Explore the vast range of titles available.

Abstract Macrophages are the primary lung phagocyte and are instrumental in maintenance of a sterile, noninflamed microenvironment. IFNs are produced in response to bacterial and viral infection, and activate the macrophage to efficiently counteract and remove pathogenic invaders. Respiratory syncytial virus (RSV) inhibits IFN-mediated signaling mechanisms in epithelial cells; however, the effects on IFN signaling in the macrophage are currently unknown. We investigated the effect of RSV infection on IFN-mediated signaling in macrophages. RSV infection inhibited IFN-β– and IFN-γ–activated transcriptional mechanisms in primary alveolar macrophages and macrophage cell lines, including the transactivation of important Nod-like receptor family genes, Nod1 and class II transactivator. RSV inhibited IFN-β– and IFN-γ–mediated transcriptional activation by two distinct mechanisms. RSV impaired IFN-β–mediated signal transducer and activator of transcription (STAT)-1 phosphorylation through a mechanism that involves inhibition of tyrosine kinase 2 phosphorylation. In contrast, RSV-impaired transcriptional activation after IFN-γ stimulation resulted from a reduction in the nuclear STAT1 interaction with the transcriptional coactivator, CBP, and was correlated with increased phosphorylation of STAT1β, a dominant-negative STAT1 splice variant, in response to IFN-γ. In support of this concept, overexpression of STAT1β was sufficient to repress the IFN-γ–mediated expression of class II transactivator. These results demonstrate that RSV inhibits IFN-mediated transcriptional activation in macrophages, and suggests that paramyxoviruses modulate an important regulatory mechanism that is critical in linking innate and adaptive immune mechanisms after infection.

Background Studies have demonstrated that multimodality therapy and surgery at high volume centers are associated with a longer survival. However, it is unknown if these data have translated into national changes in care delivery. Methods Patients with stages I–III pancreatic adenocarcinomas who underwent resections between 2004 and 2010 were identified from the National Cancer Data Base. The primary outcome was a 3-year overall survival. Temporal trends in survival outcomes and treatment variables were measured. A mediation analysis using the Lin method was used to discern the relative contribution of changes in treatment variables towards improvements in survival over time. Results A total of 22,196 patients were identified. Between 2004 and 2010, a 90-day peri-operative mortality remained unchanged (8.5 % to 8.4 %, p  = 0.488), 3-year overall survival improved from 26 to 30% ( p  < 0.001), use of adjuvant/neoadjuvant chemotherapy increased (51 % to 61 %, p  < 0.001), and more cases shifted to high volume centers (46 % at institutions performing > 10 cases/year in 2004 vs. 65 % in 2010, p  < 0.001). On multivariable analysis, 32 % of the improvement in survival over time was attributable to receipt of chemotherapy, while 12 % was due to the shift of patients towards high volume centers ( p  < 0.001). Conclusions Over the period from 2004 to 2010, a 3-year survival increased for patients undergoing resection for pancreatic cancer. This survival improvement can be partially attributed to the increasing utilization of chemotherapy and centralization of surgical care at high volume centers. A continued emphasis on these factors will likely result in further prolongation of a survival following resection.

BackgroundMany surgeons advocate the use of neoadjuvant treatment for resectable pancreatic cancer, however little is known about variation in the utilization of neoadjuvant therapy (NAT) at the hospital level.MethodsThe National Cancer Data Base was used to identify patients undergoing resection for pancreatic cancer between 2006 and 2014 at high-volume centers. Hospitals were grouped by NAT utilization using standard deviations (SD) from the mean as follows: high neoadjuvant utilizers (> 2 SDs above the mean, > 40% of patients receiving NAT); medium–high (1–2 SDs, 27–40%), medium (0–1 SD, 14–26%); or low (− 1.1 to 0 SDs, < 14%). Overall survival (OS) was compared across NAT utilization groups.ResultsAmong 107 high-volume centers, 20,119 patients underwent resection. The proportion of patients receiving NAT varied widely among hospitals, ranging from 0 to 74%, with only five centers using NAT in > 40% of patients. These five hospitals had the longest median OS at 28.9 months, compared with 21.1 months for low neoadjuvant utilizers (p < 0.001). On multivariable analysis, high and medium–high NAT utilization predicted improved OS, with a hazard ratio (HR) of 0.68 (95% confidence interval [CI] 0.56–0.83, p < 0.001) and 0.80 (95% CI 0.68–0.95, p = 0.010), respectively, compared with low utilizers. After excluding patients who underwent NAT, there remained an association of improved OS with high NAT utilization (HR 0.74, 95% CI 0.60–0.93, p = 0.009).ConclusionHigh-volume hospitals that more commonly utilize NAT demonstrated longer survival for all patients treated at those centers. In addition to altering patient selection for surgery, high neoadjuvant utilization may be a marker of institutional factors that contribute to improved outcomes.

Summary During pancreas development, endocrine progenitors differentiate into the islet-cell subtypes, which undergo further functional maturation in postnatal islet development. In islet β-cells, genes involved in glucose-stimulated insulin secretion are activated and glucose exposure increases the insulin response as β-cells mature. Here, we investigated the role of H3K4 trimethylation in endocrine cell differentiation and functional maturation by disrupting TrxG complex histone methyltransferase activity in mouse endocrine progenitors. In the embryo, genetic inactivation of TrxG component Dpy30 in NEUROG3+ cells did not affect the number of endocrine progenitors or endocrine cell differentiation. H3K4 trimethylation was progressively lost in postnatal islets and the mice displayed elevated random and fasting glycemia, as well as impaired glucose tolerance by postnatal day 24. Although postnatal endocrine cell proportions were equivalent to controls, islet RNA-sequencing revealed a downregulation of genes involved in glucose-stimulated insulin secretion and an upregulation of immature β-cell genes. Comparison of histone modification enrichment profiles in NEUROG3+ endocrine progenitors and mature islets suggested that genes downregulated by loss of H3K4 trimethylation more frequently acquire active histone modifications during maturation. Taken together, these findings suggest that H3K4 trimethylation is required for the activation of genes involved in the functional maturation of pancreatic islet endocrine cells. Competing Interest Statement The authors have declared no competing interest.

Macrophages are the primary lung phagocyte and are instrumental in maintenance of a sterile, noninflamed microenvironment. IFNs are produced in response to bacterial and viral infection, and activate the macrophage to efficiently counteract and remove pathogenic invaders. Respiratory syncytial virus (RSV) inhibits IFN-mediated signaling mechanisms in epithelial cells; however, the effects on IFN signaling in the macrophage are currently unknown. We investigated the effect of RSV infection on IFN-mediated signaling in macrophages. RSV infection inhibited IFN-beta- and IFN-gamma-activated transcriptional mechanisms in primary alveolar macrophages and macrophage cell lines, including the transactivation of important Nod-like receptor family genes, Nod1 and class II transactivator. RSV inhibited IFN-beta- and IFN-gamma-mediated transcriptional activation by two distinct mechanisms. RSV impaired IFN-beta-mediated signal transducer and activator of transcription (STAT)-1 phosphorylation through a mechanism that involves inhibition of tyrosine kinase 2 phosphorylation. In contrast, RSV-impaired transcriptional activation after IFN-gamma stimulation resulted from a reduction in the nuclear STAT1 interaction with the transcriptional coactivator, CBP, and was correlated with increased phosphorylation of STAT1beta, a dominant-negative STAT1 splice variant, in response to IFN-gamma. In support of this concept, overexpression of STAT1beta was sufficient to repress the IFN-gamma-mediated expression of class II transactivator. These results demonstrate that RSV inhibits IFN-mediated transcriptional activation in macrophages, and suggests that paramyxoviruses modulate an important regulatory mechanism that is critical in linking innate and adaptive immune mechanisms after infection.

Canada has historically been among the world leaders in hypertension care, but hypertension treatment and control rates have regressed in recent years. This guideline is intended to provide pragmatic primary care–focused recommendations to improve hypertension management in adults at the population level. We employed Grading of Recommendations Assessment, Development and Evaluation and ADAPTE frameworks in accordance with Appraisal of Guidelines for Research and Evaluation (AGREE II) quality and reporting standards to develop recommendations on managing hypertension for adults aged 18 years and older. We used the HEARTS framework — a model of care developed by the World Health Organization to improve hypertension control and reduce cardiovascular burden — to integrate these recommendations into streamlined, pragmatic, and evidence-based algorithms. The guideline committee predominantly comprised primary care providers and also included patient, methodology, and hypertension specialist representatives. Our process for managing competing interests adhered to Guidelines International Network principles. The 9 recommendations for managing hypertension in adults are grouped under the categories of diagnosis and treatment. Diagnostic recommendations include a standardized approach to measuring blood pressure (BP) and confirming hypertension, as well as providing a uniform definition for hypertension of BP ≥ 130/80 mm Hg. Treatment recommendations include targeting a systolic BP < 130 mm Hg, implementing healthy lifestyle changes, and providing stepwise guidance on optimal medication choices for patients requiring pharmacotherapy. Our aim is to enhance the standard of hypertension care in the Canadian primary care setting. Accurate diagnosis and optimal treatment of hypertension can reduce adverse cardiovascular events and risk of death.

1) To investigate the effectiveness of school-based high-intensity interval training (HIIT) interventions in promoting health outcomes of children and adolescents compared with either a control group or other exercise modality; and 2) to explore the intervention characteristics and process outcomes of published school-based HIIT interventions. We searched Medline, Embase, CINAHL, SPORTDiscus, and Web of Science from inception until 31 March 2021. Studies were eligible if 1) participants aged 5-17 years old; 2) a HIIT intervention within a school setting ≥ 2 weeks duration; 3) a control or comparative exercise group; 4) health-related, cognitive, physical activity, nutrition, or program evaluation outcomes; and 5) original research published in English. We conducted meta-analyses between HIIT and control groups for all outcomes with ≥ 4 studies and meta-regressions for all outcomes with ≥ 10 studies. We narratively synthesised results between HIIT and comparative exercise groups. Fifty-four papers met eligibility criteria, encompassing 42 unique studies (35 randomised controlled trials; 36 with a high risk of bias). Meta-analyses indicated significant improvements in waist circumference (mean difference (MD) = -2.5cm), body fat percentage (MD = -1.7%), body mass index (standardised mean difference (SMD) = -1.0), cardiorespiratory fitness (SMD = +1.0), resting heart rate (MD = -5bpm), homeostatic model assessment-insulin resistance (MD = -0.7), and low-density lipoprotein cholesterol (SMD = -0.9) for HIIT compared to the control group. Our narrative synthesis indicated mixed findings between HIIT and other comparative exercise groups. School-based HIIT is effective for improving several health outcomes. Future research should address the paucity of information on physical activity and nutrition outcomes and focus on the integration and long-term effectiveness of HIIT interventions within school settings. PROSPERO CRD42018117567.

Abstract Objective To determine the diagnostic accuracy of serological tests for coronavirus disease-2019 (covid-19). Design Systematic review and meta-analysis. Data sources Medline, bioRxiv, and medRxiv from 1 January to 30 April 2020, using subject headings or subheadings combined with text words for the concepts of covid-19 and serological tests for covid-19. Eligibility criteria and data analysis Eligible studies measured sensitivity or specificity, or both of a covid-19 serological test compared with a reference standard of viral culture or reverse transcriptase polymerase chain reaction. Studies were excluded with fewer than five participants or samples. Risk of bias was assessed using quality assessment of diagnostic accuracy studies 2 (QUADAS-2). Pooled sensitivity and specificity were estimated using random effects bivariate meta-analyses. Main outcome measures The primary outcome was overall sensitivity and specificity, stratified by method of serological testing (enzyme linked immunosorbent assays (ELISAs), lateral flow immunoassays (LFIAs), or chemiluminescent immunoassays (CLIAs)) and immunoglobulin class (IgG, IgM, or both). Secondary outcomes were stratum specific sensitivity and specificity within subgroups defined by study or participant characteristics, including time since symptom onset. Results 5016 references were identified and 40 studies included. 49 risk of bias assessments were carried out (one for each population and method evaluated). High risk of patient selection bias was found in 98% (48/49) of assessments and high or unclear risk of bias from performance or interpretation of the serological test in 73% (36/49). Only 10% (4/40) of studies included outpatients. Only two studies evaluated tests at the point of care. For each method of testing, pooled sensitivity and specificity were not associated with the immunoglobulin class measured. The pooled sensitivity of ELISAs measuring IgG or IgM was 84.3% (95% confidence interval 75.6% to 90.9%), of LFIAs was 66.0% (49.3% to 79.3%), and of CLIAs was 97.8% (46.2% to 100%). In all analyses, pooled sensitivity was lower for LFIAs, the potential point-of-care method. Pooled specificities ranged from 96.6% to 99.7%. Of the samples used for estimating specificity, 83% (10 465/12 547) were from populations tested before the epidemic or not suspected of having covid-19. Among LFIAs, pooled sensitivity of commercial kits (65.0%, 49.0% to 78.2%) was lower than that of non-commercial tests (88.2%, 83.6% to 91.3%). Heterogeneity was seen in all analyses. Sensitivity was higher at least three weeks after symptom onset (ranging from 69.9% to 98.9%) compared with within the first week (from 13.4% to 50.3%). Conclusion Higher quality clinical studies assessing the diagnostic accuracy of serological tests for covid-19 are urgently needed. Currently, available evidence does not support the continued use of existing point-of-care serological tests. Study registration PROSPERO CRD42020179452.