Governed by parasite and host factors and immunoinflammatory responses, the clinical spectrum of leishmaniasis encompasses subclinical (inapparent), localised (skin lesions), and disseminated infection (cutaneous, mucosal, or visceral). Symptomatic disease is subacute or chronic and diverse in presentation and outcome. Clinical characteristics vary further by endemic region. Despite T-cell-dependent immune responses, which produce asymptomatic and self-healing infection, or appropriate treatment, intracellular infection is probably life-long since targeted cells (tissue macrophages) allow residual parasites to persist. There is an epidemic of cutaneous leishmaniasis in Afghanistan and Pakistan and of visceral infection in India and Sudan. Diagnosis relies on visualising parasites in tissue or serology; culture and detection of parasite DNA are useful in the laboratory. Pentavalent antimony is the conventional treatment; however, resistance of visceral infection in India has spawned new treatment approaches--amphotericin B and its lipid formulations, injectable paromomycin, and oral miltefosine. Despite tangible advances in diagnosis, treatment, and basic scientific research, leishmaniasis is embedded in poverty and neglected. Current obstacles to realistic prevention and proper management include inadequate vector (sandfly) control, no vaccine, and insufficient access to or impetus for developing affordable new drugs.

The allele CHEK2*1100delC doubles the risk of breast cancer in unselected women, but could confer a greater risk in women with a family history of the disease, particularly of bilateral breast cancer. Our aim was to measure the risk of breast cancer in relatives of women with bilateral breast cancer who were carriers of this allele.

Beta blockers have been used widely in the treatment of hypertension and are recommended as first-line drugs in hypertension guidelines. However, a preliminary analysis has shown that atenolol is not very effective in hypertension. We aim to substantially enlarge the data on atenolol and analyse the effect of different beta blockers.

Genetic epidemiology is a rapidly expanding research field, but the implications of findings from such studies for individual or population health are unclear. The use of molecular genetic screening currently has some legitimacy in certain monogenic conditions, but no established value with respect to common complex diseases. Personalised medical care based on molecular genetic testing is also as yet undeveloped for common diseases. Genetic epidemiology can contribute to establishing the causal nature of environmentally modifiable risk factors, through the application of mendelian randomisation approaches and thus contribute to appropriate preventive strategies. Technological and other advances will allow the potential of genetic epidemiology to be revealed over the next few years, and the establishment of large population-based resources for such studies (biobanks) should contribute to this endeavour.

The term self-harm is commonly used to describe a wide range of behaviours and intentions including attempted hanging, impulsive self-poisoning, and superficial cutting in response to intolerable tension. As with suicide, rates of self-harm vary greatly between countries. 5-9% of adolescents in western countries report having self-harmed within the previous year. Risk factors include socioeconomic disadvantage, and psychiatric illness--particularly depression, substance abuse, and anxiety disorders. Cultural aspects of some societies may protect against suicide and self-harm and explain some of the international variation in rates of these events. Risk of repetition of self-harm and of later suicide is high. More than 5% of people who have been seen at a hospital after self-harm will have committed suicide within 9 years. Assessment after self-harm includes careful consideration of the patient's intent and beliefs about the lethality of the method used. Strong suicidal intent, high lethality, precautions against being discovered, and psychiatric illness are indicators of high suicide risk. Management after self-harm includes forming a trusting relationship with the patient, jointly identifying problems, ensuring support is available in a crisis, and treating psychiatric illness vigorously. Family and friends may also provide support. Large-scale studies of treatments for specific subgroups of people who self-harm might help to identify more effective treatments than are currently available. Although risk factors for self-harm are well established, aspects that protect people from engaging in self-harm need to be further explored.

Designs that involve families (the traditional strength of genetic epidemiology) and population-based sampling (the traditional strength of environmental epidemiology) allow investigation of both genes and environment, separately or together, and allow valid inference to the population. These case-control-family designs (including those involving twin pairs), can be regarded as retrospective cohort studies of relatives, and can be used for: determining familial risks and genetic models; estimating risk (penetrance) for measured genotypes; genetic association studies; stratifying risks by family history and known mutation status; and studying modifiers of risk in genetically susceptible individuals. Follow-up of families allows genetic and environmental risks to be studied prospectively. We discuss statistical methods, theoretical and practical strengths, limitations, and other issues. Given their versatility, population-based family studies could become a principal framework in epidemiology, and move genetics from its traditional focus on high-risk families to give it a wider clinical and population health relevance.

Small-cell lung carcinoma is an aggressive form of lung cancer that is strongly associated with cigarette smoking and has a tendency for early dissemination. Increasing evidence has implicated autocrine growth loops, proto-oncogenes, and tumour-suppressor genes in its development. At presentation, the vast majority of patients are symptomatic, and imaging typically reveals a hilar mass. Pathology, in most cases of samples obtained by bronchoscopic biopsy, should be undertaken by pathologists with pulmonary expertise, with the provision of additional tissue for immunohistochemical stains as needed. Staging should aim to identify any evidence of distant disease, by imaging of the chest, upper abdomen, head, and bones as appropriate. Limited-stage disease should be treated with etoposide and cisplatin and concurrent early chest irradiation. All patients who achieve complete remission should be considered for treatment with prophylactic cranial irradiation, owing to the high frequency of brain metastases in this disease. Extensive-stage disease should be managed by combination chemotherapy, with a regimen such as etoposide and cisplatin administered for four to six cycles. Thereafter, patients with progressive or recurrent disease should be treated with additional chemotherapy. For patients who survive long term, careful monitoring for development of a second primary tumour is necessary, with further investigation and treatment as appropriate.

Cholangiocarcinoma is a devastating malignancy that presents late, is notoriously difficult to diagnose, and is associated with a high mortality. The incidence of intrahepatic cholangiocarcinoma is increasing worldwide. The cause for this rise is unclear, although it could be related to an interplay between predisposing genetic factors and environmental triggers. MRI and CT with endoscopic ultrasound and PET provide useful diagnostic information in certain patients. Surgical resection is the only chance for cure, with results depending on careful technique and patient selection. Data suggest that liver transplantation could offer long-term survival in selected patients when combined with neoadjuvant chemoradiotherapy. Chemotherapy and radiotherapy have been ineffective for patients with inoperable tumours. For most of these patients biliary drainage is the mainstay of palliation. However, controversy exists over the type and positioning of biliary stents. Photodynamic treatment is a new palliative technique that might improve quality of life.

Results of previous randomised trials have shown that interventions that lower LDL cholesterol concentrations can significantly reduce the incidence of coronary heart disease (CHD) and other major vascular events in a wide range of individuals. But each separate trial has limited power to assess particular outcomes or particular categories of participant.

Physicians and other health-care professionals are rapidly adopting personal digital assistants (PDA). Palm pilots and other hand-held computers are also increasingly popular among medical students. PDAs can be used for medical student education and physician training, daily clinical practice, and research. PDAs and their increasing integration with information technology in hospitals could change the way health care is delivered in the future. But despite the increasing use of PDAs, evidence from well-designed research studies is still needed to show how much these devices can improve the quality of care, save patients' lives, and ultimately reduce health-care expenses. In this Review of PDA use in health care, the operating systems, basic functionality, security and safety, limitations, and future implications of PDAs are examined. A personal perspective and an introduction to medical PDA applications, software, guidelines, and programmes for health-care professionals is also provided.

Excess bodyweight is the sixth most important risk factor contributing to the overall burden of disease worldwide. 1.1 billion adults and 10% of children are now classified as overweight or obese. Average life expectancy is already diminished; the main adverse consequences are cardiovascular disease, type 2 diabetes, and several cancers. The complex pathological processes reflect environmental and genetic interactions, and individuals from disadvantaged communities seem to have greater risks than more affluent individuals partly because of fetal and postnatal imprinting. Obesity, with its array of comorbidities, necessitates careful clinical assessment to identify underlying factors and to allow coherent management. The epidemic reflects progressive secular and age-related decreases in physical activity, together with substantial dietary changes with passive over-consumption of energy despite the neurobiological processes controlling food intake. Effective long-term weight loss depends on permanent changes in dietary quality, energy intake, and activity. Neither the medical management nor the societal preventive challenges are currently being met.

Influenza vaccination of elderly individuals is recommended worldwide. Our aim was to review the evidence of efficacy and effectiveness of influenza vaccines in individuals aged 65 years or older.

The inevitable deterioration in hearing ability that occurs with age--presbycusis--is a multifactorial process that can vary in severity from mild to substantial. Left untreated, presbycusis of a moderate or greater degree affects communication and can contribute to isolation, depression, and, possibly, dementia. These psychological effects are largely reversible with rehabilitative treatment. Comprehensive rehabilitation is widely available but underused because, in part, of social attitudes that undervalue hearing, in addition to the cost and stigma of hearing aids. Remediation of presbycusis is an important contributor to quality of life in geriatric medicine and can include education about communication effectiveness, hearing aids, assistive listening devices, and cochlear implants for severe hearing loss. Primary care physicians should screen and refer their elderly patients for assessment and remediation. Where hearing aids no longer provide benefit, cochlear implantation is the treatment of choice with excellent results even in octogenarians.

Linkage analysis is used to map genetic loci by use of observations of related individuals. We provide an introduction to methods commonly used to map loci that predispose to disease. Linkage analysis methods can be applied to both major gene disorders (parametric linkage) and complex diseases (model-free or non-parametric linkage). Evidence for linkage is most commonly expressed as a logarithm of the odds score. We provide a framework for interpretation of these scores and discuss the role of simulation in assessment of statistical significance and estimation of power. Genetic and phenotypic heterogeneity can also affect the success of a study, and several methods exist to address such problems.

In low and middle income countries, health workers are essential for the delivery of health interventions. However, inadequate health-worker performance is a very widespread problem. We present an overview of issues and evidence about the determinants of performance and strategies for improving it. Health-worker practices are complex behaviours that have many potential influences. Reviews of intervention studies in low and middle income countries suggest that the simple dissemination of written guidelines is often ineffective, that supervision and audit with feedback is generally effective, and that multifaceted interventions might be more effective than single interventions. Few interventions have been evaluated with rigorous cost-effectiveness trials, and such studies are urgently needed to guide policy. We propose an international collaborative research agenda to generate knowledge about the true determinants of performance and about the effectiveness of strategies to improve performance. Furthermore, we recommend that ministries of health and international organisations should actively help translate research findings into action to improve health-worker performance, and thereby improve health.

Invasive mycoses pose a major diagnostic and therapeutic challenge. Advances in antifungal agents and diagnostic methods offer the potential for improved outcomes in patients with these infections, which are often lethal. Many fungal pathogens occur almost exclusively in opportunistic settings--in the immunocompromised host--and these infections are the focus of this review. Several areas of ongoing challenge remain, including the emergence of resistant organisms and the absence of reliable markers for early identification of patients at risk of developing invasive fungal disease. This Seminar reviews the changing epidemiology of invasive mycoses, new diagnostic methods, and recent therapeutic options and current management strategies for these opportunistic pathogens.

This article is the first in a series of seven that will provide an overview of central concepts and topical issues in modern genetic epidemiology. In this article, we provide an overall framework for investigating the role of familial factors, especially genetic determinants, in the causation of complex diseases such as diabetes. The discrete steps of the framework to be outlined integrate the biological science underlying modern genetics and the population science underpinning mainstream epidemiology. In keeping with the broad readership of The Lancet and the diverse background of today's genetic epidemiologists, we provide introductory sections to equip readers with basic concepts and vocabulary. We anticipate that, depending on their professional background and specialist knowledge, some readers will wish to skip some of this article.

Depressive disorders during youth occur frequently, are chronic and recurrent, and are associated with significant functional impairment, morbidity, and mortality. Two psychotherapeutic approaches-cognitive behavioural therapy and interpersonal therapy-are each better than wait-list or treatment-as-usual approaches. Several antidepressants have proven efficacious compared with placebo; however, more than half the studies comparing antidepressant treatment with placebo in children and adolescents with depression have not shown any benefit of the active compounds. Suicide rates are decreasing overall in adolescents, and there seems to be a correlation between the use of selective serotonin reuptake inhibitors (SSRIs) and a decrease in completed suicide. However, there was a signal for increase in suicide attempts and suicidal ideation in patients on acute antidepressant treatment when all antidepressants were assessed as a single group. Thus, there is substantial debate about the best approach to treat this serious disorder. Here, we discuss the treatment options for depression in children and adolescents.

Cluster headache is a stereotyped primary pain syndrome characterised by strictly unilateral severe pain, localised in or around the eye and accompanied by ipsilateral autonomic features. The syndrome is characterised by the circadian rhythmicity of the short-lived attacks, and the regular recurrence of headache bouts, which are interspersed by periods of complete remission in most individuals. Headaches often start about 1-2 h after falling asleep or in the early morning, and show seasonal variation, suggesting that the hypothalamus has a role in the illness. Consequently, the vascular theory has been superseded by recognition that neurovascular factors are more important. The increased familial risk suggests that cluster headache has a genetic component in some families. Neuroimaging has broadened our pathophysiological view and has led to successful treatment by deep brain stimulation of the hypothalamus. Although most patients can be treated effectively, some do not respond to therapy. Fortunately, time to diagnosis of cluster headache has improved. This is probably the result of a better understanding of the pathophysiology in combination with efficient treatment strategies, leading to a broader acceptance of the syndrome by doctors.

DDT (bis[4-chlorophenyl]-1,1,1-trichloroethane) is a persistent insecticide that was used worldwide from the mid 1940s until its ban in the USA and other countries in the 1970s. When a global ban on DDT was proposed in 2001, several countries in sub-Saharan Africa claimed that DDT was still needed as a cheap and effective means for vector control. Although DDT is generally not toxic to human beings and was banned mainly for ecological reasons, subsequent research has shown that exposure to DDT at amounts that would be needed in malaria control might cause preterm birth and early weaning, abrogating the benefit of reducing infant mortality from malaria. Historically, DDT has had mixed success in Africa; only the countries that are able to find and devote substantial resources towards malaria control have made major advances. DDT might be useful in controlling malaria, but the evidence of its adverse effects on human health needs appropriate research on whether it achieves a favourable balance of risk versus benefit.