Cerebral Venous Sinus Thrombosis in Children: A Multicenter Cohort From the United States

This study presents a large multicenter cohort of children with cerebral venous thrombosis from 5 centers in the United States and analyzes their clinical findings and risk factors. Seventy Patients were included in the study (25 neonates, 35%). The age ranged from 6 days to 12 years. Thirty-eight (55%) were younger than 6 months of age, and 28 (40%) were male. Presenting features included seizures (59%), coma (30%), headache (18%), and motor weakness (21%). Common neurological findings included decreased level of consciousness (50%), papilledema (18%), cranial nerve palsy (33%), hemiparesis (29%), and hypotonia (22%). Predisposing factors were identified in 63 (90%) Patients. These included infection (40%), perinatal complications (25%), hypercoagulable/hematological diseases (13%), and various other conditions (10%). Hemorrhagic infarcts occurred in 40% of the Patients and hydrocephalus in 10%. Transverse sinus thrombosis was more common (73%) than sagittal sinus thrombosis (35%). Three children underwent thrombolysis, 15 Patients received anticoagulation, and 49 (70%) were treated with antibiotics and hydration. Nine (13%) Patients (6 of them neonates) died. Twenty-nine Patients (41%) were normal, whereas 32 Patients (46%) had a neurological deficit at discharge. Seizures and coma at presentation were poor prognostic indicators. In conclusion, cerebral venous thrombosis predominantly affects children younger than age 6 months. Mortality is high (25%) in neonatal cerebral venous thrombosis. Only 18 (25%) Patients were treated with anticoagulation or thrombolysis

Shear friction strength of monolithic concrete interfaces

YesThis paper presents an integrated model for shear friction strength of monolithic concrete interfaces derived from the upper-bound theorem of concrete plasticity. The model accounts for the effects of applied axial stresses and transverse reinforcement on the shear friction action at interfacial shear cracks. Simple equations were also developed to generalize the effectiveness factor for compression, ratio of effective tensile to compressive strengths and angle of concrete friction. The reliability of the proposed model was then verified through comparisons with previous empirical equations and 103 push-off test specimens compiled from different sources in the literature. The previous equations considerably underestimate the concrete shear transfer capacity and the underestimation is notable for the interfaces subjected to additional axial stresses. The proposed model provides superior accuracy in predicting the shear friction strength, resulting in a mean between experimental and predicted friction strengths of 0.97 and least scatter. Moreover, the proposed model has consistent trends with test results in evaluating the effect of various parameters on the shear friction strength

E. coli metabolic protein aldehydealcohol dehydrogenase-E binds to the ribosome: a unique moonlighting action revealed

It is becoming increasingly evident that a high degree of regulation is involved in the protein synthesis machinery entailing more interacting regulatory factors. A multitude of proteins have been identified recently which show regulatory function upon binding to the ribosome. Here, we identify tight association of a metabolic protein aldehyde-alcohol dehydrogenase E (AdhE) with the E. coli 70S ribosome isolated from cell extract under low salt wash conditions. Cryo-EM reconstruction of the ribosome sample allows us to localize its position on the head of the small subunit, near the mRNA entrance. Our study demonstrates substantial RNA unwinding activity of AdhE which can account for the ability of ribosome to translate through downstream of at least certain mRNA helices. Thus far, in E. coli, no ribosome-associated factor has been identified that shows downstream mRNA helicase activity. Additionally, the cryo-EM map reveals interaction of another extracellular protein, outer membrane protein C (OmpC), with the ribosome at the peripheral solvent side of the 50S subunit. Our result also provides important insight into plausible functional role of OmpC upon ribosome binding. Visualization of the ribosome purified directly from the cell lysate unveils for the first time interactions of additional regulatory proteins with the ribosom

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Neuropathology of 16p13.11 Deletion in Epilepsy

16p13.11 genomic copy number variants are implicated in several neuropsychiatric disorders, such as schizophrenia, autism, mental retardation, ADHD and epilepsy. The mechanisms leading to the diverse clinical manifestations of deletions and duplications at this locus are unknown. Most studies favour NDE1 as the leading disease-causing candidate gene at 16p13.11. In epilepsy at least, the deletion does not appear to unmask recessive-acting mutations in NDE1, with haploinsufficiency and genetic modifiers being prime candidate disease mechanisms. NDE1 encodes a protein critical to cell positioning during cortical development. As a first step, it is important to determine whether 16p13.11 copy number change translates to detectable brain structural alteration. We undertook detailed neuropathology on surgically resected brain tissue of two patients with intractable mesial temporal lobe epilepsy (MTLE), who had the same heterozygous NDE1-containing 800 kb 16p13.11 deletion, using routine histological stains and immunohistochemical markers against a range of layer-specific, white matter, neural precursor and migratory cell proteins, and NDE1 itself. Surgical temporal lobectomy samples from a MTLE case known not to have a deletion in NDE1 and three non-epilepsy cases were included as disease controls. We found that apart from a 3 mm hamartia in the temporal cortex of one MTLE case with NDE1 deletion and known hippocampal sclerosis in the other case, cortical lamination and cytoarchitecture were normal, with no differences between cases with deletion and disease controls. How 16p13.11 copy changes lead to a variety of brain diseases remains unclear, but at least in epilepsy, it would not seem to be through structural abnormality or dyslamination as judged by microscopy or immunohistochemistry. The need to integrate additional data with genetic findings to determine their significance will become more pressing as genetic technologies generate increasingly rich datasets. Detailed examination of brain tissue, where available, will be an important part of this process in neurogenetic disease specifically

Thiram inhibits angiogenesis and slows the development of experimental tumours in mice

Thiram-tetramethylthiuram disulphide – a chelator of heavy metals, inhibited DNA synthesis and induced apoptosis in cultured bovine capillary endothelial cells. Bovine capillary endothelial cells were 10–60-fold more sensitive to thiram than other cell types. These effects were prevented by addition of antioxidants, indicating involvement of reactive oxygen species. Exogenously added Cu2+ impeded specifically and almost completely the inhibitory effect of thiram for bovine capillary endothelial cells. Moreover, thiram had markedly inhibited human recombinant Cu/Zn superoxide dismutase enzymatic activity (85%) in vitro. Moreover, PC12-SOD cells with elevated Cu/Zn superoxide dismutase were less sensitive to thiram treatment than control cells. These data indicate that the effects of thiram are mediated by inhibition of Cu/Zn superoxide dismutase activity. Oral administration of thiram (13–30 μg mouse−1), inhibited angiogenesis in CD1 nude mice. Tumour development is known to largely depend on angiogenesis. We found that oral administration of thiram (30 μg) to mice caused significant inhibition of C6 glioma tumour development (60%) and marked reduction (by 3–5-fold) in metastatic growth of Lewis lung carcinoma. The data establish thiram as a potential inhibitor of angiogenesis and raise the possibility for its use as therapy in pathologies in which neovascularisation is involved, including neoplasia

Child wasting and concurrent stunting in low- and middle-income countries

Sustainable Development Goal 2.2—to end malnutrition by 2030—includes the elimination of child wasting, defined as a weight-for-length z-score that is more than two standard deviations below the median of the World Health Organization standards for child growth 1. Prevailing methods to measure wasting rely on cross-sectional surveys that cannot measure onset, recovery and persistence—key features that inform preventive interventions and estimates of disease burden. Here we analyse 21 longitudinal cohorts and show that wasting is a highly dynamic process of onset and recovery, with incidence peaking between birth and 3 months. Many more children experience an episode of wasting at some point during their first 24 months than prevalent cases at a single point in time suggest. For example, at the age of 24 months, 5.6% of children were wasted, but by the same age (24 months), 29.2% of children had experienced at least one wasting episode and 10.0% had experienced two or more episodes. Children who were wasted before the age of 6 months had a faster recovery and shorter episodes than did children who were wasted at older ages; however, early wasting increased the risk of later growth faltering, including concurrent wasting and stunting (low length-for-age z-score), and thus increased the risk of mortality. In diverse populations with high seasonal rainfall, the population average weight-for-length z-score varied substantially (more than 0.5 z in some cohorts), with the lowest mean z-scores occurring during the rainiest months; this indicates that seasonally targeted interventions could be considered. Our results show the importance of establishing interventions to prevent wasting from birth to the age of 6 months, probably through improved maternal nutrition, to complement current programmes that focus on children aged 6–59 months

Causes and consequences of child growth faltering in low-resource settings

Growth faltering in children (low length for age or low weight for length) during the first 1,000 days of life (from conception to 2 years of age) influences short-term and long-term health and survival 1,2. Interventions such as nutritional supplementation during pregnancy and the postnatal period could help prevent growth faltering, but programmatic action has been insufficient to eliminate the high burden of stunting and wasting in low- and middle-income countries. Identification of age windows and population subgroups on which to focus will benefit future preventive efforts. Here we use a population intervention effects analysis of 33 longitudinal cohorts (83,671 children, 662,763 measurements) and 30 separate exposures to show that improving maternal anthropometry and child condition at birth accounted for population increases in length-for-age z-scores of up to 0.40 and weight-for-length z-scores of up to 0.15 by 24 months of age. Boys had consistently higher risk of all forms of growth faltering than girls. Early postnatal growth faltering predisposed children to subsequent and persistent growth faltering. Children with multiple growth deficits exhibited higher mortality rates from birth to 2 years of age than children without growth deficits (hazard ratios 1.9 to 8.7). The importance of prenatal causes and severe consequences for children who experienced early growth faltering support a focus on pre-conception and pregnancy as a key opportunity for new preventive interventions