Pulmonary embolism (PE) is a common illness that can cause death and disability. It is difficult to detect because patients present with a wide array of symptoms and signs. The clinical setting can raise suspicion, and certain inherited and acquired risk factors predispose susceptible individuals. D-dimer concentration in blood is the best laboratory screening test, and chest CT has become the most widespread imaging test. Treatment requires rapid and accurate risk stratification before haemodynamic decompensation and the development of cardiogenic shock. Anticoagulation is the foundation of therapy. Right-ventricular dysfunction on echocardiography and higher than normal concentrations of troponin identify high-risk patients who might need escalation of therapy with thrombolysis or embolectomy even if the blood pressure is normal on presentation. When patients are admitted to medical wards or when patients undergo surgery, their physicians should prescribe prophylactic measures to prevent PE. After hospital discharge, prophylaxis should continue for about a month for patients at high risk of thromboembolism.

Membrane-protein ion channels control electrical activity in the nervous system. Voltage-gated channels have four-fold symmetry, with a central pore domain surrounded by voltage-sensor regions. Each voltage-sensor region has a positively charged transmembrane helix, S4, which carries gating charges through the membrane on opening or closing. How S4 moves at gating is debated: either S4 moves in a helical screw or in a helical twist pattern. In both cases S4 is assumed to move inside the densely packed channel protein. The pore region was visualised when Roderick MacKinnon's group crystallised a bacterial K+ channel in 1998. The voltage-sensor region and the S4 movement are more difficult to visualise, because voltage-gated channels are harder to crystallise.

Leprosy remains an important health problem worldwide. The disease is caused by a chronic granulomatous infection of the skin and peripheral nerves with Mycobacterium leprae. The clinical range from tuberculoid to lepromatous leprosy is a result of variation in the cellular immune response to the mycobacterium. The resulting impairment of nerve function causes the disabilities associated with leprosy. This review summarises recent advances in understanding of the biology of leprosy, clinical features of the disease, the current diagnostic criteria, and the new approaches to treatment of the infection and the immune-mediated complications. Supervised multi-drug therapy (MDT) for fixed durations is highly effective for all forms of the disease. The widespread implementation of MDT has been associated with a fall in the prevalence of the leprosy but as yet no reduction in the case-detection rate globally. Thus, leprosy control activities must be maintained for decades to interrupt transmission of infection.

Migraine is a very common neurobiological headache disorder that is caused by increased excitability of the CNS. It ranks among the world's most disabling medical illnesses. Diagnosis is based on the headache's characteristics and associated symptoms. The economic and societal effect of migraine is substantial: it affects patients' quality of life and impairs work, social activities, and family life. There are many acute and preventive migraine treatments. Acute treatment is either specific (triptans and ergots) or non-specific (analgesics). Disabling migraine should be treated with triptans. Increased headache frequency is an indication for preventive treatment. Preventive treatment decreases migraine frequency and improves quality of life. More treatments are being developed, which provides hope to the many patients whose migraines remain uncontrolled.

Stroke-unit care can be valuable for stroke patients in hospital, but effectiveness of outpatient care is less certain. We aimed to assess the effects of therapy-based rehabilitation services targeted at stroke patients resident in the community within 1 year of stroke onset or discharge from hospital.

Late-onset sporadic Alzheimer's disease is a heterogeneous disorder. In elderly patients, increasing evidence suggests a link between this neurodegenerative disease, and vascular risk factors and atherosclerosis. The nature of this link remains speculative. Some investigators have suggested that the disease arises as a secondary event related to atherosclerosis of extracranial or intracranial vessels. A toxic effect of vascular factors on the microvasculature of susceptible brain regions has also been argued. An alternative explanation is that atherosclerosis and Alzheimer's disease are independent but convergent disease processes. This hypothesis is lent support by observations of shared epidemiology, pathophysiological elements, and response to treatment in both disorders. It provides a potential framework for an improved understanding of the pathogenesis of Alzheimer's disease, especially in elderly patients with vascular risk factors, and offers some promise toward the search for preventive and therapeutic treatments.

Maternal rubella is now rare in many developed countries that have rubella vaccination programmes. However, in many developing countries congenital rubella syndrome (CRS) remains a major cause of developmental anomalies, particularly blindness and deafness. WHO have provided recommendations for prevention of CRS, and, encouragingly, the number of countries introducing rubella vaccination programmes has risen. However, declining uptake rates due to concerns about the measles-mumps-rubella vaccine in the UK, and increasing numbers of cases in some European countries coupled with poor uptake rates might jeopardise this progress. Surveillance of postnatally and congenitally acquired infection is an essential component of CRS prevention since rubella is difficult to diagnose on clinical grounds alone. Laboratory differentiation of rubella from other rash-causing infections, such as measles, parvovirus B19, human herpesvirus 6, and enteroviruses in developed countries, and various endemic arboviruses is essential. Reverse transcriptase PCR and sequencing for diagnosis and molecular epidemiological investigation and detection of rubella-specific IgG and IgM salivary antibody responses in oral fluid are now available.

The demand for high quality care is increasing and warranted. Evidence suggests that the quality of care in hospitals can be improved. The greatest opportunity to improve outcomes for patients over the next quarter century will probably come not from discovering new treatments but from learning how to deliver existing effective therapies. To improve, caregivers need to know what to do, how they are doing, and be able to improve the processes of care. The ability to monitor performance, though challenging in healthcare, is essential to improving quality of care. We present a practical method to assess and learn from routine practice. Methods to evaluate performance from industrial engineering can be broadly applied to efforts to improve the quality of healthcare. One method that may help to provide caregivers frequent feedback is time series data--ie, results are graphically correlated with time. Broad use of these tools might lead to the necessary improvements in quality of care.

Pancreatic cancer remains a major unsolved health problem, with conventional cancer treatments having little impact on disease course. Almost all patients who have pancreatic cancer develop metastases and die. The main risk factors are smoking, age, and some genetic disorders, although the primary causes are poorly understood. Advances in molecular biology have, however, greatly improved understanding of the pathogenesis of pancreatic cancer. Many patients have mutations of the K-ras oncogene, and various tumour-suppressor genes are also inactivated. Growth factors also play an important part. However, disease prognosis is extremely poor. Around 15-20% of patients have resectable disease, but only around 20% of these survive to 5 years. For locally advanced, unresectable, and metastatic disease, treatment is palliative, although fluorouracil chemoradiation for locally advanced and gemcitabine chemotherapy for metastatic disease can provide palliative benefits. Despite pancreatic cancer's resistance to currently available treatments, new methods are being investigated. Preoperative chemoradiation is being advocated, with seemingly sound reasoning, and a wider role for gemcitabine is being explored. However, new therapeutic strategies based on the molecular biology of pancreatic cancer seem to hold the greatest promise.

The Collaborative Group on Hormonal Factors in Breast Cancer has brought together the worldwide epidemiological evidence on the possible relation between breast cancer and previous spontaneous and induced abortions.

Chronic fatigue is a typical symptom of neurological diseases, and is most disabling in multiple sclerosis, postpoliomyelitis, poststroke, and in chronic fatigue syndrome. Disorders of neuromuscular junction transmission and metabolic diseases cause muscle fatigability, which is characterised by failure to sustain the force of muscle contraction (peripheral fatigue). Fatigue is also seen in diseases that affect the central, peripheral, and autonomic nervous systems (central fatigue). Enhanced perception of effort and limited endurance of sustained physical and mental activities are the main characteristics of central fatigue. Metabolic and structural lesions that disrupt the usual process of activation in pathways interconnecting the basal ganglia, thalamus, limbic system, and higher cortical centre are implicated in the pathophysiological process of central fatigue. A state of pre-existing relative hypocortisolaemia might sensitise the hypothalamic-pituitary-adrenal axis to development of persistent central fatigue after stress. The contributions of physiological, cognitive, and affective changes underlying fatigue are variable, and treatment is largely symptomatic and rehabilitative.

Health care providers, hospital administrators, and politicians face competing challenges to reduce clinical errors, control expenditure, increase access and throughput, and improve quality of care. The safe management of the acutely ill inpatient presents particular difficulties. In the first of five Lancet articles on this topic we discuss patients' safety in the acute hospital. We also present a framework in which responsibility for improvement and better integration of care can be considered at the level of patient, local environment, hospital, and health care system; and the other four papers in the series will examine in greater detail methods for measuring, monitoring, and improving inpatient safety.

The full scale of the global burden of human rabies is unknown, owing to inadequate surveillance of this fatal disease. However, the terror of hydrophobia, a cardinal symptom of rabies encephalitis, is suffered by tens of thousands of people each year. The recent discovery of enzootic European bat lyssavirus infection in the UK is indicative of our expanding awareness of the Lyssavirus genus. The main mammalian vector species vary geographically, so the health problems created by the lyssaviruses and their management differ throughout the world. The methods by which these neurotropic viruses hijack neurophysiological mechanisms while evading immune surveillance is beginning to be unravelled by, for example, studies of molecular motor transport systems. Meanwhile, enormous challenges remain in the control of animal rabies and the provision of accessible, appropriate human prophylaxis worldwide.

Carotid endarterectomy reduces the risk of stroke in patients with recently symptomatic stenosis. Benefit depends on the degree of stenosis, and we aimed to see whether it might also depend on other clinical and angiographic characteristics, and on the timing of surgery.

Ectoparasitoses (infestations with parasites that live on or in the skin) can cause considerable morbidity. Whereas pediculosis and scabies are ubiquitous, cutaneous larva migrans and tungiasis (sand-flea disease) occur mainly in hot climates. The prevalence of ectoparasitoses in the general population is usually low, but can be high in vulnerable groups. Scientific knowledge on how to deal best with parasitic skin diseases in different settings is scanty, and evidence-based measures for control are not available. For head lice and scabies the situation is daunting, because resistance of Pediculus humanus capitis and Sarcoptes scabiei to insecticides is spreading and unpredictable.

Statins are possibly the most effective drugs for the prevention and treatment of hypercholesterolaemia and coronary heart disease. They are generally well tolerated, however, they do cause some unusual side-effects with potentially severe consequences, most prominently myopathy or rhabdomyolysis and polyneuropathy. We noted that the pattern of side-effects associated with statins resembles the pathology of selenium deficiency, and postulated that the mechanism lay in a well established, but often overlooked, biochemical pathway--the isopentenylation of selenocysteine-tRNA([Ser]Sec). A negative effect of statins on selenoprotein synthesis does seem to explain many of the enigmatic effects and side-effects of statins, in particular, statin-induced myopathy.

Multiple myeloma is a malignant disease of plasma cells that manifests as one or more of lytic bone lesions, monoclonal protein in the blood or urine, and disease in the bone marrow. Treatment for myeloma has changed beyond recognition in the past decade, and now includes state of the art supportive treatment and infusional chemotherapy courses, followed for younger patients by high-dose melphalan and an autologous transplant. Patients younger than 70 years can now expect a doubling of median survival to 5 years, a 20% chance of surviving longer than 10 years, and a 50% chance of attaining complete morphological and biochemical remission. Bisphosphonate control of bone disease is essential. Exploitation of the understanding of the biology of myeloma has led to the development of biological treatments, such as thalidomide, CC-5013, and bortezomib, which target the myeloma cell and the bone-marrow microenvironment, which plays a crucial part in the disease's pathogenesis. These treatments will hold the key to future success.

Cerebrovascular diseases are an important cause of morbidity and mortality worldwide. Endovascular treatment has emerged as a minimally invasive approach to treat cerebrovascular diseases and possibly intracranial neoplasms. Practice patterns for selection of patients for endovascular treatment are continuously being modified on the basis of new information derived from clinical studies. In this review, I discuss the various endovascular treatments for diseases such as ischaemic stroke, carotid and intracranial stenosis, intracranial aneurysms, arteriovenous malformations, malignant gliomas, and meningiomas.

Hypothyroidism is common, potentially serious, often clinically overlooked, readily diagnosed by laboratory testing, and eminently treatable. The condition is particularly prevalent in older women, in whom autoimmune thyroiditis is common. Other important causes include congenital thyroid disorders, previous thyroid surgery and irradiation, drugs such as lithium carbonate and amiodarone, and pituitary and hypothalamic disorders. Worldwide, dietary iodine deficiency remains an important cause. Hypothyroidism can present with nonspecific constitutional and neuropsychiatric complaints, or with hypercholesterolaemia, hyponatraemia, hyperprolactinaemia, or hyperhomocysteinaemia. Severe untreated hypothyroidism can lead to heart failure, psychosis, and coma. Although these manifestations are neither specific nor sensitive, the diagnosis is confirmed or excluded by measurements of serum thyrotropin and free thyroxine. Thyroxine replacement therapy is highly effective and safe, but suboptimal dosing is common in clinical practice. Patient noncompliance, drug interactions, and pregnancy can lead to inadequate treatment. Iatrogenic thyrotoxicosis can cause symptoms, and, even when mild, provoke atrial fibrillation and osteoporosis. We summarise present understanding of the history, epidemiology, pathophysiology, and clinical diagnosis and management of hypothyroidism.

Sunlight is the main environmental cause of most cutaneous melanomas. Exposure to intense bursts of ultraviolet radiation, especially in childhood, starts the transformation of benign melanocytes into a malignant phenotype. Paradoxically, outdoor workers have a decreased risk of melanoma compared with indoor workers, suggesting that chronic sunlight exposure can have a protective effect. Further, some melanomas form on sun-exposed regions; others do not. Although some melanomas arise from pre-existing melanocytic naevi (moles), many arise de novo. These observations suggest that melanoma arises from multiple pathways, with initiating and promoting factors differing for each.