There is conflicting evidence on the hypothesis that the risk of depression after stroke is influenced by the location of the brain lesion. We undertook a systematic review to examine the hypotheses that depression is more commonly associated with left-hemisphere strokes than with right-hemisphere strokes and with lesions of the left anterior brain than with other regions.

The essential trace mineral, selenium, is of fundamental importance to human health. As a constituent of selenoproteins, selenium has structural and enzymic roles, in the latter context being best-known as an antioxidant and catalyst for the production of active thyroid hormone. Selenium is needed for the proper functioning of the immune system, and appears to be a key nutrient in counteracting the development of virulence and inhibiting HIV progression to AIDS. It is required for sperm motility and may reduce the risk of miscarriage. Deficiency has been linked to adverse mood states. Findings have been equivocal in linking selenium to cardiovascular disease risk although other conditions involving oxidative stress and inflammation have shown benefits of a higher selenium status. An elevated selenium intake may be associated with reduced cancer risk. Large clinical trials are now planned to confirm or refute this hypothesis. In the context of these health effects, low or diminishing selenium status in some parts of the world, notably in some European countries, is giving cause for concern.

Inborn errors of metabolism commonly present around the time of birth. Although most affected babies are born healthy and subsequently deteriorate, some disorders may present at (or shortly after) birth and a few may be detected by antenatal ultrosonography. In many cases, it is important that the diagnosis is made quickly and a strategy to identify those at high risk is proposed. Treatment should not be delayed for a definitive diagnosis.

Serious complications after hysterectomy are estimated to occur in around six women per 10,000 hysterectomies in the USA. We did a systematic review of evidence that hysterectomy is associated with urinary incontinence.

* The high rate of proliferation required of the bone marrow renders it highly susceptible to the influence of external factors. * Anaemia is the most common haematological abnormality seen in systemic disorders. * In the anaemia of chronic disease, erythropoietin production is reduced and proliferation of erythroid progenitor cells is also impaired; this anaemia can generally be alleviated by correction of the underlying disease process. * The status of the endocrine system must always be considered in evaluation of a normocytic, normochromic anaemia. * Anaemia in infection can be due to host or parasite factors or to the treatment administered. * Anaemia due to malignant disease responds to erythropoietin therapy in many cases; failure to respond is a poor prognostic sign.

The first International Consultation on Incontinence was held under the auspices of WHO in 1998. The multidisciplinary consultation covered anatomy, physiology, pathology, and the investigation and management of incontinent individuals. Because incontinence is a prevalent global disease, the consultation was mindful of the need to make its recommendations applicable in all health-care systems. The management recommendations are presented as nine algorithms divided into basic management (five) and specialised management (four), for men, women, children, the frail elderly, and individuals with neurogenic incontinence separately. The basic algorithms are intended for all health-care professionals working with incontinent individuals and are applied worldwide. The specialised algorithms are presented on The Lancet website.

Randomised, controlled trial data show that combination antiretroviral therapy for HIV-1 infection benefits people with CD4-cell counts less than 350 cells/microL. Based on currently known risks and benefits, we believe that if CD4-cell counts and viral load are monitored carefully, and highly active antiretroviral therapy (HAART) is started commonly when the CD4-cell count drops below 350 cells/microL, then clinically relevant immune-system damage and progression to AIDS and death can be greatly delayed or prevented. This approach is dictated by three features of HIV-1 infection that are not typical of infectious diseases: no available regimen can eradicate HIV-1; all currently effective regimens may cause undesirable, sometimes life-threatening, toxic effects; and, unless regimens are strictly adhered to, multidrug resistance can develop, limiting future treatment options. If therapy is started too early, cumulative side-effects of the drugs used and the development of multidrug resistance may outweigh the net benefits of the lengthening of life. If therapy is started too late, increases in disease progression and mortality outweigh the risk of adverse events. A patients' activist (MH) and a clinician (CCJC) discuss data that justify this balanced approach and the feasibility of randomised controlled trials to provide clearer answers about when to start treatment.

An HIV-1 vaccine offers the best long-term hope to control the AIDS pandemic, especially in less-developed countries. To ensure its future availability we need to increase our research efforts today, including clinical trials. Although small-scale clinical trials of HIV-1 vaccines have been underway since 1987, the first phase III efficacy trials started only recently in the USA and Thailand. Initial results from these trials will be available within the next 2-3 years, and we must start planning now how vaccines should be used if found to be effective. In the meantime, the continuing promotion of the parallel development and assessment of other candidate vaccines is important. Financial mechanisms should also be developed as an incentive to industry and to ensure equitable distribution of future vaccines in less-developed countries. Moreover, a concerted effort is needed to ensure the development and future availability of appropriate vaccines for Africa.

Although substantial progress has been made in preventing mother-to-child HIV-1 transmission in the past decade, critical research questions remain. Two perinatal epidemics now exist. In more-developed countries, integration of prenatal HIV-1 counselling and testing programmes into an existing antenatal infrastructure, availability of effective antiretroviral prophylaxis, and access to infant formula have resulted in new perinatal infections becoming rare. However, identification of missed prevention opportunities, the causes of prophylaxis failure, and the potential effects of in-utero antiretroviral exposure have become a priority. In less-developed countries, antenatal care is limited, testing programmes are almost non-existent, effective interventions remain unimplemented, and prevention of postnatal transmission through breastmilk while maintaining adequate infant nutrition is a major dilemma. The challenge for the next decade is to simultaneously address questions relevant to both epidemics while bridging the gap in prevention of perinatal transmission between more-developed and less-developed countries.

AIDS has Invigorated and distorted the study of sexual behaviour. Because that study began so recently, there remain many unanswered questions about why we have sex at all, why we do sex one way rather than another, or even how we define sex. Yet in every instance in which well-designed and adequately resourced behavioural Interventions have been Implemented, these have netted success in the form of falling HIV incidences or prevalences. But, despite these successes, such interventions remain patchy and poorly supported. Perhaps humankind's traditional aversion for the public discussion of sexual matters underlies this reticence. Or maybe a new era of "creeping absolutism"--in which biomedical advances are given premature credit for what they can achieve in HIV control--has arrived.

The prognosis of breast cancer in very young women is generally considered to be unfavourable. Therefore, the outcome of adjuvant therapy was analysed in a population of young (<35 years) premenopausal patients treated in four randomised controlled trials.

Two randomised controlled trials of sexually transmitted disease (STD) treatment for the prevention of HIV-1 Infection, in Mwanza, Tanzania, and Rakai, Uganda, unexpectedly produced contrasting results. A decrease in population HIV-1 incidence was associated with improved STD case management in Mwanza, but was not associated with STD mass treatment in Rakai. Some reductions in curable STDs were seen in both studies. These trials tested different interventions in different HIV-1 epidemic settings and used different evaluation methods; the divergent results may be complementary rather than contradictory. Possible explanations include: differences in stage of the HIV-1 epidemic, which can influence exposure to HIV-1 and the distribution of viral load in the infected population; potential differences in the prevalence of Incurable STDs (such as genital herpes); perhaps greater Importance of symptomatic than symptomless STDs for HIV-1 transmission; and possibly greater effectiveness of continuously available services than of intermittent mass treatment to control rapid STD reinfection. Implications of the trials for policy and future research agenda are discussed.

In acute coronary syndrome without ST elevation, the role of unfractionated and low-molecular-weight heparin in aspirin-treated patients remains unclear, and there is conflicting evidence regarding the efficacy and safety of low-molecular-weight heparin (LMWH) relative to unfractionated heparin. We did a systematic overview of the randomised trials to assess the effect of unfractionated heparin and LMWH on death, myocardial infarction, and major bleeding.

Lung cancer remains a major worldwide health problem, accounting for more than a sixth of cancer deaths. The proportion of cancers that are adenocarcinomas is increasing in North America and to some degree in Europe, leading to a changing clinical picture characterised by early development of metastases. Newer diagnostic techniques have allowed for more accurate tumour staging and treatment planning. In patients with non-small-cell cancer, surgical resection offers substantial cure rates in early-stage cases. Combined chemotherapy plus radiation therapy has clearly improved the treatment results for patients with locally advanced cancers, and patients with metastatic disease are now candidates for newer chemotherapy regimens with more favourable results than in the past. Small-cell lung cancer is highly responsive to chemotherapy, and recent advances in radiation therapy have improved the prospects for long survival. New techniques for screening, and innovative approaches to both local and systemic treatment offer hope for substantial progress against this disease in the near future.

The original report of a possible association between myocardial infarction and the insertion/deletion (I/D) polymorphism of the gene for the angiotensin-1-converting enzyme (ACE) indicated a risk ratio for myocardial infarction with the DD genotype of 1.34 (95% CI 1.05-1.70), and the association was claimed to be particularly strong in a retrospectively defined low-risk subgroup (3.2 [95% CI 1.7-5.9). Subsequent investigations reached varying conclusions, but all were small, and much larger studies were needed.

The Working Party was instituted to investigate the rationale of prophylactic and therapeutic antibiotic use in penetrating craniocerebral injuries (PCCI), and to make recommendations for current practice. A systematic review of papers on civilian and military PCCI over the past 25 and 50 years, respectively, was done via electronic databases and secondary sources, and data were evaluated. Guidelines on the removal of indriven bone or metal fragments only if further neural damage can be avoided were supported. However, no publications were identified where the data on infection or its treatment and prevention were complete or satisfactorily derived, and no controlled trials have been published. All studies were retrospective or anecdotal. Working Party recommendations are based on the data available and the professional experience and knowledge of the members. Broad-spectrum antibiotic prophylaxis is recommended for both military and civilian PCCI, Including those due to sports or recreational injuries.

The long-term effects of radiotherapy on mortality from breast cancer and other causes remain uncertain.

Under normal circumstances, the coagulation system is balanced in favour of anticoagulation. Thrombin is the key effector enzyme of the clotting cascade. Antagonists of vitamin K inhibit a vitamin-K-dependent post-translational modification of several coagulation proteins, which is required for these proteins to attain a phospholipid-binding conformation. Heparin stimulates the activity of antithrombin, a serine-protease inhibitor. Analysis of knock-out mice has shown the relative importance of the coagulation factors in vivo. Gene therapy may soon be a therapeutic option for inherited deficiencies of factors VIII and IX.

We undertook a prospective systematic overview based on data from individual patients from five long-term randomised trials that assessed inhibitors of angiotensin-converting enzyme (ACE) in patients with left-ventricular dysfunction or heart failure.