Characterisation of ciclesonide metabolism in human placentae across gestation.

INTRODUCTION: Current clinical management of pregnancies at risk of preterm delivery includes maternal antenatal corticosteroid (ACS) treatment. ACS activate the glucocorticoid receptor (GR) in all fetal tissues, maturing the lungs at the cost of impaired brain development, creating a need for novel treatments. The prodrug ciclesonide (CIC) activates the GR only when converted to des-CIC by specific enzymes, including acetylcholinesterase (ACHE) and carboxylesterase 1 and 2 (CES1, CES2). Importantly, the human placenta expresses ACHE and CES, and could potentially produce des-CIC, resulting in systemic fetal exposure and GR activation in all fetal tissues. We therefore investigated CES gene expression and conversion of CIC to des-CIC in human placentae collected during the second trimester (Tri2), and at preterm and term birth. METHODS: Differential expression analysis was performed in Tri2 (n = 27), preterm (n = 34), and term (n = 40) placentae using the DESeq2 R-package. Conversion of CIC to des-CIC was measured in a subset of placenta samples (Tri2 n = 7, preterm n = 26, term n = 20) using functional assays. RESULTS: ACHE mRNA expression was higher in Tri2 male than preterm and term male placentae only, whereas CES1 mRNA expression was higher in Tri2 than preterm or term placentae of both sexes. Conversion of CIC to des-CIC did not differ between gestational ages. DISCUSSION: Conversion of CIC to des-CIC by the human placenta may preclude its use as a novel GR-agonist in threatened preterm birth. In vivo studies are required to confirm the extent to which placental activation occurs after maternal treatment.

Assessing Contraceptive Switching and Discontinuation Over 3 Years in the HER Salt Lake Study.

OBJECTIVE: To assess contraceptive switching and discontinuation among participants enrolled in a contraceptive access project over 3 years and to identify variables associated with contraceptive change. METHODS: The HER Salt Lake study enrolled individuals between 2015 and 2017 from four clinics in Salt Lake County into a prospective, longitudinal cohort. All participants were able to switch or discontinue at no cost (between March 2016 and March 2020). We collected eight follow-up surveys over 3 years after enrollment. Each survey wave included questions about method use in the previous 4 weeks. We categorized participants in three ways, allowing for time-varying outcomes by wave: 1) those who reported using the same method as previous wave (continuers), 2) those who reported using a different method from previous wave (switchers), and 3) those who reported using no contraceptive method at that wave (discontinuers). We report the frequency of outcomes and conducted multinomial regression models assessing predictors of switching and discontinuation. RESULTS: Among 4,289 participants included in this analysis, 2,179 (50.8%) reported at least one instance of switching or discontinuation, and 2,110 (49.1%) reported continuing with their baseline method at the end of the study. Those reporting method change (switching or discontinuing) reported an average of 1.93 change events over the study follow-up period (range 1-8). Among those reporting any method change, 522 participants (23.9%) reporting at least one instance of both switching and discontinuation. Among those reporting any instance of discontinuation (n=966), 498 (51.6%) never reported uptake of a subsequent method. Among those who did report a subsequent method (n=468), 210 (44.8%) reported restarting a previously used method, and 258 (55.1%) reported starting a new method. Although we identified overlap among variables associated with switching and discontinuation, other predictors were discordant between switching and discontinuation. CONCLUSION: New contraceptive users commonly switch and discontinue methods. User behavior is associated with certain demographic characteristics and pregnancy planning. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT02734199.

Population genomics provide insight into ancestral relationships and diversity of the feral horses of Theodore Roosevelt National Park.

Theodore Roosevelt National Park (TRNP) manages a herd of feral horses (Equus caballus) which was present on the landscape prior to the establishment of the park. The population presents a unique scenario in that it has experienced fairly intensive and well-documented management since the park's establishment, including herd size reductions, intentional introduction of diversity, and subsequent attempts to remove introduced lineages. This provides an interesting case study on the genetic effects of diverse evolutionary forces on an isolated feral population. To explore the effects of these forces and clarify the relationship of this feral herd with other horses, we used genome-wide markers to examine the population structure of a combined dataset containing common established breeds. Using the Illumina Equine 70k BeadChip, we sampled SNPs across the genome for 118 TRNP horses and evaluated the inbreeding coefficient f and runs of homozygosity (RoH). To identify breed relationships, we compared 23 representative TRNP samples with 792 horses from 35 different breeds using genomic population structure analyses. Mean f of TRNP horses was 0.180, while the mean f for all other breeds in the dataset was 0.116 (SD 0.079). RoH analysis indicates that the TRNP population has experienced recent inbreeding in a timeframe consistent with their management. With Bayesian clustering, PCA, and maximum likelihood phylogeny, TRNP horses show genetic differentiation from other breeds, likely due to isolation, historical population bottlenecks, and genetic drift. However, maximum likelihood phylogeny places them with moderate confidence (76.8%) among draft breeds, which is consistent with the known history of breeds used on early North Dakota ranches and stallions subsequently introduced to the park herd. These findings will help resolve speculation about the origins of the herd and inform management decisions for the TRNP herd.

Contraceptive Risk Events among Family Planning Specialists: a Cross Sectional Study.

Background: Proponents of abortion restriction cite advancements in contraceptive technology as a reason against the need for abortion care today, most recently through oral arguments in the Supreme Court of the United States case, Dobbs v. Jackson Women's Health. However, consistent and correct use of contraception requires reproductive health literacy. Our objectives were to quantify contraceptive risk events and assess contraceptive history and preferences among a population well-equipped to evade contraceptive risks, family planning specialists following initiation of their medical training. "Risk events" are defined as reported episodes of contraceptive failure, emergency contraception use and/or unprotected or underprotected intercourse. Methods: This was a cross-sectional study among current members of a professional organization of family planning specialists. Inclusion criteria included: status as a current or retired clinician, consensual penile-vaginal intercourse since the start of medical training, and personal or partner capacity to become pregnant. Descriptive statistics were performed. This study was IRB exempt. Results: Among 229 respondents, 157 (69%) reported experiencing a contraceptive risk event since training. Twenty-nine (13%) respondents reported an occurrence within the last year. By category, 47% (108/229; 3 reported unknown) reported under- or unprotected intercourse, 35% (81/229) reported emergency contraception use, and 52% of participants (117/227; 2 unknown) reported known or suspected contraceptive failure. The mean number of contraceptive methods used was 3.7 (SD 1.7) out of the 13 methods listed. Almost all (97%) participants reported at least one method was not an acceptable option, with a mean of 5.6 (SD 2.7) of the 13 listed methods. Conclusions: The majority of family planning specialists have experienced contraceptive risk events during times of active pregnancy prevention since their medical training. Contraceptive method change is common and most respondents were limited in the number of methods that were personally acceptable to them. Dialogue idealizing the role of contraception in minimizing or eliminating abortion need is simplistic and inaccurately represents the lived realities of pregnancy-capable individuals and their partners, including among those with exceptional contraceptive literacy and access.

Extracellular vesicles alter trophoblast function in pregnancies complicated by COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and resulting coronavirus disease (COVID-19) causes placental dysfunction, which increases the risk of adverse pregnancy outcomes. While abnormal placental pathology resulting from COVID-19 is common, direct infection of the placenta is rare. This suggests that pathophysiology associated with maternal COVID-19, rather than direct placental infection, is responsible for placental dysfunction and alteration of the placental transcriptome. We hypothesized that maternal circulating extracellular vesicles (EVs), altered by COVID-19 during pregnancy, contribute to placental dysfunction. To examine this hypothesis, we characterized maternal circulating EVs from pregnancies complicated by COVID-19 and tested their effects on trophoblast cell physiology in vitro . We found that the gestational timing of COVID-19 is a major determinant of circulating EV function and cargo. In vitro trophoblast exposure to EVs isolated from patients with an active infection at the time of delivery, but not EVs isolated from Controls, altered key trophoblast functions including hormone production and invasion. Thus, circulating EVs from participants with an active infection, both symptomatic and asymptomatic cases, can disrupt vital trophoblast functions. EV cargo differed between participants with COVID-19 and Controls, which may contribute to the disruption of the placental transcriptome and morphology. Our findings show that COVID-19 can have effects throughout pregnancy on circulating EVs and circulating EVs are likely to participate in placental dysfunction induced by COVID-19.

Frequency of same-day contraceptive initiation, recent unprotected intercourse, and pregnancy risk: a prospective cohort study of multiple contraceptive methods.

BACKGROUND: Same-day start removes barriers to contraceptive initiation and may reduce the risk of unintended pregnancy. It may be appropriate for all contraceptive methods, but we lack data comparing methods. OBJECTIVE: This study aimed to assess the frequency of same-day start with 6 contraceptive methods among new contraceptive users and describe the efficacy of same-day start in terms of first-cycle pregnancy risk overall and by each method. STUDY DESIGN: Using prospective data from the HER Salt Lake Contraceptive Initiative, we identified and assessed outcomes for participants initiating a new method of contraception beyond the first 7 days of their menstrual cycle (same-day start). Enrolled participants at 4 family planning clinics in Salt Lake County, Utah between September 2015 and March 2017 received their method of choice regardless of their cycle day or recent unprotected intercourse. All participants self-reported last menstrual period data and unprotected intercourse events in the previous 2 weeks. We excluded participants who received care immediately after or within 2 weeks of abortion care. Clinical electronic health records provided information on contraceptive method initiation and use of oral emergency contraception. Participants reported pregnancy outcomes in 1-, 3-, and 6-month follow-up surveys with clinic verification to identify any pregnancy resulting from same-day initiation. The primary outcomes report the frequency of same-day start use and first-cycle pregnancy risk among same-day start users of all contraceptive methods. The secondary outcomes include frequency of and pregnancy risk in the first cycle of use among same-day start contraception users by method. We also report the frequency of unprotected intercourse within 5 days and 6 to 14 days of contraception initiation, frequency of concomitant receipt of oral emergency contraception with initiation of ongoing contraception, and pregnancy risk with these exposures. We analyzed pregnancy risk for each contraceptive method initiated on the same day and assessed the simultaneous use of oral emergency contraception. RESULTS: Of the 3568 individuals enrolled, we identified most as same-day start users (n=2575/3568; 72.2%), with 1 in 8 of those reporting unprotected intercourse in the previous 5 days (n=322/2575; 12.5%) and 1 in 10 reporting unprotected intercourse 6 to 14 days before contraceptive method initiation (n=254/2575; 9.9%). We identified 11 pregnancies among same-day start users (0.4%; 95% confidence interval, 0.2-0.7), as opposed to 1 (0.1%; 95% confidence interval, 0.002-0.6) among those who initiated contraception within 7 days from the last menstrual period. Users of oral hormonal contraception and vaginal hormonal methods reported the highest first-cycle pregnancy rates (1.0-1.2). Among same-day start users, 174 (6.8%) received oral emergency contraception at enrollment in conjunction with another method. Among the same-day start users who received emergency contraception at initiation, 4 (2.3%) pregnancies were reported. CONCLUSION: Same-day start is common and associated with a low pregnancy risk. Using the "any method, any-time" approach better meets contraceptive clients' needs and maintains a low risk of pregnancy.

Factors associated with a negative Patient Acceptable Symptom State (PASS) response with intrauterine device placement: A retrospective survey of HER Salt Lake participants.

OBJECTIVES: In an established cohort of HER Salt Lake Contraceptive Initiative participants with a prior intrauterine device (IUD) placement, we sought to (1) define the proportion of participants who reported a negative Patient Acceptable Symptom State (PASS) response, (2) explore factors associated with an unacceptable PASS response, and (3) identify pain management preferences for IUD placement. STUDY DESIGN: A retrospective survey was sent to 1440 HER Salt Lake IUD users. A PASS question queried IUD placement pain experience acceptability. We explored associations between an unacceptable PASS response and sociodemographic, reproductive and other individual characteristics using t-tests, chi-square tests, and multivariable logistic regression. RESULTS: Of those surveyed, 620 responded (43%), and 41.6% reported an unacceptable PASS response. Those with an unacceptable PASS response reported a significantly higher experienced pain level (79.2 mm vs 51.8 mm; p < 0.01) than those with an acceptable response, were more likely to have an anxiety diagnosis (47.7% vs 37.1%; p < 0.01), and have a trauma history (33.7% vs 25.1%; p = 0.02). Most patients were not offered pain control options, but 29.4% used ibuprofen and 25.3% had a support person. Regardless of PASS response, if offered, 59.0% desired numbing medication, 56.8% ibuprofen, 51% heating pad, 33.2% support person, and 31.8% anti-anxiety medication, among others. In our multivariable logistic regression model, higher pain was associated with unacceptable PASS response (OR 1.07, 95% CI 1.05-1.08; p < 0.01). CONCLUSIONS: The common finding of unacceptable pain experiences with IUD placement may cause negative perceptions of an otherwise desirable method. Incorporation of the PASS response into IUD pain management studies could expand our pain experience understanding. IMPLICATIONS: IUD placement resulted in unacceptable pain experiences for 41.6% of respondents. Screening for anxiety and trauma history could identify at-risk patients to individualize pain management strategies. Incorporation of the PASS into future IUD pain management studies could result in a more comprehensive, patient-centered measure of patient experiences.

Necrophagous insect species succession on decomposed pig carcasses in North Dakota, USA.

Necrophagous insect species are widely used during death investigations primarily for the estimation of the minimum postmortem interval, since these species use decomposing organic matter for feeding, oviposition, and larval development. The development stages and successional colonization patterns provide important information for shorter or longer postmortem time intervals. Diptera species are the predominant taxa recovered from decomposed bodies. The temperature variance/seasonality is the main factor affecting the time presence and activity of these species. Other factors, such as geographical location, antemortem conditions, and cause of death, can influence the presence and succession of necrophagous entomofauna. Consequently, successional studies and information regarding species colonization patterns are needed for each geographical region to be used as reference data during death investigations. This study addressed the need to collect forensic entomological data for the State of North Dakota, within the first necrophagous entomofauna diversity report for the month of July 2022, using pig carcasses as human analogs. During the experimental period, 18 species of Diptera and Coleoptera were identified, with 10 new state records, while Calliphoridae was found to be the predominant family. The resulted data on necrophagous insect species diversity and dynamics from exposed pig carcasses will strengthen the current knowledge on forensic entomology in North Dakota and will serve as reference data to be used during death investigations in the Great Plains region.

Building an implementation framework to address unmet contraceptive care needs in a carceral setting: a systematic review.

BACKGROUND: The provision of contraceptive care for incarcerated individuals has been largely inconsistent and has contributed to, at best, inadequate care, and at worst reproductive abuses, violence, and coercion. While previous research has identified strategies to remedy known issues, to date, very few recommendations have been implemented across the carceral system. To address this, we conducted a systematic review of policy and practice recommendations to improve contraceptive care to reproductive-aged, incarcerated individuals in the United States. METHODS: We conducted this systematic review utilizing the Joanna Briggs Institute methodology and framed it within the National Implementation Research Network's (NIRN) Exploration stage. We searched PubMed, PSYCInfo, SCOPUS, ProQuest, Web of Science, MedLine, Social Science Citation Index and reference sections of included materials. Basic study information, explicitly stated policy and practice recommendations, and discussions and conclusions that subtly provide recommendations were extracted in full text. We utilized a thematic analysis approach to analyze the extracted text. RESULTS: A total of 45 materials met the inclusion criteria. Seven overarching themes were identified: 1) policy changes needed to implement care; 2) need for contraceptive care in carceral systems; 3) justice agency barriers regarding contraceptive care provision; 4) policy barriers to contraceptive access; 5) funding strategies to improve care; 6) patient preferences for contraceptive care delivery; and 7) healthcare provider knowledge regarding contraceptive care. The seven themes identified shed light on the need for, gaps, barriers, and facilitators of current contraceptive care provision to incarcerated individuals. CONCLUSION: This systematic review accomplished two goals of NIRN's Exploration stage. First, the compiled evidence identified a clear need for change regarding policies and practices pertaining to contraceptive care provision to incarcerated individuals in the United States. Second, our findings identified several evidence-based solutions supported both by research and professional healthcare organizations to address the identified need for change. This study provides an initial blueprint for correctional agencies to implement the necessary changes for improving contraceptive care provision to incarcerated populations. The correctional system is in a unique position to deliver much-needed care, which would result in many potential benefits to the individuals, correctional system, and community at large.

A stakeholder-developed logic model to improve utilization of pharmacy-prescribed contraception in Utah.

BACKGROUND: Currently, 20 states in the USA have passed policies allowing pharmacists to prescribe short-acting hormonal contraception, including pills, patches, and vaginal rings. Yet, utilization of these services remains limited. The purpose of this study was to (a) assess barriers and facilitators of pharmacy contraceptive dispensing among contraceptive users, pharmacists, and healthcare providers in Utah and (b) adapt and propose an evidence-based contraceptive intervention in the pharmacy environment. METHODS: We conducted 6 focus groups among contraceptive users, pharmacists, and healthcare providers assessing current barriers and facilitators to pharmacy prescribing. We coded transcripts of these focus groups to the Consolidated Framework for Implementation Research, Version 2.0 (CFIR) and characterized the findings based on the Expert Recommendations for Implementing Change (ERIC) Barrier-Busting tool. Based on the CFIR findings and ERIC strategies output, we adapted an existing evidence-based intervention (a contraceptive access initiative) to the Utah pharmacy environment. We then convened a pharmacy stakeholder meeting and presented elements of an Implementation Research Logic Model and obtained feedback. We coded this feedback to the CFIR framework to finalize an Implementation Research Logic Model for a proposed implementation approach to improving contraceptive prescribing. RESULTS: Initial focus group responses clustered around specific implementation barriers including financial barriers (cost for patients, as well as lack of reimbursement for pharmacist's time); lack of awareness of the service (on the part of patients, pharmacists, and health care providers); need for updated tools for contraceptive counseling and scheduling; and need for increased pharmacists education to conduct contraceptive counseling. Proposed adaptations to the existing contraceptive access intervention included development of a technology-based patient/pharmacist screener tool and a healthcare provider/pharmacist contraceptive referral network. Stakeholders identified pharmacist reimbursement as the top priority for improving utilization. CONCLUSIONS: Elements of contraceptive access initiatives mapped well as proposed implementation strategies to improving utilization of contraceptive prescribing in pharmacies.

Preconception and developmental DEHP exposure alter liver metabolism in a sex-dependent manner in adult mouse offspring.

Environmental exposure to endocrine disrupting chemicals (EDCs) during critical periods of development is associated with an increased risk of metabolic diseases, including hepatic steatosis and obesity. Di-2-ethylhexyl-phthalate (DEHP) is an EDC strongly associated with these metabolic abnormalities. DEHP developmental windows of susceptibility are unknown yet have important public health implications. The purpose of this study was to identify these windows of susceptibility and determine whether developmental DEHP exposure alters hepatic metabolism later in life. Dams were exposed to control or feed containing human exposure relevant doses of DEHP (50 µg/kg BW/d) and high dose DEHP (10 mg/kg BW/d) from preconception until weaning or only exposed to DEHP during preconception. Post-weaning, all offspring were fed a control diet throughout adulthood. Using the Metabolon Untargeted Metabolomics platform, we identified 148 significant metabolites in female adult livers that were altered by preconception-gestation-lactation DEHP exposure. We found a significant increase in the levels of acylcarnitines, diacylglycerols, sphingolipids, glutathione, purines, and pyrimidines in DEHP-exposed female livers compared to controls. These changes in fatty acid oxidation and oxidative stress-related metabolites were correlated with hepatic changes including microvesicular steatosis, hepatocyte swelling, inflammation. In contrast to females, we observed fewer metabolic alterations in male offspring, which were uniquely found in preconception-only low dose DEHP exposure group. Although we found that preconception-gestational-lactation exposure causes the most liver pathology, we surprisingly found preconception exposure linked to an abnormal liver metabolome. We also found that two doses exhibited non-monotonic DEHP-induced changes in the liver. Collectively, these findings suggest that metabolic changes in the adult liver of offspring exposed periconceptionally to DHEP depends on the timing of exposure, dose, and sex.

Wildfires and COVID-19: syndemic impact on maternal and child health.

The prevailing COVID-19 pandemic and climate change-mediated wildfires can combine to impact maternal-child health, yet this connection remains understudied. To shape policies and design interventions to mitigate the combined effects of future global catastrophes, it is vital to holistically evaluate the impact of syndemics on maternal-child health.

Embryonic Stem Cell-Derived Neurons as a Model System for Epigenome Maturation during Development.

DNA methylation in neurons is directly linked to neuronal genome regulation and maturation. Unlike other tissues, vertebrate neurons accumulate high levels of atypical DNA methylation in the CH sequence context (mCH) during early postnatal brain development. Here, we investigate to what extent neurons derived in vitro from both mouse and human pluripotent stem cells recapitulate in vivo DNA methylation patterns. While human ESC-derived neurons did not accumulate mCH in either 2D culture or 3D organoid models even after prolonged culture, cortical neurons derived from mouse ESCs acquired in vivo levels of mCH over a similar time period in both primary neuron cultures and in vivo development. mESC-derived neuron mCH deposition was coincident with a transient increase in Dnmt3a, preceded by the postmitotic marker Rbfox3 (NeuN), was enriched at the nuclear lamina, and negatively correlated with gene expression. We further found that methylation patterning subtly differed between in vitro mES-derived and in vivo neurons, suggesting the involvement of additional noncell autonomous processes. Our findings show that mouse ESC-derived neurons, in contrast to those of humans, can recapitulate the unique DNA methylation landscape of adult neurons in vitro over experimentally tractable timeframes, which allows their use as a model system to study epigenome maturation over development.

Women's Health Provider Perspectives on Reproductive Services Provision in the Veterans Health Administration.

OBJECTIVES: Women veterans are a fast-growing population in the Veterans Health Administration (VHA), and ensuring reproductive service availability is a VHA priority. As such, we sought to explore barriers and facilitators to VHA reproductive service provision across a catchment area from women's health providers' perspectives. METHODS: We performed a mixed-methods study, including semistructured, qualitative provider interviews with a quantitative survey on training, comfort, and knowledge of reproductive services. All women's health providers and their support staff from the Salt Lake City Veterans Affairs Medical Center and nine VHA community-based outpatient clinics were asked to participate. We conducted qualitative interviews and knowledge surveys with providers and staff to explore training, care processes, and improvement opportunities in reproductive service provision. We completed descriptive analyses of all of the quantitative data and used an open, iterative process to analyze provider interviews for emergent themes. RESULTS: We interviewed 15 providers (7 advanced practice nurses, 4 registered nurses, and 4 physicians) across nine sites (50% response rate). The commonly identified barriers included provider training and staffing, scheduling/referral processes, inconsistent services/supplies, and lack of veteran awareness of reproductive services. Facilitators included prior non-VHA reproductive health experience among providers, invested support staff, and the integrated VHA health system. CONCLUSIONS: Addressing barriers to VHA reproductive healthcare provision may overcome reproductive service variations related to clinic location and improve reproductive health outcomes for women veterans.

Assessing contraceptive use as a continuum: outcomes of a qualitative assessment of the contraceptive journey.

BACKGROUND: Contraceptive use is often a multi-decade experience for people who can become pregnant, yet few studies have assessed how this ongoing process impacts contraceptive decision-making in the context of the reproductive life course. METHODS: We conducted in-depth interviews assessing the contraceptive journeys of 33 reproductive-aged people who had previously received no-cost contraception through a contraceptive initiative in Utah. We coded these interviews using modified grounded theory. RESULTS: A person's contraceptive journey occurred in four phases: identification of need, method initiation, method use, and method discontinuation. Within these phases, there were five main areas of decisional influence: physiological factors, values, experiences, circumstances, and relationships. Participant stories demonstrated the ongoing and complex process of navigating contraception across these ever-changing aspects. Individuals stressed the lack of any "right" method of contraception in decision-making and advised healthcare providers to approach contraceptive conversations and provision from positions of method neutrality and whole-person perspectives. CONCLUSIONS: Contraception is a unique health intervention that requires ongoing decision-making without a particular "right" answer. As such, change over time is normal, more method options are needed, and contraceptive counseling should account for a person's contraceptive journey.

Switching and discontinuation of participant-masked randomization to a copper or levonorgestrel intrauterine device when presenting for emergency contraception.

OBJECTIVES: Examine intrauterine device (IUD) switching or discontinuation up to 6 months after participant-masked randomization to different IUDs. STUDY DESIGN: Participants were randomized 1:1 to the copper T380A or levonorgestrel 52 mg IUD for emergency contraception and informed they could switch IUD type without cost at any time. RESULTS: Of the 327 subjects allocated to the levonorgestrel IUD, 7 (2.1%) switched their IUD type by 6 months versus 18 (5.5%) of the 328 copper IUD users (RR: 0.4 [95% CI: 0.2, 0.9], p = 0.03). Six-month IUD discontinuation occurred in 34 (10.4%) levonorgestrel and 35 (10.7%) copper IUD users. CONCLUSION: Individuals randomly assigned to IUD type at presentation for emergency contraception continue their assigned IUDs at high rates over 6 months. IMPLICATIONS: While many recruited individuals declined enrollment, those who accepted randomization had high continuation rates; the high continuation and low cross-over supports using IUD randomization as a tool for future investigation. Participants' similar rates of and reasons for switching and discontinuation by IUD type over the study period may impact clinical counseling.

Major locus on ECA18 influences effectiveness of GonaCon vaccine in feral horses.

Contraceptive vaccines are used to reduce birth rates in wild and feral animal populations. While the immunocontraceptive GonaCon-Equine has proven effective in reducing fertility among female feral horses, there is individual variation in the duration of infertility following treatment. To identify genetic factors influencing the effectiveness of GonaCon-Equine, we conducted a genome-wide association study of 88 mares from a feral population genotyped using the Illumina GGP Equine 70k SNP array. Contraceptive treatment schedules and long-term foaling rates have been recorded for each individual. We used mixed linear models to control for relatedness among mares. We found a significant association (p < 5 ×10-8) with a locus on equine chromosome 18. The most likely candidate genes in this region are STAT1 and STAT4, which are both involved in immune system function. Variation in STAT function could affect the immune response to the vaccine, leading to variation in contraceptive efficacy. Additional SNPs reaching a less stringent threshold of significance (p < 5 ×10-6) were located on other chromosomes near known immune system genes, supporting the hypothesis that variation in immunocontraceptive efficacy can be attributed to genetic variation in immune response rather than fertility genes.

One-year pregnancy and continuation rates after placement of levonorgestrel or copper intrauterine devices for emergency contraception: a randomized controlled trial.

BACKGROUND: Recent evidence demonstrates the effectiveness of the levonorgestrel 52-mg intrauterine device for emergency contraception vs the copper T380A intrauterine device. Of note, 1-year pregnancy and continuation rates after intrauterine device placement for emergency contraception remain understudied. OBJECTIVE: This study compared 1-year pregnancy and intrauterine device continuation rates and reasons for discontinuation among emergency contraception users randomized to the levonorgestrel 52-mg intrauterine device or the copper intrauterine device. STUDY DESIGN: This participant-masked, randomized noninferiority trial recruited emergency contraception individuals desiring an intrauterine device from 6 Utah family planning clinics between August 2016 and December 2019. Participants were randomized 1:1 to the levonorgestrel 52-mg intrauterine device group or the copper T380A intrauterine device group. Treatment allocation was revealed to participants at the 1-month follow-up. Trained personnel followed up the participants by phone, text, or e-mail at 5 time points in 1 year and reviewed electronic health records for pregnancy and intrauterine device continuation outcomes for both confirmation and nonresponders. We assessed the reasons for the discontinuation and used Cox proportional-hazard models, Kaplan-Meier estimates, and log-rank tests to assess differences in the continuation and pregnancy rates between the groups. RESULTS: The levonorgestrel and copper intrauterine device groups included 327 and 328 participants, respectively, receiving the respective interventions. By intention-to-treat analysis at 1 year, the pregnancy rates were similar between intrauterine device types (2.8% [9/327] in levonorgestrel 52-mg intrauterine device vs 3.0% [10/328] in copper intrauterine device; risk ratio, 0.9; 95% confidence interval, 0.4-2.2; P=.82). Most pregnancies occurred in participants after intrauterine device removal, with only 1 device failure in each group. Of note, 1-year continuation rates did not differ between groups with 204 of 327 levonorgestrel 52-mg intrauterine device users (62.4%) and 183 of 328 copper T380A intrauterine device users (55.8%) continuing intrauterine device use at 1 year (risk ratio, 1.1; 95% confidence interval, 1.0-1.2; P=.09). There were differences concerning the reasons for discontinuation between intrauterine device types, with more bleeding and cramping cited among copper intrauterine device users. CONCLUSION: The pregnancy rates were low and similar between intrauterine device types. Of note, 6 of 10 intrauterine device emergency contraception users continued use at 1 year. Moreover, 1-year continuation rates were similar between intrauterine device types.

Improving access to highly effective emergency contraception: an assessment of barriers and facilitators to integrating the levonorgestrel IUD as emergency contraception using two applications of the Consolidated Framework for Implementation Research.

BACKGROUND: Emergency contraception prevents unwanted pregnancy after sexual intercourse. New evidence has demonstrated that the levonorgestrel 52 mg IUD is a highly effective method of emergency contraception. However, translating this research finding into clinical practice faces existing barriers to IUD access, including costs and provider training, novel barriers of providing IUDs for emergency contraception at unscheduled appointments. The purpose of this study was to identify barriers and facilitators to the utilization of the levonorgestrel IUD as emergency contraception from client, provider, and health systems perspectives. METHODS: We conducted English and Spanish-speaking focus groups (n=5) of both contraceptive users (n=22) and providers (n=13) to examine how the levonorgestrel IUD as EC was perceived and understood by these populations and to determine barriers and facilitators of utilization. We used findings from our focus groups to design a high-fidelity in-situ simulation scenario around EC that we pilot tested with clinical teams in three settings (a county health department, a community clinic, and a midwifery clinic), to further explore structural and health systems barriers to care. Simulation scenarios examined health system barriers to the provision of the levonorgestrel IUD as EC. We coded both focus groups and in-clinic simulations using the modified Consolidated Framework for Implementation Research (CFIR). We then applied our findings to the CFIR-Expert Recommendations for Implementing Change (ERIC) Barrier Busting Tool and mapped results to implement recommendations provided by participants. RESULTS: Ultimately, 9 constructs from the CFIR were consistently identified across focus groups and simulations. Main barriers included suboptimal knowledge and acceptability of the intervention itself, appropriately addressing knowledge and education needs among both providers and contraceptive clients, and adequately accounting for structural barriers inherent in the health system. The CFIR-ERIC Barrier Busting Tool identified eight strategies to improve levonorgestrel IUD as EC access: identifying implementation champions, conducting educational meetings, preparing educational toolkits, involving patients and their partners in implementation, conducting a local needs assessment, distributing educational materials, and obtaining patient feedback. CONCLUSIONS: To sustainably incorporate the levonorgestrel IUD as EC into clinical practice, education, health systems strengthening, and policy changes will be necessary.

Human prefrontal cortex gene regulatory dynamics from gestation to adulthood at single-cell resolution.

Human brain development is underpinned by cellular and molecular reconfigurations continuing into the third decade of life. To reveal cell dynamics orchestrating neural maturation, we profiled human prefrontal cortex gene expression and chromatin accessibility at single-cell resolution from gestation to adulthood. Integrative analyses define the dynamic trajectories of each cell type, revealing major gene expression reconfiguration at the prenatal-to-postnatal transition in all cell types followed by continuous reconfiguration into adulthood and identifying regulatory networks guiding cellular developmental programs, states, and functions. We uncover links between expression dynamics and developmental milestones, characterize the diverse timing of when cells acquire adult-like states, and identify molecular convergence from distinct developmental origins. We further reveal cellular dynamics and their regulators implicated in neurological disorders. Finally, using this reference, we benchmark cell identities and maturation states in organoid models. Together, this captures the dynamic regulatory landscape of human cortical development.