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.

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.

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.

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.

Risk for Recurrent Venous Thromboembolism and Bleeding With Apixaban Compared With Rivaroxaban: An Analysis of Real-World Data.

BACKGROUND: Apixaban and rivaroxaban are replacing vitamin K antagonists for the treatment of venous thromboembolism (VTE) in adults; however, head-to-head comparisons remain limited. OBJECTIVE: To assess the effectiveness and safety of apixaban compared with rivaroxaban in patients with VTE. DESIGN: Retrospective new-user cohort study. SETTING: U.S.-based commercial health care insurance database from 1 January 2015 to 30 June 2020. PARTICIPANTS: Adults with VTE who were newly prescribed apixaban or rivaroxaban. MEASUREMENTS: The primary effectiveness outcome was recurrent VTE, a composite of deep venous thrombosis and pulmonary embolism. The primary safety outcome was a composite of gastrointestinal and intracranial bleeding. RESULTS: Of 49 900 eligible patients with VTE, 18 618 were new users of apixaban and 18 618 were new users of rivaroxaban. Median follow-up was 102 days (25th, 75th percentiles: 30, 128 days) among apixaban and 105 days (25th, 75th percentiles: 30, 140 days) among rivaroxaban users. After propensity score matching, apixaban (vs. rivaroxaban) was associated with a lower rate for recurrent VTE (hazard ratio, 0.77 [95% CI, 0.69 to 0.87]) and bleeding (hazard ratio, 0.60 [CI, 0.53 to 0.69]). The absolute reduction in the probability of recurrent VTE with apixaban versus rivaroxaban was 0.006 (CI, 0.005 to 0.011) within 2 months and 0.011 (CI, 0.011 to 0.013) within 6 months of initiation. The absolute reduction in the probability of gastrointestinal and intracranial bleeding with apixaban versus rivaroxaban was 0.011 (CI, 0.010 to 0.011) within 2 months and 0.015 (CI, 0.013 to 0.015) within 6 months of initiation. LIMITATION: Short follow-up. CONCLUSION: In this population-based cohort study, patients with VTE who were new users of apixaban had lower rates for recurrent VTE and bleeding than new users of rivaroxaban. PRIMARY FUNDING SOURCE: None.

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.

Skeletal muscle relaxant drug-drug-drug interactions and unintentional traumatic injury: Screening to detect three-way drug interaction signals.

AIM: The aim of this study was to identify skeletal muscle relaxant (SMR) drug-drug-drug interaction (3DI) signals associated with increased rates of unintentional traumatic injury. METHODS: We conducted automated high-throughput pharmacoepidemiologic screening of 2000-2019 healthcare data for members of United States commercial and Medicare Advantage health plans. We performed a self-controlled case series study for each drug triad consisting of an SMR base-pair (i.e., concomitant use of an SMR with another medication), and a co-dispensed medication (i.e., candidate interacting precipitant) taken during ongoing use of the base-pair. We included patients aged ≥16 years with an injury occurring during base-pair-exposed observation time. We used conditional Poisson regression to calculate adjusted rate ratios (RRs) with 95% confidence intervals (CIs) for injury with each SMR base-pair + candidate interacting precipitant (i.e., triad) versus the SMR-containing base-pair alone. RESULTS: Among 58 478 triads, 29 were significantly positively associated with injury; confounder-adjusted RRs ranged from 1.39 (95% CI = 1.01-1.91) for tizanidine + omeprazole with gabapentin to 2.23 (95% CI = 1.02-4.87) for tizanidine + diclofenac with alprazolam. Most identified 3DI signals are new and have not been formally investigated. CONCLUSION: We identified 29 SMR 3DI signals associated with increased rates of injury. Future aetiologic studies should confirm or refute these SMR 3DI signals.

Self-controlled assessment of thromboembolic event (TEE) risk following intravenous immune globulin (IGIV) in the U.S. (2006-2012).

Since 2013, the U.S. Food and Drug administration (FDA) has required that intravenous immune globulin (IGIV) products carry a boxed warning concerning the risk of thromboembolic events (TEEs). This study assessed the incidence of TEEs attributable to IGIV in a large population-based cohort. A self-controlled risk interval design was used to quantify the transient increase in TEE risk during the risk interval (days 0-2 and 0-13 following IGIV for arterial and venous TEEs, respectively) relative to a later control interval (days 14-27 following IGIV). Potential IGIV-exposed TEE cases from 2006 to 2012 were identified from the FDA-sponsored Sentinel Distributed Database and confirmed through medical record review. Inpatient IGIV exposures were not included in the venous TEE analysis due to concerns about time-varying confounding. 19,069 new users of IGIV who received 93,555 treatment episodes were included. Charts were retrieved for 62% and 70% of potential venous and arterial cases, respectively. There was a transient increase in the risk of arterial TEEs during days 0-2 following IGIV treatment (RR = 4.69; 95% CI 1.87, 11.90; absolute increase in risk = 8.86 events per 10,000 patients, 95% CI 3.25, 14.6), but no significant increase in venous TEE risk during days 0-13 following outpatient IGIV treatments (RR = 1.07, 95% CI 0.34, 3.48). Our results suggest there is a small increase in the absolute risk of arterial TEEs following IGIV. However, lower-than-expected chart retrieval rates and the possibility of time-varying confounding mean that our results should be interpreted cautiously. Continued pharmacovigilance efforts are warranted.

Effectiveness and Safety of Direct Oral Anticoagulants Versus Warfarin in Patients With Valvular Atrial Fibrillation : A Population-Based Cohort Study.

BACKGROUND: Direct oral anticoagulants (DOACs) are increasingly used in place of warfarin, but evidence about their effectiveness and safety in patients with valvular atrial fibrillation (AF) remains limited. OBJECTIVE: To assess the effectiveness and safety of DOACs compared with warfarin in patients with valvular AF. DESIGN: New-user retrospective propensity score-matched cohort study. SETTING: U.S.-based commercial health care database from 1 January 2010 to 30 June 2019. PARTICIPANTS: Adults with valvular AF who were newly prescribed DOACs or warfarin. MEASUREMENTS: The primary effectiveness outcome was a composite of ischemic stroke or systemic embolism. The primary safety outcome was a composite of intracranial or gastrointestinal bleeding. RESULTS: Among a total of 56 336 patients with valvular AF matched on propensity score, use of DOACs (vs. warfarin) was associated with lower risk for ischemic stroke or systemic embolism (hazard ratio [HR], 0.64 [95% CI, 0.59 to 0.70]) and major bleeding events (HR, 0.67 [CI, 0.63 to 0.72]). The results for the effectiveness and safety outcomes remained consistent for apixaban (HRs, 0.54 [CI, 0.47 to 0.61] and 0.52 [CI, 0.47 to 0.57], respectively) and rivaroxaban (HRs, 0.74 [CI, 0.64 to 0.86] and 0.87 [CI, 0.79 to 0.96], respectively); with dabigatran, results were consistent for the major bleeding outcome (HR, 0.81 [CI, 0.68 to 0.97]) but not for effectiveness (HR, 1.03 [CI, 0.81 to 1.31]). LIMITATION: Relatively short follow-up; inability to ascertain disease severity. CONCLUSION: In this comparative effectiveness study using practice-based claims data, patients with valvular AF who were new users of DOACs had lower risks for ischemic stroke or systemic embolism and major bleeding than new users of warfarin. These data may be used to guide risk-benefit discussions regarding anticoagulant choices for patients with valvular AF. PRIMARY FUNDING SOURCE: None.

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.

Preoperative Sedative-hypnotic Medication Use and Adverse Postoperative Outcomes.

OBJECTIVE: To determine the association between preoperative benzodiazepine and nonbenzodiazepine receptor agonist ("Z-drugs") use and adverse outcomes after surgery. BACKGROUND: Prescriptions for benzodiazepines and Z-drugs have increased over the past decade. Despite this, the association of preoperative benzodiazepines and Z-drug receipt with adverse outcomes after surgery is unknown. METHODS: Using the Optum Clinformatics Datamart, we performed a retrospective cohort study of adults 18 years or older who underwent any of 10 common surgical procedures between 2010 and 2015. The principal exposure was one or more filled prescriptions for a benzodiazepine or Z-drug in the 90 days before surgery. The primary outcome was any emergency department visit or hospital admission for either (1) a drug related adverse medical event or overdose or (2) a traumatic injury in the 30 days after surgery. RESULTS: Of 785,346 patients meeting inclusion criteria, 94,887 (12.1%) filled a preoperative prescription for a benzodiazepine or Z-drug. From multivariable logistic regression, benzodiazepine or Z-drug use was associated with an increased odds of an adverse postoperative event [odds ratio 1.13; 95% confidence interval: 1.08-1.18). In a separate regression, coprescription of benzodiazepines or Z-drugs with opioids was associated with a 1.45 odds of an adverse postoperative event (95% confidence interval: 1.37-1.53). CONCLUSIONS: Preoperative benzodiazepines and Z-drug use is common and associated with increased odds of adverse outcomes after surgery, particularly when coprescribed with opioids. Counseling on appropriate benzodiazepine and Z-drug use in advance of elective surgery may potentially increase the safety of surgical care.

Cardiovascular and major bleeding outcomes with antiplatelet and direct oral anticoagulants in patients with acute coronary syndrome and atrial fibrillation: A population-based analysis.

BACKGROUND: Direct oral anticoagulants (DOACs) are replacing warfarin for stroke prevention in patients with atrial fibrillation (AF). OBJECTIVE: To assess the effectiveness and safety of concomitant treatment with antiplatelet-DOAC compared to antiplatelet-warfarin in patients with acute coronary syndrome (ACS) and AF. DESIGN: Retrospective propensity score-matched cohort study using United States-based commercial healthcare database from January 2016 to June 2019. PARTICIPANTS: New-users of antiplatelet-DOAC and antiplatelet-warfarin who initiated the combined therapy within 30 days following incident ACS diagnosis. MEASUREMENTS: Primary study outcomes were recurrent cardiovascular diseases (CVD) (ie, a composite of stroke and myocardial infarction) and major bleeding events identified via discharge diagnoses. We controlled for potential confounders via propensity score matching (PSM). We generated marginal hazard ratios (HRs) via Cox proportional hazards regression using a robust variance estimator while adjusting for calendar time. RESULTS: After PSM, a total of 2,472 persons were included (1,236 users of antiplatelet-DOAC and 1,236 users of antiplatelet-warfarin). The use of antiplatelet-DOAC (vs. antiplatelet-warfarin) was associated with a reduced rate of recurrent CVD (adjusted HR 0.72, 95% confidence interval [CI], 0.56-0.92) and major bleeding events (adjusted HR, 0.49, 95% CI 0.33-0.72). LIMITATIONS: Residual confounding. CONCLUSIONS: In real-world data of AF patients with concurrent ACS, the use of antiplatelet-DOAC following ACS diagnosis was associated with a lower rate of recurrent CVD and major bleeding events compared with antiplatelet-warfarin. These findings highlight a potential promising role for DOACs in patients with ACS and AF requiring combined antiplatelet therapy.

Pharmacosafety of fluoroquinolone and macrolide antibiotics in the clinical care of patients with myasthenia gravis.

INTRODUCTION/AIMS: Anecdotal case reports have suggested a potential association of fluoroquinolones and macrolides with myasthenia gravis (MG) exacerbation, prompting warnings against the use of these drugs in this population. However, large-scale and reliable population-based data that demonstrate this association are lacking. This study aims to examine the association between outpatient treatment with fluoroquinolones or macrolides and MG-related hospitalization. METHODS: A retrospective cohort study consisting of adult MG patients was conducted using a large de-identified healthcare claims database. Antibiotic prescription claims were identified, and MG-related hospitalizations were assessed at 15, 30, and 90 days after the date of prescription. We used mixed effects survival regression with log-logistic distribution and independent covariance matrix to estimate odds ratios (ORs) of hospitalization for each potentially exacerbating antibiotic using beta-lactam as the reference and adjusting for covariates. RESULTS: Among 1556 MG patients receiving 894 fluoroquinolone prescriptions, 729 macrolide prescriptions, and 1608 beta-lactam prescriptions during the study period, there was no difference in 15, 30, or 90-day odds of MG-related hospitalization between fluoroquinolone or macrolide users compared to prescribed beta-lactams. However, estimates were higher for fluoroquinolones than macrolides, even after covariate adjustment (adjusted OR [aOR] 4.60, 95% confidence interval [CI] 0.55-38.57 for fluoroquinolones and OR 0.56, 95% CI 0.32-0.97 for macrolides, respectively, at 15 days). DISCUSSION: Fluoroquinolone and macrolide antibiotics are prescribed frequently to patients with MG. While statistical imprecision precludes a definitive conclusion, elevated ORs for fluoroquinolones raise the possibility of an underpowered association that merits further investigation.

Validity of ICD-10-CM diagnoses to identify hospitalizations for serious infections among patients treated with biologic therapies.

PURPOSE: Identifying hospitalizations for serious infections among patients dispensed biologic therapies within healthcare databases is important for post-marketing surveillance of these drugs. We determined the positive predictive value (PPV) of an ICD-10-CM-based diagnostic coding algorithm to identify hospitalization for serious infection among patients dispensed biologic therapy within the FDA's Sentinel Distributed Database. METHODS: We identified health plan members who met the following algorithm criteria: (1) hospital ICD-10-CM discharge diagnosis of serious infection between July 1, 2016 and August 31, 2018; (2) either outpatient/emergency department infection diagnosis or outpatient antimicrobial treatment within 7 days prior to hospitalization; (3) inflammatory bowel disease, psoriasis, or rheumatological diagnosis within 1 year prior to hospitalization, and (4) were dispensed outpatient biologic therapy within 90 days prior to admission. Medical records were reviewed by infectious disease clinicians to adjudicate hospitalizations for serious infection. The PPV (95% confidence interval [CI]) for confirmed events was determined after further weighting by the prevalence of the type of serious infection in the database. RESULTS: Among 223 selected health plan members who met the algorithm, 209 (93.7% [95% CI, 90.1%-96.9%]) were confirmed to have a hospitalization for serious infection. After weighting by the prevalence of the type of serious infection, the PPV of the ICD-10-CM algorithm identifying a hospitalization for serious infection was 80.2% (95% CI, 75.3%-84.7%). CONCLUSIONS: The ICD-10-CM-based algorithm for hospitalization for serious infection among patients dispensed biologic therapies within the Sentinel Distributed Database had 80% PPV for confirmed events and could be considered for use within pharmacoepidemiologic studies.

The Medial Elevation Osteotomy for Late-presenting and Recurrent Infantile Blount Disease.

BACKGROUND: Late-presenting or recurrent infantile Blount disease (IBD) is characterized by knee instability because of medial tibial plateau depression, multiplanar proximal tibial deformity, and potential distal femoral deformity. The surgical treatment strategy includes medial elevation osteotomy to stabilize the knee, together with proximal tibial osteotomy to correct alignment, and lateral epiphysiodesis to prevent a recurrence. This study's primary aim was to describe the clinical outcomes of medial elevation osteotomy for the management of late-presenting and recurrent IBD. METHODS: The authors reviewed the records of 48 children (64 limbs) who had medial elevation osteotomies and lateral epiphysiodesis, combined with proximal tibial realignment in 78% (50/64) of cases in the same setting. IBD was bilateral in 33% (16/48), 77% (37/48) were female individuals, and 42% (20/48) were obese. RESULTS: The mean age at surgery was 8.6 years (SD, 1.6; range, 5.8 to 12.8). The mean preoperative tibiofemoral angle (TFA) was 28±11 degrees (8 to 55 degrees), and the mean angle of depression of the medial plateau (ADMP) was 49±8 degrees (26 to 65 degrees). Distal femoral valgus was present in 27% (17/62) and varus in 10% (6/62) children. At a median follow-up of 3.2 years (range, 1 to 6.2 y), the median TFA was 1-degree valgus (interquartile range, 7-degree varus to 5-degree valgus), whereas the ADMP was corrected to 25±8 degrees (8 to 45 degrees). Obesity was associated with more severe deformity as measured by TFA (P<0.001) but did not affect the extent of medial plateau depression (P=0.113). The good or excellent alignment was achieved in 75% (47/63) limbs. Obesity was associated with an increased risk of recurrence [odds ratio (OR), 5.21; 95% CI, 1.26-21.63; P=0.023]. Age at the surgery or previous surgery was not associated with recurrence (OR, 1.29; 95% CI, 0.88-1.88; P=0.195 and OR, 1.22; 95% CI, 0.36-4.17; P=0.746). Obesity and residual instability were associated with an increased risk of poor alignment at the latest follow-up (OR, 3.24; 95% CI, 1.02-10.31; P=0.047 and OR, 1.21; 95% CI, 1.05-1.40; P=0.008). CONCLUSION: Late-presenting or recurrent IBD is a surgical challenge. Obesity is associated with more severe deformity. Medial elevation osteotomy combined with lateral proximal tibial epiphysiodesis and metaphyseal tibial realignment osteotomy will result in restoration of lower limb alignment in a high proportion of cases. The recurrent deformity may be the result of failed epiphysiodesis. Obesity and residual instability are associated with an increased risk of poor alignment. Although complications are rare, surgical measures to decrease risk should be followed. LEVEL OF EVIDENCE: Level IV.

Knowledge of biosimilars and perceptions of the naming conventions for biosimilar products in clinical practice in the United States.

BACKGROUND: Biosimilar therapies and their naming conventions are both relatively new to the drug development market and in clinical practice. We studied the use of the four-letter naming convention in practice and the knowledge, perceptions, and preferences of US health care providers. METHODS: A survey was distributed among health care professionals with a history of utilizing biosimilars in clinical practice to measure key knowledge and the presence of discernable naming trends. Differences in responses across pre-hypothesized subgroups were tested for statistical significance. RESULTS: Of the 506 surveys emailed, 83 (16%) people responded. Overall, there was poor knowledge about the key concepts surrounding biosimilars. For example, only 52% of respondents correctly identified that biosimilars were not the same as the generic drug; however, frequent use correlated with superior knowledge across all groups. In reference to naming preferences, 67% of all respondents indicated that they commonly use the brand name to distinguish biosimilars in clinical practice and a majority of them (85%) indicated that the brand name was easier to remember than the nonproprietary name with the four-letter suffix. An unexpected number of neutral responses was documented. Notably, more than half of respondents (68%) indicated a neutral response when asked if the four-letter suffix promoted medical errors. CONCLUSIONS: There remains a knowledge gap with regard to biosimilars, and lack of consensus on how the naming convention is and should be utilized in clinical practice. The data also suggest that effective biosimilar education could aid in promoting familiarity with the naming convention among health care providers.

Outcomes among pediatric patients with cancer who are treated on trial versus off trial: A matched cohort study.

BACKGROUND: Approximately 50% of children with cancer in the United States who are aged <15 years receive primary treatment on a therapeutic clinical trial. To the authors' knowledge, it remains unknown whether trial enrollment has a clinical benefit compared with the best alternative standard therapy and/or off trial (ie, clinical trial effect). The authors conducted a retrospective matched cohort study to compare the morbidity and mortality of pediatric patients with cancer who are treated on a phase 3 clinical trial compared with those receiving standard therapy and/or off trial. METHODS: Subjects were aged birth to 19 years; were diagnosed between 2000 and 2010 with acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), rhabdomyosarcoma, or neuroblastoma; and had received initial treatment at the Children's Hospital of Philadelphia. On-trial and off-trial subjects were matched based on age, race, ethnicity, a diagnosis of Down syndrome (for patients with ALL or AML), prognostic risk level, date of diagnosis, and tumor type. RESULTS: A total of 428 participants were matched in 214 pairs (152 pairs for ALL, 24 pairs for AML, 32 pairs for rhabdomyosarcoma, and 6 pairs for neuroblastoma). The 5-year survival rate did not differ between those treated on trial versus those treated with standard therapy and/or off trial (86.9% vs 82.2%; P = .093). On-trial patients had a 32% lower odds of having worse (higher) mortality-morbidity composite scores, although this did not reach statistical significance (odds ratio, 0.68; 95% confidence interval, 0.45-1.03 [P = .070]). CONCLUSIONS: There was no statistically significant difference in outcomes noted between those patients treated on trial and those treated with standard therapy and/or off trial. However, in partial support of the clinical trial effect, the results of the current study indicate a trend toward more favorable outcomes in children treated on trial compared with those treated with standard therapy and/or off trial. These findings can support decision making regarding enrollment in pediatric phase 3 clinical trials.

The risk of sudden cardiac arrest and ventricular arrhythmia with rosiglitazone versus pioglitazone: real-world evidence on thiazolidinedione safety.

BACKGROUND: The low cost of thiazolidinediones makes them a potentially valuable therapeutic option for the > 300 million economically disadvantaged persons worldwide with type 2 diabetes mellitus. Differential selectivity of thiazolidinediones for peroxisome proliferator-activated receptors in the myocardium may lead to disparate arrhythmogenic effects. We examined real-world effects of thiazolidinediones on outpatient-originating sudden cardiac arrest (SCA) and ventricular arrhythmia (VA). METHODS: We conducted population-based high-dimensional propensity score-matched cohort studies in five Medicaid programs (California, Florida, New York, Ohio, Pennsylvania | 1999-2012) and a commercial health insurance plan (Optum Clinformatics | 2000-2016). We defined exposure based on incident rosiglitazone or pioglitazone dispensings; the latter served as an active comparator. We controlled for confounding by matching exposure groups on propensity score, informed by baseline covariates identified via a data adaptive approach. We ascertained SCA/VA outcomes precipitating hospital presentation using a validated, diagnosis-based algorithm. We generated marginal hazard ratios (HRs) via Cox proportional hazards regression that accounted for clustering within matched pairs. We prespecified Medicaid and Optum findings as primary and secondary, respectively; the latter served as a conceptual replication dataset. RESULTS: The adjusted HR for SCA/VA among rosiglitazone (vs. pioglitazone) users was 0.91 (0.75-1.10) in Medicaid and 0.88 (0.61-1.28) in Optum. Among Medicaid but not Optum enrollees, we found treatment effect heterogeneity by sex (adjusted HRs = 0.71 [0.54-0.93] and 1.16 [0.89-1.52] in men and women respectively, interaction term p-value = 0.01). CONCLUSIONS: Rosiglitazone and pioglitazone appear to be associated with similar risks of SCA/VA.

Twelve-year trends in pharmacologic treatment of type 2 diabetes among patients with heart failure in the United States.

We conducted a cross-sectional analysis using a database from commercial health plans in the United States to describe trends in the use of antidiabetic medications among patients with type 2 diabetes and heart failure (HF) from 2006 through 2017. We used loop diuretic dose as a surrogate for HF severity (mild HF 0-40 mg/day, moderate-severe HF >40 mg/day). We assessed antidiabetic medication dispensing in the 90 days following HF diagnosis. Over the 12-year period, we identified an increase in the use of metformin (39.2% vs. 62.6%), dipeptidyl peptidase-4 inhibitors (DPP-4i) (0.5% vs. 17.1%) and sodium-glucose co-transporter-2 inhibitors (SGLT-2i) (0.0% vs. 9.0%), but a decrease in the use of sulphonylureas (47.8% vs. 27.8%) and thiazolidinediones (TZDs) (31.7% vs. 5.3%). In 2017, patients with moderate-severe HF more commonly used insulin (43.1%); a majority of mild HF patients used metformin (62.8%). A proportion of patients with moderate-severe HF used TZDs (4.4%). Among patients with diabetes and HF, the use of metformin and DPP-4i rapidly increased, but a proportion of patients with moderate-severe HF continued to use TZDs. Despite their promising cardiovascular safety profile, SGLT-2i use remains limited.

The effects of aging on the distribution and strength of correlated neural inputs to postural muscles during unperturbed bipedal stance.

The present study investigated the effects of aging on the distribution of common descending neural drives to main postural muscles acting on the ankle, knee, hip, and lower trunk. The presence, distribution, and strength of these drives were assessed using intermuscular coherence estimations at a low-frequency band (0-55 Hz). Ten healthy older adults (68.7 ± 3.5 years) with no recent history of falls and ten healthy younger adults (26.8 ± 2.7 years) performed bipedal stances with eyes either opened or closed. Electromyographic (EMG) signals of six postural muscles were recorded. Estimations of intermuscular coherence were obtained from fifteen muscle pairs and four muscle groups. In general, single-pair and pooled coherence analyzes revealed significant levels of signal synchronization within 1-10 Hz. Significant common drives to anterior, posterior, and antagonist muscle groups were observed for both cohorts of participants. However, older participants showed significantly stronger EMG-EMG synchronization in the frequency domain compared to younger participants. It seems that age-related sarcopenia, visual-vestibular-proprioceptive decline, cortical activation increase, presynaptic inhibition modulation decrease, and co-contraction increase had a major impact on strengthening the common drives to the aforementioned muscle groups. Differently from young adults, the absence of visual inputs did not reduce the magnitude of signal synchronization in older adults. These results suggest that the aging central nervous system seems to organize similar arrangements of common drives to postural antagonist muscles at different joints, and to postural muscles pushing the body either forward or backward when visual information is not available.