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Telomere length (TL) is considered an important biomarker of whole-organism health and aging. Across humans and other vertebrates, short telomeres are associated with increased subsequent mortality risk, but the processes responsible for this correlation remain uncertain. A key unanswered question is whether TL–mortality associations arise due to positive effects of genes or early-life environment on both an individual’s average lifetime TL and their longevity, or due to more immediate effects of environmental stressors on within-individual TL loss and increased mortality risk. Addressing this question requires longitudinal TL and life history data across the entire lifetimes of many individuals, which are difficult to obtain for long-lived species like humans. Using longitudinal data and samples collected over nearly two decades, as part of a long-term study of wild Soay sheep, we dissected an observed positive association between TL and subsequent survival using multivariate quantitative genetic models. We found no evidence that telomere attrition was associated with increased mortality risk, suggesting that TL is not an important marker of biological aging or exposure to environmental stress in our study system. Instead, we find that among-individual differences in average TL are associated with increased lifespan. Our analyses suggest that this correlation between an individual’s average TL and lifespan has a genetic basis. This demonstrates that TL has the potential to evolve under natural conditions, and suggests an important role of genetics underlying the widespread observation that short telomeres predict mortality.

Telomeres are repetitive sequences of noncoding DNA found at the terminal ends of linear chromosomes, and they play an important role in maintaining DNA stability and integrity (13). Telomeres shorten during cell replication and in response to oxidative stress (4, 5), and cellular senescence and apoptosis is triggered once telomeres reach a critically short threshold (2). The important role of telomeres in cellular senescence has led to telomere shortening being considered as one of nine “hallmarks of aging,” and average telomere length (TL) as an important biomarker of whole-organism health and biological aging (6). In humans, relatively short leukocyte telomeres have been linked to a range of age-related diseases such as diabetes, cancer, and cardiovascular disease (79) and increased subsequent mortality risk (1012). A recent metaanalysis suggests this pattern may generalize beyond humans: Across studies from 20 nonmodel vertebrate species (predominantly birds), there was an overall positive association between TL and subsequent survival (13). Although evidence for a causal role for telomeres in whole-organism aging and longevity remains weak (14), these findings highlight the potential significance of TL as a biomarker of human and animal health (15, 16) and for our understanding of life history evolution (17, 18).Studies in humans and other vertebrates have found evidence for consistent differences in TL among individuals over multiple measurements (19, 20). Such repeatable among-individual differences in any trait may result from the trait being under genetic influence, from long-term effects of the early-life environment, and/or environmental conditions that persist across the lifetime. There is good evidence that variation in average TL in blood cells has a genetic basis in humans and other vertebrates, although estimates of the heritability (the proportion of variation attributed to additive genetic effects) of TL are variable (21, 22). Recent studies of wild vertebrates have also revealed considerable variation in adult TL among birth cohorts, suggesting persistent impacts of early-life environment (23, 24). At the same time, there is growing evidence that TL is highly dynamic across an individual’s lifetime, and metaanalyses of human and nonhuman animal studies show that experience of diverse forms of environmental stress are predictive of shorter TL (2527). Indeed, some studies using longitudinal TL data have found that telomere shortening over successive measurements rather than TL per se is predictive of mortality (2830). Thus, the emerging picture from studies in humans and other vertebrates is that shorter TL generally predicts increased risk of subsequent mortality, and that variation in TL is under the influence of both genetics and environmental stressors.The observation that shorter TL measurements predict increased mortality risk could be underpinned by two nonmutually exclusive processes operating across the lifetimes of individuals. Firstly, individuals may differ in their average TL across life, and individuals with shorter TL may be shorter lived. This pattern is referred to as the “selective disappearance” of individuals with shorter telomeres, and it implies that TL reflects constitutive differences among individuals (for example, due to genetics or differences in early-life environment) which shape their longevity (31, 32). Secondly, individuals may differ in their pattern of TL change over time, and individuals showing the greatest telomere loss across successive measurements are more likely to die subsequently. This pattern is consistent with the idea that within-individual telomere dynamics reflect recent and cumulative experiences of environmental stress and physiological deterioration that also predict mortality. Neither pattern necessarily implies a causal role for telomeres in driving the mortality risk of an organism, because associations between TL and survival could result from both traits being correlated with underlying, unmeasured variables which causally impact survival (14, 18). Nevertheless, unraveling the contribution of genetics, early-life environment, and more immediate telomere shortening to the observed association between TL and survival is essential for our understanding of TL as a biomarker of health and aging (19).To our knowledge, no study to date has assessed the relative importance of the different processes underlying the relationship between TL and mortality risk across the entire lifespan. To do so demands repeated measurements from across life to characterize among- and within-individual variation in TL, a population pedigree or genomic information to separate genetic and environmental sources of variation, and detailed information on individual health and fitness outcomes over the lifetime. Here, we use a multivariate mixed-effects modeling approach to analyze extensive, longitudinal data from a long-term study of wild Soay sheep living on St Kilda, Scotland, to distinguish between possible models of why shorter TL predicts increased mortality risk. We find that the observed positive association between TL and mortality in this system is underpinned by selective disappearance of individuals with shorter average TL. Importantly, our results suggest this is largely driven by genetically based differences in both TL and longevity.  相似文献   
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BackgroundSIMPL is a workplace-based operative performance assessment tool which allows for dictated feedback (DF). To better understand the value of DF, we sought to characterize the type and quality of DF generated during SIMPL evaluations.MethodsThematic analysis of DF from SIMPL assessments between June 2017 and December 2018 at a single pediatric surgery fellowship program was performed. Comments were categorized as specific, encouraging or corrective. Categories were combined to determine DF quality as effective, mediocre or ineffective.ResultsOf 781 SIMPL assessments (21 faculty, 5 trainees), 451 (57%) had DF. Most comments were encouraging (93%) and specific (65%). Only 21% were corrective, 17% had entrustment features, and 8% had an explicit learning plan. Feedback quality was deemed mediocre (45%), ineffective (33%) and effective (21%).ConclusionSIMPL dictated feedback was mostly encouraging and specific. To improve quality, feedback should incorporate learning plans as well as corrective and entrustment features.  相似文献   
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BackgroundTotal joint arthroplasty is the most common elective orthopedic procedure in the Veterans Affairs hospital system. In 2019, physical medicine and rehabilitation began screening patients before surgery to select candidates for direct transfer to acute rehab after surgery. The primary outcome of this study was to demonstrate that the accelerated program was successful in decreasing inpatient costs and length of stay (LOS). The secondary outcome was to show that there was no increase in complication, reoperation, and readmission rates.MethodsA retrospective review of total joint arthroplasty patients was conducted with three cohorts: 1) control (n = 193), 2) transfer to rehab orders on postop day #1 (n = 178), and 3) direct transfers to rehab (n = 173). To assess for demographic disparities between cohorts, multiple analysis of variance tests followed by a Bonferroni P-value correction were used. Differences between test groups regarding primary outcomes were assessed with analysis of variance tests followed by pairwise t-tests with Bonferroni P-value corrections.ResultsThere were no significant differences between the cohort demographics or comorbidities. The mean total LOS decreased from 7.0 days in the first cohort, to 6.9 in the second, and 6.0 in the third (P = .00034). The mean decrease in cost per patient was $14,006 between cohorts 1 and 3, equating to over $5.6 million in savings annually. There was no significant change in preintervention and postintervention short-term complications (P = .295).ConclusionsSignificant cost savings and decrease in total LOS was observed. In the current health care climate focused on value-based care, a similar intervention could be applied nationwide to improve Veterans Affair services.  相似文献   
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Early survivors of pediatric cancer are at increased risk of experiencing chronic conditions; however, little is known about the morbidity burden in this population. In this observational cohort study of commercially insured pediatric cancer survivors in the United States (2009–2014), we find that 22.5% of survivors had one chronic condition, and 36.3% had multiple. Compared with survivors without chronic conditions, the presence of multiple conditions significantly increased the odds of an emergency department visit by 70% (odds ratios [OR], 1.7; 95% confidence interval [CI], 1.4–2.1) and of a hospitalization almost four‐fold (OR, 3.8; 95% CI], 2.5–5.5). Findings are important for informing pediatric survivorship care plans in the years following completion of therapy.  相似文献   
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Objectives

There is growing evidence that urine cadmium is a temporally stable biomarker indicative of long-term cadmium exposure; however questions remain with regard to generalizability to older persons, the impact of changes in smoking behavior, and the degree of temporal stability when repeat sample collection spans years instead of weeks or months.

Methods

Using archived samples from cohorts of older men (Osteoporotic Fractures in Men (MrOS-US)) and women (Study of Osteoporotic Fractures (SOF)) (mean age?=?80?at study visit 2), we analyzed two morning urine samples each from 39 men and 18 women with a diverse self-reported smoking history. For MrOS, samples were collected approximately 6 years apart, and 4 years apart for SOF. Intra-class correlations were computed to assess temporal stability, and adjusted for age and body mass index.

Results

The median creatinine-adjusted urinary cadmium levels (0.39?μg/g for men, 0.89?μg/g for women) were similar to levels expected for these age/sex groups in the US according to the National Health and Nutrition Examination Survey. The overall intra-class correlation was high (ICC?=?0.85; 95% CI: 0.76–0.91) and similar between cohorts (MrOS: ICC?=?0.74; 95% CI: 0.58–0.86; SOF: ICC?=?0.81; 95% CI: 0.59–0.93), but slightly lower among those who stopped smoking between visits of sample collection (ICC?=?0.64; 95% CI: 0.31–0.87) or among former smokers who quit prior to the first sample collection (ICC?=?0.68; 95% CI: 0.25–0.93).

Conclusions

We report good-to-excellent reproducibility of urine cadmium using morning urine samples collected 4–6 years apart from older men and women, but slightly lower correlations among those with a history of smoking. Single measures of urine cadmium are a reliable biomarker in older men and women.  相似文献   
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