Alternative isoform expression of key thermogenic genes in human beige adipocytes.

Background: The beneficial effect of thermogenic adipocytes in maintaining body weight and protecting against metabolic disorders has raised interest in understanding the regulatory mechanisms defining white and beige adipocyte identity. Although alternative splicing has been shown to propagate adipose browning signals in mice, this has yet to be thoroughly investigated in human adipocytes. Methods: We performed parallel white and beige adipogenic differentiation using primary adipose stem cells from 6 unrelated healthy subjects and assessed differential gene and isoform expression in mature adipocytes by RNA sequencing. Results: We find 777 exon junctions with robust differential usage between white and beige adipocytes in all 6 subjects, mapping to 562 genes. Importantly, only 10% of these differentially spliced genes are also differentially expressed, indicating that alternative splicing constitutes an additional layer of gene expression regulation during beige adipocyte differentiation. Functional classification of alternative isoforms points to a gain of function for key thermogenic transcription factors such as PPARG and CITED1, and enzymes such as PEMT, or LPIN1. We find that a large majority of the splice variants arise from differential TSS usage, with beige-specific TSSs being enriched for PPARγ and MED1 binding compared to white-specific TSSs. Finally, we validate beige specific isoform expression at the protein level for two thermogenic regulators, PPARγ and PEMT. Discussion: These results suggest that differential isoform expression through alternative TSS usage is an important regulatory mechanism for human adipocyte thermogenic specification.

The use of social media for reproductive health advocacy among physicians: a content analysis of tweets by physicians engaged in reproductive health care.

BACKGROUND: Physician voices on social media are important for health policy advocacy. However, the extent to which physicians use best practices around health communications strategy is unknown. METHODS: We implemented a content analysis of 1373 tweets from 12 physicians who specialize in reproductive health care and participated in a reproductive health-related advocacy training program, to describe their reproductive health advocacy tweets in terms of levels of engagement, tone, framing and target audience. RESULTS: The most common framing centered on identifying abortion and contraception as essential health care services. Approximately one-third used proactive (37%), reactive (33%), and neutral (30%) strategies. Less than one-quarter (19%) of the tweets explicitly self-identified as a physician. CONCLUSIONS: Participants used a range of message frames, tones, and audience engagement tactics, suggesting a deliberate health communications strategy. Advocacy training discusses the importance of these domains when using social media for advocacy.

Cytoskeletal rearrangement precedes nucleolar remodeling during adipogenesis.

Differentiation of adipose progenitor cells into mature adipocytes entails a dramatic reorganization of the cellular architecture to accommodate lipid storage into cytoplasmic lipid droplets. Lipid droplets occupy most of the adipocyte volume, compressing the nucleus beneath the plasma membrane. How this cellular remodeling affects sub-nuclear structure, including size and number of nucleoli, remains unclear. We describe the morphological remodeling of the nucleus and the nucleolus during in vitro adipogenic differentiation of primary human adipose stem cells. We find that cell cycle arrest elicits a remodeling of nucleolar structure which correlates with a decrease in protein synthesis. Strikingly, triggering cytoskeletal rearrangements mimics the nucleolar remodeling observed during adipogenesis. Our results point to nucleolar remodeling as an active, mechano-regulated mechanism during adipogenic differentiation and demonstrate a key role of the actin cytoskeleton in defining nuclear and nucleolar architecture in differentiating human adipose stem cells.

Delays in Obtaining Abortion and Miscarriage Care Among Pregnant Persons in New York State During the COVID-19 Pandemic: The CAP Study.

Background: We sought to investigate delays obtaining abortion and miscarriage care during the COVID-19 pandemic, compared with before the pandemic, among pregnant persons in New York State (NYS). Methods: We administered a cross-sectional survey in June-July 2020 to NYS residents aged 18-44 years who identified as female or transgender male (N = 1,525). This analysis focused on a subsample who had an abortion or miscarriage during COVID-19, were seeking an abortion at the time of the survey, or had an abortion or miscarriage before COVID-19 (n = 116). We conducted bivariate analyses to determine differences in delays to seeking or obtaining an abortion or miscarriage during versus before the pandemic, as well as consideration of abortion among those pregnant during versus before the pandemic. We also asked open-ended questions about miscarriage and abortion experiences. Main Findings: Of the 21 respondents who sought or were seeking an abortion during the COVID-19 pandemic, 76.2% (n = 16) reported experiencing a delay in obtaining abortion care, compared with 18.2% (n = 4) of those who experienced a delay before the pandemic (p < 0.001). A significantly higher proportion of respondents who were pregnant during the pandemic considered abortion, compared with those who gave birth before the pandemic (39.1% vs. 7.6%; p < 0.001). Of the 39 respondents who miscarried during the pandemic, 35.9% (n = 14) delayed care, compared with 5.9% (n = 2) before the pandemic (p < 0.01). Some respondents also commented on the difficulty of accessing miscarriage services during COVID-19 in open-ended responses. Principal Conclusions: Those who sought abortion or miscarriage care during the COVID-19 pandemic experienced significant delays in getting care. These are essential services that must be available during public health emergencies, and yet access to these services is now severely limited in many states due to the Dobbs vs. Jackson Women's Health Organization decision.

Gene Regulatory Interactions at Lamina-Associated Domains.

The nuclear lamina provides a repressive chromatin environment at the nuclear periphery. However, whereas most genes in lamina-associated domains (LADs) are inactive, over ten percent reside in local euchromatic contexts and are expressed. How these genes are regulated and whether they are able to interact with regulatory elements remain unclear. Here, we integrate publicly available enhancer-capture Hi-C data with our own chromatin state and transcriptomic datasets to show that inferred enhancers of active genes in LADs are able to form connections with other enhancers within LADs and outside LADs. Fluorescence in situ hybridization analyses show proximity changes between differentially expressed genes in LADs and distant enhancers upon the induction of adipogenic differentiation. We also provide evidence of involvement of lamin A/C, but not lamin B1, in repressing genes at the border of an in-LAD active region within a topological domain. Our data favor a model where the spatial topology of chromatin at the nuclear lamina is compatible with gene expression in this dynamic nuclear compartment.

De novo annotation of lncRNA HOTAIR transcripts by long-read RNA capture-seq reveals a differentiation-driven isoform switch.

BACKGROUND: LncRNAs are tissue-specific and emerge as important regulators of various biological processes and as disease biomarkers. HOTAIR is a well-established pro-oncogenic lncRNA which has been attributed a variety of functions in cancer and native contexts. However, a lack of an exhaustive, cell type-specific annotation questions whether HOTAIR functions are supported by the expression of multiple isoforms. RESULTS: Using a capture long-read sequencing approach, we characterize HOTAIR isoforms expressed in human primary adipose stem cells. We find HOTAIR isoforms population displays varied splicing patterns, frequently leading to the exclusion or truncation of canonical LSD1 and PRC2 binding domains. We identify a highly cell type-specific HOTAIR isoform pool regulated by distinct promoter usage, and uncover a shift in the HOTAIR TSS usage that modulates the balance of HOTAIR isoforms at differentiation onset. CONCLUSION: Our results highlight the complexity and cell type-specificity of HOTAIR isoforms and open perspectives on functional implications of these variants and their balance to key cellular processes.

Long non-coding RNA HOTAIR regulates cytoskeleton remodeling and lipid storage capacity during adipogenesis.

The long non-coding RNA HOTAIR is the most differentially expressed gene between upper- and lower-body adipose tissue, yet its functional significance in adipogenesis is unclear. We report that HOTAIR expression is transiently induced during early adipogenic differentiation of gluteofemoral adipose progenitors and repressed in mature adipocytes. Upon adipogenic commitment, HOTAIR regulates protein synthesis pathways and cytoskeleton remodeling with a later impact on mature adipocyte lipid storage capacity. Our results support novel and important functions of HOTAIR in the physiological context of adipogenesis.

Factors related to delays in obtaining contraception among pregnancy-capable adults in New York state during the COVID-19 pandemic: The CAP study.

OBJECTIVES: To investigate factors associated with delays to obtaining contraception during the COVID-19 pandemic among pregnancy-capable adults in New York State. STUDY DESIGN: We administered a cross-sectional survey in June-July 2020 to female/transgender male New York State residents aged 18-44 years (n = 1,525). This analysis focused on respondents who were not pregnant and sought contraception (n = 953). We conducted bivariate and multinomial logistic regression analyses to assess sociodemographic, social, and health characteristics, by the outcome of delays to obtaining birth control (delayed due to COVID-19, delayed due to other reasons, no delay). We also analyzed a sub-sample who reported COVID-19 as a reason for delays (n = 317) and report the frequencies of type of contraceptive methods/procedures delayed and availability of telemedicine visits. RESULTS: Half of respondents had no contraceptive delays, 39% reported delays due to COVID-19, and 11% reported delays due to reasons other than COVID-19. In adjusted analyses, those who missed a rent/mortgage payment during the pandemic (aOR: 2.23; CI: 1.55, 3.22), participated in a supplemental government program in 2019 (aOR: 1.88; CI: 1.36, 2.60), and themselves/household member had COVID-19 (aOR: 1.48; CI: 1.04, 2.12) were more likely to report delays to contraception due to COVID-19 (versus no delays). In the sub-sample, 63% reported available virtual contraceptive visits, 28% unavailable, and 9% not sure. The most frequently (42%) reported delays were new prescriptions for the pill, patch, or ring. CONCLUSIONS: Reducing financial barriers that help individuals maintain their housing and living necessities, and promoting telemedicine visits, may help increase access to contraception.

molBV reveals immune landscape of bacterial vaginosis and predicts human papillomavirus infection natural history.

Bacterial vaginosis (BV) is a highly prevalent condition that is associated with adverse health outcomes. It has been proposed that BV's role as a pathogenic condition is mediated via bacteria-induced inflammation. However, the complex interplay between vaginal microbes and host immune factors has yet to be clearly elucidated. Here, we develop molBV, a 16 S rRNA gene amplicon-based classification pipeline that generates a molecular score and diagnoses BV with the same accuracy as the current gold standard method (i.e., Nugent score). Using 3 confirmatory cohorts we show that molBV is independent of the 16 S rRNA region and generalizable across populations. We use the score in a cohort without clinical BV states, but with measures of HPV infection history and immune markers, to reveal that BV-associated increases in the IL-1ß/IP-10 cytokine ratio directly predicts clearance of incident high-risk HPV infection (HR = 1.86, 95% CI: 1.19-2.9). Furthermore, we identify an alternate inflammatory BV signature characterized by elevated TNF-α/MIP-1ß ratio that is prospectively associated with progression of incident infections to CIN2 + (OR = 2.81, 95% CI: 1.62-5.42). Thus, BV is a heterogeneous condition that activates different arms of the immune response, which in turn are independent risk factors for HR-HPV clearance and progression. Clinical Trial registration number: The CVT trial has been registered under: NCT00128661.

Anti-HPV16 Antibody Titers Prior to an Incident Cervical HPV16/31 Infection.

The goal of this study was to investigate the serological titers of circulating antibodies against human papillomavirus (HPV) type 16 (anti-HPV16) prior to the detection of an incident HPV16 or HPV31 infection amongst vaccinated participants. Patients were selected from a prospective post-HPV vaccine longitudinal cohort at Mount Sinai Adolescent Health Center in Manhattan, NY. We performed a nested case-control study of 43 cases with incident detection of cervical HPV16 (n = 26) or HPV31 (n = 17) DNA who had completed the full set of immunizations of the quadrivalent HPV vaccine (4vHPV). Two control individuals whom had received three doses of the vaccine (HPV16/31-negative) were selected per case, matched on age at the first dose of vaccination and follow-up time in the study: a random control, and a high-risk control that was in the upper quartile of a sexual risk behavior score. We conducted an enzyme-linked immunosorbent assay (ELISA) for the detection of immunoglobulin G (IgG) antibodies specific to anti-HPV16 virus-like particles (VLPs). The results suggest that the average log antibody titers were higher among high-risk controls than the HPV16/31 incident cases and the randomly selected controls. We show a prospective association between anti-HPV16 VLP titers and the acquisition of an HPV16/31 incident infection post-receiving three doses of 4vHPV vaccine.

Neighborhood Profiles and Body Mass Index Trajectory in Female Adolescents and Young Adults.

PURPOSE: The purpose of this study is to identify distinct neighborhood profiles patterned by key structural, physical, and social characteristics and test whether living in different profiles are associated with body mass index trajectories during adolescence in racial/ethnic minority female youth. METHODS: Participants were 1,328 sexually active female adolescents and young adults aged 14-23 years, predominately Hispanic and black, enrolled in an human papillomavirus type 4 vaccine (Gardasil) surveillance study at a large adolescent health clinic in New York City between 2007 and 2018. Body mass index was calculated from weight and height every 6 months. A comprehensive set of neighborhood structural, social, and physical characteristics from multiple national and state datasets was linked to each participant based on home address. RESULTS: Latent profile analysis revealed five distinct neighborhood profiles in New York City: High Structural/High Social Advantage, Moderate Advantage/Low Crime, Low SES (Socioeconomic Status)/High Activity, Low SES/High Social Advantage, and High Disadvantage. Results from multilevel growth curve analysis revealed that living in Low SES/High Activity neighborhoods was associated with a lower BMI at age 22 (b = -1.32, 95% confidence interval -2.49, -.16), as well as a slower increase in BMI from age 14 to 22 years (b = -.22, 95% confidence interval -.46, .02), compared to the High Disadvantage profile. CONCLUSIONS: Our findings suggest that improving neighborhood structural, social, and physical environments may help promote healthy weight and reduce health disparities during adolescence and young adulthood.

Factors Related to Seeking Help for Postpartum Depression: A Secondary Analysis of New York City PRAMS Data.

Postpartum depression (PPD) affects 13% of mothers and can have a major impact on their lives and those of their children. However, most cases go undiagnosed, and the risk factors for this underdiagnosis are not yet fully known. We intended to analyze the influence of different sociodemographic and health factors associated with symptoms of postpartum depression. Data from the New York City Pregnancy Risk Assessment Monitoring System (PRAMS) for 2016-2017 were analyzed. 618 women met the inclusion criterion of recurring depressive symptoms. Most women who experienced PPD symptoms did not seek help. Seeking help was a much better predictor of the diagnosis of PPD when compared to questions regarding symptoms. The most important factors related to a decreased risk of not asking for help were having a previous mental health history and having doctor visits for a chronic illness. The racial group most at risk of not asking for help were Asian/Pacific Islander (API) women. Interventions aimed at reducing the stigma and increasing knowledge of PPD should be incorporated into the antenatal education of expectant mothers, particularly among women who may not have previously sought care for mental or chronic illnesses.

Risk of Oral Human Papillomavirus Infection Among Sexually Active Female Adolescents Receiving the Quadrivalent Vaccine.

Importance: Human papillomavirus (HPV) is the most common sexually transmitted infection in the United States, and oral HPV infection is associated with increased risk of oropharyngeal cancer. Objective: To describe the risk factors for oral HPV in sexually active female adolescents receiving the quadrivalent vaccine. Design, Setting, and Participants: Longitudinal cohort study involving repeated collection of oral rinse specimens from sexually active female adolescents conducted between October 19, 2007, and March 9, 2017, at a large adolescent health center in New York, New York, that provides free health care, including HPV vaccination. Exposures: Human papillomavirus vaccination and self-reported history of sexual behavior. Main Outcomes and Measures: Prevalence of HPV in the oral cavity. Results: Among the 1259 participants who were included in this study, median age at entry into the study was 18 (range, 13-21) years; 638 (50.7%) were of African American descent, 569 (45.2%) were of Hispanic descent, 43 (3.4%) reported another race/ethnicity, and race/ethnicity was unspecified for 9 (0.7%). The median (mode) age at first sexual activity was 14.8 (14) years, and 1161 (92.2%) reported having had oral sex. Human papillomavirus DNA was detected in baseline oral rinse samples of 78 of the 1259 participants (6.2%; 95% CI, 4.9%-7.6%). There was a significant decrease in oral HPV detection with time (in years) since first engaging in sexual activities, independent of age and concurrent detection of cervical HPV; comparing 4 or more years with 1 year or less, the odds ratio was 0.45 (95% CI, 0.21-0.96). Detection of vaccine types (HPV-6, HPV-11, HPV-16, and HPV-18) was significantly lower among participants who had received at least 1 dose of the quadrivalent HPV vaccine at the time of enrollment compared with those who were unvaccinated (odds ratio, 0.20; 95% CI, 0.04-0.998). Conclusions and Relevance: This study's findings suggest that detection of HPV in the oral cavity is not uncommon in sexually active female adolescents. In addition, HPV vaccination is associated with a significant decrease in detection of HPV vaccine types in the oral cavity.

Mechanistic in vitro studies confirm that inhibition of the renal apical efflux transporter multidrug and toxin extrusion (MATE) 1, and not altered absorption, underlies the increased metformin exposure observed in clinical interactions with cimetidine, trimethoprim or pyrimethamine.

Metformin is a common co-medication for many diseases and the victim of clinical drug-drug interactions (DDIs) perpetrated by cimetidine, trimethoprim and pyrimethamine, resulting in decreased active renal clearance due to inhibition of organic cation transport proteins and increased plasma exposure of metformin. To understand whether area under the plasma concentration-time curve (AUC) increases relate to absorption, in vitro inhibitory potencies of these drugs against metformin transport by human organic cation transporter (OCT) 1, and the apical to basolateral absorptive permeability of metformin across Caco-2 cells in the presence of therapeutic intestinal concentrations of cimetidine, trimethoprim or pyrimethamine, were determined. Whilst all inhibited OCT1, none enhanced metformin's absorptive permeability (~0.5 × 10-6  cm/sec) suggesting that DDI AUC changes are not related to absorption. Subsequently, to understand whether inhibition of renal transporters are responsible for AUC increases, in vitro inhibitory potencies against metformin transport by human OCT2, multidrug and toxin extrusion (MATE) 1 and MATE2-K were determined. Ensuing IC50 values were incorporated into mechanistic static equations, alongside unbound maximal plasma concentration and transporter fraction excreted values, in order to calculate theoretical increases in metformin AUC due to inhibition by cimetidine, trimethoprim or pyrimethamine. Calculated theoretical fold-increases in metformin exposure confirmed solitary inhibition of renal MATE1 to be the likely mechanism underlying the observed exposure changes in clinical DDIs. Interestingly, clinically observed increases in metformin AUC were predicted more closely when the renal transporter fraction excreted value derived from oral metformin administration, rather than intravenous, was utilized in theoretical calculations, likely reflecting the "flip-flop" pharmacokinetic profile of the drug.

Invited commentary: broadening the evidence for adolescent sexual and reproductive health and education in the United States.

Scientific research has made major contributions to adolescent health by providing insights into factors that influence it and by defining ways to improve it. However, US adolescent sexual and reproductive health policies-particularly sexuality health education policies and programs-have not benefited from the full scope of scientific understanding. From 1998 to 2009, federal funding for sexuality education focused almost exclusively on ineffective and scientifically inaccurate abstinence-only-until-marriage (AOUM) programs. Since 2010, the largest source of federal funding for sexual health education has been the "tier 1" funding of the Office of Adolescent Health's Teen Pregnancy Prevention Initiative. To be eligible for such funds, public and private entities must choose from a list of 35 programs that have been designated as "evidence-based" interventions (EBIs), determined based on their effectiveness at preventing teen pregnancies, reducing sexually transmitted infections, or reducing rates of sexual risk behaviors (i.e., sexual activity, contraceptive use, or number of partners). Although the transition from primarily AOUM to EBI is important progress, this definition of evidence is narrow and ignores factors known to play key roles in adolescent sexual and reproductive health. Important bodies of evidence are not treated as part of the essential evidence base, including research on lesbian, gay, bisexual, transgender, queer, and questioning (LGBTQ) youth; gender; and economic inequalities and health. These bodies of evidence underscore the need for sexual health education to approach adolescent sexuality holistically, to be inclusive of all youth, and to address and mitigate the impact of structural inequities. We provide recommendations to improve US sexual health education and to strengthen the translation of science into programs and policy.