The common disease asthma is probably not a single disease, but rather a complex of multiple, separate syndromes that overlap. Although clinicians have recognised these different phenotypes for many years, they have remained poorly characterised, with little known about the underlying pathobiology contributing to them. Development of targeted therapies for asthma, and phenotype-specific clinical trials have raised interest in these phenotypes. Improved understanding of these phenotypes in complex diseases such as asthma will also improve our ability to link specific genotypes to their associated disease, which should help development of biomarkers. However, there is no standardised method to define asthma phenotypes. This Review analyses some of the methods that have been used to define asthma phenotypes and proposes an integrated method of classification to improve our understanding of these phenotypes.

Patients with mild persistent asthma rarely see their doctor with symptoms of the disease. Partly as a result of this situation, mild asthma is generally undertreated. Findings of several large randomised clinical trials have shown benefits for this population of regular treatment with low doses of inhaled corticosteroids. Additional drugs are rarely needed, and although leukotriene modifiers are effective, they are less so than inhaled corticosteroids. People with moderate persistent asthma are not well controlled on low doses of inhaled corticosteroids. A combination of this drug and long-acting inhaled beta2 agonists provides improved control compared with doubling of the maintenance dose of inhaled corticosteroids. The combination of budesonide and formoterol has been assessed as both maintenance and reliever treatment. This approach further reduces the risk for severe exacerbations. With these strategies, most individuals can achieve good control of their asthma. For patients who do not achieve asthma control despite taking drugs, measurement of the inflammatory response in the airway in induced sputum could provide further information to guide treatment.

There has been a recent increase in the prevalence of asthma worldwide; however, the 5-10% of patients with severe disease account for a substantial proportion of the health costs. Although most asthma cases can be satisfactorily managed with a combination of anti-inflammatory drugs and bronchodilators, patients who remain symptomatic despite maximum combination treatment represent a heterogeneous group consisting of those who are under-treated or non-adherent with their prescribed medication. After excluding under-treatment and poor compliance, corticosteroid refractory asthma can be identified as a subphenotype characterised by a heightened neutrophilic airway inflammatory response in the presence or absence of eosinophils, with evidence of increased tissue injury and remodelling. Although a wide range of environmental factors such as allergens, smoking, air pollution, infection, hormones, and specific drugs can contribute to this phenotype, other features associated with changes in the airway inflammatory response should be taken into account. Aberrant communication between an injured airway epithelium and underlying mesenchyme contributes to disease chronicity and refractoriness to corticosteroids. The importance of identifying underlying causative factors and the recent introduction of novel therapeutic approaches, including the targeting of immunoglobulin E and tumour necrosis factor alpha with biological agents, emphasise the need for careful phenotyping of patients with severe disease to target improved management of the individual patient's needs.

Millions of individuals with coronary artery or valvular heart disease have been given a new chance at life by heart surgery, but the potential for neurological injury is an Achilles heel. Technological advancements and innovations in surgical and anaesthetic technique have allowed us to offer surgical treatment to patients at the extremes of age and infirmity-the group at greatest risk for neurological injury. Neurocognitive dysfunction is a complication of cardiac surgery that can restrict the improved quality of life that patients usually experience after heart surgery. With a broader understanding of the frequency and effects of neurological injury from cardiac surgery and its implications for patients in both the short term and the long term, we should be able to give personalised treatments and thus preserve both their quantity and quality of life. We describe these issues and the controversies that merit continued investigation.

Peripartum cardiomyopathy (PPCM) is a disorder in which initial left ventricular systolic dysfunction and symptoms of heart failure occur between the late stages of pregnancy and the early postpartum period. It is common in some countries and rare in others. The causes and pathogenesis are poorly understood. Molecular markers of an inflammatory process are found in most patients. Clinical presentation includes usual signs and symptoms of heart failure, and unusual presentations relating to thromboembolism. Clinicians should consider PPCM in any peripartum patient with unexplained disease. Conventional heart failure treatment includes use of diuretics, beta blockers, and angiotensin-converting enzyme inhibitors. Effective treatment reduces mortality rates and increases the number of women who fully recover left ventricular systolic function. Outcomes for subsequent pregnancy after PPCM are better in women who have first fully recovered heart function. Areas for future research include immune system dysfunction, the role of viruses, non-conventional treatments such as immunosuppression, immunoadsorption, apheresis, antiviral treatment, suppression of proinflammatory cytokines, and strategies for control and prevention.

Cardiovascular disease is the leading cause of death, with 80% of cases occurring in developing countries. We therefore aimed to establish whether use of evidence-based multidrug regimens for patients at high risk for cardiovascular disease would be cost-effective in low-income and middle-income countries.

Studies of the association between obesity, and total mortality and cardiovascular events in patients with coronary artery disease (CAD) have shown contradictory results. We undertook a systematic review to determine the extent and nature of this association.

Many human conceptions are genetically abnormal and end in miscarriage, which is the commonest complication of pregnancy. Recurrent miscarriage, the loss of three or more consecutive pregnancies, affects 1% of couples trying to conceive. It is associated with psychological morbidity, and has often proven to be frustrating for both patient and clinician. A third of women attending specialist clinics are clinically depressed, and one in five have levels of anxiety that are similar to those in psychiatric outpatient populations. Many conventional beliefs about the cause and treatment of women with recurrent miscarriage have not withstood scrutiny, but progress has been made. Research has emphasised the importance of recurrent miscarriage in the range of reproductive failure linking subfertility and late pregnancy complications and has allowed us to reject practice based on anecdotal evidence in favour of evidence-based management.

Angiotensin-converting-enzyme (ACE) inhibitors reduce cardiovascular mortality and morbidity in patients with heart failure or left ventricular systolic dysfunction (LVSD). Three large trials have assessed the effect of ACE inhibitors in stable patients without these conditions but with atherosclerosis. We undertook a systematic review of the Heart Outcomes Prevention Evaluation (HOPE), the European trial on Reduction Of cardiac events with Perindopril among patients with stable coronary Artery disease (EUROPA), and the Prevention of Events with ACE inhibition (PEACE) studies to determine the consistency with which ACE inhibitors reduce total mortality and fatal and non-fatal cardiovascular events.

Mother-to-child transmission (MTCT) of HIV-1 is the major mode of paediatric infection. The rapidly increasing incidence of MTCT worldwide has resulted in an urgent need for preventive strategies. Antiretroviral regimens can prevent intrapartum HIV transmission; however, these regimens do not prevent HIV transmission through breastfeeding. Furthermore, children who escape MTCT are again at risk of infection when they become sexually active as adolescents. An infant vaccine regimen, begun at birth, would hence be a more attractive strategy and might also provide the basis for lifetime protection. Unique features of MTCT and paediatric HIV disease could be helpful in understanding correlates of immune protection and could facilitate rapid assessment of vaccine efficacy. Thus, there is compelling rationale to develop safe, effective HIV vaccines for use in infants and children. Here, we discuss the scientific and logistical challenges for the development of paediatric HIV vaccines; available vaccines and completed or planned paediatric vaccine trials are also discussed.

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.