A wound-induced differentiation trajectory for neurons.

Animals capable of whole-body regeneration can replace any missing cell type and regenerate fully functional new organs, including new brains, de novo. The regeneration of a new brain requires the formation of diverse neural cell types and their assembly into an organized structure with correctly wired circuits. Recent work in various regenerative animals has revealed transcriptional programs required for the differentiation of distinct neural subpopulations, however, how these transcriptional programs are initiated in response to injury remains unknown. Here, we focused on the highly regenerative acoel worm, Hofstenia miamia, to study wound-induced transcriptional regulatory events that lead to the production of neurons and subsequently a functional brain. Footprinting analysis using chromatin accessibility data on a chromosome-scale genome assembly revealed that binding sites for the Nuclear Factor Y (NFY) transcription factor complex were significantly bound during regeneration, showing a dynamic increase in binding within one hour upon amputation specifically in tail fragments, which will regenerate a new brain. Strikingly, NFY targets were highly enriched for genes with neuronal function. Single-cell transcriptome analysis combined with functional studies identified soxC+ stem cells as a putative progenitor population for multiple neural subtypes. Further, we found that wound-induced soxC expression is likely under direct transcriptional control by NFY, uncovering a mechanism for the initiation of a neural differentiation pathway by early wound-induced binding of a transcriptional regulator.

Intersectional race and gender disparities in kidney transplant access in the United States: a scoping review.

BACKGROUND: Gender and racial disparities in kidney transplant access are well established, however how gender and race interact to shape access to kidney transplant is less clear. Therefore, we examined existing literature to assess what is known about the potential interaction of gender and race and the impact on access to kidney transplantation in the US. METHODS: Following PRISMA guidelines, we conducted a scoping review and included quantitative and qualitative studies published in English between 1990 and May 31, 2023 among adult end-stage kidney disease patients in the US. All studies reported on access to specific transplant steps or perceived barriers to transplant access in gender and race subgroups, and the intersection between the two. We narratively synthesized findings across studies. RESULTS: Fourteen studies met inclusion criteria and included outcomes of referral (n = 4, 29%), evaluation (n = 2, 14%), waitlisting (n = 4, 29%), transplantation (n = 5, 36%), provider perceptions of patient transplant candidacy (n = 3, 21%), and patient preferences and requests for a living donor (n = 5, 36%). Overall, we found that White men have the greatest access at all steps of the transplant process, from referral to eventual living or deceased donor transplantation. In contrast, women from racial or ethnic minorities tend to have the lowest access to kidney transplant, in particular living donor transplant, though this was not consistent across all studies. CONCLUSIONS: Examining how racism and sexism interact to shape kidney transplant access should be investigated in future research, in order to ultimately shape policies and interventions to improve equity.

Factors associated with increased financial toxicity after the completion of radiation treatment for gynecologic cancer.

PURPOSE: We evaluated financial toxicity (FT) in patients with gynecologic cancer treated with radiation and assessed the impact of the COVID-19 pandemic on patients' financial wellbeing. METHODS: Patients completed a survey 1 month after completing radiation from August 2019-March 2020 and November 2020-June 2021. The survey included the COmprehensive Score for Financial Toxicity (COST) tool, EQ-5D to measure quality of life (QOL) and pandemic-related questions for the second survey period. High FT was COST score ≤ 23. RESULTS: Of 97 respondents (92% response rate), 49% completed the survey pre-pandemic and 51% after; the majority were white (76%) and had uterine cancer (64%). Sixty percent received external beam radiation with or without brachytherapy; 40% had only brachytherapy. High FT was associated with worse QOL (r = -0.37, P < 0.001), younger age and type of insurance (both p ≤ 0.03). Respondents with high FT were 6.0 (95% CI 1.0-35.9) times more likely to delay/avoid medical care, 13.6 (95% CI 2.9-64.3) times more likely to borrow money, and 6.9 (95% CI 1.7-27.2) times as likely to reduce spending on basic goods. The pandemic cohort had a smaller proportion of respondents with high FT than the pre-pandemic cohort (20% vs. 35%, p = 0.10) and a higher median COST score (32 (IQR 25-35) vs. 27 (IQR 19-34), p = 0.07). CONCLUSION: Privately insured, younger respondents who received radiation for gynecologic cancer were at risk for FT. High FT was associated with worse QOL and economic cost-coping strategies. We observed less FT in the pandemic cohort, though not statistically different from the pre-pandemic cohort.

Financial toxicity in pregnancy and postpartum.

INTRODUCTION: The financial burden of pregnancy in the United States can be high and is associated with worse mental health and birth outcomes. Research on the financial burden of health care, such as the development of the COmprehensive Score for Financial Toxicity (COST) tool, has been conducted primarily among patients with cancer. This study aimed to validate the COST tool and use it to measure financial toxicity and its impacts among obstetric patients. METHODS: We used survey and medical record data from obstetric patients at a large medical center in the United States. We validated the COST tool using common factor analysis. We used linear regression to identify risk factors for financial toxicity and to investigate associations between financial toxicity and patient outcomes including satisfaction, access, mental health, and birth outcomes. RESULTS: The COST tool measured two distinct constructs of financial toxicity in this sample: current financial toxicity and concern over future financial toxicity. Racial/ethnic category, insurance, neighborhood deprivation, caregiving, and employment were associated with current financial toxicity (P < 0.05 for all). Only racial/ethnic category and caregiving were associated with concern over future financial toxicity (P < 0.05 for all). Both current and future financial toxicity were associated with worse patient-provider communication, depressive symptoms, and stress (P < 0.05 for all). Financial toxicity was not associated with birth outcomes or keeping obstetric visits. CONCLUSIONS: The COST tool captures two constructs among obstetric patients, current and future financial toxicity, both of which are associated with worse mental health and patient-provider communication.

Postmenopausal Vaginal and Cervical Cancer Risk Related to In Utero Diethylstilbestrol Exposure.

OBJECTIVES: Women exposed to diethylstilbestrol (DES) in utero have an increased risk of clear cell adenocarcinoma of the lower genital tract, requiring lifelong cervical and vaginal cancer screening. We examined the incidence of DES-related cancers in postmenopausal women 50 years and older. MATERIALS AND METHODS: We conducted a retrospective chart review of patients 50 years and older exposed to DES in utero who received care at our institution. Patients were identified using billing codes and/or searching through the electronic record for the word DES. With this 2-pronged approach, we reviewed a total of 503 charts with confirmed DES exposure to identify gynecologic cancer occurrence. RESULTS: Within the 503 selected charts, 28 cases of gynecologic cancer occurrence were identified. Ten patients had cervical cancer and one patient had vaginal cancer. Only 1 woman of 503 developed a DES-related cervical or vaginal malignancy after age 50 years. No patients were diagnosed with cervical or vaginal cancer after age 65 years. CONCLUSIONS: Diethylstilbestrol-related malignancies are rare in those older than 50 years. Current cervical cancer screening guidelines recommend cessation of screening in an average risk, adequately screened patient at age 65 years, but patients exposed to DES have historically received lifelong screening. However, we found no cases of cervical or vaginal cancer related to DES after age 65 years, suggesting that screening recommendations could be changed for these patients to align with current screening guidelines.

Coronavirus Disease 2019 Messenger RNA Vaccine Immunogenicity in Immunosuppressed Individuals.

Individuals on immunosuppressive (IS) therapy have increased mortality from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and delayed viral clearance may lead to new viral variants. IS therapy reduces antibody responses following coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccination; however, a comprehensive assessment of vaccine immunogenicity is lacking. Here we show that IS therapy reduced neutralizing, binding, and nonneutralizing antibody functions in addition to CD4 and CD8 T-cell interferon-γ responses following COVID-19 mRNA vaccination compared to immunocompetent individuals. Moreover, IS therapy reduced cross-reactivity against SARS-CoV-2 variants. These data suggest that the standard COVID-19 mRNA vaccine regimens will likely not provide optimal protection in immunocompromised individuals.

Crowdsourcing to measure financial toxicity in gynecologic oncology.

OBJECTIVE: To utilize a novel crowdsourcing method to measure financial toxicity and its effects among a national cohort of gynecologic cancer patients. METHODS: Crowdsourcing methods were used to administer an online survey to women in the United States with gynecologic cancers. We used the Comprehensive Score for Financial Toxicity (COST) tool to measure financial toxicity and the EQ-5D-3L to measure quality of life (QOL). Based on prior work, we defined high financial toxicity as a COST score ≤ 23. We assessed correlation of COST scores with QOL. We used log-binomial regression to examine associations between high financial toxicity and cost-coping strategies. RESULTS: Among the final study sample of 334 respondents, 87% were white, median age at diagnosis was 55 (interquartile range 47-63), 52% had stage III or IV disease and 90% had private insurance or Medicare. Median COST score was 24 (interquartile range 15-32) and 49% of respondents reported high financial toxicity. Greater financial toxicity was correlated with worse QOL (p < 0.001). Participants reporting high financial toxicity were more likely to use cost-coping strategies, including spending less on basic goods (RR: 3.3; 95% CI: 2.1-5.1), borrowing money or applying for financial assistance (RR: 4.0; 95% CI: 2.4-6.9), and delaying or avoiding care (RR: 5.6; 95% CI: 2.6-12.1). CONCLUSIONS: Crowdsourcing is an effective tool to measure financial toxicity. Nearly half of respondents reported high financial toxicity, which was significantly associated with worse QOL, utilization of cost-coping strategies and delays or avoidance of care.

Evaluating meaningful levels of financial toxicity in gynecologic cancers.

OBJECTIVE: The Comprehensive Score for Financial Toxicity (COST) is a validated instrument measuring the economic burden experienced by patients with cancer. We evaluated the frequency of financial toxicity at different COST levels and stratified risk factors and associations with cost-coping strategies by financial toxicity severity. METHODS: We analyzed previously collected survey data of gynecologic oncology patients from two tertiary care institutions. Both surveys included the COST tool and questions assessing economic and behavioral cost-coping strategies. We adapted a proposed grading scale to define three groups: no/mild, moderate, and severe financial toxicity and used χ2, Fisher's exact test, and Wilcoxon rank sum test to compare groups. We used Poisson regression to calculate crude and adjusted risk ratios for cost-coping strategies, comparing patients with moderate or severe to no/mild financial toxicity. RESULTS: Among 308 patients, 14.9% had severe, 32.1% had moderate, and 52.9% had no/mild financial toxicity. Younger age, non-white race, lower education, unemployment, lower income, use of systemic therapy, and shorter time since diagnosis were associated with worse financial toxicity (all p<0.05). Respondents with moderate or severe financial toxicity were significantly more likely to use economic cost-coping strategies such as changing spending habits (adjusted risk ratio (aRR) 2.7, 95% CI 1.8 to 4.0 moderate; aRR 3.6, 95% CI 2.4 to 5.4 severe) and borrowing money (aRR 5.5, 95% CI 1.8 to 16.5 moderate; aRR 12.7, 95% CI 4.3 to 37.1 severe). Those with severe financial toxicity also had a significantly higher risk of behavioral cost-coping through medication non-compliance (aRR 4.6, 95% CI 1.2 to 18.1). CONCLUSIONS: Among a geographically diverse cohort of gynecologic oncology patients, nearly half reported financial toxicity (COST <26), which was associated with economic cost-coping strategies. In those 14.9% of patients reporting severe financial toxicity (COST <14) there was also an increased risk of medication non-compliance, which may lead to worse health outcomes in this group.

Training in the implementation of sex and gender research policies: an evaluation of publicly available online courses.

BACKGROUND: Recently implemented research policies requiring the inclusion of females and males have created an urgent need for effective training in how to account for sex, and in some cases gender, in biomedical studies. METHODS: Here, we evaluated three sets of publicly available online training materials on this topic: (1) Integrating Sex & Gender in Health Research from the Canadian Institutes of Health Research (CIHR); (2) Sex as a Biological Variable: A Primer from the United States National Institutes of Health (NIH); and (3) The Sex and Gender Dimension in Biomedical Research, developed as part of "Leading Innovative measures to reach gender Balance in Research Activities" (LIBRA) from the European Commission. We reviewed each course with respect to their coverage of (1) What is required by the policy; (2) Rationale for the policy; (3) Handling of the concepts "sex" and "gender;" (4) Research design and analysis; and (5) Interpreting and reporting data. RESULTS: All three courses discussed the importance of including males and females to better generalize results, discover potential sex differences, and tailor treatments to men and women. The entangled nature of sex and gender, operationalization of sex, and potential downsides of focusing on sex more than other sources of variation were minimally discussed. Notably, all three courses explicitly endorsed invalid analytical approaches that produce bias toward false positive discoveries of difference. CONCLUSIONS: Our analysis suggests a need for revised or new training materials that incorporate four major topics: precise operationalization of sex, potential risks of over-emphasis on sex as a category, recognition of gender and sex as complex and entangled, and rigorous study design and data analysis.

Recently implemented research policies requiring the inclusion of females and males have created an urgent need for effective training in how to account for sex, and in some cases gender, in biomedical studies. We evaluated three publicly available online trainings on this topic: (1) Integrating Sex & Gender in Health Research from the Canadian Institutes of Health Research; (2) Sex as a Biological Variable: A Primer from the United States National Institutes of Health; and (3) The Sex and Gender Dimension in Biomedical Research, developed as part of "Leading Innovative Measures to Reach Gender Balance in Research Activities (LIBRA)" from the European Commission. We reviewed each course with respect to their coverage of (1) What is required by the policy; (2) Rationale for the policy; (3) Handling of the concepts "sex" and "gender;" (4) Research design and analysis; and (5) Interpreting and reporting data. All three discussed the importance of including males and females to better generalize results, discover potential sex differences, and tailor treatments to men and women. The interconnectedness of sex and gender, how to operationalize sex, and potential downsides of focusing on sex more than other sources of variation were minimally discussed. Notably, all three courses explicitly endorsed invalid analytical approaches that lead to incorrect findings of differences. Our analysis suggests a need for revised or new training materials that cover four major topics: precise operationalization of sex, attention to potential risks of over-emphasizing sex, consideration of gender and sex as complex and intertwined, and rigorous study design and data analysis.

Financial Toxicity in Relation to Childbirth.

OBJECTIVE: To measure change in financial toxicity from pregnancy to the postpartum period and to identify factors associated with this change. DESIGN: Longitudinal survey. SETTING: Obstetric clinics at an academic medical center in Massachusetts between May 2020 and May 2022. PARTICIPANTS: Obstetric patients who were 18 years of age or older (N = 242). METHODS: Respondents completed surveys that included the COmprehensive Score for financial Toxicity tool during pregnancy and in the postpartum period. We collected additional medical record data, including gestational age, birth weight, and cesarean birth. We used paired t tests to assess changes in financial toxicity before and after childbirth and one-way analysis of variance to compare average change in financial toxicity by demographic and medical variables. RESULTS: The mean current financial toxicity score was significantly lower after childbirth (M = 19.0, SD = 4.6) than during pregnancy (M = 21.8, SD = 5.4), t(241) = 13.31, p < .001. Concern for future financial toxicity was not significantly different after childbirth (M = 8.5, SD = 2.9) compared to during pregnancy (M = 8.2, SD = 3.0), t(241) = -1.80, p = .07. Individual-level sociodemographic variables (e.g., racial/ethnic category, insurance, employment) and medical factors (e.g., cesarean birth, preterm birth) were not associated with change in financial toxicity. CONCLUSION: Among respondents, financial toxicity worsened after childbirth, and patients are at risk regardless of their individual socioeconomic and medical conditions.

Sex/Gender Disparities in Preemptive Referrals for Kidney Transplantation.

Introduction: Sex/gender inequities persist in access to kidney transplantation. Whether differences in preemptive referral (i.e., referral before dialysis start) explain this inequity remains unknown. Methods: All adults (aged 18-79 years; N = 44,204) initiating kidney replacement therapy (KRT; dialysis or transplant) in Georgia (GA), North Carolina (NC), or South Carolina (SC) between 2015 and 2019 were identified from the United States Renal Data System (USRDS). Individuals were linked to the Early Steps to Kidney Transplant Access Registry (E-STAR) to obtain data on preemptive referral and followed-up with through November 13, 2020, for outcomes of waitlisting and living donor transplant. Logistic regression assessed the association between sex/gender and likelihood of preemptive referral among all KRT patients. Cox-proportional hazards assessed the association between sex/gender and waitlisting or living donor among preemptively referred patients. Results: Overall, men and women were similarly likely to be preemptively referred (odds ratio [OR]: 0.99 [0.95-1.04]). Preemptively referred women (vs. men) were, on average, younger and with fewer comorbidities. There were no sex/gender differences in waitlisting once patients were preemptively referred (hazard ratio [HR]: 0.97 [0.91-1.03]); however, women (vs. men) who were preemptively referred remained 25% (HR: 0.75 [0.66-0.86]) less likely to receive a living donor transplant. Conclusion: In the Southeast US, men and women initiating KRT are similarly likely to be preemptively referred for a kidney transplant, and this appears, at least in part, to mitigate known sex/gender inequities in access to waitlisting, but not living donor transplant. Despite this, preemptively referred women, on average, had a more favorable medical profile relative to preemptively referred men.

Triage of HPV positivity in a high HIV prevalence setting: A prospective cohort study comparing visual triage methods and HPV genotype restriction in Botswana.

OBJECTIVE: Guidelines for effective triage following positive primary high-risk human papillomavirus (HPV) screening in low- and middle-income countries with high human immunodeficiency virus (HIV)-prevalence have not previously been established. In the present study, we evaluated the performance of three triage methods for positive HPV results in women living with HIV (WLHIV) and without HIV in Botswana. METHODS: We conducted baseline enrollment of a prospective cohort study from February 2021 to August 2022 in South-East District, Botswana. Non-pregnant women aged 25 or older with an intact cervix and no prior diagnosis of cervical cancer were systematically consented for enrollment, with enrichment of the cohort for WLHIV. Those who consented completed a questionnaire and then collected vaginal self-samples for HPV testing. Primary HPV testing for 15 individual genotypes was conducted using Atila AmpFire® HPV assay. Those with positive HPV results returned for a triage visit where all underwent visual inspection with acetic acid (VIA), colposcopy, and biopsy. Triage strategies with VIA, colposcopy and 8-type HPV genotype restriction (16/18/31/33/35/45/52/58), separately and in combination, were compared using histopathology as the gold standard in diagnosing cervical intraepithelial neoplasia (CIN) 2 or worse (CIN2+). RESULTS: Among 2969 women enrolled, 1480 (50%) tested HPV positive. The cohort included 1478 (50%) WLHIV; 99% were virologically suppressed after a mean of 8 years on antiretroviral therapy. In total, 1269 (86%) women had histopathology data for analysis. Among WLHIV who tested positive for HPV, 131 (19%) of 688 had CIN2+ compared with 71 (12%) of 581 in women without HIV. Screening by 8-type HPV genotype restriction was more sensitive as triage to detect CIN2+ in WLHIV 87.79% (95% CI: 80.92-92.85) and women without HIV 85.92% (95% CI: 75.62-93.03) when compared with VIA (WLHIV 62.31% [95% CI: 53.39-70.65], women without HIV 44.29% [95% CI: 32.41-56.66]) and colposcopy (WLHIV 70.77% [95% CI: 62.15-78.41], women without HIV 45.71% [95% CI: 33.74-58.06]). However, 8-type HPV genotype restriction had low specificity in WLHIV of 30.88% (95% CI: 27.06-34.90) and women without HIV 37.06% (95% CI: 32.85-41.41). These results were similar when CIN3+ was used as the outcome. When combining 8-type HPV genotype restriction with VIA as the triage strategy, there was improved specificity to detect CIN2+ in WLHIV of 81.65% (95% CI: 78.18-84.79) but dramatically reduced sensitivity of 56.15% (95% CI: 47.18-64.84). CONCLUSIONS: Eight-type HPV genotype restriction is a promising component of effective triage for HPV positivity. However, novel triage strategies in LMICs with high HIV prevalence may be needed to avoid the trade-off between sensitivity and specificity with currently available options. CLINICAL TRIALS REGISTRATION: This study is registered on Clinicaltrials.gov no. NCT04242823, https://clinicaltrials.gov/ct2/show/NCT04242823.

Antepartum depressive symptoms are associated with significant postpartum opioid use.

BACKGROUND: Antepartum depression is common, and outside of childbirth preoperative anxiety and depression have been associated with heightened postoperative pain. In light of the national opioid epidemic, the relationship between antepartum depressive symptoms and postpartum opioid use is particularly relevant. OBJECTIVE: This study evaluated the association between antepartum depressive symptoms and significant postpartum opioid use during birth hospitalization. STUDY DESIGN: This retrospective cohort study at an urban academic medical center from 2017 to 2019 included patients who received prenatal care at the medical center and linked pharmacy and billing data with electronic medical records. The exposure was antepartum depressive symptoms, defined as Edinburgh Postnatal Depression Scale ≥10 during the antepartum period. The outcome was significant opioid use, defined as: (1) any opioid use following vaginal birth and (2) the top quartile of total opioid use following cesarean delivery. Postpartum opioid use was quantified using standard conversions for opioids dispensed on postpartum days 1 to 4 to calculate morphine milligram equivalents. Poisson regression was used to calculate risk ratios and 95% confidence intervals, stratified by mode of delivery and adjusted for suspected confounders. Mean postpartum pain score was a secondary outcome. RESULTS: The cohort included 6094 births; 2351 births (38.6%) had an antepartum Edinburgh Postnatal Depression Scale score. Of these, 11.5% had a maximum score ≥10. Significant opioid use was observed in 10.6% of births. We found that individuals with antepartum depressive symptoms were more likely to have significant postpartum opioid use, with an adjusted risk ratio of 1.5 (95% confidence interval, 1.1-2.0). When stratified by mode of delivery, this association was more pronounced for cesarean births, with an adjusted risk ratio of 1.8 (95% confidence interval, 1.1-2.7), and was no longer significant for vaginal births. Mean pain scores after cesarean delivery were significantly higher in parturients with antepartum depressive symptoms. CONCLUSION: Antepartum depressive symptoms were associated with significant postpartum inpatient opioid use, especially following cesarean delivery. Whether identifying and treating depressive symptoms in pregnancy may impact the pain experience and opioid use postpartum warrants further investigation.

Surgical Adaptation of the Situation Awareness Rating Technique (S-SART): Assessing Situational Awareness Among Medical Students.

OBJECTIVE: Situational awareness (SA) impacts team dynamics and patient care. However, few formal curricula and tools exist to teach and assess longitudinal SA in surgical environments. We sought to evaluate medical students' SA in the operating room (OR) during surgical clerkships over time. DESIGN: We prospectively administered pre- and post-rotation surveys using a surgical adaptation of the previously validated Situation Awareness Rating Technique (SART). Surgical SART (S-SART) scores were calculated as: Situational Awareness = Understanding - (Attentional Demand - Attentional Supply) + 14. Each of 10 questions was scored from 1 to 7, with a maximum possible score of 60. Two-tailed two-sample and paired t-tests were conducted to determine differences in S-SART scores. PARTICIPANTS/SETTING: Sixty-nine of 75 second- and third-year medical students rotating in Surgery and Obstetrics/Gynecology clerkships at a tertiary academic medical center from September 2018 to September 2019 completed the surveys for a response rate of 92.0%. RESULTS: The mean baseline pre-rotation baseline S-SART score was 29.5 (SD=8.3), which increased by 20.9% to 35.9 (SD=6.9) post-rotation (p<0.001). Significant predictors of higher baseline S-SART scores included age ≥25 (p=0.02), surgical career interest (p=0.01), completion of prior surgical rotations (p<0.001), confidence about pre-procedural OR steps (p<0.001), and knowledge of OR item locations (p<0.001). There were increases in each of the subdomains of Understanding-including OR familiarity (3.2 to 4.3, p<0.001), knowledge of the medical student OR role (3.5 to 5.7, p<0.001), and knowledge of others' OR roles (4.1 to 5.9, p<0.001)-along with increases in alertness within Attentional Supply (5.1 to 5.5, p=0.001). CONCLUSIONS: SA is a learnable skill with increases in S-SART scores from pre- to post-rotation, with the greatest gains in the domain of Understanding. More advanced aspects of SA such as Attentional Demand may require further surgical training or curricular innovations to address these needs.

A wound-induced differentiation trajectory for neurons.

Animals capable of whole-body regeneration can replace any missing cell type and regenerate fully-functional new organs, de novo . The regeneration of a new brain requires the formation of diverse neuronal cell types and their assembly into an organized structure and correctly-wired circuits. Recent work in various regenerative animals has revealed transcriptional programs required for the differentiation of distinct neuronal subpopulations, however how these transcriptional programs are initiated upon amputation remains unknown. Here, we focused on the highly regenerative acoel worm, Hofstenia miamia , to study wound-induced transcriptional regulatory events that lead to the production of neurons. Footprinting analysis using chromatin accessibility data on an improved genome assembly revealed that binding sites for the NFY transcription factor complex were significantly bound during regeneration, showing a dynamic increase in binding within one hour upon amputation specifically in tail fragments, which will regenerate a new brain. Strikingly, NFY targets were highly enriched for genes with neuronal functional. Single-cell transcriptome analysis combined with functional studies identified sox4 + stem cells as the likely progenitor population for multiple neuronal subtypes. Further, we found that wound-induced sox4 expression is likely under direct transcriptional control by NFY, uncovering a mechanism for how early wound-induced binding of a transcriptional regulator results in the initiation of a neuronal differentiation pathway. Highlights: A new chromosome-scale assembly for Hofstenia enables comprehensive analysis of transcription factor binding during regeneration NFY motifs become dynamically bound by 1hpa in regenerating tail fragments, particularly in the loci of neural genes A sox4 + neural-specialized stem cell is identified using scRNA-seq sox4 is wound-induced and required for differentiation of multiple neural cell types NFY regulates wound-induced expression of sox4 during regeneration.

A Gender Hypothesis of sex disparities in adverse drug events.

Pharmacovigilance databases contain larger numbers of adverse drug events (ADEs) that occurred in women compared to men. The cause of this disparity is frequently attributed to sex-linked biological factors. We offer an alternative Gender Hypothesis, positing that gendered social factors are central to the production of aggregate sex disparities in ADE reports. We describe four pathways through which gender may influence observed sex disparities in pharmacovigilance databases: healthcare utilization; bias and discrimination in the clinic; experience of a drug event as adverse; and pre-existing social and structural determinants of health. We then use data from the U.S. FDA Adverse Event Reporting System (FAERS) to explore how the Gender Hypothesis might generate novel predictions and explanations of sex disparities in ADEs in existing widely referenced datasets. Analyzing more than 3 million records of ADEs between 2014 and 2022, we find that patient-reported ADEs show a larger female skew than healthcare provider-reported ADEs and that the sex disparity is markedly smaller for outcomes involving death or hospitalization. We also find that the sex disparity varies greatly across types of ADEs, for example, cosmetically salient ADEs are skewed heavily female and sexual dysfunction ADEs are skewed male. Together, we interpret these findings as providing evidence of the promise of the Gender Hypothesis for identifying intervenable mechanisms and pathways contributing to sex disparities in ADEs. Rigorous application of the Gender Hypothesis to additional datasets and in future research studies could yield new insights into the causes of sex disparities in ADEs.

Cross-Sectional Study of Resident-Reported Surgical Experience in Female Pelvic Medicine and Reconstructive Surgery.

IMPORTANCE: Comprehensive surgical training is an essential component of obstetrics and gynecology residency, yet subspecialty experience may be declining. OBJECTIVE: The objective of this study was to describe trends in reported obstetrics and gynecology resident experience in female pelvic medicine and reconstructive surgery (FPMRS). STUDY DESIGN: This study was a retrospective analysis of national case log reports from the Accreditation Council for Graduate Medical Education (ACGME) for obstetrics and gynecology residents. RESULTS: From 2013 through 2019, ACGME collected data from a median of 241 programs (range, 239-242) with a median of 1,259 residents (range, 1,213-1,286) reporting annually. There was a 26% decrease in resident-reported experience with incontinence and pelvic floor procedures from 74 ± 38 in 2013 to 55 ± 34 in 2019 ( P < 0.001). Cystoscopy increased by 19% from 43 ± 25 in 2013 to 51 ± 29 in 2019 ( P < 0.001). From 2014 to 2019, vaginal hysterectomy cases decreased by 12% ( P < 0.001). CONCLUSIONS: There was a significant decrease in resident-reported FPMRS surgical experience from 2013 to 2019, while cystoscopy numbers increased. After laparoscopic and vaginal hysterectomies were unbundled in 2013, resident vaginal hysterectomy cases decreased from 2014 to 2019. Given that the ACGME Incontinence and Pelvic Floor designation comprises a wide range of procedures, future investigation is needed to elucidate the gaps in FPMRS-specific surgical training during residency and its implication in comprehensive resident surgical training.