Direct-Acting Oral Anticoagulants and Antiseizure Medications for Atrial Fibrillation and Epilepsy and Risk of Thromboembolic Events.

Importance: Direct-acting oral anticoagulants (DOACs) are commonly prescribed with antiseizure medications (ASMs) due to concurrency of and the association between atrial fibrillation (AF) and epilepsy. However, enzyme-inducing (EI) ASMs may reduce absorption and accelerate metabolism of DOACs, potentially lowering DOAC levels and elevating thromboembolism risk. Objective: To assess the rates of thromboembolic and major bleeding events in adults with AF and epilepsy dispensed DOACs and EI ASMs vs DOACs with non-EI ASMs. Design, Setting, and Participants: This active-comparator, new-user cohort study included US health care data from the Clinformatics Data Mart database from October 2010 to September 2021 for a nationally representative population of adults with AF and epilepsy. Exposure: Evaluations included episodes of contiguous coadministration of DOACs for AF with EI ASMs (exposed) or non-EI ASMs (referent) for epilepsy. Main Outcomes and Measures: Thromboembolic events (primary outcome) and major bleeding events (secondary outcome) were identified based on a series of validated, diagnosis-based coding algorithms. Data-adaptive, high-dimensional propensity score matching was used to control for observed confounders and proxies for unobserved confounders. Adjusted hazard ratios (AHRs) were estimated using Cox proportional hazards regression models with robust variance estimators to account for clustering within matched pairs. Results: This study included 14 078 episodes (median age, 74 [IQR, 67-81]; 52.4% female) and 14 158 episodes (median age, 74 [IQR, 67-81]; 52.4% female) of incident DOAC and ASM use that met eligibility criteria for assessment of thromboembolic and major bleeding outcomes, respectively. Incidence was 88.5 per 1000 person-years for thromboembolic events and 68.3 per 1000 person-years for bleeding events. Compared with use of non-EI ASMs, use of EI ASMs with DOACs was not associated with a difference in risk of thromboembolic events (AHR, 1.10; 95% CI, 0.82-1.46) but was associated with a reduction in risk of major bleeding events (AHR, 0.63; 95% CI, 0.44-0.89). Conclusions and Relevance: In this cohort study, EI ASMs were not associated with alteration in DOAC efficacy. Further research is needed on the reduction in bleeding risk associated with EI ASMs, as this may suggest that pharmacokinetic interactions are associated with lowering DOAC levels without negating therapeutic effects.

Thinking Three-Dimensionally: A Self- and Externally-Controlled Approach to Screening for Drug-Drug-Drug Interactions Among High-Risk Populations.

The global rise in polypharmacy has increased both the necessity and complexity of drug-drug interaction (DDI) assessments, given the growing potential for interactions involving more than two drugs. Leveraging large-scale healthcare claims data, we piloted a semi-automated, high-throughput case-crossover-based approach for drug-drug-drug interaction (3DI) screening. Cases were direct-acting oral anticoagulant (DOAC) users with either a major bleeding event during ongoing dispensings for potentially interacting, enzyme-inhibiting antihypertensive drugs (AHDs) (Study 1), or a thromboembolic event during ongoing dispensings for potentially interacting, enzyme-inducing antiseizure medications (ASMs) (Study 2). 3DI detection was based on screening for additional drug exposures that served as acute outcome triggers. To mitigate direct effects and confounding by concomitant drugs, self-controlled estimates were adjusted using negative cases (external "control" DOAC users with the same outcomes but co-dispensings for non-interacting AHDs or ASMs). Signal thresholds were set based on P-values and false discovery rate q-values to address multiple comparisons. Study 1: 285 drugs were examined among 3,306 episodes. Self-controlled assessments with q-value thresholds yielded 9 3DI signals (cases) and 40 DDI signals (negative cases). External adjustment generated 10 3DI signals from the P-value threshold and no signals from the q-value threshold. Study 2: 126 drugs were examined among 604 episodes. Assessments with P-value thresholds yielded 3 3DI and 26 DDI signals following self-control, as well as 4 3DI signals following adjustment. No 3DI signals met the q-value threshold. The presented self- and externally-controlled approach aimed to advance paradigms for real-world higher order drug interaction screening among high-susceptibility populations with pre-existent DDI risk.

Adherence with statins and all-cause mortality in days with high temperature.

PURPOSE: It has been suggested that statins may exert thermo-protective effects that can reduce mortality on hot days. We aimed to examine the relationship between statin adherence and mortality in days with high temperature. METHODS: Utilizing data from a prior historical new-user cohort study, we analyzed a cohort of 229 918 individuals within a state-mandated health provider in Israel who initiated statin therapy between 1998 and 2006. Adherence to statins was assessed through the mean proportion of days covered (PDC) with statins during the follow-up period. The study's primary outcome was all-cause mortality during hot days. RESULTS: During the study follow-up period, a total of 13 165 individuals (5.7%) died. In a multivariable model, a 10% increase in PDC with statins was associated with an HR of (0.85; 95% CI: 0.72-1.00) for deaths (n = 16) in extremely hot days (≥39°C). This association was numerically stronger compared to HR = 0.94 (0.93-0.94) in cooler days and displayed a significant difference between sexes. In males, the fully-adjusted HR for a 10% increase in PDC with statins was 0.66 (0.45-0.95), while in women, it was 0.98 (0.78-1.23). In contrast, no such effect modification was observed for death in cooler days. CONCLUSIONS: These findings align with earlier research, supporting the notion that adherence with statin treatment may be associated with a reduced risk of death during extremely hot days, particularly among men.

Comparative Risk of Injury with Concurrent Use of Opioids and Skeletal Muscle Relaxants.

Concurrent use of skeletal muscle relaxants (SMRs) and opioids has been linked to an increased risk of injury. However, it remains unclear whether the injury risks differ by specific SMR when combined with opioids. We conducted nine retrospective cohort studies within a US Medicaid population. Each cohort consisted exclusively of person-time exposed to both an SMR and one of the three most dispensed opioids-hydrocodone, oxycodone, and tramadol. Opioid users were further divided into three cohorts based on the initiation order of SMRs and opioids-synchronically triggered, opioid-triggered, and SMR-triggered. Within each cohort, we used Cox proportional hazard models to compare the injury rates for different SMRs compared to methocarbamol, adjusting for covariates. We identified 349,543, 139,458, and 218,967 concurrent users of SMRs with hydrocodone, oxycodone, and tramadol, respectively. In the oxycodone-SMR-triggered cohort, the adjusted hazard ratios (HRs) were 1.86 (95% CI, 1.23-2.82) for carisoprodol and 1.73 (1.09-2.73) for tizanidine. In the tramadol-synchronically triggered cohort, the adjusted HRs were 0.69 (0.49-0.97) for metaxalone and 0.62 (0.42-0.90) for tizanidine. In the tramadol-SMR-triggered cohort, the adjusted HRs were 1.51 (1.01-2.26) for baclofen and 1.48 (1.03-2.11) for cyclobenzaprine. All other HRs were statistically nonsignificant. In conclusion, the relative injury rate associated with different SMRs used concurrently with the three most dispensed opioids appears to vary depending on the specific opioid and the order of combination initiation. If confirmed by future studies, clinicians should consider the varying injury rates when prescribing SMRs to individuals using hydrocodone, oxycodone, and tramadol.

Impact of deceased organ donor marijuana use on donor culture positivity and solid organ transplant recipient outcomes.

With the increasing prevalence of marijuana use in the US, many deceased organ donors have a history of marijuana use, raising concerns about infectious risks to transplant recipients. We performed a multicenter retrospective cohort study in which exposed donors were those with recent marijuana use (in the prior 12 months) and unexposed donors were those with no recent marijuana use. Primary outcomes included the following: (1) positive donor cultures for bacteria or fungi, (2) recipient infection due to bacteria or fungi within 3 months posttransplant, and (3) recipient graft failure or death within 12 months posttransplant. Multivariable regression was used to evaluate the relationship between donor marijuana use and each outcome. A total of 658 recipients who received organs from 394 donors were included. Recent marijuana use was not associated with donor culture positivity (aOR: 0.84, 95% CI: 0.39-1.81, P = .65), recipient infection (aHR: 1.02, 95% CI: 0.76-1.38, P = .90), or recipient graft failure or death (aHR: 1.65, 95% CI: 0.90-3.02, P = .11). Our data suggest that organs from donors with a history of recent marijuana use do not pose significant infectious risks in the early posttransplant period.

Antibiotic Prescribing Patterns for Respiratory Tract Illnesses Following the Conclusion of an Education and Feedback Intervention in Primary Care.

BACKGROUND: A study previously conducted in primary care practices found that implementation of an educational session and peer comparison feedback was associated with reduced antibiotic prescribing for respiratory tract diagnoses (RTDs). Here, we assess the long-term effects of this intervention on antibiotic prescribing following cessation of feedback. METHODS: RTD encounters were grouped into tiers based on antibiotic prescribing appropriateness: tier 1, almost always indicated; tier 2, possibly indicated; and tier 3, rarely indicated. A χ2 test was used to compare prescribing between 3 time periods: pre-intervention, intervention, and post-intervention (14 months following cessation of feedback). A mixed-effects multivariable logistic regression analysis was performed to assess the association between period and prescribing. RESULTS: We analyzed 260 900 RTD encounters from 29 practices. Antibiotic prescribing was more frequent in the post-intervention period than in the intervention period (28.9% vs 23.0%, P < .001) but remained lower than the 35.2% pre-intervention rate (P < .001). In multivariable analysis, the odds of prescribing were higher in the post-intervention period than the intervention period for tier 2 (odds ratio [OR], 1.19; 95% confidence interval [CI]: 1.10-1.30; P < .05) and tier 3 (OR, 1.20; 95% CI: 1.12-1.30) indications but was lower compared to the pre-intervention period for each tier (OR, 0.66; 95% CI: 0.59-0.73 tier 2; OR, 0.68; 95% CI: 0.61-0.75 tier 3). CONCLUSIONS: The intervention effects appeared to last beyond the intervention period. However, without ongoing provider feedback, there was a trend toward increased prescribing. Future studies are needed to determine optimal strategies to sustain intervention effects.

Nicotine Metabolite Ratio Decreases After Switching Off Efavirenz-Based Therapy in People With HIV Who Smoke.

Rates of cigarette smoking in people with HIV (PWH) are two to three times higher than in people without HIV. Nicotine is metabolized by CYP2A6 and the nicotine metabolite ratio (NMR; 3-hydroxycotinine/cotinine) is a measure of nicotine clearance. Higher NMR has been observed in PWH and is associated with lower quit rates. Efavirenz, a mainstay antiretroviral therapy (ART) globally, partially upregulates its own metabolism through CYP2A6. We hypothesized that efavirenz also upregulates nicotine metabolism by CYP2A6, resulting in a higher NMR, and switching to non-efavirenz ART would decrease the NMR, potentially leading to improved quit rates. We compared the NMR during and after efavirenz use among PWH in a longitudinal, multisite cohort. Eligibility criteria included: (i) active cigarette smoking, (ii) ART switched from efavirenz-based to non-efavirenz-based regimen, (iii) plasma available at pre- and post-ART switch, and (iv) viral suppression during study period. Plasma cotinine and 3-hydroxycotinine were measured by liquid chromatography-tandem mass spectrometry. T-tests compared the NMR on and off efavirenz. Samples were collected between 2010 and 2019 in 72 PWH. The mean NMR difference after switching to a non-efavirenz-based regimen was -0.24 (SD: 0.37, P < 0.001); 44 PWH had at least a 0.1 decrease in NMR. Effect modification by race was present; Black PWH had a larger mean decrease. Our findings suggest that previously observed higher NMR among PWH may be due to direct pharmacologic effects of ART. Assessing the effect of ART on the NMR suggests that avoiding nicotine metabolism inducers could potentially increase quit rates.

Performance of CHROMagar ESBL media for the surveillance of extended-spectrum cephalosporin-resistant Enterobacterales (ESCrE) from rectal swabs in Botswana.

Introduction. Lack of laboratory capacity hampers consistent national antimicrobial resistance (AMR) surveillance. Chromogenic media may provide a practical screening tool for detection of individuals colonized by extended-spectrum beta-lactamase (ESBL)-producing organisms.Hypothesis. CHROMagar ESBL media represent an adequate screening method for the detection of extended-spectrum cephalosporin-resistant Enterobacterales (ESCrE), isolated from rectal swabs.Aim. To evaluate the performance of CHROMagar ESBL media to accurately identify ESCrE isolates from rectal swab samples attained from hospitalized and community participants.Methodology. All participants provided informed consent prior to enrolment. Rectal swabs from 2469 hospital and community participants were inoculated onto CHROMagar ESBL. The performance of CHROMagar ESBL to differentiate Escherichia coli and Klebsiella spp., Enterobacter spp. and Citrobacter spp. (KEC spp.) as well as select for extended-spectrum cephalosporin resistance were compared to matrix-assisted laser desorption/ionization-time-of-flight MS (MALDI-TOF-MS) and VITEK-2 automated susceptibility testing.Results. CHROMagar ESBL had a positive and negative agreement of 91.2 % (95 % CI, 88.4-93.3) and 86.8 % (95 % CI, 82.0-90.7) for E. coli and 88.1 % (95 % CI 83.2-92.1) and 87.6 % (95 % CI 84.7-90.2) for KEC spp. differentiation, respectively, when compared to species ID by MALDI-TOF-MS. When evaluated for phenotypic susceptibilities (VITEK-2), 88.1 % (714/810) of the isolates recovered on the selective agar exhibited resistance to third-generation cephalosporins.Conclusion. The performance characteristics of CHROMagar ESBL media suggest that they may be a viable screening tool for the identification of ESCrE from hospitalized and community participants and could be used to inform infection prevention and control practices in Botswana and potentially other low-and middle-income countries (LMICs). Further studies are required to analyse the costs and the impact on time-to-result of the media in comparison with available laboratory methods for ESCrE surveillance in the country.

Unique characteristics of end-of-life hospitalizations in Parkinson disease.

Introduction: Persons with Parkinson disease (PD) are hospitalized at higher rates, have longer lengths of stay, and are more likely to die in the hospital than age-matched peers. Although prior studies have compared inpatient outcomes between persons with and without PD, little is known about inpatient outcomes across the PD trajectory, or whether hospitalizations occurring in the last 6 months of life differ from earlier hospitalizations. Methods: This cross-sectional study compared Medicare Part A and B beneficiaries aged 65 and older with a qualifying PD diagnosis who were hospitalized in 2017: decedents who died between 7/1/2017 and 12/31/2017 from all causes and were hospitalized at least once in their last 6 months of life, and non-decedents who were hospitalized between 1/1/2017 and 6/30/2017 and lived 6 or more months after discharge. End-of-life (EoL) hospitalizations were defined as those occurring in the last 6 months of life. Descriptive analyses compared patient-level variables (e.g., demographics, comorbidities, treatment intensity) and encounter-level variables (e.g., length of stay, total charges) between groups. Multivariable logistic regression models also compared rates of intensive care unit (ICU) admission and 30-day readmission between hospitalized decedents and hospitalized non-decedents, adjusting for age, sex, race/ethnicity, rural residence, and Charlson Comorbidity Index Score. Results: Of 26,492 Medicare decedents with PD, 16,187 (61.1%) were hospitalized in their last 6 months of life. Of 347,512 non-decedents with PD, 62,851 (18.1%) were hospitalized in a 6-month period. Hospitalized decedents were slightly older than hospitalized non-decedents (82.3 [SD 7.40] vs. 79.5 [SD 7.54] years) and had significantly more comorbidities. Compared to non-EoL hospitalizations, EoL hospitalizations were slightly longer (5 [IQR 3-9] vs. 4 [IQR 3-7] days) and more expensive based on total charges per admission ($36,323 [IQR 20,091-69,048] vs. $32,309 [IQR 18,789-57,756]). In covariate-adjusted regression models using hospitalized non-decedents as the reference group, hospitalized decedents were more likely to experience an ICU admission (AOR 2.36; CI 2.28-2.45) and 30-day readmission (AOR 2.43; CI 2.34-2.54). Discussion: Hospitalizations occurring in the last 6 months of life among persons with PD in the United States are longer, more costly, and more resource intensive than earlier hospitalizations and may stem from medical comorbidities. Once hospitalized, ICU admission and 30-day readmission may aid in prognostication and serve as markers of transition to the EoL period.

Increasing antiretroviral therapy adherence and retention in care among adults living with HIV in Philadelphia: a study protocol for a stepped-wedge cluster-randomised type 2 hybrid effectiveness-implementation trial of managed problem-solving plus (MAPS+) delivered by community health workers.

INTRODUCTION: To end the HIV epidemic in Philadelphia, implementation of evidence-based practices (EBP) to increase viral suppression and retention in HIV care is critical. Managed problem solving (MAPS), an EBP for antiretroviral therapy adherence, follows a problem-solving approach to empower people living with HIV (PWH) to manage their health. To overcome barriers to care experienced by PWH in Philadelphia, the EBP was adapted to include a focus on care retention and delivery by community health workers (CHWs). The adapted intervention is MAPS+. To maximise the clinical impact and reach of the intervention, evaluation of the effectiveness and implementation of MAPS+ is necessary. METHODS AND ANALYSIS: This manuscript describes the protocol for a stepped-wedge cluster-randomised type 2 hybrid effectiveness-implementation trial in 10 clinics in Philadelphia. This research incorporates innovative approaches to accomplish three objectives: (1) to evaluate the effectiveness of the CHW-led MAPS+ intervention to improve viral suppression and retention in care 1 year after the individual implementation period (N=390 participants), (2) to examine the effect of the menu of implementation strategies on reach and implementation cost and (3) to examine processes, mechanisms, and sustainment of the implementation strategies for MAPS+ (N=56 participants). Due to various factors (eg, COVID-19), protocol modifications have occurred. ETHICS AND DISSEMINATION: The institutional review board (IRB) at the city of Philadelphia serves as the primary IRB; initial approval was granted on 21 December 2020. The University of Pennsylvania and Northwestern University executed reliance agreements. A safety monitoring committee comprised experts in implementation science, biostatistics and infectious diseases oversee this study. This research will offer insights into achieving the goals to end the HIV epidemic in Philadelphia as well as implementation efforts of MAPS+ and other behavioural interventions aimed at increasing medication adherence and retention in care. Dissemination will include deliverables (eg, peer-reviewed manuscripts and lay publications) to reach multiple constituents. TRIAL REGISTRATION NUMBER: NCT04560621.

Comparison of Staged vs Same-Day Circumferential Spinal Fusions for Adult Spinal Deformity.

BACKGROUND: Patients often undergo circumferential (anterior and posterior) spinal fusions to maximize adult spinal deformity (ASD) correction and achieve adequate fusion. Currently, such procedures are performed in staged (ST) or same-day (SD) procedures with limited evidence to support either strategy. This study aims to compare perioperative outcomes and costs of ST vs SD circumferential ASD corrective surgeries. METHODS: This is a retrospective review of patients undergoing circumferential ASD surgeries between 2013 and 2018 in a single institution. Patient characteristics, preoperative comorbidities, surgical details, perioperative complications, readmissions, total hospital admission costs, and 90-day postoperative care costs were identified. All variables were tested for differences between ST and SD groups unadjusted and after applying inverse probability weighting (IPW), and the results before and after IPW were compared. RESULTS: The entire cohort included a total of 211 (ST = 50, SD = 161) patients, 100 of whom (ST = 44, SD = 56) underwent more than 4 levels fused posteriorly and anterior lumbar interbody fusion (ALIF). Although patient characteristics and comorbidities were not dissimilar between the ST and SD groups, both the number of levels fused in ALIF and posterior spinal fusion (PSF) were significantly different. Thus, using IPW, we were able to minimize the cohort incongruities in the number of levels fused in ALIF and PSF while maintaining comparable patient characteristics. In both the whole cohort and the long segment fusions, postoperative pulmonary embolism was more common in ST procedures. After adjustment utilizing IPW, both groups were not significantly different in disposition, 30-day readmissions, and reoperations. However, within the whole cohort and the long segment fusion cohort, the ST group continued to show significantly increased rates of pulmonary embolism, longer length of stay, and higher hospital admission costs compared with the SD group. CONCLUSIONS: Adjusted comparisons between ST and SD groups showed staging associated with significantly increased length of stay, risk of pulmonary embolism, and admission costs.

The diagnostic likelihood ratio function and modified test for trend: Identifying, evaluating, and validating nontraditional biomarkers in case-control studies.

The ROC curve and its associated summary statistic, the AUC, are used to identify informative diagnostic biomarkers under the assumption that risk of disease is a monotone function of the biomarker. We refer to biomarkers that meet this assumption as traditional, and those that do not as nontraditional. Nontraditional biomarkers most often arise when both low and high biomarker values are associated with an outcome of interest, such as blood pressure with medical complications or leukocyte count with ICU prognosis. Since nontraditional biomarkers do not meet the assumptions for ROC-based analyses, we propose using the discrete diagnostic likelihood ratio (DLR) function to evaluate a wider class of informative biomarkers. We obtain the DLR function using the multinomial logistic regression (MLR) model to improve upon existing estimation techniques, and implement a likelihood ratio test to identify candidate informative traditional and nontraditional biomarkers. We propose a modification of the Cochran-Armitage test for trend that separates biomarkers deemed informative into traditional and nontraditional categories. The statistical properties of the likelihood ratio test and modified test for trend are explored under simulation. Together, these methods achieve the identification, evaluation, and validation of biomarkers from early discovery research. Finally, we show that incorporating covariates into the MLR model results in a covariate-adjusted DLR function that is useful for integrating multiple sources of information in clinical decision making. The methods are applied to gene expression data from subjects with high grade serous ovarian cancer, where stage, early stage vs late stage, is the outcome of interest.

Risk Factors for Community Colonization With Extended-Spectrum Cephalosporin-Resistant Enterobacterales (ESCrE) in Botswana: An Antibiotic Resistance in Communities and Hospitals (ARCH) Study.

BACKGROUND: The epidemiology of extended-spectrum cephalosporin-resistant Enterobacterales (ESCrE) in low- and middle-income countries (LMICs) is poorly described. Identifying risk factors for ESCrE colonization is critical to inform antibiotic resistance reduction strategies because colonization is typically a precursor to infection. METHODS: From 15 January 2020 to 4 September 2020, we surveyed a random sample of clinic patients at 6 sites in Botswana. We also invited each enrolled participant to refer up to 3 adults and children. All participants had rectal swabs collected that were inoculated onto chromogenic media followed by confirmatory testing. Data were collected on demographics, comorbidities, antibiotic use, healthcare exposures, travel, and farm and animal contact. Participants with ESCrE colonization (cases) were compared with noncolonized participants (controls) to identify risk factors for ESCrE colonization using bivariable, stratified, and multivariable analyses. RESULTS: A total of 2000 participants were enrolled. There were 959 (48.0%) clinic participants, 477 (23.9%) adult community participants, and 564 (28.2%) child community participants. The median (interquartile range) age was 30 (12-41) and 1463 (73%) were women. There were 555 cases and 1445 controls (ie, 27.8% of participants were ESCrE colonized). Independent risk factors (adjusted odds ratio [95% confidence interval]) for ESCrE included healthcare exposure (1.37 [1.08-1.73]), foreign travel [1.98 (1.04-3.77]), tending livestock (1.34 [1.03-1.73]), and presence of an ESCrE-colonized household member (1.57 [1.08-2.27]). CONCLUSIONS: Our results suggest healthcare exposure may be important in driving ESCrE. The strong links to livestock exposure and household member ESCrE colonization highlight the potential role of common exposure or household transmission. These findings are critical to inform strategies to curb further emergence of ESCrE in LMICs.

Sociodemographic and Geographic Disparities in End-of-Life Health Care Intensity Among Medicare Beneficiaries With Parkinson Disease.

Background and Objective: Current studies of end-of-life care in Parkinson disease (PD) do not focus on diverse patient samples or provide national views of end-of-life resource utilization. We determined sociodemographic and geographic differences in end-of-life inpatient care intensity among persons with PD in the United States (US). Methods: This retrospective cohort study included Medicare Part A and Part B beneficiaries 65 years and older with a qualifying PD diagnosis who died between January 1, 2017, and December 31, 2017. Medicare Advantage beneficiaries and those with atypical or secondary parkinsonism were excluded. Primary outcomes included rates of hospitalization, intensive care unit (ICU) admission, in-hospital death, and hospice discharge in the last 6 months of life. Descriptive analyses and multivariable logistic regression models compared differences in end-of-life resource utilization and treatment intensity. Adjusted models included demographic and geographic variables, Charlson Comorbidity Index score, and Social Deprivation Index score. The national distribution of primary outcomes was mapped and compared by hospital referral region using Moran I. Results: Of 400,791 Medicare beneficiaries with PD in 2017, 53,279 (13.3%) died. Of decedents, 33,107 (62.1%) were hospitalized in the last 6 months of life. In covariate-adjusted regression models using White male decedents as the reference category, odds of hospitalization was greater for Asian (AOR 1.38; CI 1.11-1.71) and Black (AOR 1.23; CI 1.08-1.39) male decedents and lower for White female decedents (AOR 0.80; CI 0.76-0.83). ICU admissions were less likely in female decedents and more likely in Asian, Black, and Hispanic decedents. Odds of in-hospital death was greater among Asian (AOR 2.49, CI 2.10-2.96), Black (AOR 1.11, CI 1.00-1.24), Hispanic (AOR 1.59; CI 1.33-1.91), and Native American (AOR 1.49; CI 1.05-2.10) decedents. Asian and Hispanic male decedents were less likely to be discharged to hospice. In geographical analyses, rural-dwelling decedents had lower odds of ICU admission (AOR 0.77; CI 0.73-0.81) and hospice discharge (AOR 0.69; CI 0.65-0.73) than urban-dwelling decedents. Nonrandom clusters of primary outcomes were observed across the US, with highest rates of hospitalization in the South and Midwest (Moran I = 0.134; p < 0.001). Discussion: Most persons with PD in the US are hospitalized in the last 6 months of life, and treatment intensity varies by sex, race, ethnicity, and geographic location. These group differences emphasize the importance of exploring end-of-life care preferences, service availability, and care quality among diverse populations with PD and may inform new approaches to advance care planning.

Clinical Outcomes and Risk Factors for Carbapenem-resistant Enterobacterales Bloodstream Infection in Solid Organ Transplant Recipients.

BACKGROUND: The clinical outcomes associated with, and risk factors for, carbapenem-resistant Enterobacterales (CRE) bloodstream infections (BSIs) in solid organ transplant (SOT) recipients remain ill-defined. METHODS: A multicenter retrospective cohort study was performed, including SOT recipients with an Enterobacterales BSI between 2005 and 2018. Exposed subjects were those with a CRE BSI. Unexposed subjects were those with a non-CRE BSI. A multivariable survival analysis was performed to determine the association between CRE BSI and risk of all-cause mortality within 60 d. Multivariable logistic regression analysis was performed to determine independent risk factors for CRE BSI. RESULTS: Of 897 cases of Enterobacterales BSI in SOT recipients, 70 (8%) were due to CRE. On multivariable analysis, CRE BSI was associated with a significantly increased hazard of all-cause mortality (adjusted hazard ratio, 2.85; 95% confidence interval [CI], 1.68-4.84; P < 0.001). Independent risk factors for CRE BSI included prior CRE colonization or infection (adjusted odds ratio [aOR] 9.86; 95% CI, 4.88-19.93; P < 0.001)' liver transplantation (aOR, 2.64; 95% CI, 1.23-5.65; P = 0.012)' lung transplantation (aOR, 3.76; 95% CI, 1.40-10.09; P = 0.009)' and exposure to a third-generation cephalosporin (aOR, 2.21; 95% CI, 1.17-4.17; P = 0.015) or carbapenem (aOR, 2.80; 95% CI, 1.54-5.10; P = 0.001) in the prior 6 months. CONCLUSIONS: CRE BSI is associated with significantly worse outcomes than more antibiotic-susceptible Enterobacterales BSI in SOT recipients.

Antidepressant drug-drug-drug interactions associated with unintentional traumatic injury: Screening for signals in real-world data.

Antidepressants are associated with traumatic injury and are widely used with other medications. It remains unknown how drug-drug-drug interactions (3DIs) between antidepressants and two other drugs may impact potential injury risks associated with antidepressants. We aimed to generate hypotheses regarding antidepressant 3DI signals associated with elevated injury rates. Using 2000-2020 Optum's de-identified Clinformatics Data Mart, we performed a self-controlled case series study for each drug triad consisting of an antidepressant + codispensed drug (base-pair) with a candidate interacting medication (precipitant). We included persons aged greater than or equal to 16 years who (1) experienced an injury and (2) used a candidate precipitant, during base-pair therapy. We compared injury rates during observation time exposed to the drug triad versus the base-pair only, adjusting for time-varying covariates. We calculated adjusted rate ratios (RRs) using conditional Poisson regression and accounted for multiple comparisons via semi-Bayes shrinkage. Among 147,747 eligible antidepressant users with an injury, we studied 120,714 antidepressant triads, of which 334 (0.3%) were positively associated with elevated injury rates and thus considered potential 3DI signals. Adjusted RRs for signals ranged from 1.31 (1.04-1.65) for sertraline + levothyroxine with tramadol (vs. without tramadol) to 6.60 (3.23-13.46) for escitalopram + simvastatin with aripiprazole (vs. without aripiprazole). Nearly half of the signals (137, 41.0%) had adjusted RRs greater than or equal to 2, suggesting strong associations with injury. The identified signals may represent antidepressant 3DIs of potential clinical concern and warrant future etiologic studies to test these hypotheses.

Prevalence of the metabolic syndrome and associated factors among inpatients with severe mental illness in Botswana: a cross-sectional study.

INTRODUCTION: The metabolic syndrome, a cluster of inter-related risk factors for cardiovascular diseases is highly prevalent among individuals with obesity and sedentary lifestyle. Chronic psychiatric disorders such as severe mental illness are associated with increased risk for cardiovascular diseases. We aimed to assess the prevalence and correlates of metabolic syndrome among inpatients with severe mental illness in a resource limited setting with high HIV prevalence. METHODS: This was a cross-sectional study among adult inpatients at a referral psychiatric hospital in Botswana. We used convenience sampling to enrol participants available at the time of the study. The National Cholesterol Education Program Adult Treatment Panel-III (NCEP-ATP III) criteria was used to define the metabolic syndrome. Data were analysed using descriptive statistics as well as multiple logistic regression modelling. RESULTS: A total of 137 participants were enrolled. Of these, 119 (87%) had complete data for the main analysis. The overall prevalence of metabolic syndrome was 22.6% (95% CI 15.9, 30.6) and did not differ significantly by gender or HIV status. Age was significantly associated with the risk of having the metabolic syndrome while gender, body mass index, HIV status, and days of moderate physical activity were not. CONCLUSION: There was a moderately high prevalence of metabolic syndrome. Thus, the management of individuals with severe mental illness in resource limited settings should include assessment of cardiovascular risk and target modifiable risk factors in this population. Consideration for the patient's age should be made when rationalizing the limited resources available for assessing metabolic syndrome among patients with severe mental illness.

Thromboembolic Events in Users of Warfarin Treated with Different Skeletal Muscle Relaxants.

Background and Objectives: Warfarin and a skeletal muscle relaxant are co-treatments in nearly a quarter-million annual United States (US) office visits. Despite international calls to minimize patient harm arising from anticoagulant drug interactions, scant data exist on clinical outcomes in real-world populations. We examined effects of concomitant use of warfarin and individual muscle relaxants on rates of hospitalization for thromboembolism among economically disadvantaged persons. Materials and Methods: Using 1999−2012 administrative data of four US state Medicaid programs, we conducted 16 retrospective self-controlled case series studies: half included concomitant users of warfarin + one of eight muscle relaxants; half included concomitant users of an inhaled corticosteroid (ICS) + one of eight muscle relaxants. The ICS analyses served as negative control comparisons. In each study, we calculated incidence rate ratios (IRRs) comparing thromboembolism rates in the co-exposed versus warfarin/ICS-only exposed person-time, adjusting for time-varying confounders. Results: Among ~70 million persons, we identified 8693 warfarin-treated subjects who concomitantly used a muscle relaxant, were hospitalized for thromboembolism, and met all other inclusion criteria. Time-varying confounder-adjusted IRRs ranged from 0.31 (95% confidence interval: 0.13−0.77) for metaxalone to 3.44 (95% confidence interval: 1.53−7.78) for tizanidine. The tizanidine finding was robust after quantitatively adjusting for negative control ICS findings, and in numerous prespecified secondary analyses. Conclusions: We identified a potential >3-fold increase in the rate of hospitalized thromboembolism in concomitant users of warfarin + tizanidine vs. warfarin alone. Alternative explanations for this finding include confounding by indication, a native effect of tizanidine, or chance.

Population-based screening to detect benzodiazepine drug-drug-drug interaction signals associated with unintentional traumatic injury.

Drug interactions involving benzodiazepines and related drugs (BZDs) are increasingly recognized as a contributor to increased risk of unintentional traumatic injury. Yet, it remains unknown to what extent drug interaction triads (3DIs) may amplify BZDs' inherent injury risk. We identified BZD 3DI signals associated with increased injury rates by conducting high-throughput pharmacoepidemiologic screening of 2000-2019 Optum's health insurance data. Using self-controlled case series design, we included patients aged ≥ 16 years with an injury while using a BZD + co-dispensed medication (i.e., base pair). During base pair-exposed observation time, we identified other co-dispensed medications as candidate interacting precipitants. Within each patient, we compared injury rates during time exposed to the drug triad versus to the base pair only using conditional Poisson regression, adjusting for time-varying covariates. We calculated rate ratios (RRs) with 95% confidence intervals (CIs) and accounted for multiple estimation via semi-Bayes shrinkage. Among the 65,123 BZD triads examined, 79 (0.1%) were associated with increased injury rates and considered 3DI signals. Adjusted RRs for signals ranged from 3.01 (95% CI = 1.53-5.94) for clonazepam + atorvastatin with cefuroxime to 1.42 (95% CI = 1.00-2.02, p = 0.049) for alprazolam + hydrocodone with tizanidine. These signals may help researchers prioritize future etiologic studies to investigate higher-order BZD interactions.