Synopsis of the 2020 U.S. VA/DoD Clinical Practice Guideline for the Management of Adult Overweight and Obesity

ABSTRACT Introduction In May of 2020, the U.S. Veterans Health Administration (VHA) and Department of Defense (DoD) approved a new joint clinical practice guideline for assessing and managing patients who have overweight and obesity. This guideline is intended to give healthcare teams a framework by which to screen, evaluate, treat, and manage the individual needs and preferences of VA and DoD patients who may have either of these conditions. It can be accessed at https://www.healthquality.va.gov/guidelines/CD/obesity/. Materials and Methods In January of 2019, the VA/DoD Evidence-Based Practice Work Group convened a joint VA/DoD guideline development effort that included clinical stakeholders and conformed to the Institute of Medicine's tenets for trustworthy clinical practice guidelines. Results The guideline panel developed 12 key questions, systematically searched and evaluated the literature, created a 1-page algorithm, and advanced 18 recommendations using the Grading of Recommendations Assessment, Development, and Evaluation system. Conclusions This synopsis summarizes the key recommendations of the guideline regarding management of overweight and obesity, including referral to comprehensive lifestyle interventions that combine behavioral, dietary, and physical activity change, and additional tools of pharmacologic and procedural interventions. Additionally, recommendations based on evidence found in the literature for short-term weight loss are included. A clinical practice algorithm that is part of the guideline is also included. Additional materials, such as provider and patient summaries and a provider pocket card, are also available for public use, accessible at the U.S. Veterans Health Administration (VHA) Clinical Practice Guidelines (CPG) website listed above

A Peptidoglycan Fragment Triggers β-lactam Resistance in Bacillus licheniformis

To resist to β-lactam antibiotics Eubacteria either constitutively synthesize a β-lactamase or a low affinity penicillin-binding protein target, or induce its synthesis in response to the presence of antibiotic outside the cell. In Bacillus licheniformis and Staphylococcus aureus, a membrane-bound penicillin receptor (BlaR/MecR) detects the presence of β-lactam and launches a cytoplasmic signal leading to the inactivation of BlaI/MecI repressor, and the synthesis of a β-lactamase or a low affinity target. We identified a dipeptide, resulting from the peptidoglycan turnover and present in bacterial cytoplasm, which is able to directly bind to the BlaI/MecI repressor and to destabilize the BlaI/MecI-DNA complex. We propose a general model, in which the acylation of BlaR/MecR receptor and the cellular stress induced by the antibiotic, are both necessary to generate a cell wall-derived coactivator responsible for the expression of an inducible β-lactam-resistance factor. The new model proposed confirms and emphasizes the role of peptidoglycan degradation fragments in bacterial cell regulation

The CHRNE 1293insG founder mutation is a frequent cause of congenital myasthenia in North Africa

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Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins

Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4+ T cells into distinct effector subsets

Naive CD4(+) T cells differentiate into specific effector subsets—Th1, Th2, Th17, and T follicular helper (Tfh)—that provide immunity against pathogen infection. The signaling pathways involved in generating these effector cells are partially known. However, the effects of mutations underlying human primary immunodeficiencies on these processes, and how they compromise specific immune responses, remain unresolved. By studying individuals with mutations in key signaling pathways, we identified nonredundant pathways regulating human CD4(+) T cell differentiation in vitro. IL12Rβ1/TYK2 and IFN-γR/STAT1 function in a feed-forward loop to induce Th1 cells, whereas IL-21/IL-21R/STAT3 signaling is required for Th17, Tfh, and IL-10–secreting cells. IL12Rβ1/TYK2 and NEMO are also required for Th17 induction. Strikingly, gain-of-function STAT1 mutations recapitulated the impact of dominant-negative STAT3 mutations on Tfh and Th17 cells, revealing a putative inhibitory effect of hypermorphic STAT1 over STAT3. These findings provide mechanistic insight into the requirements for human T cell effector function, and explain clinical manifestations of these immunodeficient conditions. Furthermore, they identify molecules that could be targeted to modulate CD4(+) T cell effector function in the settings of infection, vaccination, or immune dysregulation