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.

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.

Combining Super Learner with high-dimensional propensity score to improve confounding adjustment: A real-world application in chronic lymphocytic leukemia.

PURPOSE: High-dimensional propensity score (hdPS) is a semiautomated method that leverages a vast number of covariates available in healthcare databases to improve confounding adjustment. A novel combined Super Learner (SL)-hdPS approach was proposed to assist with selecting the number of covariates for propensity score inclusion, and was found in plasmode simulation studies to improve bias reduction and precision compared to hdPS alone. However, the approach has not been examined in the applied setting. METHODS: We compared SL-hdPS's performance with that of several hdPS models, each with prespecified covariates and a different number of empirically-identified covariates, using a cohort study comparing real-world bleeding rates between ibrutinib- and bendamustine-rituximab (BR)-treated individuals with chronic lymphocytic leukemia in Optum's de-identified Clinformatics® Data Mart commercial claims database (2013-2020). We used inverse probability of treatment weighting for confounding adjustment and Cox proportional hazards regression to estimate hazard ratios (HRs) for bleeding outcomes. Parameters of interest included prespecified and empirically-identified covariate balance (absolute standardized difference [ASD] thresholds of <0.10 and <0.05) and outcome HR precision (95% confidence intervals). RESULTS: We identified 2423 ibrutinib- and 1102 BR-treated individuals. Including >200 empirically-identified covariates in the hdPS model compromised covariate balance at both ASD thresholds. SL-hdPS balanced more covariates than all individual hdPS models at both ASD thresholds. The bleeding HR 95% confidence intervals were generally narrower with SL-hdPS than with individual hdPS models. CONCLUSION: In a real-world application, hdPS was sensitive to the number of covariates included, while use of SL for covariate selection resulted in improved covariate balance and possibly improved precision.

The transphyseal osteotomy for the slipped proximal tibial epiphysis in tibia vara.

This study aimed to describe a novel transphyseal osteotomy (TPO) for acute deformity correction in children with bilateral tibia vara and the atraumatic 'slipped proximal tibial epiphysis' (SPTE) entity. We described the clinical and radiological findings in five children (10 limbs) with tibia vara that were treated with the TPO. The criteria for the SPTE were met in nine (9/10) cases. The surgical technique and short-term results of the TPO are reported. The median age was 9 years (range, 6-9), with obesity (BMI > 95th centile) present in all children. The medial tibial plateau was not significantly depressed (the median angle of depression of the medial plateau measured 30° (range, 20°-32°). The mean medial proximal tibial angle of 33° (range, 8°-71°) was corrected to 82° (range, 77°-86°), the mean anatomic posterior proximal tibial angle of 48° (range, 32°-70°) was corrected to 72° (range, 61°-86°), and the median internal tibial rotation of 45° (range, 20°-50° internal rotation) was corrected to neutral rotation (range, 10° internal-10° external rotation). There were two complications: one case of recurrent deformity and one case of intra-articular extension of the osteotomy. We describe a novel TPO that aims to simultaneously correct all aspects of the deformity, stabilise the physis, and prevent recurrence through epiphysiodesis. Further research is required to determine its efficacy and safety. The atraumatic SPTE appears to represent a specific morphological presentation in tibia vara. Level of evidence: 4.

Psychotropic Medication Use in Children and Youth with Autism Enrolled in Medicaid.

Children with autism frequently present with complex mental health diagnoses and psychotropic medications are often a component of comprehensive biopsychosocial treatment plans for these conditions. The purpose of this study is to provide rates and patterns of psychotropic medication use, and predictors thereof, in children and youth with autism enrolled in Medicaid across the US. This study examined national Medicaid claims from 2008 to 2016 of all children and youth with autism ages 0-21 years enrolled in Medicaid. Psychotropic medication use was examined across several child and youth characteristics, including age, co-occurring mental health conditions, sex, and race and ethnicity. About half of children and youth with autism enrolled in Medicaid had at least one psychotropic prescription in a year, a number that decreased slightly across the study period due to decreases in the prescription of antipsychotics. As new medications for autism or co-occurring conditions are developed and deployed, and as the understanding of the characteristics of the population of children with autism evolves, studying rates of medication usage helps to understand utilization patterns and differences in access to quality care.

Avenues for Strengthening PCORnet's Capacity to Advance Patient-Centered Economic Outcomes in Patient-Centered Outcomes Research (PCOR).

PCORnet, the National Patient-Centered Clinical Research Network, provides the ability to conduct prospective and observational pragmatic research by leveraging standardized, curated electronic health records data together with patient and stakeholder engagement. PCORnet is funded by the Patient-Centered Outcomes Research Institute (PCORI) and is composed of 8 Clinical Research Networks that incorporate at total of 79 health system "sites." As the network developed, linkage to commercial health plans, federal insurance claims, disease registries, and other data resources demonstrated the value in extending the networks infrastructure to provide a more complete representation of patient's health and lived experiences. Initially, PCORnet studies avoided direct economic comparative effectiveness as a topic. However, PCORI's authorizing law was amended in 2019 to allow studies to incorporate patient-centered economic outcomes in primary research aims. With PCORI's expanded scope and PCORnet's phase 3 beginning in January 2022, there are opportunities to strengthen the network's ability to support economic patient-centered outcomes research. This commentary will discuss approaches that have been incorporated to date by the network and point to opportunities for the network to incorporate economic variables for analysis, informed by patient and stakeholder perspectives. Topics addressed include: (1) data linkage infrastructure; (2) commercial health plan partnerships; (3) Medicare and Medicaid linkage; (4) health system billing-based benchmarking; (5) area-level measures; (6) individual-level measures; (7) pharmacy benefits and retail pharmacy data; and (8) the importance of transparency and engagement while addressing the biases inherent in linking real-world data sources.

Comparative safety of antimuscarinics versus mirabegron for overactive bladder in Parkinson disease.

BACKGROUND: Overactive bladder (OAB) is a common non-motor symptom of Parkinson disease (PD), often treated with antimuscarinics or beta-3 agonists. There is lack of evidence to guide OAB management in PD. OBJECTIVES: To assess the comparative safety of antimuscarinics versus beta-3 agonists for OAB treatment in PD. METHODS: We employed a new-user, active-comparator cohort study design. We included Medicare beneficiaries age ≥65 years with PD who were new users of either antimuscarinic or beta-3 agonist. The primary outcome was any acute care encounter (i.e., non-elective hospitalization or emergency department visit) within 90 days of OAB drug initiation. The main secondary outcome was a composite measure of acute care encounters for anticholinergic related adverse events (AEs). Matching on high-dimensional propensity score (hdPS) was used to address potential confounding. We used Cox proportional hazards models to examine the association between OAB drug category and outcomes. We repeated analyses for 30- and 180-day follow-up periods. RESULTS: We identified 27,091 individuals meeting inclusion criteria (mean age: 77.8 years). After hdPS matching, antimuscarinic users had increased risks for any acute care encounter (hazard ratio [HR] 1.23, 95% confidence interval [CI] 1.12-1.37) and encounters for anticholinergic related AEs (HR 1.18, 95% CI 1.04-1.34) compared to beta-3 agonist users. Similar associations were observed for sensitivity analyses. CONCLUSIONS: Among persons with PD, anticholinergic initiation was associated with a higher risk of acute care encounters compared with beta-3 agonist initiation. The long-term safety of anticholinergic vs. beta-3 agonist therapy in the PD population should be evaluated in a prospective study.

Outcomes in infants with unprovoked venous thromboembolism: A retrospective cohort study.

Background: Although children aged <1 year have a relatively high rate of venous thromboembolism (VTE) compared to older children, most have additional prothrombotic risk factors. Unprovoked VTE is rare, and little is known about this population, particularly the risk of recurrent VTE. Objectives: We aimed to determine the rate of recurrent VTE in infants with prior unprovoked VTE and evaluate long-term, end-organ outcomes for infants with renal and intracranial vein thrombosis. Methods: Infants <1 year of age with an unprovoked VTE between 2003 and 2021 at a single institution were included. Time to recurrent event and anticoagulation duration were summarized using the Kaplan-Meier estimator. Neurologic outcomes were summarized with the pediatric stroke outcome measure for infants with cerebral sinovenous, medullary, or cortical vein thrombosis. Kidney outcomes were summarized with estimated glomerular filtration rates for infants with renal vein thrombosis. Anticoagulation was summarized. Results: Forty infants with intracranial, renal, portal, and extremity VTE met the inclusion criteria and were followed for a median of 4.7 years (IQR, 2.1-8.5). Most VTE events occurred during the first month of life. There was 1 recurrent event in 237 person-years of follow-up (incidence rate, 4 per 1000 [95% CI, 0.6-29.9] person-years). In outpatient follow-up, 40% of infants with intracranial thrombosis met criteria for moderate or severe neurologic outcomes and two-thirds of infants with a prior renal vein thrombosis had abnormal kidney function (estimated glomerular filtration rate < 90 mL/min/1.73 m2). Conclusion: There is a low rate of recurrent VTE but significant end-organ morbidity in infants with unprovoked VTE.

Off-brand: A 6-year study of medication brand and generic name usage in a multifacility academic healthcare system.

BACKGROUND: Usage of medication brand names in electronic health records may introduce conflicts of interest, perpetuate false perceptions of brand superiority, alter prescribing practices, and cause confusion leading to errors. OBJECTIVE: We sought to identify the frequency of brand name medication usage in clinical documentation, as well as factors associated with increased usage. DESIGNS, SETTINGS, AND PARTICIPANTS: We conducted a retrospective analysis of all clinical documentation written at our healthcare system (a multifacility academic urban healthcare system) between 2015 and 2020. MAIN OUTCOMES AND MEASURES: We used string-matching and regular expressions to identify medication mentions. We conducted bivariate analyses to identify associations between brand name usage and author-, note-, and medication-level factors, and a multivariate Poisson regression to clarify independent associations between individual factors and brand usage. RESULTS: A total of 104,456,653 notes from 37,285 unique authors were included in our analysis. A total of 162,906,009 medication mentions were identified, of which 36.0% were brand name mentions with a steady year-over-year decrease. Factors associated with the usage of a brand name include: author role, years since release, length and syllabic complexity of the generic name, service type, and encounter context. Over-the-counter availability did not affect usage. There was sizable individual variation between note writers.

A Systematic Review of the Heterogenous Gene Expression Patterns Associated with Multidrug Chemoresistance in Conventional Osteosarcoma.

Multidrug chemoresistance (MDR) remains the most significant obstacle to improving survival in osteosarcoma patients. Heterogeneous genetic alterations characterise the tumour microenvironment, and host molecular markers have been associated with MDR. This systematic review examines the genetic alterations of molecular biomarkers associated with multidrug chemotherapy resistance in genome-wide analysis of central high-grade conventional osteosarcoma (COS). We systematically searched MEDLINE, EMBASE, Web of Science, Wiley online library and Scopus. Only human studies involving genome-wide analysis were included, while candidate gene, in vitro and animal studies were excluded. The risk of bias of the studies was assessed using the Newcastle-Ottawa Quality Assessment Scale. The systematic search identified 1355 records. Following the screening, six studies were included in the qualitative analysis. There were 473 differentially expressed genes (DEGs) associated with chemotherapy response in COS. Fifty-seven of those were associated with MDR in osteosarcoma. The heterogeneous gene expressions were related to the mechanism of MDR in osteosarcoma. The mechanisms include drug-related sensitivity genes, bone remodelling and signal transduction. Complex, variable and heterogenous gene expression patterns underpin MDR in osteosarcoma. Further research is needed to identify the most relevant alterations for prognostication and to guide the development of possible therapeutic targets.

Channeling of New Neuropsychiatric Drugs-Impact on Safety and Effectiveness Studies.

This study aimed to examine differential prescribing due to channeling and propensity score non-overlap over time in new versus established treatments for common neurological conditions. We conducted cross-sectional analyses on a national sample of US commercially insured adults using 2005-2019 data. We compared new users of recently approved versus established medications for management of diabetic peripheral neuropathy (pregabalin versus gabapentin), Parkinson disease psychosis (pimavanserin versus quetiapine), and epilepsy (brivaracetam versus levetiracetam). Within these drug pairs, we compared demographic, clinical, and healthcare utilization characteristics of recipients of each drug. In addition, we fit yearly propensity score models for each condition and assessed propensity score non-overlap over time. For all three drug pairs, users of the more recently approved medications more frequently had prior treatment (pregabalin = 73.9%, gabapentin = 38.7%; pimavanserin = 41.1%, quetiapine = 14.0%; brivaracetam = 93.4%, levetiracetam = 32.1%). Propensity score non-overlap and its resulting sample loss after trimming were the greatest in the first year that the more recently approved medication was available (diabetic peripheral neuropathy, 12.4% non-overlap; Parkinson disease psychosis, 6.1%; epilepsy, 43.2%) and subsequently improved. Newer neuropsychiatric therapies appear to be channeled to individuals with refractory disease or intolerance to other treatments, leading to potential confounding and biased comparative effectiveness and safety study findings when compared to established treatments. Propensity score non-overlap should be reported in comparative studies that include newer medications. When studies comparing newer and established treatments are critically needed as soon as new treatments enter the market, investigators should recognize the potential for channeling bias and implement methodological approaches like those demonstrated in this study to understand and improve this issue in such studies.

Establishing a consensus on research priorities in orthopaedic trauma within South Africa.

BACKGROUND: Musculoskeletal (MSK) injuries are one of the leading causes of disability worldwide. Despite improvements in trauma-related morbidity and mortality in high-income countries over recent years, outcomes following MSK injuries in low- and middle-income countries, such as South Africa (SA), have not. Despite governmental recognition that this is required, funding and research into this significant health burden are limited within SA. This study aims to identify research priorities within MSK trauma care using a consensus-based approach amongst MSK healthcare practitioners within SA. METHOD: Members from the Orthopaedic Research Collaboration in Africa (ORCA), based in SA, collaborated using a two round modified Delphi technique to form a consensus on research priorities within orthopaedic trauma care. Members involved in the process were orthopaedic healthcare practitioners within SA. RESULTS: Participants from the ORCA network, working within SA, scored research priorities across two Delphi rounds from low to high priority. We have published the overall top 10 research priorities for this Delphi process. Questions were focused on two broad groups-clinical effectiveness in trauma care and general trauma public health care. Both groups were represented by the top two priorities, with the highest ranked question regarding the overall impact of trauma in SA and the second regarding the clinical treatment of open fractures. CONCLUSION: This study has defined research priorities within orthopaedic trauma in South Africa. Our vision is that by establishing consensus on these research priorities, policy and research funding will be directed into these areas. This should ultimately improve musculoskeletal trauma care across South Africa and its significant health and socioeconomic impacts.

High rate of recurrent venous thromboembolism in children and adolescents with unprovoked venous thromboembolism.

BACKGROUND: Unprovoked venous thromboembolism (VTE) is rare in pediatrics. Current recommendations for anticoagulation duration after unprovoked VTE differ for pediatric and adult populations. OBJECTIVES: This single-center, retrospective cohort study aimed to determine the incidence rate of recurrent VTE in children and adolescents with unprovoked VTE, evaluate the potential risk factors for recurrence, and describe the anticoagulation regimens and bleeding in this population. METHODS: Children with an index, unprovoked VTE at the age of 1 to <21 years between 2003 and 2021 were included. The time to recurrent VTE and anticoagulation duration were summarized using Kaplan-Meier estimators. Clinical covariates were assessed for association with recurrence using stratified Kaplan-Meier curves and univariate Cox proportional hazards regression. RESULTS: Eighty-five children met the inclusion criteria, and there were 26 recurrent events in 250 person-years of follow-up (incidence rate = 104 [95% CI, 71-153] per 1000 person-years). An age of ≥12 years at index VTE (hazard ratio [HR], 7.56; 95% CI, 1.60-35.83) and inherited thrombophilia (HR, 2.28; 95% CI, 1.05-4.95) were significantly associated with recurrent VTE. Female sex had a nonstatistically significant decreased hazard of recurrence (HR, 0.56; 95% CI, 0.25-1.27). Duration of anticoagulation was variable, with a median duration of 274 days (IQR, 101-2357) for outpatient therapeutic anticoagulation. Twelve of the 26 (46%) recurrent events occurred while anticoagulation was prescribed. CONCLUSION: The incidence rate of recurrent VTE in pediatric patients with a prior unprovoked VTE is high, particularly for adolescents and those with inherited thrombophilia. Therefore, future research should focus on the efficacy of prolonged anticoagulation for this population.

Evaluating the Impact of a Pharmacist-Led Antimicrobial Stewardship Intervention at Discharge in a Community, Nonteaching Hospital.

INTRODUCTION: Approximately 30% to 50% of hospital discharge antimicrobials are inappropriate. Limited data exist on approaches to improve antimicrobial prescribing practices at the time of discharge from a community hospital. Objective: To assess the impact of a comprehensive pharmacist-led antimicrobial stewardship intervention at discharge. METHODS: We conducted a quasi-experimental, pre-post study. A biphasic intervention took place on 2 medicine units from November 2019 to May 2020 at a community hospital. Baseline data were collected, followed by prescriber education on antimicrobial stewardship to both units (education phase). Next, a pharmacist-led intervention took place on one unit (intervention phase). The primary outcome was composite appropriateness of an oral antimicrobial prescribed to an adult at the time of discharge, defined by narrow spectrum of activity, dosing, and duration of therapy. The primary outcome was assessed using Fisher exact test. RESULTS: Baseline composite appropriateness was 30% (n = 12) on the control unit and 30.8% (n = 20) on the intervention unit. From baseline to posteducation, no significant change in composite appropriateness was found on the control (30% to 26.7%, P = 0.256) or intervention (30.8% to 19.4%, P = 0.09) unit. There was no significant difference between the education to intervention phase (26.7% vs 35%, P = 0.254) on the control unit. On the intervention unit, a significant difference in composite appropriateness was found from the education to intervention phase (19.4% vs 47.8%, P = 0.017). CONCLUSION AND RELEVANCE: A pharmacist-led intervention improved appropriateness of oral antimicrobials prescribed at discharge. One-time education was insufficient for improving antimicrobial stewardship.

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.

Breaking Research Silos and Stimulating "Innovation at the Edges" in Epidemiology.

Epidemiological training often requires specialization in a subdiscipline (e.g., pharmacoepidemiology, genetic epidemiology, social epidemiology, or infectious disease epidemiology). While specialization is necessary and beneficial, it comes at the cost of decreased awareness of scientific developments in other subdisciplines of epidemiology. In this commentary, we argue for the importance of promoting an exchange of ideas across seemingly disparate epidemiologic subdisciplines. Such an exchange can lead to invaluable opportunities to learn from and merge knowledge across subdisciplines. It can promote "innovation at the edges," a process of borrowing and transforming methods from one subdiscipline in order to develop something new and advance another subdiscipline. Further, we outline specific actionable steps at the researcher, institution, and professional society level that can promote such innovation.

Drug-drug interaction between dexamethasone and direct-acting oral anticoagulants: a nested case-control study in the National COVID Cohort Collaborative (N3C).

OBJECTIVE: The goal of this work is to evaluate if there is an increase in the risk of thromboembolic events (TEEs) due to concomitant exposure to dexamethasone and apixaban or rivaroxaban. Direct oral anticoagulants (DOACs), as well as corticosteroid dexamethasone, are commonly used to treat individuals hospitalised with COVID-19. Dexamethasone induces cytochrome P450-3A4 enzyme that also metabolises DOACs apixaban and rivaroxaban. This raises a concern about possible interaction between dexamethasone and DOACs that may reduce the efficacy of the DOACs and result in an increased risk of TEE. DESIGN: We used nested case-control study design. SETTING: This study was conducted in the National COVID Cohort Collaborative (N3C), the largest electronic health records repository for COVID-19 in the USA. PARTICIPANTS: Study participants were adults over 18 years who were exposed to a DOAC for 10 or more consecutive days. Exposure to dexamethasone was at least 5 or more consecutive days. PRIMARY AND SECONDARY OUTCOME MEASURES: Our primary exposure variable was concomitant exposure to dexamethasone for 5 or more days after exposure to either rivaroxaban or apixaban for 5 or more consecutive days. We used McNemar's Χ2 test and adjusted logistic regression to evaluate association between concomitant use of dexamethasone with either apixaban or rivaroxaban. RESULTS: McNemar's Χ2 test did not find a discernible association of TEE in patients concomitantly exposed to dexamethasone and a DOAC (χ2=0.5, df=1, p=0.48). In addition, a conditional logistic regression model did not find an increase in the risk of TEE (adjusted OR 1.15, 95% CI 0.32 to 4.18). CONCLUSION: This nested case-control study did not find evidence of an association between concomitant exposure to dexamethasone and a DOAC with an increase in risk of TEE. Due to small sample size, an association cannot be completely ruled out.