typically these are single or multiple non​indurated (‘soft sore’) painful ano- genital ulcers with a purulent base with contact bleeding. There is usually painful (mostly unilateral) inguinal lymphadenopathy. Complications include tissue destruction (phagedenic ulcer- ation), inguinal abscess formation (bubo) and chronic suppura- tive sinuses. Diagnosis with traditional methods of microscopy or culture have poor sensitivity, while PCR is the most sensitive and becoming increasingly available. Azithromycin 1 g single dose or ceftriaxone 250  mg IM single dose, or ciprofloxacin 500 mg orally twice daily for three days are the mainstays of treatment. Lymphogranuloma venereum Lymphogranuloma venereum (LGV) is caused by an inva- sive L serovar of Chlamydia trachomatis. It is characterized by Table 9.6.1  Causes of genital ulceration Trauma Sexually transmitted agents •  Chancroid—​Haemophilus ducreyi •  Donavanosis—​Klebsiella granulomatis •  Lymphogranuloma venereum—​Chlamydia trachomatis (LGV strains –​L serovars) •  Syphilis—​Treponema pallidum subp pallidum •  Herpes simplex Non-​STI infective agents •  Candida •  Herpes zoster •  Epstein–​Barr virus Dermatological conditions •  Erythema multiforme •  Behçet’s disease •  Aphthosis •  Crohn’s disease •  Drug reactions, e.g. Stevens-​Johnson syndrome, fixed drug eruptions •  Phemphigus •  Phemphigoid •  Balanitis xerotica obliterans/​Lichen sclerosus •  Skin malignancies

Section 9   Sexually transmitted diseases 1612 lymphangitis and inguinal lymphadenopathy together with systemic symptoms. LGV more recently has emerged as an im- portant cause of proctitis among men who have sex with men. Most individuals with LGV present with either the inguinal syn- drome (inguinal lymphadenopathy) or proctitis; however, some present with a primary ulcerative lesion at the site of inoculation. In studies looking at the frequency of the primary lesion, as few as 3% or as many as 53% of individuals with LGV recall having a genital ulcer in the early stages of infection. The ulcer usually starts as a single painless papule 3–​12 days after sexual exposure, which then ulcerates. It can occasionally be painful and multiple. It heals spontaneously. LGV is diagnosed clinically and by testing for C. trachoma- tis. In some settings, such as in the United Kingdom, the DNA from C. trachomatis identified from ulcer or genital specimens can be amplified and sequenced to determine whether it is an LGV-​associated L serovar. Serological tests for LGV are avail- able, but are of limited use (see Chapter 8.6.45) in routine clinical practice. Granuloma inguinale (Donovanosis) Granuloma inguinale (Donovanosis) is a bacterial infection caused by Klebsiella granulomatis. It is rare outside resource poor coun- tries. It is characterized by genital ulceration and granulomata which usually appear in the genital area 10–​14 days after initial in- oculation. The lesions are initially small and painless and are often raised and nodular, but may present as depressed necrotic ulcers. These nodules can coalesce to form fleshy moist genital plaques. Diagnosis is often made clinically after careful history taking (including travel history) and can be confirmed by tissue biopsy, which reveals Donovan bodies with Wright-​Giemsa staining (see Chapter 8.6.10). FURTHER READING BASHH. UK Guidelines. http://​www.bashh.org/​guidelines/

9.7 Anogenital lumps and bumps 1613

9.7 Anogenital lumps and bumps 1613

ESSENTIALS Anogenital lesions can be due to sexually transmitted infections, physiological variants that worry the patient, or dermatological conditions unrelated to infection. The clinical diagnostic approach is based on the colour of the lesion and the skin layer involved (epidermis, dermis, or subcutaneous fat compartment). A strong element of pattern recognition is involved in accurate diagnosis. This can only be learnt with experience, but is essential for deter- mination of appropriate treatment. Introduction Sexually transmitted infections (STIs) cause significant mor- bidity and mortality worldwide. In 2008 it was estimated that there were approximately 499 million new cases of curable STI, namely those due to Treponema pallidum (syphilis), Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vagina- lis, occurring every year throughout the world in men and women aged 15–​49 years, with the largest proportion in the region of South and Southeast Asia, followed by sub-​Saharan Africa, and then Latin American and the Caribbean. Many of these infec- tions are asymptomatic and undetected, enabling ongoing trans- mission. Some STIs cause symptoms, especially in the anogenital region, and therefore need to be considered in the differential diagnosis of patients presenting with anogenital lesions. As well as examination of the anogenital skin, a thorough patient history focusing on past STIs, STI treatments, and sexual risk behaviour (number of partners, sex of partners, sex techniques practised, condom use) is required. However, complaints of anogenital le- sions can be related to STIs, physiological variants that worry the patient, or dermatological manifestations unrelated to infection, hence dermatological expertise is needed for correct diagnosis and subsequent management of anogenital lesions. Clinical approach In this chapter the most common anogenital dermatological diagnoses are discussed using an approach based on the colour of the lesion and the skin layer involved. There is a strong element of pattern recognition involved in accurate diagnosis of skin le- sions that can only be learnt with experience. The three main skin layers are the epidermis, dermis, and subcutaneous fat compart- ment (Fig. 9.7.1). Lesions involving the epidermis affect the structure of the skin surface such as the skin lines. Increased epidermal cell turn- over can cause epidermal papules, hyperkeratosis, and/​or scales. Moreover, epidermal lesions can affect the skin appendages such as hairs and skin glands. If pigment cells (melanocytes) are involved, the normal pigmentation is affected. In the case of an underlying inflammatory process the dermal layer is normally involved. Dermal inflammation is characterized by redness, oedema, and skin induration and normally affects the adjacent epidermis causing scaling and deformation of the skin lines. Inflammation can affect the dermal-​epidermal junction causing detachment of the epidermis leading to (subepidermal) vesicles and pustules. Vesicles can also arise as intraepidermal vesicles. Subcutaneous lesions normally do not affect the structure of the skin surface. They are more easily defined upon palpation and can be moved independently from the overlying skin layers. Cysts and hypodermal structures such as lymph and venous vessels can manifest as subcutaneous lesions. Superficial anogenital lesions affecting the epidermis and/​or dermis Flesh-​coloured lesions Skin tags (also known as squamous papillomas, fibroepithelial polyps, acrochordons) Skin tags are benign growths frequently found in skin folds such as the inguinal folds and the perianal area (Fig. 9.7.2). They can be associated with obesity. Skin tags need to be differentiated from genital warts. Whereas the latter are characterized by changes in the epidermal structures (loss of skin lines, verrucous surface), the skin surface is unaffected and smooth in skin tags. Sometimes genital warts/​human papilloma virus (HPV) lesions can arise on the surface of skin tags. 9.7 Anogenital lumps and bumps Henry J.C. de Vries and Charles J.N. Lacey

Section 9   Sexually transmitted diseases 1614 Pearly penile papules/​Vulvar vestibular papillomatosis Pearly penile papules (PPP) (Fig. 9.7.3) and the female equivalent, vulvar vestibular papillomatosis (VVP) (Fig. 9.7.4), are a normal anatomical variant and not a disease. The condition normally de- velops at the time of acquisition of secondary sexual characteristics. They normally go unnoticed until close inspection takes place for some reason (e.g. a concern of STI). PPP are found in 20% of men, especially uncircumcised men. PPP and VVP are skin-​coloured, 1  mm, and sometimes elongated papules found, respectively, at the corona encircling the glans and on the lateral aspects of the vestibule. PPP and VVP can be mistaken for genital warts and should never be subject to ablative treatment. In contrast to warts, PPP and VVP are monomorphic with an even and symmetric distribution. The histopathological substrate of PPP and VVP are angiofibromata. Thick (hairless) skin Epidermis Superficial arteriovenous plexus Papillary dermis Reticular dermis Meissner’s corpuscle Sweat duct Deep arteriovenous plexus Subcutaneous fat Subcutis/hypodermis Dermis Dermal nerve fibres Eccrine sweat gland Eccrine sweat duct Hair follicle Sebaceous gland Arrector pilli muscle Dermal papillae Opening of sweat duct Hair shaft Pacinian corpuscle Eccrine sweet gland Thin (hairy) skin Fig. 9.7.1  The skin can be divided into three main layers: epidermis, dermis and subcutaneous fat (or hypodermis). Courtesy of Madhero88, available under the Creative Commons Attribution-​Share Alike 3.0 Unported licence. Fig. 9.7.2  Perianal skin tags, also known as acrocordons, or mariskes. Courtesy of Tmalonetn, available under the Creative Commons Attribution 3.0 Unported licence. Fig. 9.7.3  Pearly penile papules, also known as Hirsuties papillaris coronae glandis.

9.7  Anogenital lumps and bumps 1615 Fordyce spots Fordyce spots are asymptomatic physiological ectopic sebaceous glands found in mucosal tissue (Fig. 9.7.5). Typically in females they are located on the labia majora. In men they are frequently found on the penile shaft and scrotum. Both manifestations con- sist of evenly distributed white, or yellow, or skin-​coloured 1–​2 mm papules. On close inspection, or with a magnifying glass, the fol- licle outlets can be appreciated. Fordyce spots should not be treated. Fordyce spots should be distinguished from Fox-​Fordyce dis- ease, a pruritic inflammatory condition involving apocrine glands in large body folds, which can include the inguinal folds and pubic region, characterized by monomorphous skin-​coloured follicular 1–​2 mm papules. Anogenital warts Anogenital warts (also known as genital warts, or condylomata acuminata) are one of the most common STIs and are caused by the low-​risk HPV types 6 and 11. They are characterized by fili- form or verrucous, pink, skin-​coloured, or pigmented papules, (Fig. 9.7.6). They are usually self-​limiting. The main reason why medical help is sought is for cosmetic and psychological reasons, although anogenital warts can itch, bleed, and cause fissuring. There are several treatment options that can be divided into patient-​administered topical options such as podophyllotoxin, imiquimod, and sinecatechins, and provider-​administered abla- tive options such as liquid nitrogen, coagulation (electro, infrared, and/​or laser), and trichloracetic acid application. Only a few ro- bust head-​to-​head comparative studies have been performed, and as a result varying treatment guidelines and algorithms exist. The choice of treatment should be decided in collaboration with the patient, based on the location of the warts and the patient’s preference for the mode of administration. The treatment goal is to remove warts, rather than eliminating the virus. Most anogenital warts can be treated in a primary care setting. Referral to a med- ical specialist is indicated in case of children with anogenital warts, pregnancy, immunosuppression, large warts, treatment failure, internal warts, diagnostic problems, or a suspicion of neoplastic lesions. In some countries, national HPV vaccine campaigns have used the quadrivalent HPV vaccine that prevents HPV 6 and 11, and have shown dramatic decreases in the anogenital wart inci- dence in the heterosexual population. Molluscum contagiosum Molluscum contagiosum lesions are caused by the molluscum con- tagiosum virus (MCV) and are flesh-​coloured dome shaped pap- ules, sometimes with a central indentation. Infection frequently occurs in childhood in the setting of normal school and social contact. When seen in adults they are usually sexually transmitted and occur in the anogenital area. If numerous, large (>3 mm) or atypical mollusca are found in adults, immunodeficiency should be excluded, especially HIV infection (Fig. 9.7.7). Shaving of genital hair can also lead to the spread of infection, with multiple molluscs arising in the shaved area. Condyloma lata Condyloma lata are one of the cutaneous manisfestations of sec- ondary syphilis. They arise in moist, occluded areas, such as the inguinal, perianal, or perivaginal region and appear as flat pap- ules with a moist, cauliflower-​like, or velvety surface. These lesions Fig. 9.7.4  Vulvar vestibular papillomatosis. Source: STI outpatient clinic, GGD Amsterdam, Amsterdam, the Netherlands. Fig. 9.7.5  Fordyce spots on the labia majora (×5 colposcopic image). Source: Department of GU Medicine, General Infirmary, Leeds, UK. Fig. 9.7.6  Anogenital warts can have multiple manifestations. In this picture a flat and hyperpigmented lesion (left side) and comb-​shaped, verrucous, flesh-​coloured warts (right side) can be seen. Source: Department of GU Medicine, Leeds, UK.

Section 9   Sexually transmitted diseases 1616 contain numerous spirochetes, and are highly infectious, and are frequently dark ground microscopy positive (Fig. 9.7.8). Red lesions Angioma Angiomata are bright red, flat to dome-​shaped, 1–​6 mm in diam- eter papules appearing during young adulthood and increase in number with age. They appear especially in light-​skinned persons, and sites of predilection are the trunk, including the pubic and genital area. Histopathology shows a benign proliferation of capil- lary vessels. Electrocautery can be considered for cosmetic reasons or in case of bleeding upon trauma. Angiokeratoma Angiokeratoma are 1–​2  mm in diameter, smooth, dome-​ shaped papules occurring typically on the scrotal skin or labia majora. Sometimes they are connected to telangiectatic vessels (Fig. 9.7.9). Like angioma, the histopathological substrate is a benign proliferation of capillary vessels, but in angiokeratoma the overlying epidermis is thickened and shows elongated rete ridges. Numerous angiokeratoma located on the trunk can be found as symptom of Fabry’s disease, a metabolic disorder. Lichen simplex chronicus Lichen simplex chronicus is characterized by intensely itchy hyperkeratotic, and sometimes crusty plaques (Fig. 9.7.10). The lesions occur in patients who continuously scratch a specific skin region (often subconsciously), with lichenification and trauma as a result. The condition becomes chronic when the healing process produces an itch, leading to a vicious circle of scratching, trau- matization, and further itching. Some patients indicate that they feel something present in the skin that needs to be removed. In these cases delusional parasitosis should be excluded. Other pos- sible underlying psychological/​psychiatric causes like anxiety, obsessive-​compulsive disorder, and depression should also be ad- dressed. Treatment of lichen simplex chronicus can be difficult and is best managed in the hands of a dermatologist, often in a multi- disciplinary team setting. Lichen planus Lichen planus is a chronic inflammatory disease affecting various cutaneous and mucosal surfaces, and occasionally presents in the anogenital area. The lesions tend to be pink papules or plaques, scaly, show white striae and may have a bluish/​purplish hue. There are usually concomitant lichen planus lesions at other body sites. Mucosal ulcerative disease is rare, but may be pre-​malignant. Circinate balanitis C.  trachomatis infection might rarely cause a reactive auto- immune arthritis, also known as sexually acquired reactive Fig. 9.7.7  Multiple large mollusca contagiosa as seen in a severely immunodeficient HIV-​positive patient. Source: Department of GU Medicine, Leeds, UK. Fig. 9.7.8  Perianal condyloma lata in secondary syphilis. Hair growth in the lesion is not affected, in contrast to condyloma acuminata. Source: Department of GU Medicine, Leeds, UK. Fig. 9.7.9  Angiokeratoma of the scrotum. Courtesy of Jlcarter2, available under the Creative Commons Attribution-​Share Alike 3.0 Unported licence.

9.7  Anogenital lumps and bumps 1617 arthritis (SARA). SARA can be accompanied by character- istic skin signs including circinate balanitis, characterized by gyrate erythematous plaques with marginal scaling on the glans penis (Fig. 9.7.11). Other typical associated skin lesions are keratoderma blenorrhagica (i.e. hyperkeratotic plaques in the hand palms and foot soles), aphthous oral ulcers, and onycholysis. It is believed that pathogenic antigens stimulate an immune re- sponse with the production of cross-​reacting autoantibodies that recognize host structures. As a consequence, sterile inflamma- tory reactions such as dermatitis, arthritis, conjunctivitis, and tenosynovitis occur. Intraepithelial neoplasia and squamous genital malignancy Squamous cell carcinoma (SCC) of the anogenital skin can occur at the cervix, vagina, vulva, penis, perianal area, and anal canal. Such lesions occur in otherwise healthy subjects but are more fre- quent in immunosuppressed patients (either HIV or iatrogenic), and some medical conditions such as diabetes and systemic lupus erythematosus (SLE). Anal carcinoma is markedly increased in HIV-​infected men who have sex with men (MSM). SCC is strongly associated with persisting infections with high oncogenic risk HPV types. There is a spectrum of intraepithelial neoplasia at the various anogenital sites (e.g. CIN, VAIN, VIN, PIN, AIN located, respectively, at the cervix, vagina, vulva, penis, perianal area, and anal canal). Intraepithelial neoplasia is graded in increasing se- verity of neoplasia from 1 to 3 (Richart classification). The Bethesda classification is also used whereby squamous intraepithelial lesions are referred to as low-​grade SIL (LSIL—​HPV changes and IN1), and high-​grade SIL (HSIL—​IN 2 and 3). AIN can be visualized and characterized via high-​resolution anoscopy (HRA) and dir- ected biopsy. Anogenital HSIL lesions that have progressed to in- vasive SCC are characterized by exophytic tumorous lesions and chronic ulceration (Fig. 9.7.12). Especially in ulcerative, atypical, and therapy-​resistant anogenital warts, invasive disease should be excluded via histopathological analysis of suspected and represen- tative areas of the total lesion. Extramammary Paget’s disease Extramammary Paget’s disease is a rare condition but often occurs in the anogenital region, most commonly the vulva. Biopsies of the lesions show either adenocarcinoma in situ, with or without inva- sive adenomacarcinoma. The lesions are chronic, red, and fissured, and might be mistaken as eczematous. The neoplasia is usually either arising directly from apocrine glands and skin append- ages, or associated with a local anogenital (e.g. rectum, bladder) adenocarcinoma. Pigmented lesions Dermatofibroma (aka histiocytoma) These are pigmented nodular lesions and can occur at any age. They can be single or multiple, are benign, and do not require treatment. Fig. 9.7.10  Excoriated, hypertrophic, and hyperkeratotic, fissured, and partly crusty plaques on the scrotum. Source: Department of Dermatology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands Fig. 9.7.11  A autoreactive immunological manifestation in a patient with a urogenital Chlamydia trachomatis infection. Source: STI outpatient clinic, GGD Amsterdam, Amsterdam, the Netherlands. Fig. 9.7.12  HPV-​induced perianal carcinoma in an HIV-​positive patient. Source: STI outpatient clinic, GGD Amsterdam, Amsterdam, the Netherlands.

Section 9   Sexually transmitted diseases 1618 Benign melanocytic lesions (aka melanocytic naevi,
moles, freckles) These can be congenital or acquired. They are frequently multiple. There are a great variety of forms, but specialist dermatological management is required for atypical or dysplastic naevi that might show asymmetry of shape or pigmentation, or recent change in appearance Bowenoid papulosis These are pigmented papules which show a reddish-​brown to brownish-​black pigmentation. The lesions are caused by high-​risk HPV (usually HPV 16) and show high-​grade intraepithelial neo- plasia. They can be admixed with more typical genital warts, and such red pigment change with HPV lesions should trigger biopsy and histopathological evaluation. Seborrhoeic keratosis (aka basal cell papilloma, seborrhoeic warts) Seborrhoeic keratoses occur all over the body and are increasingly common with age. They are often seen on the anterior abdominal wall, and are raised papules. They can be a variety of colours from grey to dark brown, they often have a waxy surface, and appear as if stuck to the skin like a barnacle. They are entirely benign. Pustular lesions Folliculitis Foliculitis can range from small pustular lesions arising in a hair follicle with only the presence of normal skin flora, to larger mul- tiple pustular lesions associated with staphylococcus or strepto- coccus and cellulitis. Bacterial culture should be performed for significant lesions, and oral antibiotics prescribed if there are signs of cellulitis. Genital herpes simplex/​zoster Both genital herpes simplex virus (HSV) and varicella zoster virus (VZV) present with vesicular lesions that progress to ulcer- ation, accompanied by pain and often inguinal lymphadenopathy. Anogenital VZV is comparatively rare, tends to be more extensive, and with a dermatomal distribution. Primary HSV is usually much more widespread than recurrent HSV. Whereas primary genital herpes is caused by both HSV1 and HSV2, HSV2 predominates in recurrent disease. The initial diagnosis should be confirmed by HSV PCR. Hidradenitis suppurativa Hidradenitis suppurativa is an inflammatory condition of the apocrine glands. It can affect a variety of body sites including the inguinal and anogenital areas. There may be multiple com- edones, papules, abcesses, sinuses, and scarring. It may be asso- ciated with smoking, obesity, insulin resistance, Crohn’s disease, and various other factors. Specialist referral and management is indicated. Crusty lesions Scabies Scabies is caused by the ectoparasite Sarcoptes scabiei (scabies mites), and itch is the main symptom. The incubation period in a scabies naïve patient is two to six weeks; in case of repeat infec- tions, symptoms can occur sooner (1–​4 days) due to sensitization to scabies antigens (via a delayed type hypersensitive T-​cell-mediated response). Typical ‘burrows’ and excoriations can be found on the sites of predilection including the external genitalia, buttocks, and thighs, the interdigital space of the fingers, the lateral sides of the hand palms, the flexor side of the wrists, feet, armpits, and around the nipples. In the genital area, scabies normally pre- sents with larger (about 0.5–​1 cm) pruritic papules (Fig. 9.7.13). Transmission occurs during skin-​skin contact lasting longer than 15 minutes, which is usual during sexual contact and almost never the case in everyday human interaction such as shaking hands. An exception to this rule is crusted scabies, a highly transmissible form of scabies characterized by numerous mites that can cause epidemic outbreaks within institutions where the index case is being hospitalized (Fig. 9.7.14). Crusted scabies is a hyperinfective condition characterized by hyperkeratotic crust-​ like lesions and can be seen in severely immunosuppressed (e.g. AIDS), paraplegic, and severely mentally disabled patients in a hospitalized setting. Plaque/​flat lesions Psoriasis inversa Psoriasis is one of the most common diagnoses in the derma- tological practice, characterized by monomorphic erythemato-​ squamous plaques and papules. Psoriasis inversa is reserved for lesions in the genital area body folds including the peri- anal area (Figs. 9.7.15 and 9.7.16). Psoriasis is caused by an autoimmunological response directed towards the basal epi- dermal layer. T-​cell immunity and the release of TNF-α are important factors in the inflammatory response. Different treat- ment modalities are available, but topical corticosteroid oint- ments are first line. Other options are ultraviolet (UV) light therapy, topical vitamin D derivatives, and oral immunosup- pressive drugs like methotrexate and cyclosporine. Fig. 9.7.13  Pruritic papules and nodules in the genital area are a hallmark for a scabies investation. Source: Department of Dermatology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.

9.7  Anogenital lumps and bumps 1619 Lichen sclerosus (aka lichen sclerosus et atrophicus (LS&A), balanitis xerotica obliterans (BXO)) Lichen sclerosus is an autoimmune condition frequently affecting the anogenital area. It affects both children and adults. The epithe- lium is thinned, white, fissures, and bleeds easily, and telangectasia might be seen within the lesions. Histopathology shows epidermal atrophy and a mononuclear cell lichenoid infiltrate in the dermis. It has a characteristic appearance and can often be diagnosed clin- ically. In men it frequently affects the foreskin causing phimosis; most circumcision specimens from young boys with phimosis show lichen sclerosus changes. In women it often affects the vulva, clitoris, and introitus. Treatment is with potent topical steroids such as clobetasol. In older women it is a pre-​malignant condition, and perhaps half of all vulval SCCs arise in this setting. Intraepithelial neoplasia See ‘Intraepithelial neoplasia and squamous genital malignancy’, earlier. Syphilitic papules Syphilis is considered the ‘great imitator’, and can manifest itself in a spectrum of symptoms including genital lumps (Fig. 9.7.17). This is especially the case for the secondary stage. In a patient without pre-​ existing genital lesions, syphilis should be excluded, especially in MSM since they are most affected in the current syphilis epidemic. Deep palpable lesions not affecting the overlying skin (subcutaneous lesions): No loss of skin lines and appendages Cystic/​nodular lesions Steatocystoma multiplex (epidermal cysts) Steatocystoma multiplex are epidermal cysts that occur as firm, dome-​shaped smooth (0.5–​2 cm in diameter) white to yellow-​white flesh-​coloured papules in the hair-​bearing genital skin such as the scrotum or labia majora. If multiple cysts are present, the condition has the appearance of ‘a bag of marbles’ (Fig. 9.7.18). Epidermal cysts usually require no treatment unless for cosmetic reasons. Rarely the epidermal lining of the cyst ruptures, exposing its con- tent to the underlying dermis. As a result, a foreign body inflamma- tory response can occur that can mimic a furuncle. Inflamed cysts can be incised and drained. Epidermoid cysts (sebaceous cysts) Such cysts tend be single and are derived from sebaceous glands. Sometimes multiple cysts are seen on the scrotum or labia majora. Fig. 9.7.14  Highly infectious crusty lesions in a severely immunosuppressed HIV-​positive patient wiith crusted scabies. Source: Department of Dermatology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands. Fig. 9.7.15  Monomorphic sharply demarcated intensely erythematous plaque in the genital area of a new born girl. Source: Department of Dermatology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands. Fig. 9.7.16  Monomorphic sharply demarcated erythemato-​squamous plaque in the inguinal groin area. Source: Department of Dermatology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.

Section 9   Sexually transmitted diseases 1620 They might rupture and resolve spontaneously. However, they are often regarded as a cosmetic problem and patients present re- questing their removal. If attempting excision, care must be taken to remove the entire capsule. Bartholin cysts, other cysts of the vestibular glands
and median raphe There are various sites in the anogenital area where normal glan- dular structures can develop cystic changes. The most common is a Bartholin’s cyst, arising in the posterior third of the labium majus. Care should be taken to differentiate a Bartholin’s cyst which is subacute/​chronic, and non​inflammatory, from a Bartholin’s ab- scess, which is acute, can be associated with gonococcal or chla- mydial infection, and which might need urgent surgical drainage (Fig. 9.7.19). Oedema and swellings Sclerosing lymphangitis Sclerosing lymphangitis is characterized by a non​painful subcuta- neous fluctuating or fibrotic cord-​like structure in the penile cor- onal sulcus (Fig. 9.7.20). Although unproven, it is possibly a result of decompensation of lymphatic drainage caused by an inflam- matory process. It is usually found in sexually active men in their 20s to 40s following vigorous sexual intercourse or masturbation, probably resulting in mechanical trauma of the lymphatic appar- atus. In two-​thirds of the patients with sclerosing lymphangitis, an STI is diagnosed. (a) (b) Fig. 9.7.17  (a and b) In secondary stage syphilis is characterized by a large variety of anogenital skin lesions. As a result any anogenital skin manifestation justifies syphilis diagnostics. Source: STI outpatient clinic, GGD Amsterdam, Amsterdam, the Netherlands. Fig. 9.7.18  Steatocystoma multiplex scrotalis. Source: Department of Dermatology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands. Fig. 9.7.19  An inflamed Bartholin cyst in the right labia majora. This is an acute presentation with pain, fever, and discomfort. Source: Department of GU Medicine, Leeds, UK.

9.7  Anogenital lumps and bumps 1621 Mondor’s disease Mondor’s disease is a rare condition which is considered a thrombo- phlebitis of the subcutaneous veins. It commonly occurs on the anterolateral thoracoabdominal wall, but it can also occur on the penis, groin, antecubital fossa, and posterior cervical region. The clinical features are a sudden and typically asymptomatic onset of a cord-​like induration, although some patients report a feeling of ‘strain’. It is a self-​limiting process that lasts a short period of time, which might be the reason why there are few reports about its diag- nosis and treatment. As with sclerosing lymphangitis, in patients with penile Mondor’s disease it is essential to exclude STIs. Lymphogranuloma venereum Lymphogranuloma venereum (LGV) was considered an STI con- fined to equatorial regions until 2004, when an epidemic of LGV was reported among MSM in major cities throughout the Western world. LGV is caused by C. trachomatis-​type L, and is associated with a severe invasive, destructive disease. If left untreated it can eventually lead to irreversible damage to the lymphatic system, strictures, and chronic pain syndromes in the pelvic region. Depending on the progression of the infection, three stages can be distinguished in LGV. The inoculation stage is characterized by an inconspicuous and short-​lived ulcer at the inoculation site, and the regional stage by subsequent invasion of C. trachomatis in the submucosal tissue, causing a violent inflammatory reaction with oedema. In addition, C. trachomatis spreads via the lymphatics to regional lymph nodes where lymphadenopathy (bubo formation) occurs (Fig. 9.7.21). Necrosis in lymph nodes can lead to fluctu- ating abscesses that sometimes rupture and leave long-​standing fistulae. Due to the extent of the infection, many patients have sys- temic symptoms including malaise fever, weight loss, joint pains, possibly caused by a reactive arthritis. FURTHER READING Bunker CB (2004). Male genital skin disease, 1st edition. Saunders, Edinburgh/​London. de Vrieze NH, de Vries HJ (2014). Lymphogranuloma venereum among men who have sex with men: an epidemiological and clin- ical review. Expert Rev Anti Infect Ther, 12, 697–​704. Edwards L, Lynch PJ, Neill SM (2011). Genital dermatology atlas, 2nd edition. Lippincott Williams & Wilkins, Philadelphia. Fairley CK, et al. (2009). Rapid decline in presentations of genital warts after the implementation of a national quadrivalent human papillomavirus vaccination programme for young women. Sex Transm Infect, 85, 499–​502. Gottlieb SL, et al. (2014). Toward global prevention of sexually trans- mitted infections (STIs): the need for STI vaccines. Vaccine, 32, 1527–​35. Gupta S, Kumar B (2012). Sexually transmitted infections, 2nd edi- tion. Reed Elsevier, New Delhi. Holmes KK (2008). Sexually transmitted diseases, 4th edition. McGraw-​Hill Medical, New York. Machalek DA, et al. (2012). Anal human papillomavirus infection and associated neoplastic lesions in men who have sex with men: a systematic review and meta-​analysis. Lancet Oncol, 13, 487–​500. Richel O, et al. (2015). Brief report: anal cancer in the HIV-​positive population:  slowly declining incidence after a decade of cART.
J Acquir Immune Defic Syndr, 69, 602–​5. Youssef AF. (1984). Atlas of gynaecological diagnosis. Churchill Livingstone, Edinburgh/​New York. Fig. 9.7.20  Sclerosing lymphangitis in the penile sulcus as a symptom of a urethral Neisseria gonorrhoeae infection. Source: STI outpatient clinic, GGD Amsterdam, Amsterdam, the Netherlands. Fig. 9.7.21  Inguinal lymphogranuloma venereum (LGV) with a bubo in the groin area. Source: Department of Dermatology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.

9.8 Pelvic inflammatory disease 1622

9.8 Pelvic inflammatory disease 1622

ESSENTIALS Pelvic inflammatory disease is an infection of the endometrium, fallopian tubes and adnexae caused by a wide variety of bacteria, including Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium and genital tract bacteria, most notably anaerobes. Pelvic inflammatory disease is often asymptomatic but clinical manifestations can range from mild pelvic pain and tenderness to se- vere peritonitis. Pelvic abscess formation is a serious infectious compli- cation. However, only about 5% of patients with pelvic inflammatory disease have a fever or severe infectious manifestations. An accurate clinical diagnosis of pelvic inflammatory disease is difficult and it is commonly confused with other pelvic conditions, including ectopic pregnancy, appendicitis, and rupture or torsion of an ovarian cyst. Antibiotic therapy is aimed primarily at C.  trachomatis, N. gonorrhoeae, and anaerobic bacteria, with prompt identifica- tion and treatment of pelvic inflammatory disease recommended in an attempt to reduce the 15% rate of tubal infertility and 40% risk of chronic pelvic pain following this infection. Introduction Pelvic inflammatory disease (PID) occurs when infection spreads from the vagina and cervix to the uterus, fallopian tubes, and sur- rounding pelvic structures. It is a common cause of morbidity in young women leading to abdominal pain, and is associated with considerable psychological distress because of the association with sexually transmitted infections and risk of infertility. Although initial treatment is relatively inexpensive, its high prevalence and the increased risk of developing long-​term sequelae following PID result in a high financial burden to health services. Aetiology Most PID is caused by sexually transmitted bacteria spreading from the lower genital tract to the upper genital tract leading to endo- metritis, salpingitis, and oophoritis. Chlamydia trachomatis and Neisseria gonorrhoeae are the most commonly recognized pathogens but only account for around 40% of infections, although their rela- tive contribution varies considerably in different geographical areas. Anaerobic bacteria can also be detected in the fallopian tubes in women with PID although their role as primary pathogens, as op- posed to opportunistic secondary invaders, is not clear. They are im- portant in more severe PID, particularly when a pelvic abscess forms, and indicate the need for specific antimicrobial cover. A variety of newer pathogens have been identified using nucleic acid amplifica- tion to detect bacteria which are difficult to culture using traditional microbiological techniques. Mycoplasma genitalium almost cer- tainly causes PID, probably about 5–​10% of cases, and Leptotrichia, Sneathia, Atopobium, and ‘BV-​associated bacteria’ (BVABs) have also been detected, although their role is less well defined. There are several possible risk factors for women to develop to PID after contracting gonorrhoea or chlamydia, with the overall risk being around 10%. In animal models, infections acquired in the luteal phase of the menstrual cycle are more likely to cause PID, as are infections with a higher bacterial load. In humans, there is a link between PID and human leukocyte antigen (HLA) subtype or inherited polymorphisms affecting cytokine and immune cell expression, suggesting that some women are intrinsically at higher risk than others. Procedures such as termination of pregnancy and insertion of an intrauterine contra- ceptive device, which involve inserting items through the cervix, also increase the risk of introducing infection into the upper genital tract. Bacterial vaginosis, and the associated imbalance of the vaginal bacterial flora, is closely associated with PID. Bacterial vaginosis is more commonly diagnosed in women with PID and the bac- teria found in the lower genital tract in bacterial vaginosis overlap considerably with those seen in the upper genital tract in PID. Prospective studies do not suggest that all women with bacterial vaginosis have an increased chance of getting PID, but certain sub- groups are at increased risk; specifically, PID is more common if there is a high bacterial load of anaerobes in the vagina or if infec- tion with gonorrhoea or chlamydia subsequently occurs. Epidemiology The incidence of PID is falling in many countries in those pre- senting both in primary and secondary care, and particularly in younger women (Fig. 9.8.1). The decline has been particularly 9.8 Pelvic inflammatory disease Jonathan D.C. Ross

9.8  Pelvic inflammatory disease 1623 marked for chlamydia PID and might reflect an increased aware- ness of chlamydia, in both the general population and healthcare personnel, with high rates of testing picking up early infections be- fore they progress to cause salpingitis. The risk factors for PID are very similar to those of the under- lying sexually transmitted infections, and include sex without using condoms multiple and particularly concurrent partners, and low socio-​economic status. Use of the combined oral contraceptive pill reduces the risk of developing symptomatic chlamydial PID, although its effect on subclinical disease is not clear. An increase in the frequency of vaginal douching is associated with PID but prospective studies suggest that douching is not a direct cause of PID and may instead be a response to PID-​related symptoms, such as genital discharge or vaginal odour. Pathogenesis An endometrial biopsy from a woman with PID demonstrates a plasma cell infiltrate with polymorphonuclear cells and the forma- tion of lymphoid follicles. Inflammation of the fallopian tubes causes swelling and erythema with an inflammatory exudate within the fal- lopian tube, mixed with blood and necrotic epithelial cells which can lead to tubal obstruction. During healing adhesions can form causing permanent blockage of the tube, and chronic inflamma- tion can result in a pyosalpinx (abcess formation within the tube) or hydrosalpinx (fluid filled collection within the tube) if the tube becomes obstructed at both ends. Clinical features Many women with PID are asymptomatic and might only present with the consequences of tubal damage, such as infertility or ectopic pregnancy. Of those with symptoms, most have mild to moderate lower abdominal pain which is usually bilateral, constant, and of re- cent onset. An associated vaginal discharge secondary to cervicitis or bacterial vaginosis is common, and there might also be a history of post-​coital bleeding, intermenstrual bleeding, or menorrhagia as a result of cervicitis or endometritis. More rarely, with severe PID, the patient is systemically unwell with pyrexia, general malaise, and severe abdominal pain associated with peritonitis or a pelvic abscess. An associated perihepatitis might lead to right upper quad- rant pain and tenderness (the Fitz-​Hugh–​Curtis syndrome). On bimanual vaginal examination there is usually bilateral ad- nexal tenderness and cervical excitation (discomfort on moving the cervix). An inflammatory mass or abscess is sometimes palpable. The clinical diagnosis of PID has poor specificity with only around 60% of clinical diagnoses being confirmed if laparoscopy is performed, although the accuracy improves slightly if the exam- ination is performed by an experienced clinician. Despite this, current guidelines recommend a low threshold for starting treat- ment following clinical assessment because the risks of antibiotic treatment are considered low and the sequelae of untreated infec- tion potentially severe. PID should therefore be considered in any young sexually active women complaining of lower abdominal pain and who is found to have adnexal tenderness on examination. Differential diagnosis The most important alternative condition to consider in a young woman with lower abdominal pain is ectopic pregnancy and a pregnancy test should, therefore, be performed. Although a preg- nancy test is not reliable in very early pregnancy, an ectopic preg- nancy is unlikely to present at this early stage and the patient can be recalled for repeat testing at a later date if required. Other causes of abdominal pain in young women include appendicitis, irritable 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015 Year No. of PID diagnoses Gonococcal PID Chlamydia PID Nonchlamydial, nongonococcal PID Fig. 9.8.1  Pelvic infection diagnosed in sexual health clinics in England.

Section 9   Sexually transmitted diseases 1624 bowel syndrome, rupture/​torsion of an ovarian cyst, endometri- osis, urinary tract infection, or functional pain where no under- lying cause is identified (Table 9.8.1). In older women, diverticulitis or malignancy should also be considered. Clinical investigations Microbiological testing for gonorrhoea, chlamydia and M. gentalium should be performed, from a vaginal or cervical swab using a nu- cleic acid amplification-​based test (NAAT). An additional cervical sample for gonorrhoea culture should be taken to test for antibiotic sensitivities. Although a minority of women with clinical PID have gonorrhoea, chlamydia or mycoplasma, their presence makes the diagnosis more likely and, if N.  gonorrhoeae is present, the re- sistance pattern might influence the choice of antibiotic therapy. Screening for HIV and syphilis should also be offered. Other blood tests have limited value in most women with PID. An elevated neutrophil count, erythrocyte sedimentation rate (ESR), or C-​reactive protein is unusual in mild to moderate disease, and non​specific in women with severe pain. Ultrasound scanning is useful when a tubo-​ovarian abscess or hydrosalpinx is suspected clinically (e.g. severe pain with adnexal mass) but seldom helpful when trying to identify uncomplicated salpingitis because the inflamed tissue cannot easily be seen on the scan. Doppler ultrasound is potentially more useful by detecting the increased blood flow associated with pelvic inflammation. Computed tomography (CT) or MRI scanning can occasionally be helpful, especially in a patient with severe pain and an uncertain diagnosis, but are not used routinely. A transcervical endometrial biopsy can be taken and examined for histological evidence of endometritis, which is a reasonable proxy marker for salpingitis. However, the fixing, staining, and reporting of the sample takes several days and it is therefore not helpful in making decisions about whether to start therapy. Laparoscopy or laparotomy are seldom performed except where the diagnosis is in doubt in a patient with severe symptoms, or if antibiotic treatment has not been effective. Although directly visualizing the fallopian tubes is helpful in diagnosing moderate or severe PID, there is considerable inter and intraobserver vari- ation in interpreting the tissue appearances in women with mild disease. Treatment Several different antibiotic regimens are effective in treating PID, and are summarized in Table 9.8.2. Early empirical therapy, within a few days of the onset of symptoms, is important to min- imize the risk of tubal damage. The choice of antibiotic regimen will be determined by patient choice and the local epidemiology of specific infections. Antimicrobial resistance in N.  gonor- rhoeae is common for penicillin and tetracyclines, can develop rapidly for macrolides (such as azithromycin), and is beginning to emerge for cephalosporins. Moxifloxacin should be given if M. genitalium is diagnosed. First-​line empirical therapy might, therefore, need to be altered once the results of microbiology testing and antibiotic sensitivities are available. Inpatient care with parenteral antibiotics is needed for women with severe symptoms (e.g. temperature over 38oC, peritonitis, tubo-​ovarian abscess), failure to respond to oral antibiotics within 3–​4 days, or intolerance of oral treatment. Women should be given a detailed explanation about PID including the long-​term prognosis, and provided with written in- formation. A patient information leaflet is available at https://​www. bashh.org. Sexual partners should be screened for gonorrhoea and chlamydia (and/​or treated empirically with a 7 day course of doxy- cycline) before resuming sexual contact. Table 9.8.1  Differential diagnoses for pelvic inflammatory disease (PID) Ectopic pregnancy Positive pregnancy test Appendicitis Pain localizes to right iliac fossa Associated with vomiting Irritable bowel syndrome Associated altered bowel habit and abdominal pain Ovarian cyst rupture/​torsion Sudden onset of pain Endometriosis Cyclical or chronic pain Urinary tract infection Urinary frequency/​dysuria Table 9.8.2  Antibiotic treatment of PIDa Outpatient care 1. Single dose intramuscular ceftriaxone plus oral doxycycline (14 days) plus oral metronidazole (14 days) 2. Oral ofloxacin (14 days) plus oral metronidazole (14 days) 3. Oral moxifloxacin (14 days) Inpatient careb 1. Intravenous ceftriaxone plus intravenous/​oral doxycycline 2. Intravenous clindamycin plus intravenous gentamicin 3. Intravenous ofloxacin plus intravenous metronidazole 4. Intravenous ciprofloxacin plus intravenous/​oral doxycycline plus intravenous metronidazole a See also https://​www.bashh.org for UK National Guideline for the Management of Pelvic Inflammatory Disease b Switch to oral therapy 24 hours after symptoms improve to complete a total of 14 days treatment

9.8  Pelvic inflammatory disease 1625 A clinical review after three days is recommended if symptoms are not improving, and it might also be helpful after two to four weeks to review the treatment response, tracing of sexual partners, and microbiology results. It can take several weeks for symptoms to fully resolve, but if there is no significant improvement within the first week or two, then alternative causes of abdominal pain should be sought. If an intrauterine contraceptive device (IUD) is present, then its removal should be considered. If symptoms are not too severe, it is reasonable to leave the IUD in situ while treating with antibiotics, but it should be removed if clinical improvement has not occurred within a few days. Prognosis The fertility of women with a first episode of PID is usually good if they are treated without delay with appropriate antibiotics, but infertility occurs overall in around 15% of patients (defined as failing to become pregnant over several months despite not using contraception). The risk is markedly increased in women who have repeated episodes of infection (Fig. 9.8.2). The most common long-​ term consequence of PID is chronic pelvic pain, which affects up to 40% of women. The relative risk of tubal damage leading to ectopic pregnancy is also increased, but the absolute risk remains low at about 1%. The risk of sequelae can be reduced by avoiding further infec- tion through the use of barrier contraception such as condoms. Screening young women for chlamydia, which is often asymp- tomatic, and providing early treatment can also reduce rates of PID. FURTHER READING Molander P, et  al. (2001). Transvaginal power Doppler findings in laparoscopically proven acute pelvic inflammatory disease. Ultrasound Obstet Gynecol, 17, 233–​8. Ness RB, et  al. (2002). Effectiveness of inpatient and outpatient treatment strategies for women with pelvic inflammatory dis- ease: results from the Pelvic Inflammatory Disease Evaluation and Clinical Health (PEACH) Randomized Trial. Am J Obstet Gynecol, 186, 929–​37. Ness RB, et al. (2005). Douching, pelvic inflammatory disease, and incident gonococcal and chlamydial genital infection in a cohort of high-​risk women. Am J Epidemiol, 161, 186–​95. Ross JDC, Hughes G. (2014). Why is the incidence of pelvic inflam- matory disease falling? BMJ, 348, g1538. Ross JDC, et al. (2018). UK National Guideline for the Management of PID. http://​www.bashh.org/​guidelines: 2018 Scholes D, et al. (1996). Prevention of pelvic inflammatory disease by screening for cervical chlamydial infection. N Engl J Med, 334, 1362–​6. 50% 45% 50% 35% 30% 25% 20% 15% 10% Percentage 5% 0% 1st episode 3 or more episodes 2nd episode Risk of infertility Fig. 9.8.2  Risk of infertility following repeated episodes of pelvic infection.

9.9 Principles of contraception 1626

9.9 Principles of contraception 1626

9.9 Principles of contraception Zara Haider ESSENTIALS A wide range of contraceptive methods is available (increasing year on year), which can be classified as hormonal or non​hormonal, shorter or longer lasting, and reversible or irreversible. A full range of these should be available from accessible sources such as primary care facilities, sexual health clinics, and outreach clinics. When particular methods are not available from any source there should be a pathway for easy, timely access of that method from a nearby location. Clinicians must deliver up-​to-​date, accurate, unbiased informa- tion about each contraceptive method including details of efficacy, advantages, non​contraceptive benefits, side effects, disadvantages, and risks. They should discuss the contraceptive options with each patient to find the right method for them, taking into account their history (medical, drug, gynaecological, and so on), lifestyle choices, be- liefs and concerns. The patient must have enough information to make an informed choice and feel part of the negotiation process to maximize the chance of them continuing with the chosen method. No contraceptive method is 100% effective (apart from abstin- ence) and where there is potential risk of conception due to unpro- tected sex or an error with a contraceptive regimen, the patient must be informed about methods of emergency (post-​coital) contracep- tion, the most effective being the post-​coital intrauterine device. Education of the public about the benefits of contraception is vital and must be done in a timely way (e.g. through school sex educa- tion, media, and online resources). Introduction Every woman should have the right and ability to control her fer- tility. With careful history taking, explanation, and negotiation, a clinician and woman should come to agreement about the most suitable contraceptive method for her, based on a myriad of fac- tors. Encouraging women to use more cost-​effective long-​acting methods should be a priority in the current economic climate with the cost of raising a child and the cost of performing a termination of pregnancy far outweighing the cost of providing fertility control. History taking To find the most appropriate contraceptive method for an indi- vidual, an accurate, concise history needs to be taken. The clin- ician should refer to the UK Medical Eligibility Criteria (UKMEC) https://​www.fsrh.org/​standards-​and-​guidance/​documents/​ ukmec-​2016-​summary-​sheets/​ for guidance, as certain methods might be contraindicated and alternative choices should be considered where necessary. History taking should include the following: Medical history (see UKMEC for more details: https://​www.fsrh. org/​standards-​and-​guidance/​documents/​ukmec-​2016-​summary-​ sheets/​) • Enquire about medical conditions that might contraindicate use of certain methods (e.g. cardiovascular disease, hyperten- sion, venous thromboembolism, migraine, liver disease, breast cancer) • Enquire about family history of medical issues (especially if affecting <45-​year-​old first-​degree family members) Drug history: • Ask about prescribed and over-​the-​counter drugs. Is the pa- tient taking any liver enzyme-​inducing drugs, for example, St John’s Wort? (These cause reduced efficacy of COC, POP, and subdermal implant, so consider alternative methods) Gynaecological history: • Last menstrual period:  timing and nature, menstrual cycle, bleeding pattern, and consider non​contraceptive benefits of

9.9  Principles of contraception 1627 lighter, regular, less painful menses with certain contraceptive methods • Is there a risk of pregnancy? Consider the need for a preg- nancy test Sexual history: • Concise history, which should include the questions: ◾ ‘When did you last have sex?’ ◾ ‘When did you last have sex with anyone different?’ • Ask about sexually transmitted infection (STI) symptoms (e.g. change in vaginal discharge, dysuria, pelvic pain, vulval lesions, and so on) • Offer STI testing Social history: • Smoking (current or in the past) • History of sexual assault/​domestic violence Examination: • Body mass index (BMI) • Blood pressure Effectiveness of contraceptive methods Failure rates are expressed as conceptions per 100 women years. ‘Perfect use’ means that the method is used consistently and cor- rectly at every intercourse. ‘Typical use’ means imperfect use and depends on characteristics such as age, social class, acceptability of contraception in the population studied, and so on. Examples of imperfect use are missed pills, split condoms, failing to leave dia- phragm in for six hours after intercourse, and so on (see Table 9.9.1). A brief overview of contraceptive methods Long-​acting reversible contraceptive methods See Fig. 9.9.1. Combined hormonal contraception and the progestogen-​only pill See Fig. 9.9.2. Male and female sterilization See Table 9.9.2. Barrier contraceptive methods See Fig. 9.9.3. Emergency contraception See Fig. 9.9.4. Fertility awareness based methods Mechanism of action: a woman needs to identify her fertile and infertile times of the cycle using various fertility indicators (e.g. changes in cervical mucous, menstrual cycle calculations, and basal body temperature). Alternatively, there is Persona which is a small handheld com- puterized monitor which measures hormonal changes using urine sticks (94% effective). Advantages: no side effects, body awareness, and can be used to plan pregnancy. Disadvantages: need to learn method from a trained teacher, need to avoid sex or use condom during fertile times, it takes 3–​6 menstrual cycles to learn effectively, and the patient must keep daily records. Table 9.9.1  Effectiveness of contraceptive methods: percentage of US women experiencing an unintended pregnancy during the first year of use Method % Pregnant Typical use Perfect use No method 85 85 Withdrawal 22 4 Diaphragm 12 6 Female condom 21 5 Male condom 18 2 Progestogen-​only pill 9 0.3 Combined oral contraceptive pill 9 0.3 Patch 9 0.3 Vaginal ring 9 0.3 Female sterilization 0.5 0.5 Male sterilization 0.15 0.1 Medroxyprogesterone acetate injection 6 0.2 Copper intrauterine device (IUD) 0.8 0.6 Levonorgestrel intrauterine system (IUS) 0.2 0.2 Subdermal etonogestrel implant 0.05 0.05 Fertility awareness based methods Calendar 24 4–5 Ovulation method 24 3 Sympto-​thermal 24 0.4 Source data from Trussell J In: Hatcher R, Trussel J, Nelson A et al. (eds), Contraception Technology, New York, NY: Ardent Media 2011.

Section 9   Sexually transmitted diseases 1628 Fig. 9.9.1  Long-​acting reversible contraceptive methods.

9.9  Principles of contraception 1629 Fig. 9.9.1  Continued

Section 9   Sexually transmitted diseases 1630 Fig. 9.9.2  Combined hormonal contraception and the progestogen-​only pill.

9.9  Principles of contraception 1631 Fig. 9.9.2  Continued Table 9.9.2  Male and female sterilization Method Male sterilization (vasectomy) Female sterilization Mode of action The vas deferens is occluded by cutting, sealing, or tying. Most commonly done using ‘no scalpel’ method Must be considered irreversible The fallopian tubes are cut and sealed. This is done at laparoscopy, mini laparotomy, or open procedure (e.g. post caesarean section). Must be considered irreversible Advantages Difficult to reverse No serious long-​term side effects Quick to perform under local anaesthetic Difficult to reverse Periods unaffected Disadvantages Surgical procedure must be performed by trained clinician Pain post procedure and surgical risks Must wait for azoospermia (16–​18 weeks). Need to use alternative precautions during this time Chronic scrotal pain Sperm granulomata: leakage of sperm may form small painful lumps (sperm granuloma) Surgical procedure must be performed by trained clinician Pain post procedure and surgical risks Small risk of ectopic pregnancy if procedure fails

Section 9   Sexually transmitted diseases 1632 Fig. 9.9.3  Barrier contraceptive methods.

9.9  Principles of contraception 1633 Fig. 9.9.4  Emergency contraception.

Section 9   Sexually transmitted diseases 1634 FURTHER READING Faculty of Sexual and Reproductive Healthcare. Guidance on all con- traceptive methods. https://​www.fsrh.org Family Planning Association. http://​www.fpa.org.uk/​help-​and-​ advice/​contraception-​help fertility-​awareness.com Glasier A, Gebbie A (2008). Handbook of family planning and repro- ductive healthcare. Churchill Livingstone Elsevier, London. Guillebaud J (2013). Contraception—​your questions answered, 6th edition. Churchill Livingstone Elsevier, London. Trussell J (2011). Contraceptive failure in the United States, Contraception, 83, 397–404. UK Medical Eligibility Criteria (UKMEC) (2009). Available as full version and summary sheets on fsrh.org. http://​www.fsrh.org/​pdfs/​ UKMEC2009.pdf

   VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 Index Tables, figures, and boxes are indicated by t, f, and b following the page number Note: For the benefit of digital users, indexed terms that span two pages (e.g., 52–​53) may, on occasion, appear on only one of those pages. AA amyloidosis  2217, 2219, 4262, 6161 associated conditions  2219, 2220b clinical features  2220 management  2232 systemic  4259 AAI pacemakers  3359–​60 A band  6305f, 6305 abatacept (CTLA4-​Ig)  101t, 104–​5 diabetes mellitus type 1  2500 rheumatoid arthritis management  4437t systemic lupus erythematosus management  4511 Abbreviated Mental Test score (AMT-​4)  542, 6451b, 6451 confusion  6455, 6456 ABCA1 deficiency see Tangier disease (ABCA1 deficiency) ABCD2 score, transient ischaemic attacks  6014 ABCDE approach  3845 acute respiratory failure  3869 airway and breathing  3845 cardiac arrest  3845 circulation  3845 coronary reperfusion  3845 post-​intensive care syndrome  3927 ABCDEFG approach  3832t abciximab  3635 ABC mnemonic, irritable bowel syndrome  2951, 2952f ABC (airway, breathing, and circulation) traumatic brain injury  6044 abdominal actinomycoses  1173 abdominal aortic aneurysm  3685 cardiovascular syphilis  3540 definition  3685 detection pre-​rupture  3686f, 3686 endovascular aneurysm repair  3687 epidemiology  3682t, 3685 medical management  3687 ruptured aneurysm  3686 adult screening  142f, 149t, 150 surgery  3687 abdominal bruit  3758–​59 abdominal muscles  4113 abdominal pain  2730 acute abdomen  2730 acute porphyria  2039, 2050 acute rheumatic fever  3514f, 3514 arterial occlusion in acute kidney disease  4825 chronic pain  2728t, 2730, 2731f chronic upper urinary tract obstruction  5129 constipation/​faecal incontinence  598 Crohn’s disease  2927 familial chylomicronaemia  2076 hepatocellular carcinoma  3180 hereditary fructose intolerance (fructosaemia)  1997 mesenteric ischaemia  3685 recurrent pain  2728t, 2730, 2731f retroperitoneal fibrosis  5132 temporal lobe seizures  5863–​64 ulcerative colitis  2940 abdominal wall anterior defects  2968 abetalipoproteinaemia  2071 differential diagnosis  2168t, 2169t Abiotrophia infections  973 abiraterone  5145 ABO system  5566, 5566t compatibility in transplantation  404t incompatibility, haemolytic disease of the newborn  5486 matching in lung transplantation  4295 absence seizures  5864, 5865f absent pulmonary valve syndrome  3587 absorbents  5152 ABSORB III trial  3659 absorption enhancers, dermatological vehicles  5762 lipids  2064, 2065f pharmacokinetic drug interactions  93, 94t pharmacokinetics  78f, 78 older patient  572 prevention, drug overdose management  6639t rate see pharmacokinetics absorptive function tests  2878 abuse, ageing  543, 545t Academy of Medical Royal Colleges (AoMRC)  6541 acamprosate  3145, 6490 Acanthamoeba infection granulomatous amoebic encephalitis  1393 keratitis  1393, 6408t, 6427–​28, 6428f acanthocytosis  5463 acanthosis nigricans diabetes mellitus  5747f, 5747 insulin resistance  2474 acarbose  2497 Acari (ticks)  1813 ACCENT 1 study  2933 acclimatization see high terrestrial altitudes ACCORD (Action to Control CardiOvascular Risk in Diabetes) trial blood pressure control in diabetic nephropathy  4982 glycaemic control in diabetic nephropathy  4980 hypertension diagnostic thresholds  3762–​63 ACE (angiotensin-​converting enzyme) adult values  6582t assay  5785 sarcoidosis  5744 vasoconstrictors  3246f, 3249 ACE inhibitors acute kidney injury prevention  4811 acute rheumatic fever management  3516 adverse reactions  3414 ascites  3067 atherosclerotic renovascular disease  5045 autonomic nervous system disorders  6161 CKD  4836 distal renal tubular acidosis with hyperkalaemia (previous type IV)  5109 hyperkalaemia  4760 pityriasis rosea  5628 renal disease  4778 urticaria/​angioedema  5673 aortic regurgitation management  3454 blood pressure control in CKD  4842 cardiogenic anasarca management  3405 cardiorenal syndrome  3424–​25 chronic heart failure management  3414f, 3414 CKD in pregnancy  2594t congenitally corrected transposition of the great arteries  3583 contraindications, pregnancy, and breastfeeding  3414 dilated cardiomyopathy management  3481 drug interactions, lithium  6468 Duchenne’s muscular dystrophy management  6317–​18 focal segmental glomerulosclerosis management  4926, 4927 frailty and sarcopenia management  530 HIV-​related dilated cardiomyopathy  3535–​36 hypertension in diabetes  2524 hypertension management  3766t, 3768 contraindications  3767t hypertension with acute stroke  3809 left ventricular dysfunction management  3649 malignant hypertension management  3805, 3806t mechanism of action  3414 membranoproliferative glomerulonephritis  4941 minimal-​change nephrotic syndrome management  4921 mitral regurgitation management  3446 nonalcoholic fatty liver disease  3152 poisoning by  1734 post-​renal transplant hypertension  4899–​900 pregnancy  2707 primary aldosteronism screening  2354 renal disease, effects of  5155–​56 scleroderma renal crisis management  5008 stable angina prevention  3623 STEMI management  3651 acemetacin  4449 aceruloplasminaemia (ACP)  2099t, 6252t, 6253 with iron deposition (haemosiderosis) in basal ganglia  2113

2 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 acetaminophen see paracetamol (acetaminophen) acetazolamide epilepsy management  5875 familial hypokalaemic periodic paralysis management  4756 idiopathic intracranial hypertension management  6058 acetone poisoning  1762 N-​acetylaspartic aciduria (Canavan’s disease)  1968, 1969f acetylcholine (ACh)  6304–​5 nicotinic acetylcholine receptor binding  248 nitric oxide synthesis  3247 receptor deficiency  6301 acetylcholinesterase inhibitors  5851 acetyl CoA  1842 N-​acetylcysteine  1744 alcoholic liver disease management  3144 drug-​induced liver injury  3157 liver failure management  3099 meconium ileus  2972 α-​N-​acetylgalactosaminidase (NAGA)  6231 N-​acetylglutamate synthetase deficiency  1949t, 1953 acetylsalicylic acid (ASA)  4594 achalasia  2728 Achilles tendinopathy  4412t achlorhydria  2867 achondroplasia  4656 achondroplasia-​like dwarfism  4656 Achromobacter infection  4157 aciclovir adverse reactions  702t encephalopathy adverse reactions  4819 herpes simplex virus infection  2807 pregnancy  2681 resistance  740 herpes zoster infection  2808 renal disease, effects of  5163t skin disease management  5770 viral encephalitis management  6094 viral meningitis management  6094 acid–​base disorders  2182, 2182t anion gap acidosis see anion gap acidosis compensation for  2183b diagnosis  2183b, 2183 serum anion gap  2184 type characterization  2183 epithelial cell transport and  2185 extracellular fluid chemistry  2184, 2185f gastrointestinal tract  2192 colon  2194f, 2194 small intestine  2192, 2193f stomach  2192 intake associated  2197 kidney and  2186 collecting duct  2189f, 2189 distal tubule  2188f, 2188 proximal tubule  2186f, 2186 thick ascending limb of Henlé’s loop  2187, 2188f management  2198 mesenteric venous thrombosis  3002 neurological disorders  6373 skin  2194 sweat gland ducts  2194f, 2194 symptoms  2198 see also hyperchloraemic acidosis; hyperchloraemic alkalosis; metabolic acidosis; metabolic alkalosis acid–​base homeostasis arterial blood gas testing  3964, 3964t, 3965f bowel resection  2913 CKD pathophysiology  4836 collecting duct  5105 COPD  4118 proximal tubule  5105f, 5105 acid maltase deficiency (glycogenosis type II)  6337 acidosis CKD  4844 diabetic ketoacidosis  2506, 2509 hyperkalaemia causes  4761 metabolic see metabolic acidosis severe malaria infections  1405 acidotic breathing see Kussmaul respiration (acidotic breathing) acid poisoning  1762 acid suppression acute upper gastrointestinal bleeding management  2776 gastro-​oesophageal reflux disease management  2832 acinar cells  3210 carcinoma  3234 ACLF see acute-​on-​chronic liver failure (ACLF) acne  5703 aetiology  5703 clinical features  5704f, 5704 clinical investigations  5704 comorbidities  5708 complication  5708 cyanotic heart disease  3564 differential diagnosis  5704, 5705t epidemiology  5703 management  5704, 5705t pathogenesis  5704f, 5704 pregnancy  2649 prognosis  5707 psychosocial effects  5708 variants  5707 acne conglobata  5707 acne excoria  5707 acne fulminans  5707 aconite (Aconitum)  204, 1829 acoustic neuroma  464 acquired angio-​oedema  4045 acquired aplastic anaemia  5338 aetiology  5338, 5339t clinical features  5339t, 5341 clinical investigations  5341 abdominal ultrasound  5342 anti-​DNA antibodies  5341 antinuclear antibodies  5341 bone marrow aspirate  5341, 5342f bone marrow cytogenetics  5342 chest radiographs  5342 folate  5341 full blood count  5341 inherited disease screens  5342 liver function tests  5341 molecular genetics  5342 PNH screen  5341 trephine biopsy  5341 virology  5341 vitamin B12  5341 incidence  5338 management  5343f, 5343 haematopoietic stem cell transplantation  5344 immunosuppressive management  5345 infections  5343 psychological support  5343 transfusions  5343 paroxysmal nocturnal haemoglobinuria vs.  5351f, 5351 pathogenesis  5340 prognosis  5343 acquired chorea see chorea acquired coagulation disorders  5546, 5548t acquired von Willebrand’s syndrome  5555 desmopressin  5549 factor V inhibitors  5554 factor VII inhibitors  5555 factor IX inhibitors  5555 factor X inhibitors  5554 factor XI inhibitors  5555 factor XIII inhibitors  5554 general clinical approach  5546 heparin  5555 heparin-​like anticoagulants  5555 hyperfibrinolysis  5555 cardiopulmonary bypass surgery  5555 malignancies  5555 thrombotic management  5555 hypoprothrombinaemia  5554 immunoglobulin-​mediated factor deficiency  5553 acquired factor VIII inhibitor  5550t, 5554 macrovascular thrombosis  5557 adenocarcinoma-​associated disseminated intravascular coagulation  5559f, 5559 antiphospholipid antibody syndrome (lupus anticoagulant)  5559 heparin-​induced thrombocytopenia (HIT)  5557 protamine-​induced thrombocytopenia  5559 management  5547 microvascular thrombosis  5560 coumarin-​induced limb gangrene  5560 coumarin-​induced skin necrosis  5560f, 5560, 5560t purpura fulminans  5560 septicaemia  5561 symmetrical peripheral gangrene  5560, 5561f systemic inflammatory response syndromes  5561 thrombotic microangiopathy  5561 pharmacological therapies  5549 plasma cell dyscrasia  5555 prohaemorrhagic coagulation disorders  5546, 5549 acute haemolysis  5553 acute ischaemic hepatitis (shock liver)  5552 direct oral anticoagulant overanticoagulation (DOACs)  5551 disseminated intravascular coagulation see disseminated intravascular coagulation (DIC) haemodilution in transfusion  5552 immunological disorders  5553 infections  5553 liver disease see liver disease obstetric complications  5553 trauma  5552 vascular anomalies  5553 vitamin K deficiency  5549 vitamin K-​dependent coagulation factors  5549 prothrombotic coagulation disorders  5547, 5557 screening tests  5548t, 5550t secondary to plasma cell dyscrasia  5551b, 5555 specific factor conjugates  5549 thrombin inhibitors  5554 venom induced  5556 snake bites  5556, 5560t acquired haemolytic anaemia  5479 immune haemolytic anaemias  5480 alloimmune haemolytic anaemias see alloimmune haemolytic anaemias autoimmune haemolytic anaemias see autoimmune haemolytic anaemias nonimmune acquired haemolytic anaemias  5486b, 5486 chemicals  5486, 5487t infection  5486 mechanical causes  5487 thermal haemolysis  5487 acquired haemophagocytic lymphohistiocytosis  5261f, 5261 acquired hepatocerebral degeneration  6370 acquired hypoparathyroidism  2321b, 2328 acquired idiopathic sideroblastic anaemia (refractory anaemia with ring sideroblasts)  5452b, 5453 aetiology  5454 clinical features  5454 laboratory features  5454 management  5454 pathogenesis  5453f, 5454 prognosis  5454, 5454t acquired lymphangiectases (acquired lymphangioma)  5722

  Index 3 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 acquired melanocytic naevi (moles)  5733, 5734f acquired methaemoglobulinaemia 
5449 acquired nephrogenic diabetes insipidus  4770 acquired neuromyotonia  6341 acquired neutropenia, hypersplenism see hypersplenism acquired nonimmune haemolytic anaemias  5479 acquired non-​QT syndrome  3384 acquired pernicious anaemia  5408, 5413 aetiology  5413 clinical features  5414 cardiovascular disease  5416f, 5416 malignancy  5416 mental deterioration  5416 neural tube defects  5415 definition  5413 pathology  5414 acquired thrombotic thrombocytopenic purpura  5527 ACR see American College of Rheumatology (ACR) acral lentiginous melanoma  5738, 5739f acrocyanosis/​perniosis (cold injury)  5713 acrodermatitis chronica atrophicans, Lyme borreliosis  1184 acrodermatitis enteropathica  1878f, 1878 acromegaly  2266 cardiac disease  3497 clinical features  2266b, 2266 diagnosis  2267 insulin tolerance test  2263 management  2267 mortality  2267 myopathies  6339 neuropathies  6187 pregnancy  2641 acrylamide neuropathies  6188 ACS see acute coronary syndrome (ACS) ACTH see adrenocorticotrophic hormone (ACTH) ACTH-​dependent Cushing’s syndrome see Cushing’s syndrome ACTH-​independent Cushing’s syndrome see Cushing’s syndrome actin  269–​70 filaments  214–​15 actinic prurigo (AP)  5690, 5691f Actinomyces bovis infection  3174 Actinomyces israelii infection  3174, 6430 actinomycoses  1170 aetiology  1170, 1171t clinical manifestations  1173 abdominal actinomycoses  1173 bone disease  1174 cervicofacial actinomycoses  1173 CNS infections  1174 cutaneous actinomycoses  1174 endocarditis  1174 thoracic actinomycoses  1173, 1173t diagnosis  1174 bacteriology  1172f, 1174 clinical chemistry  1174 haematology  1174 radiography  1174 serology  1175 epidemiology  1171 management  1175 pathogenesis/​pathology  1171 histopathology  1172f, 1172 synergistic polymicrobial disease  1171, 1172t prognosis  1175 Action on Smoking for Health (ASH)  4104 action potentials  247 demyelination  6028 activated partial thromboplastin time (APTT)  3730 acquired coagulation disorders  5548t bleeding tendencies  5513 activation-​induced cell death (AICD)  277–​78 active tubular secretion, drug excretion  81–​82 activin  262 hormone signalling  2252, 2255f iron overload  5400 activities of daily living (ADLs)  565 ACUITY trial  3638 acupressure  109b acupuncture  109b, 203 Chinese vs. Western  203 osteoarthritis management  4479t tension-​type headaches  5995 acute abdomen  2730, 2765 aetiology  2765, 2766t clinical features  2765 examination  2766 history  2765 investigation  2766 imaging  2767f, 2767, 2768f laboratory tests  2767 management  2768 surgery  2769t medical causes  2769 acute porphyria  2770 acute urinary retention  2770 Addisonian crisis  2770 cocaine abuse  2770 constipation  2770 diabetic ketoacidosis  2769 gastroenteritis  2770 herpes zoster  2770 pneumonia  2770 rectus sheath haematoma  2770 spontaneous splenic rupture  2770 medical wards  2768 cardiac disease  2769 colonic pseudo-​obstruction (Ogilvie’s syndrome)  2768 elderly  2769 iatrogenic problems  2769 immunosuppression  2768 inflammatory bowel disease  2769 liver disease  2769 presentation  6612 acute aortic syndrome  3674 aetiology  3675f, 3676f, 3676, 3677b risk factors  3676 classification  3676f, 3676 clinical features  3674b, 3677 follow-​up  3680 investigations  3677 blood tests  3678 chest radiography  3677f, 3677 ECG  3678 imaging studies  3678f, 3678, 3678t, 3679f management  3679 emergency management  3679 surgery  3679 pathogenesis  3675f, 3675, 3676f prognosis  3680 acute asthma see asthma acute calcific periarthritis  4493f, 4493 acute calcium pyrophosphate crystal deposition  4490, 4493 acute care for elders (ACE)  553 acute cellular rejection heart transplantation  3429 liver transplantation  3103, 3105 renal transplant  4886, 4886t acute chest syndrome, sickle cell disorders  5443, 5446 acute confusional state cognitive impairment  6451 presentation  6621 acute coronary syndrome (ACS)  3626 aetiology  3627, 3628f atherosclerosis see atherosclerosis chest pain  3278 clinical definition  3627 clinical presentation  3628 definition  3628 ECG  3278, 3304, 3305t probability  3305 prognosis  3304 triage  3305 management without ST-​ elevation  3628, 3633 anticoagulant management  3636, 3638 anti-​ischaemic management  3633, 3634b antiplatelet management  3634, 3638, 3642f, 3642 coronary artery bypass surgery  3641 emergency departments  3640b, 3640 glycoprotein IIb/​IIIb inhibitors  3635, 3636b high-​risk status  3640 integrated management  3639 low molecular weight management  3642 low-​risk status  3636t, 3640 P2Y12 receptor inhibitors  3635, 3636t potassium channel activators  3634b revascularization  3638 risk stratification  3630t, 3639 secondary prevention  3642, 3643t outcomes  3629, 3630t biochemical markers  3630, 3631f, 3631t clinical syndrome  3629 ECG  3628t, 3630 imaging  3632 large-​scale observational registry studies  3629 trial data  3629 prognosis  3628t risk characterization  3632, 3633b, 3633t secondary prevention  3642, 3643t secondary prevention measures (STEMI or non-​STEMI)  3651 cardiovascular risk reduction  3651, 3651t, 3652t nonpharmacological interventions  3651 pharmacological interventions  3651 STEMI see ST-​segment elevation myocardial infarction (STEMI) see also non-​ST elevation myocardial infarction (NSTEMI); ST-​segment elevation myocardial infarction (STEMI); unstable angina (UA) acute cutaneous lupus erythematosus (ACLE)  5652b, 5653f, 5653 Acute Dialysis Quality Initiative  3422, 3422t acute disseminated encephalomyelitis (ADEM)  6038 diagnosis  6132 epidemiology  6084 acute eosinophilic pneumonia (Löffler’s syndrome, simple pulmonary eosinophilia)  4239,
4278–​79, 4600f, 4600 acute exacerbation of chronic obstructive pulmonary disorder (AECOPD) see chronic obstructive pulmonary disorder (COPD) acute fatty liver of pregnancy (AFLP)  2592, 2621, 2704 acute generalized exanthematous pustulosis (AGEP)  5754t, 5759 acute hospitals  548, 549b components  551, 552b, 561b, 561 dignity  614b, 614 acute infantile spinal muscular atrophy type I (Werdnig–​ Hoffman disease)  6173 acute inflammatory demyelinating polyradiculoneuropathy (AIDP)  6177 acute interstitial nephritis (AIN)  4951 acute kidney injury  4826 aetiology  4951, 4952b drugs  4951

4 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 immune disease  4952 infections  4952 clinical features  4954, 4954t drug-​induced  4954 clinical investigations  4955 differential diagnosis  4954 epidemiology  4954 future developments  4955 historical perspective  4951 management  4955 pathogenesis  4953 pathology  4953f, 4953 prognosis  4955 acute interstitial pneumonia (Hamman–​Rich syndrome)  4170 acute ischaemic hepatitis (shock liver)  5552 acute kidney injury (AKI)  4769, 4807 acute interstitial nephritis diagnosis  4955 age distribution  4809f causes  4808, 4809b, 4809, 4810t, 4819 acute interstitial nephritis  4826 glomerulonephritis  4823b, 4826 haematological causes  4827 hepatorenal syndrome  4827 nephrotoxins  4822b, 4822 vascular causes  4824 see also prerenal failure clinical approach  4807, 4810 clinical features  4814 biochemical changes  4815 complications  4815 hyperkalaemia  4815, 4816t pulmonary oedema  4816 definition  4808 diagnosis  4810, 4813 accuracy  4813 CT  4814 fluid input/​output  4810 inflammatory cause  4814f, 4814 physical signs  4810 serum creatinine  4810 ultrasound  4814f, 4815 urinary obstruction  4813 weight measurement  4810 epidemiology  4808 immunoglobulin A nephropathy  4912 malarial renal disease  5053 management  4807, 4818 critical care in pregnancy  2702 drugs  4819 fluid replacement  4817 haemorrhage management  4819b, 4819 immunoglobulin A nephropathy and  4915 nutrition  4818 peritoneal dialysis  4875 potassium requirements  4817 renal biopsy  4818 renal replacement therapy  4817 sepsis  4819 sodium requirements  4817 pregnancy in  2589 aetiology  2589, 2590t, 2591 clinical approach  2589, 2591t diagnosis  2589 epidemiology  2589 presentation  6613 prevention  4811f, 4811 care bundles  4811, 4812t, 4813f glycaemic control  4811 risk factors  4811, 4812t snake bites  1799 stages of  4808t systemic cancer effects  5042f tropical renal disease  5051f, 5051 urinary tract obstruction  4769 urine biomarkers  4787 volume depletion  4817 acute leg ischaemia see leg ischaemia acute leukaemias oral manifestations  2824f, 2824 primary myelofibrosis  5252 renal disease in  5025 acute liver failure (ALF)  3090t, 3094 classification  3094 clinical features  3094 cognitive changes  6369–​70 neurological disease  6369 definition  3089–​90 hepatic encephalopathy management see hepatic encephalopathy type A liver transplantation indications  3101 pathophysiology  3094b, 3095 drug-​induced  3094 prognosis  3095f, 3095 acute lower gastrointestinal bleeding  2778, 6609 aetiology  2778, 2778t angiodysplasia  2778, 2779f benign anorectal disease  2778 colonic tumours  2778 diverticular disease  2778 iatrogenic haemorrhage  2779 inflammatory bowel disease  2778 clinical features  2779 history  2779 epidemiology  2778 examination  2779 management  2779, 2780f bleeding localization  2779 capsule endoscopy  2781 obscure bleeding  2781 resuscitation  2779 surgery  2781 acute lymphatic filariasis see lymphatic filariasis acute lymphoblastic leukaemia (ALL)  5269 clinical features  5272b, 5272 clinical investigations  5272, 5273b, 5274f complications/​long-​term follow-​up  5279 long-​term toxic effects  5279 short-​term toxic effects  5279b, 5279 current multidrug chemotherapy  5273 consolidation phase  5273 induction phase  5273 intensification phase  5273 differential diagnosis  5272 epidemiology  443, 5270 future developments  5279 genetics  5270, 5271t chromosomal abnormalities  5272f immunophenotyping  5271t management  5269–​70, 5273 allogeneic haematopoietic stem cell transplantation  5275 BCR-​ABL-​like ALL  5275 BCR-​ABL-​positive ALL  5275 chimeric antigen receptor T cells  478 CNS-​directed prophylaxis  5275 elderly people  5275 initial management  5273 relapsed/​refractory ALL  5275 pathogenesis  5270 prognosis  5271t, 5272f, 5276f, 5276, 5277f, 5278f children  5278f, 5279 relapses  5271–​72 remissions  5271–​72 acute mesenteric ischaemia  2999 blood tests  3000 gangrene  3000–​01, 3001f intestinal tissue damage  3000 investigations  3000f, 3000 leucocytosis  3000 acute myeloid leukaemia (AML)  5205 causation  5205 diagnosis  5206 epidemiology  443, 5205, 5206f future developments  5205 incidence  413 management  5206 bone marrow transplantation  5209 chemotherapeutic regimens  5207 chemotherapy consolidation  5208 DNA methylation  5209 general considerations  5206, 5207f maintenance chemotherapy  5209 older patients  5208 outcomes  5208 relapsed disease  5208 remission definition  5207 targeted management  5209 prognostic factors  5206b, 5206f, 5206 supportive care  5210 blood product support  5210 during chemotherapy  5210 hyperleucocytosis  5210 infections  5211 management initiation  5210 metabolic complications  5210 prior to cytotoxic management  5210 tumour lysis syndrome  5210 acute myocardial infarction (AMI)  3307 atrial infarction  3307 cardiogenic shock  3887 coronary artery spasm  3308 C-​reactive protein  2203 definition  3629b, 3629 mitral regurgitation  3442 PCI outcomes  3662 posterior infarction  3308 right ventricular infarction  3307f, 3307 septal ischaemia  3308 acute necrotizing myelitis (Foix–​Alajouanine syndrome)  6039, 6133, 6134 acute-​on-​chronic liver failure (ACLF)  3090f,
3090, 3090t definition  3089–​90 diagnosis  3090, 3091f, 3091t pathophysiology  3092 inflammatory response  3092 organ dysfunction  3093 precipitating factors  3092, 3092t predisposing factors  3092 prognosis  3091 acute-​on-​chronic respiratory failure  6605 acute pancreatitis  3209 aetiology  3211b, 3211, 3212 alcohol  3211 autoimmune pancreatitis  3212 benign pancreatic duct stricture  3212 drugs  3211 gallstones  3211 genetics  3212 hyperlipidaemia  3212 hyperparathyroidism  3212 hypothermia  3212 iatrogenic stories  3212 parasitic infections  3213 periampullary/​obstructive pancreatic tumours  3212 sphincter of Oddi dyskinesia  3213 trauma  3212 viral infections  3211 clinical features  3210 complications  3218 acute pancreatic pseudocyst  3218 haemorrhage  3217f, 3218 pancreatic ascites  3218 portal vein thrombosis  3217f, 3218 splenic vein thrombosis  3217f, 3218 visceral fistulation  3217f, 3218 C-​reactive protein  2203 diagnosis  3210b, 3210f, 3210 biochemical abnormalities  3210 differential diagnosis  3210b, 3210 epidemiology  3209 hypertriglyceridaemia  2096 laboratory data sets  3833t management  3213 antibiotics  3214 ERCP  3214 nutrition support  3214 postacute pancreatic fluid/​ necrotic collection see postacute pancreatic fluid/​ necrotic collection surgery  2769t pathology  3210 severity grading  3210, 3213, 3213t, 3214t

  Index 5 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 acute phase response  2199 C-​reactive protein  2200 familial Mediterranean fever  2212 rheumatological diseases  4401f, 4401 see also C-​reactive protein (CRP) acute physiological conservative therapy (APCM)  6139, 6140 outcome/​prognosis  6140, 6141t acute porphyrias  6620 acute abdomen  2770 acute intermittent porphyria  2042f, 2042 5-​aminolevulinate dehydrogenase deficiency (Doss’ porphyria)  2043 attack management  2050 carbohydrate loading  2051 haem management  2051 immediate  2050 attack prevention  2052 gene management  2052 hormonal interventions  2052 liver transplantation  2052 clinical features  2039, 2040b complications  2041 acute encephalopathy  2041 CKD  2041 hepatic carcinoma  2042 neurological complications  2041 complications management  2051 hypertension  2051 hyponatraemic seizures  2051 definition  2035 diagnosis  2041 epidemiology  2035 genetic variants  2044 coproporphyrinogen oxidase  2044 ferrochelatase  2044 porphobilinogen deaminase (hydroxymethylbilane synthase)  2044 protoporphyrinogen oxidase  2044 hereditary coproporphyria  2043 pathogenesis  2038, 2039b, 2040b alcohol tolerance  2039 smoking  2039 prognosis  2041 variegate porphyria  2043 acute presentation of diseases  6591 endocrine disease  6614 gallstones  3199 gastrointestinal disease  6608 heart and circulation  6591 infectious diseases  6629 liver disease  6608 metabolic disease  6614 neurological disease  6621 psychiatric disease  6637 renal disease  6613 respiratory system  6605 acute promyelocytic leukaemia (APS)  5211 management  5211 arsenic trioxide  112 complications  5212 residual disease measurement  5212 supportive care  5212 acute pulmonary embolism  3716, 6601 clinical features  3717 accuracy  3719, 3719t signs  3718, 3719t symptoms  3717 diagnosis  3719t, 3724 differential diagnosis  3719 incidence  3716 investigations  3720 arterial blood gases  3724 biomarkers  3724 blood tests  3724 chest radiography  3723, 3724t contrast-​enhanced spiral CT  3721, 3722f, 3723t D-​dimer  3720, 3725 echocardiography  3724 electrocardiography  3723, 3723t MRI  3722 pulmonary angiography  3721, 3722f serial noninvasive leg tests  3726 SPECT ventilation–​perfusion lung scan imaging  3721 thrombus detection  3720 ventilation–​perfusion lung scans  3715t, 3720f, 3720 management  3717t, 3726 anticoagulants  3726f, 3726 antithrombotic management  3723t, 3726 catheter intervention  3728 inferior vena cava filters  3717t, 3727 pulmonary embolectomy  3728 resuscitation  3726 thrombolytic management  3726 predisposing factors  3716, 3718t recommendations  3725 elderly  3725 impaired renal function  3725 iodinated contrast material allergies  3725 male reproduction  3725 patients in extremis  3726 pregnancy  3725 women of reproductive age  3725 acute respiratory distress syndrome (ARDS)  3873 aetiology  3874f, 3874 clinical features  3875 clinical investigations  3875f, 3875 definition  3873, 3874b, 3874f differential diagnosis  3875, 3875t epidemiology  3874 general supportive measures  3879 pathogenesis  3875 pathology  3875 pharmacotherapy  3878 prognosis/​outcome  3879 ventilatory management  3875 indications/​ contraindications  3878b acute respiratory failure (ARF)  3868 clinical approach  3869 examination  3869, 3869t history  3869 clinical investigations  3869 arterial gas analysis  3869b, 3869, 3870t chest radiographs  3870 computed tomography  3870 echocardiography  3870 electrocardiography  3870 fibreoptic bronchoscopy  3870 infection screening  3870 ultrasound  3870 definition  3868 epidemiology  3868, 3868t management  3871 airway management  3871 mechanical ventilation  3872, 3872t oxygen management  3871, 3871t pregnancy  2617 respiratory monitoring  3870 arterial oxygen saturation  3870 capnography  3871 indwelling arterial catheter  3870 lung function estimation  3870 pulse oximetry  3870 acute rheumatic fever  3509 associated poststreptococcal syndromes  3514 clinical features  3512, 3512t arthritis  3512 carditis  3512 elevated acute-​phase reactants  3514 erythema marginatum  3513 fever  3513 subcutaneous nodules  3513 Sydenham’s chorea  3512 diagnosis  3514, 3515t differential diagnosis  3515t epidemiology  3510 follow-​up  3517 recurrence  3517 management  3516 bed rest  3516 cardiac failure management  3516 chorea management  3517 corticosteroids  3516 penicillin  3516 salicylates  3516 pathogenesis  3510, 3511f host factors  3510 immune response  3511 infection site  3511 infective organism  3510 prevention  3517 primary prevention  3517 secondary prevention  3517 prognosis  3517 acute sarcoid arthritis (Löfgren’s syndrome)  4600f, 4600 acute schistosomiasis (Katayama fever)  1544, 1545f acute toxic injury to respiratory tract  4267, 4268t assessment and management  4269 supportive care  4269 clinical features  4268 acute airway effects  4268 acute pneumonitis/​pulmonary oedema  4268f, 4268 asphyxiants  4269 burns  4268 fume events  4269 nonpulmonary effects  4269 soluble irritant gases  4268 sulphur mustard  4268 acute unilateral vestibulopathy (vestibular neuritis)  5930b acute upper gastrointestinal bleeding  2771 aetiology/​pathogenesis  2771, 2771t erosive disease  2772 Mallory–​Weiss tears  2772 peptic ulcer disease  2771 varices  2771 causative lesion management  2777 nonvariceal upper gastrointestinal bleeding  2777 variceal upper gastrointestinal bleeding  2777f, 2777 clinical features  2772 examination  2772 history  2772b, 2772 diagnosis and haemostasis  2775 drug management  2776 endoscopy  2774b, 2775f, 2775 radiological studies  2775 surgery  2776 differential diagnosis  2772 epidemiology  2772 investigations  2772 coagulopathy  2772 endoscopy  2772 full blood count  2772 management  2772b, 2773f, 2773 monitoring  2774 resuscitation  2773b, 2773 risk assessment  2773, 2774t, 2775t prevention  2772 prognosis  2774t, 2775t, 2778 recurrence prevention  2778 acylcarnitine  1946 acyl-​coenzyme A (CoA) oxidase deficiency  2158 AD see Alzheimer’s disease (AD) ADAGIO study  5953 adalimumab  101t drug-​induced lupus  4609–​10 psoriasis management  5627 rheumatoid arthritis management  4437t rheumatoid arthritis management in pregnancy  2662 sarcoidosis management  4216t ulcerative colitis management  2945 ADAM33  4061 ADAMTS13 deficiency  5541 adapalene  5767 adaptive immunity  325, 472 antigen specificity  326 Behçet’s syndrome  4580 dendritic cells  472 diagnosis in  334f, 335 diversity generation  329 downregulation of  334 failure of  335 pathogen response  335 drug-​induced liver injury  3158, 3159f

6 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 future developments  336f, 336 gastrointestinal tract immune system  2785 innate immune system vs.  326 management in  336 memory  330 generation  333 maintenance of  333 naive state  330, 331f priming of  331 prophylaxis in  335 psoriasis  5624 rheumatoid arthritis  4424 T cells  473 transplantation see transplantation immunology Addenbrooke’s Cognitive Assessment III (ACE-​III)  6455 Addenbrooke’s Cognitive Examination (ACE-​R)  5920–​21 Addison’s disease  2347 aetiology  2347t dementia  5857 myopathies  6340 onset of  2158 pernicious anaemia see acquired pernicious anaemia pregnancy  2640 prevalence  2347 Addisonian crisis acute abdomen  2770 acute presentation  6618 secondary hypoadrenalism (ACTH deficiency)  2350 α-​adducin  3743 adefovir  3116t adenine phosphoribosyltransferase deficiency  2027 adeno-​associated viral vectors inborn errors of metabolism management  1937 lysosomal disease gene management  2138 adenocarcinoma associated disseminated intravascular coagulation  5559f, 5559 lung cancer  4340–​41 management  4352 nasal cancer  430 oesophageal neoplasms see oesophageal cancer renal cancer  439 small-​bowel imaging  2753f,
2753 stomach cancer  2984 adenosine antiarrhythmia management  3365t stress MPS  3328 tachycardia management  3364 adenosine deaminase (ADA) deficiency  2028 severe combined immunodeficiency  352 erythrocyte enzymopathies  5470 fructose phosphatase deficiency  2001 pleural effusions  4310, 4311 adenosquamous carcinoma, pancreatic tumours  3234 S-​adenosylhomocysteine hydrolase  1949t, 1983 adenovirus infection  725t, 728 aetiology  725t bronchiectasis  4145 clinical features  728 epidemiology  728 gastrointestinal system  3010t, 3011 management and prevention  729 meningitis  6083 pneumonia  4010t subacute (Quervain’s) thyroiditis  2300–​1 transmission  3014t virus-​positive myocarditis management  3464–​65 adenylate cyclase deficiency  5469 adenylosuccinase deficiency  2027 adhesins  5077–​78 adhesive capsulitis  4412t Adie’s tonic pupil  6122 adipose tissue energy transport from  1845 hormone synthesis  2245 see also obesity adjustment disorders  6506 aetiology  6506 assessment  6507 clinical features  6507 differential diagnosis  6507 low mood  6463 epidemiology  6506 outcome  6508 Adjuvant on Line  506 ADLs see activities of daily living (ADLs) adolescents cystic fibrosis  4164 growth  2419 idiopathic scoliosis  4329 self-​harm  6459 adrenal gland(s)  2246 autopsy methods  6559 corticosteroid synthesis  2332f, 2332 function monitoring, neuropsychiatric adult peroxisomal disorders  2163 adrenal gland disorders  2331 acute failure  4085, 4086 atrophy, ACTH deficiency  2272 cardiac disease  3497 congenital hyperplasia see congenital adrenal hyperplasia (CAH) cortex disorders  2331, 2333f adrenal incidentalomas see adrenal gland incidentalomas adrenocortical carcinoma  2359 Cushing’s syndrome see Cushing’s syndrome drug-​induced secretion  2550 glucocorticoid deficiency  2347 glucocorticoid excess see Cushing’s syndrome mineralocorticoid excess see mineralocorticoid excess Cushing’s syndrome see Cushing’s syndrome lesion biopsies, adrenal incidentalomas  2359 multiple endocrine neoplasia type 1  2459 necrosis, Addison’s disease  2348 neurological disorders  6370 pregnancy  2640 adrenal gland incidentalomas  2358 imaging  2358 CT  2344f, 2358 FDG-​PET/​CT  2359 MRI  2358f, 2358 investigations  2358 adrenal lesion biopsy  2359 endocrinological tests  2358 adrenal gland insufficiency acute distributive shock  3888 secondary hypoadrenalism management  2351 acute-​on-​chronic liver failure  3094 cancer  492 drug-​induced  2550 iatrogenic Cushing’s syndrome and  2334 malabsorption  2876t mineralocorticoid deficiency  2357 neurological disorders  6371 adrenal gland tumours adenomas Cushing’s syndrome  2335, 2343 management  2343 carcinomas androgen-​secreting, hirsutism in women  2385 Cushing’s syndrome  2335 pregnancy  2640 prognosis  2343 see also adrenal gland incidentalomas lung cancer metastases  4346, 4347f adrenal hormones biosynthesis pathways  2362f diseases of  2333t measurement, drug-​induced changes  2550 replacement management in chronic acute insufficiency  2352 adrenaline (epinephrine) acute upper gastrointestinal bleeding management  2775 anaphylaxis management  3855 asthma management  4086 autoinjection, anaphylaxis  3857 circulatory support  3889 gastrointestinal bleeding  2743 hypoglycaemia  2510 macronutrient metabolism  1851t normal blood values  6583t phaeochromocytomas  3792 α-​adrenergic blocking drugs falls in elderly  583t hypertension management  3768 malignant hypertension management  3806t phaeochromocytoma management  3794 renal disease, effects of  5155 urinary incontinence  594 adrenergic receptors  3889 β2-​adrenoceptor agonists  4128 adrenocortical carcinoma  2359, 2538 Cushing’s syndrome  2339 management, metyrapone  2345–​46 adrenocorticotrophic hormone (ACTH)  2271 basal pituitary function tests  2262 circadian rhythms  86 critical care response  3909, 3911 deficiency, hyperkalaemic, hyperchloraemic alkalosis  2191 excess, myopathies  6339 glucagon stimulation test  2263 membranous nephropathy management  4932 normal blood values  6583t opsoclonus–​myoclonus  6388–​89 pancreatic neuroendocrine tumours  2455 placental production  2566 secondary hypoadrenalism  2342f, 2343f, 2350 secretion disorders  2271 Cushing’s disease  2272 deficiency  2271 Nelson’s syndrome  2272 short Synacthen test  2263 structure  2271 tuberous sclerosis complex management  6204 adrenoleucodystrophy  6040, 6210 aetiology  2157–​58 diagnosis  6133 heterozygotes  2158 historical perspective  2157 adrenomyeloneuropathy (AMN)  6210, 6211 juvenile form  2158 adult basic life support algorithm  6591f adult-​onset hereditary dystonia see hereditary dystonia adult-​onset Still’s disease (AOST)  4598 diagnosis  4598, 4599f, 4599t differential diagnosis  4598 laboratory tests  4598 management  4599 prevalence  4598 Adult Psychiatric Morbidity Survey (APMS)  6487 adult T-​cell leukaemia/​lymphoma (ATL)  443, 5301 cutaneous lymphoma  5740 HTLV-​1 infection  942 advance care plans  627 advance decisions to refuse therapy (ADRT)  618 advanced glycation end products (AGE)  2514 advance directives end-​of-​life care  618 incompetent patients  23 advanced life support (ALS)  3840 algorithm  6592f cardiac arrest  3840 nonshockable rhythms  3839, 3841, 3842, 3844b

  Index 7 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 airway and ventilation  3842 percutaneous coronary intervention  3842 reversible causes  3843 shockable rhythm management  3839, 3841, 3844b defibrillation  3841, 3844b advanced sleep phase syndrome  5894 Advanced Trauma Life Support (ATLS)  543 traumatic brain injury  6044 ADVANCE study  4981 adventitia  3242, 3252, 5494 adverse drug reactions  71, 87 classification  88 delayed effects  90 dose-​related  88 long-​term effects  90 non-​dose-​related  88 detection  92 incidence  88 older patient  574, 574t, 575 pharmacodynamics  88 pharmacokinetics  88 pharmacology in older people  574t prevention  93 skin  5593 therapeutic benefits vs.  72 type A (predicted)  72 type B  72 advocacy groups  17 adynamic bone  4847 AECOPD see chronic obstructive pulmonary disorder (COPD) AEIOU TIPS  3834b Aeromonas hydrophila
infection  1040 afamelanotide  2050 afatinib  4355 AFFIRM trial  3369–​70 affluent society disease  1891, 1892t afibrinogenaemia  5542–​43 aflatoxin  423 Africa breast cancer epidemiology  435–​36 Central Africa, drug falsification  125 cervical cancer epidemiology  436 colonic diverticular disease  2960 disease incidence/​prevalence  169 drug quality  125 fibre and cancer aetiology  423 histoplasmosis  1351f, 1351 iodine deficiency disorders  1874 large bowel cancer  429 liver cancer epidemiology  429 lyssaviruses  818 oesophageal cancer  427 rhabdovirus reservoir species  808 smoking  4339–​40 stomach cancer  428 testicular cancer epidemiology  438–​39 tick bite fever  1238 see also North Africa; sub-​Saharan Africa African-​Caribbean people hypertrophic cardiomyopathy  3471 malignant hypertension  3803 African trypanosomiasis  1451 aetiology  1452 antigenic variation  1454 clinical features  1452t, 1453f, 1454f, 1454 travellers  1455f, 1455 Trypanosoma brucei gambiense  1454f, 1454 Trypanosoma brucei rhodensiae  1455 clinical investigations  1455 laboratory findings  1456 MRI  1456 control  1453b diagnosis  1455 differential diagnosis  1455 elimination efforts  1459 epidemiology  1452f eye diseases/​disorders  6433 historical perspective  1452 individual protection  1459 management  1456 new drug candidates  1459 stage I drugs  1456, 1456t, 1457t stage II drugs  1457t, 1458 prevention  1459 transmission  1453f, 1453 afterload mitral regurgitation  3443 outflow resistance, nitric oxide  3270 agalsidase alfa (Replagal)  2139, 2146 agalsidase beta (Fabrazyme)  2139, 2146 age acute lymphoblastic leukaemia prognosis  5276 cancer aetiology  415 chronic heart failure  3409 coronary heart disease adjusted risk  1894t cryptosporidiosis  1427 drug metabolism  80–​81 fascioscapulohumeral muscular dystrophy  6319 hypertension epidemiology  3738–​39 limb-​girdle muscular dystrophies  6325f, 6325 lung transplantation donors  4295 myocarditis  3459–​60 Neisseria meningitidis infection  1013 obstructive sleep apnoea  4052 pneumonia  4013 pregnancy outcome  2576 small intestine bacterial overgrowth  2881 travel and expedition medicine  719 tuberculosis  1129 venous thromboembolism in pregnancy  2612 ageing acute abdomen  2769 acute pulmonary embolism  3725 anaemia of inflammation  5407 ANCA-​associated vasculitis  4559 aortic stiffening  3746, 3749 assessment  564 cognitive impairment  564 exercise ECG testing  3313 functional status  565 geriatric syndromes  564 multimorbidities  564 bladder and bowels  589 see also urinary incontinence (UI) cancer  492 acute lymphoblastic leukaemia management  5275 acute myeloid leukaemia management  5208 Hodgkin’s lymphoma management  5286 cognitive disorder management  568 communications/​shared decision-​making  567 comorbidities  513f constipation see constipation/​ faecal incontinence deconditioning  560 delirium see delirium dementia see dementia dignity  612 acute hospital care  614b, 614 autonomy  612 doctor conduct  613b, 613f, 613 end-​of-​life care  616 see also end-​of-​life care philosophy  612b, 612 role  612 transgressions  613b views about  613b, 613 disasters  192 disease complications  549 elder abuse  614 clinical assessment  615b, 615, 616b cultural differences  615 identification of  615 outcome  616 prevalence  614–​15, 615t prevention  616 responses to  616b, 616 risk factors  615b evolutionary implications  40 faecal incontinence see constipation/​faecal incontinence fragility fractures  586 hip fractures  587 models of care  586 vitamin D  583, 587 see also falls, ageing healthcare models  552b hierarchical model  513f HIV/​AIDS and  927 hospitalization  548 acute determination  557 discrete wards  553, 554f initial assessment  550 multidisciplinary teams  554 non-​addressed needs  550 physical deconditioning  560, 561f specialist vs. generalist care  553, 554f standardized valid assessment and  553, 555f see also acute hospitals hypertension management  3776 immobility  560 impaired functional recovery  568 intercellular communication  516 circadian rhythms  518f, 518 hypothalamic–​pituitary–​adrenal axis  518 immunosenescence  516 inflammation  516, 517f microbiome  517 macromolecular changes  511 epigenetics  513 genomic instability  513 protein structure modification  514f, 514 macular degeneration  6406f, 6407, 6408t, 6412f malignant hypertension  3803 management plans  549 medical certificate of death  6543 metabolism  515 futile cycles  515 models  519 neurodegenerative disorders  601, 601f cell death  601 disease model  602f pathology  601 see also Parkinson’s disease (PD) nonpharmacological managements  575 nutrition  515, 560 caloric restriction  515f, 515, 516f well-​being optimization  534 oncology services  563, 564 optimal management  567 orthogeriatrics  568 osteoarthritis  4473, 4474f palliative care  555 Parkinson’s disease vs.  603, 610t population figures  512f protein intake importance  1900 rheumatoid arthritis  4419, 4420t, 4421f, 4427t rich country healthcare economics  161–​62 risk prediction tools  565 risk profile modification  566 cognitive function  567 functional status  567 geriatric syndrome  566 hospital-​acquired deconditioning  567 organ-​specific pathology  566 physiological reserve  566 self-​harm  6459 skin  5594 stem cell senescence  516f, 516 parabiosis  516 stress  519 surgery  563, 564 emergency surgery  568 novel approaches  569 optimal management  567 postoperative complications  563–​64, 568 timing effects  569 urgent/​critical care  539 epidemiology  539 well-​being optimization  532

8 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 chronic disease management  536 complex multicomponent interventions  535b, 535 focused interventions  535 mental health  534 nutrition  534 physical activity  533, 534b preventative care  536 primary promotion  533 secondary promotion  535 young people vs.  549, 550f AGEP see acute generalized exanthematous pustulosis (AGEP) aggrecan  4377 Aggregatibacter actinomycetemcomitans 
2801 agraphia  5826 Aicardi–​Goutières syndrome  221t, 6246–​47, 6363 AIDA trials  3659 AIDS see HIV/​AIDS AIM-​HIGH study  60, 2093–​94 AIN see acute interstitial nephritis (AIN) air embolism  4872 airflow dynamic tests  3943 limitation, asthma diagnosis  4076 limitation in chronic respiratory failure  4285, 4286f obstruction, COPD  4110, 4111f air (atmospheric) pollution  1677 air quality guidelines and standards  1684, 1685t air quality index  1686t, 1687 ambient (outdoor) air pollution  1679 carbon monoxide (CO)  1681 nitrogen oxides  1680 ozone  1681 particulate matter  1680 polycyclic aromatic hydrocarbons (PAHs)  1681 sulphur dioxide (SO2)  1680 cancer aetiology  421 coronary heart disease risk factors  3612 health effect measurement  1679 indoor air pollution  1681, 1682 biological pollutants  1683 cooking emissions  1682 low-​ and middle-​income countries  1683 radon  1683 sick building syndrome  1683 tobacco smoke  1682 lung cancer  432, 4340 sources and types  1678, 1678t air quality index  1686t, 1687 air travel see aviation medicine airways anatomy  3938f, 3938 alveoli  3937 clearance, cystic fibrosis  4159 clinical significance  3944 collapse, emphysema  4000 dead space  3941 disease, breathlessness (dyspnoea)  3281, 3283 dynamic airway compression  3942 gas transport  3944 hyperreactivity measures, asthma diagnosis  4077 hyperresponsiveness, COPD  4102 inflammation acute exacerbations of COPD  4138 asthma diagnosis  4077 malignancy, upper airway obstruction  4042 management ABCDE approach  3845 acute respiratory failure management  3871 advanced life support  3842 hepatic encephalopathy type A management  3086 practical procedures  6650 mucociliary function  3942 obstruction, lung cancer management  4356 particle deposition  3941 patency, anaphylaxis management  3856 practical procedures see practical procedures protection larynx  3935 variceal bleeding  3072 resistance lung volume vs.  3958 respiratory function  3957 responsiveness, asthma  4070–​71 smooth muscle  3943 sport and exercise medicine  6568 surface tension  3944 surfactant  3945 akathisia  6515 AKI see acute kidney injury (AKI) akinetopsia  5920 Alagille’s syndrome neonatal cholestasis  3192, 3192t Notch mutations  264 AL amyloidosis  2221, 3495, 6161 associated conditions  2221 clinical features  2221 definition  5017 diagnosis  5017, 5018f, 5018t management  2232, 5018 renal disease in  5017 clinical presentation  5017 alanine aminotransferase (ALT) acute hepatitis  3111 alcohol abuse  6526 alcoholic liver disease  3144–​45 autoimmune hepatitis  3122 drug-​induced liver disease  3155, 3161 inflammatory myopathies  4542 jaundice  3054 liver disease in pregnancy  2620 metabolism of  1850 nitrogen disposal  1848 prehepatic jaundice  3051 alanine-​glyoxylate aminotransferase (AGT) primary hyperoxaluria  2175 structure  2176–​77, 2177f alanine transaminase  2566t albendazole ascariasis management  1509 lymphatic filariasis management  1493 Strongyloides stercoralis infection management  1502 albinism  6437 Albright’s hereditary osteodystrophy  1910t G-​protein coupled receptors  258–​59 albumin adult values  6581t CSF  5783–​84 drug binding  79 drug-​induced liver disease  3155 normal blood values  6586t transfusions  5566 urinary concentration  4785 urinary/​faecal reference intervals  6587t albumin:creatinine ratio (ACR) diabetic nephropathy diagnosis  4980t, 4984 hypertension diagnosis  3760 proteinuria  4766 urine  4785 albuminuria  5034 Alcaligenes infection  4157 AL cardiac amyloidosis  3495 alcohol/​alcohol abuse  6486, 6524 abstinence chronic pancreatitis management  3223 liver disease management  3145 acute pancreatitis  3211 acute porphyrias  2039 aetiology  6486 genetic factors  6486 psychological factors  6487 social factors  6487 assessment  6487b autonomic nervous system disorders  6161 binge drinking  2195, 6525 cancer aetiology  418, 1896, 6488 hepatocellular carcinoma  3180 liver cancer  429 mortality  425t cerebellar degeneration  6374 chronic alcoholism ataxia  5981 small intestine bacterial overgrowth  2882 chronic heart failure management  3412 clinical abuse  6489 CNS developmental abnormalities  6363 coronary heart disease risk factors  3612 defective peripheral lipolysis  2077 defective red cell maturation  5455 definition  6524 dementia  6374, 6488 diabetes management  2489 differential diagnosis bipolar disorder  6499 low mood  6463 schizophrenia  6515 drowning  1692 drug-​induced Cushing’s syndrome  2550 epidemiology  6487 epilepsy  5866 erectile dysfunction  2409t essential hypertension pathogenesis  3744 falls in elderly  582 folate deficiency  5419 harmful drinking  6487, 6525 identification  6526 hazardous drinking  6525 identification  6526 hereditary haemochromatosis  2109 hypertension  1895, 3763t, 3764 hypoglycaemia  2536 diabetes mellitus  2533 hypogonadism/​infertility  2550–​51 interventions  6526 dependence  6528 extended brief interventions  6528 simple brief advice  6526 jaundice  3053 ketoacidosis  2195 laryngeal cancer epidemiology  430–​31 legal limit  6581t male reproductive disorders  2393t management  6489 critical care  3904 hospital admission  6525 opportunities for  6525f, 6525 pharmacological management  6489 psychological management  6489, 6489t medical consequences  6487 cardiovascular system  6487 endocrinology  6488 gastrointestinal system  6487 injuries  6488 musculoskeletal system  6487 neurological system  6488 see also neurological disorders pregnancy  6488 pulmonary system  6488 metabolism of  3143, 3144f myopathies  6340, 6375 neuropathy  6189 occasional heavy (binge) drinking  6525 oesophageal disease  2841t Parkinson’s disease  603 peptic ulcer disease  2851 peripheral neuropathy  6374 porphyria cutanea tarda  2047 pregnancy  2580 preventative medicine  133t pregnancy  134t prognosis  6528 pseudo-​Cushing’s syndrome  2336 public health risk  6524 saturnine gout  2021 self-​harm  6459 steatohepatitis  3043, 3044f, 3044, 3045f tobacco and  428 violent trauma assessment  6546

  Index 9 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 withdrawal  3145, 6489b, 6489, 6489t acute presentation  6637 delirium tremens  87 management  6489b, 6489, 6489t see also delirium tremens; Wernicke’s encephalopathy alcoholic liver disease (ALD)  3142, 6487 acute-​on-​chronic liver failure prognosis  3092 clinical features  3144 alcoholic hepatitis  3145 cirrhosis  3145 diagnosis  3144 differential diagnosis hepatic encephalopathy  3084 hepatitis  3112 disease recurrence post-​liver transplantation  3106, 3106t epidemiology  3142 risk factors  3143b, 3143 hepatitis  3145 investigations  3144 jaundice  3054 management  3145 abstinence  3145 acute disease  3145 cirrhosis  3146 liver transplantation  3146 nutrition  3145 steroids  3145 pathology/​pathophysiology  3143f, 3143 alcohol metabolism  3143 patient selection in liver transplantation  3102b, 3102 prognostic scores  3146t variceal upper gastrointestinal bleeding  2777 VLDL overproduction in liver  2074 Alcoholics Anonymous (AA)  6489 alcohol use disorders identification test (AUDIT)  6526, 6527f aldolase  1996, 4542 deficiency  5469 see also hereditary fructose intolerance
(fructosaemia) aldosterone actions  2332 antagonists  5154 ascites pathogenesis  3059–​60 biosynthesis defects, mineralocorticoid deficiency  2357 distal convoluted tubule  4727f, 4727 ectopic secretion  2547 hypertension  3745 normal blood values  6583t primary aldosteronism  3783 producing adenomas (APA) (Conn’s adenomas)  2353 production  2352 renin ratio  3783 aldosteronism, primary see primary aldosteronism alemtuzumab (CAMPATH-​1)  101t, 105, 297 adverse reactions  404t, 4891 multiple sclerosis management  6037 renal transplant immunosuppression  4888 transplantation  406 transplant immunosuppression  404 alert bracelets anaphylaxis prevention  3857 chronic acute insufficiency management  2352 Alexander’s disease  6214, 6215f juvenile-​onset  6214 alexia  5921 without agraphia  5826 ALFSG (US Acute Liver Failure Study Group)  3100 alglucerase (Ceredase)  2136 Gaucher’s disease type 1 management  2143 Algrove’s syndrome  2349 alkaline phosphatase (ALP) adult values  6582t autoimmune hepatitis  3122 bone mineralization  4624 drug-​induced liver disease  3155 malabsorption  2877 plasma bone turnover measure  4626 skeletal disorders  4628 prehepatic jaundice  3051 primary biliary cholangitis  3128 PSC  3138 secondary liver tumours  3190 alkaptonuria  1975, 4608, 4616, 4652f, 4652 biochemical investigations  4629t management  1936 signs and symptoms  4629t Alkhurma virus infection  844, 954 alkylating agents cancer chemotherapy  500f, 500 essential thrombocythaemia management  5245 ALL see acute lymphoblastic leukaemia (ALL) allergens avoidance allergic rhinitis management  4064 allergy management  371, 376 anaphylaxis prevention  3858 asthma management  4082 atopic dermatitis/​eczema  5635 drug allergies  377 latex allergy  376 inhalation tests in asthma  4071 severe/​difficult-​to-​treat asthma  4092 specific IgE detection  4063 allergic (IgE-​mediated) angio-​oedema  372 allergic bronchopulmonary aspergillosis (ABPA) asthma  4078 bronchiectasis  4143 cryptogenic organizing pneumonia vs.  4189 cystic fibrosis  4159 allergic bronchopulmonary mycosis  4240f, 4240 allergic contact dermatitis  5631 causality confirmation  5633 chemical sensitization power  5632 clinical features  5632f, 5632 experimental evidence  5632 individual sensitivity  5632 management  5633 prevalence  5632 scalp  5728 allergic rhinitis  4059 aetiology  4060 environmental allergies  4060 genetic influences  4060 clinical diagnosis  4062f, 4062 examination  4063 history  4062b, 4062 clinical features  371 epidemiology  4061 history  4059 investigations  4063 allergen-​specific IgE detection  4063 skin prick tests  4063, 4064b management  4064b, 4064f, 4064 allergen avoidance  4064 immunotherapy  4062f, 4065 pharmacotherapy  4065 saline irrigation  4064 surgery  4066 occupational rhinitis  4060 pathogenesis  4061 animal models  4061, 4062f perennial allergic rhinitis  4060 seasonal allergic rhinitis  4060f, 4060 Allergic Rhinitis and its Impact on Asthma (ARIA)  4059 allergies  368 aetiology  369, 370 allergic bronchopulmonary aspergillosis (ABPA) see allergic bronchopulmonary aspergillosis (ABPA) anaphylaxis  373 blood transfusion complications  5572 clinical allergy  370f, 370 clinical features  371 angio-​oedema  372 asthma  371, 4071 atopy  369 conjunctivitis  371, 6408t eczema  372 eosinophilia  5254, 5255, 5256t hypersensitivity type I  369f, 369 non-​IgE-​mediated reactions  369 oedema  4045 urticaria  372 clinical investigations  376 challenge tests  376 intradermal tests  376 serum-​specific IgE assays  376 skin-​prick tests  376 tryptase  376 contact dermatitis see allergic contact dermatitis diagnostic criteria  376 differential diagnosis  376 drug reactions  88 anaphylactoid reactions  89 insulin  2492 oral hypoglycaemic agents  2495 pseudoallergic reactions  89 type I  89 type II  89 type III  89 type IV  89 evolutionary aetiology  40–​41 future work  378 historical perspective  369 hymenoptera venom allergy  374 management  376 allergen avoidance  371, 376 anti-​IgE  377 health economics  377 immunotherapy  377 pharmacotherapy  377 nonvenomous arthropods  1579 nuts  328–​29, 374 pathogenesis  369 steps in  369f, 369 prevalence  369 prevention  371 rhinitis see allergic rhinitis sensitization as predictor  370 uncertainty areas  377 alloantibodies  5567 allogeneic haematopoietic stem cell transplantation acute lymphoblastic leukaemia management  5275 donors  5579, 5582 myelodysplastic syndromes management  5204 plasma cell myeloma management  5317 allografts acute rejection  392, 393f definition  393t rejection, C-​reactive protein  2204 alloimmune haemolytic anaemias  5484 acute haemolytic transfusion reactions  5484 delayed haemolytic transfusion reactions  5485 haemolytic disease of the newborn  5485 passenger lymphocyte haemolysis  5485 alloimmune thrombocytopenia see platelet destruction disorders allopurinol adverse reactions  2022 hypersensitivity  4610 gout management  2022, 4489 gout post-​renal transplant  4902 hereditary renal hypouricaemia and uric acid stones management  2024 hypoxanthine-​guanine transferase deficiency management  2026 uric acid urolithiasis management  2023–​24 aloe vera drug interactions  205t skin disease management  5766 alopecia areata  5729f, 5729

10 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 Alpers–​Huttenlocher syndrome  6263, 6345t, 6346 Alpers’ syndrome  6245 α1-​adrenergic blockers chronic prostatitis management  5086 CKD in pregnancy  2594t primary aldosteronism screening  2354 α-​dystrinopathies, congenital muscular dystrophies (CMDs)  6293 α-​fetoprotein (AFP) ataxia-​oculomotor apraxia type 2  6263 ataxia telangiectasia  6209 hepatocellular carcinoma  3180 hepatocellular carcinoma biopsy  3181–​82 neural tube defects prenatal diagnosis  6352, 6354 normal blood values  6585t precocious puberty  2432 screening test  140f, 140 testicular cancer assessment  5145 alphavirus infections  821, 822t arthritis  4462 arthritis-​ and rash-​associated  823 Barmah Forest virus  824 Chikungunya virus  823 Mayaro virus  824, 825f O’nyong-​nyong virus  824 Ross River virus  824 Sindbis virus  824 laboratory diagnosis  823 neuroinvasive diseases  825 Eastern equine encephalitis virus  825 Venezuelan equine encephalitis antigenic complex  825 Western equine encephalitis virus  826 Alport’s syndrome thin membrane nephropathy vs.  4919 X-​linked  5069, 5069t ALS see advanced life support (ALS) alteplase acute pulmonary embolism management  3727 STEMI management  3648 alternative complement pathway see complement Alu elements  224 aluminium associated bone disorders  4667 normal blood values  6586t phosphide poisoning  1757 pneumoconioses  4233 poisoning  1751 alveoli  3942f anatomy  3938f, 3938 blood–​gas barrier  3938 capillary leakage, drug-​induced alveolar disease  4276 drug-​induced disease see drug-​ induced alveolar disease gas exchange  3944 hyperventilation, polycythaemias  5230 hypoventilation  4287 hypercapnia  4284f, 4284 hypoxaemia  4284 interconnected structure  3944 macrophages inhaled particles clearance  4220 sarcoidosis  4210 small  3944 ventilation, chronic respiratory failure management  4289 wall inflammation in COPD  4107 Alzheimer’s disease (AD)  603, 5835, 6234, 6478 amyloid beta (Aβ)  2222, 2226, 6234–​35 apoptosis  279 APP duplication  6235 cerebral amyloid  2222 clinical features  604t, 5839, 6478 amnesia  5839 aphasia  5825 atypical disease  5841 episodic (autobiographical) memory  5827 copy number variants  226t diagnosis  6133 histology  5835–​36 epidemiology  5836 familial disease  5836 sporadic disease  5836 histopathology  6235 historical perspective  5835 investigations  5841f, 5841 imaging  5815–​16 management  5842 drug management  6480 nonpharmacological management  5842 pharmacological management  5842 medical ethics  21 pathology  5836, 5839f, 6234–​35 pathophysiology  5836, 5840f, 5841f prognosis  5842 psychoses  6482 risk factors  5836 Amanita phalloides (death cap)  5062 amatoxin poisoning  1821, 1823f amaurosis fugax  6413 amblyopia (lazy eye)  6407 ambulatory blood pressure monitoring (ABPM)  3756b, 3756 blood pressure measurement  3755 hypertension diagnosis  3740, 3741f amenorrhoea causes  2378, 2378t CKD  4839 definition  2378 gonadotrophin deficiency  2268 hypothalamic/​pituitary disorders  2380, 2381f oligomenorrhoea vs.  2378 American Academy of Allergy, Asthma and Immunology (AAAAI)  3850, 3858 American Association for the Study of Liver Diseases (AASLD)  3080, 3123 American College of Cardiology (ACC) acute coronary syndrome  3304 endocarditis prevention  3529 lipidaemia management guidelines  2085t myocardial infarction definition  3629 stroke risk assessment  3370 American College of Chest Physicians (ACCP)  3371, 4322–​23 American College of Critical Care Medicine  3904 American College of Rheumatology (ACR)  5640 acute gouty arthritis  2019–​20, 2020b ANCA-​associated vasculitis  4557, 4565 eosinophilic granulomatosis with polyangiitis  4201–​2 giant cell arteritis  4549–​50, 4549t osteoarthritis  4470–​71, 4471t rheumatoid arthritis classification criteria  4431 rheumatoid arthritis remission criteria  4433, 4433t small-​vessel vasculitis  4573–​74 systemic lupus erythematosus classification  4500, 4500t systemic sclerosis  4519 Takayasu arteritis  4552 American College of Surgeons National Surgical Quality Improvement Program  570 American Diabetes Association (ADA)  2468–​69, 2496, 4984 American-​European Consensus Conference (AECC)  3873–​74 American Geriatrics Society  570 American Heart Association (AHA) acute rheumatic fever  3514 endocarditis prophylaxis  3530–​32 lipidaemia management guidelines  2085t myocardial infarction definition  3629 stroke risk assessment  3370 sugar consumption recommendations  1995 American mucosal leishmaniasis (espundia)  1470, 1471f American Society of Anesthesiologists (ASA)  565–​66, 3862 American Thoracic Society breathlessness  3947 COPD  4099 idiopathic interstitial pneumonia  4168, 4168t idiopathic pulmonary fibrosis  4177 occupational asthma  4073 American trypanosomiasis see Chagas’ disease (American trypanosomiasis) amikacin adverse reactions, acute kidney injury  4822 normal blood values  6588t renal disease, effects of  5163t tuberculosis management  4030 amiloride adverse reactions, hypokalaemia  4751 ascites management  3063 Gitelman’s syndrome management  5117–​19 hypertension management  3767 primary aldosteronism management  2355–​56, 3785 2-​amino/​2-​oxoadipic aciduria  1949t, 1962 amino acids aminoaciduria  5112, 5120, 5120t cystinuria  5120t, 5121 definition  5120 Hartnup’s disease  5120t, 5121 lysinuric protein intolerance (LPI)  5120t, 5121 renal lead toxicity  4969 analysis  1946b, 1946 disorders amino acidaemias  6220 eye diseases/​disorders  6437 metabolism  1846, 1847f, 1853t derivation of  1847 energy production  1848f, 1848 intertissue flux  1849, 1850f liver  3040 nutritional support  1917 proximal tubule function  4792 aminoglutethimide adverse reactions  2393t, 2545–​46 Cushing’s syndrome management  2347 aminoglycosides adverse reactions  702t, 2187, 3067, 4822 management monitoring, pharmacokinetics  99 peritonitis in peritoneal dialysis  4877 aminosalicylates Crohn’s disease management  2932 drug-​induced chronic tubulointerstitial nephritis  4957t, 4958f, 4962, 4963f inflammatory bowel disease in pregnancy  2625t renal disease, effects of  5153 ulcerative colitis management  2945, 2947 amiodarone adverse reactions  90 drug-​induced hyperthyroidism  2550 eye diseases/​disorders  6439 neuropathies  6189 thyroid disease  2550 thyroid hormone  2301 thyrotoxicosis  2301 antiarrhythmia management  3365t arrhythmias in hypertrophic cardiomyopathy management  3476 arrhythmogenic right ventricular cardiomyopathy management  3487

  Index 11 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 cardiac arrest  3844 chronic heart failure management  3416 drug-​induced interstitial pneumonitis and fibrosis  4277f, 4277, 4278f renal disease, effects of  5155t sarcoidosis management  3496 ventricular tachycardia management  3382 amitriptyline diabetic neuropathy management  2522 headache prevention  6001 migraine prevention  5993t motor neuron disease management  6166–​67 normal blood values  6588t pain management  631 tension-​type headaches  5995 AML see acute myeloid leukaemia (AML) amlodipine hypertension management  3766t, 3768 pre-​eclampsia management  2587 renal disease, effects of  5156 ammonia adult values  6581t formation of  1848–​49 hepatic encephalopathy type A  3081 hepatic encephalopathy type C pathogenesis  3082 liver metabolism  3040 poisoning  1768 amnesia Alzheimer’s disease  5839 episodic (autobiographical) memory loss  5827, 5828f, 5828t traumatic brain injury  6045 amodiaquine  1410t amoebiasis  1384 African trypanosomiasis see Chagas’ disease (American trypanosomiasis) appendicitis  1387 Chagas’ disease see Chagas’ disease (American trypanosomiasis) colitis with dysentery  1386 free-​living amoebae  1392 Acanthamoeba infection see Acanthamoeba infection Balamuthia infection  1392f, 1393, 1394f Naegleria fowleri infection
see Naegleria fowleri infection Sappinia infection  1393 parasitic gut amoebae  1391 see also Entamoeba histolytica infection amoxicillin adverse drug reactions  89 HACK endocarditis management  3529 Helicobacter pylori infection management  2857, 2858 renal disease, effects of  5163t small intestine bacterial overgrowth management  2883 amphetamines adverse reactions, erectile dysfunction  2409t drug-​induced pulmonary vasculature  4279 amphibians, animal poisons  1800f, 1800 amphotericin B adverse reactions  702t Candida albicans infection management  5091–​92 coccidioidomycosis management  1364 Cryptococcus neoformans in HIV/​ AIDS  6105 haemodialysis/​peritoneal dialysis  5151 ampulla of Vater  3033f anatomy  2723f, 3196–​97 amrinone  3890 Amsler charts  6399 amyloid beta (Aβ) Alzheimer’s disease  6234–​35 amyloid fibrils  2226 amyloid fibrils  2225 proteins/​precursors  2225 amyloid A (AA)  2226 amyloid beta (Aβ)  2226 amyloid P component  2228 apolipoprotein A-​I/​A-​II  2227 β2-​microglobulin  2228 cystatin C  2227 gelosin  2227 glycosaminoglycans  2228 immunoglobulin light chain  2225 islet amyloid polypeptide (IAPP)  2228 lysozyme  2227 transthyretin  2226 amyloidosis  2218, 4600 β-​2M  4600 AA amyloidosis see AA amyloidosis acquired syndrome  2219t AL amyloidosis see AL amyloidosis amyloid light chain  4600 amyloid protein  2218 cerebral amyloid  2222b, 2222 cerebral amyloid angiopathy  2223 hereditary cerebral amyloid angiopathy  2223 hereditary cerebral haemorrhage with amyloidosis  2223 prion disease associated  2223 sporadic cerebral Aβ amyloidosis  2223 see also Alzheimer’s disease (AD) chronic heart failure  3410t clinical types  2219 clinicopathological correlation  2219, 2219t, 2220t diagnosis  2229 biochemical tests  2230 biopsies  2229 genetic tests  2230 histochemistry  2229 scintigraphy  2230 serum amyloid P  2230, 2231f structural imaging  2230 endocrine amyloid  2225 haemodialysis-​associated  2224 heart muscle disease  3494 hereditary systemic amyloidosis  2223 familial amyloid cardiomyopathy  2220t, 2224 familial amyloid polyneuropathy (hereditary transthyretin amyloidosis)  2223 familial amyloid polyneuropathy with predominant cranial neuropathy  2224 familial Mediterranean fever  2224 non-​neuropathic systemic amyloidosis  2224 immunocyte dyscrasia associated see AL amyloidosis leprosy  5057 leucocyte chemotactic factor 2 amyloidosis  2224 malabsorption  2876t management  2232 future work  2233 general measures  2233 monoclonal immunoglobulin light-​chain associated see AL amyloidosis neuropathies  6193 pulmonary see pulmonary amyloidosis rare localized amyloidosis syndromes  2225 reactive systemic see AA amyloidosis renal disease  5039 secondary  4600 renal disease and  5008 senile amyloidosis  2221 senile focal amyloidosis  2222 wild-​type transthyretin (cardiac) amyloidosis  2221 senile focal  2222 spill-​over proteinuria  4786 systemic  4777 see also amyloid fibrils amyotrophic lateral sclerosis (ALS)  6167t, 6168, 6270 clinical features  6170f, 6170 clinical variants  6171 definition  6166 diagnostic concerns  6171 differential diagnosis  6171 epidemiology  6270–​71 family history  6168–​69 genetics  6168–​69, 6168t, 6271–​72, 6271t, 6272t chromosome 9 open reading frame 72  6273 fused in sarcoma (FUS)  6274 superoxide dismutase 1  6273 transactive response DNA-​ binding protein 43  6273 management  6171 disease-​modifying management  6171 paraneoplastic neurological syndromes  6390 pathology  6169f, 6169, 6270–​71 prognosis  6171 anaemia  5359 acquired aplastic anaemia see acquired aplastic anaemia adaptations to  5359, 5360, 5360t cardiovascular changes  5361f, 5362 erythropoietin  5361 intrinsic red cell adaptation  5360, 5361b, 5361f pulmonary function  5362 tissue perfusion local changes  5361 cardiogenic anasarca  3403 causes  5359, 5362 blood loss  5363 defective red cell maturation  5363b, 5363 haemolytic anaemia  5364b, 5364 red cell precursor defective proliferation  5362, 5363b chronic heart failure and  3412t, 3419 CKD  4852 clinical significance  4853 epidemiology  4853 management, 4853, 4854t pathogenesis  4852, 4853f classification  5359, 5362b, 5362 clinical approach  5359, 5364 clinical assessment  5364 haematological investigation  5365b, 5365 clinical manifestations  5359, 5362 consequences  5370 Crohn’s disease  2928 defective red cell maturation  5450, 5451b alcohol  5455 arsenic  5455 congenital dyserythropoietic anaemias  5455 drugs  5455 lead  5455 zinc  5455 see also sideroblastic anaemias definition  5360, 5366, 5366t erythropoietic protoporphyria  2049 eye diseases/​disorders  6417 folate deficiency see folate deficiency haematological system  4430t haemolytic see haemolytic anaemia heart failure  3395 low-​ and middle-​income countries  5367f, 5367 folate deficiency  5368 infection  5368 inherited anaemias  5369, 5369t iron deficiency  5368 malabsorption  5369 vitamin B12 deficiency  5368 management  5365 niacin deficiency  5425 nicotinic acid deficiency  5425 pantothenic acid deficiency  5425

12 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 plasma cell myeloma management  5319 post-​renal transplant  4902 pregnancy  2572, 2687 folate deficiency  2688 physiology  2687 vitamin B12 deficiency  2688 prevalence  5360, 5366, 5367t prevention  5370 primary myelofibrosis  5251 protein deficiency  5425 riboflavin deficiency  5425 scleroderma renal crisis  5008 sport and exercise medicine  6571, 6571t stomach cancer  2984 thiamine deficiency  5425 ulcerative colitis  2942 vitamin B6 deficiency  5425 vitamin B12 deficiency see vitamin B12 (cobalamin) deficiency vitamin C deficiency  5424 biochemistry  5424 nutritional aspects  5424 vitamin E deficiency  5425 world health challenge  5366 anaemia of inflammation  5402 aetiology  5402b, 5402 clinical features  5404 clinical investigation  5405b, 5405 bone marrow aspiration  5406 clinical chemistry  5405 haematology  5405 laboratory investigations  5405 controversies  5407 differential diagnosis  5404b, 5404 bone marrow failure  5405 drugs  5405 iron deficiency anaemia  5404 microangiopathic anaemia  5405 renal failure  5404 elderly  5407 epidemiology  5403 future development  5407 management  5406 blood transfusion  5406 erythropoietin-​stimulating agents  5406 iron management  5406 outcome  5407 pathogenesis  5403f, 5403 pathology  5403 prognosis  5407 anaerobic bacteria  1055 anaerobic bacteraemia  1057 antibiotic prophylaxis  1060 clinical spectrum  1057 anaerobic bacteraemia  1057 bone and joint infections  1058 central nervous system infections  1057 gastrointestinal infections  1058 genitourinary infections  1058 head and neck infections  1057 intra-​abdominal infections  1058 pleuropulmonary infections  1058 skin and soft tissue infections  1058 definition  1055 diagnosis  1059 anaerobic blood culture  1059 clinical clues  1059 specimen collection  1059 epidemiology  1055 history  1055 human commensal flora  1055 gastrointestinal tract  1056 genitourinary tract  1056, 1057f oral cavity  1056 skin  1056 upper respiratory tract  1056 management  1059 antibiotic susceptibility and resistance  1059 surgery  1060 pathogenesis  1056 small intestine bacterial overgrowth  2880 taxonomy  1055, 1056t anaerobic blood culture, anaerobic bacteria diagnosis  1059 anaesthesia anaphylaxis  375 chloride channel effects  84 leprosy  1157 renal impairment  5161 risks in, Duchenne’s muscular dystrophy  6319 topical rapid (premature) ejaculation management  2410 skin disease management  5766 see also sedation/​sedatives anakinra  101t, 104 cryopyrin-​associated periodic syndromes management  2214 gout management  4489 analgesia autosomal dominant polycystic kidney disease management  5067 chronic pancreatitis management  3223 critical limb ischaemia  3683 diabetic neuropathy management  2522 Fabry’s disease management  6227 herpes simplex virus 1 infection  2807 migraine management  5992 nonopioid  631 critical care in  3901 migraine management in pregnancy  2643 Paget’s disease management  4642 renal disease, effects of  5159, 5159t sickle cell disorder management  5446 STEMI  3646 urinary stones management  5128 see also pain therapy analgesic nephropathy  4957 clinical features  4958 diagnosis  4958, 4959f differential diagnosis  4957t epidemiology  4957 management  4958 pathogenesis  4956, 4957 pathology  4957 Anapen®  3857 anaphylaxis acute presentation  6604 anaphylaxis  373, 3849 aetiology  3851 cofactor ’summation anaphylaxis’  3852, 3852t drug-​induced  3851 exercise-​induced  3852 food-​induced  3851 idiopathic  3852 insect-​sting  3851 latex-​induced  3852 perioperative  3852 radiocontrast media  3852 allergic drug reactions  89 anaesthesia  375 clinical features  373b, 3853, 3853t cardiovascular system  3852t, 3854 cutaneous reactions  3852t, 3854f gastrointestinal system  3852t, 3854 general reactions  3853, 3854f neurological system  3852t, 3854 respiratory manifestations  3850f, 3852t, 3853 clinical investigations  3854 definition  3850b, 3850 severity grading  3850, 3851t diagnosis  3837t differential diagnosis  3854 discharge checklist  3857t drug-​induced asthma  4274 drug reactions  89 epidemiology  328–​29, 329f, 3853 future development  3858 immediate management  3855b, 3855 immunology referral  3857 observation  3856 ongoing management  3857 pathophysiology  3852 inflammatory mediators  3852 prevention  3857 second-​line management  3856 systemic  1807, 1808 Anaphylaxis Campaign  3858 anaplasmosis see human ehrlichioses and anaplasmosis anaplastic astrocytoma  6051–​52, 6052f anatomic abnormalities, oesophagus see oesophageal disease ANCA see anti-​neutrophil cytoplasmic antibodies (ANCA) Ancylostoma caninum infection  1505 Ancylostoma duodenale infection gastrointestinal system  3010t transmission  3015t Anderson–​Fabry disease (angiokeratoma corporis diffusum universale), cardiac disease  3499 Anderson–​Hynes pyeloplasty  5130 Anderson’s syndrome  252 androgen insensitivity syndromes (AIS) cryptorchidism  2402 disorders of sex development  2443–​44 androgen receptors (ARs)  2381f, 2391 blockers acne management  5706 cancer chemotherapy  501 sexual differentiation  2436–​37 testosterone metabolism  2391 androgens action defects  46, 2443 adverse reactions, liver tumours  3164 biosynthesis defects  46, 2438f replacement therapy, male hypogonadism  2399 Andrographis paniculata  203 Angelman’s syndrome  227, 5685 angina chronic heart failure and  3418 diabetic complications  2525 see also stable angina; unstable angina (UA) angina pectoris  3277, 3278f angiodysplasia acute lower gastrointestinal bleeding  2778, 2779f CT  2754 gastrointestinal vascular disorders  3004, 3005f imaging, capsule endoscopy  2754 management colonoscopy  2735, 2737f endoscopy  2743 angio-​oedema anaphylaxis  3854 skin drug reactions  5754t, 5756b, 5756 angiofollicular lymph node hyperplasia see Castleman’s disease (angiofollicular lymph node hyperplasia) angiogenesis  5709 blood vessels  3251 cancer  447 endothelium  3251f, 3251–​52 inhibitors, cancer chemotherapy  502, 503t psoriasis  5625 angiography brainstem death diagnosis  5909 cardiac surgery assessment  3667 colonic diverticular disease haemorrhage  2965 coronary artery disease in HIV/​ AIDS  3537 hepatocellular carcinoma  3181 Kawasaki’s disease  4593 myocarditis  3462–​63 quantitative  3343 renal imaging  4801f, 4801 angioimmunoblastic T-​cell lymphoma  5300 angiokeratoma  1616f, 1616 angiokeratoma corporis diffusum see Fabry’s disease (angiokeratoma corporis diffusum) angioma  1616 angiomyolipoma benign liver tumours  3189 renal tumours  5071–​72, 5072f

  Index 13 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 angio-​oedema allergy  372 upper airway obstruction  4045 angioplasty Budd–​Chiari syndrome management  3167 leg ischaemia management  3684–​85 Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) study  5047 disease outcomes  5047–​48 angiosarcoma (lymphangiosarcoma)  3186, 5719 angiostrongyliasis  1516 Angiostrongylus cantonensis infection  1517 aetiology  1517 clinical features  1517, 1518f diagnosis  1518 epidemiology  1517 management, prognosis, and control  1518 pathology  1517 Angiostrongylus costaricensis infection  1518 aetiology  1518 diagnosis and management  1519 epidemiology  1518 pathology and clinical features  1518 angiotensin-​converting enzyme see ACE (angiotensin-​ converting enzyme) angiotensin-​converting enzyme inhibitors see ACE inhibitors angiotensin II circulatory support  3890 hypertension  3744–​45, 3747f, 3747 pre-​eclampsia  2584–​85 angiotensinogen  2352, 3743 angiotensin receptor blockers (ARBs) acute kidney injury prevention  4811 adverse reactions atherosclerotic renovascular disease  5045 distal renal tubular acidosis with hyperkalaemia (previous type IV)  5109 hyperkalaemia  4760 renal disease  4778 chronic heart failure management  3414f, 3415 CKD in pregnancy  2594t dilated cardiomyopathy management  3481 drug interactions, lithium  6468 focal segmental glomerulosclerosis management  4926, 4927 hypertension management  3766t, 3768 acute stroke  3809 CKD  4842 contraindications  3767t diabetes  2525 left ventricular dysfunction management  3649 membranoproliferative glomerulonephritis  4941 minimal-​change nephrotic syndrome management  4921 nonalcoholic fatty liver disease  3152 post-​renal transplant hypertension  4899–​900 primary aldosteronism screening  2354 renal disease, effects of  5155–​56 STEMI management  3651 systemic sclerosis management  4524t angiotensin receptor–​neprilysin inhibitor (ARNI)  3414f, 3415 animal poisons/​toxins  1778, 1781 amphibians  1800f, 1800 aquatic animal ingestion  1802 carp gallbladder ingestion  1803 Ciguatera fish poisoning  1803 diagnosis  1804 histamine-​like syndrome (scombrotoxic poisoning)  1803 management  1804 paralytic shellfish poisoning  1803 prevention  1804 tetrodotoxin poisoning  1803 arthropods see venomous arthropods birds  1801f, 1801 fish  1801f, 1801, 1802f clinical features  1802 epidemiology  1801f, 1801, 1802f incidence  1801 management  1802 prevention  1802 venom composition  1802 leeches (Hirudinea)  1814 aquatic leeches  1814 land leeches  1814 lizards  1800f, 1800 mammals  1781 snakes see snake bites tropical renal disease  5060, 5061 venomous marine invertebrates see venomous marine invertebrates animals bites, acute presentation  6634 disease models allergic rhinitis  4061, 4062f antiglomerular basement membrane disease  4944 antiglomerular basement membrane disease pathogenesis  4943 cystic fibrosis  4164 gene editing  288 hypersensitivity pneumonitis  4250 inborn errors of metabolism  1939 myocarditis  3461 osteoarthritis pathology  4377 prerenal failure/​acute tubular necrosis  4820 leptospirosis  1199 mechanical injuries  1779 clinical features  1780 epidemiology  1779 management  1780 prevention  1780 rabies see rabies stings, acute presentation  6634 anion gap acidosis  2183b, 2194, 2195f acid–​base disorders diagnosis  2184 ethylene glycol  2196, 2196t metabolic acidosis  2184b, 2184 methanol  2197 5-​oxoprolinuria  2189f, 2197 salicylate intoxication  2197 see also diabetic ketoacidosis; lactic acidosis aniridia  6401t, 6437 anisakidosis  1509f, 1509 gastrointestinal system  3010t transmission  3015t ankylosing spondylitis  4446 clinical features  4446f, 4446 diagnosis  4447, 4447t epidemiology  4446 heart muscle disease  3493 immunopathology  4446 interstitial lung disease  4197 laboratory tests  4447 management  4448 medication in pregnancy  2709 neurological disorders  6378 pathogenesis  4446 physical examination extra-​articular organs  4447 spine/​thoracic cage  4447 prognosis  4449 pulmonary disease  4197 radiology  4447 sacroiliac CT  4448 sacroiliac MRI  4448 sacroiliac radiology  4447, 4448f spinal MRI  4448 spinal radiology  4448f, 4448, 4449f spinal disorders  4332 ulcerative colitis  2944 Ann Arbor staging Hodgkin’s lymphoma  5282, 5283t non-​Hodgkin’s lymphoma  5291, 5292t annular erythemas  5671 erythema annulare centrifugum  5671, 5672f erythema gyratum repens  5672 erythema migrans  5672f, 5672 lesion shape/​grouping  5598 anogenital lumps/​bumps  1613 clinical approach  1613, 1614f deep palpable lesions  1619 cystic/​nodular lesions  1619 oedema/​swellings  1620 superficial lesions  1613 crusty lesions  1618 flesh-​coloured lesions  1613 pigmented lesions  1617 plaque/​flat lesions  1618 pustular lesions  1618 red lesions  1616 anogenital warts  878, 1615f, 1615 clinical features  879, 880f, 881f diagnosis  879 epidemiology  879 management  879 anorexia nervosa acute abdomen  2766 aetiology  6510b cancer  488 classification/​diagnosis  6509b clinical features  6510 detection and diagnosis  6511 dyslipidaemia  2084 epidemiology  6510f, 6510 hypothalamopituitary function  2548 management, medical complication management  6511, 6512b outcome  6513 secondary hypoadrenalism (ACTH deficiency)  2350 ulcerative colitis  2940 anovulation  2378 bone health in athletes  6567 polycystic ovary syndrome  2382–​83 ANS see autonomic nervous system (ANS) Antabuse (disulfiram) see disulfiram (Antabuse) antenatal screening  141t, 143 anterior ischaemic optic neuropathy (AION)  5916, 6414–​16 anterior lobe (adenohypophysis), pituitary gland see pituitary gland anterior pituitary gland assessment  2262 function testing  2262 imaging  2263 neuro-​ophthalmological evaluation  2264 craniopharyngiomas see craniopharyngiomas disorders  2258 hormones  2264 adrenocorticotrophic hormone (ACTH) see adrenocorticotrophic hormone (ACTH) follicle-​stimulating hormone (FSH) see follicle-​ stimulating hormone (FSH) growth hormone (GH) see growth hormone (GH) luteinizing hormone (LH) see luteinizing hormone (LH) prolactin (PRL) see prolactin (PRL) thyroid-​stimulating hormone (TSH) see thyroid-​ stimulating hormone (TSH) hypophysitis  2276 hypopituitarism  2273b, 2273 pituitary adenomas  2273 pituitary apoplexy  2274 pituitary carcinomas  2274 radiotherapy  2264 Rathke’s cleft cysts  2276 surgery  2264

14 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 tumours, multiple endocrine neoplasia type 1 (MEN1)  2323 anterior uveitis  6420, 6421f, 6422f anthracyclines  500 anthrax  1094 aetiology  1095, 1096f clinical features  1098 cutaneous anthrax  1098, 1099f gastrointestinal anthrax  1099f, 1099 inhalational anthrax  1099, 1100f injection anthrax  1100 meningeal anthrax  1100 clinical investigations  1100 diagnosis  1098 differential diagnosis  1100 ecology  1096 epidemiology  1096 burden of disease  1097 deliberate release  1097 distribution of disease  1097f, 1097 forms of disease  1096, 1096t outbreak examples  1097 future developments  1102 historical importance  1095 management  1100 pathogenesis  1098 organ-​specific  1098 prevention  1101 prognosis  1101 special circumstances  1101 anti-​androgens adverse reactions, erectile dysfunction  2409t hidradenitis suppurativa management  5700 metastatic prostate cancer management  5145 skin disease management  5770 anti-​anxiety drugs  6465t, 6470 withdrawal of  6466 see also benzodiazepines anti-​arrhythmic drugs cardiorenal syndrome  3426 chronic heart failure management  3416 falls in elderly  583t pain management  632t pulmonary arterial hypertension  3704 renal disease, effects of  5155, 5155t STEMI/​non-​STEMI ACS  3652 tachycardia management  3364, 3364t, 3365t antibacterial agents  686t adverse reactions  702t mode of action  687, 687t nucleic acid inhibitors  687 protein synthesis inhibitors  687 poisoning by  1734 antibiotics acne management  5705, 5705t acute diverticulitis management  2963 acute pancreatitis management  3214 acute rhinitis management  4007 acute sinusitis management  4007 adverse reactions allergies  375 diarrhoea  672 induced-​anaphylaxis  4274 anaerobic bacteria management  1059 atopic dermatitis/​eczema management  5635 Bartonella infection  1270 broad-​spectrum  690, 2883 chronic osteomyelitis management  4694 colonoscopy  2736 Crohn’s disease management  2932 cystic fibrosis management  4158 endocarditis management  3529 enteric fever management  1048, 1048t gastrointestinal immune system  2783–​85 gastrointestinal infections  3023 gastrointestinal system immunology  2725–​26 Haemophilus influenzae type b management  1070 leg ulcers  5715 leptospirosis prevention  1204 liver failure management  3098 Neisseria meningitidis infection management  1021, 1022, 1022t Neisseria meningitidis infection prevention  1025 nosocomial infections  670 over-​prescription of  15 pelvic inflammatory disease management  1624, 1624t pharyngitis/​tonsillitis  4005 pharyngitis/​tonsillitis management  4005f, 4005 PSC management  3139, 3140 reactive arthritis management  4468 relapsing fever management  1196 renal disease, effects of  5162, 5163t resistance  692 Chlamydia trachomatis infection  1287 enzymatic inactivation  693 Haemophilus influenzae infection  1069 impermeability resistance  693 metabolic bypass resistance  694 Neisseria gonorrhoeae infection see Neisseria gonorrhoeae infection pneumococcal infections see pneumococcal infections prevalence  698t staphylococci infections  992 surveillance of  694 target site alterations  693 testing, Helicobacter pylori infection  2857, 2858 sepsis management  659 septic arthritis management  4460, 4461t small intestine bacterial overgrowth management  2883b, 2883 syphilis management  1220, 1220t systemic sclerosis management  4524t topical, acne management  5705 uncomplicated acute pyelonephritis management  5083 uncomplicated cystitis management  5079t, 5083f, 5083, 5084t variceal bleeding  3072 see also antimicrobial therapy antibody deficiency  357 associated with thymoma  359 autosomal recessive antibody deficiencies with B lymphopenia  358 common variable immunodeficiency see common variable immunodeficiency (CVID) IgA deficiency  359 IgG subclass deficiency  360 immunoglobulin replacement management  360 adverse reactions  360 dosages  358b, 360 physiological antibody deficiencies  359 prognosis  361 selective antibody deficiency with normal immunoglobulins  359 supplementary management  361 transient hypogammaglobulinaemia of infancy  359 X-​linked agammaglobulinaemia 
358 antibody fragments  107 antibody-​mediated rejection (ABMR) late (chronic) renal transplant rejection  4888 transplantation  400 transplant rejection  400 anti-​C1q antibodies assays of  323, 323t lupus nephritis  5002 anti-​CD20 antibody see rituximab anticholinergic drugs contraindications, Parkinson’s disease  5953 COPD management  4126, 4128f, 4128, 4128t death rattle  637 detrusor sphincter dyssynergia  6143 falls in elderly  583t Parkinson’s disease management  604 urinary incontinence  594 anticoagulants  3729 ACS management  3636, 3638 acute cerebral infarction management  6018 acute pulmonary embolism management  3726f, 3726 acute upper gastrointestinal bleeding management  2777 arrhythmias in hypertrophic cardiomyopathy management  3476 arterial occlusion in acute kidney disease  4825 atrial fibrillation  3733 cerebral infarction management  6018 cholesterol embolism  3688 chronic heart failure management  3416 CKD in pregnancy  2594t dilated cardiomyopathy management  3482 Ebstein anomaly management  3569 endothelial cells  5492, 5492t falls in elderly  587 fibrinolysis  3733 haemodialysis  4869b, 4869 heart valve surgery see heart valve surgery hypertension with myocardial infarction/​unstable angina  3808 INR control  3372, 3372t, 3373f ischaemic stroke prevention  6019 lumbar puncture contraindications  5782 mechanical heart valves  3733 oral fragility fractures  587 renal disease, effects of  5157 stroke prevention  3370, 3372t thromboembolism prevention  3370 use of  3372 oral direct inhibitors  3731, 3732f factor Xa inhibitors  3732 thrombin (IIa) inhibitors  3732 perioperative management  3734, 3734t poisoning by  1734 pregnancy in  3733 primary intracerebral haemorrhage management  6023 pulmonary arterial hypertension management  3704 renal disease, effects of  5157 restrictive cardiomyopathy management  3484 schedules  6603t STEMI/​non-​STEMI ACS  3651 vascular dementia management  5854 venous thromboembolism  3729 anticonvulsant drugs adverse reactions hypogonadism/​ infertility  2550–​51 liver enzyme induction  5876 male reproductive disorders  2393t osteomalacia/​rickets  4638 vitamin D metabolism  5876–​77 diabetic neuropathy management  2522 drug interactions, sodium valproate  6468 epilepsy management  5870f, 5870, 5873t adherence problems  5871 breastfeeding  5877 combinations  5871

  Index 15 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 dosage  5871 driving  5878 drug monitoring  5877 drug withdrawal  5877 enzyme induction  5876 first drug failure  5871 generic prescribing  5871 pregnancy  5877 rarely used medications  5876 second-​line agents  5875 third-​line agents  5875 focal epilepsy  5870–​71 folate deficiency  5419 HIV-​associated neuropathy  6108 mechanism of action  5871, 5872f migraine prevention  5993t pain management  631, 632t poisoning by  1735 antidepressant drugs  6465t, 6466, 6497t adverse reactions  6466, 6466t bulimia nervosa management  6512 depressive disorder management  6496, 6497t haemodialysis/​peritoneal dialysis  5151 low mood management  6464 mechanism of action  6466 newer types  6467 pain management  632t poisoning by  1735 somatic symptom disorder management  6462, 6519 withdrawal of  6466 see also selective serotonin reuptake inhibitors (SSRIs); tricyclic antidepressants (TCAs) antidiabetic agents, poisoning by  1736 antidiarrhoeal drugs  3020 antidiuretic hormone (ADH) ascites pathogenesis  3059 hyponatraemia  4732, 4733f pregnancy in  2564–​65 prerenal failure/​acute tubular necrosis diagnosis  4821 water excretion  4730–​31 water metabolism disorders  4730 see also vasopressin antidromic tachycardia  3378f, 3379f, 3380 antidrug antibodies (ADAs)  106 anti-​epileptic drugs N-​acetylaspartic aciduria (Canavan’s disease) management  1969 adverse reactions, eye diseases/​ disorders  6437 autoimmune encephalopathy with NMDAR antibodies  6395 autoimmune limbic encephalitis with VGKC-​ complex antibodies management  6394 drug interactions, antipsychotic drugs  6469–​70 pregnancy  2643 renal disease, effects of  5159 vertigo management  5927t antifibrotic drugs  3048, 3048t idiopathic pulmonary fibrosis management  4183 renal disease, effects of  5157 antifungal agents  686t adverse reactions  702t allergic bronchopulmonary mycosis  4240 mode of action  689 postoperative renal transplantation management  5162t skin disease management  5765, 5769 antigen-​presenting cells (APCs) B cells as  333 rheumatoid arthritis aetiology  4416 transplant rejection  399 antigens avoidance, hypersensitivity pneumonitis management  4253 hypersensitivity pneumonitis  4248 presentation B cells/​T cells  327f lysosomes  2124 receptors, lymphocytes  5264, 5265f recognition B cells  328f, 328 CD4+ T cells  328f T-​cell receptor  327 T cells, T cell subset bridging  328 specificity  326 tests bacterial meningitis  5785 pneumococcal infection  983 tuberculosis diagnosis  1141 variation in African trypanosomiasis  1454 biology of pathogenic organisms  654 antiglomerular basement membrane antibodies, ANCA-​ associated vasculitis (AAV) and  4992 antiglomerular basement membrane disease  4577, 4943 acute kidney injury causes  4826 ANCA-​associated vasculitis  4559–​60 clinical investigations  4947 diagnosis  4947, 4947t differential diagnosis  4947, 4947t epidemiology  4945 historical aspects  4943 management  4947 pathogenesis  4943 animal models  4944 autoantibody specificity  4943, 4944f disease mediators  4943 genetic susceptibility  4944 pathological findings  4945 prognosis  4948t, 4949 serological findings  4944 symptoms and signs  4945 pulmonary system  4946f, 4946 renal system  4946 variants and overlap syndromes  4946 ANCA positivity and vasculitis overlap  4946 isolated lung haemorrhage  4946 membranous nephropathy  4946 post-​transplant disease in Alport’s syndrome  4947 see also Goodpasture’s syndrome antihistamines allergic rhinitis management  4064, 4065 allergy management  371, 377 anaphylaxis management  3856 poisoning by  1737 renal disease, effects of  5158 skin disease management  5766 tongue swelling management  377 antihypertensive drugs acute kidney injury prevention  4811 advanced renal impairment management  5161t adverse reactions, erectile dysfunction  2409t blood pressure control in CKD  4842 blood pressure control in diabetic nephropathy  4981 CKD in pregnancy  2594t CKD management  4842, 4843f falls in elderly  583t ischaemic stroke prevention  6019 pharmacodynamics in older people  573 postoperative renal transplantation management  5162t pre-​eclampsia management  2587 rebound phenomena  90 renal disease, effects of  5155 anti-​inflammatory agents AA amyloidosis management  2232 acute pancreatitis management  3214 acute respiratory distress syndrome management  3879 ankylosing spondylitis management  4448 autoimmune disease management  391 bronchiectasis management  4148 bullous pemphigoid management  5614 cystic fibrosis  4160 delirium management  6477 linear IgA disease management  5616 monogenic inflammatory bowel disease  2975–​76 mucous membrane pemphigoid  5615–​16 septic shock without meningitis  1020 anti-​integrin therapy Crohn’s disease management  2933 ulcerative colitis management  2946 antimalarial drugs poisoning by  1737 rheumatoid arthritis management  4435 skin disease management  5769 antimicrobial therapy  684, 686t adverse reactions  701f, 701, 702f, 702t eye diseases/​disorders  6439 asthma management  4089 autosomal dominant polycystic kidney disease management  5067 bronchiectasis management  4148, 4149f bronchiolitis obliterans  4187 Chlamydia trachomatis infection management  1288, 1288t cystic fibrosis  4158 formularies  703, 704t future of  703 gastrointestinal infection management  3020 leptospirosis management  1202, 1203b Lyme borreliosis management  1185t pharmacokinetics  694 bioavailability  694, 696f distribution  694 excretion  696 metabolism  695 pharmacodynamics  696, 696t, 697f, 697t, 698t pharmacology  687 mode of action  687 pneumonia management  4018, 4018t, 4019t practice guidelines  703 principles of use  697, 698t, 699t bactericidal vs. bacteriostatic agents  700 dose selection  700 management duration  700 prophylactic use  698 prophylactic  698 HIV/​AIDS, pulmonary complications  4032 traumatic haemothorax  4319 Pseudomonas aeruginosa infection  1043 raised intracranial pressure  3896 skin disease management  5769 spectrum of activity  690 broad spectrum  690 combined drug management  690, 692b, 692f narrow-​spectrum  690 susceptibility testing  690, 691f urinary incontinence  594 see also antibiotics anti-​mitochondrial antibody (AMA) jaundice  3055 primary biliary cholangitis  3128 antimotility agents gastrointestinal infections management  3020 renal disease, effects of  5153 antiMüllerian hormone (AMH)  2379 sexual differentiation  2436 antimuscarinic bronchodilators acute asthma management  4095 renal disease, effects of  5158 anti-​muscle-​specific tyrosine kinase (MUSK) antibodies, myasthenia gravis  6296f, 6296–​97, 6299

16 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 anti-​neutrophil cytoplasmic antibodies (ANCA)  5640 antiglomerular basement membrane disease pathogenesis  4944–​45 cerebral vasculitis  6379 immune-​mediated alveolar haemorrhage  4236 pulmonary arterial hypertension  3700 rheumatological diseases  4403 systemic vasculitis pathogenesis  4989 vasculitis see anti-​neutrophil cytoplasmic antibodies (ANCA)-​associated vasculitis (AAV) anti-​neutrophil cytoplasmic antibodies (ANCA)-​associated vasculitis (AAV)  4405, 4496, 4556, 4557f, 5644b, 5644 aetiology  4559 secondary causes  4559, 4559t anti-​glomerular basement membrane antibodies and  4992 cholesterol embolism vs.  3689 clinical features  4561, 4561t, 4991b, 4992 cardiac system  4564 eye  4564 gastrointestinal system  4564 nervous system  4564 prodromal phase  4561 renal system  4562, 4563f respiratory system  4562f, 4562 skin  4564 systemic features  4562 diagnosis  4565 epidemiology  4496t, 4558 age  4559 ethnicity  4558 gender  4559 geography  4558 incidence  4558, 4558t prevalence  4558, 4558t eye diseases/​disorders  6424 future directions  4568 heart muscle disease  3494 history  4557, 4558t imaging  4564 infective endocarditis  5036f, 5036 laboratory features  4564 management  4565, 4565t, 4566t induction management  4565, 4567 refractory disease  4567 relapses  4567 remission maintenance management  4567, 4567t outcomes  4567, 4568f pathology  4560f, 4560 polymyalgia rheumatica vs.  4586 vasculitis overlap  4946 see also eosinophilic granulomatosis with polyangiitis (EGPA/​ Churg–​Strauss syndrome); granulomatosis with polyangiitis (GPA/​ Wegener’s granulomatosis); microscopic polyangiitis (MPA) anti-​NMDA-​receptor antibodies  5959 autoimmune encephalitis  6483 anti-​nuclear antibodies (ANA)  4497, 4497t acquired aplastic anaemia  5341 idiopathic photodermatoses  5689 pulmonary arterial hypertension  3700 rheumatological disease tests  4403, 4404b scleroderma renal crisis  5008 systemic lupus erythematosus  4508 anti-​onconeural antibodies  6385, 6385t, 6386f anti-​oxidants acute respiratory distress syndrome management  3878 cancer aetiology  1896–​97 chronic pancreatitis management  3224 dermatological vehicles  5762 drug-​induced liver injury  3158 malnutrition  1886 neuropsychiatric adult peroxisomal disorders  2163 selenium  1877 vitamin E  1861 anti-​phospholipid antibodies  4502, 5006, 5559 antiphospholipid syndrome (APL)  4502 classification criteria  2658t heart muscle disease  3492 immunological tests  4404 liver disease and  3177 pregnancy  2655, 2658 avoidance of  2667 indications  2659 management  2659, 2661t post-​partum issues  2660, 2661t pre-​eclampsia development  2659 systemic lupus erythematosus development  2659 antiplatelet drugs ACS management  3634, 3638, 3642f, 3642 acute upper gastrointestinal bleeding management  2777 bleeding tendencies  5518 cardiac surgery assessment  3667b, 3667 cerebral infarction management  6018 chronic heart failure management  3416 CKD in pregnancy  2594t clinical trials  59t, 60 ischaemic stroke prevention  6019 peptic ulcer disease  2851 peptic ulcer disease recurrence prevention  2858t, 2859 renal disease, effects of  5157 vascular dementia management  5854 antiproliferative agents immunosuppression in transplantation  402 postoperative renal transplantation management  5162t transplant immunosuppression  402 antiprotozoal agents  686t adverse reactions  702t antipsychotic drugs  6465t, 6468 adverse reactions  6469, 6515 dementia  5835 eye diseases/​disorders  6437 male reproductive disorders  2393t bipolar disorder management  6500 delirium management  558, 6477 drug interactions  6469 falls in elderly  583t indications  6469 main types  6469 poisoning by  1738 renal disease, effects of  5158 schizophrenia management  6515, 6515t, 6516 see also clozapine; olanzapine; quetiapine; risperidone antiretroviral therapy drug-​induced alveolar disease  4278 HIV/​AIDS see HIV/​AIDS antirheumatic drugs adverse reactions, renal disease  5001, 5010 pregnancy  2664t, 2666 anti-​RNA polymerase III antibodies scleroderma management in pregnancy  2666 systemic sclerosis  4522 anti-​Ro antibodies neonatal lupus syndrome  2658 systemic lupus erythematosus  4508–​9 systemic lupus erythematosus in pregnancy  4511 antisense oligonucleotides (ASOs)  232 Becker’s muscular dystrophy management  6281 Duchenne’s muscular dystrophy management  6281 familial hypercholesterolaemia management  2079 spinal muscular atrophy  6269 antispasmodic drugs colonoscopy  2736 irritable bowel syndrome management  2957, 2957t renal disease, effects of  5152 uncomplicated diverticular disease  2962–​63 antithrombin coagulation inhibitors  5505 deficiency  2240–​41 antithrombotic therapy acute pulmonary embolism management  3723t, 3726 bleeding risk  3371, 3371t, 3372t, 3373f postoperative renal transplantation management  5162t antithymocyte/​antilymphocyte globulin (ATG/​ALG) acute cellular renal transplant rejection  4886–​87 adverse reactions  404t post-​lung transplantation  4299 transplant immunosuppression  404 anti-​thyroglobulin antibodies primary thyroid epithelial tumours investigations and diagnosis  2305 thyroid status determination  2289 antithyroid drugs adverse reactions  2298b, 2298 Graves’ disease management  2298 induced hypothyroidism  2298 α1-​antitrypsin bronchiectasis  4147t COPD investigations  4118 COPD management  4132 cystic fibrosis management  4160–​61 normal blood values  6586t α1-​antitrypsin deficiency  2235, 5670, 5671f bronchiectasis  4144 clinical features  2239 emphysema  2239 liver disease  2239 clinical investigation  2240 COPD  4110 epidemiology  2239 genetic basis  221t genetics  2235, 2236t lung and liver disease  3171 management  2240 future work  2241 molecular basis  2238 liver disease  2236t, 2238f, 2238 lung disease  2239 neonatal cholestasis  3191 prognosis  2240 structure  2235 antituberculous drugs  1142, 1142t, 1143t anti-​tumour necrosis-​α (TNFα) drugs Crohn’s disease management  2933, 2934 inflammatory bowel disease in pregnancy  2625t psoriatic arthritis management  4452 rheumatoid arthritis management in pregnancy  2662, 2663t ulcerative colitis management  2945, 2946 antivenom therapy see snake bites antiviral agents  686t acute hepatitis B  3112 adverse reactions  702t Bell’s (idiopathic facial) palsy management  6124 chronic hepatitis B management  3116, 3116t human cytomegalovirus infection  749 immune complex-​mediated membranoproliferative glomerulonephritis management  4942 influenza virus infection management  732

  Index 17 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 liver failure management  3099 mode of action  688, 688t pregnancy  2617 skin disease management  5770 Antley–​Bixler syndrome  2371 anuria  4770 anxiety/​anxiety disorders  6501 aetiology  6502 constipation/​faecal incontinence  595 medical conditions  6503t assessment  6448, 6449b, 6503 detection  6502t, 6503 diagnosis  6504 clinical features  6502, 6502t differential diagnosis  6503, 6503t, 6504t epidemiology  6502 management  6504 pharmacotherapy  6504, 6505t psychological managements  6505 selective serotonin-​ noradrenaline reuptake inhibitors  6470 specialized management referral  6505, 6505t medically unexplained symptoms vs.  6461 Parkinson’s disease  610 self-​harm  6457 signs  6449 specific disorders  6502 see also generalized anxiety disorder (GAD); obsessive–​ compulsive disorder (OCD); panic disorder; phobia; social anxiety disorder (social phobia) symptoms  6448 urinary incontinence  593t aortic aneurysms cardiovascular syphilis  3540 diagnosis  4407 preventative medicine  133t aortic dissection acute  3675f, 3675 blood pressure management  3809 chest pain  3279b, 3279 diagnosis  3837t differential diagnosis, STEMI  3646 aortic regurgitation  3451 acute aortic syndrome  3677 aortic sclerosis vs.  3450 cardiovascular syphilis  3539, 3540f, 3540 causes  3451, 3451t clinical presentation  3452 physical examination  3452 symptoms  3452 differential diagnosis  3454 investigations  3452 cardiac catheterization  3454 chest radiography  3452, 3453f ECG  3452 echocardiography  3453f, 3453 management  3454 medical management  3454 surgery  3454 pathophysiology and complications  3451 pregnancy  2603 transthoracic echocardiography  3316f, 3317 aortic stenosis  3447 acute rheumatic fever  3512 causes  3447 chronic heart failure risk factor  3412t clinical presentation  3448 physical examination  3448 symptoms  3448 differential diagnosis  3450 investigations  3448 cardiac catheterization  3450 chest radiography  3448 ECG  3448 echocardiography  3448, 3449f management  3450 medical management  3450 PCI  3663 surgery  3450 pathophysiology and complications  3447 coronary circulation  3448 left ventricular response  3447 PCI  3664f pregnancy  2602 transthoracic echocardiography  3316, 3317f aortic valve disease  3447 aortic regurgitation see aortic regurgitation aortic stenosis see aortic stenosis endocarditis  3520–​21 investigations of valve stenosis  3455 mitral regurgitation vs.  3445 mixed aortic disease  3455 pathophysiology and complications  3455 right ventricular response  3455 repair/​replacement  3451 acute aortic syndrome  3675f aortic stenosis  3451 medication in pregnancy  2710 right heart valve disease  3455 AOST see adult-​onset Still’s disease (AOST) APCs see antigen-​presenting cells (APCs) aphasia  5824 anomia (naming)  5824 comprehension  5824 fluency  5824 frontotemporal dementia  5845 paraphasic errors  5824 repetition  5824 semantic  5825 syndromes  5824 Broca’s aphasia  5824 conduction aphasia  5825 degenerative dementias  5825 global aphasia  5825 Wernicke’s aphasia  5824, 5825 apixaban  3732 ACS management  3638 acute pulmonary embolism management  3727 peptic ulcer disease recurrence problem  2859 aplastic anaemia  5336, 5337 acquired see acquired aplastic anaemia definition  5337, 5338t, 5339t hereditary spherocytosis  5459 inherited  5346 pregnancy  2691 apocrine gland disorders see sweat gland disorders apolipoprotein(s)  2063, 2063t apolipoprotein A-​I/​A-​II, amyloid fibrils  2227 apolipoprotein B (apoB)  2064, 3597 apomorphine, Parkinson’s disease management  5953 apoptosis  266, 267f activation of  270 death-​signalling receptors  270, 271b, 271f mitochondrial signals  271, 272f, 273f autoimmunity  381 cell recognition  276f, 276 cell stress  273 DNA damage response  273b, 274 heat-​shock response  274 metabolic response  274 stress-​activated kinase receptor  274 unfolded protein response  274 definition  266 disease and  277 cardiovascular disease  278 CNS degeneration  279 immune disorders  277 infections  278 tumour biology  279 inflammation inhibition  267 radiotherapy  499 structural changes  266, 268f systemic lupus erythematosus pathology  4502 see also caspases apparent mineralocorticoid excess (AME)  3797f, 3798 hypokalaemia causes  4754 appendicitis  1898 acute  2769t acute ileitis vs.  2928 pregnancy  2625 APP gene Alzheimer’s disease  5836–​38, 6235 Dutch mutation  6235 familial Alzheimer’s
disease  5836 apraxia  5827 buccofacial apraxia  5829 conceptual  5828 conceptual apraxia  5829 ideomotor (conceptual) apraxia  5828 ideomotor (production) apraxia  5828 limb–​kinetic apraxia  5828 production  5828 screening for  5828–​29 apremilast  4452, 4583 APS see acute promyelocytic leukaemia (APS) aquatic animal ingestion, animal poisons see animal poisons/​ toxins aquatic leeches, animal poisons  1814 Araneae see venomous arthropods Archaebacteria  209 ARC syndrome  3192t, 5122t ARDS see acute respiratory distress syndrome (ARDS) arenaviruses  862 aetiology  863 Argentine haemorrhagic fever see South American haemorrhagic fevers clinical features  865 diagnosis  868 laboratory diagnosis  868, 869t differential diagnosis  868 epidemiology  863 future developments  870 genetics  863 management  864, 865b, 869 pathogenesis  863 pathology  863 prevention  864 ribavirin postexposure prophylaxis  864 rodent control  864 vaccines  865 Whitewater Arroyo-​like virus  868 see also Lassa fever; lymphocytic choriomeningitis virus infections ARF see acute respiratory failure (ARF) arginine stimulation tests  2427, 6587t arginine vasopressin (AVP) critical care response  3909 pancreatic neuroendocrine tumours  2455 syndrome of inappropriate antidiuresis  2544 Argyll–​Robertson pupil  6122, 6429 Aristichythys nobies  5061 Aristolachia  204 aristolochic acid drug-​induced chronic tubulointerstitial nephritis  4959 see also Balkan endemic nephropathy (BEN); Chinese herbal nephropathy poisonous plants  1832 Armillifer infections  1583f, 1583, 1584f Arnold–​Chiari malformation  5998 aromatase inhibitors adverse reactions, drug-​induced tendinopathies  4609 cancer chemotherapy  501 metastatic breast cancer  507 aromatherapy  202t arrested puberty  2434 arrhythmogenic right ventricular cardiomyopathy  3388, 3484, 3569, 3569t causes  3484 clinical features  3484 definition  3484

18 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 dilated cardiomyopathy overlap  3484 investigation  3484, 3485t cardiac MRI  3486, 3487f ECG  3486f, 3486 echocardiography  3486 endomyocardial biopsy  3487 exercise testing  3486 management  3487 pathology and pathophysiology  3484 arsenic cancer aetiology  421t, 422t defective red cell maturation  5455 neuropathies  6188 normal blood values  6586t poisoning  1752 squamous cell carcinoma  435 arsenic trioxide  112, 113f acute promyelocytic leukaemia management  112 commercial development  114 mechanism of action  112 arsine, poisoning  1763 artemisin  110, 1410t discovery of  110 history of  110, 111f arterial blood gases  3955, 3962 acid–​base balance  3964, 3964t, 3965f acute pulmonary embolism  3724 acute respiratory failure  3869b, 3869, 3870t anatomical shunt estimation  3964 COPD  4117 COPD investigations  4118 haemoglobin–​oxygen dissociation curves  3963f, 3963 metabolic acidosis  3964t, 3965, 3965t metabolic alkalosis  3964t, 3965, 3965t Pneumocystis jiroveci pneumonia investigation  1372 practical procedures  6649, 6649t respiratory acidosis  3964, 3964t, 3965t respiratory alkalosis  3964, 3964t, 3965t respiratory failure  3964 scoliosis  4331 severe asthma attacks  4094 strong ion approach  3966 ventilation–​perfusion mismatching  3963, 3963t arterial cannulation, procedure  6644, 6646 arterial occlusive disease  6012 acute kidney injury cause  4825 arterial oxygen saturation (SaO2), acute respiratory failure  3870 arterial partial pressure of carbon dioxide (PaCO2)  3962 normal blood values  6583t pregnancy  2613 arterial partial pressure of oxygen (PaO2)  3962 diffuse parenchymal lung diseases  4173 normal blood values  6583t pregnancy  2613 Arterial Revascularization Trial (ART)  3667 arteriovenous fistulae  5714 haemodialysis vascular access  4866 arteriovenous malformations (AVMs)  6362 pregnancy  2646 arteritis giant cell arteritis  4548 retina  6401t arthralgia cryoglobulinaemic vasculitis  4576 immune complexes in endocarditis  3522 rubella in pregnancy  2679 systemic lupus erythematosus  4505 arthritis acute rheumatic fever  3512 adult haemochromatosis  2107f, 2107 bacterial infections see septic arthritis Behçet’s syndrome  4581 Chlamydia pneumoniae infection  1293 Chlamydia trachomatis infection  1285 coeliac disease  4454 C-​reactive protein  2202–​3 immune complexes, Neisseria meningitidis infection  1021 inflammatory bowel disease and  4452 Mycoplasma infections  1303 Neisseria meningitidis infection  1021 psoriatic see psoriatic arthritis reactive see reactive arthritis rheumatoid see rheumatoid arthritis (RA) rubella in pregnancy  2679 septic see septic arthritis synovial membrane  4384f urinary incontinence  593t viral infections  4461 aetiology  4461, 4461t clinical features  4461 investigations  4462 management  4463 pathogenesis  4461, 4461t arthropathies collagenous colitis and  4454 crystal-​related see crystal-​related arthropathies hereditary haemochromatosis  2111 intestinal bypass surgery and  4454 psoriatic arthritis  4451 ulcerative colitis  2944 artificial nutrition support  1914, 1915f complications  1918, 1919t cost-​effectiveness  1924 ethics of  1922 future development  1924 hospital support team  1924 indications for  1916, 1916t burns  1923 critical illness  1923 gastrointestinal disease  1924 liver disease  1923 renal disease  1923 intestinal transplantation  1922f, 1922 long-​term artificial nutrition support  1922 palliative care  1924 perioperative nutrition  1924 requirement estimation  1917 carbohydrates  1918 electrolytes  1917, 1917t energy  1917 fluid  1917 lipids  1918 minerals and trace elements  1918 protein  1917, 1918f vitamins  1918 screening/​assessment  1914 body mass index  1916 examination  1916 history  1915 sepsis  1923 trauma  1923 see also enteral nutrition; parenteral feeding ASA see American Society of Anesthesiologists (ASA) asbestos amosite (brown asbestos)  4225 cancer aetiology  422t crocidolite (blue asbestos)  4225 fibre structure  4224f, 4224 lung cancer aetiology  432 macroscopic appearance  4225f, 4225 mesothelioma (of pleura/​ peritoneum) epidemiology  433 microscopic  4225f, 4225 pleural mesothelioma  4362 tobacco and  424 asbestosis  4224 aetiology and pathology  4225 clinical features  4222f, 4226, 4227f differential diagnosis  4226 investigations  4227 prevention and management  4227 prognosis  4227 asbestos-​related pleural disease, benign  4319 clinical features  4320 diffuse pleural thickening  4320 pleural effusion  4320 pleural plaques  4320f, 4320 rounded atelectasis  4321f, 4321 pathogenesis  4319, 4320f ascariasis (Ascaris lumbricoides infection)  1507 acute eosinophilic pneumonia (Löffler’s syndrome, simple pulmonary eosinophilia)  4239 acute pancreatitis  3213 clinical features  1508f, 1508 diagnosis  1508f, 1508 epidemiology  1507 gastrointestinal system  3010t life cycle  1507f, 1507, 1508f management  1508 transmission  3015t ascites  3058 aetiology  3058, 3061t amylase  3061 clinical features  3060f, 3060 complications  3065 hepatorenal syndrome  3067 hypercatabolic state  3067 paraumbilical hernia  3067 pleural effusion  3067 respiratory disease  3067 see also spontaneous bacterial peritonitis (SBP) drug prescribing  3067 fertility issues  3067 future work  3067 historical aspects  3058 investigations  3056t jaundice  3053–​54, 3055, 3056t laboratory diagnosis  3060 cell count  3061 cytology  3061 fluid culture  3061 fluid investigations  3061, 3061t paracentesis  3061 volume measures  3061 management  3062b, 3062 bed rest  3062 colloid replacement  3063 dietary salt restriction  3062 diuretics  3062 intravenous albumin infusion  3064 therapeutic paracentesis  3063 water restriction  3062 pathogenesis  3059f, 3059, 3060f renal dysfunction  3059 portal hypertension  3069 prognosis  3064 protein concentration  3061, 3061t refractory ascites management  3064 shunts  3064 ascorbic acid see vitamin C (ascorbic acid) Ashkenazi Jews Canavan’s disease  6218 cystic fibrosis epidemiology  4154 familial Mediterranean fever  2211 Gaucher’s disease type I  6227 glycogen storage disease type IV (adult polyglucosan body storage disease)  6221 GM2 gangliosidosis  6225 lysosomal storage disorders  6222–​24 Riley–​Day syndrome (familial dysautonomia)  6160–​61 Tay-​Sachs disease  2133 Asia breast cancer epidemiology  435–​36 colonic diverticular disease  2960 diffuse panbronchiolitis  4190 fibre and cancer aetiology  423 iodine deficiency disorders  1874 large bowel cancer  429 oesophageal cancer  427 oral cancer  426 prostate cancer epidemiology  438 rhabdovirus reservoir species  808 smoking  4339–​40 ASOs see antisense oligonucleotides (ASOs)

  Index 19 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 aspartate transferase (AST) acute hepatitis  3111 alcohol abuse  6526 alcoholic liver disease  3144–​45 autoimmune hepatitis  3122 inflammatory myopathies  4542 liver disease in pregnancy  2620 nitrogen disposal  1848 prehepatic jaundice  3051 aspartylglucosaminuria  6205t, 6231 aspergillosis  1354, 1534b cystic fibrosis respiratory management  4159 HIV/​AIDS  4036 liver disease  3175 post-​lung transplantation  4297, 4298f renal transplant immunosuppression  4894 severe/​difficult-​to-​treat asthma  4092 skin testing, bronchiectasis  4147t Aspergillus infections aflatoxin poisoning  1820 allergic bronchopulmonary mycosis  4240 cystic fibrosis  4157, 4159 HIV/​AIDS  3535 keratitis  6423 liver cancer  419 aspiration pneumonia  4021 polymyositis/​ dermatomyositis  4193 pregnancy  2616 aspirin ACS management  3634 acute cerebral infarction management  6018 acute myocardial infarction management, clinical trials see International Study of Infant Survival 2 (ISIS-​2) acute rheumatic fever management  3516 adverse reactions asthma  4072, 4073, 4074t, 4275 antiphospholipid syndrome management in pregnancy  2659 chronic heart failure management  3417 CKD in pregnancy  2594t diabetic nephropathy management  4984 essential thrombocythaemia management  5244 giant cell arteritis management  4550 hypertension risk management  3775 ischaemic stroke prevention  6019 leg ischaemia management  3684 metabolism  1745f migraine management  5994 peptic ulcer disease  2851 pharyngitis/​tonsillitis management  4006 polycythaemia vera management  5237–​38 pre-​eclampsia management  2586 preventative medicine  133t renal disease, effects of  5159t stable angina prevention  3623 STEMI management  3647 systemic lupus erythematosus management  4510 ASPRE study  2586 ASSERT trial  3371 Assessment of SpondyloArthritis Society (ASAS)  4464–​65 Association of British Neurologists  6036 Association of the British Pharmaceutical Industry  165 astemizole acquired long-​QT syndrome  251 allergic rhinitis management  4065 asthenozoospermia  2401 asthma  4067, 4069f acute attacks  4093 management  4094b, 4094 moderate  4093 severe  4093, 4094b acute presentation  6606 acute respiratory failure  3869 airway obstruction mechanisms  3943 allergy  371 breathlessness  3948 bronchoscopy  4000f, 4001 carbon monoxide diffusing capacity  3963t clinical features  4075 signs  4076 symptoms  4075 COPD  4102 cough  3949 diagnosis  3837t, 4076 airflow limitation  4076 airway hyperreactivity measures  4077 airway inflammation  4077 imaging  4078 reversibility and variability  4076, 4077f differential diagnosis  4080 COPD  4122, 4122t exercise-​induced breathlessness  4080 generalized airways obstruction  4080 hyperventilation  4080 localized airways obstruction  4080 vocal cord dysfunction  4080 drug-​induced  89, 90, 4273, 4274t anaphylaxis  4274 aspirin  4275 β-​adrenergic antagonists  4274 cholinergic drugs  4274 drug formulations  4275 drug masking  4275 nonsteroidal anti-​inflammatory drugs  4275 drug management  4083 anti-​IgE management  4089 antileukotrienes  4088 antimicrobial therapy  4089 β2-​adrenoceptor agonists  4083, 4084t, 4086 bronchial thermoplasty  4089 corticosteroids  4084 future therapies  4089 immunosuppressive management  4089 long-​acting muscarinic antagonists  4087 methylxanthines  4087, 4088t stepped approach  4083, 4084t epidemiology  4068 childhood microbial exposure  4069 geographical variations  4069 prevalence  4069 HIV/​AIDS  4038 inducers/​provokers  4070, 4071t, 4072f atopy and allergy  4071 drugs  4073 obesity  4073 occupation  4073 see also occupational asthma pollution  4072 psychological factors  4073 respiratory virus infections  4071 smoking  4072 management  4081, 4082f, 4082 allergen avoidance  4082 immunotherapy  4083 management selection  4081 patient education  4082b, 4082 pathophysiology  4070 biomarkers  4070 phenotype  4070 pregnancy  2616 prognosis  4075 children  4075 wheezing  4075 severe/​difficult-​to-​treat  4091 assessment  4091b Asthma Control questionnaire  4091 Asthma Control Test  4092 features  4091b management  4092 symptoms, breathlessness (dyspnoea)  3281 Asthma Control questionnaire, severe/​difficult-​to-​treat asthma  4091 Asthma Control Test, severe/​difficult-​ to-​treat asthma  4092 ASTRAL trials  3788 astrocytoma  440 astrovirus infection  801f, 801 gastroenteritis  803 gastrointestinal system  3010t, 3012 transmission  3014t asymmetric dimethylarginine (ADMA)  3270 Asymptomatic Carotid Surgery Trial (ACST-​1)  56, 57f atacicept  101t ataxia  5976 autosomal dominant cerebellar ataxias  5983t, 5984, 5985f autosomal recessive disease  5983 defective DNA repair  5982t, 5984 Friedreich’s ataxia  5982t, 5983 oculomotor apraxia and  5982t, 5984 cerebellar disease  5977 eye movements  5979 gait  5977 limb ataxia  5978 muscle tone  5978 posture  5977 speech  5978 tremor  5978 cerebellum disorders  5979 acute/​subacute onset  5979 chronic progressive course  5981 developmental disorders  5979, 5980t episodic course  5980, 5983t vascular disorders  5980 coeliac disease  2887 differential diagnosis  5978t hemiparesis  6017–​18 idiopathic degenerative late-​onset ataxia (ILOCA)  5985 investigations  5979 anatomy quantification  5979 genetics  5979, 5982t, 5983t imaging  5979 lysosomal disease  2131 management  6387t multiple sclerosis  6032 myoclonus with see myoclonus progressive metabolic ataxias  5982 degenerative disorders  5982, 5982t, 5983t endocrine disorders  5982 metabolic disorders  5982 spinal cord disorders  6130 symptoms  5977, 5978t dysarthria  5977 gait disturbances  5977 limb coordination  5977 ocular motor symptoms  5977 tremor  5977 visual symptoms  5977 vitamin E deficiency (AVED)  1861, 6263 Whipple’s disease  2910 ataxia neuropathy spectrum (ANS)  6263, 6345t ataxia-​oculomotor apraxias  6262, 6263 ataxia telangiectasia (AT)  221t, 458t, 466, 5717, 5984, 6209 ATM gene mutations  466 cancer  420 cancer susceptibility  415 clinical features  6209 gastrointestinal manifestations  2788t immunodeficiencies  356 investigations  6209 management  6209 atenolol hypertension management  3766t malignant hypertension management  3805 renal disease, effects of  5155 atezolizumab  508 ATG see antithymocyte/​ antilymphocyte globulin (ATG/​ALG) atherectomy see percutaneous coronary intervention (PCI) atheroma diabetes  2523

20 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 essential hypertension pathophysiology  3749 metabolic syndrome (syndrome X)  2475 see also atherosclerosis atherosclerosis  3596 accelerated renal transplant complications  4900, 4900t rheumatoid arthritis complications  4439 acute coronary syndromes  3600 plaque rupture/​erosion  3600 vulnerable plaques  3601 atherosclerotic plaques  3599 arterial wall remodelling  3600 cell death  3599 disease progression  3600 neovascularization  3600 plaque calcification  3600 cardiovascular disease assessment for  2089 cholesterol and  2056 epidemiology  2056, 2057f familial hypercholesterolaemia 
2079 hypertriglyceridaemia  2094 LDL-​cholesterol  2089–​90 Chlamydia pneumoniae infection  1293 extracellular matrix  3599 hypertension and  3749 initiation  3597 leucocyte recruitment  3597, 3598f management  5712 progression  3598 regression  3601, 3602f clinical studies  3601 smooth muscle cells  3599 systemic lupus erythematosus in pregnancy  2656 atherosclerotic renovascular disease (ARVD)  5044 cardiorenal syndrome  3423 clinical features  5045, 5046f clinical investigations  5045 epidemiology  5045 future development  5048 management  5045 prognosis  5048 atherothrombosis  6012–​13 Athlete Biological Passport  6572 athletes see sport and exercise medicine ATLAS 2 study  3638 atmospheric ozone, aviation medicine  1658 atmospheric pollution see air (atmospheric) pollution atopic dermatitis  5633 allergen avoidance  5635 allergy and  5634 clinical features  5631f, 5633 definitions  5633 distribution on body  5599f incidence  5633 management  5635b, 5635 allergen avoidance  5635 infections  5635 itch  5635 skin inflammation  5635b, 5635 microbes  5635 natural history  5633 pathogenesis  5633 prevalence  5633 sites  5597, 5598f see also eczema atopic eruption of pregnancy  2651f, 2651, 2651t, 2652t ATP energy production in muscle  6307 mitochondria  211 synthesis  1839 ATP7B gene Menkes’ disease  2120 Wilson’s disease  2115, 2118, 3195, 5963, 6248 ATP-​binding cassette (ABC) transporters drug-​induced liver injury  3157 drug tissue distribution  80 ATP-​sensitive K+ (KATP) channel insulin secretory disease  254 neonatal diabetes  255 Atractaspidinae (family Lamiprophilidae)  1782f, 1782, 1788 atrial arrangement, congenital heart disease  3561, 3563t atrial fibrillation  3367 aetiology  3368b, 3368 cardiac surgery complications  3672 chronic heart failure and  3418 chronic heart failure risk factor  3412t classification  3368b, 3368 diagnosis  3368f, 3368 dilated cardiomyopathy  3479 emergency presentation  3369b, 3369 malignant hypertension  3804 management  3368 anticoagulants  3733 digoxin  77–​78 mechanisms  3367 mitral stenosis complications  3438, 3441 palpitation  3292 paroxysmal atrial fibrillation  3370f permanent atrial fibrillation  3370 persistent atrial fibrillation  3369 pre-​excited atrial fibrillation  3380f, 3380 presentation  3368 stroke prevention  3371t, 3373f, 3374, 3375t, 3376f thromboembolism prevention  3370 oral anticoagulants  3370 transthoracic echocardiography  3320f, 3320 atrial flutter cardiac arrhythmias  3368b, 3375, 3377f complete transposition of the great arteries  3582 atrial hypertrophy, ECG  3301 atrial infarction  3307 atrial natriuretic peptide (ANP)  3270 AKI in pregnancy  2589 hypertension  3748 atrial septal defects (ASDs)  3570 clinical signs  3571 heart disease interactions  3571 pulmonary vascular disease  3565t, 3571 investigations  3572 management  3572 types  3570f, 3570 coronary sinus defect  3572 ostium primum atrial septal defect  3572 ostium secundum  3571 patent foramen ovale  3570 sinus venosus atrial septal defect  3572 atrial septostomy  3706 atrioventricular block  3308 aetiology  3355, 3356b myocardial infarction  3355, 3356f first-​degree  3355, 3356f second-​degree  3355–​56, 3356f third-​degree  3355, 3356f, 3357f atrioventricular (AV) node  3264, 3265f conduction disorders, bradycardias  3354 congenital heart disease  3562f, 3562 metabolism  3268 myocytes  3257–​59 re-​entry tachycardia  3377, 3378f, 3379f atrioventricular septal defects (AVSD)  3574, 3575f clinical presentation  3575 complete  3575 investigation  3575 partial  3575 atrophic vaginitis  1605 management, UTI prevention  5085 atropine anaphylaxis management  3856 bradycardia management  3353–​54 ATTITUDE trial  3768 atypical haemolytic uraemic syndrome (aHUS)  321 diagnosis  5031 genetics  5029, 5030t management  5031 noninherited type  5030 pathogenesis  4991b, 4992f, 4995b, 5028 renal transplantation  5032 atypical mycobacterial infection diagnosis  4029 management  4030, 4030t atypical neuroaxonal dystrophy (atypical NAD)  6253 auditory system  5931, 5932f higher brain function  5823 rehabilitation  5935 see also hearing disorders auscultation aortic regurgitation  3452 aortic stenosis  3448 respiratory disease see respiratory disease, clinical examination Australia multiple sclerosis  6030 stomach cancer  428 tobacco as cancer cause  417t Australia and New Zealand Dialysis and Transplant Registry  4834 Australian bat lyssavirus  819f, 819 autism macrocephaly  6356 measles persistent infection  781 autoantibodies  380 ANCA-​associated vasculitis  4557f antiglomerular basement membrane disease  4943, 4944f autoimmune diseases  389t autoimmune encephalitis  6483, 6483t autoimmune hepatitis  3122–​23, 3124f, 3124t autoimmune rheumatic disorders  4497 blood transfusions  5568 bronchiectasis  4147t congenital noninflammatory diarrhoea  2974 dermatomyositis  5661 diffuse parenchymal lung diseases  4173 inflammatory myopathies  4542, 4543t rheumatoid arthritis  4424–​25, 4432 rheumatological diseases  4403 systemic lupus erythematosus  4501t, 4508 systemic lupus erythematosus pathology  4501, 4501t, 4502 autoimmune acquired hypoparathyroidism 
2315t, 2316f, 2329 autoimmune bullous disease  5612 differential diagnosis  5614t intraepidermal diseases  5613t, 5617f, 5617 paraneoplastic pemphigus  5613t, 5619 pemphigus foliaceus  5613t, 5619 pemphigus vulgaris  5613t, 5617, 5618f pregnancy  2654 subepidermal diseases  5612, 5613t, 5614f bullous pemphigoid  5612, 5613t, 5615f dermatitis herpetiformis  5613t, 5616f, 5616 epidermolysis bullosa acquisita  5613t, 5616 linear IgA disease  5613t, 5615f, 5616 mucous membrane pemphigoid  5613t, 5614, 5615f autoimmune diseases/​disorders  379 aetiology  380 environmental factors  382 genetics  380 B-​lymphocyte stimulator  104 chorea  5959 clinical features  388, 389t, 390t coeliac disease and  2891

  Index 21 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 complement impaired activation  319 diabetes mellitus type 1 as  2477 distal renal tubular acidosis type 1  2191 encephalopathy with NMDAR antibodies  6395 epidemiology  380 Epstein–​Barr virus infection  763 evolutionary aetiology  40–​41 gastrointestinal dysmotility  2794 gastrointestinal tract see gastrointestinal tract heart muscle disease  3490 hepatitis see autoimmune hepatitis hypocalciuric hypercalcaemia (AHH)  2325 insulin syndrome (IAS: Hirata’s disease)  2539 management  390 lost function replacement  391 pathway control  391 organic psychoses  6483, 6483t pathogenesis  382 amplification principles  388 autoantigens  388 central tolerance  382 disease-​specific autoantigens  388 effector mechanisms  387 mechanisms  383 peripheral tolerance  382 pericarditis  3502 premature ovarian insufficiency  2379 prognosis  390 retroperitoneal fibrosis  5131–​32 rheumatoid arthritis complications  4439 systemic gastrointestinal tract  2795, 2795t immune complex-​mediated membranoproliferative glomerulonephritis  4937–​38 autoimmune encephalitis  6483 autoantibodies  6483, 6483t disease associations  6483, 6483t autoimmune haemolytic anaemias  389t, 5480, 5481t cold autoimmune haemolytic anaemia  5482f, 5482 drug-​induced  5483 management  4510 mixed-​type autoimmune haemolytic
anaemia  5483 paroxysmal cold haemoglobinuria  5481 ulcerative colitis  2945 warm autoimmune haemolytic anaemia  5481f, 5481 autoimmune hepatitis  389t, 3119, 3173, 3176 aetiology and pathogenesis  3120 environmental factors  3120 genetics  3120 immunology  3120 childhood liver disease  3194f, 3194 clinical features  3121, 3122t cross-​over syndromes  3126 diagnosis  3123t differential diagnosis  3122, 3122t, 3123b epidemiology  3120 hepatitis vs.  3111 inactive disease  3126 inflammatory bowel disease  3172 investigations  3122, 3124f, 3124t jaundice  3054 liver transplantation  3105 recurrence after  3106t malabsorption  2877 management  3123 liver transplantation  3123 pharmacology  3123, 3125f older children  3194 pathology  3121f, 3121 physical examination  3122 pregnancy  3126 prognosis  3126 liver transplantation  3126 type 1  3121, 3121t type 2  3121, 3121t autoimmune hypothyroidism  2292 clinical features  2292 disease associations  2293 autoimmune limbic encephalitis with VGKC-​complex antibodies  6393 clinical features  6393 differential diagnosis  6394, 6395t epidemiology  6393 investigations  6393, 6394f management  6394 pathogenesis  6394 autoimmune lymphoproliferative syndrome (ALPS)  361 autoimmune neutropenia hypersplenism  5193 pregnancy  2694 autoimmune pancreatitis  2794 acute pancreatitis  3212 chronic pancreatitis vs.  3221 autoimmune polyendocrine syndrome type I  381 eye diseases/​disorders  6434 autoimmune polyendocrinopathy–​ candidiasis–​ ectodermal dystrophy (APECED)  2329, 2477 autoimmune polyglandular syndrome type 2  2293 autoimmune pulmonary alveolar proteinosis  4259 autoimmune retinopathy (AIO)  6425 autoimmune rheumatic disorders  4387t, 4390f, 4390t, 4391, 4391t, 4495 clinical features  4498 clinical spectrum  4496, 4497t definition  4495, 4496t epidemiology  4495, 4496t heart muscle disease  3491, 3491t immunopathogenesis  4497 lung involvement  4191 ankylosing spondylitis  4197 lymphoid follicles  4191–​92, 4192f mixed connective tissue disease  4197 pleural thickening  4191–​92, 4192f polymyositis/​ dermatomyositis  4193 relapsing polychondritis  4196 rheumatoid arthritis  4194 Sjögren’s syndrome  4195 systemic lupus erythematosus  4196 systemic sclerosis  4192 undifferentiated connective tissue disease  4197 autoimmune sclerosing cholangitis  3126 autoimmune thyroid disease, coeliac disease  2887, 2888 autoinduction  87 autoinflammation and PLCγ2-​ associated antibody deficiency and immune dysregulation (APLAID)  2208t, 2215 autologous haematopoietic stem cell transplantation  5579, 5587 MALT lymphoma management  2901 metachromatic leucodystrophy management  6213 multiple sclerosis management  6037 plasma cell myeloma management  5313f, 5316 renal disease in myeloma  5020 Autologous Stem Cell Transplantation International Scleroderma (ASTIS) study  4519 autonomic nervous system (ANS) insulin secretion effects  2470 pulmonary vasomotor tone regulation  3693–​94 terminals at target organs  6151, 6152f autonomic nervous system disorders  6150, 6151f classification  6151, 6153b clinical features  6151, 6154b, 6155f, 6156t investigations  6154f, 6154, 6156b management  6154b, 6157b, 6157, 6158t multiple sclerosis  6031 primary autonomic failure  6158 acute/​subacute dysautonomias  6160 chronic autonomic failure  6158, 6160f principles  6150 secondary disorders  6160 amyloid neuropathy  6161 autonomic (neurally) mediated syncope  6161, 6163f, 6164f diabetes mellitus  6151, 6161 dopamine β-​hydroxylase deficiency  6152f, 6161 drugs  6153b, 6161 initial orthostatic hypotension  6155f, 6165 intermittent autonomic dysfunction  6153b, 6161 postural tachycardia syndrome  6164f, 6164 primary (essential) hyperhidrosis  6165 Riley–​Day syndrome (familial dysautonomia)  6160 spinal cord injury  6161, 6162f autonomic neuropathy  6371 diabetic neuropathy  2519 autophagic pathway caspases  267–​68 lysosomal hydrolases  213–​14 lysosomes  2122 autopsy see post-​mortem examination autosomal Alport’s syndrome  5069 autosomal dominant cerebellar ataxias  5983t, 5984, 5985f autosomal dominant Charcot–​ Marie–​Tooth disease see Charcot–​Marie–​Tooth (CMT) disease autosomal dominant hypercholesterolaemia 
2080 autosomal dominant hyper IgE syndrome  357 autosomal dominant hypocalcaemia  2315t, 2316f, 2327 autosomal dominant hypophosphataemic rickets (ADHR)  5114, 5115t autosomal dominant ichthyosis  5606 autosomal dominant isolated renal hypomagnesaemia  5118t, 5119 autosomal dominant limb-​ girdle muscular dystrophies  6321b, 6322 autosomal dominant nocturnal frontal lobe epilepsy  6242 autosomal dominant partial epilepsy with auditory features (ADPEAF)  6242 autosomal dominant polycystic kidney disease (ADPKD)  5065 diagnosis  5065 at-​risk subjects  5065 exclusion diagnosis  5066 family history absence  5066f, 5066, 5066t ultrasound  5066f, 5066 genetic counselling  5068 management  5067, 5068 pathogenesis  5067 pregnancy  2595 symptoms  5066 external manifestations  5067 renal manifestations  5066 UTI  5087 autosomal dominant renal hypomagnesaemia  5118t, 5119 autosomal dominant tubulointerstitial kidney disease (ADTKD)  2021 autosomal recessive ataxia (ARSACS)  5984, 5985f autosomal recessive hypercholesterolaemia (ARH)  2063f, 2080 autosomal recessive hypophosphataemic rickets (ARHR)  5114, 5115t

22 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 autosomal recessive inheritance, Mendelian inheritance  220 autosomal recessive polycystic kidney disease  5068 autosomal recessive spastic ataxia of Charlevoix-​Saguenay (ARSACS)  6262 aviation medicine  1656 clinical aspects  1662 fitness to fly  1663 infectious disease spread  1663 jet lag  1662 newly emerging infectious diseases  1664 traveller’s thrombosis  1663 cyanotic heart disease  3565 flight physiology  1658 altitude-​induced decompression illness  1662 hypoxia  1658, 1659f, 1660f oxygen equipment  1660 pressure cabins  1660, 1661f pressure change mechanical effects  1661f, 1661 oxygen equipment  1660 oxygen management in COPD management  4135 physics of the flight environment  1657f, 1657 atmospheric ozone  1658 atmospheric pressure  1657, 1658f atmospheric temperature  1658 cosmic radiation  1658 pneumothorax  4325 pressure cabins  1660, 1661f pressure change mechanical effects  1661f travel and expedition medicine  714 AVMs see arteriovenous malformations (AVMs) axillary nerve (C5, C6), neuropathies  6182 axis, 12-​lead ECG reading  3298f, 3298, 3299f axitinib  485 primary thyroid epithelial tumour management  2308 axonal polyneuropathy chronic idiopathic  6195 nerve conduction studies  5799f, 5799, 5800f Ayurvedic medicine  108, 109b azathioprine acute pancreatitis  3211 adverse reactions  404t, 4890, 4891t cancer aetiology  421t drug-​induced liver injury  3156 nodular regenerative hyperplasia  3164 antiphospholipid syndrome management in pregnancy  2660 arthritis and inflammatory bowel disease  4453 autoimmune hepatitis management  3123 Behçet’s syndrome management  4583 CKD in pregnancy  2594t Crohn’s disease management  2932, 2933 cryptogenic organizing pneumonia management  4189 dermatomyositis management  5661–​62 drug-​induced alveolar disease  4278 immunoglobulin A nephropathy management  4915–​16 interstitial nephritis with granuloma in sarcoidosis  5015 Lambert–​Eaton myasthenic syndrome management  6301 liver transplantation  3103–​4 mucous membrane pemphigoid management  2819 multiple sclerosis management, pregnancy in  2645t myasthenia gravis in pregnancy  6300 non proliferative lupus nephritis class V management  5004 ocular symptoms in myasthenia gravis management  6299 oral lichen planus management  2818 pemphigus vulgaris management  5618 polyarteritis nodosa management  4573 polymyalgia rheumatica management  4588 post-​lung transplantation  4299 primary biliary cholangitis management  3134t recurrent aphthous stomatitis management  2816 renal disease, effects of  5153 rheumatoid arthritis management in pregnancy  2664t SAPHO syndrome  4454 sarcoidosis management  4216, 4216t, 4217, 5745, 6382 skin disease management  5768 systemic lupus erythematosus management  4511 systemic vasculitis maintenance management  4996 transplant immunosuppression  402 azithromycin bronchiectasis management  4148–​49 bronchiolitis obliterans syndrome management  4301–​2 chlamydia in pregnancy  2683 COPD management  4130–​31 renal disease, effects of  5163t scrub typhus management  1255 urethritis  1608 azoospermia  2401 cystic fibrosis  4156, 4163 B cell(s) activation, transplantation  397f, 397 antigen presentation  327f, 333 antigen receptors  5264 antigen recognition  328f, 328 clonal proliferation  333f, 333 development  331 diversity generation  329f, 329, 330t functions of  333 memory  334 priming  333f, 333 progenitors  5265–​66 stimulator protein  241 stimulators  104 tolerance mechanisms  334, 383 transplantation  397f, 400 B-​cell diseases/​disorders ANCA-​associated vasculitis  4560 atherosclerosis  3599 inflammatory disease-​like immunopathology  2788t inflammatory myopathies  4538–​39 lymphopenia  358 rheumatoid arthritis  4424 synovial membrane  4385 systemic lupus erythematosus pathology  4501 ulcerative colitis  2939 B-​cell malignancies Gaucher’s disease type 1  2142 lymphoma cutaneous lymphoma  5740 renal disease in  5025 non-​Hodgkin’s lymphoma  4428–​30 B cell receptor (BCR)  328 B7.1 (CD80)  474 B7.2 (CD86)  474 Babesia divergens infection  1415, 1416f Babesia microti infection  1415 babesiosis  1414 clinical features  1415 Babesia divergens infection  1415, 1416f Babesia microti infection  1415 diagnosis  1415 epidemiology  1414 management  1415 pathogenesis  1415 prevention  1415 Bacillus anthracis infection see anthrax bacillus Calmette–​Guérin (BCG) vaccine non muscle-​invasive bladder cancer management  5139 tuberculosis prevention  1149 tuberculous meningitis prognosis  6081 Bacillus cereus infection  1040 gastrointestinal system  3009t, 3011 toxin production  3017 transmission  3014t background activity, EEG  5787f, 5787 back pain  4406 acute abdomen  2765–​66 diffuse musculoskeletal
pain  4411 regional pain disorders  4411, 4412t warning signs  4386t see also low back pain; neck pain baclofen glutaric aciduria type I management  1963 multiple sclerosis management  6035 spasticity in spinal cord injury  6144 trigeminal neuralgia management  6123 bacteraemia Bartonella infection  1268 coagulase-​negative staphylococci see coagulase-​negative staphylococci endocarditis  3521 haemodialysis access  4871 Haemophilus influenzae type b  1069 Pseudomonas aeruginosa infection  1041, 1042f Staphylococcus aureus infection  1002f, 1002, 1003t bacterial infections acute prostatitis  5085 ANCA-​associated vasculitis  4559 angiomatosis Bartonella infection  1267, 1271 HIV/​AIDS  918 asymptomatic bacteriuria  5075–​76 pregnancy  2577, 2596 screening, preventative medicine in pregnancy  134t UTI  5078 cancer aetiology  419 causative organisms  1307 CNS see bacterial meningitis cranium, imaging  5814 C-​reactive protein  2202 destructive thyroiditis  2300 endocarditis, congenital heart disease  3593t, 3594 eye diseases/​disorders  6429 gastrointestinal infections  3009t, 3011, 3014t glomerulonephritis see glomerulonephritis (GN) interstitial nephritis  5037 liver disease  3174 liver transplantation complications  3104 osteomyelitis  4692 overgrowth Crohn’s disease  2935 diarrhoea  2759t small intestine bacterial overgrowth management  2883 peliosis, Bartonella infection  1268, 1271 pericarditis  3502 pneumonia, HIV/​AIDS  911 pneumonitis, HIV/​AIDS  4032 pregnancy  2682 renal transplant immunosuppression 
4892t, 4894 respiratory tract in cystic fibrosis  4153–​54 septic arthritis  4457, 4458 skin see skin infections tropical malabsorption  2922f, 2923

  Index 23 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 tropical sprue  2918 vaginosis  1603, 1604 Mycoplasma infections  1304 pelvic inflammatory disease  1622 pregnancy  2682 bacterial meningitis  6060 aetiology  6061 bacterial species  6062t antimicrobial therapy  6070, 6072t, 6073t shunt-​associated  6072 clinical features  6066 community-​acquired  6066, 6067f CSF shunts  6068 clinical investigations  6068 CSF examination  6068 lumbar puncture  6068 pre-​lumbar puncture CT  6068, 6069b, 6069f differential diagnosis  6068 epidemiology  6064 future developments  6081 genetic factors  6081 immunization  6081 new adjunctive therapies  6081 randomized clinical trials  6081 genetics  6062 management  6070 antimicrobial therapy see antimicrobial therapy complications  6075 dexamethasone management  6073 management algorithm  6069b, 6070, 6071f pathogenesis  6062, 6064f pathology  6063 post-​traumatic stress see post-​ traumatic meningitis prevention  6065 chemoprophylaxis  6066, 6073t immunization  6065 prognosis  6075 recurrent  6069 aetiology  6061 tuberculous see tuberculous meningitis (TBM) BAL see bronchoalveolar lavage (BAL) Balamuthia infection  1392f, 1393, 1394f balantidiasis  1447 aetiology  1447f, 1447, 1448f clinical features  1448 epidemiology  1448 gastrointestinal system  3010t laboratory diagnosis  1449 management  1445, 1449 pathogenesis  1448 pathology  1448 prevention  1449 transmission  3015t Bálint’s syndrome  5826, 5921 Balkan endemic nephropathy (BEN)  4959, 4961, 5052–​53 clinical features  4962 tubular proteinuria  4787 diagnosis  4962 differential diagnosis  4957t epidemiology  4961f, 4961 management  4962 pathogenesis  4961 environmental factors  4961 genetics  4961 pathology  4962 Balo’s concentric sclerosis  6039 Baltic myoclonus see Unverricht–​ Lundberg disease (Baltic myoclonus) Bangladesh health financing and MDG  174, 175f Millennium Development Goals  172 Bannayan–​Riley–​Ruvalcaba syndrome (BRRS)  6208 Barakat’s syndrome  2329 barbiturates folate deficiency  5419 mechanism of action  5871 Bardet–​Biedl syndrome  1910t, 5072t, 6358–​59 delayed puberty  2433 eye diseases/​disorders  6436 male reproductive disorders  2393t bare metal stents  3657, 3658f bariatric surgery  2096 gastrointestinal tract hormones  2869, 2869t obstructive sleep apnoea management  4056 weight control in diabetes management  2490 baricitinib  244 rheumatoid arthritis management  4437 baritosis  4233–​34 barium studies Crohn’s disease  2753 enema  2748 colon imaging  2755 small bowel imaging  2750 small intestine malrotation with/​ without volvulus  2970, 2971f swallow  2748f, 2748 bronchiectasis  4147t extrinsic oesophageal compression  2846 gastro-​oesophageal reflux disease  2830 ulcerative colitis  2942f, 2942 Barker hypothesis of the Developmental Origins of Disease  519 Barmah Forest virus  824 barogenic oesophageal rupture (Boerhaave’s syndrome)  2846 baroreceptors, systemic arterial blood pressure regulation  3269 baroreflex stimulation, hypertension management  3775 barotrauma of ascent, diving medicine  1668 barotrauma of descent, diving medicine  1667 Barrett’s oesophagus see oesophageal columnar metaplasia (Barrett’s oesophagus) barrier contraception  1627, 1632f, 2604, 2715 barrier removal, drug compliance improvement  76 Barthel Index  550, 552f, 565 Bartholin cysts  1620f, 1620 bartholinitis, Chlamydia trachomatis infection  1284 Barth’s syndrome  1958 Bartonella infection  1262 aetiology and genetics  1263, 1264f, 1265f clinical features and pathology  1264 bacillary angiomatosis  1267, 1271 bacillary peliosis  1268, 1271 bacteraemia  1268 cat-​scratch disease (CSD)  1267f, 1267, 1271 endocarditis  1268, 1271 prolonged fever  1268 trench fever  1266, 1271 diagnosis  1268, 1268t, 1269f culture  1269f, 1269 immunodetection  1269f, 1269 molecular biology  1270 serology  1270f, 1270 specimen collection  1268 endocarditis  3525t epidemiology  1265t, 1267f management  1270 antibiotic susceptibility  1270 prevention  1271 Bartonella bacilliformis infection  1272 aetiology  1272, 1273f clinical features  1275, 1276f, 1277f diagnosis  1273f, 1277 epidemiology  1273, 1274f, 1275f laboratory features  1277 management  1278 pathogenesis  1274, 1275f, 1276f prevention  1278 prognosis  1277 Bartonella henselae infection inflammatory eye disease  6430 Parinaud oculoglandular syndrome  6407–​10 Bartter’s syndrome  2188, 3799, 4754f, 4755 aetiology  2188 clinical features, calcium urinary stones  5098t Gitelman’s syndrome vs.  5117 hypo-​/​hypermagnesaemia  5118t loop of Henle  4721f, 4726 potassium disturbances  4793–​94 type I  4755 type II  4755 type III  4755 type IV  4755 type V  4755 basal cell carcinoma (BCC)  435, 5735f, 5735 incidence, change over time  414 post-​renal transplant  4899 renal transplants  5748 basal cell naevus syndrome (Gorlin’s syndrome)  458t, 465 Hedgehog (Hh) pathways  260 PTCH gene  465 basal cell papilloma/​seborrhoeic warts (seborrhoeic keratosis)  5732, 5733f basal ganglia  5940 adult-​onset disease  2113 attention  5823 cognitive domain  5823 functional anatomy  5941 function/​dysfunction  5943 gross anatomy  5940f, 5940 hyperdirect pathway  5943 lesions, paroxysmal dyskinesia  5973 oscillations  5943 pathways  5941f, 5941, 5942f propionic aciduria  1959–​60 rate model of function  5942f, 5942 thalamus  5940f basal pontine syndrome (locked-​in syndrome)  6008 baseline electrocardiogram, exercise ECG testing  3313 Basidiobolus mucormycosis  1348 basilar artery  6006, 6012f, 6013f basiliximab  405, 4888 basophils  309–​10, 5190f, 5196 allergic rhinitis  4061 Bassen–​Kornzweig syndrome  6250 Batten’s disease see ceroid lipofuscinosis (Batten’s disease); neuronal ceroid lipofuscinoses (NCLs) batteries, poisoning  1772 BBB see bundle branch block (BBB) BCAR (benign drug-​induced skin disease) see skin drug reactions BCC see basal cell carcinoma (BCC) BCG see bacillus Calmette–​Guérin (BCG) vaccine BCL-​2 family proteins  271–​72, 273f, 275 BCNU see carmustine (BCNU) BCR-​ABL inhibitors, skin drug reactions  5759 BCR-​ABL-​like acute lymphoblastic leukaemia, acute lymphoblastic leukaemia management  5275 BCR-​ABL oncoprotein, chronic myeloid leukaemia  5217f, 5217 BCR-​ABL-​positive acute lymphoblastic leukaemia, acute lymphoblastic leukaemia management  5275 BDP see beclomethasone propionate (BDP) BEACOPP chemotherapy, Hodgkin’s lymphoma management  5284t, 5285 Beau’s lines, nail disorders  5726 Becker’s muscular dystrophy (BMD)  3478, 3497, 3557t, 6279, 6342 cardiovascular abnormalities  3491t carrier manifestation  6315 clinical symptoms  6280 diagnosis  6313–​15, 6316f management  6319

24 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 antisense oligonucleotides  6281 cell management  6281 gene management  6281 novel pharmacological approaches  6281 stop-​codon read-​through  6281 utrophin modulation  6281 presentation  6315 prognosis  6316b, 6316–​17 beclomethasone propionate (BDP)  4085, 4088, 4128 bedbugs  1570, 1571f bedsores  5714 bee stings  5061 see also venomous arthropods beetles (Coleoptera)  1808f, 1808 behaviour activation  6472 Alzheimer’s disease  5841 central auditory function tests  5934 confusion assessment  6455 dementia management  6481, 6481t frontotemporal dementia  6236 health inequalities  158 hypoxanthine-​guanine transferase deficiency  2026 neurological disorders  5829 obesity management  1910 preventative care risk modification  131 risk factors, preventative medicine  128, 129t variant Creutzfeldt–​Jakob disease  6115–​16 weight management programmes  6531, 6532f behavioural variant frontotemporal dementia (bvFTD)  5844, 5845, 6482 Behçet’s disease/​syndrome  4579, 5750, 6381 aetiology  4580 classification criteria  4582b, 4582 clinical findings  4580, 4580t cardiac system  4582 dementia  5858 eye  4581, 6421f, 6422, 6426f gastrointestinal system  2795t, 3003t, 4582 heart muscle disease  3494 hepatic artery aneurysm  3168–​69 lung involvement  4205 mucocutaneous system  4580, 4581f musculoskeletal system  4581 neurological system  4581 vascular system  4581, 4582f clinical investigations  4582 diagnosis  6133 differential diagnosis  4582 multiple sclerosis  6035 epidemiology  4580 genetics  4580 management  4583t, 4584, 6381 pathogenesis  4580 pregnancy  2665 prognosis  4584 belatacept (LEA29Y)  405, 4889–​90 belching  2729 belimumab  101t, 104, 4511, 5006 Bell’s palsy facial nerve (cranial nerve VII)  6123 herpes simplex virus infection  2807 pregnancy  2647t bendroflumethiazide  2524–​25, 3766t, 5154 Benecol  2093 Bengal famine (1943)  189, 190, 190t benign drug-​induced skin disease (BCAR) see skin drug reactions benign epilepsy with centrotemporal spikes  6241 benign familial haematuria  5070 benign familial infantile seizures  6238, 6241t benign familial neonatal infantile seizures (BFNIS)  5865–​66, 6238, 6239t benign hereditary chorea  5959 benign intracranial hypertension see idiopathic intracranial hypertension (IIH) benign melanocytic lesions (melanocytic naevi/​moles/​ freckles)  1618 benign myoclonic epilepsy of infancy  6240 benign oesophageal strictures, upper gastrointestinal tract endoscopy  2743 benign pancreatic duct stricture, acute pancreatitis  3212 benign small bowel tumours, imaging  2753 benign tumours, dementia  5857 benzathine benzylpenicillin  3516, 3517–​18, 3542 benzbromarone  2023, 4489 benzene  422t, 1763 benzimidazole  1446, 1532 benzodiazepines  6470 abuse of  6491 anxiety disorders management  6504, 6505, 6505t breathlessness  636 chorea in acute rheumatic fever management  3517 colonoscopy sedation  2735–​36 critical care  3904 delirium  558 falls in elderly  583t glutaric aciduria type I management  1963 mechanism of action  5871 multiple sclerosis management  6035 pharmacodynamics in older people  573 poisoning by  1738 renal disease, effects of  5158 seizure management in acute porphyria  2051–​52 tension-​type headaches  5995 withdrawal  6492 see also lorazepam benzofurans  1748 benzoic acid  5763 benzoyl peroxide (BPO)  5705, 5765 benzyl alcohol poisoning  1763 benzylpenicillin  2684, 5163t beriberi acute pernicious  1863 Berlin patient, HIV/​AIDS  931f, 931 Bertiella infections  1525 berylliosis  4232, 4233f beryllium  422t, 4209–​10 β-​3 agonists, urinary incontinence  594 β2-​agonists acute respiratory distress syndrome management  3879 acute severe asthma management  4095 asthma management  4083, 4084t, 4086 COPD management  4126, 4127 long-​acting  4084, 4086 moderate asthma attacks  4093 poisoning by  1739 regular use vs. as-​needed  4086 safety of  4086 β-​antagonists (beta blockers) ACS management  3634 adverse reactions asthma induction  4073, 4274 erectile dysfunction  2409t poisoning  1738 aortic regurgitation management  3454 arrhythmias in hypertrophic cardiomyopathy management  3476 arrhythmogenic right ventricular cardiomyopathy management  3487 atrial fibrillation management  3418 blood pressure in aortic dissection management  3809 cardiogenic anasarca management  3405 chest pain in hypertrophic cardiomyopathy management  3476 chronic heart failure management  3414f, 3415 CKD in pregnancy  2594t dilated cardiomyopathy management  3482 Duchenne’s muscular dystrophy management  6317–​18 dyspnoea in hypertrophic cardiomyopathy management  3476 exercise ECG testing  3313 hypertension management  3766t, 3767 acute porphyria  2051 contraindications  3767t diabetes  2525 malignant hypertension  3805, 3806t hypertrophic cardiomyopathy management  3474–​75 Marfan’s syndrome management 
3556, 4650, 4681 migraine prevention  5993t multiple sclerosis management  6035 phaeochromocytoma management  3794–​95 pharmacodynamics in older people  573 postural tachycardia syndrome management  6165 pseudoxanthoma elasticum management  4685 renal disease, effects of  5155 stable angina management  3623 tachycardia management  3364 thyrotoxic periodic paralysis management  4756 ventricular tachycardia management  3382 vertigo management  5927t withdrawal syndromes  87 β-​cell failure, diabetes mellitus type 2  2479f, 2483 betaine  1982 β-​lactam antibiotics  1059, 4954, 5079t β2-​microglobulin amyloid fibrils  2228 haemodialysis-​associated amyloidosis  2224 normal blood values  6586t renal tubular proteinuria  4786 urinary/​faecal reference intervals  6587t β-​oxidation defects, primary metabolic myopathies  6338 Bethlem myopathy  6293, 6322 bevacizumab  484–​85, 502, 2455, 6207 bezafibrate  2072t BH3-​only proapoptotic proteins, apoptosis activation  272f, 272–​73 Bhanja virus  861 Bhopal disaster  4269–​70 Bhutan health financing and MDG  174 Millennium Development Goals  172 bicalutamide  501, 2393t bicarbonate (HCO3-​) adult values  6581t normal blood values  6583t reabsorption, early (S1) proximal convoluted tubule  4723 reabsorption in proximal tubule  5105 bicipital tendonitis  4412t biclonal gammopathies, monoclonal gammopathy of undetermined significance  5313 bicuspid aortic valve  3570 pregnancy  2602, 2603f bicycle ergometry  3311, 3311t, 3968 Biermer’s anaemia see acquired pernicious anaemia bilateral adrenalectomy  2343–​44, 2546 bilateral sequential single lung transplantation  4295, 4296f bilateral tonic–​clonic seizures, epilepsy  5864 bile composition-​affecting drugs  5153

  Index 25 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 formation, liver  3038f, 3038 manufacture of  3197b, 3197 physiological functions  3038t bile acids excretion and reabsorption  2061 malabsorption diarrhoea  2759t irritable bowel syndrome  2955 primary biliary cholangitis  3130f, 3130 synthesis, cholesterol  2061f, 2061 bile acid sequestrants (resins)  2074t, 2092, 5153 bile duct congenital disorders  3207 choledochal cysts  3207f, 3207, 3208f, 3208t stones, jaundice  3055 bile salt export pump (BSEP)  3192f, 3192, 3192t bile salts diarrhoea, cholecystectomy  3204 malabsorption  2878 metabolism, liver  3039 bilharzia see schistosomiasis biliary canaculi  3036, 3037t, 3196–​97 biliary colic  2769t, 3199 biliary tract anatomy  3033f, 3034 common bile duct  3033f anatomy  2723f, 3197f stones, management  3202 drainage, pancreatic ductal adenocarcinoma management  3232 imaging, jaundice  3056 self-​expandable stents  2746f, 2746 biliary tract disorders  3196 atresia, neonatal cholestasis  3191f, 3191 biliary strictures  3206 ERCP see endoscopic retrograde cholangiopancreatography (ERCP) IgG4-​related sclerosing cholangitis  3206 primary sclerosing cholangitis  3206 secondary sclerosing cholangitis  3207 clinical features  3197, 3197t cystadenoma, benign liver tumours  3190 cystic fibrosis  4153 dyspepsia, gallstones  3200 indeterminate biliary structures  3205f, 3205, 3205t obstructive jaundice  3197t, 3205 investigations  3197 imaging  3198 laboratory investigations  3197 tumour markers  3198 leaks, endoscopic retrograde cholangiography  2745 liver transplantation  3104 obstruction chronic pancreatitis  3221 chronic pancreatitis management  3226 biliary tree anatomy  3196–​97 endoscopy see endoscopy physiology  3196 bilirubin acute hepatitis  3111 adult values  6581t circulating pool  3050 congestive hepatopathy  3168 CSF pressure  5783 drug-​induced liver disease  3155 evolutionary aspects  41 metabolism, liver  3039f, 3039 physiology of  3049, 3050f primary biliary cholangitis  3135 subarachnoid haemorrhage  6024–​25 binge eating disorder classification/​diagnosis  6509b clinical features  6511 cognitive behavioural management  6532 epidemiology  6510f management  6512, 6513b biochemical analysis  6577 amyloidosis diagnosis  2230 blood gases  6583t carcinoid syndrome  2872 chylothorax  4317 complication diagnosis  6577 congenital adrenal hyperplasia management  2364 development of  6577 diagnosis  6577 diagnostic enzymes  6582t disease monitoring  6577 faecal reference intervals  6587t hormones  6583t human prion diseases  6117 immunoproteins  6586t lysosomal disease diagnosis  2135 management response  6577 metals  6586t nonalcoholic fatty liver disease  3151 organ system profiles  6582t Paget’s disease  4640 post-​test odds  6580 pre-​test odds  6580 prognosis  6577 protein-​dependent inborn errors of metabolism emergency management  1948 proteins  6586t receiver–​operator characteristic curve see receiver–​operator characteristic (ROC) curve reference intervals  6578 respiratory chain disorders  6347 routine tests  6581t screening  6578 skeletal disorders  4628 spinal cord disorders  6131–​32 tests  6578 accuracy  6578 precision  6578 sensitivity  6578 specificity  6578 therapeutic drugs  6587t trace elements  6586t tumour markers  6585t urinary reference intervals  6587t vitamins  6585t Wilson’s disease  2117 biocompatible dialysis membranes, haemodialysis  4864b, 4864 bioimpedance scanning (BIA)  523, 1916 bioinformatics  67, 70t analytical tools  68, 69t common semantic turns  68, 68t data storage  68 digital imaging  69 infectious diseases  69 oncology research  68 pharmacogenomics  69 biological disease-​modifying anti-​ rheumatic drugs  4437, 4437t biological membranes, dynamic cells  215, 216f biological pollutants, indoor air pollution  1683 biological therapies  100, 101t biosimilars  106 B-​lymphocyte stimulators  104 classification  102, 103t cytokine management  241–​42 drug-​induced interstitial pneumonitis and fibrosis  4278 future developments  106 antibody fragments  107 stratified medicine  106 immune-​mediated inflammatory disease  101t, 102, 103f cytokine targets  102 growth factor targets  102 immunogenicity  106 immunosuppressants, adverse reactions  4890 intercellular interactions  104 adhesion molecule blockers  105 costimulation blockade  104, 105f pancreatic ductal adenocarcinoma management  3233 pathogenic cell depletion  105 pregnancy  2666 psoriasis management  5626 rheumatoid arthritis management in pregnancy  2662 skin disease management  5768, 5770 systemic lupus erythematosus management  4511 therapeutic antibodies  100, 102f see also therapeutic antibodies biological valves, heart valve surgery  3670 biological weapons see bioterrorism biomarkers ACS outcomes  3630, 3631f, 3631t acute pulmonary embolism  3724 asthma pathophysiology  4070 cardiac arrest prognosis  3846 cardiogenic pulmonary oedema  3400–​1 cardiovascular biomarkers, pneumonia  4018 coronary heart disease  3613 critical care surgery  3863 interstitial lung disease in rheumatological disease  4198 left ventricular wall stress  3632 myocardial damage  3630 nosocomial pneumonia diagnosis  4025 osteoarthritis pathogenesis  4478 osteoporosis  4699 pleural mesothelioma  4363 pneumonia management  4018 stable angina  3622 biopsies adenocarcinoma/​gastro-​ oesophageal junction tumours  2843 amyloidosis diagnosis  2229 brain see brain bronchial see bronchi cancer investigations  489 cutaneous lymphoma  5740 endomyocardium see endomyocardial biopsies hereditary fructose intolerance (fructosaemia)  1999 kidney see renal biopsies lymphoproliferative disorders  5267 McLeod’s syndrome  6251 oral cancer  2806 percutaneous  4002 pancreatic ductal adenocarcinoma  3231 percutaneous lung biopsy  4002 pleural biopsy  4002 polyarteritis nodosa  4570 pyoderma gangrenosum  4603 silicosis  4229–​30 skin see skin biopsies vascular peripheral neuropathy  6192 see also endobronchial ultrasound-​ guided fine needle aspiration biopsies (EUS-​FNA); endoscopic biopsies; fine needle aspiration biopsies; percutaneous needle biopsies; transbronchial lung biopsies (TBLB) biopterin metabolism defects  1971, 1973f clinical presentation  1973 diagnosis  1973 management  1973 outcome  1973 bioresorbable stents  3659 biosimilars  106 insulins  2493 psoriasis management  5627 bioterrorism  1718 areas of uncertainty/​ controversy  1723 biological weapons, 1719 infectious and contagious diseases  1719 infectious not contagious diseases  1720 toxins  1720 clinical features  1721 decontamination  1723 differential diagnosis  1721 dissemination of  1720 early detection  1721 epidemiology  1720f, 1720 investigations  1722

26 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 ethical aspects  1723 future developments  1723 historical perspective  1719 isolation  1722 legal aspects  1723 postexposure prophylaxis  1722 prevention  1720 public education  1722 quarantine  1722 risk communication  1722 surveillance  1721 biotin (vitamin H)  1856t, 1868 biotinidase deficiency management  1965–​66 deficiency  1868 functions  1868 holocarboxylase synthetase deficiency management  1966–​67 nutritional support  1918 requirements  1868 structure  1868f biotinidase deficiency  1955f, 1965, 1966f BiPAP  3834, 6292 biphasic anaphylaxis  3856 bipolar disorder  6498 aetiology  6498 clinical features  6498, 6499f depression  6499 hypomania  6498b, 6499 mania  6498b, 6499 differential diagnosis  6499 medical comorbidities  6500 psychiatric comorbidities  6499 schizophrenia  6515 epidemiology  6498 maintenance management  6500 drug management  6500 psychological management  6498b, 6500, 6501b management  6500, 6500t acute depression  6500 acute mania  6500 antipsychotic drugs  6469 sodium valproate  6468 mania  6448 outcome  6501 pregnancy  6501 bird fancier’s lung  4247 bird poisons  1801f, 1801 Birmingham Atrial Fibrillation in the Aged (BAFTA) study  3372 Birmingham Vasculitis Activity Score (BVAS)  4554, 4554t, 4566, 4997 birth (delivery) brachial plexus traction lesions  6180–​81 cardiac disease and  2600 decisions, critical care in pregnancy  2702, 2702t HIV/​AIDS in pregnancy  2679 inflammatory bowel disease  2625 malnutrition  1883 pregnancy in diabetes mellitus  2636 premature see premature birth preventative programme effectiveness  135 timing of, pre-​eclampsia management  2586 venous thromboembolism  2612 management  2610 see also labour birth asphyxia, cerebral palsies  6365 Birt–​Hogg–​Dubé syndrome  466, 5071t chromophobe renal cell carcinoma  5140 FOLLICULIN gene  465, 466 genetics  5071 predisposition genes  461t bismuth chelate (tripotassium dicitratobismuthate), poisoning by  1739 bisoprolol  3365t, 3415–​16 bisphosphonates adverse reactions eye diseases/​disorders  6437 osteonecrosis of the jaw  4704 bone metastases management  4357, 4712 Duchenne’s muscular dystrophy management  6318 osteoporosis management  4700 CKD  4848 Paget’s disease management  4642 septic arthritis management  4460 bites  6552, 6553f nonvenomous arthropods see nonvenomous arthropods bivalirudin  3638, 5157 BK virus infection interstitial nephritis  5037 renal transplant immunosuppression  4893 UTI post-​renal transplantation  5088 black cohosh (Actaea racemosa)  203 drug interactions  205t safety  204 black piedra  1344 black urine  4783 bladder catheterization cardiogenic shock  3406 urinary incontinence  594 diary, urinary incontinence  591 bladder cancer  5136 aetiology  5136 assessment  5137 asymptomatic nonvisible haematuria  4767 clinical features  5136 epidemiology  440, 5136 artificial sweeteners  440 medicines  440 occupation  440 parasitic infections  440 tobacco  440 incidence  413t management  5139 localized muscle-​invasive disease  5138f, 5139 metastatic muscle-​invasive disease  5140, 5140t non muscle-​invasive disease  5139, 5139t programmed death-​1 blocking  483 pathogenesis  5136 prognosis  5137 staging  5137 bladder disorders abnormal emptying, UTI  5076, 5077b, 5086 multiple sclerosis  6031, 6035 spinal cord injury  6143 Blalock–​Taussig shunt, tetralogy of Fallot  3585f, 3585, 3585t Blastocystis infection  1449 aetiology  1450 biology  1450f, 1450 clinical features  1451 diagnosis  1450 epidemiology  1450 management  1451 pathogenicity evidence  1451 blastomycosis  1352 liver disease  3175 Blau’s syndrome  2208t, 2214, 2215f bleaches  1772, 5679 bleeding see haemorrhage bleeding tendencies  5509 anaemia causes  5363 clinical assessment  5510 clinical examination  5511 general aspects  5512 mucosa  5512 musculoskeletal system  5512 skin  5511 splenomegaly  5512 haemolysis  5385 history taking  5510 bleeding patterns  5510 dental extraction  5511 drug history  5511 epistaxis  5511 family history  5511 gingival bleeding  5511 haemostatic capacity assessment  5510 menorrhagia  5511 purpura  5510 severity  5510 surgery  5511 unusual sites  5511 investigations  5512, 5517 acquired haemophilia  5519 acquired von Willebrand’s syndrome  5519 activated partial thromboplastin time  5513 anatomical imaging  5518 antiplatelet drugs  5518 bleeding time  5517 blood count  5513 blood film  5513 critically ill patients  5518 dilutional coagulopathy  5518 direct oral anticoagulants  5518 disseminated intravascular coagulation  5518 drug-​induced bleeding  5518 factor assays  5516f, 5516, 5517t fibrinogen level  5516 haemostasis assessment  5513, 5514t haemostasis global tests  5517 hyperfibrinolysis  5520 laboratory tests  5512 liver disease  5519 mixing studies  5516 neonatal bleeding  5520 platelet function analysis  5516 prothrombin time  5513 renal disease  5519 surgical bleeding  5518 thrombin time  5516 thrombocytopenia  5519 vitamin K antagonists  5518 von Willebrand protein levels  5519 iron deficiency
investigation  5388 management  5520 acute bleeding  5520 nonacute bleeding  5520 see also coagulation disorders bleeding time acquired coagulation disorders  5548t bleeding tendencies  5517 bleomycin adverse reactions, nodular regenerative hyperplasia  3164 drug-​induced alveolar disease  4278 drug-​induced pulmonary vasculature  4280 skin disease management  5768 bleomycin/​etoposide/​cisplatin (BEP)  5147 blepharitis  6408t, 6411, 6413f, 6414f blinatumomab  479 blindness causes  6400 age-​specific macular degeneration  6406f, 6407, 6408t, 6412f cataract  6400, 6401t diabetic retinopathy  6404, 6408t, 6411f glaucoma  6404, 6406f uncorrected refractive error  6407 epidemiology  6400, 6406f falls in elderly  581 giant cell arteritis  6381 gradual vision loss  6400t mitochondrial DNA point mutations  6346 paraneoplastic neurological syndromes  6390 subacute vision loss  6400t vitamin A deficiency  1856, 1888 see also vision disorders Blomstrand’s disease, hypoparathyroidism  2329 blood cellular components  5173t CSF  5783 development  5170 high terrestrial altitude acclimatization  1703 HIV/​AIDS in LMICs  935 blood-​borne infections, travel and expedition medicine  716 blood–​brain barrier  6063, 6070 blood count bleeding tendencies  5513 haematological malignancies  5182 systemic lupus erythematosus  4509

  Index 27 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 blood cultures acute osteomyelitis  4693 autosomal dominant polycystic kidney disease  5087–​88 endocarditis  3524, 3525t pneumonia management response  4020 blood diseases/​disorders  5169 folate deficiency  5419 blood disorders malignancies, oral manifestations  2824 blood films bleeding tendencies  5513 haematological malignancies  5182 lysosomal disease diagnosis  2135 blood gases biochemical analysis  6583t normal values  6583t blood gas tension  4283 gas transport in the tissues  4285, 4285t hypercapnia  4284 alveolar hypoventilation  4284f, 4284 combined effects  4284 ventilation/​perfusion abnormality  4284 hypoxaemia  4283, 4283t alveolar hypoventilation  4284 anatomical shunting  4284 diffusion limitation  4284 ventilation/​perfusion mismatch  4283f, 4283 pulmonary gas exchange  4283 special circumstances  4284 blood glucose concentration/​ measurement diabetes mellitus  2467, 2501 sports medicine  6569–​70 diabetes mellitus type 2  2484 gender assessment in DSD  2446–​47 hypoglycaemia in diabetes mellitus  2532 phaeochromocytomas  3793 status epilepticus  5878 viral infections of CNS  6091–​92 blood group systems  5566, 5567t, 5568f ABO system see ABO system compatibility in liver transplantation  3102 Rh system  5566 blood natriuretic peptide (BNP)  3282, 3283f, 3283t blood oxygen level-​dependent magnetic resonance imaging (BOLD-​MRI)  4801, 5048 blood pressure measurement monitors  3756 blood pressure (BP) acute aortic syndrome  3677 ageing  543 cardiorenal syndrome  3423 chronic heart failure  3420 chronic tubulointerstitial nephritis agricultural communities  4964 coronary heart disease risk factors  3607f, 3607, 3608f diabetic nephropathy  4976, 4983, 4984 drop, spinal cord injury  6140–​41 epidemiology trials  64f, 64, 65f hypertension  3740, 3741f, 3755b, 3755, 3756t management CKD management  4840, 4843f diabetic nephropathy prevention  4981 liver disease in pregnancy  2620–​21 melatonin  2558 measurement scleroderma management in pregnancy  2666 pregnancy  2563, 2578, 2597–​98 salt in diet  1895 stroke and  1895 urinary stones  5095f, 5095 vasopressin release  2279 blood products acute myeloid leukaemia  5210 HIV/​AIDS transmission  930 LMICs  935 blood substitutes, blood transfusion  5577 blood-​sucking flies (Diptera)  1569, 1569t, 1570f, 1571f blood tests acute aortic syndrome  3678 acute mesenteric ischaemia  3000 acute pulmonary embolism  3724 autoimmune encephalopathy with NMDAR antibodies  6395 autoimmune limbic encephalitis with VGKC-​complex antibodies  6393 bronchiolitis obliterans  4187 chronic heart failure  3420 cryptogenic organizing pneumonia  4189 dementia  6479 diabetic ketoacidosis  2506–​7 diffuse parenchymal lung disease diagnosis  4173 dyslipidaemia diagnosis  2088 hepatic encephalopathy  3085 idiopathic pulmonary fibrosis  4181 iron status evaluation  5374 liver failure investigations  3095, 3096t low back pain diagnosis  4409 malabsorption  2877 muscle disorders  6308 osteoarthritis  4478 pancreatic ductal adenocarcinoma investigations  3230 pelvic inflammatory disease management  1624 primary intracerebral haemorrhage  6023 primary thyroid epithelial tumours  2305 PSC  3138 pulmonary arterial hypertension investigations  3700 rheumatological diseases see rheumatological diseases septic arthritis  4458 Sjögren’s syndrome  4534 spinal cord disorders  6131–​32 syncope  5900 systemic lupus erythematosus  4509 blood transfusions  5563 acquired aplastic anaemia management  5343 acute respiratory distress syndrome  3879 anaemia of inflammation management  5406 antibodies  5567 alloantibodies  5567 autoantibodies  5568 compatibility testing  5568 autologous  5577 collection of  5564 complications  5564, 5571, 5571t, 5572t acute intravascular haemolytic reaction  5571 acute lung injury  5573 acute pain transfusion reaction  5574 allergic reactions  5572 associated circulatory overload  5573 associated dyspnoea  5573 delayed extravascular haemolytic reactions  5571 febrile non haemolytic reactions  5572 hypotension transfusion reaction  5574 post-​transfusion purpura  5574 septic reactions  5572 transfusion-​associated circulatory overload  5573 transfusion-​associated dyspnoea  5573 transfusion-​associated graft-​ versus-​host disease  5573 transfusion malaria  1407 transfusion-​related acute lung injury  5573 transmitted hepatitis  3111 component alternatives  5577 autologous transfusion  5577 blood substitutes  5577 growth factors  5577 component use  5563, 5566t, 5568 cryoprecipitate  5570 granulocytes  5571 plasma  5570 plasma derivatives  5570 platelets  5565f, 5569 red blood cells  5569 disease transmission  5574, 5574t gastrointestinal infections transmission  3016 haematopoietic stem cell transplantation management  5586 iron overload  5392 molecular testing  5577 Neisseria meningitidis infection management  1023 peptic ulcer bleeding management  2857 pretransfusion testing  5565f, 5565 processing  5564, 5565f special blood products  5575 cytomegalovirus-​safe products  5576 frozen products  5576 irradiation  5575 leucoreduction  5575 pathogen reduction  5576 volume reduction  5576 washed blood products  5576 variceal bleeding  3072 blood vessels adventitia  3242, 3252 angiogenesis  3251 cell growth  3251 cellular adhesion  3250 cellular constituents  3242 chest radiography  3980 disorders of cyanotic heart disease  3564 Fabry’s disease  2144 skin see skin diseases/​disorders endothelium  3242, 3243f anatomy  3243f, 3243 angiogenesis  3251f, 3251–​52 development  3242–​43 metabolism  3252 microvesicles  3252 platelet inhibition  3250 signal detection  3243 transport  3252 vascular damage and repair  3243, 3244f intima  3242 media  3242 pericytes  3244f, 3244 perivascular adipose tissue  3252 proinflammatory cytokines  3251 vascular smooth muscle cells  3245 vasoconstriction see vasoconstrictor drugs blood vessel walls  5491f, 5491 adventitia  5494 endothelial cells  5492 anticoagulant properties  5492, 5492t procoagulant properties  5492t, 5493f, 5493 receptors  5493, 5493t vascular tone  5492, 5492t extracellular matrix  5493, 5494t smooth muscle cells  5494 blood volume anaemia in pregnancy  2687 medication in pregnancy  2707 systemic arterial blood pressure regulation  3269f, 3269 bloody diarrhoea (dysentery) acute  3018 Bloom’s syndrome  458t, 467, 5689t BLM gene  467 cancer susceptibility  415 blue rubber bleb naevus syndrome  3006t, 5718 blue urine  4783 BMI see body mass index (BMI) BMPs see bone morphogenetic proteins (BMPs) BNP see brain natriuretic peptide (BNP) BOADICEA model  467 bocavirus infection  725t, 733, 953 Bochdalek posterior diaphragmatic hernia  4374

28 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 BODE index, COPD  4121, 4121t body lice  1575 body mass index (BMI) acute fatty liver of pregnancy  2622 artificial nutrition assessment  1916 COPD  4116 hypertension  3744 malabsorption  2877 obesity definition  6529f, 6531 obesity diagnosis  1903, 1908 osteoporosis clinical risk factors  4699 pregnancy  2568 pregnancy outcomes  2576 primary spontaneous pneumothorax  4322 renal transplant recipients  4882 body plethysmography  3957–​58, 4117 body temperature, C-​reactive protein  2205 Bolivian haemorrhagic fever see arenaviruses bolus consistency, dysphagia management  2842 bombesin  2866 bone biochemical measures of turnover  4626, 4626t biopsies osteomalacia/​rickets  4635 skeletal disorders  4631 calcium balance  4624f, 4624 cells  4618, 4639f collagen  4622 formation  4620 healing, spinal cord injury  6137 mass of  4621 change  4697f, 4697 see also osteoporosis mineralization  4624 noncollagen proteins  4622 pain CKD in vs., 4830 osteomalacia/​rickets  4634 skeletal disorders  4627 phosphorus balance  4624f, 4624 physiology  4616 remodelling  4698 remodelling cycle  4618–​19 resorption  4618, 4620, 4699 shape/​alignment in osteoarthritis  4474 sport and exercise medicine  6567 structure  4618 system profiles  6582t bone age  2425, 2432 bone cancer  4709 chondrosarcoma  4710, 4711f classification  4709t epidemiology  433, 434f Ewing sarcoma  4710, 4712f extrapulmonary tuberculosis  4028 investigation  4709 metastases  4712f, 4712 carcinoid syndrome management  2874 local disease vs.  4710 osteosarcoma see osteosarcoma presentation  4709 staging of  4710 warning signs  4393t bone disease  4393, 4393t actinomycoses  1174 anaerobic bacterial infections  1058 bone cancer see bone cancer cancer see bone cancer cystic fibrosis  4163 fractures, 4627 osteochondritis dissecans see osteochondritis dissecans osteochondrosis see osteochondrosis osteomyelitis see osteomyelitis osteonecrosis see osteonecrosis osteoporosis see osteoporosis Pseudomonas aeruginosa infection  1043 tuberculosis  1137 bone marrow aspirate  5341, 5342f, 5406 B cell development  331 cytogenetics, acquired aplastic anaemia  5342 decreased platelet production disorders  5530 examination, haematological malignancies  5183 haematopoiesis in adults  5174 haematopoietic stem cell transplantation  5582 megaloblastic anaemia  5420f, 5420 myelodysplastic syndromes  5202 transplantation  5172 acute myeloid leukaemia management  5209 Gaucher’s disease type 1 management  2143 haemorrhagic cystitis, human polyomaviruses  884 human cytomegalovirus infection  747 metachromatic leucodystrophy management  6212 mitochondrial myopathies  6349 mucopolysaccharidoses management  2148 paroxysmal nocturnal haemoglobinuria management  5349f, 5352 purine nucleoside phosphorylase deficiency  2029 bone marrow failure (BMF) disorders  5325, 5336, 5337f anaemia of inflammation vs.  5405 erythroid cell lineage effects  5346 see also pure red-​cell aplasia future development  5348 inherited syndromes  5325, 5325b, 5326t congenital dyserythropoietic anaemia see congenital dyserythropoietic anaemia congenital thrombocytopenias see congenital thrombocytopenias Diamond–​Blackfan anaemia see Diamond–​Blackfan anaemia dyskeratosis congenita see dyskeratosis congenita Fanconi’s anaemia see Fanconi’s anaemia severe congenital neutropenia (SCN) see severe congenital neutropenia (SCN) Shwachman–​Diamond syndrome see Shwachman–​ Diamond syndrome management, eculizumab  5353 paroxysmal nocturnal haemoglobinuria see paroxysmal nocturnal haemoglobinuria (PNH) see also aplastic anaemia; pure red cell aplasia bone mineral density (BMD)  586, 4698 bone morphogenetic proteins (BMPs)  243, 262, 3697, 4616–​18 borderline lepromatous leprosy (BL)  1158, 1159f borderline leprosy (BB)  1158, 1159f borderline tuberculoid leprosy (BT)  1158f, 1158, 1159f Bordetella infection  1073 aetiology  1073 clinical features  1074 clinical investigations  1075 diagnosis  1075 differential diagnosis  1074 epidemiology  1073 morbidity  1073 mortality  1073 prevention  1074 management  1075, 1075t pathogenesis/​pathology  1074 prognosis  1076 Bornholm disease (epidemic pleurodynia)  791, 3950 Borrelia burgdorferi infection see Lyme borreliosis Borrelia recurrens infection see relapsing fevers bortezomib  502–​3 adverse reactions, neuropathies  6188 AL amyloidosis management  2232 monoclonal Ig-​dependent diseases management  5021 renal disease in myeloma  5020 bosentan  2713, 3706, 5155 Bosniak classification, renal cancer  5141, 5141t botulinum antitoxin  3021 botulinum toxin glutaric aciduria type I management  1963 headache prevention  6001 hemifacial spasm management  6124 hyperhidrosis management  5703 idiopathic achalasia management  2839 migraine prevention  5993t neuronal ceroid fucinoses management  2152 Parkinson’s disease  607–​8 tension-​type headaches  5995 botulism  1121 diagnosis  1122 history  1121 infant botulism  1123 management  1122 occurrence  1121 pathogenesis  1121 physical examination  1122 toxin  1121 wound botulism  1123 Bourbon virus  956 Bourneville’s disease see tuberous sclerosis complex (Bourneville’s disease) bovine spongiform encephalopathy (BSE)  6110, 6115 Bowditch effect  3272, 3274 bowel resection  2911 acute phase management  2913 anatomy  2913 nutritional support  2913, 2913t sepsis  2913 surgery  2913 aetiology  2912 chronic phase management  2914 feeding and adaptation  2914f, 2914, 2914t long-​term plans  2914f, 2914, 2915t socialization  2914 long-​term complications  2915, 2915t management  2913 pathophysiology  2912 electrolyte depletion  2912f, 2912 gut motility  2912 hormones  2912 micronutrients  2913 secretion  2912 vitamins  2913 water depletion  2912f, 2912 surgery  2915 intestinal function optimization  2915 transplantation  2915 Bowenoid papulosis  1618 Bowen’s disease  5734 BPO see benzoyl peroxide (BPO) brachytherapy  499t, 503, 3661 bradycardias  3353 acute presentation  6598 aetiology  3353 cardiac syncope  3289t causes  3354 asystole  3356 atrioventricular conduction disorders  3354 see also atrioventricular block neurocardiogenic syncope  3354 sinoatrial disease  3354f, 3354, 3355f complete transposition of the great arteries  3582 management  3353 acute management  3353, 3354t pacemaker management  3356 pacemaker management see pacemakers raised intracranial pressure  3895 symptoms  3352 syncope  3289 vasovagal syncope  5897 bradykinesia, Parkinson’s disease  602, 5949

  Index 29 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 BRAF gene malignant melanoma  453–​54, 5738 non-​small cell lung cancer  4342 papillary thyroid carcinoma  2302–​3 brain abscesses, traumatic brain injury  6046 activity monitoring critical care  3904 sedatives  3904 acute-​on-​chronic liver failure  3094 anoxic damage  6369 atrophy, cerebrotendinous xanthomatosis  6221–​22 autopsy methods  6559 biopsies human prion diseases  6118 toxoplasmosis in HIV/​ AIDS  6103 cancer  414 optic chiasm disorders  5919 death  5908 brainstem-​auditory evoked potentials  5790 definition  3915t frailty in ageing  527 higher functions see higher brain function hypertension pathophysiology  3750 imaging cardiac arrest  3845 Wilson’s disease  2118 lung cancer metastases  4346f, 4346 neurological disease see paraneoplastic neurological syndromes (PNS) oxygen deprivation  6369 postmortem examinations  6559 reductive adaptation  1885 statin adverse reactions  2074t, 2092 support, liver failure management  3098 traumatic injury see traumatic brain injury weight in Alzheimer’s
disease  5836 see also central nervous system (CNS) brain natriuretic peptide (BNP)  2221, 3748, 3863, 6583t brainstem auditory evoked potentials evoked potentials  5790 hearing disorders  5934f, 5934 neuropsychiatric adult peroxisomal disorders  2162 autonomic nervous system  6150–​51 circulation  6006 coma  5903f, 5904 encephalitis  6390 glioma imaging  5813 multiple sclerosis  6031 reflexes  3846, 6542 coma  5907 reticular activating complex  5945 reticular formation nuclei  5823 syndromes see neurological disorders brainstem death  5908 actions following  5909 ancillary tests  5909, 5910f children  5909 conduct of tests  5909b, 5909 diagnostic criteria  5908 prerequisites  5908 branched-​chain amino acid metabolism disorders  1949t, 1954 3-​hydroxyisobutyryl-​CoA hydrolase deficiency  1949t, 1961 isovaleric aciduria (isovaleryl-​CoA deficiency)  1945b, 1949t, 1955f, 1956 malonic aciduria  1962 maple syrup urine disease see maple syrup urine disease 2-​methyl-​3-​hydroxybutyryl-​ CoA dehydrogenase deficiency  1949t, 1959 3-​methylcrotonylglycinuria  1949t, 1955f, 1957 3-​methylglutaconic acidosis  1957 methylmalonic aciduria  1949t, 1955f, 1960 primary 3-​methylglutaconic acidosis  1957 3-​methylglutaconic aciduria type  1957 propionic aciduria  1949t, 1955f, 1959, 1960f secondary 3-​methylglutaconic acidosis  1958 DNAJC19 defect (dilated cardiomyopathy with ataxia (DCMA) syndrome/​3-​ methylglutaconic aciduria type V)  1949t, 1958 3-​methylglutaconic aciduria type III  1958 3-​methylglutaconic aciduria type IV  1949t, 1958 OAP3 defect (Costeff’s syndrome/​3-​ methylglutaconic aciduria type III)  1949t TAZ defect (Barth’s syndrome/​
3-​methylglutaconic aciduria type II)  1949t, 1958 short-​chain enoyl-​CoA hydratase deficiency  1961 branched-​chain amino acids (BCAAs)  1849–​50, 3087 branch retinal artery occlusion  6413, 6414f, 6415f Braunwald classification, ACS  3628t, 3629–​30 Brazil  430–​31, 4228 BRCA1 gene breast cancer predisposition  133t, 462 colorectal cancer  2988–​89 DNA sequencing  450 ovarian cancer predisposition  463 BRCA2 gene breast cancer predisposition  133t, 462 coding of  447 DNA sequencing  450 Fanconi’s anaemia  467 melanoma predisposition  463 ovarian cancer predisposition  463 prostate cancer  5143 breakthrough pain  632 breast cancer adult screening  149t aetiology  424 age-​related incidence  415 carcinogenesis  459 cutaneous metastases  5741 diagnosis  505 epidemiology  435, 436f genetics  462 BRCA1 gene  462 BRCA2 gene  462 CDIII gene  462 genome-​wide association studies  224t predisposition  461t TP53 gene  462 incidence  413t migrant groups  414t management see breast cancer management paraneoplastic cerebellar degeneration  6388 paraneoplastic neurological syndromes  6386 pregnancy  2699 preventative medicine  133t prognosis  505–​6 screening  505 Breast Cancer Linkage Consortium  460–​62 breast cancer management  505 adjuvant management  506 chemotherapy  506 endocrine management  506 HER2-​positive breast cancer  505–​6 radiotherapy  506 metastatic disease  507 chemotherapy  507 endocrine management  507 neoadjuvant systemic management  507 personalized management  453t surgery  506 breast disease, benign  2406 breast inflammation  2407 breast pain (mastalgia)  2407 congenital abnormalities  2406 development abnormalities  2406 benign cystic change  2406 fibroadenomas  2406f, 2406 macrocysts  2407 diabetic mastopathy (lymphocytic lobulitis)  2407 fat necrosis  2407 fibromatosis  2407 hamartoma  2407 male breast  2408 nipple areolar complex  2407 nipple discharge  2407f, 2407 phyllodes tumour  2407 breast disorders benign disease see breast disease, benign cancer see breast cancer inflammation  2407 pain (mastalgia)  2407 breastfeeding ACE inhibitors contraindications  3414 adverse drug reactions  91, 92t anticonvulsants  5877 critical care in pregnancy  2702 diabetes mellitus and  2636 epilepsy management in  2643 hypoglycaemia in diabetes mellitus  2533 medications in  2709 promotion of  134t see also lactation breathing mechanics, respiratory function tests  3957 pattern in respiratory disease  3951 sleep, during  4049f, 4049 heart failure  4050 regulation  4050, 4051f REM sleep  4050 respiratory muscles  4050, 4051f breathlessness (dyspnoea)  3280f, 3280 causes  3281, 3281t, 3948 acute pulmonary embolism  3718–​19, 3724 airways disease  3281, 3283 asthma  3948 carcinoid syndrome  2871 chronic thromboembolic pulmonary hypertension  3708 COPD  4113 Eisenmenger’s syndrome  3565 hepatopulmonary syndrome  3070 Langerhans cell histiocytosis  4256 left ventricular failure  3277t, 3281 lung cancer  4344 metastatic pleural malignancy  4366 preserved ventricular function with  3283 pulmonary arterial hypertension  3696t, 3699 pulmonary embolism  3281, 3283 respiratory disease  3947, 3948t scoliosis  4331 classification  3281t management hypertrophic cardiomyopathy  3476 palliative care  634t, 635 normal pregnancy  2578 pregnancy  2615 time course  3281 breath sounds, respiratory disease  3954 breath tests malabsorption  2878 small intestine bacterial overgrowth  2882, 2882t brief counselling  6472

30 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 Bristol Stool Chart  598b, 598f, 598, 2759–​61, 2762f British and American Thyroid Association  2306, 2307t British Heart Foundation  58–​59, 178–​79 British Hypertension Society (BHS)  3755b, 3755, 3772, 3773f, 4984 British Medical Association (BMA)  156, 156t British Medical Council (BMC)  185, 6071f, 6081 British National Formulary (BNF)  73, 92 British Society for Allergy and Clinical Immunology  3858 British Society for Rheumatology  4587 British Society of Antimicrobial Chemotherapy  3530 British Society of Gastroenterology  2741, 3123 British Society of Rehabilitation Medicine  6043 British Thoracic Society (BTS) acute exacerbations of COPD  4138–​39 asthma management  4081, 4082f, 4083 COPD  4103 diffuse parenchymal lung diseases  4167 pneumothorax management  4322–​23 tuberculous meningitis management  6079 British United Provident Association (BUPA)  3862, 3862t Brittle Cornea Syndrome see Ehlers–​ Danlos syndrome (EDS) brittle diabetes  2485t, 2499 brivaracetam  5873t, 5875 broadband UVB  5625, 5767 broad-​complex tachycardias  3361, 3362f broad-​spectrum antibiotics  690, 2883 Broca’s aphasia  5824 brodalumab  104, 4090 bromhidrosis  5700 bromocriptine  2498 aromatic L-​amino acid decarboxylase deficiency management  1977 drug-​induced pleural disease  4280 idiopathic oedema of women management  3824–​25 Parkinson’s disease management  5953 peripartum myocarditis  3463 prolactinoma management  2270–​71 bronchi  3939, 3940, 3941f adenomas  4358 biopsies bronchoscopy  3995 chronic bronchitis  4105–​6, 4106t carcinoids  4358 carcinoma  431 cartilage rings  3943 chest radiography  3980 iron loss  5384 mainstem branching angles  3940 stent placement  3973, 3974f bronchial arteriography, thoracic imaging  3978, 3980f bronchial brushings, bronchoscopy  3995 bronchial hyper-​responsiveness HIV/​AIDS  4038 sport and exercise medicine  6568 bronchiectasis  4142 aetiology  4143, 4143t associated conditions  4145 cystic fibrosis  4147 HIV/​AIDS  4038 rheumatoid arthritis  4194 ulcerative colitis  4145 clinical features  4145 cough  3949 examination  4146 history  4145 complications  4150 definition  4142 differential diagnosis, COPD  4122t epidemiology  4142 future work  4150 idiopathic  4142 investigations and diagnosis  4146, 4147t cause determination  4147, 4147t chest radiography  3990, 3991f disease state determination  4146, 4146t imaging  4146f, 4146 management  4147b, 4147 anti-​inflammatory management  4148 antimicrobial therapy  4148, 4149f bronchodilators  4148 inhaled antibiotics  4148 lung transplants  4150 macrolides  4148 monitoring  4149 sputum clearance  4147, 4148t surgery  4149 pathogenesis  4143, 4144f developmental defects  4143 excessive immune response  4144f, 4144 immune deficiency  4144 infections  4143, 4145 mechanical obstruction  4145f, 4145 mucociliary clearance deficiency  4143, 4144 toxic insult  4145 pathology  4143 microscopic features  4143 prognosis  4150 bronchioles  3940, 3941f, 4185 terminal see terminal bronchioles bronchiolitis obliterans  4186 causes  4186t clinical features  4186, 4186t differential diagnosis  4187 histopathology  4186, 4187f investigations  4186, 4187f management  4187 rheumatoid arthritis  4194 see also cryptogenic organizing pneumonia; follicular bronchiolitis bronchiolitis obliterans syndrome (BOS)  4300–​1, 4301t bronchiolitis, severe constrictive  4270f, 4270 bronchiolitis/​small airways disease, COPD pathology  4107, 4108f bronchitis, chronic  4080, 4105, 4106f, 4106t bronchoalveolar lavage (BAL) bronchoscopy  3997, 3997t diffuse alveolar haemorrhage  4235 diffuse parenchymal lung disease diagnosis  4174 hypersensitivity pneumonitis  4250, 4252 idiopathic pulmonary fibrosis  4181 interstitial lung disease in rheumatological disease  4198 neutrophils, interstitial lung disease in rheumatological disease  4198 nosocomial pneumonia diagnosis  4025 pulmonary alveolar proteinosis  4260 sarcoidosis  4209, 4210, 4214, 4218 bronchodilators acute asthma management  4094 acute exacerbations of COPD  4139 bronchiectasis management  4148 COPD management  4126, 4127f, 4127 cystic fibrosis  4160 renal disease, effects of  5158 bronchogenic cysts  4373f, 4373 bronchoscopic lung volume reduction  4133 bronchoscopy  3993 contraindications  3993 diagnostic role  3998 diffuse lung disease  3997t, 3998 lung cancer  3998, 4351 mediastinal tumours and cysts  4370 respiratory infection  3999 equipment  3993 disinfection  3994 fibreoptic, 3870, 3875, 4203 indications  3993, 3994t patient preparation  3994, 3995b Pneumocystis jiroveci pneumonia  1373 procedure  3995, 3996f techniques  3995 bronchial biopsies  3995 bronchial brushings  3995 bronchial washing  3995 bronchoalveolar lavage  3997, 3997t endobronchial ultrasound-​ guided transbronchial needle aspiration  3998f, 3998 fluorescence bronchoscopy  3997 magnetic navigation  3998 narrow band imaging  3997 radial ultrasound  3998 transbronchial fine needle aspiration  3996 transbronchial lung biopsy  3997 therapeutic role  4000 adenocarcinoma/​gastro-​ oesophageal junction tumours  2843 ANCA-​associated vasculitis  4562 asthma  4000f, 4001 bronchiectasis  4147t diffuse alveolar haemorrhage  4235 emphysema  4000f, 4000 lung cancer  4000 nosocomial pneumonia  4025 post-​lung transplantation management  4300 pulmonary Kaposi’s sarcoma  4037f, 4037 broom (Cytisus scoparius)  204, 205t brown urine  4783 brucellosis  1102 clinical features  1103, 1104f, 1104t, 1105t cardiac involvement  1105, 1107f genitourinary tract  1105 neurologic complications  1105 osteoarticular complications  1104 sacroiliitis  1105 vertebral osteomyelitis  1104–​5, 1106f diagnosis  1107 endocarditis  3525t epidemiology  1103 inflammatory eye disease  6430 liver disease  3174, 3175t management  1107 pathogenesis  1103 prevention  1108 Bruce protocol, exercise ECG testing  3310 Brugada’s syndrome  3387f, 3387, 3387t, 5900 Brugia malayi infection chyluria  5056 filarial nephropathy  5056 geographical distribution  1489, 1490 tropical eosinophilia  4239 vectors  1489 see also lymphatic filariasis Brugia timori infection  1490 see also lymphatic filariasis B-​type natriuretic peptide (BNP)  3270, 3614 buccal drug formulations  74 Budd–​Chiari syndrome  3166 acute  3166 causes  3166t chronic  3166–​67 clinical features  3166

  Index 31 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 diagnosis  3167f, 3167, 3168f management  3167 prognosis  3167 subacute  3166–​67 budesonide  3123, 3134t, 4084–​85 Buerger’s disease see thromboangiitis obliterans (Buerger’s disease) bufavirus  953 bulimia nervosa classification/​diagnosis  6509b clinical features  6510 detection and diagnosis  6511 epidemiology  6510f, 6510 multiple sclerosis  6032 outcome  6513 bullous ichthyosiform erythroderma (epidermolytic hyperkeratosis)  5606 bullous pemphigoid  5612, 5613t, 5615f bumetanide  3414, 5154, 5161 bundle branch block (BBB)  3302, 3355 bundle of His  3264–​65, 3302 Bunyamwera virus  855 Bunyaviridae  852 Hantavirus see Hantavirus Nairovirus  857 Crimean–​Congo haemorrhagic fever virus  857, 859f novel human viruses  955 orthobunyavirus  854 Bunyamwera virus  855 California encephalitis virus  855 Inkoo virus  855 Jamestown Canyon virus  855 oropouche virus  856 snowshoe hare virus  855 Tahyna virus  855 phlebovirus  859 Rift Valley fever virus see Rift Valley fever virus sandfly fever Naples virus  859 sandfly fever Sicilian virus  859 severe fever with thrombocytopenia syndrome virus  860 heartland virus  861 taxonomy  852, 853t trivial infections  854t unassigned viruses  861 Bhanja virus  861 Bwamba virus  861 Nyando virus  861 Tataguine virus  861 Wanowrie virus  861 vectors  852 viral structure  854f bupropion  1911, 4125, 6535 Burden of Lung Disease study, COPD  4101, 4102f Burkholderia cepacia infection, cystic fibrosis  4157, 4158 Burkholderia mallei infection (glanders)  1080 Burkholderia pseudomallei infection see melioidosis Burkitt’s lymphoma  442, 5299 aetiology  2893 clinical presentation  2894 endemic (African)  759 epidemiology  2892 Epstein–​Barr virus infection  759, 760 histomorphological features  2895t, 2897, 2898f HIV/​AIDS  760 immunohistochemistry  2898f, 2898, 2901t incidence  413 management  2901 pathogenesis  2894 prognosis  2901 burns acute toxic injury to respiratory tract  4268 artificial nutrition support  1923 electrical injuries  1699 lightning  1698 skin  5593 Buruli ulcers  1167, 5697 aetiology  1167 clinical features  1168 disseminated disease  1169 localized disease  1168f, 1168 differential diagnosis  1169 epidemiology  1168 laboratory diagnosis  1169 management  1169 pathogenesis  1168 pathology  1169 prevention  1169 socioeconomic impact  1169 transmission  1168 busulfan  421t, 3164, 4278 butterflies (Lepidoptera)  1808f, 1808 butterfly rash, systemic lupus erythematosus  4506f, 4506 N-​butyldeoxynojirimycin (miglustat/​ Zavesca)  2140, 2150 butyrophenones  2409t, 6515t BVAS see Birmingham Vasculitis Activity Score (BVAS) Bwamba virus  861 C1 inhibitor assays of  323t normal blood values  6586t primary immunodeficiencies  339t C1 inhibitor deficiency  319, 372, 2240–​41 aetiology  319 antibodies to  319 clinical features  321 diagnosis  321 management  321 pathogenesis  319 see also hereditary angio-​oedema (HAE) C1q  316, 317f, 320t, 4503 C1r  317f, 320t C1s  317f, 320t C2  317f, 318, 320t, 339t C3  318–​19, 320t, 323t, 6586t C3a  316f, 317f, 398 C3b  277, 316f, 317, 318f, 398 C3 convertase  316f C3 deposition, mesangial proliferative glomerulonephritis  4934 C3 glomerulonephritis (C3GN)  321, 4939–​40, 5024 C3 nephritic factor, assays of  323, 323t C4 classical complement pathway  317f deficiency  320t lectin complement pathway  317f level measures  323t normal blood values  6586t primary immunodeficiencies  339t C4b2a  317f, 398 C5a  316f, 318, 398 C5b  316f, 318f C5 convertase  316f C6  318f, 318, 320t C7  318f, 318, 320t C8  318f, 318, 320t C9  318f, 318, 320t CA 19-​9 biliary disease  3198 cancer diagnosis  489 cholangiocarcinoma  3184 normal blood values  6585t pancreatic ductal adenocarcinoma  3230–​31 CA 125  489, 6585t cabergoline acromegaly management  2267–​68 Cushing’s syndrome management  2346 drug-​induced pleural disease  4280 ectopic ACTH production  2347 Parkinson’s disease management  5953 prolactinoma management  2270–​71 cachexia  637, 3412t cadaveric islet cell transplantation  289 cadmium associated bone disorders  4667 cancer aetiology  422t chronic tubulointerstitial nephritis  4970 normal blood values  6586t poisoning  1752 caeruloplasmin  1872, 3195, 6586t Caesarean section  2612, 2662, 2698 caffeine consumption  2581, 3765 CAGE questionnaire  6450b, 6450 calamine  5763 calcific arteriography, renal disease  5748 calcineurin inhibitors adverse reactions  4890, 4890t hyperkalaemia  4761 renal disease  5010–​11 CKD in pregnancy  2594t cutaneous lupus erythematosus management  5657 focal segmental glomerulosclerosis management  4926–​27 frequently-​relapsing minimal-​change nephrotic syndrome management  4922 immunosuppression in transplantation  402 membranous nephropathy management  4932 minimal-​change nephrotic syndrome management  4922 non proliferative lupus nephritis class I/​II management  5004 post-​lung transplantation  4299 postoperative renal transplantation management  5162t psoriasis management  5625 skin disease management  5764 transplant immunosuppression  404 calciotropic hormones, ectopic secretion  2543 calciphylaxis (calcific uraemic arteriolopathy/​small vessel calcification)  4849, 5712f, 5712 calcipotriol  5625, 5764 calcitonin bone resorption  4620–​21 calcium/​phosphate balance  4625 ectopic secretion  2547 medullary thyroid carcinoma  2461–​62 normal blood values  6585t Paget’s disease management  4642 pancreatic neuroendocrine tumours  2455 renal calcium handling  5094 calcitonin gene-​related peptide (CGRP)  2867 antagonists, migraine  5992, 5993t calcitriol (1,25-​dihydroxy-​vitamin D)  2322, 2327, 5094, 5625 calcium adult values  6581t balance in bone  4624f, 4624 bone mineralization  4624 cardiac myocyte contraction  3256f, 3263 deficiency, lactose intolerance  2905 ectopic secretion  2549 homeostasis  2314f, 2315t, 2316f malignant hyperthermia  6342 regulation in extracellular fluid  2314f, 2314 intracellular protein binding  211 metabolism  5013b, 5013, 5014t, 5497 pregnancy  2573 primary hyperparathyroidism 
2321–​22 pulmonary alveolar microlithiasis  4266–​67 sarcoidosis  4214 secondary hyperparathyroidism in CKD-​mineral bone disorder, 4850 small intestine absorption  2725t supplements chronic hypocalcaemia management  2327 CKD-​mineral bone disorder management  4845 osteoporosis management  4701 supplements, PSC management  3139 urinary/​faecal reference intervals  6587t

32 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 calcium acetate, Canavan’s disease management  6218, 6219f calcium antagonists chest pain in hypertrophic cardiomyopathy management  3476 exercise ECG testing  3313 hypertension management, contraindications  3767t hypertrophic cardiomyopathy management  3474–​75 malignant hypertension management  3805 primary aldosteronism management  2355–​56 stable angina  3623 calcium channel blockers (CCBs) anxiety disorders management  6505t aortic regurgitation management  3454 blood pressure control in diabetes nephropathy  4984 CKD in pregnancy  2594t hyperhidrosis management  5703 hypertension in diabetes  2525 hypertension management  3766t, 3767 ion movement inhibition  84 limb lymphoedema  3816 malignant hypertension management  3806t oedema management  3821 photoallergy  5692 poisoning by  1739 primary aldosteronism  3785 primary aldosteronism screening  2354 pulmonary arterial hypertension management  3705 renal disease, effects of  5156 STEMI/​non-​STEMI ACS  3652 systemic sclerosis management  4524t uncomplicated diverticular disease  2962 calcium entry blockers, ACS management  3634 calcium gluconate  2326–​27, 2587 calcium oxalate  2174 calcium pyrophosphate crystal deposition  4488t, 4490, 4491f associated diseases/​ disorders  4490 joint insult  4491 metabolic disease  4491, 4491t osteoarthritis  4491 classification  4490 familial predisposition  4490 clinical features  4490 acute type  4490 incidental findings  4490 osteoarthritis and  4490 uncommon presentation  4490 diagnosis  4492 differential diagnosis  4492 investigations  4492f, 4492 management  4493 acute attacks  4493 osteoarthritis and  4493 calcium stones  5098 calcium oxalate stones  2177, 5093, 5094t, 5096f, 5098, 5100f primary hyperoxaluria  2178 calcium phosphate stones  5093, 5094t, 5098–​99, 5100f, 5101 environment  5098, 5099t genetics  5098, 5098t hyperoxaluria  5099 dietary hyperoxaluria  5099 enteric hyperoxaluria  5100 primary hyperoxaluria  5098t, 5100 hyperuricosuria  5101 hypocitraturia  5099t, 5101 idiopathic hypercalciuria  5099, 5099t management  5098 pathogenesis  5098 pathology  5098, 5100f prevention, trials in  5099t primary hyperparathyroidism  5099 see also nephrocalcinosis California encephalitis virus  855, 6084 Callilepis laureola (impila) poisoning, renal disease  5061 caloric restriction  515f, 515, 516f, 2384 calpainopathies  6323t, 6325, 6326b, 6326 CAMPATH-​1 see alemtuzumab (CAMPATH-​1) Campbell de Morgan spots (cherry angiomas)  5710, 5716 camphor  5763 Campylobacter infection  1039 clinical features  1039 acute bloody diarrhoea (dysentery)  3018 gastrointestinal system  3009t, 3011 reactive arthritis  3021 epidemiology  1039 laboratory diagnosis  1039 management  1039 pathogenesis  1039 transmission  3014t, 3015, 3016f Campylobacter jejuni infection  2920, 6190 CAMT, congenital thrombocytopenias  5335 Camurati–​Engelmann disease (progressive diaphyseal dysplasia)  4657f, 4657 transforming growth factor beta superfamily  262–​63 canakinumab  101t, 104 atherosclerosis regression  3601 cryopyrin-​associated periodic syndromes management  2214 gout management  4489 nomenclature  103t canakinumab pegol  101t Canavan’s disease  1968, 1969f, 6210, 6218 treatment  6219f cancer  1896 apoptosis  279 breast see breast cancer causes see cancer aetiology cerebral metastases  491 childhood, later life, effects in  2697 diabetes insipidus  2280–​81 diagnosis  487 circulating DNA  299, 300f, 301 early diagnosis  488 epidemiology  411 epilepsy  5866 genetics see cancer genetics hallmarks of  446f, 446 blood supply  447 cell cycle regulation  446 cell death  447 cellular energetics dysregulation  447 metastases  447 HIV/​AIDS  3535 incidence community differences  412, 413t migrant groups  413, 414t pregnancy  2696 information and support  493 diagnosis  493 further stages  493, 494f investigations  489 biopsy  489 colonoscopy  2738f, 2738 imaging  489 molecular characterization  490 serum tumour markers  489 liver see liver cancer localized symptoms  488 management  490 chemotherapy see cancer chemotherapy genetic counselling  467 immunotherapy see cancer immunotherapy late sequelae  495t, 496 management aims  490 management modalities  491 multidisciplinary teams  490 pain  631t renal disease, effects of  5160 surgery  491 mass reduction, carcinoid syndrome management  2873 mortality  412f, 412 prevalence  487 oncological emergencies  492 patient groups  492 frail/​elderly  492 inherited cancer  493 pregnancy  492 pregnancy see pregnancy presentation of  487 preventability  412 products, malignancy-​associated renal disease  5042 protective factors  1896 regression, apoptosis  279 rickets  4638 screening  19, 142–​43, 148 cost-​effectiveness  489 small bowel imaging  2752, 2753f, 2754f staging  490 surviving  495 systemic features  488 acquired pernicious anaemia  5416 associated renal disease see malignancy-​associated renal disease cerebral vasculitis  6380 C-​reactive protein  2204 diarrhoea  2759t effusions  491 haemoptysis  3948t hyperfibrinolysis  5555 hyperthyroidism  2318b, 2324 inflammatory myopathies  4541 liver disease  3177 neutropenic sepsis  492 pain  630 palmoplantar keratosis  5610 pleural effusions  4311 PSC in  3140 systemic sclerosis  4516 upper airway obstruction  4045, 4046f vasculitis  5650 Wiskott–​Aldrich syndrome  354 urinary tract obstruction  5125 vaccines  474, 475f cell-​based vaccines  476 dendritic-​cell-​based vaccines  474 peptide-​based vaccines  475 viral vector-​based vaccines  476 cancer aetiology  415 agent interaction  424, 425t alcohol  418, 6488 mortality  425t avoidable causes  416 biological causes  415 age  415 genetics  415 sex  415 causal factors  1896, 1897t diet  423 carcinogens  423 fibre  423 meat and fat  423 mortality  425t overnutrition  423 retinoids and carotenoids  423 diphtheria  961f, 961, 962f folate deficiency  5414t, 5419 gastrointestinal tract immune deficiencies  2790 human polyomaviruses  885 immunosuppression  414 infections  419 bacterial infection  419 mortality  425t parasitic infections  420 viral infection see viral infections inherited see cancer genetics ionizing radiation  418 mortality  425t medical drugs  420, 421t mortality  425t multistep pathway  459 mutations see DNA mutations obesity  6530 occupation  420, 422t mortality  425t physical inactivity  424

  Index 33 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 pollution  420 mortality  425t post-​lung transplantation  4302 reproductive factors  424 tobacco  416 geography  417t mortality  425t ultraviolet radiation  419 mortality  425t see also carcinogenesis cancer-​associated retinopathy (CAR)  6425 cancer chemotherapy  498 acute myeloid leukaemia management  5208 adverse reactions eye diseases/​disorders  6439 gonadal failure association  2548 oesophageal disease  2846 steatohepatitis  3164 AL amyloidosis management  2232, 5019 alkylating agents  500f, 500 antimetabolites  500, 501f breast cancer adjuvant management  506 breast cancer metastatic disease  507 cancer aetiology  420 cancer in pregnancy  2696–​97 carcinoid syndrome management  2873 cell-​cycle phase specificity  498, 498t classification  498 cytokines  473 cytotoxic antibiotics  500, 501t Entamoeba histolytica infection management  1390 Ewing sarcoma management  4711 hair, effects on  5730 hormone therapies  500 androgen receptor antagonists  501 aromatase inhibitors  501 exogenous hormones  502 gonadotrophin production inhibitors  502 oestrogen receptor modulation  501 intracranial tumours management  6053 late effects  504 leprosy management  1164f, 1164, 1164t leukaemia epidemiology  444 localized muscle-​invasive
bladder cancer management  5139 lymphatic filariasis  1494 mechanism of action  498 metastatic breast cancer  507 metastatic muscle-​invasive bladder cancer management  5140, 5140t mitotic spindle agents  500 monoclonal Ig-​dependent diseases management  5021 nausea and vomiting  635 neutropenic enterocolitis  2791–​92 non-​small cell carcinoma management  4354 pancreatic ductal adenocarcinoma management  3233 platinum compounds  500 pleural mesothelioma management  4365 primary myelofibrosis management  5252 radiation pneumonitis  4271 renal disease in myeloma  5020 small-​cell lung cancer management  4355 stomach cancer  2984 targeted therapies  502, 502t angiogenesis inhibitors  502, 503t immunomodulatory agents  503 nomenclature  502t proteasome inhibitors  502 signal transduction inhibitors  502 topoisomerase inhibitors  500 cancer chemotherapy acute myeloid leukaemia management  5207 cancer genetics  456, 493 cancer types  462 chromosome fragility syndromes  466 dominant inheritance  457 gene identification  459 associated risks  460, 461t association studies  460 cytogenetics  459 direct sequencing  460 linkage analysis  460 phenotypic features  460 whole genome sequencing  460 historical perspective  457, 458t, 459f identification  467 at-​risk family identification  468 genetic testing  469 risk assessment  467 screening  468 management  467 lifestyle changes  468 management options  469 prevention strategies  468 mechanism of action  459 predisposition  462 predisposition mechanisms  457 rare syndromes  458t, 463 hereditary retinoblastoma  463b, 463 X-​linked inheritance  457–​59 Cancer Genome Anatomy Project  453–​54 Cancer Genome Atlas (TCGA)  68–​ 69, 449–​50 cancer immunotherapy chimeric antigen receptor T cells  477, 479f clinical considerations  478 generation of  477–​78 mechanism of action  477 combination therapies  484 checkpoint blockade and VEGF-​ targeted agents  484 CTLA4 and PD-​1 blockade  485 cytotoxic T lymphocyte antigen-​4 blocking  479 adverse reactions  481 clinical considerations  480 mechanism of action  479 toxicity  481 future work  485 immune agonists  484 programmed death-​1 blocking  481 adverse reactions  483 clinical considerations  482 development of  481 mechanism of action  481 toxicity  483 T-​cell redirecting engineered antibodies  478 clinical considerations  478 mechanism of action  478 cancer-​induced bone pain (CIBP)  629, 630 cancrum oris  2813 candesartan  3766t, 5993t, 6001 candidaemia  1345f, 1353b, 1353 Candida infections see candidiasis candida intertrigo  1343 candidiasis diabetes complications  2504 cutaneous infections  5747 endocarditis  3528 infective oesophagitis  2836t keratitis  6423 liver disease  3175 oral candidiasis (thrush)  1343 renal transplant immunosuppression  4894 potentially malignant oral lesions  2805 pregnancy  2685t severe/​difficult-​to-​treat asthma  4092 skin disorders, pregnancy  2650 superficial see superficial candidiasis systemic  1353 aetiology  1353b, 1353 candidaemia  1345f, 1353b, 1353 clinical features  1353 deep focal candidiasis  1354 disseminated candidiasis  1353, 1354 endocarditis  1354 epidemiology  1353 laboratory diagnosis  1344f, 1353 management  1354 urinary tract infection  1354 UTI  5091 CANDLE  2208t cannabis adverse reactions, male reproductive disorders  2393t poisoning  1748 spasticity in spinal cord injury  6144 substance misuse  6491 canthariasis, nonvenomous arthropod infestations  1579f, 1579 capacity  3161, 6457 functional capacity  3861 critical care surgery  3862 see also competence capecitabine  2981, 2994, 3233 capillariasis  1509, 2920t Capital in the Twenty-​first Century (Piketty)  163 Caplan’s syndrome, coal workers pneumoconiosis  4223f, 4223 capnography, acute respiratory failure  3871 capsaicin  4479t, 5159t capsule colonoscopy  2737 capsule endoscopy  2749 acute lower gastrointestinal bleeding management  2781 angiodysplasia  2754 small intestinal lymphangiectasia  2974 captopril  2354, 3766t, 3805, 3824–​25 CARASIL  6204f, 6246 carbamate insecticide poisoning  1758 carbamazepine adverse reactions syndrome of inappropriate antidiuresis  2551 alcohol withdrawal management  6489 bipolar disorder management  6500 chorea in acute rheumatic fever management  3517 diabetic neuropathy management  2522 epilepsy management  5872, 5873t monitoring  5876–​77 hormonal contraceptive interactions  2716 mechanism of action  5871 multiple sclerosis management  6035 neuroacanthosis management  6251–​52 normal blood values  6588t poisoning by  1735 renal disease, effects of  5159 seizure management in acute porphyria  2051–​52 trigeminal neuralgia management  6123 carbamoyl-​phosphate synthase deficiency, urea cycle defects  1949t, 1953 carbamylation, glomerular filtration rate measurement  4790 carbidopa  604, 1977, 3824–​25, 5953 carbimazole  2298, 2638, 2710 carbohydrate(s) acute porphyria management  2050–​51 artificial nutrition requirements  1918 dietary change  1899 diet, diabetes management  2489 digestion  2902 luminal phase  2902, 2903f mucosal phase  2902 eye diseases/​disorders  6437 malabsorption in diarrhoea  2759t metabolism  1841 diabetes mellitus type 1  2472f, 2480

34 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 glucose metabolism see glucose metabolism insulin  2472f, 2472 lactate and ethanol metabolism  1842f, 1842 lipid metabolism interactions  1846 liver  3039, 3040f pregnancy  2567, 2572 stores of  1839, 1840t metabolism disorders  1985 galactose see galactose metabolism disorders glycogen storage diseases see glycogen storage diseases (GSDs) restriction, hypoglycaemia  2538 carbohydrate intolerance  2903, 2903t lactose see lactose intolerance management  2906 dietary exclusion  2904b, 2906 disaccharide replacement  2907 intestinal biome manipulation  2907 carbon dioxide airway smooth muscle  3943 poisoning  1764 respiratory acidosis/​alkalosis  2185 carbon disulphide  1764, 6188 carbonic anhydrase 2 deficiency  4659 carbonic anhydrase deficiency  1954, 4616 carbon monoxide (CO) ambient (outdoor) air pollution  1681 intoxication, polycythaemias  5231 poisoning  1764 uptake, respiratory function tests  3961, 3961t, 3962t carbon skeleton metabolism, protein metabolism  1848f, 1849 carboplatin  500, 5148t carboxyhaemoglobulinaemia  5450 carboxylase deficiencies  1949t, 1964, 1965f biotinidase deficiency  1949t, 1955f, 1965, 1966f holocarboxylase synthetase deficiency  1949t, 1966 carbuncles, Staphylococcus aureus infection  996, 997f, 998t carcinoembryonic antigen (CEA)  489, 6585t carcinogenesis adverse drug reactions  90 apoptosis  279f, 279 see also cancer aetiology carcinoid crisis  2871, 2873 carcinoid syndrome  2870 biochemistry  2871f, 2871 clinical features  2870 breathlessness  2871 carcinoid crisis  2871 chronic heart failure  3410t diarrhoea  2871 flushing  2870 heart disease  2871 pellagra  2871 complication management/​ avoidance  2874 bony metastases  2874 heart disease  2874 vitamin supplements  2874 investigations  2872 biochemical tests  2872 cardiac disease screening  2873 histopathology  2872 radionuclide imaging  2872f, 2872 structural imaging  2872f, 2872 malabsorption  2876t management  2873 carcinoid crisis  2873 chemotherapy  2873 interferon-​α  2873 peptide receptor radionuclide management  2873 somatostatin analogues (SSTA)  2873 symptomatic management  2873 tumour mass reduction  2873 prognosis  2874 carcinoma erysipeloides (carcinoma telangiectasia)  5721f, 5721 cardiac action potential  3259, 3259t, 3260f, 3261t membrane potential  3259 ion channels  3259 origins of  3259, 3259t phase 0  3259, 3259t, 3260f phase 1  3260f, 3260 phase 2  3260f, 3260 phase 3  3260f, 3260, 3261t phase 4  3260f, 3262 regional variations  3261t, 3262f, 3262 cardiac arrest  3839 acute presentation  6591 advanced life support  3840 see also advanced life support (ALS) audit  3848 cardiopulmonary resuscitation  3840 see also cardiopulmonary resuscitation (CPR) Chain of Survival  3839f, 3839 critical care in pregnancy  2704, 2704t epidemiology  3839 future work  3848 historical perspective  3839 long-​term management  3847 electrophysiological assessment  3847 rehabilitation  3847 organ donation  3847 post-​resuscitation care  3845 ABCDE approach  3845 see also ABCDE approach brain imaging  3845 cerebral perfusion  3845 glucose control  3845 sedation  3845 seizure control  3845 temperature control  3845 prevention  3840 prognosis  3846, 3847f outcome prediction  3846 survival  3846 cardiac arrhythmias  3350 accelerated idioventricular rhythm  3385 acute porphyrias  2039 atrial arrhythmias  3367 see also atrial fibrillation atrial flutter  3368b, 3375, 3377f causes  3366 extrasystoles  3366 chest pain at rest  3277 CKD  3423f, 3425t, 3426 definitions  3352 diagnosis  3837t dilated cardiomyopathy  3479 Ebstein anomaly  3568 essential hypertension pathophysiology  3750 exercise ECG testing  3313 Fabry’s disease  2144 genetic syndromes  3385 genetic testing  3388 heart muscle disease  3388 see also arrhythmogenic right ventricular cardiomyopathy; dilated cardiomyopathy (DCM); hypertrophic cardiomyopathy (HCM) ion channel disease  3385 see also Brugada’s syndrome; catecholaminergic polymorphic ventricular tachycardia (CPVT);
short-​QT syndrome HIV/​AIDS  3537 investigations  3352 cardiac electrophysiology 
3353f, 3353 ECG  3352, 3352t long-​QT syndrome  3384 management dilated cardiomyopathy management  3482 hypertrophic cardiomyopathy  3476 pre-​excitation syndrome (Wolff–​Parkinson–​White syndrome)  3379f, 3379, 3380f symptoms  3352 torsades de pointes  3384 ventricular fibrillation  3385f, 3385 ventricular pre-​excitation, management  3380f, 3380, 3381 see also bradycardias; tachycardias cardiac catheterization/​ angiography  3339 aortic regurgitation  3454 aortic stenosis  3450 atrial septal defects  3572 atrioventricular septal defects  3575 cardiac flow and output  3342f, 3342 cardiovascular changes pregnancy  2598 complications  3348, 3349t constrictive pericarditis  3506 coronary arterial anatomy and function  3346 coronary arteriography/​ angiography  3346f, 3347f, 3347 coronary physiological measurements  3347 dilated cardiomyopathy  3481 Eisenmenger’s syndrome  3566 history of  3339 hypertrophic cardiomyopathy  3474 indications  3339 congenital disease  3340 congestive heart failure  3340 coronary artery disease  3339 pericardial disease  3340f, 3340 pulmonary vascular disease  3340 valvular disease  3339 intracardiac pressures  3341 methodology  3341 normal pressure  3341, 3341t waveform  3340f, 3342 intracardiac shunts  3343, 3344f intravascular ultrasound  3347, 3348f left heart catheterization  3341 left ventricular function  3345 contractility  3346 diastolic function  3346 global function  3345f, 3345 mitral regurgitation  3445 mitral stenosis  3440 patient preparation  3340 quantitative angiography  3343 right heart catheterization  3341 tetralogy of Fallot  3585 valvular regurgitation  3345 vascular access  3340 vascular resistance  3343, 3344f, 3344t vascular stenosis  3344, 3345f, 3345t cardiac computed tomography  3335 clinical uses  3336 coronary angiography  3336f, 3337f, 3337 coronary calcium scoring  3336 limitations  3336b see also computed tomographic coronary angiography (CTCA) cardiac cycle  3264, 3265f bundle of His  3264–​65 cardiac disease acute abdomen  2769 acute-​on-​chronic liver failure  3094 AL amyloidosis  2221 ANCA-​associated vasculitis  4564 Becker’s muscular dystrophy  6280 brucellosis  1105, 1107f carcinoid syndrome  2871 carcinoid syndrome management  2874 clinical presentation  3276 breathlessness (dyspnoea) see breathlessness (dyspnoea) chest pain see chest pain diagnosis, history  3276–​77 differential diagnosis vs.  3276 endocrine disorders  3496 epidemiology trials  64f, 64, 65f hypereosinophilic syndrome  5257 hypertension pathophysiology 
3749, 3750f

  Index 35 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 infections see also acute rheumatic fever; cardiovascular syphilis; endocarditis inherited metabolic disorders  3497 investigations  3277 iron overload management  5398 liver disease and  3170 malformations in antenatal screening  144t neuromuscular disorders  3497, 3498t polyarteritis nodosa  4571 pregnancy see pregnancy sarcoidosis  4210t, 4213 screening, carcinoid syndrome  2873 Sjögren’s syndrome  4533 tumours see cardiac tumours cardiac failure see heart failure cardiac genetic disease  3551 connective tissue disorders  3554 Ehlers–​Danlos syndrome see Ehlers–​Danlos syndrome (EDS) Loeys–​Dietz syndrome  3556f, 3556 Marfan’s syndrome see Marfan’s syndrome syndromic congenital heart disease  3552 aneuploidy disorders  3552 heart–​hand syndromes  3554 Mendelian syndromes  3552 cardiac glycosides  84, 1830f, 1830, 5153, 6439 cardiac hypertrophy  2144, 2148 cardiac magnetic resonance imaging (CMR)  3331 applications  3332 anatomy  3332 arrhythmogenic right ventricular cardiomyopathy  3486, 3487f blood flow  3332 cardiac myxoma  3546, 3547f chronic heart failure  3409 coarctation of the aorta  3576, 3577f, 3577 congenital heart disease  3332 coronary arteries  3334 dilated cardiomyopathy  3481 hypertrophic cardiomyopathy  3474 iron overload  3334 myocardial function and mass  3332f, 3332 myocardial oedema  3334 myocardial perfusion  3334f, 3334 myocardial viability  3333f, 3333 myocarditis  3462–​63 nonischaemic cardiomyopathies  3333f, 3333 disease prognosis  3335 mechanism of action  3331 nuclear imaging vs.  3331 perfusion imaging, stable angina  3620 phase contrast mapping  3332 safety  3331 steady state free precession images  3331 T1 and T2 parametric mapping  3334, 3335f cardiac myocytes  3255 connections between  3257, 3258f contractile apparatus structure  3255f, 3256 costameres  3256 intermediate filaments  3256 plasma membrane skeleton  3256 sarcomeres  3255–​56 thick filaments (myosin)  3256f, 3256 thin filaments (actin)  3256f, 3256 contraction  3262 control by Ca2+  3256f, 3263 excitation–​contraction coupling  3257f, 3260f, 3262 myofibrillar contraction mechanisms  3256f, 3263f, 3263, 3264f termination  3264 contraction termination Na+/​Ca2+ exchanger  3260f, 3261t, 3264 Na+/​K+ -​ATPase  3264 sarcoplasmic/​endoplasmic reticulum ATPase type 2  3257f, 3264 morphology  3255 plasma membrane currents  3261t plasma membrane–​sarcoplasmic reticulum coupling  3257f, 3257 subtypes  3257 cardiac myxoma  3544 clinical features  3545 differential diagnosis  3545 epidemiology  3544 investigations  3545 echocardiography  3545, 3546f management  3546 pathology  3544 physical signs  3545 prognosis  3546 cardiac output (CO) cardiac catheterization and angiography  3342f, 3342 cardiorenal syndrome  3423, 3424f circulatory support  3885 dye dilution  3343f, 3343 hypertension  3742 oximetry  3342, 3343f Paget’s disease  4640 pregnancy  2564f, 2564, 2597–​98 pregnancy in  2563 stroke volume  3274 thermodilution  3343 cardiac pacing procedures  6646, 6647t external (transcutaneous) pacing  6646 percussion pacing  6646 transcutaneous pacing  6647 transvenous pacing  6647, 6648f, 6648t cardiac physiology  3253 action potential see cardiac action potential cardiac myocytes see cardiac myocytes coronary blood flow  3272 function regulation  3268 heart rate  3272 outflow resistance to afterload  3269f, 3269 see also systemic arterial blood pressure regulation venous return, preload and Frank–​Starling relationship  3268f, 3268 nervous system and  3273 autonomic efferent activity  3273 cardiac reserve  3257f, 3274 sympathetic nervous system  3273 whole organ physiology  3264 cardiac cycle  3264, 3265f mechanical events  3265f, 3265, 3266f myocardial mechanics  3267f, 3267, 3267t myocardial metabolism  3268 normal volumes/​pressures/​ flows  3266, 3267t cardiac reserve  3257f, 3274 provocative test of  3410 training effects  3274 cardiac resynchronization therapy (CRT)  3359 chronic heart failure management  3414f, 3417 cardiac sarcoidosis  3466 cardiac sarcoma  3548, 3549f cardiac surgery acute renal failure  3668f, 3668 assessment  3667 operative risks  3667 complications  3672 atrial fibrillation  3672 conduction defects  3672 mortality  3672 neurological injury  3672 paravalvular leak  3673 pericardial effects  3672 pleural effusion  3672 prosthetic valve endocarditis  3673 prosthetic valve thrombosis  3673 sternal wound complications  3672 structural valve deterioration  3672 thromboembolism  3672 historical aspects  3667 pregnancy in  2599 see also coronary artery bypass grafting (CABG); heart valve surgery cardiac syncope  3285b, 3285, 3286f, 3289, 5898 epilepsy vs.  5867 cardiac tamponade acute presentation  6604 diagnosis  3837t obstructive shock  3888 cardiac transplantation  3428 complications  3430 cardiac allograft vasculopathy  3430f, 3430, 3431b hyperlipidaemia  3430 renal dysfunction  3430 dilated cardiomyopathy management  3482 liver transplantation and  3103 lung transplantation and  4295 pulmonary arterial hypertension management  3706 post-​transplantation  3429 immunosuppression  3429b, 3429 recipient selection  3428, 3431b donor–​recipient matching  3429 cardiac tumours  3544 benign tumours  3548 cardiac myxoma see cardiac myxoma involvement from other tumours  3549 liver disease  3170 cardiogenic anasarca  3403 clinical presentation  3403 differential diagnosis  3403, 3403t, 3404t investigations  3403 management  3404 pathophysiology  3403 cardiogenic pulmonary oedema  3399 clinical presentation  3399, 3401t investigations  3400, 3401f, 3402f management  3401 mechanical support  3402 medical management  3401 ventilatory support  3401 pathophysiology  3399f, 3399 pregnancy  2616 prognosis  3402 cardiogenic shock  3406, 3887 cardiomyopathy dilated see dilated cardiomyopathy (DCM) hypertrophic see hypertrophic cardiomyopathy (HCM) Noonan’s syndrome  3553 peripartum see peripartum cardiomyopathy pregnancy in  2600 restrictive see restrictive cardiomyopathy sarcoidosis  4213 cardiopulmonary exercise testing (CPET)  3862–​63, 3967f, 3968, 3969, 3969t Ebstein anomaly  3569 Eisenmenger’s syndrome  3566 cardiopulmonary resuscitation (CPR)  3840, 3841b drugs  3844 extracorporeal CPR  3844 mechanism of action  3840, 3842f related decisions  3848 renal disease, effects of  5157 rescuer, risks to  3840 cardiorenal syndrome  3421 adverse reactions  3424, 3425t definition  3422, 3422t

36 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 epidemiology  3422, 3422t haemodynamic effects  3423, 3424f management  3427, 3427t nephrotoxicity  3424, 3425t cardiotoxic plants see poisonous plants cardiovascular disease (CVD) acquired pernicious anaemia  5416f, 5416 acute coronary syndrome see acute coronary syndrome (ACS) apoptosis  278 arterial disease  3674 see also acute aortic syndrome; cholesterol embolism; peripheral arterial disease assessment, hypertension investigations  3760 autosomal dominant polycystic kidney disease  5067 biomarkers in pneumonia  4018 COPD  4136 C-​reactive protein  2206 diagnosis  3837t diphtheria  962, 963f haemoptysis  3948t HIV/​AIDS antiretroviral management  924 hypertension  3735 see also essential hypertension investigations CT see cardiac computed tomography echocardiography see echocardiography electrocardiography see electrocardiography (ECG) MRI see magnetic resonance imaging (MRI) nuclear imaging see nuclear imaging liver disease  3170 management herbal formulas  114, 115f renal disease, effects of  5153 Marfan’s syndrome  4681 neurological disorders  6369 obesity  1908 obstructive sleep apnoea  4054 oral hypoglycaemic agent adverse reactions  2495 osteoarthritis  4476 polycystic ovary syndrome  2383 polycythaemias  5230 post-​liver transplantation  3105 pulmonary circulation see pulmonary circulation smoking  6534 spinal cord injury  6138, 6142 vascular Parkinsonism  603–​4 venous thromboembolism  3711 prognosis  3712 see also acute pulmonary embolism; deep vein thrombosis (DVT) Cardiovascular Health Study (USA), heart failure  3393–​94 Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) study  5047–​48 cardiovascular syphilis  3539 clinical presentation  1217, 3539 aortic regurgitation  3540f, 3540 coronary ostial stenosis  3540 syphilitic aneurysm  3540 diagnosis  1220, 3540, 3541f differential diagnosis  1218 HIV/​AIDS  3541 investigations  3540 medical management  3542 pathogenesis  3539 pathology  3539 surgery  3542f, 3542 cardiovascular system ACS management  3651, 3651t, 3652t alcohol abuse  6487 anaemia  5361f, 5362 anaphylaxis  3852t, 3854 cardiac physiology see cardiac physiology chronic renal failure complications  4855–​56t classic myotonic dystrophy type 1  6332 confusion assessment  6456 diagnosis of death  6542 drowning  1694 electrical injuries  1699 examination, falls in elderly  583 exercise testing  3966 hypertension management  3775 Kawasaki’s disease  4593 lightning  1698 malnutrition emergency management  1881t management, nonalcoholic fatty liver disease in  3152 occupational disease  1647 Parkinson’s disease  608 polycystic ovary syndrome  2383 pregnancy see pregnancy pseudoxanthoma elasticum  4682 rabies  812, 814f reductive adaptation  1885 respiratory disease  3954, 3954t rheumatoid arthritis  4426, 4427t sport and exercise medicine  6568, 6569t structure and function  3241 systemic lupus erythematosus  4507 systemic sclerosis management  4528 cardioversion, tachycardia management  3364 cardiovirus  954 carditis  1183, 3512 care after death  645, 646b care bundle approach, acute exacerbations of COPD  4139f, 4139–​40 carfilzomib  5318 carmustine (BCNU) adverse reactions eye diseases/​disorders  6439 nodular regenerative hyperplasia  3164 cancer aetiology  421t drug-​induced alveolar disease  4278 drug-​induced pulmonary vasculature  4280 intracranial tumours  6053 Carney’s complex (CNC)  2335f, 2335, 2462, 3544 carnitine deficiency  6309f, 6338 glutaric aciduria type I management  1963 isovaleric aciduria (isovaleryl-​CoA deficiency)  1956 protein-​dependent inborn errors of metabolism emergency management  1947 protein-​dependent inborn errors of metabolism management  1946–​47 carnitine palmitoyltransferase deficiency  6338 β-​carotene  423–​24, 2050 carotenoids  423 carotid artery disease  3668, 6559 carotid body ablation, hypertension management  3775 carotid bulb expansion, hypertension management  3775 carotid endarterectomy, ischaemic stroke  6019 carotid sinus hypersensitivity  6161–​ 62, 6164f syncope vs.  3285 carotid sinus syncope, epilepsy vs.  5867 carotid sinus syndrome (CSS)  584 carp gallbladder ingestion  1803 renal disease  5061 carpal tunnel syndrome  6182, 6193 diabetic neuropathy  6371 nerve conduction studies  5798–​99 normal pregnancy  2579 pregnancy  2647t thenar wasting  6182–​83, 6183f cartilage  4379 biology  4381 collagen  4381f, 4381 development  4380 extracellular matrix  4377, 4380f glycosaminoglycans  4381 metabolism  4381 proteoglycans  4381 structure  4380f carvedilol  3076, 3415–​16, 3446 CASPAR (Classification criteria for psoriatic arthritis)  4451 caspases  267–​68, 269f, 269t cell-​cycle proteins  270 cell death  277 cryopyrin-​associated periodic syndromes  2213–​14 cytoskeletal proteins  269 DNA damage and repair  270 inhibitor activation  275 mechanism of  268 nonapoptotic roles  269t, 270 proteases and  268 protein kinases  269 see also apoptosis Castleman’s disease (angiofollicular lymph node hyperplasia)  5301 HIV/​AIDS  918 human herpesvirus 8 infection  752 catamenial pneumothorax  4325 cataplexy differential diagnosis epilepsy  5868 syncope  5900 narcolepsy and see narcolepsy cataracts  6400, 6401t Cushing’s syndrome  2337 diabetic eye disease  2518 elderly  581 galactokinase deficiency  2004 myotonic dystrophy type 1  6332 catecholaminergic polymorphic ventricular tachycardia (CPVT)  3388 catecholamines analysis, phaeochromocytomas 
3792 diabetes mellitus type 1  2480 heart failure  3271 hypoglycaemia in diabetes mellitus  2534 phaeochromocytomas  3789, 3790f, 3792 secretory pathways  2247 catechol-​O-​methyltransferase (COMT)  3790f, 3792 cathinones, poisoning  1748 cat-​scratch disease (CSD)  1267f, 1267, 1271 causalgia, skin manifestations  5713 caustic ingestion, oesophageal disease  2846 cavernous malformations, primary intracerebral haemorrhage  6023 cavitation dental caries  2798–​99 Mycobacterium tuberculosis infection diagnosis  4028f, 4028–​29 pneumonia  4020 pulmonary lesions, chest radiography  3988, 3989f CC chemokines  313 C chemokines  313 CCK see cholecystokinin (CCK) CD4+ T cells (helper T cells)  326, 473 antigen presentation to  327f, 327 MHC class II  327 antigen recognition  328f atopic dermatitis/​eczema  5634 coeliac disease  2886 Crohn’s disease aetiology  2925, 2926 function  332 hepatitis B  3043–​44 hepatitis C  3044 hypersensitivity pneumonitis  4252 inflammatory myopathies  4538–​39 MHC recognition  474 reactive arthritis  4465–​66 rheumatoid arthritis  4424 rheumatoid arthritis pathogenesis  4424 transplantation  396, 397f, 397–​98, 399 CD8+ T cells (cytotoxic T cells)  326, 473 antigen presentation  326, 327f MHC class I binding  326

  Index 37 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 peptide transport  326 proteasome  326 antigen recognition  328f apoptosis and immunity  278 cancer immunity  473 diabetes mellitus type 1  2477 function  332 hepatitis B  3043–​44 hepatitis C  3044 hypersensitivity pneumonitis  4252 MHC recognition  474 primary biliary cholangitis  3129–​30 reactive arthritis  4465–​66 skin  5593 skin hyperpigmentation  5680 systemic vasculitis  4990–​91 transplantation  396, 399 CD28  277–​78, 396 CD34  3186, 5176–​77 CD40 deficiency  355, 396 CD40L deficiency, hyper IgM syndromes  355 CD56  310 CD154 (CD40L), transplant rejection  396 Cedar Sinai Hospital, MPS study  3329f, 3329 cediranib  503t ceftriaxone  1608, 2683, 2684 cell(s)  209 cytoplasm  210 cytoskeleton  211f, 214 actin filaments  214–​15 intermediate filaments  214 microtubules  214 death atherosclerotic plaques  3599 cancer  447 caspases  277 neurodegenerative disorders  601 division DNA mutations in cancer  447 multiple endocrine neoplasia type 1  2460 selenium  1877 dynamic cells  215 alternative splicing  216 biological membranes  215, 216f differential gene expression  215 post-​transcriptional gene silencing  217 post-​translational modifications  216 endocytosis see endocytosis endosomes  214 recycling endosomes  214 future developments  217 integral membrane proteins  210 lipid bilayers  210 macromolecular crowding  210 next-​generation sequencing  67 organelles  210, 211f endoplasmic reticulum  211f, 211 Golgi apparatus  212 lysosomes  212, 213f mitochondria  210, 211 nucleus  210 peroxisomes  211 plasma membranes  209f, 209 prokaryotes vs. eukaryotes  209 transcription  210 translation  210 cell-​based therapies Becker’s muscular dystrophy management  6281 cancer vaccines  476 Duchenne’s muscular dystrophy management  6281 inborn errors of metabolism management  1936 iron overload  5400 cell cycle inhibitors, post-​lung transplantation  4299 cell-​cycle phase specificity, cancer chemotherapy  498, 498t cell-​free DNA  454f, 454 cell membranes crystal-​related inflammation  4484 glycoproteins  210 ion channels  247 potential difference, ion channels  247 proteins  210 raft domains  215 cellular immune response abnormalities, PSC  3136 autoimmune rheumatic disorders  4497–​98 deficiencies in  340t reactive arthritis  4465–​66 cellulitis (erysipelas)  3817 bacterial infections  5696 dental caries  2799–​800, 2800f gout  4485 Haemophilus influenzae type b  1069 secondary lymphoedema  3816 skin diseases/​disorders  5720 Staphylococcus aureus infection  996, 997t Streptococcus pyogenes infection  969f, 969 centipedes and millipedes (Myriapoda)  1813f, 1813 central diabetes insipidus  4743, 4746 central nervous system (CNS) ANCA-​associated vasculitis  4564 brain see brain cancer see central nervous system cancer classic myotonic dystrophy type 1  6332 cystic fibrosis  4163 degeneration, apoptosis  279 developmental abnormalities see central nervous system developmental abnormalities directed prophylaxis, acute lymphoblastic leukaemia management  5275 electrophysiology  5786 see also electroencephalography (EEG) hypernatraemia  4742 infections actinomycoses  1174 anaerobic bacterial infections  1057 bacterial infection see bacterial meningitis coccidioidomycosis  1364 extrapulmonary tuberculosis  4028 herpes simplex virus management  740 lumbar puncture  5781 tuberculoma  1137 normal development  6351, 6352f superficial siderosis  6375 central nervous system cancer CSF  5784t epidemiology  440, 441f lymphomas chemotherapy  6053 intracranial tumours  6050f, 6050–​51 central nervous system developmental abnormalities  6350 associated clinical problems  6362 external factors  6363 see also cerebral palsies fetal cerebral ventriculomegaly  6362 hydrocephalus  6362f, 6362 complex malformations  6360 corpus callosum agenesis  6360 hydranencephaly  6361 porencephaly  6361f, 6361 schizencephaly  6361f, 6361 septo-​optic dysplasia  6362 cortical development disorders  6355, 6356f cortical microdysgenesis (dysplasia)  6358f, 6358 cortical organization disorders  6358 migration disorders  6356f, 6356 see also lissencephaly proliferation disorders  6355 see also macrocephaly; microcephaly diagnosis  6365 genetic counselling  6365, 6367 neural tube formation see neural tube defects (NTDs) posterior fossa structure malformation  6358 cerebellar aplasia  6359f, 6359 cerebellar hypoplasia  6359f, 6359 Chiari malformation  6359 vermis abnormalities  6359 see also Dandy–​Walker malformations; Dandy–​ Walker variant; Joubert syndrome prenatal diagnosis  6367 regionalization disorders  6354 holoprosencephaly (prosencephaly)  6355f, 6355 risk assessment  6367 spinal cord developmental abnormalities  6354 sacral agenesis  6354 syringomyelia  6353f, 6354 vascular development anomalies  6362 central neurofibromatosis type 2 (NF-​2)  5918 central pontine myelinolysis  6039 neurological disorders  6372 central precocious puberty (CPP)  2431 central retinal artery occlusion  6413, 6414f, 6415f central retinal vein occlusion (CRVO)  6408t, 6414–​16 central sleep apnoea  4050, 4056 central vein cannulation, procedure  6644 centriacinar (centrilobular) emphysema, COPD  4106–​7 centromeres  219, 229 CEP see congenital erythropoietic porphyria (CEP: Günther’s disease) cephalic tetanus  1111–​12, 1112f cephalosporins acute osteomyelitis management  4693 gonorrhoea resistance  1591–​92 HACK endocarditis management  3529 indications  1006t peritonitis in peritoneal dialysis  4877 toxicity  1006t cercariae, schistosomiasis  1541f, 1541 cercarial dermatitis (swimmer’s itch)  1544 cercopithecine herpesvirus 1 (herpes B virus) infection  752 aetiology  752 clinical features  752 epidemiology  752 laboratory diagnosis  753 management  753 prevention and control  753 cerebellum  5938 disorders abscesses  6099 aplasia  6359f, 6359 ataxia see ataxia ataxia in pyruvate dehydrogenase deficiency  2010 degeneration in alcohol abuse  6488 dysarthria  5940 hypoplasia  6359f, 6359 functional anatomy  5938 pontocerebellum  5939f, 5939 spinocerebellum  5938, 5939 vestibulocerebellum  5938, 5939 function/​dysfunction  5939 gross anatomy  5938 cytoarchitecture  5938f, 5938 cerebral abscesses  3562, 5814 cerebral amyloid  2223, 5855 see also amyloidosis cerebral aneurysms, pregnancy  2646 cerebral angiography imaging  5805 cerebral arteriovenous malformations  6022 cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL)  5854–​55, 6034–​35, 6246, 6247f

38 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 cerebral cavernomas  6362 cerebral circulation  6012f, 6012 diagnosis of death  6542 cerebral degeneration  6488 cerebral demyelination complication, hyponatraemia management  4737 cerebral infarction classification  6016 diagnosis  6015 differential diagnosis  6015, 6016f essential hypertension pathophysiology  3750 management  6018 anticoagulants  6018 antiplatelet agents  6018 neuroprotective agents  6018 stroke units  6018 surgery  6017t, 6019 thrombectomy  6018 thrombolysis  6018 syndromes  6017 see also stroke cerebral ischaemia, investigations 
6014, 6015b cerebral malaria  1404, 1406f cerebral oedema diabetic ketoacidosis management  2508 hepatic encephalopathy type A  3086t hepatic encephalopathy type A management  3086 hyponatraemia  4732 management, liver failure  3098 cerebral palsies  6364 aetiology  6364 birth asphyxia  6365 genetics  6364 risk factors  6365 classification  6364 epidemiology  6364 imaging  6361f, 6365 cerebral perfusion pressure (CPP)  543, 3894 cerebral small vessel disease  5854, 5855f cerebral toxoplasmosis, HIV/​ AIDS  913f, 913 cerebral vasculitis  6378 clinical features  6379 diagnosis  6379 differential diagnosis  6379t management  6379, 6380 nonvasculitis systemic complications  6380 drug-​induced vasculitis  6380 infections  6380 lymphomatoid granulomatosis  6380 malignancy  6380 malignant angioendothelioma  6380 systemic vasculitis complications  6379 vascular cognitive impairment  5855 cerebral venous sinus thrombosis  5808 cerebral venous thrombosis  2646f, 2646 cerebral X-​linked adrenoleucodystrophy (CALD)  6210 cerebrospinal fluid (CSF)  5782, 5783t Alzheimer’s disease diagnosis  5842 angiotensin-​converting enzyme assay  5785 bacterial meningitis  6068 blood and pigments  5783 cell counts  5783 cytology  5783 examination Cryptococcus neoformans in HIV/​AIDS  6105 HIV dementia  6107 spinal cord disorders  6132 tuberculous meningitis  6078 glucose  5784 hypocretin levels, narcolepsy  5884 idiopathic intracranial hypertension  6055 immunoglobulins  5784 lactate  5785 longitudinally extensive transverse myelitis  6039 microbiology  5785 multiple sclerosis  6034 narcolepsy  5890 neurological conditions  5784t neurosyphilis diagnosis  6102 opening pressure  5783 bacterial meningitis  5783 PCR  5785 peripheral nerve disease diagnosis  6179 pressure, idiopathic intracranial hypertension  6057 primary thunderclap headache  5999 protein  5783 chronic inflammatory demyelinating polyradiculoneuropathy 
6191 diphtheritic polyneuropathy  6192 pyruvate dehydrogenase deficiency diagnosis  2011 serology  5785 shunting of  4732–​33 bacterial meningitis  6068 subarachnoid haemorrhage diagnosis  6024–​25 traumatic brain injury  6046 Venereal Diseases Research Laboratory (VDRL) test, neurosyphilis  6101 viral infections of CNS  6091 cerebrotendinous xanthomatosis (CTX)  6221, 6263 differential diagnosis  2168t psychoses  6485 cerebrovascular disease epilepsy  5866 Fabry’s disease  6227 herpes zoster infection  6096 imaging  5805 investigations, magnetic brain stimulation  5819 obstructive sleep apnoea  4054 cerebrovascular syncope  3289t, 3290 ceroid lipofuscinosis (Batten’s disease)  2151, 2169t, 5131 certolizumab  102, 2662, 2933 ceruloplasmin  2117 cervical cancer adult screening  148, 149t age-​related incidence  415 dietary protective factors  1897 epidemiology  436, 437f human papillomavirus and see human papillomavirus (HPV) infection incidence  413t migrant groups  414t pregnancy  2698 preventative medicine  133t cervical dystonia  5961 cervical intraepithelial neoplasia (CIN)  437, 2698 cervicitis  1284f, 1284 cervicofacial actinomycoses  1173 cervicogenic headache  6003 cestodes (tapeworms)  1520, 1522t cyclophyllidean tapeworms  1521f, 1521 gut infections  1521, 1522t cysticercosis see cysticercosis cystic hydatid disease see cystic hydatid disease (Echinococcus granulosa) Hymenolepsis nana infection  1524 pseudophyllidean tapeworms  1527 diphyllobothriasis  1527f, 1527 sparganosis  1527, 1528f Taenia  1522, 3010t Taenia asiatica infection  1522t, 1523 Taenia saginata infection see Taenia saginata infection Taenia solium infection  1522t, 1524 transmission  3015t tissue cyclophyllidean tapeworms  1525 Echinococcus multilocularis infection  1525, 1526f Multiceps infection  1526 Taenia crassiceps cysticercosis  1526 uncommon gut cestodes  1525 see also Taenia saginata infection CETP deficiency  2067f, 2083 cetrimide, skin disease management  5765 cetuximab  502, 5759 CFTR gene chronic pancreatitis  3220 cystic fibrosis  4152 meconium ileus  2972 mutations  4152f, 4152 CGA see comprehensive geriatric assessment (CGA) Chagas’ disease (American trypanosomiasis)  1459, 3466 aetiology  1460, 1461f apoptosis and infection  278 clinical features  1462f, 1463f, 1463, 1464f epidemiology  1461, 1461t eye diseases/​disorders  6433 laboratory diagnosis  1461f, 1464 management  1465 oesophageal disease  2838 pathogenesis and pathology  1462f, 1462, 1463f prevention and control  1465 unanswered questions and future research  1466f, 1466 vector  1460f, 1460 Chain of Survival, cardiac arrest  3839f, 3839 chancroid  1072, 1611 Changuinola virus  821 channelopathies, headache disorders  6247 Chapel Hill Consensus (CHC)  4391, 4392t, 4557f, 4557, 5640 hypocomplementaemic urticarial vasculitis  4577 polyarteritis nodosa management  4569 small-​vessel vasculitis  4573 Charcot joint  4605f, 4605, 4605t Charcot–​Marie–​Tooth (CMT) disease  6194 ataxia with chronic progressive course  5981 autosomal dominant  6277 type 1A  6277 type 1B  6277 type 2A  6278 type 4C  6278 type 4D  6278 type X1  6278 classification  6274, 6274t, 6275t clinical features  6194f, 6194 diagnosis  6274–​77 dominant intermediate  6278 genetics  6194 hereditary motor neuropathy (HMN)  6274 hereditary sensory and autonomic neuropathy (HSAN)  6274 hereditary sensory neuropathy (HSN)  6274 nerve conduction studies  5799–​800 type 1  6194 type 2  6194 Charcot’s arthropathy  2529 charities  17 Charlson Comorbidity Index  3862 Chédiak–​Higashi syndrome  2153 neutrophil function disorders  5195 skin hypopigmentation  5686 chelating agents  85, 202t, 5152 chemical nephrotoxins, tropical renal disease  5062 chemokines  313 autoimmune diseases  387 CD8+ T cells  332 innate immune system  472 transplant rejection  394 chemoprevention, inherited cancer prevention  468 chemoprophylaxis bacterial meningitis prevention  6066, 6073t malaria prevention  1412, 1412t chemo-​radiotherapy  504t oesophageal cancer management  2980 oesophageal squamous cell carcinoma  2845

  Index 39 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 cherry angiomas (Campbell de Morgan spots)  5710, 5716 cherry red spot-​myoclonus epilepsy syndrome (sialidosis type 1)  6244 chest aspiration  6652, 6653f decompression, procedure  6652 infections Duchenne’s muscular dystrophy  6318–​19 myotonic dystrophy type 1  6332–​33 physiotherapy, COPD management  4132f, 4132 chest drain  6652 chest pain  3277 causes  3277t, 3278 acute coronary syndromes  3278 aortic dissection  3279b, 3279 atypical angina  3279 coronary spasm  3279 pericarditis  3280 Prinzmetal’s angina  3279 syndrome X  3279 circumstances of  3277 on exertion see angina pectoris rest at  3277, 3283 differential diagnosis  3279b distribution of pain vs.  3279b exertion see angina pectoris management, hypertrophic cardiomyopathy  3476 mediastinal tumours and cysts  4371 oesophageal disease  2840 peptic stricture  2834 pericarditis  3502 respiratory disease  3950, 3950t chest radiography  3971 disease signs  3984 cavitating pulmonary lesions  3988, 3989f hemithorax transradiancy  3986, 3986t, 3987f left lower lobe collapse  3985, 3986f left upper lobe collapse  3985, 3986f multiple pulmonary nodules  3987f, 3989f, 3989, 3990b pulmonary collapse  3984 pulmonary consolidation  3984f, 3984, 3984t pulmonary nodules/​ masses  3987 right lower lobe collapse  3985f, 3985 right middle lobe collapse  3984, 3985f right upper lobe collapse  3984, 3985f interpretation  3982 normal anatomy  3979 blood vessels  3980 bronchi  3980 diaphragm  3981 hilar structure  3979, 3980–​81 mediastinum  3979, 3983f pulmonary fissures  3980 thoracic cage  3981 normal pregnancy  2578 posteroanterior (PA) chest radiography  3971,
3972–​73, 3976f specific diseases  3990 acquired aplastic anaemia  5342 acute aortic syndrome  3677f, 3677 acute pulmonary embolism 
3723, 3724, 3724t acute pulmonary oedema in pregnancy  2615 acute respiratory failure  3870 acute toxic injury to respiratory tract  4269 amyloidosis  3495 aortic regurgitation  3452, 3453f aortic stenosis  3448 arterial disorders  3576f asbestosis  4222f, 4226 atrial septal defects  3572 bacterial community-​acquired pneumonia in HIV/​ AIDS  4033f, 4033, 4034f berylliosis  4233f bronchiectasis  3990, 3991f, 4146 bronchiolitis obliterans  4186, 4194 cardiac myxoma  3545 cardiogenic anasarca  3403 cardiogenic pulmonary oedema  3400, 3402f cardiovascular changes pregnancy  2598 chest wall disease  3990 chronic diffuse lung disease  3991, 3992f chronic heart failure  3411 classic silicosis  4229f, 4229 coal workers pneumoconiosis  4223f coarctation of the aorta  3576 congenitally corrected transposition of the great arteries  3583f, 3583 constrictive pericarditis  3506 COPD  3283, 3990, 3991f, 4119f, 4119 cryptogenic organizing pneumonia  4188 cystic fibrosis  4154f, 4158 diaphragm disorders  4336 diffuse panbronchiolitis  4190 diffuse parenchymal lung disease diagnosis  4172 dilated cardiomyopathy  3480 Ebstein anomaly  3568f, 3568–​69 Eisenmenger’s syndrome  3566f, 3566 eosinophilic granulomatosis with polyangiitis  4203 fibrosing lung diseases  4172 granulomatosis with polyangiitis  4202–​3 hepatic encephalopathy  3085 hypertension diagnosis  3760 hypertrophic cardiomyopathy  3473 idiopathic pulmonary fibrosis  4179, 4181 interstitial lung disease in rheumatological disease  4197 kyphosis  4333 Langerhans cell histiocytosis  4257f, 4257 left ventricular failure  3282 lung cancer  148, 4342f, 4342, 4343f, 4344f, 4345f, 4346f, 4349 lymphangioleiomyomatosis  4258 lymphoid interstitial pneumonia  4242 lymphomatoid granulomatosis of the lung  4242 malignant hypertension  3803, 3804 mitral regurgitation  3444f, 3444 mitral stenosis  3439f, 3439 mixed mitral valve disease  3447f, 3447 Mycobacterium tuberculosis infection diagnosis  4028f nosocomial pneumonia  4024 pericardial effusion  3503f, 3503 pericardial tamponade  3503f, 3504 pericarditis  3502 pleura  4306 pleural disease  3990f, 3990 pleural effusions  4309f, 4309, 4310f pneumoconiosis imaging  4220 Pneumocystis jiroveci infection  1372f, 1372, 1373f, 4034f, 4034 pneumonia  4020 pulmonary alveolar microlithiasis  4266f, 4266 pulmonary alveolar proteinosis  4260 pulmonary arterial hypertension  3701f, 3701 pulmonary atresia with ventricular septal defect  3587f, 3587 pulmonary embolism in pregnancy  2609 radiation pneumonitis  4271, 4272f re-​expansion pulmonary oedema  4325, 4326f renal disease  4794 sarcoidosis  5744 stannosis  4233f suspected infections  663 tension pneumothorax  4322 thoracoplasty  4334 tricuspid regurgitation  3456f, 3456 tricuspid stenosis  3456 tuberculous meningitis  6078 uncomplicated pneumothorax  4323f univentricular atrioventricular connection  3589 ventricular septal defects  3574 standard views  3971 technical considerations  3971, 3972f chest wall chest radiography  3990 chronic respiratory failure  4286 pregnancy, changes in  2613 Cheyne–​Stokes respiration  5905 Chiari malformation  6359 Chikungunya virus  823, 4611 eye diseases/​disorders  6432 chilblain lupus  5652b chilblains  5713 childhood/​adolescent-​onset hereditary dystonia see hereditary dystonia Child–​Pugh scores  3090–​91, 3092, 3095f Child–​Pugh–​Turcotte scoring system  3047, 3072 children absence epilepsy  6241, 6242t acute lymphoblastic leukaemia prognosis  5278f, 5279 asthma prognosis  4075 brainstem death  5909 Cushing’s syndrome  2339 diagnosis of brainstem death  6542 Duchenne’s muscular dystrophy  6280 endocarditis  3524 enteric fevers  1047 focal segmental glomerulosclerosis management  4927 gastrointestinal infections  3013 growth  2419 HIV/​AIDS  927 hypertension management  3776 imaging, neurological disorders  5816 immune-​mediated platelet disorders  5526 magnetic brain stimulation  5819 malaria  1407 malnutrition  1881 meningitis antimicrobial therapy  6072 causative agents  6061 multiple sclerosis  6032 myotonic dystrophy  6333 nonaccidental injury, bruises  6549 obesity prevalence  1904, 1907f pneumonia  4012 preventative medicine  127 self-​harm  6459 toxoplasmosis  1419 ulcerative colitis  2949 vaccinations, travel and expedition medicine  716 chimeric antibodies  297f IgG  296 chimeric antigen receptor
T cells see cancer immunotherapy China cholangiosarcoma epidemiology  429 coal workers pneumoconiosis  4221 coeliac disease  2884 diabetes mellitus type 2  1896 GBD  47, 48f liver cancer epidemiology  429 lung cancer epidemiology  433 oesophageal cancer  427 silicosis  4228 stomach cancer  428 tobacco as cancer cause  417–​18 Chinese herbal nephropathy  4959 clinical features  4960

40 Index VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 diagnosis  4960 differential diagnosis  4957t management  4960 pathogenesis  4960 pathology  4960f, 4960 tubular proteinuria  4787 see also traditional Chinese medicine (TCM) chiropractic therapy  108, 109b, 202t Chlamydia infections  1278 apoptosis and infection  278 asthma  4072 classification  1280 developed countries  1592, 1593f diagnosis  1294 genomics  1280 growth cycle  1280f, 1280 immune response  1281 management  1288t, 1295 pathogenesis  1281 genotype effects  1282 human genome and disease risk  1282 point-​of-​care test  1595 pregnancy  2683 preventative medicine  133t serovars  1280 urethritis  5081 Chlamydia pneumoniae infection  1293 clinical features  1293 arthritis  1293 atherosclerosis  1293 respiratory tract disease  1293 epidemiology  1294 reactive arthritis  4465, 4467–​68 Chlamydia psittaci infection  1294 bird fancier’s lung  4247 clinical features  1294 pneumonia, antimicrobial therapy  4019t Chlamydia trachomatis infection adult screening  149t, 150 associated diseases  1285 adult paratrachoma and otitis media  1285 arthritis  1285 immunocompromised patients  1285 inflammatory eye disease  6408t, 6429 neonatal infections  1285, 1286f diagnosis  1286 culture  1287 nucleic acid amplification tests (NAATs)  1286 point-​of-​care tests  1287 serological tests  1287 specimen type  1286 management  1287 antimicrobial resistance  1287 antimicrobial therapy  1288, 1288t compliance  1289 complicated infections  1289 partner notification  1289 repeated testing  1289 test of cure  1289 oculo-​anogenital tract infection  1282, 1283t bartholinitis  1284 cervicitis  1284f, 1284 epididymitis  1282 nongonococcal urethritis  1282 pelvic inflammatory disease  1284f, 1284, 1285f prostatitis  1282 rectal and pharyngeal infection  1285 urethritis  1606 vaginitis  1284 prevention  1289 health promotion  1289 screening  1289 see also lymphogranuloma venereum (LGV); pelvic inflammatory disease (PID); trachoma Chlamydophila pneumoniae infection coronary heart disease risk factors  3613 investigations  4016 pneumonia  4009t, 4010t, 4011 antimicrobial therapy  4019t chloralose, poisoning  1759 chlorambucil  421t, 3134t, 3164 chloramphenicol  1059, 1255, 5163t chlorates, poisoning  1759 chlorhexidine, skin disease management  5765 chloride adult values  6581t urinary/​faecal reference intervals  6587t chloride channel drugs, ion movement inhibition  84 chlorine, poisoning  1768 chlornaphazine  421t, 440 bis-​chloromethyl ether  422t, 432 chlorophenoxy herbicides, poisoning  1759, 1759t chloroquine  1410t adverse reactions  90 neuropathies  6189 poisoning by  1737 calcium metabolism disorders in sarcoidosis  5014 porphyria cutanea tarda management  2048 sarcoidosis management  4215–​16 skin disease management  5769 chlorpheniramine  2653, 5635 chlorpromazine abdominal pain in acute porphyria  2050 adverse reactions drug-​induced prolactin changes  2551 eye diseases/​disorders  6438–​39 syndrome of inappropriate antidiuresis  2551 chorea in acute rheumatic fever management  3517 drug-​induced parkinsonism  5954 schizophrenia management  6515t cholangiocarcinoma  3184 aetiology  3184 clinical features  3184 epidemiology  3184 investigations  3184, 3185f liver transplantation contraindication  3102 management  3185 pathogenesis  3184 pathology  3184f, 3184 prognosis  3185 PSC complications  3140 cholangiocarcinoma screening and care programme (CASCAP)  1555 cholangiography  3198f, 3198, 4162 cholangitis acute  3201 management in PSC  3139 cholecalciferol see vitamin D3 (cholecalciferol) cholecystectomy alternatives to  3204 complications  3204 bile salt diarrhoea  3204 gastro-​oesophageal reflux  3204 endoscopic retrograde cholangiography  2745 cholecystitis acute gallstones  3199, 3200f, 3200 pregnancy  2625 surgery  2769t chronic  3200 cholecystoduodenal fistula, gallstones  3201 cholecystokinin (CCK)  2726t, 2863f, 2863, 3204 choledochal cysts, bile ducts  3207f, 3207, 3208f, 3208t cholera  1060 aetiology  1061 clinical features  1064, 1064t diagnosis  1064 differential diagnosis  1064 epidemiology  1061, 1063f gastrointestinal system  3009t genetics  1061 historical perspective  1061 immunizations, travel and expedition medicine  716 management  1065f, 1065, 1065t mucosal adherence  3017 pathophysiology  1061, 1062f prevention  1063b, 1063 prognosis  1066 transmission  3013, 3014t vaccinations  3022 vaccines  1063 cholestasis  3171 cholestatic hepatitis  3109 cholestatic liver function tests  3055, 3055t, 3105 cholesterol  2059 atherosclerotic cardiovascular disease and  2056 bile acid synthesis  2061f, 2061 clearance by bile salts  3039 dietary sources  2061 macronutrient metabolism  1853t oxidation  2061 reduction, dyslipidaemia management  2061f, 2085t, 2087f, 2089, 2090f structure  2060f synthesis  2061 regulation  2061, 2062f cholesterol crystals  4311, 4494 cholesterol embolism  3688 clinical features  3689f, 3689 differential diagnosis  3689 epidemiology  3688 investigations  3689 histology  3690f, 3690 management  3690 prevention  3688 prognosis  3690 cholesterol ester storage disease  2150 cholesteryl ester storage disease  2080 cholestyramine  2072t erythropoietic protoporphyria management  2049 primary biliary cholangitis management  3133–​34, 3134t cholinergic drugs, drug-​induced asthma  4274 cholinesterase inhibitors Alzheimer’s disease management  5842, 6480 delirium management  6477 dementia management  6481t vascular dementia  5854, 6480 chondrocalcinosis  4662 chondrocytes  4377, 4381f, 4382 chondrodysplasia  4629t chondrosarcoma  4710, 4711f CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)  4898, 5296 chorea  5957 acquired  5957t, 5959 anti-​NMDAR encephalitis  5959 autoimmune chorea  5959 Sydenham’s chorea  5959 acute rheumatic fever management  3517 causes  5957t inherited  5957t, 5958 benign hereditary chorea  5959 see also Huntington’s disease (HD) chorea–​acanthocytosis  6250 chromhidrosis  5701 chromium  422t, 1753, 1872, 6586t chromoblastomycosis  1346, 1347f chromosome microarray analysis (CMA)  219 copy-​number variants  225 chromosomes  219 disorders acute lymphoblastic leukaemia  5272f eye diseases/​disorders  6435 genomic disorders  228 male infertility  2401 myelodysplastic syndromes  5199 premature ovarian insufficiency  2379 fragility syndromes, inherited cancer genetics  466 megaloblastic anaemia  5421 mosaicism, genomic disorders  230 Neisseria gonorrhoeae antimicrobial resistance  1030 chromothripsis, genetic variation  225 chronic actinic dermatitis (CAP)  5690f, 5690 chronic atypical neutrophilic dermatitis with lipodystrophy and elevated temperature (CANDLE) syndrome  2215

  Index 41 VOLUME 1  pp. 1–1634      VOLUME 2  pp. 1635–3238      VOLUME 3  pp. 3239–5166      VOLUME 4  pp. 5167–6654 chronic childhood spinal muscular atrophy (Kugelberg–​ Welander disease)  6173 chronic cutaneous lupus erythematosus (CCLE)  5652b, 5654f, 5654, 5655f chronic eosinophilic leukaemia (CEL)  453t chronic eosinophilic pneumonia (prolonged pulmonary eosinophilia)  4239 asthma  4078 chronic erythematous oral candidosis (denture stomatitis)  2811 chronic fatigue syndrome  792 chronic fibrosing interstitial pneumonia see major idiopathic interstitial pneumonia chronic granulomatous disease (CGD) gastrointestinal manifestations  2788t infections  362 neutrophils  5194 chronic heart failure  3407 aetiology  3409, 3410t cardiac phenotypes  3408, 3409f, 3409t cardiac MRI  3409 HFrEF (left ventricular systolic dysfunction)  3409 left ventricular diastolic dysfunction  3409 cardiopulmonary exercise tests  3969 central sleep apnoea  4050 clinical physiology  3408f, 3408 comorbidities  3412, 3412t, 3417 anaemia  3419 angina  3418 atrial fibrillation  3418 gout  3419 myocardial ischaemia  3418 renal dysfunction  3418 respiratory disease  3418 sleep-​disordered breathing  3418 valve disease  3417 definition  3407, 3408f diagnosis  3410 cardiac dysfunction causes  3409f, 3411 cardiac phenotype  3411 case ascertainment  3410 differential diagnosis  3411, 3411t drug management  3413, 3414f ACE inhibitors  3414 angiotensin receptor blockers  3415 angiotensin receptor–​neprilysin inhibitors  3415 antiarrhythmic agents  3416 anticoagulants  3416 antiplatelet agents  3416 β-​blockers  3415 drug avoidance  3417 inotropic agents  3416 lipid-​modifying management  3416 loop diuretics  3413 mineralocorticoid receptor antagonists  3415 renin inhibitors  3415 thiazide diuretics  3413 vasodilators  3416 end-​stage heart failure  3419 exacerbation of  3419 investigations  3412, 3413t blood tests  3420 ECG  3420 haemoglobin  3420 renal function  3420 serum potassium  3420 management  3412, 3417 cardiac resynchronization management  3417 gene management  3417 implantable cardioverter-​ defibrillators  3417 lifestyle  3413 normal ejection fraction  3419 organization of care  3420t, 3421 practical aspects  3419 monitoring  3419 prognosis  3412, 3414f risk factor  3409, 3409t age  3409 hypertension  3409 ischaemic heart disease  3409 symptoms and signs  3419 blood pressure  3420 heart rate  3419 chronic hepatitis B  893, 3109, 3114 clinical features  3115 hepatocellular carcinoma  3115–​16 liver fibrosis  3115 histology  3115 investigations  3115f, 3115 management  3116 antiviral drugs  3116, 3116t interferons  3116 phases  3114 physical examination  3115 serology  3114t chronic hepatitis C  3109, 3117 clinical features  898, 3117, 3117t investigations  3117 management  900f, 900, 3118 HIV co-​infection  3118 interferon  3118 ribavirin  3118 chronic infantile neurological cutaneous articular syndrome (CINCA)  2208t management, biologics  104 chronic kidney disease (CKD)  4767b, 4768 acute porphyrias  2041 cardiac involvement  3423b, 3423f arrhythmias  3423f, 3425t, 3426 chronic heart failure risk factor  3412t coronary heart disease risk factors  3613 left ventricular hypertrophy  3422, 3427 vascular calcification  3427 see also cardiorenal syndrome causes  4830, 4834, 4835t, 4850b clinical assessment  4838 family history  4839 investigations  4840, 4841–​42t personal history  4838 physical examination  4839, 4840t uraemia  4839 clinical presentation  4837 associated disease  4838 asymptomatic patients  4838 symptomatic patients  4838 complication management  4832, 4844 acidosis  4844 anaemia  4852 electrolytes  4844 nutrition  4844 water  4844 definition  4831 diabetic nephropathy  4978, 4979 diuretic resistance  3426 drug metabolism  5151 dyslipidaemia  2084 epidemiology  4830 immunoglobulin A nephropathy  4912 immunoglobulin A nephropathy vs.  4913 indications of  4852b infections and  4777 management anaemia see anaemia mineral and bone disorder see chronic kidney disease–​ mineral bone disorder (CKD–​MRD) peritoneal dialysis  4875 renal replacement therapy see renal replacement therapy (RRT) mortality  4833, 4833t pathophysiology  4830, 4835 acid–​base balance  4836 electrolytes  4836 endocrine dysfunction  4836 middle molecules  4837 uraemic syndrome  4837 water  4836 pregnancy avoidance  2667 pregnancy in  2589, 2592, 2592t, 2593t, 2594t medication use  2594t prevalence  4765f, 4765 prevalence and incidence  4833, 4833t, 4834f, 4835t progression management  4831, 4840 blood pressure control  4840, 4843f dietary protein restriction  4843 lifestyle changes  4843, 4844f, 4851b pharmacological intervention  4843 proteinuria reduction  4842 progression of  4837, 4851b glomerular filtration rate 
4831–​32, 4833f kidney function assessment  4832 renal ultrasound  4796 screening  4765 sickle cell nephropathy  5034 stages of  3423t, 4789t staging  4830, 4831–​32, 4832f glomerular filtration rate  4832 tropics  5052f, 5052 Chronic Kidney Disease Epidemiology Collaboration (CKD-​EPI)  4832 chronic kidney disease–​mineral bone disorder (CKD–​ MRD)  3427, 4845, 4846 biochemical abnormalities, 4849, 4850t lesion types, 4847 adynamic bone  4847 hyperparathyroidism  4847, 4848f osteomalacia/​rickets  4847 osteopenia  4848 osteoporosis  4848 parathyroid growth, 4852 pathogenesis  4846 1,25-​dihydroxyvitamin D deficiency  4846f, 4846 hypercalcaemia  4846 phosphate excess  4846 renal osteodystrophy  4847 secondary hyperparathyroidism  4849 serum calcium control, 4850 serum phosphate control  4849 symptoms and signs, 4848f, 4848, 4849f chronic leg ischaemia see leg ischaemia Chronic Liver Failure Consortium ACLF score (CLIF-​ CACLFs)  3091, 3096f Chronic Liver Failure Consortium Organ Failure score (CLIF-​ OFs)  3090–​91, 3091t chronic lung allograft dysfunction (CLAD)  4300, 4301f chronic lymphatic filariasis see lymphatic filariasis chronic lymphocytic leukaemia (CLL)  5266–​67, 5302 aetiology  5303 areas of uncertainty/​ controversy  5308 biology  5308 management  5308 prognostic markers  5308 clinical features  5302, 5304 clinical investigations  5305b, 5305 clinical staging  5302 diagnosis  5302, 5305 staging  5305b, 5305 differential diagnosis  5304, 5305f epidemiology  443, 5304 future developments  5308 biology  5308 management  5309 genetics  5303 historical perspective  5302 management  5302, 5306 complication management  5307 initial management  5306 quality of life  5308 refractory disease  5307 relapses  5307 secondary malignancies  5308 transplantation  5307

Contents

Contents

Contents Volume 1 List of abbreviations  xxxv List of contributors  xlv SECTION 1 Patients and their treatment Section editors: John D. Firth, Christopher P. Conlon,
and Timothy M. Cox 1.1 On being a patient  3 Christopher Booth† 1.2 A young person’s experience of chronic
disease  6 1.3 What patients wish you understood  8 Rosamund Snow† 1.4 Why do patients attend and what do they want from the consultation?  14 Des Spence 1.5 Medical ethics  20 Mike Parker, Mehrunisha Suleman, and Tony Hope 1.6 Clinical decision-​making  26 Timothy E.A. Peto and Philippa Peto SECTION 2 Background to medicine Section editors: John D. Firth, Christopher P. Conlon, and Timothy M. Cox 2.1 Science in medicine: When, how, and what  33 William F. Bynum 2.2 Evolution: Medicine’s most basic science  39 Randolph M. Nesse and Richard Dawkins 2.3 The Global Burden of Disease: Measuring the health of populations  43 Theo Vos, Alan Lopez, and Christopher Murray 2.4 Large-​scale randomized evidence: Trials and meta-​analyses of trials  51 Colin Baigent, Richard Peto, Richard Gray, Natalie Staplin, Sarah Parish, and Rory Collins 2.5 Bioinformatics  67 Afzal Chaudhry 2.6 Principles of clinical pharmacology and drug therapy  71 Kevin O’Shaughnessy 2.7 Biological therapies for immune, inflammatory, and allergic diseases  100 John D. Isaacs and Nishanthi Thalayasingam 2.8 Traditional medicine exemplified by traditional Chinese medicine  108 Fulong Liao, Tingliang Jiang, and Youyou Tu 2.9 Engaging patients in therapeutic development  118 Emil Kakkis and Max Bronstein 2.10 Medicine quality, physicians, and patients  124 Paul N. Newton 2.11 Preventive medicine  127 David Mant 2.12 Medical screening  137 Nicholas Wald and Malcolm Law 2.13 Health promotion  152 Evelyne de Leeuw † It is with great regret that we report that Christopher Booth died on 13 July, 2012 and Rosamund Snow died on 2 February, 2017.

Contents xiv 2.14 Deprivation and health  157 Harry Burns 2.15 How much should rich countries’ governments spend on healthcare?  161 Allyson M. Pollock and David Price 2.16 Financing healthcare in low-​income developing countries: A challenge for equity in health  168 Luis G. Sambo, Jorge Simões, and Maria do Rosario O. Martins 2.17 Research in the developed world  177 Jeremy Farrar 2.18 Fostering medical and health research in resource-​constrained countries  181 Malegapuru W. Makgoba and Stephen M. Tollman 2.19 Regulation versus innovation in medicine  185 Michael Rawlins 2.20 Human disasters  188 Amartya Sen 2.21 Humanitarian medicine  193 Amy S. Kravitz 2.22 Complementary and alternative medicine  201 Edzard Ernst SECTION 3 Cell biology Section editors: John D. Firth, Christopher P. Conlon, and Timothy M. Cox 3.1 The cell  209 George Banting and Jean Paul Luzio 3.2 The genomic basis of medicine  218 Paweł Stankiewicz and James R. Lupski 3.3 Cytokines  236 Iain B. McInnes 3.4 Ion channels and disease  246 Frances Ashcroft and Paolo Tammaro 3.5 Intracellular signalling  256 R. Andres Floto 3.6 Apoptosis in health and disease  266 Mark J. Arends and Christopher D. Gregory 3.7 Stem cells and regenerative medicine  281 Alexis J. Joannides, Bhuvaneish T. Selvaraj, and
Siddharthan Chandran 3.8 The evolution of therapeutic antibodies  296 Herman Waldmann and Greg Winter 3.9 Circulating DNA for molecular diagnostics  299 Y.M. Dennis Lo and Rossa W.K. Chiu SECTION 4 Immunological mechanisms Section editors: John D. Firth, Christopher P. Conlon, and Timothy M. Cox 4.1 The innate immune system  307 Paul Bowness 4.2 The complement system  315 Marina Botto and Matthew C. Pickering 4.3 Adaptive immunity  325 Paul Klenerman and Constantino López-​Macias 4.4 Immunodeficiency  337 Sophie Hambleton, Sara Marshall, and Dinakantha S. Kumararatne 4.5 Allergy  368 Pamela Ewan 4.6 Autoimmunity  379 Antony Rosen 4.7 Principles of transplantation immunology  392 Elizabeth Wallin and Kathryn J. Wood SECTION 5 Principles of clinical oncology Section editors: John D. Firth, Christopher P. Conlon, and Timothy M. Cox 5.1 Epidemiology of cancer  411 Anthony Swerdlow and Richard Peto 5.2 The nature and development of cancer: Cancer mutations and their implications  445 James D. Brenton and Tim Eisen 5.3 The genetics of inherited cancers  456 Rosalind A. Eeles 5.4 Cancer immunity and immunotherapy  471 Charles G. Drake 5.5 Clinical features and management  487 Tim Eisen and Martin Gore† 5.6 Systemic treatment and radiotherapy  497 Rajesh Jena and Peter Harper † It is with great regret that we report that Martin Gore died on 10 January, 2019.

Contents xv 5.7 Medical management of breast cancer  505 Tim Crook, Su Li, and Peter Harper SECTION 6 Old age medicine Section editor: Finbarr C. Martin 6.1 Ageing and clinical medicine  511 Claire Steves and Neil Pendleton 6.2 Frailty and sarcopenia  521 Andrew Clegg and Harnish Patel 6.3 Optimizing well-​being into old age  532 Steve Iliffe 6.4 Older people and urgent care  539 Simon Conroy and Jay Banerjee 6.5 Older people in hospital  548 Graham Ellis, Alasdair MacLullich, and Rowan Harwood 6.6 Supporting older peoples’ care in surgical and oncological services  563 Jugdeep Dhesi and Judith Partridge 6.7 Drugs and prescribing in the older patient  571 Miles Witham, Jacob George, and Denis O’Mahony 6.8 Falls, faints, and fragility fractures  579 Fiona Kearney and Tahir Masud 6.9 Bladder and bowels  589 Susie Orme and Danielle Harari 6.10 Neurodegenerative disorders in older people  601 John Hindle 6.11 Promotion of dignity in the life and death of older patients  612 Eileen Burns and Claire Scampion SECTION 7 Pain and palliative care Section editor: Bee Wee 7.1 Introduction to palliative care  623 Susan Salt 7.2 Pain management  629 Marie Fallon 7.3 Symptoms other than pain  634 Regina McQuillan 7.4 Care of the dying person  639 Suzanne Kite and Adam Hurlow SECTION 8 Infectious diseases Section editor: Christopher P. Conlon 8.1 Pathogenic microorganisms and the host  651

8.1.1 Biology of pathogenic microorganisms  651 Duncan J. Maskell and James L.N. Wood

8.1.2 Clinical features and general management of patients with severe infections  656 Peter Watkinson and Duncan Young 8.2 The patient with suspected infection  662

8.2.1 Clinical approach  662 Christopher J. Ellis

8.2.2 Fever of unknown origin  664 Steven Vanderschueren

8.2.3 Nosocomial infections  669 Ian C.J.W. Bowler and Matthew Scarborough

8.2.4 Infection in the immunocompromised host  673 Jon Cohen and Elham Khatamzas

8.2.5 Antimicrobial chemotherapy  684 Maha Albur, Alasdair MacGowan, and Roger G. Finch 8.3 Immunization  706 David Goldblatt and Mary Ramsay 8.4 Travel and expedition medicine  713 Susanna Dunachie and Christopher P. Conlon 8.5 Viruses  723

8.5.1 Respiratory tract viruses  723 Malik Peiris

8.5.2 Herpesviruses (excluding Epstein–​Barr virus)  734 J.G.P. Sissons†

8.5.3 Epstein–​Barr virus  754 Alan B. Rickinson and M.A. Epstein

8.5.4 Poxviruses  764 Geoffrey L. Smith

8.5.5 Mumps: Epidemic parotitis  769 B.K. Rima

8.5.6 Measles  772 Hilton C. Whittle and Peter Aaby

8.5.7 Nipah and Hendra virus encephalitides  784 C.T. Tan † It is with great regret that we report that J.G.P. Sissons died on 25 September, 2016.

Contents xvi

8.5.8 Enterovirus infections  787 Philip Minor and Ulrich Desselberger

8.5.9 Virus infections causing diarrhoea and vomiting  797 Philip R. Dormitzer and Ulrich Desselberger

8.5.10 Rhabdoviruses: Rabies and rabies-​related lyssaviruses  805 Mary J. Warrell and David A. Warrell

8.5.11 Colorado tick fever and other arthropod-​borne reoviruses  819 Mary J. Warrell and David A. Warrell

8.5.12 Alphaviruses  821 Ann M. Powers, E.E. Ooi, L.R. Petersen, and D.J. Gubler

8.5.13 Rubella  827 Pat Tookey and J.M. Best

8.5.14 Flaviviruses excluding dengue  830 Shannan Lee Rossi and Nikos Vasilakis

8.5.15 Dengue  845 Bridget Wills and Yee-​Sin Leo

8.5.16 Bunyaviridae  852 James W. Le Duc and D.A. Bente

8.5.17 Arenaviruses  862 Jan H. ter Meulen

8.5.18 Filoviruses  870 Jan H. ter Meulen

8.5.19 Papillomaviruses and polyomaviruses  877 Raphael P. Viscidi, Chen Sabrina Tan, and
Carole Fakhry

8.5.20 Parvovirus B19  886 Kevin E. Brown

8.5.21 Hepatitis viruses (excluding hepatitis C virus)  889 Matthew Cramp, Ashwin Dhanda, and
Nikolai V. Naoumov

8.5.22 Hepatitis C virus  896 Paul Klenerman, Katie J.M. Jeffery, Ellie J. Barnes, and
Jane Collier

8.5.23 HIV/​AIDS  901 Sarah Fidler, Timothy E.A. Peto, Philip Goulder, and Christopher P. Conlon

8.5.24 HIV in low-​ and middle-​income countries  933 Alison D. Grant and Kevin M. De Cock

8.5.25 HTLV-​1, HTLV-​2, and associated diseases  941 Kristien Verdonck and Eduardo Gotuzzo

8.5.26 Viruses and cancer  945 Robin A. Weiss

8.5.27 Orf and Milker’s nodule  947 Emma Aarons and David A. Warrell

8.5.28 Molluscum contagiosum  949 David A. Warrell and Christopher P. Conlon

8.5.29 Newly discovered viruses  951 Susannah J.A. Froude and Harriet C. Hughes 8.6 Bacteria  958

8.6.1 Diphtheria  959 Delia B. Bethell and Tran Tinh Hien

8.6.2 Streptococci and enterococci  965 Dennis L. Stevens and Sarah Hobdey

8.6.3 Pneumococcal infections  975 Anthony Scott

8.6.4 Staphylococci  991 Kyle J. Popovich, Robert A. Weinstein, and Bala Hota

8.6.5 Meningococcal infections  1010 Petter Brandtzaeg

8.6.6 Neisseria gonorrhoeae  1025 Jackie Sherrard and Magnus Unemo

8.6.7 Enterobacteria and bacterial food poisoning  1032 Hugh Pennington

8.6.8 Pseudomonas aeruginosa  1041 G.C.K.W. Koh and Sharon J. Peacock

8.6.9 Typhoid and paratyphoid fevers  1044 Christopher M. Parry and Buddha Basnyat

8.6.10 Intracellular klebsiella infections (donovanosis and rhinoscleroma)  1051 John Richens and Nicole Stoesser

8.6.11 Anaerobic bacteria  1055 Anilrudh A. Venugopal and David W. Hecht

8.6.12 Cholera  1060 Aldo A.M. Lima and Richard L. Guerrant

8.6.13 Haemophilus influenzae  1066 Esther Robinson

8.6.14 Haemophilus ducreyi and chancroid  1071 Nigel O’Farrell

8.6.15 Bordetella infection  1073 Cameron C. Grant

8.6.16 Melioidosis and glanders  1076 Sharon J. Peacock

8.6.17 Plague: Yersinia pestis  1081 Michael Prentice

8.6.18 Other Yersinia infections: Yersiniosis  1086 Michael Prentice

8.6.19 Pasteurella  1088 Marina S. Morgan

8.6.20 Francisella tularensis infection  1091 Petra C.F. Oyston

Contents xvii

8.6.21 Anthrax  1094 Arthur E. Brown

8.6.22 Brucellosis  1102 Juan D. Colmenero and Pilar Morata

8.6.23 Tetanus  1109 C. Louise Thwaites and Lam Minh Yen

8.6.24 Clostridium difficile  1115 David W. Eyre and Mark H. Wilcox

8.6.25 Botulism, gas gangrene, and clostridial gastrointestinal infections  1120 Dennis L. Stevens, Michael J. Aldape, and Amy E. Bryant

8.6.26 Tuberculosis  1126 Richard E. Chaisson and Jean B. Nachega

8.6.27 Disease caused by environmental mycobacteria  1150 Jakko van Ingen

8.6.28 Leprosy (Hansen’s disease)  1154 Diana N.J. Lockwood

8.6.29 Buruli ulcer: Mycobacterium ulcerans infection  1167 Bouke de Jong, Françoise Portaels, and Wayne M. Meyers

8.6.30 Actinomycoses  1170 Klaus P. Schaal

8.6.31 Nocardiosis  1176 Roderick J. Hay

8.6.32 Rat bite fevers (Streptobacillus moniliformis and Spirillum minus infection)  1179 Andrew F. Woodhouse

8.6.33 Lyme borreliosis  1181 Gary P. Wormser, John Nowakowski, and
Robert B. Nadelman

8.6.34 Relapsing fevers  1188 David A. Warrell

8.6.35 Leptospirosis  1198 Nicholas P.J. Day

8.6.36 Nonvenereal endemic treponematoses: Yaws, endemic syphilis (bejel), and pinta  1204 Michael Marks, Oriol Mitjà, and David Mabey

8.6.37 Syphilis  1210 Phillip Read and Basil Donovan

8.6.38 Listeriosis  1223 Herbert Hof

8.6.39 Legionellosis and Legionnaires’ disease  1226 Diego Viasus and Jordi Carratalà

8.6.40 Rickettsioses  1230 Karolina Griffiths, Carole Eldin, Didier Raoult, and Philippe Parola

8.6.41 Scrub typhus  1252 Daniel H. Paris and Nicholas P.J. Day

8.6.42 Coxiella burnetii infections (Q fever)  1257 Thomas J. Marrie

8.6.43 Bartonellas excluding B. bacilliformis  1262 Bruno B. Chomel, Henri-​Jean Boulouis, Matthew J. Stuckey, and Jean-​Marc Rolain

8.6.44 Bartonella bacilliformis infection  1272 A. Llanos-​Cuentas and C. Maguiña-​Vargas

8.6.45 Chlamydial infections  1278 Patrick Horner, David Mabey, David Taylor-​Robinson, and Magnus Unemo

8.6.46 Mycoplasmas  1295 Jørgen Skov Jensen and David Taylor-​Robinson

8.6.47 A checklist of bacteria associated with infection
in humans  1307 John Paul 8.7 Fungi (mycoses)  1338

8.7.1 Fungal infections  1338 Roderick J. Hay

8.7.2 Cryptococcosis  1359 William G. Powderly, J. William Campbell, and
Larry J. Shapiro

8.7.3 Coccidioidomycosis  1361 Gregory M. Anstead

8.7.4 Paracoccidioidomycosis  1364 M.A. Shikanai-​Yasuda

8.7.5 Pneumocystis jirovecii  1371 Robert F. Miller and Christopher P. Eades

8.7.6 Talaromyces (Penicillium) marneffei infection  1375 Romanee Chaiwarith, Khuanchai Supparatpinyo, and Thira Sirisanthana

8.7.7 Microsporidiosis  1378 Louis M. Weiss 8.8 Protozoa  1384

8.8.1 Amoebic infections  1384 Richard Knight

8.8.2 Malaria  1395 Nicholas J. White and Arjen M. Dondorp

8.8.3 Babesiosis  1414 Philippe Brasseur

8.8.4 Toxoplasmosis  1416 Oliver Liesenfeld and Eskild Petersen

8.8.5 Cryptosporidium and cryptosporidiosis  1424 Simone M. Cacciò

8.8.6 Cyclospora and cyclosporiasis  1432 Paul Kelly and Ralph Lainson† † It is with great regret that we report that Ralph Lainson died on 5 May, 2015.

Contents xviii

8.8.7 Cystoisosporiasis  1436 Louis M. Weiss

8.8.8 Sarcocystosis (sarcosporidiosis)  1438 John E. Cooper

8.8.9 Giardiasis and balantidiasis  1440 Lars Eckmann and Martin F. Heyworth

8.8.10 Blastocystis infection  1449 Richard Knight

8.8.11 Human African trypanosomiasis  1451 Reto Brun and Johannes Blum

8.8.12 Chagas disease  1459 Michael A. Miles

8.8.13 Leishmaniasis  1467 Antony D.M. Bryceson and Diana N.J. Lockwood

8.8.14 Trichomoniasis  1475 Jane Schwebke 8.9 Nematodes (roundworms)  1478

8.9.1 Cutaneous filariasis  1478 Gilbert Burnham

8.9.2 Lymphatic filariasis  1487 Richard Knight

8.9.3 Guinea worm disease (dracunculiasis)  1495 Richard Knight

8.9.4 Strongyloidiasis, hookworm, and other gut strongyloid nematodes  1500 Michael Brown

8.9.5 Gut and tissue nematode infections acquired
by ingestion  1506 Peter L. Chiodini

8.9.6 Angiostrongyliasis  1516 Richard Knight 8.10 Cestodes (tapeworms)  1520

8.10.1 Cestodes (tapeworms)  1520 Richard Knight

8.10.2 Cystic hydatid disease (Echinococcus
granulosus)  1529 Pedro L. Moro, Hector H. Garcia, and
Armando E. Gonzalez

8.10.3 Cysticercosis  1533 Hector H. Garcia and Robert H. Gilman 8.11 Trematodes (flukes)  1540

8.11.1 Schistosomiasis  1540 David Dunne and Birgitte Vennervald

8.11.2 Liver fluke infections  1551 Ross H. Andrews, Narong Khuntikeo,
Paiboon Sithithaworn, and Trevor N. Petney

8.11.3 Lung flukes (paragonimiasis)  1558 Udomsak Silachamroon and Sirivan Vanijanonta

8.11.4 Intestinal trematode infections  1562 Alastair McGregor 8.12 Nonvenomous arthropods  1568 John Paul 8.13 Pentastomiasis (porocephalosis,
linguatulosis/​linguatuliasis, or tongue
worm infection)  1582 David A. Warrell SECTION 9 Sexually transmitted diseases Section editor: Jackie Sherrard 9.1 Epidemiology of sexually transmitted infections  1589 David Mabey and Anita Vas-​Falcao 9.2 Sexual behaviour  1597 Catherine H. Mercer and Anne M. Johnson 9.3 Sexual history and examination  1600 Gary Brook, Jackie Sherrard, and Graz A. Luzzi 9.4 Vaginal discharge  1603 Paul Nyirjesy 9.5 Urethritis  1606 Patrick Horner 9.6 Genital ulceration  1610 Patrick French and Raj Patel 9.7 Anogenital lumps and bumps  1613 Henry J.C. de Vries and Charles J.N. Lacey 9.8 Pelvic inflammatory disease  1622 Jonathan D.C. Ross 9.9 Principles of contraception  1626 Zara Haider Index

Contents xix Volume 2 List of abbreviations  xxxv List of contributors  xlv SECTION 10 Environmental medicine, occupational medicine, and poisoning Section editor: Jon G. Ayres 10.1 Environmental medicine, occupational medicine, and poisoning—​Introduction  1637 Jon G. Ayres 10.2 Occupational health  1638

10.2.1 Occupational and environmental health  1638 Raymond Agius and Debasish Sen

10.2.2 Occupational safety  1652 Lawrence Waterman

10.2.3 Aviation medicine  1656 Michael Bagshaw

10.2.4 Diving medicine  1664 David M. Denison and Mark A. Glover

10.2.5 Noise  1671 David Koh and Tar-​Ching Aw†

10.2.6 Vibration  1673 Tar-​Ching Aw† 10.3 Environment and health  1677

10.3.1 Air pollution and health  1677 Om P. Kurmi, Kin Bong Hubert Lam, and Jon G. Ayres

10.3.2 Heat  1687 Michael A. Stroud

10.3.3 Cold  1689 Michael A. Stroud

10.3.4 Drowning  1691 Peter J. Fenner

10.3.5 Lightning and electrical injuries  1696 Chris Andrews

10.3.6 Diseases of high terrestrial altitudes  1701 Tyler Albert, Erik R. Swenson, Andrew J. Pollard, Buddha Basnyat, and David R. Murdoch

10.3.7 Radiation  1709 Jill Meara

10.3.8 Disasters: Earthquakes, hurricanes, floods, and volcanic eruptions  1713 Peter J. Baxter

10.3.9 Bioterrorism  1718 Manfred S. Green 10.4 Poisoning  1725

10.4.1 Poisoning by drugs and chemicals  1725 John A. Vale, Sally M. Bradberry, and D. Nicholas Bateman

10.4.2 Injuries, envenoming, poisoning, and allergic reactions caused by animals  1778 David A. Warrell

10.4.3 Poisonous fungi  1817 Hans Persson and David A. Warrell

10.4.4 Poisonous plants  1828 Michael Eddleston and Hans Persson 10.5 Podoconiosis (nonfilarial elephantiasis)  1833 Gail Davey SECTION 11 Nutrition Section editor: Katherine Younger 11.1 Nutrition: Macronutrient metabolism  1839 Keith N. Frayn and Rhys D. Evans 11.2 Vitamins  1855 Tom R. Hill and David A. Bender 11.3 Minerals and trace elements  1871 Katherine Younger 11.4 Severe malnutrition  1880 Alan A. Jackson 11.5 Diseases of affluent societies and the need for dietary change  1891 J.I. Mann and A.S. Truswell 11.6 Obesity  1903 I. Sadaf Farooqi 11.7 Artificial nutrition support  1914 Jeremy Woodward † It is with great regret that we report that Tar-Ching Aw died on 18 July, 2017.

Contents xx SECTION 12 Metabolic disorders Section editor: Timothy M. Cox 12.1 The inborn errors of metabolism: General aspects  1929 Timothy M. Cox and Richard W.E. Watts† 12.2 Protein-​dependent inborn errors of metabolism  1942 Georg F. Hoffmann and Stefan Kölker 12.3 Disorders of carbohydrate metabolism  1985

12.3.1 Glycogen storage diseases  1985 Robin H. Lachmann and Timothy M. Cox

12.3.2 Inborn errors of fructose metabolism  1993 Timothy M. Cox

12.3.3 Disorders of galactose, pentose, and pyruvate metabolism  2003 Timothy M. Cox 12.4 Disorders of purine and pyrimidine metabolism  2015 Anthony M. Marinaki, Lynette D. Fairbanks, and Richard W.E. Watts† 12.5 The porphyrias  2032 Timothy M. Cox 12.6 Lipid disorders  2055 Jaimini Cegla and James Scott 12.7 Trace metal disorders  2098

12.7.1 Hereditary haemochromatosis  2098 William J.H. Griffiths and Timothy M. Cox

12.7.2 Inherited diseases of copper metabolism:
Wilson’s disease and Menkes’ disease  2115 Michael L. Schilsky and Pramod K. Mistry 12.8 Lysosomal disease  2121 Patrick B. Deegan and Timothy M. Cox 12.9 Disorders of peroxisomal metabolism in adults  2157 Anthony S. Wierzbicki 12.10 Hereditary disorders of oxalate metabolism: The primary hyperoxalurias  2174 Sonia Fargue, Dawn S. Milliner, and Christopher J. Danpure 12.11 A physiological approach to acid–​base disorders: The roles of ion transport and body fluid compartments  2182 Julian Seifter 12.12 The acute phase response, hereditary periodic fever syndromes, and amyloidosis  2199

12.12.1 The acute phase response and C-​reactive protein  2199 Mark B. Pepys

12.12.2 Hereditary periodic fever syndromes  2207 Helen J. Lachmann, Stefan Berg, and Philip N. Hawkins

12.12.3 Amyloidosis  2218 Mark B. Pepys and Philip N. Hawkins 12.13 α1-​Antitrypsin deficiency and the serpinopathies  2235 David A. Lomas SECTION 13 Endocrine disorders Section editor: Mark Gurnell 13.1 Principles of hormone action  2245 Rob Fowkes, V. Krishna Chatterjee, and Mark Gurnell 13.2 Pituitary disorders  2258

13.2.1 Disorders of the anterior pituitary gland  2258 Niki Karavitaki and John A.H. Wass

13.2.2 Disorders of the posterior pituitary gland  2277 Niki Karavitaki, Shahzada K. Ahmed, and John A.H. Wass 13.3 Thyroid disorders  2284

13.3.1 The thyroid gland and disorders of thyroid function  2284 Anthony P. Weetman and Kristien Boelaert

13.3.2 Thyroid cancer  2302 Kristien Boelaert and Anthony P. Weetman 13.4 Parathyroid disorders and diseases altering calcium metabolism  2313 R.V. Thakker 13.5 Adrenal disorders  2331

13.5.1 Disorders of the adrenal cortex  2331 Mark Sherlock and Mark Gurnell

13.5.2 Congenital adrenal hyperplasia  2360 Nils P. Krone and Ieuan A. Hughes 13.6 Reproductive disorders  2374

13.6.1 Ovarian disorders  2374 Stephen Franks, Kate Hardy, and Lisa J. Webber

13.6.2 Disorders of male reproduction and male hypogonadism  2386 P.-​M.G. Bouloux

13.6.3 Benign breast disease  2406 Gael M. MacLean † It is with great regret that we report that Richard W.E. Watts died on 11 February, 2018.

Contents xxi

13.6.4 Sexual dysfunction  2408 Ian Eardley 13.7 Disorders of growth and development  2416

13.7.1 Normal growth and its disorders  2416 Gary Butler

13.7.2 Normal puberty and its disorders  2428 Fiona Ryan and Sejal Patel

13.7.3 Normal and abnormal sexual differentiation  2435 S. Faisal Ahmed and Angela K. Lucas-​Herald 13.8 Pancreatic endocrine disorders and multiple endocrine neoplasia  2449 B. Khoo, T.M. Tan, and S.R. Bloom 13.9 Diabetes and hypoglycaemia  2464

13.9.1 Diabetes  2464 Colin Dayan and Julia Platts

13.9.2 Hypoglycaemia  2531 Mark Evans and Ben Challis 13.10 Hormonal manifestations of nonendocrine disease  2541 Thomas M. Barber and John A.H. Wass 13.11 The pineal gland and melatonin  2553 J. Arendt and Timothy M. Cox SECTION 14 Medical disorders in pregnancy Section editor: Catherine Nelson-​Piercy 14.1 Physiological changes of normal pregnancy  2563 David J. Williams 14.2 Nutrition in pregnancy  2568 David J. Williams 14.3 Medical management of normal pregnancy  2575 David J. Williams 14.4 Hypertension in pregnancy  2583 Fergus McCarthy 14.5 Renal disease in pregnancy  2589 Kate Wiles 14.6 Heart disease in pregnancy  2597 Catherine E.G. Head 14.7 Thrombosis in pregnancy  2606 Peter K. MacCallum and Louise Bowles 14.8 Chest diseases in pregnancy  2613 Meredith Pugh and Tina Hartert 14.9 Liver and gastrointestinal diseases of pregnancy  2619 Michael Heneghan and Catherine Williamson 14.10 Diabetes in pregnancy  2627 Bryony Jones and Anne Dornhorst 14.11 Endocrine disease in pregnancy  2638 David Carty 14.12 Neurological conditions in pregnancy  2642 Pooja Dassan 14.13 The skin in pregnancy  2648 Gudula Kirtschig and Fenella Wojnarowska 14.14 Autoimmune rheumatic disorders and vasculitis in pregnancy  2655 May Ching Soh and Catherine Nelson-​Piercy 14.15 Maternal infection in pregnancy  2671 Rosie Burton 14.16 Fetal effects of maternal infection  2678 Lawrence Impey 14.17 Blood disorders in pregnancy  2687 David J. Perry and Katharine Lowndes 14.18 Malignant disease in pregnancy  2696 Robin A.F. Crawford 14.19 Maternal critical care  2701 Rupert Gauntlett 14.20 Prescribing in pregnancy  2706 Lucy MacKillop and Charlotte Frise 14.21 Contraception for women with medical diseases  2711 Aarthi R. Mohan SECTION 15 Gastroenterological disorders Section editor: Jack Satsangi 15.1 Structure and function of the gastrointestinal tract  2721 Michael E.B. FitzPatrick and Satish Keshav† 15.2 Symptoms of gastrointestinal disease  2727 Jeremy Woodward 15.3 Methods for investigation of
gastroenterological disease  2734

15.3.1 Colonoscopy and flexible sigmoidoscopy  2734 James E. East and Brian P. Saunders † It is with great regret that we report that Satish Keshav died on 23 January, 2019.

Contents xxii

15.3.2 Upper gastrointestinal endoscopy  2740 James E. East and George J. Webster

15.3.3 Radiology of the gastrointestinal tract  2748 Fiachra Moloney and Michael Maher

15.3.4 Investigation of gastrointestinal function  2757 Jervoise Andreyev 15.4 Common acute abdominal presentations  2765

15.4.1 The acute abdomen  2765 Simon J.A. Buczacki and R. Justin Davies

15.4.2 Gastrointestinal bleeding  2771 Vanessa Brown and T.A. Rockall 15.5 Immune disorders of the gastrointestinal tract  2783 Joya Bhattacharyya and Arthur Kaser 15.6 The mouth and salivary glands  2797 John Gibson and Douglas Robertson 15.7 Diseases of the oesophagus  2828 Rebecca C. Fitzgerald and Massimiliano di Pietro 15.8 Peptic ulcer disease  2849 Joseph Sung 15.9 Hormones and the gastrointestinal tract  2862

15.9.1 Hormones and the gastrointestinal tract  2862 Rebecca Scott, T.M. Tan, and S.R. Bloom

15.9.2 Carcinoid syndrome  2870 B. Khoo, T.M. Tan, and S.R. Bloom 15.10 Malabsorption  2875

15.10.1 Differential diagnosis and investigation of malabsorption  2875 Alastair Forbes and Victoria Mulcahy

15.10.2 Bacterial overgrowth of the small
intestine  2879 Stephen J. Middleton and Raymond J. Playford

15.10.3 Coeliac disease  2884 Peter D. Mooney and David S. Sanders

15.10.4 Gastrointestinal lymphomas  2892 Kikkeri N. Naresh

15.10.5 Disaccharidase deficiency  2902 Timothy M. Cox

15.10.6 Whipple’s disease  2909 Florence Fenollar and Didier Raoult

15.10.7 Effects of massive bowel resection  2911 Stephen J. Middleton, Simon M. Gabe, and
Raymond J. Playford

15.10.8 Malabsorption syndromes in the tropics  2916 Vineet Ahuja and Govind K. Makharia 15.11 Crohn’s disease  2925 Miles Parkes and Tim Raine 15.12 Ulcerative colitis  2937 Jeremy Sanderson and Peter Irving 15.13 Irritable bowel syndrome  2951 Adam D. Farmer and Qasim Aziz 15.14 Colonic diverticular disease  2960 Nicolas C. Buchs, Roel Hompes, Shazad Q. Ashraf, and
Neil J.McC. Mortensen 15.15 Congenital abnormalities of the gastrointestinal tract  2967 Holm H. Uhlig 15.16 Cancers of the gastrointestinal tract  2977 Peter L. Labib, J.A. Bridgewater, and Stephen P. Pereira 15.17 Vascular disorders of the gastrointestinal tract  2997 Ray Boyapati 15.18 Gastrointestinal infections  3008 Sarah O’Brien 15.19 Miscellaneous disorders of the bowel  3025 Alexander Gimson 15.20 Structure and function of the liver, biliary tract, and pancreas  3032 William Gelson and Alexander Gimson 15.21 Pathobiology of chronic liver disease  3043 Wajahat Z. Mehal 15.22 Presentations and management of liver disease  3049

15.22.1 Investigation and management of
jaundice  3049 Jane Collier

15.22.2 Cirrhosis and ascites  3058 Javier Fernández and Vicente Arroyo

15.22.3 Portal hypertension and variceal bleeding  3068 Marcus Robertson and Peter Hayes

15.22.4 Hepatic encephalopathy  3080 Paul K. Middleton and Debbie L. Shawcross

15.22.5 Liver failure  3089 Jane Macnaughtan and Rajiv Jalan

15.22.6 Liver transplantation  3100 John G. O’Grady 15.23 Hepatitis and autoimmune liver disease  3108

15.23.1 Hepatitis A to E  3108 Graeme J.M. Alexander and Kate Nash

Contents xxiii

15.23.2 Autoimmune hepatitis  3119 G.J. Webb and Gideon M. Hirschfield

15.23.3 Primary biliary cholangitis  3127 Jessica K. Dyson and David E.J. Jones

15.23.4 Primary sclerosing cholangitis  3135 Kate D. Lynch and Roger W. Chapman 15.24 Other liver diseases  3142

15.24.1 Alcoholic liver disease  3142 Ewan Forrest

15.24.2 Nonalcoholic fatty liver disease  3147 Quentin M. Anstee and Christopher P. Day

15.24.3 Drug-​induced liver disease  3155 Guruprasad P. Aithal

15.24.4 Vascular disorders of the liver  3166 Alexander Gimson

15.24.5 The liver in systemic disease  3169 James Neuberger

15.24.6 Primary and secondary liver tumours  3178 Graeme J.M. Alexander, David J. Lomas,
William J.H. Griffiths, Simon M. Rushbrook, and Michael E.D. Allison

15.24.7 Liver and biliary diseases in infancy and childhood  3191 Richard J. Thompson 15.25 Diseases of the gallbladder and biliary tree  3196 Colin Johnson and Mark Wright 15.26 Diseases of the pancreas  3209

15.26.1 Acute pancreatitis  3209 R. Carter, Euan J. Dickson, and C.J. McKay

15.26.2 Chronic pancreatitis  3218 Marco J. Bruno and Djuna L. Cahen

15.26.3 Tumours of the pancreas  3227 James R.A. Skipworth and Stephen P. Pereira Index Volume 3 List of abbreviations  xxxv List of contributors  xlv SECTION 16 Cardiovascular disorders Section editor: Jeremy Dwight 16.1 Structure and function  3241

16.1.1 Blood vessels and the endothelium  3241 Keith Channon and Patrick Vallance

16.1.2 Cardiac physiology  3253 Rhys D. Evans, Kenneth T. MacLeod,
Steven B. Marston, Nicholas J. Severs, and Peter H. Sugden 16.2 Clinical presentation of heart disease  3276

16.2.1 Chest pain, breathlessness, and fatigue  3276 Jeremy Dwight

16.2.2 Syncope and palpitation  3284 K. Rajappan, A.C. Rankin, A.D. McGavigan, and S.M. Cobbe 16.3 Clinical investigation of cardiac disorders  3294

16.3.1 Electrocardiography  3294 Andrew R. Houghton and David Gray

16.3.2 Echocardiography  3314 James D. Newton, Adrian P. Banning, and
Andrew R.J. Mitchell

16.3.3 Cardiac investigations: Nuclear, MRI, and CT  3326 Nikant Sabharwal, Andrew Kelion, Theodoros Karamitos, and Stefan Neubauer

16.3.4 Cardiac catheterization and angiography  3339 Edward D. Folland 16.4 Cardiac arrhythmias  3350 Matthew R. Ginks, D.A. Lane, A.D. McGavigan, and
Gregory Y.H. Lip 16.5 Cardiac failure  3390

16.5.1 Epidemiology and general pathophysiological classification of heart failure  3390 Theresa A. McDonagh and Kaushik Guha

16.5.2 Acute cardiac failure: Definitions, investigation, and management  3397 Andrew L. Clark and John G.F. Cleland

16.5.3 Chronic heart failure: Definitions, investigation, and management  3407 John G.F. Cleland and Andrew L. Clark

Contents xxiv

16.5.4 Cardiorenal syndrome  3421 Darren Green and Philip A. Kalra

16.5.5 Cardiac transplantation and mechanical circulatory support  3428 Jayan Parameshwar and Steven Tsui 16.6 Valvular heart disease  3436 Michael Henein 16.7 Diseases of heart muscle  3459

16.7.1 Myocarditis  3459 Jay W. Mason and Heinz-​Peter Schultheiss

16.7.2 The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular  3468 Oliver P. Guttmann and Perry Elliott

16.7.3 Specific heart muscle disorders  3489 Oliver P. Guttmann and Perry Elliott 16.8 Pericardial disease  3501 Michael Henein 16.9 Cardiac involvement in infectious
disease  3509

16.9.1 Acute rheumatic fever  3509 Jonathan R. Carapetis

16.9.2 Endocarditis  3519 James L. Harrison, John L. Klein, William A. Littler, and Bernard D. Prendergast

16.9.3 Cardiac disease in HIV infection  3534 Peter F. Currie

16.9.4 Cardiovascular syphilis  3539 Krishna Somers 16.10 Tumours of the heart  3544 Thomas A. Traill 16.11 Cardiac involvement in genetic disease  3551 Thomas A. Traill 16.12 Congenital heart disease in the adult  3559 S.A. Thorne 16.13 Coronary heart disease  3596

16.13.1 Biology and pathology of atherosclerosis  3596 Robin P. Choudhury, Joshua T. Chai, and
Edward A. Fisher

16.13.2 Coronary heart disease: Epidemiology and prevention  3603 Goodarz Danaei and Kazem Rahimi

16.13.3 Management of stable angina  3616 Adam D. Timmis

16.13.4 Management of acute coronary syndrome  3626 Rajesh K. Kharbanda and Keith A.A. Fox

16.13.5 Percutaneous interventional cardiac procedures  3655 Edward D. Folland

16.13.6 Coronary artery bypass and valve surgery  3666 Rana Sayeed and David Taggart 16.14 Diseases of the arteries  3674

16.14.1 Acute aortic syndromes  3674 James D. Newton, Andrew R.J. Mitchell, and
Adrian P. Banning

16.14.2 Peripheral arterial disease  3680 Janet Powell and Alun Davies

16.14.3 Cholesterol embolism  3688 Christopher Dudley 16.15 The pulmonary circulation  3691

16.15.1 Structure and function of the pulmonary circulation  3691 Nicholas W. Morrell

16.15.2 Pulmonary hypertension  3695 Nicholas W. Morrell 16.16 Venous thromboembolism  3711

16.16.1 Deep venous thrombosis and pulmonary embolism  3711 Paul D. Stein, Fadi Matta, and John D. Firth

16.16.2 Therapeutic anticoagulation  3729 David Keeling 16.17 Hypertension  3735

16.17.1 Essential hypertension: Definition, epidemiology, and pathophysiology  3735 Bryan Williams and John D. Firth

16.17.2 Essential hypertension: Diagnosis, assessment, and treatment  3753 Bryan Williams and John D. Firth

16.17.3 Secondary hypertension  3778 Morris J. Brown and Fraz A. Mir

16.17.4 Mendelian disorders causing
hypertension  3796 Nilesh J. Samani and Maciej Tomaszewski

16.17.5 Hypertensive urgencies and emergencies  3800 Gregory Y.H. Lip and Alena Shantsila 16.18 Chronic peripheral oedema and lymphoedema  3811 Peter S. Mortimer 16.19 Idiopathic oedema of women  3823 John D. Firth

Contents xxv SECTION 17 Critical care medicine Section editor: Simon Finfer 17.1 The seriously ill or deteriorating patient  3829 Carole Foot and Liz Hickson 17.2 Cardiac arrest  3839 Gavin D. Perkins, Jasmeet Soar, Jerry P. Nolan, and
David A. Gabbott 17.3 Anaphylaxis  3849 Anthony F.T. Brown 17.4 Assessing and preparing patients with medical conditions for major surgery  3860 Tom Abbott and Rupert Pearse 17.5 Acute respiratory failure  3867 Susannah Leaver, Jeremy Cordingley, Simon Finney, and Mark Griffiths 17.6 Circulation and circulatory support in the critically ill  3881 Michael R. Pinsky 17.7 Management of raised intracranial pressure  3892 David K. Menon 17.8 Sedation and analgesia in the ICU  3898 Michael C. Reade 17.9 Metabolic and endocrine changes in acute and chronic critical illness  3906 Eva Boonen and Greet Van den Berghe 17.10 Palliative and end-​of-​life care in the ICU  3914 Phillip D. Levin and Charles L. Sprung 17.11 Diagnosis of death and organ donation  3918 Paul Murphy 17.12 Persistent problems and recovery after critical illness  3925 Mark E. Mikkelsen and Theodore J. Iwashyna SECTION 18 Respiratory disorders Section editor: Pallav L. Shah 18.1 Structure and function  3933

18.1.1 The upper respiratory tract  3933 Pallav L. Shah, J.R. Stradling, and S.E. Craig

18.1.2 Airways and alveoli  3937 Peter D. Wagner and Pallav L. Shah 18.2 The clinical presentation of respiratory disease  3947 Samuel Kemp and Julian Hopkin 18.3 Clinical investigation of respiratory disorders  3956

18.3.1 Respiratory function tests  3956 G.J. Gibson

18.3.2 Thoracic imaging  3970 Susan J. Copley and David M. Hansell

18.3.3 Bronchoscopy, thoracoscopy, and tissue biopsy  3992 Pallav L. Shah 18.4 Respiratory infection  4004

18.4.1 Upper respiratory tract
infections  4004 P. Little

18.4.2 Pneumonia in the normal host  4008 Wei Shen Lim

18.4.3 Nosocomial pneumonia  4022 Wei Shen Lim

18.4.4 Mycobacteria  4026 Hannah Jarvis and Onn Min Kon

18.4.5 Pulmonary complications of HIV
infection  4031 Julia Choy and Anton Pozniak 18.5 The upper respiratory tract  4040

18.5.1 Upper airway obstruction  4040 James H. Hull and Matthew Hind

18.5.2 Sleep-​related breathing disorders  4048 Mary J. Morrell, Julia Kelly, Alison McMillan, and Matthew Hind 18.6 Allergic rhinitis  4059 Stephen R. Durham and Hesham A. Saleh 18.7 Asthma  4067 Alexandra Nanzer-​Kelly, Paul Cullinan, and Andrew Menzies-​Gow 18.8 Chronic obstructive pulmonary
disease  4098 Nicholas S. Hopkinson 18.9 Bronchiectasis  4142 R. Wilson and D. Bilton 18.10 Cystic fibrosis  4151 Andrew Bush and Caroline Elston

Contents xxvi 18.11 Diffuse parenchymal lung diseases  4166

18.11.1 Diffuse parenchymal lung disease: An introduction  4166 F. Teo and A.U. Wells

18.11.2 Idiopathic pulmonary fibrosis  4177 P.L. Molyneaux, A.G. Nicholson, N. Hirani, and A.U. Wells

18.11.3 Bronchiolitis obliterans and cryptogenic
organizing pneumonia  4185 Vasilis Kouranos and A.U. Wells

18.11.4 The lung in autoimmune rheumatic disorders  4191 M.A. Kokosi and A.U. Wells

18.11.5 The lung in vasculitis  4200 G.A. Margaritopoulos and A.U. Wells 18.12 Sarcoidosis  4208 Robert P. Baughman and Elyse E. Lower 18.13 Pneumoconioses  4219 P.T. Reid 18.14 Miscellaneous conditions  4235

18.14.1 Diffuse alveolar haemorrhage  4235 S.J. Bourke and G.P. Spickett

18.14.2 Eosinophilic pneumonia  4238 S.J. Bourke and G.P. Spickett

18.14.3 Lymphocytic infiltrations of the
lung  4241 S.J. Bourke

18.14.4 Hypersensitivity pneumonitis  4244 S.J. Bourke and G.P. Spickett

18.14.5 Pulmonary Langerhans’ cell
histiocytosis  4256 S.J. Bourke

18.14.6 Lymphangioleiomyomatosis  4257 S.J. Bourke

18.14.7 Pulmonary alveolar proteinosis  4259 S.J. Bourke

18.14.8 Pulmonary amyloidosis  4261 S.J. Bourke

18.14.9 Lipoid (lipid) pneumonia  4263 S.J. Bourke

18.14.10 Pulmonary alveolar microlithiasis  4265 S.J. Bourke

18.14.11 Toxic gases and aerosols  4267 Chris Stenton

18.14.12 Radiation pneumonitis  4271 S.J. Bourke

18.14.13 Drug-​induced lung disease  4272 S.J. Bourke 18.15 Chronic respiratory failure  4282 Michael I. Polkey and P.M.A. Calverley 18.16 Lung transplantation  4292 P. Hopkins and A.J. Fisher 18.17 Pleural diseases  4305 D. de Fonseka, Y.C. Gary Lee, and N.A. Maskell 18.18 Disorders of the thoracic cage and diaphragm  4328 John M. Shneerson and Michael I. Polkey 18.19 Malignant diseases  4338

18.19.1 Lung cancer  4338 S.G. Spiro and N. Navani

18.19.2 Pulmonary metastases  4360 S.G. Spiro

18.19.3 Pleural tumours  4361 Y.C. Gary Lee

18.19.4 Mediastinal tumours and cysts  4368 Y.C. Gary Lee and Helen E. Davies SECTION 19 Rheumatological disorders Section editor: Richard A. Watts 19.1 Joints and connective tissue—​structure and function  4379 Thomas Pap, Adelheid Korb-​Pap, Christine Hartmann, and Jessica Bertrand 19.2 Clinical presentation and diagnosis of rheumatological disorders  4386 Christopher Deighton and Fiona Pearce 19.3 Clinical investigation  4395 Michael Doherty and Peter C. Lanyon 19.4 Back pain and regional disorders  4406 Carlo Ammendolia and Danielle Southerst 19.5 Rheumatoid arthritis  4415 Kenneth F. Baker and John D. Isaacs 19.6 Spondyloarthritis and related conditions  4441 Jürgen Braun and Joachim Sieper 19.7 Infection and arthritis  4457 Graham Raftery and Muddassir Shaikh 19.8 Reactive arthritis  4464 Carmel B. Stober and Hill Gaston 19.9 Osteoarthritis  4470 Andrew J. Barr and Philip G. Conaghan

Contents xxvii 19.10 Crystal-​related arthropathies  4482 Edward Roddy and Michael Doherty 19.11 Autoimmune rheumatic disorders and vasculitides  4495

19.11.1 Introduction  4495 David A. Isenberg and Ian Giles

19.11.2 Systemic lupus erythematosus and related disorders  4499 Anisur Rahman and David A. Isenberg

19.11.3 Systemic sclerosis (scleroderma)  4513 Christopher P. Denton and Carol M. Black

19.11.4 Sjögren’s syndrome  4532 Wan-​Fai Ng

19.11.5 Inflammatory myopathies  4537 Ingrid E. Lundberg, Hector Chinoy, and
Robert Cooper

19.11.6 Large vessel vasculitis  4546 Raashid Luqmani and Cristina Ponte

19.11.7 ANCA-​associated vasculitis  4556 David Jayne

19.11.8 Polyarteritis nodosa  4569 Loïc Guillevin

19.11.9 Small vessel vasculitis  4573 Richard A. Watts

19.11.10 Behçet’s syndrome  4579 Sebahattin Yurdakul, Izzet Fresko, and
Hasan Yazici

19.11.11 Polymyalgia rheumatica  4584 Bhaskar Dasgupta and Eric L. Matteson

19.11.12 Kawasaki disease  4590 Brian W. McCrindle 19.12 Miscellaneous conditions presenting to the rheumatologist  4598 Stuart Carter, Lisa Dunkley, and Ade Adebajo SECTION 20 Disorders of the skeleton Section editor: Cyrus Cooper 20.1 Skeletal disorders—​general approach and clinical conditions  4615 B. Paul Wordsworth and M.K. Javaid 20.2 Inherited defects of connective tissue:
Ehlers–​Danlos syndrome, Marfan’s syndrome, and pseudoxanthoma elasticum  4670 N.P. Burrows 20.3 Osteomyelitis  4688 Martin A. McNally and Anthony R. Berendt 20.4 Osteoporosis  4696 Nicholas C. Harvey, Juliet Compston, and Cyrus Cooper 20.5 Osteonecrosis, osteochondrosis, and osteochondritis dissecans  4703 Gavin Clunie 20.6 Bone cancer  4709 Helen Hatcher SECTION 21 Disorders of the kidney and
urinary tract Section editor: John D. Firth 21.1 Structure and function of the kidney  4717 Steve Harper and Robert Unwin 21.2 Electrolyte disorders  4729

21.2.1 Disorders of water and sodium homeostasis  4729 Michael L. Moritz and Juan Carlos Ayus

21.2.2 Disorders of potassium homeostasis  4748 John D. Firth 21.3 Clinical presentation of renal disease  4764 Richard E. Fielding and Ken Farrington 21.4 Clinical investigation of renal disease  4781 Andrew Davenport 21.5 Acute kidney injury  4807 John D. Firth 21.6 Chronic kidney disease  4830 Alastair Hutchison 21.7 Renal replacement therapy  4861

21.7.1 Haemodialysis  4861 Robert Mactier

21.7.2 Peritoneal dialysis  4874 Simon Davies

21.7.3 Renal transplantation  4879 Nicholas Torpey and John D. Firth 21.8 Glomerular diseases  4909

21.8.1 Immunoglobulin A nephropathy and IgA
vasculitis (HSP)  4909 Jonathan Barratt and John Feehally

21.8.2 Thin membrane nephropathy  4918 Peter Topham and John Feehally

Contents xxviii

21.8.3 Minimal-​change nephropathy and focal segmental glomerulosclerosis  4919 Moin Saleem and Lisa Willcocks

21.8.4 Membranous nephropathy  4928 An S. De Vriese and Fernando C. Fervenza

21.8.5 Proliferative glomerulonephritis  4933 Alan D. Salama and Mark A. Little

21.8.6 Membranoproliferative glomerulonephritis  4937 Tabitha Turner-​Stokes and Mark A. Little

21.8.7 Antiglomerular basement membrane
disease  4943 Mårten Segelmark and Thomas Hellmark 21.9 Tubulointerstitial diseases  4951

21.9.1 Acute interstitial nephritis  4951 Simon D. Roger

21.9.2 Chronic tubulointerstitial nephritis  4956 Marc E. De Broe, Channa Yamasumana,
Patrick C. D’Haese, Monique M. Elseviers, and
Benjamin Vervaet 21.10 The kidney in systemic disease  4975

21.10.1 Diabetes mellitus and the kidney  4975 Rudolf Bilous

21.10.2 The kidney in systemic vasculitis  4988 David Jayne

21.10.3 The kidney in rheumatological
disorders  5001 Liz Lightstone and Hannah Beckwith

21.10.4 The kidney in sarcoidosis  5012 Ingeborg Hilderson and Jan Donck

21.10.5 Renal involvement in plasma cell dyscrasias, immunoglobulin-​based amyloidoses, and fibrillary glomerulopathies, lymphomas, and leukaemias  5016 Pierre Ronco, Frank Bridoux, and Arnaud Jaccard

21.10.6 Haemolytic uraemic syndrome  5027 Edwin K.S. Wong and David Kavanagh

21.10.7 Sickle cell disease and the kidney  5032 Claire C. Sharpe

21.10.8 Infection-​associated nephropathies  5034 A. Neil Turner

21.10.9 Malignancy-​associated renal disease  5041 A. Neil Turner

21.10.10 Atherosclerotic renovascular disease  5044 Philip A. Kalra and Diana Vassallo 21.11 Renal diseases in the tropics  5049 Vivekanand Jha 21.12 Renal involvement in genetic disease  5065 D. Joly and J.P. Grünfeld 21.13 Urinary tract infection  5074 Charles Tomson and Neil Sheerin 21.14 Disorders of renal calcium handling, urinary stones, and nephrocalcinosis  5093 Christopher Pugh, Elaine M. Worcester, Andrew P. Evan, and Fredric L. Coe 21.15 The renal tubular acidoses  5104 John A. Sayer and Fiona E. Karet 21.16 Disorders of tubular electrolyte handling  5112 Nine V.A.M. Knoers and Elena N. Levtchenko 21.17 Urinary tract obstruction  5124 Muhammad M. Yaqoob and Kieran McCafferty 21.18 Malignant diseases of the urinary tract  5136 Tim Eisen, Freddie C. Hamdy, and Robert A. Huddart 21.19 Drugs and the kidney  5150 Aine Burns and Caroline Ashley Index Volume 4 List of abbreviations  xxxv List of contributors  xlv SECTION 22 Haematological disorders Section editors: Chris Hatton and Deborah Hay 22.1 Introduction to haematology  5169 Chris Hatton 22.2 Haematopoiesis  5172

22.2.1 Cellular and molecular basis of haematopoiesis  5172 Paresh Vyas and N. Asger Jakobsen

22.2.2 Diagnostic techniques in the assessment of haematological malignancies  5181 Wendy N. Erber

Contents xxix 22.3 Myeloid disease  5189

22.3.1 Granulocytes in health and disease  5189 Joseph Sinning and Nancy Berliner

22.3.2 Myelodysplastic syndromes  5197 Charlotte K. Brierley and David P. Steensma

22.3.3 Acute myeloid leukaemia  5205 Nigel Russell and Alan Burnett

22.3.4 Chronic myeloid leukaemia  5213 Mhairi Copland and Tessa L. Holyoake†

22.3.5 The polycythaemias  5227 Daniel Aruch and Ronald Hoffman

22.3.6 Thrombocytosis and essential thrombocythaemia  5239 Daniel Aruch and Ronald Hoffman

22.3.7 Primary myelofibrosis  5247 Evan M. Braunstein and Jerry L. Spivak

22.3.8 Eosinophilia  5254 Peter F. Weller

22.3.9 Histiocytosis  5259 Chris Hatton 22.4 Lymphoid disease  5263

22.4.1 Introduction to lymphopoiesis  5263 Caron A. Jacobson and Nancy Berliner

22.4.2 Acute lymphoblastic leukaemia  5269 H. Josef Vormoor, Tobias F. Menne, and
Anthony V. Moorman

22.4.3 Hodgkin lymphoma  5280 Vijaya Raj Bhatt and James O. Armitage

22.4.4 Non-​Hodgkin lymphoma  5288 Vijaya Raj Bhatt and James O. Armitage

22.4.5 Chronic lymphocytic leukaemia  5302 Clive S. Zent and Aaron Polliack

22.4.6 Plasma cell myeloma and related monoclonal gammopathies  5310 S. Vincent Rajkumar and Robert A. Kyle 22.5 Bone marrow failure  5325

22.5.1 Inherited bone marrow failure syndromes  5325 Irene Roberts and Inderjeet S. Dokal

22.5.2 Acquired aplastic anaemia and pure red cell aplasia  5336 Judith C.W. Marsh, Shreyans Gandhi,
and Ghulam J. Mufti

22.5.3 Paroxysmal nocturnal haemoglobinuria  5348 Lucio Luzzatto 22.6 Erythroid disorders  5354

22.6.1 Erythropoiesis  5354 Vijay G. Sankaran

22.6.2 Anaemia: pathophysiology, classification, and clinical features  5359 David J. Weatherall† and Chris Hatton

22.6.3 Anaemia as a challenge to world health  5366 David J. Roberts and David J. Weatherall†

22.6.4 Iron metabolism and its disorders  5371 Timothy M. Cox and John B. Porter

22.6.5 Anaemia of inflammation  5402 Sant-​Rayn Pasricha and Hal Drakesmith

22.6.6 Megaloblastic anaemia and miscellaneous deficiency anaemias  5407 A.V. Hoffbrand

22.6.7 Disorders of the synthesis or function of haemoglobin  5426 Deborah Hay and David J. Weatherall†

22.6.8 Anaemias resulting from defective maturation
of red cells  5450 Stephen J. Fuller and James S. Wiley

22.6.9 Disorders of the red cell membrane  5456 Patrick G. Gallagher

22.6.10 Erythrocyte enzymopathies  5463 Alberto Zanella and Paola Bianchi

22.6.11 Glucose-​6-​phosphate dehydrogenase deficiency  5472 Lucio Luzzatto

22.6.12 Acquired haemolytic anaemia  5479 Amy Powers and Leslie Silberstein 22.7 Haemostasis  5490

22.7.1 The biology of haemostasis and
thrombosis  5490 Gilbert C. White, II, Harold R. Roberts,
and Nigel S. Key

22.7.2 Evaluation of the patient with a bleeding tendency  5509 Trevor Baglin

22.7.3 Thrombocytopenia and disorders of platelet function  5520 Nicola Curry and Susie Shapiro

22.7.4 Genetic disorders of coagulation  5532 Eleanor S. Pollak and Katherine A. High

22.7.5 Acquired coagulation disorders  5546 T.E. Warkentin † It is with great regret that we report that Tessa L. Holyoake died on 30 August, 2017. † It is with great regret that we report that David J. Weatherall died on 8 December, 2018.

Contents xxx 22.8 Transfusion and transplantation  5563

22.8.1 Blood transfusion  5563 D.S. Giovanniello and E.L. Snyder

22.8.2 Haemopoietic stem cell transplantation  5579 E.C. Gordon-​Smith and Emma C. Morris SECTION 23 Disorders of the skin Section editor: Roderick J. Hay 23.1 Structure and function of skin  5591 John A. McGrath 23.2 Clinical approach to the diagnosis of skin disease  5596 Vanessa Venning 23.3 Inherited skin disease  5602 Thiviyani Maruthappu and David P. Kelsell 23.4 Autoimmune bullous diseases  5612 Kathy Taghipour and Fenella Wojnarowska 23.5 Papulosquamous disease  5621 Christopher E.M. Griffiths 23.6 Dermatitis/​eczema  5630 Peter S. Friedmann, Michael J. Arden-​Jones, and Roderick J. Hay 23.7 Cutaneous vasculitis, connective tissue diseases, and urticaria  5639 Volha Shpadaruk and Karen E. Harman 23.8 Disorders of pigmentation  5677 Eugene Healy 23.9 Photosensitivity  5688 Hiva Fassihi and Jane McGregor 23.10 Infections of the skin  5695 Roderick J. Hay 23.11 Sebaceous and sweat gland disorders  5699 Alison M. Layton 23.12 Blood and lymphatic vessel disorders  5709 Peter S. Mortimer and Roderick J. Hay 23.13 Hair and nail disorders  5724 David de Berker 23.14 Tumours of the skin  5732 Edel O’Toole 23.15 Skin and systemic diseases  5743 Clive B. Archer and Charles M.G. Archer 23.16 Cutaneous reactions to drugs  5752 Sarah Walsh, Daniel Creamer, and Haur Yueh Lee 23.17 Management of skin disease  5761 Rod Sinclair SECTION 24 Neurological disorders Section editor: Christopher Kennard 24.1 Introduction and approach to the patient with neurological disease  5775 Alastair Compston and Christopher Kennard 24.2 Mind and brain: Building bridges
between neurology, psychiatry, and psychology  5778 Adam Zeman 24.3 Clinical investigation of neurological disease  5781

24.3.1 Lumbar puncture  5781 R. Rhys Davies and Andrew J. Larner

24.3.2 Electrophysiology of the central and peripheral nervous systems  5785 Christian Krarup

24.3.3 Imaging in neurological diseases  5802 Andrew J. Molyneux, Shelley Renowden, and
Marcus Bradley

24.3.4 Investigation of central motor pathways:
Magnetic brain stimulation  5817 K.R. Mills 24.4 Higher cerebral function  5821

24.4.1 Disturbances of higher cerebral function  5821 Peter J. Nestor

24.4.2 Alzheimer’s disease and other dementias  5830 Jonathan M. Schott 24.5 Epilepsy and disorders of consciousness  5860

24.5.1 Epilepsy in later childhood and adulthood  5860 Arjune Sen and M.R. Johnson

24.5.2 Narcolepsy  5882 Matthew C. Walker

24.5.3 Sleep disorders  5886 Paul J. Reading

24.5.4 Syncope  5896 Andrew J. Larner

24.5.5 The unconscious patient  5901 David Bates

Contents xxxi

24.5.6 Brainstem death and prolonged disorders of consciousness  5908 Ari Ercole, Peter J. Hutchinson, and John D. Pickard 24.6 Disorders of the special senses  5913

24.6.1 Visual pathways  5913 Sara Ajina and Christopher Kennard

24.6.2 Eye movements and balance  5922 Michael Strupp and Thomas Brandt

24.6.3 Hearing loss  5931 Linda Luxon 24.7 Disorders of movement  5937

24.7.1 Subcortical structures: The cerebellum, basal ganglia, and thalamus  5937 Mark J. Edwards and Penelope Talelli

24.7.2 Parkinsonism and other extrapyramidal diseases  5946 Elisaveta Sokolov, Vinod K. Metta, and K. Ray Chaudhuri

24.7.3 Movement disorders other than Parkinson’s disease  5956 Bettina Balint and Kailash Bhatia

24.7.4 Ataxic disorders  5976 Nicholas Wood 24.8 Headache  5987 Peter J. Goadsby 24.9 Brainstem syndromes  6006 David Bates 24.10 Specific conditions affecting the central nervous system  6010

24.10.1 Stroke: Cerebrovascular disease  6010 J. van Gijn (revised by Peter M. Rothwell)

24.10.2 Demyelinating disorders of the central nervous system  6026 Alasdair Coles and Siddharthan Chandran

24.10.3 Traumatic brain injury  6042 Tim Lawrence and Laurence Watkins

24.10.4 Intracranial tumours  6048 Jeremy Rees

24.10.5 Idiopathic intracranial hypertension  6054 Alexandra Sinclair 24.11 Infections of the central nervous system  6060

24.11.1 Bacterial infections  6060 Diederik van de Beek and Guy E. Thwaites

24.11.2 Viral infections  6082 Fiona McGill, Jeremy Farrar, Bridget Wills, Menno
De Jong, David A. Warrell, and Tom Solomon

24.11.3 Intracranial abscesses  6097 Tim Lawrence and Richard S.C. Kerr

24.11.4 Neurosyphilis and neuro-​AIDS  6100 Hadi Manji

24.11.5 Human prion diseases  6109 Simon Mead and R.G. Will 24.12 Disorders of cranial nerves  6120 Robert D.M. Hadden 24.13 Disorders of the spinal cord  6127

24.13.1 Diseases of the spinal cord  6127 Anu Jacob and Andrew J. Larner

24.13.2 Spinal cord injury and its management  6135 Wagih El Masri(y) and Michael Barnes 24.14 Diseases of the autonomic nervous system  6150 Christopher J. Mathias and David A. Low 24.15 The motor neuron diseases  6166 Tom Jenkins, Alice Brockington, and Pamela J. Shaw 24.16 Diseases of the peripheral nerves  6176 Robert D.M. Hadden 24.17 Inherited neurodegenerative diseases  6197 Swati Sathe 24.18 Disorders of the neuromuscular junction  6295 David Hilton-​Jones and Jacqueline Palace 24.19 Disorders of muscle  6304

24.19.1 Structure and function of muscle  6304 Michael G. Hanna and Enrico Bugiardini

24.19.2 Muscular dystrophy  6310 Kate Bushby and Chiara Marini-​Bettolo

24.19.3 Myotonia  6328 David Hilton-​Jones

24.19.4 Metabolic and endocrine disorders  6334 David Hilton-​Jones and Richard Edwards

24.19.5 Mitochondrial disease  6343 Patrick F. Chinnery and D.M. Turnbull 24.20 Developmental abnormalities of the central nervous system  6350 Chris M. Verity, Jane A. Hurst, and Helen V. Firth 24.21 Acquired metabolic disorders and the nervous system  6368 Neil Scolding 24.22 Neurological complications of systemic disease  6376 Neil Scolding

Contents xxxii 24.23 Paraneoplastic neurological syndromes  6384 Jeremy Rees 24.24 Autoimmune encephalitis and Morvan’s syndrome  6393 Camilla Buckley and Angela Vincent SECTION 25 Disorders of the eye Section editor: Christopher P. Conlon 25.1 The eye in general medicine  6399 Tasanee Braithwaite, Richard W.J. Lee, and Peng T. Khaw SECTION 26 Psychiatric and drug-​related disorders Section editor: Michael Sharpe 26.1 General introduction  6445 Michael Sharpe 26.2 The psychiatric assessment of the medical patient  6447 Jane Walker, Roger Smyth, and Michael Sharpe 26.3 Common psychiatric presentations in medical patients  6454

26.3.1 Confusion  6454 Bart Sheehan and Thomas Jackson

26.3.2 Self-​harm  6457 Kate E.A. Saunders and Keith Hawton

26.3.3 Medically unexplained symptoms  6460 Michael Sharpe

26.3.4 Low mood  6462 Jane Walker 26.4 Psychiatric treatments in the medically ill  6465

26.4.1 Psychopharmacology in medical practice  6465 Philip J. Cowen

26.4.2 Psychological treatments  6470 Michael Sharpe and Simon Wessely 26.5 Specific psychiatric disorders  6475

26.5.1 Delirium  6475 Bart Sheehan

26.5.2 Dementia  6478 Bart Sheehan

26.5.3 Organic psychoses  6482 Curtis McKnight and Jason Caplan

26.5.4 Alcohol misuse  6486 Jonathan Wood

26.5.5 Substance misuse  6490 Stephen Potts

26.5.6 Depressive disorder  6493 Joseph Cerimele and Lydia Chwastiak

26.5.7 Bipolar disorder  6498 Kate E.A. Saunders and John Geddes

26.5.8 Anxiety disorders  6501 Ted Liao and Steve Epstein

26.5.9 Acute stress disorder, adjustment disorders,
and post-​traumatic stress disorder  6506 Jonathan I. Bisson

26.5.10 Eating disorders  6509 Christopher G. Fairburn

26.5.11 Schizophrenia  6513 Stephen M. Lawrie

26.5.12 Somatic symptom and related
disorders  6517 Michael Sharpe

26.5.13 Personality disorders  6520 Iain Jordan 26.6 Changing unhealthy behaviours  6524

26.6.1 Brief interventions for excessive alcohol consumption  6524 Amy O’Donnell, Eileen Kaner, and Nick Heather

26.6.2 Obesity and weight management  6529 Susan Jebb and Paul Aveyard

26.6.3 Smoking cessation  6533 Paul Aveyard 26.7 Psychiatry, liaison psychiatry, and
psychological medicine  6536 Michael Sharpe SECTION 27 Forensic medicine Section editor: John D. Firth 27.1 Forensic and legal medicine  6541 Jason Payne-​James, Paul Marks, Ralph Bouhaidar, and
Steven B. Karch

Contents xxxiii SECTION 28 Sport and exercise medicine Section editor: John D. Firth 28.1 Sport and exercise medicine  6565 Cathy Speed SECTION 29 Biochemistry in medicine Section editor: Christopher P. Conlon 29.1 The use of biochemical analysis for diagnosis
and management  6577 Brian Shine and Nishan Guha SECTION 30 Acute medicine Section editor: John D. Firth 30.1 Acute medical presentations  6591 Sian Coggle, Elaine Jolly, and John D. Firth 30.2 Practical procedures  6644 Elaine Jolly, Sian Coggle, and John D. Firth Index

Copyright

Copyright

3 Great Clarendon Street, Oxford, OX2 6DP, United Kingdom Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide. Oxford is a registered trade mark of Oxford University Press in the UK and in certain other countries © Oxford University Press 2020 The moral rights of the authors have been asserted First Edition published in 1983 Second Edition published in 1987 Third Edition published in 1996 Fourth Edition published in 2003 Fifth Edition published in 2010 Sixth Edition published in 2020 Impression: 1 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, by licence or under terms agreed with the appropriate reprographics rights organization. Enquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above You must not circulate this work in any other form and you must impose this same condition on any acquirer Published in the United States of America by Oxford University Press 198 Madison Avenue, New York, NY 10016, United States of America British Library Cataloguing in Publication Data Data available Library of Congress Control Number: 2018933144 Set ISBN: 978–0–19–874669–0 Volume 1: 978–0–19–881533–4 Volume 2: 978–0–19–881535–8 Volume 3: 978–0–19–881537–2 Volume 4: 978–0–19–884741–0 Only available as part of a set Printed in Malaysia by Vivar Printing Oxford University Press makes no representation, express or implied, that the drug dosages in this book are correct. Readers must therefore always check the product information and clinical procedures with the most up-​to-​date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulations. The authors and the publishers do not accept responsibility or legal liability for any errors in the text or for the misuse or misapplication of material in this work. Except where otherwise stated, drug dosages and recommendations are for the non-​pregnant adult who is not breast-​feeding Links to third party websites are provided by Oxford in good faith and for information only. Oxford disclaims any responsibility for the materials contained in any third party website referenced in this work.

Foreword

Foreword

Foreword Professor Sir John Bell, Regius Professor of Medicine, University of Oxford In 1983, David Weatherall, John Ledingham, and David Warrell launched the first edition of the Oxford Textbook of Medicine. That era of medicine looked entirely different from today but the need for a scholarly repository of medical knowledge remains as important as ever. Medicine is now firmly in a digital age; sources of information abound and are readily available and the field is moving so quickly that it is harder than ever to provide up to date relevant informa- tion for the profession. Despite this, the sixth edition of the Oxford Textbook of Medicine still provides the foundation of knowledge upon which good clinical practice is based. Never before has there been such a rapid advance of medical know- ledge and practice. Since the first edition of the Oxford Textbook of Medicine, medical practice has reduced cardiovascular mortality by up to 70% in Western countries, there are now multiple new ther- apies for diseases such as rheumatoid arthritis and multiple scler- osis, disorders where the descriptions of therapeutic options in the first edition were necessarily brief. Cancer is now increasingly man- aged with immune and targeted therapies. Whole new diseases have appeared (Hepatitis C and HIV) and have been either controlled or conquered with drug therapy. The sequencing of the human genome seemed an impossible dream in 1983 while today we have sequenced more than a million genomes and have had insights into rare disease and cancer that were unimaginable then. Life expectancy has risen by nine years for men and ten for women in the United Kingdom, creating a demographic shift that will fundamentally change society and medicine forever. The pace of change has been dramatic. The Oxford Textbook of Medicine gained a reputation by moving medical practice forward from the Oslerian view of medicine ori- ginally expounded in his text book the Principles and Practice of Medicine into an era of more molecular and scientifically based understanding of disease. Constrained by the lack of tools for ex- ploring the molecular basis of pathogenesis, Osler was limited in how he could describe the world of disease, largely based on bed- side observations or those from the post-​mortem room. The Oxford Textbook of Medicine shifted this focus and aligned it with the emerging field of molecular medicine which has begun to create a new taxonomy of disease but also an approach to therapy which is based on pathogenesis. There has been a wave of new information, with new insights appearing weekly into the underlying molecular events associated with disease. Diseases characterized by phenotype are now broken down into multiple subtypes and disease is being individualized. This is rapidly leading to a very significant change in our perception of pathogenesis as well as the classification and nomenclature of disease, all crucial roles for a textbook of medicine. We now are aware that many of the classic definitions of diseases such as diabetes or cancer were descriptions of phenotypic charac- teristics. Interrogation of these disorders at a molecular level has demonstrated that these terms mask disease subtypes defined by molecular pathology where natural history and response to therapy may differ. Combine this with the explosion of new diseases coming from studies of rare disease and there is a challenge to conventional disease nomenclature. This molecular precision creates real oppor- tunities for targeted highly effective therapies, but it also creates challenges for the model of drug discovery when novel treatments can only be used in increasingly small patient populations. These are major issues for medicine, health systems, but also textbooks such as this one where, historically, the stewardship of disease nomenclature has been maintained. The therapeutic options available to practising clinicians have also advanced beyond all recognition since the first edition of the Oxford Textbook of Medicine. We have seen an era of biologic therapy which has provided important new therapeutic alternatives for many hard-​ to-​treat diseases including cancer. We are now entering a new era where modalities such as gene therapy and interfering RNA thera- peutics have demonstrated their utility in the clinic. Similarly, an era of cell therapy has also begun which will provide important new alternatives to some diseases. These new therapeutic alterna- tives and other opportunities for improving healthcare using med- ical technology or novel diagnostics such as sequencing also bring with them the challenge of how healthcare systems can continue to be affordable, either for individuals in private healthcare settings, or in state-​funded, single-​payer systems. In this context, it is remark- able that the authors and editors of the Oxford Textbook of Medicine have managed to sustain both its relevance and the accuracy of its content. The pace at which our understanding of disease, our therapeutic options, and our healthcare systems are likely to change makes it nearly impossible for a textbook of medicine to be truly comprehen- sive given the speed of change, the impact of new innovations and the multiple additional sources of information available to practi- tioners. The Oxford Textbook of Medicine has provided remarkable levels of detail in this rapidly changing world but, more importantly, the textbook continues to provide a source for readers to access information on the fundamental features of disease. This founda- tional knowledge remains crucial to our ability to understand, diag- nose, and treat patients whether they are in the developing world or

Foreword vi Western healthcare systems. Having a source of such information across all major diseases accessible in a single source remains the bedrock of both teaching and practising medicine. The foundations provided by the Oxford Textbook of Medicine form a core of know- ledge which practising clinicians will continue to need. The editors of this edition have been faithful to the vision of the original three editors. Science, in all its forms, is at the heart of our understanding of disease and has enabled progress in clinical medi- cine to occur at a remarkable pace. By providing a textbook that describes the foundations of our understanding of disease and its management, the editors have successfully given us an authoritative text which practising clinicians will find invaluable to support their day-​to-​day decisions. David Weatherall, one of the three original editors and who died in 2018, would be gratified by this new edition.

List of abbreviations

List of abbreviations

Abbreviations 5-​FU 5-​fluorouracil 5-​HIAA 5-​hydroxyindoleacetic acid 5-​HT 5-​hydroxytryptamine 5-​HT 5-​hydroxytryptamine AAA acquired aplastic anaemia AAFB acid-​ and alcohol-​fast bacilli AASLD American Association for the Study of Liver Diseases AAV antineutrophil cytoplasm autoantibody-associated vasculitis (also aplastic anaemia ABC ATP-​binding cassette ABCDE airway, breathing, circulation, disability, and exposure ABG arterial blood gas ABMR antibody-​mediated rejection ABPA allergic bronchopulmonary aspergillosis ABPM ambulatory blood pressure measurement ACE angiotensin-​converting enzyme AChE acetylcholinesterase, define at first mention ACPA anticitrullinated peptide/​protein antibodies ACR American College of Rheumatology (also albumin:creatinine ratio) ACS acute coronary syndromes ACTH adrenocorticotropic hormone AD Alzheimer’s disease ADEM acute disseminated encephalomyelitis ADH antidiuretic hormone ADL activities of daily living ADME absorption, distribution, metabolism, and excretion ADPKD autosomal dominant polycystic kidney disease ADR adverse drug reaction ADRT advanced decision to refuse treatment AECA antiendothelial cell antibodies AF atrial fibrillation AFP α-​fetoprotein AGT alanine–​glyoxylate aminotransferase aGVHD acute graft-​versus-​host disease AHA American Heart Association aHUS atypical haemolytic uraemic syndrome AIF apoptosis-​inducing factor AIHA autoimmune haemolytic anaemia AIN acute interstitial nephritis AIP autoimmune pancreatitis (also acute interstitial pneumonia) AIS androgen insensitivity syndromes AKI acute kidney injury ALD alcoholic liver disease ALF acute liver failure ALL acute lymphoblastic leukaemia alloSCT allogeneic stem cell transplantation ALP alkaline phosphatase ALS amyotrophic lateral sclerosis ALT alanine aminotransferase AMA antimitochondrial antibody AML acute myeloid leukaemia AMLR autologous mixed lymphocyte reactions AMT Abbreviated Mental Test ANA antinuclear autoantibodies ANC absolute neutrophil count ANCA antineutrophil cytoplasmic antibodies ANP atrial natriuretic peptide AOSD adult-​onset Still’s disease AP alternative pathway APA aldosterone-​producing adenoma APC antigen presenting cell APCM active physiological conservative management APL acute promyelocytic leukaemia APS antiphospholipid syndrome APTT activated partial thromboplastin time AR androgen receptor ara-​C cytosine arabinoside ARB angiotensin receptor blocker ARDS adult respiratory distress syndrome ARF acute renal failure ARH autosomal recessive hypercholesterolaemia ARPKD autosomal recessive polycystic kidney disease ART antiretroviral therapy ARVC arrhythmogenic right ventricular cardiomyopathy ARVD atherosclerotic renovascular disease AS ankylosing spondylitis ASAS Assessment of SpondyloArthritis International Society ASCT autologous stem cell transplantation ASD atrial septal defect ASH Action on Smoking and Health ASOT antistreptolysin O titre AST aspartate aminotransferase ATG antithymocyte globulin ATP adenosine triphosphate ATRA all-​trans-​retinoic acid AV aortic valve AVN arteriovenous nipping

Abbreviations xxxvi AVSD atrioventricular septal defect AZA azacitidine BCAA branched-​chain amino acid BCC basal cell carcinoma BCG bacillus Calmette–​Guérin BEN Balkan endemic nephropathy BH4 tetrahydrobiopterin BHS British Hypertension Society BICC betaferon in chronic viral cardiomyopathy BKV BK polyomavirus BM bone marrow BMD bone mineral density BMF bone marrow failure BMI body mass index BMP bone morphogenic protein BNF British National Formulary BNP B-​type natriuretic peptide BOS bronchiolitis obliterans syndrome BP blood pressure BPG biphosphoglycerate BRAO branch artery occlusion BRVO branch retinal vein occlusion BSEP haemolysis, elevated liver enzymes, and low platelet count BSP bromosulphthalein BTS British Thoracic Society BUN blood urea nitrogen CA carbohydrate antigen CABG coronary artery bypass grafting CAF Comprehensive Assessment for Frailty CAH congenital adrenal hyperplasia CAM Confusion Assessment Method CAMT congenital amegakaryocytic thrombocytopenia CAP community-​acquired pneumonia CAPS cryopyrin-​associated periodic syndromes CaR calcium-​sensing receptor CAT COPD assessment test CBT cognitive behaviour therapy CCB calcium channel blocker CCK cholecystokinin CCP anticyclic citrullinated peptide CCQ Clinical COPD questionnaire CCV clathrin-​coated vesicles CCyR complete cytogenetic response CD cluster of differentiation CDA congenital dyserythropoietic anaemia CDC donation after circulatory death CEA carcinoembryonic antigen CETP cholesteryl ester transfer protein CF cystic fibrosis CFA cryptogenic fibrosing alveolitis cfDNA cell-​free DNA CFS Clinical Frailty Scale CFTR cystic fibrosis transmembrane regulator CFU colony forming unit CGA comprehensive geriatric assessment CGRP calcitonin gene-​related peptide cGVHD chronic graft-​versus-​host disease CHAD cold haemagglutinin disease CHD coronary heart disease CHF congestive heart failure CHM Commission on Human Medicines CINAC chronic interstitial nephritis in agricultural communities CINCA chronic infantile neurological, cutaneous, and articular syndrome CISN coumarin-​induced skin necrosis CK creatine kinase CKD chronic kidney disease CKD-​EPI Chronic Kidney Disease Epidemiology Collaboration CLL chronic lymphocytic leukaemia CML chronic myeloid leukaemia CMR cardiac magnetic resonance CMS congenital myasthenic syndrome CMT Charcot–​Marie–​Tooth disease CMV cytomegalovirus CNI calcineurin inhibitor CNS central nervous system CNSHA congenital non-​spherocytic haemolytic anaemia CO cardiac output CoA coenzyme A COPD chronic obstructive pulmonary disease COX cyclooxygenase CPAP continuous positive airway pressure CPM central pontine myelosis CPP central precocious puberty CPPS chronic pelvic pain syndrome CPR cardiopulmonary resuscitation CR complete remission CRDQ Chronic Respiratory Disease Questionnaire CREST calcinosis, Raynaud’s, oesophageal dysmotility, sclerodactyly, telangiectasia CRF chronic renal failure CRH corticotropin-​releasing hormone CRIM cross-​immunoreactive material CRP C-​reactive protein CRT cardiac resynchronization therapy CS continuous smokers CSF cerebrospinal fluid/​colony-​stimulating factor CT computed tomography CTA computed tomography angiography CTCA computed tomography coronary angiography CTD connective tissue disease CTEPH chronic thromboembolic pulmonary hypertension CTL cytotoxic T-​lymphocyte CVD cardiovascular disease CVID common variable immunodeficiency CVS chorionic villus sampling CXR chest radiograph CYP cytochrome P450 CZT cadmium zinc telluride DAEC diffusely adherent Escherichia coli DALY disability-​adjusted life year DAMP damage-​associated molecular pattern DASH Dietary Approaches to Stop Hypertension DAT direct antiglobulin test

  Abbreviations xxxvii DBA Diamond–​Blackfan anaemia DBD donation after brain death DBP diastolic blood pressure DC dyskeratosis congenita (also dendritic cell) DCA directional coronary atherectomy DCCT Diabetes Control and Complications Trial DCD donation after circulatory death DCI decompression illness dcSSc diffuse cutaneous systemic sclerosis DCT distal convoluted tubule DDAVP 1-​deamino-​8-​d-​arginine vasopressin DDD dense deposit disease DECAF dyspnoea, eosinopenia, consolidation, acidosis, and atrial fibrillation DGP deamidated gliadin peptide DHG dihydroxyglutarate DIC disseminated intravascular coagulation DIC disseminated intravascular coagulation DILI drug-​induced liver injury DILV double-​inlet left ventricle DIP desquamative interstitial pneumonia DISC death-​initiating signalling complex DISH diffuse idiopathic skeletal hyperostosis DLB dementia with Lewy bodies DLBCL diffuse large B-​cell lymphoma DMARD disease-​modifying antirheumatic drug DMD disease-​modifying drugs (can also mean Duchenne muscular dystrophy) DMSA dimercaptosuccinic acid DNACPR do-​not-​attempt-​cardiopulmonary resuscitation DNR do not resuscitate DOAC direct oral anticoagulant DOCA desoxycorticosterone DOPPS Dialysis Outcomes and Practice Patterns Study DORV double-​outlet right ventricle DPI dry powder inhalers DRE digital rectal examination DRESS drug reaction with eosinophilia and systemic symptoms dRTA distal renal tubular acidosis DSA donor-​specific antibodies DTC direct to consumer DTPA diethylenetriaminepentaacetic acid DVT deep vein thrombosis DXA dual energy X-​ray absorptiometry EACTS European Association for Cardio-​Thoracic Surgery EAggEC enteroaggregative Escherichia coli EANM European Association of Nuclear Medicine EAPCI European Association of Percutaneous Cardiovascular Interventions EASL European Association for the Study of the Liver EATL enteropathy-​associated T-​cell lymphoma EBV Epstein–​Barr virus ECD extended criteria donor ECF extracellular fluid ECG electrocardiogram ECLAM European community lupus activity measure ECM extracellular matrix ECV extracellular volume EDMD Emery–​Dreifuss muscular dystrophy EDRF endothelial-​derived relaxing factor EDTA European Dialysis and Transplant Association EDV end-​diastolic volume EEG electroencephalography EELV end expiratory lung volume EGF epidermal growth factor eGFR estimated glomerular filtration rate EGPA eosinophilic granulomatosis with polyangiitis EIEC enteroinvasive Escherichia coli EIS endoscopic injection sclerotherapy ELCA excimer laser coronary atherectomy ELISA enzyme-​linked immunosorbent assay EM erythema multiforme (also electron microscopy) EMA endomysial antibody EMG electromyography EMS early morning urethral smear ENA extractable nuclear antigens ENaC epithelial sodium channel ENT ear, nose, or throat EOL end of life EoO eosinophilic oesophagitis EPCR endothelial cell protein C receptor EPEC enteropathogenic Escherichia coli EPO erythropoietin ER endoplasmic reticulum ERA European Renal Association ERC endoscopic retrograde cholangiography ERCP endoscopic retrograde cholangiopancreatography ERNV equilibrium radionuclide ventriculography ERS European Respiratory Society ESA erythropoiesis-​stimulating agent ESC European Society of Cardiology ESGE European Society of Gastrointestinal Endoscopy ESH European Society of Hypertension ESKD end-​stage kidney disease ESR erythrocyte sedimentation rate ESRD end-​stage renal disease ESS EULAR sicca score ESWL extracorporeal shock-​wave lithotripsy ETEC enterotoxigenic Escherichia coli EUS endoscopic ultrasonography EVLP ex-​vivo lung perfusion EVO endoscopic variceal obturation FA Fanconi’s anaemia FACIT fibril-​associated collagen with interrupted triple FAK focal adhesion kinase FAP familial adenomatous polyposis FBC full blood count FCAS familial cold autoinflammatory syndrome FCHL familial combined hyperlipidaemia FDA Food and Drug Administration FDG fluorodeoxyglucose FDG-​PET fluorodeoxyglucose-​positron emission tomography FDP fibrinogen-​degradation product FEV forced expiratory volume FEV1 forced expiratory volume in 1 s

Abbreviations xxxviii FFR fractional flow reserve FGF fibroblast growth factor FH familial hypercholesterolaemia FISH fluorescent in situ hybridization FL follicular lymphoma FLC free light chain FMF familial Mediterranean fever FMTC familial medullary thyroid carcinoma FNAB fine needle aspiration biopsy FNH focal nodular hyperplasia FOB faecal occult blood FODMAPs fermentable oligosaccharides, disaccharides, monosaccharides, and polyols FRC functional residual capacity FSGS focal segmental glomerulosclerosis FSH follicular stimulating hormone FTD frontotemporal dementia FVC forced vital capacity FVU first voided urine G6PD glucose-​6-​phosphate dehydrogenase GABA γ-​aminobutyric acid GAD generalized anxiety disorder GALT gut-​associated lymphoid tissue GAVE gastric antral vascular ectasia GBD Global Burden of Disease GBM glomerular basement membrane G-​CSF granulocyte colony-​stimulating factor GCA giant cell arteritis GCS Glasgow Coma Score GDF growth differentiation factors GEP gastroenteropancreatic GFB glomerular filtration barrier GFR glomerular filtration rate GH growth hormone GI gastrointestinal GIB gastrointestinal bleeding GIE glucocorticoid inhibitory element GIP gastric inhibitor peptide GIST gastrointestinal stromal tumour GLP glucagon-​like peptide GM-​CSF granulocyte–​macrophage colony-​stimulating factor GM/​MS gas chromatography–​mass spectrometry GN glomerulonephritis GnRH gonadotropin-​releasing hormone GOLD Global Initiative for Obstructive Lung Disease GOMMID glomerulonephritis with organized microtubular monoclonal immunoglobulin deposits GORD gastro-​oesophageal reflux disease GOV gastro-​oesophageal varices GP glycoprotein (also general practitioner) GPA granulomatosis with polyangiitis GPCR G-​protein-​coupled-​receptors GPI glycosylphosphatidylinositol GRACE Global Registry of Acute Coronary Events GRADE Grading of Recommendations, Assessment, Development and Evaluations GRHPR glyoxylate/​hydroxypyruvate reductase GSD glycogen storage disease GSGS focal segmental glomerulosclerosis GSH glutathione GU gonococcal urethritis GUM genitourinary medicine GVHD graft-​versus-​host disease GVL graft-​versus-​leukaemia GWAS genome-​wide association study H&E haematoxylin and eosin stain HAART highly active antiretroviral therapy HAND HIV-​associated neurocognitive disorder HAV hepatitis A virus HBc hepatitis B core HBeAG hepatitis B e antigen HBIg hepatitis B immunoglobulin HBPM home blood pressure measurement HBsAG hepatitis B surface antigen HBV hepatitis B virus HCC hepatocellular carcinoma HCG human chorionic gonadotropin HCV hepatitis C virus HD haemodialysis HDF haemodiafiltration HDL high-​density lipoprotein HDL-​C high-​density lipoprotein cholesterol HDU high-​dependency unit HDV hepatitis D virus HE hepatic encephalopathy or hereditary elliptocytosis HELLP haemolysis, elevated liver enzymes and low platelets HES hypereosinophilic syndrome hESC human embryonic stem cell HETE hydroxyeicosatetraenoic acid HEV hepatitis E virus HF haemofiltration HFA Heart Failure Association HFnEF heart failure with a normal ejection fraction HFOV high-​frequency oscillatory ventilation HFV high-​frequency ventilation HHT hereditary haemorrhagic telangiectasis/​ 15-​hydroxy-​5,8,10-​hepatrotrienoic acid HHV human herpesvirus HIF hypoxia-​inducible factors HIV human immunodeficiency virus HIV-​OL human immunodeficiency virus oral lesion HK high molecular weight kininogen HL hepatic lipase HLA human leucocyte antigen HLH haemophagocytic lymphohistiocytosis HLHS hypoplastic left heart syndrome HMA hypomethylating agent HOGA 4-​hydroxy-​2-​oxoglutarate aldolase HPA hypothalamic-​pituitary-​adrenal HPG hypothalamic-​pituitary-​gonadal HPLC high-​performance liquid chromatography HPP hereditary pyropoikilocytosis HPRT hypoxanthine-​guanine phosphoribosyltransferase HPV human papillomavirus

  Abbreviations xxxix HRA high-​resolution anoscopy HRCT high-​resolution computed tomography HRT hormone replacement therapy HS hereditary spherocytosis HSC haematopoietic stem cell or hepatic stellate cell HSCT haemopoietic stem cell transplantation HSP Henoch–​Schönlein purpura HSPC haematopoietic stem and progenitor cell HSV herpes simplex virus HUS haemolytic uraemic syndrome HUV hypocomplementaemic urticarial vasculitis IADL instrumental activities of daily living IAS insulin autoimmune syndrome IBD irritable bowel disease IBS irritable bowel syndrome IBS-​C irritable bowel syndrome with constipation IBS-​D irritable bowel syndrome with diarrhoea IBS-​M irritable bowel syndrome with alternating constipation and diarrhoea IC intercalated cell ICAM intercell adhesion molecules ICD implantable cardioverter-​defibrillator ICP intracranial pressure ICS inhaled oral corticosteroids ICU intensive care unit IDA iminodiacetic acid IDL intermediate-​density lipoprotein IEC intestinal epithelial cell IF intrinsic factor IFG impaired fasting glucose IFN interferon Ig immunoglobulin IgAN immunoglobulin A nephropathy IgE immunoglobulin E IGF insulin-​like growth factors IgG4-​RD immunoglobulin G4-​related disease IgG4-​SC immunoglobulin G4-​related sclerosing cholangitis IGV isolated gastric varices IHD ischaemic heart disease IHME Institute for Health Metrics and Evaluation IIH idiopathic intracranial hypertension IIP idiopathic interstitial pneumonias IL interleukin ILC innate lymphoid cell ILD interstitial lung disease IMA inferior mesenteric artery INR international normalized ratio IPAF interstitial pneumonitis with autoimmune features IPEX immunodysregulation polyendocrinopathy enteropathy X-​linked IPF idiopathic pulmonary fibrosis IPI International Prognostic Index iPSC induced pluripotent stem cell IPSID immunoproliferative small intestinal disease IRIDA iron-​refractory iron deficiency anaemia IRIS immune reconstitution inflammatory syndrome IRM immunoradiographic assay IRV Inspiratory and expiratory reserve volume ISH International Society of Hypertension ISHLT International Society for Heart and Lung Transplantation ISIS International Study of Infarct Survival ISWT incremental shuttle walking test ITP immune thrombocytopenia ITU intensive care unit IV intravenous IVC inferior vena cava IVF in vitro fertilization IVIG intravenous immunoglobulin IVU intravenous urography JE Japanese encephalitis JIA juvenile idiopathic arthritis JNC Joint National Committee KDIGO Kidney Disease: Improving Global Outcomes LA left atrium LAMA long-​acting antimuscarinic agents LBBB left bundle branch block LCAT lecithin–​cholesterol acyltransferase LCH Langerhans’ cell histiocytosis lcSSc limited cutaneous systemic sclerosis LDH lactate dehydrogenase LDL low-​density lipoprotein LDL-​C low-​density lipoprotein cholesterol LFT liver function test LGE late gadolinium enhancement LGMD limb-​girdle muscular dystrophy LGV lymphogranuloma venereum LH luteinizing hormone LIC liver iron content LINQ Lung Information Needs Questionnaire LIP lymphocytic interstitial pneumonia LKM liver–​kidney microsomal LMICs low-​ and middle-​income countries LMN lower motor neuron LMWH low molecular weight heparin LMWP low molecular weight protein LOLA l-​ornithine l-​arginine LP lumbar puncture LPL lipoprotein lipase LPLR lipoprotein lipase receptor LTOT long-​term oxygen therapy LV left ventricle LVDD left ventricular diastolic dysfunction LVEF left ventricular ejection fraction LVOT left ventricular outflow tract LVRS lung volume reduction surgery LVSD left ventricular systolic dysfunction MAG3 mercaptoacetyltriglycine MAGIC MAGnesium in Coronaries MAHA microangiopathic haemolytic anaemia MALT mucosa-​associated lymphoid tissue MAO monoamine oxidase inhibitor MAP mean arterial pressure MAPK mitogen-​activated protein kinase MBD mineral and bone disorder M-​CSF macrophage colony-​stimulating factor

Abbreviations xl MCHC mean cell haemoglobin concentration MCL mantle cell lymphoma MCNS minimal change nephrotic syndrome MCpEF myocarditis with preserved left ventricular ejection fraction MCV mean corpuscular volume MDE myeloma-​defining event MDI metered dose inhalers MDRD Modification of Diet in Renal Disease MDS myelodysplastic syndrome MED minimal erythema dose MELD Model for End-​Stage Liver Disease MEN multiple endocrine neoplasia MERFF myoclonic epilepsy and ragged red fibres mESC mouse embryonic stem cell MGRS monoclonal gammopathy of renal significance MGUS monoclonal gammopathy of undetermined significance MHC major histocompatibility complex MHRA Medicines and Healthcare Products Regulatory Agency MIC minimum inhibitory concentration MIDD monoclonal immunoglobulin deposition diseases MKD mevalonate kinase deficiency MM malignant melanoma MMA methylmalonic acid MMF mycophenolate mofetil MMP matrix metalloproteinase MMR mismatch repair MN membranous nephropathy MND motor neuron disease MoCA Montreal Cognitive Assessment MPA microscopic polyangiitis MPO myeloperoxidase MPS mucopolysaccharidosis (also myocardial perfusion scintigraphy) MR magnetic resonance MRA magnetic resonance angiography (can also be medicine regulatory authority) MRC Medical Research Council MRCP magnetic resonance cholangiopancreatography MRI magnetic resonance imaging MRSA methicillin-​resistant Staphylococcus aureus MS multiple sclerosis MS/​MS tandem mass spectroscopy MSA multiple-​system atrophy MSC mesenchymal stromal cell MSH melanocyte-​stimulating hormone MSU midstream urine MTC medullary thyroid carcinoma mTOR mammalian target of rapamycin MUS medically unexplained symptoms MWS Muckle–​Wells syndrome NAAT nucleic acid amplification testing NABQI N-​acetyl-​p-​benzoquinone imine NADH reduced nicotinamide-​adenine dinucleotide NADPH reduced nicotinamide-​adenine dinucleotide phosphate NAFLD nonalcoholic fatty liver disease NAIT neonatal alloimmune thrombocytopenia NASH nonalcoholic steatohepatitis NCAM neural-​cell adhesion molecule NEP neutral endopeptidase NET neuroendocrine tumour or neutrophil extracellular trap NETT National Emphysema Therapy Trial NEWS National Early Warning Score NGF nerve growth factor NGS next-​generation sequencing NHDL-​C non-​high-​density lipoprotein cholesterol NHL non-​Hodgkin’s lymphoma NHS National Health Service (UK) NICE National Institute for Health and Care Excellence NIPPV non-​invasive nasal positive-​pressure ventilation NIPT non-​invasive prenatal testing NIV non-​invasive ventilation NK natural killer NKT natural killer T NLST National Lung Screening Trial NMS neuroleptic malignant syndrome NMSC non-​melanoma skin cancer NNH number needed to harm NNT number needed to treat NOTT Nocturnal Oxygen Treatment Trial NREM non-​rapid eye movement NRT nicotine replacement therapy NSAID non-​steroidal anti-​inflammatory drug NSCLC non-​small cell lung cancer NSIP non-​specific interstitial pneumonia NSTEMI non-​ST-​elevation myocardial infarction NTD neural tube defect NTM non-​tuberculous mycobacterial NT-​proBNP N-​terminal B-​type natriuretic peptide NYHA New York Heart Association OAF osteoclast-​activating factor OAPR odds of being affected given a positive result OB obliterative bronchiolitis OCD obsessive–​compulsive disorder OCT optical coherence tomography OD once daily OECD Organisation for Economic Cooperation and Development OED other eating disorders OLP oral lichen planus OMIM Online Mendelian Inheritance in Man OMT optimal medical therapy OPAT outpatient parenteral antibiotic therapy OR odds ratio OS overall survival OSA obstructive sleep apnoea OTB oral tuberculosis PA pernicious anaemia (also pulmonary artery) PACAP pituitary adenylate cyclase activating polypeptide PAF platelet activating factor PAH polycyclic aromatic hydrocarbons (can also mean pulmonary hypertension)

  Abbreviations xli PAOP pulmonary artery occlusion pressure PAS periodic acid–​Schiff PASI Psoriasis Area and Severity Index PASP pulmonary artery systolic pressure PBD polyglucosan body disease PBM peripheral blood mononuclear cell PCC prothrombin complex concentrate PCH paroxysmal cold haemoglobinuria (also pulmonary capillary haemangiomatosis) PCI percutaneous coronary intervention PCNSL primary central nervous system lymphoma Pco partial pressure of carbon dioxide PCP Pneumocystis jirovecii pneumonia PCR polymerase chain reaction (also protein:creatinine ratio) PCT proximal convoluted tubule PCV pneumococcal conjugate vaccine PCWP pulmonary capillary wedge pressure PD peritoneal dialysis (also Parkinson’s disease) PDA patent ductus arteriosus PDC pyruvate dehydrogenase complex PDD Parkinson’s disease dementia PDGF platelet-​derived growth factor PE pleural effusion (can also mean pulmonary embolism) PEACH Pelvic Inflammatory Disease Evaluation and Clinical Health PEEP positive end expiratory pressure PEF peak expiratory flow PEG percutaneous endoscopic gastrostomy PET position emission tomography PFO patent foramen ovale PFS progression-​free survival PGK phosphoglycerate kinase PHARC polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract PICS post-​intensive care syndrome PID pelvic inflammatory disease PIGN postinfectious glomerulonephritis PK pyruvate kinase PKD pyruvate kinase deficiency (also polycystic kidney disease) PKU phenylketonuria PLA2R phospholipase A2 receptor PMN polymorphonuclear neutrophil PMR polymyalgia rheumatica PNH paroxysmal nocturnal haemoglobinuria Po2 partial pressure of oxygen POC point of care POMC pro-​opiomelanocortin PP polypeptide PPI proton pump inhibitor ppm parts per million PPS Palliative Performance Scale PPV porcine parvovirus PR3 proteinase 3 PRCA pure red cell aplasia PRI population reference intake PRPP phosphoribosyl pyrophosphate PRR pattern-​recognition receptor PRrP parathyroid-​hormone-​related protein PSA prostate-​specific antigen PSC primary sclerosing cholangitis PSP primary spontaneous pneumothorax PT prothrombin time PTC percutaneous transhepatic cholangiography PTCA percutaneous transluminal coronary angioplasty PTH parathyroid hormone PTHrP PTH/​PTH-​related peptide PTLD post-​transplant lymphoproliferative disorder PTP post-​transfusion purpura PTSD post-​traumatic stress disorder PUVA psoralen ultraviolet A PV pemphigus vulgaris (also plasmas viscosity test) PVE prosthetic valve endocarditis PVOD pulmonary veno-​occlusive disease PVR pulmonary vascular resistance PYY peptide tyrosine-​tyrosine QALY quality-​adjusted life year RA rheumatoid arthritis (can also mean right atrium) RAAS renin–​angiotensin–​aldosterone system RAS renin–​angiotensin system (also renal artery stenosis or restrictive allograft syndrome RAVV right atrioventricular valve RBBB right bundle branch block RBF rat bite fevers RCA right coronary artery RCC renal cell carcinoma RCDP rhizomelic chondrodysplasia punctata RCT randomized controlled trial RDA recommended dietary allowance REM rapid eye movement RF rheumatoid factor RI resistivity index RNA ribonucleic acid RNI reference nutrient intake RNP ribonucleoprotein ROC receiver–​operator characteristic RP ribosomal protein RRT renal replacement therapy RTA renal tubular acidosis RV residual volume (also right ventricle) RVOTO right ventricular outflow tract obstruction SA short-​axis SABR stereotactic ablative body radiotherapy SBP spontaneous bacterial peritonitis (also systolic blood pressure) SCC squamous cell carcinoma SCD sickle cell disease (also sudden cardiac death) SCI spinal cord injuries SCID severe combined immunodeficiency SCLC small cell lung cancer SCMR Society for Cardiovascular Magnetic Resonance SCN sickle cell nephropathy or severe congenital neutropenia sdLDL small dense low-​density lipoprotein SDS Shwachman–​Diamond syndrome

Abbreviations xlii SEER Surveillance, Epidemiology, and End Results SGRQ St George’s Respiratory Questionnaire SHBG sex hormone binding globulin SHEC Shiga toxin-​producing Escherichia coli SIADH syndrome of inappropriate antidiuretic hormone secretion SIRS systemic inflammatory response syndrome SLB surgical lung biopsy SLE systemic lupus erythematosus SM smouldering myeloma SMA superior mesenteric artery (also smooth muscle antibody) SMC smooth muscle cell sMDRD simplified Modification of Diet in Renal Disease SMR standardized mortality ratio SNGFR single-​nephron glomerular filtration rate SNP single nucleotide polymorphism SNS sympathetic nervous system SOD sphincter of Oddi disorder SPC Summary of Product Characteristics SPD storage pool deficiency SPECT single-​positron emission computed tomography SPF sun protection factor SSc systemic sclerosis SSD somatic symptom disorder SSFP steady-​state free precession SSRI selective serotonin reuptake inhibitor STEMI ST elevation myocardial infarction STI sexually transmitted infection STOPP/​START set of inappropriate combinations of medicines and disease (STOPP) and a set of recommended treatments for given conditions (START) suPAR soluble urokinase plasminogen activating receptor SVC superior vena cava SVR systemic vascular resistance TACE transarterial chemoembolization TAE transarterial embolization TALH thick ascending limb of Henle TAR thrombocytopenia with absent radii TAVI transcatheter aortic valve implantation TB tuberculosis TBLC transbronchial lung cryobiopsy TBM tuberculous meningitis TC total cholesterol TCA tricyclic antidepressant TCPC total cavopulmonary connection TCR T-​cell receptor TCT thrombin clotting time TdT terminal deoxyribonucleotidyl transferase TEC transient erythroblastopenia of childhood TEN toxic epidermal necrolysis TF transcription factor (also tissue factor) TFPI tissue factor pathway inhibitor TG triglyceride TGF transforming growth factor TGFα, TGFβ transforming growth factor-​α, -​β TGN trans Golgi network THR total hip replacement THRIVE Treatment of HDL to Reduce the Incidence of Vascular Events TIA transient ischaemic attack TIBC total iron-​binding capacity TIMI thrombolysis in myocardial infarction TINU tubulointerstitial nephritis uveitis TIPS transjugular intrahepatic portosystemic shunt TK tyrosine kinase TKI tyrosine kinase inhibitor TKR total knee replacement TLC total lung capacity TLR Toll-​like receptor TMA thrombotic microangiopathy t-​MDS therapy-​related myelodysplastic syndrome(s) TNF tumour necrosis factor TNFα tumour necrosis factor-​α tPA tissue plasminogen activator TPN total parenteral nutrition TPN total parenteral nutrition TRAIL TNF-​related apoptosis-​inducing ligand TRAPS tumour necrosis factor receptor-​associated periodic syndrome Treg regulatory T (cell) TROPHY Trial of Preventing Hypertension TSH thyroid-​stimulating hormone TTD thiazide-​type diuretic tTG tissue transglutaminase TTIP Transatlantic Trade and Investment Partnership TTKG transtubular potassium concentration gradient TTP thrombotic thrombocytopenic purpura TURBT transurethral resection of bladder tumour TV tricuspid valve UAER urinary albumin excretion rate UCB umbilical cord blood UDCA ursodeoxycholic acid UDP uridine diphosphate UI urinary incontinence UIP usual interstitial pneumonia UKELD United Kingdom Model for End-​Stage Liver Disease UKM urea kinetic modelling UKMEC UK Medical Eligibility Criteria UKPDS United Kingdom Prospective Diabetes Study ULN upper limit of normal UMN upper motor neuron UPR unfolded protein response URR urea reduction ratio URTI upper respiratory tract infection UTI urinary tract infection UV ultraviolet UVL ultraviolet light UVR ultraviolet radiation V/​Q ventilation/​perfusion VARD video-​assisted retroperitoneal debridement VATS video-​assisted thoracoscopic surgery VC vital capacity vCJD variant Creutzfeldt–​Jakob disease

  Abbreviations xliii VDRL Venereal Diseases Research Laboratory VEGF vascular endothelial growth factor VEOIBD very early-​onset inflammatory bowel disease VIP vasoactive intestinal peptide VKA vitamin K antagonist VLA vertical long axis VLCFA very long-​chain fatty acid VLDL very low-​density lipoprotein VSD ventricular septal defect VTE venous thromboembolism VWD von Willebrand’s disease VWF von Willebrand factor VZV varicella zoster virus WBC white blood cell WCC white cell count WGS whole genome sequencing WHO World Health Organization WM Waldenström’s macroglobulinaemia X-​ALD X-​linked adrenoleukodystrophy XLH X-​linked hypophosphataemia YLDs years lived with disability YLL years of life lost ZASP Z-​line associated protein

Contributors Peter Aaby Bandim Health Project, INDEPTH Network, Bissau, Guinea-​Bissau, West Africa 8.5.6: Measles Emma Aarons Consultant Virologist and Infectious Disease Physician, Rare and Imported Pathogens Laboratory, Public Health England, Salisbury, Wiltshire, UK 8.5.27: Orf and Milker’s nodule Tom Abbott William Harvey Research Institute, Queen Mary University of London, UK 17.4: Assessing and preparing patients with medical conditions for major surgery Ade Adebajo Faculty of Medicine, Dentistry and Health, University of Sheffield, UK 19.12: Miscellaneous conditions presenting to the rheumatologist Raymond Agius Occupational Medicine, University of Manchester, UK 10.2.1: Occupational and environmental health S. Faisal Ahmed School of Medicine, University of Glasgow, Royal Hospital for Children, Glasgow, UK 13.7.3: Normal and abnormal sexual differentiation Shahzada K. Ahmed Department of Otorhinolaryngology, Queen Elizabeth Hospital, Birmingham, UK 13.2.2: Disorders of the posterior pituitary gland Vineet Ahuja Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India 15.10.8: Malabsorption syndromes in the tropics Guruprasad P. Aithal NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham; Nottingham Digestive Diseases Centre, The University of Nottingham, Nottingham, UK 15.24.3: Drug-​induced liver disease Sara Ajina Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 24.6.1: Visual pathways Tyler Albert VA Puget Sound Health Care System, Division of General Internal Medicine, University of Washington, Seattle, WA, USA 10.3.6: Diseases of high terrestrial altitudes Maha Albur University of Bristol, Bristol, UK 8.2.5: Antimicrobial chemotherapy Michael J. Aldape Veterans Affairs Medical Center, Infectious Diseases Section, Boise, ID, USA 8.6.25: Botulism, gas gangrene, and clostridial gastrointestinal infections Graeme J.M. Alexander UCL Professor, UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK 15.23.1: Hepatitis A to E; 15.24.6: Primary and secondary liver tumours Michael E.D. Allison Liver Unit, Cambridge Biomedical Research Centre, Addenbrooke’s Hospital, Cambridge, UK 15.24.6: Primary and secondary liver tumours Carlo Ammendolia Faculty of Medicine, University of Toronto, Toronto, Canada; Rebecca MacDonald Centre for Arthritis and Autoimmune Diseases, Division of Rheumatology, Mount Sinai Hospital, Toronto, Canada 19.4: Back pain and regional disorders Chris Andrews Faculty of Medicine, University of Queensland, Herston, Qld 4029, Australia 10.3.5: Lightning and electrical injuries Ross H. Andrews Professor, Cholangiocarcinoma Research Institute (CARI), Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; Professor of Parasitology, Imperial College London, Faculty of Medicine, St Mary’s Campus, London, UK 8.11.2: Liver fluke infections Jervoise Andreyev Consultant Gastroenterologist, United Lincolnshire Hospitals Trust; Honorary Professor, The School of Medicine, University of Nottingham, UK 15.3.4: Investigation of gastrointestinal
function Gregory M. Anstead Division of Infectious Diseases, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Immunosuppression and Infectious Diseases Clinics, Department of Medicine, South Texas Veterans Health Care System, San Antonio, TX, USA 8.7.3: Coccidioidomycosis Quentin M. Anstee Professor of Experimental Hepatology and Honorary Consultant Hepatologist, Faculty of Medical Sciences, Newcastle University and Freeman Hospital Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 15.24.2: Non​alcoholic fatty liver disease Charles M.G. Archer Department of Dermatology, Oxford University Hospitals NHS Trust, Oxford, UK 23.15: Skin and systemic diseases Clive B. Archer Consultant Dermatologist and Honorary Senior Clinical Lecturer, St John’s Institute of Dermatology, Guy’s and St Thomas’ NHS Foundation Trust & King’s College London, Guy’s Hospital, London, UK 23.15: Skin and systemic diseases Michael J. Arden-​Jones  Consultant
Dermatologist, University of Southampton, Southampton, UK 23.6: Dermatitis/​eczema Mark J. Arends University of Edinburgh Division of Pathology, Cancer Research UK Edinburgh Centre, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK 3.6: Apoptosis in health and disease J. Arendt Emeritus Professor of
Endocrinology, University of Surrey,
Guildford, UK 13.11: The pineal gland and melatonin James O. Armitage The Joe Shapiro Professor of Medicine, Division of Oncology/​Hematology, University of Nebraska Medical Center, Omaha, NE, USA 22.4.3: Hodgkin lymphoma; 22.4.4: Non-​Hodgkin lymphoma Vicente Arroyo Professor of Medicine at the University of Barcelona Medical School; Chairman of the European Association
for the Study of the Liver Chronic Liver
Failure Consortium (EASL-​CLIF
Consortium) and President of the European Foundation for the Study of Chronic Liver Failure (EF-​CLIF), Barcelona, Spain 15.22.2: Cirrhosis and ascites Daniel Aruch Icahn School of Medicine at Mount Sinai, New York, NY, USA 22.3.5: The polycythaemias; 22.3.6: Thrombocytosis and essential thrombocythaemia Frances Ashcroft Professor of Physiology, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK 3.4: Ion channels and disease Caroline Ashley Lead Specialist Pharmacist, Centre for Nephrology, Royal Free Hospital, London, UK 21.19: Drugs and the kidney Shazad Q. Ashraf Consultant Colorectal Surgeon, Department of Colorectal Surgery, Queen Elizabeth Hospital, Birmingham University Hospitals, Birmingham, UK 15.14: Colonic diverticular disease

Contributors xlvi Paul Aveyard Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK 26.6.2: Obesity and weight management; 26.6.3: Smoking cessation Tar-​Ching Aw† Abu Dhabi National Oil Company, United Arab Emirates 10.2.5: Noise; 10.2.6 Vibration Jon G. Ayres Emeritus Professor of Environmental and Respiratory Medicine, Universty of Birmingham, Birmingham, UK 10.1: Environmental medicine, occupational medicine, and poisoning; 10.3.1: Air pollution and health Juan Carlos Ayus Renal Consultants of Houston, Houston, TX, USA; University of California Irvine, Orange, CA, USA 21.2.1: Disorders of water and sodium homeostasis Qasim Aziz Centre for Neuroscience, Surgery and Trauma, Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK 15.13: Irritable bowel syndrome Trevor Baglin Previously Cambridge Haemophilia and Thrombophilia Centre, Department of Haematology, Addenbrooke’s Hospital, Cambridge University Hospitals, Cambridge, UK 22.7.2: Evaluation of the patient with a bleeding tendency Michael Bagshaw Aviation Medicine, King’s College, London, UK 10.2.3: Aviation medicine Colin Baigent Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK 2.4: Large-​scale randomized evidence: Trials and meta-​analyses of trials Kenneth F. Baker Faculty of Medical Sciences, Newcastle University and Musculoskeletal Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 19.5: Rheumatoid arthritis Bettina Balint Sobell Department of Motor Neuroscience and Movement Disorders, University College London Institute of Neurology, Queen Square, London, UK; Department of Neurology, University Hospital Heidelberg, University of Heidelberg, Germany 24.7.3: Movement disorders other than Parkinson’s disease Jay Banerjee College of Life Sciences, University of Leicester, Leicester, UK 6.4: Older people and urgent care Adrian P. Banning Oxford University Hospitals NHS Trust, Oxford, UK 16.3.2: Echocardiography; 16.14.1 Acute aortic syndromes George Banting Medical Sciences Building, University of Bristol, Bristol, UK 3.1: The cell Thomas M. Barber University of Warwick, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK 13.10: Hormonal manifestations of non-​endocrine disease E.J. Barnes Nuffield Department of Medicine, University of Oxford, Oxford, UK 8.5.22: Hepatitis C virus Michael Barnes University of Newcastle, Newcastle upon Tyne, UK; Christchurch Group, Janet Barnes Unit, Birmingham, UK 24.13.2: Spinal cord injury and its management Andrew J. Barr Leeds Institute of Rheumatic and Musculoskeletal Medicine, Leeds, UK 19.9: Osteoarthritis Jonathan Barratt Professor of Renal Medicine, University of Leicester; Honorary Consultant Nephrologist, University Hospitals of Leicester, Leicester, UK 21.8.1: Immunoglobulin A nephropathy and IgA vasculitis (HSP) Buddha Basnyat Oxford University Clinical Research Unit -​ Nepal; Patan Academy of Health Sciences, Nepal 8.6.9 Typhoid and paratyphoid fevers; 10.3.6: Diseases of high terrestrial altitudes D. Nicholas Bateman, Pharmacology, Toxicology and Therapeutics, University of Edinburgh, Edinburgh, UK 10.4.1: Poisoning by drugs and chemicals David Bates Clinical Neurology, Newcastle University, Newcastle on Tyne, UK 24.5.5: The unconscious patient; 24.9: Brainstem syndromes Robert P. Baughman University of Cincinnati Medical Center, Cincinnati, OH, USA 18.12: Sarcoidosis Peter J. Baxter School of Clinical Medicine,
Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK 10.3.8: Disasters: Earthquakes, hurricanes, floods, and volcanic eruptions Hannah Beckwith Specialist Registrar, Imperial College Healthcare NHS Trust Renal and Transplant Centre, Hammersmith Hospital, London, UK 21.10.3: The kidney in rheumatological
disorders Diederik van de Beek Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands 24.11.1: Bacterial infections David A. Bender University College London, London, UK 11.2: Vitamins D.A. Bente University of Texas Medical Branch, Galveston, TX, USA 8.5.16: Bunyaviridae Anthony R. Berendt Oxford University Hospitals NHS Foundation Trust, Oxford, UK 20.3: Osteomyelitis Stefan Berg Consultant in Pediatric Rheumatology and Immunology, Queen Silvia Children’s Hospital, Goteborg, Sweden 12.12.2 Hereditary periodic fever syndromes David de Berker Bristol Dermatology
Centre, University Hospitals Bristol,
Bristol, UK 23.13: Hair and nail disorders Nancy Berliner H. Franklin Bunn Professor of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 22.3.1: Granulocytes in health and disease; 22.4.1: Introduction to lymphopoiesis Jessica Bertrand Experimental Orthopedics, University Hospital Magdeburg, Magdeburg, Germany 19.1: Joints and connective tissue—​structure
and function J.M. Best King’s College London, London, UK 8.5.13: Rubella Delia B. Bethell Oxford University Hospitals NHS Foundation Trust, Oxford, UK 8.6.1: Diphtheria Kailash Bhatia Sobell Department of Motor Neuroscience and Movement Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, UK 24.7.3: Movement disorders other than
Parkinson’s disease Vijaya Raj Bhatt Assistant Professor, Division of Hematology-​Oncology, University of Nebraska Medical Center, Omaha, NE, USA 22.4.3: Hodgkin lymphoma; 22.4.4: Non-​Hodgkin lymphoma Joya Bhattacharyya Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK 15.5: Immune disorders of the gastrointestinal tract Paola Bianchi Oncohematology Unit—​ Pathophysiology of Anemias Unit, Foundation IRCCS Ca’ Granda Ospedale Maggiore, Milan, Italy 22.6.10: Erythrocyte enzymopathies Rudolf Bilous Professor of Clinical Medicine, Newcastle University, Newcastle upon Tyne; Academic Centre, James Cook University Hospital, Middlesbrough, UK 21.10.1: Diabetes mellitus and the kidney D. Bilton Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, UK 18.9: Bronchiectasis Jonathan I. Bisson Division of Psychological Medicine and Clinical Neurosciences, University of Cardiff, Cardiff, UK 26.5.9: Acute stress disorder, adjustment disorders, and post-​traumatic stress disorder Carol M. Black Newnham College, Cambridge, UK 19.11.3: Systemic sclerosis (scleroderma) S.R. Bloom Head of Division of Diabetes, Endocrinology and Metabolism, Hammersmith Hospital, Imperial College London, London, UK 13.8: Pancreatic endocrine disorders and multiple endocrine neoplasia; 15.9.1: Hormones and the gastrointestinal tract; 15.9.2: Carcinoid syndrome Johannes Blum Medical Services, Swiss
Tropical and Public Health Institute, Basel, Switzerland 8.8.11: Human African trypanosomiasis † It is with great regret that we report that Tar-Ching Aw died on 18 July, 2017.

Contributors xlvii Kristien Boelaert University of Birmingham, Birmingham, UK 13.3.1: The thyroid gland and disorders of thyroid function; 13.3.2: Thyroid cancer Eva Boonen Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven University, B-​3000 Leuven, Belgium 17.9: Metabolic and endocrine changes in acute and chronic critical illness Christopher Booth† Wellcome Institute for the History of Medicine, Wellcome Building, London, UK 1.1: On being a patient Marina Botto Professor, Imperial College London, London, UK 4.2: The complement system Ralph Bouhaidar Consultant Forensic Pathologist, NHS Lothian; Honorary Senior Lecturer, Edinburgh University, Edinburgh; Training Programme Director for Forensic Histopathology (Scotland), UK 27.1: Forensic and legal medicine Henri-​Jean Boulouis Ecole Nationale Vétérinaire d’Alfort, Maisons-​Alfort, France 8.6.43: Bartonellas excluding B. bacilliformis P.-​M.G. Bouloux Centre for Neuroendocrinology, University College London Medical School, London, UK 13.6.2: Disorders of male reproduction and male hypogonadism S.J. Bourke Royal Victoria Infirmary, Newcastle upon Tyne, UK 18.14.1: Diffuse alveolar haemorrhage; 18.14.2: Eosinophilic pneumonia; 18.14.3: Lymphocytic infiltrations of the lung; 18.14.4: Hypersensitivity pneumonitis; 18.14.5: Pulmonary Langerhans’ cell histiocytosis; 18.14.6: Lymphangioleiomyomatosis; 18.14.7: Pulmonary alveolar proteinosis; 18.14.8: Pulmonary amyloidosis; 18.14.9: Lipoid (lipid) pneumonia; 18.14.10: Pulmonary alveolar microlithiasis; 18.14.12: Radiation pneumonitis; 18.14.13: Drug-​induced
lung disease Ian C.J.W. Bowler Oxford University Hospitals NHS Foundation Trust, Oxford, UK; University of Oxford, Oxford, UK 8.2.3: Nosocomial infections Louise Bowles Consultant Haematologist, Barts Health NHS Trust, London, UK 14.7: Thrombosis in pregnancy Paul Bowness Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, UK 4.1: The innate immune system Ray Boyapati Department of Gastroenterology, Monash Health, Victoria, Australia; Faculty of Medicine, Nursing and Health Sciences, Monash University, Vic, Australia 15.17: Vascular disorders of the gastrointestinal tract Sally M. Bradberry NPIS (Birmingham Unit) and West Midlands Poisons Unit, City Hospital, Birmingham; School of Biosciences, University of Birmingham, Birmingham, UK 10.4.1: Poisoning by drugs and chemicals Marcus Bradley North Bristol NHS Trust, Bristol, UK 24.3.3: Imaging in neurological diseases Tasanee Braithwaite Locum Consultant, Moorfields Eye Hospital NHS Foundation Trust, London, UK 25.1: The eye in general medicine Thomas Brandt Ludwig Maximilians University, Munich, Germany 24.6.2: Eye movements and balance Petter Brandtzaeg Emeritus Professor, Department of Paediatrics, Oslo University Hospital, Oslo, Norway 8.6.5: Meningococcal infections Philippe Brasseur Institut de Recherche pour le Développement, Dakar, Sénégal, West Africa 8.8.3: Babesiosis Jürgen Braun Medical Director, Rheumazentrum Ruhrgebiet, Herne, Germany; Chair of Rheumatology, Ruhr University, Bochum, Germany 19.6: Spondyloarthritis and related
conditions Evan M. Braunstein Hematology Division, Johns Hopkins University School of Medicine, Baltimore, MD, USA 22.3.7: Primary myelofibrosis James D. Brenton Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK 5.2: The nature and development of cancer: Cancer mutations and their implications J.A. Bridgewater Professor and Consultant in Medical Oncology, UCL Cancer Institute, London, UK 15.16: Cancers of the gastrointestinal tract Frank Bridoux Professor of Nephrology, Department of Nephrology, Hôpital Jean Bernard, Poitiers, France 21.10.5: Renal involvement in plasma cell dyscrasias, immunoglobulin-​based amyloidoses, and fibrillary glomerulopathies, lymphomas, and leukaemias Charlotte K. Brierley Department of Haematology, Cancer and Haematology Centre, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, UK 22.3.2: Myelodysplastic syndromes Alice Brockington University of Sheffield, Sheffield, UK 24.15: The motor neuron diseases Max Bronstein Advocacy and Science
Policy, Every Life Foundation, Washington, DC, USA 2.9: Engaging patients in therapeutic development Gary Brook London North West University Healthcare NHS Trust, London, UK 9.3: Sexual history and examination Arthur E. Brown Research Consultant, Faculty of Medical Technology, Mahidol University, Nakhon Pathom, Thailand 8.6.21: Anthrax Anthony F.T. Brown Department of Emergency Medicine, Royal Brisbane and Women’s Hospital, Brisbane, Qld, Australia 17.3: Anaphylaxis Kevin E. Brown Virus Reference Department, Public Health England, London, UK 8.5.20: Parvovirus B19 Michael Brown Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK 8.9.4: Strongyloidiasis, hookworm, and other gut strongyloid nematodes Morris J. Brown Professor of Endocrine Hypertension, Queen Mary University of London, William Harvey Heart Centre, London, UK 16.17.3: Secondary hypertension Vanessa Brown Specialist Registrar, Royal Surrey County Hospital, Guildford, UK 15.4.2: Gastrointestinal bleeding Reto Brun Parasite Chemotherapy Unit, Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland 8.8.11: Human African trypanosomiasis Marco J. Bruno Erasmus Medical Center, University Medical Center Rotterdam, Department of Gastroenterology and Hepatology, Rotterdam, the Netherlands 15.26.2: Chronic pancreatitis Amy E. Bryant Research Professor, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, Idaho State University, ID, USA 8.6.25: Botulism, gas gangrene, and clostridial gastrointestinal infections Antony D.M. Bryceson London School of Hygiene and Tropical Medicine, London, UK 8.8.13: Leishmaniasis Nicolas C. Buchs Consultant Colorectal Surgeon, Clinic for Visceral and Transplantation Surgery, Department of Surgery, University Hospitals of Geneva, Geneva, Switzerland 15.14: Colonic diverticular disease Camilla Buckley MRC Clinician Scientist and Honorary Consultant, Department of Clinical Neurology, University of Oxford, Oxford, UK 24.24: Autoimmune encephalitis and Morvan’s syndrome Simon J.A. Buczacki Honorary Consultant Colorectal Surgeon, Cambridge Colorectal Unit, Addenbrooke’s Hospital, Cambridge, UK 15.4.1: The acute abdomen Enrico Bugiardini MRC Centre for Neuromuscular Disease, University College London, London, UK 24.19.1: Structure and function of muscle Alan Burnett Former Professor of Haematology, Cardiff University, Cardiff, UK 22.3.3: Acute myeloid leukaemia Gilbert Burnham John Hopkins Bloomberg School of Public Health, Baltimore, MD, USA 8.9.1: Cutaneous filariasis Aine Burns Consultant Nephrologist and Director of Postgraduate Medical Education, Centre for Nephrology, Royal Free NHS Trust and University College Medical School, London, UK 21.19: Drugs and the kidney † It is with great regret that we report that Christopher Booth died on 13 July, 2012.

Contributors xlviii Eileen Burns Leeds Centre for Older People’s Medicine, Leeds Teaching Hospitals NHS Trust, Leeds, UK 6.11: Promotion of dignity in the life and death of older patients Harry Burns University of Strathclyde, UK 2.14: Deprivation and health N.P. Burrows Consultant Dermatologist, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 20.2: Inherited defects of connective tissue: Ehlers–​Danlos syndrome, Marfan syndrome, and pseudoxanthoma elasticum Rosie Burton Khayelitsha District Hospital, Corner of Walter Sisulu and Streve Biko
Roads, Khayelitsha, Cape Town, Africa; Department of Medicine, University of Cape Town, Cape Town, Africa 14.15: Maternal infection in pregnancy Andrew Bush Imperial College London, London, UK; National Heart and Lung Institute, London, UK; Royal Brompton and Harefield NHS Foundation Trust, London, UK 18.10: Cystic fibrosis Kate Bushby Newcastle University John Walton Centre for Muscular Dystrophy Research, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, International Centre for Life, Newcastle upon Tyne, UK 24.19.2: Muscular dystrophy Gary Butler University College London Hospital and UCL Great Ormond Street Institute of Child Health, London, UK 13.7.1: Normal growth and its disorders William F. Bynum Professor Emeritus, University College London, London, UK 2.1: Science in medicine: When, how,
and what Simone M. Cacciò European Union Reference Laboratory for Parasites, Department of Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanità, Rome, Italy 8.8.5: Cryptosporidium and cryptosporidiosis Djuna L. Cahen Erasmus Medical Center, University Medical Center Rotterdam, Department of Gastroenterology and Hepatology, Rotterdam, the Netherlands 15.26.2: Chronic pancreatitis P.M.A. Calverley School of Clinical Sciences, University of Liverpool, Liverpool, UK 18.15: Chronic respiratory failure Jason Caplan Dignity Health Medical Group; St. Joseph’s Hospital and Medical Center; Creighton University School of Medicine; Phoenix, AZ, USA 26.5.3: Organic psychoses Jonathan R. Carapetis Telethon Kids Institute, University of Western Australia and Perth Children’s Hospital, Perth, Australia 16.9.1: Acute rheumatic fever Jordi Carratalà Department of Infectious Diseases, Hospital Universitari de Bellvitge -​ IDIBELL, Division of Health Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain 8.6.39: Legionellosis and Legionnaires’ disease R. Carter Consultant Pancreaticobiliary Surgeon, West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK 15.26.1: Acute pancreatitis Stuart Carter Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK 19.12: Miscellaneous conditions presenting to the rheumatologist David Carty Department of Diabetes, Endocrinology and Clinical Pharmacology, Glasgow Royal Infirmary, Glasgow, UK 14.11: Endocrine disease in pregnancy Jaimini Cegla Imperial College London, London, UK 12.6: Lipid disorders Joseph Cerimele University of Washington, Washington, DC, USA 26.5.6: Depressive disorder Joshua T. Chai Department of Cardiovascular Medicine, University of Oxford,
Oxford, UK 16.13.1: Biology and pathology of
atherosclerosis Richard E. Chaisson Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA 8.6.26: Tuberculosis Romanee Chaiwarith Division of Infectious Diseases, Department of Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand 8.7.6: Talaromyces (Penicillium) marneffei infection Ben Challis University of Cambridge Medical School, Cambridge, UK 13.9.2: Hypoglycaemia Siddharthan Chandran Euan MacDonald Centre for Clinical Brain Sciences (CCBS), University of Edinburgh, Edinburgh, UK 3.7: Stem cells and regenerative medicine; 24.10.2: Demyelinating disorders of the central nervous system Keith Channon John Radcliffe Hospital, Oxford, UK 16.1.1: Blood vessels and the endothelium Roger W. Chapman Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford; Nuffield Department of Medicine, University of Oxford, Oxford, UK 15.23.4: Primary sclerosing cholangitis V. Krishna Chatterjee University of Cambridge Medical School, Cambridge, UK 13.1: Principles of hormone action Afzal Chaudhry Chief Clinical Information Officer, Cambridge University Hospitals, Cambridge, UK 2.5: Bioinformatics K. Ray Chaudhuri National Parkinson Foundation Centre of Excellence, King’s College, Denmark Hill Campus, London, UK 24.7.2: Parkinsonism and other extrapyramidal diseases Patrick F. Chinnery University of Newcastle, Newcastle upon Tyne, UK 24.19.5: Mitochondrial disease Hector Chinoy University of Manchester, Manchester, UK 19.11.5: Inflammatory myopathies Peter L. Chiodini Hospital for Tropical Diseases, University College London Hospitals,
London, UK 8.9.5: Gut and tissue nematode infections acquired by ingestion Rossa W.K. Chiu Choh-​Ming Li Professor of Chemical Pathology, Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong, China 3.9: Circulating DNA for molecular diagnostics Bruno B. Chomel School of Veterinary Medicine, University of California, CA, USA 8.6.43: Bartonellas excluding B. bacilliformis Robin P. Choudhury University of Oxford, Oxford, UK 16.13.1: Biology and pathology of atherosclerosis Julia Choy National Health Service, London, UK 18.4.5: Pulmonary complications of HIV infection Lydia Chwastiak Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA 26.5.6: Depressive disorder Andrew L. Clark Chair of Clinical Cardiology
and Honorary Consultant Cardiologist,
Hull York Medical School, Castle Hill Hospital, Hull, UK 16.5.2: Acute cardiac failure: Definitions, investigation, and management; 16.5.3: Chronic heart failure: Definitions, investigation, and management Andrew Clegg Academic Unit of Elderly Care and Rehabilitation, University of Leeds, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK 6.2: Frailty and sarcopenia John G.F. Cleland National Heart and Lung Institute, Royal Brompton and Harefield Hospitals Trust London, UK; Hull York Medical School, University of Hull, Hull, UK 16.5.2: Acute cardiac failure: Definitions, investigation, and management; 16.5.3 Chronic heart failure: Definitions, investigation, and management Gavin Clunie Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 20.5: Osteonecrosis, osteochondrosis, and osteochondritis dissecans S.M. Cobbe Previously Consultant Cardiologist, Glasgow Royal Infirmary; former BHF Walton Professor of Medical Cardiology, University of Glasgow, Glasgow, UK 16.2.2: Syncope and palpitation Fredric L. Coe The University of Chicago Medicine, Chicago, IL, US 21.1: Structure and function of the kidney Sian Coggle Consultant Physician, Cambridge University Hospitals, Cambridge, UK 30.1: Acute medical presentations; 30.2: Practical procedures Jon Cohen Brighton and Sussex Medical School, Brighton, UK 8.2.4: Infection in the immunocompromised host

Contributors xlix Alasdair Coles Cambridge School of Clinical Medicine, Cambridge, UK 24.10.2: Demyelinating disorders of the central nervous system Jane Collier Consultant Hepatologist, John Radcliffe Hospital, Oxford, UK 8.5.22: Hepatitis C virus; 15.22.1: Investigation and management of jaundice Rory Collins Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK 2.4: Large-​scale randomized evidence: Trials and meta-​analyses of trials Juan D. Colmenero Infectious Diseases Service, Regional University Hospital, Málaga, Spain 8.6.22: Brucellosis Alastair Compston Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK 24.1: Introduction and approach to the patient with neurological disease Juliet Compston University of Cambridge School of Clinical Medicine and Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 20.4: Osteoporosis Philip G. Conaghan Leeds University,
Leeds, UK 19.9: Osteoarthritis Christopher P. Conlon Professor of Infectious Diseases, Nuffield Department of Medicine, University of Oxford, Oxford, UK 8.4: Travel and expedition medicine; 8.5.23: HIV/​ AIDS; 8.5.28: Molluscum contagiosum Simon Conroy Department of Health Sciences, University of Leicester, Leicester, UK 6.4: Older people and urgent care Cyrus Cooper MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK; NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK 20.4: Osteoporosis John E. Cooper University of Cambridge, Cambridge, UK 8.8.8: Sarcocystosis (sarcosporidiosis) Robert Cooper University of Liverpool, Liverpool, UK 19.11.5: Inflammatory myopathies Mhairi Copland Professor of Translational Haematology, Section of Experimental Haematology, Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK 22.3.4: Chronic myeloid leukaemia Susan J. Copley Imperial College Healthcare NHS Trust, London, UK 18.3.2: Thoracic imaging Jeremy Cordingley Peri-​Operative Medicine, St Bartholomew’s Hospital, London, UK 17.5: Acute respiratory failure Philip J. Cowen University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK 26.4.1: Psychopharmacology in medical practice Timothy M. Cox Professor of Medicine Emeritus, Director of Research, University of Cambridge; Honorary Consultant Physician, Addenbrooke’s Hospital, Cambridge, UK 1.1: An older patient’s story; 12.1: The inborn errors of metabolism: General aspects; 12.3.1: Glycogen storage diseases; 12.3.2: Inborn errors of fructose metabolism; 12.3.3: Disorders of galactose, pentose, and pyruvate metabolism; 12.5: The porphyrias; 12.7.1: Hereditary haemochromatosis; 12.8: Lysosomal disease; 13.11: The pineal gland and melatonin; 15.10.5: Disaccharidase deficiency; 22.6.4: Iron metabolism and its disorders S.E. Craig Oxford Sleep Unit, Churchill Hospital, Oxford, UK 18.1.1: The upper respiratory tract Matthew Cramp South West Liver Unit and Peninsula Schools of Medicine and Dentistry, Derriford Hospital, Plymouth, UK 8.5.21: Hepatitis viruses (excluding hepatitis C virus) Robin A.F. Crawford Addenbrooke’s Hospital, Cambridge, UK 14.18: Malignant disease in pregnancy Daniel Creamer King’s College Hospital, London, UK 23.16: Cutaneous reactions to drugs Tim Crook North Middlesex Hospital,
London, UK 5.7: Medical management of breast cancer Paul Cullinan Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, UK 18.7: Asthma Peter F. Currie Perth Royal Infirmary, Perth and Ninewells Hospital and Medical School, Dundee, UK 16.9.3: Cardiac disease in HIV infection Nicola Curry Consultant Haematologist, Oxford University Hospitals NHS Foundation Trust, Oxford Haemophilia and Thrombosis Centre, Churchill Hospital, Oxford, UK 22.7.3: Thrombocytopenia and disorders of
platelet function Goodarz Danaei Department of Global Health and Population, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA 16.13.2: Coronary heart disease: Epidemiology and prevention Christopher J. Danpure Emeritus Professor of Molecular Cell Biology, University College London, London, UK 12.10: Hereditary disorders of oxalate metabolism: The primary hyperoxalurias Bhaskar Dasgupta University of Essex, Essex, UK; Anglia Ruskin University, East Anglia, UK; Southend University Hospital NHS Foundation Trust, Essex, UK 19.11.11: Polymyalgia rheumatica Pooja Dassan Consultant Neurologist, Imperial College Healthcare NHS Trust and London
North West University Healthcare NHS Trust, London, UK 14.12: Neurological conditions in
pregnancy Andrew Davenport Professor of Dialysis and ICU Nephrology, UCL Department of Nephrology, Royal Free Hospital, University College London, London, UK 21.4: Clinical investigation of renal disease Gail Davey Centre for Global Health Research, Brighton and Sussex Medical School,
Brighton, UK 10.5: Podoconiosis Alun Davies Imperial College School of Medicine, London, UK 16.14.2: Peripheral arterial disease Helen E. Davies University Hospital of Wales, Cardiff, UK 18.19.4: Mediastinal tumours and cysts R Justin Davies Consultant Colorectal Surgeon, Cambridge Colorectal Unit, Addenbrooke’s Hospital, Cambridge, UK 15.4.1: The acute abdomen P.D.O. Davies Liverpool Heart and Chest Hospital NHS Foundation Trust, Liverpool, UK 8.6.27: Disease caused by environmental mycobacteria R. Rhys Davies Cognitive Function Clinic, Walton Centre for Neurology and Neurosurgery, Liverpool, UK 24.3.1: Lumbar puncture Simon Davies Professor of Nephrology and Dialysis Medicine, Institute for Science and Technology in Medicine, Keele University, Keele; Consultant Nephrologist, University Hospital of North Midlands, Stoke-​on-​Trent, UK 21.7.2: Peritoneal dialysis Richard Dawkins New College, University of Oxford, Oxford, UK 2.2: Evolution: Medicine’s most basic science Christopher P. Day Vice-​Chancellor and President, Newcastle University and Freeman Hospital Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 15.24.2: Non​alcoholic fatty liver disease Nicholas P.J. Day Mahidol-​Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK 8.6.35: Leptospirosis; 8.6.41: Scrub typhus Colin Dayan University of Cardiff, Wales, UK 13.9.1: Diabetes Marc E. De Broe Professor of Medicine, Laboratory of Pathophysiology, University of Antwerp, Antwerp, Belgium 21.9.2: Chronic tubulointerstitial nephritis Kevin M. De Cock Center for Global Health, Atlanta, GA, USA 8.5.24: HIV in low-​ and middle-​income
countries An S. De Vriese Division of Nephrology, AZ Sint-​Jan Brugge-​Oostende AV, Brugge, Belgium 21.8.4: Membranous nephropathy Patrick B. Deegan Consultant Metabolic Physician, Lysosomal Disorders Unit, Cambridge University Hospitals, Cambridge, UK 12.8 Lysosomal disease

Contributors l Christopher Deighton Royal Derby Hospital, Derby, UK 19.2 Clinical presentation and diagnosis of rheumatological disorders David M. Denison Emeritus Professor of Clinical Physiology, Royal Brompton Hospital and Imperial College London, London, UK 10.2.4: Diving medicine Christopher P. Denton Centre for Rheumatology, Division of Medicine, University College London (UCL) Medical School, Royal Free Hospital, London, UK 19.11.3: Systemic sclerosis (scleroderma) Ulrich Desselberger University of Cambridge, Cambridge, UK 8.5.8: Enterovirus infections; 8.5.9: Virus
infections causing diarrhoea and vomiting Patrick C. D’Haese Head of Laboratory of Pathophysiology, University of Antwerp, Campus Drie Eiken, Wilrijk, Belgium 21.9.2: Chronic tubulointerstitial nephritis Ashwin Dhanda Plymouth Hospitals NHS Trust, Plymouth, UK 8.5.21: Hepatitis viruses (excluding hepatitis C virus) Jugdeep Dhesi Guys and St Thomas’ Hospitals, London, UK 6.6: Supporting older peoples’ care in surgical and oncological services Euan J. Dickson Consultant Pancreaticobiliary Surgeon, West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK 15.26.1: Acute pancreatitis Michael Doherty University of Nottingham, Nottingham, UK 19.3: Clinical investigation; 19.10: Crystal-​related arthropathies Inderjeet S. Dokal Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Barts Health NHS Trust, London, UK 22.5.1: Inherited bone marrow failure
syndromes Jan Donck Department of Nephrology, AZ Sint-​ Lucas, Ghent, Belgium 21.10.4: The kidney in sarcoidosis Arjen M. Dondorp Mahidol-​Oxford Tropical Medicine Research Unit, Bangkok,
Thailand 8.8.2: Malaria Basil Donovan University of New South Wales, NSW, Australia 8.6.37: Syphilis Philip R. Dormitzer Pfizer Vaccine Research and Development, Pearl River, NY, USA 8.5.9: Virus infections causing diarrhoea and vomiting Anne Dornhorst Imperial College Hospital, London, UK 14.10: Diabetes in pregnancy Charles G. Drake New York Presbyterian and Columbia University Medical Center, New York, USA 5.4: Cancer immunity and immunotherapy Hal Drakesmith MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital and University of Oxford, Oxford, UK 22.6.5: Anaemia of inflammation Christopher Dudley Consultant Nephrologist, The Richard Bright Renal Unit, Southmead Hospital, North Bristol NHS Trust, Bristol, UK 16.14.3: Cholesterol embolism Susanna Dunachie Oxford University Hospitals NHS Trust, Oxford, UK 8.4: Travel and expedition medicine Lisa Dunkley Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK 19.12: Miscellaneous conditions presenting to the rheumatologist David Dunne University of Cambridge,
Cambridge, UK; Wellcome Trust-​Cambridge, Centre for Global Health Research, UK; CAPREx, THRiVE-​Cambridge, and Cambridge-​Africa 8.11.1: Schistosomiasis Stephen R. Durham National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, London, UK 18.6: Allergic rhinitis Jeremy Dwight John Radcliffe Hospital, Oxford, UK 16.2.1: Chest pain, breathlessness, and fatigue Jessica K. Dyson Newcastle University and Liver Unit, Freeman Hospital, Newcastle upon Tyne, UK 15.23.3: Primary biliary cholangitis Christopher P. Eades University College London, London, UK 8.7.5: Pneumocystis jirovecii Ian Eardley St James’s Hospital, Leeds, UK 13.6.4: Sexual dysfunction James E. East Consultant Gastroenterologist, Translational Gastroenterology Unit, John Radcliffe Hospital; Associate Professor of Gastroenterology and Endoscopy, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK 15.3.1: Colonoscopy and flexible
sigmoidoscopy; 15.3.2: Upper gastrointestinal endoscopy Lars Eckmann Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA 8.8.9: Giardiasis and balantidiasis Michael Eddleston Pharmacology, Toxicology and Therapeutics, Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK 10.4.4: Poisonous plants Mark J. Edwards St George’s University of London, London, UK 24.7.1: Subcortical structures: The cerebellum, basal ganglia, and thalamus Richard Edwards School of Clinical Sciences, University of Bristol, Bristol, UK 24.19.4: Metabolic and endocrine disorders Rosalind A. Eeles The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK 5.3: The genetics of inherited cancers Tim Eisen Department of Oncology, University of Cambridge, Cambridge, UK; Oncology Early Clinical Development, AstraZeneca, Cambridge, UK 5.2: The nature and development of cancer: Cancer mutations and their implications; 5.5: Clinical features and management; 21.18: Malignant diseases of the urinary tract Wagih El Masri(y) Keele University, Newcastle-​ under-​Lyme, UK; The Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, UK 24.13.2: Spinal cord injury and its management Carole Eldin University Hospital Institute Méditerranée Infection, Marseille, France 8.6.40: Rickettsioses Perry Elliott St Bartholomew’s Hospital, London, UK; Institute of Cardiovascular Science, University College London, London, UK 16.7.2: The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular; 16.7.3: Specific heart muscle disorders Christopher J. Ellis Heart of England Foundation Trust, Birmingham, UK; University of Birmingham, Birmingham, UK 8.2.1: Clinical approach Graham Ellis Monklands Hospital, Airdrie, Lanarkshire, UK 6.5: Older people in hospital Monique M. Elseviers Centre for Research and Innovation in Care (CRIC), University of Antwerp, Antwerp; Heymans Institute of Clinical Pharmacology, Ghent University, Ghent, Belgium 21.9.2: Chronic tubulointerstitial nephritis Caroline Elston Respiratory Medicine and Adult Cystic Fibrosis, King’s College Hospital, London, UK 18.10: Cystic fibrosis M.A. Epstein Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, UK 8.5.3: Epstein–​Barr virus Steve Epstein MedStar Georgetown University Hospital and Georgetown University School of Medicine, Washington, DC, USA 26.5.8: Anxiety disorders Wendy N. Erber Medical School, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, WA, Australia 22.2.2: Diagnostic techniques in the assessment of haematological malignancies Ari Ercole Neurosciences Critical Care Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 24.5.6: Brainstem death and prolonged disorders of consciousness Edzard Ernst Emeritus Professor, University of Exeter, Exeter, UK 2.22: Complementary and alternative medicine Andrew P. Evan Indiana University School of Medicine, Indianapolis, IN, USA 21.14: Disorders of renal calcium handling, urinary stones, and nephrocalcinosis Mark Evans University of Cambridge Medical School, Cambridge, UK 13.9.2: Hypoglycaemia

Contributors li Rhys D. Evans Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK 11.1 Nutrition: Macronutrient metabolism; 16.1.2: Cardiac physiology Pamela Ewan Allergy Department, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 4.5: Allergy David W. Eyre Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK 8.6.24 Clostridium difficile Lynette D. Fairbanks Purine Research Laboratory, Viapath, St Thomas’ Hospital, London, UK 12.4 Disorders of purine and pyrimidine metabolism Christopher G. Fairburn Oxford University Hospitals NHS Foundation Trust, Oxford, UK 26.5.10: Eating disorders Carole Fakhry Johns Hopkins Medical Institution, Baltimore, MD, USA 8.5.19: Papillomaviruses and polyomaviruses Marie Fallon St Columba’s Hospice Chair of Palliative Medicine, University of Edinburgh, Edinburgh, UK 7.2: Pain management Sonia Fargue University of Alabama at Birmingham, Birmingham, AL, USA 12.10: Hereditary disorders of oxalate metabolism: The primary hyperoxalurias Adam D. Farmer Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London; Department of Gastroenterology, University Hospitals of North Midlands, Stoke-​on-​Trent, UK 15.13: Irritable bowel syndrome I. Sadaf Farooqi Wellcome-​MRC Institute of Metabolic Science, University of Cambridge, UK 11.6: Obesity Jeremy Farrar Wellcome Trust, London, UK 2.17: Research in the developed world; 24.11.2: Viral infections Ken Farrington Lister Hospital, East and North Hertfordshire NHS Trust, Stevenage, UK 21.3: Clinical presentation of renal disease Hiva Fassihi King’s College London,
London, UK 23.9: Photosensitivity John Feehally Emeritus Consultant Nephrologist, University Hospitals of Leicester; Honorary Professor of Renal Medicine, University of Leicester, Leicester, UK 21.8.1: Immunoglobulin A nephropathy and IgA vasculitis (HSP); 21.8.2: Thin membrane nephropathy Peter J. Fenner School of Public Health, Tropical Medicine and Rehabilitation Sciences, James Cook University, Townsville, Qld, Australia 10.3.4: Drowning Florence Fenollar Aix-​Marseille Université, URMITE, UM63, CNRS 7278, IRD 198, INSERM 1095, IHU Méditerranée Infection, Marseille, France 15.10.6: Whipple’s disease Javier Fernández Consultant Hepatologist, Head of Liver ICU, Liver Unit, Hospital Clinic Barcelona; Associate Professor, University of Barcelona Medical School, Barcelona, Spain; Member of the European Foundation for the Study of Chronic Liver Failure (EF-​CLIF) 15.22.2: Cirrhosis and ascites Fernando C. Fervenza Professor of Medicine, Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, MN, USA 21.8.4: Membranous nephropathy Sarah Fidler Professor of HIV Medicine, Imperial College London, London, UK 8.5.23: HIV/​AIDS Richard E. Fielding Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon
Tyne, UK 21.3: Clinical presentation of renal disease Roger G. Finch Nottingham University Hospitals, NHS Trust, Nottingham, UK 8.2.5: Antimicrobial chemotherapy Simon Finney Peri-​Operative Medicine, St Bartholomew’s Hospital, London, UK 17.5: Acute respiratory failure Helen V. Firth Addenbrookes Hospital Cambridge, Cambridge, UK 24.20: Developmental abnormalities of the central nervous system John D. Firth Consultant Physician and Nephrologist, Cambridge University
Hospitals, Cambridge, UK 16.16.1: Deep venous thrombosis and pulmonary embolism; 16.17.1: Essential hypertension: Definition, epidemiology, and pathophysiology; 16.17.2: Essential hypertension: Diagnosis, assessment, and treatment; 16.19: Idiopathic oedema of women; 21.2.2: Disorders of potassium homeostasis; 21.5: Acute kidney injury; 21.7.3: Renal transplantation; 30.1: Acute medical presentations; 30.2: Practical procedures A.J. Fisher Professor of Respiratory Transplant Medicine, Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, UK 18.16: Lung transplantation Edward A. Fisher Departments of Medicine, Pediatrics, and Cell Biology, Smilow Research Centre, New York, NY, USA 16.13.1: Biology and pathology of atherosclerosis Rebecca C. Fitzgerald Professor of Cancer Prevention and MRC Programme Leader, MRC Cancer Unit, University of Cambridge, Hutchison/​MRC Research Centre, Cambridge, UK 15.7: Diseases of the oesophagus Michael E.B. FitzPatrick Department of Gastroenterology, Oxford University Hospitals, Oxford; Senior Research Fellow, Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK 15.1: Structure and function of the gastrointestinal tract R. Andres Floto Molecular Immunity Unit, Department of Medicine, University of Cambridge, UK; Cambridge Centre for Lung Infection, Royal Papworth Hospital, Cambridge, UK 3.5: Intracellular signalling Edward D. Folland University of Massachusetts Medical School, MA, USA 16.3.4: Cardiac catheterization and angiography; 16.13.5: Percutaneous interventional cardiac procedures D. de Fonseka Academic Respiratory Unit, University of Bristol, Bristol, UK 18.17: Pleural diseases Carole Foot Royal North Shore Hospital, NSW, Australia 17.1: The seriously ill or deteriorating patient Alastair Forbes Norwich Medical School,  University of East Anglia, Norwich, UK 15.10.1: Differential diagnosis and investigation of malabsorption Ewan Forrest Consultant Hepatologist and Honorary Clinical Associate Professor, Department of Gastroenterology, Glasgow Royal Infirmary and the University of Glasgow, Glasgow UK 15.24.1: Alcoholic liver disease Rob Fowkes Royal Veterinary College,
London, UK 13.1: Principles of hormone action Keith A.A. Fox Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK 16.13.4: Management of acute coronary
syndrome Stephen Franks Imperial College London, London, UK 13.6.1: Ovarian disorders Keith N. Frayn Radcliffe Department of Medicine, University of Oxford, Oxford, UK 11.1: Nutrition: Macronutrient metabolism Patrick French Mortimer Market Centre, Central and North West London NHS Trust, London, UK; University College London, London, UK 9.6: Genital ulceration Izzet Fresko Division of Rheumatology, Department of Medicine, Cerrahpasa Medical Faculty, University of Istanbul, Istanbul, Turkey 19.11.10: Behçet’s syndrome Peter S. Friedmann Emeritus Professor of Dermatology, University of Southampton, Southampton, UK 23.6: Dermatitis/​eczema Charlotte Frise Obstetric Medicine and Acute General Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK 14.20: Prescribing in pregnancy Susannah J.A. Froude Consultant Microbiology and Infectious Diseases, Public Health Wales, Cardiff, UK 8.5.29: Newly discovered viruses Stephen J. Fuller Associate Professor, Medicine Sydney Medical School Nepean, The University of Sydney, Sydney, Australia 22.6.8: Anaemias resulting from defective maturation of red cells David A. Gabbott Gloucestershire Hospitals NHS Foundation Trust, Gloucester, UK 17.2: Cardiac arrest

Contributors lii Simon M. Gabe Consultant Gastroenterologist, Intestinal Failure and Academic Unit, St Mark’s Hospital, London, UK 15.10.7: Effects of massive bowel resection Patrick G. Gallagher Professor of Pediatrics, Genetics and Pathology, Yale University, New Haven, CT, USA 22.6.9: Disorders of the red cell membrane Shreyans Gandhi King’s College Hospital/​King’s College London, London, UK 22.5.2: Acquired aplastic anaemia and pure red cell aplasia Hector H. Garcia Center for Global Health, Tumbes and Department of Microbiology, Universidad Peruana Cayetano Heredia, and Cysticercosis Unit, Instituto Nacional de Ciencias Neurologicas, Lima, Peru 8.10.2: Cystic hydatid disease (Echinococcus granulosus); 8.10.3: Cysticercosis Hill Gaston University of Cambridge, Cambridge, UK 19.8: Reactive arthritis Rupert Gauntlett Critical Care Medicine and Obstetric Anaesthesia, Royal Victoria Infirmary, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, UK 14.19: Maternal critical care John Geddes University of Oxford, Oxford, UK 26.5.7: Bipolar disorder William Gelson Consultant Hepatologist, Hepatobiliary and Liver Transplant Unit, Addenbrooke’s Hospital, Cambridge, UK 15.20: Structure and function of the liver, biliary tract, and pancreas Jacob George Department of Clinical Pharmacology and Therapeutics, University of Dundee, Dundee, UK 6.7: Drugs and prescribing in the older patient G.J. Gibson Newcastle University, Newcastle upon Tyne, UK 18.3.1: Respiratory function tests John Gibson Professor of Oral Medicine and Honorary Consultant in Oral Medicine, Institute of Dentistry, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK 15.6: The mouth and salivary glands J. van Gijn University Medical Center Utrecht, Utrecht, the Netherlands 24.10.1 Stroke: Cerebrovascular disease Ian Giles Centre for Rheumatology, Department of Medicine, University College London, London, UK 19.11.1: Introduction Robert H. Gilman Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD, USA 8.10.3: Cysticercosis Alexander Gimson Consultant Hepatologist, Hepatobiliary and Liver Transplant Unit, Addenbrooke’s Hospital, Cambridge, UK 15.19: Miscellaneous disorders of the bowel; 15.20: Structure and function of the liver, biliary tract, and pancreas; 15.24.4: Vascular disorders of the liver Matthew R. Ginks Oxford University Hospitals NHS Trust, Oxford, UK 16.4: Cardiac arrhythmias D.S. Giovanniello Medical Director, American Red Cross, Biomedical Services, Connecticut Blood Services Region, Farmington, CT, USA 22.8.1: Blood transfusion Mark A. Glover Hyperbaric Medicine Unit, St Richard’s Hospital, Chichester, UK 10.2.4: Diving medicine Peter J. Goadsby NIHR-​Wellcome Trust King’s Clinical Research Facility, King’s College London, London, UK 24.8: Headache David Goldblatt University College London, London, UK 8.3: Immunization Armando E. Gonzalez Center for Global Health, Tumbes, Universidad Peruana Cayetano Heredia, and Department of Veterinary Epidemiology and Economics, School of Veterinary Medicine, Universidad Nacional Mayor de San Marcos, Lima, Peru 8.10.2: Cystic hydatid disease (Echinococcus granulosus) E.C. Gordon-​Smith Professor of Haematology, St George’s Hospital, University of London, London, UK 22.8.2: Haemopoietic stem cell transplantation Martin Gore† The Royal Marsden, London, UK; The Institute of Cancer Research, University of London, London, UK 5.5: Clinical features and management Eduardo Gotuzzo Universidad Peruana Cayetano Heredia, Lima, Peru 8.5.25: HTLV-​1, HTLV-​2, and associated diseases Philip Goulder University of Oxford, Oxford, UK 8.5.23: HIV/​AIDS Alison D. Grant Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK 8.5.24: HIV in low-​ and middle-​income
countries Cameron C. Grant The University of Auckland, New Zealand; Starship Children’s Health, Auckland, New Zealand 8.6.15: Bordetella infection David Gray Department of Cardiovascular Medicine, Nottingham University Hospitals NHS Trust, Nottingham, UK 16.3.1: Electrocardiography Richard Gray Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK 2.4: Large-​scale randomized evidence: Trials and meta-​analyses of trials John R. Graybill Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA 8.7.3: Coccidioidomycosis Darren Green Division of Cardiovascular Sciences, University of Manchester, Manchester, UK 16.5.4: Cardiorenal syndrome Manfred S. Green Hyperbaric Medicine Unit, St Richard’s Hospital, Chichester, UK 10.3.9: Bioterrorism Christopher D. Gregory University of Edinburgh Centre for Inflammation Research, Queen’s Medical Research Institute, Edinburgh, UK 3.6: Apoptosis in health and disease Christopher E.M. Griffiths Salford Royal NHS Foundation Trust, University of Manchester, Manchester, UK 23.5: Papulosquamous disease Karolina Griffiths University Hospital Institute Méditerranée Infection, Marseille, France 8.6.40: Rickettsioses Mark Griffiths Peri-​Operative Medicine, St Bartholomew’s Hospital, London, UK; Imperial College London, London, UK 17.5: Acute respiratory failure William J.H. Griffiths Consultant Hepatologist, Department of Hepatology, Addenbrooke’s Hospital, Cambridge, UK 12.7.1: Hereditary haemochromatosis; 15.24.6: Primary and secondary liver tumours J.P. Grünfeld Hôpital Universitaire Necker, Paris, France 21.12: Renal involvement in genetic disease D.J. Gubler Director, Program on Emerging Infectious Disease, Duke-NUS Graduate Medical School, Singapore; Asian Pacific Institute of Tropical Medicine and Infectious Diseases, University of Hawaii, Honolulu 8.5.12: Alphaviruses Richard L. Guerrant Center for Global Health, School of Medicine, University of Virginia, VA, USA 8.6.12: Cholera Kaushik Guha Portsmouth Hospitals NHS Trust, Portsmouth, UK 16.5.1: Epidemiology and general pathophysiological classification of
heart failure Nishan Guha Oxford University Hospitals NHS Foundation Trust, Oxford, UK 29.1: The use of biochemical analysis for diagnosis and management Loïc Guillevin Department of Internal Medicine, National Referral Center for Rare Autoimmune and Systemic Diseases, INSERM U1060, Hôpital Cochin, Assistance Publique–​ Hôpitaux de Paris, University Paris Descartes, Paris, France 19.11.8: Polyarteritis nodosa Mark Gurnell University of Cambridge Medical School, Cambridge, UK 13.1: Principles of hormone action; 13.5.1 Disorders of the adrenal cortex Oliver P. Guttmann St Bartholomew’s Hospital, London, UK; Institute of Cardiovascular
Science, University College London, London, UK 16.7.2: The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular; 16.7.3: Specific heart muscle disorders Robert D.M. Hadden Consultant Neurologist, King’s College Hospital, London, UK 24.12: Disorders of cranial nerves; 24.16: Diseases of the peripheral nerves † It is with great regret that we report that Martin Gore died on 10 January, 2019.

Contributors liii Zara Haider Kingston Hospital NHS Trust, Surrey, UK 9.9: Principles of contraception Sophie Hambleton Institute of Cellular Medicine, Newcastle University Medical School, Newcastle upon Tyne, UK; Paediatric Immunology and Infectious Diseases, Great North Children’s Hospital, Newcastle upon Tyne, UK 4.4: Immunodeficiency Freddie C. Hamdy Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK 21.18: Malignant diseases of the
urinary tract Michael G. Hanna National Hospital for Neurology and Neurosurgery, Queen Square, London, UK 24.19.1: Structure and function of muscle David M. Hansell Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, UK 18.3.2: Thoracic imaging Danielle Harari Guy’s and St Thomas’ Hospitals and King’s College London, London, UK 6.9: Bladder and bowels Kate Hardy Faculty of Medicine, Department of Surgery and Cancer, Imperial College London, London, UK 13.6.1: Ovarian disorders Karen E. Harman Department of Dermatology, University Hospitals of Leicester NHS Trust, Leicester, UK 23.7: Cutaneous vasculitis, connective tissue diseases, and urticaria Peter Harper London Oncology Centre, London, UK 5.6: Systemic treatment and radiotherapy; 5.7: Medical management of breast cancer Steve Harper Consultant Renal and Transplant Medicine, Southmead Hospital, Bristol; Honorary Professor, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK; Honorary Professor, School of Medicine, University of Exeter, Exeter, UK 21.1: Structure and function of the kidney James L. Harrison London Deanery, London, UK 16.9.2: Endocarditis Tina Hartert Division of Pulmonary and Critical Care, Vanderbilt University Medical Center, Nashville, TN, USA 14.8: Chest diseases in pregnancy Christine Hartmann Institute of Musculoskeletal Medicine, University of Münster, Münster, Germany 19.1: Joints and connective tissue—​structure and function Nicholas C. Harvey MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK 20.4: Osteoporosis Rowan Harwood Nottingham University Hospitals NHS Trust and University of Nottingham, Queens Medical Centre, Nottingham, UK 6.5: Older people in hospital Helen Hatcher Consultant Medical Oncologist, Cambridge University Hospitals, Cambridge, UK 20.6: Bone cancer Chris Hatton Cancer and Haematology Centre, Churchill Hospital, Oxford, UK 22.1: Introduction to haematology; 22.3.9: Histiocytosis; 22.6.2: Anaemia: Pathophysiology, classification, and clinical features Philip N. Hawkins Professor of Medicine, National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, University College London, London, UK 12.12.2 Hereditary periodic fever syndromes; 12.12.3 Amyloidosis Keith Hawton Centre for Suicide Research, University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK 26.3.2: Self-​harm Deborah Hay Honorary Consultant Haematologist, Nuffield Department of Medicine, University of Oxford, Oxford, UK 22.6.7: Disorders of the synthesis or function of haemoglobin; 22.6.9: Disorders of the red cell membrane Roderick J. Hay King’s College London,
London, UK 8.6.31: Nocardiosis; 8.7.1: Fungal infections; 23.6: Dermatitis/​eczema; 23.10: Infections of the skin; 23.12: Blood and lymphatic vessel disorders Peter Hayes Professor of Hepatology, Liver Unit, University of Edinburgh; and Royal Infirmary of Edinburgh, Edinburgh, UK 15.22.3: Portal hypertension and variceal
bleeding Catherine E.G. Head Consultant Cardiologist, Guy’s and St Thomas’ NHS Foundation Trust, London, UK 14.6: Heart disease in pregnancy Eugene Healy Dermatopharmacology, Southampton General Hospital, University of Southampton, UK 23.8: Disorders of pigmentation Nick Heather Department of Psychology, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, UK 26.6.1: Brief interventions for excessive alcohol consumption David W. Hecht Loyola University Health System, IL, USA 8.6.11: Anaerobic bacteria Thomas Hellmark Department of Clinical Sciences, Lund University, Lund, Sweden 21.8.7: Antiglomerular basement membrane
disease Michael Heneghan Professor of Hepatology and Consultant Hepatologist, Institute of Liver Studies, King’s College Hospital, London, UK 14.9: Liver and gastrointestinal diseases of pregnancy Michael Henein Umeå University, Sweden; Canterbury Christ Church University, Canterbury, UK 16.6: Valvular heart disease; 16.8: Pericardial disease Martin F. Heyworth Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA 8.8.9: Giardiasis and balantidiasis Liz Hickson Royal North Shore Hospital, NSW, Australia 17.1: The seriously ill or deteriorating
patient Tran Tinh Hien Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam 8.6.1: Diphtheria Katherine A. High Professor of Pediatrics Emerita, Perelman School of Medicine, University of Pennsylvania, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; President and Head of R&D, Spark Therapeutics, Philadelphia, PA, USA 22.7.4: Genetic disorders of coagulation Ingeborg Hilderson Department of Medical Oncology, University Hospital Ghent, Ghent, Belgium 21.10.4: The kidney in sarcoidosis Tom R. Hill Population Health Sciences
Institute, Newcastle University, Newcastle
upon Tyne, UK 11.2: Vitamins David Hilton-​Jones Muscular Dystrophy Campaign, Muscle and Nerve Centre, Department of Clinical Neurology, John Radcliffe Hospital, Oxford, UK 24.18: Disorders of the neuromuscular junction; 24.19.3: Myotonia; 24.19.4 Metabolic and endocrine disorders Matthew Hind Royal Brompton Hospital
and National Heart and Lung Institute,
Imperial College School of Medicine, London, UK 18.5.1: Upper airway obstruction; 18.5.2: Sleep-​ related breathing disorders John Hindle Betsi Cadwaladr University Health Board, Llandudno Hospital; School of Psychology, Bangor University, Bangor, UK 6.10: Neurodegenerative disorders in
older people N. Hirani Royal Infirmary, Edinburgh, UK 18.11.2: Idiopathic pulmonary fibrosis Gideon M. Hirschfield Lily and Terry Horner
Chair in Autoimmune Liver Disease Research,
Toronto Centre for Liver Disease,
Department of Medicine, University of
Toronto, Toronto General Hospital, Toronto, Canada 15.23.2: Autoimmune hepatitis Sarah Hobdey Veterans Medical Hospital, Boise, ID, USA 8.6.2: Streptococci and enterococci Herbert Hof MVZ Labor Limbach, Heidelberg, Germany 8.6.38: Listeriosis A.V. Hoffbrand Emeritus Professor of Haematology, University College, London, UK 22.6.6: Megaloblastic anaemia and miscellaneous deficiency anaemias

Contributors liv Ronald Hoffman Albert A. and Vera G. List, Professor of Medicine, Division of Hematology/​ Oncology; Director, Myeloproliferative Disorders Program, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA 22.3.5: The polycythaemias; 22.3.6: Thrombocytosis and essential thrombocythaemia Georg F. Hoffmann Department of General Pediatrics, University of Heidelberg, Heidelberg, Germany 12.2 Protein-​dependent inborn errors of metabolism Tessa L. Holyoake† Professor of Experimental Haematology, Section of Experimental Haematology, Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK 22.3.4: Chronic myeloid leukaemia Roel Hompes Consultant Colorectal Surgeon, Academic Medical Centre Amsterdam, University of Amsterdam, the Netherlands 15.14: Colonic diverticular disease Tony Hope St Cross College, University of Oxford, Oxford, UK 1.5: Medical ethics Julian Hopkin Medicine and Health, School of Medicine, Swansea University, Swansea, UK 18.2: The clinical presentation of respiratory disease P. Hopkins Medical Director, Queensland Lung Transplant Service, Chermside, Qld, Australia 18.16: Lung transplantation Nicholas S. Hopkinson National Heart and Lung Institute, Imperial College, London, UK 18.8: Chronic obstructive pulmonary disease Patrick Horner Population Health Sciences, University of Bristol, Bristol, UK 8.6.45: Chlamydial infections; 9.5: Urethritis Bala Hota Rush University, Chicago, IL USA 8.6.4: Staphylococci Andrew R. Houghton Grantham and District Hospital, Grantham, UK; University of Lincoln, Lincoln, UK 16.3.1: Electrocardiography Robert A. Huddart The Institute of Cancer Research, London, UK 21.18: Malignant diseases of the urinary tract Harriet C. Hughes Consultant Microbiology and Infectious Diseases, Public Health Wales, Cardiff, UK 8.5.29: Newly discovered viruses Ieuan A. Hughes University of Cambridge, Cambridge, UK 13.5.2: Congenital adrenal hyperplasia James H. Hull The Royal Brompton Hospital, London, UK 18.5.1: Upper airway obstruction Adam Hurlow Leeds Teaching Hospitals NHS Trust, Leeds, UK 7.4: Care of the dying person Jane A. Hurst Great Ormond Street Hospital, London, UK 24.20: Developmental abnormalities of the central nervous system Alastair Hutchison Medical Director and Professor of Renal Medicine, Dorset County Hospital, Dorchester, UK 21.6: Chronic kidney disease Peter J. Hutchinson University of Cambridge, Cambridge, UK 24.5.6: Brainstem death and prolonged disorders of consciousness Steve Iliffe Research Department of Primary Care and Population Health, University College London, London, UK 6.3: Optimizing well-​being into old age Lawrence Impey Obstetrics and Fetal Medicine, The Women’s Centre, John Radcliffe Hospital, Oxford, UK 14.16: Fetal effects of maternal infection Jakko van Ingen Radboud University Medical Centre, Nijmegen, the Netherlands 8.6.27: Disease caused by environmental mycobacteria Peter Irving Department of Gastroenterology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK 15.12: Ulcerative colitis John D. Isaacs Faculty of Medical Sciences, Newcastle University and Musculoskeletal Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 2.7 Biological therapies for immune, inflammatory, and allergic diseases; 19.5: Rheumatoid arthritis David A. Isenberg Centre for Rheumatology, Department of Medicine, University College London, London, UK 19.11.1: Introduction; 19.11.2: Systemic lupus erythematosus and related disorders Theodore J. Iwashyna Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Center for Clinical Management Research, Department of Veterans Affairs,
Ann Arbor, MI, USA; Australian and New Zealand Intensive Care Research Centre, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Vic, Australia 17.12: Persistent problems and recovery after critical illness Arnaud Jaccard Service d’hématologie clinique et de thérapie cellulaire, CHU de Limoges—​Hôpital Dupuytren, Limoges, France 21.10.5: Renal involvement in plasma cell dyscrasias, immunoglobulin-​based amyloidoses, and fibrillary glomerulopathies, lymphomas, and leukaemias Alan A. Jackson Southampton General Hospital, Southampton, UK 11.4: Severe malnutrition Thomas Jackson Queen Elizabeth Hospital, Birmingham, UK 26.3.1: Confusion Anu Jacob National Neuromyelitis Optica Service, Walton Centre for Neurology and Neurosurgery, Liverpool, UK 24.13.1: Diseases of the spinal cord Caron A. Jacobson Division of Hematologic Malignancies, Dana-​Farber Cancer Institute, Boston, MA, USA 22.4.1: Introduction to lymphopoiesis N. Asger Jakobsen Clinical Research Fellow, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK 22.2.1: Cellular and molecular basis of haematopoiesis Rajiv Jalan Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK 15.22.5: Liver failure Hannah Jarvis Respiratory Medicine, St Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK 18.4.4: Mycobacteria M.K. Javaid Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, Nuffield Orthopaedic Centre, Oxford, UK 20.1: Skeletal disorders—​general approach and clinical conditions David Jayne Professor of Clinical Autoimmunity, Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge, UK 19.11.7: ANCA-​associated vasculitis; 21.10.2: The kidney in systemic vasculitis Susan Jebb Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK 26.6.2: Obesity and weight management Katie J.M. Jeffery Oxford University Hospitals NHS Foundation Trust, Department of Microbiology, John Radcliffe Hospital, Oxford, UK 8.5.22: Hepatitis C virus Rajesh Jena Cambridge University Hospitals, Cambridge, UK 5.6: Systemic treatment and radiotherapy Tom Jenkins University of Sheffield, Sheffield, UK 24.15: The motor neuron diseases Jørgen Skov Jensen Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark 8.6.46: Mycoplasmas Vivekanand Jha Executive Director, The George Institute for Global Health, New Delhi, India; Professor of Nephrology, University of Oxford, Oxford, UK 21.11: Renal diseases in the tropics Tingliang Jiang Professor, Department of Pharmacology, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China 2.8: Traditional medicine exemplified by traditional Chinese medicine Alexis J. Joannides University of Cambridge, Cambridge, UK 3.7: Stem cells and regenerative medicine Anne M. Johnson Centre for Molecular Epidemiology and Translational Research, Institute for Global Health, University College London, London, UK 9.2: Sexual behaviour † It is with great regret that we report that Tessa L. Holyoake died on 30 August, 2017.

Contributors lv Colin Johnson Emeritus Professor of Surgical Sciences, University of Southampton, Southampton, UK 15.15: Diseases of the gallbladder and biliary tree M.R. Johnson Professor of Neurology and Genomic Medicine, Faculty of Medicine, Department of Brain Sciences, Imperial College, London, UK 24.5.1: Epilepsy in later childhood and adulthood Elaine Jolly University of Cambridge, Cambridge, UK 30.1: Acute medical presentations; 30.2: Practical procedures D. Joly Necker-​Enfants Malades Hospital, Paris, France 21.12: Renal involvement in genetic disease Bryony Jones Imperial College Hospital, London, UK 14.10: Diabetes in pregnancy David E.J. Jones Institute of Cellular Medicine, Newcastle University and Liver Unit, Freeman Hospital, Newcastle upon Tyne, UK 15.23.3: Primary biliary cholangitis Bouke de Jong Institute of Tropical Medicine, Antwerp, Belgium 8.6.29: Buruli ulcer: Mycobacterium ulcerans infection Menno De Jong Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands 24.11.2: Viral infections Iain Jordan Oxford University Hospitals NHS Foundation Trust, Oxford, UK 26.5.13: Personality disorders Emil Kakkis Ultragenyx Pharmaceutical Inc., Novato, CA, USA 2.9: Engaging patients in therapeutic development Philip A. Kalra Consultant and Honorary Professor of Nephrology, Department of Renal Medicine, Salford Royal NHS Foundation Trust, Salford, UK 16.5.4 Cardiorenal syndrome; 21.10.10: Atherosclerotic renovascular disease Eileen Kaner Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK 26.6.1: Brief interventions for excessive alcohol consumption Theodoros Karamitos Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK 16.3.3: Cardiac investigations: Nuclear, MRI, and CT Niki Karavitaki Queen Elizabeth Hospital, Birmingham, UK 13.2.1: Disorders of the anterior pituitary gland; 13.2.2: Disorders of the posterior pituitary gland Steven B. Karch Consultant in Cardiac Pathology and Toxicology, Berkeley, CA, USA 27.1: Forensic and legal medicine Fiona E. Karet Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 21.15: The renal tubular acidoses Arthur Kaser Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK 15.5: Immune disorders of the
gastrointestinal tract David Kavanagh Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK 21.10.6: Haemolytic uraemic syndrome Fiona Kearney Nottingham University Hospitals Trust, Nottingham, UK 6.8: Falls, faints, and fragility fractures David Keeling Oxford Haemophilia and Thrombosis Centre, Churchill Hospital, Oxford, UK 16.16.2: Therapeutic anticoagulation Andrew Kelion Oxford University Hospitals NHS Foundation Trust, Oxford, UK 16.3.3: Cardiac investigations: Nuclear, MRI, and CT Julia Kelly Royal Brompton and Harefield NHS Trust, London, UK 18.5.2: Sleep-​related breathing disorders Paul Kelly Professor of Tropical Gastroenterology, Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK; TROPGAN Group, Department of Internal Medicine, University of Zambia School of Medicine, Lusaka, Zambia 8.8.6: Cyclospora and cyclosporiasis David P. Kelsell London Medical School, London, UK 23.3: Inherited skin disease Samuel Kemp Royal Brompton Hospital, London, UK 18.2: The clinical presentation of respiratory disease Christopher Kennard Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 24.1: Introduction and approach to the patient with neurological disease; 24.6.1: Visual pathways Richard S.C. Kerr Oxford University Hospitals NHS Foundation Trust, Oxford, UK 24.11.3: Intracranial abscesses Satish Keshav† Department of Gastroenterology, Oxford University Hospitals NHS Foundation Trust, Oxford; Professor of Gastroenterology, Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK 15.1: Structure and function of the gastrointestinal tract Nigel S. Key Harold R. Roberts Professor of Medicine, Division of Hematology-​Oncology, University of North Carolina, Chapel Hill, NC, USA 22.7.1: The biology of haemostasis and thrombosis Rajesh K. Kharbanda John Radcliffe Hospital, Oxford, UK 16.13.4: Management of acute coronary syndrome Elham Khatamzas Regional Infectious Diseases Unit, NHS Lothian, Edinburgh, UK 8.2.4: Infection in the immunocompromised host Peng T. Khaw Professor and Consultant Ophthalmic Surgeon; Director of Research, Development and Innovation; Director, NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK 25.1: The eye in general medicine B. Khoo University College London, London, UK 13.8: Pancreatic endocrine disorders and multiple endocrine neoplasia; 15.9.2: Carcinoid syndrome Nine V.A.M. Knoers Professor in Clinical Genetics, Department of Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands 21.16: Disorders of tubular electrolyte handling Stefan Kölker Consultant, Pediatric Metabolic Medicine, University Children’s Hospital, Heidelberg; Department of General Pediatrics, Division of Inborn Metabolic Diseases, Heidelberg, Germany 12.2 Protein-​dependent inborn errors of metabolism Nils P. Krone University of Sheffield,
Sheffield, UK 13.5.2: Congenital adrenal hyperplasia Narong Khuntikeo Director, Cholangiocarcinoma Research Institute (CARI), Director, Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University, Thailand; Faculty of Medicine, Khon Kaen University, Thailand; Associate Professor, Department of Surgery, Faculty of Medicine, Khon Kaen University, Thailand 8.11.2: Liver fluke infections Gudula Kirtschig Tübingen, Germany 14.13: The skin in pregnancy Suzanne Kite Leeds Teaching Hospitals NHS Trust, Leeds, UK 7.4: Care of the dying person John L. Klein Guy’s and St Thomas’ NHS Foundation Trust, London, UK 16.9.2: Endocarditis Paul Klenerman Nuffield Department of Medicine, University of Oxford, Oxford, UK 4.3: Adaptive immunity; 8.5.22: Hepatitis
C virus Richard Knight Department of Microbiology, University of Nairobi, Nairobi, Kenya 8.8.1: Amoebic infections; 8.8.10: Blastocystis infection; 8.9.2: Lymphatic filariasis; 8.9.3: Guinea worm disease (dracunculiasis); 8.9.6: Angiostrongyliasis; 8.10.1: Cestodes (tapeworms) David Koh PAPRSB Institute of Health Sciences, Universiti Brunei Darussalam, SSH School of Public Health, National University of Singapore, Singapore 10.2.5: Noise G.C.K.W. Koh Diseases of the Developing World, Alternative Drug Development, GlaxoSmithKline, UK 8.6.8: Pseudomonas aeruginosa M.A. Kokosi Royal Brompton and Harefield NHS Trust, London, UK 18.11.4: The lung in autoimmune rheumatic disorders Onn Min Kon Respiratory Medicine, St Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK; National Heart and Lung Institute, Imperial College London, London, UK 18.4.4: Mycobacteria † It is with great regret that we report that Satish Keshav died on 23 January, 2019.

Contributors lvi Adelheid Korb-​Pap Institute of Experimental Musculoskeletal Medicine, University Hospital Münster, Münster, Germany 19.1: Joints and connective tissue—​structure and function Vasilis Kouranos Royal Brompton and Harefield NHS Trust, London, UK 18.11.3: Bronchiolitis obliterans and cryptogenic organizing pneumonia Christian Krarup Region Hovedstaden, Denmark 24.3.2: Electrophysiology of the central and peripheral nervous systems Amy S. Kravitz United States Agency for International Development (USAID), Washington DC, USA 2.21: Humanitarian medicine Dinakantha S. Kumararatne Depatment of Clinical Immunology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 4.4: Immunodeficiency Om P. Kurmi Hyperbaric Medicine Unit,
St Richard’s Hospital, Chichester, UK 10.3.1: Air pollution and health Robert A. Kyle Professor of Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA 22.4.6: Plasma cell myeloma and related monoclonal gammopathies Peter L. Labib Clinical Research Fellow, Institute for Liver and Digestive Health, Royal Free Campus, University College London, London, UK 15.16: Cancers of the gastrointestinal tract Charles J.N. Lacey Hull York Medical School, University of York, York, UK 9.7: Anogenital lumps and bumps Helen J. Lachmann Senior Lecturer, National Amyloidosis Centre and Centre for Acute Phase Proteins, University College London Medical School, London, UK 12.12.2: Hereditary periodic fever syndromes Robin H. Lachmann Consultant in Inherited Metabolic Disease, Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK 12.3.1: Glycogen storage diseases Ralph Lainson† Ex Director, the Wellcome Parisitology Unit, and research-worker, Department of Parasitology, Instiuto Evandro Chagas, Rodovia, Barro Levilầndia, Ananindeua, Pará, Brazil 8.8.6: Cyclospora and cyclosporiasis Kin Bong Hubert Lam University of Oxford, Oxford, UK 10.3.1: Air pollution and health D.A. Lane Faculty of Medicine, Department of Medicine, Imperial College London,
London, UK 16.4: Cardiac arrhythmias Peter C. Lanyon Nottingham University Hospitals Trust, Nottingham, UK 19.3: Clinical investigation Andrew J. Larner Cognitive Function Clinic, Walton Centre for Neurology and Neurosurgery, Liverpool, UK 24.3.1: Lumbar puncture; 24.5.4: Syncope; 24.13.1: Diseases of the spinal cord Malcolm Law Wolfson Institute of Preventive Medicine, St Bartholomew’s and the Royal London School of Medicine and Dentistry, Queen Mary University of London, London, UK 2.12 Medical screening Tim Lawrence Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 24.10.3: Traumatic brain injury; 24.11.3: Intracranial abscesses Stephen M. Lawrie Division of Psychiatry, University of Edinburgh, Edinburgh, UK 26.5.11: Schizophrenia Alison M. Layton Harrogate and District NHS Foundation Trust, Harrogate, UK 23.11: Sebaceous and sweat gland disorders James W. Le Duc Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX, USA 8.5.16: Bunyaviridae Susannah Leaver St George’s NHS Foundation Trust, London, UK 17.5: Acute respiratory failure Y.C. Gary Lee Faculty of Health and Medical Sciences, UWA Medical School, University of Western Australia, Perth, WA, Australia 18.17: Pleural diseases; 18.19.3 Pleural tumours; 18.19.4 Mediastinal tumours and cysts Haur Yueh Lee National Heart Centre Singapore, Singapore, China; Kings Drugs Reaction Group, King’s College London, London, UK 23.16: Cutaneous reactions to drugs Richard W.J. Lee Director, Uveitis and Scleritis Service, National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and University College London Institute of Ophthalmology, London, UK 25.1: The eye in general medicine Evelyne de Leeuw Centre for Health Equity Training, Research and Evaluation, UNSW Sydney, South Western Sydney Local Health District, Ingham Institute, Australia 2.13: Health promotion Yee-​Sin Leo National Centre for Infectious Disease, Tan Tock Seng Hospital, Singapore; Yong Loo Lin School of Medicine and Saw Swee Hock School of Public Health, National University of Singapore, Singapore; Lee Kong Chian School of Medicine, Singapore 8.5.15: Dengue Phillip D. Levin Intensive Care Unit, Shaare Zedek Medical Center, Jerusalem, Hebrew University of Jerusalem, Faculty of Medicine, Jerusalem, Israel 17.10: Palliative and end-​of-​life care in the ICU Elena N. Levtchenko Professor in Pediatric Nephrology, Catholic University Leuven, Leuven, the Netherlands 21.16: Disorders of tubular electrolyte handling Su Li Department of Epidemiology, Guangxi Medical University, Nanning, Guangxi, China 5.7: Medical management of breast cancer Fulong Liao Professor, Biomechanopharmacology, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China 2.8: Traditional medicine exemplified by traditional Chinese medicine Ted Liao MedStar Georgetown University Hospital and Georgetown University School of Medicine, Washington DC, USA 26.5.8: Anxiety disorders Oliver Liesenfeld Roche Molecular Systems, Pleasanton, CA, USA 8.8.4: Toxoplasmosis Liz Lightstone, Professor of Renal Medicine, Centre for Inflammatory Disease, Faculty of Medicine, Imperial College London, London, UK 21.10.3: The kidney in rheumatological disorders Wei Shen Lim Consultant Respiratory Physician and Honorary Professor of Medicine, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK 18.4.2: Pneumonia in the normal host; 18.4.3: Nosocomial pneumonia Aldo A.M. Lima Biomedicine Center and Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil 8.6.12: Cholera Gregory Y.H. Lip Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart and Chest Hospital, Liverpool, UK; Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark 16.4: Cardiac arrhythmias; 16.17.5: Hypertensive urgencies and emergencies Mark A. Little Professor of Nephrology and Consultant Nephrologist, Trinity Health Kidney Centre, Trinity College Dublin; Tallaght and Beaumont Hospitals, Dublin, Ireland 21.8.5: Proliferative glomerulonephritis; 21.8.6: Membranoproliferative glomerulonephritis P. Little University of Southampton, Southampton, UK 18.4.1: Upper respiratory tract infections William A. Littler The Priory Hospital, Birmingham, UK 16.9.2: Endocarditis A. Llanos-​Cuentas School of Public Health and Administration, Universidad Peruana Cayetano Heredia, Lima, Peru 8.6.44: Bartonella bacilliformis infection Y.M. Dennis Lo Li Ka Shing Professor of Medicine, Department of Chemical Pathology, The Chinese University of Hong Kong, China 3.9: Circulating DNA for molecular diagnostics Diana N.J. Lockwood London School of Hygiene and Tropical Medicine, London, UK 8.6.28: Leprosy (Hansen’s disease); 8.8.13: Leishmaniasis David A. Lomas Vice Provost (Health) and Head of UCL Medical School, University College London, London, UK 12.13: α1-​Antitrypsin deficiency and the serpinopathies; 15.24.6 Primary and secondary liver tumours Alan Lopez University of Melbourne, Melbourne, Vic, Australia 2.3: The Global Burden of Disease: Measuring the health of populations † It is with great regret that we report that Ralph Lainson died on 5 May, 2015.

Contributors lvii Constantino López-Macias Mexican Society of Immunology, Mexico; University of Oxford, Oxford, UK 4.3: Adaptive immunity David A. Low Liverpool John Moores University, Liverpool, UK 24.14: Diseases of the autonomic nervous system Elyse E. Lower University of Cincinnati Medical Center, Cincinnati, OH, USA 18.12: Sarcoidosis Katharine Lowndes Department of Haematology, Royal Hampshire County Hospital, Winchester UK 14.17: Blood disorders in pregnancy Angela K. Lucas-​Herald School of Medicine, University of Glasgow, Royal Hospital for Children, Glasgow, UK 13.7.3: Normal and abnormal sexual differentiation Ingrid E. Lundberg Rheumatology Unit, Department of Medicine, Sloan, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden 19.11.5: Inflammatory myopathies James R. Lupski Department of Molecular and Human Genetics, Department of Pediatrics, Human Genome Sequencing Center, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA 3.2: The genomic basis of medicine Raashid Luqmani Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford Rheumatology Department, Nuffield Orthopaedic Centre, Oxford, UK 19.11.6: Large vessel vasculitis Linda Luxon National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, Queen Square, London, UK 24.6.3: Hearing loss Jean Paul Luzio Cambridge Institute for Medical Research, Cambridge, UK 3.1: The cell Lucio Luzzatto Department of Haematology, Muhimbili University of Health and Allied Sciences Dar es Salaam, Tanzania 22.5.3: Paroxysmal nocturnal haemoglobinuria; 22.6.11: Glucose-​6-​phosphate dehydrogenase deficiency Graz A. Luzzi Wycombe General Hospital, High Wycombe, UK 9.3: Sexual history and examination Kate D. Lynch Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford; Nuffield Department of Medicine, University of Oxford, Oxford, UK 15.23.4: Primary sclerosing cholangitis David Mabey Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK 8.6.36: Non-​venereal endemic treponematoses: Yaws, endemic syphilis (bejel), and pinta; 8.6.45: Chlamydial infections; 9.1: Epidemiology of sexually transmitted infections Peter K. MacCallum Senior Lecturer in Haematology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK 14.7: Thrombosis in pregnancy Alasdair MacGowan Department of Medical Microbiology, North Bristol NHS Trust, Bristol, UK 8.2.5: Antimicrobial chemotherapy Lucy Mackillop Obstetric Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK 14.20 Prescribing in pregnancy Gael M. MacLean Oxford University Hospitals NHS Foundation Trust, Oxford, UK 13.6.3: Benign breast disease Kenneth T. MacLeod National Heart and Lung Institute (NHLI) Division, Faculty of Medicine, Imperial College London, London, UK 16.1.2: Cardiac physiology Alasdair MacLullich Edinburgh University, Edinburgh, UK 6.5: Older people in hospital Jane Macnaughtan Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK 15.22.5: Liver failure Robert Mactier Consultant Nephrologist, Glasgow Renal and Transplant Unit, South Glasgow University Hospital, NHS Greater Glasgow and Clyde, Glasgow, UK 21.7.1: Haemodialysis C. Maguiña-​Vargas School of Medicine, Universidad Peruana Cayetano Heredia, Lima, Peru 8.6.44: Bartonella bacilliformis infection Michael Maher Professor of Radiology, University College Cork and Consultant Radiologist, Cork University Hospital and Mercy University Hospital, Cork, Ireland 15.3.3: Radiology of the gastrointestinal tract Malegapuru W. Makgoba National Health Ombud, Pretoria, South Africa; College of Health Science, University of KwaZulu-​Natal, Durban, South Africa; National Planning Commission of South Africa; Universities of Natal and KwaZulu-​Natal, Durban, South Africa; MRC (SA), Cape Town, South Africa 2.18: Fostering medical and health research in resource-​constrained countries Govind K. Makharia Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India 15.10.8: Malabsorption syndromes in
the tropics Hadi Manji The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK 24.11.4: Neurosyphilis and neuro-​AIDS J.I. Mann Edgar Diabetes and Obesity Research Centre (EDOR), Department of Human Nutrition, University of Otago, Dunedin, New Zealand 11.5: Diseases of affluent societies and the need for dietary change David Mant University of Oxford, Oxford, UK 2.11: Preventive medicine G.A. Margaritopoulos Royal Brompton and Harefield NHS Trust, London, UK 18.11.5: The lung in vasculitis Anthony M. Marinaki Purine Research Laboratory, Viapath, St Thomas’ Hospital, London, UK 12.4: Disorders of purine and pyrimidine metabolism Chiara Marini-​Bettolo Newcastle University
John Walton Centre for Muscular Dystrophy Research, Newcastle upon Tyne Hospital NHS Foundation Trust, Institute of Genetic Medicine, International Centre for Life, Newcastle upon Tyne, UK 24.19.2: Muscular dystrophy Michael Marks Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK 8.6.36: Non-​venereal endemic treponematoses: Yaws, endemic syphilis (bejel), and pinta Paul Marks Honorary Consultant Neurosurgeon, Harrogate District Hospital, Harrogate;
Her Majesty’s Senior Coroner for the City
of Kingston upon Hull and the County of
the East Riding of Yorkshire; Vice President, Faculty of Forensic and Legal Medicine,
London, UK; Honorary Professor of Neurosurgery, College of Medicine,
University of Malawi, Malawi 27.1: Forensic and legal medicine Thomas J. Marrie Department of Medicine, Dalhousie University, Nova Scotia, Canada 8.6.42: Coxiella burnetii infections (Q fever) Judith C.W. Marsh King’s College Hospital, King’s College London, London, UK 22.5.2: Acquired aplastic anaemia and pure red cell aplasia Sara Marshall Wellcome Trust, London, UK 4.4: Immunodeficiency Steven B. Marston National Heart and Lung Institute (NHLI) Division, Faculty of Medicine, Imperial College London, UK 16.1.2: Cardiac physiology Maria do Rosario O. Martins University Nova de Lisboa, Lisbon, Portugal 2.16: Financing healthcare in low-​income developing countries: A challenge for equity in health Thiviyani Maruthappu Kelsell Group, Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London, Queen Mary University of London, London, UK 23.3: Inherited skin disease Duncan J. Maskell University of Cambridge, Cambridge, UK 8.1.1: Biology of pathogenic microorganisms N.A. Maskell Academic Respiratory Unit,
University of Bristol, UK 18.17: Pleural diseases Jay W. Mason Cardiology Division, University
of Utah College of Medicine, Salt Lake City, UT, USA 16.7.1: Myocarditis Tahir Masud Nottingham University Hospitals Trust, Nottingham, UK 6.8: Falls, faints, and fragility fractures Christopher J. Mathias Stoke Poges, UK 24.14: Diseases of the autonomic nervous
system

Contributors lviii Fadi Matta Associate Professor, Department of Osteopathic Medical Specialties, Collage of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA 16.16.1: Deep venous thrombosis and pulmonary embolism Eric L. Matteson Division of Rheumatology, Divisions of Rheumatology and Epidemiology, Mayo Clinic College of Medicine, Rochester, MN, USA 19.11.11: Polymyalgia rheumatica Kieran McCafferty Consultant Nephrologist, Barts Health NHS Trust, London, UK 21.17: Urinary tract obstruction Fergus McCarthy Division of Women’s Health, Women’s Health Academic Centre KHP, St. Thomas’ Hospital, London, UK 14.4: Hypertension in pregnancy Brian W. McCrindle University of Toronto, Toronto, Canada; The Hospital for Sick Children, Toronto, ON, Canada 19.11.12: Kawasaki disease Theresa A. McDonagh King’s College Hospital, Denmark Hill, London, UK 16.5.1: Epidemiology and general pathophysiological classification of heart failure A.D. McGavigan Flinders University,
SA, Australia 16.2.2: Syncope and palpitation; 16.4: Cardiac arrhythmias Fiona McGill Institute of Infection and Global Health, University of Liverpool, Liverpool, UK 24.11.2: Viral infections John A. McGrath Genetic Skin Disease Group, St John’s Institute of Dermatology, King’s College London (Guy’s Campus), London, UK 23.1: Structure and function of skin Alastair McGregor Department of Tropical Medicine and Infectious Diseases, London Northwest Hospitals NHS Trust, London, UK; Department of Medicine, Imperial College London, London, UK 8.11.4: Intestinal trematode infections Jane McGregor Clinical Senior Lecturer and Honorary Consultant Dermatologist, Blizard Institute, Barts and the London School Medicine and Dentistry, London, UK 23.9: Photosensitivity Iain B. McInnes University of Glasgow, Glasgow, UK 3.3: Cytokines C.J. McKay Consultant Pancreaticobiliary Surgeon, West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK 15.26.1: Acute pancreatitis William J. McKenna The Heart Hospital, University College London, London, UK 16.7.2: The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular Curtis McKnight Dignity Health Medical Group;
St. Joseph’s Hospital and Medical Center; Creighton University School of Medicine,
Phoenix, AZ, USA 26.5.3: Organic psychoses Alison McMillan East and North Hertfordshire NHS Trust, Stevenage, UK 18.5.2: Sleep-​related breathing disorders Martin A. McNally The Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford University Hospitals, Oxford, UK 20.3: Osteomyelitis Regina McQuillan St Francis Hospice and Beaumont Hospital, Dublin, Ireland 7.3: Symptoms other than pain Simon Mead MRC Prion Unit, University College London, Institute of Prion Diseases; NHS National Prion Clinic, National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, Queen Square, London, UK 24.11.5: Human prion diseases Jill Meara Hyperbaric Medicine Unit, St Richard’s Hospital, Chichester, UK 10.3.7: Radiation Wajahat Z. Mehal Section of Digestive Diseases Yale University, New Haven, CT, USA 15.21: Pathobiology of chronic liver disease Tobias F. Menne Consultant Haematologist, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK 22.4.2: Acute lymphoblastic leukaemia David K. Menon Division of Anaesthesia, University of Cambridge, UK; Neurosciences Critical Care Unit, Royal College of Anaesthetists, London, UK; Queens’ College, Cambridge, UK; National Institute for Health Research, UK 17.7: Management of raised intracranial pressure Andrew Menzies-​Gow Royal Brompton Hospital, London, UK 18.7: Asthma Catherine H. Mercer Professor of Sexual
Health Science, Centre for Population Research in Sexual Health and HIV, Institute for Global Health, University College London, London, UK 9.2: Sexual behaviour Vinod K. Metta Neurology, National Hospital for Neurology and Neurosurgery, University College London, London, UK 24.7.2: Parkinsonism and other extrapyramidal diseases Jan H. ter Meulen Philipps University Marburg, 35043 Marburg, Germany 8.5.17: Arenaviruses; 8.5.18: Filoviruses Wayne M. Meyers Department of Environmental and Infectious Disease Sciences, Armed
Forces Institute of Pathology, Washington DC, USA 8.6.29: Buruli ulcer: Mycobacterium ulcerans infection Paul K. Middleton Clinical Research Fellow, Institute of Liver Studies, Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, UK 15.22.4: Hepatic encephalopathy Stephen J. Middleton Consultant Gastroenterologist, Addenbrooke’s Hospital, Cambridge University Hospitals, Cambridge; Consultant Gastroenterologist (Hon.) St Mark’s Hospital, Harrow, London; Associate Professor (Hon.) Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK 15.10.2: Bacterial overgrowth of the small intestine; 15.10.7: Effects of massive bowel resection Mark E. Mikkelsen Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA 17.12: Persistent problems and recovery after critical illness Michael A. Miles Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK 8.8.12: Chagas disease Robert F. Miller University College London, London, UK 8.7.5: Pneumocystis jirovecii Dawn S. Milliner Emeritus Professor of Medicine and Pediatrics at the Mayo Clinic Alix School of Medicine, Rochester, MN, USA 12.10 Hereditary disorders of oxalate metabolism: The primary hyperoxalurias K.R. Mills King’s College London, London, UK 24.3.4: Investigation of central motor pathways: Magnetic brain stimulation Philip Minor National Institute for Biological Standards and Control (NIBSC), Ridge, UK 8.5.8: Enterovirus infections Fraz A. Mir Department of Medicine, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge, UK 16.17.3: Secondary hypertension Pramod K. Mistry Professor of Pediatrics and Medicine, Chief, Pediatric Gastroenterology and Hepatology, Yale School of Medicine, New Haven, CT, USA 12.7.2 Inherited diseases of copper metabolism: Wilson’s disease and Menkes’ disease Andrew R.J. Mitchell Jersey General Hospital, Jersey, UK 16.3.2: Echocardiography; 16.14.1: Acute aortic syndromes Oriol Mitjà Barcelona Institute for Global Health, University of Barcelona, Spain; Lihir Medical Centre, InternationalSOS, Lihir Island, Papua New Guinea 8.6.36: Non-​venereal endemic treponematoses: Yaws, endemic syphilis (bejel), and pinta Aarthi R. Mohan Obstetrics and Maternal Medicine, University Hospitals Bristol NHS Foundation Trust, Bristol, UK 14.21: Contraception for women with medical diseases Fiachra Moloney Consultant Radiologist, Department of Radiology, Cork University Hospital, Cork, Ireland 15.3.3: Radiology of the gastrointestinal tract P.L. Molyneaux Royal Brompton and Harefield NHS Trust, London, UK 18.11.2: Idiopathic pulmonary fibrosis

Contributors lix Andrew J. Molyneux The Manor Hospital, Oxford, UK 24.3.3: Imaging in neurological diseases Peter D. Mooney Royal Hallamshire Hospital and University of Sheffield, Sheffield, UK 15.10.3: Coeliac disease Anthony V. Moorman Professor of Genetic Epidemiology, Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK 22.4.2: Acute lymphoblastic leukaemia Pilar Morata Department of Biochemistry and Molecular Biology, School of Medicine, University of Málaga, Málaga, Spain 8.6.22: Brucellosis Marina S. Morgan Royal Devon and Exeter NHS Foundation Trust, Exeter, UK 8.6.19: Pasteurella Michael L. Moritz Professor of Pediatrics, University of Pittsburgh School of Medicine, Clinical Director, Division of Nephrology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA 21.2.1: Disorders of water and sodium homeostasis Pedro L. Moro Immunization Safety Office, Division of Healthcare Quality Promotion, NCEZID, Centers for Disease Control and Prevention, Atlanta, GA, USA 8.10.2: Cystic hydatid disease (Echinococcus granulosus) Mary J. Morrell Imperial College London, London, UK 18.5.2: Sleep-​related breathing disorders Nicholas W. Morrell British Heart Foundation Professor of Cardiopulmonary Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospitals, Cambridge, UK 16.15.1: Structure and function of the pulmonary circulation; 16.15.2: Pulmonary hypertension Emma C. Morris Professor, Division of Infection and Immunity, UCL Institute of Immunity and Transplantation, Royal Free Campus, Royal Free Hospital, London, UK and Honorary Consultant, University College London Medical School, London, UK 22.8.2: Haemopoietic stem cell transplantation Neil J.McC. Mortensen Professor of Colorectal Surgery, Nuffield Department of Surgery, University of Oxford; Honorary Consultant Colorectal Surgeon, Oxford University Hospitals NHS Foundation Trust, Oxford, UK 15.14: Colonic diverticular disease Peter S. Mortimer St George’s University of London; St George’s Hospital, London; Royal Marsden Hospital, London, UK 16.18: Chronic peripheral oedema and lymphoedema; 23.12: Blood and lymphatic vessel disorders Ghulam J. Mufti King’s College Hospital/​King’s College London, London, UK 22.5.2: Acquired aplastic anaemia and pure red cell aplasia Victoria Mulcahy Norwich Medical School, University of East Anglia, Norwich, UK 15.10.1: Differential diagnosis and investigation of malabsorption David R. Murdoch Professor and Head of Pathology, University of Otago, Christchurch, New Zealand 10.3.6: Diseases of high terrestrial altitudes Paul Murphy NHS Blood and Transplant, Bristol, UK 17.11: Diagnosis of death and organ donation Christopher Murray University of Washington, WA, USA 2.3: The Global Burden of Disease: Measuring the health of populations Jean B. Nachega Departments of Epidemiology,
Infectious Diseases and Microbiology,
Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA USA; Department of Medicine, Centre for Infectious Diseases,
Stellenbosch University, Tygerberg, Cape Town, South Africa 8.6.26: Tuberculosis Robert B. Nadelman Division of Infectious Diseases, Department of Medicine, New York Medical College, Valhalla, NY, USA 8.6.33: Lyme borreliosis Alexandra Nanzer-​Kelly Guys and St Thomas’ Hospital, London, UK 18.7: Asthma Nikolai V. Naoumov Novartis Pharma, Basel, Switzerland 8.5.21: Hepatitis viruses (excluding hepatitis C virus) Kikkeri N. Naresh Department of Histopathology, Imperial College Healthcare NHS Trust and Imperial College, London, UK 15.10.4: Gastrointestinal lymphomas Kate Nash University Hospital Southampton NHS Foundation Trust, Southampton, UK 15.23.1: Hepatitis A to E N. Navani University College Hospital,
London, UK 18.19.1: Lung cancer Catherine Nelson-​Piercy Obstetric Medicine, Women’s Health Academic Centre, King’s Health Partners, King’s College London, London, UK 14.14: Autoimmune rheumatic disorders and vasculitis in pregnancy Randolph M. Nesse Center for Evolution and Medicine, Arizona State University, AZ, USA 2.2: Evolution: Medicine’s most basic science Peter J. Nestor German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany 24.4.1: Disturbances of higher cerebral function Stefan Neubauer Oxford Centre for Clinical Magnetic Resonance Research (OCMR), Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK 16.3.3: Cardiac investigations: Nuclear, MRI, and CT James Neuberger Hon Consultant Physician, Liver Unit, Queen Elizabeth Hospital, Birmingham, UK 15.24.5: The liver in systemic disease James D. Newton Oxford University Hospitals NHS Trust, Oxford, UK 16.3.2: Echocardiography; 16.14.1: Acute aortic syndromes Paul N. Newton Lao-​Oxford-​Mahosot Hospital-​ Wellcome Trust Research Unit (LOMWRU), Microbiology Laboratory, Mahosot Hospital, Vientiane, Lao PDR; Nuffield Department of Medicine, University of Oxford, Oxford; Infectious Diseases Data Observatory (IDDO), University of Oxford, Oxford, UK 2.10: Medicine quality, physicians,
and patients Wan-​Fai Ng Newcastle University and NIHR Newcastle Biomedical, Research Centre for
Ageing and Chronic Diseases, Newcastle upon Tyne, UK 19.11.4: Sjögren’s syndrome A.G. Nicholson Royal Brompton and Harefield NHS Trust; Professor of Respiratory Pathology, National Heart and Lung Institute, Imperial College School of Medicine, London, UK 18.11.2: Idiopathic pulmonary fibrosis Jerry P. Nolan Warwick Medical School, Coventry; Royal United Hospital, Bath, UK 17.2: Cardiac arrest John Nowakowski New York Medical College,
NY, USA 8.6.33: Lyme borreliosis Paul Nyirjesy Drexel University College of Medicine, Philadelphia, PA, USA 9.4: Vaginal discharge Sarah O’Brien Modelling, Evidence and Policy
Group, School of Natural and Environmental Sciences, Newcastle University, Newcastle upon Tyne, UK 15.18: Gastrointestinal infections Amy O’Donnell Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK 26.6.1: Brief interventions for excessive alcohol consumption Nigel O’Farrell Ealing Hospital, London North West University Healthcare NHS Trust, London, UK 8.6.14: Haemophilus ducreyi and chancroid John G. O’Grady Institute of Liver Studies, King’s College Hospital, London, UK 15.22.6: Liver transplantation Denis O’Mahony Department of Medicine, University College Cork and Department of Geriatric Medicine, Cork University Hospital, Cork, Ireland 6.7: Drugs and prescribing in the older patient E.E. Ooi Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore 8.5.12: Alphaviruses Susie Orme Barnsley Hospital NHS Foundation Trust, Barnsley, UK 6.9: Bladder and bowels Kevin O’Shaughnessy Division of Experimental Medicine and Immunotherapeutics,
Department of Medicine, University of Cambridge, Cambridge, UK 2.6: Principles of clinical pharmacology and drug therapy

Contributors lx Edel O’Toole Centre for Cutaneous Research, Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry; and Department of Dermatology, Barts and the London NHS Trust, London, UK 23.14: Tumours of the skin Petra C.F. Oyston Biomedical Sciences, DSTL Porton Down, Salisbury, UK 8.6.20: Francisella tularensis infection Jacqueline Palace Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 24.18: Disorders of the neuromuscular junction Thomas Pap Institute of Experimental Musculoskeletal Medicine, University Hospital Münster, Münster, Germany 19.1: Joints and connective tissue—​structure and function Jayan Parameshwar Consultant Cardiologist, Royal Papworth Hospital, Cambridge, UK 16.5.5: Cardiac transplantation and mechanical circulatory support Daniel H. Paris University of Oxford, Oxford, UK; Rickettsial Research (Oxford Tropical Network); Mahidol-​Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand 8.6.41: Scrub typhus Sarah Parish Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK 2.4: Large-​scale randomized evidence: Trials and meta-​analyses of trials Mike Parker Ethox Centre, Oxford, UK 1.5: Medical ethics Miles Parkes Consultant Gastroenterologist, Cambridge University Hospitals,
Cambridge, UK 15.11: Crohn’s disease Philippe Parola University Hospital Institute Méditerranée Infection, Marseille, France 8.6.40: Rickettsioses Christopher M. Parry Clinical Sciences, Liverpool School of Tropical Medicine, and Institute of Infection and Global Health, University of Liverpool, UK; School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan 8.6.9: Typhoid and paratyphoid fevers Judith Partridge Guys and St Thomas’ Hospitals London, UK 6.6: Supporting older peoples’ care in surgical and oncological services Sant-​Rayn Pasricha MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital and University of Oxford, Oxford, UK 22.6.5: Anaemia of inflammation Harnish Patel Academic Geriatric Medicine, University of Southampton, Southampton, UK 6.2: Frailty and sarcopenia Raj Patel Solent NHS Trust, Southampton, UK 9.6: Genital ulceration Sejal Patel Oxford Childrens Hospital, Oxford University Hospitals NHS Trust, Oxford, UK 13.7.2: Normal puberty and its disorders John Paul SE region, National Infection Service, Public Health England, UK 8.6.47: A checklist of bacteria associated with infection in humans; 8.12: Non​venomous arthropods Jason Payne-​James Specialist in Forensic and Legal Medicine and Consultant Forensic Physician; Lead Medical Examiner, Norfolk and Norwich University Hospital, Norfolk, UK; Honorary Clinical Professor, William Harvey Research Institute, Queen Mary University of London, UK; Consultant Editor-​in-​Chief, Journal of Forensic and Legal Medicine; Director, Forensic Healthcare Services Ltd, Southminster, UK 27.1: Forensic and legal medicine Sharon J. Peacock University of Cambridge, Cambridge, UK 8.6.8: Pseudomonas aeruginosa; 8.6.16: Melioidosis and glanders Fiona Pearce Clinical Lecturer, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham City Hospital, Nottingham, UK 19.2: Clinical presentation and diagnosis of rheumatological disorders Rupert Pearse Queen Mary University of London, London, UK 17.4: Assessing and preparing patients with medical conditions for major surgery Malik Peiris School of Public Health, The University of Hong Kong, Hong Kong, Special Administrative Region of China 8.5.1: Respiratory tract viruses Neil Pendleton School of Biological Sciences, Faculty Biology Medicine and Health and Manchester Institute for Collaborative Research in Ageing, University of Manchester, Manchester, UK 6.1: Ageing and clinical medicine Hugh Pennington University of Aberdeen, Aberdeen, UK 8.6.7: Enterobacteria and bacterial food poisoning Mark B. Pepys Director, Wolfson Drug Discovery Unit, and Honorary Consultant Physician, National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, University College London, London, UK 12.12.1 The acute phase response and C-​reactive protein; 12.12.3 Amyloidosis Stephen P. Pereira Professor of Hepatology and Gastroenterology, Institute for Liver and Digestive Health, University College London; Consultant Hepatologist and Gastroenterologist, University College Hospital and Royal Free Hospital, London, UK 15.16: Cancers of the gastrointestinal tract; 15.26.3: Tumours of the pancreas Gavin D. Perkins Warwick Medical School, Coventry; Intensive Care Unit, Heartlands Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK 17.2: Cardiac arrest David J. Perry Previously Department of Haematology, Addenbrooke’s Hospital, Cambridge, UK 14.17: Blood disorders in pregnancy Hans Persson Swedish Poisons Centre, Stockholm, Sweden 10.4.3: Poisonous fungi; 10.4.4: Poisonous plants Eskild Petersen Department of Infectious Diseases and Clinical Microbiology, Aarhus University Hospital Skejby, Aarhus, Denmark 8.8.4: Toxoplasmosis L.R. Petersen Director, Division of Vector-borne Infectious Diseases, Centers for Disease
Control and Prevention, Fort Collins,
Colorado, USA 8.5.12: Alphaviruses Trevor N. Petney Professor, Cholangiocarcinoma Research Institute (CARI), Cholangiocarcinoma Screening and Care Program (CASCAP),
Faculty of Medicine, Khon Kaen University,
Khon Kaen, Thailand; Department of Paleontology and Evolution, Organization/​ University State Museum of Natural History, Karlsruhe, Germany 8.11.2: Liver fluke infections Philippa Peto Consultant in Renal and Acute Medicine, Queen Elizabeth Hospital, Lewisham and Greenwich NHS Trust, London, UK 1.6: Clinical decision-​making Richard Peto Nuffield Department of Population Health, University of Oxford, Oxford, UK 2.4: Large-​scale randomized evidence: Trials
and meta-​analyses of trials; 5.1: Epidemiology of cancer Timothy E.A. Peto Nuffield Department of Clinical Medicine, University of Oxford; John Radcliffe Hospital, Oxford, UK 1.6: Clinical decision-​making; 8.5.23: HIV/​AIDS John D. Pickard University of Cambridge, Cambridge, UK 24.5.6: Brainstem death and prolonged disorders of consciousness Matthew C. Pickering Imperial College London, London, UK 4.2: The complement system Massimiliano di Pietro Senior Clinical Investigator Scientist and Consultant Gastroenterologist,
MRC Cancer Unit, University of Cambridge, Hutchison/​MRC Research Centre,
Cambridge, UK 15.7: Diseases of the oesophagus Michael R. Pinsky Professor Critical Care Medicine, Bio­engineering, Cardiovascular Disease and Anesthesiology, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA 17.6: Circulation and circulatory support in the critically ill Julia Platts University of Cardiff, Cardiff, UK 13.9.1: Diabetes Raymond J. Playford, Professor of Medicine, University of Plymouth, Plymouth, UK; Vice President Research Strategy, Pantheryx Inc., Boulder, CO, USA 15.10.2: Bacterial overgrowth of the small intestine; 15.10.7: Effects of massive bowel resection Michael I. Polkey Royal Brompton and Harefield NHS Trust, London, UK 18.15: Chronic respiratory failure; 18.18 Disorders of the thoracic cage and diaphragm

Contributors lxi Eleanor S. Pollak Associate Professor of Pathology and Laboratory Medicine (retired), Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA 22.7.4: Genetic disorders of coagulation Andrew J. Pollard Professor of Paediatric Infection and Immunity at the University of Oxford,
Director of the Oxford Vaccine Group, Fellow of St Cross College and Honorary Consultant Paediatrician at the Children’s Hospital,
Oxford, UK 10.3.6: Diseases of high terrestrial altitudes Aaron Polliack Emeritus Professor, Hadassah University Hospital and Hebrew University Medical School, Jerusalem, Israel 22.4.5: Chronic lymphocytic leukaemia Allyson M. Pollock Queen Mary University of London, London, UK 2.15: How much should rich countries’ governments spend on healthcare? Cristina Ponte Department of Rheumatology, Hospital de Santa Maria -​ CHLN, Lisbon Academic Medical Centre, Lisbon, Portugal; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK 19.11.6: Large vessel vasculitis Kyle J. Popovich Rush University, Chicago,
IL, USA 8.6.4: Staphylococci Françoise Portaels Institute of Tropical Medicine, Antwerp, Belgium 8.6.29: Buruli ulcer: Mycobacterium ulcerans infection John B. Porter Professor of Haematology and Consultant Haematologist, University College London Hospitals, London, UK 22.6.4: Iron metabolism and its disorders Stephen Potts Department of Psychological Medicine, Edinburgh Royal Infirmary, Edinburgh, UK 26.5.5: Substance misuse William G. Powderly Division of Infectious Diseases and Institute for Public Health, Washington University in St. Louis, MO, USA 8.7.2: Cryptococcosis Janet Powell Department of Surgery and Cancer, Imperial College, London, UK 16.14.2: Peripheral arterial disease Amy Powers Associate Professor of Pathology, John A Burns School of Medicine, University of Hawaii, Department of Pathology, Honolulu, HI, USA 22.6.12: Acquired haemolytic anaemia Ann M. Powers Centers for Disease Control and Prevention, Atlanta, GA, USA 8.5.12: Alphaviruses Anton Pozniak Department of HIV and GUM, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK 18.4.5: Pulmonary complications of
HIV infection Bernard D. Prendergast John Radcliffe Hospital, Oxford, UK 16.9.2: Endocarditis Michael Prentice School of Microbiology, University College Cork, Cork, Ireland 8.6.17: Plague: Yersinia pestis; 8.6.18: Other Yersinia infections: Yersiniosis David Price Queen Mary University of London, London, UK 2.15: How much should rich countries’ governments spend on healthcare? Christopher Pugh Nuffield Department of Medicine, University of Oxford, Oxford, UK 21.14: Disorders of renal calcium handling, urinary stones, and nephrocalcinosis Meredith Pugh Division of Pulmonary and Critical Care, Vanderbilt University Medical Center, Nashville, TN, USA 14.8: Chest diseases in pregnancy Graham Raftery South Tyneside and Sunderland NHS Foundation Trust, Sunderland, UK 19.7: Infection and arthritis Kazem Rahimi The George Institute for Global Health, University of Oxford,
Oxford, UK 16.13.2: Coronary heart disease: Epidemiology and prevention Anisur Rahman Centre for Rheumatology, University College London, London, UK 19.11.2: Systemic lupus erythematosus and related disorders Tim Raine IBD Lead and Consultant Gastroenterologist, Cambridge University Hospital, Cambridge, UK 15.11: Crohn’s disease K. Rajappan Oxford University Hospitals NHS Foundation Trust, Oxford, UK 16.2.2: Syncope and palpitation S. Vincent Rajkumar Edward W. and Betty Knight Scripps Professor of Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA 22.4.6: Plasma cell myeloma and related monoclonal gammopathies Mary Ramsay Health Protection Agency,
London, UK 8.3: Immunization A.C. Rankin Glasgow Royal Infirmary, Glasgow, UK 16.2.2: Syncope and palpitation Didier Raoult University Hospital Institute  Méditerranée Infection, Marseille, France 8.6.40: Rickettsioses; 15.10.6: Whipple’s disease Michael Rawlins Medicines and Healthcare Products Regulatory Agency, London, UK 2.19: Regulation versus innovation in medicine Phillip Read University of New South Wales, Kensington, NSW, Australia 8.6.37: Syphilis Michael C. Reade Burns, Trauma and Critical Care Research Centre, Royal Brisbane and Women’s Hospital, University of Queensland, Brisbane, Qld, Australia; Joint Health Command, Australian Defence Force, Canberra, ACT, Australia 17.8: Sedation and analgesia in the ICU Paul J. Reading Department of Sleep Medicine, The James Cook University Hospital, Middlesbrough, UK 24.5.3: Sleep disorders Jeremy Rees National Hospital for Neurology and Neurosurgery, London, UK; UCL Institute of Neurology, London, UK 24.23: Paraneoplastic neurological syndromes; 24.10.4: Intracranial tumours P.T. Reid Respiratory Unit, Western General Hospital, Edinburgh, UK 18.13: Pneumoconioses Shelley Renowden North Bristol NHS Trust, Bristol, UK 24.3.3: Imaging in neurological diseases John Richens Research Department of Infection and Population Health, University College London, London, UK 8.6.10: Intracellular klebsiella infections (donovanosis and rhinoscleroma) Alan B. Rickinson Institute for Cancer Studies, University of Birmingham, Birmingham, UK 8.5.3: Epstein–​Barr virus B.K. Rima Wellcome-​Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, UK 8.5.5: Mumps: Epidemic parotitis David J. Roberts Radcliffe Department of Medicine, University of Oxford; Department of
Haematology, Oxford University Hospitals
NHS Trust and NHS Blood and Transplant,
Oxford, UK 22.6.3: Anaemia as a challenge to world health Harold R. Roberts Sarah Graham Kenan Professor of Medicine, Division of Hematology-​Oncology, University of North Carolina, Chapel Hill, NC, USA 22.7.1: The biology of haemostasis and thrombosis Irene Roberts Department of Paediatrics and MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK 22.5.1: Inherited bone marrow failure syndromes Douglas Robertson Senior Lecturer and Honorary Consultant in Restorative Dentistry, University of Glasgow, Glasgow, UK 15.6: The mouth and salivary glands Marcus Robertson Gastroenterologist and Hepatologist, Monash Health, Vic, Australia; Monash University Department of Medicine,
Vic, Australia 15.22.3: Portal hypertension and variceal
bleeding Esther Robinson Public Health England, Birmingham, UK 8.6.13: Haemophilus influenzae T.A. Rockall Professor of Colorectal Surgery, University of Surrey; Consultant Colorectal Surgeon, Royal Surrey County Hospital Guildford, UK 15.4.2: Gastrointestinal bleeding Edward Roddy Keele University, Keele, UK 19.10: Crystal-​related arthropathies Simon D. Roger Renal Physician, Conjoint Professor, School of Medicine and Public Health, University of Newcastle, Newcastle; Director, Department of Renal Medicine, Central Coast Local Health District, Gosford, NSW, Australia 21.9.1: Acute interstitial nephritis

Contributors lxii Jean-​Marc Rolain IHU Méditerranée Infection, Marseille, France 8.6.43: Bartonellas excluding B. bacilliformis Pierre Ronco Professor of Renal Medicine, University Pierre et Marie Curie, and Inserm Unit UMR_​S1155, Tenon Hospital, Paris, France 21.10.5: Renal involvement in plasma cell dyscrasias, immunoglobulin-​based amyloidoses, and fibrillary glomerulopathies, lymphomas, and leukaemias Antony Rosen Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA 4.6: Autoimmunity Jonathan D.C. Ross University Hospitals Birmingham NHS Trust, Birmingham, UK 9.8: Pelvic inflammatory disease Shannan Lee Rossi Department of Pathology, Center for Biodefense and Emerging Infectious Diseases; Member, Center for Tropical Diseases, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA 8.5.14: Flaviviruses excluding dengue Peter M. Rothwell Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 24.10.1 Stroke: Cerebrovascular disease Simon M. Rushbrook Department of Hepatology, Norfolk and Norwich University Hospitals NHS Trust, Norwich, UK 15.24.6: Primary and secondary liver tumours Nigel Russell Professor of Haematology, Nottingham University, Nottingham, UK 22.3.3: Acute myeloid leukaemia Fiona Ryan Oxford Childrens Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK 13.7.2: Normal puberty and its disorders Nikant Sabharwal Department of Cardiology, John Radcliffe Hospital, Oxford, UK 16.3.3: Cardiac investigations: Nuclear, MRI, and CT Alan D. Salama University College London, London, UK 21.8.5: Proliferative glomerulonephritis Moin Saleem Professor of Paediatric Renal Medicine, University of Bristol Children’s Renal Unit, Bristol Royal Hospital for Children, Bristol, UK 21.8.3: Minimal change nephropathy and focal segmental glomerulosclerosis Hesham A. Saleh Charing Cross Hospital and Royal Brompton Hospital, London; Imperial College London, London, UK 18.6: Allergic rhinitis Susan Salt Trinity Hospice, Blackpool, UK 7.1: Introduction to palliative care Nilesh J. Samani Department of Cardiovascular Sciences, University of Leicester, Leicester, UK 16.17.4: Mendelian disorders causing hypertension Luis G. Sambo University Nova de Lisboa, Lisbon, Portugal 2.16: Financing healthcare in low-​income developing countries: A challenge for equity in health David S. Sanders Royal Hallamshire Hospital and University of Sheffield, Sheffield, UK 15.10.3: Coeliac disease Jeremy Sanderson Department of Gastroenterology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK 15.12: Ulcerative colitis Vijay G. Sankaran Associate Professor of Pediatrics, Harvard Medical School, Division of Hematology/​Oncology, Boston Children’s Hospital, Dana-​Farber/​Boston Children’s Cancer and Blood Disorders Center, Boston, MA, USA 22.6.1: Erythropoiesis Swati Sathe Rutgers New Jersey Medical School, Newark, NJ, USA 24.17: Inherited neurodegenerative diseases Brian P. Saunders Consultant Gastroenterologist, St Mark’s Hospital, North West London Hospitals Trust; Adjunct Professor of Endoscopy, Imperial College London, London, UK 15.3.1: Colonoscopy and flexible sigmoidoscopy Kate E.A. Saunders University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK 26.3.2: Self-​harm; 26.5.7: Bipolar disorder Rana Sayeed Oxford Heart Centre, Oxford University Hospitals NHS Trust, Oxford, UK 16.13.6: Coronary artery bypass and valve surgery John A. Sayer Institute Of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, UK 21.15: The renal tubular acidoses Claire Scampion Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK 6.11: Promotion of dignity in the life and death of older patients Matthew Scarborough Oxford University Hospitals NHS Foundation Trust, Oxford, UK; University of Oxford, Oxford, UK 8.2.3: Nosocomial infections Klaus P. Schaal Institute for Medical Microbiology, Immunology and Parasitology, University Hospital of Bonn, Bonn, Germany 8.6.30: Actinomycoses Michael L. Schilsky Associate Professor of Medicine, Medical Director, Adult Liver Transplant, Yale-​New Haven Transplantation Center, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA 12.7.2: Inherited diseases of copper metabolism: Wilson’s disease and Menkes’ disease Jonathan M. Schott Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK 24.4.2: Alzheimer’s disease and other dementias Heinz-​Peter Schultheiss Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany 16.7.1: Myocarditis Jane Schwebke University of Alabama at Birmingham, AL, USA 8.8.14: Trichomoniasis Neil Scolding University of Bristol Institute of Clinical Neurosciences, Southmead Hospital, Bristol, UK 24.21: Acquired metabolic disorders and the nervous system; 24.22: Neurological complications of systemic disease Anthony Scott KEMRI-​Wellcome Trust Research Programme, Kilifi, Kenya; London School of Hygiene and Tropical Medicine,
London, UK 8.6.3: Pneumococcal infections James Scott Imperial College London, London, UK 12.6: Lipid disorders Rebecca Scott Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK 15.9.1: Hormones and the gastrointestinal tract Mårten Segelmark Professor of Nephrology, Department of Clinical Sciences, Lund
University and Department of Nephrology
Skane University Hospital, Lund, Sweden 21.8.7: Antiglomerular basement membrane disease Julian Seifter Associate Professor of Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, USA 12.11: A physiological approach to acid–base disorders: The roles of ion transport and body fluid compartments Bhuvaneish T. Selvaraj University of Edinburgh, Edinburgh, UK 3.7: Stem cells and regenerative medicine Amartya Sen Harvard University, Cambridge, MA, USA 2.20: Human disasters Arjune Sen Oxford Epilepsy Research Group, NIHR Oxford Biomedical Research Centre,
John Radcliffe Hospital, Oxford, UK 24.5.1: Epilepsy in later childhood and adulthood Debasish Sen Occupational Medicine, University of Manchester, UK 10.2.1: Occupational and environmental health Nicholas J. Severs National Heart and Lung Institute (NHLI) Division, Faculty of Medicine, Imperial College London, London, UK 16.1.2: Cardiac physiology Pallav L. Shah Imperial College London, London, UK 18.1.1: The upper respiratory tract; 18.1.2: Airways and alveoli; 18.3.3: Bronchoscopy, thoracoscopy, and tissue biopsy Muddassir Shaikh James Cook University Hospital, Middlesbrough, UK 19.7: Infection and arthritis Alena Shantsila University of Liverpool, Liverpool, UK 16.17.5: Hypertensive urgencies and
emergencies Susie Shapiro Consultant Haematologist,
Oxford University Hospitals NHS Foundation Trust, Oxford Haemophilia and
Thrombosis Centre, Churchill Hospital,
Oxford, UK 22.7.3: Thrombocytopenia and disorders of platelet function Claire C. Sharpe Professor of Renal Medicine, Faculty of Life Sciences and Medicine, King’s College London, London, UK 21.10.7: Sickle cell disease and the kidney

Contributors lxiii Michael Sharpe Psychological Medicine Research, University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK 26.1: General introduction; 26.2: The psychiatric assessment of the medical patient; 26.3.3: Medically unexplained symptoms; 26.4.2: Psychological treatments; 26.5.12: Somatic symptom and related disorders; 26.7: Psychiatry, liaison psychiatry, and psychological medicine Pamela J. Shaw Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield; Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK 24.15: The motor neuron diseases Debbie L. Shawcross Professor of Hepatology and Chronic Liver Failure, Institute of Liver Studies, Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, UK 15.22.4: Hepatic encephalopathy Bart Sheehan Oxford University Hospitals NHS Foundation Trust, Oxford, UK 26.3.1: Confusion; 26.5.1: Delirium; 26.5.2: Dementia Neil Sheerin Professor of Nephrology, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK 21.13: Urinary tract infection Mark Sherlock General Medicine and Emergency Medicine, NHS, UK; Médecins Sans Frontières (MSF), Paris, France 13.5.1: Disorders of the adrenal cortex Jackie Sherrard Wycombe General Hospital, High Wycombe, UK 8.6.6: Neisseria gonorrhoeae; 9.3: Sexual history and examination M.A. Shikanai-​Yasuda Faculdade Medicina, University of São Paulo (FMUSP), Brazil 8.7.4: Paracoccidioidomycosis Brian Shine Oxford University Hospitals NHS Foundation Trust, Oxford, UK 29.1: The use of biochemical analysis for diagnosis and management John M. Shneerson Papworth Hospital, Papworth Everard, UK 18.18: Disorders of the thoracic cage and diaphragm Volha Shpadaruk Department of Dermatology, University Hospitals of Leicester NHS Trust, Leicester, UK 23.7: Cutaneous vasculitis, connective tissue diseases, and urticaria Joachim Sieper Free University, Berlin, Germany 19.6: Spondyloarthritis and related conditions Udomsak Silachamroon Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand 8.11.3: Lung flukes (paragonimiasis) Leslie Silberstein Director, Transfusion Medicine, Boston Children’s Hospital, Boston, MA, USA 22.6.12: Acquired haemolytic anaemia Jorge Simões University Nova de Lisboa, Lisbon, Portugal 2.16: Financing healthcare in low-​income developing countries: A challenge for equity in health Alexandra Sinclair Institute of Metabolism and Systems Research, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, The Medical School, University of Birmingham, Birmingham, UK 24.10.5: Idiopathic intracranial hypertension Rod Sinclair Department of Dermatology, University of Melbourne, Melbourne, Vic, Australia; Epworth Healthcare, Sinclair Dermatology Investigational Research, Education and Clinical Trials, East Melbourne, Vic, Australia 23.17: Management of skin disease Joseph Sinning Regional Cancer Care Associates, Hartford, CT, USA 22.3.1: Granulocytes in health and disease Thira Sirisanthana Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand 8.7.6: Talaromyces (Penicillium) marneffei infection J.G.P. Sissons† University of Cambridge School of Clinical Medicine, Cambridge, UK 8.5.2: Herpesviruses (excluding Epstein–​Barr virus) Paiboon Sithithaworn Professor, Cholangiocarcinoma Research Institute (CARI), Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University, Thailand; Professor Parasitology, Department of Parasitology, Faculty of Medicine, Khon Kaen University, Thailand 8.11.2: Liver fluke infections James R.A. Skipworth Consultant HPB and General Surgeon, Bristol Royal Infirmary, University Hospitals Bristol NHS Trust, Bristol, UK 15.26.3: Tumours of the pancreas Geoffrey L. Smith University of Cambridge, Cambridge, UK 8.5.4: Poxviruses Roger Smyth Department of Psychological Medicine, Edinburgh Royal Infirmary, Edinburgh, UK 26.2: The psychiatric assessment of the medical patient Rosamund Snow† BMJ, Tavistock Square, London, UK 1.3: What patients wish you understood E.L. Snyder Professor, Laboratory Medicine, Yale University Medical School; Director, Transfusion/​ Apheresis/​Tissue/​Cell Processing Services,
Yale-​New Haven Hospital, New Haven, CT, USA 22.8.1: Blood transfusion Jasmeet Soar Intensive Care Unit, Southmead Hospital, North Bristol NHS Trust, Bristol, UK 17.2: Cardiac arrest May Ching Soh Silver Star Unit, Women’s Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford, UK 14.14: Autoimmune rheumatic disorders and vasculitis in pregnancy Elisaveta Sokolov Kings College Hospital, London, UK 24.7.2: Parkinsonism and other extrapyramidal diseases Tom Solomon Institute of Infection and Global Health, University of Liverpool, Liverpool, UK 24.11.2: Viral infections Krishna Somers Royal Perth Hospital, Perth, WA, Australia 16.9.4: Cardiovascular syphilis Danielle Southerst NYU Langone Health, New York, NY, USA 19.4: Back pain and regional disorders Cathy Speed Consultant in Rheumatology, Sport and Exercise Medicine, Senior Physician, English Institute of Sport, Cambridge Centre for Health and Performance, Cambridge, UK 28.1: Sport and exercise medicine Des Spence Barclay Medical Centre, Maryhill Health Centre, Glasgow, UK 1.4: Why do patients attend and what do they want from the consultation? G.P. Spickett Regional Department of Immunology, Royal Victoria Infirmary, Newcastle upon Tyne, UK 18.14.1: Diffuse alveolar haemorrhage; 18.14.2: Eosinophilic pneumonia; 18.14.4: Hypersensitivity pneumonitis S.G. Spiro University College Hospital,
London, UK 18.19.1: Lung cancer; 18.19.2: Pulmonary metastases David P. Steensma Institute Physician, Division of Hematologic Malignancies, Department of Medical Oncology, Dana-​Farber Cancer Institute; Associate Professor of Medicine, Harvard Medical School, Boston, MA, USA 22.3.2: Myelodysplastic syndromes Jerry L. Spivak Hematology Division,
Johns Hopkins University School of Medicine, Baltimore, MD, USA 22.3.7: Primary myelofibrosis Charles L. Sprung Department of Anesthesiology, Critical Care Medicine and Pain Medicine, Hadassah Medical Center, Hebrew
University of Jerusalem, Faculty of Medicine, Jerusalem, Israel 17.10: Palliative and end-​of-​life care in the ICU Paweł Stankiewicz Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA 3.2: The genomic basis of medicine Natalie Staplin Clinical Trial Service Unit, University of Oxford, Oxford, UK 2.4: Large-​scale randomized evidence: Trials and meta-​analyses of trials Paul D. Stein Professor, Department of Osteopathic Medical Specialties, College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA 16.16.1: Deep venous thrombosis and pulmonary embolism Chris Stenton Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK 18.14.11: Toxic gases and aerosols Dennis L. Stevens Infectious Diseases Section, VA Medical Center, Boise, ID, USA 8.6.2: Streptococci and enterococci; 8.6.25: Botulism, gas gangrene, and clostridial gastrointestinal infections Claire Steves King’s College London, London, UK 6.1: Ageing and clinical medicine † It is with great regret that we report that J.G.P. Sissons died on 25 September, 2016 and Rosamund Snow died on 2 February, 2017.

Contributors lxiv Carmel B. Stober University of Cambridge, Cambridge, UK 19.8: Reactive arthritis Nicole Stoesser Nuffield Department of Medicine Medical Sciences Division, University of Oxford, Oxford, UK 8.6.10: Intracellular klebsiella infections (donovanosis and rhinoscleroma) John R. Stradling Oxford Centre for Respiratory Medicine, John Radcliffe Hospital, Oxford, UK 18.1.1: The upper respiratory tract Michael A. Stroud Department of Medicine, University of Southampton, Southampton, UK 10.3.2: Heat; 10.3.3: Cold Michael Strupp Ludwig Maximilians University, Munich, Germany 24.6.2: Eye movements and balance Matthew J. Stuckey School of Veterinary Medicine, University of California, CA, USA 8.6.43: Bartonellas excluding B. bacilliformis Peter H. Sugden National Heart and Lung Institute (NHLI) Division, Faculty of Medicine, Imperial College London, UK 16.1.2: Cardiac physiology Mehrunisha Suleman Ethox Centre,
Oxford, UK 1.5: Medical ethics Joseph Sung Professor of Medicine, lately President and Vice Chancellor, The Chinese University of Hong Kong, Shatin, Hong Kong, China 15.8: Peptic ulcer disease Khuanchai Supparatpinyo Division of Infectious Diseases, Department of Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand 8.7.6: Talaromyces (Penicillium) marneffei infection Erik R. Swenson VA Puget Sound Health Care System, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA, USA 10.3.6: Diseases of high terrestrial altitudes Anthony Swerdlow The Institute of Cancer Research, University of London, London, UK 5.1: Epidemiology of cancer David Taggart University of Oxford, Oxford, UK 16.13.6: Coronary artery bypass and valve surgery Kathy Taghipour The Whittington Health NHS Trust, London, UK 23.4: Autoimmune bullous diseases Penelope Talelli Homerton University Hospitals NHS Trust, UK 24.7.1: Subcortical structures: The cerebellum, basal ganglia, and thalamus Paolo Tammaro Associate Professor, Department of Pharmacology, University of Oxford, Oxford, UK 3.4: Ion channels and disease C.T. Tan University of Malaya, Kuala Lumpur, Malaysia 8.5.7: Nipah and Hendra virus encephalitides Chen Sabrina Tan Harvard Medical School, Boston, MA, USA 8.5.19: Papillomaviruses and polyomaviruses T.M. Tan Consultant in Diabetes, Endocrinology, and Metabolic Medicine, Imperial College London, London, UK 13.8: Pancreatic endocrine disorders and multiple endocrine neoplasia; 15.9.1: Hormones and the gastrointestinal tract; 15.9.2: Carcinoid syndrome David Taylor-​Robinson Section of Retrovirology and GU Medicine, Department of Infectious Diseases, Wright-​Fleming Institute, Faculty of Medicine, Imperial College London, London, UK 8.6.45: Chlamydial infections; 8.6.46: Mycoplasmas F. Teo National University Hospital, National University Health System, Singapore, China 18.11.1: Diffuse parenchymal lung disease: An introduction R.V. Thakker Academic Endocrine Unit, University of Oxford, OCDEM, Churchill Hospital, Oxford, UK 13.4: Parathyroid disorders and diseases altering calcium metabolism Nishanthi Thalayasingam Faculty of Medical Sciences, Newcastle University and Musculoskeletal Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 2.7: Biological therapies for immune, inflammatory, and allergic diseases Richard J. Thompson Professor of Molecular Hepatology, Institute of Liver Studies, King’s College London, London, UK 15.24.7: Liver and biliary diseases in infancy and childhood S.A. Thorne University Hospital, Birmingham, UK 16.12: Congenital heart disease in the adult Guy E. Thwaites Oxford University Clinical Research Unit (OUCRU), Ho Chi Minh City, Vietnam 24.11.1: Bacterial infections C. Louise Thwaites Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK 8.6.23: Tetanus Adam D. Timmis Barts Heart Centre, Queen Mary University London, London, UK 16.13.3: Management of stable angina Stephen M. Tollman University of the Witwatersrand, Johannesburg, South Africa; MRC/​Wits Rural Public Health and Health Transitions Research Unit, School of Public Health, Faculty of Health Sciences; INDEPTH Network (International Network for the Demographic Evaluation of Populations and Their Health), Accra, Ghana, South Africa; Centre for Global Health Research, Umeå University, Sweden 2.18: Fostering medical and health research in resource-​constrained countries Maciej Tomaszewski Division of Cardiovascular Sciences, University of Manchester, Manchester, UK 16.17.4: Mendelian disorders causing hypertension Charles Tomson Consultant Nephrologist,
Freeman Hospital, Newcastle upon
Tyne, UK 21.13: Urinary tract infection Pat Tookey Honorary Associate Professor, Population, Policy and Practice Research
and Teaching Department, University College London Institute of Child Health,
London, UK 8.5.13: Rubella Peter Topham Consultant Nephrologist,
John Walls Renal Unit, University Hospitals
of Leicester NHS Trust, Leicester, UK 21.8.2: Thin membrane nephropathy Nicholas Torpey Consultant Physician and Nephrologist, Cambridge University Hospitals, Cambridge, UK 21.7.3: Renal transplantation Thomas A. Traill Division of Cardiology, Johns Hopkins Hospital, Baltimore, MD, USA 16.10: Tumours of the heart; 16.11: Cardiac involvement in genetic disease A.S. Truswell University of Sydney, Sydney, NSW, Australia 11.5: Diseases of affluent societies and the need for dietary change Steven Tsui Consultant Cardiac Surgeon, Royal Papworth Hospital, Cambridge, UK 16.5.5: Cardiac transplantation and mechanical circulatory support Youyou Tu Professor, Department of Chemistry, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China 2.8: Traditional medicine exemplified by traditional Chinese medicine D.M. Turnbull Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK 24.19.5: Mitochondrial disease A. Neil Turner Professor of Nephrology,
University of Edinburgh, Queen’s Medical Research Institute (CIR), Edinburgh, UK 21.10.8: Infection-​associated nephropathies; 21.10.9: Malignancy-​associated renal disease Tabitha Turner-​Stokes MRC Clinical Research Fellow, Centre for Inflammatory Disease, Department of Medicine, Imperial College London, London, UK 21.8.6: Membranoproliferative glomerulonephritis Holm H. Uhlig Translational Gastroenterology Unit and Department of Paediatrics, University of Oxford, John Radcliffe Hospital, Oxford, UK 15.15: Congenital abnormalities of the gastrointestinal tract Magnus Unemo WHO Collaborating Centre for Gonorrhoea and other STIs, Örebro University Hospital, Örebro, Sweden 8.6.6: Neisseria gonorrhoeae; 8.6.45 Chlamydial infections Robert Unwin Department of Renal Medicine, University College London, London, UK 21.1: Structure and function of the kidney

Contributors lxv John A. Vale National Poisons Information Service (Birmingham Unit) and West Midlands Poisons Unit; City Hospital, Birmingham; School of Biosciences, University of Birmingham, Birmingham, UK 10.4.1: Poisoning by drugs and chemicals Patrick Vallance GlaxoSmithKline, London, UK 16.1.1: Blood vessels and the endothelium Greet Van den Berghe Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven University, B-​3000 Leuven, Belgium 17.9: Metabolic and endocrine changes in acute and chronic critical illness Steven Vanderschueren Leuven Research Department of Microbiology, Immunology and Transplantation, Laboratory for Clinical Infectious and Inflammatory Disorders, Clinical Department of General Internal Medicine, University Hospital Leuven, B-​3000 Leuven, Belgium 8.2.2: Fever of unknown origin Sirivan Vanijanonta Department of Clinical
Tropical Medicine, Faculty of Tropical
Medicine, Mahidol University,
Bangkok, Thailand 8.11.3: Lung flukes (paragonimiasis) Anita Vas-​Falcao London School of Hygiene and Tropical Medicine, London, UK 9.1: Epidemiology of sexually transmitted infections Nikos Vasilakis Department of Pathology,
Center for Biodefense and Emerging Infectious Diseases, Center for Tropical Diseases,
Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA 8.5.14: Flaviviruses excluding dengue Diana Vassallo Specialist Registrar, Department of Renal Medicine, Salford Royal NHS Foundation Trust, Salford, UK 21.10.10: Atherosclerotic renovascular disease Birgitte Vennervald Section for Parasitology and Aquatic Diseases, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 8.11.1: Schistosomiasis Vanessa Venning Department of Dermatology, Churchill Hospital, Oxford, UK 23.2: Clinical approach to the diagnosis of skin disease Anilrudh A. Venugopal Los Angeles, CA, USA 8.6.11: Anaerobic bacteria Kristien Verdonck Institute of Tropical Medicine, Antwerp, Belgium 8.5.25: HTLV-​1, HTLV-​2, and associated
diseases Christopher M. Verity Addenbrookes Hospital, Cambridge, UK 24.20: Developmental abnormalities of the central nervous system Benjamin A. Vervaet Laboratory of Pathophysiology, University of Antwerp, Antwerp, Belgium 21.9.2: Chronic tubulointerstitial nephritis Diego Viasus Division of Health Sciences, Faculty of Medicine, Universidad del Norte, Barranquilla, Colombia 8.6.39: Legionellosis and Legionnaires’ disease Angela Vincent Hon Cons Immunology, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK 24.24: Autoimmune encephalitis and Morvan’s syndrome Raphael P. Viscidi Johns Hopkins Medical Institution, Baltimore, MD, USA 8.5.19: Papillomaviruses and polyomaviruses H. Josef Vormoor Clinical Director,
Department of Hemato-​oncology, Princess Máxima Center for Pediatric Oncology,
Utrecht, the Netherlands 22.4.2: Acute lymphoblastic leukaemia Theo Vos University of Washington, WA, USA 2.3: The Global Burden of Disease: Measuring the health of populations Henry J.C. de Vries Academic Medical Centre,
University of Amsterdam, Amsterdam, the Netherlands 9.7: Anogenital lumps and bumps Paresh Vyas Professor of Haematology, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe
Department of Medicine, University of Oxford; Consultant Haematologist, Department of
Haematology, Cancer and Haematology
Centre, Churchill Hospital, Oxford
University Hospitals NHS Foundation Trust,
Oxford, UK 22.2.1: Cellular and molecular basis of haematopoiesis Peter D. Wagner Division of Physiology at the Department of Medicine, University of California San Diego, CA, USA 18.1.2: Airways and alveoli Nicholas Wald Institute of Health Informatics, University College London, London; Population Health Research Institute, St George’s University of London, London; Division of Medical Screening and Special Testing, Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School of Brown University, Rhode Island, USA 2.12: Medical screening Herman Waldmann Sir William Dunn School of Pathology, University of Oxford, Oxford, UK 3.8: The evolution of therapeutic antibodies Jane Walker Psychological Medicine Research, University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK 26.2: The psychiatric assessment of the medical patient; 26.3.4: Low mood Matthew C. Walker National Hospital of Neurology and Neurosurgery and UCL Institute of Neurology, Queen Square, London, UK 24.5.2: Narcolepsy Elizabeth Wallin Transplant Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK 4.7: Principles of transplantation immunology Sarah Walsh King’s College Hospital,
London, UK 23.16: Cutaneous reactions to drugs T.E. Warkentin Professor, Department of Pathology and Molecular Medicine and Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada 22.7.5: Acquired coagulation disorders David A. Warrell Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK 8.5.10: Rhabdoviruses: Rabies and rabies-​related lyssaviruses; 8.5.11: Colorado tick fever and other arthropod-​borne reoviruses; 8.5.27: Orf and Milker’s nodule; 8.5.28: Molluscum contagiosum; 8.6.34: Relapsing fevers; 8.13: Pentastomiasis (porocephalosis, linguatulosis/​linguatuliasis, or tongue worm infection); 10.4.2: Injuries, envenoming, poisoning, and allergic reactions caused by animals; 10.4.3: Poisonous fungi; 24.11.2: Viral infections Mary J. Warrell Oxford Vaccine Group, University of Oxford, Oxford, UK 8.5.10: Rhabdoviruses: Rabies and rabies-​related lyssaviruses; 8.5.11: Colorado tick fever and other arthropod-​borne reoviruses John A.H. Wass University of Oxford, Oxford, UK 13.2.1: Disorders of the anterior pituitary gland; 13.2.2: Disorders of the posterior pituitary gland; 13.10: Hormonal manifestations of non-​endocrine disease Lawrence Waterman Loughborough University, Loughborough, UK; Park Health and Safety Partnership, Aylesbury, UK 10.2.2: Occupational safety Laurence Watkins The National Hospital for Neurology and Neurosurgery, London, UK 24.10.3: Traumatic brain injury Peter Watkinson Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 8.1.2: Clinical features and general management of patients with severe infections Richard A. Watts Department of Rheumatology, Ipswich Hospital, Ipswich; Norwich Medical School, University of East Anglia, Norwich, UK 19.11.9: Small vessel vasculitis Richard W.E. Watts† Division of Inherited Metabolic Diseases, Northwick Park Hospital, London, UK 12.1: The inborn errors of metabolism: general aspects; 12.4: Disorders of purine and pyrimidine metabolism David J. Weatherall† Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK 22.6.2: Anaemia: Pathophysiology, classification, and clinical features; 22.6.3: Anaemia as a challenge to world health; 22.6.7: Disorders of the synthesis or function of haemoglobin G.J. Webb Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK 15.23.2: Autoimmune hepatitis Lisa J. Webber St Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK 13.6.1: Ovarian disorders George J. Webster Consultant Hepatologist and Gastroenterologist, University College Hospital and Royal Free Hospital, London, UK 15.3.2: Upper gastrointestinal endoscopy † It is with great regret that we report that Richard W.E. Watts died on 11 February, 2018 and David J. Weatherall died on 8 December, 2018.

Contributors lxvi Anthony P. Weetman University of Sheffield, Sheffield, UK 13.3.1: The thyroid gland and disorders of thyroid function; 13.3.2: Thyroid cancer Robert A. Weinstein Rush University, Chicago, IL, USA 8.6.4: Staphylococci Louis M. Weiss Department of Pathology, Division of Parasitology and Tropical Medicine; Department of Medicine, Division of Infectious Diseases, Albert Einstein College of Medicine, Bronx, NY, USA 8.7.7: Microsporidiosis; 8.8.7: Cystoisosporiasis Robin A. Weiss University College London, London, UK 8.5.26: Viruses and cancer Peter F. Weller William Bosworth Castle Professor of Medicine, Harvard Medical School, Boston; Chief of the Infectious Diseases and the Allergy and Inflammation Divisions, Beth Israel Deaconess Medical Center, Boston, MD, USA 22.3.8: Eosinophilia A.U. Wells Interstitial Lung Disease Unit, Royal Brompton Hospital, London, UK 18.11.1: Diffuse parenchymal lung disease: An introduction; 18.11.2: Idiopathic pulmonary fibrosis; 18.11.3: Bronchiolitis obliterans and cryptogenic organizing pneumonia; 18.11.4: The lung in autoimmune rheumatic disorders; 18.11.5: The lung in vasculitis Simon Wessely Department of Psychological Medicine, King’s College London, London, UK 26.4.2: Psychological treatments Gilbert C. White, II Aster Chair for Medical Research, Executive Vice President for Research, Director, Blood Research Institute, Versiti; Professor of Medicine, Biochemistry, and Pharmacology, Associate Dean for Research, Medical College of Wisconsin, Milwaukee, WI, USA 22.7.1: The biology of haemostasis and thrombosis Nicholas J. White Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK 8.8.2: Malaria Hilton C. Whittle Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK 8.5.6: Measles Anthony S. Wierzbicki Department of Metabolic Medicine/​Chemical Pathology, Guy’s and St Thomas’ Hospitals, London, UK 12.9: Disorders of peroxisomal metabolism in adults Mark H. Wilcox Professor of Medical Microbiology, Microbiology, Old Medical School, Leeds General Infirmary, and University of Leeds, Leeds, UK 8.6.24: Clostridium difficile Kate Wiles Department of Women and Children’s Health, King’s College London, London, UK 14.5: Renal disease in pregnancy James S. Wiley Principal Research Fellow, Florey Institute of Neuroscience, and Mental Health Honorary Professor, University of Melbourne, Melbourne, Vic, Australia 22.6.8: Anaemias resulting from defective maturation of red cells R.G. Will Professor of Clinical Neurology, Department of Clinical Neurosciences, University of Edinburgh, Edinburgh, UK 24.11.5: Human prion diseases Lisa Willcocks Consultant Physician and Nephrologist, Cambridge University Hospitals, Cambridge, UK 21.8.3: Minimal change nephropathy and focal segmental glomerulosclerosis Bryan Williams University College London, London, UK 16.17.1: Essential hypertension: Definition, epidemiology, and pathophysiology; 16.17.2: Essential hypertension: Diagnosis, assessment, and treatment David J. Williams Obstetric Physician, Institute for Women’s Health, University College London Hospital, London, UK 14.1: Physiological changes of normal pregnancy; 14.2: Nutrition in pregnancy; 14.3: Medical management of normal pregnancy Catherine Williamson Professor of Women’s Health, King’s College London and Honorary Consultant in Obstetric Medicine, St Thomas’ and King’s College Hospitals, London, UK 14.9: Liver and gastrointestinal diseases of pregnancy Bridget Wills Centre for Tropical Medicine
and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam 8.5.15: Dengue; 24.11.2: Viral infections R. Wilson Royal Brompton and Harefield NHS Trust, London, UK 18.9: Bronchiectasis Greg Winter MRC Laboratory of Molecular Biology, Cambridge, UK 3.8: The evolution of therapeutic antibodies Miles Witham AGE Research Group, NIHR Newcastle Biomedical Research Centre, Newcastle University and Newcastle upon Tyne Hospitals Trust, Newcastle upon Tyne, UK 6.7: Drugs and prescribing in the older patient Fenella Wojnarowska Nuffield Department of Medicine, University of Oxford, Oxford, UK 14.13: The skin in pregnancy; 23.4: Autoimmune bullous diseases Edwin K.S. Wong Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK 21.10.6: Haemolytic uraemic syndrome James L.N. Wood University of Cambridge, Cambridge, UK 8.1.1: Biology of pathogenic microorganisms Jonathan Wood Substance Misuse Psychiatry, Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK 26.5.4: Alcohol misuse Kathryn J. Wood Transplant Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK 4.7: Principles of transplantation immunology Nicholas Wood University College London, London, UK 24.7.4: Ataxic disorders Andrew F. Woodhouse Department of Infection and Tropical Medicine, Birmingham Heartlands Hospital, Birmingham, UK 8.6.32: Rat bite fevers (Streptobacillus moniliformis and Spirillum minus infection) Jeremy Woodward Cambridge Intestinal Failure and Transplant Unit, Addenbrooke’s Hospital, Cambridge, UK 11.7: Artificial nutrition support; 15.2: Symptoms of gastrointestinal disease Elaine M. Worcester Professor of Medicine, Nephrology Section, Department of Medicine, University of Chicago, Chicago, USA 21.14: Disorders of renal calcium handling, urinary stones, and nephrocalcinosis B. Paul Wordsworth Emeritus Professor of Clinical Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, Nuffield Orthopaedic Centre, Headington, Oxford, UK 20.1: Skeletal disorders—​general approach and clinical conditions Gary P. Wormser New York Medical College, NY, USA 8.6.33: Lyme borreliosis Mark Wright Consultant Gastroenterologist, University Hospital Southampton, Southampton, UK 15.25: Diseases of the gallbladder and biliary tree Channa Jayasumana Faculty of Medicine, Rajatrata University of Sri Lanka, Anuradhapura, Sri Lanka 21.9.2: Chronic tubulointerstitial nephritis Muhammad M. Yaqoob Barts Health NHS Trust, Renal Unit, Royal London Hospital, London, UK 21.17: Urinary tract obstruction Hasan Yazici Department of Medicine (Rheumatology), Academic Hospital, Istanbul, Turkey 19.11.10: Behçet’s syndrome Lam Minh Yen Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam 8.6.23: Tetanus Duncan Young Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 8.1.2: Clinical features and general management of patients with severe infections Katherine Younger School of Biological and Health Sciences, Technological University Dublin, Dublin, Ireland 11.3: Minerals and trace elements Sebahattin Yurdakul Division of Rheumatology, Department of Medicine, Cerrahpasa Medical Faculty, University of Istanbul, Istanbul, Turkey 19.11.10: Behçet’s syndrome Alberto Zanella Oncohematology Unit—​ Pathophysiology of Anemias Unit, Foundation IRCCS Ca’ Granda Ospedale Maggiore, Milan, Italy 22.6.10: Erythrocyte enzymopathies Adam Zeman Professor of Cognitive and Behavioural Neurology, University of Exeter Medical School, Exeter, UK 24.2: Mind and brain: Building bridges between neurology, psychiatry, and psychology Clive S. Zent University of Rochester Medical Center, Rochester, NY, USA 22.4.5: Chronic lymphocytic leukaemia

SECTION 10 Environmental medicine, occupational medicine, and poisoning Section editor: Jon G. Ayres 10.1 Environmental medicine, occupational medicine, and poisoning—Introduction   1637 Jon G. Ayres 10.2 Occupational health   1638 10.2.1 Occupational and environmental health  1638 Raymond Agius and Debasish Sen 10.2.2 Occupational safety  1652 Lawrence Waterman and Michelle Twigg 10.2.3 Aviation medicine  1656 Michael Bagshaw 10.2.4 Diving medicine  1664 David M. Denison and Mark A. Glover 10.2.5 Noise  1671 David Koh and Tar-Ching Aw 10.2.6 Vibration  1673 Tar-Ching Aw 10.3 Environment and health   1677 10.3.1 Air pollution and health  1677 Om P. Kurmi, Kin Bong Hubert Lam,
and Jon G. Ayres 10.3.2 Heat  1687 Michael A. Stroud 10.3.3 Cold  1689 Michael A. Stroud 10.3.4 Drowning  1691 Peter J. Fenner 10.3.5 Lightning and electrical injuries  1696 Chris Andrews 10.3.6 Diseases of high terrestrial altitudes  1701 Tyler Albert, Erik R. Swenson, Andrew J. Pollard, Buddha Basnyat, and David R. Murdoch 10.3.7 Radiation  1709 Jill Meara 10.3.8 Disasters: Earthquakes, hurricanes, floods, and volcanic eruptions  1713 Peter J. Baxter 10.3.9 Bioterrorism  1718 Manfred S. Green 10.4 Poisoning   1725 10.4.1 Poisoning by drugs and chemicals  1725 John A. Vale, Sally M. Bradberry, and D. Nicholas Bateman 10.4.2 Injuries, envenoming, poisoning, and
allergic reactions caused by animals  1778 David A. Warrell 10.4.3 Poisonous fungi  1817 Hans Persson and David A. Warrell 10.4.4 Poisonous plants  1828 Michael Eddleston and Hans Persson 10.5 Podoconiosis (nonfilarial elephantiasis)   1833 Gail Davey

Oxford Textbook of Medicine-Volume 2, 6e (May 6, 2

Oxford Textbook of Medicine-Volume 2, 6e (May 6, 2020)(0198746695)(Oxford University Press)

Oxford Textbook of Medicine

Oxford Textbook of Medicine

Oxford Textbook of Medicine

1 Oxford Textbook of Medicine SIXTH EDITION Volume 2: Sections 10–15 EDITED BY John D. Firth Christopher P. Conlon Timothy M. Cox

Preface

Preface

Preface Changes in medicine The Oxford Textbook of Medicine is published online and has been regularly updated for many years, but the production of a new and very substantially updated edition provides a moment when it is nat- ural and proper to reflect on what has changed in medicine—​and what has not—​in recent years. In the context of burgeoning social changes and inequality across the world, we have cause to weigh and consider exactly what modern medicine has to offer patients and their doctors. Here we reflect on aspects of Medicine that are chan- ging rapidly and set out a vision for this in the sixth edition of the Oxford Textbook of Medicine. Demand, capacity, magic solutions, and the need for perspective Within all healthcare systems, in rich and poor nations alike, most physicians feel the inexorable rise in demand and are strug- gling to provide adequate ‘capacity’—​the term commonly applied by healthcare managers charged with the impossible task of con- straining expenditure while serving political masters who, almost without exception, promise more and more and blame inefficiency and ‘unwarranted variation’ for the failure to deliver. In response to the difficulties, claims are made that some new technological advance, be it sequencing of patients’ genomes, healthcare apps, the application of artificial intelligence or ‘Quality Improvement’ methodology, will provide the solutions. In the Oxford Textbook of Medicine, we do not shy away from these aspects and have several new chapters that consider how rich and ‘resource-​poor’ countries might best invest their revenues on health. It is often very hard for practising physicians, who care for patients as individuals, to maintain their bearings within the unfamiliar and depersonalized world of modern healthcare management. Many are left wondering whether those who organize health services ‘live on this planet’, or ‘did any working doctor check out that latest directive from above?’. When clinical outcomes that really matter are diffi- cult to quantify, doctors find themselves and their services judged by spurious measures of ‘productivity’ in the process of healthcare ‘de- livery’. Unrealistic and often clinically irrelevant targets might drive the thinking of the insurers, managers, and politicians, but who can determine the human and clinical value of the care provided? Timeliness of care is important and sometimes crucial for salutary outcomes, but disaster strikes when clock-​driven targets are blindly pursued for all patients irrespective of clinical urgency and to the ex- clusion of all else, including patients with greater clinical need. In the morass created by financial constraints and zealous pol- itical control of health services exercised by those without clinical responsibility, it is rare for doctors be able to stand back and perceive genuine improvements. However, it is certainly true that today we have greater potential to prevent and treat disease and to maintain health than ever before. It is our hope that the Oxford Textbook of Medicine will inform doctors about these changes and provide good guidance as to how they can be translated into clinical practice. Advances in biomedical sciences We seek to embody advances in understanding and practice that have arisen through scientific research. In the ten years since publication of the last edition of this book there has been spec- tacular progress in the application of science in medicine, espe- cially the understanding of genomics and molecular cell biology. These include: in diagnostics, non-​invasive prenatal diagnosis of chromosome abnormalities and monogenic disease by sampling maternal plasma for cell-​free fetal DNA, a technique which also holds promise for screening and monitoring of cancers; in meta- bolic disease, the introduction of molecular therapies that address the defective chloride transport in cystic fibrosis; in oncology, in- creased understanding of cancer immunity leading to the develop- ment of immunotherapies for cancers. Our authors include the very best in their fields. The founding editor and author in this edition, the late David Weatherall, was a recipient of the Lasker-​Koshland Special Achievement Award in Medical Science. Two new authors have received the Nobel Prize recently—​Professor Tu Youyou the 2015 prize for Medicine or Physiology, and Sir Greg Winter the 2018 prize for Chemistry. Another new author, Professor Y.M. Dennis Lo, was one of two winners of China’s inaugural Future Science Prize in 2016. Beyond scientific development, the introduction of new technolo- gies into practice typically leads to a sequence of events including initial ‘hype’ from many in the field, with extravagant claims of po- tential benefit. After an interval, these claims are followed by a more realistic assessment of what the technology can—​and cannot—​ provide. Frequently, this familiar pattern is driven by powerful com- mercial influences which can corrupt thinking in a manner that generates a climate in which those with views contrary to the big battalions are inevitably marginalized. In this edition of the Oxford Textbook of Medicine we have strived to bring an authentic perspec- tive and realism to recommendations for treatment. We sense, for in- stance, that the excitement generated by the sequencing of patients’ genomes continues to increase, but that this trajectory is flattening and expectations becoming more realistic. For patients very likely to have genetic disorders, diagnoses can be made for a proportion that was unimaginable until recently, but for most patients with the degenerative and/​or polygenic diseases that are the greatest burden

Preface viii to health, evidence of clinical benefit from genome sequencing re- mains elusive. Beyond the progress in genomics and cell biology there has been immense interest in bioinformatics and, especially with the enthu- siasm of major biomedical charities such as The Wellcome Trust, for ‘big data’, and the opportunities that these bring to the practice of medicine. However, while there are plentiful examples of gen- omics and cell biology having been translated productively from the bench to the bedside, with enormous benefit to patients, examples of transforming clinical impact from big data and bioinformatics are sparse. But examples there are, such as in the analysis of out- breaks of the scourges Clostridium difficile and methicillin-​resistant Staphylococcus aureus (MRSA). These discoveries give hope for the future as we learn which problems are tractable with this type of approach and which are not. Clinical skill Until recently, it would have been, to paraphrase Thomas Jefferson, regarded as self-​evident that the key requirements of a good phys- ician are the ability and will to obtain an informative history, carry out a thorough physical examination, formulate a relevant differ- ential diagnosis, instigate appropriate investigations, advise and administer correct treatment, including best efforts to relieve symp- toms in all cases. These skills, and the commitment to use them, are often forgotten when healthcare is described in the commercial terms of demand and capacity. While advances in biomedical sciences have dramatically im- proved the outcome for some diseases, and Paul Erhlich’s century-​ old magische Kugel (magic bullet) has whetted our appetite for wonder, it is prudent to recall Thomas Szasz: ‘Formerly, when reli- gion was strong and science weak, men mistook magic for medicine; now, when science is strong and religion weak, men mistake medi- cine for magic’. The term ‘personalized’ medicine imputes remark- able and as yet unproven powers, excepting in a very few cases, to gene sequencing and molecular therapies, while the patient wants to be treated as a person. It is also alarming to us that some medical curricula increasingly focus on process, ‘behaviours’, and ‘communi- cation skills’, to the detriment of medical content or mature guidance and attitudes to lifelong learning. There is a tendency to forget the very essence of being, and how to become, a physician in the time-​ honoured understanding of the role. In the Oxford Textbook of Medicine we unashamedly emphasize the primacy of history, examination, differential diagnosis, investi- gation, and treatment. Without a firm grasp of these essentials the doctor cannot provide good care for patients, and nor can anyone else. Furthermore, having a firm understanding of clinical context and a well-​informed clinical perspective is an essential prerequisite for driving biomedical research into avenues that really matter. The broader context of health and disease The world has become a smaller place. We are now in an era when many regard not having a smartphone as an index of deprivation. An event that has happened on a different continent can, as a re- sult of social media, become known to millions of people within hours—​the term ‘viral’ has been rightfully translated from commu- nicable illness to global phenomenon. Narratives transmitted in this way often concern disasters, wars, and disease, and they are typically handled by the media in a sensationalized and superficial manner. One hundred and fifty years ago, Darwin’s 1859 masterpiece on evolution was entitled ‘On the Origin of Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life’. The ‘less favoured’ undoubtedly have poorer health outcomes, due largely to the persistent social ill of inequality, in poor as well as ostensibly rich countries. Continuing the tradition of previous edi- tions, we have contributions that discuss the impact of social deter- minants of health, also thoughtful chapters on human disasters (by another Nobel laureate, Prof Amartya Sen), and the practical and critically important aspects of humanitarian medicine. In addition, the modern problems of pollution and climate change are exam- ined. We contend that all doctors would benefit from reading these chapters. Patients and their expectations There are continuing changes in patients’ expectations, particularly those of articulate patients suffering from long-​term conditions and residing in countries with a rich provision of healthcare. A paternal- istic medical approach is no longer acceptable, and several patients have contributed greatly to the book by taking the opportunity to tell us how they think doctors should behave towards them and care for them. However, we are very aware that one size does not fit all, and that many patients want a doctor who will give them clear recom- mendations and not keep repeating a bewildering (to the patient) variety of options and ask them to choose. The mature and able physician will be alert and sensitive to those patients who want this and will provide them with clear advice, and we have endeavoured to ensure that the Oxford Textbook of Medicine will assist. Access to medical knowledge The ever-​expanding world of the smartphone and tablet device gives patients, families, doctors, and other healthcare professionals ready access to more information about medicine than all but a very few would have thought possible a decade ago. This has many benefits but often leaves users of the internet thoroughly perplexed, and some desperate people vulnerable to online quackery. Those wanting de- tails of particular studies will naturally refer to the original literature. Those wanting in-​depth reviews of particular subjects can refer to diverse resources: these are typically good at apprising the reader of plentiful options for investigation, diagnosis, or management, but often leave them uncertain of what a clinically experienced expert in the field would actually recommend. In the sections that form the bulk of the Oxford Textbook of Medicine, we have selected experts with specific clinical experience and given them this task, and we contend that they have met the challenge. Acknowledgements The Oxford Textbook of Medicine is a large undertaking: this edition, the most substantial so far, comprises 647 chapters and covers 6654 printed pages, and its production has required an extraordinary co- ordination of effort from many quarters. In darker moments the edi- tors feared that the process would never end, but as we have read and edited the chapters along the way, we have experienced the joy of learning a huge amount of medicine, often in fields far removed from our own. For this we are very grateful to our contributors, including those whose submissions were delayed!

Preface ix We wish to make particular acknowledgement of our friend and senior colleague, David Warrell, an editor from the first edition of this textbook, senior editor of the fourth and fifth editions, and au- thor in this edition. We and our readers, notably those seeking in- formation on tropical diseases and especially any who have been bitten by snakes, about which his knowledge is truly prodigious, owe him a great debt. We thank Helen Liepman, with whom we remain good friends: she has overseen and directed matters at Oxford University Press and coped in a steadfastly pleasant and professional way with expres- sions of editorial frustration caused by our failure to understand a publishing process that at times seemed to be Byzantine in its com- plexity, as might perhaps be expected in an ancient university. We also thank Anna Kirton, Jamie Oates, and Jess White at Oxford University Press for their considerable efforts on behalf of the book. Finally, we record that the editors’ personal lives have remained calm, and we are very grateful to Helen, Jenny, and Sue for their in- dulgence of our bizarre editorial pursuit. John D. Firth Christopher P. Conlon Timothy M. Cox

Section editors Jon G. Ayres  Emeritus Professor of Environmental
and Respiratory Medicine, University of Birmingham, Birmingham, UK Section 10: Environmental medicine, occupational medicine, and poisoning Christopher P. Conlon  Professor of Infectious Diseases, Nuffield Department of Medicine, University of Oxford, Oxford, UK Section 1: Patients and their treatment; Section 2: Background to medicine; Section 3: Cell biology; Section 4: Immunological mechanisms; Section 5: Principles of clinical oncology; Section 8: Infectious diseases; Section 25: Disorders of the eye; Section 29: Biochemistry in medicine Cyrus Cooper  MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK; NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK Section 20: Disorders of the skeleton Timothy M. Cox  Professor of Medicine Emeritus, Director of Research, University of Cambridge; Honorary Consultant Physician, Addenbrooke’s Hospital, Cambridge, UK Section 1: Patients and their treatment; Section 2: Background to medicine; Section 3: Cell biology; Section 4: Immunological mechanisms; Section 5: Principles of clinical oncology; Section 12: Metabolic disorders Jeremy Dwight  Previously John Radcliffe Hospital, Oxford, UK Section 16: Cardiovascular disorders Simon Finfer  Malcolm Fisher Department of Intensive Care Medicine, Royal North Shore Hospital, and The George Institute for Global Health, University of New South Wales, Sydney, Australia Section 17: Critical care medicine John D. Firth  Consultant Physician and Nephrologist, Cambridge University Hospitals, Cambridge, UK Section 1: Patients and their treatment; Section 2: Background to medicine; Section 3: Cell biology; Section 4: Immunological mechanisms; Section 5: Principles of clinical oncology; Section 21: Disorders of the kidney and urinary tract; Section 27: Forensic medicine; Section 28: Sport and exercise medicine; Section 30: Acute medicine Mark Gurnell  University of Cambridge Medical School, Cambridge, UK Section 13: Endocrine disorders Chris Hatton  Cancer and Haematology Centre, Churchill Hospital, Oxford, UK Section 22: Haematological disorders Deborah Hay  Honorary Consultant Haematologist, Nuffield Department of Medicine, University of Oxford, Oxford, UK Section 22: Haematological disorders Roderick J. Hay  King’s College London, London, UK Section 23: Disorders of the skin Christopher Kennard  Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK Section 24: Neurological disorders Finbarr C. Martin  Population Health Sciences, King’s College London, London, UK Section 6: Old age medicine Catherine Nelson-Piercy  Obstetric Medicine, Women’s Health Academic Centre, King’s Health Partners, King’s College London, London, UK Section 14: Medical disorders in pregnancy Jack Satsangi  Oxford Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK Section 15: Gastroenterological disorders Pallav L. Shah  Imperial College London, London, UK Section 18: Respiratory disorders Michael Sharpe  Psychological Medicine Research, University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK Section 26: Psychiatric and drug-related disorders Jackie Sherrard  Wycombe General Hospital, High Wycombe, Bucks, UK Section 9: Sexually transmitted diseases Richard A. Watts  Department of Rheumatology, Ipswich Hospital, Ipswich, UK; Norwich Medical School, University of East Anglia, Norwich, UK Section 19: Rheumatological disorders Bee Wee  Associate Professor of Palliative Care, University of Oxford, Oxford, UK Section 7: Pain and palliative care Katherine Younger  School of Biological and Health Sciences, Technological University Dublin, Ireland Section 11: Nutrition

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