We review data from controlled trials and randomised controlled trials to examine the hypothesis for the pathogenesis of systemic sclerosis. Strategies used to treat the vascular complications in systemic sclerosis have so far shown the biggest successes, especially in the management of renal crisis and pulmonary arterial hypertension. Because these drugs have improved function and quality of life and have increased survival rates, they can truly be classified as disease-modifying compounds. Immunosuppressive therapy with cyclophosphamide in particular has also shown evidence of efficacy, and randomised controlled trials of autologous stem-cell transplantation are underway. So far, strategies to reduce or control fibrosis directly (bosentan, interferon gamma, and relaxin) have been disappointing but new strategies against fibrosis based on advanced understanding of the molecular biology of systemic sclerosis hold promise. Treatments against several cardinal features of the disorder simultaneously have not yet been examined but are being considered for future trials.

Acute postoperative pain is followed by persistent pain in 10-50% of individuals after common operations, such as groin hernia repair, breast and thoracic surgery, leg amputation, and coronary artery bypass surgery. Since chronic pain can be severe in about 2-10% of these patients, persistent postsurgical pain represents a major, largely unrecognised clinical problem. Iatrogenic neuropathic pain is probably the most important cause of long-term postsurgical pain. Consequently, surgical techniques that avoid nerve damage should be applied whenever possible. Also, the effect of aggressive, early therapy for postoperative pain should be investigated, since the intensity of acute postoperative pain correlates with the risk of developing a persistent pain state. Finally, the role of genetic factors should be studied, since only a proportion of patients with intraoperative nerve damage develop chronic pain. Based on information about the molecular mechanisms that affect changes to the peripheral and central nervous system in neuropathic pain, several opportunities exist for multimodal pharmacological intervention. Here, we outline strategies for identification of patients at risk and for prevention and possible treatment of this important entity of chronic pain.

Cushing's syndrome results from lengthy and inappropriate exposure to excessive glucocorticoids. Untreated, it has significant morbidity and mortality. The syndrome remains a challenge to diagnose and manage. Here, we review the current understanding of pathogenesis, clinical features, diagnostic, and differential diagnostic approaches. We provide diagnostic algorithms and recommendations for management.

Evidence suggests that the present and projected global burden of road-traffic injuries is disproportionately borne by countries that can least afford to meet the health service, economic, and societal challenges posed. Although the evidence base on which these estimates are made remains somewhat precarious in view of the limited data systems in most low-income and middle-income countries (as per the classification on the World Bank website), these projections highlight the essential need to address road-traffic injuries as a public-health priority. Most well-evaluated effective interventions do not directly focus on efforts to protect vulnerable road users, such as motorcyclists and pedestrians. Yet, these groups comprise the majority of road-traffic victims in low-income and middle-income countries, and consequently, the majority of the road-traffic victims globally. Appropriately responding to these disparities in available evidence and prevention efforts is necessary if we are to comprehensively address this global-health dilemma.

The three main soil-transmitted helminth infections, ascariasis, trichuriasis, and hookworm, are common clinical disorders in man. The gastrointestinal tract of a child living in poverty in a less developed country is likely to be parasitised with at least one, and in many cases all three soil-transmitted helminths, with resultant impairments in physical, intellectual, and cognitive development. The benzimidazole anthelmintics, mebendazole and albendazole, are commonly used to remove these infections. The use of these drugs is not limited to treatment of symptomatic soil-transmitted helminth infections, but also for large-scale prevention of morbidity in children living in endemic areas. As a result of data showing improvements in child health and education after deworming, and the burden of disease attributed to soil-transmitted helminths, the worldwide community is awakening to the importance of these infections. Concerns about the sustainability of periodic deworming with benzimidazole anthelmintics and the emergence of resistance have prompted efforts to develop and test new control tools.

Accurate carotid imaging is important for effective secondary stroke prevention. Non-invasive imaging, now widely available, is replacing intra-arterial angiography for carotid stenosis, but the accuracy remains uncertain despite an extensive literature. We systematically reviewed the accuracy of non-invasive imaging compared with intra-arterial angiography for diagnosing carotid stenosis in patients with carotid territory ischaemic symptoms.

AIDS-associated Kaposi's sarcoma remains common in individuals with HIV-1 infection in the era of highly active antiretroviral therapy (HAART). We developed a simple model for predicting mortality on the basis of clinical characteristics present at the time of diagnosis of Kaposi's sarcoma.

While information about 4 million neonatal deaths worldwide is limited, even less information is available for stillbirths (babies born dead in the last 12 weeks of pregnancy) and there are no published, systematic global estimates. We sought to identify available data and use these to estimate the rates and numbers of stillbirths for 190 countries for the year 2000, and provide uncertainty estimates.

Several laser and non-laser refractive surgical procedures have been used to modify the shape of the cornea and correct myopia, hyperopia, astigmatism, and presbyopia. Introduction of the excimer laser to reshape the cornea has resulted in remarkable developments in the correction of these refractive errors. Combined with other advanced ophthalmological instruments, laser refractive eye surgery has resulted in a substantial rise in the safety, efficacy, and predictability of surgical outcomes. Despite these advances, certain limitations and complications persist. In this review, we describe the history, preoperative assessment, surgical techniques, outcomes, and complications of laser refractive surgery.

Bronchopulmonary dysplasia is a chronic lung disease that affects premature babies and contributes to their morbidity and mortality. Improved survival of very immature infants has led to increased numbers of infants with this disorder. This increase puts a heavy burden on health resources since these infants need frequent re-admission to hospital in the first 2 years after birth and, even as adolescents, have lung-function abnormalities and persistent respiratory symptoms. Unlike the original description of the disease in 1967, premature infants can develop chronic oxygen dependency without severe, acute respiratory distress; this "new bronchopulmonary dysplasia" could be the result of impaired postnatal lung growth. Whether such infants subsequently have catch-up lung growth, especially if given corticosteroids postnatally, is unknown. No safe and effective preventive therapy has been identified, but promising new treatments directed either at reducing lung injury or improving lung growth are under study.

Despite worldwide public-health campaigns recommending periconceptional daily supplementation of synthetic folic acid to reduce the risk of neural tube defects, many women are not following these recommendations. At the same time, in most European countries no decline in defects has been recorded in recent years. Vulnerable groups are those with a low standard of education, young people, and women with unplanned pregnancies. Furthermore, in most countries without mandatory fortification, the general population is not consuming the recommended 0.4 mg of food folate per day. Voluntary fortification improves the situation, but does not reach all parts of the population. In the USA, Canada, and Chile, mandatory fortification of flour substantially improved folate and homocysteine status, and neural tube defects rates fell by between 31% and 78%. Nevertheless, many countries do not choose mandatory folic acid fortification, in part because expected additional health benefits are not yet scientifically proven in clinical trials, in part because of feared health risks, and because of the issue of freedom of choice. Thus, additional creative public-health approaches need to be developed to prevent neural tube defects and improve the folate status of the general population.

Results from recent randomised clinical trials in amblyopia should change our approach to screening for and treatment of amblyopia. Based on the current evidence, if one screening session is used, screening at school entry could be the most reasonable time. Clinicians should preferably use age-appropriate LogMAR acuity tests, and treatment should only be considered for children who are clearly not in the typical range for their age. Any substantial refractive error should be corrected before further treatment is considered and the child should be followed in spectacles until no further improvement is recorded, which can take up to 6 months. Parents and carers should then be offered an informed choice between patching and atropine drops. Successful patching regimens can last as little as 1 h or 2 h a day, and successful atropine regimens as little as one drop twice a week. Intense and extended regimens might not be needed in initial therapy.

Few attempts have been made to estimate the public return on investment in medical research. The total costs and benefits to society of a clinical trial, the final step in testing an intervention, can be estimated by evaluating the effect of trial results on medical care and health.

The chronic inflammatory bowel diseases Crohn's disease and ulcerative colitis are common causes of gastrointestinal disease in northern Europe, affecting as many as one in 250 people. Although mortality is low, morbidity associated with these diseases is substantial. We review the recent advances in the genetics of inflammatory bowel disease, with particular emphasis on the data that have been generated since the discovery of the CARD15 (NOD2) gene in 2001.

Mild cognitive impairment is a syndrome defined as cognitive decline greater than expected for an individual's age and education level but that does not interfere notably with activities of daily life. Prevalence in population-based epidemiological studies ranges from 3% to 19% in adults older than 65 years. Some people with mild cognitive impairment seem to remain stable or return to normal over time, but more than half progress to dementia within 5 years. Mild cognitive impairment can thus be regarded as a risk state for dementia, and its identification could lead to secondary prevention by controlling risk factors such as systolic hypertension. The amnestic subtype of mild cognitive impairment has a high risk of progression to Alzheimer's disease, and it could constitute a prodromal stage of this disorder. Other definitions and subtypes of mild cognitive impairment need to be studied as potential prodromes of Alzheimer's disease and other types of dementia.

The vegetative state and the minimally conscious state are disorders of consciousness that can be acute and reversible or chronic and irreversible. Diffuse lesions of the thalami, cortical neurons, or the white-matter tracts that connect them cause the vegetative state, which is wakefulness without awareness. Functional imaging with PET and functional MRI shows activation of primary cortical areas with stimulation, but not of secondary areas or distributed neural networks that would indicate awareness. Vegetative state has a poor prognosis for recovery of awareness when present for more than a year in traumatic cases and for 3 months in non-traumatic cases. Patients in minimally conscious state are poorly responsive to stimuli, but show intermittent awareness behaviours. Indeed, findings of preliminary functional imaging studies suggest that some patients could have substantially intact awareness. The outcomes of minimally conscious state are variable. Stimulation treatments have been disappointing in vegetative state but occasionally improve minimally conscious state. Treatment decisions for patients in vegetative state or minimally conscious state should follow established ethical and legal principles and accepted practice guidelines of professional medical specialty societies.

BCG vaccine has shown consistently high efficacy against childhood tuberculous meningitis and miliary tuberculosis, but variable efficacy against adult pulmonary tuberculosis and other mycobacterial diseases. We assess and compare the costs and effects of BCG as an intervention against severe childhood tuberculosis in different regions of the world.

Non-invasive positive pressure ventilation (NIPPV), using continuous positive airway pressure (CPAP) or bilevel ventilation, has been shown to reduce the need for invasive mechanical ventilation in patients with acute cardiogenic pulmonary oedema. We assessed additional benefits of NIPPV in a meta-analysis.

Malnutrition is a common comorbidity that places inpatients at risk of complications, infections, long length of stay, higher costs, and increased mortality. Thus, nutrition support has become an important therapeutic adjunctive to the care of these patients. For patients unable to feed themselves, nutrition can be delivered via the parenteral or enteral routes. The formulations used to deliver nutrients and the route of nutrient delivery, absorption, and processing differ substantially between parenteral and enteral nutrition. Over the past two decades, many randomised clinical trials have assessed the effects of parenteral versus enteral nutrition on outcomes (ie, complications, infections, length of stay, costs, mortality) in diverse inpatient populations. From a search of medical publications, studies were selected that assessed important clinical outcomes of parenteral versus enteral feeding or intravenous fluids in patients with trauma/burn injuries, surgery, cancer, pancreatic disease, inflammatory bowel disease, critical illness, liver failure, acute renal failure, and organ transplantation. Our goal was to determine the optimum route of feeding in these patient groups. The available evidence lends support to the use of enteral over parenteral feeding in inpatients with functioning gastrointestinal tracts.

The epilepsies are one of the most common serious brain disorders, can occur at all ages, and have many possible presentations and causes. Although incidence in childhood has fallen over the past three decades in developed countries, this reduction is matched by an increase in elderly people. Monogenic Mendelian epilepsies are rare. A clinical syndrome often has multiple possible genetic causes, and conversely, different mutations in one gene can lead to various epileptic syndromes. Most common epilepsies, however, are probably complex traits with environmental effects acting on inherited susceptibility, mediated by common variation in particular genes. Diagnosis of epilepsy remains clinical, and neurophysiological investigations assist with diagnosis of the syndrome. Brain imaging is making great progress in identifying the structural and functional causes and consequences of the epilepsies. Current antiepileptic drugs suppress seizures without influencing the underlying tendency to generate seizures, and are effective in 60-70% of individuals. Pharmacogenetic studies hold the promise of being able to better individualise treatment for each patient, with maximum possibility of benefit and minimum risk of adverse effects. For people with refractory focal epilepsy, neurosurgical resection offers the possibility of a life-changing cure. Potential new treatments include precise prediction of seizures and focal therapy with drug delivery, neural stimulation, and biological grafts.