Post-traumatic stress and future substance use outcomes: leveraging antecedent factors to stratify risk.

Background: Post-traumatic stress disorder (PTSD) and substance use (tobacco, alcohol, and cannabis) are highly comorbid. Many factors affect this relationship, including sociodemographic and psychosocial characteristics, other prior traumas, and physical health. However, few prior studies have investigated this prospectively, examining new substance use and the extent to which a wide range of factors may modify the relationship to PTSD. Methods: The Advancing Understanding of RecOvery afteR traumA (AURORA) study is a prospective cohort of adults presenting at emergency departments (N = 2,943). Participants self-reported PTSD symptoms and the frequency and quantity of tobacco, alcohol, and cannabis use at six total timepoints. We assessed the associations of PTSD and future substance use, lagged by one timepoint, using the Poisson generalized estimating equations. We also stratified by incident and prevalent substance use and generated causal forests to identify the most important effect modifiers of this relationship out of 128 potential variables. Results: At baseline, 37.3% (N = 1,099) of participants reported likely PTSD. PTSD was associated with tobacco frequency (incidence rate ratio (IRR): 1.003, 95% CI: 1.00, 1.01, p = 0.02) and quantity (IRR: 1.01, 95% CI: 1.001, 1.01, p = 0.01), and alcohol frequency (IRR: 1.002, 95% CI: 1.00, 1.004, p = 0.03) and quantity (IRR: 1.003, 95% CI: 1.001, 1.01, p = 0.001), but not with cannabis use. There were slight differences in incident compared to prevalent tobacco frequency and quantity of use; prevalent tobacco frequency and quantity were associated with PTSD symptoms, while incident tobacco frequency and quantity were not. Using causal forests, lifetime worst use of cigarettes, overall self-rated physical health, and prior childhood trauma were major moderators of the relationship between PTSD symptoms and the three substances investigated. Conclusion: PTSD symptoms were highly associated with tobacco and alcohol use, while the association with prospective cannabis use is not clear. Findings suggest that understanding the different risk stratification that occurs can aid in tailoring interventions to populations at greatest risk to best mitigate the comorbidity between PTSD symptoms and future substance use outcomes. We demonstrate that this is particularly salient for tobacco use and, to some extent, alcohol use, while cannabis is less likely to be impacted by PTSD symptoms across the strata.

Addressing the smoking-hypertension paradox in pregnancy: insight from a multiethnic US birth cohort.

Background: Smoking during pregnancy has been associated with reduced risk of a spectrum of hypertensive (HTN) disorders, known as the "smoking-hypertension paradox." Objective: We sought to test potential epidemiologic explanations for the smoking-hypertension paradox. Methods: We analyzed 8510 pregnant people in the Boston Birth Cohort, including 4027 non-Hispanic Black and 2428 Hispanic pregnancies. Study participants self-reported tobacco, alcohol, cannabis, opioids, or cocaine use during pregnancy. We used logistic regression to assess effect modification by race/ethnicity, and confounding of concurrent substances on hypertensive disorders or prior pregnancy. We also investigated early gestational age as a collider or competing risk for pre-eclampsia, using cause-specific Cox models and Fine-Gray models, respectively. Results: We replicated the paradox showing smoking to be protective against hypertensive disorders among Black participants who used other substances as well (aOR: 0.61, 95% CI: 0.41, 0.93), but observed null effects for Hispanic participants (aOR: 1.14, 95% CI: 0.55, 2.36). In our cause-specific Cox regression, the effects of tobacco use were reduced to null effects with pre-eclampsia (aOR: 0.81, 95% CI: 0.63, 1.04) after stratifying for preterm birth. For the Fine-Gray competing risk analysis, the paradoxical associations remained. The smoking paradox was either not observed or reversed after accounting for race/ethnicity, other substance use, and collider-stratification due to preterm birth. Conclusions: These findings offer new insights into this paradox and underscore the importance of considering multiple sources of bias in assessing the smoking-hypertension association in pregnancy.

Experiences of violence and discrimination among LGBTQ+ individuals during the COVID-19 pandemic: a global cross-sectional analysis.

OBJECTIVES: To characterise the extent to which the levels of violence and discrimination against lesbian, gay, bisexual, transgender and queer (LGBTQ+) people have changed amid COVID-19. DESIGN: Cross-sectional, secondary analysis. SETTING: 79 countries. PARTICIPANTS: All adults (aged ≥18 years) who used the Hornet social networking application and provided consent to participate. MAIN OUTCOME MEASURE: The main outcome was whether individuals have experienced less, or the same or more levels of discrimination and violence from specific groups (eg, police and/or military, government representatives, healthcare providers). RESULTS: 7758 LGBTQ+ individuals provided responses regarding levels of discrimination and violence. A majority identified as gay (78.95%) and cisgender (94.8%). Identifying as gay or queer was associated with increased odds of experiencing the same or more discrimination from government representatives (OR=1.89, 95% CI 1.04 to 3.45, p=0.045) and healthcare providers (OR=2.51, 95% CI 0.86 to 7.36, p=0.002) due to COVID-19. Being a member of an ethnic minority was associated with increased odds of discrimination and violence from police and/or military (OR=1.32, 95% CI 1.13 to 1.54, p=0.0) and government representatives (OR=1.47, 95% CI 1.29 to 1.69, p=0.0) since COVID-19. Having a disability was significantly associated with increased odds of violence and discrimination from police and/or military (OR=1.38, 95% CI 1.15 to 1.71, p=0.0) and healthcare providers (OR=1.35, 95% CI 1.07 to 1.71, p=0.009). CONCLUSIONS: Our results suggest that despite the upending nature of the COVID-19 pandemic, around the world, government representatives, policymakers and healthcare providers continue to perpetuate systemic discrimination and fail to prevent violence against members of the LGBTQ+ community.

Individual and Combined Association Between Prenatal Polysubstance Exposure and Childhood Risk of Attention-Deficit/Hyperactivity Disorder.

Importance: Polysubstance use among pregnant women has increased because of the opioid epidemic and the increasing legalization of cannabis along with persistent tobacco and alcohol consumption. Previous research on prenatal substance use and the child's risk of attention-deficit/hyperactivity disorder (ADHD) has mostly focused on single-substance exposures; simultaneous examination of multiple substance use and assessment of their synergistic health consequences is needed. Objectives: To assess the consequences of the use of specific substances during pregnancy, investigate whether the interaction of multiple prenatal substance exposures is associated with increases in the risk of childhood ADHD, and estimate the aggregate burden of polysubstance exposure during gestation. Design, Setting, and Participants: This cohort study analyzed data from the Boston Birth Cohort from 1998 to 2019. The sample of the present study comprised a multiethnic urban cohort of mother-child pairs who were predominantly low income. A total of 3138 children who were enrolled shortly after birth at Boston Medical Center were included and followed up from age 6 months to 21 years. Exposures: Substance use during pregnancy was identified based on self-reported tobacco smoking, alcohol consumption, and use of cannabis, cocaine, or opioids in any trimester of pregnancy. Diagnostic codes for neonatal opioid withdrawal syndrome or neonatal abstinence syndrome from the International Classification of Diseases, Ninth Revision, and the International Classification of Diseases, Tenth Revision, were also used to identify opioid exposure during gestation. Main Outcomes and Measures: ADHD diagnosis in the child's electronic medical record. Results: Among 3138 children (1583 boys [50.4%]; median age, 12 years [IQR, 9-14 years]; median follow-up, 10 years [IQR, 7-12 years]) in the final analytic sample, 486 (15.5%) had an ADHD diagnosis and 2652 (84.5%) were neurotypical. The median postnatal follow-up duration was 12 years (IQR, 9-14 years). Among mothers, 46 women (1.5%) self-identified as Asian (non-Pacific Islander), 701 (22.3%) as Hispanic, 1838 (58.6%) as non-Hispanic Black, 227 (7.2%) as non-Hispanic White, and 326 (10.4%) as other races and/or ethnicities (including American Indian or Indigenous, Cape Verdean, Pacific Islander, multiracial, other, or unknown). A total of 759 women (24.2%) reported the use of at least 1 substance during pregnancy, with tobacco being the most frequently reported (580 women [18.5%]). Cox proportional hazards models revealed that opioid exposure (60 children) had the highest adjusted hazard ratio (HR) for ADHD (2.19; 95% CI, 1.10-4.37). After including main statistical effects of all individual substances in an elastic net regression model, the HR of opioids was reduced to 1.60, and evidence of a statistical interaction between opioids and both cannabis and alcohol was found, producing 1.42 and 1.15 times higher risk of ADHD, respectively. The interaction between opioids and smoking was also associated with a higher risk of ADHD (HR, 1.17). Conclusions and Relevance: The findings of this study suggest that it is important to consider prenatal concurrent exposure to multiple substances and their possible interactions when counseling women regarding substance use during pregnancy, the future risk of ADHD for their children, and strategies for cessation and treatment programs.

Prevalence and associations of COVID-19 testing in an online sample of transgender and non-binary individuals.

BACKGROUND: Testing for COVID-19 and linkage to services is fundamental to successful containment and control of transmission. Yet, knowledge on COVID-19 testing among transgender and non-binary communities remains limited. METHODS: Between October 2020 and November 2020, we examined the prevalence and associations of COVID-19 testing in an online sample of transgender and non-binary people (n=536). Multivariable hierarchical logistic regression analyses examined associations between COVID-19 testing and participants' sociodemographic, mental health, substance use, gender affirmation, economic changes and healthcare experiences. RESULTS: Prevalence of COVID-19 testing in this sample was 35.5% (n=190/536). In the final model, transgender and non-binary participants from upper socioeconomic income background and Europe, who reported having active alcohol use disorder, limited access to gender-affirming surgery, had more than 20% reduction in income, and experienced mistreatment in a health facility due to gender identity had significantly increased odds of COVID-19 testing (all p<0.05); those who reported recent tobacco use had significantly lower odds of COVID-19 testing (p=0.007). CONCLUSIONS: These findings highlight structural disparities in COVID-19 testing and reinforce the importance of increasing testing strategies for transgender and non-binary populations.

DNA methylation and behavioral dysfunction in males with 47,XXY and 49,XXXXY: a pilot study.

BACKGROUND: Equal dosage of X-linked genes between males and females is maintained by the X-inactivation of the second X chromosome in females through epigenetic mechanisms. Boys with aneuploidy of the X chromosome exhibit a host of symptoms such as low fertility, musculoskeletal anomalies, and cognitive and behavioral deficits that are presumed to be caused by the abnormal dosage of these genes. The objective of this pilot study is to assess the relationship between CpG methylation, an epigenetic modification, at several genes on the X chromosome and behavioral dysfunction in boys with supernumerary X chromosomes. RESULTS: Two parental questionnaires, the Behavior Rating Inventory of Executive Function (BRIEF) and Child Behavior Checklist (CBCL), were analyzed, and they showed expected differences in both internal and external behaviors between neurotypical (46,XY) boys and boys with 49,XXXXY. There were several CpGs in AR and MAOA of boys with 49,XXXXY whose methylation levels were skewed from levels predicted from having one active (Xa) and three inactive (Xi) X chromosomes. Further, methylation levels of multiple CpGs in MAOA showed nominally significant association with externalizing behavior on the CBCL, and the methylation level of one CpG in AR showed nominally significant association with the BRIEF Regulation Index. CONCLUSIONS: Boys with 49,XXXXY displayed higher levels of CpG methylation at regulatory intronic regions in X-linked genes encoding the androgen receptor (AR) and monoamine oxidase A (MAOA), compared to that in boys with 47,XXY and neurotypical boys. Our pilot study results suggest a link between CpG methylation levels and behavior in boys with 49,XXXXY.

COVID-19 vaccine prioritization of incarcerated people relative to other vulnerable groups: An analysis of state plans.

BACKGROUND: Carceral facilities are epicenters of the COVID-19 pandemic, placing incarcerated people at an elevated risk of COVID-19 infection. Due to the initial limited availability of COVID-19 vaccines in the United States, all states have developed allocation plans that outline a phased distribution. This study uses document analysis to compare the relative prioritization of incarcerated people, correctional staff, and other groups at increased risk of COVID-19 infection and morbidity. METHODS AND FINDINGS: We conducted a document analysis of the vaccine dissemination plans of all 50 US states and the District of Columbia using a triple-coding method. Documents included state COVID-19 vaccination plans and supplemental materials on vaccine prioritization from state health department websites as of December 31, 2020. We found that 22% of states prioritized incarcerated people in Phase 1, 29% of states in Phase 2, and 2% in Phase 3, while 47% of states did not explicitly specify in which phase people who are incarcerated will be eligible for vaccination. Incarcerated people were consistently not prioritized in Phase 1, while other vulnerable groups who shared similar environmental risk received this early prioritization. States' plans prioritized in Phase 1: prison and jail workers (49%), law enforcement (63%), seniors (65+ years, 59%), and long-term care facility residents (100%). CONCLUSIONS: This study demonstrates that states' COVID-19 vaccine allocation plans do not prioritize incarcerated people and provide little to no guidance on vaccination protocols if they fall under other high-risk categories that receive earlier priority. Deprioritizing incarcerated people for vaccination misses a crucial opportunity for COVID-19 mitigation. It also raises ethical and equity concerns. As states move forward with their vaccine distribution, further work must be done to prioritize ethical allocation and distribution of COVID-19 vaccines to incarcerated people.

HIV treatment engagement in the context of COVID-19: an observational global sample of transgender and nonbinary people living with HIV.

BACKGROUND: HIV services, like many medical services, have been disrupted by the COVID-19 pandemic. However, there are limited data on the impacts of the COVID-19 pandemic on HIV treatment engagement outcomes among transgender (trans) and nonbinary people. This study addresses a pressing knowledge gap and is important in its global scope, its use of technology for recruitment, and focus on transgender people living with HIV. The objective of this study is to examine correlates of HIV infection and HIV treatment engagement outcomes (i.e., currently on ART, having an HIV provider, having access to HIV treatment without burden, and remote refills) since the COVID-19 pandemic began. METHODS: We utilized observational data from the Global COVID-19 Disparities Survey 2020, an online study that globally sampled trans and nonbinary people (n = 902) between April and August 2020. We conducted a series of multivariable logistic regressions with lasso selection to explore correlates of HIV treatment engagement outcomes in the context of COVID-19. RESULTS: Of the 120 (13.3%) trans and nonbinary people living with HIV in this survey, the majority (85.8%) were currently on HIV treatment. A smaller proportion (69.2%) reported having access to an HIV provider since COVID-19 control measures were implemented. Less than half reported being able to access treatment without burdens related to COVID-19 (48.3%) and having the ability to remotely refill HIV prescription (44.2%). After adjusting for gender in the multivariable models, younger age and anticipated job loss were significantly associated with not having access to HIV treatment without burden. Outcomes also significantly varied by geographic region, with respondents reporting less access to an HIV provider in nearly every region outside of South-East Asia. CONCLUSION: Our results suggest that currently taking ART, having access to an HIV provider, and being able to access HIV treatment without burden and remotely refill HIV medication are suboptimal among trans and nonbinary people living with HIV across the world. Strengthening support for HIV programs that are well-connected to trans and nonbinary communities, increasing remote access to HIV providers and prescription refills, and providing socioeconomic support could significantly improve HIV engagement in trans and nonbinary communities.

The role of gender power relations on women's health outcomes: evidence from a maternal health coverage survey in Simiyu region, Tanzania.

BACKGROUND: Gender is a crucial consideration of human rights that impacts many priority maternal health outcomes. However, gender is often only reported in relation to sex-disaggregated data in health coverage surveys. Few coverage surveys to date have integrated a more expansive set of gender-related questions and indicators, especially in low- to middle-income countries that have high levels of reported gender inequality. Using various gender-sensitive indicators, we investigated the role of gender power relations within households on women's health outcomes in Simiyu region, Tanzania. METHODS: We assessed 34 questions around gender dynamics reported by men and women against 18 women's health outcomes. We created directed acyclic graphs (DAGs) to theorize the relationship between indicators, outcomes, and sociodemographic covariates. We grouped gender variables into four categories using an established gender framework: (1) women's decision-making, (2) household labor-sharing, (3) women's resource access, and (4) norms/beliefs. Gender indicators that were most proximate to the health outcomes in the DAG were tested using multivariate logistic regression, adjusting for sociodemographic factors. RESULTS: The overall percent agreement of gender-related indicators within couples was 68.6%. The lowest couple concordance was a woman's autonomy to decide to see family/friends without permission from her husband/partner (40.1%). A number of relationships between gender-related indicators and health outcomes emerged: questions from the decision-making domain were found to play a large role in women's health outcomes, and condoms and contraceptive outcomes had the most robust relationship with gender indicators. Women who reported being able to make their own health decisions were 1.57 times (95% CI: 1.12, 2.20) more likely to use condoms. Women who reported that they decide how many children they had also reported high contraception use (OR: 1.79, 95% CI: 1.34, 2.39). Seeking care at the health facility was also associated with women's autonomy for making major household purchases (OR: 1.35, 95% CI: 1.13, 1.62). CONCLUSIONS: The association between decision-making and other gender domains with women's health outcomes highlights the need for heightened attention to gender dimensions of intervention coverage in maternal health. Future studies should integrate and analyze gender-sensitive questions within coverage surveys.

Adaptation and psychometric validation of the Prolonged Grief Disorder scale among widows in central Nepal.

BACKGROUND: Symptoms of grief vary by culture and societal reactions to death may be gender specific. We aimed to validate a Nepali language version of the Prolonged Grief-13 item scale (PG-13) among widows. METHODS: We tested two adapted versions of a Prolonged Grief Disorder (PGD) instrument with 204 Nepali-speaking widows: one was a Nepali translation of the original PG-13 items, while the other contained five additional items derived from qualitative research. We evaluated internal consistency, factor structure, and construct and criterion validity. RESULTS: Participants were on average 44 years old (SD=9.3), completed 6.7 years of school (SD=3.3) and had survived their husbands by 10 years (SD=8.1). Thirteen percent met global criteria for PGD. The removal of one original PG-13 item (felt emotionally numb) from both versions due to poor discriminant validity resulted in 12- and 17-item versions. Exploratory factor analysis supported a one-factor structure for the PG-12 and PG-17. Both versions of the scale exhibited high internal consistency (0.89 and 0.93 respectively). Confirmatory factor analysis suggested that symptoms of PGD were distinct from post-traumatic stress disorder (PTSD), anxiety and depressive symptoms. The PG-12 had lower sensitivity (74.1%) but higher specificity (83.6%) compared to the PG-17 (81.5% and 73.5% respectively). LIMITATIONS: Psychosocial counselors' clinical interview global ratings were used as the standard for comparison in criterion validity analyses. Generalizability to other socio-cultural (e.g. non-widowed, low-caste) populations and men in Nepal cannot be assumed. CONCLUSIONS: Results indicate satisfactory psychometric properties and validity of both versions of the PG instruments, supporting their use with Nepali speaking widows.

Characterization of glucocorticoid-induced loss of DNA methylation of the stress-response gene Fkbp5 in neuronal cells.

Exposure to stress or glucocorticoids (GCs) is associated with epigenetic and transcriptional changes in genes that either mediate or are targets of GC signalling. FKBP5 (FK506 binding protein 5) is one such gene that also plays a central role in negative feedback regulation of GC signalling and several stress-related psychiatric disorders. In this study, we sought to examine how the mouse Fkbp5 gene is regulated in a neuronal context and identify requisite factors that can mediate the epigenetic sequelae of excess GC exposure. Mice treated with GCs were used to establish the widespread changes in DNA methylation (DNAm) and expression of Fkbp5 across four brain regions. Then two cell lines were used to test the persistence, decay, and functional significance of GC-induced methylation changes near two GC response elements (GREs) in the fifth intron of Fkbp5. We also tested the involvement of DNMT1, cell proliferation, and MeCP2 in mediating the effect of GCs on DNAm and gene activation. DNAm changes at some CpGs persist while others decay, and reduced methylation states are associated with a more robust transcriptional response. Importantly, the ability to undergo GC-induced DNAm loss is tied to DNMT1 function during cell division. Further, GC-induced DNAm loss is associated with reduced binding of MeCP2 at intron 5 and a physical interaction between the fifth intron and promoter of Fkbp5. Our results highlight several key factors at the Fkbp5 locus that may have important implications for GC- or stress-exposure during early stages of neurodevelopment.

Maternal persistent marijuana use and cigarette smoking are independently associated with shorter gestational age.

BACKGROUND: Research assessing the effects of marijuana use on preterm birth has found mixed results, in part, due to lack of attention to the role of maternal tobacco smoking during pregnancy. OBJECTIVES: The study objective was to investigate whether maternal marijuana use was independently associated with gestational age, preterm birth, and two preterm birth subtypes (spontaneous vs clinician-initiated). METHODS: Participants included 8261 mother-newborn pairs from the Boston Birth Cohort. Information on gestational age was collected from electronic medical records. Marijuana use and tobacco smoking during pregnancy were assessed through a standard questionnaire after birth. Linear and log-linear regression models were used to assess associations between marijuana use with and without tobacco smoking during pregnancy and the outcomes of interest. RESULTS: Of the 8261 mothers, 27.5% had preterm births. About 3.5% of mothers with term deliveries and 5.2% of mothers with preterm births used marijuana during pregnancy. Marijuana use and cigarette smoking were independently associated with a decrease in gestational age by 0.50 weeks (95% confidence interval [CI] -0.87, -0.13) and 0.52 weeks (95% CI -0.76, -0.28), respectively. Marijuana use during early or late pregnancy was associated with a similar decrease in gestational age by 0.50 weeks. When we examined the effects on the preterm birth subtypes, simultaneous marijuana use and tobacco smoking were associated with higher risk of spontaneous preterm birth (RR 1.64, 95% CI 1.23, 2.18). The elevated risk was not observed with clinician-initiated preterm birth. CONCLUSIONS: In this high-risk US population, maternal marijuana use and cigarette smoking during pregnancy were independently associated with shorter gestational age. When we examined the effects on preterm birth subtypes, the elevated risk was only observed with spontaneous preterm birth.

Polydrug Use During Pregnancy and Preterm Birth in a Low-Income, Multiethnic Birth Cohort, Boston, 1998-2018.

OBJECTIVE: The opioid epidemic in the United States increasingly affects women of reproductive age and has resulted in a rise in concurrent polydrug use. The objective of this study was to investigate the effect of this polydrug use on preterm birth in a multiethnic birth cohort. METHODS: We analyzed data from 8261 mothers enrolled in the Boston Birth Cohort from 1998 to 2018 in Boston, Massachusetts. We grouped substances used during pregnancy based on their primary effects (stimulant or depressant) and assessed independent and combined associations with smoking on preterm birth. RESULTS: Of 8261 mothers, 131 used stimulant drugs and 193 used depressant drugs during pregnancy. The preterm birth rate was 27.5% (2271 of 8261) in the sample. Mothers who smoked had 35% increased odds of preterm birth across adjusted models. Mothers who used stimulant drugs without smoking were not at increased risk of preterm delivery compared with mothers who used neither (odds ratio [OR] = 0.69; 95% confidence interval [CI], 0.19-1.98), whereas mothers who used depressant drugs without smoking had more than twice the odds of having preterm delivery (OR = 2.31; 95% CI, 1.19-4.44), and infants were at risk of a 1-week reduction in gestational age (OR = -1.05; 95% CI, -2.07 to -0.03). Concurrently smoking and using depressant drugs was associated with increased odds of preterm birth (OR = 1.83; 95% CI, 1.28-2.61), as was concurrently smoking and using stimulant drugs (OR = 1.73; 95% CI, 1.14-2.59). CONCLUSIONS: Using stimulant drugs and depressant drugs during pregnancy is a risk factor for preterm birth. The individual and combined effects of using these drugs with smoking must be considered together to reduce the risk of preterm birth in the United States.