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Background: Attention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) are associated, but it is unclear if this is a causal relationship or confounding. We used genetic analyses and sibling comparisons to clarify the direction of this relationship. Methods: Linkage disequilibrium score regression and 2-sample Mendelian randomization were used to test for genetic correlation (r g) and bidirectional causal effects using European ancestry genome-wide association studies of ADHD (20,183 cases and 35,191 controls) and 6 PTSD definitions (up to 320,369 individuals). Several additional variables were included in the analysis to verify the independence of the ADHD-PTSD relationship. In a population-based sibling comparison (N = 2,082,118 individuals), Cox regression models were fitted to account for time at risk, a range of sociodemographic factors, and unmeasured familial confounders (via sibling comparisons). Results: ADHD and PTSD had consistent r g (r g range, 0.43–0.52; p < .001). ADHD genetic liability was causally linked with increased risk for PTSD (β = 0.367; 95% CI, 0.186–0.552; p = 7.68 × 10 −5). This result was not affected by heterogeneity, horizontal pleiotropy (Mendelian randomization Egger intercept = 4.34 × 10 −4, p = .961), or other phenotypes and was consistent across PTSD datasets. However, we found no consistent associations between PTSD genetic liability and ADHD risk. Individuals diagnosed with ADHD were at a higher risk for developing PTSD than their undiagnosed sibling (hazard ratio = 2.37; 95% CI, 1.98–3.53). Conclusions: Our findings add novel evidence supporting the need for early and effective treatment of ADHD, as patients with this diagnosis are at significantly higher risk to develop PTSD later in life.

This study conceptualizes carceral violence to include the intimate sphere, highlighting a form of systemic racialized-gendered violence I term intimate carceral violence, which consists of two distinct violent effects of carcerality on relationships in Black communities: prisonized romance and coercive carceral care. I conducted qualitative interviews with 31 criminal-legal system–impacted Black women aged between 18 and 65 years in Southern California. Findings revealed that their romantic precarity included the challenge of finding partners due to the encroachment of the carceral state on Black communities. This study establishes how women engage in intimate carceral labor to mitigate their experiences of intimate carceral violence. I focus on the hidden work of managing an intimate partner’s emotions and behavior engendered by incarceration.

Objective: This study examined the extent to which political beliefs and public health behaviors cluster together and define distinct groups of individuals and whether those groups differ on firearm purchasing behaviors. Methods: 6,404 US residents (Minnesota, n = 1,789; Mississippi, n = 1,418; New Jersey, n = 3,197) were recruited via Qualtrics panels. Participants were matched to 2010 census data. Results: Fit statistics determined a four-class solution fit the data best. The Liberal-Many Health Behaviors class had high probabilities of voting for President Biden, reporting more liberal political beliefs than other classes, and engaging in multiple health behaviors (e.g., mask wearing, vaccination). The Moderate-Few Health Behaviors class had high probabilities of voting for President Biden, reporting moderate political beliefs, and engaging in few health behaviors. The Conservative-Few Health Behaviors class had high probabilities of voting for former President Trump, reporting conservative political beliefs, and engaging in few health behaviors. The Conservative-Many Health Behaviors class had high probabilities of voting for former President Trump, having conservative political beliefs, and engaging in many health behaviors. Of the participants in the study who reported owning firearms, those in the Few Health Behavior classes were more likely to have purchased firearms during the purchasing surge, whereas those in the Many Health Behavior classes were likely to have become first-time firearm owners in 2020-2021. Lastly, the Few Health Behavior classes exhibited significantly less trust in the intentions of scientists. Conclusion: Different subgroups of firearm owners may evaluate and respond to risk differently, resulting in a pattern of adopting or avoiding a range of public health recommendations. Those who avoided mask wearing and COVID-19 vaccinations and who purchased firearms during the firearm purchasing surge appear to have less trust in science, highlighting the need for trusted messengers to increase the reach of behavioral interventions.

Dental calculus and other preserved microbiome substrates are an attractive target for dietary reconstruction in past populations through a variety of physical, chemical, and molecular means. Recently, studies have attempted to reconstruct diet from archaeological dental calculus using archaeogenetic techniques. While dental calculus may provide a relatively stable environment for DNA preservation, the detection of plants and animals possibly consumed by an individual through DNA analysis is primarily hindered by microbial richness and incomplete reference databases. Moreover, high genomic similarity within eukaryotic groups 1. Introduction 2. Materials and methods 3. Results 3.1. Effects of low read counts on damage patterns 3.2. Identification of dietary reads from synthetic datasets 3.3. Identification of dietary reads from real datasets 4. Discussion and conclusions 4.1. Checklist for authors and reviewers 4.1.1. Field/storage contamination 4.1.2. Is the laboratory methodology suitable for aDNA authentication? 4.1.3. Is the database and pipeline suitable? 4.1.4. Is the taxonomic resolution analyzed sufficient for reliable interpretation? 4.1.5. Have unexpected taxa been reported and evaluated? 4.1.6. Have laboratory controls been evaluated alongside samples? 4.1.7. Has evidence of aDNA authenticity been provided? 4.1.8. Is there other evidence supporting that dietary organisms were consumed?

Background Surgery causes transient impairment in cognition and function, which may impact driving safety. The authors hypothesized that the risk of a motor vehicle crash would increase after compared to before surgery. Methods The authors performed a nested case-crossover study within population-based observational data from the New Jersey Safety Health Outcomes Data Warehouse. The study included adults 18 yr or older with a valid driver’s license who underwent general surgery in an acute care hospital in New Jersey between January 1, 2016, and November 30, 2017, and were discharged home. Individuals served as their own controls within a presurgery interval (56 days to 28 days before surgery) and postsurgery interval (discharge through 28 days after surgery). General surgery was defined by Common Procedural Terminology Codes. The primary outcome was a police-reported motor vehicle crash. Results In a cohort of 70,722 drivers, the number of crashes after surgery was 263 (0.37%) compared to 279 (0.39%) before surgery. Surgery was not associated with a change in crash incidence greater than 28 days using a case-crossover design (adjusted incidence rate ratio, 0.92; 95% CI, 0.78 to 1.09; P = 0.340). Statistical interaction was present for sex and hospital length of stay. Younger versus older adults (adjusted risk ratio, 1.87; 95% CI, 1.10 to 3.18; P = 0.021) and non-Hispanic Black individuals (adjusted risk ratio, 1.96; 95% CI, 1.33 to 2.88; P = 0.001) and Hispanic individuals (adjusted risk ratio, 1.38; 95% CI, 1.00 to 1.91; P = 0.047) versus non-Hispanic White individuals had a greater risk of a crash after surgery. Conclusions Using population-based crash and hospital discharge data, the incidence of motor vehicle crashes over a 28-day period did not change on average before compared to after surgery. The authors provide data on crash risk after surgery and highlight specific populations at risk. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Objective Patients with hormone receptor positive (HR+), HER2- metastatic breast cancer frequently require radiation therapy (RT) in addition to systemic therapy for disease control and symptom management. CDK 4/6 inhibitors are increasingly used in the care of hormone positive breast cancers. Stereotactic body radiotherapy (SBRT), a form of very focused high dose radiation, is also increasingly used in the care of metastatic breast cancer. Limited data have reported on the safety of palliative RT with CDK4/6 inhibitors, with some reports demonstrating synergistic effects with potential for increased toxicity. The objective of our study is to assess toxicity among patients who received SBRT, stereotactic radiosurgery (SRS), or other high dose RT along with CDK 4/6 inhibitors for treatment of metastatic breast cancer. Methods Women with metastatic breast cancer who received SBRT, SRS, or other higher dose RT with CDK 4/6 inhibitors at any point in their treatment between 2013 and 2021 were retrospectively identified. Timing of radiation therapy, either before, during, or after CDK 4/6 inhibitor use was assessed, as well as the interval between the two treatments. Treatment sites for radiotherapy included lung/chest, spine, and brain metastases. Physician assessed adverse events were obtained through clinical follow up and graded using CTCAE v5. Local control and OS were reported. Results Twenty patients met study inclusion criteria. Patients received radiation therapy and CDK 4/6 inhibitors concurrently (within 7 days) [n=7, 35%], within 30 days (RT pre-CDK 4/6 inhibitor use) [n=3, 15%], and greater than 30 days (RT pre-CDK 4/6 inhibitor use [n=6, 30%] and RT post-CDK 4/6 inhibitor use [n=4, 20%]). Radiation treatment sites were spine [n=10, 55%], brain [n=6, 30%], and lung/chest wall [n=3, 15%]. Radiation doses were as follows: 60 Gy in 5 fractions [n=1, 5%], 50 Gy in 5 fractions [n=2, 10%], 55 Gy in 20 fractions (chest wall recurrence) [n=1, 5%], 35 Gy in 15 fractions [n=1, 5%], 30 Gy in 10 fractions [n=6, 30%], 30 Gy in 3 fractions [n= 4, 20%], 24 Gy in 1 fraction [n=3, 15%], 20 Gy in 5 fractions [n=2, 10%]. Palbociclib was used in 85% of patients [n=17] and abemaciclib in 15% [n=3]. Median follow up for surviving patients was 4.7 years [IQR: 2.5-6.8 years]. Local control was achieved in 85% of patients [n=17]. Median OS was 2.7 years [IQR: 0.1-6.8 years]. Grade 2 toxicity [n=9, 45%] and grade 3 toxicity [n=3, 15%] was reported across all three treatment areas, with grade 2 or 3 fatigue [n=7, 35%] being the most frequently reported toxicity. In the spine treatment group, 1 patient who had CDK 4/6 inhibitor use within 30 days of radiotherapy experienced a grade 3 vertebral compression fracture as well as grade 3 fatigue. In the lung/chest wall treatment group, the patient treated to 55 Gy in 20 fractions to the chest wall with concurrent use had grade 3 skin/wound toxicity requiring prolonged wound care before healing. In the intra-cranial SRS group, grade 3 fatigue was reported in 1 patient with concurrent use. Conclusion The use of CDK 4/6 inhibitors concurrently with or within 30 days of radiation therapy was generally well tolerated with limited grade 3 toxicity. Two of three reports of grade 3 toxicity occurred with concurrent treatment. Due to the potential radiosensitizing properties of CDK 4/6 inhibitors, it may be prudent to hold combined treatment when clinically feasible. Further study is needed to validate these results. Citation Format: Kiran Chauhan, Roman O. Kowalchuk, Allison E. Garda, Dean A. Shumway, Mark R. Waddle, Robert Mutter, Kimberly Corbin. Safety of stereotactic body radiation therapy, stereotactic radiosurgery, and other radiation therapy with use of CDK 4/6 inhibitors for hormone receptor positive (HR+), HER2- metastatic breast cancer: a retrospective cohort study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-10-05.

The purpose of this document is to highlight practical recommendations to assist acute-care hospitals in prioritization and implementation of strategies to prevent healthcare-associated infections through hand hygiene. This document updates the Strategies to Prevent Healthcare-Associated Infections in Acute Care Hospitals through Hand Hygiene, published in 2014. This expert guidance document is sponsored by the Society for Healthcare Epidemiology (SHEA). It is the product of a collaborative effort led by SHEA, the Infectious Diseases Society of America, the Association for Professionals in Infection Control and Epidemiology, the American Hospital Association, and The Joint Commission, with major contributions from representatives of a number of organizations and societies with content expertise.

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.

Two-thirds of military suicides are by firearm, and unsafe storage increases the risk of suicide. Understanding who is at risk for suicide, their interactions with behavioral healthcare, and their firearm storage habits have implications for suicide prevention.Probability-based sampling was used. Inclusion criteria were current military service and firearm ownership. Analyses focused on those who endorsed past year (n = 180) or past month suicidal ideation (n = 85).Servicemembers with undisclosed past year ideation stored firearms at home more often and with a locking device less often. Servicemembers with past year ideation who did not attend recent behavioral health sessions stored firearms with a locking device and loaded less often. Servicemembers with undisclosed suicidal ideation in the past month stored firearms with a locking device less often. Servicemembers with past month ideation who have not attended recent behavioral health sessions stored firearms with a locking device and loaded less often.Servicemembers experiencing undisclosed suicidal ideation and who are not receiving treatment generally have more ready access to firearms. Safe firearm storage messaging needs to be disseminated in a manner that shifts social norms around firearm storage, whether or not suicide risk is known.

To determine if women Veterans who deployed in support of Operations Enduring Freedom/Iraqi Freedom (OEF/OIF) would show a greater likelihood of breast cancer (BC) than other women Veterans.This was a retrospective cohort study of women aged60 years who received Veterans Affairs medical center primary care, 2001-2021. The exposure was OEF/OIF deployment and the outcome was a BC diagnosis after entering Veterans Affairs care. Poisson models evaluated the association between deployment and BC incidence, covarying demographics, lifestyle factors, and hormonal contraceptive and hormone replacement therapy use. Analyses were also stratified by age and race, and a sensitivity analysis adjusted for healthcare utilization over the initial 2 years.Of 576,601 women, 24.6% (n = 141,935) deployed during post-9/11 conflicts. Across follow-up [median: 8.2 years], 1.2% women were diagnosed with BC. Those who deployed in support of OEF/OIF were 21% less likely to be diagnosed with BC than women who did not deploy (95% CI: 0.73, 0.86). The association remained in stratified models and when including healthcare utilization.Despite the exposures of OEF/OIF deployment, there was a significantly lower incidence of BC among women who deployed versus not, possibly due to a healthy soldier effect or to differences in screening.

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In 30 states, licensing agencies can restrict the distance from home that "medically-at-risk" drivers are permitted to drive. However, where older drivers crash relative to their home or how distance to crash varies by medical condition is unknown. Using geocoded crash locations and residential addresses linked to Medicare claims, we describe how the relationship between distance from home to crash varies by driver characteristics. We find that a majority of crashes occur within a few miles from home with little variation across driver demographics or medical conditions. Thus, distance restrictions may not reduce crash rates among older adults, and the tradeoff between safety and mobility warrants consideration.

This study describes the type of firearm used and location of bodily injury among demographic subgroups of suicide decedents. Data on those who died by suicide via firearm from the National Violent Death Reporting System (

Purpose To compare Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) in patients with endometrial cancer receiving adjuvant pelvic radiation therapy with proton beam therapy (PT) versus intensity-modulated radiation therapy (IMRT). Materials and Methods Patients with uterine cancer treated with curative intent who received either adjuvant PT or IMRT between 2014 and 2020 were identified. Patients were enrolled into a prospective registry using a gynecologic-specific subset of PRO-CTCAE designed to assess symptom impact on daily living. Questions included gastrointestinal (GI) symptoms of diarrhea, flatulence, bowel incontinence, and constipation in addition to other pertinent gynecologic, urinary, and other general symptoms. Symptom-based questions were on a 0- to 4-point scale, with grade 3+ symptoms occurring frequently or almost always. Patient-reported toxicity was analyzed at baseline, end of treatment (EOT), and at 3, 6, 9, and 12 months after treatment. Unequal variance t tests were used to determine if treatment type was a significant factor in baseline-adjusted PRO-CTCAE. Results Sixty-seven patients met inclusion criteria. Twenty-two received PT and 45 patients received IMRT. Brachytherapy boost was delivered in 73% of patients. Median external beam dose was 45 Gy for both PT and IMRT (range, 45-58.8 Gy). When comparing PRO-CTCAE, PT was associated with less diarrhea at EOT (P = .01) and at 12 months (P = .24) than IMRT. Loss of bowel control at 12 months was more common in patients receiving IMRT (P = .15). Any patient reporting grade 3+ GI toxicity was noted more frequently with IMRT (31% versus 9%, P = .09). Discussion Adjuvant PT is a promising treatment for patients with uterine cancer and may reduce patient-reported GI toxicity as compared with IMRT.

Much of the heterogeneity in the rate of cognitive decline and the age of dementia onset remains unexplained, and there is compelling data supporting psychosocial stressors as important risk factors. However, the literature has yet to come to a consensus on whether there is a causal relationship and, if there is, its direction and strength. This study estimates the relationship between lifecourse traumatic events and cognitive trajectories and predicted dementia incidence.Using data on 7,785 participants aged ≥65 years from the Health and Retirement Study, this study estimated the association between lifecourse experience of 10 traumatic events (e.g., losing a child) and trajectories of Telephone Interview for Cognitive Status from 2006 to 2016 using linear mixed-effects models and predicted incident dementia from 2006 to 2014 using cumulative incidence functions (data analysis was in 2020-2022). Inverse probability weights accounted for loss to follow-up and confounding by sex, education, race/ethnicity, and age.Experiencing 1 or more traumatic events over the lifecourse was associated with accelerated decline compared with experiencing no events (e.g., β= -0.05 [95% CI= -0.07, -0.02] Health and Retirement Study-Telephone Interview for Cognitive Status units/year; 1 vs 0 events). In contrast, experiencing traumatic events was associated with better cognitive function cross-sectionally. Furthermore, the impact of trauma on cognitive decline was of greater magnitude when it occurred after the age of 64 years. However, the magnitude and direction of association varied by the specific traumatic event. There were no associations with predicted incident dementia.These results suggest that researchers and clinicians should not aggregate traumatic events for understanding the risk of accelerated cognitive decline.

Psychological distress-elevated symptoms of depression, anxiety, post-traumatic stress disorder (PTSD), or psychosocial stress-has been associated with risk for cardiovascular disease (CVD). Despite increasing attention to the importance of these factors for CVD prevention, the state of this science requires updated synthesis to enable practice recommendations. Moreover, it is unknown whether psychological distress based on screeners, validated self-report instruments that efficiently identify those who may require mental health services or additional support, is associated with incident CVD.MEDLINE, Embase, and PsycInfo were searched for studies published 2017-2022, including adults without a past psychiatric diagnosis, who were screened at baseline for depression, anxiety, PTSD, stress, or general mental health symptoms, and followed forgt;6 mo to determine their risk for incident CVD (ie, atrial fibrillation, acute coronary syndrome, coronary heart disease, peripheral vascular disease, heart failure, or a composite). A meta-analysis was used to aggregate results to determine whether clinically significant levels of psychological distress were associated with CVD onset.The search identified 28 investigations that represented 658 331 participants (58% women). Fifteen studies had adequate data for the primary meta-analysis, which indicated that those reporting high psychological distress showed a 28% greater risk of incident CVD compared with those with low or no distress.Rapid screening for psychological distress is a helpful and efficient approach to understanding the CVD risk profile of an individual. Additional investigations are needed to improve prospective evidence concerning psychosocial stress. Conducting analyses by sex may better elucidate the benefits of psychological distress screening for men and women, respectively, and encourage more widespread adoption in CVD prevention.

Cardiovascular disease remains the leading cause of morbidity and mortality in industrialized nations. Many patients living with chronic cardiovascular disease suffer from complex multimorbidities requiring high-intensity care and behavioral risk factor management, and about a third copresent with a mental health disorder. These comanifestations are extremely taxing for patients and our health care system, complicate treatment, and increase the risk of adverse health outcomes. Health psychology emerged in response to a need for specialists who could design, deliver, and test evidence-based approaches to manage behavioral risk factors and the mental health burden of chronic diseases. We aimed to conduct a state-of-the-art review as to how health psychology emerged as a key specialty in delivering integrated care for cardiovascular populations, and to review challenges and opportunities that lie ahead of further integration of the specialty for integrated cardiovascular care.As our health care system embraces more patient-centered care and big data science to detect at-risk patients and predict outcomes, health psychologists should be at the forefront to apply their expertise and demonstrate their value in designing and applying intervention models to improve outcomes. We first review challenges, then illustrate this framework using the Wagner chronic care model, present business case considerations, and conclude with an action agenda to promote the integration of health psychology as a cotreating specialty into cardiovascular care.To provide direction for this undertaking, we present a roadmap for the field of health psychology to sustainably extend existing holistic, integrated approaches in cardiovascular care.To lessen the burden and improve outcomes in cardiovascular disease, care must shift away from siloed delivery models that are focused on traditional atherosclerotic risk factors to holistic, integrated approaches that address biological, psychological, social, and behavioral factors relevant to cardiovascular disease. Using the presented roadmap, health psychology can play a major role to address these needs of integrated cardiovascular care. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Current guidelines recommend that patients with choledocholithiasis undergo same-admission cholecystectomy. The compliance with this guideline is poor in elderly patients. We hypothesized that elderly patients treated with endoscopic retrograde cholangiopancreatography (ERCP) alone would have higher complication and readmission rates than the patients treated with cholecystectomy.The Nationwide Readmissions Database was queried for all patients aged ≥65 years with admission for choledocholithiasis January to June 2016. The patients were divided based on index treatment received: (1) no intervention; (2) ERCP alone; or (3) cholecystectomy. Multivariate analyses identified predictors of cholecystectomy during index admission and of readmissions.A total of 16,121 patients with choledocholithiasis were admitted; 38.4% underwent cholecystectomy, 37.6% endoscopic retrograde cholangiopancreatography alone, and 24.0% no intervention. The patients not receiving a cholecystectomy were more likely to be older, female, have a higher Elixhauser score, do-not-resuscitate status, and at a teaching hospital (all P.001). Emergency readmissions for recurrent biliary disease were lowest in patients undoing a cholecystectomy (2.2% vs 9.2% endoscopic retrograde cholangiopancreatography and 12.4% no intervention, P.001), as were readmissions for complications (3.6% vs 5.5% and 7.8%, P.001). Cholecystectomy reduced rates of readmissions for recurrent disease (odds ratio 0.168, P.001), for complications (odds ratio 0.540, P.001), and death during readmission (odds ratio 0.503, P = .007); endoscopic retrograde cholangiopancreatography alone reduced only rates of readmissions. Age was not a predictor of readmission or death.Index admission cholecystectomy is associated with a lower risk of readmission for biliary disease or complications, as well as death during readmission, in elderly patients. Age alone is not predictive of outcomes; surgical intervention should be guided by clinical condition, comorbidities, and patient preference.

Some research has suggested that social presence may improve performance. However, results in this area have been inconsistent, and it may be the case that individual differences in personality are crucial moderators of the effect of social presence on vigilance performance. Thus, the present study examined the effect of personality traits on performing a vigilance task in various social contexts. 124 participants completed a 24-minute vigilance task either alone, with an evaluative observer, with an independent co-actor, or both. Results indicated that conscientiousness was the only trait to interact with experimental condition, such that conscientious individuals reported higher task motivation when completing the task either alone or in the presence of both an evaluator and co-actor. The present results suggest that while conscientiousness may not affect performance, it may be an important moderator of motivation for vigilance tasks.

Glomerular hyperfiltration is common in young sickle cell anemia patients and precedes development of overt kidney disease. In this multicenter pooled cohort, we characterized hyperfiltration and its decline to normal range in adult patients. Glomerular filtration rate (GFR) was estimated using the creatinine-based 2009 CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation omitting race adjustment and the 2021 CKD-EPI equation. Using CKD-EPI–2009, 506 patients had baseline estimated GFR (eGFR) ≥90 mL/min per 1.73 m2, median age of 24 (interquartile range [IQR], 19-34) years and 5.17 years of follow-up. The prevalence of hyperfiltration (eGFR ≥140 and ≥130 mL/min per 1.73 m2 for men and women, respectively) was 38.3%. Using CKD-EPI–2009, baseline hyperfiltration was less likely with older age (odds ratio [OR], 0.78; 95% confidence interval [CI], 0.73-0.83; P < .0001), male sex (OR, 0.32; 95% CI, 0.18-0.58; P = .0002), and higher weight (OR, 0.96; 95% CI, 0.94-0.99; P = .001). Using CKD-EPI–2021, hyperfiltration was similarly less likely with older age (OR, 0.75; 95% CI, 0.70-0.81; P < .0001), male sex (OR, 0.24; 95% CI, 0.13-0.44; P < .0001), and higher weight (OR, 0.97; 95% CI, 0.95-0.99; P = .004). In patients with baseline hyperfiltration, eGFR declined to normal values at a median age of 26.2 years. Using CKD-EPI–2009, this decline was associated with male sex (HR, 2.20; 95% CI, 1.26-3.87; P = .006), systolic blood pressure (hazard ratio [HR], 1.02; 95% CI, 1.01-1.04; P = .01), and hydroxyurea use (HR, 1.74; 95% CI, 1.002-3.03; P = .05). Using CKD-EPI–2021, decline of eGFR to normal was only associated with male sex (HR, 3.39; 95% CI, 2.01-5.69; P < .0001). Decline to normal eGFR range from hyperfiltration occurs earlier in males, those on hydroxyurea, and with higher systolic blood pressure.

A-to-I RNA editing is widespread in human cells but is uncommon in the coding regions of proteins outside the nervous system. An unusual target for recoding by the adenosine deaminase ADAR1 is the pre-mRNA of the base excision DNA repair enzyme NEIL1 that results in the conversion of a lysine (K) to arginine (R) within the lesion recognition loop and alters substrate specificity. Differences in base removal by unedited (UE, K242) vs edited (Ed, R242) NEIL1 were evaluated using a series of oxidatively modified DNA bases to provide insight into the chemical and structural features of the lesion base that impact isoform-specific repair. We find that UE NEIL1 exhibits higher activity than Ed NEIL1 toward the removal of oxidized pyrimidines, such as thymine glycol, uracil glycol, 5-hydroxyuracil, and 5-hydroxymethyluracil. Gas-phase calculations indicate that the relative rates in excision track with the more stable lactim tautomer and the proton affinity of N3 of the base lesion. These trends support the contribution of tautomerization and N3 protonation in NEIL1 excision catalysis of these pyrimidine base lesions. Structurally similar but distinct substrate lesions, 5-hydroxycytosine and guanidinohydantoin, are more efficiently removed by the Ed NEIL1 isoform, consistent with the inherent differences in tautomerization, proton affinities, and lability. We also observed biphasic kinetic profiles and lack of complete base removal with specific combinations of the lesion and NEIL1 isoform, suggestive of multiple lesion binding modes. The complexity of NEIL1 isoform activity implies multiple roles for NEIL1 in safeguarding accurate repair and as an epigenetic regulator.

Adolescents with attention-deficit/hyperactivity disorder (ADHD) have 30%-40% higher crash rates. However, we still do not understand which factors underlie heightened crash risk and if crash circumstances differ for drivers with ADHD. We compared prevalences of crash responsibility, driver actions, and crash types among adolescent and young adult drivers with and without ADHD who crashed within 48 months of licensure.In this exploratory retrospective cohort study, we identified patients of Children's Hospital of Philadelphia's (CHOP) New Jersey (NJ) primary care locations who were born between 1987 and 2000, NJ residents, had their last CHOP visit ≥ age 12 years, and acquired a driver's license. We linked CHOP electronic health records to NJ's licensing and crash databases. ADHD diagnosis was based on International Classification of Diseases, Ninth Revision, Clinical Modification/International Classification of Diseases, Tenth Revision, Clinical Modification codes. Prevalence ratios were estimated using generalized estimating equation log-binomial regression.We identified 934 drivers with ADHD in 1,308 crashes and 5,158 drivers without ADHD in 6,676 crashes. Within 48 months postlicensure, drivers with ADHD were more likely to be at fault for their crash (prevalence ratio: 1.09 [1.05-1.14]) and noted as inattentive (1.15 [1.07-1.23]). With the exception that drivers with ADHD were less likely to crash while making a left/U-turn, we did not find substantial differences in crash types by diagnosis. Analyses also suggest females with ADHD may have a higher risk of colliding with a nonmotor vehicle and crashing due to unsafe speed than females without ADHD.The results suggest crash circumstances do not widely differ for drivers with and without ADHD but highlight several factors that may be particularly challenging for young drivers with ADHD.

BACKGROUND Penicillin allergy labels are often inaccurate in children and removing unnecessary labels results in improved outcomes and lower health care costs. Although the hospital setting is a frequent point of contact for children, strategies to evaluate penicillin allergies in the hospital are lacking. METHODS We performed a prospective pilot study to determine the feasibility of a centralized, pharmacy-led approach to penicillin allergy evaluation. Children with a reported history of penicillin allergy admitted to our children’s hospital were risk-stratified and those stratified as low-risk underwent a single-dose oral challenge by a central pharmacist, regardless of the need for antibiotics. After the completion of each patient’s delabeling process, surveys were distributed to health care personnel involved in the patient’s care to collect perceptions on the acceptability, appropriateness, and feasibility of this intervention. Measures were scored by using a 5-point Likert scale. RESULTS Of the 23 patients who screened as low-risk, 20 underwent a penicillin allergy evaluation and an oral challenge. Of these, the penicillin allergy label was removed in 19 (95%) patients (Fig 1). The median age was 7 years (range 11 months–18 years). Participants rated the risk stratification and delabeling favorably overall, with high ratings on all 3 implementation measures: acceptability (mean 4.55, ± standard deviation [STD] 0.65), appropriateness (mean 4.58, STD ± 0.6), and feasibility (mean 4.51, STD ± 0.73). Measures of acceptability, appropriateness, and feasibility remained high when stratified by health care worker type and provider type. CONCLUSIONS Our findings provide support for systemic implementation of penicillin allergy delabeling strategies in hospitalized children.

IntroductionThe U.S. suicide mortality rate has steadily increased during the past two decades, particularly among military veterans; however, the epigenetic basis of suicidal thoughts and behaviors (STB) remains largely unknown.MethodsTo address this issue, we conducted an epigenome-wide association study of DNA methylation (DNAm) of peripheral blood samples obtained from 2,712 U.S. military veterans.ResultsThree DNAm probes were significantly associated with suicide attempts, surpassing the multiple testing threshold (FDR q-value SLC4A2 and CDK5; cg04724646 in PDE3A; and cg04999352 in RARRES3. cg13301722 was also found to be differentially methylated in the cerebral cortex of suicide decedents in a publicly-available dataset (p = 0.03). Trait enrichment analysis revealed that the CpG sites most strongly associated with STB in the present sample were also associated with smoking, alcohol consumption, maternal smoking, and maternal alcohol consumption, whereas pathway enrichment analysis revealed significant associations with circadian rhythm, adherens junction, insulin secretion, and RAP-1 signaling, each of which was recently associated with suicide attempts in a large, independent genome-wide association study of suicide attempts of veterans.DiscussionTaken together, the present findings suggest that SLC4A2, CDK5, PDE3A, and RARRES3 may play a role in STB. CDK5, a member of the cyclin-dependent kinase family that is highly expressed in the brain and essential for learning and memory, appears to be a particularly promising candidate worthy of future study; however, additional work is still needed to replicate these finding in independent samples.

The striatum in the brain is involved in various behavioral functions, including reward, and disease processes, such as opioid use disorder (OUD). Further understanding of the role of striatal subregions in reward behaviors and their potential associations with OUD requires molecular identification of specific striatal cell types in human brain. The human striatum contains subregions based on different anatomical, functional, and physiological properties, with the dorsal striatum further divided into caudate and putamen. Both caudate and putamen are associated with alterations in reward processing, formation of habits, and development of negative affect states in OUD. Using single nuclei RNA- sequencing of human postmortem caudate and putamen, we identified canonical neuronal cell types in striatum (e.g.,dopamine receptor 1 or 2 expressing neurons, D1 or D2) and less abundant subpopulations, including D1/D2 hybrid neurons and multiple classes of interneurons. By comparing unaffected subjects to subjects with OUD, we found neuronal-specific differences in pathways related to neurodegeneration, interferon response, and DNA damage. DNA damage markers were also elevated in striatal neurons of rhesus macaques following chronic opioid administration. We identified sex-dependent differences in the expression of stress-induced transcripts (e.g., FKBP5) among astrocytes and oligodendrocytes from female subjects with OUD. Thus, we describe striatal cell types and leverage these data to gain insights into molecular alterations in human striatum associated with opioid addiction.

BackgroundThe genetic underpinnings of late-onset Alzheimer’s disease (LOAD) are yet to be fully elucidated. Although numerous LOAD-associated loci have been discovered, the causal variants and their target genes remain largely unknown. Since the brain is composed of heterogenous cell subtypes, it is imperative to study the brain on a cell subtype specific level to explore the biological processes underlying LOAD.MethodsHere, we present the largestparallelsingle-nucleus (sn) multi-omics study to simultaneously profile gene expression (snRNA-seq) and chromatin accessibility (snATAC-seq) to date, using nuclei from 12 normal and 12 LOAD brains. We identified cell subtype clusters based on gene expression and chromatin accessibility profiles and characterized cell subtype-specific LOAD-associated differentially expressed genes (DEGs), differentially accessible peaks (DAPs) andcisco-accessibility networks (CCANs).ResultsIntegrative analysis defined disease-relevant CCANs in multiple cell subtypes and discovered LOAD-associated cell subtype specific candidatecisregulatory elements (cCREs), their candidate target genes, andtrans-interacting transcription factors (TFs), some of which were LOAD-DEG, for example,ELK1in excitatory neurons (Exc1) andKLF13andJUN, found in multiple cell subtypes. Finally, we focused on a subset of cell subtype-specific CCANs that overlap known LOAD-GWAS regions and catalogued putative functional SNPs changing the affinities of TF motifs within LOAD-cCREs linked to LOAD-DEGs including,APOEandMYO1Ein a specific subtype of microglia andBIN1in a subpopulation of oligodendrocytes.ConclusionsTo our knowledge, this study represents the most comprehensive systematic interrogation to date of regulatory networks and the impact of genetic variants on gene dysregulation in LOAD at a cell subtype resolution. Our findings revealed crosstalk between epigenetic, genomic, and transcriptomic determinates of LOAD pathogenesis and define catalogues of candidate genes, cCREs, and variants involved in LOAD genetic etiology and the cell subtypes in which they act to exert their pathogenic effects. Overall, these results suggest that cell subtype-specificcis-transinteractions between regulatory elements and TFs, and the genes dysregulated by these networks contribute to the development of LOAD.

Objectives. To assess SARS-CoV-2 transmission within a correctional facility and recommend mitigation strategies. Methods. From April 29 to May 15, 2020, we established the point prevalence of COVID-19 among incarcerated persons and staff within a correctional facility in Arkansas. Participants provided respiratory specimens for SARS-CoV-2 testing and completed questionnaires on symptoms and factors associated with transmission. Results. Of 1647 incarcerated persons and 128 staff tested, 30.5% of incarcerated persons (range by housing unit = 0.0%–58.2%) and 2.3% of staff tested positive for SARS-CoV-2. Among those who tested positive and responded to symptom questions (431 incarcerated persons, 3 staff), 81.2% and 33.3% were asymptomatic, respectively. Most incarcerated persons (58.0%) reported wearing cloth face coverings 8 hours or less per day, and 63.3% reported close contact with someone other than their bunkmate. Conclusions. If testing remained limited to symptomatic individuals, fewer cases would have been detected or detection would have been delayed, allowing transmission to continue. Rapid implementation of mass testing and strict enforcement of infection prevention and control measures may be needed to mitigate spread of SARS-CoV-2 in this setting.

Interference, the dependency of an individual's potential outcome on the exposure of other individuals, is a common occurrence in medicine and public health. Recently, targeted maximum likelihood estimation (TMLE) has been extended to settings of interference, including in the context of estimation of the mean of an outcome under a specified distribution of exposure, referred to as a policy. This paper summarizes how TMLE for independent data is extended to general interference (network-TMLE). An extensive simulation study is presented of network-TMLE, consisting of four data generating mechanisms (unit-treatment effect only, spillover effects only, unit-treatment and spillover effects, infection transmission) in networks of varying structures. Simulations show that network-TMLE performs well across scenarios with interference, but issues manifest when policies are not well-supported by the observed data, potentially leading to poor confidence interval coverage. Guidance for practical application, freely available software, and areas of future work are provided.

The optimal enoxaparin dosing strategy to achieve venous thromboembolism (VTE) prophylaxis in trauma patients remains unclear. Current dosing guidelines often include weight, age, and renal function but still fail to achieve appropriate prophylactic anti-Xa levels in many patients. We hypothesized that additional patient factors influence anti-Xa response to enoxaparin in trauma patients.This is a retrospective review of patients admitted to a Level 1 trauma center for ≥4 days from July 2015 to September 2020, who received enoxaparin VTE prophylaxis per protocol (50-59 kg, 30 mg/dose; 60-99 kg, 40 mg/dose; ≥100 kg, 50 mg/dose; all doses every 12 hours) and had an appropriately timed peak anti-Xa level. Multivariate regression was performed to identify independent predictors of prophylactic anti-Xa levels (0.2-0.4 IU/mL) upon first measurement.The cohort (N = 1,435) was 76.4% male, with a mean ± SD age of 49.9 ± 20.0 years and a mean ± SD weight of 82.5 ± 20.2 kg (males, 85.2 kg; females, 73.7 kg; p0.001). Overall, 68.6% of patients (n = 984) had a prophylactic anti-Xa level on first assessment (69.6% of males, 65.1% of females). Males were more likely to have a subprophylactic level than females (22.1% vs. 8.0%, p0.001), whereas females were more likely to have supraprophylactic levels than males (26.9% vs. 8.3%, p0.001). When controlling for creatinine clearance, anti-Xa level was independently associated with dose-to-weight ratio (odds ratio, 0.191 for 0.5 mg/kg; p0.001; confidence interval, 0.151-0.230) and female sex (odds ratio, 0.060; p0.001; confidence interval, 0.047-0.072). Weight and age were not significant when controlling for the other factors.Male patients have a decreased anti-Xa response to enoxaparin when compared with female patients, leading to a greater incidence of subprophylactic anti-Xa levels in male patients at all dose-to-weight ratios. To improve the accuracy of VTE chemoprophylaxis, sex should be considered as a variable in enoxaparin dosing models.Therapeutic/Care Management; Level III.