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Background: Postural tachycardia syndrome (POTS) is characterized by excessive orthostatic tachycardia and significant functional disability. We have previously found that patients with POTS have increases in plasma angiotensin II (Ang II) that are twice as high as healthy subjects despite normal blood pressures (BPs). In this study, we assess systemic and renal hemodynamic and functional responses to Ang II infusion in patients with POTS compared with healthy controls.Methods and Results: Following a 3-day sodium-controlled diet, we infused Ang II (3 ng/kg per minute) for 1 hour in patients with POTS (n=15) and healthy controls (n=13) in the supine position. All study subjects were women with normal BP. Ages were similar for patients with POTS and controls (mean±SEM, 30±2 versus 26±1 years; P=0.11). We measured the changes from baseline mean arterial pressure, renal plasma flow, plasma renin activity, aldosterone, urine sodium, and baroreflex sensitivity in both groups. In response to Ang II infusion, patients with POTS had a blunted increase compared with controls in mean arterial pressure (10±1 versus 14±1 mm Hg, P=0.01) and diastolic BP (9±1 versus 13±1 mm Hg, P=0.01) but not systolic BP (13±2 versus 15±2 mm Hg, P=0.40). Renal plasma flow decreased similarly with Ang II infusion in patients with POTS versus controls (-166±20 versus -181±17 mL/min per 1.73 kg/m(2), P=0.58). Postinfusion, the decrease in plasma renin activity (-0.9±0.2 versus -0.6±0.2 ng/mL per hour, P=0.43) and the increase in aldosterone (17±1 versus 15±2 pg/mL, P=0.34) were similar in both groups. The decrease in urine sodium excretion was similar in patients with POTS and controls (-49±12 versus -60±16 mEq/g creatinine, P=0.55). The spontaneous baroreflex sensitivity at baseline was significantly lower in patients with POTS compared with controls (10.1±1.2 versus 16.8±1.5 ms/mm Hg, P=0.003), and it was further reduced with Ang II infusion.Conclusions: Patients with POTS have blunted vasopressor response to Ang II and impaired baroreflex function. This impaired vasoconstrictive response might be exaggerated with upright posture and may contribute to the subsequent orthostatic tachycardia that is the hallmark of this disorder. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00962949. [ABSTRACT FROM AUTHOR]

A multi-institutional collaboration was forged to implement a study of the relationship between Vitamin D and breast density among medically underserved women. This effort resulted in techniques to measure vitamin D levels, breast density, and sunlight exposure. Outcomes from this collaboration may provide insight to researchers conducting similar investigations. [ABSTRACT FROM AUTHOR]

Background: The mechanisms underlying interindividual variability in pain perception and cognitive responses are undefined but highly heritable. alpha(2C)- and alpha(2A)-adrenergic receptors regulate noradrenergic activity and are important mediators of pain perception and analgesia. We hypothesized that common genetic variants in these genes, particularly the ADRA2C 322-325 deletion variant, affect pain perception or cognitive responses.Methods: We studied 73 healthy subjects (37 Caucasians and 36 African-Americans) aged 25.4+/-4.6years. Pain response to a cold pressor test was measured using a 10cm visual analog scale and again on the next day, after three infusions of the selective alpha(2)-agonist dexmedetomidine. Standardized cognitive tests were administered at baseline and after each infusion. The contribution of ADRA2C deletion genotype, dexmedetomidine concentration, and other covariates to pain perception and cognitive responses was determined using multiple linear regression models. Secondary analysis examined the effects of ADRA2A and other ADRA2C variants on pain perception.Results: ADRA2C Del homozygotes had higher pain scores in response to cold at baseline (6.3+/-1.8cm) and after dexmedetomidine (5.6+/-2.2cm) than insertion allele carriers (4.6+/-2.1cm [baseline] and 3.8+/-1.9cm [after dexmedetomidine]; adjusted P-values=0.019 and 0.004, respectively). Cognitive responses were unrelated to ADRA2C Ins/Del genotype. None of the other ADRA2A and ADRA2C variants was significantly related to cold pain sensitivity before dexmedetomidine; after dexmedetomidine, ADRA2A rs1800038 was marginally associated (P=0.03).Conclusion: The common ADRA2C del322-325 variant affected pain perception before and after dexmedetomidine but did not affect other cognitive responses, suggesting that it contributes to interindividual variability in pain perception. [ABSTRACT FROM AUTHOR]

Rationale: Bronchiolitis during infancy is associated with an increased risk of childhood asthma. Whether winter viral infections cause asthma or are a manifestation of a predisposition to asthma development is unknown.Objectives: To study the relationship of winter virus infection during infancy and the development of childhood asthma.Methods: We studied over 95,000 infants born between 1995 and 2000 and followed through 2005 who were enrolled in the Tennessee Medicaid program from birth through early childhood to determine whether infant birth in relationship to the winter virus peak alters the risk of developing early childhood asthma.Measurements and Main Results: Among 95,310 children studied during five winter virus seasons from birth through early childhood, the risk of developing asthma tracked with the timing of infant birth in relationship to the winter virus peak. Infant birth approximately 4 months before the winter virus peak carried the highest risk, with a 29% increase in odds of developing asthma compared with birth 12 months before the peak (adjusted odds ratio, 1.29; 95% confidence interval, 1.19-1.40). Infant age at the winter virus peak was comparable to or greater than other known risk factors for asthma.Conclusions: Timing of birth in relationship to winter virus season confers a differential and definable risk of developing early childhood asthma, establishing winter virus seasonality as a causal factor in asthma development. Delay of exposure or prevention of winter viral infection during early infancy could prevent asthma. [ABSTRACT FROM AUTHOR]

During the 2004-2005 influenza season two independent influenza surveillance systems operated simultaneously in three United States counties. The New Vaccine Surveillance Network (NVSN) prospectively enrolled children hospitalized for respiratory symptoms/fever and tested them using culture and RT-PCR. The Emerging Infections Program (EIP) and a similar clinical-laboratory surveillance system identified hospitalized children who had positive influenza tests obtained as part of their usual medical care. Using data from these systems, we applied capture-recapture analyses to estimate the burden of influenza related-hospitalizations in children aged<5 years. During the 2004-2005 influenza season the influenza-related hospitalization rate estimated by capture-recapture analysis was 8.6/10,000 children aged<5 years. When compared to this estimate, the sensitivity of the prospective surveillance system was 69% and the sensitivity of the clinical-laboratory based system was 39%. In the face of limited resources and an increasing need for influenza surveillance, capture-recapture analysis provides better estimates than either system alone. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Several studies have explored posttreatment voice outcomes for early glottic cancer with varying results. To further clarify the voice-related quality of life (QOL) of T1 glottic cancer patients treated by external beam radiotherapy (EBRT) compared to endoscopic carbon dioxide laser excision (CLE), we performed a meta-analysis. METHODS: We performed a meta-analysis review for the years 1966 to 2005 for the Voice Handicap Index (VHI), laryngeal cancer, voice outcome, voice quality, and quality of life. Studies in which the VHI was assessed at least 3 months after treatment for T1 glottic cancer were identified and analyzed by meta-analysis techniques. RESULTS: Six studies with 208 patients (6 T1b and 202 T1a) treated with CLE and 91 patients (6 T1b and 85 T1a) treated with EBRT were identified. The posttreatment VHI scores were similar for the EBRT- and CLE-treated patients (p = .1, Wilcoxon rank sum test). CONCLUSIONS: We conclude that CLE and EBRT provide comparable levels of voice handicap for patients with T1 glottic cancer. [ABSTRACT FROM AUTHOR]

Objective: Authors evaluated whether displaying context sensitive links to infrequently accessed educational materials and patient information via the user interface of an inpatient computerized care provider order entry (CPOE) system would affect access rates to the materials.Design: The CPOE of Vanderbilt University Hospital (VUH) included "baseline" clinical decision support advice for safety and quality. Authors augmented this with seven new primarily educational decision support features. A prospective, randomized, controlled trial compared clinicians' utilization rates for the new materials via two interfaces. Control subjects could access study-related decision support from a menu in the standard CPOE interface. Intervention subjects received active notification when study-related decision support was available through context sensitive, visibly highlighted, selectable hyperlinks.Measurements: Rates of opportunities to access and utilization of study-related decision support materials from April 1999 through March 2000 on seven VUH Internal Medicine wards.Results: During 4,466 intervention subject-days, there were 240,504 (53.9/subject-day) opportunities for study-related decision support, while during 3,397 control subject-days, there were 178,235 (52.5/subject-day) opportunities for such decision support, respectively (p = 0.11). Individual intervention subjects accessed the decision support features at least once on 3.8% of subject-days logged on (278 responses); controls accessed it at least once on 0.6% of subject-days (18 responses), with a response rate ratio adjusted for decision support frequency of 9.17 (95% confidence interval 4.6-18, p < 0.0005). On average, intervention subjects accessed study-related decision support materials once every 16 days individually and once every 1.26 days in aggregate.Conclusion: Highlighting availability of context-sensitive educational materials and patient information through visible hyperlinks significantly increased utilization rates for study-related decision support when compared to "standard" VUH CPOE methods, although absolute response rates were low. [ABSTRACT FROM AUTHOR]

Background: Laboratory testing of hospitalized patients, although essential, can be expensive and sometimes excessive. Attempts to reduce unnecessary testing have often been difficult to implement or sustain.Objective: Use of peer management through a resource utilization committee (RUC) to favorably modify test-ordering behavior in a large academic medical center.Design: Interrupted time-series study.Setting: Medical center with inpatient care provider order entry (CPOE) system and database of ordered tests.Participants: Predominantly housestaff physicians but all clinical staff (attending physicians, housestaff, medical students, nurses, advance practice nurses, and other clinical staff) at Vanderbilt University Hospital who used CPOE systems.Intervention: The RUC analyzed the ordering habits of providers during previous years and made 2 interventions by modifying software for the CPOE system. The committee first initiated a daily prompt in the system that asked providers whether they wanted to discontinue tests scheduled beyond 72 hours. After evaluating this first intervention, the committee further constrained testing options by unbundling serum metabolic panel tests (sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen, and creatinine tests) into single components and by reducing the ease of repeating targeted tests (including electrolyte, blood urea nitrogen, creatinine, and glucose tests; electrocardiography; and portable chest radiography).Measurements: Pre- and postintervention volumes of tests; proportion of patients with abnormal targeted chemistry levels after 48 hours; rates of repeated admission, transfer to intensive care units, and mortality; adjusted coefficient of variation for test ordering; and length of stay.Results: Voluntary reduction of testing beyond 72 hours (first intervention) decreased orders for metabolic panel component tests by 24% (P = 0.02) and electrocardiograms by 57% (P = 0.006) but not orders for portable chest radiographs. Prospective constraints on recurrent test ordering with panel unbundling (second intervention) produced an additional decrease of 51% for metabolic panel component tests (P < 0.001) and 16% for portable chest radiographs (P = 0.03). Incidence of patients with abnormal targeted blood chemistry levels after 48 hours decreased after the intervention (P = 0.02). Postintervention-adjusted coefficients of variation decreased for metabolic panel component tests (P = 0.03) and electrocardiography (P = 0.04). Rates of (adjusted) monthly readmission, transfers to intensive care units, hospital length of stay, and mortality were unchanged.Limitations: Other activities occurring during the time period of the interventions might have influenced some test-ordering behaviors, and we assessed effects on only a limited number of commonly ordered tests.Conclusions: Peer management reduced provider variability by addressing the imperfect ability of clinicians to rescind testing in a timely manner. Hospitals with growing health care costs can improve their resource utilization through peer management of testing behaviors by using CPOE systems. [ABSTRACT FROM AUTHOR]

Background: In breast cancer patients, about two thirds of the tumors are estrogen receptor (ER)-positive and one third are ER-negative. The molecular mechanisms leading to the ER-negative phenotype are poorly understood. Nearly all ER-negative and about 40% of ER-positive cancers are resistant to endocrine therapy.Purpose: In this study, we examined the entire coding region of the ER gene in ER-positive and ER-negative primary breast tumors to determine whether deletions/insertions or point mutations might account for the ER-negative phenotype.Methods: We amplified exons 1 through 8 of the ER gene in 118 ER-positive and 70 ER-negative primary breast tumors and searched for mutations by single-strand conformation polymorphism analysis, denaturing gradient gel electrophoresis, and DNA sequencing.Results: Both ER-negative and ER-positive tumors contained neutral polymorphisms in codons 10 [TCT-->TCC (Ser)], 87 [GCG-->GCC (Ala)], 243 [CGC-->CGT (Arg)], 325 [CCC-->CCG (Pro)], and 594 [ACA-->ACG (Thr)]. There was no correlation of any of the polymorphic alleles with the ER phenotype or other clinicopathologic parameters including tumor type, size, grade, or stage. However, the polymorphism in codon 325 showed a strong association with a family history of breast cancer (P = .0005). This association was observed both in premenopausal and postmenopausal patients. Despite extensive searching in exons 1 through 8, we found no deletions/insertions and only two missense mutations in codons 69 [AAC (Asn)-->AAG (Lys)] and 396 [ATG (Met)-->GTG (Val)] of the same ER-negative tumor. Thus, only 1% of the primary breast cancers had point mutations in the ER gene.Conclusions: In the majority of primary breast cancers, the ER-negative phenotype is not the result of mutations in the coding region of the ER gene, but is due to deficient ER expression at the transcriptional or post-transcriptional level.Implications: The correlation reported previously, as well as our current findings, suggest that further investigations are warranted to understand the possible linkage of the ER gene locus to hereditary breast cancer. [ABSTRACT FROM AUTHOR]

The Human Epidemiology and Response to SARS-CoV-2 (HEROS) Study is a prospective, multicity, 6-month incidence study conducted from May 2020 to February 2021. The objectives were to identify risk factors for SARS-CoV-2 infection and household transmission among children and people with asthma and allergic diseases, and to use the host nasal transcriptome sampled longitudinally to understand infection risk and sequelae at the molecular level. To overcome challenges of clinical study implementation due to the coronavirus pandemic, this surveillance study used direct-to-participant methods to remotely enroll and prospectively follow eligible children who are participants in other National Institutes of Health-funded pediatric research studies and their household members. Households participated in weekly surveys and biweekly nasal sampling regardless of symptoms. The aim of this report is to widely share the methods and study instruments and to describe the rationale, design, execution, logistics, and characteristics of a large, observational, household-based, remote cohort study of SARS-CoV-2 infection and transmission in households with children. The study enrolled a total of 5598 individuals, including 1913 principal participants (children), 1913 primary caregivers, 729 secondary caregivers, and 1043 other household children. This study was successfully implemented without necessitating any in-person research visits and provides an approach for rapid execution of clinical research. Trial registration: ClinicalTrials.gov. Identifier: NCT04375761., (Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2024.)

Background: The contribution of prenatal anthropometric measures to the development of specific childhood asthma phenotypes is not known., Objective: We aimed to evaluate associations between prepregnancy body mass index (BMI) and gestational weight gain (GWG) with allergic and nonallergic asthma phenotypes in childhood., Methods: Our study population included term, healthy infants in the middle Tennessee region of the United States. Prepregnancy BMI and GWG were ascertained from questionnaires administered during early infancy and categorized based on World Health Organization and Institute of Medicine recommendations, respectively. Allergic asthma was defined as 5-year current asthma and a positive skin test or specific IgE to aeroallergen(s). We used multivariable logistic regression models for asthma and multinomial logistic regression models for nonasthma, allergic asthma, and nonallergic asthma., Results: A total of 1266 children were included. At the 5-year follow-up, 194 (15.3%) had asthma; among them, 102 (52.6%) had allergic asthma. Both inadequate and excessive GWG, compared with adequate GWG, were associated with increased odds of asthma (inadequate: adjusted odds ratio [aOR]: 1.76 [95% confidence interval (CI): 1.03-2.98]; excessive: aOR: 1.70 [95% CI: 1.12-2.57]) and increased odds of allergic asthma compared with no asthma (inadequate: aOR: 3.49 [95% CI: 1.66-7.32]; excessive: aOR: 2.55 [95% CI: 1.34-4.85]). Prepregnancy BMI was not associated with asthma nor with asthma phenotypes., Conclusions: Both inadequate and excessive GWG were associated with allergic asthma risk. These results support the benefits of optimal GWG during pregnancy on child health outcomes., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Despite the major use of mice in biomedical research, little information is available with regard to identifying their postmortem changes and using that information to determine the postmortem interval (PMI), defined as the time after death. Both PMI and environmental conditions influence decomposition (autolysis and putrefaction) and other postmortem changes. Severe decomposition compromises lesion interpretation and disease detection and wastes limited pathology resources. The goal of this study was to assess postmortem changes in mice in room temperature cage conditions and under refrigeration at 4 °C to develop gross criteria for the potential value of further gross and histologic evaluation. We used 108 experimentally naïve C57BL/6 mice that were humanely euthanized and then allocated them into 2 experimental groups for evaluation of postmortem change: room temperature (20 to 22 °C) or refrigeration (4 °C). PMI assessments, including gross changes and histologic scoring, were performed at hours 0, 4, 8, and 12 and on days 1 to 14. Factors such as temperature, humidity, ammonia in the cage, and weight change were also documented. Our data indicates that carcasses held at room temperature decomposed faster than refrigerated carcasses. For most tissues, decomposition was evident by 12 h at room temperature as compared with 5 d under refrigeration. At room temperature, gross changes were present by day 2 as compared with day 7 under refrigeration. Mice at room temperature lost 0.78% of their baseline body weight per day as compared with 0.06% for refrigerated mice (95% CI for difference 0.67% to 0.76%, P < 0.0005). This study supports the consideration of temperature and PMI as important factors affecting the suitability of postmortem tissues for gross and histologic evaluation and indicates that storage of carcasses under refrigeration will significantly slow autolysis.

Importance: Diltiazem, a commonly prescribed ventricular rate-control medication for patients with atrial fibrillation, inhibits apixaban and rivaroxaban elimination, possibly causing overanticoagulation., Objective: To compare serious bleeding risk for new users of apixaban or rivaroxaban with atrial fibrillation treated with diltiazem or metoprolol., Design, Setting, and Participants: This retrospective cohort study included Medicare beneficiaries aged 65 years or older with atrial fibrillation who initiated apixaban or rivaroxaban use and also began treatment with diltiazem or metoprolol between January 1, 2012, and November 29, 2020. Patients were followed up to 365 days through November 30, 2020. Data were analyzed from August 2023 to February 2024., Exposures: Diltiazem and metoprolol., Main Outcomes and Measures: The primary outcome was a composite of bleeding-related hospitalization and death with recent evidence of bleeding. Secondary outcomes were ischemic stroke or systemic embolism, major ischemic or hemorrhagic events (ischemic stroke, systemic embolism, intracranial or fatal extracranial bleeding, or death with recent evidence of bleeding), and death without recent evidence of bleeding. Hazard ratios (HRs) and rate differences (RDs) were adjusted for covariate differences with overlap weighting., Results: The study included 204 155 US Medicare beneficiaries, of whom 53 275 received diltiazem and 150 880 received metoprolol. Study patients (mean [SD] age, 76.9 [7.0] years; 52.7% female) had 90 927 person-years (PY) of follow-up (median, 120 [IQR, 59-281] days). Patients receiving diltiazem treatment had increased risk for the primary outcome (RD, 10.6 [95% CI, 7.0-14.2] per 1000 PY; HR, 1.21 [95% CI, 1.13-1.29]) and its components of bleeding-related hospitalization (RD, 8.2 [95% CI, 5.1-11.4] per 1000 PY; HR, 1.22 [95% CI, 1.13-1.31]) and death with recent evidence of bleeding (RD, 2.4 [95% CI, 0.6-4.2] per 1000 PY; HR, 1.19 [95% CI, 1.05-1.34]) compared with patients receiving metoprolol. Risk for the primary outcome with initial diltiazem doses exceeding 120 mg/d (RD, 15.1 [95% CI, 10.2-20.1] per 1000 PY; HR, 1.29 [95% CI, 1.19-1.39]) was greater than that for lower doses (RD, 6.7 [95% CI, 2.0-11.4] per 1000 PY; HR, 1.13 [95% CI, 1.04-1.24]). For doses exceeding 120 mg/d, the risk of major ischemic or hemorrhagic events was increased (HR, 1.14 [95% CI, 1.02-1.27]). Neither dose group had significant changes in the risk for ischemic stroke or systemic embolism or death without recent evidence of bleeding. When patients receiving high- and low-dose diltiazem treatment were directly compared, the HR for the primary outcome was 1.14 (95% CI, 1.02-1.26)., Conclusions and Relevance: In Medicare patients with atrial fibrillation receiving apixaban or rivaroxaban, diltiazem was associated with greater risk of serious bleeding than metoprolol, particularly for diltiazem doses exceeding 120 mg/d.

Importance: The incidence of gastroschisis, a birth defect involving the herniation of the small bowel through the abdominal wall, has increased in the US since the 1960s. The pesticide atrazine is a hypothesized cause of gastroschisis; however, examination of the association between atrazine and gastroschisis has been limited., Objective: To evaluate national trends in gastroschisis incidence, maternal and infant characteristics associated with gastroschisis, and whether county-level atrazine use is associated with gastroschisis., Design, Setting, and Participants: This retrospective, repeated cross-sectional study examined birth certificate data of all live births in the US and data on atrazine use from the US Geological Survey from January 1, 2009, through December 31, 2019. The data analysis was performed between August 5, 2021, and May 26, 2023., Exposures: County-level atrazine use., Main Outcomes and Measures: The primary outcome was gastroschisis incidence. Covariates included maternal age, race and ethnicity, body mass index (measured by weight in kilograms divided by height in meters squared), parity, insurance type, Chlamydia infection during pregnancy, smoking, and rurality. Mixed-effects logistic regression models (year fixed effects and county random effects) were constructed using different county-level atrazine exposure variables (1-, 5-, and 10-year means)., Results: Between 2009 and 2019, 39 282 566 live births were identified, with 10 527 infant diagnoses of gastroschisis. Infants with gastroschisis were more likely to have mothers who identified as non-Hispanic White (61% vs 54%; P < .001), had a lower body mass index (median [IQR], 23.4 [20.8-27.2] vs 25.4 [22.0-30.8]; P < .001), were more likely to be nulliparous (median [IQR], 0 [0-1] vs 1 [0-2]; P < .001), and were more commonly covered by Medicaid (63% vs 43%; P < .001). During the study period, the rate (per 1000 live births) of gastroschisis decreased from 0.31 (95% CI, 0.29-0.33) to 0.22 (95% CI, 0.21-0.24). The median (IQR) county-level atrazine use estimates were higher among infants with gastroschisis (1 year, 1389 [IQR, 198-10 162] vs 1023 [IQR, 167-6960] kg; 5 years, 1425 [IQR, 273-9895] vs 1057 [IQR, 199-6926] kg; 10 years, 1508 [IQR, 286-10 271] vs 1113 [IQR, 200-6650] kg; P < .001). In adjusted models, higher county levels of atrazine (each 100 000-kg increase) were associated with a higher incidence of gastroschisis (1 year: adjusted odds ratio [AOR], 1.12 [95% CI, 1.01-1.24]; 5 years: AOR, 1.15 [95% CI, 1.02-1.30]; 10 years: AOR, 1.21 [95% CI, 1.07-1.38])., Conclusions and Relevance: In this cross-sectional study, higher county levels of atrazine were associated with infant diagnoses of gastroschisis. While atrazine is the second-most used herbicide in the US, numerous countries around the world have banned it out of concern for adverse effects on human health. These findings suggest that exploring alternatives to atrazine in the US may be warranted.

Objective: Underrepresentation of women on editorial boards of biomedical journals has occurred for decades. The JAMA Network Journals have substantial and broad impact on advances in the biomedical sciences. We sought to determine the current status of gender representation on editorial boards of the 12 JAMA Network Journals. Methods: The gender of each editorial board member of the 12 JAMA Network Journals was classified based on review of online sources. The percentage of women on each board ( i.e. , number of women relative to total members) was calculated and compared to gender equity and parity benchmarks. The gender equity benchmark for each journal was defined as the percentage of women physicians in the medical specialty reflecting the journal's content based on Association of American Medical Colleges data. The gender parity benchmark for all journals was defined as 50% women. Results: There was considerable variation in the representation of women on the editorial boards of the JAMA Network Journals relative to gender equity and parity benchmarks. Women were underrepresented on 50% (6 of 12) of boards relative to gender equity and 67% (8 of 12) of boards relative to gender parity. Conclusions: Women were found to be underrepresented on 50% or more of the editorial boards of the JAMA Network Journals. This finding reflects gender inequities in academic publishing and the broader biomedical enterprise, which limits advances in the biomedical sciences and health care. Those JAMA Network Journals that continue to underrepresent women on their editorial boards are urged to remediate this longstanding issue.

Background: An over 40% increase in overdose deaths within the past 2 years and low levels of engagement in treatment call for a better understanding of factors that influence access to medication for opioid use disorder (OUD)., Objective: To examine whether county-level characteristics influence a caller's ability to secure an appointment with an OUD treatment practitioner, either a buprenorphine-waivered prescriber or an opioid treatment program (OTP)., Research Design and Subjects: We leveraged data from a randomized field experiment comprised of simulated pregnant and nonpregnant women of reproductive age seeking treatment for OUD among 10 states in the US. We employed a mixed-effects logistic regression model with random intercepts for counties to examine the relationship between appointments received and salient county-level factors related to OUD., Measures: Our primary outcome was the caller's ability to secure an appointment with an OUD treatment practitioner. County-level predictor variables included socioeconomic disadvantage rankings, rurality, and OUD treatment/practitioner density., Results: Our sample comprised 3956 reproductive-aged callers; 86% reached a buprenorphine-waivered prescriber and 14% an OTP. We found that 1 additional OTP per 100,000 population was associated with an increase (OR=1.36, 95% CI: 1.08 to 1.71) in the likelihood that a nonpregnant caller receives an OUD treatment appointment from any practitioner., Conclusions: When OTPs are highly concentrated within a county, women of reproductive age with OUD have an easier time securing an appointment with any practitioner. This finding may suggest greater practitioners' comfort in prescribing when there are robust OUD specialty safety nets in the county., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Gabapentin is prescribed for pain and is perceived as safe generally. However, gabapentin can cause respiratory depression, exacerbated by concomitant central nervous system depressants (e.g., opioids), a concern for vulnerable populations. We compared mortality rates among new users of either gabapentin or duloxetine with or without concurrent opioids in the 20% Medicare sample. We conducted a new-user design retrospective cohort study, in Medicare enrollees ages 65-89 years with noncancer chronic pain and no severe illness who filled prescriptions between 2015 and 2018 for gabapentin (n = 233,060) or duloxetine (n = 34,009). Daily opioid doses, estimated in morphine milligram equivalents (MMEs), were classified into none, low (0 < MME < 50), and high (≥ 50 MME), based on Centers for Disease Control and Prevention (CDC) recommendations. The outcomes were all-cause mortality (primary) and out-of-hospital mortality (secondary). We used inverse probability of treatment weighting to adjust for differences between gabapentin and duloxetine users. During 116,707 person-years of follow-up, 1,379 patients died. All-cause mortality rate in gabapentin users was 12.16 per 1,000 person-years vs. 9.94 per 1,000 in duloxetine users. Risks were similar for users with no concurrent opioids (adjusted hazard ratio (aHR) = 1.03, 95% confidence interval (CI): 0.80-1.31) or low-dose daily opioids (aHR = 1.06, 95% CI: 0.63-1.76). However, gabapentin users receiving concurrent high-dose daily opioids had an increased rate of all-cause mortality compared with duloxetine users on high-dose opioids (aHR = 2.03, 95% CI: 1.19-3.46). Out-of-hospital mortality yielded similar results. In this retrospective cohort study of Medicare beneficiaries, concurrent use of high-dose opioids and gabapentin was associated with a higher all-cause mortality risk than that for concurrent use of high-dose opioids and duloxetine., (© 2023 The Authors. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics.)

Introduction: Simulation-based studies indicate that crisis checklist use improves management of patients with critical conditions in the emergency department (ED). An interview-based study suggests that use of an emergency manual (EM)-a collection of crisis checklists-improves management of clinical perioperative crises. There is a need for in-depth prospective studies of EM use during clinical practice, evaluating when and how EMs are used and impact on patient management., Methods and Analysis: This 6-month long study prospectively evaluates a digital EM during management of priority 1 patients in the Skåne University Hospital at Lund's ED. Resuscitation teams are encouraged to use the EM after a management plan has been derived ('Do-Confirm'). The documenting nurse activates and reads from the EM, and checklists are displayed on a large screen visible to all team members. Whether the EM is activated, and which sections are displayed, are automatically recorded. Interventions performed thanks to Do-Confirm EM use are registered by the nurse. Fifty cases featuring such interventions are reviewed by specialists in emergency medicine blinded to whether the interventions were performed prior to or after EM use. All interventions are graded as indicated, of neutral relevance or not indicated. The primary outcome measures are the proportions of interventions performed thanks to Do-Confirm EM use graded as indicated, of neutral relevance, and not indicated. A secondary outcome measure is the team's subjective evaluation of the EM's value on a Likert scale of 1-6. Team members can report events related to EM use, and information from these events is extracted through structured interviews., Ethics and Dissemination: The study is approved by the Swedish Ethical Review Authority (Dnr 2022-01896-01). Results will be published in a peer-reviewed journal and abstracts submitted to national and international conferences to disseminate our findings., Trial Registration Number: NCT05649891., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Bacterial biofilms are critical to pathogenesis and infection. They are associated with rising rates of antimicrobial resistance. Biofilms are correlated with worse clinical outcomes, making them important to infectious diseases research. There is a gap in knowledge surrounding biofilm kinetics and dynamics which makes biofilm research difficult to translate from bench to bedside. To address this gap, this work employs a well-characterized crystal violet biomass accrual and planktonic cell density assay across a clinically relevant time course and expands statistical analysis to include kinetic information in a protocol termed the TMBL (Temporal Mapping of the Biofilm Lifecycle) assay. TMBL's statistical framework quantitatively compares biofilm communities across time, species, and media conditions in a 96-well format. Measurements from TMBL can reliably be condensed into response features that inform the time-dependent behavior of adherent biomass and planktonic cell populations. Staphylococcus aureus and Pseudomonas aeruginosa biofilms were grown in conditions of metal starvation in nutrient-variable media to demonstrate the rigor and translational potential of this strategy. Significant differences in single-species biofilm formation are seen in metal-deplete conditions as compared to their controls which is consistent with the consensus literature on nutritional immunity that metal availability drives transcriptomic and metabolomic changes in numerous pathogens. Taken together, these results suggest that kinetic analysis of biofilm by TMBL represents a statistically and biologically rigorous approach to studying the biofilm lifecycle as a time-dependent process. In addition to current methods to study the impact of microbe and environmental factors on the biofilm lifecycle, this kinetic assay can inform biological discovery in biofilm formation and maintenance., 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 © 2023 Elsevier B.V. All rights reserved.)

Background: Many patients with postural orthostatic tachycardia syndrome (POTS) are hypovolemic with plasma volume deficits of 10-30 %. Some also have low levels of aldosterone and diminished aldosterone-renin ratios despite elevations in angiotensin II, pointing to potential adrenal dysfunction. To assess adrenal gland responsiveness in POTS, we measured circulating levels of aldosterone and cortisol following adrenocorticotropin hormone (ACTH) stimulation., Methods: While on a low Na + diet (∼10 mEq/day), 8 female patients with POTS and 5 female healthy controls (HC) received a low dose (1 μg) ACTH bolus following a baseline blood sample. After 60 min, a high dose (249 μg) infusion of ACTH was administered to ensure maximal adrenal response. Venous aldosterone and cortisol levels were sampled every 30 min for 2 h., Results: Aldosterone increased in both groups in response to ACTH but was not different between POTS vs. HC at 60 min (53.5 ng/dL [37.8-61.8 ng/dL] vs. 46.1 ng/dL [36.7-84.9 ng/dL]; P = 1.000) or maximally (56.4 ng/dL [49.2-67.1 ng/dL] vs. 49.5 ng/dL [39.1-82.8 ng/dL]; P = 0.524). Cortisol increased in both groups in response to ACTH but was not different in patients with POTS vs. HC at 60 min (39.9 μg/dL [36.1-47.7 μg/dL] vs. 39.3 μg/dL [35.4-46.6 μg/dL]; P = 0.724) or maximally (39.9 μg/dL [33.9-45.4 μg/dL] vs. 42.0 μg/dL [37.6-49.7 μg/dL]; P = 0.354)., Conclusions: ACTH appropriately increased the aldosterone and cortisol levels in patients with POTS. These findings suggest that the response of the adrenal cortex to hormonal stimulation is intact in patients with POTS., Competing Interests: Declaration of competing interest CAS has served as a consultant for Lundbeck NA Ltd. and Theravance RSS. IB has served as a consultant for Lundbeck NA Ltd., Theravance RSS, Ammeal Pharmaceuticals, Regeneron, and Takeda Pharmaceutical. Patent holder of automated binder for treatment of Orthostatic Hypotension. RSS is a Cardiac Arrhythmia Network of Canada (CANet) Network Investigator. SRR is a consultant to Lundbeck LLC, Theravance Biopharma Inc., and Amneal Pharma related to neurogenic orthostatic hypotension; Consultant to Servier Affaires Medicales, Regeneron, argenx BV, and Antag Pharma related to postural orthostatic tachycardia syndrome. Honoraria from Spire Learning and Medscape for developing CME materials on neurogenic orthostatic hypotension. DMSB Chair for a Phase 2 study of an irritable bowel syndrome medication for Arena Pharmaceuticals with compensation. Past-President of the American Autonomic Society without financial compensation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: To examine whether access to treatment for women with opioid use disorder (OUD) varied by race and ethnicity, community characteristics, and pregnancy status., Methods: We conducted a secondary data analysis of a simulated patient caller study of buprenorphine-waivered prescribers and opioid-treatment programs in 10 U.S. states. We conducted multivariable analyses, accounting for potential confounders, to evaluate factors associated with likelihood of successfully securing an appointment. Descriptive statistics and significance testing examined 1) caller characteristics and call outcome by assigned race and ethnicity and clinic type (combined, opioid-treatment programs, and buprenorphine-waivered prescribers) and 2) clinic and community characteristics and call outcome by community race and ethnicity distribution (majority White vs majority Black, Hispanic, Asian, American Indian, Alaska Native, Native Hawaiian, or Pacific Islander) and clinic type. A multiple logistic regression model was fitted to assess the likelihood of obtaining an appointment by callers' race and ethnicity and pregnancy status with the exposure of interest being majority Black, Hispanic, Asian, American Indian, Alaska Native, Native Hawaiian, or Pacific Islander community distribution., Results: In total, 3,547 calls reached clinics to schedule appointments. Buprenorphine-waivered prescribers were more likely to be in communities that were more than 50% White (88.9% vs 77.3%, P<.001), and opioid-treatment programs were more likely to be in communities that were less than 50% White (11.1% vs 22.7%, P<.001). Callers were more likely to be granted appointments in majority Black, Hispanic, Asian, American Indian, Alaska Native, Native Hawaiian, or Pacific Islander communities (adjusted odds ratio [aOR] 1.06, 95% CI 1.02-1.10 per 10% Black, Hispanic, Asian, American Indian, Alaska Native, Native Hawaiian, or Pacific Islander community population) and at opioid-treatment programs (aOR 4.94, 95% CI 3.52-6.92) and if they were not pregnant (aOR 1.79, 95% CI 1.53-2.09)., Conclusion: Clinic distribution and likelihood of acceptance for treatment varied by community race and ethnicity distribution. Access to treatment for OUD remains challenging for pregnant people and in many historically marginalized U.S. communities., Competing Interests: Financial Disclosure Stephen W. Patrick reports money was paid to his institution from the Center for Medicare & Medicaid Innovation, NICHD, and NIDA. He received additional grants from The Boedecker Foundation, Agency for Healthcare Research and Quality, National Institute of Mental Health, and the Robert Wood Johnson Foundation. The other authors did not report any potential conflicts of interest., (Copyright © 2023 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: Amiodarone, the most effective antiarrhythmic drug in atrial fibrillation, inhibits apixaban and rivaroxaban elimination, thus possibly increasing anticoagulant-related risk for bleeding., Objective: For patients receiving apixaban or rivaroxaban, to compare risk for bleeding-related hospitalizations during treatment with amiodarone versus flecainide or sotalol, antiarrhythmic drugs that do not inhibit these anticoagulants' elimination., Design: Retrospective cohort study., Setting: U.S. Medicare beneficiaries aged 65 years or older., Patients: Patients with atrial fibrillation began anticoagulant use between 1 January 2012 and 30 November 2018 and subsequently initiated treatment with study antiarrhythmic drugs., Measurements: Time to event for bleeding-related hospitalizations (primary outcome) and ischemic stroke, systemic embolism, and death with or without recent (past 30 days) evidence of bleeding (secondary outcomes), adjusted with propensity score overlap weighting., Results: There were 91 590 patients (mean age, 76.3 years; 52.5% female) initiating use of study anticoagulants and antiarrhythmic drugs, 54 977 with amiodarone and 36 613 with flecainide or sotalol. Risk for bleeding-related hospitalizations increased with amiodarone use (rate difference [RD], 17.5 events [95% CI, 12.0 to 23.0 events] per 1000 person-years; hazard ratio [HR], 1.44 [CI, 1.27 to 1.63]). Incidence of ischemic stroke or systemic embolism did not increase (RD, -2.1 events [CI, -4.7 to 0.4 events] per 1000 person-years; HR, 0.80 [CI, 0.62 to 1.03]). The risk for death with recent evidence of bleeding (RD, 9.1 events [CI, 5.8 to 12.3 events] per 1000 person-years; HR, 1.66 [CI, 1.35 to 2.03]) was greater than that for other deaths (RD, 5.6 events [CI, 0.5 to 10.6 events] per 1000 person-years; HR, 1.15 [CI, 1.00 to 1.31]) (HR comparison: P  = 0.003). The increased incidence of bleeding-related hospitalizations for rivaroxaban (RD, 28.0 events [CI, 18.4 to 37.6 events] per 1000 person-years) was greater than that for apixaban (RD, 9.1 events [CI, 2.8 to 15.3 events] per 1000 person-years) ( P  = 0.001)., Limitation: Possible residual confounding., Conclusion: In this retrospective cohort study, patients aged 65 years or older with atrial fibrillation treated with amiodarone during apixaban or rivaroxaban use had greater risk for bleeding-related hospitalizations than those treated with flecainide or sotalol., Primary Funding Source: National Heart, Lung, and Blood Institute., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M22-3238.

Purpose: Long-standing clinical predictors of cancer survival have included histopathologic type, stage, and grade. We hypothesized that the principal categories of tumor somatic mutations might also portend survival. We investigated this hypothesis using the Pan-Cancer Atlas, encompassing clinical, genomic, and outcome data of 10,652 patients and 32 cancer types., Methods: We evaluated the prognostic capability of cancer type, stage, grade and the burden of each major mutation category on overall and disease-specific survival. Mutation categories included short substitution and insertion-deletion mutations (SMs), copy number alterations (CNAs), and gene fusions., Results: SM count and CNA fraction proved to be strong independent predictors of survival (joint P = 5.3e-95) that remained highly significant when adjusted for the traditional factors. Importantly, the relationship between mutation burden and survival proved to be nonlinear ( P = 9.5e-56); survival improved at both low- and high-burden extremes. In clinically predictive modeling, SM count together with CNA fraction meaningfully distinguished survival even among patients sharing a given cancer type, stage, or grade., Conclusion: Burden of somatic mutation is a key index of survival of analogous clinical utility to these traditional factors.

Background: Early-life severe respiratory syncytial virus (RSV) infection has been associated with the onset of childhood wheezing illnesses. However, the relationship between RSV infection during infancy and the development of childhood asthma is unclear. We aimed to assess the association between RSV infection during infancy and childhood asthma., Methods: INSPIRE is a large, population-based, birth cohort of healthy infants with non-low birthweight born at term between June and December, 2012, or between June and December, 2013. Infants were recruited from 11 paediatric practices across middle Tennessee, USA. We ascertained RSV infection status (no infection vs infection) in the first year of life using a combination of passive and active surveillance with viral identification through molecular and serological techniques. Children were then followed up prospectively for the primary outcome of 5-year current asthma, which we analysed in all participants who completed 5-year follow-up. Statistical models, which were done for children with available data, were adjusted for child's sex, race and ethnicity, any breastfeeding, day-care attendance during infancy, exposure to second-hand smoke in utero or during early infancy, and maternal asthma., Findings: Of 1946 eligible children who were enrolled in the study, 1741 (89%) had available data to assess RSV infection status in the first year of life. The proportion of children with RSV infection during infancy was 944 (54%; 95% CI 52-57) of 1741 children. The proportion of children with 5-year current asthma was lower among those without RSV infection during infancy (91 [16%] of 587) than those with RSV infection during infancy (139 [21%] of 670; p=0·016). Not being infected with RSV during infancy was associated with a 26% lower risk of 5-year current asthma than being infected with RSV during infancy (adjusted RR 0·74, 95% CI 0·58-0·94, p=0·014). The estimated proportion of 5-year current asthma cases that could be prevented by avoiding RSV infection during infancy was 15% (95% CI 2·2-26·8)., Interpretation: Among healthy children born at term, not being infected with RSV in the first year of life was associated with a substantially reduced risk of developing childhood asthma. Our findings show an age-dependent association between RSV infection during infancy and childhood asthma. However, to definitively establish causality, the effect of interventions that prevent, delay, or decrease the severity of the initial RSV infection on childhood asthma will need to be studied., Funding: US National Institutes of Health., Competing Interests: Declaration of interests LJA has served on RSV vaccine advisory boards for Bavarian Nordic, Novavax, Daiichi-Sankyo, ClearPath Development Company, ADVI, Pfizer, and Jansen Pharmaceuticals. Through Emory University, LJA's laboratory currently receives funding from Pfizer for RSV surveillance studies in adults, from Advaccine Biopharmacueticals Suzhou for serological studies of RSV vaccine recipients, and from Sciogen for animal studies on RSV vaccines. LJA is a co-inventor on several Centers for Disease Control and Prevention patents on the RSV G protein and its CX3C chemokine motif relative to immune therapy and vaccine development. LJA is also co-inventor on a patent filing for the use of RSV platform virus-like particles with the F protein and G protein for vaccines. TVH has served on a data safety monitoring board for Pfizer and RSV vaccine advisory boards for Sanofi-Pasteur and Pfizer. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objective: Duloxetine is a serotonin-norepinephrine reuptake inhibitor prescribed for musculoskeletal and other forms of chronic pain. Its dual pharmacologic properties have the potential to either raise or lower cardiovascular risk: adrenergic activity may increase the risk for acute myocardial infarction (AMI) and stroke, but antiplatelet activity may decrease risk. Gabapentin is another nonopioid medication used to treat pain, which is not thought to have adrenergic/antiplatelet effects. With the current emphasis on the use of nonopioid medications to treat patients with chronic pain, assessing cardiovascular risks associated with these medications among high-risk patients is important., Materials and Methods: We conducted a retrospective cohort study among a 20% sample of Medicare enrollees, aged 65 to 89, with chronic pain who were new users between 2015 and 2018 of either duloxetine (n = 34,009) or gabapentin (n = 233,060). We excluded individuals with cancer or other life-threatening conditions at study drug initiation. The primary outcome was a composite of AMI, stroke, and out-of-hospital mortality. We adjusted for comorbidity differences with time-dependent inverse probability of treatment weighting., Results: During 115,668 person-years of follow-up, 2361 patients had the composite primary outcome; the rate among new users of duloxetine was 16.7/1000 person-years compared with new users of gabapentin (21.1/1000 person-years), adjusted hazard ratio = 0.98 (95% CI: 0.83, 1.16). Results were similar for the individual components of the composite outcome as well as in analyses stratified by demographic and clinical characteristics., Discussion: In summary, cohort Medicare patients with non-cancer pain beginning treatment with duloxetine had rates of AMI, stroke, and out-of-hospital mortality comparable to those who initiated gabapentin., Competing Interests: Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland of the National Institutes of Health under award number R01AR073764. M.A.C. has started working for Vertex Pharmaceuticals. The remaining authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

We aimed first to assess associations between maternal health characteristics and newborn metabolite concentrations and second to assess associations between metabolites associated with maternal health characteristics and child body mass index (BMI). This study included 3492 infants enrolled in three birth cohorts with linked newborn screening metabolic data. Maternal health characteristics were ascertained from questionnaires, birth certificates, and medical records. Child BMI was ascertained from medical records and study visits. We used multivariate analysis of variance, followed by multivariable linear/proportional odds regression, to determine maternal health characteristic-newborn metabolite associations. Significant associations were found in discovery and replication cohorts of higher pre-pregnancy BMI with increased C0 and higher maternal age at delivery with increased C2 (C0: discovery: aβ 0.05 [95% CI 0.03, 0.07]; replication: aβ 0.04 [95% CI 0.006, 0.06]; C2: discovery: aβ 0.04 [95% CI 0.003, 0.08]; replication: aβ 0.04 [95% CI 0.02, 0.07]). Social Vulnerability Index, insurance, and residence were also associated with metabolite concentrations in a discovery cohort. Associations between metabolites associated with maternal health characteristics and child BMI were modified from 1-3 years (interaction: p < 0.05). These findings may provide insights on potential biologic pathways through which maternal health characteristics may impact fetal metabolic programming and child growth patterns.

Background: Sublingual nitroglycerin (SL NTG) is useful for treating acute decompensated heart failure, possibly by increasing splanchnic capacitance and reducing left ventricular (LV) preload. We evaluated a radionuclide method to study these effects, initially in subjects without heart failure., Methods and Results: Red blood cells were labelled by an in vitro method. Abdominal and chest images were obtained at rest, showing relative regional blood volumes. The abdomen was then re-imaged during progressive escalation of intrathoracic pressure using continuous positive airway pressure to assess baseline splanchnic capacitance (pressure-volume relationship, PVR) and compliance (slope of PVR). The procedure was repeated after 0.6 mg SL NTG, followed by chest images. Relative splanchnic blood volume increased at rest after SL NTG (P < .002), signifying an increase in splanchnic capacitance. The slope of the splanchnic PVR decreased in proportion to the baseline PVR (P = .0014), signifying increased compliance. The relative pulmonary blood volume decreased in proportion to the increase in splanchnic blood volume (P = .01)., Conclusions: A semi-quantitative radionuclide method demonstrated the effect of SL NTG for increasing splanchnic capacitance and compliance, with a proportional decrease in pulmonary blood volume. These data may be applied to quantitatively evaluate the importance of splanchnic vasodilation as a mechanism of LV preload reduction in the treatment of heart failure., Clinical Trials Registration: NCT02425566., (© 2021. American Society of Nuclear Cardiology.)

Background: Whether children and people with asthma and allergic diseases are at increased risk for severe acute respiratory syndrome virus 2 (SARS-CoV-2) infection is unknown., Objective: Our aims were to determine the incidence of SARS-CoV-2 infection in households with children and to also determine whether self-reported asthma and/or other allergic diseases are associated with infection and household transmission., Methods: For 6 months, biweekly nasal swabs and weekly surveys were conducted within 1394 households (N = 4142 participants) to identify incident SARS-CoV-2 infections from May 2020 to February 2021, which was the pandemic period largely before a vaccine and before the emergence of SARS-CoV-2 variants. Participant and household infection and household transmission probabilities were calculated by using time-to-event analyses, and factors associated with infection and transmission risk were determined by using regression analyses., Results: In all, 147 households (261 participants) tested positive for SARS-CoV-2. The household SARS-CoV-2 infection probability was 25.8%; the participant infection probability was similar for children (14.0% [95% CI = 8.0%-19.6%]), teenagers (12.1% [95% CI = 8.2%-15.9%]), and adults (14.0% [95% CI = 9.5%-18.4%]). Infections were symptomatic in 24.5% of children, 41.2% of teenagers, and 62.5% of adults. Self-reported doctor-diagnosed asthma was not a risk factor for infection (adjusted hazard ratio [aHR] = 1.04 [95% CI = 0.73-1.46]), nor was upper respiratory allergy or eczema. Self-reported doctor-diagnosed food allergy was associated with lower infection risk (aHR = 0.50 [95% CI = 0.32-0.81]); higher body mass index was associated with increased infection risk (aHR per 10-point increase = 1.09 [95% CI = 1.03-1.15]). The household secondary attack rate was 57.7%. Asthma was not associated with household transmission, but transmission was lower in households with food allergy (adjusted odds ratio = 0.43 [95% CI = 0.19-0.96]; P = .04)., Conclusion: Asthma does not increase the risk of SARS-CoV-2 infection. Food allergy is associated with lower infection risk, whereas body mass index is associated with increased infection risk. Understanding how these factors modify infection risk may offer new avenues for preventing infection., (Copyright © 2022. Published by Elsevier Inc.)

Background: Thiopurines are an important class of immunosuppressants despite their risk for hematopoietic toxicity and narrow therapeutic indices. Benign neutropenia related to an ACKR1 variant (rs2814778-CC) is common among persons of African ancestries., Objective: To test whether rs2814778-CC was associated with azathioprine discontinuation attributed to hematopoietic toxicity and lower thiopurine dosing., Design: Retrospective cohort study., Setting: Two tertiary care centers., Patients: Thiopurine users with White or Black race., Measurements: Azathioprine discontinuation attributed to hematopoietic toxicity. Secondary outcomes included weight-adjusted final dose, leukocyte count, and change in leukocyte count., Results: The rate of azathioprine discontinuation attributed to hematopoietic toxicity was 3.92 per 100 person-years among patients with the CC genotype ( n  = 101) and 1.34 per 100 person-years among those with the TT or TC genotype ( n  = 1365) (hazard ratio [HR] from competing-risk model, 2.92 [95% CI, 1.57 to 5.41]). The risk remained significant after adjustment for race (HR, 2.61 [CI, 1.01 to 6.71]). The risk associated with race alone (HR, 2.13 [CI, 1.21 to 3.75]) was abrogated by adjustment for genotype (HR, 1.13 [CI, 0.48 to 2.69]). Lower last leukocyte count and lower dosing were significant among patients with the CC genotype. Lower dosing was validated in an external cohort of 94 children of African ancestries prescribed the thiopurine 6-mercaptopurine (6-MP) for acute lymphoblastic leukemia. The CC genotype was independently associated with lower 6-MP dose intensity relative to the target daily dose of 75 mg/m 2 (median, 0.83 [IQR, 0.70 to 0.94] for the CC genotype vs. 0.94 [IQR, 0.72 to 1.13] for the TT or TC genotype; P  = 0.013)., Limitations: Unmeasured confounding; data limited to tertiary centers., Conclusion: Patients with the CC genotype had higher risk for azathioprine discontinuation attributed to hematopoietic toxicity and lower thiopurine doses. Genotype was associated with those risks, even after adjustment for race., Primary Funding Source: National Institutes of Health.

Isoflurane has been characterized as a distressing agent for rodents, causing both physiologic and behavioral effects. Using a "darkened home cage" has been recommended during CO₂ administration for rodent euthanasia; this is arguably a similar animal experience to anesthetic induction with isoflurane. Based on the premise that rodents perceive red light as darkness via the primary optic tract, we compared physiologic and behavioral markers of stress in 2 inbred strains of mice (C57BL/6J and BALB/cJ) anesthetized with isoflurane in either a red-tinted (dark) induction chamber or a traditional translucent induction chamber. Physiologic stress was assessed based on plasma levels of norepinephrine, epinephrine, and corticosterone. Stress-related behaviors (rearing, face wiping, and jumping) were recorded on video and scored from initiation of induction to loss of consciousness. No significant correlations were found between chamber type and physiologic stress hormones. As compared with the translucent chamber, stress-related behaviors were more frequent in the red-tinted chamber, including: 1) significantly higher rearing frequencies in BALB/cJ mice; 2) higher behavioral stress scores in BALB/cJ and male C57BL/6J mice; and 3) more face wiping behavior when considering all mice combined. These findings suggest that mice do not experience significant alleviation of physiologic indices of stress when anesthetized in a red-tinted induction chamber. Furthermore, isoflurane induction in the red-tinted chamber appeared to increase the expression of stress-related behaviors, particularly in BALB/cJ mice. Based on our findings and a growing body of literature on the unintended effects of red light, we do not recommend using red-tinted chambers for induction of anesthesia in mice.

As the coronavirus pandemic continues to impact families and children, understanding parental attitudes and likely acceptance of the COVID-19 vaccine is essential. We conducted a statewide survey with a representative sample of parents in Tennessee focused on COVID-19 and influenza vaccine acceptance and perspectives. Data from 1066 parents were analyzed using weighted survey methods to generalize results to the state of Tennessee. About 53% of parents reported a likelihood to vaccinate their children against COVID-19, and 45% were likely to vaccinate their child against COVID-19 and influenza. Female parents were less likely to vaccinate their children against COVID-19, but the strongest predictor of likely COVID-19 vaccine acceptance was influenza vaccine acceptance (adjusted odds ratio = 5.46; 95% confidence interval: 3.20-9.30). Parental acceptance of COVID-19 vaccines for children is closely tied to influenza vaccine acceptance. Public health approaches to maximize vaccine uptake could focus on children who have not been receiving influenza vaccines.

TPMT and NUDT15 variants explain less than 25% of azathioprine-associated myelotoxicity. There are 25 additional genes in the thiopurine pathway that could also contribute to azathioprine myelotoxicity. We hypothesized that among TPMT and NUDT15 normal metabolizers, a score combining the genetically predicted expression of other proteins in the thiopurine pathway would be associated with a higher risk for azathioprine discontinuation due to myelotoxicity. We conducted a retrospective cohort study of new users of azathioprine who were normal TPMT and NUDT15 metabolizers. In 1201 White patients receiving azathioprine for an inflammatory disease, we used relaxed Least Absolute Shrinkage and Selection Operator (LASSO) regression to select genes that built a score for discontinuing azathioprine due to myelotoxicity. The score incorporated the predicted expression of AOX1 and NME1. Patients in the highest score tertile had a higher risk of discontinuing azathioprine compared to those in the lowest tertile (hazard ratio [HR] = 2.15, 95% confidence interval [CI] = 1.11-4.19, p = 0.024). Results remained significant after adjusting for a propensity score, including sex, tertile of calendar year at initial dose, initial dose, age at baseline, indication, prior TPMT testing, and the first 10 principal components of the genetic data (HR = 2.11, 95% CI = 1.08-4.13, p = 0.030). We validated the results in a cohort (N = 517 non-White patients and those receiving azathioprine to prevent transplant rejection) that included all other patients receiving azathioprine (HR = 2.00, (95% CI = 1.09-3.65, p = 0.024). In conclusion, among patients who were TPMT and NUDT15 normal metabolizers, a score combining the predicted expression of AOX1 and NME1 was associated with an increased risk for discontinuing azathioprine due to myelotoxicity., (© 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: It is unknown whether RSV infection in infancy alters subsequent RSV immune responses., Methods: In a nested cohort of healthy, term children, peripheral blood mononuclear cells (PBMCs) were collected at ages 2-3 years to examine RSV memory T cell responses among children previously RSV infected during infancy (first year of life) compared to those RSV-uninfected during infancy. The presence vs . absence of infant RSV infection was determined through a combination of RSV molecular and serologic testing. Memory responses were measured in RSV stimulated PBMCs., Results: Compared to children not infected with RSV during the first year of life, children infected with RSV during infancy had lower memory T cell responses at ages 2-3 years to in vitro stimulation with RSV for most tested type-1 and type-17 markers for a number of memory T cell subsets., Conclusions: RSV infection in infancy has long-term effects on memory T cell responses. This is the first study to show the potential for RSV infection in infancy to have long-term effects on the immune memory irrespective of the severity of the infection. Our results suggest a possible mechanism through which infant RSV infection may result in greater risk of subsequent childhood respiratory viral morbidity, findings also relevant to vaccine development., Competing Interests: LA has served on respiratory syncytial virus (RSV) vaccine advisory boards for Bavarian Nordic, Novavax, Daiichi-Sankyo, ClearPath Vaccines Company, ADVI, and Pfizer. Through Emory University, his laboratory currently receives funding from Pfizer for surveillance studies of RSV infection in adults, from Advaccine Biopharmacueticals Suzhou Co., Ltd. For serologic studies of RSV vaccine recipients, and from Sciogen for animal studies on RSV vaccines. He is a co-inventor on several Centers for Disease Control and Prevention patents on the RSV G protein and its CX3C chemokine motif relative to immune therapy and vaccine development. He is also co-inventor on a patent filing for the use of RSV platform virus-like particles with the F and G proteins for vaccines. TH has served on RSV vaccine advisory boards for Sanofi-Pasteur and Pfizer. The remaining 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 © 2022 Chirkova, Rosas-Salazar, Gebretsadik, Jadhao, Chappell, Peebles, Dupont, Newcomb, Berdnikovs, Gergen, Hartert and Anderson.)

Azathioprine is used frequently to treat several inflammatory conditions. However, treatment is limited by adverse events-in particular, myelotoxicity. Thiopurine-S-methyltransferase (TPMT) and nudix hydrolase-15 (NUDT15) are enzymes involved in azathioprine metabolism; variants in the genes encoding these enzymes increase the risk for azathioprine myelotoxicity. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has recommended dose adjustments based on the results of TPMT and NUDT15 genotyping. However, little is known about the importance of this genetic information in routine clinical care. We hypothesized that in patients with inflammatory diseases, TPMT and NUDT15 genotype data predict the risk of discontinuing azathioprine due to myelotoxicity. This was a retrospective cohort study in 1,403 new adult azathioprine users for the management of inflammatory conditions for whom we had genetic information and clinical data. Among patients who discontinued azathioprine, we adjudicated the reason(s). Genotyping was performed using the Illumina Infinium Expanded Multi-Ethnic Genotyping Array plus custom content. We used CPIC guidelines to determine TPMT and NUDT15 metabolizer status; patients were grouped as either: (i) poor/intermediate, or (ii) normal/indeterminate metabolizers. We classified 110 patients as poor/intermediate, and 1,293 patients as normal/indeterminate metabolizers. Poor/intermediate status was associated with a higher risk for azathioprine discontinuation due to myelotoxicity compared to normal/indeterminate metabolizers (hazard ratio (HR) = 2.90, 95% confidence interval (CI): 1.58-5.31, P = 0.001). This association remained significant after adjustment for race, age at initiation, sex, primary indication, and initial daily dose of azathioprine (adjusted HR (aHR) = 2.67, 95% CI: 1.44-4.94, P = 0.002). In conclusion, TPMT and NUDT15 metabolizer status predicts discontinuation due to myelotoxicity for patients taking azathioprine for inflammatory conditions., (© 2021 The Authors. Clinical Pharmacology & Therapeutics © 2021 American Society for Clinical Pharmacology and Therapeutics.)

Importance: The comparative effectiveness of rivaroxaban and apixaban, the most frequently prescribed oral anticoagulants for ischemic stroke prevention in patients with atrial fibrillation, is uncertain., Objective: To compare major ischemic and hemorrhagic outcomes in patients with atrial fibrillation treated with rivaroxaban or apixaban., Design, Setting, and Participants: Retrospective cohort study using computerized enrollment and claims files for US Medicare beneficiaries 65 years or older. Between January 1, 2013, and November 30, 2018, a total of 581 451 patients with atrial fibrillation began rivaroxaban or apixaban treatment and were followed up for 4 years, through November 30, 2018., Exposures: Rivaroxaban (n = 227 572) and apixaban (n = 353 879), either standard or reduced dose., Main Outcomes and Measures: The primary outcome was a composite of major ischemic (stroke/systemic embolism) and hemorrhagic (intracerebral hemorrhage/other intracranial bleeding/fatal extracranial bleeding) events. Secondary outcomes were nonfatal extracranial bleeding and total mortality (fatal ischemic/hemorrhagic event or other death during follow-up). Rates, hazard ratios (HRs), and rate differences (RDs) were adjusted for baseline differences in comorbidity with inverse probability of treatment weighting., Results: Study patients (mean age, 77.0 years; 291 966 [50.2%] women; 134 393 [23.1%] receiving reduced dose) had 474 605 person-years of follow-up (median [IQR] of 174 [62-397] days). The adjusted primary outcome rate for rivaroxaban was 16.1 per 1000 person-years vs 13.4 per 1000 person-years for apixaban (RD, 2.7 [95% CI, 1.9-3.5]; HR, 1.18 [95% CI, 1.12-1.24]). The rivaroxaban group had increased risk for both major ischemic events (8.6 vs 7.6 per 1000 person-years; RD, 1.1 [95% CI, 0.5-1.7]; HR, 1.12 [95% CI, 1.04-1.20]) and hemorrhagic events (7.5 vs 5.9 per 1000 person-years; RD, 1.6 [95% CI, 1.1-2.1]; HR, 1.26 [95% CI, 1.16-1.36]), including fatal extracranial bleeding (1.4 vs 1.0 per 1000 person-years; RD, 0.4 [95% CI, 0.2-0.7]; HR, 1.41 [95% CI, 1.18-1.70]). Patients receiving rivaroxaban had increased risk of nonfatal extracranial bleeding (39.7 vs 18.5 per 1000 person-years; RD, 21.1 [95% CI, 20.0-22.3]; HR, 2.07 [95% CI, 1.99-2.15]), fatal ischemic/hemorrhagic events (4.5 vs 3.3 per 1000 person-years; RD, 1.2 [95% CI, 0.8-1.6]; HR, 1.34 [95% CI, 1.21-1.48]), and total mortality (44.2 vs 41.0 per 1000 person-years; RD, 3.1 [95% CI, 1.8-4.5]; HR, 1.06 [95% CI, 1.02-1.09]). The risk of the primary outcome was increased for rivaroxaban in both those receiving the reduced dose (27.4 vs 21.0 per 1000 person-years; RD, 6.4 [95% CI, 4.1-8.7]; HR, 1.28 [95% CI, 1.16-1.40]) and the standard dose (13.2 vs 11.4 per 1000 person-years; RD, 1.8 [95% CI, 1.0-2.6]; HR, 1.13 [95% CI, 1.06-1.21]) groups., Conclusions and Relevance: Among Medicare beneficiaries 65 years or older with atrial fibrillation, treatment with rivaroxaban compared with apixaban was associated with a significantly increased risk of major ischemic or hemorrhagic events.

Oropharyngeal squamous cell carcinoma (SCC) is increasing in incidence and, in Western countries, strongly associated with transcriptionally-active high-risk human papillomavirus (HPV). Within HPV-positive tumors, there is wide morphologic diversity with numerous histologic subtypes of SCC. There are also variable degrees of keratinization, anaplasia, stromal fibrosis, and maturing squamous differentiation. Unlike in the uterine cervix, where associations between HPV types and lineages/sublineages within types have been investigated with some clear correlations identified, little to no data exists for oropharyngeal SCC. In this study, for a large cohort of oropharyngeal SCC patients, we performed RTPCR for high-risk HPV. For the HPV positive patients, we sequenced the DNA of the entire HPV16 genome and determined lineages and sublineages, correlating HPV status, genotype, and HPV16 lineages/sublineages with SCC subtype and various histologic features. Of the 259 patients, 224 (86.5%) were high-risk HPV positive, of which 210/224 (93.8%) were HPV type 16 and 6/224 (2.7%) HPV type 33. Of the four HPV16 lineages, A was the most frequent (192/214 or 89.8%) and of the HPV16 A sublineages, A1 was the most frequent (112/210 or 53.3%). Patients with HPV negative tumors were more often keratinizing vs other types (23/35 or 65.7%) and thus more likely to have more maturing squamous differentiation and stromal desmoplasia. There was no significant correlation between HPV type (16 versus other), between HPV16 lineage (A versus others), or HPV16 A sublineages (A1 or A2 versus others) and morphologic type of SCC nor the various morphologic features of anaplasia/multinucleation, degree of keratinization, nor amount of stromal desmoplasia. In summary, in our cohort, there was no correlation between the type of HPV, the HPV 16 lineage or sublineage, and any of the histologic features or morphologic SCC subtypes., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)