Reproducible research practices: A tool for effective and efficient leadership in collaborative statistics.

With data and code sharing policies more common and version control more widely used in statistics, standards for reproducible research are higher than ever. Reproducible research practices must keep up with the fast pace of research. To do so, we propose combining modern practices of leadership with best practices for reproducible research in collaborative statistics as an effective tool for ensuring quality and accuracy while developing stewardship and autonomy in the people we lead. First, we establish a framework for expectations of reproducible statistical research. Then, we introduce Stephen M.R. Covey's theory of trusting and inspiring leadership. These two are combined as we show how stewardship agreements can be used to make reproducible coding a team norm. We provide an illustrative code example and highlight how this method creates a more collaborative rather than evaluative culture where team members hold themselves accountable. The goal of this manuscript is for statisticians to find this application of leadership theory useful and to inspire them to intentionally develop their personal approach to leadership.

Stress increases sperm respiration and motility in mice and men.

Semen quality and fertility has declined over the last 50 years, corresponding to ever-increasing environmental stressors. However, the cellular mechanisms involved and their impact on sperm functions remain unknown. In a repeated sampling human cohort study, we identify a significant effect of prior perceived stress to increase sperm motility 2-3 months following stress, timing that expands upon our previous studies revealing significant stress-associated changes in sperm RNA important for fertility. We mechanistically examine this post-stress timing in mice using an in vitro stress model in the epididymal epithelial cells responsible for sperm maturation and find 7282 differentially H3K27me3 bound DNA regions involving genes critical for mitochondrial and metabolic pathways. Further, prior stress exposure significantly changes the composition and size of epithelial cell-secreted extracellular vesicles that when incubated with mouse sperm, increase mitochondrial respiration and sperm motility, adding to our prior work showing impacts on embryo development. Together, these studies identify a time-dependent, translational signaling pathway that communicates stress experience to sperm, ultimately affecting reproductive functions.

Sleep Disturbance and Subsequent Suicidal Behaviors in Preadolescence.

Importance: Suicide is a leading cause of death among adolescents, who demonstrate high rates of sleep disturbance. Poor sleep appears to confer risk for suicide, but longitudinal investigation of suicidal behaviors remains rare, particularly in the transition from childhood to early adolescence. Objective: To evaluate sleep disturbances in preadolescent children (aged 9 and 10 years) in association with longitudinal risk for suicidal ideation and suicide attempts at the 2-year follow-up. Design, Setting, and Participants: This cohort study used data from the Adolescent Brain Cognitive Development Study between June 2016 and January 2021. This dataset included children aged 9 or 10 years at baseline and their parents or caregivers who were recruited at 21 sites across the US. Data were analyzed July 2023 to June 2024. Exposures: The Sleep Disturbance Scale for Children, a 26-item parent-reported inventory, was administered at baseline, generating a total score and 6 subscales. Central covariates included the Child Behavior Checklist Anxiety and Depression subscale and demographic variables. Main Outcomes and Measures: The computerized Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS-COMP) assessed parent- and youth-reported suicidal behaviors and outcomes (none; passive, active nonspecific, and active specific suicidal ideation; and suicide attempt) at the 2-year follow-up. Sleep disturbance was further grouped by symptom severity (minimal, moderate, elevated, high, and severe). Results: Of the 10 136 youths who reported no baseline suicidal ideation or behavior, 8807 youths (mean [SD] age, 9.9 [0.6] years; 4507 males [51.2%]; 197 Asian individuals [2.2%], 1273 Black individuals [14.5%], and 5775 White individuals [65.6%]) completed the K-SADS-COMP assessment at the 2-year follow-up and were included in the analysis. At the follow-up, 8044 participants (91.3%) had no suicidal behavior, 317 (3.6%) had passive suicidal ideation, 258 (2.9%) had active nonspecific suicidal ideation, 130 (1.5%) had active specific suicidal ideation, and 58 (0.7%) had a first-time suicide attempt. Baseline sleep disturbance was associated with increased incidence risk for suicidal behavior at age 12 years (odds ratio, 2.68; 95% CI, 1.44-4.98; P = .002), adjusting for covariates. Individual subscales or items demonstrating associations with risk included disorders of excessive somnolence and frequency of nightmares. Conclusions and Relevance: Results of this longitudinal cohort study revealed that disturbed sleep at age 10 years was associated with risk for suicidal thoughts and behaviors in the next 2 years. The findings highlight the potential importance of sleep as a visible risk factor and intervention target in the prevention of youth suicide.

Treating new-onset cognitive complaints after risk-reducing salpingo-oophorectomy: A randomized controlled crossover trial of lisdexamfetamine.

OBJECTIVE: To determine whether the psychostimulant lisdexamfetamine improves subjective and objective measures of cognitive functioning among women genetically at-risk for cancer who have undergone risk-reducing salpingo-oophorectomy and report new-onset executive functioning difficulties. METHODS: 69 participants were assigned to a randomized controlled crossover trial with 6-week trials of active medication (lisdexamfetamine) and placebo, separated by a minimum 2-week washout in an intent-to-treat framework (clinical trial registration number: NCT03187353). At trial baseline, midpoint, and endpoint, participants completed a self-report measure of executive functioning (Brown Attention Deficit Disorder Scale). At study baseline and trial endpoint, participants completed sustained attention, attention/working memory, and verbal learning/memory cognitive tasks. Side effects were assessed at 2, 3, 4, and 6 weeks for each trial. RESULTS: From trial baseline to trial endpoint, lisdexamfetamine - relative to placebo - significantly improved total scores on the self-report Brown Attention Deficit Disorder Scale (and scores on four of five subdomains) as well as attention and working memory performance. Significantly more participants endorsed side effects across the lisdexamfetamine trial versus placebo; however, trial completion rates were similar, indicating that lisdexamfetamine was nonetheless well-tolerated. CONCLUSIONS: Lisdexamfetamine improved both subjective and objective measures of attention and working memory and could offer women experiencing cognitive difficulties post-risk-reducing salpingo-oophorectomy an alternative therapeutic option.

Traumatic experiences and place of occurrence: An analysis of sex differences among a sample of recently arrived immigrant adults from Latin America.

With increasing violence, political, and economic instability in Latin America, there is a record number of migrants crossing the U.S. southern border. Latin American migrants are often exposed to traumatic events before leaving their home country and during migration. While prior studies document that sex may play a role in types of traumatic exposure, few studies compare differences in traumatic exposure by sex and place of occurrence of recently arrived immigrants. Addressing this gap, we recruited 120 adults who had recently crossed the U.S.-Mexico border. Participants completed questionnaires to characterize trauma exposures in their home country and during their migration journey. Results found that men reported higher levels of exposure to combat situations, while women were more likely to experience sexual assault. Both combat exposure and sexual traumas occurred more often in home countries than during migration. More than half of the full sample reported being threatened with a firearm. These data confirm gender differences in type of trauma and that exposures in the country of origin may provide the impetus to migrate.

Natural vs. Surgical Postmenopause and Psychological Symptoms Confound the Effect of Menopause on Executive Functioning Domains of Cognitive Experience.

Objective: The menopause transition is associated with difficulties in executive function. However, it is unclear whether these difficulties persist past perimenopause. This study investigated whether potential confounders, including natural vs. surgical postmenopause and menopause-related psychological symptoms, influence whether executive dysfunction persists into postmenopause. Study Design: A cross-sectional sample of women aged 35-65 years (N = 1971) in one of four groups, premenopause, perimenopause, natural postmenopause, and surgical postmenopause, were surveyed. Participants self-reported executive functioning with the Brown Attention Deficit Disorder Scale (BADDS), anxiety symptom severity with the Generalized Anxiety Disorder Questionnaire (GAD-7), and depression symptom severity with the Center for Epidemiologic Studies Depression Scale (CES-D). Main Outcome Measures: We analyzed the association between group and BADDS scores using linear regression models - first, by controlling for age, education, and self-reported attention deficit hyperactivity disorder (ADHD) diagnosis (Model #1) and, second, by further controlling for current difficulty sleeping, anxiety, and depression (Model #2). Results: In both models, BADDS scores were significantly elevated (indicating more difficulties in executive function) among women in the perimenopausal and surgical postmenopausal groups compared with those in the premenopausal group. Likewise, the perimenopausal and surgical postmenopausal groups had the highest proportions of participants who reported difficulty sleeping and clinical levels of anxiety and depression. BADDS scores were significantly higher in natural postmenopausal vs. premenopausal women without controlling for difficulty sleeping, anxiety, and depression (Model #1), but not when adjusting for these variables (Model #2). Conclusions: The type of menopause and psychological symptoms are important confounders of the relationship between the menopause transition and executive dysfunction, and help explain whether executive dysfunction persists or recovers in postmenopause.Reprinted from Maturitas 2023; 170:64-73, with permission from Elsevier. Copyright © 2023.

Evaluating the Accuracy of Off-Label Placement of Pulse Oximetry Sensors in Comparison to On-Label Placement in the Adult Cardiac Intensive Care Unit Patient Population.

BACKGROUND: Continuous pulse oximetry (Spo2) is a commonly utilized tool to obtain an indirect, noninvasive measurement of hemoglobin oxygen saturation. Difficulty obtaining measurement with Spo2 sensors can lead nurses to try off-label sites until they find placement that provides a signal. Currently, there is limited evidence to support this application. PURPOSE: The purpose of this study was to evaluate the accuracy of off-label placement of pulse oximetry sensors in comparison to on-label placement in adult cardiac intensive care patients. METHODS: Data were collected on 24 participants. At the time of a medically necessary arterial blood gas laboratory draws, 4 Spo2 measurements were gathered from an on-label finger sensor, an off-label finger sensor, an on-label ear sensor, and an off-label ear sensor. Results were analyzed using 4 Pearson correlation coefficients, Bland-Altman plots, and 2 linear mixed-effect models. RESULTS: Our study found that while both our on-label finger and off-label finger pulse oximetry sensor overestimated when compared to the arterial hemoglobin saturation (gold standard), there was greater overestimation found with the off-label placement. Though there was not a significant difference observed between the ear probe on the nose and the gold standard, figures examining off-label ear probe and gold standard measures show that, in lower ranges of oxygen saturation, the off-site probe substantially overestimates true oxygen saturation, while in higher ranges of oxygen saturation, the off-site ear probe underestimates true oxygen saturation. CONCLUSIONS: No changes should be made to the current practice of using pulse oximetry sensor placement.

Sex Differences in Stress-Induced Cortisol Response Among Infants of Mothers Exposed to Childhood Adversity.

BACKGROUND: Adverse childhood experiences (ACEs) increase risk for mental illness in women and their children, and dysregulation of the hypothalamic-pituitary-adrenal axis may play a role. The impact of ACEs on the hypothalamic-pituitary-adrenal axis may be strongest when ACEs occur prepubertally and in people who are exposed to abuse ACEs. METHODS: To test this, we measured salivary cortisol in 96 mother-infant dyads while mothers were separated from their infants, who were experiencing a laboratory stressor. Mothers completed the Adverse Childhood Experiences Questionnaire; ACEs that occurred prepubertally (pACEs) were measured, and mother-infant dyads were grouped based on maternal pACE history as follows: no pACEs, ≥1 pACEs with abuse, or ≥1 pACEs but no abuse. RESULTS: Mothers with ≥1 pACEs exhibited decreases in cortisol (relative to preinfant stressor), which differed significantly from the cortisol increase experienced by mothers with no pACEs, regardless of abuse presence (p = .001) or absence (p = .002). These pACE groups did not differ from one another (p = .929). Significant sex differences in infant cortisol were observed in infants of mothers with ≥1 pACEs (regardless of abuse) but not in infants of mothers with no pACEs. When mothers had experienced ≥1 pACEs, males showed decreases in cortisol in response to a stressor whereas females demonstrated increases, and males and females differed significantly when their mothers had ≥1 pACEs with (p = .025) and without (p = .032) abuse. CONCLUSIONS: Regardless of maternal exposure to childhood abuse, in response to a stressor, pACEs were associated with lower cortisol response in mothers and sex differences in 6-month-old infants, with males showing a lower cortisol response than females.

High estradiol levels in fresh embryo transfer cycles are not associated with detrimental impact on birth outcomes.

PURPOSE: There is an unclear relationship between estradiol levels and fresh embryo transfer (ET) outcomes. We determined the relationship between estradiol on the day of trigger, in fresh ET cycles without premature progesterone elevation, and good birth outcomes (GBO). METHODS: We identified autologous fresh ET cycles from 2015 to 2021 at multiple clinics in the USA. Patients with recurrent pregnancy loss, uterine factor, and elevated progesterone on the day of trigger (progesterone > 2 ng/mL or 3-day area under the curve > 4.5 ng/mL) were excluded. The primary outcome was GBO (singleton, term, live birth with appropriate weight). Log-binomial generalized estimating equations determined the likelihood of outcomes. RESULTS: Of 17,608 fresh ET cycles, 5025 (29%) yielded GBO. Cycles with estradiol ≥ 4000 pg/mL had a greater likelihood of GBO compared to cycles < 1000 pg/mL (aRR = 1.32, 95% CI 1.13-1.54). Pairwise comparisons of estradiol between < 1000 pg/mL versus 1000-1999 pg/mL and 1000-1999 pg/mL versus 2000-2999 pg/mL revealed a higher likelihood of GBO with higher estradiol (aRR 0.83, 95% CI 0.73-0.95; aRR 0.91, 95% CI 0.85-0.97, respectively). Comparisons amongst more elevated estradiol levels revealed that the likelihood of GBO remained similar between groups (2000-2999 pg/mL versus 3000-3999 pg/mL, aRR 1.04, 95% CI 0.97-1.11; 3000-3999 pg/mL versus ≥ 4000 pg/mL, aRR 0.96, 95% CI 0.9-1.04). CONCLUSION: In fresh ET cycles, higher estradiol levels were associated with an increased prevalence of GBO until estradiol 2000-2999 pg/mL, thereafter plateauing. In fresh ET candidates, elevated estradiol levels should not preclude eligibility though premature progesterone rise, and risk of ovarian hyperstimulation syndrome must still be considered.

Harnessing technology to improve sleep in frontline healthcare workers: A pilot study of electronic noise-masking earbuds on subjective and objective sleep measures.

Objective: This pilot study assessed the effects of electronic noise-masking earbuds on subjective sleep perception and objective sleep parameters among healthcare workers (HCWs) reporting sleep difficulties during the COVID-19 pandemic. Methods: Using a pre-post design, 77 HCWs underwent 3 nights of baseline assessment followed by a 7-night intervention period. Participants wore an at-home sleep monitoring headband to assess objective sleep measures and completed subjective self-report assessments. The difference in mean sleep measures from baseline to intervention was estimated in linear mixed models. Results: Compared to baseline assessments, HCWs reported significant improvements in sleep quality as measured by the Insomnia Severity Index (ISI) (Cohen's d = 1.74, p < 0.001) and a significant reduction in perceived sleep onset latency (SOL) during the intervention (M = 17.2 minutes, SD = 7.7) compared to baseline (M = 24.7 minutes, SD = 16.1), (Cohen's d = -0.42, p = 0.001). There were no significant changes in objective SOL (p = 0.703). However, there was a significant interaction between baseline objective SOL (<20 minutes vs >20 minutes) and condition (baseline vs intervention) (p = 0.002), such that individuals with objective SOL >20 minutes experienced a significant decrease in objective SOL during the intervention period compared to baseline (p = 0.015). Conclusions: HCWs experienced a significant improvement in perceived SOL and ISI scores after using the electronic noise-masking earbuds. Our data provide preliminary evidence for a nonpharmacological intervention to improve the sleep quality of HCWs which should be confirmed by future controlled studies.

The details matter: personalized prediction of live birth after in vitro fertilization in women with polycystic ovary syndrome.

OBJECTIVE: To derive and internally validate a clinical prediction model for live birth (LB) in women with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization (IVF). DESIGN: Retrospective cohort study. SETTING: Four academic reproductive endocrinology clinics. PATIENTS: A total of 207 women with PCOS confirmed using Rotterdam criteria undergoing their first fresh IVF cycle. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: The primary outcome was cumulative LB per IVF cycle start. This included any LB that resulted from either fresh embryo transfer or any subsequent frozen embryo transfer from embryos obtained at the index oocyte retrieval. A prediction model was derived using multivariable logistic regression. Covariates considered for inclusion in the prediction model included demographic characteristics, medical history, and prior fertility treatment. Predicted probabilities for LB were calculated using the prediction model which included the 90% shrinkage factor for each adjusted odds ratio. RESULTS: The final model, on the basis of maximization of the area under the receiver operating characteristic curve, included age < 35 years, White race, presence of polycystic ovaries on ultrasound (polycystic ovary morphology), normal body mass index (<25 kg/m2), being metabolically healthy (no metabolic risk factors), and being a nonresponder to ovulation induction agents including letrozole and clomiphene citrate. The area under the receiver operating characteristic curve score for the model was 0.68 (95% confidence interval [CI]: 0.60, 0.77). Predicted probabilities of LB ranged from 8.1% (95% CI: 2.8, 21.5) for a woman who had no favorable predictors to 74.2% (95% CI: 59.5, 84.9) for a woman who had all favorable predictors. CONCLUSION: Our study demonstrated that, in addition to anovulation, the underlying pathophysiology and associated comorbidities alter the likelihood of a successful pregnancy in women with PCOS undergoing IVF. Further validation of this model is needed before it can serve as a tool to personalize prediction estimates for the probability of LB in women with PCOS.

Placental differences between severe fetal growth restriction and hypertensive disorders of pregnancy requiring early preterm delivery: morphometric analysis of the villous tree supported by artificial intelligence.

BACKGROUND: The great obstetrical syndromes of fetal growth restriction and hypertensive disorders of pregnancy can occur individually or be interrelated. Placental pathologic findings often overlap between these conditions, regardless of whether 1 or both diagnoses are present. Quantification of placental villous structures in each of these settings may identify distinct differences in developmental pathways. OBJECTIVE: This study aimed to determine how the quantity and surface area of placental villi and vessels differ between severe, early-onset fetal growth restriction with absent or reversed umbilical artery Doppler indices and hypertensive disorders of pregnancy or the 2 conditions combined among subjects with disease severity that warrant early preterm delivery. We hypothesized that the trajectories of placental morphogenesis diverge after a common initiating insult of deep defective placentation. Specifically, we postulated that only villi are affected in pregnancy-related hypertension, whereas both villous and vascular structures are proportionally diminished in severe fetal growth restriction with no additional effect when hypertension is concomitantly present. STUDY DESIGN: In this retrospective cohort study, paraffin-embedded placental tissue was obtained from 4 groups, namely (1) patients with severe fetal growth restriction with absent or reversed umbilical artery end-diastolic velocities and hypertensive disorders of pregnancy, (2) patients with severe fetal growth restriction with absent or reversed umbilical artery Doppler indices and no hypertension, (3) gestational age-matched, appropriately grown pregnancies with hypertensive disease, and (4) gestational age-matched, appropriately grown pregnancies without hypertension. Dual immunohistochemistry for cytokeratin-7 (trophoblast) and CD34 (endothelial cells) was performed, followed by artificial intelligence-driven morphometric analyses. The number of villi, total villous area, number of fetoplacental vessels, and total vascular area across villi within a uniform region of interest were quantified. Quantitative analyses of placental structures were modeled using linear regression. RESULTS: Placentas from pregnancies complicated by hypertensive disorders of pregnancy exhibited significantly fewer stem villi (-282 stem villi; 95% confidence interval, -467 to -98; P<.01), a smaller stem villous area (-4.3 mm2; 95% confidence interval, -7.3 to -1.2; P<.01), and fewer stem villous vessels (-4967 stem villous vessels; 95% confidence interval, -8501 to -1433; P<.01) with no difference in the total vascular area. In contrast, placental abnormalities in cases with severe growth restriction were limited to terminal villi with global decreases in the number of villi (-873 terminal villi; 95% confidence interval, -1501 to -246; P<.01), the villous area (-1.5 mm2; 95% confidence interval, -2.7 to -0.4; P<.01), the number of blood vessels (-5165 terminal villous vessels; 95% confidence interval, -8201 to -2128; P<.01), and the vascular area (-0.6 mm2; 95% confidence interval, -1.1 to -0.1; P=.02). The combination of hypertension and growth restriction had no additional effect beyond the individual impact of each state. CONCLUSION: Pregnancies complicated by hypertensive disorders of pregnancy exhibited defects in the stem villi only, whereas placental abnormalities in severely growth restricted pregnancies with absent or reversed umbilical artery end-diastolic velocities were limited to the terminal villi. There were no significant statistical interactions in the combination of growth restriction and hypertension, suggesting that distinct pathophysiological pathways downstream of the initial insult of defective placentation are involved in each entity and do not synergize to lead to more severe pathologic consequences. Delineating mechanisms that underly the divergence in placental development after a common inciting event of defective deep placentation may shed light on new targets for prevention or treatment.

Association of duration of embryo culture with risk of large for gestational age delivery in cryopreserved embryo transfer cycles.

OBJECTIVE: To examine the relationship between the day of embryo cryopreservation and large for gestational age (LGA) infants in women undergoing frozen embryo transfers (FETs) after cryopreservation on days 2-7 after fertilization and to compare the risk of the day of embryo cryopreservation to other possible risk factors of LGA after FET cycles. DESIGN: Retrospective cohort study. SETTING: Society of Assisted Reproduction Clinical Outcomes Reporting System. PATIENTS: Women undergoing FET cycles. INTERVENTION: Day of cryopreservation. MAIN OUTCOME MEASURE: Singleton LGA infant. RESULTS: A total of 33,030 (18.2%) FET cycles in the study group (n = 181,592) resulted in LGA infants during the study period of 2014-2019. There was an increase in LGA risk when cryopreservation was performed from day 2 (13.7%) to days 3-7 (14.4%, 15.0%, 18.2%, 18.5%, and 18.9%). In the log-binomial model, the risk increased compared with days 2-3 combined when cryopreservation was performed on days 5-7 (adjusted relative risk [aRR] 1.32, 95% confidence interval [CI] 1.22-1.44 for day 5, aRR 1.34, 95% CI 1.23-1.46 for day 6, and aRR 1.42, 95% CI 1.25-1.61 for day 7). Other factors most associated with LGA risk in the log-binomial model were preterm parity of >3 compared with 0 (aRR 1.82, 95% CI 1.24-2.69) and body mass index (BMI) of >35 kg/m2 compared with normal weight (aRR 1.94, 95% CI 1.88-2.01). Increasing gravity, parity, BMI, number of oocytes, and embryo grade were also associated with LGA in this model. Asian, Black, Hispanic, and combined Hawaiian and Pacific Islander were protective factors in the model compared with White patients. Low BMI (<18.5 kg/m2) was also considered a protective factor in the model compared with normal BMI. CONCLUSION: Duration of embryo culture was associated with an increased risk of LGA in this study cohort when controlling for known confounders such as maternal BMI and parity. This study sheds new light on the possible link between FET and LGA infants.

Mathematical recapitulation of the end stages of human ovarian aging.

Ovarian aging in women can be described as highly unpredictable within individuals but predictable across large populations. We showed previously that modeling an individual woman's ovarian reserve of primordial follicles using mathematical random walks replicates the natural pattern of growing follicles exiting the reserve. Compiling many simulations yields the observed population distribution of the age at natural menopause (ANM). Here, we have probed how stochastic control of primordial follicle loss might relate to the distribution of the preceding menopausal transition (MT), when women begin to experience menstrual cycle irregularity. We show that identical random walk model conditions produce both the reported MT distribution and the ANM distribution when thresholds are set for growing follicle availability. The MT and ANM are shown to correspond to gaps when primordial follicles fail to grow for 7 and 12 days, respectively. Modeling growing follicle supply is shown to precisely recapitulate epidemiological data and provides quantitative criteria for the MT and ANM in humans.

Depressed, stressed, and inflamed: C-reactive protein linked with depression symptoms in midlife women with both childhood and current life stress.

To determine whether the relationship between inflammatory factors and clinically significant depression symptoms is moderated by high exposure to adverse childhood experiences and current life stressors in a longitudinal community cohort of midlife women. Methods: Participants from the Penn Ovarian Ageing Study community cohort (age at baseline: M = 45.3 [SD = 3.8]) were included in analyses if they had a blood sample measuring basal inflammatory markers during at least one visit where depression symptom severity and current stressful life events were also assessed (N = 142, average number of visits per participant = 1.75 [SD = 0.92]). Approximately annually over the course of 16 years, participants self-reported depression symptom severity using the Centre for Epidemiologic Studies Depression (CESD) Scale, provided menstrual diaries to determine menopause stage, and contributed blood samples. Residual blood samples were assayed for interleukin (IL)-6, IL 1-beta (IL-1ß), tumour necrosis factor alpha (TNF-α), and high sensitivity C-reactive protein (hsCRP). Early life stress was quantified using the Adverse Childhood Experiences questionnaire (low [0-1 experience(s)] versus high [≥ 2 experiences]). Current stressful life events were assessed using a structured interview (low [0-1 events] vs. high [≥ 2 events]). Generalised estimating equation models were used to model associations with the outcome of interest-clinically significant depression symptoms (CESD ≥16)-and risk factors: inflammatory marker levels (log transformed), adverse childhood experiences group, and current life stressors group. Covariates included menopause stage, age at study baseline, body mass index, race, and smoking status. We found a significant three-way interaction between log hsCRP levels, adverse childhood experiences group, and current life stressors group on likelihood of experiencing clinically significant depression symptoms (OR: 4.33; 95% CI: 1.22, 15.46; p = 0.024) after adjusting for covariates. Solely for women with high adverse childhood experiences and with high current life stressors, higher hsCRP was associated with higher odds of having clinically significant depression symptoms (OR: 1.46; 95% CI 1.07, 1.98; p = 0.016). This three-way interaction was not significant for IL-6, IL-1ß, or TNF-α. For women in midlife with exposure to high adverse childhood experiences and multiple current life stressors, elevated levels of CRP were uniquely associated with clinically significant depression symptoms. Early life adversity and current life stressors represent identifiable individual risk factors whose negative impact may be curtailed with inventions to target inflammation in midlife women.

Increased adherence to ACOG diagnostic guidelines for HDP following a workshop in Bolivia, a LMIC.

OBJECTIVES: Hypertensive disorders of pregnancy (HDP) exert a heavy mortality burden in low- to middle-income countries (LMIC). ACOG revised HDP diagnostic guidelines to improve identifying pregnancies at greatest risk but whether they are used in LMIC is unknown. STUDY DESIGN: We held a workshop to review ACOG guidelines in La Paz, Bolivia (BO) and then reviewed prenatal, labor and delivery records for all HDP diagnoses and twice as many controls at its three largest delivery sites during the year before and the nine months after a workshop (n = 1376 cases, 2851 controls during the two periods). MAIN OUTCOME MEASURES: HDP diagnoses, maternal, and infant characteristics. RESULTS: Bolivian and ACOG criteria identified similar frequencies of gestational hypertension (GH) or eclampsia, but preeclampsia with severe features (sPE) was under- and preeclampsia without severe features (PE) over-reported during both periods. Increases occurred after the workshop in testing for proteinuria and the detection of abnormal laboratory values and severe hypertension in HDP women. Any adverse maternal outcome occurred more frequently after the workshop in women with BO PE or sPE diagnoses who met ACOG sPE criteria. CONCLUSIONS: Utilization of ACOG guidelines increased following the workshop and improved identification of PE or sPE pregnancies with adverse maternal outcomes. Continued use of a CLAP perinatal form recognizing HELLP as the only kind of sPE resulted in under-reporting of sPE. FUNDING: NIH TW010797, HD088590, HL138181.

Identification and verification of plasma protein biomarkers that accurately identify an ectopic pregnancy.

BACKGROUND: Differentiating between a normal intrauterine pregnancy (IUP) and abnormal conditions including early pregnancy loss (EPL) or ectopic pregnancy (EP) is a major clinical challenge in early pregnancy. Currently, serial ß-human chorionic gonadotropin (ß-hCG) and progesterone are the most commonly used plasma biomarkers for evaluating pregnancy prognosis when ultrasound is inconclusive. However, neither biomarker can predict an EP with sufficient and reproducible accuracy. Hence, identification of new plasma biomarkers that can accurately diagnose EP would have great clinical value. METHODS: Plasma was collected from a discovery cohort of 48 consenting women having an IUP, EPL, or EP. Samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) followed by a label-free proteomics analysis to identify significant changes between pregnancy outcomes. A panel of 14 candidate biomarkers were then verified in an independent cohort of 74 women using absolute quantitation by targeted parallel reaction monitoring mass spectrometry (PRM-MS) which provided the capacity to distinguish between closely related protein isoforms. Logistic regression and Lasso feature selection were used to evaluate the performance of individual biomarkers and panels of multiple biomarkers to predict EP. RESULTS: A total of 1391 proteins were identified in an unbiased plasma proteome discovery. A number of significant changes (FDR ≤ 5%) were identified when comparing EP vs. non-EP (IUP + EPL). Next, 14 candidate biomarkers (ADAM12, CGA, CGB, ISM2, NOTUM, PAEP, PAPPA, PSG1, PSG2, PSG3, PSG9, PSG11, PSG6/9, and PSG8/1) were verified as being significantly different between EP and non-EP in an independent cohort (FDR ≤ 5%). Using logistic regression models, a risk score for EP was calculated for each subject, and four multiple biomarker logistic models were identified that performed similarly and had higher AUCs than models with single predictors. CONCLUSIONS: Overall, four multivariable logistic models were identified that had significantly better prediction of having EP than those logistic models with single biomarkers. Model 4 (NOTUM, PAEP, PAPPA, ADAM12) had the highest AUC (0.987) and accuracy (96%). However, because the models are statistically similar, all markers in the four models and other highly correlated markers should be considered in further validation studies.

A Latent Variable Analysis of Psychomotor and Neurocognitive Performance After Acute Cannabis Smoking.

Objective: This paper evaluated a novel, tablet-based neurocognitive and psychomotor test battery for detecting impairment from acute cannabis smoking using advanced quantitative methods. The study was conducted in a state with legal, recreational cannabis use and included participants who use cannabis occasionally or daily, and a no use comparison group. Methods: Participants completed a tablet-based test assessing reaction time, decision making, working memory and spatial-motor performance. The test was completed before and after participants smoked cannabis (or after a rest period in the case of controls). An Exploratory Factor Analysis approach was implemented to reduce dimensionality and evaluate correlations across the four assessed domains. Linear regression models were utilized to quantify associations between factor scores and cannabis use groups (daily vs. occasional vs. no use). Results: Seven factors were identified explaining 56.7% of the variance among the 18 measures. Regression models of the change in factors after cannabis smoking indicated those who use cannabis daily demonstrated poorer performance on a latent factor termed Displaced and Delayed (standardized coefficient 0.567, 95% CI: 0.178, 0.955; P = 0.005) compared to those with no use. Those who use cannabis occasionally exhibited a decline in performance on a latent factor termed Recall and Reaction (standardized coefficient 0.714, 95% CI: 0.092, 1.336; P = 0.025) compared to no use. Conclusions: This analysis demonstrates an innovative, quantitative approach to study how cannabis consumption affects neurocognitive and psychomotor performance. Results demonstrated that acute cannabis use is associated with changes in neurocognitive and psychomotor performance, with differences based on the pattern of occasional or daily use.

Abnormal uterine bleeding in anticoagulated patients by drug class: outcomes and management.

BACKGROUND: Although abnormal uterine bleeding is a known adverse effect of anticoagulant drugs, true rates have not been widely studied. Society-backed recommendations and guidelines do not yet exist for prevention and management of abnormal uterine bleeding among anticoagulated patients. OBJECTIVE: This study aimed to describe the incidence of new-onset abnormal uterine bleeding among patients receiving therapeutic anticoagulation by anticoagulant class, and to evaluate gynecologic treatment patterns. STUDY DESIGN: We conducted an institutional review board-waived retrospective chart review of female patients aged 18 to 55 years and prescribed therapeutic anticoagulants, including vitamin-K antagonists, low-molecular-weight heparins, and direct oral anticoagulants, in an urban hospital network from January 2015 through January 2020. We excluded patients with antecedent abnormal uterine bleeding and menopause. Associations between abnormal uterine bleeding, anticoagulant class, and other covariates were evaluated with Pearson chi-square and analysis-of-variance tests. The primary outcome, abnormal uterine bleeding odds by anticoagulant class, was modeled with logistic regression. Age, antiplatelet therapy, body mass index, and race were included in our multivariable model. Secondary outcomes included emergency department visits and treatment patterns. RESULTS: Of the 2479 patients who met the inclusion criteria, 645 were diagnosed with abnormal uterine bleeding after initiating therapeutic anticoagulation. After adjusting for age, race, body mass index, and concurrent use of antiplatelet therapy, those receiving all 3 classes of anticoagulants had higher odds of experiencing abnormal uterine bleeding (adjusted odds ratio, 2.63; confidence interval, 1.70-4.08; P<.001), whereas those taking only direct oral anticoagulants had the lowest odds (adjusted odds ratio, 0.70; confidence interval, 0.51-0.97; P=.032), with vitamin-K antagonists as the reference group. Race other than White was associated with higher odds of abnormal uterine bleeding, as was lower age. The most common hormone therapies used among patients with abnormal uterine bleeding were levonorgestrel intrauterine devices (7.6%; 49/645) and oral progestins (7.6%; 49/645). Sixty-eight patients (10.5%; 68/645) had an emergency department visit for abnormal uterine bleeding; 29.5% (190/645) of patients received a blood transfusion; 12.2% (79/645) began any pharmacologic therapy for bleeding; and 18.8% (121/645) underwent any gynecologic procedure. CONCLUSION: Abnormal uterine bleeding occurs frequently among patients on therapeutic anticoagulation. Incidence in this sample varied considerably by anticoagulant class and race; use of single-agent direct oral anticoagulation carried the lowest risk. Important sequelae such as bleeding-related emergency department visits, blood transfusions, and gynecologic procedures were common. Balancing bleeding and clotting risk in patients on therapeutic anticoagulation requires a nuanced approach and should involve collaborative management between hematologists and gynecologists.

Intersectionality and Adverse Childhood Experiences: Comparing Subgroups of Sex, Race/Ethnicity, and Sexual Orientation.

INTRODUCTION: This study investigated the intersectionality of adverse childhood experiences (ACEs) among subgroups of sex, race/ethnicity, and sexual orientation. METHODS: Using data from the Behavioral Risk Factor Surveillance Survey across 34 states (N=116,712) from 2009 to 2018, authors stratified subgroups of sex (male/female), race/ethnicity (White/Hispanic/Black/multiracial/other), and sexual orientation (heterosexual/bisexual/gay) to investigate the number of ACEs across groups. Analyses were conducted in 2022. RESULTS: Stratification resulted in 30 distinct subgroups (e.g., bisexual Black females, straight multiracial males) with significant post hoc differences per group. Generally, those identifying as sexual minority individuals had the highest number of ACEs (the top 14 of 30 subgroups), whereas seven of the top ten subgroups were female. Surprisingly, no clear patterns emerged by race/ethnicity, although the two largest groups (straight White females and straight White males) were 27th and 28th of 30, respectively. CONCLUSIONS: Although studies have examined ACEs by individual demographic variables, less is known about the extent to which ACEs are present in stratified subgroups. Sexual minority subgroups (particularly female bisexual subgroups) trend toward a higher number of ACEs, whereas heterosexual subgroups (regardless of sex) comprised the lowest 6 groups with respect to ACEs. Implications include further examination of bisexual and female subgroups (including specific ACE domain investigations) to identify the vulnerable population.