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Lewisite (Military Code: L) is an arsenical vesicant chemical warfare agent (CWA) that was developed in the United States during World War I. Even though its use has not been documented in warfare, large stockpiles were created and still exist in various locations around the world. Given that large quantities exist as well as the relative straightforward process for its creation, Lewisite still presents itself as a serious threat agent. In this study, we examined the effects of Lewisite on human dermal equivalent tissues (EpiDerm™/EpiDerm™-FT) through the evaluation of cellular viability, histology, and multiomic analysis., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Elizabeth Dhummakupt reports financial support was provided by Defense Threat Reduction Agency. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

In this article, we report sterically-controlled iron sites based on non-chelating bulky imidazole ligands. Adding 6 equiv. of 1,2-dimethylimidazole (1,2-Me 2 Im) to Fe(OTf) 2 ⋅2CH 3 CN affords the first example of a 5-coordinate imidazole‑iron complex ([Fe(1,2-Me 2 Im) 5 ](OTf) 2 , 1). The structure is distorted square pyramidal (τ 5  = 0.41). When an i Pr group is substituted for the methyl group at the 2-position on the imidazole (2- i Pr-1-MeIm), the 14-electron complex ([Fe(2- i Pr-1-MeIm) 4 ](OTf) 2 , 2) is obtained. This complex exhibits slightly distorted tetrahedral geometry (τ' 4  = 0.93) with four N-donors and serves as a 4-His iron structural model complex for carotenoid cleavage dioxygenases (CCD). The electronic structure of 1 and 2 were characterized by Mössbauer spectroscopy. Reactions of 1 and 2 with model olefin substrates (1-R-4-(1-methoxyprop-1-en-2-yl)benzene; R = Me or Br) in the presence of oxygen result in olefin cleavage yielding ketone and aldehyde products, although 2 yields more products than 1. Support for a proposed reaction mechanism for 2 is offered from Density Functional Theory (DFT) calculations., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Military sexual trauma (MST) is more common among post-9/11 Veterans and women versus older Veterans and men. Despite mandatory screening, the concordance of electronic health record (EHR) documentation and survey-reported MST, and associations with health care utilization and mental health diagnoses, are unknown for this younger group. Materials and Methods: Veterans' Health Administration (VHA) EHR (2001-2021) were merged with data from the observational, nationwide WomenVeterans Cohort Study (collected 2016-2020, n = 1058; 51% women). Experiencing MST was defined as positive endorsement of sexual harassment and/or assault. From the EHR, we derived Veterans' number of primary care and mental health visits in the initial two years of VHA care and diagnoses of posttraumatic stress disorder (PTSD), depression, and anxiety. First, the concordance of EHR MST screening and survey-reported MST was compared. Next, multivariate analyses tested the cross-sectional associations of EHR screening and survey-reported MST with Veterans' health care utilization, and compared the likelihood of PTSD, depression, and anxiety diagnoses by MST group, while covarying demographics and service-related characteristics. With few MST cases among men, multivariate analyses were only pursued for women. Results: Overall, 29% of women and 2% of men screened positive for MST in the EHR, but 64% of women and 9% of men had survey-reported MST. Primary care utilization was similar between women with concordant, positive MST reports in the EHR and survey versus those with survey-reported MST only. Women with survey-reported MST only were less likely to have a PTSD or depression diagnosis than those with concordant, positive MST reports. There was no group difference in women's likelihood of anxiety. Conclusions: EHR MST documentation is discordant for many post-9/11 Veterans-both for men and women. Improving MST screening and better supporting MST disclosure are each critical to provide appropriate and timely care for younger Veterans, particularly women.

Background: Traumatic rib fractures are associated with pain lasting weeks to months and a decreased ability to inspire deeply or cough to clear secretions. Ultrasound-guided percutaneous cryoneurolysis involves reversibly ablating peripheral nerve(s) using exceptionally low temperature with a transdermal probe, resulting in a prolonged nerve block with a duration measured in months. We hypothesized that cryoneurolysis would improve analgesia and inspired volume following rib fracture., Methods: Adults with 1-6 traumatic rib fractures were randomized to either active cryoneurolysis and a sham peripheral nerve block (PNB), or sham cryoneurolysis and active PNB in a participant/observer-masked fashion. The primary endpoint was the maximum inspired volume the day after the procedure as measured with an incentive spirometer., Results: The day after the procedure, the unadjusted median [IQR] maximum inspired volume for participants who received cryoneurolysis (n=11) was 2,250 mL [1,500; 2,500] versus 1,300 mL [750; 2,500] for PNB (n=9, mean difference 496; 95%CI -428 to 1420; t-test P=0.269). When adjusted for covariates (e.g., baseline lung volume), the cryoneurolysis group had an estimated 793 mL greater mean volume than PNB (95%CI 273 to 1,312; ANCOVA P=0.005). Improvement from baseline in maximum inspired volume for cryoneurolysis was 1,000 mL [1,000; 1,375] versus 300 mL [0; 1,000] for PNB (t-test P=0.002). This was equivalent to an improvement over baseline of 100% [90%, 188%] for cryoneurolysis versus 30% [0%, 50%] for PNB (t-test P=0.003). Average daily pain scores were generally lower for the cryoneurolysis group throughout the first month. Total cumulative oxycodone equivalents were 5 mg [0, 13] for cryoneurolysis vs 45 mg [43, 135] for PNB (t-test P=0.013)., Conclusions: Ultrasound-guided percutaneous cryoneurolysis improves maximum inspired lung volume while concurrently decreasing pain and opioid consumption after traumatic rib fracture. These results should be considered preliminary, requiring confirmation with a trial including a larger sample size., Competing Interests: Conflicts of Interest: Drs. Finneran and Ilfeld. These authors’ institution has received funding and/or product from Epimed International (Dallas, TX) for other research studies, SPR Therapeutics (Cleveland, OH), Infutronix (Natick, MA), Masimo (Irvine, CA), Varian Medical Systems (Palo Alto, CA), and Avanos Medical (Irvine, CA)., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Anesthesiologists.)

Importance: Since work-hour restrictions were instituted in 2003, sustainably complying with duty-hour regulations remains a challenge for general surgery residency programs across the nation., Objective: To determine whether industry-based process improvement techniques could be leveraged to increase compliance with work-hour restrictions within a general surgery residency., Design, Setting, and Participants: This quality improvement project using Lean methodology was conducted from October to November of the 2021 to 2022 academic year. The setting was a university-based general surgery residency program in southern California with rotations across 5 regional hospitals. The program trains 7 categorical general surgery residents per postgraduate year (PGY) and offers an optional 1 to 3 years for research and career development., Interventions: Programmatic structures were examined, current and target states were analyzed, opportunities for improvement were identified, root-cause analyses were conducted, and targeted interventions were developed., Main Outcomes and Measures: Resident time logs and annual Accreditation Council for Graduate Medical Education resident and faculty surveys were reviewed from academic years 2019/2020 to 2022/2023. Attending faculty were surveyed on resident preparedness using a 5-point Likert scale. Differences between means and proportions were calculated with corresponding 95% CIs., Results: The web-based survey responses of 29 residents (residents per PGY, 7 [PGY1], 14 [PGY2/3], 8 [PGY4/5]; 17 female [54.7%]) were included in this study. Root causes included maxed baseline schedules, late in shift work, culture, service variability, clinical volume, and inefficient workflows. Fifteen multifactorial interventions impacting call and weekend scheduling, work practices and efficiencies, intern and service orientations, and faculty and cultural expectations were implemented. The mean number of residents per block who logged more than 80 hours per week decreased by 3.6 violations per block (95% CI, 2.98-4.22), from 4.4 (12.4%) to 0.8 (2.2%) for a difference of 10.2% (95% CI, 8.4%-16.2%). On the annual resident survey, perceived compliance with 80 hours was 72%, 83%, 83%, and 88%, respectively, over the following study periods: 2019 to 2020, 2020 to 2021, 2021 to 2022, and 2022 to 2023. Faculty perception of resident preparedness for the case increased from a mean (SD) of 2.6 (0.8) to 3.0 (0.5), with a difference of 0.47 (95% CI, -0.52 to 0.68). There were no statistically significant differences in technical skill, clinical judgment, sense of responsibility, efficiency, or sense of well-being., Conclusions and Relevance: Results of this quality improvement study suggest that through Lean methodology, surgical residency programs can improve working environments. This novel approach can increase compliance with resident work hours by engaging front line trainees in the process.

Introduction: Alzheimer's disease (AD), Dementia with Lewy bodies (DLB), and Parkinson's disease (PD) represent a spectrum of neurodegenerative disorders (NDDs). Here, we performed the first direct comparison of their transcriptomic landscapes., Methods: We profiled the whole transcriptomes of NDD cortical tissue by snRNA-seq. We used computational analyses to identify common and distinct differentially expressed genes (DEGs), biological pathways, vulnerable and disease-driver cell subtypes, and alteration in cell-to-cell interactions., Results: The same vulnerable inhibitory neuron subtype was depleted in both AD and DLB. Potentially disease-driving neuronal cell subtypes were present in both PD and DLB. Cell-cell communication was predicted to be increased in AD but decreased in DLB and PD. DEGs were most commonly shared across NDDs within inhibitory neuron subtypes. Overall, we observed the greatest transcriptomic divergence between AD and PD, while DLB exhibited an intermediate transcriptomic signature., Discussion: These results help explain the clinicopathological spectrum of this group of NDDs and provide unique insights into the shared and distinct molecular mechanisms underlying the pathogenesis of NDDs., Competing Interests: Declarations of interest: none.

Introduction: Large social inequities have been repeatedly observed in physical disability. While inflammation has been identified as a potential underlying biological mechanism to proxy immune processes, the general inflammatory measures available in many population health studies lack specificity in capturing the complex nature of immune function. Therefore, we sought to examine whether specific biomarkers of immune function are associated with the prevalence of physical disability., Methods: We leveraged data from 8,543 adults (mean age = 69 years, 54 % women) in the nationally-representative Health and Retirement Study and employed gender-stratified Poisson regression models to examine whether a more aged immune profile, indicated by higher values in each marker of immune aging (CD8+:CD4+, EMRA CD4+:Naïve CD4+, EMRA CD8+:Naïve CD8+, and CMV IgG), was associated with a higher prevalence of activities of daily living (ADL) disability., Results: After adjustment, among women, one standard deviation (SD) increase in CMV IgG was associated with 12 % higher prevalence of ADL disability (PR: 1.12; 95 % CI: 1.04, 1.21). Similarly each 1-SD increase in the CD8 + CD4 + ratio was associated with a 9 % higher prevalence of ADL disability (PR: 1.09; 95 % CI: 1.03, 1.16). No associations were observed among men across any of the immune measures., Discussion: Our findings provide initial support that biomarkers of immune aging may serve as an important mechanism in understanding physical disability, particularly among women., Competing Interests: Declaration of Competing Interest 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., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Service members with mental health difficulties and access to a firearm are at an increased risk for suicide. Mental healthcare providers are well-positioned to discuss firearms and create safety plans; however, many service members do not seek treatment. This study aims to identify potential sociodemographic predictors of recent mental healthcare utilization among firearm-owning service members who report past month distress., Methods: The sample included 268 US military service members. Participants reported whether they attended at least one behavioral health visit in the 3 months prior to participation., Results: Females, individuals of a racial background other than Black or White, older individuals, and those who have never been active-duty were more likely to have attended a session. Additionally, the likelihood of utilization was higher among those who reported past week wish to die and suicidal behaviors in the past year., Conclusion: While certain service members are less likely to have utilized mental healthcare, findings suggest that those with suicidal ideation and access to a firearm are likely to engage in at least one appointment. As such, providing mental healthcare providers with training and resources for promoting secure firearm storage is an important avenue for suicide prevention., (© 2024 The Author(s). Suicide and Life‐Threatening Behavior published by Wiley Periodicals LLC on behalf of American Association of Suicidology.)

Vaccines are lifesaving interventions that reduce the morbidity and mortality of disease. Fortunately, serious adverse events with vaccination are uncommon, but they must promptly be recognized and evaluated to assess and clarify the safety of future administration, a process that the public must understand in order to feel safe in receiving vaccines. In this article, we provide a review of vaccine development, discuss the process by which safety is ensured, and describe key adverse events associated with their administration. We review in detail existing mechanisms for reporting these events and assessing them following recovery, as well as communication related to vaccine safety. We also describe barriers to vaccination, such as nocebo effects and antivaccination groups, and use lessons learned from the successful development of COVID-19 vaccines during the recent pandemic to define future opportunities and directions for vaccine safety.

Fungal polysaccharide monooxygenases (PMOs) oxidatively degrade cellulose and other carbohydrate polymers via a mononuclear copper active site using either O 2 or H 2 O 2 as a cosubstrate. Cellulose-active fungal PMOs in the auxiliary activity 9 (AA9) family have a conserved second-sphere hydrogen-bonding network consisting of histidine, glutamine, and tyrosine residues. The second-sphere histidine has been hypothesized to play a role in proton transfer in the O 2 -dependent PMO reaction. Here the role of the second-sphere histidine (H157) in an AA9 PMO, Mt PMO9E, was investigated. This PMO is active on soluble cello-oligosaccharides such as cellohexaose (Glc6), thus enabling kinetic analysis with the point variants H157A and H157Q. The variants appeared to fold similarly to the wild-type (WT) enzyme and yet exhibited weaker affinity toward Glc6 than WT (WT K D = 20 ± 3 μM). The variants had comparable oxidase (O 2 reduction to H 2 O 2 ) activity to WT at all pH values tested. Using O 2 as a cosubstrate, the variants were less active for Glc6 hydroxylation than WT, with H157A being the least active. Similarly, H157Q was competent for Glc6 hydroxylation with H 2 O 2 , but H157A was less active. Comparison of the crystal structures of H157Q and WT Mt PMO9E reveals that a terminal heteroatom of Q157 overlays with N ε of H157. Altogether, the data suggest that H157 is not important for proton transfer, but support a role for H157 as a hydrogen-bond donor to diatomic-oxygen intermediates, thus facilitating catalysis with either O 2 or H 2 O 2 .

Objective: To explore advanced pharmacy practice experience (APPE) preceptor perspectives including implementation recommendations, barriers, and facilitators to using entrustable professional activity (EPA) assessment in pharmacy experiential education., Methods: Two 90-min virtual focus group sessions were conducted to elucidate preceptor perspectives on EPA integration into APPEs through semistructured discussion. Preceptors with experience utilizing entrustment-supervision scales with EPAs for assessments for at least 4 APPE learners in the last year were eligible. The primary outcome was a description of implementation guidance for assessing learners using an EPA framework. Secondary outcomes include descriptions of barriers and facilitators to using an EPA framework in APPE learner assessment. All sessions were recorded, transcribed, and analyzed using inductive thematic analysis., Results: Eleven APPE preceptors representing 9 institutions participated. Commonly identified implementation recommendations were regular, repetitive preceptor education using case practice vignettes, student orientation to assessment expectations, clear delineation of minimum competency level, frequent discussions with preceptors, and use of institutional resources. Identified barriers were the abstractness of entrustability, subjectivity of the entrustment-supervision scale and preceptor assessments, unclear grading schemes, length and complexity of the assessments, and EPA applicability to the specific practice setting. Commonly identified facilitators were clearly defined scales and expectations, preceptor education, student education, pass/fail grading schemes, and shorter, more frequent assessments., Conclusion: EPA-based assessments can be used by preceptors for workplace-based assessments during APPEs. Faculty/preceptor development and student orientation with benchmarking and clear expectations are needed to support implementation., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2024 American Association of Colleges of Pharmacy. Published by Elsevier Inc. All rights reserved.)

People with lower levels of social connection are at increased risk for suicidal thoughts and behaviors. This extends to populations at greater risk of death by suicide, including U.S. military veterans. Despite this well-established association, it is unclear which measures of social connection are most useful in identifying veterans who could benefit from intervention to prevent suicide. To this end, we used data from the Million Veteran Program (MVP) to investigate the measures of social connection most strongly associated with suicidal thoughts and behaviors. Our sample included 264,626 veterans who reported on three measures of social connection-marital status, household size, and perceived social support-and were assessed for suicidal thoughts and behaviors using electronic health records. Veterans who were partnered (OR = 0.78, 95% CI [0.76-0.80], p < .001), living with others (OR = 0.71, 95% CI [0.70-0.73], p < .001), or reported higher levels of social support (OR = 0.67, 95% CI [0.65-0.69], p < .001), were less likely to have suicidal thoughts and behaviors. These associations varied by veterans' age, sex, and era of military service. When combined into a single risk score, lower levels of social connection were associated with greater likelihood of suicidal thoughts and behaviors (β = 1.42, 95% CI [1.40-1.43], p < .001). Social support, particularly positive social interactions, showed the strongest associations with suicidal thoughts and behaviors in elastic net regression models. Common measures of social connection, particularly social support, could be useful in assessing suicide risk and treatment needs for veterans., Competing Interests: Declaration of competing interest The authors have no outside interests to declare., (Published by Elsevier Ltd.)

Objective: To assess the health disparities across social determinants of health (SDoH) domains for the risk of severe acidosis independent of demographical and clinical factors., Materials and Methods: A retrospective case-control study (n = 13 310, 1:4 matching) is performed using electronic health records (EHRs), SDoH surveys, and genomics data from the All of Us participants. The propensity score matching controls confounding effects due to EHR data availability. Conditional logistic regressions are used to estimate odds ratios describing associations between SDoHs and the risk of acidosis events, adjusted for demographic features, and clinical conditions., Results: Those with employer-provided insurance and those with Medicaid plans show dramatically different risks [adjusted odds ratio (AOR): 0.761 vs 1.41]. Low-income groups demonstrate higher risk (household income less than $25k, AOR: 1.3-1.57) than high-income groups ($100-$200k, AOR: 0.597-0.867). Other high-risk factors include impaired mobility (AOR: 1.32), unemployment (AOR: 1.32), renters (AOR: 1.41), other non-house-owners (AOR: 1.7), and house instability (AOR: 1.25). Education was negatively associated with acidosis risk., Discussion: Our work provides real-world evidence of the comprehensive health disparities due to socioeconomic and behavioral contributors in a cohort enriched in minority groups or underrepresented populations., Conclusions: SDoHs are strongly associated with systematic health disparities in the risk of severe metabolic acidosis. Types of health insurance, household income levels, housing status and stability, employment status, educational level, and mobility disability play significant roles after being adjusted for demographic features and clinical conditions. Comprehensive solutions are needed to improve equity in healthcare and reduce the risk of severe acidosis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Study Objectives: Insufficient sleep alters emotional processing, leading to mood disturbances, reduced gratitude, and potentially the withdrawal of compassionate helping. Using data from two national surveys, we investigated whether sleep quality and sleep duration were associated with willingness to donate to local charities and places of worship., Methods: We conducted secondary analyses of two Gallup-administered studies that used random address-based sampling methodologies to approximate population-representative samples. BRS-5 included 1501 respondents and BRS-6 included 1336 respondents (independent samples). Each survey inquired about sleep quality and whether participants had donated in the last year to local organizations and places of worship. In addition, BRS-5 included questions about sleep duration., Results: In both studies, participants who had better sleep quality and better sleep durations were more likely to donate charitably to local organizations and places of worship (ORs of 1.07-1.45). Most associations remained significant when accounting for age, gender, and income., Conclusion: Better sleep was associated with a greater likelihood to donate charitably. Experimental work is needed to determine if the relationship between sleep health and prosocial behaviors is uni- or bi-directional., Competing Interests: Declaration of competing interest 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., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Suicide is a major public health concern within the United States, and prevention efforts are essential for decreasing the suicide rate. Researchers and clinicians have knowledge and effective treatments for preventing suicide; however, their impact is limited to those with access to services. Science Communication (SciComm) is an effective tool that can be integrated into the field of suicide prevention and can bridge the gap between scientific findings and the general population. SciComm can help disseminate evidence-based strategies for suicide prevention, dispel misinformation on suicide, and normalize help-seeking., Purpose: In this article, we propose specific, tangible ways that SciComm can be integrated into graduate school programs, mentorship, career advancement requirements and can help enact systemic change within the field of suicide prevention. Additionally, we discuss why it is important that the field of suicide prevention, specifically, adopts a SciComm framework. Embracing SciComm can help the field of suicide prevention to have a broader impact and can help to reduce rates of suicide., (© 2024 The Author(s). Suicide and Life‐Threatening Behavior published by Wiley Periodicals LLC on behalf of American Association of Suicidology.)

In this paper, dedicated to Dante Cicchetti's contributions and enduring influence, we explore the prospective directions of developmental psychopathology. Our focus centers on key domains where Cicchetti's significant achievements have continually shaped our evolving thinking about psychological development. These domains include (a) the concepts of equifinality and multifinality, along with the challenges in predicting developmental trajectories, (b) the imperative to integrate wider sociocultural viewpoints into developmental psychopathology frameworks, (c) the interplay of genetic and environmental influences in developmental courses, (d) the significance of mental state language, and (e) the progress, or its absence, in the development of prevention and intervention tactics for children, adolescents, and their caregivers. While many of our forecasts regarding the future of developmental psychopathology may not materialize, we maintain optimistic that the essential ideas presented will influence the research agenda in this field and contribute to its growth over the next fifty years.

Introduction: Prior work has found incongruencies in injury information reported by crash and hospital records. However, no work has focused on child passengers. The objective of this study was to compare crash scene and hospital-reported injury information for crash-involved child passengers. This study also explored injury location and severity by child age and restraint type., Methods: Utilizing linked New Jersey data from 2017 through 2019, the authors identified crash-involved child passengers <13 years old and their injuries in crash and hospital reports. Then, they characterized the congruency of injury frequency, severity, and location, as well as the frequency of injuries by child age and restraint type. Analyses were conducted from December 2023 through February 2024., Results: Of 84,060 crash-involved child passengers, crash reports documented 7,858 (9%) children with at least "possible" injuries, while 2,577 (3%) had at least one injury in hospital events. Crash report and hospital data were incongruent for both body region of injury and injury severity. The proportion of children injured increased as children's ages increased and as restraint type progressed., Conclusions: Crash reports overestimated the number of injured child passengers and misrepresented injury severity and locations. Child restraint systems mitigated a child's injury risk. Importantly, injury information documented on crash reports currently informs the allocation of traffic safety resources. These results highlight the importance of improving these reports' accuracy and underscore calls to link administrative datasets for public health efforts., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: There is an increasing awareness that aging of the immune system, or immunosenescence, is a key biological process underlying many of the hallmark diseases of aging and age-related decline broadly. While immunosenescence can be in part due to normal age-related changes in the immune system, emerging evidence posits that viral infections may be biological stressors of the immune system that accelerate the pace of immunosenescence., Methods: We used a convenience sample of 42 individuals aged 65 years and older to examine correlations between antiviral immunoglobulin G (IgG) levels for 4 human herpesviruses (cytomegalovirus [CMV], herpes simplex virus [types 1 and 2], and Epstein-Barr virus) and multiple indicators of T-cell immunosenescence., Results: We found that most of the sample (n = 33) was antiviral IgG positive for 2 or more of the 4 herpesvirus infections. We also examined correlations between both the total number of viruses for which an individual had antiviral IgG and each individual virus and multiple indicators of T-cell immunosenescence, particularly p16 expression. The strongest correlations were observed between the total number of viruses for which an individual had detectable antiviral IgG and p16 mean fluorescent intensity (MFI) among CD27-CD28-CD57+ CD4+ cells ( r = 0.60; P < .001) and between anti-CMV IgG and p16 MFI of CD27-CD57+ CD4+ cells ( r = 0.59; P < .001)., Conclusions: Broadly, our findings offer compelling preliminary evidence for future investigations to incorporate multiple indicators of persistent viral infections and a more comprehensive set of markers of T-cell immunosenescence in population-based studies of aging., Competing Interests: Potential conflicts of interest. The authors have no conflicts of interest to disclose., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Introduction: Rehabilitation is facing a critical practice gap: Patients seek out rehabilitation services to improve their activity in daily life, yet recent work demonstrates that rehabilitation may be having a limited impact on improving this outcome due to lack of objective data on patients' activity in daily life. Remote monitoring using wearable sensor technology is a promising solution to this address this gap. The purpose of this study was to understand patient and clinician awareness of the practice gap and preferences for integrating wearable sensor technology into rehabilitation care., Methods: This study used a mixed-methods approach consisting of surveys and 1:1 interviews with clinicians (physical and occupational therapists or assistants) employed at an outpatient rehabilitation clinic within an academic medical center and patients seeking care at this clinic. Data were analyzed using descriptive statistics and thematic analysis., Results: Data saturation was reached from recruiting nineteen clinicians and ten patients. Both clinicians and patients recognized the importance of measuring activity outside the clinic and viewed wearable sensor technology as an objective measurement tool. Most clinicians (63%) preferred continuous (vs. intermittent) monitoring within a care episode and most patients (60%) were willing to sync their sensor data as often as instructed by their provider. To maximize integration into clinical workflows, clinicians voiced a preference for availability of sensor data in the electronic health record., Conclusions: Clinicians and patients value the use of wearable sensor technology to improve measurement of activity outside the clinic environment and expressed preferences for how this technology could best be integrated into routine rehabilitation care., Competing Interests: Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

In humans and in mice, maternal allergy predisposes offspring to development of allergy. In murine models, increased levels of maternal β-glucosylceramides are both necessary and sufficient for the development of allergic predisposition in offspring. Furthermore, increased numbers of CD11b+ dendritic cell subsets in the offspring of allergic mothers are associated with allergic predisposition. In vitro, β-glucosylceramides increase CD11b+ dendritic cell subset numbers through increased PKCδ signaling, but it is not known if enhanced PKCδ signaling in dendritic cells is required in vivo. We demonstrate that dendritic cell-specific deletion of PKCδ prevents the β-glucosylceramide-induced increase in CD11b+ dendritic cell subset numbers both in vitro as well as in vivo in the fetal liver of offspring of mothers injected with β-glucosylceramides. Furthermore, dendritic cell-specific deletion of PKCδ in offspring prevents the maternal allergy-induced increase in CD11b+ dendritic cell subsets and decreases allergen-induced interleukin-5 and eosinophilia in lungs of offspring. However, loss of PKCδ in dendritic cells did not prevent development of allergen-specific IgE. Our study provides mechanistic insight into the function of PKCδ in the origins of allergic disease beginning in utero as well as in the development of postnatal allergic lung inflammation., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology. 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.)

Introduction: The Faroe Islands are a small archipelago located in the North Atlantic likely colonized by a small group of founders sometime between 50 and 300 CE. Post colonization, the Faroese people have been largely isolated from admixture with mainland and other island populations in the region. As such, the initial founder effect and subsequent genetic drift are likely major contributors to the modern genetic diversity found among the Faroese., Methods: In this study, we assess the utility of Y-chromosomal microsatellites to detect founder effect in the Faroe Islands through the construction of haplotype networks and a novel empirical method, mutational distance from modal haplotype histograms (MDM), for the visualization and evaluation of population bottlenecks., Results: We compared samples from the Faroe Islands and Iceland to possible regional source populations and documented a loss of diversity associated with founder events. Additionally, within-haplogroup diversity statistics reveal lower haplotype diversity and richness within both the Faroe Islands and Iceland, consistent with a small founder population colonizing both regions. However, in the within haplogroup networks, the Faroe Islands are found within the larger set of potential source populations while Iceland is consistently found on isolated branches. Moreover, comparisons of within-haplogroup MDM histograms document a clear founder signal in the Faroes and Iceland, but the strength of this signal is haplogroup-dependent which may be indicative of more recent admixture or other demographic processes., Discussion: The results of the current study and lack of conformity between Icelandic and Faroese haplotypes implies that the two populations were founded by different paternal gene pools and there is no detectable post-founder admixture between the two groups., Competing Interests: The authors declare 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 © 2024 Mann, Magnussen and Tillquist.)

Introduction: The geroscience hypothesis proposes systemic biological aging is a root cause of cognitive decline., Methods: We analyzed Framingham Heart Study Offspring Cohort data ( n  = 2296; 46% male; baseline age M  = 62, SD = 9, range = 25-101 y). We measured cognitive decline across two decades of neuropsychological-testing follow-up. We measured pace of aging using the DunedinPACE epigenetic clock. Analysis tested if participants with faster DunedinPACE values experienced more rapid cognitive decline compared with those with slower DunedinPACE values., Results: Participants with faster DunedinPACE had poorer cognitive functioning at baseline and experienced more rapid cognitive decline over follow-up. Results were robust to confounders and consistent across population strata. Findings were similar for the PhenoAge and GrimAge epigenetic clocks., Discussion: Faster pace of aging is a risk factor for preclinical cognitive decline. Metrics of biological aging may inform risk stratification in clinical trials and prognosis in patient care., Highlights: Faster DunedinPACE is associated with preclinical cognitive aging.Higher baseline cognition was protective of DunedinPACE-associated cognitive decline.The DunedinPACE association with cognitive decline explained a fourth of dementia risk., Competing Interests: A.C., T.E.M., K.S., and D.W.B. are inventors of the Duke University and University of Otago Invention DunedinPACE, which is licensed to TruDiagnostic. There are no other conflicts of interest., (© 2024 The Author(s). Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Licensure is an option for some autistic adolescents and families that increases mobility by enabling independent travel to employment, school, and social activities. The objective of this study was to identify current strategies used by healthcare providers (HCPs) in their guidance to autistic adolescents and families on the transition to independent driving. Semi-structured interviews were conducted with 15 HCPs. The team's previous research, literature review and expert feedback informed the development of the interview guide. A content analysis approach was used in the coding of transcripts, nine of which were double coded. Study team members reviewed coded transcripts, provided and discussed narrative summaries, and identified themes. Interviews were conducted with physicians, social workers, psychologists, therapist and a nurse practitioner. HCP identified their perceptions of autistic adolescents' strengths and weaknesses to be addressed in their individualized approaches. They described using clinical interactions as time to address licensure and driving, but also referred to specialists as needed. HCPs described using existing resources, but also provided a wish list of future resources. HCPs use an individualized approach for guidance in the transition to independent driving, considering the unique needs of autistic adolescent patients and families. These HCPs identified a clear need for tailored resources and guidance they can use in support of independent driving when appropriate for their patients and families., Competing Interests: Declarations Ethical Approval The study was determined to be exempt of oversight by the Children’s Hospital of Philadelphia Institutional Review Board (Approval #18-015740) with a waiver of written documentation of consent. The study was determined to meet exemption criteria per 45 CFR 46.104(d)2. Competing Interests Dr. Yerys serves as an Associate Editor of the Journal of Autism and Development Disabilities. None of the other authors have real or perceived potential conflicts of., (© 2024. The Author(s).)

Striatal medium spiny neurons (MSNs) integrate multiple external inputs to shape motor output. In addition, MSNs form local inhibitory synaptic connections with one another. The function of striatal lateral inhibition is unknown, but one possibility is in selecting an intended action while suppressing alternatives. Action selection is disrupted in several movement disorders, including levodopa-induced dyskinesia (LID), a complication of Parkinson's disease (PD) therapy characterized by involuntary movements. Here, we identify chronic changes in the strength of striatal lateral inhibitory synapses in a mouse model of PD/LID. These synapses are also modulated by acute dopamine signaling. Chemogenetic suppression of lateral inhibition originating from dopamine D2 receptor-expressing MSNs lowers the threshold to develop involuntary movements in vivo , supporting a role in motor control. By examining the role of lateral inhibition in basal ganglia function and dysfunction, we expand the framework surrounding the role of striatal microcircuitry in action selection.

Purpose: To design, construct, and evaluate a system for image-guided placement of brachytherapy applicators using electromagnetic tracking (EMT) technology for improved procedure quality and efficiency. The system, named EMVision, provides a three-dimensional display of planned needle sites, visibility of the anatomy and needle position during placement, and reference tracking to account for generator or target anatomy shifts., Methods: The EMVision EMT guidance system registers CT and EMT reference frames using an automated point-based algorithm according to tandem/ovoid locations. Subsequent needle placement and digitization is guided with an intraluminal EMT sensor and user interface that displays the needle's location in axial, coronal, sagittal, and 3D-volumetric CT views. The interface can overlay contours, preplanned needles, and provide 6DOF compensation for tandem movement during needle placement/manipulation. EMVision accuracy was evaluated in phantom and human cadaver by comparing EMVision's DICOM needle positions with a ground-truth, postimplant CT., Results: Proof of concept was demonstrated for EMT-assisted placement of brachytherapy needles. EMVision accuracy in phantom (mean ± standard deviation) on a brachysuite CT table was 0.76 ± 0.13 mm for needle tips placed up to 75 mm from the tandem/ovoids and 0.52 ± 0.27 mm for needle shafts at distances up to 100 mm from the tandem/ovoids. Performance in human cadaver was similar, with tip and shaft accuracies of 0.77 ± 0.14 mm and 0.40 ± 0.21 mm, respectively., Conclusion: EMVision provides sub-millimeter accuracy for the placement of brachytherapy needles without repeated or continuous imaging. The technology can be used to reduce brachytherapy procedure times, improve the correspondence between intended and actual needle positions, or decrease the trainee learning curve., (Copyright © 2024 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Background: Sickle cell disease (SCD) is a chronic medical condition characterized by red blood cell sickling, vaso-occlusion, hemolytic anemia, and subsequently, end-organ damage and reduced survival. Because of this significant pathophysiology and early mortality, we hypothesized that patients with SCD are experiencing accelerated biological aging compared with individuals without SCD., Methods: We utilized the DunedinPACE measure to compare the epigenetic pace of aging in 131 Black Americans with SCD to 1391 Black American veterans without SCD., Results: SCD patients displayed a significantly accelerated pace of aging (DunedinPACE mean difference of 0.057 points) compared with the veterans without SCD, whereby SCD patients were aging ≈0.7 months more per year than those without SCD (p = 4.49 × 10-8). This was true, even though the SCD patients were significantly younger according to chronological age than the individuals without SCD, making the epigenetic aging discrepancy even more apparent. This association became stronger when we removed individuals with posttraumatic stress disorder from the non-SCD group (p = 2.18 × 10-9), and stronger still when we restricted the SCD patients to those with hemoglobin SS and Sβ0 thalassemia genotypes (p = 1.61 × 10-10)., Conclusions: These data support our hypothesis that individuals with SCD experience accelerated biological aging as measured by global epigenetic variation. The assessment of epigenetic measures of biological aging may prove useful to identify which SCD patients would most benefit from clinical interventions to reduce mortality., (© The Author(s) 2024. 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.)

Objective: The American Board of Surgery In-Training Examination (ABSITE) is an important factor in general surgery resident career development. The use of practice question banks for ABSITE preparation improves exam scores and completing more practice questions results in higher scores. The objective of this study is to describe the design of a novel, team-based ABSITE competition implemented into our residency program and analyze its effect on exam performance., Design: For the 2023 to 2024 academic year (AY), residents were randomly sorted into teams. The number of TrueLearn (TL) practice questions completed by each team during the 6-month period preceding the 2024 ABSITE was monitored at regular intervals. Paired sample t-test was used to compare total questions completed and ABSITE percent scores from the prior AY. Simple linear regression was performed to determine if total completed questions predicted ABSITE percent scores, and if the change in total completed questions predicted a change in ABSITE percent scores for unique residents., Setting: University-affiliated general surgery residency program., Participants: 34 clinical and research general surgery residents., Results: Mean total TL questions completed per resident increased by 175.2, with a difference trending toward statistical significance (1037.9 ± 583.6 vs 1213.1 ± 596.0, p = 0.08). Mean ABSITE percent scores significantly increased by 4.6% (68.2 ± 8.7 vs 72.8 ± 5.7, p < 0.001). Total completed questions positively correlated with ABSITE percent scores (R 2  = 0.21, F (1,66) = 17.04, p < 0.001). Among individual residents, completing more questions than the prior AY predicted improvement in ABSITE percent scores (R 2 =.18, F (1,32) = 7.02, p = 0.01). Our model predicts that by completing 300 additional practice questions (e.g. 10 more questions/day for 1 month) a resident's ABSITE percent score will increase by 4.8 percentage points., Conclusion: Implementation of a team-based ABSITE competition is a straightforward and effective intervention that increases general surgery resident question bank utilization and significantly improves ABSITE percent scores., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Among younger adults, to determine the associations of actigraph- and self-reported sleep duration with arterial stiffness (AS) assessed in clinic and in ecologically valid contexts, and to examine sex-specific associations., Methods: Healthy adults ( n = 282, median age = 29 years, 67% women) completed a state-of-the-art assessment of AS at rest (SphygmoCor; carotid femoral pulse wave velocity [cfPWV]; central augmentation index [cAIx]) and 7 days of actigraphy-assessed sleep with concurrent, momentary cAIx assessment for 36 hours (Oscar-2). Multivariable regressions were conducted on the full sample and sex-stratified to examine cross-sectional linear and quadratic associations of average sleep duration with resting PWV and cAIx, average cAIx while awake and asleep, and nocturnal cAIx dipping, adjusted for demographic and health covariates. Exploratory analyses included self-reported sleep duration with AS, and actigraphy and self-reported sleep duration with the ambulatory arterial stiffness index (AASI; Oscar-2)., Results: Overall and by sex, associations of average sleep duration with resting cfPWV, resting cAIx, and awake cAIx were not significant. Sleep duration showed a positive, linear association with sleep cAIx in women (95% confidence interval =1.07 to 5.86, Δ R2 = 0.021). Among women, sleep duration was also inversely associated with cAIx dipping (95% confidence interval = -4.48 to -0.95, Δ R2 = 0.020). Analyses with self-reported sleep duration and AASI as alternate predictors and outcomes were not significant., Conclusions: Certain sleep duration-AS associations may be sex-specific. Assessing sleep and momentary AS in ecologically valid conditions outside the research laboratory is valuable to understand these relations. Although this investigation should be replicated, findings raise the question of whether interventions to target sleep duration also reduce AS., (Copyright © 2024 by the American Psychosomatic Society.)

Objective: Biological markers of stress have been associated with HIV progression and pathogenesis but not with HIV incidence. We sought to determine if elevated stress-responsive biomarkers would be associated with incident HIV among adolescent girls and young women (AGYW)., Design: We conducted a case-cohort study within the HIV Prevention Trials Network (HPTN) 068 study among 949 AGYW in South Africa. Cases were AGYW who tested HIV-positive during the eight-year follow-up. Unmatched controls were randomly selected from the HIV-negative population at enrollment., Methods: Dried blood spots from cases and controls were tested from enrollment (2011-2012) for C-reactive protein (CRP), herpes simplex virus type-1 (HSV-1) antibody titers, and cytomegalovirus (CMV) antibody titers. Cox proportional hazards models estimated the association between each biomarker and time to incident HIV., Results: Compared to AGYW with the lowest CRP levels, those with medium and high CRP levels had a higher hazard ratio (HR) of incident HIV [HR: 1.45, 95% confidence interval (CI): 0.95, 2.21; HR: 1.50, 95% CI: 0.98, 2.30, respectively], although not statistically significant. The relative hazard of incident HIV was also higher among AGYW who were CMV seropositive vs. seronegative (low antibodies HR: 2.18, 95% CI: 1.2, 3.87; medium HR: 2.25, 95% CI: 1.28, 3.95; high HR: 1.78, 95% CI: 0.99, 3.21). Those with the highest HSV-1 antibody levels experienced an increased hazard of HIV compared to those who were HSV-1 seronegative (HR: 1.58, 95% CI: 1.03, 2.44)., Conclusions: Biological stress may increase AGYW's susceptibility to HIV acquisition through changes in immune function, viral infection, and increased biological vulnerability to disease., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Retained hemothorax (rHTX) requiring intervention occurs in up to 20% of patients who undergo chest tube (TT) placement for a hemothorax (HTX). Thoracic irrigation at the time of TT placement decreases the need for secondary intervention in this patient group but those findings are limited because of the single-center design. A multicenter study was conducted to evaluate the effectiveness of thoracic irrigation., Methods: A multicenter, prospective, observational study was conducted between June 2018 and July 2023. Eleven sites contributed patients. Patients were included if they had a TT placed for a HTX and were excluded if: younger than 18 years, TT for pneumothorax, thoracotomy or video-assisted thoracoscopic surgery performed within 6 hours of TT, TT >24 hours after injury, TT removed <24 hours, or death within 48 hours. Thoracic irrigation was performed at the discretion of the attending. Each hemithorax was considered separately if bilateral HTX. The primary outcome was secondary intervention for HTX-related complications (rHTX, effusion, or empyema). Secondary intervention was defined as: TT placement, instillation of thrombolytics, video-assisted thoracoscopic surgery, or thoracotomy. Irrigated and nonirrigated hemithoraces were compared using a propensity weighted analysis with age, sex, mechanism of injury, Abbreviated Injury Scale chest, and TT size as predictors., Results: Four hundred ninety-three patients with 462 treated hemothoraces were included, 123 (25%) had thoracic irrigation at TT placement. There were no significant demographic differences between the cohorts. Fifty-seven secondary interventions were performed, 10 (8%) and 47 (13%) in the irrigated and non-irrigated groups, respectively ( p = 0.015). Propensity weighted analysis demonstrated a reduction in secondary interventions in the irrigated cohort (odds ratio, 0.56 (0.34-0.85); p = 0.005)., Conclusion: This Western Trauma Association multicenter study demonstrates a benefit of thoracic irrigation at the time of TT placement for a HTX. Thoracic irrigation reduces the odds of a secondary intervention for rHTX-related complications by 44%., Level of Evidence: Therapeutic/Care Management; Level II., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Novel H-bond-rich iridium(iii) complexes with different systems of cyclometalating ligands bearing the general formula [Ir(C^N) 2 (N^N)] were synthesised, characterised and their photophysical properties determined. The incorporated guanidine moieties allow us to introduce a hydrogen-bonding array for the formation of self-assembled iridium-bound hydrogen-bonded systems. Through a series of experimental and computational studies we demonstrated the host-guest chemistry of these systems. These hydrogen-bonding interactions were shown to have significant impacts on chromaticity, quantum yields and lifetimes with emphasis on energy transfer studies based on this second-sphere coordination approach., Competing Interests: The authors declare no conflicts of interest., (This journal is © The Royal Society of Chemistry.)

Background/objectives: Our objective was to describe the use of intraoperative radiation therapy (IORT) for the treatment of recurrent/persistent cervical or endometrial cancer and assess predictors of postoperative complications and 3-year mortality., Methods: In this multi-site retrospective study, data were abstracted for recurrent/persistent endometrial or cervical cancer patients who underwent IORT from June 2004 to May 2021. Complications were graded on the six-point Accordion scale. Variables associated with complications were analyzed with univariate logistic regression, while variables associated with death within 3 years were analyzed with Cox proportional hazards modeling. Survival was analyzed with the Kaplan-Meier method., Results: Eighty patients had planned IORT for recurrent/persistent endometrial (n = 35) or cervical cancer (n = 45). The mean age of the cohort was 56.8 years (SD = 13.7), and the median disease-free interval from primary disease to recurrence was 20.0 months (IQR 10.0-63.1). The overall survival at 3 years was 48.6% (95% CI: 38.3-61.6%) with a median survival of 2.8 years. Within 30 days postoperative, 16 patients (20.1%) had grade 3-5 complications and one death (1.3%) occurred. Factors associated with grade 3+ complication included ECOG PS 2-3 (OR 18.00, p = 0.04), neoadjuvant chemotherapy and/or immunotherapy (OR 6.98, p < 0.01), and pelvic sidewall involvement (OR 8.80, p = 0.04). Factors associated with death within 3 years of surgery included ECOG PS 2-3 (HR 8.97, p < 0.01), neoadjuvant chemotherapy and/or immunotherapy (HR 2.34, p = 0.03), whether exenteration was performed (HR 2.64, p = 0.01), and positive resection margin (HR 3.37, p < 0.01)., Conclusions: In well-selected patients, IORT is a feasible and safe option for the treatment of recurrent/persistent gynecologic malignancy with an appreciable survival benefit.

Ras homolog family member A (RhoA) acts as a signaling hub in many cellular processes, including cytoskeletal dynamics, division, migration, and adhesion. RhoA activity is tightly spatiotemporally controlled, but whether downstream effectors share these activation dynamics is unknown. We developed a novel single-color FRET biosensor to measure Rho-associated kinase (ROCK) activity with high spatiotemporal resolution in live cells. We report the validation of the Rho-Kinase Activity Reporter (RhoKAR) biosensor. RhoKAR activation was specific to ROCK activity and was insensitive to PKA activity. We then assessed the mechanisms of ROCK activation in mouse fibroblasts. Increasing intracellular calcium with ionomycin increased RhoKAR activity and depleting intracellular calcium with EGTA decreased RhoKAR activity. We also investigated the signaling intermediates in this process. Blocking calmodulin or CaMKII prevented calcium-dependent activation of ROCK. These results indicate that ROCK activity is increased by calcium in fibroblasts and that this activation occurs downstream of CaM/CaMKII.

Genetic contributions to human cortical structure manifest pervasive pleiotropy. This pleiotropy may be harnessed to identify unique genetically-informed parcellations of the cortex that are neurobiologically distinct from functional, cytoarchitectural, or other cortical parcellation schemes. We investigated genetic pleiotropy by applying genomic structural equation modeling (SEM) to map the genetic architecture of cortical surface area (SA) and cortical thickness (CT) for 34 brain regions recently reported in the ENIGMA cortical GWAS. Genomic SEM uses the empirical genetic covariance estimated from GWAS summary statistics with LD score regression (LDSC) to discover factors underlying genetic covariance, which we are denoting genetically informed brain networks (GIBNs). Genomic SEM can fit a multivariate GWAS from summary statistics for each of the GIBNs, which can subsequently be used for LD score regression (LDSC). We found the best-fitting model of cortical SA identified 6 GIBNs and CT identified 4 GIBNs, although sensitivity analyses indicated that other structures were plausible. The multivariate GWASs of the GIBNs identified 74 genome-wide significant (GWS) loci (p < 5 × 10 - 8 ), including many previously implicated in neuroimaging phenotypes, behavioral traits, and psychiatric conditions. LDSC of GIBN GWASs found that SA-derived GIBNs had a positive genetic correlation with bipolar disorder (BPD), and cannabis use disorder, indicating genetic predisposition to a larger SA in the specific GIBN is associated with greater genetic risk of these disorders. A negative genetic correlation was observed between attention deficit hyperactivity disorder (ADHD) and major depressive disorder (MDD). CT GIBNs displayed a negative genetic correlation with alcohol dependence. Even though we observed model instability in our application of genomic SEM to high-dimensional data, jointly modeling the genetic architecture of complex traits and investigating multivariate genetic links across neuroimaging phenotypes offers new insights into the genetics of cortical structure and relationships to psychopathology., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Epigenetic measures of aging derived from DNA methylation are promising biomarkers associated with prospective morbidity and mortality, but require validation in real-world medical settings. Using data from 2,216 post-9/11 veterans, we examined whether accelerated DunedinPACE aging scores were associated with chronic disease morbidity, predicted healthcare costs, and mortality assessed over an average of 13.1 years of follow up in VA electronic health records. Veterans with faster DunedinPACE aging scores developed more chronic disease and showed larger increases in predicted healthcare costs over the subsequent 5, 10, and 15 years. Faster aging was associated with incident myocardial infarction, stroke, diabetes, cancer, liver disease, and renal disease, as well greater risk of mortality due to all-causes and chronic disease. These findings provide evidence that accelerated epigenetic aging is associated with worsening prospective health across multiple chronic diseases and organ systems assessed using electronic health records from an integrated healthcare system., Competing Interests: Conflicts of interest: Drs. Terrie Moffitt, Avshalom Caspi, and Karen Sugden are named as an inventor on a license issued by Duke University for the DunedinPACE. The algorithm to calculate DunedinPACE is publicly available on Github, https://github.com/danbelsky/DunedinPACE. No other authors have conflicts of interest to report.

Purpose: Sybil is a validated publicly available deep learning-based algorithm that can accurately predict lung cancer risk from a single low-dose computed tomography (LDCT) scan. We aimed to study the effect of image reconstruction parameters and CT scanner manufacturer on Sybil's performance., Materials and Methods: Using LDCTs of a subset of the National Lung Screening Trial participants, which we previously used for internal validation of the Sybil algorithm (test set), we ran the Sybil algorithm on LDCT series pairs matched on kilovoltage peak, milliampere-seconds, reconstruction interval, reconstruction diameter, and either reconstruction filter or axial slice thickness. We also evaluated the cumulative effect of these parameters by combining the best- and the worst-performing parameters. A subanalysis compared Sybil's performance by CT manufacturer. We considered any LDCT positive if future lung cancer was subsequently confirmed by biopsy or surgical resection. The areas under the curve (AUCs) for each series pair were compared using DeLong's test., Results: There was no difference in Sybil's performance between 1049 pairs of standard versus bone reconstruction filter (AUC at 1 year 0.84 [95% confidence interval (CI): 0.70-0.99] vs 0.86 [95% CI: 0.75-0.98], P = 0.87) and 1961 pairs of standard versus lung reconstruction filter (AUC at 1 year 0.98 [95% CI: 0.97-0.99] vs 0.98 [95% CI: 0.96-0.99], P = 0.81). Similarly, there was no difference in 1288 pairs comparing 2-mm versus 5-mm axial slice thickness (AUC at 1 year 0.98 [95% CI: 0.94-1.00] vs 0.99 [95% CI: 0.97-0.99], P = 0.68). The best-case scenario combining a lung reconstruction filter with 2-mm slice thickness compared with the worst-case scenario combining a bone reconstruction filter with 2.5-mm slice thickness uncovered a significantly different performance at years 2-4 (P = 0.03). Subanalysis showed no significant difference in performance between Siemens and Toshiba scanners., Conclusions: Sybil's predictive performance for future lung cancer risk is robust across different reconstruction filters and axial slice thicknesses, demonstrating its versatility in various imaging settings. Combining favorable reconstruction parameters can significantly enhance predictive ability at years 2-4. The absence of significant differences between Siemens and Toshiba scanners further supports Sybil's versatility., Competing Interests: Conflicts of interest and sources of funding: S.J.S. received grants from the US National Cancer Institute. S.J.S. additionally reports funding from Concord (MA) Detect Ovarian Cancer Early Fund and Mercy Bioanalytics. S.J.S. participated in clinical advisory board for Mercy BioAnalytics and in a scientific advisory board for SISCAPA Assay Technologies. S.J.S. participated in a clinical advisory board for Guardant Health for which he was paid consulting fees. R.U.O. has US patents for a surgical specimen collection kit and method of lymph node collection; owns stocks in Bridge BIO, Eli Lilly, Gilead Sciences, Immunocore, and Pfizer; and has worked as a paid consultant for AstraZeneca, GE Healthcare, Genentech/Roche, Median Technologies, and Tryptych Healthcare Partners. L.V.S. receives institutional research support from Novartis, AstraZeneca, and Delfi. She is leading a clinical demonstration project funded by Grail and Point32 Health. S.J.S. reports stock options from SISCAPA Assay Technologies for participation on a scientific advisory board. F.J.F. reports research support from Pfizer, consulting for BD, and serving as a consultant and speaker for Boston Scientific. The other authors declare no relevant conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Burnout is a proven challenge in surgeons and surgical trainees, associated with higher rates of attrition compared to other medical specialties. Here we report the impact of a mental performance coaching program as it relates to surgery trainee wellbeing., Methods: A mixed-format mental performance coaching program was implemented at a large academic medical center's general surgery residency over a single academic year. Survey scores related to burnout, self-efficacy, and professional fulfillment were used to analyze the impact of the program as a whole, as well as by large group, small group, and one-on-one format attendance., Results: Residents that attended the small group or one-on-one sessions demonstrated a trend towards improved burnout and professional fulfillment. The PGY3 group attended the most small format sessions and demonstrated a significant decrease in burnout (p ​= ​0.03)., Conclusion: This offers an adaptable intervention for residency programs to improve the wellbeing of their trainees., (Published by Elsevier Inc.)

Objective:  Neonatal resuscitation is a high-acuity, low-occurrence event and many rural pediatricians report feeling underprepared for these events. We piloted a longitudinal telesimulation (TS) program with a rural hospital's interprofessional delivery room teams aimed at improving adherence to Neonatal Resuscitation Program (NRP) guidelines and teamwork., Study Design:  A TS study was conducted monthly in one rural hospital over a 10-month period from November 2020 to August 2021. TS sessions were remotely viewed and debriefed by experts, a neonatologist and a simulation educator. Sessions were video recorded and assessed using a scoring tool with validity evidence for NRP adherence. Teamwork was assessed using both TeamSTEPPS 2.0 Team Performance Observation Tool and Mayo High-Performance Teamwork Scale., Results:  We conducted 10 TS sessions in one rural hospital. There were 24 total participants, who rotated through monthly sessions, ensuring interdisciplinary team composition was reflective of realistic staffing. NRP adherence rate for full code scenarios improved from a baseline of 39 to 95%. Compared with baseline data for efficiency, multiple NRP skills improved (e.g., cardiac lead placement occurred 12× faster, 0:31 seconds vs. 6:21 minutes). Teamwork scores showed improvement in all domains., Conclusion:  Our results demonstrate that a TS program aimed at improving NRP and team performance is possible to implement in a rural setting. Our pilot study showed a trend toward improved NRP adherence, increased skill efficiency, and higher-quality teamwork and communication in one rural hospital. Additional research is needed to analyze program efficacy on a larger scale and to understand the impact of training on patient outcomes., Key Points: · Optimal newborn outcomes depend on skillful implementation of NRP.. · Telesimulation can deliver medical education that circumvents challenges in rural areas.. · A longitudinal NRP TS program is possible to implement in a rural setting.. · A rural NRP telesimulation program may improve interprofessional resuscitation performance.. · A rural NRP telesimulation program may improve interprofessional resuscitation teamwork.., Competing Interests: None declared., (Thieme. All rights reserved.)

Genome-wide association studies (GWAS) identify genetic variants underlying complex traits but are limited by stringent genome-wide significance thresholds. We present GRIN (Gene set Refinement through Interacting Networks), which increases confidence in the expanded gene set by retaining genes strongly connected by biological networks when GWAS thresholds are relaxed. GRIN was validated on both simulated interrelated gene sets as well as multiple GWAS traits. From multiple GWAS summary statistics of suicide attempt, a complex phenotype, GRIN identified additional genes that replicated across independent cohorts and retained biologically interrelated genes despite a relaxed significance threshold. We present a conceptual model of how these retained genes interact through neurobiological pathways that may influence suicidal behavior, and identify existing drugs associated with these pathways that would not have been identified under traditional GWAS thresholds. We demonstrate GRIN's utility in boosting GWAS results by increasing the number of true positive genes identified from GWAS results., (© 2024. The Author(s).)

Ene reductases (EREDs) catalyze asymmetric reduction with exquisite chemo-, stereo-, and regioselectivity. Recent discoveries led to unlocking other types of reactivities toward oxime reduction and reductive C-C bond formation. Exploring nontypical reactions can further expand the biocatalytic knowledgebase, and evidence alludes to yet another variant reaction where flavin mononucleotide (FMN)-bound ERs from the old yellow enzyme family (OYE) have unconventional activity with α,β-dicarbonyl substrates. In this study, we demonstrate the nonconventional stereoselective monoreduction of α,β-dicarbonyl to the corresponding chiral hydroxycarbonyl, which are valuable building blocks for asymmetric synthesis. We explored ten α,β-dicarbonyl aliphatic, cyclic, or aromatic compounds and tested their reduction with five OYEs and one nonflavin-dependent double bond reductase (DBR). Only GluER reduced aliphatic α,β-dicarbonyls, with up to 19% conversion of 2,3-hexanedione to 2-hydroxyhexan-3-one with an R -selectivity of 83% ee . The best substrate was the aromatic α,β-dicarbonyl 1-phenyl-1,2-propanedione, with 91% conversion to phenylacetylcarbinol using OYE3 with R -selectivity >99.9% ee . Michaelis-Menten kinetics for 1-phenyl-1,2-propanedione with OYE3 gave a turnover k cat of 0.71 ± 0.03 s -1 and a K m of 2.46 ± 0.25 mM. Twenty-four EREDs from multiple classes of OYEs and DBRs were further screened on 1-phenyl-1,2-propanedione, showing that class II OYEs (OYE3-like) have the best overall selectivity and conversion. EPR studies detected no radical signal, whereas NMR studies with deuterium labeling indicate proton incorporation at the benzylic carbonyl carbon from the solvent and not the FMN hydride. A crystal structure of OYE2 with 1.5 Å resolution was obtained, and docking studies showed a productive pose with the substrate., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

The role of rare non-coding variation in complex human phenotypes is still largely unknown. To elucidate the impact of rare variants in regulatory elements, we performed a whole-genome sequencing association analysis for height using 333,100 individuals from three datasets: UK Biobank (N = 200,003), TOPMed (N = 87,652) and All of Us (N = 45,445). We performed rare ( < 0.1% minor-allele-frequency) single-variant and aggregate testing of non-coding variants in regulatory regions based on proximal-regulatory, intergenic-regulatory and deep-intronic annotation. We observed 29 independent variants associated with height at P <  6 × 10 - 10 after conditioning on previously reported variants, with effect sizes ranging from -7cm to +4.7 cm. We also identified and replicated non-coding aggregate-based associations proximal to HMGA1 containing variants associated with a 5 cm taller height and of highly-conserved variants in MIR497HG on chromosome 17. We have developed an approach for identifying non-coding rare variants in regulatory regions with large effects from whole-genome sequencing data associated with complex traits., (© 2024. The Author(s).)

Animals adapt to environmental conditions by modifying the function of their internal organs, including the brain. To be adaptive, alterations in behavior must be coordinated with the functional state of organs throughout the body. Here, we find that thyroid hormone-a regulator of metabolism in many peripheral organs-directly activates cell-type-specific transcriptional programs in the frontal cortex of adult male mice. These programs are enriched for axon-guidance genes in glutamatergic projection neurons, synaptic regulatory genes in both astrocytes and neurons, and pro-myelination factors in oligodendrocytes, suggesting widespread plasticity of cortical circuits. Indeed, whole-cell electrophysiology revealed that thyroid hormone alters excitatory and inhibitory synaptic transmission, an effect that requires thyroid hormone-induced gene regulatory programs in presynaptic neurons. Furthermore, thyroid hormone action in the frontal cortex regulates innate exploratory behaviors and causally promotes exploratory decision-making. Thus, thyroid hormone acts directly on the cerebral cortex in males to coordinate exploratory behaviors with whole-body metabolic state., Competing Interests: Declaration of interests T.S.S. is an advisor and founder of Autobahn Therapeutics and is an inventor on several patents related to sobetirome and its derivatives. T.S.S. provided the sobetirome used in this study but was not involved in the study design, performing the work described, or in the analysis and presentation of the results., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The duration and magnitude of haematological changes following non-targeted low-dose radiation have not been well explored. We previously reported that low-dose radiation (150 mGy 2x/week for 5 consecutive weeks) was well tolerated by participants (n = 15) with minimal toxicities and no changes in quality of life. Leukocytes, platelets and erythrocytes decreased from baseline measurement 12 months following treatment, however changes were not clinically significant. T-cells, NK-cells, B-cells and neutrophils were found to decrease during treatment and return to baseline levels by 3 months. The monocyte activation marker CD64 (FcγRI) was lower in participants whose cancer did not progress during the 12 month study follow up period, potentially giving insights into a biomarker of treatment success. Herein, we provide one of the most detailed descriptions of hematologic changes during low dose radiation treatment and during one year follow up. Low-dose radiation was associated with minor hematologic changes that mostly resolved by 3 months. (Clinical Trial Registered with the United States National Library of Medicine and National Institutes of Health under the title 'Low Dose Hemi-Body Radiation for Recurrent Prostate Cancer'; ID: NCT03196778)., 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) 2024.)

Background: A shortage of images of pathology on diverse skin tones has been recognized for decades in health professions education. Identifying skin manifestations of disease depends on pattern recognition, which is difficult without visual examples. Lack of familiarity with visual diagnosis on skin of color can lead to delayed or missed diagnoses with increased morbidity and mortality. As the United States continues to increase in ethnic and racial diversity, addressing the disparity in health outcomes with education is vital., Case Presentation: At the Hackensack Meridian School of Medicine, students, librarians, and faculty came together to address this problem and develop a database of dermatological conditions in people with darker skin tones. A student group initiated a series of meetings with faculty to determine the best approach to address and enhance the representation of diversity in disease images within the curriculum. With the guidance of faculty and librarians, students performed a literature search and created a database of images of skin pathologies in people with darker skin tones. The database was disseminated to course directors and lecturers, and the noted disparities were corrected for the next cohort of students. The database provides an easily accessible resource for creating lecture slides., Conclusion: This project brought awareness of the need for inclusivity and generated a broad review of the curriculum to be more representative of all patient populations. Most importantly, our experience provides a roadmap for institutional change through student, librarian and faculty collaboration and cultivation of a culture of optimism and acceptance., Competing Interests: The authors declare no conflict of interest. There is no funding source associated with this manuscript., (Copyright © 2024 Ellen M. Hong, Rami Atoot, Megan E. Decker, Alexander C. Ekwueme, Cairo Stanislaus, Tadé Ayeni, Christopher P. Duffy, Allison E. Piazza, Mariela Mitre, Linda D. Siracusa, Jennifer F. Zepf.)

Importance: Although older adults may use potentially driver-impairing (PDI) medications that can produce psychomotor impairment, little is known about changes to PDI medication use among older adults from the time before to the time after a motor vehicle crash (MVC)., Objective: To quantify use of and changes in PDI medications among older adults before and after an MVC., Design, Setting, and Participants: This cohort study used linked Medicare claims and police-reported MVC data on 154 096 person-crashes among 121 846 older drivers. Eligible persons were drivers aged 66 years or older, involved in a police-reported MVC in New Jersey from May 1, 2007, through December 31, 2017, and with continuous enrollment in Medicare fee-for-service Parts A and B for at least 12 months and Part D for at least 120 days prior to the MVC. Data were analyzed from January 2022 to May 2024., Main Outcomes and Measures: Use of benzodiazepines, nonbenzodiazepine hypnotics, opioid analgesics, and other PDI medications in the 120 days before and 120 days after the MVC. Because each person could contribute multiple MVCs during the study period if they met eligibility criteria, the unit of analysis was the number of person-crashes. The proportion of person-crashes after which PDI medications were started, discontinued, or continued was quantified as well., Results: Among 154 096 eligible person-crashes, the mean (SD) age of the drivers was 75.2 (6.7) years at the time of the MVC. Of 121 846 unique persons, 51.6% were women. In 80.0% of the person-crashes, drivers used 1 or more PDI medications before the crash, and in 81.0% of the person-crashes, drivers used 1 or more PDI medications after the crash. Use of benzodiazepines (8.1% before the crash and 8.8% after the crash), nonbenzodiazepine hypnotics (5.9% before the crash and 6.0% after the crash), and opioid analgesics (15.4% before the crash and 17.5% after the crash) was slightly higher after the MVC. After the MVC, drivers in 2.1% of person-crashes started benzodiazepines and 1.4% stopped benzodiazepines, drivers in 1.2% of person-crashes started nonbenzodiazepine hypnotics and 1.2% stopped nonbenzodiazepine hypnotics, and drivers in 8.4% of person-crashes started opioid analgesics and 6.3% stopped opioid analgesics., Conclusions and Relevance: This cohort study suggests that most older drivers involved in MVCs did not use fewer PDI medications after crashes than before crashes. Qualitative research of perceived risks vs benefits of PDI medications is necessary to understand the reasons why MVCs do not appear to motivate clinicians to deprescribe PDI medications as a strategy to avert potential harms, including additional MVCs.

Background: The perseverative cognition hypothesis stipulates that rumination (repetitive, passive, uncontrollable negative thinking) prolongs the experience of a stressor which impacts stress physiology. In line with this hypothesis, we proposed that in response to real-life experiences of social rejection, adolescent girls who ruminate would show a blunted diurnal cortisol slope the next day relative to girls who do not ruminate. We also examined the effects of social rejection and rumination on waking cortisol levels and the cortisol awakening response., Method: Participants were ( n = 50) adolescent girls (mean age = 13.30, SD = 2.34) who varied on psychiatric risk and provided saliva samples 4 times a day for 3 days, as well as, daily diary reports of social rejection and rumination. A lagged multilevel model was utilized to examine the interactive effects of rejection and rumination on diurnal cortisol., Results: There was a significant interaction between social rejection and rumination. Specifically, rumination following social rejection was associated with a flatter diurnal cortisol slope. In the absence of rumination, social rejection was marginally associated with a steeper diurnal cortisol slope. The effects for waking cortisol levels and the cortisol awakening response were null., Conclusion: Findings support the perseverative cognition hypothesis and suggest that cognitive mechanisms such as rumination can impact stress physiology., Competing Interests: Conflict of Interest Chrystal Vergara-Lopez, Matthew D. Scalco, Allison E. Gaffey, Brie M. Reid, Margaret H. Bublitz, Sharon Y. Lee, Andrea Gomez, Nadia Mercado and Laura R. Stroud declare that they have no conflict of interest.

High levels of social connectivity among group-living animals have been hypothesized to benefit individuals by creating opportunities to rapidly reseed the microbiome and maintain stability against disruption. We tested this hypothesis by perturbing the microbiome of a wild population of Grant's gazelles with an antibiotic and asking whether microbiome recovery differs between individuals with high versus low levels of social connectivity. We found that after treatment, individuals with high social connectivity experienced a faster increase in microbiome richness than less socially connected individuals. Unexpectedly, the rapid increase in microbiome richness of highly connected individuals that received treatment led to their microbiomes becoming more distinct relative to the background population. Our results suggest that the microbiome of individuals with high social connectivity can be rapidly recolonized after a perturbation event, but this leads to a microbiome that is more distinct from, rather than more similar to the unperturbed state. This work provides new insight into the role of social interactions in shaping the microbiome.

Importance: Poststroke cognitive impairment is common, but the cognitive trajectory following a first stroke, relative to prestroke cognitive function, remains unclear., Objective: To map the trajectory of cognitive function before any stroke and after stroke in global cognition and in 4 cognitive domains, as well as to compare the cognitive trajectory prestroke in stroke survivors with the trajectory of individuals without incident stroke over follow-up., Design, Setting, and Participants: The study used harmonized and pooled data from 14 population-based cohort studies included in the Cohort Studies of Memory in an International Consortium collaboration. These studies were conducted from 1993 to 2019 across 11 countries among community-dwelling older adults without a history of stroke or dementia. For this study, linear mixed-effects models were used to estimate trajectories of cognitive function poststroke relative to a stroke-free cognitive trajectory. The full model adjusted for demographic and vascular risk factors. Data were analyzed from July 2022 to March 2024., Exposure: Incident stroke., Main Outcomes and Measures: The primary outcome was global cognition, defined as the standardized average of 4 cognitive domains (language, memory, processing speed, and executive function). Cognitive domain scores were formed by selecting the most commonly administered test within each domain and standardizing the scores., Results: The study included 20 860 participants (12 261 [58.8%] female) with a mean (SD) age of 72.9 (8.0) years and follow-up of 7.51 (4.2) years. Incident stroke was associated with a substantial acute decline in global cognition (-0.25 SD; 95% CI, -0.33 to -0.17 SD), the Mini-Mental State Examination, and all cognitive domains (ranging from -0.17 SD to -0.22 SD), as well as accelerated decline in global cognition (-0.038 SD per year; 95% CI, -0.057 to -0.019 SD per year) and all domains except memory (ranging from -0.020 to -0.055 SD per year), relative to a stroke-free cognitive trajectory. There was no significant difference in prestroke slope in stroke survivors compared with the rate of decline in individuals without stroke in all cognitive measures. The mean rate of decline without a previous stroke was -0.049 SD per year (95% CI, -0.051 to -0.047 SD) in global cognition., Conclusions and Relevance: In this cohort study using pooled data from 14 cohorts, incident stroke was associated with acute and accelerated long-term cognitive decline in older stroke survivors.

Class Ia ribonucleotide reductases (RNRs) are allosterically regulated by ATP and dATP to maintain the appropriate deoxyribonucleotide levels inside the cell for DNA biosynthesis and repair. RNR activity requires precise positioning of the β 2 and α 2 subunits for the transfer of a catalytically essential radical species. Excess dATP inhibits RNR through the creation of an α-β interface that restricts the ability of β 2 to obtain a position that is capable of radical transfer. ATP breaks the α-β interface, freeing β 2 and restoring enzyme activity. Here, we investigate the molecular basis for allosteric activity regulation in the well-studied Escherichia coli class Ia RNR through the determination of six crystal structures and accompanying biochemical and mutagenesis studies. We find that when dATP is bound to the N-terminal regulatory cone domain in α, a helix unwinds, creating a binding surface for β. When ATP displaces dATP, the helix rewinds, dismantling the α-β interface. This reversal of enzyme inhibition requires that two ATP molecules are bound in the cone domain: one in the canonical nucleotide-binding site (site 1) and one in a site (site 2) that is blocked by phenylalanine-87 and tryptophan-28 unless ATP is bound in site 1. When ATP binds to site 1, histidine-59 rearranges, prompting the movement of phenylalanine-87 and trytophan-28, and creating site 2. dATP hydrogen bonds to histidine-59, preventing its movement. The importance of site 2 in the restoration of RNR activity by ATP is confirmed by mutagenesis. These findings have implications for the design of bacterial RNR inhibitors.