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Lost work opportunity and forced retirement demonstrate negative health impacts related to occupational deprivation. Measuring occupational loss during the retirement transition can be problematic. The objective of the study is to clarify measurement of involuntary retirement in its relationship to occupational loss and deprivation. Using an explanatory sequential mixed-methods design, survey data on unemployment, forced retirement, and earlier-than-planned retirement from 195 screened retirees yielded 102 reporting at least one lost work opportunity event, with 18 interviewed about occupational loss within the analytic timeframe. Planned retirement age was similar for full-employment and lost work opportunity groups. Actual retirement age was earlier in the lost work opportunity sample (age 57.5 compared with 61.2). Interviews identified a 22% discrepancy between forced retirement reported in survey versus interview data. Themes emerging from the interviews indicated financial and identity challenges from lost work opportunity, a dialectical trade-off between lost opportunity and daily freedom, and overall resilience., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: Unemployment is a known health stressor that also increases early retirements. This study addresses mixed literature on retiree health and underreporting of forced retirement to better identify potential health impacts of lost work opportunity., Methods: A Lost-work Opportunity Score (LOS) was created using variables from the Health and Retirement Study assessing unemployment, forced retirement, and earlier-than-planned retirement for 2576 respondents. Reliability and unidimensionality of the score with multivariate regression analyses examined health impacts controlling for demographics and prior health status., Results: The LOS possessed unidimensionality with a Cronbach's alpha of a = 0.76 while predicting self-reported health declines (LOS = 2; β = 0.381, OR = 1.464, P < 0.05) and depression increase (LOS = 2; β = 0.417, OR = 1.517, P < 0.05)., Conclusions: LOS predicts 46% increased odds of negative self-reported health change after retirement associated with two LOS events, with implications to support aging workers., Competing Interests: Conflict of interest: None declared., (Copyright © 2024 American College of Occupational and Environmental Medicine.)

Clinical genetic laboratories must have access to clinically validated biomedical data for precision medicine. A lack of accessibility, normalized structure, and consistency in evaluation complicates interpretation of disease causality, resulting in confusion in assessing the clinical validity of genes and genetic variants for diagnosis. A key goal of the Clinical Genome Resource (ClinGen) is to fill the knowledge gap concerning the strength of evidence supporting the role of a gene in a monogenic disease, which is achieved through a process known as Gene-Disease Validity curation. Here we review the work of ClinGen in developing a curation infrastructure that supports the standardization, harmonization, and dissemination of Gene-Disease Validity data through the creation of frameworks and the utilization of common data standards. This infrastructure is based on several applications, including the ClinGen GeneTracker, Gene Curation Interface, Data Exchange, GeneGraph, and website.

Background: Among patients with cirrhosis and pre-malignant or early malignant mucosal lesions, surgical intervention carries a much higher bleeding risk. When such lesions are discovered, endoscopic submucosal dissection (ESD) may offer curative therapy with lower risks than surgery and improved outcomes compared to traditional endoscopic resection., Aim: To evaluate the outcomes of ESD in patients with cirrhosis., Methods: Patients with cirrhosis undergoing ESD between July 2015 and August 2022 were retrospectively matched in 1:2 fashion to controls based on lesion location, size, and anticoagulation use. Procedural outcomes were compared between groups., Results: A total of 64 Lesions from 59 patients were included (16 cirrhosis, 43 control). There were no differences in patient or lesion characteristics between groups. En bloc and curative resection was achieved in 84.21%, 78.94% of the cirrhosis group and 88.89%, 68.89% of controls, respectively, with no significant differences. Cirrhotic patients had significantly higher rates of intra-procedural coagulation grasper use for control of bleeding (47.37% vs 20%; P = 0.02). There were otherwise no significant differences in adverse event rates. In the 29 patients with follow up, we found higher rates of recurrence in the cirrhosis group compared to controls (40% vs 5.26%; P = 0.019), however this effect did not persist on multivariable analysis controlling for known confounders., Conclusion: ESD may be safe and effective in patients with cirrhosis. Most procedure related outcomes were not significantly different between groups. Intra-procedural bleeding requiring use of the coagulation grasper use was expectedly higher in the cirrhosis group given the known effects of liver disease on hemostasis., Competing Interests: Conflict-of-interest statement: Robert Luke Pecha, Fares Ayoub, Ankur Patel, Abdullah Muftah, Michael Wright, Mai Khalaf: No conflicts of interest to disclose. Mohamed O. Othman: Mohamed O Othman is a consultant for Olympus, Boston Scientific Corporation, Abbvie, ConMed, Lumendi and Apollo. Mohamed O Othman received research grants from Lucid Diagnostics, AbbVie and ConMed., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Exposure and cognitive-based therapies are both effective for PTSD, but knowledge of which intervention is best for which patient is lacking. This lack of knowledge is particularly noticeable for group treatments, as no study has examined whether responses to different group therapies are associated with different pretreatment characteristics. Here, we explored whether pretreatment levels of three types of psychological characteristics-PTSD symptom clusters, posttraumatic cognitions, and emotion regulation difficulties-were associated with symptom reduction during group-delivered cognitive versus exposure-based PTSD treatment. Participants were Veterans with PTSD drawn from two previous clinical trials: one of group CPT (GCPT; n  = 32) and the other of group-based exposure therapy (GBET; n  = 21). Growth curve modeling was used to identify pretreatment variables that predicted weekly PTSD symptom changes during each therapy. Higher posttraumatic cognitions at pretreatment predicted steeper PTSD symptom reduction during GCPT but not GBET. Additionally, symptom reduction during each therapy was associated with different pretreatment emotion regulation difficulties: difficulties with goal-directed behavior for GBET and lack of emotional clarity and limited access to emotion regulation strategies for GCPT. These findings suggest that assigning Veterans to a group PTSD therapy that better matches their pretreatment psychological profile might facilitate a better therapeutic response.

Grating magneto-optical traps are an enabling quantum technology for portable metrological devices with ultracold atoms. However, beam diffraction efficiency and angle are affected by wavelength, creating a single-optic design challenge for laser cooling in two stages at two distinct wavelengths - as commonly used for loading, e.g., Sr or Yb atoms into optical lattice or tweezer clocks. Here, we optically characterize a wide variety of binary gratings at different wavelengths to find a simple empirical fit to experimental grating diffraction efficiency data in terms of dimensionless etch depth and period for various duty cycles. The model avoids complex 3D light-grating surface calculations, yet still yields results accurate to a few percent across a broad range of parameters. Gratings optimized for two (or more) wavelengths can now be designed in an informed manner suitable for a wide class of atomic species enabling advanced quantum technologies.

Background: Posttraumatic stress disorder (PTSD) is a significant burden among combat Veterans returning from the wars in Iraq and Afghanistan. While empirically supported treatments have demonstrated reductions in PTSD symptomatology, there remains a need to improve treatment effectiveness. Functional magnetic resonance imaging (fMRI) neurofeedback has emerged as a possible treatment to ameliorate PTSD symptom severity. Virtual reality (VR) approaches have also shown promise in increasing treatment compliance and outcomes. To facilitate fMRI neurofeedback-associated therapies, it would be advantageous to accurately classify internal brain stress levels while Veterans are exposed to trauma-associated VR imagery. Methods: Across 2 sessions, we used fMRI to collect neural responses to trauma-associated VR-like stimuli among male combat Veterans with PTSD symptoms (N = 8). Veterans reported their self-perceived stress level on a scale from 1 to 8 every 15 s throughout the fMRI sessions. In our proposed framework, we precisely sample the fMRI data on cortical gray matter, blurring the data along the gray-matter manifold to reduce noise and dimensionality while preserving maximum neural information. Then, we independently applied 3 machine learning (ML) algorithms to this fMRI data collected across 2 sessions, separately for each Veteran, to build individualized ML models that predicted their internal brain states (self-reported stress responses). Results: We accurately classified the 8-class self-reported stress responses with a mean (± standard error) root mean square error of 0.6 (± 0.1) across all Veterans using the best ML approach. Conclusions: The findings demonstrate the predictive ability of ML algorithms applied to whole-brain cortical fMRI data collected during individual Veteran sessions. The framework we have developed to preprocess whole-brain cortical fMRI data and train ML models across sessions would provide a valuable tool to enable individualized real-time fMRI neurofeedback during VR-like exposure therapy for PTSD., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

The Clinical Genome Resource (ClinGen) serves as an authoritative resource on the clinical relevance of genes and variants. In order to support our curation activities and to disseminate our findings to the community, we have developed a Data Platform of informatics resources backed by standardized data models. In this workshop we demonstrate our publicly available resources including curation interfaces, (Variant Curation Interface, CIViC), supporting infrastructure (Allele Registry, Genegraph), and data models (SEPIO, GA4GH VRS, VA).

Background: Prior to the COVID-19 pandemic, medical students exhibited poorer mental health relative to the general population and other students. This research aimed to assess American medical student mental health during the pandemic's height, while also identifying stressors and vulnerable populations., Methods: In this cross-sectional study, 960 US allopathic and osteopathic medical students completed a mental health survey screening for depression, anxiety, burnout, suicidal ideation and increased substance use during the height of the COVID-19 pandemic. Potential relationships were explored between these mental health indicators and demographic and environmental factors, such as COVID-19 exposure., Findings: Of the 960 medical students surveyed, 25.1% (n = 241) screened positive for depression, 40.4% (n = 388) screened positive for anxiety, 21.3% (n = 201) met criteria for at least one dimension of burnout, 19.0% (n = 182) started or increased substance use and 7.2% (n = 69) experienced thoughts of self-harm or suicide. Significant differences (p ≤ 0.01) in measures of mental health were associated with those who had accessed mental health care, had a personal COVID-19 diagnosis, knew someone who died of COVID-19 or were female., Conclusions: Although rates of anxiety and substance use among medical students in our study were higher than previously reported, rates of burnout and thoughts of self-harm or suicide were surprisingly lower. These results indicate that some aspects of remote learning imposed by the pandemic could be protective, warranting additional study for post-pandemic medical education. Meanwhile, medical schools and clerkships should offer additional resources to students particularly vulnerable to stressors, including females and those with personal pandemic impacts., (© 2022 Association for the Study of Medical Education and John Wiley & Sons Ltd.)

Background: Treatment dropout has been problematic with evidence-based treatments for posttraumatic stress disorder (PTSD), including cognitive processing therapy (CPT). This study sought to evaluate whether CPT group contributed to symptom improvement among treatment completers and non-completers., Methods: Sixty-one Iraq and Afghanistan combat Veterans self-selected CPT group or treatment as usual (TAU) forming a convenience sample. Defining treatment completion as attending at least nine sessions: 18 completed treatment, 20 dropped-out (DOs); 20 completed TAU, 3 lost to TAU follow-up., Results: Multiple Regression revealed significant pre-post-treatment improvement, the Clinician-Administered PTSD Scale (CAPS-IV, F(5, 40.1) = 2.53, p = 0.0436). Reviewing DOs' last available PTSD Checklist-Military Version scores before leaving treatment, six achieved clinically significant improvement of >10 points; seven a clinically reliable change of 5-10 points., Conclusion: These findings highlight that CPT group may be effective at reducing trauma-related symptoms among treatment completers and dropouts and point to the utility of a clinical definition of good treatment end-state., (© 2022 Wiley Periodicals LLC.)

Mild Traumatic brain injury (mTBI) is a signature wound in military personnel, and repetitive mTBI has been linked to age-related neurogenerative disorders that affect white matter (WM) in the brain. However, findings of injury to specific WM tracts have been variable and inconsistent. This may be due to the heterogeneity of mechanisms, etiology, and comorbid disorders related to mTBI. Non-negative matrix factorization (NMF) is a data-driven approach that detects covarying patterns (components) within high-dimensional data. We applied NMF to diffusion imaging data from military Veterans with and without a self-reported TBI history. NMF identified 12 independent components derived from fractional anisotropy (FA) in a large dataset (n = 1,475) gathered through the ENIGMA (Enhancing Neuroimaging Genetics through Meta-Analysis) Military Brain Injury working group. Regressions were used to examine TBI- and mTBI-related associations in NMF-derived components while adjusting for age, sex, post-traumatic stress disorder, depression, and data acquisition site/scanner. We found significantly stronger age-dependent effects of lower FA in Veterans with TBI than Veterans without in four components (q < 0.05), which are spatially unconstrained by traditionally defined WM tracts. One component, occupying the most peripheral location, exhibited significantly stronger age-dependent differences in Veterans with mTBI. We found NMF to be powerful and effective in detecting covarying patterns of FA associated with mTBI by applying standard parametric regression modeling. Our results highlight patterns of WM alteration that are differentially affected by TBI and mTBI in younger compared to older military Veterans., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Purpose: According to the American College of Medical Genetics and Genomics/Association of Medical Pathology (ACMG/AMP) guidelines, in silico evidence is applied at the supporting strength level for pathogenic (PP3) and benign (BP4) evidence. Although PP3 is commonly used, less is known about the effect of these criteria on variant classification outcomes., Methods: A total of 727 missense variants curated by Clinical Genome Resource expert groups were analyzed to determine how often PP3 and BP4 were applied and their impact on variant classification. The ACMG/AMP categorical system of variant classification was compared with a quantitative point-based system. The pathogenicity likelihood ratios of REVEL, VEST, FATHMM, and MPC were calibrated using a gold standard set of 237 pathogenic and benign variants (classified independent of the PP3/BP4 criteria)., Results: The PP3 and BP4 criteria were applied by Variant Curation Expert Panels to 55% of missense variants. Application of those criteria changed the classification of 15% of missense variants for which either criterion was applied. The point-based system resolved borderline classifications. REVEL and VEST performed best at a strength level consistent with moderate evidence., Conclusion: We show that in silico criteria are commonly applied and often affect the final variant classifications. When appropriate thresholds for in silico predictors are established, our results show that PP3 and BP4 can be used at a moderate strength., Competing Interests: Conflict of Interest The authors declare that they have no competing interests. L.G.B. reports serving as an advisor for the Illumina, Inc and receiving in-kind research support from Merck & Co, Inc., (Copyright © 2021 American College of Medical Genetics and Genomics. All rights reserved.)

Objective: This article overviews the current statistics and factors related to increased rates of opioid use disorder (OUD) in rural areas, uncovering factors that may contribute to increased vulnerability to opioid overdose. We qualitatively review opinions, feelings, and thoughts surrounding this issue in rural areas of Utah, analyzing participant stories in reference to three themes through qualitative interviews, including the solitude of addiction, the beguiling strength of addiction, and one way out of addiction., Design: In 2018, three focus groups were convened with 25 individuals from the rural area. Participants either currently or formerly (selfreported substance free for 6 months or more) experienced OUD with prescription opioids and heroin, or were family members of individuals who currently and formerly experienced OUD. These focus groups addressed current issues in OUDs in a rural Utah community related to person, place, and time. Following the focus groups, six individuals were invited to participate in semi-structured interviews. In-depth, semi-structured interviews queried individual experiences through a phenomenological approach, using a moderator guide with queries focused on identified themes related to the solitude, the intensity, and the difficulty escaping substance use disorder (SUD). Methodology included training community scholars with lived experience and member-checking to ensure phenomenological emphasis., Results: Our qualitative reviews of the experience of OUD and SUD in rural Utah discussed the relevance and the nuance of the three identified themes. The interviewee statements further underscore the solitude, intensity, and difficulty of an individual's journey through SUD, the all-consuming nature of OUD, and the trouble that these factors cause in rural recovery., Conclusions: We conclude that even during difficult situations in the rural experience with the opioid crisis, hope persists. OUD support in rurality may differ from the expected urban experience and include more coordination with criminal justice workers. Rural Americans have insights to share that could help turn the tide of this crisis.

Background: Identification of clinically significant genetic alterations involved in human disease has been dramatically accelerated by developments in next-generation sequencing technologies. However, the infrastructure and accessible comprehensive curation tools necessary for analyzing an individual patient genome and interpreting genetic variants to inform healthcare management have been lacking., Results: Here we present the ClinGen Variant Curation Interface (VCI), a global open-source variant classification platform for supporting the application of evidence criteria and classification of variants based on the ACMG/AMP variant classification guidelines. The VCI is among a suite of tools developed by the NIH-funded Clinical Genome Resource (ClinGen) Consortium and supports an FDA-recognized human variant curation process. Essential to this is the ability to enable collaboration and peer review across ClinGen Expert Panels supporting users in comprehensively identifying, annotating, and sharing relevant evidence while making variant pathogenicity assertions. To facilitate evidence-based improvements in human variant classification, the VCI is publicly available to the genomics community. Navigation workflows support users providing guidance to comprehensively apply the ACMG/AMP evidence criteria and document provenance for asserting variant classifications., Conclusions: The VCI offers a central platform for clinical variant classification that fills a gap in the learning healthcare system, facilitates widespread adoption of standards for clinical curation, and is available at https://curation.clinicalgenome.org., (© 2021. The Author(s).)

Precision medicine faces many challenges, including the gap of knowledge between disease genetics and pharmacogenomics (PGx). Disease genetics interprets the pathogenicity of genetic variants for diagnostic purposes, while PGx investigates the genetic influences on drug responses. Ideally, the quality of health care would be improved from the point of disease diagnosis to drug prescribing if PGx is integrated with disease genetics in clinical care. However, PGx genes or variants are usually not reported as a secondary finding even if they are included in a clinical genetic test for diagnostic purposes. This happens even though the detection of PGx variants can provide valuable drug prescribing recommendations. One underlying reason is the lack of systematic classification of the knowledge overlap between PGx and disease genetics. Here, we address this issue by analyzing gene and genetic variant annotations from multiple expert-curated knowledge databases, including PharmGKB, CPIC, ClinGen and ClinVar. We further classified genes based on the strength of evidence supporting a gene's pathogenic role or PGx effect as well as the level of clinical actionability of a gene. Twenty-six genes were found to have pathogenic variation associated with germline diseases as well as strong evidence for a PGx association. These genes were classified into four sub-categories based on the distinct connection between the gene's pathogenic role and PGx effect. Moreover, we have also found thirteen RYR1 genetic variants that were annotated as pathogenic and at the same time whose PGx effect was supported by a preponderance of evidence and given drug prescribing recommendations. Overall, we identified a nontrivial number of gene and genetic variant overlaps between disease genetics and PGx, which laid out a foundation for combining PGx and disease genetics to improve clinical care from disease diagnoses to drug prescribing and adherence.

Genetics researchers and clinical professionals rely on diversity measures such as race, ethnicity, and ancestry (REA) to stratify study participants and patients for a variety of applications in research and precision medicine. However, there are no comprehensive, widely accepted standards or guidelines for collecting and using such data in clinical genetics practice. Two NIH-funded research consortia, the Clinical Genome Resource (ClinGen) and Clinical Sequencing Evidence-generating Research (CSER), have partnered to address this issue and report how REA are currently collected, conceptualized, and used. Surveying clinical genetics professionals and researchers (n = 448), we found heterogeneity in the way REA are perceived, defined, and measured, with variation in the perceived importance of REA in both clinical and research settings. The majority of respondents (>55%) felt that REA are at least somewhat important for clinical variant interpretation, ordering genetic tests, and communicating results to patients. However, there was no consensus on the relevance of REA, including how each of these measures should be used in different scenarios and what information they can convey in the context of human genetics. A lack of common definitions and applications of REA across the precision medicine pipeline may contribute to inconsistencies in data collection, missing or inaccurate classifications, and misleading or inconclusive results. Thus, our findings support the need for standardization and harmonization of REA data collection and use in clinical genetics and precision health research., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: There is a dearth of research on the impact of pre-treatment assessment effort and symptom exaggeration on the treatment outcomes of Veterans engaging in trauma-focused therapy, handicapping therapists providing these treatments. Research suggests a multi-method approach for assessing symptom exaggeration in Veterans with posttraumatic stress disorder (PTSD), which includes effort and symptom validity tests, is preferable. Symptom exaggeration has also been considered a "cry for help," associated with increased PTSD and depressive symptoms. Recently, research has identified resilience as a moderator of PTSD and depressive symptom severity and an important predictor of treatment response among individuals with PTSD. Thus, it is important to examine the intersection of symptom exaggeration, resilience, and treatment outcome to determine whether assessment effort and symptom exaggeration compromise treatment response., Materials and Methods: We recruited Veterans, aged 18-50 who served during the Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND) era, from mental health clinics and fliers posted in a large Veterans Affairs Medical Center. Veterans met inclusion criteria if they were diagnosed with PTSD via a clinician-administered assessment. Sixty-one Veterans consented to participate and self-selected into a cognitive processing therapy (CPT) group or treatment-as-usual. We offered self-selection because low recruitment rates delayed treatment start dates and were consistent with a Veteran-centered care philosophy. Veterans were assessed before and after treatment to determine the impact of assessment effort and symptom exaggeration scores on measures of PTSD and depressive symptoms and resilience. This study examined whether assessment effort failure and symptom exaggeration were associated with compromised psychotherapy outcomes in Veterans with PTSD undergoing CPT group. We hypothesized that a pattern of responding consistent with both effort and symptom exaggeration would result in higher (ie, more severe) pre- and post-treatment scores on PTSD and depressive symptom outcome measures and lower resiliency when compared to Veterans providing good effort and genuine responding. Hypotheses were evaluated using bivariate correlation analyses, analysis of variance, and chi-square analyses., Results: Pre-treatment scores on measures of PTSD and depressive symptoms were higher among Veterans whose pattern of responding was consistent with poor assessment effort and symptom exaggeration; these Veterans also scored lower on a measure of resiliency. At post-treatment, there were no differences between Veterans displaying good and failed effort testing on measures of PTSD and depressive symptoms or in whether they completed treatment. Post-treatment resiliency scores remained significantly lower in those with failed effort testing., Conclusion: These results suggest that Veterans with PTSD whose validity testing scores are indicative of poor effort and symptom exaggeration may be less resilient but may still complete a CPT group treatment and benefit from treatment at a rate comparable to Veterans who evidence good assessment effort and genuine symptom reporting pre-treatment. These findings also challenge the assumption that pre-treatment assessment effort failure and symptom exaggeration accurately predict poor effort in trauma-focused psychotherapy., (© Association of Military Surgeons of the United States 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

There is uncertainty related to whether retirement negatively affects health-possibly due to complexity around retirement decisions. Lost-work opportunity through unemployment or forced retirement has been shown to negatively affect health. Lost-work opportunity can be captured in two measurement fields, either a reported experience of being forced into retirement or reported unemployment. However, 17% of individuals retiring due to the loss of work opportunity identified in qualitative interviewing (i.e., unemployment, temporary lay-offs, company buy-outs, forced relocations, etc.) do not report this unemployment or involuntary retirement in quantitative survey responses. We propose broadening the conceptualization of late-career unemployment to incorporate other lost work opportunity scenarios. Using the Health and Retirement Study (HRS), a lost-work opportunity score (LOS) was computed from items indicating unemployment and forced or unplanned retirement. Correlations were computed between this LOS and all continuous variables in the RAND longitudinal compilation of the HRS to determine its convergent and discriminant validity. The LOS demonstrated a Chronbach's alpha of α = .82 and had convergent validity with constructs of employment (9 variables), finances (36 variables), and health (14 variables), as predicted by the literature on retirement timing. No other continuous variables in the HRS were identified with a moderate or strong correlation to LOS, demonstrating discriminant validity. Further research should explore whether a combination of variables in the HRS can improve the accuracy of measuring lost-work opportunity. Improved precision in measurement, through an expanded conceptualization of lost-work opportunity, may help explicate the retirement-related factors that affect health, to inform policy and support healthy aging decisions at a societal level., (© The Author(s) 2019. Published by Oxford University Press. For permissions please e-mail: journals.permissions@oup.com.)

Objective: Job loss has a demonstrated negative impact on physical and mental health. Involuntary retirement has also been linked to poorer physical and mental health outcomes. This study examined whether late-career unemployment is related to involuntary retirement and health declines postretirement. Method: Analysis was conducted using the 2000-2012 U.S. Health and Retirement Study (HRS) survey data with unemployment months regressed with demographic and baseline health measures on physical and mental health. Results: Individuals with late-career unemployment reported more involuntary retirement timing (47.0%) compared with those reporting no unemployment (27.9%). Late-career unemployment had no significant effect on self-reported physical health (β = .003, p = .84), but was significantly associated with lower levels of mental health (β = .039; p < .01). Conclusion: Self-reports of late-career unemployment are not associated with physical health in retirement, but unemployment is associated with involuntary retirement timing and mental health declines in retirement. Unemployment late in the working career should be addressed as a public mental health concern.

As genetic sequencing costs decrease, the lack of clinical interpretation of variants has become the bottleneck in using genetics data. A major rate limiting step in clinical interpretation is the manual curation of evidence in the genetic literature by highly trained biocurators. What makes curation particularly time-consuming is that the curator needs to identify papers that study variant pathogenicity using different types of approaches and evidences-e.g. biochemical assays or case control analysis. In collaboration with the Clinical Genomic Resource (ClinGen)-the flagship NIH program for clinical curation-we propose the first machine learning system, LitGen, that can retrieve papers for a particular variant and filter them by specific evidence types used by curators to assess for pathogenicity. LitGen uses semi-supervised deep learning to predict the type of evi+dence provided by each paper. It is trained on papers annotated by ClinGen curators and systematically evaluated on new test data collected by ClinGen. LitGen further leverages rich human explanations and unlabeled data to gain 7.9%-12.6% relative performance improvement over models learned only on the annotated papers. It is a useful framework to improve clinical variant curation.

Background: The American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) clinical variant interpretation guidelines established criteria for different types of evidence. This includes the strong evidence codes PS3 and BS3 for "well-established" functional assays demonstrating a variant has abnormal or normal gene/protein function, respectively. However, they did not provide detailed guidance on how functional evidence should be evaluated, and differences in the application of the PS3/BS3 codes are a contributor to variant interpretation discordance between laboratories. This recommendation seeks to provide a more structured approach to the assessment of functional assays for variant interpretation and guidance on the use of various levels of strength based on assay validation., Methods: The Clinical Genome Resource (ClinGen) Sequence Variant Interpretation (SVI) Working Group used curated functional evidence from ClinGen Variant Curation Expert Panel-developed rule specifications and expert opinions to refine the PS3/BS3 criteria over multiple in-person and virtual meetings. We estimated the odds of pathogenicity for assays using various numbers of variant controls to determine the minimum controls required to reach moderate level evidence. Feedback from the ClinGen Steering Committee and outside experts were incorporated into the recommendations at multiple stages of development., Results: The SVI Working Group developed recommendations for evaluators regarding the assessment of the clinical validity of functional data and a four-step provisional framework to determine the appropriate strength of evidence that can be applied in clinical variant interpretation. These steps are as follows: (1) define the disease mechanism, (2) evaluate the applicability of general classes of assays used in the field, (3) evaluate the validity of specific instances of assays, and (4) apply evidence to individual variant interpretation. We found that a minimum of 11 total pathogenic and benign variant controls are required to reach moderate-level evidence in the absence of rigorous statistical analysis., Conclusions: The recommendations and approach to functional evidence evaluation described here should help clarify the clinical variant interpretation process for functional assays. Further, we hope that these recommendations will help develop productive partnerships with basic scientists who have developed functional assays that are useful for interrogating the function of a variety of genes.

This study examined the role of relationship quality on physical and psychological health among older adults. It included 2,298 adults aged 50 and older who participated in the Midlife in the US national longitudinal study of health and well-being. We assessed the effect of spousal support and strain on psychological and physical health, controlling for age, education, income, depression levels and prior health. Results indicated that spousal support and strain affected psychological health but not physical health. Despite prior research showing an association between marital quality and physical health, this study did not support the conceptualization that relationship quality measured by spousal support or strain has a direct effect on long-term health in this sample of older adults. This study does not preclude the presence of a mediated or moderated association between relationship quality and physical health. Higher levels of spousal support are associated with positive psychological health among adults over age 50 while spousal strain is associated with negative psychological health. This study supports the premise that relationship quality has an ongoing impact on the psychological health of mature adults, bolstering arguments to include psychological health screening and couples relationship education among health services provided to older adults.

The ClinGen Inborn Errors of Metabolism Working Group was tasked with creating a comprehensive, standardized knowledge base of genes and variants for metabolic diseases. Phenylalanine hydroxylase (PAH) deficiency was chosen to pilot development of the Working Group's standards and guidelines. A PAH variant curation expert panel (VCEP) was created to facilitate this process. Following ACMG-AMP variant interpretation guidelines, we present the development of these standards in the context of PAH variant curation and interpretation. Existing ACMG-AMP rules were adjusted based on disease (6) or strength (5) or both (2). Disease adjustments include allele frequency thresholds, functional assay thresholds, and phenotype-specific guidelines. Our validation of PAH-specific variant interpretation guidelines is presented using 85 variants. The PAH VCEP interpretations were concordant with existing interpretations in ClinVar for 69 variants (81%). Development of biocurator tools and standards are also described. Using the PAH-specific ACMG-AMP guidelines, 714 PAH variants have been curated and will be submitted to ClinVar. We also discuss strategies and challenges in applying ACMG-AMP guidelines to autosomal recessive metabolic disease, and the curation of variants in these genes., (© 2018 Wiley Periodicals, Inc.)

The Clinical Genome Resource (ClinGen) Ancestry and Diversity Working Group highlights the need to develop guidance on race, ethnicity, and ancestry (REA) data collection and use in clinical genomics. We present quantitative and qualitative evidence to characterize: (1) acquisition of REA data via clinical laboratory requisition forms, and (2) information disparity across populations in the Genome Aggregation Database (gnomAD) at clinically relevant sites ascertained from annotations in ClinVar. Our requisition form analysis showed substantial heterogeneity in clinical laboratory ascertainment of REA, as well as marked incongruity among terms used to define REA categories. There was also striking disparity across REA populations in the amount of information available about clinically relevant variants in gnomAD. European ancestral populations constituted the majority of observations (55.8%), allele counts (59.7%), and private alleles (56.1%) in gnomAD at 550 loci with "pathogenic" and "likely pathogenic" expert-reviewed variants in ClinVar. Our findings highlight the importance of implementing and supporting programs to increase diversity in genome sequencing and clinical genomics, as well as measuring uncertainty around population-level datasets that are used in variant interpretation. Finally, we suggest the need for a standardized REA data collection framework to be developed through partnerships and collaborations and adopted across clinical genomics., (© 2018 Wiley Periodicals, Inc.)

Effective exchange of information about genetic variants is currently hampered by the lack of readily available globally unique variant identifiers that would enable aggregation of information from different sources. The ClinGen Allele Registry addresses this problem by providing (1) globally unique "canonical" variant identifiers (CAids) on demand, either individually or in large batches; (2) access to variant-identifying information in a searchable Registry; (3) links to allele-related records in many commonly used databases; and (4) services for adding links to information about registered variants in external sources. A core element of the Registry is a canonicalization service, implemented using in-memory sequence alignment-based index, which groups variant identifiers denoting the same nucleotide variant and assigns unique and dereferenceable CAids. More than 650 million distinct variants are currently registered, including those from gnomAD, ExAC, dbSNP, and ClinVar, including a small number of variants registered by Registry users. The Registry is accessible both via a web interface and programmatically via well-documented Hypertext Transfer Protocol (HTTP) Representational State Transfer Application Programming Interface (REST-APIs). For programmatic interoperability, the Registry content is accessible in the JavaScript Object Notation for Linked Data (JSON-LD) format. We present several use cases and demonstrate how the linked information may provide raw material for reasoning about variant's pathogenicity., (© 2018 The Authors. Human Mutation published by Wiley Periodicals, Inc.)

Purpose: Previous oncological studies showed that lymph node ratio (LNR) (ratio of number of lymph nodes that tested positive for metastasis to the total number of lymph nodes examined) is a negative indicator of cancer survival. The American Joint Committee on Cancer (AJCC) staging system incorporates tumor size, lymph node involvement, and metastasis in a comprehensive model of cancer progression, but LNR alone has been shown to outperform the AJCC system in prognostic and survival predictions for various types of cancer. The effectiveness of LNR has not been evaluated in breast cancer staging. Evaluating LNR for predicting cancer staging in breast cancer has the potential to improve treatment recommendations., Methods: The Surveillance, Epidemiology, and End Results dataset was used to identify 10,655 breast cancer patients who underwent nodal evaluation from 2010 to 2013, and their LNRs were calculated. Descriptive statistics of lymph node evaluation in the patients are provided. Logistic regression with LNR as the continuous independent variable was conducted to determine whether LNR could predict cancer progression, coded as regional or distant. Analysis was conducted using SPSS version 24., Results: Patient's mean age was 59.43±18.62. Logistic regression analysis revealed that for every 1.3% increase in LNR, the odds of falling into the distant stage of the TNM staging system increased by 13.7% (odds ratio, 14.73; 95% confidence interval, 12.00-18.08)., Conclusion: LNR, while correlated with breast cancer staging, serves as a better predictor of survival. Precision staging can influence treatment modality, and improved treatments can significantly improve quality of life. Additional research and diagnostic examinations using LNR as a potential tool for accurate staging in breast cancer patients are warranted., Competing Interests: CONFLICT OF INTEREST: The authors declare that they have no competing interests.

Background: Critically analyzing research is a key skill in evidence-based practice and requires knowledge of research methods, results interpretation, and applications, all of which rely on a foundation based in statistics. Evidence-based practice makes high demands on trained medical professionals to interpret an ever-expanding array of research evidence., Objective: As clinical training emphasizes medical care rather than statistics, it is useful to review the basics of statistical methods and what they mean for interpreting clinical studies., Methods: We reviewed the basic concepts of correlational associations, violations of normality, unobserved variable bias, sample size, and alpha inflation. The foundations of causal inference were discussed and sound statistical analyses were examined. We discuss four ways in which correlational analysis is misused, including causal inference overreach, over-reliance on significance, alpha inflation, and sample size bias., Results: Recent published studies in the medical field provide evidence of causal assertion overreach drawn from correlational findings. The findings present a primer on the assumptions and nature of correlational methods of analysis and urge clinicians to exercise appropriate caution as they critically analyze the evidence before them and evaluate evidence that supports practice., Conclusion: Critically analyzing new evidence requires statistical knowledge in addition to clinical knowledge. Studies can overstate relationships, expressing causal assertions when only correlational evidence is available. Failure to account for the effect of sample size in the analyses tends to overstate the importance of predictive variables. It is important not to overemphasize the statistical significance without consideration of effect size and whether differences could be considered clinically meaningful.

With advances in genomic sequencing technology, the number of reported gene-disease relationships has rapidly expanded. However, the evidence supporting these claims varies widely, confounding accurate evaluation of genomic variation in a clinical setting. Despite the critical need to differentiate clinically valid relationships from less well-substantiated relationships, standard guidelines for such evaluation do not currently exist. The NIH-funded Clinical Genome Resource (ClinGen) has developed a framework to define and evaluate the clinical validity of gene-disease pairs across a variety of Mendelian disorders. In this manuscript we describe a proposed framework to evaluate relevant genetic and experimental evidence supporting or contradicting a gene-disease relationship and the subsequent validation of this framework using a set of representative gene-disease pairs. The framework provides a semiquantitative measurement for the strength of evidence of a gene-disease relationship that correlates to a qualitative classification: "Definitive," "Strong," "Moderate," "Limited," "No Reported Evidence," or "Conflicting Evidence." Within the ClinGen structure, classifications derived with this framework are reviewed and confirmed or adjusted based on clinical expertise of appropriate disease experts. Detailed guidance for utilizing this framework and access to the curation interface is available on our website. This evidence-based, systematic method to assess the strength of gene-disease relationships will facilitate more knowledgeable utilization of genomic variants in clinical and research settings., (Copyright © 2017 American Society of Human Genetics. All rights reserved.)

Objective: Unemployment among older adults during recessionary cycles has been tied to early retirement decisions and negative health outcomes. This study explored episodes of unemployment experienced between age 50 and retirement as predictors of retirement age and health outcomes., Methods: A total of 1540 participants from the U.S. Health and Retirement Study aged 50 years and older who transitioned from workforce to retirement were analyzed with descriptive statistics and multiple regression controlling for unemployment, demographics, and health status., Results: Late-life unemployment significantly related to earlier retirement age and lowered life satisfaction, independent of income effects. We found no main effect for late-life unemployment on physical health status., Conclusions: Potential improvements in future life satisfaction might be gained if job search obstacles are removed for older unemployed adults, reducing reliance on involuntary early retirement as an income source.

Varying types of health information sources may influence health outcomes, but not much is known about their impact. The purpose of our study was to explore the association between health information sources and individuals' health status. A total of 14,966 participants who responded to the Annenberg National Health Communication Survey between 2005 and 2012 were included. Controlling for demographics, comorbidities, communication patterns, and socioeconomic status, we utilized regression analysis to examine the relationship between sources of health information and perceived health status. Included in the study were a total of 8,103 females and 6,863 males between 18 and 101 years old (M = 49.14, SD = 16.13). Health information from the Internet and pharmaceutical companies was significantly associated with better health status (p < .05), whereas information from social media, health care apps, news outlets, and health care companies was not. Information from the Internet was significantly associated with better health status, suggesting that health information from the Internet may have benefits. However, use of social media and health care apps did not relate to better health status, which may indicate that these sources are not as useful to consumers or that these sources have not yet saturated the health information marketplace.

The HUGO Gene Nomenclature Committee (HGNC) approves unique gene symbols and names for human loci. As well as naming genomic loci, we manually curate genes into family sets based on shared characteristics such as function, homology or phenotype. Each HGNC gene family has its own dedicated gene family report on our website, www.genenames.org . We have recently redesigned these reports to support the visualisation and browsing of complex relationships between families and to provide extra curated information such as family descriptions, protein domain graphics and gene family aliases. Here, we review how our gene families are curated and explain how to view, search and download the gene family data.

The RefSeq project at the National Center for Biotechnology Information (NCBI) maintains and curates a publicly available database of annotated genomic, transcript, and protein sequence records (http://www.ncbi.nlm.nih.gov/refseq/). The RefSeq project leverages the data submitted to the International Nucleotide Sequence Database Collaboration (INSDC) against a combination of computation, manual curation, and collaboration to produce a standard set of stable, non-redundant reference sequences. The RefSeq project augments these reference sequences with current knowledge including publications, functional features and informative nomenclature. The database currently represents sequences from more than 55,000 organisms (>4800 viruses, >40,000 prokaryotes and >10,000 eukaryotes; RefSeq release 71), ranging from a single record to complete genomes. This paper summarizes the current status of the viral, prokaryotic, and eukaryotic branches of the RefSeq project, reports on improvements to data access and details efforts to further expand the taxonomic representation of the collection. We also highlight diverse functional curation initiatives that support multiple uses of RefSeq data including taxonomic validation, genome annotation, comparative genomics, and clinical testing. We summarize our approach to utilizing available RNA-Seq and other data types in our manual curation process for vertebrate, plant, and other species, and describe a new direction for prokaryotic genomes and protein name management., (Published by Oxford University Press on behalf of Nucleic Acids Research 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

An adaptive optics (AO) testbed was integrated to the Optical PAyload for Lasercomm Science (OPALS) ground station telescope at the Optical Communications Telescope Laboratory (OCTL) as part of the free space laser communications experiment with the flight system on board the International Space Station (ISS). Atmospheric turbulence induced aberrations on the optical downlink were adaptively corrected during an overflight of the ISS so that the transmitted laser signal could be efficiently coupled into a single mode fiber continuously. A stable output Strehl ratio of around 0.6 was demonstrated along with the recovery of a 50 Mbps encoded high definition (HD) video transmission from the ISS at the output of the single mode fiber. This proof of concept demonstration validates multi-Gbps optical downlinks from fast slewing low-Earth orbiting (LEO) spacecraft to ground assets in a manner that potentially allows seamless space to ground connectivity for future high data-rates network.

Complete and accurate annotation of the mouse genome is critical to the advancement of research conducted on this important model organism. The National Center for Biotechnology Information (NCBI) develops and maintains many useful resources to assist the mouse research community. In particular, the reference sequence (RefSeq) database provides high-quality annotation of multiple mouse genome assemblies using a combinatorial approach that leverages computation, manual curation, and collaboration. Implementation of this conservative and rigorous approach, which focuses on representation of only full-length and non-redundant data, produces high-quality annotation products. RefSeq records explicitly link sequences to current knowledge in a timely manner, updating public records regularly and rapidly in response to nomenclature updates, addition of new relevant publications, collaborator discussion, and user feedback. Whole genome re-annotation is also conducted at least every 12-18 months, and often more frequently in response to assembly updates or availability of informative data. This article highlights key features and advantages of RefSeq genome annotation products and presents an overview of NCBI processes to generate these data. Further discussion of NCBI's resources highlights useful features and the best methods for accessing our data.

The field of non-coding RNA biology has been hampered by the lack of availability of a comprehensive, up-to-date collection of accessioned RNA sequences. Here we present the first release of RNAcentral, a database that collates and integrates information from an international consortium of established RNA sequence databases. The initial release contains over 8.1 million sequences, including representatives of all major functional classes. A web portal (http://rnacentral.org) provides free access to data, search functionality, cross-references, source code and an integrated genome browser for selected species., (© The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The Adhesion family forms a large branch of the pharmacologically important superfamily of G protein-coupled receptors (GPCRs). As Adhesion GPCRs increasingly receive attention from a wide spectrum of biomedical fields, the Adhesion GPCR Consortium, together with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification, proposes a unified nomenclature for Adhesion GPCRs. The new names have ADGR as common dominator followed by a letter and a number to denote each subfamily and subtype, respectively. The new names, with old and alternative names within parentheses, are: ADGRA1 (GPR123), ADGRA2 (GPR124), ADGRA3 (GPR125), ADGRB1 (BAI1), ADGRB2 (BAI2), ADGRB3 (BAI3), ADGRC1 (CELSR1), ADGRC2 (CELSR2), ADGRC3 (CELSR3), ADGRD1 (GPR133), ADGRD2 (GPR144), ADGRE1 (EMR1, F4/80), ADGRE2 (EMR2), ADGRE3 (EMR3), ADGRE4 (EMR4), ADGRE5 (CD97), ADGRF1 (GPR110), ADGRF2 (GPR111), ADGRF3 (GPR113), ADGRF4 (GPR115), ADGRF5 (GPR116, Ig-Hepta), ADGRG1 (GPR56), ADGRG2 (GPR64, HE6), ADGRG3 (GPR97), ADGRG4 (GPR112), ADGRG5 (GPR114), ADGRG6 (GPR126), ADGRG7 (GPR128), ADGRL1 (latrophilin-1, CIRL-1, CL1), ADGRL2 (latrophilin-2, CIRL-2, CL2), ADGRL3 (latrophilin-3, CIRL-3, CL3), ADGRL4 (ELTD1, ETL), and ADGRV1 (VLGR1, GPR98). This review covers all major biologic aspects of Adhesion GPCRs, including evolutionary origins, interaction partners, signaling, expression, physiologic functions, and therapeutic potential., (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)

The HUGO Gene Nomenclature Committee (HGNC) based at the European Bioinformatics Institute (EMBL-EBI) assigns unique symbols and names to human genes. To date the HGNC have assigned over 39,000 gene names and, representing an increase of over 5000 entries in the past two years. As well as increasing the size of our database, we have continued redesigning our website http://www.genenames.org and have modified, updated and improved many aspects of the site including a faster and more powerful search, a vastly improved HCOP tool and a REST service to increase the number of ways users can retrieve our data. This article provides an overview of our current online data and resources, and highlights the changes we have made in recent years., (© The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Lasers for use in deep-space applications such as interplanetary optical communications employ multiwatt resonantly pumped dual-clad erbium-doped fiber amplifiers and the pulse-position modulation scheme. Nonlinear optical effects and dynamic gain effects often impair their performance and limit their operational range. These effects are analyzed theoretically and numerically with a time-dependent two-level propagation model, respectively. Self-phase modulation and stimulated Raman scattering are found to limit the usable data format space. In operational regimes free from nonlinear effects, dynamic gain effects such as the variation in the output pulse energy and square-pulse distortion are quantified. Both are found to primarily depend on the symbol duration and can be as large as 28% and 21%, respectively.

The preparation of a variety of sulfonated carbons and their use in the esterification of oleic acid is reported. All sulfonated materials show some loss in activity associated with the leaching of active sites. Exhaustive leaching shows that a finite amount of activity is lost from the carbons in the form of colloids. Fully leached catalysts show no loss in activity upon recycling. The best catalysts; 1, 3, and 6; show initial TOFs of 0.07 s(-1), 0.05 s(-1), and 0.14 s(-1), respectively. These compare favorably with literature values. Significantly, the leachate solutions obtained from catalysts 1, 3, and 6, also show excellent esterification activity. The results of TEM and catalyst poisoning experiments on the leachate solutions associate the catalytic activity of these solutions with carbon colloids. This mechanism for leaching active sites from sulfonated carbons is previously unrecognized., (Copyright © 2013 Elsevier Ltd. All rights reserved.)