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.

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.

The reduction of maternal deaths is a key international development goal. Evidence-based health policies and programmes aiming to reduce maternal deaths need reliable and valid information. We undertook a systematic review to determine the distribution of causes of maternal deaths.

Autoinflammatory diseases are a group of disorders characterised by seemingly unprovoked inflammation in the absence of high-titre autoantibodies or antigen-specific T cells, and include the hereditary periodic fever syndromes. Familial Mediterranean fever (FMF) is an archetypal autoinflammatory disorder, which is autosomal recessive and has a high prevalence in non-Ashkenazi Jews, Armenians, Turks, and Arabs. The classic clinical picture is recurrent acute short-lived febrile and painful attacks with variable periods of remission. In a subset of patients, the disorder is complicated by amyloidosis that leads to renal failure. The gene responsible for FMF--MEFV--has been identified and its role in inflammation is being assessed. There seems to be a distinctive clinical picture in Arab patients with FMF, and the range and distribution of MEFV mutations is different from that noted in other affected ethnic groups. Here, we discuss the clinical and molecular aspects of FMF in Arabs.

Annually, millions of Muslims embark on a religious pilgrimage called the "Hajj" to Mecca in Saudi Arabia. The mass migration during the Hajj is unparalleled in scale, and pilgrims face numerous health hazards. The extreme congestion of people and vehicles during this time amplifies health risks, such as those from infectious diseases, that vary each year. Since the Hajj is dictated by the lunar calendar, which is shorter than the Gregorian calendar, it presents public-health policy planners with a moving target, demanding constant preparedness. We review the communicable and non-communicable hazards that pilgrims face. With the rise in global travel, preventing disease transmission has become paramount to avoid the spread of infectious diseases, including SARS (severe acute respiratory syndrome), avian influenza, and haemorrhagic fever. We examine the response of clinicians, the Saudi Ministry of Health, and Hajj authorities to these unique problems, and list health recommendations for prospective pilgrims.

Rapid scale-up of antiretroviral treatment programmes is happening in Africa, driven by international advocacy and policy directives and supported by unprecedented donor funding and technical assistance. This welcome development offers hope to millions of HIV-infected Africans, among whom tuberculosis is the major cause of serious illness and death. Little in the way of HIV diagnosis or care was previously offered to patients with tuberculosis, by either national tuberculosis or AIDS control programmes, with tuberculosis services focused exclusively on diagnosis and treatment of rising numbers of patients. Tuberculosis control in Africa has yet to adapt to the new climate of antiretroviral availability. Many barriers exist, from drug interactions to historic differences in the way that tuberculosis and HIV are perceived, but failure to successfully integrate HIV and tuberculosis control will threaten the viability of both programmes. Here, we review tuberculosis epidemiology in Africa and policy implications of HIV/AIDS treatment scale-up.

The mortality rate in documented avian influenza A virus subtype H5N1 infection is still high, which is currently reported by WHO at about 50%. Post-mortem analyses in affected patients have revealed haemophagocytosis similar to that found in patients with haemophagocytic lymphohistiocytosis (HLH); such haemophagocytosis could be a very prominent post-mortem feature in H5N1 infection. There are also clinical similarities between H5N1 infection and HLH, such as massive hypercytokinaemia, cytopenia, and acute encephalitis. Importantly, patients with another severe viral infection that may be complicated by secondary HLH, severe Epstein-Barr-virus-associated HLH, have significantly better survival if specific HLH therapy (including the cytotoxic and pro-apoptotic drug etoposide) is initiated early, with survival reported to rise from about 50% to 90%. With this notable improvement in survival, specific HLH treatment, including cytotoxic therapy, could be considered in patients with severe avian influenza A infection complicated by secondary HLH.

There is near unanimous scientific consensus that greenhouse gas emissions generated by human activity will change Earth's climate. The recent (globally averaged) warming by 0.5 degrees C is partly attributable to such anthropogenic emissions. Climate change will affect human health in many ways-mostly adversely. Here, we summarise the epidemiological evidence of how climate variations and trends affect various health outcomes. We assess the little evidence there is that recent global warming has already affected some health outcomes. We review the published estimates of future health effects of climate change over coming decades. Research so far has mostly focused on thermal stress, extreme weather events, and infectious diseases, with some attention to estimates of future regional food yields and hunger prevalence. An emerging broader approach addresses a wider spectrum of health risks due to the social, demographic, and economic disruptions of climate change. Evidence and anticipation of adverse health effects will strengthen the case for pre-emptive policies, and will also guide priorities for planned adaptive strategies.

Type 1 diabetes accounts for only about 5-10% of all cases of diabetes; however, its incidence continues to increase worldwide and it has serious short-term and long-term implications. The disorder has a strong genetic component, inherited mainly through the HLA complex, but the factors that trigger onset of clinical disease remain largely unknown. Management of type 1 diabetes is best undertaken in the context of a multidisciplinary health team and requires continuing attention to many aspects, including insulin administration, blood glucose monitoring, meal planning, and screening for comorbid conditions and diabetes-related complications. These complications consist of microvascular and macrovascular disease, which account for the major morbidity and mortality associated with type 1 diabetes. Newer treatment approaches have facilitated improved outcomes in terms of both glycaemic control and reduced risks for development of complications. Nonetheless, major challenges remain in the development of approaches to the prevention and management of type 1 diabetes and its complications.

A lack of scientific data remains the principal obstacle to regulating cigarette toxicity. In particular, there is an immediate need to improve our understanding of the interaction between smoking behaviour and product design, and its influence on cigarette deliveries. This article reviews internal tobacco industry documents on smoking behaviour research undertaken by Imperial Tobacco Limited (ITL) and British-American Tobacco (BAT). BAT documents indicate that smokers vary their puffing behaviour to regulate nicotine levels and compensate for low-yield cigarettes by smoking them more intensely. BAT research also shows that the tar and nicotine delivered to smokers is substantially greater than the machine-smoked yields reported to consumers and regulators. Internal documents describe a strategy to maximise this discrepancy through product design. In particular, BAT developed elastic cigarettes that produced low yields under standard testing protocols, whereas in consumers' hands they elicited more intensive smoking and provided higher concentrations of tar and nicotine to smokers. Documents also show that BAT pursued this product strategy despite the health risks to consumers and ethical concerns raised by senior scientists, and paired it with an equally successful marketing campaign that promoted these cigarettes as low-tar alternatives for health-concerned smokers. Overall, the documents seem to reveal a product strategy intended to exploit the limitations of the testing protocols and to intentionally conceal from consumers and regulators the potential toxicity of BAT products revealed by BAT's own research. Tobacco industry research underscores the serious limitations of the current cigarette testing protocols and the documents describe deceptive business practices that remain in place.

Procedural sedation and analgesia for children--the use of sedative, analgesic, or dissociative drugs to relieve anxiety and pain associated with diagnostic and therapeutic procedures--is now widely practised by a diverse group of specialists outside the operating theatre. We review the principles underlying safe and effective procedural sedation and analgesia and the spectrum of procedures for which it is currently done. We discuss the decision-making process used to determine appropriate drug selection, dosing, and sedation endpoint. We detail the pharmacopoeia for procedural sedation and analgesia, reviewing the pharmacology and adverse effects of these drugs. International differences in practice are described along with current areas of controversy and future directions.

Testicular germ-cell tumours (TGCTs) represent the model of a curable malignancy; sensitive tumour markers, accurate prognostic classification, logical series of management trials, and high cure rates in both seminomas and non-seminomas have enabled a framework of effective cancer therapy. Understanding the molecular biology of TGCT could help improve treatment of other cancers. The typical presentation in young adults means that issues of long-term toxicity become especially important in judging appropriate management. A focus of recent developments has been to tailor aggressiveness of treatment to the severity of the prognosis. Recent changes affect the most common subtypes and include the reduction of chemotherapy for patients who have metastastic non-seminomas and a good prognosis, and alternatives to adjuvant radiotherapy in stage I seminomas. We summarise advances in the understanding and management of TGCT during the past decade.