Stable and robust Xi and Y transcriptomes drive cell-type-specific autosomal and Xa responses in vivo and in vitro in four human cell types.

Recent in vitro studies of human sex chromosome aneuploidy showed that the Xi ("inactive" X) and Y chromosomes broadly modulate autosomal and Xa ("active" X) gene expression in two cell types. We tested these findings in vivo in two additional cell types. Using linear modeling in CD4+ T cells and monocytes from individuals with one to three X chromosomes and zero to two Y chromosomes, we identified 82 sex-chromosomal and 344 autosomal genes whose expression changed significantly with Xi and/or Y dosage in vivo . Changes in sex-chromosomal expression were remarkably constant in vivo and in vitro across all four cell types examined. In contrast, autosomal responses to Xi and/or Y dosage were largely cell-type-specific, with up to 2.6-fold more variation than sex-chromosomal responses. Targets of the X- and Y-encoded transcription factors ZFX and ZFY accounted for a significant fraction of these autosomal responses both in vivo and in vitro . We conclude that the human Xi and Y transcriptomes are surprisingly robust and stable across the four cell types examined, yet they modulate autosomal and Xa genes - and cell function - in a cell-type-specific fashion. These emerging principles offer a foundation for exploring the wide-ranging regulatory roles of the sex chromosomes across the human body.

Identifying Subgroups of Youth Suicide Decedents Based on Clinical Profiles of Psychiatric and Medical Diagnoses: A Latent Class Analysis.

PURPOSE: To identify risk subgroups of youth suicide decedents using demographic and clinical psychiatric and medical diagnostic profiles to inform tailored youth suicide prevention efforts. METHODS: This study linked Ohio Medicaid and death certificate data for Medicaid enrolled youth aged 8-25 years who died by suicide between January 1, 2010, and December 31, 2020 (N = 511). Latent class analysis was used to identify distinct clinical risk subgroups. RESULTS: Three latent classes were identified. Internalizing problems were common across all classes, but especially prevalent in class 1, the High Internalizing + Multiple Comorbidities group (n = 152, 30%). A prior history of suicidal behavior was confined to class 1 decedents, who were otherwise characterized by substance misuse, and multiple psychiatric and medical comorbidities. Class 2 decedents, the Internalizing + Externalizing group (n = 176, 34%), were more often younger, male, Black, and unlikely to have a history of substance misuse. Decedents in class 3, the Internalizing + Substance Misuse group (n = 183, 36%), were more often older and likely to have a history of substance misuse, but unlikely to exhibit other externalizing problems. DISCUSSION: Internalizing psychopathology is particularly common among youth who die by suicide, with comorbid externalizing psychopathology, substance misuse, and medical problems contributing to youth suicide risk. Because less than a third of youth who die by suicide have a prior history of recognized suicidal thinking or behavior, universal screening for youth suicide risk should be considered, particularly in younger children, and efforts to integrate suicide prevention in traditional health care settings should be prioritized.

Remission, Recovery, Relapse, and Recurrence Rates for Suicide Attempts and Nonsuicidal Self-Injury for Suicidal Youth Treated With Dialectical Behavior Therapy or Supportive Therapy.

OBJECTIVE: To evaluate rates of remission, recovery, relapse, and recurrence in suicidal youth who participated in a clinical trial comparing Dialectical Behavior Therapy (DBT) and Individual and Group Supportive Therapy (IGST). METHOD: Participants were 173 youth, aged 12 to 18 years, with repetitive self-harm (including at least 1 prior suicide attempt [SA]) and elevated suicidal ideation (SI). Participants received 6 months of DBT or IGST and were followed for 6 months post-treatment. The sample was 95% female, 56.4% White, and 27.49% Latina. Remission was defined as absence of SA or nonsuicidal self-injury (NSSI) across one 3-month interval; recovery was defined across 2 or more consecutive intervals. Relapse and recurrence were defined as SA or NSSI following remission or recovery. Cross-tabulation with χ2 was used for between-group contrasts. RESULTS: Over 70% of the sample reported remission of SA at each treatment and follow-up interval. There were significantly higher rates of remission and recovery and lower rates of relapse and recurrence for SA in DBT than for IGST. Across treatments and time points, SA had higher remission and recovery rates and lower relapse and recurrence rates than NSSI. There were no significant differences in NSSI remission between conditions; however, participants receiving DBT had significantly higher NSSI recovery rates than those receiving IGST for the 3- to 9-month, 3- to 12-month, and 6- to 12-month intervals. CONCLUSION: Results showed higher percentages of SA remission and recovery for DBT as compared to IGST. NSSI was less likely to remit than SA. DIVERSITY & INCLUSION STATEMENT: We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. CLINICAL TRIAL REGISTRATION INFORMATION: Collaborative Adolescent Research on Emotions and Suicide (CARES); https://www. CLINICALTRIALS: gov/; NCT01528020.

Characterizing Measurement-Based Care in the Texas Youth Depression and Suicide Research Network (TX-YDSRN).

Integration of measurement-based care (MBC) into clinical practice has shown promise in improving treatment outcomes for depression. Yet, without a gold standard measure of MBC, assessing fidelity to the MBC model across various clinical settings is difficult. A central goal of the Texas Youth Depression and Suicide Research Network (TX-YDSRN) was to characterize MBC across the state of Texas through the development of a standardized tool to assess the use of MBC strategies when assessing depression, anxiety, side effects, and treatment adherence. A chart review of clinical visits indicated standardized depression measures (71.2%) and anxiety measures (64%) were being utilized across sites. The use of standardized measures to assess medication adherence and side effects was limited to less than six percent for both, with the majority utilizing clinical interviews to assess adherence and side effects; yet medication was changed in nearly half. Rates of utilization of standardized measures for participants with multiple MBC forms were similar to those who only provided one form.

Association between tuberculosis and pregnancy outcomes: a retrospective cohort study of women in Cape Town, South Africa.

BACKGROUND: Tuberculosis (TB) remains a leading cause of mortality among women of childbearing age and a significant contributor to maternal mortality. Pregnant women with TB are at high risk of adverse pregnancy outcomes. This study aimed to determine risk factors for an adverse pregnancy outcome among pregnant women diagnosed with TB. METHODS: Using TB programmatic data, this retrospective cohort analysis included all women who were routinely diagnosed with TB in the public sector between October 2018 and March 2020 in two health subdistricts of Cape Town, and who were documented to be pregnant during their TB episode. Adverse pregnancy outcome was defined as either a live birth of an infant weighing <2500 g and/or with a gestation period <37 weeks or as stillbirth, miscarriage, termination of pregnancy, maternal or early neonatal death. Demographics, TB and pregnancy characteristics were described by HIV status. Logistic regression was used to determine risk factors for adverse pregnancy outcome. RESULTS: Of 248 pregnant women, half (52%) were living with HIV; all were on antiretroviral therapy at the time of their TB diagnosis. Pregnancy outcomes were documented in 215 (87%) women, of whom 74 (34%) had an adverse pregnancy outcome. Being older (35-44 years vs 25-34 years (adjusted OR (aOR): 3.99; 95% CI: 1.37 to 11.57), living with HIV (aOR: 2.72; 95% CI: 0.99 to 4.63), having an unfavourable TB outcome (aOR: 2.29; 95% CI: 1.03 to 5.08) and having presented to antenatal services ≤1 month prior to delivery (aOR: 10.57; 95% CI: 4.01 to 27.89) were associated with higher odds of an adverse pregnancy outcome. CONCLUSIONS: Pregnancy outcomes among women with TB were poor, irrespective of HIV status. Pregnant women with TB are a complex population who need additional support prior to, during and after TB treatment to improve TB treatment and pregnancy outcomes. Pregnancy status should be considered for inclusion in TB registries.

The human Y and inactive X chromosomes similarly modulate autosomal gene expression.

Somatic cells of human males and females have 45 chromosomes in common, including the "active" X chromosome. In males the 46th chromosome is a Y; in females it is an "inactive" X (Xi). Through linear modeling of autosomal gene expression in cells from individuals with zero to three Xi and zero to four Y chromosomes, we found that Xi and Y impact autosomal expression broadly and with remarkably similar effects. Studying sex chromosome structural anomalies, promoters of Xi- and Y-responsive genes, and CRISPR inhibition, we traced part of this shared effect to homologous transcription factors-ZFX and ZFY-encoded by Chr X and Y. This demonstrates sex-shared mechanisms by which Xi and Y modulate autosomal expression. Combined with earlier analyses of sex-linked gene expression, our studies show that 21% of all genes expressed in lymphoblastoid cells or fibroblasts change expression significantly in response to Xi or Y chromosomes.

Intestinal dysbiosis and inflammation in children with repaired esophageal atresia.

OBJECTIVES: This study aims to compare the intestinal microbiota and intestinal inflammation of children with esophageal atresia (EA) to matched healthy controls, and to investigate the relationship between these factors and clinical outcomes. METHODS: A cross-sectional study of 35 children with EA and 35 matched healthy controls (HC) from a single tertiary pediatric hospital in Australia was conducted. Demographic and dietary data were collected using surveys. Stool samples were analyzed using 16S rRNA sequencing, and fecal calprotectin measurements were used to measure intestinal inflammation. Comparisons were made between the groups, and correlations between the microbiota and clinical factors were investigated in the EA cohort. RESULTS: Compared to HC, children with EA had similar alpha diversity, but beta diversity analysis revealed clustering of EA and HC cohorts. Children with EA had a significantly higher relative abundance of the order Lactobacillales, and a lower abundance of the genus uncultured Bacteroidales S24-7. Fecal calprotectin was significantly higher in children with EA compared to HC. In the EA cohort, children taking proton pump inhibitors (PPI's) had lower alpha diversity and higher calprotectin levels compared to those not taking PPI's. There was a negative correlation between calprotectin and length/height-for-age z scores, and children with higher calprotectin levels had a greater burden of gastrointestinal symptoms. CONCLUSIONS: Children with EA have an altered intestinal microbiota compared to HC, which is likely related to PPI use, and may be impacting on growth and quality of life. It is important to rationalize PPI use in this cohort.

Trends in the relationship between suicide behaviors and obesity among adolescents in the United States from 1999 to 2019.

Previous studies indicate that obesity is a risk factor of suicide behaviors among adolescents. Whether this association has remained consistent during the ongoing obesity epidemic remains unknown. The time trends of the obesity-suicide association were examined using the 1999-2019 biannual Youth Risk Behavior Survey data (n = 161,606). Prevalence odds ratio of suicide behaviors among adolescents with obesity (vs. adolescents with no obesity) for each survey year and time trends using National Cancer Institute Joinpoint regression analysis was calculated. For each year post-baseline, there was a significant increase of prevalence odds ratio of 1.4 (1.2-1.6)-1.6 (1.3-2.0) for suicide ideation, 1.3 (1.1-1.7) -1.7 (1.4-2.0) for plan, and 1.3 (1.0-1.7) -1.9 (1.5-2.4) for an attempt, except for the 2013 survey for attempt (1.19 [0.9-1.6]). Significant positive trends were found from1999 to 2019 for ideation and plan, with biannual %-changes of + 0.92 and + 1.22%, respectively. Adolescents with obesity have consistently higher odds of engaging in suicide behaviors than their peers without obesity since the beginning of the United States obesity epidemic, and this association grew stronger as the obesity epidemic continued.

Effect of Anti-TNF Biologic Exposure During Pregnancy on Villitis of Unknown Etiology Diagnoses in Patients with Autoimmune Disease.

Tumor necrosis factor-α (TNF-α) antagonists are highly effective in controlling autoimmune diseases. This has led to speculation that they might also be useful in treating inflammatory placental conditions, such as chronic villitis of unknown etiology (VUE). VUE affects 10-15% of term placentas and is associated with recurrent fetal growth restriction (FGR) and pregnancy loss. We aimed to evaluate outcomes in patients with autoimmune diseases with and without anti-TNF-α biologic exposure during gestation. This retrospective cohort study compared pregnant women with autoimmune disease taking anti-TNF-α biologics (n = 89) to pregnant women with autoimmune disease but not taking a biologic (n = 53). We extracted data on all patients meeting our inclusion criteria over a 20-year period. Our primary outcome was the diagnosis of VUE by histology. Our secondary outcomes were maternal and neonatal complications such as preeclampsia, FGR, and neonatal intensive care admission. Kruskal-Wallis and chi-squared tests were performed as appropriate for statistical analysis. Maternal characteristics were comparable between groups, and there was no increase in adverse pregnancy outcomes based on anti-TNF-α treatment. Exposure to anti-TNF-α therapy had no significant effect on the incidence of VUE or other obstetric complications. Within the cohort exposed to anti-TNF-α biologics during pregnancy, the rate of VUE was 9.3%, which is comparable to the reported general population risk. Our data support the safety profile of biologic use in pregnancy.

Pharmacokinetics and cardiac safety of clofazimine in children with rifampicin-resistant tuberculosis.

Clofazimine is recommended for the treatment of rifampicin-resistant tuberculosis (RR-TB), but there is currently no verified dosing guideline for its use in children. There is only limited safety and no pharmacokinetic (PK) data available for children. We aimed to characterize clofazimine PK and its relationship with QT-interval prolongation in children. An observational cohort study of South African children <18 years old routinely treated for RR-TB with a clofazimine-containing regimen was analyzed. Clofazimine 100 mg gelatin capsules were given orally once daily (≥20 kg body weight), every second day (10 to <20 kg), or thrice weekly (<10 kg). PK sampling and electrocardiograms were completed pre-dose and at 1, 4, and 10 hours post-dose, and the population PK and Fridericia-corrected QT (QTcF) interval prolongation were characterized. Fifty-four children contributed both PK and QTcF data, with a median age (2.5th-97.5th centiles) of 3.3 (0.5-15.6) years; five children were living with HIV. Weekly area under the time-concentration curve at steady state was 79.1 (15.0-271) mg.h/L compared to an adult target of 60.9 (56.0-66.6) mg.h/L. Children living with HIV had four times higher clearance compared to those without. No child had a QTcF ≥500 ms. A linear concentration-QTcF relationship was found, with a drug effect of 0.05 (0.027, 0.075) ms/µg/L. In some of the first PK data in children, we found clofazimine exposure using an off-label dosing strategy was higher in children versus adults. Clofazimine concentrations were associated with an increase in QTcF, but severe prolongation was not observed. More data are required to inform dosing strategies in children.

Tertiary Inpatient Palliative Care within Region-Wide Services: A Retrospective Examination of Psychosocial and Medical Demographics at Admissions.

Palliative care offers symptom relief and improved quality of life. Tertiary palliative care units (TPCUs) focus on complex suffering under the care of specialist palliative physicians and interdisciplinary teams. The Intensive Palliative Care Unit (IPCU) is a TPCU integrated in well-developed region-wide palliative services in Calgary, Canada. We compared the population accessing the IPCU to published data from other Canadian sites. METHODS: A retrospective chart review was conducted using 8 sample months over a 2-year period. We gleaned psychosocial and medical demographics alongside the self-reported symptom burden on the Edmonton Symptom Assessment System. Descriptive statistics were calculated. RESULTS: Adults (n = 117) with cancer admitted to the IPCU were 5-10 years younger, had later-stage cancer, and had higher discharges to preferred locations than other published Canadian TPCUs. Up to two months before admission, most commonly reported symptoms were consistent with the outpatient literature although with higher reported intensity. DISCUSSION: With more advanced disease, younger age, and elevated symptom burden before admission, the IPCU still discharged patients to preferred locations at higher rates than other sites. This may be due to integration in the region's organized palliative care services. CONCLUSION: With proper integration, a TPCU may be able to improve quality of life and reduce deaths in hospitals.

Advancing Suicide Intervention Strategies for Teens (ASSIST): study protocol for a multisite randomised controlled trial.

INTRODUCTION: Brief interventions that reduce suicide risk following youth's experience with acute care due to suicidality are needed. METHODS AND ANALYSIS: The study will use a three-arm randomised controlled trial designed to test the effectiveness of the Safety Planning Intervention with structured follow-up (SPI+) and the Collaborative Assessment and Management of Suicidality (CAMS) compared with enhanced usual care. The primary outcomes measure will be suicidal events, defined as death by suicide, attempted suicide, preparatory acts toward imminent suicidal behaviour or suicidal ideation resulting in a change in emergency evaluation or inpatient admission. Secondary measures will be the number of suicide attempts and severity of suicidal ideation. The experimental interventions, SPI+ and CAMS, consist of up to eight sessions over approximately 8 weeks that are designed to manage (SPI+) or treat (CAMS) patient-identified 'drivers' of suicidal thoughts and behaviours. Mechanisms and moderators of change will be evaluated to understand treatment impacts. ETHICS AND DISSEMINATION: This study has been approved by the Seattle Children's Institutional Review Board and is monitored by external agencies including the University of Washington Institute for Translational Health Sciences, and a National Institute of Mental Health (NIMH)-appointed Data Safety and Monitoring Board. Trial results will help establish evidence towards safe and effective treatment strategies for youth transitioning from acute to outpatient care due to a suicidal crisis. The data will be shared with the NIMH Data Archives and disseminated through publications and conferences. TRIAL REGISTRATION NUMBER: NCT05078970.

Pharmacokinetics and Safety of Group A and B Anti-Tuberculosis Drugs Used in Treatment of Rifampicin-Resistant Tuberculosis during Pregnancy and Post-Partum: A Narrative Review.

Recommendations for treatment of rifampicin-resistant tuberculosis (RR-TB) during pregnancy and post-partum now include Group A and B antituberculosis drugs. While pharmacokinetic data for most of these drugs among adults receiving treatment for RR-TB are limited, the data from pregnant patients and their infants are extremely scarce. Existing data suggest that fluoroquinolones, bedaquiline, clofazimine and terizidone may be used safely in pregnancy. Pharmacokinetic exposures, particularly between trimesters, are potentially sub-optimal; however, there is currently no evidence to support dose adjustment during pregnancy. Linezolid poses a potentially serious toxicity risk, particularly as exposures appear to be high in the later stages of pregnancy and post-partum following extended use, but this should be considered alongside the benefits of this extremely effective drug in the treatment of this life-threatening disease. While plenty of questions remain regarding the exposure to Group A and B antituberculosis drugs through breastmilk, existing literature suggests minimal harm to the breastfed infant. Pregnant patients and their infants should be included in therapeutic trials and pharmacokinetic studies of effective antituberculosis drugs.

Measurement Choices for Youth Suicidality.

Suicide is among the leading causes of death among individuals ages 10-24, making suicidal thoughts and behaviors (STBs) a serious public health crisis among youth. Suicide risk screening and assessment are vital to addressing this public health crisis. In fact, many youths that screen positive for suicidal ideation do not have known mental health concerns and would have been missed if not asked directly. Medical settings are an optimal setting to detect suicidality early and provide appropriate follow-up monitoring and care as needed. To support effective and efficient screening and assessment of suicidal thoughts and behaviors, providers must choose measures with both strong psychometric properties and clinical utility. While measurement of STBs can vary across health settings, suicide risk screening and assessment typically involves gathering information about current suicidal ideation, suicidal behaviors, and suicidal plans via self-report questionnaires, clinical interviews, and/or computerized adaptive screens. In alignment with measurement-based care efforts, the current manuscript will provide a scoping review of measures of youth suicidal ideation, behavior, plans, and their risk factors. Specifically, the psychometric properties, clinical utility, and other key considerations for screening and assessment of adolescent suicide risk are discussed.

Current Treatment of Drug-Resistant Tuberculosis in Children.

Optimal diagnosis and management of children aged <15 y with rifampicin- or multidrug-resistant tuberculosis (RR/MDR-TB) relies on identification of adults with the disease and pro-active screening of their close contacts. Children may be diagnosed with RR/MDR-TB based on microbiological confirmation from clinical specimens (sputum, gastric washings, stool), but usually the diagnosis is presumptive, with a history of exposure to RR/MDR-TB and clinical/radiological signs and symptoms suggestive of TB disease. RR/MDR-TB should also be considered in children where first-line TB treatment fails despite good adherence to therapy. Composition and duration of all-oral RR/MDR-TB treatment regimens in children are based on site and severity of TB disease, drug resistance profile of the Mycobacterium tuberculosis strain (isolated from the child or from the most likely source patient), inclusion of at least four drugs considered to be effective (with priority given to World Health Organization Group A and B drugs), toxicity and tolerability of medications (and feasibility of adverse effect monitoring in the child's setting), and availability of child-friendly formulations of TB medications. Individualized RR/MDR-TB regimens are preferable to the standardised 9-12-mo regimen for children, and injectable agents must not be used. Optimal adherence to treatment relies on education, training and support for caregivers and others who are responsible for administering medications to children, as well as close clinical monitoring and early management of adverse effects. Children who are initiated on adequate RR/MDR-TB regimens have high treatment success rates, but efforts to find and treat more children with undiagnosed RR/MDR-TB are crucial to reduce childhood TB mortality.

Suicidal thoughts and behaviors in youth seeking mental health treatment in Texas: Youth Depression and Suicide Network research registry.

INTRODUCTION: Suicidality in youth is a serious public health problem. The Texas Youth Depression and Suicide Research Network (TX-YDSRN) was initiated in 2020 to create a research registry for youth with depression and/or suicidality in Texas. This report presents baseline clinical/demographic characteristics of the first 1000 participants, focusing on suicidal thoughts and behaviors. METHODS: The registry includes 8-20-year-old youth receiving treatment for depression, or who screen positive for depression and/or suicidal ideation/behavior. Baseline data include diagnosis, depression/anxiety severity, suicidal ideation/behavior, trauma history, and measures of resilience. RESULTS: We present baseline data on the first 1000 participants. Most (79.6%) of the sample had a primary depressive disorder. The sample had moderate to severe depression (Patient Health Questionnaire for Adolescents, PHQ-A; 12.9 ± 6.4) and anxiety (Generalized Anxiety Disorder, GAD-7; 11.3 ± 5.9). Nearly half reported ≥1 lifetime suicide attempts and 90% reported lifetime or current suicidal ideation. Participants with past/current suicidality (attempts and/or ideation) had greater illness severity (depression, anxiety, and suicidal thoughts/behaviors), lower resilience, and higher rates of trauma exposure than those without suicidality. CONCLUSIONS: Baseline data indicate moderate levels of depression, anxiety, and suicidality and their correlates in this cohort. Future reports will determine trajectories of outcomes and predictors, moderators, and social determinants related to these outcomes.

Human microglia maturation is underpinned by specific gene regulatory networks.

Microglia phenotypes are highly regulated by the brain environment, but the transcriptional networks that specify the maturation of human microglia are poorly understood. Here, we characterized stage-specific transcriptomes and epigenetic landscapes of fetal and postnatal human microglia and acquired corresponding data in induced pluripotent stem cell (iPSC)-derived microglia, in cerebral organoids, and following engraftment into humanized mice. Parallel development of computational approaches that considered transcription factor (TF) co-occurrence and enhancer activity allowed prediction of shared and state-specific gene regulatory networks associated with fetal and postnatal microglia. Additionally, many features of the human fetal-to-postnatal transition were recapitulated in a time-dependent manner following the engraftment of iPSC cells into humanized mice. These data and accompanying computational approaches will facilitate further efforts to elucidate mechanisms by which human microglia acquire stage- and disease-specific phenotypes.

Texas Youth Depression and Suicide Research Network (TX-YDSRN) research registry and learning healthcare network: Rationale, design, and baseline characteristics.

BACKGROUND: American youth are seriously impacted by depression and suicide. The Texas Youth Depression and Suicide Research Network (TX-YDSRN) Participant Registry Study was initiated in 2020 to develop predictive models for treatment outcomes in youth with depression and/or suicidality. This report presents the study rationale, design and baseline characteristics of the first 1000 participants. METHODS: TX-YDSRN consists of the Network Hub (coordinating center), 12 medical school "Nodes" (manage/implement study), each with 1-5 primary care, inpatient, and/or outpatient Sub-Sites (recruitment, data collection). Participants are 8-20-year-olds who receive treatment or screen positive for depression and/or suicidality. Baseline data include mood and suicidality symptoms, associated comorbidities, treatment history, services used, and social determinants of health. Subsequent assessments occur every two months for 24 months. RESULTS: Among 1000 participants, 68.7 % were 12-17 years, 24.6 % were ≥ 18 years, and 6.7 % were < 12. Overall, 36.8 % were non-Hispanic Caucasian, 73.4 % were female, and 79.9 % had a primary depressive disorder. Nearly half of the sample reported ≥1 suicide attempt, with rates similar in youth 12-17 years old (49.9 %) and those 18 years and older (45.5 %); 29.9 % of children <12 reported at least one suicide attempt. Depression and anxiety scores were in the moderate-severe range for all age groups (Patient Health Questionnaire for Adolescents [PHQ-A]: 12.9 ± 6.4; Generalized Anxiety Disorder [GAD-7]: 11.3 ± 5.9). LIMITATIONS: The sample includes youth who are receiving depression care at enrollment and may not be representative of non-diagnosed, non-treatment seeking youth. CONCLUSIONS: The TX-YDSRN is one of the largest prospective longitudinal cohort registries designed to develop predictive models for outcome trajectories based on disorder heterogeneity, social determinants of health, and treatment availability.

An oviduct glycan increases sperm lifespan by diminishing the production of ubiquinone and reactive oxygen species†.

Sperm storage by females after mating for species-dependent periods is used widely among animals with internal fertilization to allow asynchrony between mating and ovulation. Many mammals store sperm in the lower oviduct where specific glycans on oviduct epithelial cells retain sperm to form a reservoir. Binding to oviduct cells suppresses sperm intracellular Ca2+ and increases sperm longevity. We investigated the mechanisms by which a specific oviduct glycan, 3-O-sulfated Lewis X trisaccharide (suLeX), prolongs the lifespan of porcine sperm. Using targeted metabolomics, we found that binding to suLeX diminishes the abundance of 4-hydroxybenzoic acid, the precursor to ubiquinone (also known as Coenzyme Q), 30 min after addition. Ubiquinone functions as an electron acceptor in the electron transport chain (ETC). 3-O-sulfated Lewis X trisaccharide also suppressed the formation of fumarate. A component of the citric acid cycle, fumarate is synthesized by succinate-coenzyme Q reductase, which employs ubiquinone and is also known as Complex II in the ETC. Consistent with the reduced activity of the ETC, the production of harmful reactive oxygen species (ROS) was diminished. The enhanced sperm lifespan in the oviduct may be because of suppressed ROS production because high ROS concentrations have toxic effects on sperm.