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Background: The role of prescribed opioids and benzodiazepines as risk factors for opioid overdose are well established, however, their role as potential 'triggers' of opioid overdose has not been formally investigated., Objective: The objective of this study was to evaluate the temporal relationship between controlled substance acquisition and opioid overdose utilizing a case-crossover design., Methods: This study utilized Arkansas statewide data between 2014 and 2020. Prescription Drug Monitoring Program (PDMP) data were used to assess controlled substance acquisition and fatal and non-fatal opioid overdose were assessed using linked death certificate, inpatient discharge, and emergency department (ED) data. All persons residing in Arkansas who experienced an opioid overdose or had ≥ 1 Arkansas PDMP prescription fill(s) were included. Controlled substance characteristics were described in the 7 days prior to overdose and compared to the controlled substance characteristics in 11 weekly (7-day) control windows prior to overdose. Binary controlled substance variables indicating presence or absence of: any controlled substance, opioid, benzodiazepine, stimulant, sedative, carisoprodol, opioid and benzodiazepine, and opioid and benzodiazepine and carisoprodol were created. Additionally, total morphine milliequivalents were calculated for each time window. Conditional logistic regression models were estimated and adjusted odds ratios for each controlled substance characteristic after accounting for other controlled substance, and prior overdose, and clinical characteristics derived from ED and inpatient data are reported., Results: A total of 2,818,135 individuals with ≥1 Arkansas PDMP record(s) (45.10 % male; 39.94 mean age) were included, of which 28,670 (1.02 %) experienced ≥1 opioid overdose. There was a significant association between opioid overdose and the acquisition of a controlled substance (OR=1.785; p < 0.001), opioid (OR=1.992; p < 0.001), benzodiazepine (OR=1.379; p < 0.001), carisoprodol (OR=1.744; p < 0.001), opioid and benzodiazepine (OR=2.203; p < 0.001), and opioid and benzodiazepine and carisoprodol (OR=2.503; p < 0.001), in the 7 days prior to an opioid overdose event., Conclusion: Controlled substance prescription acquisition, particularly opioids in combination with carisoprodol and/or benzodiazepines, are potential triggers of opioid overdose., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Martin receives royalties from TrestleTree, LLC for the commercialization of an opioid risk prediction tool that used separate data sources and methods and is unrelated to this investigation., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: This retrospective cohort study provides an updated view on the association between the likelihood of long-term opioid use (LTOU) and characteristics of the initial opioid prescription (dose, opioid type) and initial opioid prescription episode (days' supplied) among opioid-naïve patients utilizing IQVIA PharMetrics®Plus for Academics database representative of commercially insured patients in the US., Methods: Kaplan-Meier estimates were used to determine opioid continuation likelihood at 365 days stratified by the characteristics of the initial opioid prescription and initial opioid prescription episode. Cox-proportional hazard models were estimated to determine the strength of association between initial opioid prescription characteristics and opioid continuation., Results: A total of 578,403 cancer-free, SUD-free, opioid-naïve subjects aged ≥14 years that filled ≥1 opioid prescriptions between April 13, 2016 and April 18, 2020 were identified and categorized based on time to opioid discontinuation. After accounting for censoring, 5.05 % of persons continued opioid use for ≥365 days. Compared to a 1-2 days' supply (DS), the likelihood of opioid discontinuation was consistently lower with higher DS [HRs (CIs): 3-4 days' supply = 0.66 (0.65-0.66); 5-7 DS = 0.41 (0.41-0.41); 8-10 DS = 0.33 (0.33-0.34); 11-14 DS = 0.30 (0.29-0.31); 15-21 DS = 0.26 (0.26-0.27); ≥22 DS = 0.17 (0.17-0.18)]. These associations between increased DS and decreased likelihood of discontinuing opioid remained consistent across different pain etiologies., Conclusions: In this era of more conservative opioid prescribing, increases in DS remains the strongest factor associated with a higher likelihood of LTOU., Competing Interests: Declaration of Competing Interest Data acquisition for this study was supported by the University of Arkansas for Medical Sciences (UAMS) Translational Research Institute [grant number UL1 TR003107] through the National Center for Advancing Translational Sciences. Additionally, Dr. Smith was supported by the National Institute on Drug Abuse under the Translational Training in Addiction Grant [grant number 5T32 DA022981-14]. The content of this work is solely the responsibility of the authors and does not necessarily represent the official views of UAMS or the NIH. The funding sources listed above were not involved in the data preparation, analysis, and interpretation; in the writing of the article; and in the decision for the article to be submitted for publication. Conflict of Interest Dr. Martin receives royalties from TrestleTree, LLC for the commercialization of an opioid risk prediction tool that used separate data sources and methods and is unrelated to this investigation. Dr. Shah is an employee of AstraZeneca and has stocks of Gilead Sciences and Roche, none of which are related to this study, (Copyright © 2024. Published by Elsevier B.V.)

Introduction: The U.S. Veterans Health Administration has undertaken several initiatives to improve veterans' access to and retention on buprenorphine because it prevents overdose and reduces drug-related morbidity. We aimed to determine whether improvements in retention duration over time was equitable across veterans of different races and ethnicities., Methods: This retrospective cohort study was conducted among veterans who initiated buprenorphine from federal fiscal years (FY) 2006 to 2020 after diagnosis of opioid use disorder. Using an accelerated failure time model, we estimated the association between time to buprenorphine discontinuation and FY of initiation, race and ethnicity, and other control covariates. We followed veterans from buprenorphine initiation until they discontinued or had a censoring event. We then estimated the predicted median days retained on buprenorphine, the average marginal effect of initiating in a later FY, the same measure by race and ethnicity, the incremental effect of the various racial and ethnic identities in contrast to non-Hispanic White, and the total change in the size of the gap over the 15 years of the study between veterans with a minoritized racial or ethnic identity compared to non-Hispanic White veterans., Results: Most of the 31,797 veterans in the sample were non-Hispanic White (74.5 %), from urban areas (83.5 %), male (92.0 %), and had significant comorbidities, most frequently anxiety disorders (51.0 %) and depression (63.0 %). Overall, 49.8 % of veterans were retained at least 180 days. The average marginal effect of FY was 7.0 days [95%CI:5.3, 8.8] but was significantly smaller among veterans identifying as Black or African American [3.2 days; 95%CI:2.4, 4.1] or Asian [3.6 days; 95%CI:1.6, 5.7] compared to veterans who identify as non-Hispanic White [7.9 days; 95%CI:5.9, 9.9]. Additional measures of change were significant for veterans identifying as Hispanic White or with two or more races., Conclusion: Although buprenorphine retention in OUD treatment improved for all veterans over the 15-year study period, veterans from most minoritized racial and ethnic groups fell further behind as gains in duration on therapy accrued primarily to non-Hispanic White veterans. Targeted interventions addressing specific challenges experienced by veterans with minoritized identities are needed to close gaps in retention on buprenorphine., Competing Interests: Declaration of competing interest None., (Published by Elsevier Inc.)

Background: High-dose (≥24 mg) buprenorphine daily doses (BDD) may be important in treating patients with opioid use disorder (OUD) to improve retention and prevent overdose, particularly in the context of increased illicit fentanyl use. This study sought to: (1) identify trajectories for average BDD among patients initiating buprenorphine treatment for OUD and (2) assess patient characteristics associated with these identified trajectories., Methods: Buprenorphine treatment episodes among patients in the US Veterans Healthcare Administration (VHA) from federal fiscal years 2006 to 2020 were identified. Group-based trajectory modeling (GBTM) was used to identify BDD trajectories based on weekly averages of BDD over the 180 days after buprenorphine episode initiation., Results: A total of 79 303 buprenorphine treatment episodes among 44 583 patients were included in the analytic sample. GBTM identified 9 latent trajectories for BDD: (1) moderate dose, early discontinuation (10.1%), (2) moderate dose, delayed discontinuation (4.5%), (3) moderate dose, moderate-paced discontinuation (5.2%), (4) low-moderate dose, delayed discontinuation (7.0%), and (5) low-moderate dose, early discontinuation (21.1%), (6) low dose retention (9.6%), (7) low-moderate dose retention (16.7%), (8) moderate dose retention (18.6%), and (9) high dose retention (7.4%). Patient BDD can broadly be characterized as low [2-4 mg/day], low-moderate (6-8 mg/day), moderate (12-18 mg/day), and high dose (≥ 24 mg/day). Patients with episodes in the high BDD trajectory have the lowest social risk (eg, lowest rate of past-year history of homelessness) and the lowest diagnosed rate of physical and mental health-related comorbidities compared to those following other trajectories., Conclusions: BDD ranges widely and patient characteristics are significantly different between those episodes following differing BDD trajectories. Future research on the association between BDD and subsequent patient outcomes (eg, overdose) needs to carefully consider these differences in baseline characteristics., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: The use of medical cannabis (MC) to treat a host of conditions has expanded considerably in the United States; however, precise quantitative assessments of purchasing characteristics are unknown. This study sought to characterize the trends in MC purchases, US dollars spent, and type and amount purchased by demographic and clinical characteristics. Materials and Methods: This descriptive exploratory association study examined statewide MC registry data in Arkansas linked at the person level with statewide transaction data documenting each MC purchase. MC transaction data (May 11, 2019-August 31, 2022) were assessed to identify persons who could be linked to the registry data and made at least one purchase. Individual demographic characteristics and MC qualifying conditions (QCs) were ascertained. Product types were classified into plant cannabis, cannabis extract for inhalation (vape), edibles, and others. The average daily total delta-9-tetrahydrocannabinol (THC) purchased was calculated based on the concentration and quantity purchased. Purchasing characteristics are described and demographic and clinical factors associated with THC purchased per day and dollars spent per year were estimated by ordinary least square regression and general linear models with a gamma distribution. Results: On average, 89,057 MC purchasers spent $3343 (interquartile range [IQR], $907-$4802), had 33.34 (IQR, 8.32-46.03) transaction days per year, and purchased 162.32 mg (IQR, 30.51-237.69) of THC per day. Most persons predominantly purchased plant cannabis (68.27%), followed by edibles (14.92%) and vape (11.96%). Individuals younger than 18 years of age (β=-78.23; 95% confidence interval [CI], -116.599 to -39.863), persons 70 and older (β = -122.30; 95% CI, -128.18 to -116.422), and women (β=-33.70; 95% CI, -35.95 to -31.446) purchased less THC per day than their counterparts after multivariate adjustment. The most common QCs were pain and post-traumatic stress disorder (PTSD), and compared to those with cancer, persons with pain (β = 26.30; 95% CI, 18.636-33.96) and PTSD (β = 38.34; 95% CI, 30.467-46.222) purchased more THC per day. Conclusion: The average THC purchased per person per day exceeds typically recommended daily doses for therapeutic uses, and further research is warranted to assess the safety and benefits of MC across these conditions.

Annona emarginata is a native Brazilian species capable of producing at least ten alkaloids of ecological, agronomic, and pharmacological importance. Some studies have explored the effect of external phytoregulators on the production of alkaloids, including the effect of auxins, which, like alkaloids, derive from the shikimic acid pathway. Thus, this study aimed to evaluate how indole acetic acid (IAA) and its inhibitor 2,3,5-triiodobenzoic acid (TIBA) impact the production of alkaloids and the primary metabolism of A. emarginata , which brings advances in the understanding of the mechanisms of alkaloid synthesis and can aid in the bioprospection of molecules of interest in Annonaceae. The design was completely randomized, with three treatments (control, IAA [10 -6 M] and TIBA [10 -6 M]) and five collection times (12, 36, 84, 156, and 324 h). The following variables were analyzed: total alkaloids, alkaloid profile, nitrate reductase activity, gas exchange in photosynthesis, chlorophyll a fluorescence, sugars, starch, and antioxidant activity. Of the twelve alkaloids analyzed, discretine and xylopine were not detected in the control plants; however, both were detected when IAA was applied (in roots and leaves) and xylopine (in roots) when the inhibitor was applied. The alkaloid asimilobine was not detected with the use of TIBA. Variations in alkaloid concentrations occurred in a punctual manner, without significant variations in photosynthesis and nitrate reductase activity, but with variations in the antioxidant system and sugar concentrations, mainly at 156 h, when the highest alkaloid concentrations were observed with the use of TIBA. It could be concluded that IAA is capable of selectively modulating the production of alkaloids in A. emarginata , either due to an external source or by the application of its inhibitor (TIBA).

Background: Immune checkpoint inhibitors (ICIs) have become the mainstay treatment for non-small cell lung cancer (NSCLC). However, there is a lack of studies assessing ICIs as subsequent treatment in older adults with NSCLC and brain metastasis (BM). This retrospective cohort study compared the real-world survival of older patients with NSCLC and BM at diagnosis [synchronous BM (SBM)] previously treated with chemotherapy receiving ICI versus chemotherapy as subsequent treatment., Methods: Patients with NSCLC and SBM ≥65 years previously treated with chemotherapy were identified using the SEER-Medicare database (2010-2019). Patients receiving new chemotherapy and/or Food and Drug Administration (FDA)-approved ICIs as second/third-line treatment were included, excluding those ever-receiving targeted therapies. Each ICI patient was matched to one chemotherapy patient by time to subsequent treatment (within ±30 days) from diagnosis. Overall survival (OS) time was measured from the start of subsequent treatment to death, censored at disenrollment from Medicare Part A/B, enrollment in Part C, or end of study (December 31, 2019), whichever came first. OS curves were estimated and compared using the Kaplan-Meier (KM) method and log-rank test. Hazard ratio (HR) was estimated using a multivariable-adjusted Cox proportional hazards model., Results: Matched cohorts included 546 patients [273 in each group; median age 71 (range, 65-87) years]. ICI patients were older, more likely non-Hispanic, with squamous cell carcinoma, and liver metastasis compared to chemotherapy. KM estimated better survival in ICI than chemotherapy {median survival: 209 days [95% confidence interval (CI): 160-275] vs. 155 days (95% CI: 135-187); log-rank P<0.001}. ICI was associated with a lower adjusted hazard of death [HR =0.63; 95% CI: 0.52-0.75; P<0.001] compared to subsequent chemotherapy treatment., Conclusions: In this population-based study of older patients with NSCLC and SBM previously treated with chemotherapy, subsequent treatment with ICI was associated with improved survival compared to chemotherapy., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-205/coif). B.C.M. receives royalties from Trestle Tree LLC for the commercialization of an opioid risk prediction tool that is unrelated to this investigation and receives honoraria for his service on the Midwest CEPAC which assesses the clinical and economic value of new health technologies. A.R. has obtained grant funding from Bristol Myers Squibb, Nico Corporation and the NIH which are not related to this work. She serves on multiple advisory boards (Nico Corporation, Medexus, and UCSC) which are not in conflict with this work. C.L. is supported by the American Cancer Society under award number RSGI‐23‐1039245‐01‐HOPS, and was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1 TR003107-02S2. Support of data acquisition was provided by the Arkansas Biosciences Institute, the major research component of the Arkansas Tobacco Settlement Proceeds Act of 2000. C.L. received research support (payment to the university) for unrelated projects sponsored by University of Utah/AstraZeneca, and received honoraria from PCORI for grant review. The other authors have no conflicts of interest to declare., (2024 Translational Lung Cancer Research. All rights reserved.)

Aims: To assess the cost-effectiveness of a two-layer compression bandage versus a standard wool and crepe bandage following total knee arthroplasty, using patient-level data from the Knee Replacement Bandage Study (KReBS)., Methods: A cost-utility analysis was undertaken alongside KReBS, a pragmatic, two-arm, open label, parallel-group, randomized controlled trial, in terms of the cost per quality-adjusted life year (QALY). Overall, 2,330 participants scheduled for total knee arthroplasty (TKA) were randomized to either a two-layer compression bandage or a standard wool and crepe bandage. Costs were estimated over a 12-month period from the UK NHS perspective, and health outcomes were reported as QALYs based on participants' EuroQol five-dimesion five-level questionnaire responses. Multiple imputation was used to deal with missing data and sensitivity analyses included a complete case analysis and testing of costing assumptions, with a secondary analysis exploring the inclusion of productivity losses., Results: The base case analysis found participants in the compression bandage group accrued marginally fewer QALYs, on average, compared with those in the standard bandage group (reduction of 0.0050 QALYs (95% confidence interval (CI) -0.0051 to -0.0049)), and accumulated additional mean costs (incremental cost of £52.68 per participant (95% CI 50.56 to 54.80)). Findings remained robust to assumptions tested in sensitivity analyses, although considerable uncertainty surrounded the outcome estimates., Conclusion: Use of a two-layer compression bandage is marginally less effective in terms of health-related quality of life, and more expensive when compared with a standard bandage following TKA, so therefore is unlikely to provide a cost-effective option., Competing Interests: All authors report no competing interests., (© 2024 Ronaldson et al.)

Background: Buprenorphine for opioid use disorder (B-MOUD) is essential to improving patient outcomes; however, retention is essential., Objective: To develop and validate machine-learning algorithms predicting retention, overdoses, and all-cause mortality among US military veterans initiating B-MOUD., Methods: Veterans initiating B-MOUD from fiscal years 2006-2020 were identified. Veterans' B-MOUD episodes were randomly divided into training (80%; n  = 45,238) and testing samples (20%; n  = 11,309). Candidate algorithms [multiple logistic regression, least absolute shrinkage and selection operator regression, random forest (RF), gradient boosting machine (GBM), and deep neural network (DNN)] were used to build and validate classification models to predict six binary outcomes: 1) B-MOUD retention, 2) any overdose, 3) opioid-related overdose, 4) overdose death, 5) opioid overdose death, and 6) all-cause mortality. Model performance was assessed using standard classification statistics [e.g., area under the receiver operating characteristic curve (AUC-ROC)]., Results: Episodes in the training sample were 93.0% male, 78.0% White, 72.3% unemployed, and 48.3% had a concurrent drug use disorder. The GBM model slightly outperformed others in predicting B-MOUD retention (AUC-ROC = 0.72). RF models outperformed others in predicting any overdose (AUC-ROC = 0.77) and opioid overdose (AUC-ROC = 0.77). RF and GBM outperformed other models for overdose death (AUC-ROC = 0.74 for both), and RF and DNN outperformed other models for opioid overdose death (RF AUC-ROC = 0.79; DNN AUC-ROC = 0.78). RF and GBM also outperformed other models for all-cause mortality (AUC-ROC = 0.76 for both). No single predictor accounted for >3% of the model's variance., Conclusions: Machine-learning algorithms can accurately predict OUD-related outcomes with moderate predictive performance; however, prediction of these outcomes is driven by many characteristics.

Background: Studies examining racial and ethnic disparities in-hospital mortality for patients hospitalized with COVID-19 had mixed results. Findings from patients within academic medical centers (AMCs) are lacking, but important given the role of AMCs in improving health equity., Objective: The purpose of this study is to assess whether minority patients hospitalized with COVID-19 in National COVID Cohort Collaborative (N3C) institutions, which consist predominantly of AMCs, have higher mortality rates relative to White patients., Design: A retrospective analysis of patients hospitalized with COVID-19 was performed. Logistic regression analysis was used to test the primary hypothesis. A separate analysis tested whether there were differences by race and ethnicity during the delta variant phase of the pandemic., Patients: All hospitalized patients with COVID-19 who were above 17 years old were categorized by race and ethnicity as Black, Hispanic, Asian, White, Other, and Unknown., Main Measures: In-hospital mortality for patients with a known hospital outcome formed the primary outcome measure. Race and ethnicity were the primary independent variables., Key Results: There were 103,702 in-hospital Covid-19 admissions with 14,207 (13.7%) hospital deaths. Unadjusted in-hospital mortality for White patients was approximately 26% higher than for Black patients. After multivariable adjustment, none of the racial and ethnic groups had significantly different odds of in-hospital mortality compared to White patients. Only Hispanic patients had an odds ratio greater than one that was insignificant (OR = 1.06; 95% CI = 0.92-1.20). Findings for the delta variant phase were similar with the exception of the unknown category (OR = 1.90; 95% CI = 1.05-3.46)., Conclusions: Disparities in-hospital mortality outcomes by race or ethnicity were not found in COVID-19 patients hospitalized in AMCs. AMCs are expected to lead health delivery systems in eliminating disparities associated with structural racism. The null findings are consistent with the hypothesis of no difference in hospital outcomes by race or ethnicity in academic medical centers., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Martin and Dr. Tilford receive royalties from Trestle Tree LLC for an opioid risk prediction tool that is unrelated to the current manuscript. Dr. Tilford also receives consulting fees from Merck for work unrelated to the current manuscript. No other author has any conflict of interest to disclose., (© 2024 The Authors.)

Objective: This study compared opioid utilization trajectories of persons initiating tramadol, short-acting hydrocodone, or short-acting oxycodone, and it characterized opioid dose trajectories and type of opioid in persistent opioid therapy subsamples., Methods: A retrospective cohort study of adults with chronic non-cancer pain who were initiating opioid therapy was conducted with the IQVIA PharMetrics® Plus for Academics data (2008-2018). Continuous enrollment was required for 6 months before ("baseline") and 12 months after ("follow-up") the first opioid prescription ("index date"). Opioid therapy measures were assessed every 7 days over follow-up. Group-based trajectory modeling (GBTM) was used to identify trajectories for any opioid and total morphine milligram equivalent measures, and longitudinal latent class analysis was used for opioid therapy type., Results: A total of 40 276 tramadol, 141 023 hydrocodone, and 45 221 oxycodone initiators were included. GBTM on any opioid therapy identified 3 latent trajectories: early discontinuers (tramadol 39.0%, hydrocodone 54.1%, oxycodone 61.4%), late discontinuers (tramadol 37.9%, hydrocodone 39.4%, oxycodone 33.3%), and persistent therapy (tramadol 6.7%, hydrocodone 6.5%, oxycodone 5.3%). An additional fourth trajectory, intermittent therapy (tramadol 16.4%), was identified for tramadol initiators. Of those on persistent therapy, 2687 individuals were on persistent therapy with tramadol, 9169 with hydrocodone, and 2377 with oxycodone. GBTM on opioid dose resulted in 6 similar trajectory groups in each persistent therapy group. Longitudinal latent class analysis on opioid therapy type identified 6 latent classes for tramadol and oxycodone and 7 classes for hydrocodone., Conclusion: Opioid therapy patterns meaningfully differed by the initial opioid prescribed, notably the presence of intermittent therapy among tramadol initiators and higher morphine milligram equivalents and prescribing of long-acting opioids among oxycodone initiators., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: This study sought to determine the association between suspected long-COVID and receipt of a stimulant prescription among persons diagnosed with COVID-19 and to describe clinical and demographic factors associated with receiving a stimulant prescription., Methods: US patients 18 and older who had a COVID-19 diagnosis or a positive COVID-19 PCR test from April 1st, 2020 through December 21st, 2022 recorded in a national electronic health record data set obtained from TriNetX were assessed. Comparison subjects were propensity score matched on baseline covariates to those with a symptom of or diagnosis of long-COVID. A Cox Proportional Hazards models was used to estimate the influence of long-COVID on stimulant prescription receipt., Results: Those with long-COVID (n = 65,329) were twice as likely to be prescribed a stimulant as persons with only acute COVID-19 (n = 189,438, HR=2.162; 1.929-2.423). Among persons with long-COVID, persons with new onset ADHD (HR=7.196; 5.749- 9.007), opioid-related disorders (HR=2.140; 1.264-3.621) and mood disorders (HR=1.649; 1.336-2.035) were more likely to be prescribed a stimulant., Conclusion: Further research describing the risks associated with increased stimulant use among persons with long-COVID is warranted., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Microbiomics is the science of characterizing microbial community structure, function, and dynamics. It has great potential to advance our understanding of plant-soil-microbe processes and interaction networks which can be applied to improve ecosystem restoration. However, microbiomics may be perceived as complex and the technology is not accessible to all. The opportunities of microbiomics in restoration ecology are considerable, but so are the practical challenges. Applying microbiomics in restoration must move beyond compositional assessments to incorporate tools to study the complexity of ecosystem recovery. Advances in metaomic tools provide unprecedented possibilities to aid restoration interventions. Moreover, complementary non-omic applications, such as microbial inoculants and biopriming, have the potential to improve restoration objectives by enhancing the establishment and health of vegetation communities., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: This study assessed real-world survival among older patients with non-small-cell lung cancer (NSCLC) and brain metastases (BMs) at diagnosis (synchronous BM [SBM]) receiving first-line immune checkpoint inhibitors (ICIs) compared with chemotherapy only., Methods: Patients with NSCLC and SBM age 65 years or older at diagnosis from 2010 to 2019 SEER-Medicare database and received US Food and Drug Administration-approved ICIs (pembrolizumab/nivolumab/ipilimumab/atezolizumab/durvalumab/cemiplimab) and/or chemotherapy (platinum-based doublets/taxane/pemetrexed/gemcitabine) as first-line systemic treatment were included, excluding those with no cranial radiation or ever being treated with targeted therapies. Overall survival time was from the start of systemic treatment (ICI/chemotherapy) to death, censored at disenrollment from Medicare part A/B, enrollment in part C, or end of the study period (December 31, 2019). Kaplan-Meier (KM) survival curves were compared between treatment groups using the log-rank test. Multivariable Cox proportional hazards (CPH) model was used to estimate hazard ratio (HR) between groups, adjusting for patients' sociodemographic and clinical characteristics., Results: The study included 1,481 patients (1,303 chemotherapy and 178 ICI). The median (range) age was 71 (65-91) years. First-line ICI patients were more likely to be older, live in urban areas, and less likely to be non-White than the chemotherapy group. KM estimates showed that survival curves initially overlapped but diverged approximately 6 months after initiating first-line systemic treatment (median survival [95% CI]: ICI, 190 [131 to 303] days versus chemotherapy, 189 [177 to 201] days), with ICI showing a better survival than the chemotherapy group (log-rank test P < .0001). First-line ICI was associated with a lower risk of death compared with chemotherapy in adjusted CPH model (HR [95% CI], 0.67 [0.55 to 0.80]; P < .0001)., Conclusion: Among older patients with NSCLC and SBM, first-line ICI use was associated with improved survival occurring 6 months after treatment initiation compared with chemotherapy only.

Background: Clinical guidelines recommend extended venous thromboembolism (VTE) prophylaxis for cancer patients after major gastrointestinal (GI) operations. However, adherence to the guidelines has been low, and the clinical outcomes not well defined., Methods: This study retrospectively analyzed a random 10 % sample of the 2009-2022 IQVIA LifeLink PharMetrics Plus database, an administrative claims database representative of the commercially insured population of the United States. The study selected cancer patients undergoing major pancreas, liver, gastric, or esophageal surgery. The primary outcomes were 90-day post-discharge VTE and bleeding., Results: The study identified 2296 unique eligible operations. During the index hospitalization, 52 patients (2.2 %) experienced VTE, 74 patients (3.2 %) had postoperative bleeding, and 140 patients (6.1 %) had a hospital stay of at least 28 days. The remaining 2069 operations comprised 833 pancreatectomies, 664 hepatectomies, 295 gastrectomies, and 277 esophagectomies. The median age of the patients was 49 years, and 44 % were female. Extended VTE prophylaxis prescriptions were filled for 176 patients (10.4 % for pancreas, 8.1 % for liver, 5.8 % for gastric cancer, and 6.5 % for esophageal cancer), and the most used agent was enoxaparin (96 % of the patients). After discharge, VTE occurred for 5.2 % and bleeding for 5.2 % of the patients. The findings showed no association of extended VTE prophylaxis with post-discharge VTE (odds ratio [OR], 1.54; 95 % confidence interval [CI], 0.81-2.96) or bleeding (OR, 0.72, 95 % CI, 0.32-1.61)., Conclusions: The majority of the cancer patients undergoing complex GI surgery did not receive extended VTE prophylaxis according to the current guidelines, and their VTE rate was not higher than for the patients who received it., (© 2023. The Author(s).)

Climate change and extreme climatic events, such as marine heatwaves (MHWs), are threatening seagrass ecosystems. Metabolomics can be used to gain insight into early stress responses in seagrasses and help to develop targeted management and conservation measures. We used metabolomics to understand the temporal and mechanistic response of leaf metabolism in seagrasses to climate change. Two species, temperate Posidonia australis and tropical Halodule uninervis, were exposed to a combination of future warming, simulated MHW with subsequent recovery period, and light deprivation in a mesocosm experiment. The leaf metabolome of P. australis was altered under MHW exposure at ambient light while H. uninervis was unaffected. Light deprivation impacted both seagrasses, with combined effects of heat and low light causing greater alterations in leaf metabolism. There was no MHW recovery in P. australis. Conversely, the heat-resistant leaf metabolome of H. uninervis showed recovery of sugars and intermediates of the tricarboxylic acid cycle under combined heat and low light exposure, suggesting adaptive strategies to long-term light deprivation. Overall, this research highlights how metabolomics can be used to study the metabolic pathways of seagrasses, identifies early indicators of environmental stress and analyses the effects of environmental factors on plant metabolism and health., (© 2023 The Authors. New Phytologist © 2023 New Phytologist Foundation.)

Objective: To assess the concordance between and benefit of adding prescription drug monitoring program (PDMP) data to all-payer claims database (APCD) data for identifying and classifying opioid exposure among insured individuals., Data Sources and Study Setting: Arkansas APCD and PDMP., Study Design: Enrollees in APCD were classified as (1) true positives: if they received opioids in both databases, (2) false positives: if they only received opioids in APCD, (3) true negatives: if they had no opioid exposure in both databases, (4) false negatives: if they only received opioids in the PDMP database. Specificity, sensitivity, negative, and positive predictive values were calculated using PDMP as the "gold standard" database source. Subjects were also categorized as those who received any opioid, chronic opioid, high-dose opioid, or high-risk opioid therapies., Data Collection/extraction Methods: Arkansas residents continuously enrolled with pharmacy coverage in 2016 were included. APCD and PDMP were linked using an encrypted enrollee identifier, gender, and year of birth., Principal Findings: The degree of concordance in opioid exposure between the two databases among 1,411,565 enrollees was high (sensitivity = 92.67%, specificity = 96.13%, positive predictive value = 91.60%, negative predictive value = 96.65%). Enrollees classified as having any opioid (APCD: 31.64% vs. PDMP: 31.26% vs. APCD+PDMP: 33.93%), chronic opioid (APCD: 7.81% vs. PDMP: 7.54% vs. APCD+PDMP: 8.24%), high-dose opioid (APCD: 10.60% vs. PDMP: 9.62% vs. APCD+PDMP: 11.33%), or high-risk opioid (APCD: 5.28% vs. PDMP: 5.33% vs. APCD+PDMP: 6.20%) therapies, were similar using only APCD versus PDMP versus the combined APCD and PDMP data sources., Conclusions: Claims data sources, such as APCDs, are fairly accurate in identifying opioid exposure and the level of opioid exposure among persons with continuous pharmacy coverage., (© 2022 Health Research and Educational Trust.)

Radiation therapy, one of the most effective therapies to treat cancer, is highly toxic to healthy tissue. The delivery of radiation at ultra-high dose rates, FLASH radiation therapy (FLASH), has been shown to maintain therapeutic anti-tumor efficacy while sparing normal tissues compared to conventional dose rate irradiation (CONV). Though promising, these studies have been limited mainly to murine models. Here, we leveraged enteroids, three-dimensional cell clusters that mimic the intestine, to study human-specific tissue response to radiation. We observed enteroids have a greater colony growth potential following FLASH compared with CONV. In addition, the enteroids that reformed following FLASH more frequently exhibited proper intestinal polarity. While we did not observe differences in enteroid damage across groups, we did see distinct transcriptomic changes. Specifically, the FLASH enteroids upregulated the expression of genes associated with the WNT-family, cell-cell adhesion, and hypoxia response. These studies validate human enteroids as a model to investigate FLASH and provide further evidence supporting clinical study of this therapy. Insight Box Promising work has been done to demonstrate the potential of ultra-high dose rate radiation (FLASH) to ablate cancerous tissue, while preserving healthy tissue. While encouraging, these findings have been primarily observed using pre-clinical murine and traditional two-dimensional cell culture. This study validates the use of human enteroids as a tool to investigate human-specific tissue response to FLASH. Specifically, the work described demonstrates the ability of enteroids to recapitulate previous in vivo findings, while also providing a lens through which to probe cellular and molecular-level responses to FLASH. The human enteroids described herein offer a powerful model that can be used to probe the underlying mechanisms of FLASH in future studies., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Sulfide intrusion from sediments is an increasingly recognized contributor to seagrass declines globally, yet the relationship between sediment microorganisms and sulfide intrusion has received little attention. Here, we use metagenomic sequencing and stable isotope ( 34 S) analysis to examine this relationship in Cockburn Sound, Australia, a seagrass-dominated embayment with a gradient of sulfide stress and seagrass declines. There was a significant positive relationship between sulfide intrusion into seagrasses and sulfate reduction genes in sediment microbial communities, which was greatest at sites with long term seagrass declines. This is the first demonstration of a significant link between sulfur cycling genes present in seagrass sediments and sulfide intrusion in a habitat-forming seagrass that is experiencing long-term shoot density decline. Given that microorganisms respond rapidly to environmental change, the quantitative links established in this study can be used as a potential management tool to enable the prediction of sulfide stress on large habitat forming seagrasses; a global issue expected to worsen with climate change., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Matthew Fraser reports financial support was provided by Fremantle Ports. Matthew Fraser reports a relationship with Jock Clough Marine Foundation that includes: funding grants. Matthew Fraser reports a relationship with The University of Western Australia Indian Ocean Marine Research Centre that includes: funding grants. Seagrass data was collected as part of the annual seagrass monitoring carried out by Matthew Fraser and Belinda Martin with support from the Cockburn Sound Management Council., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: To compare the safety profiles of low and high-dose tramadol, short-acting hydrocodone, and short-acting oxycodone therapies among chronic noncancer pain individuals., Materials and Methods: A retrospective cohort study of individuals with back/neck pain/osteoarthritis with an initial opioid prescription for tramadol, hydrocodone, or oxycodone was conducted using IQVIA PharMetrics Plus claims for Academics database (2006 to 2020). Two cohorts were created for separately studying opioid-related adverse events (overdoses, accidents, self-inflicted injuries, and violence-related injuries) and substance use disorders (opioid and nonopioid). Patients were followed from the index date until an outcome event, end of enrollment, or data end. Time-varying exposure groups were constructed and Cox regression models were estimated., Results: A total of 1,062,167 (tramadol [16.5%], hydrocodone [61.1%], and oxycodone [22.4%]) and 986,809 (tramadol [16.5%], hydrocodone [61.3%], and oxycodone [22.2%]) individuals were in the adverse event and substance use disorder cohorts. All high-dose groups had elevated risk of nearly all outcomes, compared with low-dose hydrocodone. Compared with low-dose hydrocodone, low-dose oxycodone was associated with a higher risk of opioid overdose (hazard ratio: 1.79 [1.37 to 2.33]). No difference in risk was observed between low-dose tramadol and low-dose hydrocodone (hazard ratio: 0.85 [0.64 to 1.13]). Low-dose oxycodone had higher risks of an opioid use disorder, and low-dose tramadol had a lower risk of accidents, self-inflicted injuries, and opioid use disorder compared with low-dose hydrocodone., Discussion: Low-dose oxycodone had a higher risk of opioid-related adverse outcomes compared with low-dose tramadol and hydrocodone. This should be interpreted in conjunction with the benefits of pain control and functioning associated with oxycodone use in future research., Competing Interests: The data used for this study were supported by the UAMS Translational Research Institute (TRI), NIH grant UL1TR000039. B.C.M. has received royalties from TrestleTree, (Little Rock, Arkansas) LLC for the commercialization of an opioid risk prediction tool, which is unrelated to this investigation. The remaining authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Previous studies have explored psychosocial effects as possible triggers of opioid overdose (OOD). However, little is known about the temporal association between OOD and prescribed controlled substance (CS) acquisition., Objective: The objective of this study was to evaluate the temporal relationship between OOD and acquiring prescribed CSs prior to OOD., Methods: This study is an exploratory descriptive analysis using Arkansas Prescription Drug Monitoring Program (AR-PDMP) data linked to death certificate and statewide inpatient discharge records. All persons with ≥1 AR-PDMP prescription fill(s) between 1 January 2014 and 31 December 2017 were included (n = 1,946,686). For persons that experienced OOD and had ≥1 PDMP record(s), the difference in days between OOD and the most recent AR-PDMP prescription filled prior to an OOD was recorded. To account for censoring, a sensitivity analysis was conducted restricting the study group to "New AR-PDMP Entrants" that had at least a 180-day gap between consecutive AR-PDMP fill dates., Results: 28,998,307 AR-PDMP records were analyzed for 1,946,686 individuals. 7195 persons experienced 9223 OODs and 414 (4.49%) of those were fatal. Of these, 6236 experienced ≥1 OOD and acquired prescribed CSs prior to or on the day of the first OOD. Of those that experienced ≥1 OOD(s), 2201 (30.59%) had an AR-PDMP record in the 0- to 5-day period prior to their overdose and 497 (6.91%) had an AR-PDMP record the day prior to their overdose. Among New AR-PDMP Entrants that experienced ≥1 OOD(s), 408 (27.38%) had an AR-PDMP record in the 0- to 5-day period prior to their overdose., Conclusion: Though the vast majority of persons accessing CSs in Arkansas did not experience an OOD, a sizable proportion of persons that experience an OOD(s) obtained prescribed CSs immediately prior., (Copyright © 2022 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Objective: This study sought to: (1) construct and validate a composite potential opioid misuse score; and (2) compare potential opioid misuse among individuals prescribed long-term therapy on tramadol, short-acting hydrocodone or short-acting oxycodone., Methods: A retrospective cohort study was conducted using Arkansas All-Payer Claims Database (APCD; 2013-2018) linked to Arkansas Prescription Drug Monitoring Program (PDMP; 2014-2017) and state death certificate data (2013-2018). The study subjects were ambulatory, cancer-free adults with incident long-term therapy on tramadol, short-acting hydrocodone or short-acting oxycodone. The number of opioid prescribers/pharmacies, cash payment for opioid prescriptions, overlapping prescribers/pharmacies and a composite misuse score (derived from opioid prescribers/pharmacies and cash payment) were assessed in two 180 day windows as potential measures of misuse. The composite score was developed based on associations observed with opioid overdose and opioid-related injuries., Results: A total of 17,816 (tramadol), 23,660 (hydrocodone) and 4799 (oxycodone) persons were included. The composite score had modest discrimination for overdose ( c -index = 0.65). In the first 180 day period, the average composite misuse scores were 1.28 (tramadol), 1.93 (hydrocodone) and 2.18 (oxycodone). Compared to long-term hydrocodone, long-term tramadol had lower misuse (IRR [95% CI]: 0.75 [0.73-0.76]), and long-term oxycodone had higher misuse (1.09 [1.07-1.11]) in adjusted analyses. Qualitatively similar associations were observed for nearly all individual component measures of misuse., Conclusion: A composite measure of potential opioid misuse had modest levels of discrimination in detecting overdose. In comparison to long-term hydrocodone therapy, long-term oxycodone had higher and tramadol had lower risk of potential opioid misuse.

Purpose: We identified associations between membership in seven group-based trajectories based on supply of filled opioid prescriptions and potential opioid-related adverse health events over a 720-day window., Methods: We identified two veteran cohorts with chronic non-cancer pain who initiated treatment with long-term opioid therapy between 2008 and 2015, excluding those with prior substance use disorder (n = 373 941) or non-SUD, opioid-related adverse outcome (n = 405 631) diagnoses. Outcomes of interest included opioid use disorder, non-opioid drug use disorder, and alcohol use disorder for the first cohort; or accidents resulting in wounds or injuries, self-inflicted injuries, opioid-related accidents and overdoses, alcohol and non-opioid drug-related accidents and overdoses, and violence-related injuries for the second cohort. Using a cross-sectional design, Veterans were followed until the specific outcome of interest was diagnosed, they died, the study ended, or they were lost to follow up. Accelerated failure time models were estimated for each outcome., Results: Membership in persistent moderate days covered and persistent modest days covered trajectories was associated with decreased risk of opioid use disorder (Moderate: θ = 0.59, 95%CI:0.54, 0.64; Modest: θ = 0.54, 95%CI:0.50, 0.59) and opioid overdose (Moderate: θ = 0.67,95%CI: 0.57, 0.79; Modest: θ = 0.72, 95%CI:0.61, 0.85) versus higher-utilizing persistent users. Rapid discontinuation was associated with decreased risk of opioid use disorder (θ = 0.86, 95% CI:0.77, 0.95) and opioid overdose (θ = 0.54, 95%CI:0.41, 0.71), but increased risk of alcohol use disorder (θ = 1.07, 95%CI:1.00, 1.15) and other substance use disorders. Delayed discontinuation or delayed reduction was associated with increased risk for most opioid related adverse health events., Conclusion: Persistent use trajectories with low levels of opioid utilization were associated with lower risks of potential opioid-related adverse health events., (© 2022 John Wiley & Sons Ltd.)

Objective: The objective of this study was to estimate the association between early use of physical therapy (PT) or chiropractic care and incident opioid use and long-term opioid use in individuals with a low back pain (LBP) diagnosis., Methods: A retrospective cohort study was conducted using data from Arkansas All Payers' Claims Database. Adults with incident LBP diagnosed in primary care or emergency departments between July 1, 2013, and June 30, 2017, were identified. Participants were required to be opioid naïve in the 6-month baseline period and without cancer, cauda equina syndrome, osteomyelitis, lumbar fracture, and paraplegia/quadriplegia in the entire study period. PT and chiropractic treatment were documented over the ensuing 30 days starting on the date of LBP. Any opioid use and long-term opioid use (LTOU) in 1-year follow-up were assessed. Multivariable logistic regressions controlling for covariates were estimated., Results: A total of 40 929 individuals were included in the final sample, with an average age of 41 years and 65% being women. Only 5% and 6% received PT and chiropractic service, respectively, within the first 30 days. Sixty-four percent had incident opioid use, and 4% had LTOU in the follow-up period. PT was not associated with incident opioid use (odds ratio [OR], 1.07; 95% confidence interval [CI], 0.98-1.18) or LTOU (OR, 1.19; 95% CI, 0.97-1.45). Chiropractic care decreased the odds of opioid use (OR, 0.88; 95% CI, 0.80-0.97) and LTOU (OR, 0.56; 95% CI, 0.40-0.77)., Conclusion: In this study we found that receipt of chiropractic care, though not PT, may have disrupted the need for opioids and, in particular, LTOU in newly diagnosed LBP., (© 2022 by National University of Health Sciences.)

Background: Early identification of hereditary cancer risk would save lives, but genetic testing (GT) has been inadequate. We assessed i) trends for hereditary breast and ovarian cancer (HBOC), Lynch syndrome, and other GT and ii) factors associated with receipt of GT., Methods: We used data from the Arkansas All-Payer Claims Database from January 2013 through June 2018 (commercial, Medicaid), December 2017 (state employee), or December 2016 (Medicare) and identified enrollees with ≥1 month of enrollment. Using Current Procedural Terminology (CPT-4) codes, rates for GT were calculated per 100,000 person-quarters and time series regressions estimated. Second, GT and covariate information for enrollees with 24 months of continuous enrollment were used to estimate separate logistic regression models for each GT category., Results: Among 2,520,575 unique enrollees, HBOC testing rates were 2.2 (Medicaid), 22.0 (commercial), 40.4 (state employee), and 13.1(Medicare) per 100,000 person-quarters and increased linearly across all plans. Older age (OR=1.24; 95%CI 1.20 - 1.28), female sex (OR=18.91; 95%CI 13.01 - 28.86), higher comorbidity burden (OR=1.08; 95%CI 1.05 - 1.12), mental disorders (OR=1.53; 95%CI 1.15 - 2.00), and state employee coverage (OR=1.65; 95%CI 1.37 - 1.97) were positively associated with HBOC testing. Less than 1 of 10,000 enrollees received Lynch syndrome testing, while < 5 of 10,000 received HBOC testing., Conclusion: GT rates for hereditary cancer syndromes have increased in Arkansas but remain low. Receipt of GT was explained with high discrimination by sex and plan type., Impact: Expansion of GT for hereditary cancer risk in Arkansas is needed to identify high-risk individuals who could benefit from risk-reduction strategies., (© 2022. The Author(s).)

Background: Individuals aged ≥75 years are the fastest-growing population starting dialysis for end-stage kidney disease (ESKD) due to living longer with coronary artery disease. ESKD alone can increase bleeding risk, but P2Y 12 inhibitor (P2Y12-I) antiplatelet medications prescribed for cardiovascular treatment can exacerbate this risk in patients with ESKD. The age-specific rates of bleeding complications in dialysis patients with ESKD on P2Y12-I remain unclear, as does how age modifies the bleeding risk from P2Y12-I use in these patients., Methods: In a retrospective cohort study, we collected data on 40,972 patients receiving maintenance hemo- or peritoneal dialysis who were newly prescribed P2Y12-I therapy between 2011 and 2015 from the USRDS registry. We analyzed the effect of age on the time to first bleed and the interactions between age and P2Y12-I type on modifying the effects of a bleed., Results: Twenty percent of the cohort were aged ≥75 years. There were 3096 (8%) gastrointestinal (GI) and 1298 (3%) intracranial (IC) bleeding events during a median follow-up of 1 year. Annual incidence rates for IC bleeds were 2% in those aged <55 years and 3% in those aged ≥75 years. Rates for GI bleeds were 4% in those aged <55 years and 9% in those aged ≥75 years. On clopidogrel, prasugrel, and ticagrelor, for every decade increase in age of the cohort members, the risk of IC bleed increased by 9%, 55%, and 59%, and the risk of GI bleed increased by 21%, 28%, and 39%, respectively. At age ≥75 years, prasugrel was associated with a greater risk of IC bleed than clopidogrel. At age ≥60 years, ticagrelor was associated with a greater risk of GI bleed than clopidogrel., Conclusions: More potent P2Y12-Is (prasugrel and ticagrelor) were associated with a disproportionately higher risk of IC bleed with increasing age compared with that of clopidogrel-prasugrel was much worse than clopidogrel at age ≥75 years. All three drugs were associated with only modest increase in the risk of GI bleed with every decade increase in age-ticagrelor was much worse than clopidogrel at ≥60 years of age. These results highlight the need for head-to-head clinical trials for the use of P2Y12-Is in patients with ESKD to determine age cutoffs where the risk of bleeding outweighs the benefits of thrombosis prevention., Competing Interests: S.S. Hedayati reports honoraria from the American College of Physicians for participation in Nephrology MKSAP and the American Society of Nephrology Post-Graduate Education Program; and an advisory or leadership role for the American Heart Association (study sections), ACP, and the MKSAP Nephrology Committee. B. Martin reports consultancy for eMaxHealth LLC; honoraria from the Institute of Clinical and Economic Review (ICER) as a member of the Midwest Comparative Effectiveness Public Advisory Council; and patents or royalties for Trestle Tree LLC. All remaining authors have nothing to disclose., (Copyright © 2022 by the American Society of Nephrology.)

Background and Aim: Prescribers are commonly confronted with discontinuing opioid therapy among patients prescribed chronic opioid therapy (COT). This study aimed to measure the association between discontinuing COT and diagnoses of substance use disorders (SUDs) and opioid-related adverse outcomes (AOs)., Design: Retrospective cohort study., Setting: United States Veterans Healthcare Administration., Participants: Veterans with chronic pain on COT who discontinued opioid therapy were compared with those continuing COT using data from fiscal years 2009 to 2015., Measurements: Newly diagnosed substance use disorders (SUD composite; individual types: opioid, non-opioid drug and alcohol use disorders) and opioid-related adverse outcomes (AO composite; individual types: accidents resulting in wounds/injuries, opioid-related accidents/overdoses, alcohol and non-opioid medication-related accidents/overdoses, self-inflicted injuries and violence-related injuries) were evaluated. Primary analyses were conducted using 1:1 matching of discontinuers with those continuing COT based on propensity score and index date (±180-day window). Sensitivity analyses were conducted using logistic regressions with stabilized inverse probability of treatment weighting (SIPTW) and instrumental variable (IV) models., Findings: A total of 15 695 (75.4%) and 17 337 (76.6%) discontinuers were matched with those continuing COT among the cohorts testing SUD and AO development respectively. In the primary propensity score matched analyses, the composite SUD outcome was not different between discontinuers and those continuing COT (OR = 0.932, 95% CI = 0.850, 1.022). The composite AO outcome was lower among discontinuers (OR = 0.660, 95% CI = 0.623, 0.699) compared with those continuing COT. SIPTW analyses found lower SUD (OR = 0.789, 95% CI = 0.743, 0.837), and AO (OR = 0.660, 95% CI = 0.623, 0.699) rates among discontinuers. IV models found mixed and sometimes contradictory results., Conclusions: Discontinuing patients from chronic opioid therapy appears to be associated with decreased diagnoses for opioid-related adverse outcomes. The association with substance use disorders appears to be inconclusive., (© 2021 Society for the Study of Addiction.)

Background: Increasing pressures exist to reduce or discontinue opioid use among patients currently on long-term opioid therapy (LTOT). It is essential to understand the potential effects of opioid reduction., Methods: This retrospective cohort study was conducted among veterans with chronic pain and on LTOT. Using 1:1 propensity score-matched samples of veterans switching to intermittent opioid therapy and those continuing LTOT, we examined the development of subsequent substance use disorders (SUD composite; individual SUD types: opioid, non-opioid drug, and alcohol use disorders) and opioid-related adverse outcomes (ORAO composite; individual ORAO types: accidents resulting in wounds/injuries, opioid-related and alcohol/non-opioid medication-related accidents and overdoses, self-inflicted and violence-related injuries). Sensitivity analyses were conducted using logistic regression with stabilized inverse probability of treatment weighting (SIPTW) and instrumental variable (IV) models., Results: A total of 29,293 veterans switching to intermittent therapy were matched to veterans continuing LTOT. With matched samples, no differences were found in composite SUDs and ORAOs between the groups. With SIPTW, veterans switching to intermittent opioid therapy had higher odds of composite SUDs and ORAOs (SUDs aOR=1.12, 95%CI: 1.07,1.17; ORAOs aOR=1.05, 95%CI:1.00,1.09). IV models found lower risks for composite SUDs and ORAOs among veterans switching to intermittent opioid therapy (SUDs: β = -0.38, 95%CI:-0.63,-0.13; ORAOs: β = -0.27, 95%CI:-0.50,-0.04)., Conclusions: There were no consistent associations between transitioning patients from LTOT to intermittent opioid therapy and the risk of SUDs and ORAOs., (Copyright © 2021. Published by Elsevier B.V.)