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The initial Global Burden of Disease study found that depression was the fourth leading cause of disease burden, accounting for 3.7% of total disability adjusted life years (DALYs) in the world in 1990. To present the new estimates of depression burden for the year 2000. DALYs for depressive disorders in each world region were calculated, based on new estimates of mortality, prevalence, incidence, average age at onset, duration and disability severity. Depression is the fourth leading cause of disease burden, accounting for 4.4% of total DALYs in the year 2000, and it causes the largest amount of non-fatal burden, accounting for almost 12% of all total years lived with disability worldwide. These data on the burden of depression worldwide represent a major public health problem that affects patients and society.

Since the year 2000, a concerted campaign against malaria has led to unprecedented levels of intervention coverage across sub-Saharan Africa. Understanding the effect of this control effort is vital to inform future control planning. However, the effect of malaria interventions across the varied epidemiological settings of Africa remains poorly understood owing to the absence of reliable surveillance data and the simplistic approaches underlying current disease estimates. Here we link a large database of malaria field surveys with detailed reconstructions of changing intervention coverage to directly evaluate trends from 2000 to 2015, and quantify the attributable effect of malaria disease control efforts. We found that Plasmodium falciparum infection prevalence in endemic Africa halved and the incidence of clinical disease fell by 40% between 2000 and 2015. We estimate that interventions have averted 663 (542–753 credible interval) million clinical cases since 2000. Insecticide-treated nets, the most widespread intervention, were by far the largest contributor (68% of cases averted). Although still below target levels, current malaria interventions have substantially reduced malaria disease incidence across the continent. Increasing access to these interventions, and maintaining their effectiveness in the face of insecticide and drug resistance, should form a cornerstone of post-2015 control strategies. In this study, the authors present an analysis of the malaria burden in sub-Saharan Africa between 2000 and 2015, and quantify the effects of the interventions that have been implemented to combat the disease; they find that the prevalence of Plasmodium falciparum infection has been reduced by 50% since 2000 and the incidence of clinical disease by 40%, and that interventions have averted approximately 663 million clinical cases since 2000, with insecticide-treated bed nets being the largest contributor. Malaria control measures assessed In one of the largest public health campaigns in history, a concerted malaria control campaign has been under way in sub-Saharan Africa for the past 15 years. Billions of dollars have been invested to provide interventions such as bed nets and antimalarial drugs but the overall effect on malaria burden remains unclear. This study uses field data from 30,000 population clusters in a sophisticated space–time modelling framework to quantify the changing Plasmodium falciparum risk (a 40% decline in case incidence since 2000) and the role of malaria interventions (around 700 million cases averted). Although below target levels, the current campaign has substantially reduced the incidence of malaria across the continent. Continued success will depend upon increasing access to these interventions, and maintaining their effectiveness in the face of insecticide and drug resistance.

Immune escape describes a critical event whereby tumor cells adopt an immunoresistant phenotype to escape adaptive surveillance. We show that expression of a pivotal negative regulator of T-cell function, B7-H1, correlates with PI(3) kinase activation in breast and prostate cancer patients. B7-H1-mediated immunoresistance can be attenuated by inhibitors of the PI(3) kinase pathway, and is dependent on S6K1-mediated translational regulation of B7-H1 protein. Breast and prostate carcinoma cells with activated PI(3) kinase lose the immunoresistant phenotype after treatment with B7-H1 siRNA. Conversely, breast and prostate carcinoma cells with minimal PI(3) kinase activation adopt an immunoresistant phenotype when engineered to overexpress B7-H1 protein. These observations describe a mechanism for immune escape from tumor dormancy in humans that relates to oncogenesis.

Health systems vary widely in performance, and countries with similar levels of income, education and health expenditure differ in their ability to attain key health goals. This paper proposes a framework to advance the understanding of health system performance. A first step is to define the boundaries of the health system, based on the concept of health action. Health action is defined as any set of activities whose primary intent is to improve or maintain health. Within these boundaries, the concept of performance is centred around three fundamental goals: improving health, enhancing responsiveness to the expectations of the population, and assuring fairness of financial contribution. Improving health means both increasing the average health status and reducing health inequalities. Responsiveness includes two major components: (a) respect for persons (including dignity, confidentiality and autonomy of individuals and families to decide about their own health); and (b) client orientation (including prompt attention, access to social support networks during care, quality of basic amenities and choice of provider). Fairness of financial contribution means that every household pays a fair share of the total health bill for a country (which may mean that very poor households pay nothing at all). This implies that everyone is protected from financial risks due to health care. The measurement of performance relates goal attainment to the resources available. Variation in performance is a function of the way in which the health system organizes four key functions: stewardship (a broader concept than regulation); financing (including revenue collection, fund pooling and purchasing); service provision (for personal and non-personal health services); and resource generation (including personnel, facilities and knowledge). By investigating these four functions and how they combine, it is possible not only to understand the proximate determinants of health system performance, but also to contemplate major policy challenges.

Key summary points Aim To describe the prevalence of probable sarcopenia in a sample of older adults and to investigate (1) the SARC-F tool and (2) clinical risk factors in the identification of probable sarcopenia. Findings The prevalence of probable sarcopenia at age 69 was 19%, and a SARC-F score of ≥ 1 had a reasonable balance of sensitivity (65%) and specificity (72%) for probable sarcopenia. Three clinical risk factors were independently associated with probable sarcopenia: polypharmacy, lower body osteoarthritis and physical inactivity. Message Those with any positive responses to the questions in the SARC-F tool, a history of polypharmacy, lower body osteoarthritis or physical inactivity should be prioritised for the assessment of muscle strength. Purpose The European Working Group on Sarcopenia in Older People 2 (EWGSOP2) consensus definition introduced the concept of probable sarcopenia as a basis on which to begin treatment. Our aims were to describe the prevalence of probable sarcopenia in older adults and to investigate the utility of (1) the SARC-F tool and (2) clinical risk factors for the identification of those likely to have probable sarcopenia. Methods We used data from the 1946 British birth cohort at age 69, with 1686 participants included in the analyses. We used the EWGSOP2 cut points for weak grip strength and slow chair rise time, with the presence of one or both indicating probable sarcopenia. We examined the sensitivity and specificity of the SARC-F tool for probable sarcopenia. We also examined associations between clinical risk factors and probable sarcopenia. Results The prevalence of probable sarcopenia was 19%. A SARC-F score of ≥ 4 had low sensitivity (15%) and high specificity (99%) for probable sarcopenia, whereas a score of ≥ 1 had higher sensitivity (65%) and reasonable specificity (72%). Three clinical risk factors were independently associated with probable sarcopenia: polypharmacy [OR 2.7 (95% CI 1.7, 4.2)], lower body osteoarthritis [OR 1.8 (95% CI 1.3, 2.6)] and physical inactivity [OR of 2.1 (95% CI 1.5, 2.8)]. Conclusion We have shown that EWGSOP2 probable sarcopenia is common in community-dwelling adults in early old age. Those with any positive responses to the questions in the SARC-F tool, a history of polypharmacy, lower body osteoarthritis or physical inactivity should be prioritised for the assessment of muscle strength.

A collection of 1,108 case–parent trios ascertained through an isolated, nonsyndromic cleft lip with or without cleft palate (CL/P) was used to replicate the findings from a genome-wide association study (GWAS) conducted by Beaty et al. (Nat Genet 42:525–529, 2010 ), where four different genes/regions were identified as influencing risk to CL/P. Tagging SNPs for 33 different genes were genotyped (1,269 SNPs). All four of the genes originally identified as showing genome-wide significance ( IRF6 , ABCA4 and MAF , plus the 8q24 region) were confirmed in this independent sample of trios (who were primarily of European and Southeast Asian ancestry). In addition, eight genes classified as ‘second tier’ hits in the original study ( PAX7 , THADA , COL8A1/FILIP1L , DCAF4L2 , GADD45G , NTN1 , RBFOX3 and FOXE1 ) showed evidence of linkage and association in this replication sample. Meta-analysis between the original GWAS trios and these replication trios showed PAX7 , COL8A1/FILIP1L and NTN1 achieved genome-wide significance. Tests for gene–environment interaction between these 33 genes and maternal smoking found evidence for interaction with two additional genes: GRID2 and ELAVL2 among European mothers (who had a higher rate of smoking than Asian mothers). Formal tests for gene–gene interaction (epistasis) failed to show evidence of statistical interaction in any simple fashion. This study confirms that many different genes influence risk to CL/P.

Met is a receptor tyrosine kinase that promotes cancer progression. In addition, Met has been implicated in resistance of tumors to various targeted therapies such as epidermal growth factor receptor inhibitors in lung cancers, and has been prioritized as a key molecular target for cancer therapy. However, the underlying mechanism of resistance to Met-targeting drugs is poorly understood. Here, we describe screening of 1310 genes to search for key regulators related to drug resistance to an anti-Met therapeutic antibody (SAIT301) by using a small interfering RNA-based synthetic lethal screening method. We found that knockdown of 69 genes in Met-amplified MKN45 cells sensitized the antitumor activity of SAIT301. Pathway analysis of these 69 genes implicated fibroblast growth factor receptor (FGFR) as a key regulator for antiproliferative effects of Met-targeting drugs. Inhibition of FGFR3 increased target cell apoptosis through the suppression of Bcl-xL expression, followed by reduced cancer cell growth in the presence of Met-targeting drugs. Treatment of cells with the FGFR inhibitors substantially restored the efficacy of SAIT301 in SAIT301-resistant cells and enhanced the efficacy in SAIT301-sensitive cells. In addition to FGFR3, integrin β3 is another potential target for combination treatment with SAIT301. Suppression of integrin β3 decreased AKT phosphorylation in SAIT301-resistant cells and restored SAIT301 responsiveness in HCC1954 cells, which are resistant to SAIT301. Gene expression analysis using CCLE database shows that cancer cells with high levels of FGFR and integrin β3 are resistant to crizotinib treatment, suggesting that FGFR and integrin β3 could be used as predictive markers for Met-targeted therapy and provide a potential therapeutic option to overcome acquired and innate resistance for the Met-targeting drugs.

In this study, we sought to determine the association between tooth agenesis and DNA sequence variation in the genes MSX1 and PAX9 in an ethnically diverse human population. Since cleft lip/palate is also associated with both tooth agenesis and the gene TGFA, we included TGFA in the analysis as well. Cheek swab samples were obtained for DNA analysis from 116 case/parent trios. Probands had at least one developmentally missing tooth, excluding third molars. Genotyping was performed by single-strand conformational polymorphism or kinetic polymerase chain-reaction assays. Transmission distortion of the marker alleles and DNA sequence analysis was performed. Results showed that tooth agenesis is associated with markers of the genes MSX1 and TGFA. No mutations were found in MSX1 or PAX9 coding regions. There were statistically significant data suggesting that MSX1 interacts with PAX9. These findings suggest that MSX1, PAX9, and TGFA play a role in isolated dental agenesis.