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.

I'm eating for two: parental dietary effects on offspring metabolism.

It has long been understood that the pathogenesis of complex diseases such as diabetes includes both genetic and environmental components. More recently, it has become clear that not only does an individual's environment influence their own metabolism, but in some cases, the environment experienced by their parents may also contribute to their risk of metabolic disease. Here, we review the evidence that parental diet influences metabolic phenotype in offspring in mammals and provide a current survey of our mechanistic understanding of these effects.

Levonorgestrel vs. Copper Intrauterine Devices for Emergency Contraception.

BACKGROUND: In the United States, more intrauterine device (IUD) users select levonorgestrel IUDs than copper IUDs for long-term contraception. Currently, clinicians offer only copper IUDs for emergency contraception because data are lacking on the efficacy of the levonorgestrel IUD for this purpose. METHODS: This randomized noninferiority trial, in which participants were unaware of the group assignments, was conducted at six clinics in Utah and included women who sought emergency contraception after at least one episode of unprotected intercourse within 5 days before presentation and agreed to placement of an IUD. We randomly assigned participants in a 1:1 ratio to receive a levonorgestrel 52-mg IUD or a copper T380A IUD. The primary outcome was a positive urine pregnancy test 1 month after IUD insertion. When a 1-month urine pregnancy test was unavailable, we used survey and health record data to determine pregnancy status. The prespecified noninferiority margin was 2.5 percentage points. RESULTS: Among the 355 participants randomly assigned to receive levonorgestrel IUDs and 356 assigned to receive copper IUDs, 317 and 321, respectively, received the interventions and provided 1-month outcome data. Of these, 290 in the levonorgestrel group and 300 in the copper IUD group had a 1-month urine pregnancy test. In the modified intention-to-treat and per-protocol analyses, pregnancy rates were 1 in 317 (0.3%; 95% confidence interval [CI], 0.01 to 1.7) in the levonorgestrel group and 0 in 321 (0%; 95% CI, 0 to 1.1) in the copper IUD group; the between-group absolute difference in both analyses was 0.3 percentage points (95% CI, -0.9 to 1.8), consistent with the noninferiority of the levonorgestrel IUD to the copper IUD. Adverse events resulting in participants seeking medical care in the first month after IUD placement occurred in 5.2% of participants in the levonorgestrel IUD group and 4.9% of those in the copper IUD group. CONCLUSIONS: The levonorgestrel IUD was noninferior to the copper IUD for emergency contraception. (Supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT02175030.).

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.

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 and personal or partner capacity to become pregnant since the start of medical training. 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.

ANTECEDENTES: Los que apoyan la restricción del aborto citan los avances en la tecnología anticonceptiva como una razón en contra de la necesidad de la atención del aborto hoy en día, más recientemente a través de los argumentos orales en el caso de la Corte Suprema de los Estados Unidos, Dobbs v. Jackson Women's Health. Sin embargo, el uso sistemático y indicado de los anticonceptivos requiere unos conocimientos sobre salud reproductive. Nuestros objetivos eran cuantificar los eventos de riesgo anticonceptivo y evaluar los antecedentes y las preferencias entre una población bien equipada para eludir los riesgos anticonceptivos, los especialistas en planificación familiar tras el inicio de su formación médica. Los "eventos de riesgo" se definen como episodios reportados de fallo anticonceptivo, uso de anticoncepción de emergencia y/o relaciones sexuales sin protección o con protección insuficiente. MéTODOS: Este fue un estudio transversal entre miembros actuales de una organización profesional de especialistas en planificación familiar. Los criterios de inclusión incluyeron: condición de clínico/a en activo/a o jubilado/a, relaciones sexuales consentidas pene-vagina desde el inicio de la formación médica y capacidad personal o de la pareja para quedarse embarazada. Se realizaron estadísticas descriptivas. Este estudio estaba exento de IRB. RESULTADOS: De las 229 encuestadas, 157 (69%) declararon haber sufrido un evento de riesgo anticonceptivo desde la formación. Veintinueve (13%) encuestadas declararon haberlo sufrido un incidente en el último año. Por categoría, el 47% (108/229; 3 informaron de forma desconocida) informaron de relaciones sexuales sin protección o con poca protección, el 35% (81/229) informaron del uso de anticonceptivos de emergencia y el 52% de los participantes (117/227; 2 informaron de forma desconocida) informaron de un fallo anticonceptivo conocido o sospechado. El promedio de métodos anticonceptivos utilizados fue 3,7 (DE 1,7) de los 13 métodos enumerados. Casi todas las participantes (97%) informaron de que al menos un método no era una opción aceptable, con un promedio de 5,6 (DE 2,7) de los 13 métodos enumerados. CONCLUSIONES: La mayoría de los especialistas en planificación familiar han experimentado eventos de riesgo anticonceptivo en momentos de prevención activa del embarazo desde su formación médica. El cambio de método anticonceptivo es frecuente y la mayoría de los encuestados tenían un número limitado de métodos que les resultaban personalmente aceptables. El diálogo que idealiza el papel de la planificación familiar a la hora de minimizar o eliminar la necesidad de abortar es simplista y representa de forma inexacta las realidades vividas por las personas con capacidad de embarazo y sus parejas, incluso entre aquellas con conocimientos y acceso excepcionales a la anticoncepción.

Evaluating Pregnancy Rates in Fertility Awareness-Based Methods for Family Planning: Simulated Comparison of Correct Use to Avoid, Method-Related, and Total Pregnancy Rates.

Fertility awareness-based methods (FABMs), also known as natural family planning (NFP), enable couples to identify the days of the menstrual cycle when intercourse may result in pregnancy ("fertile days"), and to avoid intercourse on fertile days if they wish to avoid pregnancy. Thus, these methods are fully dependent on user behavior for effectiveness to avoid pregnancy. For couples and clinicians considering the use of an FABM, one important metric to consider is the highest expected effectiveness (lowest possible pregnancy rate) during the correct use of the method to avoid pregnancy. To assess this, most studies of FABMs have reported a method-related pregnancy rate (a cumulative proportion), which is calculated based on all cycles (or months) in the study. In contrast, the correct use to avoid pregnancy rate (also a cumulative proportion) has the denominator of cycles with the correct use of the FABM to avoid pregnancy. The relationship between these measures has not been evaluated quantitatively. We conducted a series of simulations demonstrating that the method-related pregnancy rate is artificially decreased in direct proportion to the proportion of cycles with intermediate use (any use other than correct use to avoid or targeted use to conceive), which also increases the total pregnancy rate. Thus, as the total pregnancy rate rises (related to intermediate use), the method-related pregnancy rate falls artificially while the correct use pregnancy rate remains constant. For practical application, we propose the core elements needed to assess correct use cycles in FABM studies. Summary: Fertility awareness-based methods (FABMs) can be used by couples to avoid pregnancy, by avoiding intercourse on fertile days. Users want to know what the highest effectiveness (lowest pregnancy rate) would be if they use an FABM correctly and consistently to avoid pregnancy. In this simulation study, we compare two different measures: (1) the method-related pregnancy rate; and (2) the correct use pregnancy rate. We show that the method-related pregnancy rate is biased too low if some users in the study are not using the method consistently to avoid pregnancy, while the correct use pregnancy rate obtains an accurate estimate. Short Summary: In FABM studies, the method-related pregnancy rate is biased too low, but the correct use pregnancy rate is unbiased.

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.

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.

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.

Implementation and Monitoring of the Family Planning Elevated Contraceptive Access Program, Utah, 2018‒2019.

Family Planning Elevated (FPE) is a contraceptive access initiative in Utah. FPE designed and utilized a comprehensive monitoring system to identify and respond to challenges implementing our initiative as they arose. Here, we describe the components of our monitoring system, and highlight how FPE's monitoring system successfully identified that Utah's Medicaid expansion was not widely adopted by eligible individuals. We then describe how FPE adapted to this challenge. (Am J Public Health. 2022;112(S5):S528-S531. https://doi.org/10.2105/AJPH.2022.306935).

Does access to no-cost contraception change method selection among individuals who report difficulty paying for health-related care?

BACKGROUND: Out-of-pocket costs continue to be a barrier to accessing necessary healthcare services, including contraception. We explored how eliminating out-of-pocket cost affects contraceptive method choice among people reporting difficulty paying for healthcare in the previous year, and whether method satisfaction differed by method choice. METHODS: We used data from the HER Salt Lake Contraceptive Initiative. This prospective cohort study provided participants with no-cost contraception (April 2016-March 2017) following a control period that provided no reduction in cost for the contraceptive implant, a reduced price for the hormonal IUD, and a sliding scale that decreased to no-cost for the copper IUD (September 2015-March 2016). We restricted the study population to those who reported difficulty paying for healthcare in the past 12 months. For our primary outcome assessing changes in method selection between intervention and control periods, we ran simultaneous multivariable logistic regression models for each method, applying test corrections for multiple comparisons. Among participants who continued their method for 1 year, we explored differences in method satisfaction using multivariable logistic regression. RESULTS: Of the 1,029 participants reporting difficulty paying for healthcare and controlling for other factors, participants more frequently selected the implant (aOR 6.0, 95% CI 2.7, 13.2) and the hormonal IUD (aOR 3.2, 95% CI 1.7, 5.9) during the intervention than control period. Comparing the same periods, participants less frequently chose the injection (aOR 0.5, 95% CI 0.3, 0.8) and the pill (aOR 0.4, 95% CI 0.3, 0.6). We did not observe a difference in uptake of the copper IUD (aOR 2.0, 95% CI 1.0, 4.1).Contraceptive satisfaction scores differed minimally by contraceptive method used among contraceptive continuers (n = 534). Those who selected LNG IUDs were less likely to report low satisfaction with their method (aOR 0.5, 95% CI 0.3, 0.97). CONCLUSION: With costs removed, participants who reported difficulty paying for healthcare were more likely to select hormonal IUDs and implants and less likely to select the injectable or contraceptive pills. Among continuers, there were few differences in method satisfaction. CLINICALTRIALS: gov Identifier NCT02734199.

Obesity-related IL-18 Impairs T-Regulatory Cell Function and Promotes Lung Ischemia-Reperfusion Injury.

Rationale: Primary graft dysfunction (PGD) is a severe form of acute lung injury, leading to increased early morbidity and mortality after lung transplant. Obesity is a major health problem, and recipient obesity is one of the most significant risk factors for developing PGD. Objectives: We hypothesized that T-regulatory cells (Tregs) are able to dampen early ischemia-reperfusion events and thereby decrease the risk of PGD, whereas that action is impaired in obese recipients. Methods: We evaluated Tregs, T cells, and inflammatory markers, plus clinical data, in 79 lung transplant recipients and 41 liver or kidney transplant recipients and studied two groups of mice on a high-fat diet (HFD), which did ("inflammatory" HFD) or did not ("healthy" HFD) develop low-grade inflammation with decreased Treg function. Measurements and Main Results: We identified increased levels of IL-18 as a previously unrecognized mechanism that impairs Tregs' suppressive function in obese individuals. IL-18 decreases levels of FOXP3, the key Treg transcription factor, decreases FOXP3 di- and oligomerization, and increases the ubiquitination and proteasomal degradation of FOXP3. IL-18-treated Tregs or Tregs from obese mice fail to control PGD, whereas IL-18 inhibition ameliorates lung inflammation. The IL-18-driven impairment in Tregs' suppressive function before transplant was associated with an increased risk and severity of PGD in clinical lung transplant recipients. Conclusions: Obesity-related IL-18 induces Treg dysfunction that may contribute to the pathogenesis of PGD. Evaluation of Tregs' suppressive function together with evaluation of IL-18 levels may serve as a screening tool to identify obese individuals with an increased risk of PGD before transplant.

Facility-based simulation as a programmatic tool for implementing a statewide contraceptive initiative.

BACKGROUND: Assessing implementation fidelity is highly recommended, but successful approaches can be challenging. Family Planning Elevated (FPE) is a statewide contraceptive initiative which partnered with 28 health clinics across Utah. To assess implementation fidelity, we developed in-situ high-fidelity simulation training to both determine clinic adherence to FPE and offer education to implementing teams. This study aimed to develop, pilot, and assess the use of simulation as a tool for measuring implementation fidelity. METHODS: We developed two simulation scenarios to determine implementation fidelity: one scenario wherein a client is seeking a new method of contraception and another in which the same client has returned to discontinue the method. Both simulations contained multiple aspects of program implementation (e.g., determining program eligibility). We then offered simulations to all FPE partner organizations. To assess simulation training as a tool for determining implementation fidelity, we developed strategies aligned with each aspect of an adapted RE-AIM framework, including pre-post surveys, acceptability and self-efficacy testing, a checklist for programmatic adherence, field notes, action planning and analysis of monitoring data. RESULTS: Fifteen clinical sites and 71 team members participated in the in-situ simulations. Assessment of the checklist showed that 90% of the clinics successfully demonstrated key program components, including person-centered counseling techniques such as sitting at the patient's level (95.8%); asking open-ended questions (100%); and explaining how to use the contraceptive method selected (91.7%). More than half of clinics fell short in programmatic areas including: confirmation that the FPE program covered same-day intrauterine device insertion (54.2%), and education on health risks associated with the selected contraceptive method (58.3%). After simulation, participants reported improved knowledge of how FPE works (p = < 0.001), increased ability to identify FPE-eligible clients (p = 0.02) and heightened self-efficacy in helping clients select a method (p = 0.03). Participants were satisfied with the simulations, with most (84.1%) reporting that the simulation exceeded their expectations. CONCLUSIONS: Highly-realistic in-situ family planning simulations are acceptable to participants, positively change knowledge and clinical team confidence, and can identify systems gaps in clinical care and program implementation. Simulation offers a reciprocal way of monitoring implementation fidelity of a family planning access initiative. TRIAL REGISTRATION: This project was determined to be exempt by the IRB of the University of Utah, the larger Family Planning Elevated program under which this pilot study was nested is registered at ClinicalTrials.gov Identifier: NCT03877757 .

Exposure to high fructose corn syrup during adolescence in the mouse alters hepatic metabolism and the microbiome in a sex-specific manner.

KEY POINTS: The prevalence of obesity and non-alcoholic fatty liver disease in children is dramatically increasing at the same time as consumption of foods with a high sugar content. Intake of high fructose corn syrup (HFCS) is a possible aetiology as it is thought to be more lipogenic than glucose. In a mouse model, HFCS intake during adolescence increased fat mass and hepatic lipid levels in male and female mice. However, only males showed impaired glucose tolerance. Multiple metabolites including lipids, bile acids, carbohydrates and amino acids were altered in liver in a sex-specific manner at 6 weeks of age. Some of these changes were also present in adulthood even though HFCS exposure ended at 6 weeks. HFCS significantly altered the gut microbiome, which was associated with changes in key microbial metabolites. These results suggest that HFCS intake during adolescence has profound metabolic changes that are linked to changes in the microbiome and these changes are sex-specific. ABSTRACT: The rapid increase in obesity, diabetes and fatty liver disease in children over the past 20 years has been linked to increased consumption of high fructose corn syrup (HFCS), making it essential to determine the short- and long-term effects of HFCS during this vulnerable developmental window. We hypothesized that HFCS exposure during adolescence significantly impairs hepatic metabolic signalling pathways and alters gut microbial composition, contributing to changes in energy metabolism with sex-specific effects. C57bl/6J mice with free access to HFCS during adolescence (3-6 weeks of age) underwent glucose tolerance and body composition testing and hepatic metabolomics, gene expression and triglyceride content analysis at 6 and 30 weeks of age (n = 6-8 per sex). At 6 weeks HFCS-exposed mice had significant increases in fat mass, glucose intolerance, hepatic triglycerides (females) and de novo lipogenesis gene expression (ACC, DGAT, FAS, ChREBP, SCD, SREBP, CPT and PPARα) with sex-specific effects. At 30 weeks, HFCS-exposed mice also had abnormalities in glucose tolerance (males) and fat mass (females). HFCS exposure enriched carbohydrate, amino acid, long chain fatty acid and secondary bile acid metabolism at 6 weeks with changes in secondary bile metabolism at 6 and 30 weeks. Microbiome studies performed immediately before and after HFCS exposure identified profound shifts of microbial species in male mice only. In summary, short-term HFCS exposure during adolescence induces fatty liver, alters important metabolic pathways, some of which continue to be altered in adulthood, and changes the microbiome in a sex-specific manner.

Neonatal IL-4 exposure decreases adipogenesis of male rats into adulthood.

The cytokine interleukin 4 (IL-4) can increase beige adipogenesis in adult rodents. However, neonatal animals use a distinct adipocyte precursor compartment for adipogenesis as compared with adults. In this study, we address whether IL-4 can induce persistent effects on adipose tissue when administered subcutaneously in the interscapular region during the neonatal period in Sprague-Dawley rats. We injected IL-4 into neonatal male rats during postnatal days 1-6, followed by analysis of adipose tissue and adipocyte precursors at 2 wk and 10 wk of age. Adipocyte precursors were cultured and subjected to differentiation in vitro. We found that a short and transient IL-4 exposure in neonates upregulated uncoupling protein 1 (Ucp1) mRNA expression and decreased fat cell size in subcutaneous white adipose tissue (WAT). Adipocyte precursors from mature rats that had been treated with IL-4 as neonates displayed a decrease in adiponectin (Adipoq) but no change in Ucp1 expression, as compared with controls. Thus, neonatal IL-4 induces acute beige adipogenesis and decreases adipogenic differentiation capacity long term. Overall, these findings indicate that the neonatal period is critical for adipocyte development and may influence the later onset of obesity.NEW & NOTEWORTHY We used neonatal injections in rat to show that IL-4 decreases adipogenesis and increases browning of white fat. In adulthood, adipocyte precursors show persistently decreased adipogenesis but not increased browning. These studies in the neonate are the first, to our knowledge, to show that IL-4 can have long-lasting effects.

Comparison of levonorgestrel level and creamatocrit in milk following immediate versus delayed postpartum placement of the levonorgestrel IUD.

BACKGROUND: Breastfeeding and postpartum contraception critically influence infant and maternal health outcomes. In this pilot study, we explore the effects of timing and duration of postpartum levonorgestrel exposure on milk lipid and levonorgestrel content to establish baseline data for future research. METHODS: This sub-study recruited a balanced convenience sample from 259 participants enrolled in a parent randomized controlled trial comparing immediate to delayed (4-8 weeks) postpartum levonorgestrel IUD placement. All planned to breastfeed, self-selected for sub-study participation, and provided the first sample at 4-8 weeks postpartum (before IUD placement for the delayed group) and the second four weeks later. We used the Wilcoxon rank sum (inter-group) and signed rank (intra-group) tests to compare milk lipid content (creamatocrit) and levonorgestrel levels between groups and time points. RESULTS: We recruited 15 participants from the immediate group and 17 from the delayed group with 10 and 12, respectively, providing both early and late samples. Initially, median levonorgestrel concentration of the immediate group (n = 10) (32.5 pg/mL, IQR: 24.8, 59.4) exceeded that of the delayed group (n = 12) (17.5 pg/mL, IQR: 0.0, 25.8) (p = 0.01). Four weeks later, the values aligned: 26.2 pg/mL (IQR: 20.3, 37.3) vs. 28.0 pg/mL (IQR: 25.2, 40.8). Creamatocrits were similar between both groups and timepoints. CONCLUSIONS: Immediate postpartum levonorgestrel IUD placement results in steady, low levels of levonorgestrel in milk without apparent effects on lipid content. These findings provide initial support for the safety of immediate postpartum levonorgestrel IUD initiation, though the study was not powered to detect noninferiority between groups. TRIAL REGISTRATION: This randomized controlled trial was registered with ClinicalTrials.gov (Registry No. NCT01990703) on November 21, 2013.

Determining the impact of the Zika pandemic on primary care providers' contraceptive counseling of non-pregnant patients in the US: a mixed methods study.

BACKGROUND: Global pandemics like Zika (ZIKV) factor into pregnancy planning and avoidance, yet little is known about how primary care providers (PCPs) incorporate public health guidance into contraceptive counseling. Study objectives include: 1) determining the impact of the ZIKV pandemic on contraceptive counseling changes; and 2) assessing PCP knowledge and practice regarding contraception, ZIKV, and CDC ZIKV guidelines. METHODS: Study components included: (1) a retrospective review of electronic health records of non-pregnant, reproductive age women presenting for preventive health visits between 2014 and 2017 assessed using interrupted time series analyses (ITSA) to identify changes in documentation of ZIKV risk assessment and contraceptive counseling; and (2) a sequential, cross-sectional study with quantitative surveys and qualitative, semi-structured interviews of PCPs providing preventive care to non-pregnant patients at eight federally qualified health centers in Utah. We performed descriptive analyses on survey data and analyzed qualitative data for dominant themes using a modified Health Belief Model. RESULTS: We conducted 6634 chart reviews yielding 9840 visits. The ITSA did not reveal changes in ZIKV risk assessment or contraceptive counseling. Twenty-two out of 40 (55%) eligible providers participated in the provider component. Participants averaged 69 and 81% correct on contraceptive and ZIKV knowledge questions, respectively. Sixty-five percent reported counseling consistent with CDC ZIKV guidelines. Qualitative analysis found providers unlikely to prioritize ZIKV risk assessment in contraceptive counseling for non-pregnant patients. CONCLUSIONS: PCPs who care for non-pregnant women are knowledgeable about contraception and ZIKV; however, there was no change in ZIKV risk assessment or contraceptive counseling. This stresses the importance of developing strategies to improve guideline uptake.

Pregnancy Risk Screening and Counseling for Women Veterans: Piloting the One Key Question in the Veterans Healthcare Administration.

OBJECTIVES: Women veterans have a high prevalence of comorbidities that increase the risk of adverse pregnancy outcomes. Screening for pregnancy desires in primary care provider (PCP) visits offers an opportunity to optimize preconception health. This pilot quality improvement initiative sought to assess Veterans Healthcare Administration provider preferences on One Key Question (OKQ) implementation, identification of veterans' reproductive needs, and the effect of training on documentation in a women's primary care clinic in Salt Lake City, Utah. METHODS: We hosted OKQ training sessions for providers and staff, audio recorded group discussions on implementation barriers, and explored themes. Women veterans presenting for a PCP visit in July 2018 self-completed a paper OKQ screening tool. We calculated summary statistics on responses. We conducted a pre-post analysis, with respect to training sessions, to measure for changes in family planning documentation during PCP visits. RESULTS: Nineteen providers and staff completed the training. They acknowledged the importance, but believed that the screening tool should be completed by veterans and not be provider prompted. Forty-two women veterans completed the screening tool: 21% desired pregnancy in the next year and 26% desired contraceptive information. Chart reviews found a nonsignificant increase in current contraceptive method documentation between periods (20% vs 37%; P = 0.08), a decline in documentation of reproductive goals (22% vs 3%; P = 0.02), and no significant change in counseling. CONCLUSIONS: Veterans identify reproductive needs via the OKQ screening tool, but provider documentation did not reflect changes in care following training. Further study is necessary to develop an optimal, patient-centered tool and implementation plan to support women veterans in their reproductive goals.