Genetic Influences on Patient-Oriented Outcomes in Traumatic Brain Injury : A Living Systematic Review of Non-Apolipoprotein E Single-Nucleotide Polymorphisms

There is a growing literature on the impact of genetic variation on outcome in traumatic brain injury (TBI). Whereas a substantial proportion of these publications have focused on the apolipoprotein E (APOE) gene, several have explored the influence of other polymorphisms. We undertook a systematic review of the impact of single-nucleotide polymorphisms (SNPs) in non-apolipoprotein E (non-APOE) genes associated with patient outcomes in adult TBI). We searched EMBASE, MEDLINE, CINAHL, and gray literature from inception to the beginning of August 2017 for studies of genetic variance in relation to patient outcomes in adult TBI. Sixty-eight articles were deemed eligible for inclusion into the systematic review. The SNPs described were in the following categories: neurotransmitter (NT) in 23, cytokine in nine, brain-derived neurotrophic factor (BDNF) in 12, mitochondrial genes in three, and miscellaneous SNPs in 21. All studies were based on small patient cohorts and suffered from potential bias. A range of SNPs associated with genes coding for monoamine NTs, BDNF, cytokines, and mitochondrial proteins have been reported to be associated with variation in global, neuropsychiatric, and behavioral outcomes. An analysis of the tissue, cellular, and subcellular location of the genes that harbored the SNPs studied showed that they could be clustered into blood-brain barrier associated, neuroprotective/regulatory, and neuropsychiatric/degenerative groups. Several small studies report that various NT, cytokine, and BDNF-related SNPs are associated with variations in global outcome at 6-12 months post-TBI. The association of these SNPs with neuropsychiatric and behavioral outcomes is less clear. A definitive assessment of role and effect size of genetic variation in these genes on outcome remains uncertain, but could be clarified by an adequately powered genome-wide association study with appropriate recording of outcomes.Peer reviewe

Emergence of Variability in Isogenic Escherichia coli Populations Infected by a Filamentous Virus

The spread of epidemics not only depends on the average number of parasites produced per host, but also on the existence of highly infectious individuals. It is widely accepted that infectiousness depends on genetic and environmental determinants. However, even in clonal populations of host and viruses growing in homogeneous conditions, high variability can exist. Here we show that Escherichia coli cells commonly display high differentials in viral burst size, and address the kinetics of emergence of such variability with the non-lytic filamentous virus M13. By single-cell imaging of a virally-encoded fluorescent reporter, we monitor the viral charge distribution in infected bacterial populations at different time following infection. A mathematical model assuming autocatalytic virus replication and inheritance of bacterial growth rates quantitatively reproduces the experimental distributions, demonstrating that deterministic amplification of small host inhomogeneities is a mechanism sufficient to explain large and highly skewed distributions. This mechanism of amplification is general and may occur whenever a parasite has an initial phase of exponential growth within its host. Moreover, it naturally reproduces the shift towards higher virulence when the host is experimenting poor conditions, as observed commonly in host-parasite systems

Shades of empire: police photography in German South-West Africa

This article looks at a photographic album produced by the German police in colonial Namibia just before World War I. Late 19th- and early 20th-century police photography has often been interpreted as a form of visual production that epitomized power and regimes of surveillance imposed by the state apparatuses on the poor, the criminal and the Other. On the other hand police and prison institutions became favored sites where photography could be put at the service of the emergent sciences of the human body—physiognomy, anthropometry and anthropology. While the conjuncture of institutionalized colonial state power and the production of scientific knowledge remain important for this Namibian case study, the article explores a slightly different set of questions. Echoing recent scholarship on visuality and materiality the photographic album is treated as an archival object and visual narrative that was at the same time constituted by and constitutive of material and discursive practices within early 20th-century police and prison institutions in the German colony. By shifting attention away from image content and visual codification alone toward the question of visual practice the article traces the ways in which the photo album, with its ambivalent, unstable and uncontained narrative, became historically active and meaningful. Therein the photographs were less informed by an abstract theory of anthropological and racial classification but rather entrenched with historically contingent processes of colonial state constitution, socioeconomic and racial stratification, and the institutional integration of photography as a medium and a technology into colonial policing. The photo album provides a textured sense of how fragmented and contested these processes remained throughout the German colonial period, but also how photography could offer a means of transcending the limits and frailties brought by the realities on the ground.International Bibliography of Social Science

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

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 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

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Cross-sectional associations of reallocating time between sedentary and active behaviours on cardiometabolic risk factors in young people: An International Children’s Accelerometry Database (ICAD) analysis

Introduction: Sedentary time and time spent in various intensity-specific physical activity are co-dependent, and increasing time spent in one behaviour requires decreased time in another. Objective: The aim of the present study was to examine the theoretical associations with reallocating time between categories of intensities and cardiometabolic risk factors in a large and heterogeneous sample of children and adolescents. Methods: We analysed pooled data from 13 studies comprising 18,200 children and adolescents aged 4–18 years from the International Children’s Accelerometry Database (ICAD). Waist-mounted accelerometers measured sedentary time, light physical activity (LPA) and moderate-to-vigorous physical activity (MVPA). Cardiometabolic risk factors included waist circumference (WC), systolic blood pressure (SBP), fasting high- and low-density lipoprotein cholesterol (HDL-C and LDL-C), triglycerides, insulin, and glucose. Associations of reallocating time between the various intensity categories with cardiometabolic risk factors were explored using isotemporal substitution modelling. Results: Replacing 10 min of sedentary time with 10 min of MVPA showed favourable associations with WC, SBP, LDL-C, insulin, triglycerides, and glucose; the greatest magnitude was observed for insulin (reduction of 2–4%), WC (reduction of 0.5–1%), and triglycerides (1–2%). In addition, replacing 10 min of sedentary time with an equal amount of LPA showed beneficial associations with WC, although only in adolescents. Conclusions: Replacing sedentary time and/or LPA with MVPA in children and adolescents is favourably associated with most markers of cardiometabolic risk. Efforts aimed at replacing sedentary time with active behaviours, particularly those of at least moderate intensity, appear to be an effective strategy to reduce cardiometabolic risk in young people

Cross-Sectional Associations of Reallocating Time Between Sedentary and Active Behaviours on Cardiometabolic Risk Factors in Young People:An International Children’s Accelerometry Database (ICAD) Analysis

Introduction: Sedentary time and time spent in various intensity-specific physical activity are co-dependent, and increasing time spent in one behaviour requires decreased time in another. Objective: The aim of the present study was to examine the theoretical associations with reallocating time between categories of intensities and cardiometabolic risk factors in a large and heterogeneous sample of children and adolescents. Methods: We analysed pooled data from 13 studies comprising 18,200 children and adolescents aged 4–18 years from the International Children’s Accelerometry Database (ICAD). Waist-mounted accelerometers measured sedentary time, light physical activity (LPA) and moderate-to-vigorous physical activity (MVPA). Cardiometabolic risk factors included waist circumference (WC), systolic blood pressure (SBP), fasting high- and low-density lipoprotein cholesterol (HDL-C and LDL-C), triglycerides, insulin, and glucose. Associations of reallocating time between the various intensity categories with cardiometabolic risk factors were explored using isotemporal substitution modelling. Results: Replacing 10 min of sedentary time with 10 min of MVPA showed favourable associations with WC, SBP, LDL-C, insulin, triglycerides, and glucose; the greatest magnitude was observed for insulin (reduction of 2–4%), WC (reduction of 0.5–1%), and triglycerides (1–2%). In addition, replacing 10 min of sedentary time with an equal amount of LPA showed beneficial associations with WC, although only in adolescents. Conclusions: Replacing sedentary time and/or LPA with MVPA in children and adolescents is favourably associated with most markers of cardiometabolic risk. Efforts aimed at replacing sedentary time with active behaviours, particularly those of at least moderate intensity, appear to be an effective strategy to reduce cardiometabolic risk in young people

The Australasian Resuscitation In Sepsis Evaluation : fluids or vasopressors in emergency department sepsis (ARISE FLUIDS), a multi-centre observational study describing current practice in Australia and New Zealand

Objectives: To describe haemodynamic resuscitation practices in ED patients with suspected sepsis and hypotension. Methods: This was a prospective, multicentre, observational study conducted in 70 hospitals in Australia and New Zealand between September 2018 and January 2019. Consecutive adults presenting to the ED during a 30-day period at each site, with suspected sepsis and hypotension (systolic blood pressure <100 mmHg) despite at least 1000 mL fluid resuscitation, were eligible. Data included baseline demographics, clinical and laboratory variables and intravenous fluid volume administered, vasopressor administration at baseline and 6- and 24-h post-enrolment, time to antimicrobial administration, intensive care admission, organ support and in-hospital mortality. Results: A total of 4477 patients were screened and 591 were included with a mean (standard deviation) age of 62 (19) years, Acute Physiology and Chronic Health Evaluation II score 15.2 (6.6) and a median (interquartile range) systolic blood pressure of 94 mmHg (87–100). Median time to first intravenous antimicrobials was 77 min (42–148). A vasopressor infusion was commenced within 24 h in 177 (30.2%) patients, with noradrenaline the most frequently used (n = 138, 78%). A median of 2000 mL (1500–3000) of intravenous fluids was administered prior to commencing vasopressors. The total volume of fluid administered from pre-enrolment to 24 h was 4200 mL (3000–5661), with a range from 1000 to 12 200 mL. Two hundred and eighteen patients (37.1%) were admitted to an intensive care unit. Overall in-hospital mortality was 6.2% (95% confidence interval 4.4–8.5%). Conclusion: Current resuscitation practice in patients with sepsis and hypotension varies widely and occupies the spectrum between a restricted volume/earlier vasopressor and liberal fluid/later vasopressor strategy