The magnitude of the clinical benefits produced by inhibitors of the renin-angiotensin system in heart failure has been modest, possibly because of the ability of renin-angiotensin activity to escape from suppression during long-term treatment. Efforts to intensify pharmacological blockade by use of dual inhibitors that interfere with the renin-angiotensin system at multiple sites have not yielded consistent incremental clinical benefits, but have been associated with serious adverse reactions. By contrast, potentiation of endogenous compensatory vasoactive peptides can act to enhance the survival effects of inhibitors of the renin-angiotensin system, as evidenced by trials that have compared angiotensin-converting enzyme inhibitors with drugs that inhibit both the renin-angiotensin system and neprilysin. Several endogenous vasoactive peptides act as adaptive mechanisms, and their augmentation could help to broaden the benefits of renin-angiotensin system inhibitors for patients with heart failure.

This paper reviews the evidence for the effectiveness and cost-effectiveness of policies to reduce alcohol-related harm. Policies focus on price, marketing, availability, information and education, the drinking environment, drink-driving, and brief interventions and treatment. Although there is variability in research design and measured outcomes, evidence supports the effectiveness and cost-effectiveness of policies that address affordability and marketing. An adequate reduction in temporal availability, particularly late night on-sale availability, is effective and cost-effective. Individually-directed interventions delivered to at-risk drinkers and enforced legislative measures are also effective. Providing information and education increases awareness, but is not sufficient to produce long-lasting changes in behaviour. At best, interventions enacted in and around the drinking environment lead to small reductions in acute alcohol-related harm. Overall, there is a rich evidence base to support the decisions of policy makers in implementing the most effective and cost-effective policies to reduce alcohol-related harm.

The Rohingya people of Myanmar (known as Burma before 1989) were stripped of citizenship in 1982, because they could not meet the requirement of proving their forefathers settled in Burma before 1823, and now account for one in seven of the global population of stateless people. Of the total 1·5 million Rohingya people living in Myanmar and across southeast Asia, only 82 000 have any legal protection obtained through UN-designated refugee status. Since 2012, more than 159 000 people, most of whom are Rohingya, have fled Myanmar in poorly constructed boats for journeys lasting several weeks to neighbouring nations, causing hundreds of deaths. We outline historical events preceding this complex emergency in health and human rights. The Rohingya people face a cycle of poor infant and child health, malnutrition, waterborne illness, and lack of obstetric care. In December, 2014, a UN resolution called for an end to the crisis. We discuss the Myanmar Government's ongoing treatment of Rohingya through the lens of international law, and the steps that the newly elected parliament must pursue for a durable solution.

Phantom limb pain is a debilitating condition for which no effective treatment has been found. We hypothesised that re-engagement of central and peripheral circuitry involved in motor execution could reduce phantom limb pain via competitive plasticity and reversal of cortical reorganisation.

Ulcerative colitis is a chronic inflammatory disease affecting the colon, and its incidence is rising worldwide. The pathogenesis is multifactorial, involving genetic predisposition, epithelial barrier defects, dysregulated immune responses, and environmental factors. Patients with ulcerative colitis have mucosal inflammation starting in the rectum that can extend continuously to proximal segments of the colon. Ulcerative colitis usually presents with bloody diarrhoea and is diagnosed by colonoscopy and histological findings. The aim of management is to induce and then maintain remission, defined as resolution of symptoms and endoscopic healing. Treatments for ulcerative colitis include 5-aminosalicylic acid drugs, steroids, and immunosuppressants. Some patients can require colectomy for medically refractory disease or to treat colonic neoplasia. The therapeutic armamentarium for ulcerative colitis is expanding, and the number of drugs with new targets will rapidly increase in coming years.

Impaired contractility is a feature of heart failure with reduced ejection fraction. We assessed the pharmacokinetics and effects on cardiac function and structure of the cardiac myosin activator, omecamtiv mecarbil.

Crohn's disease is a chronic inflammatory disease of the gastrointestinal tract, with increasing incidence worldwide. Crohn's disease might result from a complex interplay between genetic susceptibility, environmental factors, and altered gut microbiota, leading to dysregulated innate and adaptive immune responses. The typical clinical scenario is a young patient presenting with abdominal pain, chronic diarrhoea, weight loss, and fatigue. Assessment of disease extent and of prognostic factors for complications is paramount to guide therapeutic decisions. Current strategies aim for deep and long-lasting remission, with the goal of preventing complications, such as surgery, and blocking disease progression. Central to these strategies is the introduction of early immunosuppression or combination therapy with biologicals in high-risk patients, combined with a tight and frequent control of inflammation, and adjustment of therapy on the basis of that assessment (treat to target strategy). The therapeutic armamentarium for Crohn's disease is expanding, and therefore the need to develop biomarkers that can predict response to therapies will become increasingly important for personalised medicine decisions in the near future. In this Seminar, we provide a physician-oriented overview of Crohn's disease in adults, ranging from epidemiology and cause to clinical diagnosis, natural history, patient stratification and clinical management, and ending with an overview of emerging therapies and future directions for research.

Hypertrophic obstructive cardiomyopathy is an inherited myocardial disease defined by cardiac hypertrophy (wall thickness ≥15 mm) that is not explained by abnormal loading conditions, and left ventricular obstruction greater than or equal to 30 mm Hg. Typical symptoms include dyspnoea, chest pain, palpitations, and syncope. The diagnosis is usually suspected on clinical examination and confirmed by imaging. Some patients are at increased risk of sudden cardiac death, heart failure, and atrial fibrillation. Patients with an increased risk of sudden cardiac death undergo cardioverter-defibrillator implantation; in patients with severe symptoms related to ventricular obstruction, septal reduction therapy (myectomy or alcohol septal ablation) is recommended. Life-long anticoagulation is indicated after the first episode of atrial fibrillation.

Low-dose inhaled corticosteroids (ICS) are highly effective for reducing asthma exacerbations and mortality. Conventionally, ICS treatment is recommended for patients with symptoms on more than 2 days per week, but this criterion has scant evidence. We aimed to assess the validity of the previous symptom-based cutoff for starting ICS by establishing whether there was a differential response to budesonide versus placebo for severe asthma exacerbations, lung function, and asthma symptom control across subgroups identified by baseline asthma symptom frequency.