Faculty Bibliography

This activity is a paper presentation on a secondary analysis of factors associated with opioid abstinence three months following the treatment trial. While abstinence is not required for improvement in opioid use outcomes, better understanding of abstinence-related factors can inform efforts to facilitate stable recovery for opioid-dependent individuals. XXBackground(s): Opioid use disorder (OUD) is associated with substantial mortality. There are effective treatments in reducing opioid use and overdose events. However, many patients that successfully initiate OUD pharmacotherapy will discontinue treatment within the first few weeks or months. Upon treatment discontinuation, patients are at risk for relapse and overdose, however, not all patients relapse. There is a need to better understand predictors of relapse and abstinence after medication discontinuation. XXObjective(s): 1) Demonstrate general understanding of effective treatments for OUD and current barriers to treatment retention. 2) Describe factors associated with opioid abstinence from this secondary analysis. 3) Identify limitations in analyses and interpreting results. XXMethod(s): This secondary analysis examines correlates of opioid abstinence in 428 participants at week 36 follow-up from the National Drug Abuse Treatment Clinical Trials Network CTN-0051) X:BOT trial. X:BOT randomized participants to buprenorphine-naloxone (BUP-NX) or extended-release injectable naltrexone (XR-NTX) for up to 24 weeks of outpatient treatment. Study medications were discontinued at study completion or relapse. Follow-up assessments in the community were done at weeks 28 and 36. XXResult(s): Participants had higher odds of being abstinent at week 36 if randomized to XR-NTX compared with BUP-NX (odds ratio [OR] [95% confidence interval [CI]] = 2.47 [1.63, 3.74]), were on XR-NTX at follow-up compared with those off medication (OR = 2.33 [1.40, 3.90]), had longer time to relapse (OR = 1.04 [1.02, 1.07]), successfully inducted onto study medication compared with those who failed induction (OR = 3.16 [1.45, 6.92]), had longer time on study medication (OR = 1.03[1.01, 1.05]), and had more abstinent weeks during the trial (OR = 1.04 [1.02, 1.07]). XXConclusion(s): In general, participants that had better outcomes during the treatment trial were found to be abstinent from opioids at follow-up in the community. This included successful induction onto study medication, longer time on medication, greater time to relapse, and more abstinent weeks. While abstinence is not required for improvement in opioid use outcomes, better understanding of abstinence-related factors can inform efforts to facilitate stable recovery for opioid-dependent individuals. Scientific Significance: There is a need to better understand predictors of relapse and abstinence after medication discontinuation in order to better advise patients that may discontinue medications. Barriers to treatment retention and sustained abstinence are factors generally considered to be proxies for greater disease severity. Less is understood about factors associated with sustained abstinence

Embedded pragmatic clinical trials (ePCTs) and quality improvement (QI) activities often occur simultaneously within healthcare systems (HCSs). Embedded PCTs within HCSs are conducted to test interventions and provide evidence that may impact public health, health system operations, and quality of care. They are larger and more broadly generalizable than QI initiatives, and may generate what is considered high-quality evidence for potential use in care and clinical practice guidelines. QI initiatives often co-occur with ePCTs and address the same high-impact health questions, and this co-occurrence may dilute or confound the ability to detect change as a result of the ePCT intervention. During the design, pilot, and conduct phases of the large-scale NIH Collaboratory Demonstration ePCTs, many QI initiatives occurred at the same time within the HCSs. Although the challenges varied across the projects, some common, generalizable strategies and solutions emerged, and we share these as case studies. KEY LESSONS: Study teams often need to monitor, adapt, and respond to QI during design and the course of the trial. Routine collaboration between ePCT researchers and health systems stakeholders throughout the trial can help ensure research and QI are optimally aligned to support high-quality patient-centered care.

OBJECTIVE:To determine feasibility and explore effects of literacy promotion using e-books versus board books on the home reading environment, book reading, television use, and child development. METHODS:Randomized controlled trial comparing digital literacy promotion (DLP) using e-books to standard literacy promotion (SLP) using board books among Medicaid-eligible infants. DLP participants received e-books on home digital devices, while SLP participants received board books at well visits between 6 and 12 months of age. Differences in StimQ Read Subscale (StimQ-Read) scores, parent-reported reading and television use, and Bayley Scales of Infant Development-3rd Edition (Bayley-3) scores between groups were assessed using intention-to-treat analysis. RESULTS:A total of 104 Medicaid-eligible infants were enrolled and randomized from 3 pediatric practices. There were no differences in sociodemographic characteristics between groups at baseline. Children in the DLP group initially had lower StimQ-Read scores but showed similar increases in StimQ-Read scores over time as children in the SLP group. Parents in the DLP group reported greater use of digital devices to read or engage their child (65% vs 23%, P < .001) but similar board book reading and television viewing. There were no differences between groups in cognitive or motor scale scores, but DLP participants had marginally lower language scales scores (DLP 85.7 vs SLP 89.7; P = .10) at the 6-month follow-up. CONCLUSIONS/DISCUSSION/UNASSIGNED:Literacy promotion using e-books was feasible and associated with greater e-book usage but no difference in board book reading, television viewing, or home reading environment scores. A potential adverse impact of e-books on language development should be confirmed in future study.

BACKGROUND:Studies have demonstrated that Black men may undergo definitive prostate cancer (CaP) treatment less often than men of other races, but it is unclear whether they are avoiding overtreatment of low-risk disease or experiencing a reduction in appropriate care. The authors' aim was to assess the role of race as it relates to treatment benefit in access to CaP treatment in a single-payer population. METHODS:The authors used the Veterans Health Administration (VHA) Corporate Data Warehouse to perform a retrospective cohort study of veterans diagnosed with low- or intermediate-risk CaP between 2011 and 2017. RESULTS:The authors identified 35,427 men with incident low- or intermediate-risk CaP. When they controlled for covariates, Black men had 1.05 times the odds of receiving treatment in comparison with non-Black men (P < .001), and high-treatment-benefit men had 1.4 times the odds of receiving treatment in comparison with those in the low-treatment-benefit group (P < .001). The interaction of race and treatment benefit was significant, with Black men in the high-treatment-benefit category less likely to receive treatment than non-Black men in the same treatment category (odds ratio, 0.89; P < .001). CONCLUSIONS:Although race does appear to influence the receipt of definitive treatment in the VHA, this relationship varies in the context of the patient's treatment benefit, with Black men receiving less definitive treatment in high-benefit situations. The influence of patient race at high treatment benefit levels invites further investigation into the driving forces behind this persistent disparity in this consequential group.

BACKGROUND:Severe hypoxic respiratory failure from COVID-19 pneumonia carries a high mortality risk. There is uncertainty surrounding which patients benefit from corticosteroids in combination with tocilizumab and the dosage and timing of these agents. The balance of controlling inflammation without increasing the risk of secondary infection is difficult. At present, dexamethasone 6 mg is the standard of care in COVID-19 hypoxia; whether this is the ideal choice of steroid or dosage remains to be proven. OBJECTIVES/OBJECTIVE:The primary objective was to assess the impact on mortality of tocilizumab only, corticosteroids only, and combination therapy in patients with COVID-19 respiratory failure. METHODS:A multihospital, retrospective study of adult patients with severe respiratory failure from COVID-19 who received supportive therapy, corticosteroids, tocilizumab, or combination therapy were assessed for 28-day mortality, biomarker improvement, and relative risk of infection. Propensity-matched analysis was performed between corticosteroid alone and combination therapies to further assess mortality benefit. RESULTS:= 0.005] without increasing the risk of infection. CONCLUSION AND RELEVANCE/UNASSIGNED:Combination of tocilizumab and corticosteroids was associated with improved 28-day survival when compared with corticosteroids alone. Modification of steroid dosing strategy as well as steroid type may further optimize therapeutic effect of the COVID-19 treatment.

Importance/UNASSIGNED:Prescription opioids are involved in more than half of opioid overdoses among younger persons. Understanding opioid prescribing practices is essential for developing appropriate interventions for this population. Objective/UNASSIGNED:To examine temporal trends in opioid prescribing practices in children, adolescents, and younger adults in the US from 2006 to 2018. Design, Setting, and Participants/UNASSIGNED:A population-based, cross-sectional analysis of opioid prescription data was conducted from January 1, 2006, to December 31, 2018. Longitudinal data on retail pharmacy-dispensed opioids for patients younger than 25 years were used in the analysis. Data analysis was performed from December 26, 2019, to July 8, 2020. Main Outcomes and Measures/UNASSIGNED:Opioid dispensing rate, mean amount of opioid dispensed in morphine milligram equivalents (MME) per day (individuals aged 15-24 years) or MME per kilogram per day (age <15 years), duration of prescription (mean, short [≤3 days], and long [≥30 days] duration), high-dosage prescriptions, and extended-release or long-acting (ER/LA) formulation prescriptions. Outcomes were calculated for age groups: 0 to 5, 6 to 9, 10 to 14, 15 to 19, and 20 to 24 years. Joinpoint regression was used to examine opioid prescribing trends. Results/UNASSIGNED:From 2006 to 2018, the opioid dispensing rate for patients younger than 25 years decreased from 14.28 to 6.45, with an annual decrease of 15.15% (95% CI, -17.26% to -12.99%) from 2013 to 2018. The mean amount of opioids dispensed and rates of short-duration and high-dosage prescriptions decreased for all age groups older than 5 years, with the largest decreases in individuals aged 15 to 24 years. Mean duration per prescription increased initially for all ages, but then decreased for individuals aged 10 years or older. The duration remained longer than 5 days across all ages. The rate of long-duration prescriptions increased for all age groups younger than 15 years and initially increased, but then decreased after 2014 for individuals aged 15 to 24 years. For children aged 0 to 5 years dispensed an opioid, annual increases from 2011 to 2014 were noted for the mean amount of opioids dispensed (annual percent change [APC], 10.58%; 95% CI, 1.77% to 20.16%) and rates of long-duration (APC, 30.42%; 95% CI, 14.13% to 49.03%), high-dosage (APC, 31.27%; 95% CI, 16.81% to 47.53%), and ER/LA formulation (APC, 27.86%; 95% CI, 12.04% to 45.91%) prescriptions, although the mean amount dispensed and rate of high-dosage prescriptions decreased from 2014 to 2018. Conclusions and Relevance/UNASSIGNED:These findings suggest that opioid dispensing rates decreased for patients younger than 25 years, with decreasing rates of high-dosage and long-duration prescriptions for adolescents and younger adults. However, opioids remain readily dispensed, and possible high-risk prescribing practices appear to be common, especially in younger children.

Studies reporting significant associations between maternal prenatal stress and child outcomes are frequently confounded by correlates of prenatal stress that influence the postnatal rearing environment. The major objective of this study is to identify whether maternal prenatal stress is associated with variation in human brain functional connectivity prior to birth. We utilized fetal fMRI in 118 fetuses [48 female; mean age 32.9 weeks (SD = 3.87)] to evaluate this association and further addressed whether fetal neural differences were related to maternal health behaviors, social support, or birth outcomes. Community detection was used to empirically define networks and enrichment was used to isolate differential within- or between-network connectivity effects. Significance for χ² enrichment was determined by randomly permuting the subject pairing of fetal brain connectivity and maternal stress values 10,000 times. Mixtures modelling was used to test whether fetal neural differences were related to maternal health behaviors, social support, or birth outcomes. Increased maternal prenatal negative affect/stress was associated with alterations in fetal frontoparietal, striatal, and temporoparietal connectivity (β = 0.82, p < 0.001). Follow-up analysis demonstrated that these associations were stronger in women with better health behaviors, more positive interpersonal support, and lower overall stress (β = 0.16, p = 0.02). Additionally, magnitude of stress-related differences in neural connectivity was marginally correlated with younger gestational age at delivery (β = -0.18, p = 0.05). This is the first evidence that negative affect/stress during pregnancy is reflected in functional network differences in the human brain in utero, and also provides information about how positive interpersonal and health behaviors could mitigate prenatal brain programming.

BACKGROUND:In women with BRCA mutations, risk-reducing bilateral salpingo-oophorectomy (RRSO) has been shown to decrease gynecologic cancer-specific and overall mortality. The National Comprehensive Cancer Network (NCCN) recommends that patients with BRCA mutations undergo RRSO between the ages of 35-40 years for BRCA1 mutation carriers and between the ages of 40-45 years for BRCA2 mutation carriers, or after childbearing is complete. Currently, uptake and timing of RRSO and reasons for delays in RRSO are not well understood. OBJECTIVE:We sought to evaluate uptake and timing of RRSO among women with BRCA1/2 mutations in relation to NCCN guidelines, and reasons for delays in RRSO. STUDY DESIGN/METHODS:In this retrospective chart review, we identified women with BRCA1/2 mutations who discussed RRSO with a provider between 2012 and 2021. Uptake of RRSO was documented, and patients were classified as having timely or delay in RRSO based on NCCN guidelines. For those with delay in RRSO, reasons cited for delay were collected. Comparative statistical analyses were performed to evaluate characteristics of those with timely vs delayed RRSO. A multivariable logistic regression model was used to evaluate the associations between factors related to timing of RRSO. RESULTS:We identified 638 BRCA1/2 mutation carriers seen between 2012 and 2021. Of these patients, 306 (48.0%) had undergone RRSO and 332 (52.0%) had not. When evaluating timing of RRSO, 136 (21.3%) underwent timely RRSO, 239 (37.5%) had delay in RRSO, and 263 (41.2%) had not undergone RRSO but were younger than NCCN age guidelines so were neither timely nor delayed. Patients with delay in RRSO were significantly older at the time of genetic testing compared to those with timely RRSO (mean 49.8 vs 36.3 years; p < 0.001). Of the 306 patients who underwent RRSO, those with delayed RRSO had a significantly shorter interval between BRCA identification and RRSO compared to those with timely RRSO (median 8.7 vs 17.6 months; p < 0.001). Patients with delay in RRSO were more likely to have a personal history of cancer than those with timely RRSO (49.8% vs 37.5%; p=0.028). Of the 239 women with delay in RRSO, reasons included: 188 (78.7%) for delayed BRCA mutation identification; 29 (12.1%) for menopausal concerns; 17 (7.1%) for ongoing cancer treatment; 12 (5.0%) for coordination with breast surgery; 20 (8.4%) for miscellaneous reasons; and 19 (7.9%) with no reasons documented. In the multivariate model, older age at BRCA diagnosis (OR 0.73; 95%CI [0.68-0.78]; p<0.001) was significantly associated with delayed RRSO timing; those with BRCA2 mutation type were 7.54 times as likely to have timely RRSO compared to BRCA1 mutation carriers (OR 7.54; 95%CI [3.70-16.42]; p<0.001). CONCLUSION/CONCLUSIONS:Nearly 38% of BRCA1/2 mutation carriers undergo or have yet to undergo RRSO beyond the NCCN recommended age. The most common reason for delay in RRSO was delayed identification of BRCA mutation, noted in 79% of patients with delayed RRSO. Timely genetic testing for eligible patients can increase appropriately timed RRSO for prevention of ovarian cancer and reduction of mortality in BRCA mutation carriers.

INTRODUCTION/BACKGROUND:Kratom is a plant with partial opioid agonist effects, and its use has become popular to ameliorate symptoms of opioid withdrawal. However, use has been linked to thousands of poisonings, although most have involved use of other drugs. Little is known regarding prevalence and correlates of use in the general U.S. POPULATION/METHODS/: METHODS:Data were examined from the 2019 National Survey on Drug Use and Health, a nationally representative probability sample of non-institutionalized individuals aged ≥12 years in the U.S. (N=56,136). Prevalence and correlates of past-year kratom use were estimated. Data were analyzed in 2020. RESULTS:An estimated 0.7% (95% CI=0.6, 0.8) of individuals in the U.S. have used kratom in the past year. Past-year proxy diagnosis of prescription opioid use disorder was associated with increased odds for kratom use (AOR=3.20, 95% CI=1.38, 7.41), with 10.4% (95% CI=6.7, 15.9) of those with use disorder reporting use. Opioid misuse not accompanied with use disorder was not associated with kratom use. Those reporting past-year cannabis use both with (AOR=4.33, 95% CI=2.61, 7.19) and without (AOR=4.57, 95% CI=3.29, 6.35) use disorder and those reporting past-year cocaine use (AOR=1.69, 95% CI=1.06, 2.69) and prescription stimulant misuse (AOR=2.10, 95% CI=1.44, 3.05) not accompanied with use disorder were at higher odds for kratom use. CONCLUSIONS:Kratom use is particularly prevalent among those with prescription opioid use disorder, but it is also prevalent among people who use other drugs. Research is needed to determine reasons for use and potential dangers associated with adding kratom to drug repertoires.