Statewide Evaluation of SARS-CoV-2 Diagnoses and Sexual Orientation and Gender Identity.

OBJECTIVE: Understanding and identifying disparities in COVID-19 testing outcomes can help allocate resources to where they are most needed. The objective of this study was to estimate the association between lesbian, gay, bisexual, transgender, and queer (LGBTQ+) identity and SARS-CoV-2 test positivity. METHODS: Data were from the Rhode Island SARS-CoV-2 surveillance database and included tests scheduled from June 8, 2020, through January 15, 2021. We used multivariable generalized estimating equations accounting for repeat testing to estimate the odds of receiving a positive test result for SARS-CoV-2 by LGBTQ+ identity and race/ethnicity, adjusting for sociodemographic and temporal confounders. RESULTS: In multivariable analysis of 232 025 tests, LGBTQ+ people had lower odds of receiving a positive test result than cisgender heterosexual people (5.4% vs 8.7%; adjusted odds ratio [aOR] = 0.63; 95% CI, 0.59-0.68). Compared with cisgender heterosexual White people, LGBTQ+ White people were significantly less likely (aOR = 0.67; 95% CI, 0.61-0.73) and cisgender heterosexual people of color were significantly more likely (aOR = 1.71; 95% CI, 1.64-1.78) to receive a positive test result. LGBTQ+ people of color had similar test positivity (aOR = 0.90; 95% CI, 0.79-1.02) as cisgender heterosexual White people. People in sexual minority groups were significantly less likely than heterosexual people to receive a positive test result, but we found no significant differences in test results among cisgender, transgender, and gender nonconforming people. CONCLUSIONS: LGBTQ+ people may be less likely than heterosexual people to receive a positive test result for SARS-CoV-2, potentially related to protective health practices and greater social isolation. Addressing racial and ethnic disparities among both LGBTQ+ people and cisgender heterosexual people should be a priority of the public health workforce.

Prenatal substance exposure: What predicts behavioral resilience by early adolescence?

Understanding behavioral resilience among at-risk adolescents may guide public policy decisions and future programs. We examined factors predicting behavioral resilience following intrauterine substance exposure in a prospective longitudinal birth-cohort study of 136 early adolescents (ages 12.4-15.9 years) at risk for poor behavioral outcomes. We defined behavioral resilience as a composite measure of lack of early substance use initiation (before age 14), lack of risky sexual behavior, or lack of delinquency. Intrauterine substance exposures included in this analysis were cocaine, tobacco, alcohol, and marijuana. We recruited participants from Boston Medical Center as mother-infant dyads between 1990 and 1993. The majority of the sample was African American/Caribbean (88%) and 49% female. In bivariate analyses, none and lower intrauterine cocaine exposure level predicted resilience compared with higher cocaine exposure, but this effect was not found in an adjusted model. Instead, strict caregiver supervision (adjusted odds ratio [AOR] = 6.02, 95% confidence interval (CI) [1.90, 19.00], p = .002), lower violence exposure (AOR = 4.07, 95% CI [1.77, 9.38], p < .001), and absence of intrauterine tobacco exposure (AOR = 3.71, 95% CI [1.28, 10.74], p = .02) predicted behavioral resilience. In conclusion, caregiver supervision in early adolescence, lower violence exposure in childhood, and lack of intrauterine tobacco exposure predicted behavioral resilience among a cohort of early adolescents with significant social and environmental risk. Future interventions should work to enhance parental supervision as a way to mitigate the effects of adversity on high-risk groups of adolescents. (PsycINFO Database Record

Differential risk factors for HIV drug and sex risk-taking among non-treatment-seeking hospitalized injection drug users.

Injection drug users (IDUs) are at increased risk of contracting HIV. From a clinical trial assessing an intervention to enhance the linkage of hospitalized patients to opioid treatment after discharge, we conducted multivariate analysis of baseline data from hospitalized IDUs with a history of opioid dependence (n = 104) to identify differences in factors predicting HIV drug and sex risk behaviors. Factors significantly associated with HIV drug risk were being non-Hispanic Caucasian and recent cocaine use. Being female, binge drinking, and poorer mental health were significantly associated with higher sex risk. Because factors predicting HIV sex risk behaviors differ from those predicting HIV drug risk, interventions aimed at specific HIV risks should have different behavioral and substance use targets.

Adherence to prescription opioid monitoring guidelines among residents and attending physicians in the primary care setting.

OBJECTIVE: The aim of this study was to compare adherence to opioid prescribing guidelines and potential opioid misuse in patients of resident vs attending physicians. DESIGN: Retrospective cross-sectional study. SETTING: Large primary care practice at a safety net hospital in New England. SUBJECTS: Patients 18-89 years old, with at least one visit to the primary care clinic within the past year and were prescribed long-term opioid treatment for chronic noncancer pain. METHODS: Data were abstracted from the electronic medical record by a trained data analyst through a clinical data warehouse. The primary outcomes were adherence to any one of two American Pain Society Guidelines: (1) documentation of at least one opioid agreement (contract) ever and (2) any urine drug testing in the past year, and evidence of potential prescription misuse defined as ≥2 early refills. We employed logistic regression analysis to assess whether patients' physician status predicts guideline adherence and/or potential opioid misuse. RESULTS: Similar proportions of resident and attending patients had a controlled substance agreement (45.1% of resident patients vs. 42.4% of attending patient, P = 0.47) or urine drug testing (58.6% of resident patients vs. 63.6% of attending patients, P = 0.16). Resident patients were more likely to have two or more early refills in the past year relative to attending patients (42.8% vs. 32.5%; P = 0.004). In the adjusted regression analysis, resident patients were more likely to receive early refills (odds ratio 1.82, 95% confidence interval 1.26-2.62) than attending patients. CONCLUSIONS: With some variability, residents and attending physicians were only partly compliant with national guidelines. Residents were more likely to manage patients with a higher likelihood of opioid misuse.

Buprenorphine treatment for hospitalized, opioid-dependent patients: a randomized clinical trial.

IMPORTANCE: Buprenorphine opioid agonist treatment (OAT) has established efficacy for treating opioid dependency among persons seeking addiction treatment. However, effectiveness for out-of-treatment, hospitalized patients is not known. OBJECTIVE: To determine whether buprenorphine administration during medical hospitalization and linkage to office-based buprenorphine OAT after discharge increase entry into office-based OAT, increase sustained engagement in OAT, and decrease illicit opioid use at 6 months after hospitalization. DESIGN, SETTING, AND PARTICIPANTS: From August 1, 2009, through October 31, 2012, a total of 663 hospitalized, opioid-dependent patients in a general medical hospital were identified. Of these, 369 did not meet eligibility criteria. A total of 145 eligible patients consented to participation in the randomized clinical trial. Of these, 139 completed the baseline interview and were assigned to the detoxification (n = 67) or linkage (n = 72) group. INTERVENTIONS: Five-day buprenorphine detoxification protocol or buprenorphine induction, intrahospital dose stabilization, and postdischarge transition to maintenance buprenorphine OAT affiliated with the hospital's primary care clinic (linkage). MAIN OUTCOMES AND MEASURES: Entry and sustained engagement with buprenorphine OAT at 1, 3, and 6 months (medical record verified) and prior 30-day use of illicit opioids (self-report). RESULTS: During follow-up, linkage participants were more likely to enter buprenorphine OAT than those in the detoxification group (52 [72.2%] vs 8 [11.9%], P < .001). At 6 months, 12 linkage participants (16.7%) and 2 detoxification participants (3.0%) were receiving buprenorphine OAT (P = .007). Compared with those in the detoxification group, participants randomized to the linkage group reported less illicit opioid use in the 30 days before the 6-month interview (incidence rate ratio, 0.60; 95% CI, 0.46-0.73; P < .01) in an intent-to-treat analysis. CONCLUSIONS AND RELEVANCE: Compared with an inpatient detoxification protocol, initiation of and linkage to buprenorphine treatment is an effective means for engaging medically hospitalized patients who are not seeking addiction treatment and reduces illicit opioid use 6 months after hospitalization. However, maintaining engagement in treatment remains a challenge. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00987961.

Problematic substance use in urban adolescents: role of intrauterine exposures to cocaine and marijuana and post-natal environment.

BACKGROUND: Linkages between intrauterine exposures to cocaine and marijuana and adolescents' problematic substance use have not been fully delineated. METHODS: Prospective longitudinal study with assessors unaware of intrauterine exposure history followed 157 urban participants from birth until late adolescence. Level of intrauterine exposures was identified by mother's report and infant's meconium. Problematic substance use, identified by the Voice Diagnostic Interview Schedule for Children (V-DISC) or the Audio Computer Assisted Self-Interview (ACASI) and urine assay, was a composite encompassing DSM-IV indication of tolerance, abuse, and dependence on alcohol, marijuana, and tobacco and any use of cocaine, glue, or opiates. RESULTS: Twenty percent (32/157) of the sample experienced problematic substance use by age 18 years, of whom the majority (22/157) acknowledged abuse, tolerance or dependence on marijuana with or without other substances. Structural equation models examining direct and indirect pathways linking a Cox survival model for early substance initiation to a logistic regression models found effects of post-natal factors including childhood exposure to violence and household substance use, early youth substance initiation, and ongoing youth violence exposure contributing to adolescent problematic substance use. CONCLUSION: We did not identify direct relationships between intrauterine cocaine or marijuana exposure and problematic substance use, but did find potentially modifiable post-natal risk factors also noted to be associated with problematic substance use in the general population including earlier substance initiation, exposure to violence and to household substance use.

Days of heroin use predict poor self-reported health in hospitalized heroin users.

This study examined associations between substance use behaviors and self-reported health among hospitalized heroin users. Of the 112 participants, 53 (47%) reported good or better health. In multivariable logistic regression models, each day of heroin use in the last month was associated with an 8% lower odds of reporting health as good or better (OR=.92; 95% CI 0.87, 0.97, p<.05). Cocaine, cannabis, cigarettes, alcohol use, unintentional overdose, nor injection drug use was associated with health status.

Are there effects of intrauterine cocaine exposure on delinquency during early adolescence? A preliminary report.

OBJECTIVE: To ascertain whether level of intrauterine cocaine exposure (IUCE) is associated with early adolescent delinquent behavior, after accounting for prenatal exposures to other psychoactive substances and relevant psychosocial factors. METHODS: Ninety-three early adolescents (12.5-14.5 years old) participating since birth in a longitudinal study of IUCE reported delinquent acts via an audio computer-assisted self-interview. Level of IUCE and exposure to cigarettes, alcohol, and marijuana were determined by maternal report, maternal and infant urine assays, and infant meconium assays at birth. Participants reported their exposure to violence on the Violence Exposure Scale for Children-Revised at ages 8.5, 9.5, and 11 years and during early adolescence, and the strictness of supervision by their caregivers during early adolescence. RESULTS: Of the 93 participants, 24 (26%) reported ≥ 3 delinquent behaviors during early adolescence. In the final multivariate model (including level of IUCE and cigarette exposure, childhood exposure to violence, and caregiver strictness/supervision) ≥ 3 delinquent behaviors were not significantly associated with level of IUCE but were significantly associated with intrauterine exposure to half a pack or more of cigarettes per day and higher levels of childhood exposure to violence, effects substantially unchanged after control for early adolescent violence exposure. CONCLUSIONS: In this cohort, prospectively ascertained prenatal exposure to cigarettes and childhood exposure to violence are associated with self-reported delinquent behaviors during early adolescence. Contrary to initial popular predictions, intrauterine cocaine is not a strong predictor of adolescent delinquent behaviors in this cohort.

Adolescent initiation of licit and illicit substance use: Impact of intrauterine exposures and post-natal exposure to violence.

Whether intrauterine exposures to alcohol, tobacco, marijuana, or cocaine predispose offspring to substance use in adolescence has not been established. We followed a sample of 149 primarily African American/African Caribbean, urban adolescents, recruited at term birth, until age 16 to investigate intrauterine cocaine exposure (IUCE). We found that in Kaplan-Meier analyses higher levels of IUCE were associated with a greater likelihood of initiation of any substance (licit or illicit), as well as marijuana and alcohol specifically. Adolescent initiation of other illicit drugs and cigarettes were analyzed only in the "any" summary variable since they were used too infrequently to analyze as individual outcomes. In Cox proportional hazard models controlling for intrauterine exposure to alcohol, tobacco, and marijuana and demographic and post-natal covariates, those who experienced heavier IUCE had a greater likelihood of initiation of any substance, and those with lighter intrauterine marijuana exposure had a greater likelihood of initiation of any substance as well as of marijuana specifically. Time-dependent higher levels of exposure to violence between ages of 8 and 16 were also robustly associated with initiation of any licit or illicit substance, and of marijuana, and alcohol particularly.

Barriers to initiation of antiretroviral treatment in rural and urban areas of Zambia: a cross-sectional study of cost, stigma, and perceptions about ART.

BACKGROUND: While the number of HIV-positive patients on antiretroviral therapy (ART) in resource-limited settings has increased dramatically, some patients eligible for treatment do not initiate ART even when it is available to them. Understanding why patients opt out of care, or are unable to opt in, is important to achieving the goal of universal access. METHODS: We conducted a cross-sectional survey among 400 patients on ART (those who were able to access care) and 400 patients accessing home-based care (HBC), but who had not initiated ART (either they were not able to, or chose not to, access care) in two rural and two urban sites in Zambia to identify barriers to and facilitators of ART uptake. RESULTS: HBC patients were 50% more likely to report that it would be very difficult to get to the ART clinic than those on ART (RR: 1.48; 95% CI: 1.21-1.82). Stigma was common in all areas, with 54% of HBC patients, but only 15% of ART patients, being afraid to go to the clinic (RR: 3.61; 95% CI: 3.12-4.18). Cost barriers differed by location: urban HBC patients were three times more likely to report needing to pay to travel to the clinic than those on ART (RR: 2.84; 95% CI: 2.02-3.98) and 10 times more likely to believe they would need to pay a fee at the clinic (RR: 9.50; 95% CI: 2.24-40.3). In rural areas, HBC subjects were more likely to report needing to pay non-transport costs to attend the clinic than those on ART (RR: 4.52; 95% CI: 1.91-10.7). HBC patients were twice as likely as ART patients to report not having enough food to take ART being a concern (27% vs. 13%, RR: 2.03; 95% CI: 1.71-2.41), regardless of location and gender. CONCLUSIONS: Patients in home-based care for HIV/AIDS who never initiated ART perceived greater financial and logistical barriers to seeking HIV care and had more negative perceptions about the benefits of the treatment. Future efforts to expand access to antiretroviral care should consider ways to reduce these barriers in order to encourage more of those medically eligible for antiretrovirals to initiate care.

TSC2 loss in lymphangioleiomyomatosis cells correlated with expression of CD44v6, a molecular determinant of metastasis.

Lymphangioleiomyomatosis (LAM), a rare multisystem disease found primarily in women of childbearing age, is characterized by the proliferation of abnormal smooth muscle-like cells, LAM cells, that form nodules in the pulmonary interstitium. Proliferation of LAM cells results, in part, from dysfunction in tuberous sclerosis complex (TSC) genes TSC1 (hamartin) and/or TSC2 (tuberin). Identification of LAM cells in donor lungs, their isolation from blood, and their presence in urine, chylous ascites, and pleural effusions are consistent with their ability to metastasize. Here, we investigated the presence on LAM cells of the hyaluronic acid receptor CD44 and its splice variants associated with metastasis. The heterogeneous populations of cells grown from lungs of 12 LAM patients contain cells expressing mRNA for the variant CD44v6. Histologically, CD44v6 was present in LAM lung nodules, but not in normal vascular smooth muscle cells. CD44v6-positive sorted cells showed loss of heterozygosity at the TSC2 locus; binding of CD44v6 antibody resulted in loss of cell viability. Levels of CD44 were higher in cultured Eker rat (Tsc2-/-) cells than in Tsc2+/+ cells, but unlike human LAM cells, the Tsc2-/- Eker rat cells did not contain CD44v6 splice variant mRNA. CD44 splicing and signaling is regulated by osteopontin. Plasma from LAM patients contained higher concentrations of osteopontin than plasma of healthy, age-, and sex-matched volunteers (P = 0.00003) and may be a biomarker for LAM. The cell surface receptor CD44 and its splice variant CD44v6 may contribute to the metastatic potential of LAM cells.

A tyrosine-based signal plays a critical role in the targeting and function of adenovirus RIDalpha protein.

Early region 3 genes of human adenoviruses contribute to the virus life cycle by altering the trafficking of cellular proteins involved in adaptive immunity and inflammatory responses. The ability of early region 3 genes to target specific molecules suggests that they could be used to curtail pathological processes associated with these molecules and treat human disease. However, this approach requires genetic dissection of the multiple functions attributed to early region 3 genes. The purpose of this study was to determine the role of targeting on the ability of the early region 3-encoded protein RIDalpha to downregulate the EGF receptor. A fusion protein between the RIDalpha cytoplasmic tail and glutathione S-transferase was used to isolate clathrin-associated adaptor 1 and adaptor 2 protein complexes from mammalian cells. Deletion and site-directed mutagenesis studies showed that residues 71-AYLRH of RIDalpha are necessary for in vitro binding to both adaptor complexes and that Tyr72 has an important role in these interactions. In addition, RIDalpha containing a Y72A point mutation accumulates in the trans-Golgi network and fails to downregulate the EGF receptor when it is introduced into mammalian cells as a transgene. Altogether, our data suggest a model where RIDalpha is trafficked directly from the trans-Golgi network to an endosomal compartment, where it intercepts EGF receptors undergoing constitutive recycling to the plasma membrane and redirects them to lysosomes.

Molecular and genetic analysis of disseminated neoplastic cells in lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a multisystem disorder of women, characterized by cystic degeneration of the lungs, renal angiomyolipomas (AML), and lymphatic abnormalities. LAM lesions result from the proliferation of benign-appearing, smooth muscle-like LAM cells, which are characterized by loss of heterozygosity (LOH) of one of the tuberous sclerosis complex (TSC) genes. LAM cells are believed to migrate among the involved organs. Because of the apparently metastatic behavior of LAM, we tried to isolate LAM cells from body fluids. A cell fraction separated by density gradient centrifugation from blood had TSC2 LOH in 33 of 60 (55%) LAM patients. Cells with TSC2 LOH were also found in urine from 11 of 14 (79%) patients with AML and in chylous fluid from 1 of 3 (33%) patients. Identification of LAM cells with TSC2 LOH in body fluids was not correlated with severity of lung disease or extrapulmonary involvement and was found in one patient after double lung transplantation. These studies are compatible with a multisite origin for LAM cells. They establish the existence of disseminated, potentially metastatic LAM cells through a relatively simple, noninvasive procedure that should be valuable for molecular and genetic studies of somatic mutations in LAM and perhaps other metastatic diseases.

Giles F. Filley Lecture. Genetics and gene expression in lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a disease of unknown etiology that is characterized by the proliferation of abnormal smooth muscle cells (LAM cells) in the lung, which leads to cystic parenchymal destruction and progressive respiratory failure. Recent evidence suggests that the proliferative and invasive nature of LAM cells may be due, in part, to somatic mutations in the TSC2 gene, which has been implicated in the pathogenesis of tuberous sclerosis complex. Here, we describe the clinical and molecular characteristics of LAM, as well as the efforts now under way to understand the genetic and biochemical factors that lead to progressive pulmonary destruction and, ultimately, to lung transplantation or death.