17 research outputs found

    New genetic loci link adipose and insulin biology to body fat distribution.

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    Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

    31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

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    Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

    Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

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    IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

    The use of resources during shift hand-offs in a pediatric intensive care unit

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    The nursing handoff is a fundamental aspect of continued patient care that involves the transfer of vital medical information through various means. This project qualitatively examined nursing dyads to determine the types of resources used during handoffs and their frequency through the theoretical framework of distributed cognition. Forty handoffs between nurses, with experience ranging from 3 to 40 or more years, were observed within the intensive care unit of a pediatric hospital. The findings revealed that a variety of resources were referred to and appear mildly correlated with handoff durations, where more experienced individuals displayed a greater frequency of resource use in prolonged handoffs. Copyright 2010 by Human Factors and Ergonomics Society, Inc. All rights reserved

    Exploring similarities and differences in teamwork across diverse healthcare contexts using communication analysis

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    Teamwork is prevalent in many work contexts. This study explored the similarities and differences in teamwork processes across different healthcare work contexts with the aim of assessing knowledge transfer feasibility. The research approach was to aggregate team communication analyses from four healthcare contexts to uncover teamwork similarities and differences. The four healthcare contexts included two handoffs and two surgery contexts. The communication analysis segmented communication into meaningful sequences. It categorized utterances into content categories and verbal behaviors. There were a few similar content categories across the four contexts. A clear information structure emerged in the two handoff contexts. In addition, there were more dialogues and requests in the surgeries compared to more reports in the handoffs. The content similarities suggest that some knowledge is transferable among the contexts. However, the differences in communication patterns reflect fundamental differences between handoff and surgery contexts in some teamwork processes. This research demonstrated that using communication analysis can uncover similarities and differences in team cognition and teamwork processes across work contexts. This in turn can help determine what knowledge and methods pertaining to team training, procedures, and technology are transferable across the contexts

    Information structure and organisation in change of shift reports: An observational study of nursing hand-offs in a Paediatric Intensive Care Unit

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    Patient hand-offs involve the exchange of critical information. Ineffective hand-offs can result in reduced patient safety by leading to wrong treatment, delayed diagnoses or other outcomes that can negatively affect the healthcare system. The objectives of this study were to uncover the structure of the information conveyed during patient hand-offs and look for principles characterising the organisation of the information. With an observational study approach, data was gathered during the morning and evening nursing change of shift hand-offs in a Paediatric Intensive Care Unit. Content analysis identified a common meta-structure used for information transfer that contained categories with varying degrees of information integration and the repetition of high consequence information. Differences were found in the organisation of the hand-off structures, and these varied as a function of nursing experience. The findings are discussed in terms of the potential benefits of computerised tools which utilise standardised structure for information transfer and the implications for future education and critical care skill acquisition

    Communication and team situation awareness in the OR: Implications for augmentative information display

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    Team Situation Awareness (TSA) is one of the critical factors in effective Operating Room (OR) teamwork and can impact patient safety and quality of care. While previous research showed a relationship between situation awareness, as measured by communication events, and team performance, the implications for developing technology to augment and facilitate TSA were not examined. This research aims to further study situation-related communications in the cardiac OR in order to uncover potential degradation in TSA which may lead to adverse events. The communication loop construct-the full cycle of information flow between the participants in the sequence-was used to assess susceptibility to breakdown. Previous research and the findings here suggest that communication loops that are open, non-directed, or with delayed closure, can be susceptible to information loss. These were quantit

    A communication analysis methodology for developing a cardiac operating room team-oriented display

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    This paper outlines an empirical method to analyze human communication in the context of a cardiac Operating Room (OR) and derive design requirements for a team-oriented information display. Its first phase was to identify and categorize shared information within teamwork. The subsequent analysis of the shared information included aggregating shared information instances into unique items, and then scoping and generating the display requirements. The analysis resulted in 52 unique shared information items out of 845 information sharing instances. These unique information items were considered as the requirements for a cardiac OR team-oriented display. While the method was implemented on operating room teamwork, it can be generalized to a variety of domains with a need for a team-oriented display

    Genetic studies of body mass index yield new insights for obesity biology

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    Note: A full list of authors and affiliations appears at the end of the article. Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P 20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.</p
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