Gambling disorders, including pathological gambling and problem gambling, have received increased attention from clinicians and researchers over the past three decades since gambling opportunities have expanded around the world. This Seminar reviews prevalence, causes and associated features, screening and diagnosis, and treatment approaches. Gambling disorders affect 0·2-5·3% of adults worldwide, although measurement and prevalence varies according to the screening instruments and methods used, and availability and accessibility of gambling opportunities. Several distinct treatment approaches have been favourably evaluated, such as cognitive behavioural and brief treatment models and pharmacological interventions. Although promising, family therapy and support from Gamblers Anonymous are less well empirically supported. Gambling disorders are highly comorbid with other mental health and substance use disorders, and a further understanding is needed of both the causes and treatment implications of this disorder.

Major depression is one of the leading causes of premature death and disability. Although available drugs are effective, they also have substantial limitations. Recent advances in our understanding of the fundamental links between chronobiology and major mood disorders, as well as the development of new drugs that target the circadian system, have led to a renewed focus on this area. In this review, we summarise the associations between disrupted chronobiology and major depression and outline new antidepressant treatment strategies that target the circadian system. In particular, we highlight agomelatine, a melatonin-receptor agonist and selective serotonergic receptor subtype (ie, 5-HT(2C)) antagonist that has chronobiotic, antidepressant, and anxiolytic effects. In the short-term, agomelatine has similar antidepressant efficacy to venlafaxine, fluoxetine, and sertraline and, in the longer term, fewer patients on agomelatine relapse (23·9%) than do those receiving placebo (50·0%). Patients with depression treated with agomelatine report improved sleep quality and reduced waking after sleep onset. As agomelatine does not raise serotonin levels, it has less potential for the common gastrointestinal, sexual, or metabolic side-effects that characterise many other antidepressant compounds.

Stroke is a common, serious, and disabling global health-care problem, and rehabilitation is a major part of patient care. There is evidence to support rehabilitation in well coordinated multidisciplinary stroke units or through provision of early supported provision of discharge teams. Potentially beneficial treatment options for motor recovery of the arm include constraint-induced movement therapy and robotics. Promising interventions that could be beneficial to improve aspects of gait include fitness training, high-intensity therapy, and repetitive-task training. Repetitive-task training might also improve transfer functions. Occupational therapy can improve activities of daily living; however, information about the clinical effect of various strategies of cognitive rehabilitation and strategies for aphasia and dysarthria is scarce. Several large trials of rehabilitation practice and of novel therapies (eg, stem-cell therapy, repetitive transcranial magnetic stimulation, virtual reality, robotic therapies, and drug augmentation) are underway to inform future practice.

Stroke is a major cause of death and disability worldwide. Without improvements in prevention, the burden will increase during the next 20 years because of the ageing population, especially in developing countries. Major advances have occurred in secondary prevention during the past three decades, which demonstrate the broader potential to prevent stroke. We review the main medical treatments that should be considered for most patients with transient ischaemic attack or ischaemic stroke in the acute phase and the long term, and draw attention to recent developments.

In the decade since the last Lancet Seminar on lung cancer there have been advances in many aspects of the classification, diagnosis, and treatment of non-small-cell lung cancer (NSCLC). An international panel of experts has been brought together to focus on changes in the epidemiology and pathological classification of NSCLC, the role of CT screening and other techniques that could allow earlier diagnosis and more effective treatment of the disease, and the recently introduced seventh edition of the TNM classification and its relation to other prognostic factors such as biological markers. We also describe advances in treatment that have seen the introduction of a new generation of chemotherapy agents, a proven advantage to adjuvant chemotherapy after complete resection for specific stage groups, new techniques for the planning and administration of radiotherapy, and new surgical approaches to assess and reduce the risks of surgical treatment.

The incidence and mortality of small-cell lung cancer worldwide make this disease a notable health-care issue. Diagnosis relies on histology, with the use of immunohistochemical studies to confirm difficult cases. Typical patients are men older than 70 years who are current or past heavy smokers and who have pulmonary and cardiovascular comorbidities. Patients often present with rapid-onset symptoms due to local intrathoracic tumour growth, extrapulmonary distant spread, paraneoplastic syndromes, or a combination of these features. Staging aims ultimately to define disease as metastatic or non-metastatic. Combination chemotherapy, generally platinum-based plus etoposide or irinotecan, is the mainstay first-line treatment for metastatic small-cell lung cancer. For non-metastatic disease, evidence supports early concurrent thoracic radiotherapy. Prophylactic cranial irradiation should be considered for patients with or without metastases whose disease does not progress after induction chemotherapy and radiotherapy. Despite high initial response rates, most patients eventually relapse. Except for topotecan, few treatment options then remain. Signalling pathways have been identified that might yield new drug targets.

Hepatitis delta virus (HDV) is a small, defective RNA virus that can infect only individuals who have hepatitis B virus (HBV); worldwide more than 15 million people are co-infected. There are eight reported genotypes of HDV with unexplained variations in their geographical distribution and pathogenicity. The hepatitis D virion is composed of a coat of HBV envelope proteins surrounding the nucleocapsid, which consists of a single-stranded, circular RNA genome complexed with delta antigen, the viral protein. HDV is clinically important because although it suppresses HBV replication, it causes severe liver disease with rapid progression to cirrhosis and hepatic decompensation. The range of clinical presentation is wide, varying from mild disease to fulminant liver failure. The prevalence of HDV is declining in some endemic areas but increasing in northern and central Europe because of immigration. Treatment of HDV is with pegylated interferon alfa; however, response rates are poor. Increased understanding of the molecular virology of HDV will identify novel therapeutic targets for this most severe form of chronic viral hepatitis.

Stillbirth rates in high-income countries have shown little or no improvement over the past two decades. Prevention strategies that target risk factors could be important in rate reduction. This systematic review and meta-analysis was done to identify priority areas for stillbirth prevention relevant to those countries.

In this first paper of The Lancet's Stillbirths Series we explore the present status of stillbirths in the world-from global health policy to a survey of community perceptions in 135 countries. Our findings highlight the need for a strong call for action. In times of global focus on motherhood, the mother's own aspiration of a liveborn baby is not recognised on the world's health agenda. Millions of deaths are not counted; stillbirths are not in the Global Burden of Disease, nor in disability-adjusted life-years lost, and they are not part of the UN Millennium Development Goals. The grief of mothers might be aggravated by social stigma, blame, and marginalisation in regions where most deaths occur. Most stillborn babies are disposed of without any recognition or ritual, such as naming, funeral rites, or the mother holding or dressing the baby. Beliefs in the mother's sins and evil spirits as causes of stillbirth are rife, and stillbirth is widely believed to be a natural selection of babies never meant to live. Stillbirth prevention is closely linked with prevention of maternal and neonatal deaths. Knowledge of causes and feasible solutions for prevention is key to health professionals' priorities, to which this Stillbirths Series paper aims to contribute.

Worldwide, 2·65 million (uncertainty range 2·08 million to 3·79 million) stillbirths occur yearly, of which 98% occur in countries of low and middle income. Despite the fact that more than 45% of the global burden of stillbirths occur intrapartum, the perception is that little is known about effective interventions, especially those that can be implemented in low-resource settings. We undertook a systematic review of randomised trials and observational studies of interventions which could reduce the burden of stillbirths, particularly in low-income and middle-income countries. We identified several interventions with sufficient evidence to recommend implementation in health systems, including periconceptional folic acid supplementation or fortification, prevention of malaria, and improved detection and management of syphilis during pregnancy in endemic areas. Basic and comprehensive emergency obstetric care were identified as key effective interventions to reduce intrapartum stillbirths. Broad-scale implementation of intervention packages across 68 countries listed as priorities in the Countdown to 2015 report could avert up to 45% of stillbirths according to a model generated from the Lives Saved Tool. The overall costs for these interventions are within the general estimates of cost-effective interventions for maternal care, especially in view of the effects on outcomes across maternal, fetal, and neonatal health.

Vaccination with heptavalent pneumococcal conjugate vaccine (PCV7) has significantly reduced the burden of pneumococcal disease and has had an important public health benefit. Because this vaccine targets only seven of the more than 92 pneumococcal serotypes, concerns have been raised that non-vaccine serotypes (NVTs) could increase in prevalence and reduce the benefits of vaccination. Indeed, among asymptomatic carriers, the prevalence of NVTs has increased substantially, and consequently, there has been little or no net change in the bacterial carriage prevalence. In many populations, pneumococcal disease caused by NVT has increased, but in most cases this increase has been less than the increase in NVT carriage. We review the evidence for serotype replacement in carriage and disease, and address the surveillance biases that might affect these findings. We then discuss possible reasons for the discrepancy between near-complete replacement in carriage and partial replacement for disease, including differences in invasiveness between vaccine serotypes. We contend that the magnitude of serotype replacement in disease can be attributed, in part, to a combination of lower invasiveness of the replacing serotypes, biases in the pre-vaccine carriage data (unmasking), and biases in the disease surveillance systems that could underestimate the true amount of replacement. We conclude by discussing the future potential for serotype replacement in disease and the need for continuing surveillance.

Modelling is valuable in the planning and evaluation of interventions, especially when a controlled trial is ethically or logistically impossible. Models are often used to calculate the expected course of events in the absence of more formal assessments. They are also used to derive estimates of rare or future events from recorded intermediate points. When developing models, decisions are needed about the appropriate level of complexity to be represented and about model structure and assumptions. The degree of rigor in model development and assessment can vary greatly, and there is a danger that existing beliefs inappropriately influence judgments about model assumptions and results.

The spleen is crucial in regulating immune homoeostasis through its ability to link innate and adaptive immunity and in protecting against infections. The impairment of splenic function is defined as hyposplenism, an acquired disorder caused by several haematological and immunological diseases. The term asplenia refers to the absence of the spleen, a condition that is rarely congenital and mostly post-surgical. Although hyposplenism and asplenia might predispose individuals to thromboembolic events, in this Review we focus on infectious complications, which are the most widely recognised consequences of these states. Because of the high mortality, the fulminant course, and the refractoriness to common treatment of overwhelming infections caused by encapsulated bacteria, prevention through vaccination and antibiotic prophylaxis is the basis of the management of patients who have had splenectomy or have hyposplenism. In this Review, we critically assess clinical and diagnostic aspects of splenic dysfunction and highlight new perspectives in the prevention of overwhelming post-splenectomy infections.

Introduction of effective combined antiretroviral therapy has made HIV infection a chronic illness. Substantial reductions in the number of AIDS-related deaths have been accompanied by an increase in liver-related morbidity and mortality due to co-infection with chronic hepatitis B and C viruses. Increases in non-alcoholic fatty liver disease and drug-induced hepatotoxicity, together with development of hepatocellular carcinoma, also potentiate the burden of liver disease in individuals with HIV infection. We provide an overview of the key causes, disease mechanisms of pathogenesis, and recommendations for treatment options including the evolving role of liver transplantation.

Most medical practitioners have regular contact with adults who have one of the two forms of glaucoma: open-angle glaucoma or angle-closure glaucoma. Data from population-based surveys indicate that one in 40 adults older than 40 years has glaucoma with loss of visual function, which equates to 60 million people worldwide being affected and 8·4 million being bilaterally blind. Even in developed countries, half of glaucoma cases are undiagnosed. Glaucoma is mostly asymptomatic until late in the disease when visual problems arise. Vision loss from glaucoma cannot be recovered, and improved case-detection methods for glaucoma are needed. Glaucoma is commonly treated with daily eye-drop drugs, but adherence to treatment is often unsatisfactory. As a usually asymptomatic and chronic disease, glaucoma has similar treatment challenges to chronic systemic diseases. Similarities to the pathogenesis of common CNS diseases mean that common neuroprotective strategies might exist. Successful gene therapy, which has been used for other eye diseases might be possible for the treatment of glaucoma in the future.

Osteoporosis is a common disease characterised by a systemic impairment of bone mass and microarchitecture that results in fragility fractures. With an ageing population, the medical and socioeconomic effect of osteoporosis, particularly postmenopausal osteoporosis, will increase further. A detailed knowledge of bone biology with molecular insights into the communication between bone-forming osteoblasts and bone-resorbing osteoclasts and the orchestrating signalling network has led to the identification of novel therapeutic targets. Novel treatment strategies have been developed that aim to inhibit excessive bone resorption and increase bone formation. The most promising novel treatments include: denosumab, a monoclonal antibody for receptor activator of NF-κB ligand, a key osteoclast cytokine; odanacatib, a specific inhibitor of the osteoclast protease cathepsin K; and antibodies against the proteins sclerostin and dickkopf-1, two endogenous inhibitors of bone formation. This overview discusses these novel therapies and explains their underlying physiology.

About 200 million cases of viral community-acquired pneumonia occur every year-100 million in children and 100 million in adults. Molecular diagnostic tests have greatly increased our understanding of the role of viruses in pneumonia, and findings indicate that the incidence of viral pneumonia has been underestimated. In children, respiratory syncytial virus, rhinovirus, human metapneumovirus, human bocavirus, and parainfluenza viruses are the agents identified most frequently in both developed and developing countries. Dual viral infections are common, and a third of children have evidence of viral-bacterial co-infection. In adults, viruses are the putative causative agents in a third of cases of community-acquired pneumonia, in particular influenza viruses, rhinoviruses, and coronaviruses. Bacteria continue to have a predominant role in adults with pneumonia. Presence of viral epidemics in the community, patient's age, speed of onset of illness, symptoms, biomarkers, radiographic changes, and response to treatment can help differentiate viral from bacterial pneumonia. However, no clinical algorithm exists that will distinguish clearly the cause of pneumonia. No clear consensus has been reached about whether patients with obvious viral community-acquired pneumonia need to be treated with antibiotics. Apart from neuraminidase inhibitors for pneumonia caused by influenza viruses, there is no clear role for use of specific antivirals to treat viral community-acquired pneumonia. Influenza vaccines are the only available specific preventive measures. Further studies are needed to better understand the cause and pathogenesis of community-acquired pneumonia. Furthermore, regional differences in cause of pneumonia should be investigated, in particular to obtain more data from developing countries.

Tuberculosis results in an estimated 1·7 million deaths each year and the worldwide number of new cases (more than 9 million) is higher than at any other time in history. 22 low-income and middle-income countries account for more than 80% of the active cases in the world. Due to the devastating effect of HIV on susceptibility to tuberculosis, sub-Saharan Africa has been disproportionately affected and accounts for four of every five cases of HIV-associated tuberculosis. In many regions highly endemic for tuberculosis, diagnosis continues to rely on century-old sputum microscopy; there is no vaccine with adequate effectiveness and tuberculosis treatment regimens are protracted and have a risk of toxic effects. Increasing rates of drug-resistant tuberculosis in eastern Europe, Asia, and sub-Saharan Africa now threaten to undermine the gains made by worldwide tuberculosis control programmes. Moreover, our fundamental understanding of the pathogenesis of this disease is inadequate. However, increased investment has allowed basic science and translational and applied research to produce new data, leading to promising progress in the development of improved tuberculosis diagnostics, biomarkers of disease activity, drugs, and vaccines. The growing scientific momentum must be accompanied by much greater investment and political commitment to meet this huge persisting challenge to public health. Our Seminar presents current perspectives on the scale of the epidemic, the pathogen and the host response, present and emerging methods for disease control (including diagnostics, drugs, biomarkers, and vaccines), and the ongoing challenge of tuberculosis control in adults in the 21st century.

Although heart rate and respiratory rate in children are measured routinely in acute settings, current reference ranges are not based on evidence. We aimed to derive new centile charts for these vital signs and to compare these centiles with existing international ranges.

Chronic pancreatitis is a progressive fibroinflammatory disease that exists in large-duct (often with intraductal calculi) or small-duct form. In many patients this disease results from a complex mix of environmental (eg, alcohol, cigarettes, and occupational chemicals) and genetic factors (eg, mutation in a trypsin-controlling gene or the cystic fibrosis transmembrane conductance regulator); a few patients have hereditary or autoimmune disease. Pain in the form of recurrent attacks of pancreatitis (representing paralysis of apical exocytosis in acinar cells) or constant and disabling pain is usually the main symptom. Management of the pain is mainly empirical, involving potent analgesics, duct drainage by endoscopic or surgical means, and partial or total pancreatectomy. However, steroids rapidly reduce symptoms in patients with autoimmune pancreatitis, and micronutrient therapy to correct electrophilic stress is emerging as a promising treatment in the other patients. Steatorrhoea, diabetes, local complications, and psychosocial issues associated with the disease are additional therapeutic challenges.