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To develop age- and BMI-adjusted alignment targets to improve patient-specific management and operative treatment outcomes.Retrospective review of a single-center stereographic database. ASD patients receiving operative or non-operative treatment, ≥ 18y/o with complete baseline (BL) ODI scores and radiographic parameters (PT, SVA, PILL, TPA) were included. Patients were stratified by age consistent with US-Normative values (norms) of SF-36( 35, 35-55, 45-54, 55-64, 65-74, ≥ 75y/o), and dichotomized by BMI (Non-Obese 30; Obese ≥ 30). Linear regression analysis established normative age- and BMI-specific radiographic thresholds, utilizing previously published age-specific US-Normative ODI values converted from SF-36 PCS (Lafage et al.), in conjunction with BL age and BMI means.486 patients were included (Age: 52.5, Gender: 68.7%F, mean BMI: 26.2, mean ODI: 32.7), 135 of which were obese. Linear regression analysis developed age- and BMI-specific alignment thresholds, indicating PT, SVA, PILL, and TPA to increase with both increased age and increased BMI (all R 0.5, p 0.001). For non-obese patients, PT, SVA, PILL, and TPA ranged from 10.0, - 25.8, - 9.0, 3.1 in patients 35y/o to 27.8, 53.4, 17.7, 25.8 in patients ≥ 75 y/o. Obese patients' PT, SVA, PILL, and TPA ranged from 10.5, - 7.6, - 7.1, 5.8 in patients 35 y/o to 28.3, 67.0, 19.15, 27.7 in patients ≥ 75y/o. Normative SVA values in obese patients were consistently ≥ 10 mm greater compared to non-obese values, at all ages.Significant associations exist between age, BMI, and sagittal alignment. While BMI influenced age-adjusted alignment norms for PT, SVA, PILL, and TPA at all ages, obesity most greatly influenced SVA, with normative values similar to non-obese patients who were 10 years older. Age-adjusted alignment thresholds should take BMI into account, calling for less rigorous alignment objectives in older and obese patients.

OBJECTIVE: To assess whether surgical cervical deformity (CD) patients meet spinopelvic age-adjusted alignment targets, reciprocal, and lower limb compensation changes. STUDY DESIGN: Retrospective review. METHODS: CD was defined as C2-C7 lordosis >10°, cervical sagittal vertical angle (cSVA) >4 cm, or T1 slope minus cervical lordosis (TS-CL) >20°. Inclusion criteria were age >18 years and undergoing surgical correction with complete baseline and postoperative imaging. Published formulas were used to create age-adjusted alignment target for pelvic tilt (PT), pelvic incidence and lumbar lordosis (PI-LL), sagittal vertical angle (SVA), and lumbar lordosis and thoracic kyphosis (LL-TK). Actual alignment was compared with age-adjusted ideal values. Patients who matched ±10-year thresholds for age-adjusted targets were compared with unmatched cases (under- or overcorrected). RESULTS: A total of 120 CD patients were included (mean age, 55.1 years; 48.4% women; body mass index, 28.8 kg/m(2)). For PT, only 24.4% of patients matched age-adjusted alignment, 51.1% overcorrected for PT, and 24.4% undercorrected. For PI-LL, only 27.6% of CD patients matched age-adjusted targets, with 49.4% overcorrected and 23% undercorrected postoperatively. Forty percent of patients matched age-adjusted target for SVA, 41.3% overcorrected, and 18.8% undercorrected. CD patients who had worsened in TS-CL or cSVA postoperatively displayed increased TK (−41.1° to −45.3°, P = 1.06). With lower extremity compensation, CD patients decreased in ankle flexion angle postoperatively (6.1°–5.5°, P = 0.036) and trended toward smaller sacrofemoral angle (199.6–195.6 mm, P = 0.286) and knee flexion (2.6° to −1.1°, P = 0.269). CONCLUSIONS: In response to worsening CD postoperatively, patients increased in TK and recruited less lower limb compensation. Almost 75% of CD patients did not meet previously established spinopelvic alignment goals, of whom a subset of patients were actually made worse off in these parameters following surgery. This finding raises the question of whether we should be looking at the entire spine when treating CD. LEVEL OF EVIDENCE: 3.

Background Infections are a feared complication following primary total elbow arthroplasty (TEA). Studies comparing baseline demographic profiles and identifying risk factors associated with developing surgical site infections (SSIs) or peri-prosthetic joint infections (PJIs), following primary TEA are limited. This study was therefore aimed to: (1) compare patient demographics; and (2) identify patient-related risk factors for the development of infections following a primary TEA. Methods Patients who underwent primary TEA from January 1, 2005 to March 31, 2014 were identified in an administrative claims database. The study group consisted of all patients who developed either SSIs within 90-days or PJIs within 2-years following the index procedure, respectively. A total of 23,134 primary TEAs were identified between 2005 and 2014, of which 757 (3.3%) were coded as being infected. Primary outcomes that were assessed included comparing baseline patient demographics and identifying patient-related risk factors for developing PJIs. Pearson's chi-square analyses were used to compare study group demographics to their counterparts. Welch's t-test was used to compare mean Elixhauser-Comorbidity Index scores between the cohorts. Multivariate binomial logistics regression was used to calculate odds-ratios (OR) for patient-related risk factors. A P value less than .05 was considered statistically significant. Results Patients who developed infections were significantly different compared to their counterparts with respect to the variables analyzed. Patients developing infections were found to have a higher prevalence of comorbidities as measured by mean Elixhauser-Comorbidity Index scores in patients who developed SSIs (7 vs. 5, P Conclusion This study demonstrated statistically significant differences between patients who developed and did not develop infections following primary TEA and identified a myriad of risk factors associated with these adverse events. The results from this study can help identify high risk patients by orthopedic surgeon in order to potentially mitigate the incidence of either SSIs or PJIs in patients undergoing TEA. Level of evidence Level III

Background A recently proposed risk factor for periprosthetic joint infections (PJI) in men is benign prostatic hyperplasia (BPH). The objective was to explore the association of BPH on 1) 90-day complications, 2) length of stay (LOS), 3) readmission rates, and 4) healthcare expenditures following total shoulder arthroplasty (TSA). Methods A retrospective query was performed using a nationwide claims database from January 2005 to March 2014 for male patients undergoing primary TSA. The study cohort included 5067 patients with BPH while 50,720 patients served as the comparison cohort. Logistic regression determined the association of BPH on complications and readmissions. A p value less than 0.001 was significant. Results Patients with BPH had higher incidence and odds (36.8 vs. 6.2%; OR: 2.73, p Conclusions BPH is associated with increased complications and healthcare expenditures following total shoulder arthroplasty. The investigation can be used to educate BPH patients of the possible adverse events which may occur within ninety-days following primary TSA for the treatment of glenohumeral osteoarthritis.

Despite experiencing a significant trauma, only a subset of World Trade Center (WTC) rescue and recovery workers developed posttraumatic stress disorder (PTSD). Identification of biomarkers is critical to the development of targeted interventions for treating disaster responders and potentially preventing the development of PTSD in this population. Analysis of gene expression from these individuals can help in identifying biomarkers of PTSD. We established a well-phenotyped sample of 371 WTC responders, recruited from a longitudinal WTC responder cohort using stratified random sampling, by obtaining blood, self-reported and clinical interview data. Using bulk RNA-sequencing from whole blood, we examined the association between gene expression and WTC-related PTSD symptom severity on (i) highest lifetime Clinician-Administered PTSD Scale (CAPS) score, (ii) past-month CAPS score, and (iii) PTSD symptom dimensions using a 5-factor model of re-experiencing, avoidance, emotional numbing, dysphoric arousal and anxious arousal symptoms. We corrected for sex, age, genotype-derived principal components and surrogate variables. Finally, we performed a meta-analysis with existing PTSD studies (total N = 1016), using case/control status as the predictor and correcting for these variables. We identified 66 genes significantly associated with total highest lifetime CAPS score (FDR-corrected p 0.05), and 31 genes associated with total past-month CAPS score. Our more granular analyses of PTSD symptom dimensions identified additional genes that did not reach statistical significance in our analyses with total CAPS scores. In particular, we identified 82 genes significantly associated with lifetime anxious arousal symptoms. Several genes significantly associated with multiple PTSD symptom dimensions and total lifetime CAPS score (SERPINA1, RPS6KA1, and STAT3) have been previously associated with PTSD. Geneset enrichment of these findings has identified pathways significant in metabolism, immune signaling, other psychiatric disorders, neurological signaling, and cellular structure. Our meta-analysis revealed 10 genes that reached genome-wide significance, all of which were downregulated in cases compared to controls (CIRBP, TMSB10, FCGRT, CLIC1, RPS6KB2, HNRNPUL1, ALDOA, NACA, ZNF429 and COPE). Additionally, cellular deconvolution highlighted an enrichment in CD4 T cells and eosinophils in responders with PTSD compared to controls. The distinction in significant genes between total lifetime CAPS score and the anxious arousal symptom dimension of PTSD highlights a potential biological difference in the mechanism underlying the heterogeneity of the PTSD phenotype. Future studies should be clear about methods used to analyze PTSD status, as phenotypes based on PTSD symptom dimensions may yield different gene sets than combined CAPS score analysis. Potential biomarkers implicated from our meta-analysis may help improve therapeutic target development for PTSD.

BACKGROUND: The Elixhauser Comorbidity Index (ECI) is a stratification tool to predict adverse surgical outcomes. No studies have explored the relationship between ECI and outcomes following primary 1- to 2-level lumbar fusion (1-2LF). The purpose was to determine whether an ECI score greater than 1 correlated with (1) longer in-hospital length of stay (LOS) and (2) greater odds of developing 90-day medical complications. METHODS: A retrospective review from 2004 to 2015 was performed using the Medicare Standard Analytical Files for patients undergoing primary LF. Patients with ECI scores from 2 to 5 served as the study cohorts (1 for each ECI score), and patients with an ECI score of 1 served as the control cohort. In-hospital LOS and 90-day medical complications were compared between cohorts. A P value of

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.

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.

Promising initial data indicate that the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine may be beneficial in post-traumatic stress disorder (PTSD). Here, we explore the neural correlates of ketamine-related changes in PTSD symptoms, using a rich battery of functional imaging data (two emotion-processing tasks and one task-free scan), collected from a subset of participants of a randomized clinical trial of repeated-dose intravenous ketamine vs midazolam (total N=21). In a pre-registered analysis, we tested whether changes in an a priori set of imaging measures from a target neural circuit were predictive of improvement in PTSD symptoms, using leave-one-out cross-validated elastic-net regression models (regions of interest in the target circuit consisted of the dorsal and rostral anterior cingulate cortex, ventromedial prefrontal cortex, anterior hippocampus, anterior insula, and amygdala). Improvements in PTSD severity were associated with increased functional connectivity between the ventromedial prefrontal cortex (vmPFC) and amygdala during emotional face-viewing (change score retained in model with minimum predictive error in left-out subjects, standardized regression coefficient [β]=2.90). This effect was stronger in participants who received ketamine compared to midazolam (interaction β=0.86), and persisted following inclusion of concomitant change in depressive symptoms in the analysis model (β=0.69). Improvement following ketamine was also predicted by decreased dorsal anterior cingulate activity during emotional conflict regulation, and increased task-free connectivity between the vmPFC and anterior insula (βs=-2.82, 0.60). Exploratory follow-up analysis via dynamic causal modelling revealed that whilst improvement in PTSD symptoms following either drug was associated with decreased excitatory modulation of amygdala→vmPFC connectivity during emotional face-viewing, increased top-down inhibition of the amygdala by the vmPFC was only observed in participants who improved under ketamine. Individuals with low prefrontal inhibition of amygdala responses to faces at baseline also showed greater improvements following ketamine treatment. These preliminary findings suggest that, specifically under ketamine, improvements in PTSD symptoms are accompanied by normalization of hypofrontal control over amygdala responses to social signals of threat.

Background As the incidence and prevalence of Crohn’s disease continues to change worldwide, rates within North America have been increasing. The objective of this study was to evaluate whether patients who have Crohn’s disease undergoing primary total hip arthroplasties have worse outcomes compared with matched cohorts. Specifically, we evaluated 1) medical complications, 2) in-hospital lengths of stay (LOS), and 3) costs of care. Methods Two cohorts of patients who underwent primary total hip arthroplasties from January 1, 2005 to March 31, 2014 were identified from the Medicare claims of the PearlDiver platform. Cohorts were matched by age, sex, and following comorbidities—anemia, diabetes, hyperlipidemia, hypertension, malnutrition, pulmonary disease, and renal failure, yielding 55,361 patients within the study (n = 9229) and matching cohorts (n = 46,132). Outcomes assessed included 90-day medical complications, in-hospital LOS, and costs of care. A P-value less than .005 was considered statistically significant. Results Patients with Crohn’s disease were found to have significantly higher incidences and odds ratios of 90-day medical complications (30.2 vs 13.8; odds ratios: 2.2, P Conclusion Crohn’s disease is associated with higher rates of medical complications, longer in-hospital LOS, and increased costs of care. This study may aid physicians to perform appropriate risk adjustment for adverse outcomes and to educate these patients about potential postoperative complications in these patients.

Ineffective computerized alerts for potential Drug-Drug Interactions (DDI) is a longstanding informatics issue. Prescribing clinicians often ignore or override such alerts due to lack of context and clinical relevance, among various other reasons. In this study, we reveiwed published data on the rate of DDI alert overrides and medications involved in the overrides. We identified 34 eligible studies from sites across Asia, Europe, the United States, and the United Kingdom. The override rate of DDI alerts ranged from 55% to 98%, with more than half of the studies reporting the most common drug pairs or medications involved in acceptance or overriding of alerts. The high prevalance of alert overrides highlights the need for decision support systems that take user, drug, and institutional factors into consideration, as well as actionable metrics to better characterize harm associated with overrides.

Ineffective computerized alerts for potential Drug-Drug Interactions (DDI) is a longstanding informatics issue. Prescribing clinicians often ignore or override such alerts due to lack of context and clinical relevance, among various other reasons. In this study, we reveiwed published data on the rate of DDI alert overrides and medications involved in the overrides. We identified 34 eligible studies from sites across Asia, Europe, the United States, and the United Kingdom. The override rate of DDI alerts ranged from 55% to 98%, with more than half of the studies reporting the most common drug pairs or medications involved in acceptance or overriding of alerts. The high prevalance of alert overrides highlights the need for decision support systems that take user, drug, and institutional factors into consideration, as well as actionable metrics to better characterize harm associated with overrides.

Purpose To provide evidence of serum potassium changes in individuals taking angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs) concomitantly with spironolactone compared to ACEI/ARB therapy alone. Methods PubMed, Embase, Scopus, and Web of Science were searched for studies including exposure to both spironolactone and ACEI/ARB therapy compared to ACEI/ARB therapy alone. The primary outcome was serum potassium change over time. Main effects were calculated to estimate average treatment effect using random effects models. Heterogeneity was assessed using Cochran’s Q and I2. Risk of bias was assessed using the revised Cochrane risk of bias tool. Results From the total of 1,225 articles identified, 20 randomized controlled studies were included in the meta-analysis. The spironolactone plus ACEI/ARB group included 570 patients, while the ACEI/ARB group included 547 patients. Treatment with spironolactone and ACEI/ARB combination therapy compared to ACEI/ARB therapy alone increased the mean serum potassium concentration by 0.19 mEq/L (95% CI, 0.12-0.26 mEq/L), with intermediate heterogeneity across studies (Q statistic = 46.5, P = 0.004; I2 = 59). Sensitivity analyses showed that the direction and magnitude of this outcome did not change with the exclusion of individual studies, indicating a high level of reliability. Reporting risk of bias was low for 16 studies (80%), unclear for 3 studies (15%) and high for 1 study (5%). Conclusion Treatment with spironolactone in combination with ACEI/ARB therapy increases the mean serum potassium concentration by less than 0.20 mEq/L compared to ACEI/ARB therapy alone. However, serum potassium and renal function must be monitored in patients starting combination therapy to avoid changes in serum potassium that could lead to hyperkalemia.

Antidepressants are very widely used and associated with traumatic injury, yet little is known about their potential for harmful drug interactions. We aimed to identify potential drug interaction signals by assessing concomitant medications (precipitant drugs) taken with individual antidepressants (object drugs) that were associated with unintentional traumatic injury. We conducted pharmacoepidemiologic screening of 2000–2015 Optum Clinformatics data, identifying drug interaction signals by performing self-controlled case series studies for antidepressant + precipitant pairs and injury. We included persons aged 16–90 years co-dispensed an antidepressant and ≥1 precipitant drug(s), with an injury during antidepressant therapy. We classified antidepressant person-days as either precipitant-exposed or precipitant-unexposed. The outcome was an emergency department or inpatient discharge diagnosis for unintentional traumatic injury. We used conditional Poisson regression to calculate confounder adjusted rate ratios (RRs) and accounted for multiple estimation via semi-Bayes shrinkage. We identified 330,884 new users of antidepressants who experienced an injury. Among such persons, we studied concomitant use of 7,953 antidepressant + precipitant pairs. Two hundred fifty-six (3.2%) pairs were positively associated with injury and deemed potential drug interaction signals; twenty-two of these signals had adjusted RRs > 2.00. Adjusted RRs ranged from 1.06 (95% confidence interval: 1.00–1.12, p=0.04) for citalopram + gabapentin to 3.06 (1.42–6.60) for nefazodone + levonorgestrel. Sixty-five (25.4%) signals are currently reported in a seminal drug interaction knowledgebase. We identified numerous new population-based signals of antidepressant drug interactions associated with unintentional traumatic injury. Future studies, intended to test hypotheses, should confirm or refute these potential interactions.

Overactive bladder (OAB) is a common disorder in the general population, and the prevalence increases with age. Adults with OAB typically have a greater number of comorbid conditions, such as hypertension, depression, and dementia, compared with adults without OAB. Subsequent to an increased number of comorbidities, adults with OAB take a greater number of concomitant medications, which may increase the risk of potentially harmful drug‒drug interactions. There are two important considerations for many of the medications approved for the treatment of OAB in the USA: anticholinergic burden and potential for drug‒drug interactions, notably related to cytochrome P450 (CYP) 2D6, which is responsible for the metabolism of approximately 25% of all drugs. A substantial number of drugs used for the treatment of OAB and comorbid conditions (e.g., cardiovascular and neurologic disorders) are CYP2D6 substrates or inhibitors. Furthermore, a substantial number of drugs with CYP2D6 properties also have strong anticholinergic properties. Here, we review polypharmacy associated with OAB and its common comorbidities, identify drugs with reported anticholinergic properties, and provide an overview of clinically relevant drug‒drug interactions in the treatment of OAB as they relate to CYP2D6 metabolism. This review aims to provide clinicians with essential information necessary for making treatment decisions when managing OAB.

Introduction Medication organizations across the USA have adopted electronic health records, and one of the most anticipated benefits of these was improved medication safety, but alert fatigue has been a major issue. Objective We compared the appropriateness of medication-related clinical decision support alerts triggered by two commercial applications: EPIC and Seegnal’s platform. Methods This was a retrospective comparison of two commercial applications. We provided Seegnal with deidentified inpatient, outpatient, and inpatient genetic electronic medical record (EMR)-extracted datasets for 657, 2731, and 413 patients, respectively. Seegnal then provided the alerts that would have triggered, which we compared with those triggered by EPIC in clinical care. A random sample of the alerts triggered were reviewed for appropriateness, and the positive predictive value (PPV) and negative predictive value (NPV) were calculated. We also reviewed all the inpatient and outpatient charts for patients within our cohort who were receiving ten or more concomitant medications with alerts we found to be appropriate to assess whether any adverse events had occurred and whether Seegnal’s platform could have prevented them. Results Results from EPIC and the Seegnal platform were compared based on alert load, PPV, NPV, and potential adverse events. Overall, compared with EPIC, the Seegnal platform triggered fewer alerts in the inpatient (1697 vs. 27,540), outpatient (2341 vs. 35,134), and inpatient genetic (1493 vs. 20,975) cohorts. The Seegnal platform had higher specificity in the inpatient (99 vs. 0.3%; p < 0.0001), outpatient (99 vs. 0.3%; p < 0.0001), and inpatient genetic (97.9 vs. 1.2%; p < 0.0001) groups and higher sensitivity in the inpatient (100 vs. 68.8%; p < 0.0001) and outpatient (88.6 vs.78.3%; p < 0.0001) groups but not in the inpatient genetic cohort (81 vs. 78.5%; p = 0.11). We identified 16 adverse events that occurred in the inpatient setting, 11 (69%) of which potentially could have been prevented with the Seegnal platform. Conclusions Overall, the Seegnal platform triggered 94% fewer alerts than EPIC in the inpatient setting and 93% fewer in the outpatient setting, with much higher sensitivity and specificity. This application could substantially reduce alert fatigue and improve medication safety at the same time. Supplementary Information The online version of this article (10.1007/s40264-021-01048-0) contains supplementary material, which is available to authorized users.

Growing evidence suggests that drug interactions may be responsible for much of the known association between opioid use and unintentional traumatic injury. While prior research has focused on pairwise drug interactions, the role of higher-order (i.e., drug-drug-drug) interactions (3DIs) has not been examined. We aimed to identify signals of opioid 3DIs with commonly co-dispensed medications leading to unintentional traumatic injury, using semi-automated high-throughput screening of US commercial health insurance data. We conducted bi-directional, self-controlled case series studies using 2000–2015 Optum Data Mart database. Rates of unintentional traumatic injury were examined in individuals dispensed opioid-precipitant base pairs during time exposed vs unexposed to a candidate interacting precipitant. Underlying cohorts consisted of 16–90-year-olds with new use of opioid-precipitant base pairs and ≥1 injury during observation periods. We used conditional Poisson regression to estimate rate ratios adjusted for time-varying confounders, and semi-Bayes shrinkage to address multiple estimation. For hydrocodone, tramadol, and oxycodone (the most commonly used opioids), we examined 16,024, 8185, and 9330 drug triplets, respectively. Among these, 75 (0.5%; hydrocodone), 57 (0.7%; tramadol), and 42 (0.5%; oxycodone) were significantly positively associated with unintentional traumatic injury (50 unique base precipitants, 34 unique candidate precipitants) and therefore deemed potential 3DI signals. The signals found in this study provide valuable foundations for future research into opioid 3DIs, generating hypotheses to motivate crucially needed etiologic investigations. Further, this study applies a novel approach for 3DI signal detection using pharmacoepidemiologic screening of health insurance data, which could have broad applicability across drug classes and databases.

Hydroxychloroquine can induce QT/QTc interval prolongation for some patients; however, little is known about its interactions with other QT-prolonging drugs.The purpose of this retrospective electronic health records study was to evaluate changes in the QTc interval in patients taking hydroxychloroquine with or without concomitant QT-prolonging medications.De-identified health records were obtained from the Cerner Health FactsA statistically significant increase in QTc interval from the last measurement prior to concomitant exposure of 18.0 ms (95% CI 3.5-32.5; p 0.05) was found in the hydroxychloroquine monotherapy cohort. QTc changes varied considerably across cohorts, with standard deviations ranging from 40.9 (hydroxychloroquine monotherapy) to 57.8 (hydroxychloroquine + sulfasalazine). There was no difference in QTc measurements among cohorts. The hydroxychloroquine + QTc-prolonging agent cohort had the highest average Tisdale Risk Score compared with those without concomitant exposure (p 0.05).Our analysis of retrospective electronic health records found hydroxychloroquine to be associated with a moderate increase in the QTc interval compared with sulfasalazine or methotrexate. However, the QTc was not significantly increased with concomitant exposure to other drugs known to increase QTc interval.

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.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.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.We identified 29 SMR 3DI signals associated with increased rates of injury. Future aetiologic studies should confirm or refute these SMR 3DI signals.

Benzodiazepine receptor agonists and related medications, such as Z-drugs and dual orexin receptor antagonists (BZDs), have been associated with unintentional traumatic injury due to their central nervous system (CNS)-depressant effects. Drug-drug interactions (DDIs) may contribute to the known relationship between BZD use and unintentional traumatic injury, yet evidence is still lacking. We conducted high-throughput pharmacoepidemiologic screening using the self-controlled case series design in a large US commercial health insurance database to identify potentially clinically relevant DDI signals among new users of BZDs. We used conditional Poisson regression to estimate rate ratios (RRs) between each co-exposure (vs. not) and unintentional traumatic injury (primary outcome), typical hip fracture (secondary outcome), and motor vehicle crash (secondary outcome). We identified 48 potential DDI signals (1.1%, involving 39 unique co-dispensed drugs), i.e., with statistically significant elevated adjusted RRs for injury. Signals were strongest for DDI pairs involving zolpidem, lorazepam, temazepam, alprazolam, eszopiclone, triazolam, and clonazepam. We also identified four potential DDI signals for typical hip fracture, but none for motor vehicle crash. Many signals have biologically plausible explanations through additive or synergistic pharmacodynamic effects of co-dispensed antidepressants, opioids, or muscle relaxants on CNS depression, impaired psychomotor and cognitive function, and/or somnolence. While other signals that lack an obvious mechanism may represent true associations that place patients at risk of injury, it is also prudent to consider the roles of chance, reverse causation, and/or confounding by indication, which merit further exploration. Given the high-throughput nature of our investigation, findings should be interpreted as hypothesis generating.

BACKGROUND: More sophisticated surgical techniques for correcting adult spinal deformity (ASD) have increased operative times, adding to physiologic stress on patients and increased complication incidence. This study aims to determine factors associated with operative time using a statistical learning algorithm. METHODS: Retrospective review of a prospective multicenter database containing 837 patients undergoing long spinal fusions for ASD. Conditional inference decision trees identified factors associated with skin-to-skin operative time and cutoff points at which factors have a global effect. A conditional variable-importance table was constructed based on a nonreplacement sampling set of 2000 conditional inference trees. Means comparison for the top 15 variables at their respective significant cutoffs indicated effect sizes. RESULTS: Included: 544 surgical ASD patients (mean age: 58.0 years; fusion length 11.3 levels; operative time: 378 minutes). The strongest predictor for operative time was institution/surgeon. Center/surgeons, grouped by decision tree hierarchy, a and b were, on average, 2 hours faster than center/surgeons c-f, who were 43 minutes faster than centers g-j, all P < 0.001. The next most important predictors were, in order, approach (combined vs posterior increases time by 139 minutes, P < 0.001), levels fused (