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.

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.

By contrast with patients with asthma, those with chronic obstructive pulmonary disease (COPD) are poorly responsive to the anti-inflammatory actions of corticosteroids, and these drugs provide little clinical benefit. In both diseases, multiple inflammatory genes are activated, which results from acetylation of core histones around which DNA is wound. This acetylation opens up the chromatin structure allowing gene transcription and synthesis of inflammatory proteins to proceed. Corticosteroids recruit histone deacetylase 2 (HDAC2) to the actively transcribing gene, which reverses this process and switches off inflammatory gene transcription. We propose that in patients with COPD, HDAC2 function is impaired by cigarette smoking and oxidative stress, leading to a pronounced reduction in responsiveness to corticosteroids. Oxidative stress could generate peroxynitrite, which impairs HDAC2 activity through nitration of critical tyrosine residues. This hypothesis raises the possibility that novel therapeutic approaches might unlock this corticosteroid resistance, leading to more effective anti-inflammatory treatments for COPD and other severe inflammatory diseases.

Pericarditis is a common disorder that has multiple causes and presents in various primary-care and secondary-care settings. New diagnostic techniques have improved the sampling and analysis of pericardial fluid and allow comprehensive characterisation of cause. Despite this advance, pericarditis is most commonly idiopathic, and radiation therapy, cardiac surgery, and percutaneous procedures have become important causes. Pericarditis is frequently self-limiting, and non-steroidal anti-inflammatory agents remain the first-line treatment for uncomplicated cases. Integrated use of new imaging methods facilitates accurate detection and management of complications such as pericardial effusion or constriction. Differentiation of constrictive pericarditis from restrictive cardiomyopathy remains a clinical challenge but is facilitated by tissue doppler and colour M-mode echocardiography. Most pericardial effusions can be safely managed with an echo-guided percutaneous approach. Pericardiectomy remains the definitive treatment for constrictive pericarditis and provides symptomatic relief in most cases. In the future, the pericardial space might become a conduit for treatments directed at the pericardium and myocardium.

Despite much progress in the understanding of pathogenesis and of management, diarrhoeal illnesses remain one of the most important causes of global childhood mortality and morbidity. Infections account for most illnesses, with pathogens employing ingenious mechanisms to establish disease. In the developed world, an upsurge in immune-mediated gut disorders might have resulted from a disruption of normal bacterial-epithelial cross-talk and impaired maturation of the gut's immune system. Oral rehydration therapies are the mainstay of management of gastroenteritis, and their composition continues to improve. Malnutrition remains the major adverse prognostic indicator for diarrhoea-related mortality, emphasising the importance of nutrition in early management. Drugs are of little use, except for specific indications although new agents that target mechanisms of secretory diarrhoea show promise, as do probiotics. However, preventive strategies on a global scale might ultimately hold the greatest potential to reduce the burden of diarrhoeal disease. These strategies include vaccines and, most importantly, policies to address persisting inequalities between the developed and developing worlds with respect to nutrition, sanitation, and access to safe drinking water.

Colonic diverticulosis refers to small outpouchings from the colonic lumen due to mucosal herniation through the colonic wall at sites of vascular perforation. Abnormal colonic motility and inadequate intake of dietary fibre have been implicated in its pathogenesis. This acquired abnormality is typically found in developed countries, and its prevalence rises with age. Most patients affected will remain entirely asymptomatic; however, 10-20% of those affected can manifest clinical syndromes, mainly diverticulitis and diverticular haemorrhage. As our elderly population grows, we can anticipate a concomitant rise in the number of patients with diverticular disease. Here, we review the incidence, pathophysiology, clinical presentation, and management of diverticular disease of the colon and its complications.

Identification of asymptomatic high-risk individuals is integral to current policies for preventing coronary heart disease, but existing methods of estimating risk lack sensitivity. To overcome this limitation increasing use is being made of non-invasive methods to detect subclinical coronary artery disease--eg, computed tomography (CT) to scan for coronary artery calcification. The location and extent of calcification correlate closely with pathological and angiographic abnormalities, but whether such calcification predicts clinical events, especially in younger individuals, is equivocal. Most data on coronary calcification have been obtained with electron-beam CT, but recently multislice CT, which is more versatile, less expensive, and available in most large hospitals, has been increasingly used.

Sexually transmitted infections (STIs) are notable for their fastidious requirements for transmission and growth in the laboratory and for their high physical and psychosocial morbidity. The combination of subtle or absent symptoms and stigma preventing the seeking of health care, leaves many infections undiagnosed. The development of nucleic-acid amplification tests heralded a new era in sensitive and robust diagnostic procedures for STIs. Unfortunately, many of these tests are not commercially available or are too expensive for the populations that need them most. Single-dose oral azithromycin has improved the treatment of several bacterial STIs, but quinolones are rapidly becoming ineffective for gonorrhoea. Self-treatment of genital warts with podophyllotoxin or imiquimod preparations is attractive to patients and might be cost effective for health services. The prospect of effective vaccines against genital papillomaviruses in the near future is real. Such vaccines could reduce the global incidence of some anogenital cancers. Episodic treatment of genital herpes is getting easier and cheaper, and suppressive treatment can reduce transmission to regular sexual partners. A vaccine against herpes simplex virus type 2 has shown some limited efficacy. Ultimately, better control of STIs, and reduction of their contribution to the spread of HIV, will require a broad health-sector response with adequate resourcing, and a change in social and political attitudes.

Multidrug-resistant tuberculosis (MDR-TB) presents an increasing threat to global tuberculosis control. Many crucial management issues in MDR-TB treatment remain unanswered. We reviewed the existing scientific research on MDR-TB treatment, which consists entirely of retrospective cohort studies. Although direct comparisons of these studies are impossible, some insights can be gained: MDR-TB can and should be addressed therapeutically in resource-poor settings; starting of treatment early is crucial; aggressive treatment regimens and high-end dosing are recommended given the lower potency of second-line antituberculosis drugs; and strategies to improve treatment adherence, such as directly observed therapy, should be used. Opportunities to treat MDR-TB in developing countries are now possible through the Global Fund to Fight AIDS, TB, and Malaria, and the Green Light Committee for Access to Second-line Anti-tuberculosis Drugs. As treatment of MDR-TB becomes increasingly available in resource-poor areas, where it is needed most, further clinical and operational research is urgently needed to guide clinicians in the management of this disease.