RATIONALE:The thoracic aortic wall can degenerate over time with catastrophic consequences. Vascular smooth muscle cells (SMCs) can resist and repair artery damage, but their capacities decline with ...age and stress. Recently, cellular production of nicotinamide adenine dinucleotide (NAD) via nicotinamide phosphoribosyltransferase (Nampt) has emerged as a mediator of cell vitality. However, a role for Nampt in aortic SMCs in vivo is unknown.
OBJECTIVES:To determine whether a Nampt-NAD control system exists within the aortic media and is required for aortic health.
METHODS AND RESULTS:Ascending aortas from patients with dilated aortopathy were immunostained for NAMPT, revealing an inverse relationship between SMC NAMPT content and aortic diameter. To determine whether a Nampt-NAD control system in SMCs impacts aortic integrity, mice with Nampt-deficient SMCs were generated. SMC-Nampt knockout mice were viable but with mildly dilated aortas that had a 43% reduction in NAD in the media. Infusion of angiotensin II led to aortic medial hemorrhage and dissection. SMCs were not apoptotic but displayed senescence associated-ß-galactosidase activity and upregulated p16, indicating premature senescence. Furthermore, there was evidence for oxidized DNA lesions, double-strand DNA strand breaks, and pronounced susceptibility to single-strand breakage. This was linked to suppressed poly(ADP-ribose) polymerase-1 activity and was reversible on resupplying NAD with nicotinamide riboside. Remarkably, we discovered unrepaired DNA strand breaks in SMCs within the human ascending aorta, which were specifically enriched in SMCs with low NAMPT. NAMPT promoter analysis revealed CpG hypermethylation within the dilated human thoracic aorta and in SMCs cultured from these tissues, which inversely correlated with NAMPT expression.
CONCLUSIONS:The aortic media depends on an intrinsic NAD fueling system to protect against DNA damage and premature SMC senescence, with relevance to human thoracic aortopathy.
Vaccines provide substantial indirect protection of unvaccinated children and adults through community protection. This protection has sometimes been greater than the direct impact of vaccines on ...disease.
Abstract
The direct impact of vaccines on children is well described, but the major public health impact of indirect protection provided to the community by vaccines is underappreciated. Community protection occurs when vaccinated persons block the chain of transmission, protecting undervaccinated or unvaccinated susceptible community members by preventing exposure and limiting the spread of the pathogen through the community. Substantial declines in disease incidence have occurred shortly after implementing new childhood vaccines, including declines among vaccine-ineligible children, adolescents, and adults. Protection of susceptible community members depends on maintaining high vaccination rates. Improved recognition of community protection will strengthen childhood vaccination strategies that will protect our communities into the future.
Nearly 40% of mortality in the United States is linked to social and behavioral factors such as smoking, diet and sedentary lifestyle. Autonomous self-regulation of health-related behaviors is thus ...an important aspect of human behavior to assess. In 1997, the Behavior Change Consortium (BCC) was formed. Within the BCC, seven health behaviors, 18 theoretical models, five intervention settings and 26 mediating variables were studied across diverse populations. One of the measures included across settings and health behaviors was the Treatment Self-Regulation Questionnaire (TSRQ). The purpose of the present study was to examine the validity of the TSRQ across settings and health behaviors (tobacco, diet and exercise). The TSRQ is composed of subscales assessing different forms of motivation: amotivation, external, introjection, identification and integration. Data were obtained from four different sites and a total of 2731 participants completed the TSRQ. Invariance analyses support the validity of the TSRQ across all four sites and all three health behaviors. Overall, the internal consistency of each subscale was acceptable (most α values >0.73). The present study provides further evidence of the validity of the TSRQ and its usefulness as an assessment tool across various settings and for different health behaviors.
The 2020 European Society of Cardiology (ESC) guidelines recommend using the 0/1-hour and 0/2-hour algorithms over the 0/3-hour algorithm as the first and second choices of high-sensitivity cardiac ...troponin (hs-cTn)-based strategies for triage of patients with suspected acute myocardial infarction (AMI).
To evaluate the diagnostic accuracies of the ESC 0/1-hour, 0/2-hour, and 0/3-hour algorithms.
PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus from 1 January 2011 to 31 December 2020. (PROSPERO: CRD42020216479).
Prospective studies that evaluated the ESC 0/1-hour, 0/2-hour, or 0/3-hour algorithms in adult patients presenting with suspected AMI.
The primary outcome was index AMI. Twenty unique cohorts were identified. Primary data were obtained from investigators of 16 cohorts and aggregate data were extracted from 4 cohorts. Two independent authors assessed each study for methodological quality.
A total of 32 studies (20 cohorts) with 30 066 patients were analyzed. The 0/1-hour algorithm had a pooled sensitivity of 99.1% (95% CI, 98.5% to 99.5%) and negative predictive value (NPV) of 99.8% (CI, 99.6% to 99.9%) for ruling out AMI. The 0/2-hour algorithm had a pooled sensitivity of 98.6% (CI, 97.2% to 99.3%) and NPV of 99.6% (CI, 99.4% to 99.8%). The 0/3-hour algorithm had a pooled sensitivity of 93.7% (CI, 87.4% to 97.0%) and NPV of 98.7% (CI, 97.7% to 99.3%). Sensitivity of the 0/3-hour algorithm was attenuated in studies that did not use clinical criteria (GRACE score <140 and pain-free) compared with studies that used clinical criteria (90.2% CI, 82.9 to 94.6 vs. 98.4% CI, 88.6 to 99.8). All 3 algorithms had similar specificities and positive predictive values for ruling in AMI, but heterogeneity across studies was substantial. Diagnostic performance was similar across the hs-cTnT (Elecsys; Roche), hs-cTnI (Architect; Abbott), and hs-cTnI (Centaur/Atellica; Siemens) assays.
Diagnostic accuracy, inclusion and exclusion criteria, and cardiac troponin sampling time varied among studies.
The ESC 0/1-hour and 0/2-hour algorithms have higher sensitivities and NPVs than the 0/3-hour algorithm for index AMI.
National Taiwan University Hospital.
The Disablement in the Physically Active (DPA) scale is a patient-reported outcome instrument recommended for use in clinical practice and research. Analysis of the scale has indicated a need for ...further psychometric testing.
To assess the model fit of the original DPA scale using a larger and more diverse sample and explore the potential for a short-form (SF) version.
Observational study.
Twenty-four clinical settings.
Responses were randomly split into 2 samples: sample 1 (n = 690: 353 males, 330 females, and 7 not reported; mean age = 23.1 ± 9.3 years, age range = 11-75 years) and sample 2 (n = 690: 351 males, 337 females, and 2 not reported; mean age = 22.9 ± 9.3 years, age range = 8-74 years). Participants were physically active individuals who were healthy or experiencing acute, subacute, or persistent musculoskeletal injury.
Confirmatory factor analysis was conducted to assess the factor structure of the original DPA scale. Exploratory factor, internal consistency, covariance modeling, correlational, and confirmatory factor analyses were conducted to assess potential DPA scale SFs.
The subdimensions of the disablement construct were highly correlated (≥0.89). The fit indices for the DPA scale approached recommended levels, but the first-order correlational values and second-order path coefficients provided evidence for multicollinearity, suggesting that clear distinctions between the disablement subdimensions cannot be made. An 8-item, 2-dimensional solution and a 10-item, 3-dimensional solution were extracted to produce SF versions. The DPA SF-8 was highly correlated (
= 0.94,
≤ .001,
= 0.88) with the DPA scale, and the fit indices exceeded all of the strictest recommendations. The DPA SF-10 was highly correlated (
= 0.97,
≤ .001,
= 0.94) with the DPA scale, and its fit indices values also exceeded the strictest recommendations.
The DPA SF-8 and SF-10 are psychometrically sound alternatives to the DPA scale.
Sleep has long been understood as an essential component for overall well-being, substantially affecting physical health, cognitive functioning, mental health, and quality of life. Currently, the ...Athlete Sleep Behavior Questionnaire (ASBQ) is the only known instrument designed to measure sleep behaviors in the athletic population. However, the psychometric properties of the scale in a collegiate student-athlete and dance population have not been established.
To assess model fit of the ASBQ in a sample of collegiate traditional student-athletes and dancers.
Observational study.
Twelve colleges and universities.
A total of 556 (104 men, 452 women; age = 19.84 ± 1.62 years) traditional student-athletes and dancers competing at the collegiate level.
A confirmatory factor analysis (CFA) was computed to assess the factor structure of the ASBQ. We performed principal component analysis extraction and covariance modeling analyses to identify an alternate model. Multigroup invariance testing was conducted on the alternate model to identify if group differences existed for sex, sport type, injury status, and level of competition.
The CFA on the ASBQ indicated that the model did not meet recommended model fit indices. An alternate 3-factor, 9-item model with improved fit was identified; however, the scale structure was not consistently supported during multigroup invariance testing procedures.
The original 3-factor, 18-item ASBQ was not supported for use with collegiate athletes in our study. The alternate ASBQ was substantially improved, although more research should be completed to ensure that the 9-item instrument accurately captures all dimensions of sleep behavior relevant for collegiate athletes.
The purpose of this study is to identify profiles based on the reasons adults have for being physically active. A secondary purpose was to examine how profiles differ on motivational regulation and ...physical activity (PA). A total of 1275 (46.5 ± 16.8 years) participants were solicited from a hospital-affiliated wellness center, social media promotions, and a research volunteer registry. The Reasons to Exercise (REX-2) scale, International PA Questionnaire, Behavioral Regulation in Exercise Questionnaire-3, and demographic questionnaire were utilized to assess variables of interest with a cross-sectional survey. Using SPSS Version 26, K-cluster analysis was used to identify profiles based on the reasons for exercise that individuals identified as important. Multivariate analysis of variance (MANOVA) was used to assess profile differences followed by ANOVA. Four profiles were derived based on reason for exercise scores: a multi-reason positive (N = 361), a multi-reason negative (N = 232), an autonomous-focused (N = 259), and a control-focused cluster (N = 382) (p < .001). These unique clusters differed significantly (p < .001) from each other with respect to motivation to be active and PA. The multi-reason positive cluster engaged in higher levels of total moderate and vigorous PA minutes/week compared to the other clusters. Therefore, adult’s motivation for PA may be likely to be affected by a combination of different informal goals and valuing a number of goals that are both extrinsic/controlling (e.g., to look good) and autonomous/intrinsic (e.g., to feel good), may promote greater autonomous motivation regulation and greater PA levels than highly autonomous/intrinsic goals alone.
Summary
Collagen fibrils become resistant to cleavage over time. We hypothesized that resistance to type I collagen proteolysis not only marks biological aging but also drives it. To test this, we ...followed mice with a targeted mutation (Col1a1r/r) that yields collagenase‐resistant type I collagen. Compared with wild‐type littermates, Col1a1r/r mice had a shortened lifespan and developed features of premature aging including kyphosis, weight loss, decreased bone mineral density, and hypertension. We also found that vascular smooth muscle cells (SMCs) in the aortic wall of Col1a1r/r mice were susceptible to stress‐induced senescence, displaying senescence‐associated ß‐galactosidase (SA‐ßGal) activity and upregulated p16INK4A in response to angiotensin II infusion. To elucidate the basis of this pro‐aging effect, vascular SMCs from twelve patients undergoing coronary artery bypass surgery were cultured on collagen derived from Col1a1r/r or wild‐type mice. This revealed that mutant collagen directly reduced replicative lifespan and increased stress‐induced SA‐ßGal activity, p16INK4A expression, and p21CIP1 expression. The pro‐senescence effect of mutant collagen was blocked by vitronectin, a ligand for αvß3 integrin that is presented by denatured but not native collagen. Moreover, inhibition of αvß3 with echistatin or with αvß3‐blocking antibody increased senescence of SMCs on wild‐type collagen. These findings reveal a novel aging cascade whereby resistance to collagen cleavage accelerates cellular aging. This interplay between extracellular and cellular compartments could hasten mammalian aging and the progression of aging‐related diseases.
Neutralizing antibodies are important for immunity against SARS-CoV-2 and as therapeutics for the prevention and treatment of COVID-19. Here, we identified high-affinity nanobodies from alpacas ...immunized with coronavirus spike and receptor-binding domains (RBD) that disrupted RBD engagement with the human receptor angiotensin-converting enzyme 2 (ACE2) and potently neutralized SARS-CoV-2. Epitope mapping, X-ray crystallography, and cryo-electron microscopy revealed two distinct antigenic sites and showed two neutralizing nanobodies from different epitope classes bound simultaneously to the spike trimer. Nanobody-Fc fusions of the four most potent nanobodies blocked ACE2 engagement with RBD variants present in human populations and potently neutralized both wild-type SARS-CoV-2 and the N501Y D614G variant at concentrations as low as 0.1 nM. Prophylactic administration of either single nanobody-Fc or as mixtures reduced viral loads by up to 10
-fold in mice infected with the N501Y D614G SARS-CoV-2 virus. These results suggest a role for nanobody-Fc fusions as prophylactic agents against SARS-CoV-2.
Cognitive skills training has been linked to greater skills, self-efficacy, and performance. Although research in a variety of organizational settings has demonstrated training efficacy, few studies ...have assessed cognitive skills training using rigorous, longitudinal, randomized trials with active controls. The present study examined cognitive skills training in a high-risk occupation by randomizing 48 platoons (N = 2,432 soldiers) in basic combat training to either (a) mental skills training or (b) an active comparison condition (military history). Surveys were conducted at baseline and 3 times across the 10-week course. Multilevel mixed-effects models revealed that soldiers in the mental skills training condition reported greater use of a range of cognitive skills and increased confidence relative to those in the control condition. Soldiers in the mental skills training condition also performed better on obstacle course events, rappelling, physical fitness, and initial weapons qualification scores, although effects were generally moderated by gender and previous experience. Overall, effects were small; however, given the rigor of the design, the findings clearly contribute to the broader literature by providing supporting evidence that cognitive training skills can enhance performance in occupational and sports settings. Future research should address gender and experience to determine the need for targeting such training appropriately.
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