Blunt Abdominal Trauma Patients Are at Very Low Risk for Intra-Abdominal Injury after Emergency Department Observation

<p>Introduction: Patients are commonly admitted to the hospital for observation following blunt abdominal trauma (BAT), despite initially negative emergency department (ED) evaluations. With the current use of screening technology, such as computed tomography (CT) of the abdomen and pelvis, ultrasound, and laboratory evaluations, it is unclear which patients require observation. The objective of this study was to determine the prevalence of intra-abdominal injury (IAI) and death in hemodynamically normal and stable BAT patients with initially negative ED evaluations admitted to an ED observation unit and to define a low-risk subgroup of patients and assess whether they may be discharged without abdominal/pelvic CT or observation. Methods: This was a retrospective cohort study performed at an urban level 1 trauma center and included all BAT patients admitted to an ED observation unit as part of a BAT key clinical pathway. All were observed for at least 8 hours as part of the key clinical pathway, and only minors and pregnant women were excluded. Outcomes included the presence of IAI or death during a 40-month follow-up period. Prior to data collection, low-risk criteria were defined as no intoxication, no hypotension or tachycardia, no abdominal pain or tenderness, no hematuria, and no distracting injury. To be considered low risk, patients needed to meet all low-risk criteria. Results: Of the 1,169 patients included over the 2-year study period, 29% received a CT of the abdomen and pelvis, 6% were admitted to the hospital from the observation unit for further management, 0.4% (95% confidence interval [CI], 0.1%–1%) were diagnosed with IAI, and 0% (95% CI, 0%–0.3%) died. Patients had a median combined ED and observation length of stay of 9.5 hours. Of the 237 (20%) patients who met low-risk criteria, 7% had a CT of the abdomen and pelvis and 0% (95% CI, 0%–1.5%) were diagnosed with IAI or died. Conclusion: Most BAT patients who have initially negative ED evaluations are at low risk for IAI but still require some combination of observation and CT. A subgroup of BAT patients may be safely discharged without CT or observation after the initial evaluation. [West J Emerg Med. 2011;12(4):496–504.]</p

Training Hospital Providers in Basic CPR Skills in Botswana: Acquisition, Retention and Impact of Novel Training Techniques

Objective Globally, one third of deaths each year are from cardiovascular diseases, yet no strong evidence supports any specific method of CPR instruction in a resource-limited setting. We hypothesized that both existing and novel CPR training programs significantly impact skills of hospital-based healthcare providers (HCP) in Botswana. Methods HCP were prospectively randomized to 3 training groups: instructor led, limited instructor with manikin feedback, or self-directed learning. Data was collected prior to training, immediately after and at 3 and 6 months. Excellent CPR was prospectively defined as having at least 4 of 5 characteristics: depth, rate, release, no flow fraction, and no excessive ventilation. GEE was performed to account for within subject correlation. Results Of 214 HCP trained, 40% resuscitate ≥1/month, 28% had previous formal CPR training, and 65% required additional skills remediation to pass using AHA criteria. Excellent CPR skill acquisition was significant (infant: 32% vs. 71%, p \u3c 0.01; adult 28% vs. 48%, p \u3c 0.01). Infant CPR skill retention was significant at 3 (39% vs. 70%, p \u3c 0.01) and 6 months (38% vs. 67%, p \u3c 0.01), and adult CPR skills were retained to 3 months (34% vs. 51%, p = 0.02). On multivariable analysis, low cognitive score and need for skill remediation, but not instruction method, impacted CPR skill performance. Conclusions HCP in resource-limited settings resuscitate frequently, with little CPR training. Using existing training, HCP acquire and retain skills, yet often require remediation. Novel techniques with increased student: instructor ratio and feedback manikins were not different compared to traditional instruction

Outcomes in HIV-Infected Adults With Tuberculosis at Clinics With and Without Co-Located HIV Clinics in Botswana

SETTING Gaborone, Botswana. OBJECTIVE To determine if starting anti-tuberculosis treatment at clinics in Gaborone without co-located human immunodeficiency virus (HIV) clinics would delay time to highly active antiretroviral therapy (HAART) initiation and be associated with lower survival compared to starting anti-tuberculosis treatment at clinics with on-site HIV clinics. DESIGN Retrospective cohort study. Subjects were HAART-naïve, aged ≥21 years with pulmonary tuberculosis (TB), HIV and CD4 counts ≤250 cells/mm3 initiating anti-tuberculosis treatment between 2005 and 2010. Survival at completion of anti-tuberculosis treatment or at 6 months post-treatment initiation and time to HAART after anti-tuberculosis treatment initiation were compared by clinic type. RESULTS Respectively 259 and 80 patients from clinics without and with on-site HIV facilities qualified for the study. Age, sex, CD4, baseline sputum smears and loss to follow-up rate were similar by clinic type. Mortality did not differ between clinics without or with on-site HIV clinics (20/250, 8.0% vs. 8/79, 10.1%, relative risk 0.79, 95%CI 0.36–1.72), nor did median time to HAART initiation (respectively 63 and 66 days, P = 0.53). CONCLUSION In urban areas where TB and HIV programs are separate, geographic co-location alone without further integration may not reduce mortality or time to HAART initiation among co-infected patients

Species-Specific Activity of SIV Nef and HIV-1 Vpu in Overcoming Restriction by Tetherin/BST2

Tetherin, also known as BST2, CD317 or HM1.24, was recently identified as an interferon-inducible host–cell factor that interferes with the detachment of virus particles from infected cells. HIV-1 overcomes this restriction by expressing an accessory protein, Vpu, which counteracts tetherin. Since lentiviruses of the SIVsmm/mac/HIV-2 lineage do not have a vpu gene, this activity has likely been assumed by other viral gene products. We found that deletion of the SIVmac239 nef gene significantly impaired virus release in cells expressing rhesus macaque tetherin. Virus release could be restored by expressing Nef in trans. However, Nef was unable to facilitate virus release in the presence of human tetherin. Conversely, Vpu enhanced virus release in the presence of human tetherin, but not in the presence of rhesus tetherin. In accordance with the species-specificity of Nef in mediating virus release, SIV Nef downregulated cell-surface expression of rhesus tetherin, but did not downregulate human tetherin. The specificity of SIV Nef for rhesus tetherin mapped to four amino acids in the cytoplasmic domain of the molecule that are missing from human tetherin, whereas the specificity of Vpu for human tetherin mapped to amino acid differences in the transmembrane domain. Nef alleles of SIVsmm, HIV-2 and HIV-1 were also able to rescue virus release in the presence of both rhesus macaque and sooty mangabey tetherin, but were generally ineffective against human tetherin. Thus, the ability of Nef to antagonize tetherin from these Old World primates appears to be conserved among the primate lentiviruses. These results identify Nef as the viral gene product of SIV that opposes restriction by tetherin in rhesus macaques and sooty mangabeys, and reveal species-specificity in the activities of both Nef and Vpu in overcoming tetherin in their respective hosts

A High-Level Language for Rule-Based Modelling

Rule-based languages such as Kappa excel in their support for handling the combinatorial complexities prevalent in many biological systems, including signalling pathways. But Kappa provides little structure for organising rules, and large models can therefore be hard to read and maintain. This paper introduces a high-level, modular extension of Kappa called LBS-κ. We demonstrate the constructs of the language through examples and three case studies: a chemotaxis switch ring, a MAPK cascade, and an insulin signalling pathway. We then provide a formal definition of LBS-κ through an abstract syntax and a translation to plain Kappa. The translation is implemented in a compiler tool which is available as a web application. We finally demonstrate how to increase the expressivity of LBS-κ through embedded scripts in a general-purpose programming language, a technique which we view as generally applicable to other domain specific languages

Profound CD4+/CCR5+ T cell expansion is induced by CD8+ lymphocyte depletion but does not account for accelerated SIV pathogenesis

Depletion of CD8+ lymphocytes during acute simian immunodeficiency virus (SIV) infection of rhesus macaques (RMs) results in irreversible prolongation of peak-level viral replication and rapid disease progression, consistent with a major role for CD8+ lymphocytes in determining postacute-phase viral replication set points. However, we report that CD8+ lymphocyte depletion is also associated with a dramatic induction of proliferation among CD4+ effector memory T (TEM) cells and, to a lesser extent, transitional memory T (TTrM) cells, raising the question of whether an increased availability of optimal (activated/proliferating), CD4+/CCR5+ SIV “target” cells contributes to this accelerated pathogenesis. In keeping with this, depletion of CD8+ lymphocytes in SIV− RMs led to a sustained increase in the number of potential CD4+ SIV targets, whereas such depletion in acute SIV infection led to increased target cell consumption. However, we found that the excess CD4+ TEM cell proliferation of CD8+ lymphocyte–depleted, acutely SIV-infected RMs was completely inhibited by interleukin (IL)-15 neutralization, and that this inhibition did not abrogate the rapidly progressive infection in these RMs. Moreover, although administration of IL-15 during acute infection induced robust CD4+ TEM and TTrM cell proliferation, it did not recapitulate the viral dynamics of CD8+ lymphocyte depletion. These data suggest that CD8+ lymphocyte function has a larger impact on the outcome of acute SIV infection than the number and/or activation status of target cells available for infection and viral production

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

An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans.

To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 × 10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.Please refer to the manuscript or visit the publisher's website for funding infomation