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The luminescence and inner structure of GaAs-AlGaAs quantum well tube (QWT) nanowires were studied using low-temperature cathodoluminescence (CL) spectroscopic imaging, in combination with scanning transmission electron microscopy (STEM) tomography, allowing for the first time a robust correlation between the luminescence properties of these nanowires and their size and inner 3D structure down to the nanoscale. Besides the core luminescence and minor defects-related contributions, each nanowire showed one or more QWT peaks associated with nanowire regions of different diameters. The values of the GaAs shell thickness corresponding to each QWT peak were then determined from the nanowire diameters by employing a multishell growth model upon validation against experimental data (core diameter and GaAs and AlGaAs shell thickness) obtained from the analysis of the 3D reconstructed STEM tomogram of a GaAs-AlGaAs QWT nanowire. We found that QWT peak energies as a function of thus-estimated (3–7 nm) GaAs shell thickness are 40–120 meV below the theoretical values of exciton recombination for uniform QWTs symmetrically wrapped around a central core. However, the analysis of the 3D tomogram further evidenced azimuthal asymmetries as well as (azimuthal and axial) random fluctuations of the GaAs shell thickness, suggesting that the red-shift of QWT emissions is prominently due to carrier localization. The CL mapping of QWT emission intensities along the nanowire axis allowed to directly image the nanoscale localization of the emission, supporting the above picture. Our findings contribute to a deeper understanding of the luminescence-structure relationship in QWT nanowires and will foster their applications as efficient nanolaser sources for future monolithic integration onto silicon.

Qualitative research suggests that day-to-day problems with child care produce significant costs for low-income mothers. But the relevance of daily child care problems for mothers of all socioeconomic backgrounds has been largely overlooked. This article asks two interrelated questions: What factors shape how often mothers experience child care disruptions? and What factors shape how often care disruptions lead mothers to miss work? Using the Fragile Families and Child Well-Being Study (N = 1,309), which includes mothers across the socioeconomic spectrum, this research finds that low-income mothers, mothers whose shifts vary, mothers who rely on patchwork care, and mothers with low social support are likely to experience care disruptions. But only mothers with low social support and mothers who use certain types of child care face an elevated risk of missing work. The findings underscore the widespread nature of child care problems and their heightened impact on socially isolated mothers. [ABSTRACT FROM AUTHOR]

This study focuses on gender differences in health profiles, and examines which health profiles drive gender differences in remaining life expectancy in women and men aged 65 and over in The Netherlands. Data from the first two cycles of the Longitudinal Aging Study Amsterdam (n = 2,141 and 1,659, respectively) were used to calculate health profiles for individuals of 65-85 years. For both women and men, six profiles were found: I. cancer; II. 'other ' chronic diseases; III. cognitive impairment; IV. frailty or multimorbidity; V. cardiovascular diseases; and VI. good health. The further characterization of these types showed some gender differences. Remaining life expectancy for women was greater than for men in each health profile. A decomposition into health expectancies showed that both women and men could expect to live about 5 years in good health from age 66. The greatest gender differences in years spent with health problems were found for profile IV and for profile III. Their greater number of years spent in these health states have direct consequences for the type and cost of care women need. [ABSTRACT FROM AUTHOR]

Abstract Background Genomic methylation patterns are established during gametogenesis, and perpetuated in somatic cells by faithful maintenance methylation. There have been previous indications that genomic methylation patterns may be less stable in embryonic stem (ES) cells than in differentiated somatic cells, but it is not known whether different mechanisms of de novo and maintenance methylation operate in pluripotent stem cells compared with differentiating somatic cells. Results In this paper, we show that ablation of the DNA methyltransferase regulator DNMT3L (DNA methyltransferase 3-like) in mouse ES cells renders them essentially incapable of de novo methylation of newly integrated retroviral DNA. We also show that ES cells lacking DNMT3L lose DNA methylation over time in culture, suggesting that DNA methylation in ES cells is the result of dynamic loss and gain of DNA methylation. We found that wild-type female ES cells lose DNA methylation at a much faster rate than do male ES cells; this defect could not be attributed to sex-specific differences in expression of DNMT3L or of any DNA methyltransferase. We also found that human ES and induced pluripotent stem cell lines showed marked but variable loss of methylation that could not be attributed to sex chromosome constitution or time in culture. Conclusions These data indicate that DNA methylation in pluripotent stem cells is much more dynamic and error-prone than is maintenance methylation in differentiated cells. DNA methylation requires DNMT3L in stem cells, but DNMT3L is not expressed in differentiating somatic cells. Error-prone maintenance methylation will introduce unpredictable phenotypic variation into clonal populations of pluripotent stem cells, and this variation is likely to be much more pronounced in cultured female cells. This epigenetic variability has obvious negative implications for the clinical applications of stem cells.

Abstract Human cytomegalovirus (HCMV) is familiar to pediatric rheumatologists mainly as a cause of opportunistic disease in pharmacologically immune suppressed patients. However, HCMV also has a variety of immuno-modulatory effects, through which it may influence the course of rheumatic conditions. In this article we discuss the interplay between HCMV and the immune system, and review the clinical manifestations, diagnosis, and treatment of HCMV infection in children with rheumatic disease.

Abstract Background Periodontitis is a chronic inflammatory disease caused by the microbiota of the periodontal pocket. We investigated the association between subgingival bacterial profiles and gene expression patterns in gingival tissues of patients with periodontitis. A total of 120 patients undergoing periodontal surgery contributed with a minimum of two interproximal gingival papillae (range 2-4) from a maxillary posterior region. Prior to tissue harvesting, subgingival plaque samples were collected from the mesial and distal aspects of each tissue sample. Gingival tissue RNA was extracted, reverse-transcribed, labeled, and hybridized with whole-genome microarrays (310 in total). Plaque samples were analyzed using checkerboard DNA-DNA hybridizations with respect to 11 bacterial species. Random effects linear regression models considered bacterial levels as exposure and expression profiles as outcome variables. Gene Ontology analyses summarized the expression patterns into biologically relevant categories. Results Wide inter-species variation was noted in the number of differentially expressed gingival tissue genes according to subgingival bacterial levels: Using a Bonferroni correction (p < 9.15 × 10-7), 9,392 probe sets were differentially associated with levels of Tannerella forsythia, 8,537 with Porphyromonas gingivalis, 6,460 with Aggregatibacter actinomycetemcomitans, 506 with Eikenella corrodens and only 8 with Actinomyces naeslundii. Cluster analysis identified commonalities and differences among tissue gene expression patterns differentially regulated according to bacterial levels. Conclusion Our findings suggest that the microbial content of the periodontal pocket is a determinant of gene expression in the gingival tissues and provide new insights into the differential ability of periodontal species to elicit a local host response.

Live case presentations are increasingly common at interventional cardiology conferences. Taking advantage of significant advances in communication technology, broadcasts of procedures can be viewed as an extension of traditional medical education targeted to large groups of practitioners. However, there are important ethical, commercial, and patient safety issues associated with live cases that deserve attention. Use of investigational devices in live case demonstrations is subject to review and approval by FDA's Center for Devices and Radiological Health (CDRH), and the outcomes of patients participating in live cases are considered in the overall clinical study results. This article discusses CDRH's regulatory view of live case presentations with a focus on patient safety, clinical trial integrity, and concerns regarding improper medical device promotion. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Although there is substantial evidence of declining prevalence of disability among the older population during the late 1980s and 1990s, evidence on trends in the underlying dynamics of disability is lacking. For this study, we estimated models of transitions between discrete disability and vital states that incorporated simple linear time trends. METHODS: We analyzed data from the 1982-1994 interviews of the New Haven Established Populations for Epidemiologic Studies of the Elderly study and used three alternative measures of disability status. We estimated separate models of disability prevalence and disability transitions by gender. RESULTS: Eleven of 12 estimated trends in transition rates were statistically significant. For men and women, and for three alternative disability indicators, we found downward trends in rates of both onset of and recovery from disability among people aged 75 and older. We did not find any consistent pattern of trends in disability among those aging into the 75 and older group during this period. DISCUSSION: Our findings are consistent with declining population-level disability prevalence only if any downward trend in onset outweighs the downward trend in recovery. These findings are also consistent with a trend toward more severe disability problems among the disabled population. [ABSTRACT FROM AUTHOR]

OBJECTIVE: . The purpose of this study was to test with panel data an extended model of the stress process recognizing the separate effects of a parent's need for care and an adult child's caring activities. Methods. Using data from the 1996, 1998, and 2000 waves of the Health and Retirement Study, we estimated nonlinear mixed models of mental health outcomes. We assessed mental health for separate samples of 3,350 men and 3,659 women by using an 8-item scale of depressive symptoms. We also explored the sensitivity of results to alternative measures and model specifications. RESULT: . We found that female, but not male, caregivers whose parents needed care exhibited adverse mental health consequences. However, we found that, generally, both male and female noncaregivers whose parents needed care were more likely to report symptoms of depression than were noncaregivers without disabled parents. Additional findings suggest that the stress process is still more complex among married couples. Discussion. This study distinguishes the outcomes of parental care needs from those attributable to caregiving activities. Adverse psychological outcomes appear to be dispersed throughout the family. To focus narrowly on active caregivers is to underestimate the social burdens of disability at older ages. [ABSTRACT FROM AUTHOR]

OBJECTIVES: We describe how paid and unpaid home care hours received by older unmarried Americans change in response to disability dynamics. We test whether responses to disability declines and improvements are symmetric; that is, we test whether reductions in care hours that are due to disability improvements are of similar magnitude to increases in care hours that are due to disability declines. METHODS: Using a national sample of older unmarried Americans, we examine changes in total hours, paid hours, and unpaid hours of care in response to declines and improvements in personal care (activities of daily living, or ADLs) and routine care (instrumental ADLs, or IADLs) disability. We model changes in the total hours of care received in the past month and jointly model changes in unpaid and paid hours, using Tobit models. RESULTS: Changes in the total hours of care received respond to both increases and decreases in the count of ADL limitations and appear close to symmetric. In contrast, responses to IADL disability dynamics appear to be far less symmetric: Although increases in the count of IADL limitations are met with substantial increases in the total hours of care, decreases are not met with correspondingly large declines in care. The same general pattern is found for unpaid and paid care, and for Medicaid-funded home care. DISCUSSION: Disability and care are not static constructs in old age. Older unmarried persons experience worsening, stabilizing, and recovery of function, and their care hours change accordingly. Evaluations of home care programs must be cognizant of such dynamic realities. [ABSTRACT FROM AUTHOR]

RESUMO Objetivo Caracterizar pacientes com acidente vascular cerebral (AVC), verificar a prevalência de distúrbios de comunicação oral relacionados e a frequência de encaminhamento para reabilitação fonoaudiológica. Métodos Estudo retrospectivo dos prontuários de 95 pacientes internados por AVC, entre junho de 2007 e junho de 2008, em hospital público da região metropolitana de Porto Alegre. Resultados Dos 95 pacientes, 51 (53,7%) eram do sexo masculino, com média de idade de 59,8 anos; 48 (59,3%) apresentavam histórico de hipertensão arterial; 82 (86,3%) apresentaram AVC tipo isquêmico e 53 (55,8%), distúrbios de comunicação oral. O tempo médio de internação foi de cinco dias. Não houve relação significativa entre o tipo de AVC e distúrbio de comunicação oral, tampouco entre o local da lesão neurológica decorrente do AVC e a ocorrência de distúrbio de comunicação oral. Nenhum dos sujeitos recebeu indicação de avaliação ou tratamento fonoaudiológico durante a internação ou na alta. Conclusão Mais de 50% dos indivíduos acometidos por AVC apresentam distúrbios de comunicação oral durante o período de internação hospitalar. Não houve nenhuma indicação ou solicitação de atendimento fonoaudiológico neste período, tampouco em encaminhamento para atendimento após a alta hospitalar. Estes achados indicam provável falha da inserção fonoaudiológica em equipes que atendem pacientes acometidos por doenças neurológicas, sendo necessário avaliar mais profundamente se isto ocorre devido à ausência do fonoaudiólogo na equipe, ou ao pouco conhecimento dos profissionais sobre a atuação fonoaudiológica junto aos distúrbios de comunicação oral decorrentes de AVC.

The National Institute on Aging (NIA) has contributed to the remarkable growth in the field of gerontology. One of the many ways the NIA has contributed is through the creation and support of an extensive body of relevant data resources. This paper focuses primarily on NIA's support for the creation and use of these data sources in research, including mention of related documentation, archiving, harmonization, and dissemination/data access activities. Through all of these efforts, NIA-supported data have been used by researchers and policy analysts across a wide range of scholarly disciplines, producing a large body of research that provides a scientific foundation for policy and practice., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The role of sickle cell trait (SCT) in sudden exertional death is well-recognized in sports and military training. However, it is not yet studied for non-firearm arrest-related death (NF-ARD). With extensive multi-pronged searches, a large database (n = 1389) of NF-ARDs was established. For the years 2006-2021 (inclusive) there were 50 NF-ARDs of Black persons in which postmortem evidence of SCT was found. A control cohort consisted of 414 NF-ARDs of Black persons with no reported SCT. The mean age for SCT cases was 33.1 ± 10.4 years versus 37.0 ± 10.4 years for the control group (p = 0.01). The body-mass index for SCT cases was 28.3 ± 6.6 kg/m 2 versus 30.7 ± 7.6 kg/m 2 for the control group (p = 0.03). The prevalence of cardiomegaly was 21% for SCT cases versus 39% in the control cohort (p = 0.008). The postmortem prevalence of SCT in NF-ARDs of Black persons (n = 50, 10.7%) was higher than the prevalence of SCT in the US Black population, which is 7.1% (p = 0.003). In this study of NF-ARDs in Black persons, the prevalence of SCT and the differences between the SCT cases and the control cohort suggest that exertional collapse associated with sickle cell trait may be a contributory factor in NF-ARDs., (© 2024 American Academy of Forensic Sciences.)

The contextual predictors of mortality in the United States are well documented, but the COVID-19 pandemic may have upended those associations. Informed by the social history of disease framework (SHDF), this study examined how the importance of county contexts on adult deaths from all causes, drug poisonings, and COVID-19-related causes fluctuated during the pandemic. Using 2018 to 2021 vital statistics data, for each quarter, we estimated associations between county-level deaths among adults ages 25 to 64 and prepandemic county-level contexts (economic conditions, racial-ethnic composition, population health profile, and physician supply). The pandemic significantly elevated the importance of county contexts-particularly median household income and counties' preexisting health profile-on all-cause and drug poisoning deaths. The elevated importance of household income may be long-lasting. Contextual inequalities in COVID-19-related deaths rose and then fell, as the SHDF predicts, but rose again along with socio-political disruptions. The findings support and extend the SHDF.

Policy Points We examined the effect of the Paid Family Leave policy (PFL) and Paid Sick Leave policy (PSL) on care provision to older parents. We found that PSL adoption led to an increase in care provision, an effect mainly attributable to respondents in states/periods when PSL and PFL were concurrently offered. Some of the strongest effects were found among women and unpartnered adult children. PFL adoption by itself was not associated with care provision to parents except when PFL also offered job protection. Paid leave policies have heterogeneous effects on eldercare and their design and implementation should be carefully considered., Context: Family caregivers play a critical role in the American long-term care system. However, care responsibilities are known to potentially conflict with paid work, as about half of family caregivers are employed. The federal Family and Medical Leave Act passed by the US Congress in 1993 provides a nonuniversal, unpaid work benefit. In response, several states and localities have adopted the Paid Family Leave policy (PFL) and Paid Sick Leave policy (PSL) over the last two decades. Our objective is to examine the effect of these policies on the probability of personal care provision to older parents., Methods: This study used longitudinal data from the Health and Retirement Study (1998-2020). Difference-in-differences regression models were estimated to examine associations between state- and local-level PFL and PSL mandates and personal care provision to older parents. We analyzed heterogeneous effects by the type of paid leave exposure (provision of job protection with PFL and availability of both PSL and PFL [with or without job protection] concurrently). We also examined results for different population subgroups., Findings: PSL implementation was associated with a four- to five-percentage point increase in the probability of personal care provision. These effects were mainly attributable to respondents in states/periods when PSL and PFL were concurrently offered. The strongest effects were found among adult children who were employed at baseline, women, younger, unpartnered, and college educated. PFL implementation by itself was not associated with care provision to parents except when the policy also offered job protection., Conclusions: Paid leave policies have heterogeneous impacts on personal care provision, potentially owing to differences in program features, variation in caregiving needs, and respondent characteristics. Overall, the results indicate that offering paid sick leave and paid family leave, when combined with job protection, could support potential family caregivers., (© 2024 The Author(s). The Milbank Quarterly published by Wiley Periodicals LLC on behalf of The Milbank Memorial Fund.)

Objectives. To identify relationships between US states' COVID-19 in-person activity limitation and economic support policies and drug overdose deaths among working-age adults in 2020. Methods. We used county-level data on 140 435 drug overdoses among adults aged 25 to 64 years during January 2019 to December 2020 from the National Vital Statistics System and data on states' COVID-19 policies from the Oxford COVID-19 Government Response Tracker to assess US trends in overdose deaths by sex in 3138 counties. Results. Policies limiting in-person activities significantly increased, whereas economic support policies significantly decreased, overdose rates. A 1-unit increase in policies restricting activities predicted a 15% average monthly increase in overdose rates for men (incident rate ratio [IRR] = 1.15; 95% confidence interval [CI] = 1.09, 1.20) and a 14% increase for women (IRR = 1.14; 95% CI = 1.09, 1.20). A 1-unit increase in economic support policies predicted a 3% average monthly decrease for men (IRR = 0.97; 95% CI = 0.95, 1.00) and a 4% decrease for women (IRR = 0.96; 95% CI = 0.93, 0.99). All states' policy combinations are predicted to have increased drug-poisoning mortality. Conclusions. The economic supports that states enacted were insufficient to fully mitigate the adverse relationship between activity limitations and drug overdoses. ( Am J Public Health . 2024;114(7):714-722. https://doi.org/10.2105/AJPH.2024.307621).

The differentiation of human pluripotent stem cells into ventral mesencephalic dopaminergic (DA) fate is relevant for the treatment of Parkinson's disease. Shortcuts to obtaining DA cells through direct reprogramming often include forced expression of the transcription factor LMX1A. Although reprogramming with LMX1A can generate tyrosine hydroxylase (TH)-positive cells, their regional identity remains elusive. Using an in vitro model of early human neural tube patterning, we report that forced LMX1A expression induced a ventral-to-dorsal fate shift along the entire neuroaxis with the emergence of roof plate fates despite the presence of ventralizing molecules. The LMX1A-expressing progenitors gave rise to grafts containing roof plate-derived choroid plexus cysts as well as ectopically induced TH-positive neurons of a forebrain identity. Early activation of LMX1A prior to floor plate specification was necessary for the dorsalizing effect. Our work suggests using caution in employing LMX1A for the induction of DA fate, as this factor may generate roof plate rather than midbrain fates., Competing Interests: Declaration of interests A.K. is the owner of Kirkeby Cell Therapy APS, performs paid consultancy to Novo Nordisk A/S, and is a co-inventor on patents WO2016162747A2/A3 and WO2019016113A1 on the generation of DA cells for treatment of PD., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract: Multiple studies have documented various factors that influence or determine forensic pathologist classification of manner of death. There do not appear to be any published studies on manner of death classification specifically regarding arrest-related deaths (ARDs). The goal of this study was to consider a large body of cases of nonfirearm ARDs to analyze the homicide classification with regards to numerous decedent and practitioner (medical examiner/coroner [ME/C]) variables. We analyzed 1145 US autopsy reports from the years 2006-2020, inclusive, and considered decedent variables of age, ethnicity, height, weight, body mass index, toxicology, and mention of a conducted electrical weapon and ME/C influence variables of gender, country region, and year. We found that the homicide classification likelihood increased by a factor of 1.04-1.05 per year, 1.34-1.37 for a female medical examiner, and 1.4-1.5 going from Southern states to Western states. There is an increasing trend for ME/C to label nonfirearm ARDs as homicides in the United States. The homicide classification is more common in Western states and less common in Southern states, and it was more common with a female ME/C., Competing Interests: Conflicts of interest and sources of funding: M.W.K. is a member of the Axon Corporate as well as Scientific and Medical Advisory Board. H.E.W. is a retired police chief. S.N.K. is a member of the AXON Scientific and Medical Advisory Board. The other authors report no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Repeated claims that a dwindling supply of potential caregivers is creating a crisis in care for the U.S. aging population have not been well-grounded in empirical research. Concerns about the supply of family care do not adequately recognize factors that may modify the availability and willingness of family and friends to provide care to older persons in need of assistance or the increasing heterogeneity of the older population. In this paper, we set forth a framework that places family caregiving in the context of older adults' care needs, the alternatives available to them, and the outcomes of that care. We focus on care networks, rather than individuals, and discuss the demographic and social changes that may alter the formation of care networks in the future. Last, we identify research areas to prioritize in order to better support planning efforts to care for the aging U.S. population., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Pulmonary embolism (PE) is a recognized cause of death in hospitalized trauma patients, yet less is known about PE after discharge., Patients & Methods: All post-discharge, autopsy-demonstrated, fatal PE resulting from trauma within a large US county over six years were analyzed. Counts, percentages, mean values, SD, and IQR were calculated for all variables., Results: 1848 trauma deaths were reviewed, of which 85% had an autopsy. Eighty-five patients died from PE after discharge from their initial injury. 53% were initially treated at non-trauma centers, and 9% did not seek medical assistance. 75% were injured by falling, and most injuries occurred in the lower extremities. 86% had an ISS <16, but 87% needed assistance or were bed-bound after injury, despite 75% having no mobility limitations before the injury. 53% died within one month of injury, and 91% within the first year. Before death, only 11% were prescribed chemical thromboprophylaxis or an antiplatelet agent, and only 8% were diagnosed with venous thromboembolism before death., Conclusions: Fatal PE after discharge typically occurred following activity-limiting lower extremity injuries with an ISS<16., Competing Interests: Declaration of Competing Interest Dr. Kalkwarf is the Trauma Medical Consultant for the Arkansas Trauma System (ATS). He a trauma center site surveyor for the ATS and he is a QSource consultant for the Arkansas Preventable Mortality Committee. He also teaches ATLS for the Arkansas Trauma Society. Dr. Holcomb has received research grants from the DoD, DARPA, NIH and CSL focused on hemorrhage control and resuscitation. He is on the Board of Directors of Decisio Health, CCJ Medical Devices, QinFlow, Hemostatics, Zibrio, Oxyband, and is a consultant to WFIRM, Aspen Medical, is a co-inventor of the Junctional Emergency Tourniquet Tool and receive royalties from UT Health. Dr. Drake is the principal for Stacy Drake consulting, LLC which focuses on forensic death investigations, education, training, and research., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

In the early months of the COVID-19 pandemic, states enacted multiple policies to reduce in-person interactions. Scholars have speculated that these policies may have contributed to adverse mental health outcomes. This study examines potential associations between states' COVID-19 physical distancing policies and working-age (18-64) adults' self-reported mental health. Mental health outcomes (depression, anxiety, worsened mental health, and sought treatment for anxiety or depression) are from the National Wellbeing Survey collected from working-age adults in the United States (U.S.) February 1 to March 18, 2021 (N = 3,804). Data on 12 state policies are from the COVID-19 U.S. State Policy Database. Analyses included logistic regression and Bayesian group index modeling, which identified sets, or "bundles," of policies that were associated with each mental health outcome. Multiple policies (both separately and in bundles) were associated with adverse mental health outcomes, with certain policies (closures and curfews on retail and other businesses) being particularly important. A one-month increase in exposure to respective model-derived physical distancing policy bundles was associated with a 36% increase in the odds of reporting that COVID-19 worsened one's mental health (odds ratio [OR] = 1·36; 95% credible interval [CRI] = 1·01 to 1·80), a 6% increase in the odds of meeting the clinical threshold for anxiety (OR = 1·06; CRI = 0·99 to 1·16), and a 15% increase in the odds of seeking treatment for anxiety or depression (OR = 1·15; CRI = 1·02 to 1·49). To accurately understand the role of states' COVID-19 policies on mental health during the pandemic, researchers must consider how collections of policies might influence outcomes., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Purpose: Whereas most human genes encode multiple mRNA isoforms with distinct function, clinical workflows for assessing this heterogeneity are not readily available. This is a substantial shortcoming, considering that up to 25% of disease-causing gene variants are suspected of disrupting mRNA splicing or mRNA abundance. Long-read sequencing can readily portray mRNA isoform diversity, but its sensitivity is relatively low due to insufficient transcriptome penetration., Methods: We developed and applied capture-based target enrichment from patient RNA samples combined with Oxford Nanopore long-read sequencing for the analysis of 123 hereditary cancer transcripts (capture and ultradeep long-read RNA sequencing (CAPLRseq))., Results: Validating CAPLRseq, we confirmed 17 cases of hereditary non-polyposis colorectal cancer/Lynch syndrome based on the demonstration of splicing defects and loss of allele expression of mismatch repair genes MLH1 , PMS2 , MSH2 and MSH6 . Using CAPLRseq, we reclassified two variants of uncertain significance in MSH6 and PMS2 as either likely pathogenic or benign., Conclusion: Our data show that CAPLRseq is an automatable and adaptable workflow for effective transcriptome-based identification of disease variants in a clinical diagnostic setting., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Severely injured patients often depend on prompt prehospital triage for survival. This study aimed to examine the under-triage of preventable or potentially preventable traumatic deaths. A retrospective review of Harris County, TX, revealed 1848 deaths within 24 hours of injury, with 186 being preventable or potentially preventable (P/PP). The analysis evaluated the geospatial relationship between each death and the receiving hospital. Out of the 186 P/PP deaths, these were more commonly male, minority, and penetrating mechanisms when compared with NP deaths. Of the 186 PP/P, 97 patients were transported to hospital care, 35 (36%) were transported to Level III, IV, or non-designated hospitals. Geospatial analysis revealed an association between the location of initial injury and proximity to receiving Level III, IV, and non-designated centers. Geospatial analysis supports proximity to the nearest hospital as one of the primary reasons for under-triage.

eIF3, whose subunits are frequently overexpressed in cancer, regulates mRNA translation from initiation to termination, but mRNA-selective functions of individual subunits remain poorly defined. Using multiomic profiling upon acute depletion of eIF3 subunits, we observed that while eIF3a, b, e, and f markedly differed in their impact on eIF3 holo-complex formation and translation, they were each required for cancer cell proliferation and tumor growth. Remarkably, eIF3k showed the opposite pattern with depletion promoting global translation, cell proliferation, tumor growth, and stress resistance through repressing the synthesis of ribosomal proteins, especially RPS15A. Whereas ectopic expression of RPS15A mimicked the anabolic effects of eIF3k depletion, disruption of eIF3 binding to the 5'-UTR of RSP15A mRNA negated them. eIF3k and eIF3l are selectively downregulated in response to endoplasmic reticulum and oxidative stress. Supported by mathematical modeling, our data uncover eIF3k-l as a mRNA-specific module which, through controlling RPS15A translation, serves as a rheostat of ribosome content, possibly to secure spare translational capacity that can be mobilized during stress., (© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)

Instability of simple DNA repeats has been known as a common cause of hereditary ataxias for over 20 years. Routine genetic diagnostics of these phenotypically similar diseases still rely on an iterative workflow for quantification of repeat units by PCR-based methods of limited precision. We established and validated clinical nanopore Cas9-targeted sequencing, an amplification-free method for simultaneous analysis of 10 repeat loci associated with clinically overlapping hereditary ataxias. The method combines target enrichment by CRISPR-Cas9, Oxford Nanopore long-read sequencing and a bioinformatics pipeline using the tools STRique and Megalodon for parallel detection of length, sequence, methylation and composition of the repeat loci. Clinical nanopore Cas9-targeted sequencing allowed for the precise and parallel analysis of 10 repeat loci associated with adult-onset ataxia and revealed additional parameter such as FMR1 promotor methylation and repeat sequence required for diagnosis at the same time. Using clinical nanopore Cas9-targeted sequencing we analysed 100 clinical samples of undiagnosed ataxia patients and identified causative repeat expansions in 28 patients. Parallel repeat analysis enabled a molecular diagnosis of ataxias independent of preconceptions on the basis of clinical presentation. Biallelic expansions within RFC1 were identified as the most frequent cause of ataxia. We characterized the RFC1 repeat composition of all patients and identified a novel repeat motif, AGGGG. Our results highlight the power of clinical nanopore Cas9-targeted sequencing as a readily expandable workflow for the in-depth analysis and diagnosis of phenotypically overlapping repeat expansion disorders., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Chronic pain remains a significant burden worldwide, and treatments are often limited by safety or efficacy. The decarboxylated form of L-arginine, agmatine, antagonizes N-methyl-d-aspartate receptors, inhibits nitric oxide synthase, and reverses behavioral neuroplasticity. We hypothesized that expressing the proposed synthetic enzyme for agmatine in the sensory pathway could reduce chronic pain without motor deficits. Intrathecal delivery of an adeno-associated viral (AAV) vector carrying the gene for arginine decarboxylase (ADC) prevented the development of chronic neuropathic pain as induced by spared nerve injury in mice and rats and persistently reversed established hypersensitivity 266 days post-injury. Spinal long-term potentiation was inhibited by both exogenous agmatine and AAV-human ADC (hADC) vector pre-treatment but was enhanced in rats treated with anti-agmatine immunoneutralizing antibodies. These data suggest that endogenous agmatine modulates the neuroplasticity associated with chronic pain. Development of approaches to access this inhibitory control of neuroplasticity associated with chronic pain may yield important non-opioid pain-relieving options., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

∼30% of clear cell renal cell carcinoma (ccRCC) patients present with metastatic disease at the time of diagnosis, causing a dire 5-year survival rate of 13%. Although anti-PD-1 immunotherapy has improved survival, a strong need remains for new therapeutic options. Using integrated network analysis, we identified the mitotic regulator NDC80 as a predictor of ccRCC progression. Overexpression of NDC80 fosters the malignant phenotype by promoting cell cycle progression through S phase as well as boosting glycolysis and mitochondrial respiration. Despite high levels of immune infiltration, particularly derived from tumor resident CD8 + T cells with an exhausted phenotype, NDC80 defines a class of ccRCCs that poorly respond to immune checkpoint blockade. Instead, bioinformatics identified NDC80-high ccRCCs as sensitive to inhibitors of mitotic kinases, PLK1 and AURK, therapeutic approaches we validated in cell lines and mouse xenograft studies. Thus, NDC80 status pinpoints mitotic kinase inhibitors as promising therapeutic options in difficult-to-treat ccRCCs., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Social isolation and lack of social support are risk factors for cardiovascular and cerebrovascular disease (CVD). This study explored the relationship between measures of social support and subclinical measures of CVD risk. 58 healthy adults ages 18 to 85 years participated in this study. The Berkman-Syme Social Network Inventory (SNI) was used to assess social isolation, with higher scores signifying less isolation. Social support was defined using the 12-Item Interpersonal Support Evaluation List (ISEL-12) with a higher score signifying higher social support. Subclinical CVD measures included carotid-femoral pulse wave velocity (cfPWV), carotid beta-stiffness index, and middle cerebral artery (MCA) pulsatility index. Path analysis models for both the SNI and ISEL appraisal domain predicting cfPWV and cerebrovascular pulsatility fit the data well. Path analyses showed significant direct paths from the SNI (β = -.363, t = -2.91) and ISEL appraisal domain (β = -.264, t = -2.05) to cfPWV. From cfPWV, both models revealed significant direct paths to carotid stiffness (β = .488, t = 4.18) to carotid pulse pressure (β = .311, t = 2.45) to MCA pulsatility (β = .527, t = 4.64). Social isolation and appraisal of social support are related to unfavorably higher aortic stiffness, with subsequent detrimental effects on cerebrovascular hemodynamic pulsatility.

Introduction: The COVID-19 pandemic has changed the dynamics of healthcare in the USA. In early 2020, most states issued orders to stop non-emergent elective surgeries. This contracted the overall revenue generated by the hospital systems. The impact of COVID-19 pandemic on volume has not been well studied but effects on surgeon professional fees generated remains unexplored. The goal of this study was to assess if COVID-19 pandemic has affected surgeon professional fees and revenues generated from emergency general surgeries., Methods: This is a retrospective review to compare surgical case volume in 2019 and 2020. We obtained our data from a tertiary care referral center database. Data were collected from February to April of 2019 and 2020, corresponding to the duration of statewide ban on non-emergent surgical cases. We used the most reported current procedural terminology (CPT) Code for each surgical procedure to calculate the surgeon professional fees generated. We calculated the percentage difference in surgeon professional fees between 2019 and 2020 for comparison., Results: There was a statistically significant decrease in daily emergent operations between 2019 and 2020 time periods (6.13/day vs 4.64/day). There was a statistically significant decrease in hospital admissions for appendicitis, cholecystitis, diverticulitis, skin and soft tissue infections, small bowel obstruction and GI bleed. Additionally, a statistically significant decrease in number of appendectomy, cholecystectomy, sigmoid colectomy with anastomosis, small bowel resection, operation for incarcerated and reducible hernia procedures was observed. There is a decline in surgeon professional fees generated in 2020 compared to 2019 for all emergent surgeries. When compared to 2019, we observed an increase of 238 more inquests in February to April of 2020, which is the same time period when we noticed a significant decrease in hospital admissions and procedures for emergency general surgery., Conclusion: The COVID-19 pandemic has negatively impacted surgical case volumes in 2020 compared to 2019. This includes both emergent and non-emergent cases. There is a need for more broad cost analysis which considers hospital expenditures and cost benefit analysis., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The United States has no national requirement that employers provide paid sick leave (PSL) to their employees, despite the many established public health benefits of PSL access. Many states, and some localities, have passed laws requiring PSL within their jurisdictions. Past studies have shown that these PSL mandates are effective in promoting increased PSL access. However, past studies have not considered two other commonly-used state policy initiatives-PSL preemption and right-to-work laws-that could hypothetically influence employers' decisions to provide PSL. During the past few decades, all possible combinations of these policy interventions can be found in one or more U.S. states. This study estimates the combined associations of these 3 policies with PSL access. The estimates support recent research on the positive effects of PSL mandates, but also suggest that PSL preemption and right-to-work laws may have offsetting effects. Failure to take account of these additional policies may lead to an over-estimate of the effectiveness of PSL mandates., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wolf.)

Introduction: The goal of this study was to estimate how state preemption laws that prohibit local authority to raise the minimum wage or mandate paid sick leave have contributed to working-age mortality from suicide, homicide, drug overdose, alcohol poisoning, and transport accidents., Methods: County-by-quarter death counts by cause and sex for 1999-2019 were regressed on minimum wage levels and hours of paid sick-leave requirements, controlling for time-varying covariates and place- and time-specific fixed effects. The model coefficients were then used to predict expected reductions in mortality if the preemption laws were repealed. Analyses were conducted during January 2022-April 2022., Results: Paid sick-leave requirements were associated with lower mortality. These associations were statistically significant for suicide and homicide deaths among men and for homicide and alcohol-related deaths among women. Mortality may decline by more than 5% in large central metropolitan counties currently constrained by preemption laws if they were able to mandate a 40-hour annual paid sick-leave requirement., Conclusions: State legislatures' preemption of local authority to enact health-promoting legislation may be contributing to the worrisome trends in external causes of death., (Copyright © 2022 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: Approximately 20% of patients with clinical familial adenomatous polyposis (FAP) remain unsolved after molecular genetic analysis of the APC and other polyposis genes, suggesting additional pathomechanisms., Methods: We applied multidimensional genomic analysis employing chromosomal microarray profiling, optical mapping, long-read genome and RNA sequencing combined with FISH and standard PCR of genomic and complementary DNA to decode a patient with an attenuated FAP that had remained unsolved by Sanger sequencing and multigene panel next-generation sequencing for years., Results: We identified a complex 3.9 Mb rearrangement involving 14 fragments from chromosome 5q22.1q22.3 of which three were lost, 1 reinserted into chromosome 5 and 10 inserted into chromosome 10q21.3 in a seemingly random order and orientation thus fulfilling the major criteria of chromothripsis. The rearrangement separates APC promoter 1B from the coding ORF (open reading frame) thus leading to allele-specific downregulation of APC mRNA. The rearrangement also involves three additional genes implicated in the APC -Axin-GSK3B-β-catenin signalling pathway., Conclusions: Based on comprehensive genomic analysis, we propose that constitutional chromothripsis dampening APC expression, possibly modified by additional APC -Axin-GSK3B-β-catenin pathway disruptions, underlies the patient's clinical phenotype. The combinatorial approach we deployed provides a powerful tool set for deciphering unsolved familial polyposis and potentially other tumour syndromes and monogenic diseases., Competing Interests: Competing interests: AH is an employee of Bionano Genomics., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

To explore the role of contextual information in determining manner of death, four cases involving single gunshot wounds were presented to participants (n = 252) involved in medicolegal death investigation. The participants received identical autopsy information but different contextual information. The data demonstrated that participants tended to rely on contextual information more than autopsy information: In the suicide context, participants across the four cases reached 153 final decisions of suicide (and 25 of homicide), whereas in the homicide context, participants reached only 10 final decisions of suicide (and 181 of homicide) --all while examining identical autopsy information. The impact of the contextual information was so powerful that many participants changed initial autopsy-based conclusions to align with the contextual information. Given the significant role and impact that contextual information has on expert decision making, one must consider what, how, and when contextual information should be used., Competing Interests: No conflict of interest., (© 2022 The Author(s).)

Adolescent substance use is a growing problem that causes a myriad of negative outcomes. Using substances during adolescence can lead to decreased executive functioning and is correlated with the top three causes of deaths for adolescents. Treatment options vary and the impact on outcomes are mixed, with engagement being of the most important indicators. Gaming is a popular activity among adolescents, and yet smartphone applications are relatively unexplored within substance use disorder treatment programs. This paper explores the feasibility and acceptability of implementing a mobile application as a supplement to existing adolescent substance use disorder treatment in a behavioral health agency in eastern Missouri. Feedback was received from staff and clients to assess feasibility and acceptability of implementation with barriers discussed. Results indicate there is promise with incorporation of smartphone-based applications into existing interventions and act as recommendations for other providers., Competing Interests: Conflict of Interest Statement: The authors declare they have no conflict of interest.

The volume of hemopericardium requiring hemodynamic changes in the trauma patient is not well understood. We performed a study using autopsy data from trauma patients who died with hemopericardium (>20 mL). Of 1848 traumatic deaths, 54 had hemopericardium at autopsy. The median pericardial blood in this group was 150 mL, which is more than the previously assumed volume to be lethal in trauma patients. Therefore, it may be appropriate to redefine the estimated volume required to cause lethal hemopericardium in trauma patients.