Systemic anticoagulation in the setting of vascular extremity trauma

Introduction There is conflicting data regarding if patients with vascular extremity trauma who undergo surgical treatment need to be systematically anticoagulated. We hypothesized that intraoperative systemic anticoagulation (ISA) decreased the risk of repair thrombosis or limb amputation after traumatic vascular injury of the extremities. Methods We analyzed a composite risk of repair thrombosis and/or limb amputation (RTLA) between patients who did and did not undergo ISA during arterial injury repair. Patient data was collected in the American Association for the Surgery of Trauma PROspective Vascular Injury Treatment (PROOVIT) registry. This registry contains demographic, diagnostic, treatment, and outcome data. Results Between February 2013 and August 2015, 193 patients with upper or lower extremity arterial injuries who underwent open operative repair were entered into the PROOVIT registry. The majority were male (87%) with a mean age of 32.6 years (range 4–91) and 74% injured by penetrating mechanism. 63% of the injuries were described as arterial transection and 37% had concomitant venous injury. 62% of patients underwent ISA. RTLA occurred in 22 patients (11%) overall, with no significant difference in these outcomes between patients who received ISA and those that did not (10% vs. 14%, p = 0.6). There was, however, significantly higher total blood product use noted among patients treated with ISA versus those that did not receive ISA (median 3 units vs. 1 unit, p = 0.002). Patients treated with ISA also stayed longer in the ICU (median 3 days vs. 1 day, p = 0.001) and hospital (median 9.5 days vs. 6 days, p = 0.01). Discussion In this multicenter prospective cohort, intraoperative systemic anticoagulation was not associated with a difference in rate of repair thrombosis or limb loss; but was associated with an increase in blood product requirements and prolonged hospital stay. Our data suggest there is no significant difference in outcome to support use of ISA for repair of traumatic arterial injuries

Homotopic functional connectivity disruptions in glioma patients are associated with tumor malignancy and overall survival

BACKGROUND: Gliomas exhibit widespread bilateral functional connectivity (FC) alterations that may be associated with tumor grade. Limited studies have examined the connection-level mechanisms responsible for these effects. Given the typically strong FC observed between mirroring/homotopic brain regions in healthy subjects, we hypothesized that homotopic connectivity (HC) is altered in low-grade and high-grade glioma patients and the extent of disruption is associated with tumor grade and predictive of overall survival (OS) in a cohort of METHODS: We used a mirrored FC-derived cortical parcellation to extract blood-oxygen-level-dependent (BOLD) signals and to quantify FC differences between homotopic pairs in normal-appearing brain in a retrospective cohort of glioma patients and healthy controls. RESULTS: Fifty-nine glioma patients (WHO grade 2, CONCLUSIONS: These findings demonstrate an association between tumor grade and HC alterations that may underlie global FC changes and provide prognostic information

Functional connectivity within glioblastoma impacts overall survival

BACKGROUND: Glioblastoma (GBM; World Health Organization grade IV) assumes a variable appearance on MRI owing to heterogeneous proliferation and infiltration of its cells. As a result, the neurovascular units responsible for functional connectivity (FC) may exist within gross tumor boundaries, albeit with altered magnitude. Therefore, we hypothesize that the strength of FC within GBMs is predictive of overall survival. METHODS: We used predefined FC regions of interest (ROIs) in de novo GBM patients to characterize the presence of within-tumor FC observable via resting-state functional MRI and its relationship to survival outcomes. RESULTS: Fifty-seven GBM patients (mean age, 57.8 ± 13.9 y) were analyzed. Functionally connected voxels, not identifiable on conventional structural images, can be routinely found within the tumor mass and was not significantly correlated to tumor size. In patients with known survival times (n = 31), higher intranetwork FC strength within GBM tumors was associated with better overall survival even after accounting for clinical and demographic covariates. CONCLUSIONS: These findings suggest the possibility that functionally intact regions may persist within GBMs and that the extent to which FC is maintained may carry prognostic value and inform treatment planning

Consensus Recommendation for Mouse Models of Ocular Hypertension to Study Aqueous Humor Outflow and Its Mechanisms.

Due to their similarities in anatomy, physiology, and pharmacology to humans, mice are a valuable model system to study the generation and mechanisms modulating conventional outflow resistance and thus intraocular pressure. In addition, mouse models are critical for understanding the complex nature of conventional outflow homeostasis and dysfunction that results in ocular hypertension. In this review, we describe a set of minimum acceptable standards for developing, characterizing, and utilizing mouse models of open-angle ocular hypertension. We expect that this set of standard practices will increase scientific rigor when using mouse models and will better enable researchers to replicate and build upon previous findings

Dopamine, affordance and active inference.

The role of dopamine in behaviour and decision-making is often cast in terms of reinforcement learning and optimal decision theory. Here, we present an alternative view that frames the physiology of dopamine in terms of Bayes-optimal behaviour. In this account, dopamine controls the precision or salience of (external or internal) cues that engender action. In other words, dopamine balances bottom-up sensory information and top-down prior beliefs when making hierarchical inferences (predictions) about cues that have affordance. In this paper, we focus on the consequences of changing tonic levels of dopamine firing using simulations of cued sequential movements. Crucially, the predictions driving movements are based upon a hierarchical generative model that infers the context in which movements are made. This means that we can confuse agents by changing the context (order) in which cues are presented. These simulations provide a (Bayes-optimal) model of contextual uncertainty and set switching that can be quantified in terms of behavioural and electrophysiological responses. Furthermore, one can simulate dopaminergic lesions (by changing the precision of prediction errors) to produce pathological behaviours that are reminiscent of those seen in neurological disorders such as Parkinson's disease. We use these simulations to demonstrate how a single functional role for dopamine at the synaptic level can manifest in different ways at the behavioural level

HIV infection of non-dividing cells: a divisive problem

Understanding how lentiviruses can infect terminally differentiated, non-dividing cells has proven a very complex and controversial problem. It is, however, a problem worth investigating, for it is central to HIV-1 transmission and AIDS pathogenesis. Here I shall attempt to summarise what is our current understanding for HIV-1 infection of non-dividing cells. In some cases I shall also attempt to make sense of controversies in the field and advance one or two modest proposals

Citizen science breathes new life into participatory agricultural research : A review

Participatory research can improve the efficiency, effectiveness, and scope of research processes, and foster social inclusion, empowerment and sustainability. Yet despite four decades of agricultural research institutions exploring and developing methods for participatory research, it has never become mainstream in the agricultural technology development cycle. Citizen science promises an innovative approach to participation in research, using the unique facilities of new digital technologies, but its potential in agricultural research participation has not been systematically probed. To this end, we conducted a critical literature review. We found that citizen science opens up four opportunities for creatively reshaping research: i) new possibilities for interdisciplinary collaboration, ii) rethinking configurations of socio-computational systems, iii) research on democratization of science more broadly, and iv) new accountabilities. Citizen science also brings a fresh perspective on the barriers to institutionalizing participation in the agricultural sciences. Specifically, we show how citizen science can reconfigure cost-motivation-accountability combinations using digital tools, open up a larger conceptual space of experimentation, and stimulate new collaborations. With appropriate and persistent institutional support and investment, citizen science can therefore have a lasting impact on how agricultural science engages with farming communities and wider society, and more fully realize the promises of participation

Large-Scale Gene-Centric Meta-Analysis across 39 Studies Identifies Type 2 Diabetes Loci

To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with similar to 2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 x 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p <2.4 x 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 x 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 x 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 x 10(-8)). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups

Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease