Prediction and validation of exenatide risk marker effects on progression of renal disease:Insights from EXSCEL

Aim To assess whether the previously developed multivariable risk prediction framework (PRE score) could predict the renal effects observed in the EXSCEL cardiovascular outcomes trial using short-term changes in cardio-renal risk markers. Materials and Methods Changes from baseline to 6 months in HbA1c, systolic blood pressure (SBP), body mass index (BMI), haemoglobin, total cholesterol, and new micro- or macroalbuminuria were evaluated. The renal outcomes were defined as a composite of a sustained 30% or 40% decline in estimated glomerular filtration rate (eGFR) or end-stage renal disease (ESRD). Relationships between risk markers and long-term renal outcomes were determined in patients with type 2 diabetes from the ALTITUDE study using multivariable Cox regression analysis, and then applied to short-term changes in risk markers observed in EXSCEL to predict the exenatide-induced impact on renal outcomes. Results Compared with placebo, mean HbA1c, BMI, SBP and total cholesterol were lower at 6 months with exenatide, as was the incidence of new microalbuminuria. The PRE score predicted a relative risk reduction for the 30% eGFR decline + ESRD endpoint of 11.3% (HR 0.89; 95% CI 0.83-0.94), compared with 12.7% (HR 0.87; 0.77-0.99) observed risk reduction. For the 40% eGFR decline + ESRD endpoint, the predicted and observed risk reductions were 11.0% (HR 0.89; 0.82-0.97) and 13.7% (HR 0.86, 0.72-1.04), respectively. Conclusions Integrating short-term risk marker changes into a multivariable risk score predicted the magnitude of renal risk reduction observed in EXSCEL

Effects of exenatide and open-label SGLT2 inhibitor treatment, given in parallel or sequentially, on mortality and cardiovascular and renal outcomes in type 2 diabetes:insights from the EXSCEL trial

Background Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve cardiovascular and renal outcomes in patients with type 2 diabetes through distinct mechanisms. However, evidence on clinical outcomes in patients treated with both GLP-1 RA and SGLT2i is lacking. We aim to provide insight into the effects of open-label SGLT2i use in parallel with or shortly after once-weekly GLP-1 RA exenatide (EQW) on cardiorenal outcomes. Methods In the EXSCEL cardiovascular outcomes trial EQW arm, SGLT2i drop-in occurred in 8.7% of participants. These EQW+SGLT2i users were propensity-matched to: (1) placebo-arm participants not taking SGLT2i (n = 572 per group); and to (2) EQW-arm participants not taking SGLT2i (n = 575), based on their last measured characteristics before SGLT2i initiation, and equivalent study visit in comparator groups. Time-to-first major adverse cardiovascular event (MACE) and all-cause mortality (ACM) were compared using Cox regression analyses. eGFR slopes were quantified using mixed model repeated measurement analyses. Results In adjusted analyses, the risk for MACE with combination EQW+SGLT2i use was numerically lower compared with both placebo (adjusted hazard ratio 0.68, 95% CI 0.39-1.17) and EQW alone (0.85, 0.48-1.49). Risk of ACM was nominally significantly reduced compared with placebo (0.38, 0.16-0.90) and compared with EQW (0.41, 0.17-0.95). Combination EQW+SGLT2i use also nominally significantly improved estimated eGFR slope compared with placebo (+ 1.94, 95% CI 0.94-2.94 mL/min/1.73 m(2)/year) and EQW alone (+ 2.38, 1.40-3.35 mL/min/1.73 m(2)/year). Conclusions This post hoc analysis supports the hypothesis that combinatorial EQW and SGLT2i therapy may provide benefit on cardiovascular outcomes and mortality. Trial registration Clinicaltrials.gov, Identifying number: NCT01144338, Date of registration: June 15, 2010

Social, emotional, and behavioral functioning of secondary school students with low academic and language performance: perspectives from students, teachers, and parents

Adolescence is a time of transition when young people with language difficulties are at increased risk of experiencing social, emotional, and behavioral difficulties (SEBD). Most studies of social, emotional, and behavioral functioning (SEBF) in individuals with language difficulties focus on children with a clinical diagnosis of language impairment. This study explores SEBF in a nonclinical group of 12-year-old students with low educational and language performance from their own perspectives and those of their parents and teachers

Depression and Anxiety Change from Adolescence to Adulthood in Individuals with and without Language Impairment

This prospective longitudinal study aims to determine patterns and predictors of change in depression and anxiety from adolescence to adulthood in individuals with language impairment (LI). Individuals with LI originally recruited at age 7 years and a comparison group of age-matched peers (AMPs) were followed from adolescence (16 years) to adulthood (24 years). We determine patterns of change in depression and anxiety using the Child Manifest Anxiety Scale-Revised (CMAS-R) and Short Moods and Feelings Questionnaire (SMFQ). In addition to examining associations with gender, verbal and nonverbal skills, we use a time-varying variable to investigate relationships between depression and anxiety symptoms and transitions in educational/employment circumstances. The results show that anxiety was higher in participants with LI than age matched peers and remained so from adolescence to adulthood. Individuals with LI had higher levels of depression symptoms than did AMPs at 16 years. Levels in those with LI decreased post-compulsory schooling but rose again by 24 years of age. Those who left compulsory school provision (regardless of school type) for more choice-driven college but who were not in full-time employment or study by 24 years of age were more likely to show this depression pathway. Verbal and nonverbal skills were not predictive of this pattern of depression over time. The typical female vulnerability for depression and anxiety was observed for AMPs but not for individuals with LI. These findings have implications for service provision, career/employment advice and support for individuals with a history of LI during different transitions from adolescence to adulthood

Need for recovery amongst emergency physicians in the UK and Ireland: A cross-sectional survey

OBJECTIVES: To determine the need for recovery (NFR) among emergency physicians and to identify demographic and occupational characteristics associated with higher NFR scores. DESIGN: Cross-sectional electronic survey. SETTING: Emergency departments (EDs) (n=112) in the UK and Ireland. PARTICIPANTS: Emergency physicians, defined as any registered physician working principally within the ED, responding between June and July 2019. MAIN OUTCOME MEASURE: NFR Scale, an 11-item self-administered questionnaire that assesses how work demands affect intershift recovery. RESULTS: The median NFR Score for all 4247 eligible, consented participants with a valid NFR Score was 70.0 (95% CI: 65.5 to 74.5), with an IQR of 45.5-90.0. A linear regression model indicated statistically significant associations between gender, health conditions, type of ED, clinical grade, access to annual and study leave, and time spent working out-of-hours. Groups including male physicians, consultants, general practitioners (GPs) within the ED, those working in paediatric EDs and those with no long-term health condition or disability had a lower NFR Score. After adjusting for these characteristics, the NFR Score increased by 3.7 (95% CI: 0.3 to 7.1) and 6.43 (95% CI: 2.0 to 10.8) for those with difficulty accessing annual and study leave, respectively. Increased percentage of out-of-hours work increased NFR Score almost linearly: 26%-50% out-of-hours work=5.7 (95% CI: 3.1 to 8.4); 51%-75% out-of-hours work=10.3 (95% CI: 7.6 to 13.0); 76%-100% out-of-hours work=14.5 (95% CI: 11.0 to 17.9). CONCLUSION: Higher NFR scores were observed among emergency physicians than reported in any other profession or population to date. While out-of-hours working is unavoidable, the linear relationship observed suggests that any reduction may result in NFR improvement. Evidence-based strategies to improve well-being such as proportional out-of-hours working and improved access to annual and study leave should be carefully considered and implemented where feasible

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits

Peer reviewe

A computational analysis of <i>in vivo</i> VEGFR activation by multiple co-expressed ligands

<div><p>The splice isoforms of vascular endothelial growth A (VEGF) each have different affinities for the extracellular matrix (ECM) and the coreceptor NRP1, which leads to distinct vascular phenotypes in model systems expressing only a single VEGF isoform. ECM-immobilized VEGF can bind to and activate VEGF receptor 2 (VEGFR2) directly, with a different pattern of site-specific phosphorylation than diffusible VEGF. To date, the way in which ECM binding alters the distribution of isoforms of VEGF and of the related placental growth factor (PlGF) in the body and resulting angiogenic signaling is not well-understood. Here, we extend our previous validated cell-level computational model of VEGFR2 ligation, intracellular trafficking, and site-specific phosphorylation, which captured differences in signaling by soluble and immobilized VEGF, to a multi-scale whole-body framework. This computational systems pharmacology model captures the ability of the ECM to regulate isoform-specific growth factor distribution distinctly for VEGF and PlGF, and to buffer free VEGF and PlGF levels in tissue. We show that binding of immobilized growth factor to VEGF receptors, both on endothelial cells and soluble VEGFR1, is likely important to signaling <i>in vivo</i>. Additionally, our model predicts that VEGF isoform-specific properties lead to distinct profiles of VEGFR1 and VEGFR2 binding and VEGFR2 site-specific phosphorylation <i>in vivo</i>, mediated by Neuropilin-1. These predicted signaling changes mirror those observed in murine systems expressing single VEGF isoforms. Simulations predict that, contrary to the ‘ligand-shifting hypothesis,’ VEGF and PlGF do not compete for receptor binding at physiological concentrations, though PlGF is predicted to slightly increase VEGFR2 phosphorylation when over-expressed by 10-fold. These results are critical to design of appropriate therapeutic strategies to control VEGF availability and signaling in regenerative medicine applications.</p></div

Predicted signaling changes in the human body with expression of single VEGF isoforms mirror experimentally observed murine phenotypes.

<p><b>(A)</b> Levels of free VEGF, PlGF, and sR1 in tissue interstitial fluid, normalized to baseline, when all VEGF production is VEGF₁₂₁, VEGF₁₆₅, or VEGF₁₈₉. <b>(B)</b> Endothelial cell surface ligation of VEGFR1 and phosphorylation of VEGFR2. Changes in pR2 and ligated VEGFR2 were very similar. <b>(C)</b> Ratio of total VEGFR2 phosphorylation on tyrosine Y1214 to phosphorylation of tyrosine Y1175. <b>(D)</b> Percent of ligated EC surface VEGFR1 and VEGFR2 bound to EBM-immobilized ligand.</p