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Background Child survival initiatives historically prioritized efforts to reduce child morbidity and mortality from infectious diseases and maternal conditions. Little attention has been devoted to paediatric injuries in resource‐limited settings. This study aimed to evaluate the demographics and outcomes of paediatric injury in a sub‐Saharan African country in an effort to improve prevention and treatment. Methods A prospective trauma registry was established at the two university teaching campuses of the University of Rwanda to record systematically patient demographics, prehospital care, initial physiology and patient outcomes from May 2011 to July 2015. Univariable analysis was performed for demographic characteristics, injury mechanisms, geographical location and outcomes. Multivariable analysis was performed for mortality estimates. Results Of 11 036 patients in the registry, 3010 (27·3 per cent) were under 18 years of age. Paediatric patients were predominantly boys (69·9 per cent) and the median age was 8 years. The mortality rate was 4·8 per cent. Falls were the most common injury (45·3 per cent), followed by road traffic accidents (30·9 per cent), burns (10·7 per cent) and blunt force/assault (7·5 per cent). Patients treated in the capital city, Kigali, had a higher incidence of head injury (7·6 per cent versus 2·0 per cent in a rural town, P < 0·001; odds ratio (OR) 4·08, 95 per cent c.i. 2·61 to 6·38) and a higher overall injury‐related mortality rate (adjusted OR 3·00, 1·50 to 6·01; P = 0·019). Pedestrians had higher overall injury‐related mortality compared with other road users (adjusted OR 3·26, 1·37 to 7·73; P = 0·007). Conclusion Paediatric injury is a significant contributor to morbidity and mortality. Delineating trauma demographics is important when planning resource utilization and capacity‐building efforts to address paediatric injury in low‐resource settings and identify vulnerable populations. This study evaluated the demographics and outcomes of paediatric injury in Rwanda through a prospective trauma registry to inform capacity‐building for prevention and treatment. Patients treated in the capital city had a higher incidence of head injury and a higher overall injury‐related mortality than those in a rural town. Pedestrians had higher overall injury‐related mortality compared with other road‐users. Falls and road traffic accidents significant contributors to pediatric injury in Rwanda

Limited data exist evaluating the effect of blood pressure (BP) on clinical outcomes among patients with acute ischemic stroke with large vessel occlusion treated with mechanical thrombectomy (MT). We sought to evaluate the association of BP levels on clinical outcomes among patients with acute ischemic stroke with large vessel occlusion treated with MT. Studies were identified that reported the association of systolic BP (SBP) or diastolic BP levels before, during, or after MT on the outcomes of patients with acute ischemic stroke treated with MT. Unadjusted and adjusted analyses of studies reporting odds ratios (OR adj ) per 10 mm Hg BP increment were performed. Our analysis included 25 studies comprising 6474 patients. Higher pre-MT mean SBP ( P =0.008) and post-MT maximum SBP ( P =0.009) levels were observed in patients who died within 3 months. Patients with 3-month functional independence were noted to have lower pre-MT ( P <0.001) and post-MT maximum SBP levels ( P <0.001). In adjusted analyses, increasing post-MT maximum SBP and diastolic BP levels were associated with 3-month mortality (OR adj , 1.19 [95% CI,1.00–1.43]; I 2 =78%, P value for Cochran Q test: 0.001) and symptomatic intracranial hemorrhage (OR adj , 1.65 [95% CI, 1.11–2.44]; I 2 =0%, P value for Cochran Q test: 0.80), respectively. Increasing pre- and post-MT mean SBP levels were associated with lower odds of 3-month functional independence (OR adj , 0.86 [95% CI, 0.77–0.96]; I 2 =18%, P value for Cochran Q test: 0.30) and (OR adj , 0.80 [95% CI, 0.72–0.89]; I 2 =0%, P value for Cochran Q test: 0.51), respectively. In conclusion, elevated BP levels before and after MT are associated with adverse outcomes among patients with acute ischemic stroke with large vessel occlusion.

The HIV Research for Prevention (HIVR4P) conference is dedicated to advancing HIV prevention research, responding to a growing consensus that effective and durable prevention will require a combination of approaches as well as unprecedented collaboration among scientists, practitioners, and community workers from different fields and geographic areas. The conference theme in 2018, "From Research to Impact," acknowledged an increasing focus on translation of promising research findings into practical, accessible, and affordable HIV prevention options for those who need them worldwide. HIVR4P 2018 was held in Madrid, Spain, on 21-25 October, with >1,400 participants from 52 countries around the globe, representing all aspects of HIV prevention research and implementation. The program included 137 oral and 610 poster presentations. This article presents a brief summary of highlights from the conference. More detailed information, complete abstracts as well as webcasts and daily Rapporteur summaries may be found on the conference website. Supported by Gilead who provided funding. Gilead has had no input into the content of the materials used at this meeting/conference. No other pharmaceutical company has had input into the content of the materials used at this conference. HIVR4P 2018 was made possible in part by 1 R13 AI136762-01 from the National Institute of Allergy and Infectious Diseases (NIAID). The views expressed in written conference materials or publications and by speakers and moderators do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention of trade names, commercial practices, or organizations imply endorsement by the U.S. Government. Sí

Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10−8) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction. B.C.A.C. was funded through a European Community Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175; COGS); Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692); the National Institutes of Health Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), R01 grants (CA128978, CA176785, CA192393), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative); the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Breast Cancer Res. Foundation, and the Ovarian Cancer Research Fund. CIMBA genotyping was supported by National Institutes of Health grant (CA128978); the Department of Defence (W81XWH-10-1-0341); and the Breast Cancer Res. Foundation. CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. This study made use of data generated by the Wellcome Trust Case Control consortium. Functional studies were supported by the Florida Breast Cancer Foundation. A full description of funding and acknowledgments is provided in Supplementary Note 1.

Phospholamban and sarcolipin interact with the sarcoplasmic reticulum calcium pump (SERCA) and regulate contractility in smooth, cardiac and skeletal muscle. While both proteins can form oligomers, it is thought that only the monomers interact with and inhibit SERCA. To address the role of the phospholamban and sarcolipin pentamers, we have studied their interaction with SERCA using electron cryo-microscopy of two-dimensional co-crystals. In our previous studies, phospholamban oligomers were found interspersed between SERCA dimers and we constructed a three-dimensional model of the complex. We also addressed the molecular characteristics of phospholamban that contribute to its interaction with SERCA and we examined the effects of phosphorylation and mutation of phospholamban on the structure of the complex with SERCA. In our recent work, we compared two crystal forms of SERCA in the absence and presence of phospholamban by electron cryo-microscopy - namely, small helical crystals and large two-dimensional crystals. The SERCA dimer ribbons that are found in both crystal forms consist of a rigid assembly of calcium-free SERCA molecules. While the lattice formed by the SERCA dimer ribbons is different in the helical and two-dimensional crystals, we show that a phospholamban oligomer interacts with SERCA in a similar manner in both crystal types. With this information, we next undertook a structural investigation of SERCA and sarcolipin in the two-dimensional crystals. A projection map was determined for SERCA in the presence of sarcolipin to a resolution of 8.5 A and was consistent with a pentameric state for sarcolipin. While both phospholamban and sarcolipin interacted with transmembrane segment M3 of SERCA, the interaction of the sarcolipin pentamer was mediated by an additional density consistent with a SLN monomer. We conclude that pentameric forms of both phospholamban and sarcolipin naturally associate with SERCA.

Background: A long-standing epidemiological puzzle is the reduced rate of rheumatoid arthritis (RA) in those with schizophrenia (SZ) and vice versa. Traditional epidemiological approaches to determine if this negative association is underpinned by genetic factors would test for reduced rates of one disorder in relatives of the other, but sufficiently powered data sets are difficult to achieve. The genomics era presents an alternative paradigm for investigating the genetic relationship between two uncommon disorders. Methods: We use genome-wide common single nucleotide polymorphism (SNP) data from independently collected SZ and RA case-control cohorts to estimate the SNP correlation between the disorders. We test a genotype X environment (GxE) hypothesis for SZ with environment defined as winter- vs summer-born. Results: We estimate a small but significant negative SNP-genetic correlation between SZ and RA (−0.046, s.e. 0.026, P = 0.036). The negative correlation was stronger for the SNP set attributed to coding or regulatory regions (−0.174, s.e. 0.071, P = 0.0075). Our analyses led us to hypothesize a gene-environment interaction for SZ in the form of immune challenge. We used month of birth as a proxy for environmental immune challenge and estimated the genetic correlation between winter-born and non-winter born SZ to be significantly less than 1 for coding/regulatory region SNPs (0.56, s.e. 0.14, P = 0.00090). Conclusions: Our results are consistent with epidemiological observations of a negative relationship between SZ and RA reflecting, at least in part, genetic factors. Results of the month of birth analysis are consistent with pleiotropic effects of genetic variants dependent on environmental context. Refereed/Peer-reviewed

AbstractThe nature and distribution of the synaptic changes that underlie memory are not well understood. We examined the synaptic plasticity behind context fear learning and found that conditioning produced potentiation of excitatory synapses specifically onto the basolateral amygdala neurons activated during learning. This synaptic potentiation lasted at least 7 days, and its disruption impaired memory recall. High frequency optogenetic stimulation of the CS and US-activated ensembles or biochemical induction of synaptic potentiation in US-responsive neurons alone was sufficient to produce a context fear association without prior associative training. These results suggest that plasticity of CS inputs onto US-responsive amygdala neurons is a necessary and sufficient step in forming context fear associations, and that context discrimination is determined by the CS-specific amygdala inputs activated during retrieval.

Proteomic technologies, such as yeast two-hybrid, mass spectrometry (MS), protein/peptide arrays and fluorescence microscopy, yield multi-dimensional data sets, which are often quite large and either not published or published as supplementary information that is not easily searchable. Without a system in place for standardizing and sharing data, it is not fruitful for the biomedical community to contribute these types of data to centralized repositories.

© 2016 Elyashiv et al. Natural selection at one site shapes patterns of genetic variation at linked sites. Quantifying the effects of “linked selection” on levels of genetic diversity is key to making reliable inference about demography, building a null model in scans for targets of adaptation, and learning about the dynamics of natural selection. Here, we introduce the first method that jointly infers parameters of distinct modes of linked selection, notably background selection and selective sweeps, from genome-wide diversity data, functional annotations and genetic maps. The central idea is to calculate the probability that a neutral site is polymorphic given local annotations, substitution patterns, and recombination rates. Information is then combined across sites and samples using composite likelihood in order to estimate genome-wide parameters of distinct modes of selection. In addition to parameter estimation, this approach yields a map of the expected neutral diversity levels along the genome. To illustrate the utility of our approach, we apply it to genome-wide resequencing data from 125 lines in Drosophila melanogaster and reliably predict diversity levels at the 1Mb scale. Our results corroborate estimates of a high fraction of beneficial substitutions in proteins and untranslated regions (UTR). They allow us to distinguish between the contribution of sweeps and other modes of selection around amino acid substitutions and to uncover evidence for pervasive sweeps in untranslated regions (UTRs). Our inference further suggests a substantial effect of other modes of linked selection and of adaptation in particular. More generally, we demonstrate that linked selection has had a larger effect in reducing diversity levels and increasing their variance in D. melanogaster than previously appreciated.

The genetic association of the major histocompatibility complex (MHC) to rheumatoid arthritis risk has commonly been attributed to alleles in HLA-DRB1. However, debate persists about the identity of the causal variants in HLA-DRB1 and the presence of independent effects elsewhere in the MHC. Using existing genome-wide SNP data in 5,018 individuals with seropositive rheumatoid arthritis (cases) and 14,974 unaffected controls, we imputed and tested classical alleles and amino acid polymorphisms in HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1 and HLA-DRB1, as well as 3,117 SNPs across the MHC. Conditional and haplotype analyses identified that three amino acid positions (11, 71 and 74) in HLA-DRβ1 and single-amino-acid polymorphisms in HLA-B (at position 9) and HLA-DPβ1 (at position 9), which are all located in peptide-binding grooves, almost completely explain the MHC association to rheumatoid arthritis risk. This study shows how imputation of functional variation from large reference panels can help fine map association signals in the MHC.