Association Between Prescription Drug Monitoring Program Use Mandate and Opioid Prescribing and Patient-Reported Outcomes After Surgery.

OBJECTIVE: To evaluate changes in opioid prescribing and patient-reported outcomes after surgery following implementation of Michigan's prescription drug monitoring program (PDMP) use mandate in June 2018. BACKGROUND: Most states mandate clinicians to query prescription drug monitoring program (PDMP) databases before prescribing controlled substances. Whether these PDMP use mandates affect opioid prescribing and patient-reported outcomes after surgery is unclear, especially among patients with elevated "Narx" scores, a risk score for overdose death used in most PDMPs. METHODS: We conducted an interrupted time series analysis of a statewide surgical registry linked to Michigan's PDMP database. Analyses included adults undergoing general surgical procedures during January 2017-October 2019. Outcomes included monthly mean days supplied in dispensed opioid prescriptions (those filled within 3 days of discharge) and monthly mean scores for 3 patient-reported outcomes (pain in the week after surgery, care satisfaction, regret undergoing surgery). Segmented regression models were used to assess for level and slope changes in outcomes in June 2018. Analyses were repeated among patients with Narx scores ≥200, a threshold that defines the top quartile. RESULTS: Analyses included 21,897 patients. The mandate was associated with a -0.5 (95% CI: -0.8, -0.2) level decrease in mean days supplied in dispensed opioid prescriptions, but not with worsened patient-reported outcomes. Findings were similar among patients with Narx scores ≥200. CONCLUSIONS: Following implementation of Michigan's PDMP use mandate, the duration of opioid prescriptions decreased, but patient-reported outcomes did not worsen. Findings suggest PDMP use mandates may not be associated with worsened experience among general surgical patients.

Association Between Cost-Sharing and Buprenorphine Prescription Abandonment.

BACKGROUND: Prior studies suggest cost-sharing decreases buprenorphine dispensing. However, these studies used databases that only report prescriptions filled by patients, not those that were "abandoned." Consequently, the studies could not calculate the probability of buprenorphine prescription abandonment or evaluate whether cost-sharing is associated with abandonment. OBJECTIVE: To evaluate the association between cost-sharing and buprenorphine prescription abandonment. DESIGN: Cross-sectional analysis of the IQVIA Formulary Impact Analyzer, a pharmacy transaction database representing 63% of U.S. retail pharmacies. The database includes transaction records ("claims") for prescriptions even if they are not filled. PARTICIPANTS: Buprenorphine claims in 2022 among commercially insured and Medicare patients. MAIN MEASURES: We evaluated the association between cost-sharing per 30-day supply and abandonment using logistic regression, controlling for patient characteristics, product type, and buprenorphine use in the prior 180 days. We assessed for effect modification by prior buprenorphine use. KEY RESULTS: Analyses included 2,346,994 and 1,242,596 buprenorphine prescription claims for commercially insured and Medicare patients, respectively. Among these claims, mean (SD) cost-sharing per 30-day supply was $28.1 (46.4) and $8.4 (20.2), and 1.5% and 1.2% were abandoned. Each $10 increase in cost-sharing per 30-day supply was associated with a 0.09 (95% CI: 0.09, 0.10) and 0.09 (95% CI: 0.08, 0.10) percentage-point increase in abandonment among commercially insured and Medicare patients. Among commercially insured and Medicare patients without prior buprenorphine use, respectively, a $10 increase in cost-sharing per 30-day supply was associated with a 0.12 (95% CI: 0.11, 0.14) and 0.13 (95% CI: 0.07, 0.18) percentage-point higher increase in the probability of abandonment compared with patients with > 90 days of prior buprenorphine use. CONCLUSIONS: Among commercially insured and Medicare patients, buprenorphine prescription abandonment is rare and only minimally associated with cost-sharing. Findings suggest elimination of buprenorphine cost-sharing should only be one component of a larger, multi-faceted campaign to increase buprenorphine dispensing.

Impact of SARS-CoV-2 Infection on Long-Term Depression Symptoms among Veterans.

BACKGROUND: Prior research demonstrates that SARS-COV-2 infection can be associated with a broad range of mental health outcomes including depression symptoms. Veterans, in particular, may be at elevated risk of increased depression following SARS-COV-2 infection given their high rates of pre-existing mental and physical health comorbidities. However, few studies have tried to isolate SARS-COV-2 infection associations with long term, patient-reported depression symptoms from other factors (e.g., physical health comorbidities, pandemic-related stress). OBJECTIVE: To evaluate the association between SARS-COV-2 infection and subsequent depression symptoms among United States Military Veterans. DESIGN: Survey-based non-randomized cohort study with matched comparators. PARTICIPANTS: A matched-dyadic sample from a larger, stratified random sample of participants with and without known to SARS-COV-2 infection were invited to participate in a survey evaluating mental health and wellness 18-months after their index infection date. Sampled participants were stratified by infection severity of the participant infected with SARS-COV-2 (hospitalized or not) and by month of index date. A total of 186 participants in each group agreed to participate in the survey and had sufficient data for inclusion in analyses. Those in the uninfected group who were later infected were excluded from analyses. MAIN MEASURES: Participants were administered the Patient Health Questionnaire-9 as part of a phone interview survey. Demographics, physical and mental health comorbidities were extracted from VHA administrative data. KEY RESULTS: Veterans infected with SARS-COV-2 had significantly higher depression symptoms scores compared with those uninfected. In particular, psychological symptoms (e.g., low mood, suicidal ideation) scores were elevated relative to the comparator group (MInfected = 3.16, 95%CI: 2.5, 3.8; MUninfected = 1.96, 95%CI: 1.4, 2.5). Findings were similar regardless of history of depression. CONCLUSION: SARS-COV-2 infection was associated with more depression symptoms among Veterans at 18-months post-infection. Routine evaluation of depression symptoms over time following SARS-COV-2 infection is important to facilitate adequate assessment and treatment.

Risk of Suicide-Related Outcomes After SARS-COV-2 Infection: Results from a Nationwide Observational Matched Cohort of US Veterans.

BACKGROUND: Negative mental health-related effects of SARS-COV-2 infection are increasingly evident. However, the impact on suicide-related outcomes is poorly understood, especially among populations at elevated risk. OBJECTIVE: To determine risk of suicide attempts and other self-directed violence (SDV) after SARS-COV-2 infection in a high-risk population. DESIGN: We employed an observational design supported by comprehensive electronic health records from the Veterans Health Administration (VHA) to examine the association of SARS-COV-2 infection with suicide attempts and other SDV within one year of infection. Veterans with SARS-COV-2 infections were matched 1:5 with non-infected comparators each month. Three periods after index were evaluated: days 1-30, days 31-365, and days 1-365. PARTICIPANTS: VHA patients infected with SARS-COV-2 between March 1, 2020 and March 31, 2021 and matched non-infected Veteran comparators. MAIN MEASURES: Suicide attempt and other SDV events for the COVID-19 and non-infected comparator groups were analyzed using incidence rates per 100,000 person years and hazard ratios from Cox regressions modeling time from matched index date to first event. Subgroups were also examined. KEY RESULTS: 198,938 veterans with SARS-COV-2 (COVID-19 group) and 992,036 comparators were included. Unadjusted one-year incidence per 100,000 for suicide attempt and other SDV was higher among the COVID-19 group: 355 vs 250 and 327 vs 235, respectively. The COVID-19 group had higher risk than comparators for suicide attempts: days 1-30 hazard ratio (HR) = 2.54 (CI:2.05, 3.15), days 31-365 HR = 1.30 (CI:1.19, 1.43) and days 1-365 HR = 1.41 (CI:1.30, 1.54), and for other SDV: days 1-30 HR = 1.94 (CI:1.51, 2.49), days 31-365 HR = 1.32 (CI:1.20, 1.45) and days 1-365 HR = 1.38 (CI:1.26, 1.51). CONCLUSIONS: COVID-19 patients had higher risks of both suicide attempts and other forms of SDV compared to uninfected comparators, which persisted for at least one year after infection. Results support suicide risk screening of those infected with SARS-COV-2 to identify opportunities to prevent self-harm.

A multidimensional appraisal of early menstrual pain experience.

BACKGROUND: Symptomatic dysmenorrhea is a global problem, affecting more than 40% of menstruating persons. Cross-sectional studies have implicated psychosocial, biological, and sensory factors in dysmenorrhea but the mechanisms are not fully understood. Only a few prospective longitudinal studies have evaluated such factors in relation to the emergence and course of dysmenorrhea at menarche. OBJECTIVE: This study aimed to describe the initial menstruation experience and to evaluate the association of premenarchal psychosocial and sensory factors with the intensity of dysmenorrhea during the period in the fourth month. STUDY DESIGN: This was a prospective cohort study of adolescents who completed premenarchal assessments and postmenarchal daily menstrual diaries for their first (n=149) and fourth month periods (n=114). They were recruited shortly before menarche and completed baseline assessments, including psychosocial questionnaires and experimental pain sensitivity (pressure testing, bladder provocation), and their parents completed related pain questionnaires. The relation between the hypothesized premenarchal factors and month 4 dysmenorrhea intensity was evaluated using Kruskal-Wallis and chi-square tests for low (<3 on a 0-10 scale) vs higher (≥3) menstrual pain groups based on maximal pain ratings recorded in a daily diary. RESULTS: Low levels of dysmenorrhea characterized the first (median, 1; interquartile range, 0-2) and fourth month periods (1; 0-3). Maximal pain ratings increased from the first to the fourth period (3; 1-5 vs 4; 1-6; P=.007). The distribution of dysmenorrhea was multimodal at month 4 with 31.6% of the participants having low levels of maximal pain (1; 0-1) and 68.4% having higher levels (5; 4-6; Hartigan's dip test P<.001). The baseline demographic, psychosocial, and parental pain characteristics were not associated with the development of worse dysmenorrhea. The baseline experimental pain sensitivity, based on pressure pain thresholds, did not differ between the low (15.7 N; 12.5-22.3) and higher (15.0 N; 10.9-21.4]) level dysmenorrhea groups. Baseline bladder pain at first urge also did not differ (low, 6; 0-20 vs higher, 7; 0-19). CONCLUSION: By their fourth month period, two-thirds of adolescents fell into the higher group for maximal dysmenorrhea, half reported some related impairments in physical activity, and one-seventh reported some related school absence. Premenarchal factors (experimental pain sensitivity, psychosocial profile, parental pain experience) linked to chronic pain emergence in the adult literature did not predict dysmenorrhea intensity, suggesting the dominant factor at menarche may be peripheral afferent activation. Further research is needed to understand the evolution of psychosocial and sensory mechanisms in the development and course of dysmenorrhea.

Lifetime non-fatal overdose experiences among at-risk adolescents and young adults in the emergency department with past-year opioid use in the USA.

BACKGROUND: Adolescents and young adults with risk factors for opioid misuse and opioid use disorder are at elevated risk for overdose. We examined prior non-fatal overdose experiences among at-risk adolescents/young adults to inform prevention efforts. METHODS: Adolescents/young adults (ages 16-30) in two US emergency departments self-reporting past year opioid misuse or opioid use plus a misuse risk factor completed a baseline survey as part of an ongoing randomised controlled trial. We describe baseline factors associated with (a) overall non-fatal overdose experiences and (b) groups based on substance(s) used during the worst overdose experience. RESULTS: Among 771 participants (27.9% male), 40.7% reported a non-fatal overdose experience. Compared with those without a prior overdose experience, those with prior overdose experience(s) were less likely to be heterosexual, and more likely to report a prior suicide attempt and greater peer substance misuse. Regarding the worst overdose experience, substance(s) included: 36.6% alcohol only, 28.0% alcohol and cannabis, 22.6% alcohol with other substance(s) and 12.7% other substance(s) only (eg, opioids). Compared with the alcohol only group, the alcohol and cannabis group were younger and less likely to be heterosexual; the alcohol with other substance(s) group were older and had greater peer substance misuse; and the other substance(s) only group were more likely to be male, receive public assistance, screen positive for anxiety and less likely to be heterosexual. CONCLUSIONS: Among at-risk adolescents/young adults, findings support the need for tailored overdose prevention efforts based on substance(s) used, with consideration of sexuality, mental health and peer substance use. TRIAL REGISTRATION NUMBER: NCT04550715.

Financial hardship after COVID-19 infection among US Veterans: a national prospective cohort study.

BACKGROUND: Research suggests an association between COVID-19 infection and certain financial hardships in the shorter term and among single-state and privately insured samples. Whether COVID-19 is associated with financial hardship in the longer-term or among socially vulnerable populations is unknown. Therefore, we examined whether COVID-19 was associated with a range of financial hardships 18 months after initial infection among a national cohort of Veterans enrolled in the Veterans Health Administration (VHA)-the largest national integrated health system in the US. We additionally explored the association between Veteran characteristics and financial hardship during the pandemic, irrespective of COVID-19. METHODS: We conducted a prospective, telephone-based survey. Out of 600 Veterans with COVID-19 from October 2020 through April 2021 who were invited to participate, 194 Veterans with COVID-19 and 194 matched comparators without a history of infection participated. Financial hardship outcomes included overall health-related financial strain, two behavioral financial hardships (e.g., taking less medication than prescribed due to cost), and seven material financial hardships (e.g., using up most or all savings). Weighted generalized estimating equations were used to estimate risk ratios (RR) and 95% confidence intervals (CI) of financial hardship by COVID-19 status, and to assess the relationship between infection and Veteran age, VHA copay status, and comorbidity score, irrespective of COVID-19 status. RESULTS: Among 388 respondents, 67% reported at least one type of financial hardship since March 2020, with 21% reporting behavioral hardships and 64% material hardships; 8% reported severe-to-extreme health-related financial strain. Compared with uninfected matched comparators, Veterans with a history of COVID-19 had greater risks of severe-to-extreme health-related financial strain (RR: 4.0, CI: 1.4-11.2), taking less medication due to cost (RR: 2.9, 95% CI: 1.0-8.6), and having a loved one take time off work to care for them (RR: 1.9, CI: 1.1-3.6). Irrespective of COVID-19 status, Veterans aged < 65 years had a greater risk of most financial hardships compared with Veterans aged ≥ 65 years. CONCLUSIONS: Health-related financial hardships such as taking less medication due to cost and severe-to-extreme health-related financial strain were more common among Veterans with a history of COVID-19 than among matched comparators. Strategies are needed to address health-related financial hardship after COVID-19. TRIAL REGISTRATION: NCT05394025, registered 05-27-2022.

Effectiveness of Nirmatrelvir-Ritonavir Against the Development of Post-COVID-19 Conditions Among U.S. Veterans : A Target Trial Emulation.

BACKGROUND: COVID-19 has been linked to the development of many post-COVID-19 conditions (PCCs) after acute infection. Limited information is available on the effectiveness of oral antivirals used to treat acute COVID-19 in preventing the development of PCCs. OBJECTIVE: To measure the effectiveness of outpatient treatment of COVID-19 with nirmatrelvir-ritonavir in preventing PCCs. DESIGN: Retrospective target trial emulation study comparing matched cohorts receiving nirmatrelvir-ritonavir versus no treatment. SETTING: Veterans Health Administration (VHA). PARTICIPANTS: Nonhospitalized veterans in VHA care who were at risk for severe COVID-19 and tested positive for SARS-CoV-2 during January through July 2022. INTERVENTION: Nirmatrelvir-ritonavir treatment for acute COVID-19. MEASUREMENTS: Cumulative incidence of 31 potential PCCs at 31 to 180 days after treatment or a matched index date, including cardiac, pulmonary, renal, thromboembolic, gastrointestinal, neurologic, mental health, musculoskeletal, endocrine, and general conditions and symptoms. RESULTS: Eighty-six percent of the participants were male, with a median age of 66 years, and 17.5% were unvaccinated. Baseline characteristics were well balanced between participants treated with nirmatrelvir-ritonavir and matched untreated comparators. No differences were observed between participants treated with nirmatrelvir-ritonavir (n = 9593) and their matched untreated comparators in the incidence of most PCCs examined individually or grouped by organ system, except for lower combined risk for venous thromboembolism and pulmonary embolism (subhazard ratio, 0.65 [95% CI, 0.44 to 0.97]; cumulative incidence difference, -0.29 percentage points [CI, -0.52 to -0.05 percentage points]). LIMITATIONS: Ascertainment of PCCs using International Classification of Diseases, 10th Revision, codes may be inaccurate. Evaluation of many outcomes could have resulted in spurious associations with combined thromboembolic events by chance. CONCLUSION: Out of 31 potential PCCs, only combined thromboembolic events seemed to be reduced by nirmatrelvir-ritonavir. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs.

Effectiveness of COVID-19 Treatment With Nirmatrelvir-Ritonavir or Molnupiravir Among U.S. Veterans: Target Trial Emulation Studies With One-Month and Six-Month Outcomes.

BACKGROUND: Information about the effectiveness of oral antivirals in preventing short- and long-term COVID-19-related outcomes in the setting of Omicron variant transmission and COVID-19 vaccination is limited. OBJECTIVE: To measure the effectiveness of nirmatrelvir-ritonavir and molnupiravir for outpatient treatment of COVID-19. DESIGN: Three retrospective target trial emulation studies comparing matched cohorts of nirmatrelvir-ritonavir versus no treatment, molnupiravir versus no treatment, and nirmatrelvir-ritonavir versus molnupiravir. SETTING: Veterans Health Administration (VHA). PARTICIPANTS: Nonhospitalized veterans in VHA care who were at risk for severe COVID-19 and tested positive for SARS-CoV-2 during January through July 2022. INTERVENTION: Nirmatrelvir-ritonavir or molnupiravir pharmacotherapy. MEASUREMENTS: Incidence of any hospitalization or all-cause mortality at 30 days and from 31 to 180 days. RESULTS: Eighty-seven percent of participants were male; the median age was 66 years, and 18% were unvaccinated. Compared with matched untreated control participants, those treated with nirmatrelvir-ritonavir (n = 9607) had lower 30-day risk for hospitalization (22.07 vs. 30.32 per 1000 participants; risk difference [RD], -8.25 [95% CI, -12.27 to -4.23] per 1000 participants) and death (1.25 vs. 5.47 per 1000 participants; RD, -4.22 [CI, -5.45 to -3.00] per 1000 participants). Among persons alive at day 31, reductions were seen in 31- to 180-day incidence of death (hazard ratio, 0.66 [CI, 0.49 to 0.89]) but not hospitalization (subhazard ratio, 0.90 [CI, 0.79 to 1.02]). Molnupiravir-treated participants (n = 3504) had lower 30-day and 31- to 180-day risks for death (3.14 vs. 13.56 per 1000 participants at 30 days; RD, -10.42 [CI, -13.49 to -7.35] per 1000 participants; hazard ratio at 31 to 180 days, 0.67 [CI, 0.48 to 0.95]) but not hospitalization. A difference in 30-day or 31- to 180-day risk for hospitalization or death was not observed between matched nirmatrelvir- or molnupiravir-treated participants. LIMITATION: The date of COVID-19 symptom onset for most veterans was unknown. CONCLUSION: Nirmatrelvir-ritonavir was effective in reducing 30-day hospitalization and death. Molnupiravir was associated with a benefit for 30-day mortality but not hospitalization. Further reductions in mortality from 31 to 180 days were observed with both antivirals. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs.

Association Between Cost Sharing and Naloxone Prescription Dispensing.

Importance: Increasing access to naloxone (an opioid antagonist that can reverse overdose) could slow the US opioid epidemic. Prior studies suggest cost sharing may be a barrier to dispensing of naloxone prescriptions, but these studies were limited by their cross-sectional designs and use of databases that do not capture prescriptions that are not filled (abandoned). Objective: To evaluate the association between cost sharing and naloxone prescription abandonment (nondispensing of naloxone prescriptions). Design, Setting, and Participants: This cross-sectional, regression discontinuity analysis exploited the fact that deductibles typically reset at the beginning of the year in commercial and Medicare plans. The included data were derived from the 2020-2021 IQVIA Formulary Impact Analyzer (a pharmacy transactions database that represents 63% of prescriptions at US pharmacies). The analysis included claims for naloxone nasal spray among commercially insured patients and Medicare patients that occurred during the 60 days before January 1, 2021, through 59 days after January 1, 2021. Exposure: Cost sharing, which is defined as the amount patients would have to pay to fill prescriptions. Main Outcomes and Measures: Local linear regression models were used to assess for abrupt changes in cost sharing and the probability of prescription abandonment on January 1, 2021. To estimate the association between cost sharing and prescription abandonment, a fuzzy regression discontinuity analysis was conducted. Results: These analyses included naloxone claims for 71 306 commercially insured patients and 101 706 Medicare patients (40 019 [56.1%] and 61 410 [60.4%], respectively, were female). The commercially insured patients and Medicare patients accounted for 73 311 and 106 076 naloxone claims, respectively. On January 1, 2021, the mean cost sharing per claim increased by $15.0 (95% CI, $13.8-$16.2) for commercially insured patients and increased by $12.3 (95% CI, $10.9-$13.6) for Medicare patients and the probability of abandonment increased by 4.7 (95% CI, 3.2-6.2) percentage points and 2.8 (95% CI, 1.6-4.1) percentage points, respectively. The results from the fuzzy regression discontinuity analysis suggest a decision by commercial and Medicare plans to increase naloxone cost sharing by $10 would be associated with percentage-point increases of 3.1 (95% CI, 2.2-4.1) and 2.3 (95% CI, 1.4-3.2), respectively, in the probability of abandonment. Conclusions: The elimination of cost sharing might be associated with increased naloxone dispensing to commercially insured and Medicare patients.

Identifying Persistent Opioid Use After Surgery: The Reliability of Pharmacy Dispensation Databases.

OBJECTIVE: The present study assessed concordance in perioperative opioid fulfillment data between Michigan's prescription drug monitoring program (PDMP) and a national pharmacy prescription database. BACKGROUND: PDMPs and pharmacy dispensation databases are widely utilized, yet no research has compared their opioid fulfilment data postoperatively. METHODS: This retrospective study included participants (N=19,823) from 2 registry studies at Michigan Medicine between July 1, 2016, and February 7, 2019. We assessed the concordance of opioid prescription fulfilment between the Michigan PDMP and a national pharmacy prescription database (Surescripts). The primary outcome was concordance of opioid fill data in the 91 to 180 days after surgical discharge, a time period frequently used to define persistent opioid use. Secondary outcomes included concordance of opioid dose and number of prescriptions fulfilled. Multinomial logistic regression analysis examined concordance across key subgroups. RESULTS: In total, 3076 participants had ≥1 opioid fulfillments 91 to 180 days after discharge, with 1489 (49%) documented in PDMP only, 243 (8%) in Surescripts only, and 1332 (43%) in both databases. Among participants with fulfillments in both databases, there were differences in the number (n=239; 18%) and dose (n=227; 17%). The PDMP database was more likely to capture fulfillment among younger and publicly insured participants, while Surescripts was more likely to capture fulfillment from counties bordering neighboring states. The prevalence of persistent opioid use was 10.7% using PDMP data, 5.5% using Surescripts data only, and 11.7% using both data resources. CONCLUSIONS: The state PDMP appears reliable for detecting opioid fulfillment after surgery, detecting 2 times more patients with persistent opioid use compared with Surescripts.

Variation in Clinical Characteristics and Longitudinal Outcomes in Individuals with Opioid Use Disorder Diagnosis Codes.

BACKGROUND: Patterns of opioid use vary, including prescribed use without aberrancy, limited aberrant use, and potential opioid use disorder (OUD). In clinical practice, similar opioid-related International Classification of Disease (ICD) codes are applied across this spectrum, limiting understanding of how groups vary by sociodemographic factors, comorbidities, and long-term risks. OBJECTIVE: (1) Examine how Veterans assigned opioid abuse/dependence ICD codes vary at diagnosis and with respect to long-term risks. (2) Determine whether those with limited aberrant use share more similarities to likely OUD vs those using opioids as prescribed. DESIGN: Longitudinal observational cohort study. PARTICIPANTS: National sample of Veterans categorized as having (1) likely OUD, (2) limited aberrant opioid use, or (3) prescribed, non-aberrant use based upon enhanced medical chart review. MAIN MEASURES: Comparison of sociodemographic and clinical factors at diagnosis and rates of age-adjusted mortality, non-fatal opioid overdose, and hospitalization after diagnosis. An exploratory machine learning analysis investigated how closely those with limited aberrant use resembled those with likely OUD. KEY RESULTS: Veterans (n = 483) were categorized as likely OUD (62.1%), limited aberrant use (17.8%), and prescribed, non-aberrant use (20.1%). Age, proportion experiencing homelessness, chronic pain, anxiety disorders, and non-opioid substance use disorders differed by group. All-cause mortality was high (44.2 per 1000 person-years (95% CI 33.9, 56.7)). Hospitalization rates per 1000 person-years were highest in the likely OUD group (831.5 (95% CI 771.0, 895.5)), compared to limited aberrant use (739.8 (95% CI 637.1, 854.4)) and prescribed, non-aberrant use (411.9 (95% CI 342.6, 490.4). The exploratory analysis reclassified 29.1% of those with limited aberrant use as having likely OUD with high confidence. CONCLUSIONS: Veterans assigned opioid abuse/dependence ICD codes are heterogeneous and face variable long-term risks. Limited aberrant use confers increased risk compared to no aberrant use, and some may already have OUD. Findings warrant future investigation of this understudied population.

Design and analysis of outcomes following SARS-CoV-2 infection in veterans.

BACKGROUND: Understanding how SARS-CoV-2 infection impacts long-term patient outcomes requires identification of comparable persons with and without infection. We report the design and implementation of a matching strategy employed by the Department of Veterans Affairs' (VA) COVID-19 Observational Research Collaboratory (CORC) to develop comparable cohorts of SARS-CoV-2 infected and uninfected persons for the purpose of inferring potential causative long-term adverse effects of SARS-CoV-2 infection in the Veteran population. METHODS: In a retrospective cohort study, we identified VA health care system patients who were and were not infected with SARS-CoV-2 on a rolling monthly basis. We generated matched cohorts within each month utilizing a combination of exact and time-varying propensity score matching based on electronic health record (EHR)-derived covariates that can be confounders or risk factors across a range of outcomes. RESULTS: From an initial pool of 126,689,864 person-months of observation, we generated final matched cohorts of 208,536 Veterans infected between March 2020-April 2021 and 3,014,091 uninfected Veterans. Matched cohorts were well-balanced on all 39 covariates used in matching after excluding patients for: no VA health care utilization; implausible age, weight, or height; living outside of the 50 states or Washington, D.C.; prior SARS-CoV-2 diagnosis per Medicare claims; or lack of a suitable match. Most Veterans in the matched cohort were male (88.3%), non-Hispanic (87.1%), white (67.2%), and living in urban areas (71.5%), with a mean age of 60.6, BMI of 31.3, Gagne comorbidity score of 1.4 and a mean of 2.3 CDC high-risk conditions. The most common diagnoses were hypertension (61.4%), diabetes (34.3%), major depression (32.2%), coronary heart disease (28.5%), PTSD (25.5%), anxiety (22.5%), and chronic kidney disease (22.5%). CONCLUSION: This successful creation of matched SARS-CoV-2 infected and uninfected patient cohorts from the largest integrated health system in the United States will support cohort studies of outcomes derived from EHRs and sample selection for qualitative interviews and patient surveys. These studies will increase our understanding of the long-term outcomes of Veterans who were infected with SARS-CoV-2.

A developmental perspective on sleep consistency: Preschool age through emerging adulthood.

OBJECTIVE/BACKGROUND: Beyond sleep duration, the regularity of sleep patterns (e.g., sleep consistency), including variability in sleep timing (e.g., bedtime, wake time) and duration, is a critical marker of sleep health. Sleep consistency is captured using a variety of methods within the literature (e.g., sleep intraindividual variability, social jetlag), but most of the research focuses on adolescents. METHODS: Drawing on a developmental perspective, this narrative review highlights how normative changes at the individual (e.g., biological, cognitive, and social) and contextual (e.g., home, school, sociocultural) levels may contribute to inconsistent sleep patterns across development. RESULTS AND CONCLUSIONS: This review emphasizes how inconsistent sleep may increase across pivotal transitions throughout development (e.g., elimination of naps, puberty, summertime, entering college). Finally, recommendations for measuring sleep consistency and areas to address in future research are discussed.

Sleep, Affect, and Emotion Reactivity in First-Year College Students: A Daily Diary Study.

BACKGROUND: Sleep is an important factor in well-being, especially during the transition to college when academic and social commitments increase. Identifying factors that contribute to poor sleep (including short duration and increased variability in duration) can support development of interventions. Affect and emotion reactivity are factors that could contribute to sleep, and have not been studied in relation to sleep variables among first-year college students during their adjustment to the college environment. This adjustment might be difficult for some students, and therefore elicit affect fluctuations that contribute to poor sleep. Alternatively, sleep could contribute to daily affect. The present daily diary study examined bidirectional relations between daily sleep and affect, as well as between emotion reactivity and sleep (duration and variability) and affect (daily and overall variability) in first-year college students. METHOD: First-year college students (n = 244; 86.1% female) completed a baseline survey including measures of emotion reactivity and anxiety and depressive symptoms, followed by 7 days of a once-per-day diary, reporting on their affect and sleep duration. RESULTS: On days when individuals reported increased sleep duration, they also tended to experience greater positive affect the following day (p = .01). Those who experienced high levels of emotion reactivity also experienced more negative affect (p < .001) and negative affect variability (p < .001). CONCLUSION: Emotion reactivity might identify college students who experience more negative affect and are possibly at risk to develop mental health disorders. The importance of sleep health should continue to be emphasized to students as they transition to college.

Trends in Depressive Symptoms and Associated Factors During Residency, 2007 to 2019 : A Repeated Annual Cohort Study.

BACKGROUND: Efforts to address the high depression rates among training physicians have been implemented at various levels of the U.S. medical education system. The cumulative effect of these efforts is unknown. OBJECTIVE: To assess how the increase in depressive symptoms with residency has shifted over time and to identify parallel trends in factors that have previously been associated with resident physician depression. DESIGN: Repeated annual cohort study. SETTING: U.S. health care organizations. PARTICIPANTS: First-year resident physicians (interns) who started training between 2007 and 2019. MEASUREMENTS: Depressive symptoms (9-item Patient Health Questionnaire [PHQ-9]) assessed at baseline and quarterly throughout internship. RESULTS: Among 16 965 interns, baseline depressive symptoms increased from 2007 to 2019 (PHQ-9 score, 2.3 to 2.9; difference, 0.6 [95% CI, 0.3 to 0.8]). The prevalence of baseline predictors of greater increase in depressive symptoms with internship also increased across cohorts. Despite the higher prevalence of baseline risk factors, the average change in depressive symptoms with internship decreased 24.4% from 2007 to 2019 (change in PHQ-9 score, 4.1 to 3.0; difference, -1.0 [CI, -1.5 to -0.6]). This change across cohorts was greater among women (4.7 to 3.3; difference, -1.4 [CI, -1.9 to -0.9]) than men (3.5 to 2.9; difference, -0.6 [CI, -1.2 to -0.05]) and greater among nonsurgical interns (4.1 to 3.0; difference, -1.1 [CI, -1.6 to -0.6]) than surgical interns (4.0 to 3.2; difference, -0.8 [CI, -1.2 to -0.4]). In parallel to the decrease in depressive symptom change, there were increases in sleep hours, quality of faculty feedback, and use of mental health services and a decrease in work hours across cohorts. The decrease in work hours was greater for nonsurgical than surgical interns. Further, the increase in mental health treatment across cohorts was greater for women than men. LIMITATION: Data are observational and subject to biases due to nonrandom sampling, missing data, and unmeasured confounders, limiting causal conclusions. CONCLUSION: Although depression during physician training remains high, the average increase in depressive symptoms associated with internship decreased between 2007 and 2019. PRIMARY FUNDING SOURCE: National Institute of Mental Health.

COVID-19 Vaccination Effectiveness Against Infection or Death in a National U.S. Health Care System : A Target Trial Emulation Study.

BACKGROUND: Little is known about real-world COVID-19 vaccine effectiveness (VE) in racially and ethnically diverse, elderly populations with high comorbidity burden. OBJECTIVE: To determine the effectiveness of messenger RNA COVID-19 vaccines. DESIGN: Target trial emulation study comparing newly vaccinated persons with matched unvaccinated controls. SETTING: U.S. Department of Veterans Affairs health care system. PARTICIPANTS: Among persons receiving care in the Veterans Affairs health care system (n = 5 766 638), those who received at least 1 dose of the Moderna or Pfizer-BioNTech COVID-19 vaccine from 11 December 2020 to 25 March 2021 (n = 2 099 871) were matched to unvaccinated controls in a 1:1 ratio according to demographic, clinical, and geographic characteristics. INTERVENTION: Follow-up for SARS-CoV-2 infection or SARS-CoV-2-related death, defined as death within 30 days of infection, began after the vaccination date or an identical index date for the matched unvaccinated controls and continued until up to 30 June 2021. MEASUREMENTS: Vaccine effectiveness against SARS-CoV-2 infection or SARS-CoV-2-related death. RESULTS: Vaccinated and unvaccinated groups were well matched; both were predominantly male (92.9% vs. 93.4%), had advanced age (mean, 68.7 years in both groups), had diverse racial and ethnic distribution (for example, Black: 17.3% vs. 17.0%, Hispanic: 6.5% vs. 6.1%), and had substantial comorbidity burden. Vaccine effectiveness 7 or more days after the second vaccine dose was 69% (95% CI, 67% to 70%) against SARS-CoV-2 infection and 86% (CI, 82% to 89%) against SARS-CoV-2-related death and was similar when follow-up was extended to 31 March versus 30 June. Vaccine effectiveness against infection decreased with increasing age and comorbidity burden. LIMITATION: Predominantly male population and lack of data on SARS-CoV-2 variants. CONCLUSION: In an elderly, diverse, high-comorbidity population, COVID-19 VE against infection was substantially lower than previously reported, but VE against death was high. Complementary infection mitigation efforts remain important for pandemic control, even with vaccination. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs.

Effectiveness of mRNA COVID-19 Vaccine Boosters Against Infection, Hospitalization, and Death: A Target Trial Emulation in the Omicron (B.1.1.529) Variant Era.

BACKGROUND: The effectiveness of a third mRNA COVID-19 vaccine dose (booster dose) against the Omicron (B.1.1.529) variant is uncertain, especially in older, high-risk populations. OBJECTIVE: To determine mRNA booster vaccine effectiveness (VE) against SARS-CoV-2 infection, hospitalization, and death in the Omicron era by booster type, primary vaccine type, time since primary vaccination, age, and comorbidity burden. DESIGN: Retrospective matched cohort study designed to emulate a target trial of booster vaccination versus no booster, conducted from 1 December 2021 to 31 March 2022. SETTING: U.S. Department of Veterans Affairs health care system. PARTICIPANTS: Persons who had received 2 mRNA COVID-19 vaccine doses at least 5 months earlier. INTERVENTION: Booster monovalent mRNA vaccination (Pfizer-BioNTech's BNT162b2 or Moderna's mRNA-1273) versus no booster. MEASUREMENTS: Booster VE. RESULTS: Each group included 490 838 well-matched persons, who were predominantly male (88%), had a mean age of 63.0 years (SD, 14.0), and were followed for up to 121 days (mean, 79.8 days). Booster VE more than 10 days after a booster dose was 42.3% (95% CI, 40.6% to 43.9%) against SARS-CoV-2 infection, 53.3% (CI, 48.1% to 58.0%) against SARS-CoV-2-related hospitalization, and 79.1% (CI, 71.2% to 84.9%) against SARS-CoV-2-related death. Booster VE was similar for different booster types (BNT162b2 or mRNA-1273), age groups, and primary vaccination regimens but was significantly higher with longer time since primary vaccination and higher comorbidity burden. LIMITATION: Predominantly male population. CONCLUSION: Booster mRNA vaccination was highly effective in preventing death and moderately effective in preventing infection and hospitalization for up to 4 months after administration in the Omicron era. Increased uptake of booster vaccination, which is currently suboptimal, should be pursued to limit the morbidity and mortality of SARS-CoV-2 infection, especially in persons with high comorbidity burden. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs.

An Automatically Adaptive Digital Health Intervention to Decrease Opioid-Related Risk While Conserving Counselor Time: Quantitative Analysis of Treatment Decisions Based on Artificial Intelligence and Patient-Reported Risk Measures.

BACKGROUND: Some patients prescribed opioid analgesic (OA) medications for pain experience serious side effects, including dependence, sedation, and overdose. As most patients are at low risk for OA-related harms, risk reduction interventions requiring multiple counseling sessions are impractical on a large scale. OBJECTIVE: This study evaluates whether an intervention based on reinforcement learning (RL), a field of artificial intelligence, learned through experience to personalize interactions with patients with pain discharged from the emergency department (ED) and decreased self-reported OA misuse behaviors while conserving counselors' time. METHODS: We used data representing 2439 weekly interactions between a digital health intervention ("Prescription Opioid Wellness and Engagement Research in the ED" [PowerED]) and 228 patients with pain discharged from 2 EDs who reported recent opioid misuse. During each patient's 12 weeks of intervention, PowerED used RL to select from 3 treatment options: a brief motivational message delivered via an interactive voice response (IVR) call, a longer motivational IVR call, or a live call from a counselor. The algorithm selected session types for each patient each week, with the goal of minimizing OA risk, defined in terms of a dynamic score reflecting patient reports during IVR monitoring calls. When a live counseling call was predicted to have a similar impact on future risk as an IVR message, the algorithm favored IVR to conserve counselor time. We used logit models to estimate changes in the relative frequency of each session type as PowerED gained experience. Poisson regression was used to examine the changes in self-reported OA risk scores over calendar time, controlling for the ordinal session number (1st to 12th). RESULTS: Participants on average were 40 (SD 12.7) years of age; 66.7% (152/228) were women and 51.3% (117/228) were unemployed. Most participants (175/228, 76.8%) reported chronic pain, and 46.2% (104/225) had moderate to severe depressive symptoms. As PowerED gained experience through interactions over a period of 142 weeks, it delivered fewer live counseling sessions than brief IVR sessions (P=.006) and extended IVR sessions (P<.001). Live counseling sessions were selected 33.5% of the time in the first 5 weeks of interactions (95% CI 27.4%-39.7%) but only for 16.4% of sessions (95% CI 12.7%-20%) after 125 weeks. Controlling for each patient's changes during the course of treatment, this adaptation of treatment-type allocation led to progressively greater improvements in self-reported OA risk scores (P<.001) over calendar time, as measured by the number of weeks since enrollment began. Improvement in risk behaviors over time was especially pronounced among patients with the highest risk at baseline (P=.02). CONCLUSIONS: The RL-supported program learned which treatment modalities worked best to improve self-reported OA risk behaviors while conserving counselors' time. RL-supported interventions represent a scalable solution for patients with pain receiving OA prescriptions. TRIAL REGISTRATION: Clinicaltrials.gov NCT02990377; https://classic.clinicaltrials.gov/ct2/show/NCT02990377.

Depression, Anxiety, and Patterns of Mental Health Care Among Men With Prostate Cancer Receiving Androgen Deprivation Therapy.

BACKGROUND: Androgen deprivation therapy (ADT) use is associated with an increased risk of developing depression and anxiety. Little is known about how the mental health of these men is treated. MATERIALS AND METHODS: We identified men with prostate cancer who received ADT between 2001 and 2015 using Optum's de-identified Clinformatics Data Mart Database. We determined the incidence of depression or anxiety diagnoses, mental health treatments, and the specialty of providers initiating psychotropic medications, after the start of ADT. Outcomes were compared with those of men with prostate cancer not receiving ADT and men without prostate cancer. RESULTS: Of 37 388 men with prostate cancer treated with ADT, 3964 (10.6%) received a new diagnosis of depression or anxiety. Of those 3964 men, 1892 (47.7%) did not receive a documented treatment, 10 (0.3%) received psychotherapy, 1321 (33.3%) a selective serotonin reuptake inhibitor, and 744 (18.8%) a benzodiazepine. The median time from initiation of ADT to a depression or anxiety diagnosis was 9.3 months. Primary care physicians were the most common prescribers of psychotropic medications (72.2%). The proportion of men not receiving mental health treatments of interest (47.7%) was similar compared to men without prostate cancer (49.1%), but statistically significantly lower compared to men with prostate cancer not receiving ADT (52.7%). CONCLUSIONS: In men with prostate cancer receiving ADT with a new diagnosis of depression or anxiety, nearly half are not receiving mental health care while one in five is introduced to a benzodiazepine. Further investigation toward improving the mental health care for men on ADT is needed.