The HIV-1 pandemic is a complex mix of diverse epidemics within and between countries and regions of the world, and is undoubtedly the defining public-health crisis of our time. Research has deepened our understanding of how the virus replicates, manipulates, and hides in an infected person. Although our understanding of pathogenesis and transmission dynamics has become more nuanced and prevention options have expanded, a cure or protective vaccine remains elusive. Antiretroviral treatment has transformed AIDS from an inevitably fatal condition to a chronic, manageable disease in some settings. This transformation has yet to be realised in those parts of the world that continue to bear a disproportionate burden of new HIV-1 infections and are most affected by increasing morbidity and mortality. This Seminar provides an update on epidemiology, pathogenesis, treatment, and prevention interventions pertinent to HIV-1.

Highly active antiretroviral therapy (HAART) for the treatment of HIV infection was introduced a decade ago. We aimed to examine trends in the characteristics of patients starting HAART in Europe and North America, and their treatment response and short-term prognosis.

Much like other autoantibodies (eg, anti-double stranded DNA in systemic lupus erythematosus or antiglomerular basement membrane antibodies in Goodpasture's syndrome), antineutrophil cytoplasmic antibodies (ANCA) have provided doctors with a useful serological test to assist in diagnosis of small-vessel vasculitides, including Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, and their localised forms (eg, pauci-immune necrotising and crescentic glomerulonephritis). 85-95% of patients with Wegener's granulomatosis, microscopic polyangiitis, and pauci-immune necrotising and crescentic glomerulonephritis have serum ANCA. ANCA directed to either proteinase 3 or myeloperoxidase are clinically relevant, yet the relevance of other ANCA remains unknown. Besides their diagnostic potential, ANCA might be valuable in disease monitoring. In addition, data seem to confirm the long-disputed pathogenic role of these antibodies. Present treatments for ANCA-associated vasculitis are not free from side-effects and as many as 50% of patients relapse within 5 years. Accurate understanding of the key pathogenic points of ANCA-associated vasculitis can undoubtedly provide a more rational therapeutic approach.

Alzheimer's disease is the most common cause of dementia. Research advances have enabled detailed understanding of the molecular pathogenesis of the hallmarks of the disease--ie, plaques, composed of amyloid beta (Abeta), and tangles, composed of hyperphosphorylated tau. However, as our knowledge increases so does our appreciation for the pathogenic complexity of the disorder. Familial Alzheimer's disease is a very rare autosomal dominant disease with early onset, caused by mutations in the amyloid precursor protein and presenilin genes, both linked to Abeta metabolism. By contrast with familial disease, sporadic Alzheimer's disease is very common with more than 15 million people affected worldwide. The cause of the sporadic form of the disease is unknown, probably because the disease is heterogeneous, caused by ageing in concert with a complex interaction of both genetic and environmental risk factors. This seminar reviews the key aspects of the disease, including epidemiology, genetics, pathogenesis, diagnosis, and treatment, as well as recent developments and controversies.

Individual risk of recurrent venous thromboembolism affects patient management and might differ between men and women. We did a meta-analysis to assess from available evidence whether men and women have the same risk of recurrent venous thromboembolism after stopping anticoagulant treatment.

Rotavirus is the most common cause of severe diarrhoea in children worldwide and diarrhoeal deaths in children in developing countries. Accelerated development and introduction of rotavirus vaccines into global immunisation programmes has been a high priority for many international agencies, including WHO and the Global Alliance for Vaccines and Immunizations. Vaccines have been developed that could prevent the enormous morbidity and mortality from rotavirus and their effect should be measurable within 2-3 years. Two live oral rotavirus vaccines have been licensed in many countries; one is derived from an attenuated human strain of rotavirus and the other combines five bovine-human reassortant strains. Each vaccine has proven highly effective in preventing severe rotavirus diarrhoea in children and safe from the possible complication of intussusception. In developed countries, these vaccines could substantially reduce the number and associated costs of child hospitalisations and clinical visits for acute diarrhoea. In developing countries, they could reduce deaths from diarrhoea and improve child survival through programmes for childhood immunisations and diarrhoeal disease control. Although many scientific, programmatic, and financial challenges face the global use of rotavirus vaccines, these vaccines-and new candidates in the pipeline-hold promise to make an immediate and measurable effect to improve child health and survival from this common burden affecting all children.

Bronchiolitis is a distressing, potentially life-threatening respiratory condition that affects young babies. Around 2-3% of all infants younger than 1 year are admitted to hospital with bronchiolitis, usually during the seasonal epidemic. The majority of these infants are infected with respiratory syncytial virus and all have an intense inflammatory response in their airways. Although most infants recover, they have an increased risk of recurrent wheezing. Although bronchiolitis is common, little is known about what causes infants to be susceptible. Diagnostic interventions have little effect on clinical outcome, and apart from supportive measures, there is no specific treatment. Bronchiolitis therefore presents an intriguing clinical conundrum and a major challenge to researchers. High quality clinical studies are needed to clarify assessment of disease severity and criteria for hospital admission, particularly the use of pulse oximetry and chest radiography. Careful mapping of the inflammatory pathways in the pathogenesis of bronchiolitis should lead to development of new therapies to alleviate symptoms.

Although the direct costs of the medical liability system account for a small fraction of total health spending, the system's indirect effects on cost and quality of care can be much more important. Here, we summarise findings of existing research on the effects of the medical liability systems of Australia, the UK, and the USA. We find systematic evidence of defensive medicine--medical practice based on fear of legal liability rather than on patients' best interests. We conclude with discussion of four avenues for reform of traditional tort compensation for medical injury and several suggestions for future research.

With a prevalence of 10-15% in adults in Europe and the USA, gallstones are the most common digestive disease needing admission to hospital in the West. The interplay between interprandial and postprandial physiological responses to endogenous and dietary lipids underscores the importance of coordinated hepatobiliary and gastrointestinal functions to prevent crystallisation and precipitation of excess biliary cholesterol. Indeed, identifying the metabolic and transcriptional pathways that drive the regulation of biliary lipid secretion has been a major achievement in the field. We highlight scientific advances in protein and gene regulation of cholesterol absorption, synthesis, and catabolism, and biliary lipid secretion with respect to the pathogenesis of cholesterol gallstone disease. We discuss the physical-chemical mechanisms of gallstone formation in bile and the active role of the gallbladder and the intestine. We also discuss gaps in our knowledge of the pathogenesis of gallstone formation and the potential for gene targeting in therapy.

Multiple organ failure is a major threat to the survival of patients with sepsis and systemic inflammation. In the UK and in the USA, mortality rates are currently comparable with and projected to exceed those from myocardial infarction. The immune system combats microbial infections but, in severe sepsis, its untoward activity seems to contribute to organ dysfunction. In this Review we propose that an inappropriate activation and positioning of neutrophils within the microvasculature contributes to the pathological manifestations of multiple organ failure. We further suggest that targeting neutrophils and their interactions with blood vessel walls could be a worthwhile therapeutic strategy for sepsis.

Noma is an opportunistic infection promoted by extreme poverty. It evolves rapidly from a gingival inflammation to grotesque orofacial gangrene. It occurs worldwide, but is most common in sub-Saharan Africa. The peak incidence of acute noma is at ages 1-4 years, coinciding with the period of linear growth retardation in deprived children. Noma is a scourge in communities with poor environmental sanitation. It results from complex interactions between malnutrition, infections, and compromised immunity. Diseases that commonly precede noma include measles, malaria, severe diarrhoea, and necrotising ulcerative gingivitis. The acute stage responds readily to antibiotic treatment. The sequelae after healing include variable functional and aesthetic impairments, which require reconstructive surgery. Noma can be prevented through promotion of national awareness of the disease, poverty reduction, improved nutrition, promotion of exclusive breastfeeding in the first 3-6 months of life, optimum prenatal care, and timely immunisations against the common childhood diseases.

There are many reasons why the dietary-heart-cholesterol hypothesis should be questioned, and why statins might be acting in some other way to reduce the risk of coronary heart disease. Here, I propose that rather than being cholesterol-lowering drugs per se, statins act as vitamin D analogues, and explain why. This proposition is based on published observations that the unexpected and unexplained clinical benefits produced by statins have also been shown to be properties of vitamin D. It seems likely that statins activate vitamin D receptors.

Defects of mitochondrial metabolism cause a wide range of human diseases that include examples from all medical subspecialties. This review updates the topic of mitochondrial diseases by reviewing the most important recent advances in this area. The factors influencing inheritance, maintenance and replication of mtDNA are reviewed and the genotype-phenotype of mtDNA disorders has been expanded, with new insights into epidemiology, pathogenesis and its role in ageing. Recently identified nuclear gene mutations of mitochondrial proteins include mutations of frataxin causing Friedreich's ataxia, PINK1, DJ1 causing Parkinson's disease and POLG causing infantile mtDNA depletion syndrome, ophthalmoplegia, parkinsonism, male subfertility and, in a transgenic mouse model, premature senescence. Mitochondrial defects in neurodegenerative diseases include Parkinson's, Alzheimer's and Huntington's disease. Improved understanding of mtDNA inheritance and mutation penetrance patterns, and novel techniques for mtDNA modification offer significant prospects for more accurate genetic counselling and effective future therapies.

During the past two decades, several advances have resulted in marked improvement in medium-term survival for infants and children undergoing heart transplantation. Unfortunately, progress has been less dramatic in the field of lung and heart-lung transplantation, where there is little evidence of improved outcomes. The procedures remain palliative and all transplant recipients are at risk for the adverse effects of non-specific immunosuppression, including infections, lymphoproliferative disorders, and non-lymphoid malignancies. In addition, current immunosuppressive agents have narrow therapeutic windows and exhibit a wide array of organ toxicities, posing special challenges for the young patient who must endure life-long immunosuppression. New immunosuppressive regimens have lowered the rates of acute rejection but appear to have had relatively little impact on the incidence of chronic rejection, the principal cause of late graft loss. The ultimate goal is to induce a state of donor-specific tolerance, wherein the recipient will accept the allograft indefinitely without the need for long-term immunosuppression. This quest is currently being realised in animal models of solid organ transplantation, and offers great hope for children undergoing heart and lung transplantation in the future.

Gastro-oesophageal reflux disease refers to reflux of gastric contents into the oesophagus leading to oesophagitis, reflux symptoms sufficient to impair quality of life, or long-term complications. Transient relaxation of the lower oesophageal sphincter is believed to be the primary mechanism of the disease although the underlying cause remains uncertain. Obesity and smoking are weakly associated with the disease and genetic factors might be important. A negative association with Helicobacter pylori exists, but eradication of H pylori does not seem to cause reflux disease. Diagnosis is imprecise as there is no gold standard. Reflux symptoms are helpful in diagnosis but they lack sensitivity. Ambulatory oesophageal pH monitoring also seems to be insensitive despite high specificity. Empirical acid suppression with a proton-pump inhibitor (PPI) has reasonable sensitivity but poor specificity. Some evidence suggests that once patients develop the disease, severity is determined early and patients seem to continue with that phenotype long term. Unfortunately, most patients do not respond to life-style advice and require further therapy. H2 receptor antagonists and PPIs are better than placebo in oesophagitis, with a number needed to treat of five and two, respectively. In non-erosive reflux disease, acid suppression is better than placebo but the response rate is lower. Most patients need long-term treatment because the disease usually relapses. The role of endoscopic therapy is uncertain. Anti-reflux surgery is probably as effective as PPI therapy although there is a low operative mortality and morbidity.

"What sets worlds in motion is the interplay of differences, their attractions and repulsions. Life is plurality, death is uniformity. By suppressing differences and peculiarities, by eliminating different civilisations and cultures, progress weakens life and favours death. The ideal of a single civilisation for everyone implicit in the cult of progress and technique, impoverishes and mutilates us. Every view of the world that becomes extinct, every culture that disappears, diminishes a possibility of life!"

Osteoporosis is a serious public health issue. The past 10 years have seen great advances in our understanding of its epidemiology, pathophysiology, and treatment, and further advances are rapidly being made. Clinical assessment will probably evolve from decisions mainly being made on the basis of bone densitometry, to use of algorithms of absolute fracture risk. Biochemical markers of bone turnover are also likely to become more widely used. Bisphosphonates will probably remain the mainstay of therapy, but improved understanding of the optimum amount of remodelling suppression and duration of therapy will be important. At the same time, other diagnostic and therapeutic approaches, including biological agents, are likely to become more widespread.

Our paper is part of a series focusing on Indigenous peoples' health in different world regions. Indigenous peoples worldwide are subject to marginalisation and discrimination, systematically experiencing poorer health than do majority groups. In Africa, poor health in the general population is widely recognised, but the consistently lower health position and social status of Indigenous peoples are rarely noted. Disputed conceptual understandings of indigeneity, a history of discriminatory colonial and post-colonial policies, and non-recognition of Indigenous groups by some governments complicate the situation. We discuss two case studies, of the central African Pygmy peoples and the San of southern Africa, to illustrate recurring issues in Indigenous health in the continent. We make recommendations for the recognition of Indigenous peoples in Africa and improvements needed in the collection of health data and the provision of services. Finally, we argue that wider changes are needed to address the social determinants of Indigenous peoples' health.