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Nitric oxide (NO) is an important signaling molecule in the process of muscle repair. It is involved in inflammatory signaling as well as satellite cell signaling– specifically satellite cell proliferation, differentiation and maturation. Previous studies have shown that NO impacts exercise performance and fatigue resistance, but there are less studies on the impact of NO after exercise, during muscle repair. We investigated the role that nitric oxide modulation may play in muscle repair with a GSNOR inhibitor (SPL-334), ISDN (isosorbide dinitrate–NO donor), and L-NIL (iNOS inhibitor). We found that GSNORi attenuated reduction of force after exercise-induced muscle damage (EIMD) in a lengthening-contractions model in EDL (extensor digitorum longus) muscle but did not affect the number of Tdt+ myofibers or cross-sectional area of the Tdt+ myofibers in the TA (tibialis anterior) muscle. ISDN had no effect on force production but decreased the number of Tdt+ myofibers and increased the CSA (cross-sectional area) of Tdt+ myofibers. L-NIL did not affect the force reduction but did increase the total number of Tdt+ myofibers post-EIMD. These data suggest that excess NO via ISDN may reduce quiescent satellite cell activation, iNOS inhibition may increase regeneration via macrophage signaling, and GSNORi may not impact muscle regeneration but instead affect the force produced post-LCP via ryanodine receptor hypernitrosylation.

HypothesisThe prevalence of type 2 diabetes is higher in Latino populations compared with other major ancestry groups. Not only has the Latino population been systematically underrepresented in large-scale genetic analyses, but previous studies relied on the imputation of ungenotyped variants based on the 1000 Genomes (1000G) imputation reference panel, which results in suboptimal capture of low-frequency or Latino-enriched variants. The NHLBI Trans-Omics for Precision Medicine (TOPMed) reference panel represents a unique opportunity to analyze rare genetic variations in the Latino population.MethodsWe evaluate the TOPMed imputation performance using genotyping array and whole-exome sequence data in 6 Latino cohorts. To evaluate the ability of TOPMed imputation of increasing the identified loci, we performed a Latino type 2 diabetes GWAS meta-analysis in 8,150 type 2 diabetes cases and 10,735 controls and replicated the results in 6 additional cohorts including whole-genome sequence data from the All of Us cohort.ResultsWe show that, compared to imputation with 1000G, the TOPMed panel improves the identification of rare and low-frequency variants. We identified 26 distinct signals including a novel genome-wide significant variant (minor allele frequency 1.6%, OR=2.0, P=3.4×10−9) near ORC5. A Latino-tailored polygenic score constructed from our data and GWAS data from East Asian and European populations improves the prediction accuracy in a Latino target dataset, explaining up to 7.6% of the type 2 diabetes risk variance.ConclusionsOur results demonstrate the utility of TOPMed imputation for identifying low-frequency variation in understudied populations, leading to the discovery of novel disease associations and the improvement of polygenic scores.

OBJECTIVE To examine the effect of different patterns of durable glycemic control on the development of comorbidities among youth with type 2 diabetes (T2D) and to assess the impact of fasting glucose (FG) variability on the clinical course of T2D. RESEARCH DESIGN AND METHODS From the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, 457 participants (mean age, 14 years) with mean diabetes duration RESULTS Higher baseline HbA1c concentration, lower β-cell function, and maternal history of diabetes were strongly associated with loss of glycemic control in youth with T2D. Higher cumulative HbA1c concentration over 4 years and greater FG variability over a year within 3 years of diagnosis were related to higher prevalence of dyslipidemia, nephropathy, and retinopathy progression over the subsequent 10 years. A coefficient of variability in FG ≥8.3% predicted future loss of glycemic control and development of comorbidities. CONCLUSIONS Higher baseline HbA1c concentration and FG variability during year 1 accurately predicted youth with T2D who will experience metabolic decompensation and comorbidities. These values may be useful tools for clinicians when considering early intensification of therapy.

Background The coronavirus disease 2019 (COVID-19) pandemic has led to a focus on non-face-to-face (NF2F) orthopedic clinics. In this study, our aim was to establish whether NF2F clinics are sustainable according to the "triple bottom line" framework by taking into account the impact on patients, the planet, and the financial cost. Methodology This retrospective cohort study was carried out at a large district general hospital with 261 patients identified as having undergone face-to-face (F2F) or NF2F orthopedic consultations (April 2020). These patients were contacted by telephone to establish their experience, mode of transport, and preference for future consultations. Data were also collected relating to environmental and financial costs to the patient and the trust. Results The final analysis included 180 (69%) patients: 42% had an F2F consultation and 58% NF2F consultation. There was no significant difference between each group in terms of convenience, ease of communication, subjective patient safety, or overall satisfaction rating (p > 0.05). Overall, 80% of NF2F patients would be happy with virtual consultations in the future. The mean journey distance was 18.6 miles leading to a reduction in total carbon emissions of 563.9 kgCO2e (66%), equating to 2,106 miles in a medium-sized car. The hospital visit carbon cost (heating, lighting, and waste generation) was reduced by 3,967 kgCO2e (58%). The financial cost (petrol and parking) was also reduced by an average of £8.96 per person. Conclusions NF2F consultations are aligned to the National Health Service's "Long Term Plan": (i) delivering high patient satisfaction with equivalent outcomes as F2F consultations; (ii) reducing carbon emissions from transportation and hospital running; and (iii) becoming cheaper.

The National Institutes of Health (NIH) Office of Research in Women’s Health now functions under a mandate calling for the systematic inclusion of both female and male cells, animals, and human subjects in all types of research, so that sex as a biological variable is understood in health and disease. Sex-specific data can improve disease prevention, diagnosis, and treatment as well as reduce inequities. Inclusion of women in research studies has modestly improved over the last 20 years, yet preclinical research is still primarily done using male animal models and male-derived cells, with the result that many conclusions are made based on incomplete and sex-biased data. There are important, yet poorly studied, sex differences in cardiometabolic disease. To begin to address these sex differences, the Center for Women’s Health Research at the University of Colorado held its inaugural National Conference, “Sex Differences Across the Lifespan: A Focus on Metabolism,” in September 2016 (cwhr@ucdenver.edu). Research to address the important goal of understanding key sex differences in cardiometabolic disease across the life span is lacking. The goal of this article is to discuss the current state of research addressing sex differences in cardiometabolic health across the life span, to outline critical research gaps that must be addressed in response to NIH mandates, and, importantly, to develop strategies to address sex as a biological variable to understand disease mechanisms as well as develop diagnostic and therapeutic modalities.

Third and fourth degree perineal tears, or obstetric anal sphincter injuries (OASI), sustained during childbirth can result in anal incontinence and psychosocial problems which require ongoing treatment. Within the English National Health System (NHS) reported rates of OASI have gradually increased. In response, a care bundle was developed incorporating four elements: 1) antenatal information to women, 2) manual perineal protection during all vaginal births, 3) episiotomy to be performed with a 60° mediolateral angle at crowning (when clinically indicated) and 4) perineal examination (including per rectum) after childbirth. Implementation of the OASI Care Bundle is aided by a skills development module and an awareness campaign. The project is a collaboration between two national professional bodies, an NHS hospital trust and an academic institution. Implementation of the OASI Care Bundle will be evaluated using a stepped-wedge design. From January 2017 sixteen maternity units across England, Wales and Scotland will participate in the study over a 15-month period, with sequential roll-out of the intervention in four blocks (regions) of four units. The primary clinical outcome is OASI rate. Regression analysis will adjust for differences in organisational characteristics and obstetric risk factors in women who gave birth before and after implementation of the care bundle. Focus group discussions and in-depth interviews with clinicians will evaluate the feasibility of integrating the care bundle into routine practice. Interviews with women will explore the acceptability of the intervention. This protocol outlines the evaluation of our quality improvement project which aims to prevent OASI using a bundle of evidence-based interventions that are each widely used in practice. The OASI project aims to 1) standardise practice to prevent OASI in a way that is acceptable to clinicians and women and 2) identify the barriers and enablers associated with upscaling interventions within maternity units. If found to be effective, feasible and acceptable, the OASI Care Bundle will be shared with a range of audiences using the communication channels available to the professional bodies. The OASI Project was retrospectively registered on the ISCTRN12143325 database date assigned 03/10/2017.

Hemoglobin A1c (HbA1c) is increasingly performed over the oral glucose tolerance test (OGTT) as the initial screening test for type 2 diabetes in youth. However, the optimal strategy for identifying type 2 diabetes in youth remains controversial. Alternate glycemic markers have been proposed as potentially useful tools for diabetes screening. We examined the relationships among fructosamine (FA), glycated albumin (GA), and 1,5-anhydroglucitol (1,5-AG) with traditional screening tests, HbA1c and OGTT. Youth 10-18 yrs, BMI ≥85th‰, and HbA1c7.5% had a single visit with measurement of HbA1c, 1,5-AG, FA, GA, and a standard OGTT. Distributions of FA, GA, and 1,5-AG by HbA1c and 2-hour glucose (2hG) categories were compared. Receiver operating characteristic (ROC)-curves were generated to determine the cut points at which alternate markers maximized sensitivity and specificity for predicting prediabetes and diabetes. One hundred and seventeen, 62% female, 59% Hispanic, 22% White, 17% black, median 14.1 yr, and body mass index (BMI) z-score 2.3 participated. Median values of each alternate marker differed significantly between prediabetes and diabetes HbA1c and 2hG categories (p0.017). Only GA medians differed (p = 0.006) between normal and prediabetes HbA1c. Area under the receiver operating characteristic curves (ROC-AUCs) for alternate markers as predictors of prediabetes (0.5-0.66) were low; however, alternate marker ROC-AUCs for identifying diabetes (0.82-0.98) were excellent. Although the alternate markers were poor predictors of prediabetes, they all performed well predicting diabetes by 2hG and HbA1c. Whereas the usefulness of these markers for identifying prediabetes is limited, they may be useful in certain scenarios as second line screening tools for diabetes in overweight/obese youth.