Excess bodyweight, expressed as increased body-mass index (BMI), is associated with the risk of some common adult cancers. We did a systematic review and meta-analysis to assess the strength of associations between BMI and different sites of cancer and to investigate differences in these associations between sex and ethnic groups.

Substantial evidence shows that inflammation promotes oncogenesis and, occasionally, participates in cancer rejection. This paradox can be accounted for by a dynamic switch from chronic smouldering inflammation promoting cancer-cell survival to florid, tissue-disruptive inflammatory reactions that trigger cancer-cell destruction. Clinical and experimental observations suggest that the mechanism of this switch recapitulates the events associated with pathogen infection, which stimulate immune cells to recognise danger signals and activate immune effector functions. Generally, cancers do not have danger signals and, therefore, they cannot elicit strong immune reactions. Synthetic molecules have been developed that mimic pathogen invasion at the tumour site. These compounds activate dendritic cells to produce proinflammatory cytokines, which in turn trigger cytotoxic mechanisms leading to cancer death. Simultaneously, dendritic cells capture antigen shed by dying cancer cells, undergo activation, and stimulate antigen-specific T and B cells. This process results in massive amplification of the antineoplastic inflammatory process. Thus, although anti-inflammatory drugs can prevent onset of some malignant diseases, induction of T cells specific for tumour antigen by active immunisation, combined with powerful activation signals within the cancer microenvironment, might yield the best strategy for treatment of established cancers.

Haemorrhagic disease, encephalitis, biphasic fever, flaccid paralysis, and jaundice are typical manifestations of diseases in human beings after infections by mosquito-borne or tick-borne flaviviruses such as yellow fever, dengue, West Nile, St Louis encephalitis, Japanese encephalitis, tick-borne encephalitis, Kyasanur Forest disease, and Omsk haemorrhagic fever. Although the characteristics of these viruses are well defined, they are still unpredictable with increases in disease severity, unusual clinical manifestations, unexpected methods of transmission, long-term persistence, and the discovery of new species. This Seminar will compare the epidemiological and clinical features of the medically important flaviviruses, consider the effect of human activity on their evolution and dispersal, and draw attention to new findings and some of the unanswered questions, unresolved issues, and controversies that remain.

Survival rates have greatly improved in recent years for infants of borderline viability; however, these infants remain at risk of developing a wide array of complications, not only in the neonatal unit, but also in the long term. Morbidity is inversely related to gestational age; however, there is no gestational age, including term, that is wholly exempt. Neurodevelopmental disabilities and recurrent health problems take a toll in early childhood. Subsequently hidden disabilities such as school difficulties and behavioural problems become apparent and persist into adolescence. Reassuringly, however, most children born very preterm adjust remarkably well during their transition into adulthood. Because mortality rates have fallen, the focus for perinatal interventions is to develop strategies to reduce long-term morbidity, especially the prevention of brain injury and abnormal brain development. In addition, follow-up to middle age and beyond is warranted to identify the risks, especially for cardiovascular and metabolic disorders that are likely to be experienced by preterm survivors.

We reviewed interventions that affect maternal and child undernutrition and nutrition-related outcomes. These interventions included promotion of breastfeeding; strategies to promote complementary feeding, with or without provision of food supplements; micronutrient interventions; general supportive strategies to improve family and community nutrition; and reduction of disease burden (promotion of handwashing and strategies to reduce the burden of malaria in pregnancy). We showed that although strategies for breastfeeding promotion have a large effect on survival, their effect on stunting is small. In populations with sufficient food, education about complementary feeding increased height-for-age Z score by 0.25 (95% CI 0.01-0.49), whereas provision of food supplements (with or without education) in populations with insufficient food increased the height-for-age Z score by 0.41 (0.05-0.76). Management of severe acute malnutrition according to WHO guidelines reduced the case-fatality rate by 55% (risk ratio 0.45, 0.32-0.62), and recent studies suggest that newer commodities, such as ready-to-use therapeutic foods, can be used to manage severe acute malnutrition in community settings. Effective micronutrient interventions for pregnant women included supplementation with iron folate (which increased haemoglobin at term by 12 g/L, 2.93-21.07) and micronutrients (which reduced the risk of low birthweight at term by 16% (relative risk 0.84, 0.74-0.95). Recommended micronutrient interventions for children included strategies for supplementation of vitamin A (in the neonatal period and late infancy), preventive zinc supplements, iron supplements for children in areas where malaria is not endemic, and universal promotion of iodised salt. We used a cohort model to assess the potential effect of these interventions on mothers and children in the 36 countries that have 90% of children with stunted linear growth. The model showed that existing interventions that were designed to improve nutrition and prevent related disease could reduce stunting at 36 months by 36%; mortality between birth and 36 months by about 25%; and disability-adjusted life-years associated with stunting, severe wasting, intrauterine growth restriction, and micronutrient deficiencies by about 25%. To eliminate stunting in the longer term, these interventions should be supplemented by improvements in the underlying determinants of undernutrition, such as poverty, poor education, disease burden, and lack of women's empowerment.

In this paper we review the associations between maternal and child undernutrition with human capital and risk of adult diseases in low-income and middle-income countries. We analysed data from five long-standing prospective cohort studies from Brazil, Guatemala, India, the Philippines, and South Africa and noted that indices of maternal and child undernutrition (maternal height, birthweight, intrauterine growth restriction, and weight, height, and body-mass index at 2 years according to the new WHO growth standards) were related to adult outcomes (height, schooling, income or assets, offspring birthweight, body-mass index, glucose concentrations, blood pressure). We undertook systematic reviews of studies from low-income and middle-income countries for these outcomes and for indicators related to blood lipids, cardiovascular disease, lung and immune function, cancers, osteoporosis, and mental illness. Undernutrition was strongly associated, both in the review of published work and in new analyses, with shorter adult height, less schooling, reduced economic productivity, and--for women--lower offspring birthweight. Associations with adult disease indicators were not so clear-cut. Increased size at birth and in childhood were positively associated with adult body-mass index and to a lesser extent with blood pressure values, but not with blood glucose concentrations. In our new analyses and in published work, lower birthweight and undernutrition in childhood were risk factors for high glucose concentrations, blood pressure, and harmful lipid profiles once adult body-mass index and height were adjusted for, suggesting that rapid postnatal weight gain--especially after infancy--is linked to these conditions. The review of published works indicates that there is insufficient information about long-term changes in immune function, blood lipids, or osteoporosis indicators. Birthweight is positively associated with lung function and with the incidence of some cancers, and undernutrition could be associated with mental illness. We noted that height-for-age at 2 years was the best predictor of human capital and that undernutrition is associated with lower human capital. We conclude that damage suffered in early life leads to permanent impairment, and might also affect future generations. Its prevention will probably bring about important health, educational, and economic benefits. Chronic diseases are especially common in undernourished children who experience rapid weight gain after infancy.

Interventions to reduce the morbidity and mortality of preterm birth can be primary (directed to all women), secondary (aimed at eliminating or reducing existing risk), or tertiary (intended to improve outcomes for preterm infants). Most efforts so far have been tertiary interventions, such as regionalised care, and treatment with antenatal corticosteroids, tocolytic agents, and antibiotics. These measures have reduced perinatal morbidity and mortality, but the incidence of preterm birth is increasing. Advances in primary and secondary care, following strategies used for other complex health problems, such as cervical cancer, will be needed to prevent prematurity-related illness in infants and children.

Acute pancreatitis is an inflammatory disease of the pancreas. Acute abdominal pain is the most common symptom, and increased concentrations of serum amylase and lipase confirm the diagnosis. Pancreatic injury is mild in 80% of patients, who recover without complications. The remaining patients have a severe disease with local and systemic complications. Gallstone migration into the common bile duct and alcohol abuse are the most frequent causes of pancreatitis in adults. About 15-25% of pancreatitis episodes are of unknown origin. Treatment of mild disease is supportive, but severe episodes need management by a multidisciplinary team including gastroenterologists, interventional radiologists, intensivists, and surgeons. Improved understanding of pathophysiology and better assessments of disease severity should ameliorate the management and outcome of this complex disease.

This paper is the first in a three-part series on preterm birth, which is the leading cause of perinatal morbidity and mortality in developed countries. Infants are born preterm at less than 37 weeks' gestational age after: (1) spontaneous labour with intact membranes, (2) preterm premature rupture of the membranes (PPROM), and (3) labour induction or caesarean delivery for maternal or fetal indications. The frequency of preterm births is about 12-13% in the USA and 5-9% in many other developed countries; however, the rate of preterm birth has increased in many locations, predominantly because of increasing indicated preterm births and preterm delivery of artificially conceived multiple pregnancies. Common reasons for indicated preterm births include pre-eclampsia or eclampsia, and intrauterine growth restriction. Births that follow spontaneous preterm labour and PPROM-together called spontaneous preterm births-are regarded as a syndrome resulting from multiple causes, including infection or inflammation, vascular disease, and uterine overdistension. Risk factors for spontaneous preterm births include a previous preterm birth, black race, periodontal disease, and low maternal body-mass index. A short cervical length and a raised cervical-vaginal fetal fibronectin concentration are the strongest predictors of spontaneous preterm birth.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme defect, being present in more than 400 million people worldwide. The global distribution of this disorder is remarkably similar to that of malaria, lending support to the so-called malaria protection hypothesis. G6PD deficiency is an X-linked, hereditary genetic defect due to mutations in the G6PD gene, which cause functional variants with many biochemical and clinical phenotypes. About 140 mutations have been described: most are single base changes, leading to aminoacid substitutions. The most frequent clinical manifestations of G6PD deficiency are neonatal jaundice, and acute haemolytic anaemia, which is usually triggered by an exogenous agent. Some G6PD variants cause chronic haemolysis, leading to congenital non-spherocytic haemolytic anaemia. The most effective management of G6PD deficiency is to prevent haemolysis by avoiding oxidative stress. Screening programmes for the disorder are undertaken, depending on the prevalence of G6PD deficiency in a particular community.

The long-term effects of adjuvant polychemotherapy regimens in oestrogen-receptor-poor (ER-poor) breast cancer, and the extent to which these effects are modified by age or tamoxifen use, can be assessed by an updated meta-analysis of individual patient data from randomised trials.

Cyclo-oxygenase-2 selective inhibitors and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) are associated with increased risk of acute cardiovascular events. Only aspirin offers primary and secondary cardiovascular prophylaxis, but trials have not answered directly whether low-dose aspirin is cardioprotective with COX-2 inhibitors. A large inception cohort study showed that concomitant use of aspirin reduced risk of cardiovascular events when given with rofecoxib, celecoxib, sulindac, meloxicam, and indometacin but not when given with ibuprofen. In large trials assessing gastrointestinal safety, there were fewer gastrointestinal events in patients using both COX-2 inhibitors and aspirin than in those using non-selective NSAIDs and aspirin; significantly fewer uncomplicated upper gastrointestinal events took place in the MEDAL trial. Analysis of VIGOR and two capsule endoscopy studies showed significantly less distal gastrointestinal blood loss with COX-2 inhibitors than with non-selective NSAIDs. Endoscopy trials showed that low-dose aspirin does not diminish the gastrointestinal benefits of COX-2 inibitors over non-selective NSAIDs. In an elderly epidemiological cohort receiving aspirin, both celecoxib and rofecoxib reduced risk of admission for gastrointestinal events. Comparison of the cardiovascular and gastrointestinal risks is difficult: likelihood and severity of cardiovascular events differ between individuals, agents, and exposure. Mortality associated with gastrointestinal events is less frequent than with cardiovascular events, but asymptomatic ulcers can result in severe complications. Data support the conclusion that COX-2 inhibitors are preferable to non-selective NSAIDs in patients with chronic pain and cardiovascular risk needing low-dose aspirin, but relative risks and benefits should be assessed individually for each patient.

Genital herpes is the main cause of genital ulcers worldwide; the prevalence of herpes simplex virus (HSV) type 2 infections in the general population ranges from 10% to 60%. Most genital herpes is caused by HSV-2, although HSV-1 accounts for about half of new cases in developed countries. The risk of HIV acquisition is three times higher in people with HSV-2. Neonatal herpes is an uncommon but serious complication of genital herpes. Most genital HSV-2 infections are unrecognised and undiagnosed; infected individuals, even with mild symptoms, shed HSV, and can infect sexual partners. Since clinical diagnosis is neither sensitive nor specific, virological and type-specific serological tests should be used routinely. Oral antiviral drugs for HSV infections are safe and effective and can be used both to treat episodes and to prevent recurrences. Antiviral treatment of the infected partners and condom use reduce the risk of sexual transmission of HSV-2.

New evidence has suggested that people with asthma who are homozygous for arginine at aminoacid 16 of the beta2-adrenergic receptor (ADRB2) might not benefit from longacting beta2-agonist therapy. We, therefore, investigated whether ADRB2 polymorphisms affect response to longacting beta2-agonists in combination with inhaled corticosteroids.

In 1977, the US Food and Drug Administration revoked all licences for fibrinogen concentrate because of the risk for hepatitis infection and suspected lack of effectiveness. However, in Japan, fibrinogen concentrate was used routinely for treatment of obstetric bleeding until 1988. Even in 1997, academic texts by Japanese authorities in obstetrics still recommended that obstetricians use the product. An estimated 10 000 cases of hepatitis C infection are attributable to use of fibrinogen in Japan and are a result of authoritarianism that hindered effective policy changes. Scientists have a duty to refine repeatedly the quality of their evidence, and policymakers need to adjust existing policies continually to accord with the latest scientific evidence.

In this Review, we look at the relation between bereavement and physical and mental health. Although grief is not a disease and most people adjust without professional psychological intervention, bereavement is associated with excess risk of mortality, particularly in the early weeks and months after loss. It is related to decrements in physical health, indicated by presence of symptoms and illnesses, and use of medical services. Furthermore, bereaved individuals report diverse psychological reactions. For a few people, mental disorders or complications in the grieving process ensue. We summarise research on risk factors that increase vulnerability of some bereaved individuals. Diverse factors (circumstances of death, intrapersonal and interpersonal variables, ways of coping) are likely to co-determine excesses in ill-health. We also assess the effectiveness of psychological intervention programmes. Intervention should be targeted at high-risk people and those with complicated grief or bereavement-related depression and stress disorders.

This paper estimates the disease burden and loss of economic output associated with chronic diseases-mainly cardiovascular diseases, cancer, chronic respiratory diseases, and diabetes-in 23 selected countries which account for around 80% of the total burden of chronic disease mortality in developing countries. In these 23 selected low-income and middle-income countries, chronic diseases were responsible for 50% of the total disease burden in 2005. For 15 of the selected countries where death registration data are available, the estimated age-standardised death rates for chronic diseases in 2005 were 54% higher for men and 86% higher for women than those for men and women in high-income countries. If nothing is done to reduce the risk of chronic diseases, an estimated US$84 billion of economic production will be lost from heart disease, stroke, and diabetes alone in these 23 countries between 2006 and 2015. Achievement of a global goal for chronic disease prevention and control-an additional 2% yearly reduction in chronic disease death rates over the next 10 years-would avert 24 million deaths in these countries, and would save an estimated $8 billion, which is almost 10% of the projected loss in national income over the next 10 years.

Interventions to prevent morbidity and mortality from chronic diseases need to be cost effective and financially feasible in countries of low or middle income before recommendations for their scale-up can be made. We review the cost-effectiveness estimates on policy interventions (both population-based and personal) that are likely to lead to substantial reductions in chronic diseases--in particular, cardiovascular disease, diabetes, cancer, and chronic respiratory disease. We reviewed data from regions of low, middle, and high income, where available, as well as the evidence for making policy interventions where available effectiveness or cost-effectiveness data are lacking. The results confirm that the cost-effectiveness evidence for tobacco control measures, salt reduction, and the use of multidrug regimens for patients with high-risk cardiovascular disease strongly supports the feasibility of the scale-up of these interventions. Further assessment to determine the best national policies to achieve reductions in consumption of saturated and trans fat--chemically hydrogenated plant oils--could eventually lead to substantial reductions in cardiovascular disease. Finally, we review evidence for policy implementation in areas of strong causality or highly probable benefit--eg, changes in personal interventions for diabetes reduction, restructuring of health systems, and wider policy decisions.