Neuropathic pain develops normally in mice lacking both Na(v)1.7 and Na(v)1.8

Two voltage gated sodium channel α-subunits, Na(v)1.7 and Na(v)1.8, are expressed at high levels in nociceptor terminals and have been implicated in the development of inflammatory pain. Mis-expression of voltage-gated sodium channels by damaged sensory neurons has also been implicated in the development of neuropathic pain, but the role of Na(v)1.7 and Na(v)1.8 is uncertain. Here we show that deleting Na(v)1.7 has no effect on the development of neuropathic pain. Double knockouts of both Na(v)1.7 and Na(v)1.8 also develop normal levels of neuropathic pain, despite a lack of inflammatory pain symptoms and altered mechanical and thermal acute pain thresholds. These studies demonstrate that, in contrast to the highly significant role for Na(v)1.7 in determining inflammatory pain thresholds, the development of neuropathic pain does not require the presence of either Na(v)1.7 or Na(v)1.8 alone or in combination

Investigating the effects of APSIM model configuration on model outputs across different environments

IntroductionSoil type plays a major role in nutrient dynamics and soil water which impacts crop growth and yield. The influence of soil characteristics on crop growth is usually evaluated through field experimentation (in the short term) and through crop-soil modelling (in the long-term). However, there has been limited research which has looked at the effect of model structural uncertainty of model outputs in different soil types.MethodsTo analyze the impact of soil inputs on model structural uncertainty, we developed eight model structures (a combination of two crop models, two soil water models and two irrigation models) within the Agricultural Production Systems sIMulator (APSIM) across three soil types (Ferralsols, Alisols and Chernozems). By decomposing the mean proportion of variance and simulated values of the model outputs (yield, irrigation, drainage, nitrogen leaching and partial gross margin) we identified the influence of soil type on the magnitude of model structural uncertainty.ResultsFor all soil types, crop model was the most significant source of structural uncertainty, contributing >60% to variability for most modelled variables, except irrigation demand which was dominated by the choice of irrigation model applied. Relative to first order interactions, there were minimal (<12%) contributions to uncertainty from the second order interactions (i.e., inter-model components). We found that a higher mean proportion of variance does not necessarily imply a high magnitude of uncertainty in actual values. Despite the significant impact of the choice of crop model on yield and PGM variance (contributing over 90%), the small standard deviations in simulated yield (ranging from 0.2 to 1 t ha-1) and PGM (ranging from 50.6 to 374.4 USD ha-1) compared to the mean values (yield: 14.6 t ha-1, PGM: 4901 USD ha-1) indicate relatively low actual uncertainty in the values. Similarly, the choice of irrigation model had a contribution of over 45% to variance, but the relatively small standard deviations ranging from 11 to 33.3 mm compared to the overall mean irrigation of 500 mm suggest low actual uncertainty in the values. In contrast, for the environmental variables- drainage and nitrogen leaching, the choice of crop model had contributions of more than 60% and 70% respectively, yet the relatively large standard deviations ranging from 7.1 to 30.6 mm and 0.6 to 7.7 kg ha-1 respectively, compared to the overall mean values of drainage (44.4 mm) and nitrogen leaching (3.2 kg ha-1), indicate significant actual uncertainty.DiscussionWe identified the need to include not only fractional variance of model uncertainty, but also magnitude of the contribution in measured units (e.g. t ha-1, mm, kg ha-1, USD ha-1) for crop model uncertainty assessments to provide more useful agronomic or policy decision-making information. The findings of this study highlight the sensitivity of agricultural models to the impacts of moisture availability, suggesting that it is important to give more attention to structural uncertainty when modelling dry/wet conditions depending on the output analyzed

Using participatory workshops to assess alignment or tension in the community for minimally invasive tissue sampling prior to start of child mortality surveillance: lessons From 5 sites across the CHAMPS network

The Child Health and Mortality Prevention Surveillance (CHAMPS) program is a 7-country network (as of December 2018) established by the Bill & Melinda Gates Foundation to identify the causes of death in children in communities with high rates of under-5 mortality. The program carries out both mortality and pregnancy surveillance, and mortality surveillance employs minimally invasive tissue sampling (MITS) to gather small samples of body fluids and tissue from the bodies of children who have died. While this method will lead to greater knowledge of the specific causes of childhood mortality, the procedure is in tension with cultural and religious norms in many of the countries where CHAMPS works - Bangladesh, Ethiopia, Kenya, Mali, Mozambique, Sierra Leone, and South Africa. Participatory Inquiry Into Community Knowledge of Child Health and Mortality Prevention (PICK-CHAMP) is a community entry activity designed to introduce CHAMPS to communities and gather initial perspectives on alignments and tensions between CHAMPS activities and community perceptions and priorities. Participants' responses revealed medium levels of overall alignment in all sites (with the exception of South Africa, where alignment was high) and medium levels of tension (with the exception of Ethiopia, where tension was high). Alignment was high and tension was low for pregnancy surveillance across all sites, whereas Ethiopia reflected low alignment and high tension for MITS. Participants across all sites indicated that support for MITS was possible only if the procedure did not interfere with burial practices and rituals

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Global, regional, and national burden of chronic kidney disease, 1990–2017 : a systematic analysis for the Global Burden of Disease Study 2017

Background Health system planning requires careful assessment of chronic kidney disease (CKD) epidemiology, but data for morbidity and mortality of this disease are scarce or non-existent in many countries. We estimated the global, regional, and national burden of CKD, as well as the burden of cardiovascular disease and gout attributable to impaired kidney function, for the Global Burden of Diseases, Injuries, and Risk Factors Study 2017. We use the term CKD to refer to the morbidity and mortality that can be directly attributed to all stages of CKD, and we use the term impaired kidney function to refer to the additional risk of CKD from cardiovascular disease and gout. Methods The main data sources we used were published literature, vital registration systems, end-stage kidney disease registries, and household surveys. Estimates of CKD burden were produced using a Cause of Death Ensemble model and a Bayesian meta-regression analytical tool, and included incidence, prevalence, years lived with disability, mortality, years of life lost, and disability-adjusted life-years (DALYs). A comparative risk assessment approach was used to estimate the proportion of cardiovascular diseases and gout burden attributable to impaired kidney function. Findings Globally, in 2017, 1·2 million (95% uncertainty interval [UI] 1·2 to 1·3) people died from CKD. The global all-age mortality rate from CKD increased 41·5% (95% UI 35·2 to 46·5) between 1990 and 2017, although there was no significant change in the age-standardised mortality rate (2·8%, −1·5 to 6·3). In 2017, 697·5 million (95% UI 649·2 to 752·0) cases of all-stage CKD were recorded, for a global prevalence of 9·1% (8·5 to 9·8). The global all-age prevalence of CKD increased 29·3% (95% UI 26·4 to 32·6) since 1990, whereas the age-standardised prevalence remained stable (1·2%, −1·1 to 3·5). CKD resulted in 35·8 million (95% UI 33·7 to 38·0) DALYs in 2017, with diabetic nephropathy accounting for almost a third of DALYs. Most of the burden of CKD was concentrated in the three lowest quintiles of Socio-demographic Index (SDI). In several regions, particularly Oceania, sub-Saharan Africa, and Latin America, the burden of CKD was much higher than expected for the level of development, whereas the disease burden in western, eastern, and central sub-Saharan Africa, east Asia, south Asia, central and eastern Europe, Australasia, and western Europe was lower than expected. 1·4 million (95% UI 1·2 to 1·6) cardiovascular disease-related deaths and 25·3 million (22·2 to 28·9) cardiovascular disease DALYs were attributable to impaired kidney function. Interpretation Kidney disease has a major effect on global health, both as a direct cause of global morbidity and mortality and as an important risk factor for cardiovascular disease. CKD is largely preventable and treatable and deserves greater attention in global health policy decision making, particularly in locations with low and middle SDI

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN