Sonic Hedgehog activates prostaglandin signaling to stabilize primary cilium length.

Sonic Hedgehog (SHH) is a driver of embryonic patterning that, when corrupted, triggers developmental disorders and cancers. SHH effector responses are organized through primary cilia (PC) that grow and retract with the cell cycle and in response to extracellular cues. Disruption of PC homeostasis corrupts SHH regulation, placing significant pressure on the pathway to maintain ciliary fitness. Mechanisms by which ciliary robustness is ensured in SHH-stimulated cells are not yet known. Herein, we reveal a crosstalk circuit induced by SHH activation of Phospholipase A2α that drives ciliary E-type prostanoid receptor 4 (EP4) signaling to ensure PC function and stabilize ciliary length. We demonstrate that blockade of SHH-EP4 crosstalk destabilizes PC cyclic AMP (cAMP) equilibrium, slows ciliary transport, reduces ciliary length, and attenuates SHH pathway induction. Accordingly, Ep4-/- mice display shortened neuroepithelial PC and altered SHH-dependent neuronal cell fate specification. Thus, SHH initiates coordination between distinct ciliary receptors to maintain PC function and length homeostasis for robust downstream signaling.

Associations between mycoestrogen exposure and sex steroid hormone concentrations in maternal serum and cord blood in the UPSIDE pregnancy cohort.

Zearalenone (ZEN) is a fungal-derived toxin found in global food supplies including cereal grains and processed foods, impacting populations worldwide through diet. Because the chemical structure of ZEN and metabolites closely resembles 17ß-estradiol (E2), they interact with estrogen receptors α/ß earning their designation as 'mycoestrogens'. In animal models, gestational exposure to mycoestrogens disrupts estrogen activity and impairs fetal growth. Here, our objective was to evaluate relationships between mycoestrogen exposure and sex steroid hormone concentrations in maternal circulation and cord blood for the first time in humans. In each trimester, pregnant participants in the UPSIDE study (n = 297) provided urine for mycoestrogen analysis and serum for hormone analysis. At birth, placental mycoestrogens and cord steroids were measured. We fitted longitudinal models examining log-transformed mycoestrogen concentrations in relation to log-transformed hormones, adjusting for covariates. Secondarily, multivariable linear models examined associations at each time point (1st, 2nd, 3rd trimesters, delivery). We additionally considered effect modification by fetal sex. ZEN and its metabolite, α-zearalenol (α-ZOL), were detected in >93% and >75% of urine samples; >80% of placentas had detectable mycoestrogens. Longitudinal models from the full cohort exhibited few significant associations. In sex-stratified analyses, in pregnancies with male fetuses, estrone (E1) and free testosterone (fT) were inversely associated with ZEN (E1 %Δ: -6.68 95%CI: -12.34, -0.65; fT %Δ: -3.22 95%CI: -5.68, -0.70); while α-ZOL was positively associated with E2 (%Δ: 5.61 95%CI: -1.54, 9.85) in pregnancies with female fetuses. In analysis with cord hormones, urinary mycoestrogens were inversely associated with androstenedione (%Δ: 9.15 95%CI: 14.64, -3.30) in both sexes, and placental mycoestrogens were positively associated with cord fT (%Δ: 37.13, 95%CI: 4.86, 79.34) amongst male offspring. Findings support the hypothesis that mycoestrogens act as endocrine disruptors in humans, as in animal models and livestock. Additional work is needed to understand impacts on maternal and child health.

First Results from a Broadband Search for Dark Photon Dark Matter in the 44 to 52 µeV Range with a Coaxial Dish Antenna.

We present first results from a dark photon dark matter search in the mass range from 44 to 52 µeV (10.7-12.5 GHz) using a room-temperature dish antenna setup called GigaBREAD. Dark photon dark matter converts to ordinary photons on a cylindrical metallic emission surface with area 0.5 m^{2} and is focused by a novel parabolic reflector onto a horn antenna. Signals are read out with a low-noise receiver system. A first data taking run with 24 days of data does not show evidence for dark photon dark matter in this mass range, excluding dark photon photon mixing parameters χ≳10^{-12} in this range at 90% confidence level. This surpasses existing constraints by about 2 orders of magnitude and is the most stringent bound on dark photons in this range below 49 µeV.

The role of prenatal maternal sex steroid hormones in weight and adiposity at birth and growth trajectories during infancy.

Objective: Intrauterine factors can impact fetal and child growth and may underlie the developmental origins of childhood obesity. Sex steroid hormone exposure during pregnancy is a plausible target because of the impact on placental vascularization, nutrient transportation, bone growth, adipogenesis, and epigenetic modifications. In this study we assessed maternal sex steroid hormones in each trimester in relation to birthweight, neonatal adiposity, and infant growth trajectories, and evaluate sensitive windows of development. Methods: Participants from a prospective pregnancy cohort who delivered at term were included in the analysis (n=252). Estrone, estradiol, and estriol, as well as total and free testosterone throughout gestation were assessed using high-performance liquid chromatography and tandem mass spectrometry. Path analyses were used to assess the direct associations of sex steroid hormones in each trimester with birth outcomes and infant growth trajectories (birth to 12 months) adjusting for covariates and considering moderation by sex. Results: The associations between prenatal sex steroid hormones and fetal/infant growth varied by sex and hormone assessment timing. First trimester estrone were associated with higher birthweight z-scores (ß=0.37, 95%CI: 0.02, 0.73) and truncal skinfold thickness (TST) at birth (ß=0.94, 95%CI: 0.34, 1.54) in female infants. Third trimester total testosterone was associated with higher TST at birth (ß=0.61, 95%CI: 0.02, 1.21) in male infants. First trimester estrone/estradiol and first and third trimesters testosterone were associated with lower probabilities of high stable weight trajectory compared to low stable weight trajectory (Estrone: ß=-3.87, 95%CI: -6.59, -1.16; First trimester testosterone: ß=-3.53, 95%CI: -6.63, -0.43; Third trimester testosterone: ß=-3.67, 95%CI: -6.66, -0.69) during infancy in male infants. Conclusions: We observed associations between prenatal sex steroid hormone exposure and birthweight, neonatal adiposity and infant growth that were sex and gestational timing dependent. Our findings suggest further investigation on additional mechanisms linking prenatal sex steroid exposure and fetal/postnatal growth is needed.

Fixed prosthodontic rehabilitation of a patient after bariatric surgery using a facially driven fully digital workflow: A clinical report with a 3-year follow-up.

Patients who have received bariatric surgery have specific and complex dental needs. After surgery, nutrient deficiencies, osteoporosis, gastroesophageal reflux, and changes to the oral cavity may be seen, and erosion, caries, wear, xerostomia, hypersensitivity, and changes to the salivary buffering capacity may occur. In addition, patients are advised to ingest smaller, more frequent, meals throughout the day, and the oral condition may decline rapidly after surgery. Without oversight, this accelerated decline may even necessitate complete mouth rehabilitation postoperatively. Dental providers should be an integral part of the multidisciplinary management team of these patients. This clinical report describes a patient with a terminal dentition following bariatric surgery who underwent prosthodontic rehabilitation with a facially driven fully digital workflow.

Risk for diagnosis or treatment of mood or anxiety disorders in adults after SARS-CoV-2 infection, 2020-2022.

COVID-19 is associated with increased risks for mood or anxiety disorders, but it remains uncertain how the association evolves over time or which patient groups are most affected. We conducted a retrospective cohort study using a nationwide database of electronic health records to determine the risk of depressive or anxiety disorder diagnoses after SARS-CoV-2 infection by 3-month blocks from January 2020 to April 2022. The study population comprised 822,756 patients (51.8% female; mean age 42.8 years) with COVID-19 and 2,034,353 patients with other respiratory tract infections (RTIs) (53.5% female, mean age 30.6 years). First time diagnoses of depressive or anxiety disorders 14 days to 3 months after infection, as well as new or new plus recurrent prescriptions of antidepressants or anxiolytics, were compared between propensity score matched cohorts using Kaplan-Meier survival analysis, including hazard ratio (HR) and 95% confidence interval (CI). Risk of a new diagnosis or prescription was also stratified by age, sex, and race to better characterize which groups were most affected. In the first three months of the pandemic, patients infected with SARS-CoV-2 had significantly increased risk of depression or anxiety disorder diagnosis (HR 1.65 [95% CI, 1.30-2.08]). October 2021 to January 2022 (HR, 1.12 [95% CI, 1.06-1.18]) and January to April 2022 (HR, 1.08 [95% CI, 1.01-1.14]). Similar temporal patterns were observed for antidepressant and anxiolytic prescriptions, when the control group was patients with bone fracture, when anxiety and depressive disorders were considered separately, when recurrent depressive disorder was tested, and when the test period was extended to 6 months. COVID-19 patients ≥65 years old demonstrated greatest absolute risk at the start of the pandemic (6.8%), which remained consistently higher throughout the study period (HR, 1.20 [95% CI, 1.13-1.27]), and overall, women with COVID-19 had greater risk than men (HR 1.35 [95% CI 1.30-1.40]).

Prosthodontic rehabilitation of two siblings with hypoplastic (type 1) amelogenesis imperfecta: A case report.

Amelogenesis imperfecta is a rare genetic disorder that interferes with normal enamel formation. Of the 4 main types of amelogenesis imperfecta, hypoplastic (type 1) is the most prevalent, characterized by a quantitative alteration in enamel. The pitting or reduced thickness of the enamel results in generalized hypersensitivity, increased susceptibility to caries and infection, attrition, and a loss in vertical dimension of occlusion. Prosthodontic management of these patients can be challenging not only functionally and restoratively, but also from an emotional and psychosocial standpoint. This clinical report describes the prosthodontic management and rehabilitation of two young adult siblings with hypoplastic (type 1) amelogenesis imperfecta.

CD4+ T cell-derived IFN-γ and LIGHT synergistically upregulate chemokine production from airway smooth muscle cells.

Airway smooth muscle (ASM) remodeling in asthmatic airways may contribute to persistent airflow limitation and airway hyperresponsiveness. CD4+ T cells infiltrate the ASM layer where they may induce a proliferative and secretory ASM cell phenotype. We studied the interaction between activated CD4+ T cells and ASM cells in co-culture in vitro and investigated the effects of CD4+ T cells on chemokine production by ASM cells. CD4+ T cells induced marked upregulation of C-X-C motif chemokine ligands (CXCL) 9, 10, and 11 in ASM cells. Blockade of the IFN-γ receptor on ASM cells prevented this upregulation. Furthermore, T cell-derived IFN-γ and LIGHT (lymphotoxin, exhibits inducible expression and competes with HSV glycoprotein D for binding to herpesvirus entry mediator, a receptor expressed on T lymphocytes) synergize in a dose-dependent manner to coordinately enhance CXCL9, 10, and 11 expression. The synergistic property of LIGHT was mediated exclusively through the lymphotoxin-ß receptor (LTBR), but not herpes virus entry mediator (HVEM). Disruption of LTBR signaling in ASM cells reduced CXCL9, 10, and 11 production and ASM cell-mediated CD4+ T cell chemotaxis. We conclude that the LIGHT-LTBR signaling axis acts together with IFN-γ to regulate chemokines that mediate lymphocyte infiltration in asthmatics.

The Effect of Testosterone Replacement Therapy on Nonalcoholic Fatty Liver Disease in Older Hypogonadal Men.

CONTEXT: Male hypogonadism is associated with visceral obesity and the metabolic syndrome: factors important for the development of nonalcoholic fatty liver disease (NAFLD). The Testosterone Trials (The T Trials) showed testosterone (T) treatment compared with placebo in older hypogonadal men was associated with decreases in cholesterol and insulin levels suggesting that T treatment may improve NAFLD. OBJECTIVE: Compare effects of T vs placebo treatment on NAFLD scores and liver scans in elderly hypogonadal men. METHODS: Secondary data analyses from 479 older hypogonadal men with total T < 275 ng/dL from The T Trials were performed. Three clinical liver fat scores-lipid accumulation product index, hepatic steatosis index, nonalcoholic fatty liver disease-metabolic syndrome score-and liver computed tomography (CT) Hounsfield units and liver to spleen ratio were evaluated at baseline and 12 months after treatment. RESULTS: There were no statistically significant differences of change in lipid accumulation product index (P = .98), hepatic steatosis index (P = .67), and nonalcoholic fatty liver disease-metabolic syndrome (P = .52) in 246 men treated with T compared with 233 treated with placebo for 12 months. Liver CT showed no statistically significant difference of change in Hounsfield units (P = .24; n = 71 for T, n = 69 for placebo) and liver to spleen ratio (P = .74; n = 55 for T, n = 62 for placebo) between the 2 groups. CONCLUSIONS: Our study did not show improvement of NAFLD in older hypogonadal men after 12 months of T vs placebo treatment, as assessed by 3 clinical scores and liver CT for hepatic steatosis. Future studies with longer treatment duration and additional NAFLD diagnostic modalities as primary outcome are warranted.

Surgical training of minimally invasive mitral valve repair on a patient-specific simulator improves surgical skills.

OBJECTIVES: Minimally invasive mitral valve repair (MVR) is considered one of the most challenging operations in cardiac surgery and requires much practice and experience. Simulation-based surgical training might be a method to support the learning process and help to flatten the steep learning curve of novices. The purpose of this study was to show the possible effects on learning of surgical training using a high-fidelity simulator with patient-specific mitral valve replicas. METHODS: Twenty-five participants were recruited to perform MVR on anatomically realistic valve models during different training sessions. After every session their performance was evaluated by a surgical expert regarding accuracy and duration for each step. A second blinded rater similarly assessed the performance after the study. Through repeated documentation of those parameters, their progress in learning was analysed, and gains in proficiency were evaluated. RESULTS: Participants showed significant performance enhancements in terms of both accuracy and time. Their surgical skills showed sizeable improvements after only 1 session. For example, the time to implant neo-chordae decreased by 24.64% (354 s-264 s, P < 0.001) and the time for annuloplasty by 4.01% (54 s-50 s, P = 0.165), whereas the number of irregular stitches for annuloplasty decreased from 52% to 24%.The significance of simulation-based surgical training as a tool for acquiring and training surgical skills was reviewed positively. CONCLUSIONS: The results of this study indicate that simulation-based surgical training is a valuable and effective method for learning reconstructive techniques of minimally invasive MVR and overall general dexterity.The novel learning and training options should be implemented in the surgical traineeship for systematic teaching of various surgical skills.

Racial and Ethnic Disparities in Phthalate Exposure and Preterm Birth: A Pooled Study of Sixteen U.S. Cohorts.

BACKGROUND: Phthalate exposures are ubiquitous during pregnancy and may contribute to racial and ethnic disparities in preterm birth. OBJECTIVES: We investigated race and ethnicity in the relationship between biomarkers of phthalate exposure and preterm birth by examining: a) how hypothetical reductions in racial and ethnic disparities in phthalate metabolites might reduce the probability of preterm birth; and b) exposure-response models stratified by race and ethnicity. METHODS: We pooled individual-level data on 6,045 pregnancies from 16 U.S. cohorts. We investigated covariate-adjusted differences in nine urinary phthalate metabolite concentrations by race and ethnicity [non-Hispanic White (White, 43%), non-Hispanic Black (Black, 13%), Hispanic/Latina (38%), and Asian/Pacific Islander (3%)]. Using g-computation, we estimated changes in the probability of preterm birth under hypothetical interventions to eliminate disparities in levels of urinary phthalate metabolites by proportionally lowering average concentrations in Black and Hispanic/Latina participants to be approximately equal to the averages in White participants. We also used race and ethnicity-stratified logistic regression to characterize associations between phthalate metabolites and preterm birth. RESULTS: In comparison with concentrations among White participants, adjusted mean phthalate metabolite concentrations were consistently higher among Black and Hispanic/Latina participants by 23%-148% and 4%-94%, respectively. Asian/Pacific Islander participants had metabolite levels that were similar to those of White participants. Hypothetical interventions to reduce disparities in metabolite mixtures were associated with lower probabilities of preterm birth for Black [13% relative reduction; 95% confidence interval (CI): -34%, 8.6%] and Hispanic/Latina (9% relative reduction; 95% CI: -19%, 0.8%) participants. Odds ratios for preterm birth in association with phthalate metabolites demonstrated heterogeneity by race and ethnicity for two individual metabolites (mono-n-butyl and monoisobutyl phthalate), with positive associations that were larger in magnitude observed among Black or Hispanic/Latina participants. CONCLUSIONS: Phthalate metabolite concentrations differed substantially by race and ethnicity. Our results show hypothetical interventions to reduce population-level racial and ethnic disparities in biomarkers of phthalate exposure could potentially reduce the probability of preterm birth. https://doi.org/10.1289/EHP12831.

Community-Based Wound Care Programs for Unhoused Individuals.

Wound care management for unhoused individuals is challenging due to the lack of healthcare infrastructure to handle the unique needs of this population. Therefore, we aimed to obtain insights for best practices and to establish a care clinic that is low threshold, community-based and meets the needs of unhoused people. We employed two approaches: (1) conduct a targeted narrative review of the literature of existing or proposed community-based program models that can address the wound care needs of unhoused individuals, and (2) assess cost-effectiveness and describe the results of a survey administered to unhoused clients and their health care providers at a community-based wound care program in Honolulu, Hawai'i. The literature search and screening yielded 11 articles relevant to the topic. Per the literature, existing community-based healthcare programs were successful when: (1) wound care services were incorporated into a broader social/health program, (2) cost-effective, and (3) comprehensive services were provided. Survey results in Honolulu found that the wound care program matched the needs of the targeted population and was cost-effective. Difficulty in following clients until wound closure and the sustainability of the program, particularly the lack of insurance reimbursement for street-based services, were perceived challenges. Additionally, the lack of insurance reimbursement for street-based wound care services continues to impact sustainability. Community-based programs can be successful in addressing the wound care needs of unhoused individuals if they address complex fundamental issues. This paper highlights existing gaps in logistics and policies that must be addressed to meet the specific medical needs of these vulnerable individuals.

Associations between neighborhood stress and maternal sex steroid hormones in pregnancy.

BACKGROUND: Neighborhood stressors (e.g., crime and deprivation) have been associated with adverse pregnancy outcomes including preterm birth and low birth weight. A potential mechanism is disruption of maternal endocrine pathways. While stress hormones (e.g., cortisol) have received much attention, other relevant hormones, including sex steroids, have been overlooked. METHODS: Pregnant women in the Understanding Pregnancy Signals and Infant Development (UPSIDE) study contributed biospecimens, questionnaires, and medical record data (n = 262). In each trimester, maternal serum total testosterone [TT], estrone, estradiol, and estriol were measured using LC/MS-MS and serum free testosterone was measured by equilibrium dialysis. In the third trimester, participants reported on neighborhood stress over the last year through the validated City Stress Inventory. We examined two subscales: 11-item neighborhood disorder (e.g., vacant buildings, crime) and 7-item exposure to violence (personal experiences of violence). Composite scores were calculated and examined categorically (quartile (Q) for neighborhood disorder and any/none for exposure to violence). We fitted linear mixed models examining associations between neighborhood stressors and sex steroid hormones across pregnancy as well as trimester-specific linear regression models, all adjusting for confounders. Secondarily, we stratified by fetal sex. Results are presented as percentage change (∆%) and 95% confidence interval (CI) in hormones. RESULTS: Most participants (73%) reported one or more exposures to neighborhood disorder; 22% reported any exposure to violence. In adjusted models, neighborhood disorder was associated with higher TT across pregnancy (Q2: %∆= 37.3, 95%CI: 13.2, 66.5; Q3: %∆= 22.2, 95%CI: 1.2, 47.5; and Q4: %∆= 25.7, 95%CI: 1.6, 55.3), with the strongest associations observed in the third trimester (Q2: %∆= 38.0, 95%CI: 10.6, 72.1; Q3: %∆= 29.2, 95%CI: 4.4, 59.9; and Q4: %∆=33.4, 95%CI: 4.9, 69.6). In stratified models, neighborhood disorder was associated with higher TT among women carrying male fetuses (%∆ range: 48.2-84.8). Exposure to violence was not associated with any hormones. CONCLUSION: Neighborhood disorder is associated with higher maternal testosterone levels, which may have implications for maternal and child health. Additional research is needed to understand the mechanisms by which neighborhood stress impacts endocrine physiology.

Practice and development of male contraception: European Academy of Andrology and American Society of Andrology guidelines.

BACKGROUNDS: Despite a wide spectrum of contraceptive methods for women, the unintended pregnancy rate remains high (45% in the US), with 50% resulting in abortion. Currently, 20% of global contraceptive use is male-directed, with a wide variation among countries due to limited availability and lack of efficacy. Worldwide studies indicate that >50% of men would opt to use a reversible method, and 90% of women would rely on their partner to use a contraceptive. Additional reasons for novel male contraceptive methods to be available include the increased life expectancy, sharing the reproductive risks among partners, social issues, the lack of pharma industry involvement and the lack of opinion makers advocating for male contraception. AIM: The present guidelines aim to review the status regarding male contraception, the current state of the art to support the clinical practice, recommend minimal requirements for new male contraceptive development and provide and grade updated, evidence-based recommendations from the European Society of Andrology (EAA) and the American Society of Andrology (ASA). METHODS: An expert panel of academicians appointed by the EAA and the ASA generated a consensus guideline according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system. RESULTS: Sixty evidence-based and graded recommendations were produced on couple-centered communication, behaviors, barrier methods, semen analysis and contraceptive efficacy, physical agents, surgical methods, actions before initiating male contraception, hormonal methods, non-hormonal methods, vaccines, and social and ethical considerations. CONCLUSION: As gender roles transform and gender equity is established in relationships, the male contribution to family planning must be facilitated. Efficient and safe male-directed methods must be evaluated and introduced into clinical practice, preferably reversible, either hormonal or non-hormonal. From a future perspective, identifying new hormonal combinations, suitable testicular targets, and emerging vas occlusion methods will produce novel molecules and products for male contraception.

Association between sex steroid hormones and subsequent hyperglycemia during pregnancy.

Objective: Sex steroid hormones may play a role in insulin resistance and glucose dysregulation. However, evidence regarding associations between early-pregnancy sex steroid hormones and hyperglycemia during pregnancy is limited. The primary objective of this study was to assess the relationships between first trimester sex steroid hormones and the subsequent development of hyperglycemia during pregnancy; with secondary evaluation of sex steroid hormones levels in mid-late pregnancy, concurrent with and subsequent to diagnosis of gestational diabetes. Methods: Retrospective analysis of a prospective pregnancy cohort study was conducted. Medically low-risk participants with no known major endocrine disorders were recruited in the first trimester of pregnancy (n=319). Sex steroid hormones in each trimester, including total testosterone, free testosterone, estrone, estradiol, and estriol, were assessed using high-performance liquid chromatography and tandem mass spectrometry. Glucose levels of the 1-hour oral glucose tolerance test and gestational diabetes diagnosis were abstracted from medical records. Multivariable linear regression models were fitted to assess the associations of individual first trimester sex steroids and glucose levels. Results: In adjusted models, first trimester total testosterone (ß=5.24, 95% CI: 0.01, 10.46, p=0.05) and free testosterone (ß=5.98, 95% CI: 0.97, 10.98, p=0.02) were positively associated with subsequent glucose concentrations and gestational diabetes diagnosis (total testosterone: OR=3.63, 95% CI: 1.50, 8.78; free testosterone: OR=3.69; 95% CI: 1.56, 8.73). First trimester estrone was also positively associated with gestational diabetes (OR=3.66, 95% CI: 1.56, 8.55). In mid-late pregnancy, pregnant people with gestational diabetes had lower total testosterone levels (ß=-0.19, 95% CI: -0.36, -0.02) after adjustment for first trimester total testosterone. Conclusion: Early-pregnancy sex steroid hormones, including total testosterone, free testosterone, and estrone, were positively associated with glucose levels and gestational diabetes in mid-late pregnancy. These hormones may serve as early predictors of gestational diabetes in combination with other risk factors.

Early prenatal sex steroids and sex-typed play behavior at 4 years of age.

During pregnancy, estrogens and testosterone influence brain development, resulting in sex-typical behavioral phenotypes. Prenatal testosterone exposure is associated with more male-typical behaviors in rodents, monkeys, and humans; however, few studies have examined the relationship between maternal sex hormones within the normal range and sex-dimorphic behaviors. In this study, we examined associations between prenatal estrogens and testosterone and sex-typical play in The Infant Development and the Environment Study (TIDES), a multicenter pregnancy cohort. We collected prenatal serum during the first trimester (mean=11.1 ± 2.6 weeks) and assessed child play behavior using the maternally completed Pre-School Activities Inventory (PSAI) at a mean age of 4.5 ± 0.3 years. This analysis includes mother-child pairs with complete data on hormones, play behavior, and covariates (n = 192 boys and 207 girls). No associations were seen between testosterone and PSAI scores in boys or girls or between estrogens and PSAI scores in boys. In girls, we observed an inverse relationship between feminine PSAI scores and both estradiol (E2) and estriol (E3) in multivariable linear regression analyses (E2: -0.11 [95% CI -0.20, -0.02]; E3: -0.44 [95% CI -0.83,-0.04]). Because the relationship between sex hormones and PSAI scores appeared nonlinear, we fit piecewise regression models to better fit the data and identify inflection points (point at which there is a significant change in slope). Piecewise regression analyses yielded inverse associations between masculine PSAI scores and estrone (E1) at values of E1 > 1340 pg/mL and E2 at values of E2 > 2870 pg/mL in girls. Further studies are needed to better understand the role of prenatal sex steroids on sexually dimorphic behavior.

Prenatal Cadmium Exposure and Maternal Sex Steroid Hormone Concentrations across Pregnancy.

Cadmium exposure has been associated with adverse perinatal outcomes. One possible mechanism is endocrine disruption. Studies of non-pregnant adults suggest that cadmium impacts androgen production; here, we examined these associations during pregnancy. Participants in the Understanding Pregnancy Signals and Infant Development (UPSIDE) cohort provided biospecimens and questionnaire data in each trimester (n = 272). We quantified urinary cadmium, serum total testosterone (TT), estrone, estradiol, and estriol and serum free testosterone (fT). In adjusted longitudinal models, we examined sex steroid concentrations across pregnancy in relation to specific gravity-adjusted, ln-transformed cadmium concentrations. Additionally, we examined trimester-specific associations and stratified models by fetal sex. Results are presented as percent change (%∆) in hormone concentrations. In longitudinal models, higher cadmium concentrations were associated with lower fT across pregnancy (%∆ = -5.19, 95%CI: -8.33, -1.93), with no differences in other hormones observed. In trimester-specific models, higher cadmium concentrations were associated with lower TT in trimester 2 (%∆ = -15.26, 95%CI: -25.15, -4.06) and lower fT in trimester 3 (%∆ = -14.35, 95%CI: -19.75, -8.59). Associations with TT were stronger in pregnancies carrying female fetuses. Maternal cadmium exposure may be associated with reduced testosterone in pregnancy. Additional work is necessary to understand how alterations in gestational testosterone activity may impact pregnancy and child health.

Tools for deprescribing in severe dementia: A scoping review.

OBJECTIVES: Identification of inappropriate medications in people living with severe dementia is a complex task which has the potential to reduce avoidable adverse events and increase quality of life. This scoping review (i) identifies published tools intended to aid deprescribing in people living with severe dementia and (ii) describes evaluations of their usefulness in clinical practice. METHODS: A scoping review was undertaken, with Medline, Medline in Process, EMBASE, Cochrane Library, CINAHL, Scopus and Web of Science databases, from inception to April 2023, identifying tools for deprescribing in severe dementia. A tool was considered as any resource for deprescribing, including clinical study, scientific publication, health guideline, website, algorithm, model or framework. Two reviewers assessed the eligibility of articles through abstract and full text review. Data extracted from included studies were summarized through narrative synthesis. RESULTS: Twelve studies were identified from 18,633 articles screened. Tools were categorized into three groups: deprescribing interventions (n = 2), consensus-based deprescribing criteria (n = 5), and medication-specific recommendations (n = 5). Six studies developed tools using expert opinion and ten tools were tested in people living with severe dementia. Only one of the four studies that evaluated patient outcomes (cognitive change and adverse events) identified clear clinical benefit from medication withdrawal. CONCLUSIONS: Clinical application of current deprescribing tools is limited due to the lack of evidence-based research on the clinical effects of individual medication deprescribing in people with severe dementia. Further research on patient outcomes, including cognitive change and adverse events, will help clarify the role of these tools in clinical care.