The killifish germline regulates longevity and somatic repair in a sex-specific manner.

Classical evolutionary theories propose tradeoffs among reproduction, damage repair and lifespan. However, the specific role of the germline in shaping vertebrate aging remains largely unknown. In this study, we used the turquoise killifish (Nothobranchius furzeri) to genetically arrest germline development at discrete stages and examine how different modes of infertility impact life history. We first constructed a comprehensive single-cell gonadal atlas, providing cell-type-specific markers for downstream phenotypic analysis. We show here that germline depletion-but not arresting germline differentiation-enhances damage repair in female killifish. Conversely, germline-depleted males instead showed an extension in lifespan and rejuvenated metabolic functions. Through further transcriptomic analysis, we highlight enrichment of pro-longevity pathways and genes in germline-depleted male killifish and demonstrate functional conservation of how these factors may regulate longevity in germline-depleted Caenorhabditis elegans. Our results, therefore, demonstrate that different germline manipulation paradigms can yield pronounced sexually dimorphic phenotypes, implying alternative responses to classical evolutionary tradeoffs.

The killifish germline regulates longevity and somatic repair in a sex-specific manner.

Classical evolutionary theories propose tradeoffs between reproduction, damage repair, and lifespan. However, the specific role of the germline in shaping vertebrate aging remains largely unknown. Here, we use the turquoise killifish ( N. furzeri ) to genetically arrest germline development at discrete stages, and examine how different modes of infertility impact life-history. We first construct a comprehensive single-cell gonadal atlas, providing cell-type-specific markers for downstream phenotypic analysis. Next, we show that germline depletion - but not arresting germline differentiation - enhances damage repair in female killifish. Conversely, germline-depleted males instead showed an extension in lifespan and rejuvenated metabolic functions. Through further transcriptomic analysis, we highlight enrichment of pro-longevity pathways and genes in germline-depleted male killifish and demonstrate functional conservation of how these factors may regulate longevity in germline-depleted C. elegans . Our results therefore demonstrate that different germline manipulation paradigms can yield pronounced sexually dimorphic phenotypes, implying alternative responses to classical evolutionary tradeoffs.

Power of testing for exposure effects under incomplete mediation.

Mediation analysis studies situations where an exposure may affect an outcome both directly and indirectly through intervening variables called mediators. It is frequently of interest to test for the effect of the exposure on the outcome, and the standard approach is simply to regress the latter on the former. However, it seems plausible that a more powerful test statistic could be achieved by also incorporating the mediators. This would be useful in cases where the exposure effect size might be small, which for example is common in genomics applications. Previous work has shown that this is indeed possible under complete mediation, where there is no direct effect. In most applications, however, the direct effect is likely nonzero. In this paper we study linear mediation models and find that under certain conditions, power gain is still possible under this incomplete mediation setting for testing the null hypothesis that there is neither a direct nor an indirect effect. We study a class of procedures that can achieve this performance and develop their application to both low- and high-dimensional mediators. We then illustrate their performances in simulations as well as in an analysis using DNA methylation mediators to study the effect of cigarette smoking on gene expression.

Tobacco Smoke Exposure According to Location of Home Smoking in Israel: Findings from the Project Zero Exposure Study.

Young children are particularly vulnerable to harms from tobacco smoke exposure (TSE). This study aimed to compare TSE: (1) between children who live in smoking families and those who do not; and (2) among children who live in smoking households with varying smoking locations. The data came from two studies that were conducted concurrently in Israel (2016-2018). Study 1: a randomized controlled trial of smoking families (n = 159); Study 2: a cohort study of TSE among children in non-smoking families (n = 20). Hair samples were collected from one child in each household. Baseline hair nicotine data were analyzed for 141 children in Study 1 and 17 children in Study 2. Using a logistic regression analysis (exposed vs. not exposed as per laboratory determination) and a linear regression (log hair nicotine), we compared TSE between: (1) children in Study 1 vs. Study 2; (2) children in families with different smoking locations in Study 1: balcony; garden, yard, or other place outside of the home; or inside the home (designated smoking areas within the home (DSAs) or anywhere). A higher proportion of children living in smoking households were measurably exposed to tobacco smoke (68.8%) compared to children living in non-smoking households (35.3%, p = 0.006). Among children from smoking families, 75.0% of those whose parents smoked in the house were exposed, while 61.8% of children whose parents restricted smoking to the porch (n = 55) were exposed, and 71.4% of those whose parents smoked outside the home (including gardens and yards) (n = 42) were exposed. In univariable and multivariable models, smoking location was not significantly associated with exposure. The majority of children in smoking families were measurably exposed to TSE, even if smoking was restricted to designated areas in the home, balconies, orgarden/yard/other outdoor areas. Reducing population smoking rates, particularly among parents, restricting smoking to at least 10 meters from homes and children, and denormalizing smoking around others are recommended to reduce population-level child TSE and tobacco-attributable disease and death.

Risk factors for reduced function in women with a history of breast cancer.

PURPOSE: People with a history of breast cancer are at risk of losing function during and after treatment. Unfortunately, little is known about the individual and additive effects of specific treatment, disease-related, and demographic factors that may contribute to functional decline. This manuscript reports the results of a multi-center study to evaluate the effects of these factors on function. METHODS: In this cross-sectional study, women with a history of breast cancer referred to physical medicine and rehabilitation cancer rehabilitation clinics were administered the PROMIS® Cancer Function Brief 3D Profile to evaluate function in the domains of physical function, fatigue, and social participation. Clinical and demographic information, including treatment history and disease status, was recorded by clinicians. Patients were analyzed in two groups: those with active disease on antineoplastic treatment, and those with no evidence of disease (NED). A multivariable model was constructed to detect associations between clinical and demographic factors. RESULTS: In patients with NED, the presence of chemotherapy-induced peripheral neuropathy (CIPN) was strongly associated with reduced function in all three domains. In those with active disease, having brain metastases was significantly associated with reduced function in all domains and CIPN with reduced physical function. Radiation was associated with improved function in both cohorts. CONCLUSIONS: Among women seeking rehabilitative care, CIPN and the presence of brain metastases were most strongly associated with a decline in function. The effects of radiation on function were unexpected and may be partially explained by the treatment's role in symptom management. Clinicians who treat breast cancer should consider a patient's functional status when providing supportive care.

Responsiveness and interpretation of the PROMIS Cancer Function Brief 3D Profile.

BACKGROUND: Measuring function with valid and responsive tools in patients with cancer is essential for driving clinical decision-making and for the end points of clinical trials. Current patient-reported outcome measurements of function fall short for many reasons. This study evaluates the responsiveness of the Patient-Reported Outcomes Measurement Information System (PROMIS) Cancer Function Brief 3D Profile, a novel measure of function across multiple domains. METHODS: Two hundred nine participants across five geographically distinct tertiary care centers completed the assessment and pain rating at two outpatient cancer rehabilitation clinic visits. Patients and providers completed a global rating of change measure at the second visit to indicate whether the patient was improving or worsening in function. Multiple response indices and linear models measured whether the measure was responsive to self-reported and clinician-rated changes over time. Correlations between changes in function and changes in anchors (pain rating and performance status) were also calculated. RESULTS: Function as measured by the PROMIS Cancer Function Brief 3D Profile changed appropriately as both patients and clinicians rated change. Small to moderate effect sizes supported the tool's responsiveness. Function was moderately correlated with pain and more strongly correlated with performance status, and changes in function corresponded with changes in anchor variables. No floor/ceiling effect was found. CONCLUSIONS: The PROMIS Cancer Function Brief 3D Profile is sensitive to changes over time in patients with cancer. The measure may be useful in clinical practice and as an end point in clinical trials. LAY SUMMARY: We gave patients a questionnaire by which they told their physicians how well they were functioning, including how fatigued they were. This study tested that questionnaire to see whether the scores would change if patients got better or worse.

Utility of Continuous Disease Subtyping Systems for Improved Evaluation of Etiologic Heterogeneity.

Molecular pathologic diagnosis is important in clinical (oncology) practice. Integration of molecular pathology into epidemiological methods (i.e., molecular pathological epidemiology) allows for investigating the distinct etiology of disease subtypes based on biomarker analyses, thereby contributing to precision medicine and prevention. However, existing approaches for investigating etiological heterogeneity deal with categorical subtypes. We aimed to fully leverage continuous measures available in most biomarker readouts (gene/protein expression levels, signaling pathway activation, immune cell counts, microbiome/microbial abundance in tumor microenvironment, etc.). We present a cause-specific Cox proportional hazards regression model for evaluating how the exposure-disease subtype association changes across continuous subtyping biomarker levels. Utilizing two longitudinal observational prospective cohort studies, we investigated how the association of alcohol intake (a risk factor) with colorectal cancer incidence differed across the continuous values of tumor epigenetic DNA methylation at long interspersed nucleotide element-1 (LINE-1). The heterogeneous alcohol effect was modeled using different functions of the LINE-1 marker to demonstrate the method's flexibility. This real-world proof-of-principle computational application demonstrates how the new method enables visualizing the trend of the exposure effect over continuous marker levels. The utilization of continuous biomarker data without categorization for investigating etiological heterogeneity can advance our understanding of biological and pathogenic mechanisms.

Psychometric Characteristics and Validity of the PROMIS Cancer Function Brief 3D Profile.

OBJECTIVE: To develop an item response theory (IRT)-calibrated, patient-reported outcome measure (the PROMIS Cancer Function Brief 3D Profile) of physical function, including associations with fatigue and social participation, in cancer rehabilitation patients. DESIGN: Large-scale field testing, graded response model IRT analyses, and multivariate regression analysis. SETTING: Six cancer rehabilitation clinics associated with cancer centers across the United States. PARTICIPANTS: Adults (N=616) treated in outpatient cancer rehabilitation medicine clinics. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: The PROMIS(r) Cancer Function 3D Profile (including existing items from PROMIS(r) item banks). RESULTS: A total of 616 patients completed 21 items in the initial item pool. Nine items were removed because of comparatively lower information that they provide according to the IRT item calibrations, low item-total correlations, or bimodal distributions. The remaining items generated a 12-item short form. Regression analyses determined that the items were responsive to and representative of the patient population across trait ranges and multiple domains and subdomains of function. CONCLUSIONS: This psychometric investigation supports the use of the PROMIS Cancer Function Brief 3D Profile for evaluating function in outpatient cancer rehabilitation patients.

Translating 2019 ACSM Cancer Exercise Recommendations for a Physiatric Practice: Derived Recommendations from an International Expert Panel.

In 2018, the American College of Sports Medicine (ACSM) reconvened an international, multi-disciplinary group of professionals to review pertinent published literature on exercise for people with cancer. The 2018 roundtable resulted in the publication of three articles in 2019. The three articles serve as an important update to the original ACSM Roundtable on Cancer, which convened in 2010. Although the focus of the three 2019 articles is on exercise, which is only one part of comprehensive cancer rehabilitation, the evidence presented in the 2019 ACSM articles has direct implications for physiatrists and other rehabilitation professionals who care for people with cancer. As such, the narrative review presented here has two primary objectives. First, we summarize the evidence within the three ACSM articles and interpret it within a familiar rehabilitation framework, namely the Dietz model of Cancer Rehabilitation, in order to facilitate implementation broadly within rehabilitation practice. Second, via expert consensus, we have tabulated relevant exercise recommendations for specific cancer populations at different points in the cancer care continuum and translated them into text, tables, and figures for ease of reference. Notably, the authors of this article are members of the Cancer Rehabilitation Physician Consortium (CRPC), a group of physicians who subspecialize in cancer rehabilitation medicine (CRM).

Promoting Empowerment: "Give Me Your Hand" - Whose Hand/What Goal?

Dealing with painful suffering is discussed in a passage featuring an interchange between several rabbis in the Babylonian Talmud. As part of that discussion someone says, "Give me your hand." Who speaks that phrase, and what is the purpose behind this request? What practical lessons can this passage teach us today? The explanations offered here propose an alternative understanding to the conventional explanation of who initiates the action. I suggest that it is the sufferer who speaks, thereby achieving self-empowerment.

Protecting Children From Tobacco Smoke Exposure: A Randomized Controlled Trial of Project Zero Exposure.

INTRODUCTION: Young children are vulnerable to harm from tobacco smoke exposure (TSE). This study assessed the effect of Project Zero Exposure-an intervention program designed to help parents protect children from TSE-on children's exposure. METHODS: Randomized controlled trial of a home-based, theory-driven intervention. Parents of young children (<8 y) in families with a smoking parent were eligible. The intervention included feedback on child TSE (hair nicotine), and home air quality (PM2.5), with motivational interviewing. Families were randomized to: intervention group (IG, N = 69), regular control group (RCG, N = 70), or to a secondary enhanced control group, (ECG, N = 20). Child hair samples were taken at baseline and follow-up. We report on child TSE in the IG versus RCG at six months. RESULTS: Most enrolled families completed the trial (IG: 98.6%[68/69], RCG: 97.1%[68/70]). Log hair nicotine (LHN [ng/mg]) decreased in both the IG (Baseline: -1.78 ± 1.91, Follow-up: -2.82 ± 1.87, p = .003) and RCG (Baseline: -1.79 ± 1.54, Follow-up: -2.85 ± 1.73, p = .002), but did not differ between groups at study end (p = .635). Three of five parentally-reported outcomes showed improvement over time in the IG, and one in the RCG. Among IG participants, 90% found hair nicotine feedback useful. CONCLUSIONS: No difference between the intervention and control groups was found on the objective biomarker, LHN. Child TSE decreased during the trial in intervention and control groups. Trial participation, which included hair nicotine monitoring, may have contributed to decreasing exposure in both groups. Concurrent control group improvements may partially explain lack of proven intervention benefit. Biomarker monitoring warrants further investigation for reduction of child TSE. IMPLICATIONS: Project Zero Exposure is an intervention program designed to help parents protect their children from TSE. Results from the randomized controlled trial of the program showed no difference between groups at study end, but a clear and substantial reduction in child exposure to tobacco smoke from beginning to end of the trial, in both intervention and control groups. Biomarker monitoring, a key element of the trial, was used with all participants. Biomarker monitoring of child exposure to tobacco smoke may help parents become aware of their child's exposure and better protect them, and should be explored as a means to reduce child TSE. Clinical Trial Registration: NCT02867241.

Testing the acceptability and feasibility of a tablet-based supportive cancer platform for patients with metastatic breast cancer.

BACKGROUND: Although metastatic breast cancer (MBC) survival is improving, symptoms remain a significant burden. Returning to a cancer center for symptom management can be challenging. Technology-enabled supportive care platforms are worth exploration. METHODS: Seventeen patients with MBC were randomized to immediate or delayed start for a 3-month intervention that included daily tablet-based guideline-concordant self-care for pain, distress, fatigue, and sleep disturbance, as well as weekly calls with a patient navigator. The primary outcome was patient acceptability. We also assessed feasibility, patient satisfaction, and cost and compared between group differences for symptoms. RM-ANOVA examined between group differences over time. Hedges' d effect sizes quantified magnitude of differences in change between immediate and delayed start. RESULTS: Sixty-eight percent of patients approached accepted the tablet-based intervention. Patients interacted with the tablet 48% of possible days. Patient satisfaction ranged from 83 for walking to 49% for the psychological interventions. The cost of delivering Nurse AMIE for 3 months was $570.23. Small nonsignificant improvements were found for fatigue (d=0.24). Nonsignificant, but potentially clinically meaningful, moderate reductions were found for sleep (d=0.65) and distress (d=0.74). DISCUSSION: A tablet-based supportive care platform that offers guideline-concordant self-care for pain, fatigue, sleep, and distress was observed to be highly acceptable and feasible for patients with metastatic breast cancer. Patient satisfaction scores and initial evaluation of efficacy are promising, and the platform warrants further investigation. IMPLICATIONS FOR CANCER SURVIVORS: Technology-based self-care is a promising option to address symptoms in patients with metastatic breast cancer.

Bringing prevost's sign into the third dimension: Artificial intelligence estimation of conjugate gaze adjusted length (CGAL) and correlation with acute ischemic stroke.

Conjugate gaze deviation is associated with acute ischemic stroke (AIS), although previously only measured on a 2D plane. The current study evaluates 3D imaging efficacy to assess conjugate gaze deviation and correlate direction and strength of deviation to neuro-clinical findings.A retrospective analysis of 519 patients who had CT scans for suspected AIS at our institution. Direction and angle of eye deviation were calculated based on 2D axial images. Volumetric reconstruction of CT scans allowed for calculation of 3D conjugate gaze adjusted length (CGAL). Angle, direction, and vector strength of both 2D and 3D scans were calculated by an artificial intelligence algorithm and tested for agreement with hemispheric ischemia location. CGAL measurements were correlated to NIHSS scores. Follow up MRI data was used to evaluate the sensitivity and specificity of CGAL in the identification of AIS.The final analysis included 122 patients. A strong agreement was found between 3D gaze direction and hemispheric ischemia location. CGAL measurements were highly correlated with NIHSS score (r = .72, P = .01). A CGAL >0.25, >0.28, and >0.35 exhibited a sensitivity of 91%, 86%, and 82% and specificity of 66%, 89%, and 89%, respectively, in AIS identification. A CGAL >0.28 has the best sensitivity-specificity balance in the identification of AIS. A CGAL >0.25 has the highest sensitivity.Given CED's correlation with NIHSS score a 1/4 deviation in the ipsilateral direction is a sensitive ancillary radiographic sign to assist radiologists in making a correct diagnosis even when not presented with full clinical data.

He said/She said; Shaming, Blaming Reframing: Impacts and Implications of Childlessness on Relationships in an Ancient Text.

Describing the terms of "shaming, blaming, naming, claiming, and reframing" as the possible changing dynamics in some human relationships to achieve a resolution, is a fairly recent insight. Through analyzing a short section of an ancient text, Biblical Antiquities, we show how those matters, although not named as dynamics, were recognized as stages in human interactions millennia ago. They were played out in the announcement and subsequent birth of the biblical judge Samson.

Minimally Invasive Repair of Ascending Aortic Pseudoaneurysms: An Alternative to Open Surgical Repair in High-Risk Patients.

Development of a pseudoaneurysm of the ascending aorta is an uncommon complication of aortic surgery. Several nonsurgical techniques are available for treatment of ascending aortic pseudoaneurysms (AAPs). This report outlines a single-center retrospective experience with 14 nonsurgical procedures for treatment of AAPs in 10 patients. Modified stent grafts, septal defect occlusion devices, coil embolics, and liquid embolics were deployed by transthoracic and endovascular approaches. Complete stasis of the AAP was achieved in 7 of 10 patients (70%). Mean postprocedural recoveries occurred within 3.5 days. Nonsurgical techniques for repair of AAPs offer a comparatively safe and effective alternative to open surgical repair.

Parental Perceptions of Children's Exposure to Tobacco Smoke and Parental Smoking Behaviour.

Around 40% of children are exposed to tobacco smoke, increasing their risk of poor health. Previous research has demonstrated misunderstanding among smoking parents regarding children's exposure. The parental perceptions of exposure (PPE) measure uses visual and textual vignettes to assess awareness of exposure to smoke. The study aimed to determine whether PPE is related to biochemical and reported measures of exposure in children with smoking parents. Families with at least one smoking parent and a child ≤ age 8 were recruited. In total, 82 parents completed the PPE questionnaire, which was assessed on a scale of 1-7 with higher scores denoting a broader perception of exposure. Parents provided a sample of their child's hair and a self-report of parental smoking habits. Parents who reported smoking away from home had higher PPE ratings than parents who smoke in and around the home (p = 0.026), constituting a medium effect size. PPE corresponded with home smoking frequency, with rare or no home exposure associated with higher PPE scores compared to daily or weekly exposure (p < 0.001). PPE was not significantly related to hair nicotine but was a significant explanatory factor for home smoking location. PPE was significantly associated with parental smoking behaviour, including location and frequency. High PPE was associated with lower exposure according to parental report. This implies that parental understanding of exposure affects protective behaviour and constitutes a potential target for intervention to help protect children.

Changing Exposure Perceptions: A Randomized Controlled Trial of an Intervention with Smoking Parents.

Children who live with smokers are at risk of poor health, and of becoming smokers themselves. Misperceptions of the nature of tobacco smoke exposure have been demonstrated among parents, resulting in continued smoking in their children's environment. This study aimed to change parents' perceptions of exposure by providing information on second- and third-hand exposure and personalised information on children's exposure [NIH registry (NCT02867241)]. One hundred and fifty-nine families with a child < 8 years and at least one smoking parent were randomized into intervention (69), control (70), and enhanced control (20) groups. Reported exposure, parental smoking details, and a child hair sample were obtained at the start of the study and 6-8 months later. Parental perceptions of exposure (PPE) were assessed via a questionnaire. The intervention consisted of motivational interviews, feedback of home air quality and child's hair nicotine level, and information brochures. PPE were significantly higher at the study end (94.6 ± 17.6) compared to study beginning (86.5 ± 19.3) in intervention and enhanced control groups (t(72) = -3.950; p < 0.001). PPE at study end were significantly higher in the intervention group compared to the regular control group (p = 0.020). There was no significant interaction between time and group. Parallel changes in parental smoking behaviour were found. Parental perceptions of exposure were increased significantly post intervention, indicating that they can be altered. By making parents more aware of exposure and the circumstances in which it occurs, we can help parents change their smoking behaviour and better protect their children.

Estimation in the Cox survival regression model with covariate measurement error and a changepoint.

The Cox regression model is a popular model for analyzing the relationship between a covariate vector and a survival endpoint. The standard Cox model assumes a constant covariate effect across the entire covariate domain. However, in many epidemiological and other applications, the covariate of main interest is subject to a threshold effect: a change in the slope at a certain point within the covariate domain. Often, the covariate of interest is subject to some degree of measurement error. In this paper, we study measurement error correction in the case where the threshold is known. Several bias correction methods are examined: two versions of regression calibration (RC1 and RC2, the latter of which is new), two methods based on the induced relative risk under a rare event assumption (RR1 and RR2, the latter of which is new), a maximum pseudo-partial likelihood estimator (MPPLE), and simulation-extrapolation (SIMEX). We develop the theory, present simulations comparing the methods, and illustrate their use on data concerning the relationship between chronic air pollution exposure to particulate matter PM10 and fatal myocardial infarction (Nurses Health Study (NHS)), and on data concerning the effect of a subject's long-term underlying systolic blood pressure level on the risk of cardiovascular disease death (Framingham Heart Study (FHS)). The simulations indicate that the best methods are RR2 and MPPLE.

The Cancer Rehabilitation Medicine Metrics Consortium: A Path to Enhanced, Multi-Site Outcome Assessment to Enhance Care and Demonstrate Value.

PURPOSE: A primary objective stated at the Cancer Rehabilitation Symposium at the National Institutes of Health was to improve outcome measurement. The purpose of this project was for the Cancer Rehabilitation Medicine Metrics Consortium (CRMMC) to develop an assessment tool to evaluate function in cancer patients via a data-driven and methodologically sound process. There is no agreed-upon measure of physical and cognitive function for cancer patients, making it difficult to demonstrate the value of rehabilitation interventions. Cancer patients are a particularly challenging population, with many tumor- and treatment-related variables impacting function. METHODS: Investigators from nine different cancer rehabilitation programs participated in a modified-Delphi process to delineate necessary aspects of an ideal patient assessment tool, including instrument type, domains evaluated, applicability across a range of patient traits, clinical feasibility, and item response characteristics. This involved numerous meetings, data review, and analysis of items involved in patient assessment. RESULTS: The CRMMC developed a 21-item patient-reported outcome measure based on item response theory. The process by which the short form was developed was documented and provides a framework for other clinicians to follow. CONCLUSION: This document provides a framework for rehabilitation providers to follow when developing an assessment tool. This process is described in a stepwise fashion for reproducibility even in different, non-cancer populations.