An increasing amount of research is beginning to offer a global overview of the extent of violence against women. In this paper we discuss the magnitude of some of the most common and most severe forms of violence against women: intimate partner violence; sexual abuse by non-intimate partners; trafficking, forced prostitution, exploitation of labour, and debt bondage of women and girls; physical and sexual violence against prostitutes; sex selective abortion, female infanticide, and the deliberate neglect of girls; and rape in war. There are many potential perpetrators, including spouses and partners, parents, other family members, neighbours, and men in positions of power or influence. Most forms of violence are not unique incidents but are ongoing, and can even continue for decades. Because of the sensitivity of the subject, violence is almost universally under-reported. Nevertheless, the prevalence of such violence suggests that globally, millions of women are experiencing violence or living with its consequences.

Multiple sclerosis is the prototype inflammatory autoimmune disorder of the central nervous system and, with a lifetime risk of one in 400, potentially the most common cause of neurological disability in young adults. As with all complex traits, the disorder results from an interplay between as yet unidentified environmental factors and susceptibility genes. Together, these factors trigger a cascade of events, involving engagement of the immune system, acute inflammatory injury of axons and glia, recovery of function and structural repair, post-inflammatory gliosis, and neurodegeneration. The sequential involvement of these processes underlies the clinical course characterised by episodes with recovery, episodes leaving persistent deficits, and secondary progression. The aim of treatment is to reduce the frequency, and limit the lasting effects, of relapses, relieve symptoms, prevent disability arising from disease progression, and promote tissue repair. Despite limited success in each of these categories, everyone touched by multiple sclerosis looks for a better dividend from applying an improved understanding of the pathogenesis to clinical management.

Pathogenic fungi have many complex mechanisms of resistance to antifungal drugs. Information about the clinical, cellular, and molecular factors contributing to antifungal-drug resistance continues to accumulate. We critically review the diagnosis, epidemiology, and mechanisms of antifungal drug resistance of pathogenic fungi. Better understanding of this resistance should assist in developing better detection strategies for preventing and treating refractory mycoses in the future.

Stem cells in adult tissues have attracted a great deal of interest. These cells are self-renewing and can give rise to diverse progeny. An extraordinary finding was the presence of stem cells in the mature human brain. This tissue was previously believed incapable of generating new neurons, but neuropoiesis is now an established phenomenon in the adult brains of mammals, including human beings. This persistent neurogenesis has potential therapeutic applications for various neurological disorders as a source for tissue engraftment and as self-repair by a person's own indigenous population of pluripotent cells or biogenic by-products of their proliferation and differentiation.

Trials on the effect of systemic chemotherapy on survival and recurrence in adults with high-grade glioma have had inconclusive results. We undertook a systematic review and meta-analysis to assess the effects of such treatment on survival and recurrence.

Solid-organ transplant recipients are at increased risk of various infectious diseases, some of which are vaccine preventable mmunisations are among the most efficient interventions available. Solid-organ tranplant recipients would greatly benefit from effective immunisations, provided the recommendations are based on a careful risk-benefit analysis in which the effectiveness of the vaccine is weighed against possible adverse reactions, including graft rejection. In this review, we summarise the data from studies on relevant immunisations in solid-organ transplant recipients. The major issues are the immunogenicity and safety of immunisations, the factors associated with poor immune response, and recommendations for immunisation schemes.

There has been much debate about the value of screening mammography. Here we update the overview of the Swedish randomised controlled trials on mammography screening up to and including 1996. The Kopparberg part of the Two-County trial was not available for the overview, but the continuation of the Malmö trial (MMST II) has been added. The article also contains basic data from the trials that have not been presented before. Methods The trials (n=247010, invited group 129750, control group 117260) have been followed up by record linkage to the Swedish Cancer and Cause of Death Registers. The relative risks (RR) for breast cancer death and mortality were calculated for the invited and the control groups. The trial-specific as well as the age-specific effects were analysed. RRs were calculated by the density method, with total person-time experience of the cohort by time interval of follow-up as a basis for estimating mortality rates. We calculated weighted RRs and 95% CI with the Mantel-Haenszel procedure.

Screening tests are ubiquitous in contemporary practice, yet the principles of screening are widely misunderstood. Screening is the testing of apparently well people to find those at increased risk of having a disease or disorder. Although an earlier diagnosis generally has intuitive appeal, earlier might not always be better, or worth the cost. Four terms describe the validity of a screening test: sensitivity, specificity, and predictive value of positive and negative results. For tests with continuous variables--eg, blood glucose--sensitivity and specificity are inversely related; where the cutoff for abnormal is placed should indicate the clinical effect of wrong results. The prevalence of disease in a population affects screening test performance: in low-prevalence settings, even very good tests have poor predictive value positives. Hence, knowledge of the approximate prevalence of disease is a prerequisite to interpreting screening test results. Tests are often done in sequence, as is true for syphilis and HIV-1 infection. Lead-time and length biases distort the apparent value of screening programmes; randomised controlled trials are the only way to avoid these biases. Screening can improve health; strong indirect evidence links cervical cytology programmes to declines in cervical cancer mortality. However, inappropriate application or interpretation of screening tests can rob people of their perceived health, initiate harmful diagnostic testing, and squander health-care resources.

Arteriovenous malformations of the brain are congenital vascular lesions that affect 0.01-0.50% of the population, and are generally present in patients aged 20-40 years. The usual clinical presentations are haemorrhage, seizures, progressive neurological deficit, or headache. Results of natural history studies have shown a yearly haemorrhage rate of 1-4%. Frequency of rebleeding has increased over the years, and several factors that increase risk of haemorrhage have been identified. Although substantial, the morbidity associated with haemorrhages could be less than previously thought. Over the past decade, great advances have been made in application of endovascular embolisation techniques, stereotactic radiosurgery, and microsurgery, allowing effective multidisciplinary treatment of arteriovenous malformations, including those previously deemed to be untreatable. Increasing attention has been paid to management of flow-related aneurysms associated with these malformations. Finally, many reports of recurrent arteriovenous malformations have coincided with new theories regarding the embryogenesis of these disorders and laboratory work suggesting their proliferative potential.

The muscular dystrophies are inherited myogenic disorders characterised by progressive muscle wasting and weakness of variable distribution and severity. They can be subdivided into several groups, including congenital forms, in accordance with the distribution of predominant muscle weakness: Duchenne and Becker; Emery-Dreifuss; distal; facioscapulohumeral; oculopharyngeal; and limb-girdle which is the most heterogeneous group. In several dystrophies the heart can be seriously affected, sometimes in the absence of clinically significant weakness. The genes and their protein products that cause most of these disorders have now been identified. This information is essential to establish an accurate diagnosis and for reliable genetic counselling and prenatal diagnosis. There is, as yet, no way of greatly affecting the long-term course of any of these diseases. However, advances in gene manipulation and stem-cell therapy suggest cautious optimism for finding an effective treatment in the not-too-distant future.

Proper randomisation rests on adequate allocation concealment. An allocation concealment process keeps clinicians and participants unaware of upcoming assignments. Without it, even properly developed random allocation sequences can be subverted. Within this concealment process, the crucial unbiased nature of randomised controlled trials collides with their most vexing implementation problems. Proper allocation concealment frequently frustrates clinical inclinations, which annoys those who do the trials. Randomised controlled trials are anathema to clinicians. Many involved with trials will be tempted to decipher assignments, which subverts randomisation. For some implementing a trial, deciphering the allocation scheme might frequently become too great an intellectual challenge to resist. Whether their motives indicate innocent or pernicious intents, such tampering undermines the validity of a trial. Indeed, inadequate allocation concealment leads to exaggerated estimates of treatment effect, on average, but with scope for bias in either direction. Trial investigators will be crafty in any potential efforts to decipher the allocation sequence, so trial designers must be just as clever in their design efforts to prevent deciphering. Investigators must effectively immunise trials against selection and confounding biases with proper allocation concealment. Furthermore, investigators should report baseline comparisons on important prognostic variables. Hypothesis tests of baseline characteristics, however, are superfluous and could be harmful if they lead investigators to suppress reporting any baseline imbalances.

The clinical boundaries of transplantation have been set in an era of simple cold storage. Research in organ preservation has led to the development of flush solutions that buffer the harsh molecular conditions which develop during ischaemia, and provide stored organs that are fit to sustain life after transplantation. Although simple and efficient, this method might be reaching its limit with respect to the duration, preservation, and the quality of organs that can be preserved. In addition, flush preservation does not allow for adequate viability assessment. There is good evidence that preservation times will be extended by the provision of continuous cellular substrate. Stimulation of in-vivo conditions by ex-vivo perfusion could also mean that marginal organs will be salvaged for transplantation. Perfusion will also allow for assessing the viability of organs before transplantation in a continuous fashion. The cumulative effect of these benefits would include expansion of the donor pool, less risk of primary non-function, and extension of the safe preservation period. Use of non-heart-beating donors, international organ sharing, and precise calculation of the risk of primary organ failure could become standard.

Atrial fibrillation is the commonest clinical arrhythmia, is increasing in incidence and prevalence, and is associated with substantial morbidity and mortality. The arrhythmia may be paroxysmal (self-limiting), persistent (amenable to cardioversion), or permanent. Especially in its paroxysmal form, atrial fibrillation may be initiated by rapidly firing foci, generally located in the proximal pulmonary veins. Sustained atrial fibrillation is maintained by an atrial tissue substrate capable of accommodating many meandering wavelets. With continuing arrhythmia, the electrophysiological properties of the atria change and further facilitate continuing fibrillation. Treatment is aimed at prevention of thromboembolic complications, restoration and maintenance of sinus rhythm, and control of ventricular rate during atrial fibrillation. With greater understanding of the arrhythmia mechanisms, it is becoming possible to offer targeted curative treatments to more and more patients.

About 9 million people are imprisoned worldwide, but the number with serious mental disorders (psychosis, major depression, and antisocial personality disorder) is unknown. We did a systematic review of surveys on such disorders in general prison populations in western countries.

The randomised controlled trial sets the gold standard of clinical research. However, randomisation persists as perhaps the least-understood aspect of a trial. Moreover, anything short of proper randomisation courts selection and confounding biases. Researchers should spurn all systematic, non-random methods of allocation. Trial participants should be assigned to comparison groups based on a random process. Simple (unrestricted) randomisation, analogous to repeated fair coin-tossing, is the most basic of sequence generation approaches. Furthermore, no other approach, irrespective of its complexity and sophistication, surpasses simple randomisation for prevention of bias. Investigators should, therefore, use this method more often than they do, and readers should expect and accept disparities in group sizes. Several other complicated restricted randomisation procedures limit the likelihood of undesirable sample size imbalances in the intervention groups. The most frequently used restricted sequence generation procedure is blocked randomisation. If this method is used, investigators should randomly vary the block sizes and use larger block sizes, particularly in an unblinded trial. Other restricted procedures, such as urn randomisation, combine beneficial attributes of simple and restricted randomisation by preserving most of the unpredictability while achieving some balance. The effectiveness of stratified randomisation depends on use of a restricted randomisation approach to balance the allocation sequences for each stratum. Generation of a proper randomisation sequence takes little time and effort but affords big rewards in scientific accuracy and credibility. Investigators should devote appropriate resources to the generation of properly randomised trials and reporting their methods clearly.

Significant advances have been made in our understanding of the natural history and pathogenesis of viral encephalitides. The development of PCR has greatly increased our ability to diagnose viral infections of the central nervous system, particularly for herpes and enteroviral infections. Advancing knowledge has led to the recognition that some encephalitides can be reliably prevented by vaccination (eg, Japanese encephalitis and rabies). For other pathogens such as the arboviruses, the focus has been on prevention by vector control. Finally, effective therapy has been established for a very limited number of viral infections (eg, acyclovir for herpes simplex encephalitis). Other potentially useful treatments, such as pleconaril for enteroviral meningoencephalitis are under clinical evaluation. We review current understanding of viral encephalitides with particular reference to emerging viral infections and the availability of existing treatment regimens.

Velo-cardio-facial syndrome (VCFS), the most frequent known interstitial deletion identified in man, is associated with chromosomal microdeletions in the q11 band of chromosome 22. The VCFS phenotype is complex, with multiple congenital abnormalities affecting several tissues and organs, many of which are derived from neural crest cells. Although phenotypic variability occurs, individuals with VCFS have high rates of psychiatric disorder, especially schizophrenia. Additionally, an increased prevalence of chromosome 22q11 deletions has been reported in populations of people with schizophrenia. Furthermore, results of molecular genetic studies suggest that a schizophrenia susceptibility locus maps to chromosome 22q. These data indicate that aside from being the child of two parents with schizophrenia or the monozygotic co-twin of an affected individual, VCFS and deletion 22q11 represents the highest known risk factor for the development of schizophrenia. Since the entire sequence of chromosome 22 has now been identified, the study of VCFS offers a timely and uniquely powerful opportunity to identify susceptibility genes for schizophrenia in the general population. Furthermore, the strength of the association between schizophrenia and VCFS has important implications for the clinical management of these disorders.

More than a decade ago, spinal-cord injury meant confinement to a wheelchair and a lifetime of medical comorbidity. The physician's armamentarium of treatments was very limited, and provision of care for individuals with spinal-cord injury was usually met with frustration. Advances in the neurosciences have drawn attention to research into spinal-cord injury. Nowadays, advanced interventions provide high hope for regeneration and functional restoration. As scientific advances become more frequent, scepticism is giving way to the ideas that spinal-cord injury will eventually be repairable and that strategies to restore function are within our grasp. We address the present understanding of spinal-cord injury, its cause, pathophysiology, diagnosis, and treatment, and look at promising research avenues. We also discuss new treatment options, including functional electric stimulation and part-weight-supported walking.

Ulcerative colitis is a chronic inflammatory disease of the rectum and colon. Results from many studies in people and animals of intestinal inflammation suggest that ulcerative colitis results from environmental factors triggering a loss of tolerance for normal intestinal flora in genetically susceptible individuals. Although progress has been made in the overall management of the disease, no innovative treatment has been developed. By contrast with Crohn's disease, there are few clinical data on biological agents. Probiotics seem the most promising of several experimental and traditional agents that have been investigated in controlled clinical trials.