Although hypertension is the most prevalent treatable vascular risk factor, how it causes end-organ damage and vascular events is poorly understood. Yet, a widespread belief exists that underlying usual blood pressure can alone account for all blood-pressure-related risk of vascular events and for the benefits of antihypertensive drugs, and this notion has come to underpin all major clinical guidelines on diagnosis and treatment of hypertension. Other potentially informative measures, such as variability in clinic blood pressure or maximum blood pressure reached, have been neglected, and effects of antihypertensive drugs on such measures are largely unknown. Clinical guidelines recommend that episodic hypertension is not treated, and the potential risks of residual variability in blood pressure in treated hypertensive patients have been ignored. This Review discusses shortcomings of the usual blood-pressure hypothesis, provides background to accompanying reports on the importance of blood-pressure variability in prediction of risk of vascular events and in accounting for benefits of antihypertensive drugs, and draws attention to clinical implications and directions for future research.

Hereditary porphyrias are a group of eight metabolic disorders of the haem biosynthesis pathway that are characterised by acute neurovisceral symptoms, skin lesions, or both. Every porphyria is caused by abnormal function of a separate enzymatic step, resulting in a specific accumulation of haem precursors. Seven porphyrias are the result of a partial enzyme deficiency, and a gain of function mechanism has been characterised in a new porphyria. Acute porphyrias present with acute attacks, typically consisting of severe abdominal pain, nausea, constipation, confusion, and seizure, and can be life-threatening. Cutaneous porphyrias present with either acute painful photosensitivity or skin fragility and blisters. Rare recessive porphyrias usually manifest in early childhood with either severe cutaneous photosensitivity and chronic haemolysis or chronic neurological symptoms with or without photosensitivity. Porphyrias are still underdiagnosed, but when they are suspected, and dependent on clinical presentation, simple first-line tests can be used to establish the diagnosis in all symptomatic patients. Diagnosis is essential to enable specific treatments to be started as soon as possible. Screening of families to identify presymptomatic carriers is crucial to decrease risk of overt disease of acute porphyrias through counselling about avoidance of potential precipitants.

Unexplained differences between classes of antihypertensive drugs in their effectiveness in preventing stroke might be due to class effects on intraindividual variability in blood pressure. We did a systematic review to assess any such effects in randomised controlled trials.

Meticillin-resistant Staphylococcus aureus (MRSA) is endemic in hospitals worldwide, and causes substantial morbidity and mortality. Health-care-associated MRSA infections arise in individuals with predisposing risk factors, such as surgery or presence of an indwelling medical device. By contrast, many community-associated MRSA (CA-MRSA) infections arise in otherwise healthy individuals who do not have such risk factors. Additionally, CA-MRSA infections are epidemic in some countries. These features suggest that CA-MRSA strains are more virulent and transmissible than are traditional hospital-associated MRSA strains. The restricted treatment options for CA-MRSA infections compound the effect of enhanced virulence and transmission. Although progress has been made towards understanding emergence of CA-MRSA, virulence, and treatment of infections, our knowledge remains incomplete. Here we review the most up-to-date knowledge and provide a perspective for the future prophylaxis or new treatments for CA-MRSA infections.

Symptoms and signs of septic arthritis are an important medical emergency, with high morbidity and mortality. We review the changing epidemiology of septic arthritis of native joints in adults, encompassing the increasing frequency of the disorder and its evolving antibiotic resistance. We discuss various risk factors for development of septic arthritis and examine host factors (tumour necrosis factor alpha, interleukins 1 and 10) and bacterial proteins, toxins, and enzymes reported to be important determinants of pathogenesis in mouse models. Diagnosis of disease is largely clinical, guided by investigations and the opinion of skilled clinicians. We emphasise the need for timely medical and surgical intervention-most importantly, through diagnostic aspiration of relevant joints, choice of suitable antibiotic, and appropriate supportive measures. Management is growing in complexity with the advent of novel and antibiotic-resistant causative microorganisms and within the current climate of increased immunosuppression. Findings from animal models and patients are shedding light on disease pathogenesis and the possibility of novel adjunctive treatments, including systemic corticosteroids, cytokines and anticytokines, and bisphosphonates.

Previous reviews have examined the existence of HIV prevention, treatment, and care services for injecting drug users (IDUs) worldwide, but they did not quantify the scale of coverage. We undertook a systematic review to estimate national, regional, and global coverage of HIV services in IDUs.

Results of two randomised controlled trials for the management of mild-to-moderate chronic stable coronary artery disease (Clinical Outcomes Utilizing Revascularization and Aggressive drug Evaluation [COURAGE] and Bypass Angioplasty Revascularization Investigation type-2 Diabetes [BARI-2D]) have stimulated a vigorous debate about whether an initial strategy of revascularisation or a conservative approach with drugs is most effective. The conclusions of these two trials were clear: for some patients randomly assigned after angiography to revascularisation or pharmacological therapy, rates of death and myocardial infarction did not differ between the two strategies. What remains unresolved is how to generalise these data to patients without angiography, the role of stress testing, and the preferred approach to patients with relevant ischaemia on stress testing. This Review draws attention to the controversial issues in both management approaches, analyses the strengths and limitations of recent trials, and proposes a treatment algorithm that is applicable to daily clinical practice. Findings suggest that the severity of anginal symptoms and the extent of ischaemia in stress testing could help to identify patients who are at increased risk and who might benefit from an early invasive strategy. On the basis of the data and considerations presented, a strategy of initial optimum pharmacological therapy or direct invasive management can be tailored to an individual's circumstances and preferences.

For many years, placebos have been defined by their inert content and their use as controls in clinical trials and treatments in clinical practice. Recent research shows that placebo effects are genuine psychobiological events attributable to the overall therapeutic context, and that these effects can be robust in both laboratory and clinical settings. There is also evidence that placebo effects can exist in clinical practice, even if no placebo is given. Further promotion and integration of laboratory and clinical research will allow advances in the ethical use of placebo mechanisms that are inherent in routine clinical care, and encourage the use of treatments that stimulate placebo effects.

Severe liver disease in pregnancy is rare. Pregnancy-related liver disease is the most frequent cause of liver dysfunction in pregnancy and provides a real threat to fetal and maternal survival. A rapid diagnosis differentiating between liver disease related and unrelated to pregnancy is required in women who present with liver dysfunction during pregnancy. Research has improved our understanding of the pathogenesis of pregnancy-related liver disease, which has translated into improved maternal and fetal outcomes. Here, we provide an overview of liver diseases that occur in pregnancy, an update on the key mechanisms involved in their pathogenesis, and assessment of available treatment options.

Because of the increasing concerns about climate change and deadly heatwaves in the past, the health effects of hot weather are fast becoming a global public health challenge for the 21st century. Some cities across the world have introduced public health protection measures, with the timely provision of appropriate home-based prevention advice to the general public being the most crucial point of intervention. In this Review, we report current epidemiological and physiological evidence about the range of health effects associated with hot weather, and draw attention to the interplay between climate factors, human susceptibility, and adaptation measures that contribute to heat burdens. We focus on the evidence base for the most commonly provided heat-protection advice, and make recommendations about the optimum clinical and public health practice that are expected to reduce health problems associated with current and future hot weather.

Our aim was to identify which clinical features have value in confirming or excluding the possibility of serious infection in children presenting to ambulatory care settings in developed countries.

Snake bite is a common and frequently devastating environmental and occupational disease, especially in rural areas of tropical developing countries. Its public health importance has been largely ignored by medical science. Snake venoms are rich in protein and peptide toxins that have specificity for a wide range of tissue receptors, making them clinically challenging and scientifically fascinating, especially for drug design. Although the full burden of human suffering attributable to snake bite remains obscure, hundreds of thousands of people are known to be envenomed and tens of thousands are killed or maimed by snakes every year. Preventive efforts should be aimed towards education of affected communities to use proper footwear and to reduce the risk of contact with snakes to a minimum through understanding of snakes' behaviour. To treat envenoming, the production and clinical use of antivenom must be improved. Increased collaboration between clinicians, epidemiologists, and laboratory toxinologists should enhance the understanding and treatment of envenoming.

Neglected tropical diseases represent one of the most serious burdens to public health. Many can be treated cost-effectively, yet they have been largely ignored on the global health policy agenda until recently. In this first paper in the Series we review the fragmented structure of elimination and control programmes for these diseases, starting with the ambiguous definition of a neglected tropical disease. We describe selected international control initiatives and present their effect, governance arrangements, and financing mechanisms, including substantial drug-donation programmes. We also discuss efforts to exploit shared features of these diseases by integration of selected control activities within countries, thus creating economies of scope. Finally we address the challenges, resulting from the diversity of disease control approaches and governance structures-both nationally and internationally-and provide some suggestions for the way forward.

Directly observed therapy has been recommended to improve adherence for patients with HIV infection who are on highly active antiretroviral therapy, but the benefit and cost-effectiveness of this approach has not been established conclusively. We did a systematic review and meta-analysis of randomised trials of directly observed versus self-administered antiretroviral treatment.

Muscular dystrophies are individually rare genetic disorders that cause much chronic disability, affecting young children and adults. In the past 20 years, more than 30 genetic types of muscular dystrophy have been defined. During this time, precise diagnosis, genetic counselling, and medical management have improved. These advances in medical practice have occurred while definitive therapies based on an improved knowledge of disease pathogenesis are awaited. A wide range of therapeutic options have been tested in animal models, and some are being tested in clinical trials. Various therapeutic targets are being investigated, from personalised medicines targeting specific mutations and drugs targeting cellular pathways to gene-based and cell-based therapies.

This Series has examined the health implications of policies aimed at tackling climate change. Assessments of mitigation strategies in four domains-household energy, transport, food and agriculture, and electricity generation-suggest an important message: that actions to reduce greenhouse-gas emissions often, although not always, entail net benefits for health. In some cases, the potential benefits seem to be substantial. This evidence provides an additional and immediate rationale for reductions in greenhouse-gas emissions beyond that of climate change mitigation alone. Climate change is an increasing and evolving threat to the health of populations worldwide. At the same time, major public health burdens remain in many regions. Climate change therefore adds further urgency to the task of addressing international health priorities, such as the UN Millennium Development Goals. Recognition that mitigation strategies can have substantial benefits for both health and climate protection offers the possibility of policy choices that are potentially both more cost effective and socially attractive than are those that address these priorities independently.

This Seminar adds to the previous Lancet Seminar about eating disorders, published in 2003, with an emphasis on the biological contributions to illness onset and maintenance. The diagnostic criteria are in the process of review, and the probable four new categories are: anorexia nervosa, bulimia nervosa, binge eating disorder, and eating disorder not otherwise specified. These categories will also be broader than they were previously, which will affect the population prevalence; the present lifetime prevalence of all eating disorders is about 5%. Eating disorders can be associated with profound and protracted physical and psychosocial morbidity. The causal factors underpinning eating disorders have been clarified by understanding about the central control of appetite. Cultural, social, and interpersonal elements can trigger onset, and changes in neural networks can sustain the illness. Overall, apart from studies reporting pharmacological treatments for binge eating disorder, advances in treatment for adults have been scarce, other than interest in new forms of treatment delivery.

Mass gatherings of people challenge public health capacities at host locations and the visitors' places of origin. Hajj--the yearly pilgrimage by Muslims to Saudi Arabia--is one of the largest, most culturally and geographically diverse mass gatherings in the world. With the 2009 pandemic influenza A H1N1 and upcoming Hajj, the Saudi Arabian Ministry of Health (MoH) convened a preparedness consultation in June, 2009. Consultants from global public health agencies met in their official capacities with their Saudi Arabian counterparts. The MoH aimed to pool and share public health knowledge about mass gatherings, and review the country's preparedness plans, focusing on the prevention and control of pandemic influenza. This process resulted in several practical recommendations, many to be put into practice before the start of Hajj and the rest during Hajj. These preparedness plans should ensure the optimum provision of health services for pilgrims to Saudi Arabia, and minimum disease transmission on their return home. Review of the implementation of these recommendations and their effect will not only inform future mass gatherings in Saudi Arabia, but will also strengthen preparedness efforts in other settings.

When physicians are unwell, the performance of health-care systems can be suboptimum. Physician wellness might not only benefit the individual physician, it could also be vital to the delivery of high-quality health care. We review the work stresses faced by physicians, the barriers to attending to wellness, and the consequences of unwell physicians to the individual and to health-care systems. We show that health systems should routinely measure physician wellness, and discuss the challenges associated with implementation.

Biliary atresia is a rare disease of infancy, which has changed within 30 years from being fatal to being a disorder for which effective palliative surgery or curative liver transplantation, or both, are available. Good outcomes for infants depend on early referral and timely Kasai portoenterostomy, and thus a high index of suspicion is needed for investigation of infants with persistent jaundice. In centres with much experience of treating this disorder, up to 60% of children will achieve biliary drainage after Kasai portoenterostomy and will have serum bilirubin within the normal range within 6 months. 80% of children who attain satisfactory biliary drainage will reach adolescence with a good quality of life without undergoing liver transplantation. Although much is known about management of biliary atresia, many aspects are poorly understood, including its pathogenesis. Several hypotheses exist, implicating genetic predisposition and dysregulation of immunity, but the cause is probably multifactorial, with obliterative extrahepatic cholangiopathy as the common endpoint. Researchers are focused on identification of relevant genetic and immune factors and understanding serum and hepatic factors that drive liver fibrosis after Kasai portoenterostomy. These factors might become therapeutic targets to halt the inevitable development of cirrhosis and need for liver transplantation.