Target trial emulation for comparative effectiveness research with observational data: Promise and challenges for studying medications for opioid use disorder.

Medications for opioid use disorder (MOUD) increase retention in care and decrease mortality during active treatment; however, information about the comparative effectiveness of different forms of MOUD is sparse. Observational comparative effectiveness studies are subject to many types of bias; a robust framework to minimize bias would improve the quality of comparative effectiveness evidence. This paper discusses the use of target trial emulation as a framework to conduct comparative effectiveness studies of MOUD with administrative data. Using examples from our planned research project comparing buprenorphine-naloxone and extended-release naltrexone with respect to the rates of MOUD discontinuation, we provide a primer on the challenges and approaches to employing target trial emulation in the study of MOUD.

Novel Uses of Methadone Under the "72-Hour Rule" to Facilitate Transitions of Care and Low-Dose Buprenorphine Induction in an Outpatient Bridge Clinic.

BACKGROUND: Federal regulations restrict methadone for opioid use disorder (OUD) treatment to licensed opioid treatment programs (OTPs). However, providers in other settings can administer methadone for opioid withdrawal under the "72-hour rule" while linking to further care. Prior work has demonstrated that methadone initiation in a low-barrier bridge clinic is associated with high OTP linkage and 1-month retention rates. We describe 2 other novel applications of the 72-hour rule in which methadone withdrawal management facilitated linkage to inpatient hospitalization and outpatient buprenorphine induction. CASE PRESENTATIONS: Patient 1 was a 46-year-old woman with OUD complicated by serious injection-related infections. Severe opioid withdrawal limited her ability to tolerate emergency department wait times and receive inpatient care. We administered methadone for opioid withdrawal in an outpatient bridge clinic immediately before emergency department referral; this enabled hospital admission for intravenous antibiotics and anticoagulation. Patient 2 was a 36-year-old man with OUD desiring buprenorphine treatment. He had been unable to complete traditional buprenorphine induction without experiencing precipitated withdrawal. Thus, we recommended a low-dose buprenorphine induction overlapping with a full opioid agonist. Given the patient's preference to stop using fentanyl immediately, he received 72 hours of methadone for withdrawal treatment during the induction phase and successfully transitioned to buprenorphine without significant concomitant fentanyl use. CONCLUSION: In addition to facilitating OTP linkage, on-demand 72-hour methadone administration for opioid withdrawal can reduce barriers to acute medical care and buprenorphine treatment.

Minnesota Data Sharing May Be Model For Near-Real-Time Tracking Of Drug Overdose Hospital And ED Trends.

The drug overdose epidemic in the US necessitates detailed and timely data to inform public health responses. In this article we describe how an electronic health record (EHR) data-sharing collaboration across health systems in Minnesota that was developed in response to the COVID-19 pandemic was adapted to monitor trends in substance use-related hospital and emergency department (ED) visits. We found large increases in methamphetamine- and opioid-involved hospital and ED visits. Throughout the study period, Native American, Black, and multiple-race people experienced the highest rates of drug-involved hospital and ED visits. Monitoring drug-involved health care use through EHR data has the potential to help public health officials detect trends in near real time before mortality spikes and may also inform early intervention. The use of EHR data also allows for detailed monitoring of the impact of the drug overdose epidemic across racial and ethnic groups.

Removal of Medicaid Prior Authorization Requirements and Buprenorphine Treatment for Opioid Use Disorder.

Importance: Buprenorphine treatment for opioid use disorder (OUD) is associated with decreased morbidity and mortality. Despite its effectiveness, buprenorphine uptake has been limited relative to the burden of OUD. Prior authorization (PA) policies may present a barrier to treatment, though research is limited, particularly in Medicaid populations. Objective: To assess whether removal of Medicaid PAs for buprenorphine to treat OUD is associated with changes in buprenorphine prescriptions for Medicaid enrollees. Design, Setting, and Participants: This state-level, serial cross-sectional study used quarterly data from 2015 through the first quarter (January-March) of 2019 to compare buprenorphine prescriptions in states that did and did not remove Medicaid PAs. Analyses were conducted between June 10, 2021, and August 15, 2023. The study included 23 states with active Medicaid PAs for buprenorphine in 2015 that required similar PA policies in fee-for-service and managed care plans and had at least 2 quarters of pre- and postperiod buprenorphine prescribing data. Exposures: Removal of Medicaid PA for at least 1 formulation of buprenorphine for OUD. Main Outcomes and Measures: The main outcome was number of quarterly buprenorphine prescriptions per 1000 Medicaid enrollees. Results: Between 2015 and the first quarter of 2019, 6 states in the sample removed Medicaid PAs for at least 1 formulation of buprenorphine and had at least 2 quarters of pre- and postpolicy change data. Seventeen states maintained buprenorphine PAs throughout the study period. At baseline, relative to states that repealed PAs, states that maintained PAs had lower buprenorphine prescribing per 1000 Medicaid enrollees (median, 6.6 [IQR, 2.6-13.9] vs 24.1 [IQR, 8.7-27.5] prescriptions) and lower Medicaid managed care penetration (median, 38.5% [IQR, 0.0%-74.1%] vs 79.5% [IQR, 78.1%-83.5%] of enrollees) but similar opioid overdose rates and X-waivered buprenorphine clinicians per 100 000 population. In fully adjusted difference-in-differences models, removal of Medicaid PAs for buprenorphine was not associated with buprenorphine prescribing (1.4% decrease; 95% CI, -31.2% to 41.4%). For states with below-median baseline buprenorphine prescribing, PA removal was associated with increased buprenorphine prescriptions per 1000 Medicaid enrollees (40.1%; 95% CI, 0.6% to 95.1%), while states with above-median prescribing showed no change (-20.7%; 95% CI, -41.0% to 6.6%). Conclusions and Relevance: In this serial cross-sectional study of Medicaid PA policies for buprenorphine for OUD, removal of PAs was not associated with overall changes in buprenorphine prescribing among Medicaid enrollees. Given the ongoing burden of opioid overdoses, continued multipronged efforts are needed to remove barriers to buprenorphine care and increase availability of this lifesaving treatment.

Bridge clinic implementation of "72-hour rule" methadone for opioid withdrawal management: Impact on opioid treatment program linkage and retention in care.

BACKGROUND: Methadone for opioid use disorder (OUD) treatment is restricted to licensed opioid treatment programs (OTPs) with substantial barriers to entry. Underutilized regulations allow non-OTP providers to administer methadone for opioid withdrawal for up to 72 h while arranging ongoing care. Our low-barrier bridge clinic implemented a new pathway to treat opioid withdrawal and facilitate OTP linkage utilizing the "72-hour rule." METHODS: Patients presenting to a hospital-based bridge clinic were evaluated for OUD, opioid withdrawal, and treatment goals. Eligible patients were offered methadone opioid withdrawal management with rapid OTP referral. OTPs accepted patients as direct admissions. We described bridge clinic patients who received at least one dose of methadone between March-August 2021 and key clinical outcomes including OTP referral completion within 72 h. For the subset of patients referred to our two primary OTP partners, we described OTP linkage (i.e., attended at least one OTP visit within one month) and OTP retention at one month. RESULTS: Methadone was administered during 150 episodes of care for 142 unique patients, the majority of whom were male (73%), white (67%), and used fentanyl (85%). In 92% of episodes (138/150), a plan for ongoing care was in place within 72 h. Among 121 referrals to two primary OTP partners, 87% (105/121) linked and 58% (70/121) were retained at one month. CONCLUSIONS: Methadone administration for opioid withdrawal with direct OTP admission under the "72-hour rule" is feasible in an outpatient bridge clinic and resulted in high OTP linkage and 1-month retention rates. This model has the potential to improve methadone access.

Examining the Role of Neighborhood-Level Foreclosure in Smoking and Alcohol Use Among Older Adults in the Multi-Ethnic Study of Atherosclerosis.

The US Great Recession resulted in an alarming number of home foreclosures that weakened the social and physical environment of thousands of neighborhoods. Few studies have evaluated whether these neighborhood changes were related to changes in individual behaviors. We examined the relationship between changes in neighborhood-level home foreclosure within a quarter-mile (0.4-km) buffer of the residence and changes in cigarette smoking and alcohol use among 3,807 adults enrolled in the Multi-Ethnic Study of Atherosclerosis during 2005-2012, using econometric individual-level fixed-effects models. Increases in neighborhood-level foreclosure were associated with small decreases in the number of cigarettes smoked per day (mean difference = -0.08, 95% confidence interval: -0.11, -0.04) and small increases in the number of alcoholic beverages consumed per week (mean difference = 0.11, 95% confidence interval: 0.05, 0.17). Neighborhood-level foreclosure may not uniformly influence high-risk behaviors. The impact of home foreclosure on adult drinking should be further explored, given its potentially negative implications for health.

Cardiovascular Risk Factors, Depression, and Alcohol Consumption During Joblessness and During Recessions Among Young Adults in CARDIA.

Research has shown that recessions are associated with lower cardiovascular mortality, but unemployed individuals have a higher risk of cardiovascular disease (CVD) or death. We used data from 8 consecutive examinations (1985-2011) of the Coronary Artery Risk Development in Young Adults (CARDIA) cohort, modeled in fixed-effect panel regressions, to investigate simultaneously the associations of CVD risk factors with the employment status of individuals and the macroeconomic conditions prevalent in the state where the individual lives. We found that unemployed individuals had lower levels of blood pressure, high-density lipoprotein cholesterol, and physical activity, and they had significantly higher depression scores, but they were similar to their counterparts in smoking status, alcohol consumption, low-density lipoprotein cholesterol levels, body mass index, and waist circumference. A 1-percentage-point higher unemployment rate at the state level was associated with lower systolic (-0.41 mm Hg, 95% CI: -0.65, -0.17) and diastolic (-0.19, 95% CI: -0.39, 0.01) blood pressure, higher physical activity levels, higher depressive symptom scores, lower waist circumference, and less smoking. We conclude that levels of CVD risk factors tend to improve during recessions, but mental health tends to deteriorate. Unemployed individuals are significantly more depressed, and they likely have lower levels of physical activity and high-density lipoprotein cholesterol.

Socioeconomic position and markers of adiposity among female teachers in Mexico.

BACKGROUND: Occupation is often used as an indicator of socioeconomic position (SEP) in epidemiological studies, although it is unclear whether variation in SEP within a single occupational group is associated with health outcomes, including adiposity measures. METHODS: We created a multidimensional SEP index using principal component analysis based on self-reported data from 36 704 female teachers in Mexico from 2008 to 2011. Multivariable Poisson regression models with robust variance were used to evaluate cross-sectional associations of SEP and markers of adiposity, including obesity (body mass index (BMI) ≥30 kg/m2), elevated waist-to-hip ratio (WHR >85) and high waist circumference (WC >88 cm). RESULTS: The most relevant indicators of SEP in this study were internet access and private health insurance. We observed significant inverse trends in obesity, WHR and WC in relation to SEP (all ptrend<0.001). Compared with women with low SEP, women in the middle (prevalence ratio (PR) 0.97, 95% CI 0.93 to 1.02) and high (PR 0.85, 95% CI 0.81 to 0.90) SEP tertiles were less likely to be obese in multivariable models. Results were similar in models of WHR and WC adjusting for BMI. For example, women with high versus low SEP were 14% less likely to have an elevated WHR (PR 0.86, 95% CI 0.83 to 0.89) and 7% less likely to have a high WC (PR 0.93, 95% CI 0.89 to 0.97). CONCLUSIONS: Our findings suggest that SEP remains relevant for adiposity within a single occupational setting and indicate that a stronger conceptualisation of SEP in epidemiological studies may be warranted.

Individual- and Area-Level SES in Diabetes Risk Prediction: The Multi-Ethnic Study of Atherosclerosis.

INTRODUCTION: The purpose of this study was to evaluate if adding SES to risk prediction models based upon traditional risk factors improves the prediction of diabetes. METHODS: Risk prediction models without and with individual- and area-level SES predictors were compared using the prospective Multi-Ethnic Study of Atherosclerosis. Cox proportional hazards models were utilized to estimate hazard ratios for SES predictors and to generate 10-year predicted risks for 5,021 individuals without diabetes at baseline followed from 2000 to 2012. C-statistics were used to compare model discrimination, and the proportion of individuals reclassified into higher or lower risk categories with the addition of SES predictors was calculated. The accuracy of risk prediction by SES was assessed by comparing observed and predicted risks across tertiles of the SES variables. Statistical analyses were performed in 2015-2016. RESULTS: Over a median of 9.2 years of follow-up, 615 individuals developed diabetes. Individual- and area-level SES variables did not significantly improve model discrimination or reclassify substantial numbers of individuals across risk categories. Models without SES predictors generally underestimated risk for low-SES individuals or individuals residing in low-SES areas (underestimates ranging from 0.31% to 1.07%) and overestimated risk for high-SES individuals or individuals residing in high-SES areas (overestimates ranging from 0.70% to 1.30%), and the addition of SES variables largely mitigated these differences. CONCLUSIONS: Standard diabetes risk models may underestimate risk for low-SES individuals and overestimate risk for those of high SES. Adding SES predictors helps correct this systematic misestimation, but may not improve model discrimination.

Exposure to Neighborhood Foreclosures and Changes in Cardiometabolic Health: Results From MESA.

Home foreclosures can precipitate declines in health among the individuals who lost their homes. Whether home foreclosures can "spillover" to affect the health of other neighborhood residents is largely unknown. Using longitudinal data from the Multi-Ethnic Study of Atherosclerosis that were linked to foreclosure data from 2005 to 2012, we assessed whether greater exposure to neighborhood foreclosures was associated with temporal changes in 3 objectively measured cardiometabolic risk factors: body mass index, systolic blood pressure, and fasting glucose level. We used fixed-effects models to estimate mean changes in cardiometabolic risk factors associated with changes in neighborhood foreclosures over time. In models in which we controlled for time-varying income, working status, medication use, neighborhood poverty, neighborhood unemployment, and interactions of age, sex, race, and state foreclosure laws with time, a standard-deviation increase in neighborhood foreclosures (1.9 foreclosures per quarter mile) was associated with increases in fasting glucose (mean = 0.22 mg/dL, 95% confidence interval: -0.05, 0.50) and decreases in blood pressure (mean = -0.27 mm Hg, 95% confidence interval: -0.49, -0.04). Changes in neighborhood foreclosure rates were not associated with changes in body mass index. Overall, greater exposure to neighborhood foreclosures had mixed associations with cardiometabolic risk factors over time. Given the millions of mortgages still in default, further research clarifying the potential health effects of neighborhood foreclosures is needed.

Modeling the Effects of E-cigarettes on Smoking Behavior: Implications for Future Adult Smoking Prevalence.

BACKGROUND: Electronic cigarette (e-cigarette) use has increased rapidly in recent years. Given the unknown effects of e-cigarette use on cigarette smoking behaviors, e-cigarette regulation has become the subject of considerable controversy. In the absence of longitudinal data documenting the long-term effects of e-cigarette use on smoking behavior and population smoking outcomes, computational models can guide future empirical research and provide insights into the possible effects of e-cigarette use on smoking prevalence over time. METHODS: Agent-based model examining hypothetical scenarios of e-cigarette use by smoking status and e-cigarette effects on smoking initiation and smoking cessation. RESULTS: If e-cigarettes increase individual-level smoking cessation probabilities by 20%, the model estimates a 6% reduction in smoking prevalence by 2060 compared with baseline model (no effects) outcomes. In contrast, e-cigarette use prevalence among never smokers would have to rise dramatically from current estimates, with e-cigarettes increasing smoking initiation by more than 200% relative to baseline model estimates to achieve a corresponding 6% increase in smoking prevalence by 2060. CONCLUSIONS: Based on current knowledge of the patterns of e-cigarette use by smoking status and the heavy concentration of e-cigarette use among current smokers, the simulated effects of e-cigarettes on smoking cessation generate substantially larger changes to smoking prevalence compared with their effects on smoking initiation.

Behaviours and opinions towards outdoor smoking bans and cigarette littering in Baja California, Mexico.

OBJECTIVE: Outdoor smoking bans have been implemented to reduce secondhand smoke exposure and cigarette littering. We aimed to explore outdoor smoking behaviours, cigarette littering, and support towards a recently enacted outdoor smoking ban in Baja California, Mexico. METHODS: From October 2013 to April 2014 a representative sample of 800 adults from urban areas of Baja California was surveyed to obtain information on demographics, smoking status, opinion towards outdoor smoking bans in general and in specific locations, and perceptions and habits regarding cigarette littering. Descriptive statistics and Poisson regression analyses were conducted to estimate prevalence ratios and corresponding 95% CI taking into account the complex survey design. RESULTS: Outdoor smoking was frequently observed, as 86.8% of the population reported having seen people smoking in parks and beaches and 94.4% in open venues such as concerts or stadiums. A smoking ban in all outdoor areas was supported by 71.8% of Baja California residents. Site-specific support ranged from 80% (stadiums) to 89% (public parks). Support for the ban was higher among never and ex-smokers than in current smokers. Cigarette littering was negatively perceived by 98% of the participants, yet 45% of all cigarettes smoked were thrown on the ground. Based on cigarette consumption and butt littering reported in the survey, we estimated that 27 million cigarette butts become litter every month in urban areas of Baja California. CONCLUSIONS: Outdoor smoking is still frequent in outdoor areas where people gather, and an important source of littering. We found substantial public support towards the outdoor smoking ban, which should translate into easier implementation and compliance in Baja California, Mexico.

Longitudinal Associations Between Neighborhood Physical and Social Environments and Incident Type 2 Diabetes Mellitus: The Multi-Ethnic Study of Atherosclerosis (MESA).

IMPORTANCE: Neighborhood environments may influence the risk for developing type 2 diabetes mellitus (T2DM), but, to our knowledge, no longitudinal study has evaluated specific neighborhood exposures. OBJECTIVE: To determine whether long-term exposures to neighborhood physical and social environments, including the availability of healthy food and physical activity resources and levels of social cohesion and safety, are associated with incident T2DM during a 10-year period. DESIGN, SETTING, AND PARTICIPANTS: We used data from the Multi-Ethnic Study of Atherosclerosis, a population-based cohort study of adults aged 45 to 84 years at baseline (July 17, 2000, through August 29, 2002). A total of 5124 participants free of T2DM at baseline underwent 5 clinical follow-up examinations from July 17, 2000, through February 4, 2012. Time-varying measurements of neighborhood healthy food and physical activity resources and social environments were linked to individual participant addresses. Neighborhood environments were measured using geographic information system (GIS)- and survey-based methods and combined into a summary score. We estimated hazard ratios (HRs) of incident T2DM associated with cumulative exposure to neighborhood resources using Cox proportional hazards regression models adjusted for age, sex, income, educational level, race/ethnicity, alcohol use, and cigarette smoking. Data were analyzed from December 15, 2013, through September 22, 2014. MAIN OUTCOMES AND MEASURES: Incident T2DM defined as a fasting glucose level of at least 126 mg/dL or use of insulin or oral antihyperglycemics. RESULTS: During a median follow-up of 8.9 years (37,394 person-years), 616 of 5124 participants (12.0%) developed T2DM (crude incidence rate, 16.47 [95% CI, 15.22-17.83] per 1000 person-years). In adjusted models, a lower risk for developing T2DM was associated with greater cumulative exposure to indicators of neighborhood healthy food (12%; HR per interquartile range [IQR] increase in summary score, 0.88 [95% CI, 0.79-0.98]) and physical activity resources (21%; HR per IQR increase in summary score, 0.79 [95% CI, 0.71-0.88]), with associations driven primarily by the survey exposure measures. Neighborhood social environment was not associated with incident T2DM (HR per IQR increase in summary score, 0.96 [95% CI, 0.88-1.07]). CONCLUSIONS AND RELEVANCE: Long-term exposure to residential environments with greater resources to support physical activity and, to a lesser extent, healthy diets was associated with a lower incidence of T2DM, although results varied by measurement method. Modifying neighborhood environments may represent a complementary, population-based approach to prevention of T2DM, although further intervention studies are needed.

Temporal trends in BMI in Argentina by socio-economic position and province-level economic development, 2005-2009.

OBJECTIVE: We investigated temporal trends in BMI, and assessed hypothesized predictors of trends including socio-economic position (SEP) and province-level economic development, in Argentina. DESIGN: Using multivariable linear regression, we evaluated cross-sectional patterning and temporal trends in BMI and examined heterogeneity in these associations by SEP and province-level economic development with nationally representative samples from Argentina in 2005 and 2009. We calculated mean annual changes in BMI for men and women to assess secular trends. RESULTS: Women, but not men, exhibited a strong cross-sectional inverse association between SEP and BMI, with the lowest-SEP women having an average BMI 2.55 kg/m(2) greater than the highest-SEP women. Analysis of trends revealed a mean annual increase in BMI of 0.19 kg/m(2) and 0.15 kg/m(2) for women and men, respectively, with slightly greater increases occurring in provinces with greater economic growth. No significant heterogeneity in trends existed by individual SEP. CONCLUSIONS: BMI is increasing rapidly over time in Argentina irrespective of various sociodemographic characteristics. Higher BMI remains more common in women of lower SEP compared with those of higher SEP.

Genome-wide analysis of DNA methylation in human amnion.

The amnion is a specialized tissue in contact with the amniotic fluid, which is in a constantly changing state. To investigate the importance of epigenetic events in this tissue in the physiology and pathophysiology of pregnancy, we performed genome-wide DNA methylation profiling of human amnion from term (with and without labor) and preterm deliveries. Using the Illumina Infinium HumanMethylation27 BeadChip, we identified genes exhibiting differential methylation associated with normal labor and preterm birth. Functional analysis of the differentially methylated genes revealed biologically relevant enriched gene sets. Bisulfite sequencing analysis of the promoter region of the oxytocin receptor (OXTR) gene detected two CpG dinucleotides showing significant methylation differences among the three groups of samples. Hypermethylation of the CpG island of the solute carrier family 30 member 3 (SLC30A3) gene in preterm amnion was confirmed by methylation-specific PCR. This work provides preliminary evidence that DNA methylation changes in the amnion may be at least partially involved in the physiological process of labor and the etiology of preterm birth and suggests that DNA methylation profiles, in combination with other biological data, may provide valuable insight into the mechanisms underlying normal and pathological pregnancies.