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Jay Visaria,1 Neeraj N Iyer,2 Amit D Raval,3 Sheldon X Kong,2 Todd Hobbs,2 Jonathan Bouchard,2 David M Kern,4 Vincent J Willey1 1HealthCore, Inc., Wilmington, DE, USA; 2Novo Nordisk, Inc., Plainsboro Township, NJ, USA; 3Merck & Co., Inc, Kenilworth, NJ, USA; 4Janssen Research and Development, Titusville, NJ, USACorrespondence: Jay VisariaHealthCore, Inc., 123 Justison Street, Suite 200, Wilmington, DE 19801, USATel +1 302 230-2117Email jvisaria@healthcore.comObjective: The objective of this study was to estimate the incremental long-term costs associated with T2DM attributable to vascular diseases.Research Design and Methods: This retrospective cohort study identified newly diagnosed (incident) T2DM patients in 2007 (baseline to 01/01/2006) using the HealthCore Integrated Research Database, a repository of nationally representative claims data. Incident T2DM patients were 1:1 exact matched on age, gender and other factors of interest to non-DM patients, and followed until the earlier of 8 follow-up years or death. Patients with documented vascular disease diagnosis were identified during the study period. All-cause and T2DM/vascular disease-related annual healthcare costs were examined for each follow-up year.Results: The study included 13,883 individuals with T2DM and matched non-DM controls. Among individuals with T2DM, 11,792 (85%) had vascular disease versus 9251 (66.6%) non-T2DM between 01/01/2006 and 12/31/2015. Among T2DM patients, mean all-cause annual costs were greater than in non-T2DM patients ($13,806 vs $7,243, baseline, $21,745 vs $8,524, post-index year 1, $12,756-$14,793 vs $8,349-$9,940 years 2– 8, p< 0.001), respectively. A similar trend was observed for T2DM/vascular disease-related costs (p< 0. 001). T2DM/vascular disease-related costs were largest during post-index year 1, accounting for the majority of all-cause cost difference between T2DM patients and matched non-DM controls. Incident T2DM individuals without vascular disease at any time had significantly lower costs compared to non-DM controls (p< 0. 001) between years 2– 8 of follow-up.Conclusion: Vascular disease increased the cost burden for individuals with T2DM. The cost impact of diabetes and vascular disease was highest in the year after diagnosis, and persisted for at least seven additional years, while the cost of T2DM patients without vascular disease trended lower than for matched non-DM patients. These data highlight potential costs that could be offset by earlier and more effective detection and management of T2DM aimed at reducing vascular disease burden.Keywords: type 2 diabetes mellitus, microvascular complications, macrovascular complications, diabetes, healthcare costs, diabetes costs

Judith J Stephenson,1 M Soledad Cepeda,2 Jie Zhang,3,4 Jade Dinh,4 Kelsey Hall,4 Daina B Esposito,4– 6 David M Kern2 1Scientific Affairs, HealthCore, Inc, Wilmington, DE, USA; 2Epidemiology, Janssen Research and Development, Titusville, NJ, USA; 3Center for Observational Research, Amgen Inc., Thousand Oaks, CA, USA; 4Safety and Epidemiology, HealthCore, Inc., Wilmington, DE, USA; 5Ciconia, Inc, Westford, MA, USA; 6Epidemiology, Boston University, Boston, MA, USACorrespondence: Judith J StephensonHealthCore, Inc., 123 Justison Street, Suite 200, Wilmington, DE 19801, USATel +1 302-230-2142Email jstephenson@healthcore.comBackground/Rationale: Little is known about the reasons for visiting multiple doctors/pharmacies, known as doctor/pharmacy shopping, to obtain opioids.Objective: To investigate patients’ self-reported reasons for doctor/pharmacy shopping and assess whether doctor/pharmacy shopping behavior can be used as a surrogate measure of opioid abuse/misuse.Methods: We conducted a cross-sectional web-based survey among adult patients with ≥ 2 pharmacy claims for immediate-release or extended-release/long-acting opioids between 7/1/2015 and 12/31/2016, identified from a large United States (US) commercial claims database. Patients were classified into no, mild, moderate, or severe shopping categories based on their claims. Reasons for doctor/pharmacy shopping and opioid abuse/misuse were determined from patient responses to the Prescription Opioid Misuse and Abuse Questionnaire.Results: A random sample of 10,081 patients was invited to participate in the survey and 1085 (11%) completed surveys. The most frequently reported reasons for doctor/pharmacy shopping were convenience, availability, price, and multiple morbidities requiring pain management. Among patients in the no, minimal, moderate, and severe shopping categories, only 7.8%, 8.5%, 11.8% and 12.6% reported opioid abuse/misuse, respectively.Conclusion: In this commercially-insured population, patient-reported reasons for doctor/pharmacy shopping do not suggest opioid abuse/misuse. Less than 15% of patients with shopping behavior in the past 3 months reported any reasons attributable to opioid abuse/misuse, indicating that shopping behavior in this population may not be a good surrogate for abuse/misuse.Keywords: doctor/pharmacy shopping, prescription opioid, abuse and misuse

Michael J Fisch,1 Michael Grabner,2 Daniel S Mytelka,3 Amit D Raval,2 Lee Bowman,3 David M Kern,2 Collin Churchill,3 Joseph Singer,2 Stewart Wetmore,3 John Barron,2 Michael Eleff4 1AIM Specialty Health, Chicago, IL, USA; 2HealthCore, Inc., Wilmington, DE, USA; 3Eli Lilly and Company, Indianapolis, IN, USA; 4Anthem, Inc., Indianapolis, IN, USACorrespondence: Michael GrabnerHealthCore, Inc., 123 Justison St, Suite 200, Wilmington, DE 19801, USATel +1 302-230-2000Fax +1 302-230-2020Email mgrabner@healthcore.comObjective: Choosing chemotherapy for metastatic colorectal cancer (mCRC) requires balancing clinical effectiveness and risk of complications. This study characterized real-world inpatient/emergency department (ED) hospitalizations during first-line chemotherapy among individuals with mCRC.Methods: This retrospective cohort study used data from medical and pharmacy claims. All patients had mCRC with ≥ 1 claim for ≥ 1 of the 5 most frequently utilized first-line chemotherapy agents (fluorouracil, oxaliplatin, bevacizumab, irinotecan, capecitabine). The main outcome was all-cause hospitalizations (inpatient or ED setting) identified from claims via ICD-9/10-CM coding from index date until 30 days after the end of first-line chemotherapy or last available data.Results: A total of 717 individuals (mean age 55 years; 58% male; ECOG 0/1/2+/missing in 44%/39%/6%/11%; median follow-up 116 days) met study criteria. Thirty-four distinct chemotherapy regimens were used. Overall, 40% of patients had ≥ 1 hospitalization (n=285; total 415 hospitalizations); 12% (n=85) had ≥ 2 hospitalizations. The median time to first hospitalization was 52 days; median inpatient length of stay was 4 days; infections/neutropenia (21%) and bowel-related complications (17%) were the most common issues associated with inpatient hospitalizations. In univariate analyses, insurance plan type, geographical location, ECOG, and renal disease were associated with hospitalization. In multivariable analyses, ECOG ≥ 1 was associated with a 67% increase (p< 0.01) in the odds of hospitalization vs ECOG= 0.Conclusion: Approximately 40% of patients with mCRC were hospitalized during the study period. Hospital stays were typically short. Further research is needed to determine how many of these hospitalizations may be avoidable. We also observed a large amount of variation in regimens used in the first-line setting.Keywords: colorectal cancer, chemotherapy-associated hospitalization, outcomes research, observational study, claims analysis

Frank Trudo,1 David M Kern,2 Jill R Davis,1 Ozgur Tunceli,2 Siting Zhou,2 Emma L Graham,3 Charlie Strange,4 Setareh A Williams1 1AstraZeneca Pharmaceuticals LP, 2HealthCore, Inc., Wilmington, DE, USA; 3AstraZeneca Pharmaceuticals LP, Alderley Park, Cheshire, UK; 4Division of Pulmonary and Critical Care Medicine, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA Background: Inhaled corticosteroid/long-acting β2-agonist combinations and/or long-acting muscarinic antagonists are recommended first-line therapies for preventing chronic obstructive pulmonary disease (COPD) exacerbation. Comparative effectiveness of budesonide/formoterol combination (BFC, an inhaled corticosteroid/long-acting β2-agonist combination) vs tiotropium (long-acting muscarinic antagonist) in the US has not yet been studied.Methods: Using US claims data from the HealthCore Integrated Research Environment, COPD patients (with or without comorbid asthma) ≥40 years old initiating BFC or tiotropium between March 1, 2009 and February 28, 2012 and at risk for exacerbation were identified and followed for 12 months. Patients were propensity score matched on demographics and COPD disease severity indicators. The primary outcome was time to first COPD exacerbation. Secondary outcomes included COPD exacerbation rate, health care resource utilization, and costs.Results: The Cox proportional hazards model for time to first exacerbation yielded a hazard ratio (HR) of 0.78 (95% CI =[0.70, 0.87], P

David M Kern,1 Jill Davis,2 Setareh A Williams,3 Ozgur Tunceli,1 Bingcao Wu,1 Sally Hollis,4 Charlie Strange,5 Frank Trudo2 1HealthCore, Inc., Wilmington, DE, 2AstraZeneca Pharmaceuticals, Wilmington, DE, 3AstraZeneca Pharmaceuticals, Gaithersburg, MD, USA; 4AstraZeneca Pharmaceuticals, Cheshire, UK; 5Department of Medicine, Division of Pulmonary and Critical Care Medicine, Medical University of South Carolina, Charleston, SC, USA Objective: To estimate the accuracy of claims-based pneumonia diagnoses in COPD patients using clinical information in medical records as the reference standard.Methods: Selecting from a repository containing members’ data from 14 regional United States health plans, this validation study identified pneumonia diagnoses within a group of patients initiating treatment for COPD between March 1, 2009 and March 31, 2012. Patients with ≥1 claim for pneumonia (International Classification of Diseases Version 9-CM code 480.xx–486.xx) were identified during the 12 months following treatment initiation. A subset of 800 patients was randomly selected to abstract medical record data (paper based and electronic) for a target sample of 400 patients, to estimate validity within 5% margin of error. Positive predictive value (PPV) was calculated for the claims diagnosis of pneumonia relative to the reference standard, defined as a documented diagnosis in the medical record.Results: A total of 388 records were reviewed; 311 included a documented pneumonia diagnosis, indicating 80.2% (95% confidence interval [CI]: 75.8% to 84.0%) of claims-identified pneumonia diagnoses were validated by the medical charts. Claims-based diagnoses in inpatient or emergency departments (n=185) had greater PPV versus outpatient settings (n=203), 87.6% (95% CI: 81.9%–92.0%) versus 73.4% (95% CI: 66.8%–79.3%), respectively. Claims-diagnoses verified with paper-based charts had similar PPV as the overall study sample, 80.2% (95% CI: 71.1%–87.5%), and higher PPV than those linked to electronic medical records, 73.3% (95% CI: 65.5%–80.2%). Combined paper-based and electronic records had a higher PPV, 87.6% (95% CI: 80.9%–92.6%).Conclusion: Administrative claims data indicating a diagnosis of pneumonia in COPD patients are supported by medical records. The accuracy of a medical record diagnosis of pneumonia remains unknown. With increased use of claims data in medical research, COPD researchers can study pneumonia with confidence that claims data are a valid tool when studying the safety of COPD therapies that could potentially lead to increased pneumonia susceptibility or severity. Keywords: positive predictive value, pneumonia, validation, claims data, medical record review

David M Kern,1 Setareh A Williams,2 Ozgur Tunceli,1 Catrin Wessman,3 Siting Zhou,1 Ned Pethick,2 Hanaa Elhefni,2 Frank Trudo2 1HealthCore Inc., 2AstraZeneca, Wilmington, DE, USA; 3AstraZeneca, Mölndal, Sweden Objective: To compare clinical and demographic characteristics, resource utilization and costs of chronic obstructive pulmonary disease (COPD) patients prior to initiating budesonide–formoterol combination (BFC) or tiotropium-maintenance therapy. Materials and methods: This cross-sectional study used claims-based diagnosis to identify COPD patients in the HealthCore Integrated Research Database who initiated BFC or tiotropium therapy between March 1, 2009 and January 31, 2012 (intake period); the index date was defined as the initial prescription fill for either agent. Patients diagnosed with respiratory tract cancer or receiving inhaled corticosteroids/long-acting β2-adrenergic agonists or tiotropium in 12 months prior to index date were excluded. Categorical variables were evaluated with Χ2 tests; mean cost differences were evaluated using γ-regression. Results: Overall, 6,940 BFC and 10,831 tiotropium patients were identified. The BFC group was younger (mean age 64 versus 67 years), with a greater proportion of females (54% versus 51%). BFC-treated patients had more comorbid respiratory conditions, including asthma (25% versus 13%), but fewer comorbid cardiovascular conditions, including atherosclerosis (7% versus 10%) and myocardial infarction (4% versus 6%). A greater proportion of BFC patients received prior respiratory medication, including oral corticosteroids (46% versus 35%) and short-acting β2-agonists (44% versus 35%). Tiotropium-treated patients had a greater mean number of COPD-related outpatient visits (4.6 versus 4.1). BFC-treated patients had lower total all-cause ($17,259 versus $17,926) and COPD-related ($1,718 versus $1,930) health care costs, driven by lower all-cause and COPD-related inpatient expenditures. Conclusion: Initiators of BFC or tiotropium showed differences in clinical and demographic characteristics and health care utilization and costs prior to starting COPD maintenance therapy. Keywords: observational study, retrospective analysis, chronic respiratory condition, outcome research, health care utilization and costs

Background: Four sphingosine-1-phosphate receptor (S1PR) modulators are currently available in the USA for treating relapsing forms of multiple sclerosis (MS). These S1PR modulators have similar efficacy. Clinicians may therefore consider other factors, such as clinical management considerations, when distinguishing among treatments. This study estimated which S1PR modulator clinicians would choose on the basis of a treatment's clinical management and quantified how individual aspects of clinical management might drive this choice., Methods: A multi-criteria decision analysis (MCDA) was conducted on the basis of clinical management preferences elicited in a discrete choice experiment (DCE) and real-world clinical management profiles of the S1PR modulators currently available to treat relapsing forms of MS (fingolimod, ozanimod, ponesimod, siponimod). The DCE was completed by neurologists in the USA experienced in treating MS and included eight clinical management attributes: first-dose observations, genotyping, liver function tests, eye exams, drug-drug interactions, interactions with antidepressants, interactions with foods high in tyramine, and immune system recovery time. Attribute levels were selected on the basis of S1PR modulator product labels. In the MCDA, partial MCDA scores were created for each attribute and summed to produce an overall MCDA score for each S1PR modulator., Results: The DCE was completed by 200 neurologists. The overall MCDA score was highest for ponesimod (4.78 points), followed by siponimod (4.10 points), fingolimod (3.61 points), and ozanimod (2.38 points). Having fewer drug-drug interactions contributed most to the overall scores (up to 1.56 points), followed by having no first-dose observations (0.95 points), the shortest immune system recovery time (0.94 points), and not interacting with foods high in tyramine (0.86 points)., Conclusion: When considering clinical management convenience, the average US-based neurologist treating MS is likely to choose ponesimod over siponimod, fingolimod, or ozanimod. The strongest driver of preferences was the number of drug-drug interactions. This information can help inform recommendations for the treatment of MS and facilitate shared decision-making between clinicians and patients., (© 2024. The Author(s).)

Background: Several sphingosine-1-phosphate receptor (S1PR) modulators are available in the US for treating relapsing forms of multiple sclerosis (RMS). Given that these S1PR modulators have similar efficacy and safety, patients may consider the clinical management characteristics of the S1PR modulators when deciding among treatments. However, none of the S1PR modulators is clearly superior in every aspect of clinical management, and for some treatments, clinical management varies based on a patient's comorbid health conditions (e.g., heart conditions [HC])., Objectives: This study aimed to determine which S1PR modulator patients with relapsing-remitting multiple sclerosis (RRMS) would prefer based on clinical management considerations, and to estimate how different clinical management considerations might drive these preferences. Preferences were explored separately for patients with and without comorbid HC., Methods: A multicriteria decision analysis was conducted on S1PR modulators approved to treat RMS: fingolimod, ozanimod, siponimod, and ponesimod. Clinical management preferences of patients with RRMS were elicited in a discrete choice experiment (DCE) in which participants repeatedly chose between hypothetical S1PR modulator profiles based on their clinical management attributes. Attributes included first-dose observations, genotyping, liver function tests, eye examinations, drug-drug interactions, interactions with antidepressants, interactions with foods high in tyramine, and immune system recovery time. Preferences were estimated separately for patients with HC and without HC (noHC). Marginal utilities were calculated from the DCE data for each attribute and level using a mixed logit model. In the multicriteria decision analysis, partial value scores were created by applying the marginal utilities for each attribute and level to the real-world profiles of S1PR modulators. Partial value scores were summed to determine an overall clinical management value score for each S1PR modulator., Results: Four hundred patients with RRMS completed the DCE. Ponesimod had the highest overall value score for patients both without (n = 341) and with (n = 59) HC (noHC: 5.1; HC: 4.0), followed by siponimod (noHC: 4.9; HC: 3.3), fingolimod (noHC: 3.4; HC: 2.8), and ozanimod (noHC: 0.9; HC: 0.8). Overall, immune system recovery time contributed the highest partial value scores (noHC: up to 1.9 points; HC: up to 1.2 points), followed by the number of drug-drug interactions (noHC: up to 1.2 points; HC: up to 1.7 points)., Conclusions: When considering the clinical management of S1PR modulators, the average patient with RRMS is expected to choose a treatment with shorter immune system recovery time and fewer interactions with other drugs. Patients both with and without heart conditions are likely to prefer the clinical management profile of ponesimod over those of siponimod, fingolimod, and ozanimod. This information can help inform recommendations for treating RRMS and facilitate shared decision making between patients and their doctors., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: People with mental health conditions were potentially more vulnerable than others to the neuropsychiatric effects of the COVID-19 pandemic and the global efforts taken to contain it. The aim of this multinational study was to examine the changes in psychotropic drug prescribing during the pandemic among people with depressive and anxiety disorders., Methods: This study included electronic medical records and claims data from nine databases in six countries (France, Germany, Italy, the UK, South Korea, and the USA) of patients with a diagnosis of depressive or anxiety disorders between 2016 and 2021. The outcomes were monthly prevalence rates of antidepressant, antipsychotic, and anxiolytic drug prescribing. The associations between the pandemic and psychotropic drug prescribing were examined with interrupted time series analyses for the total sample and stratified by sex and age group. People with lived experience were not involved in the research and writing process., Findings: Between Jan 1, 2016 and Dec 31, 2020, an average of 16 567 914 patients with depressive disorders (10 820 956 females [65·31%] and 5 746 958 males [34·69%]) and 15 988 451 patients with anxiety disorders (10 688 788 females [66·85%] and 5 299 663 males [33·15%]) were identified annually. Most patients with depressive disorders and anxiety disorders were aged 45-64 years. Ethnicity data were not available. Two distinct trends in prescribing rates were identified. The first pattern shows an initial surge at the start of the pandemic (eg, antipsychotics among patients with depressive disorders in MDCD&#95;US (rate ratio [RR] 1·077, 95% CI 1·055-1·100), followed by a gradual decline towards the counterfactual level (RR 0·990, 95% CI 0·988-0·992). The second pattern, observed in four databases for anxiolytics among patients with depressive disorders and two for antipsychotics among patients with anxiety disorders, shows an immediate increase (eg, antipsychotics among patients with anxiety disorders in IQVIA&#95;UK: RR 1·467, 95% CI 1·282-1·675) without a subsequent change in slope (RR 0·985, 95% CI 0·969-1·003). In MDCD&#95;US and IQVIA&#95;US, the anxiolytic prescribing rate continued to increase among patients younger than 25 years for both disorders., Interpretation: The study reveals persistently elevated rates of psychotropic drug prescriptions beyond the initial phase of the pandemic. These findings underscore the importance of enhanced mental health support and emphasise the need for regular review of psychotropic drug use among this patient group in the post-pandemic era., Funding: University Grants Committee, Research Grants Council, The Government of the Hong Kong Special Administrative Region., Competing Interests: Declaration of interests HL reports grants from Research Grants Council of Hong Kong, outside the submitted work. WCYL reports research grants from AIR@InnoHK administered by Innovation and Technology Commission, outside the submitted work. JH reports grants from UKRI, Consultancy Fees from Wellcome Trust and Juli Health, and patents pending and stock from Juli Health, outside the submitted work. COT reports stock or stock options and other financial or non-financial interests from Roche Pharmaceutical as an employee, outside the submitted work. XL reports grants from IQVIA, outside the submitted work. SF and DMK report stock or stock options and other financial or non-financial interests from Johnson and Johnson as employees, outside the submitted work. JL reports stock or stock options and other financial or non-financial interests from IQVIA as an employee, outside the submitted work. KKCM reports grants from the CW Maplethorpe Fellowship, National Institute of Health Research, UK, Hong Kong Research Grant Council, and the European Commission Horizon 2020 Framework, outside the submitted work. ICKW reports grants from Amgen, Bristol-Myers Squibb, Pfizer, Janssen, Bayer, GSK and Novartis, the Hong Kong RGC, and the Hong Kong Health and Medical Research Fund, National Institute for Health Research in England, European Commission, and National Health and Medical Research Council in Australia, consulting fees from IQVIA, payment for expert testimony and a role as an independent non-executive director of Jacobson Medical, Hong Kong, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objective: Our study examined the impact of sex, ADHD subtype, and comorbid illnesses (depression/anxiety) on the timing of diagnosis and treatment for ADHD., Method: To analyze ADHD patients, four health databases were used to assess subtype, comorbid mood, and antidepressant or anxiolytic drug exposure. Analyses were stratified by sex and age. Standardized mean differences measured intergroup differences., Results: Females with ADHD were identified at older ages and had higher rates of depression and anxiety diagnoses and treatments before and after their initial ADHD diagnosis. Predominantly inattentive ADHD patients were diagnosed later and more likely to receive mood disorder diagnosis and treatment than hyperactive impulsive ADHD patients., Conclusions: Results suggest a more complex ADHD presentation in females, potentially causing late diagnosis and delayed treatment., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JA, MMC, DMK, and US are employees of Janssen Research & Development, LLC, and shareholders of Johnson & Johnson (J&J) stock.

Introduction: Results of retrospective studies examining the relationship between prolactin increasing antipsychotics and incident breast cancer have been inconsistent. This study assessed the association between use of high prolactin increasing antipsychotics (HPD) and the incidence of breast cancer using best practices in pharmacoepidemiology., Methods: Using administrative claims data from the MarketScan Medicaid database, schizophrenia patients initiating antipsychotics were identified. Those initiating HPD were compared with new users of non/low prolactin increasing drugs (NPD). Two definitions of breast cancer, two at-risk periods, and two large-scale propensity score (PS) adjustment methods were used in separate analyses. PS models included all previously diagnosed conditions, medication use, demographics, and other available medical history. Negative control outcomes were used for empirical calibration., Results: Five analysis variants passed all diagnostics for sufficient statistical power and balance across all covariates. Four of the five variants used an intent-to-treat (ITT) approach. Between 4,256 and 6,341 patients were included in each group for the ITT analyses, and patients contributed approximately four years of follow-up time on average. There was no statistically significant association between exposure to HPD and risk of incident breast cancer in any analysis, and hazard ratios remained close to 1.0, ranging from 0.96 (95% confidence interval 0.62 - 1.48) to 1.28 (0.40 - 4.07)., Discussion: Using multiple PS methods, outcome definitions and at-risk periods provided robust and consistent results which found no evidence of an association between use of HPD and risk of breast cancer., Competing Interests: Authors are employees or former employees of Janssen Research & Development, LLC, which markets antipsychotic medications, and are shareholders of Johnson & Johnson, Inc., (Copyright © 2024 Kern, Shoaibi, Shearer, Richarz, Killion and Knight.)

Aims: Population-wide restrictions during the COVID-19 pandemic may create barriers to mental health diagnosis. This study aims to examine changes in the number of incident cases and the incidence rates of mental health diagnoses during the COVID-19 pandemic., Methods: By using electronic health records from France, Germany, Italy, South Korea and the UK and claims data from the US, this study conducted interrupted time-series analyses to compare the monthly incident cases and the incidence of depressive disorders, anxiety disorders, alcohol misuse or dependence, substance misuse or dependence, bipolar disorders, personality disorders and psychoses diagnoses before (January 2017 to February 2020) and after (April 2020 to the latest available date of each database [up to November 2021]) the introduction of COVID-related restrictions., Results: A total of 629,712,954 individuals were enrolled across nine databases. Following the introduction of restrictions, an immediate decline was observed in the number of incident cases of all mental health diagnoses in the US (rate ratios (RRs) ranged from 0.005 to 0.677) and in the incidence of all conditions in France, Germany, Italy and the US (RRs ranged from 0.002 to 0.422). In the UK, significant reductions were only observed in common mental illnesses. The number of incident cases and the incidence began to return to or exceed pre-pandemic levels in most countries from mid-2020 through 2021., Conclusions: Healthcare providers should be prepared to deliver service adaptations to mitigate burdens directly or indirectly caused by delays in the diagnosis and treatment of mental health conditions.

Background: The impact of treatment-resistant depression (TRD) or prior suicidal ideation/suicide attempt (SI/SA) on mortality by suicide among patients with major depressive disorder (MDD) is not well known. This retrospective, observational, descriptive cohort study characterized real-world rates of suicide-specific mortality among patients with MDD with or without TRD or SI/SA., Methods: Adult patients with MDD among commercially insured and Medicare enrollees in Optum Research Database were included and assigned to three cohorts: those with treatment-resistant MDD (TRD), those with MDD and SI/SA (MDD+SI/SA), and those with MDD without TRD or SI/SA (MDD alone). Suicide-specific mortality was obtained from the National Death Index. The effects of demographic characteristics and SI/SA in the year prior to the end of observation on suicide-specific mortality were assessed., Results: For the 139,753 TRD, 85,602 MDD+SI/SA, and 572,098 MDD alone cohort patients, mean age ranged from 55 to 59 years and the majority were female. At baseline, anxiety disorders were present in 53.92%, 44.11%, and 21.72% of patients with TRD, MDD+SI/SA, and MDD alone, respectively. Suicide-mortality rates in the three cohorts were 0.14/100 person-years for TRD, 0.27/100 person-years for MDD+SI/SA, and 0.04/100 person-years for MDD alone. SI/SA during the year prior to the end of observation, younger age, and male sex were associated with increased suicide risk., Conclusions: Patients with TRD and MDD+SI/SA have a heightened risk of mortality by suicide compared with patients with MDD alone. Suicide rates were higher in patients with recent history versus older or no history of SI/SA, men versus women, and those of young age versus older age., (© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Leucine-rich repeat-containing protein 8 (LRRC8) family members form volume-regulated anion channels activated by hypoosmotic cell swelling. LRRC8 channels are ubiquitously expressed in vertebrate cells as heteromeric assemblies of LRRC8A (SWELL1) and LRRC8B-E subunits. Channels of different subunit composition have distinct properties that explain the functional diversity of LRRC8 currents across cell types. However, the basis for heteromeric LRRC8 channel assembly and function is unknown. Here we leverage a fiducial-tagging strategy to determine single-particle cryo-EM structures of heterohexameric LRRC8A:C channels in multiple conformations. Compared to homomers, LRRC8A:C channels show pronounced differences in architecture due to heterotypic LRR interactions that displace subunits away from the conduction axis and poise the channel for activation. Structures and functional studies further reveal that lipids embedded in the channel pore block ion conduction in the closed state. These results provide insight into determinants for heteromeric LRRC8 channel assembly, activity and gating by lipids., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: Few studies have examined the use of embedded validity indicators (EVIs) in criminal-forensic practice settings, where judgements regarding performance validity can carry severe consequences for the individual and society. This study sought to examine how various EVIs perform in criminal defendant populations, and determine relationships between EVI scores and intrapersonal variables thought to influence performance validity., Method: Performance on 16 empirically established EVI cutoffs were examined in a sample of 164 criminal defendants with valid performance who were referred for forensic neuropsychological evaluation. Subsequent analyses examined the relationship between EVI scores and intrapersonal variables in 83 of these defendants., Results: Half of the EVIs (within the Wechsler Adult Intelligence Scale Digit Span Total, Conners' Continuous Performance Test Commissions, Wechsler Memory Scale Logical Memory I and II, Controlled Oral Word Association Test, Trail Making Test Part B, and Stroop Word and Color) performed as intended in this sample. The EVIs that did not perform as intended were significantly influenced by relevant intrapersonal variables, including below-average intellectual functioning and history of moderate-severe traumatic brain injury and neurodevelopmental disorder., Conclusions: This study identifies multiple EVIs appropriate for use in criminal-forensic settings. However, based on these findings, practitioners may wish to be selective in choosing and interpreting EVIs for forensic evaluations of criminal court defendants., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Objective: Observational studies can impact patient care but must be robust and reproducible. Nonreproducibility is primarily caused by unclear reporting of design choices and analytic procedures. This study aimed to: (1) assess how the study logic described in an observational study could be interpreted by independent researchers and (2) quantify the impact of interpretations' variability on patient characteristics., Materials and Methods: Nine teams of highly qualified researchers reproduced a cohort from a study by Albogami et al. The teams were provided the clinical codes and access to the tools to create cohort definitions such that the only variable part was their logic choices. We executed teams' cohort definitions against the database and compared the number of subjects, patient overlap, and patient characteristics., Results: On average, the teams' interpretations fully aligned with the master implementation in 4 out of 10 inclusion criteria with at least 4 deviations per team. Cohorts' size varied from one-third of the master cohort size to 10 times the cohort size (2159-63 619 subjects compared to 6196 subjects). Median agreement was 9.4% (interquartile range 15.3-16.2%). The teams' cohorts significantly differed from the master implementation by at least 2 baseline characteristics, and most of the teams differed by at least 5., Conclusions: Independent research teams attempting to reproduce the study based on its free-text description alone produce different implementations that vary in the population size and composition. Sharing analytical code supported by a common data model and open-source tools allows reproducing a study unambiguously thereby preserving initial design choices., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To assess the impact of extended-release (ER)/long-acting (LA) opioid prescriber training on prescribing behaviors., Design: Retrospective cohort study., Setting: Prescriber training was evaluated from June 1, 2013 through December 31, 2016. The full study period was 2 years longer, from June 1, 2012 through December 31, 2017, to include data for all prescribers' 1-year pretraining and post-training periods., Participants: 24,428 prescribers who wrote ER/LA opioid prescriptions for eligible patients, with a record of training from the partner continuing education provider between June 1, 2013 and December 31, 2016., Intervention: ER/LA opioid prescriber training., Main Outcome Measures: Prescribing behaviors 1-year before (pretraining) and after (post-training) prescribers completed training, specifically the proportion of opioid-nontolerant patients receiving ER/LA opioids indicated for opioid-tolerant patients and for patients receiving ≥100 morphine equivalents dose daily, and the proportion of concomitant users of central nervous system depressant drugs., Results: The differences in the proportion of opioid-nontolerant patients receiving ER/LA opioids indicated for opi-oid-tolerant patients and for patients receiving ≥100 morphine equivalents dose daily were -0.69 percent (95 percent confidence interval [CI]: -1.78 percent, 0.40 percent) and -0.23 percent (95 percent CI: -1.18 percent, 0.68 percent), respectively. The differences in the proportion of concomitant users of central nervous system depressant drugs were -0.94 percent (95 percent CI: -1.39 percent; -0.48 percent) for benzodiazepines, 0.06 percent (95 percent CI: -0.13 percent; 0.25 percent) for antipsychotics, -0.41 percent (95 percent CI: -0.69 percent; -0.13 percent) for hypnotics/sedatives, and 0.08 percent (95 percent CI: -0.40 percent; 0.57 percent) for muscle relaxants., Conclusions: While prescribers showed some changes in prescribing behavior after completing training, training was not associated with clinically relevant changes in prescribing behaviors.

Importance: Concerns have been raised that the use of antipsychotic medication for people living with dementia might have increased during the COVID-19 pandemic., Objective: To examine multinational trends in antipsychotic drug prescribing for people living with dementia before and during the COVID-19 pandemic., Design, Setting, and Participants: This multinational network cohort study used electronic health records and claims data from 8 databases in 6 countries (France, Germany, Italy, South Korea, the UK, and the US) for individuals aged 65 years or older between January 1, 2016, and November 30, 2021. Two databases each were included for South Korea and the US., Exposures: The introduction of population-wide COVID-19 restrictions from April 2020 to the latest available date of each database., Main Outcomes and Measures: The main outcomes were yearly and monthly incidence of dementia diagnosis and prevalence of people living with dementia who were prescribed antipsychotic drugs in each database. Interrupted time series analyses were used to quantify changes in prescribing rates before and after the introduction of population-wide COVID-19 restrictions., Results: A total of 857 238 people with dementia aged 65 years or older (58.0% female) were identified in 2016. Reductions in the incidence of dementia were observed in 7 databases in the early phase of the pandemic (April, May, and June 2020), with the most pronounced reduction observed in 1 of the 2 US databases (rate ratio [RR], 0.30; 95% CI, 0.27-0.32); reductions were also observed in the total number of people with dementia prescribed antipsychotic drugs in France, Italy, South Korea, the UK, and the US. Rates of antipsychotic drug prescribing for people with dementia increased in 6 databases representing all countries. Compared with the corresponding month in 2019, the most pronounced increase in 2020 was observed in May in South Korea (Kangwon National University database) (RR, 2.11; 95% CI, 1.47-3.02) and June in the UK (RR, 1.96; 95% CI, 1.24-3.09). The rates of antipsychotic drug prescribing in these 6 databases remained high in 2021. Interrupted time series analyses revealed immediate increases in the prescribing rate in Italy (RR, 1.31; 95% CI, 1.08-1.58) and in the US Medicare database (RR, 1.43; 95% CI, 1.20-1.71) after the introduction of COVID-19 restrictions., Conclusions and Relevance: This cohort study found converging evidence that the rate of antipsychotic drug prescribing to people with dementia increased in the initial months of the COVID-19 pandemic in the 6 countries studied and did not decrease to prepandemic levels after the acute phase of the pandemic had ended. These findings suggest that the pandemic disrupted the care of people living with dementia and that the development of intervention strategies is needed to ensure the quality of care.

Problem: Ambiguity in communication of key study parameters limits the utility of real-world evidence (RWE) studies in healthcare decision-making. Clear communication about data provenance, design, analysis, and implementation is needed. This would facilitate reproducibility, replication in independent data, and assessment of potential sources of bias., What We Did: The International Society for Pharmacoepidemiology (ISPE) and ISPOR-The Professional Society for Health Economics and Outcomes Research (ISPOR) convened a joint task force, including representation from key international stakeholders, to create a harmonized protocol template for RWE studies that evaluate a treatment effect and are intended to inform decision-making. The template builds on existing efforts to improve transparency and incorporates recent insights regarding the level of detail needed to enable RWE study reproducibility. The overarching principle was to reach for sufficient clarity regarding data, design, analysis, and implementation to achieve 3 main goals. One, to help investigators thoroughly consider, then document their choices and rationale for key study parameters that define the causal question (e.g., target estimand), two, to facilitate decision-making by enabling reviewers to readily assess potential for biases related to these choices, and three, to facilitate reproducibility., Strategies to Disseminate and Facilitate Use: Recognizing that the impact of this harmonized template relies on uptake, we have outlined a plan to introduce and pilot the template with key international stakeholders over the next 2 years., Conclusion: The HARmonized Protocol Template to Enhance Reproducibility (HARPER) helps to create a shared understanding of intended scientific decisions through a common text, tabular and visual structure. The template provides a set of core recommendations for clear and reproducible RWE study protocols and is intended to be used as a backbone throughout the research process from developing a valid study protocol, to registration, through implementation and reporting on those implementation decisions., (© 2022 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Objective: The prevalence of epilepsy is slightly higher in women than in men and sensitivity to seizure stimuli differs between sexes. Some evidence suggests sex differences in response to antiseizure medications exist mainly due to inconsistent pharmacokinetic differences; however, there is a lack of real-world evidence examining differences in response to antiseizure medications between men and women., Methods: This was a retrospective population-based cohort study in five large US healthcare databases. The population included adult patients with epilepsy, newly exposed to levetiracetam, and naive to antiseizure medication. The first exposure to levetiracetam was the index date. The requirement that all patients received the same medication was done to avoid potential confounding due to differences in index treatment. The outcome was the development of treatment resistant epilepsy (TRE), defined as having at least three distinct antiseizure medications in 1 year. The proportion of patients who developed TRE within 1 year following the index date was calculated. To compare the risk of developing TRE between sexes, relative risks (RR) and 95% confidence intervals (CI) were calculated, and estimates were pooled using meta-analytic techniques stratified by gender and age., Results: A total of 147 334 subjects were included in the databases, 50.8% were women, and 4.27% developed TRE. The comorbid profile differed greatly between men and women; however, the types of epilepsy syndromes observed during baseline were similar between the two groups. Across all databases, women were more likely to develop TRE than men (pooled RR 1.27, 95% CI 1.17-1.38). Results remained similar when stratified by age., Significance: This study assessed sex differences in response to antiseizure medications using the development of TRE as a proxy for effectiveness. Women newly exposed to levetiracetam were 27% more likely to develop TRE than men, independent of age., (© 2022 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

SARS-CoV-2 encodes four structural proteins incorporated into virions, spike (S), envelope (E), nucleocapsid (N), and membrane (M). M plays an essential role in viral assembly by organizing other structural proteins through physical interactions and directing them to sites of viral budding. As the most abundant protein in the viral envelope and a target of patient antibodies, M is a compelling target for vaccines and therapeutics. Still, the structure of M and molecular basis for its role in virion formation are unknown. Here, we present the cryo-EM structure of SARS-CoV-2 M in lipid nanodiscs to 3.5 Å resolution. M forms a 50 kDa homodimer that is structurally related to the SARS-CoV-2 ORF3a viroporin, suggesting a shared ancestral origin. Structural comparisons reveal how intersubunit gaps create a small, enclosed pocket in M and large open cavity in ORF3a, consistent with a structural role and ion channel activity, respectively. M displays a strikingly electropositive cytosolic surface that may be important for interactions with N, S, and viral RNA. Molecular dynamics simulations show a high degree of structural rigidity in a simple lipid bilayer and support a role for M homodimers in scaffolding viral assembly. Together, these results provide insight into roles for M in coronavirus assembly and structure., Competing Interests: KD, MD, DK, GV, SB No competing interests declared, AK is an employee of Thermo Fisher Scientific, (© 2022, Dolan et al.)

Objectives: Ambiguity in communication of key study parameters limits the utility of real-world evidence (RWE) studies in healthcare decision-making. Clear communication about data provenance, design, analysis, and implementation is needed. This would facilitate reproducibility, replication in independent data, and assessment of potential sources of bias., Methods: The International Society for Pharmacoepidemiology (ISPE) and ISPOR-The Professional Society for Health Economics and Outcomes Research (ISPOR) convened a joint task force, including representation from key international stakeholders, to create a harmonized protocol template for RWE studies that evaluate a treatment effect and are intended to inform decision-making. The template builds on existing efforts to improve transparency and incorporates recent insights regarding the level of detail needed to enable RWE study reproducibility. The over-arching principle was to reach for sufficient clarity regarding data, design, analysis, and implementation to achieve 3 main goals. One, to help investigators thoroughly consider, then document their choices and rationale for key study parameters that define the causal question (e.g., target estimand), two, to facilitate decision-making by enabling reviewers to readily assess potential for biases related to these choices, and three, to facilitate reproducibility., Strategies to Disseminate and Facilitate Use: Recognizing that the impact of this harmonized template relies on uptake, we have outlined a plan to introduce and pilot the template with key international stakeholders over the next 2 years., Conclusion: The HARmonized Protocol Template to Enhance Reproducibility (HARPER) helps to create a shared understanding of intended scientific decisions through a common text, tabular and visual structure. The template provides a set of core recommendations for clear and reproducible RWE study protocols and is intended to be used as a backbone throughout the research process from developing a valid study protocol, to registration, through implementation and reporting on those implementation decisions., (Copyright © 2022. Published by Elsevier Inc.)

Type 2 diabetes is associated with insulin resistance, impaired pancreatic β-cell insulin secretion, and nonalcoholic fatty liver disease. Tissue-specific SWELL1 ablation impairs insulin signaling in adipose, skeletal muscle, and endothelium, and impairs β-cell insulin secretion and glycemic control. Here, we show that I Cl,SWELL and SWELL1 protein are reduced in adipose and β-cells in murine and human diabetes. Combining cryo-electron microscopy, molecular docking, medicinal chemistry, and functional studies, we define a structure activity relationship to rationally-design active derivatives of a SWELL1 channel inhibitor (DCPIB/SN-401), that bind the SWELL1 hexameric complex, restore SWELL1 protein, plasma membrane trafficking, signaling, glycemic control and islet insulin secretion via SWELL1-dependent mechanisms. In vivo, SN-401 restores glycemic control, reduces hepatic steatosis/injury, improves insulin-sensitivity and insulin secretion in murine diabetes. These findings demonstrate that SWELL1 channel modulators improve SWELL1-dependent systemic metabolism in Type 2 diabetes, representing a first-in-class therapeutic approach for diabetes and nonalcoholic fatty liver disease., (© 2022. The Author(s).)

Objective: To provide current estimates of the number of patients with prevalent systemic lupus erythematosus (SLE) by major health insurance types in the US and to describe patient characteristics. Four large US health insurance claims databases were analyzed to represent different types of insurance coverage, including private insurance, Medicaid, and Medicare Supplemental., Results: Overall unadjusted SLE prevalence per 100,000 persons in the US ranged from 150.1 (private insurance) to 252.9 (Medicare Supplemental insurance). Extrapolating to the US civilian population in 2016, we estimated roughly 345,000 to 404,000 prevalent SLE patients with private/Medicare insurance and 99,000 prevalent SLE patients with Medicaid insurance. Comorbidities, including renal failure/dialysis were commonly observed across multiple organ systems in SLE patients (8.4-21.1%). We estimated a larger number of prevalent SLE cases in the US civilian population than previous reports and observed extensive disease burden based on a 1-year cross-sectional analysis., (© 2021. The Author(s).)

Objective: To systematically identify novel pharmacological strategies for preventing or treating post-traumatic stress disorder (PTSD) by leveraging large-scale analysis of real-world observational data., Methods: Using a self-controlled study design, the association between 1399 medications and the incidence of PTSD across four US insurance claims databases covering commercially insured, Medicare eligible, and Medicaid patients was examined. A validated algorithm for identifying PTSD in claims data was used, and medications were identified by their RxNorm ingredient. Medications used to treat PTSD or its symptoms (e.g., antidepressants, antipsychotics) were excluded. Medications associated with ≥30% reduction in risk of PTSD in ≥2 databases were identified., Results: A total of 137,182,179 individuals were included in the analysis. Fifteen medications met the threshold criteria for a potential protective effect on PTSD; six were categorized as "primary signals" while the remaining nine were considered "potential signals". The primary signals include a beta blocker that has been previously studied for PTSD, and five medications used to treat attention-deficit/hyperactivity disorder. The potential signals include four medications used to treat substance use disorders and five medications used to treat sleep disorders., Discussion: The medications identified in this analysis provide targets for further research in studies that are designed to examine specific hypotheses regarding these medications and the incidence of PTSD. This work may aid in discovering novel therapeutic approaches to treat PTSD, wherein new and effective treatments are badly needed., (© 2021 The Authors. Psychiatric Research and Clinical Practice published by Wiley Periodicals LLC on behalf of American Psychiatric Association.)

Background: There is a knowledge gap regarding the treatment patterns of patients with major depressive disorder (MDD) who experience suicidal ideation or a suicide attempt (SI/SA)., Methods: Patients with SI/SA were identified from a large US-based claims database covering 84 million lives, during 1/1/2014-3/31/2020. Patients with MDD were indexed at their first diagnosis for SI/SA and followed up to 365 days. Treatment patterns were captured at the class level and included procedures of electroconvulsive therapy and transcranial magnetic stimulation, and pharmacotherapy including selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, other antidepressants, anxiolytics, hypnotics/sedatives, antipsychotics, psychostimulants, and lithium., Results: There were 42,204 MDD + SI/SA patients identified. In the year prior to the index event > 40% of individuals received an SSRI and more than one-third received an anxiolytic. Within 1 year following, 84.4% received ≥1 of the treatments of interest. Of those, 70.2% went on to a subsequent class-based regimen, 46.3% received a third, and 28.1% received ≥4. More than three-quarters of patients received multiple treatment classes simultaneously. SSRIs were the most common treatments during follow-up (61.9%), followed by other antidepressants (51.3%), anxiolytics (50.8%) and anticonvulsants (43.6%)., Conclusions: There was a large amount of variability and polypharmacy in the treatments received by MDD patients with SI/SA, and is much more complex than what has been previously observed in the general MDD population. Within one-year, many patients received four or more unique class-based regimens and most patients received treatments from multiple classes simultaneously, indicating the high unmet medical need and therapy refractoriness of this patient population., (© 2021. The Author(s).)

Introduction: Epilepsy is a neurological disease characterized by recurrent, unprovoked seizures and its impact on biological, cognitive, psychological, and social outcomes. An unmet need for finding effective treatment options exists. Identifying medical diagnoses present prior to a diagnosis of epilepsy is an important step in increasing our understanding of how people with epilepsy may respond to therapy, help guide clinicians in managing associated comorbid conditions, and inform future research., Methods: A population-based retrospective comparative cohort study was conducted using administrative claims data to explore differences in medical diagnoses prior to an initial diagnosis of epilepsy between patients with and without drug-resistant epilepsy (DRE) identified within one-year post diagnosis by evaluating standardized mean differences between the groups., Results: A total of 205,183 patients with newly diagnosed epilepsy were identified. Of those, 4.1% (n = 8340) were considered drug resistant one-year post diagnosis. Pain and mood disorders were the common physical and psychiatric diagnoses in both cohorts. Differences between the newly diagnosed epilepsy and DRE cohorts were observed. Patients in the DRE cohort were younger, had more encounters with the healthcare system, and higher burden of disease for both physical (e.g., headache, neuropathy, muscular-skeletal disorders, and traumatic brain injury) and psychiatric diagnoses (e.g., depression, anxiety, bipolar disorder, suicidal thoughts, drug dependency, and sleep disorders)., Conclusion: Physical and psychiatric diagnoses are common one year prior to first diagnosis of epilepsy in administrative claims data. Compared to patients without DRE, those who develop DRE within one-year post initial diagnosis demonstrated a higher burden of disease., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors are employees of Janssen Research & Development, LLC and stockholders of Johnson & Johnson., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Peripheral inhibition of tumor necrosis factor (TNF)-α, outside of the central nervous system, may result in clinical improvement of Alzheimer's disease (AD) outcomes. TNF-α inhibitors (TNFIs) are effective treatments for various autoimmune conditions and may be effective for preventing and/or treating AD. The objective of this study was to compare the risk of dementia and AD in patients initiating methotrexate versus those initiating TNFIs., Methods: Insurance claims data from databases of commercially insured and Medicare-eligible patients were used to estimate the risk of dementia and AD within patients with rheumatoid arthritis (RA) initiating a TNFI versus initiation of methotrexate. A sensitivity analysis included all patients without the RA diagnosis requirement. The at-risk period spanned from the index date until a diagnosis of the outcome, loss-to-follow-up, or receipt of the comparator drug. Patients were matched 1-to-1 using propensity scores. A Cox proportional hazards model was used to estimate the hazard ratio (HR). Negative controls were used to calibrate the results., Results: A total of 11,092 new TNFI patients and 44,023 new methotrexate patients were identified, and 8925 from each group were matched. The outcome of dementia occurred in 1.4% of patients in both groups. The calibrated results from the Cox regression found no difference between the two groups (commercially insured database: calibrated HR = 0.69, 95% confidence interval = 0.45 to 1.05; Medicare-only database: 1.14, 0.66 to 1.96). Results were similar in all sensitivity analyses: outcome of AD and including patients without RA., Discussion: No significant difference for the risk of dementia or AD was seen between patients initiating a TNFI versus methotrexate. Although this study cannot conclude whether use of TNFIs is protective against dementia and AD compared with receiving no treatment, there was no evidence that it is more protective than the active comparator methotrexate., Competing Interests: All authors are employees of Janssen Research & Development, LLC and stockholders of Johnson & Johnson., (© 2021 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Background: Following a partial response of first-line antidepressant therapy for the treatment of major depressive disorder (MDD), there is a choice to augment treatment with another agent or switch to a different antidepressant., Objective: To report the prevalence and compare the characteristics of patients switching from their initial selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor (SSRI/SNRI) to a new SSRI/SNRI versus those augmenting SSRI/SNRI therapy with a second-generation antipsychotic (SGA)., Methods: MDD patients receiving first-line SSRI/SNRI treatment were identified from a large US-based claims database during 2000-2019. Patients augmenting therapy with an SGA were compared with those who switched to a new SSRI/SNRI. The date of the treatment change was the index date. Previously diagnosed comorbid conditions, medication use and demographics were captured. Treatment patterns following the index date were also captured. Standardized differences (StdDiff) were used to quantify dissimilarities between the two groups., Results: There were 4572 SGA add-on and 24,409 switching patients identified. SGA augmentation patients had more severe disease (diagnosed severe recurrent major depression: 24.7% vs. 9.5%, StdDiff = 0.41) and more diagnosed psychiatric conditions, including: suicidal thoughts (10.7% vs. 3.2%, StdDiff = 0.29), post-traumatic stress disorder (6.1% vs. 2.6%, StdDiff = 0.17) and alcohol abuse (5.4% vs. 2.7%, StdDiff = 0.14). SGA augmentation patients had higher rates of prior use of anxiolytics (37.4% vs. 28.2%, StdDiff = 0.20) and anticonvulsants (26.0% vs. 13.1%, StdDiff = 0.33)., Conclusions: Patients adding an SGA to their SSRI/SNRI therapy appeared to have more severe depression and comorbid psychiatric profile than those switching their SSRI/SNRI. These differences are important to consider and adequately control for in any future comparative outcome research between these two groups.

SARS-CoV-2 ORF3a is a putative viral ion channel implicated in autophagy inhibition, inflammasome activation and apoptosis. 3a protein and anti-3a antibodies are found in infected patient tissues and plasma. Deletion of 3a in SARS-CoV-1 reduces viral titer and morbidity in mice, suggesting it could be an effective target for vaccines or therapeutics. Here, we present structures of SARS-CoV-2 3a determined by cryo-EM to 2.1-Å resolution. 3a adopts a new fold with a polar cavity that opens to the cytosol and membrane through separate water- and lipid-filled openings. Hydrophilic grooves along outer helices could form ion-conduction paths. Using electrophysiology and fluorescent ion imaging of 3a-reconstituted liposomes, we observe Ca 2+ -permeable, nonselective cation channel activity, identify mutations that alter ion permeability and discover polycationic inhibitors of 3a activity. 3a-like proteins are found across coronavirus lineages that infect bats and humans, suggesting that 3a-targeted approaches could treat COVID-19 and other coronavirus diseases., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Major depressive and bipolar disorders are associated with impaired quality of life and high economic burden. Although progress has been made in our understanding of the underlying pathophysiology and the development of novel pharmacological treatments, a large unmet need remains for finding effective treatment options. The purpose of this study was to identify potential new mechanisms of actions or treatment targets that could inform future research and development opportunities for major depressive and bipolar disorders., Methods: A self-controlled cohort study was conducted to examine associations between 1933 medications and incidence of major depressive and bipolar disorders across four US insurance claims databases. Presence of incident depressive or bipolar disorders were captured for each patient prior to or after drug exposure and incident rate ratios were calculated. Medications that demonstrated ≥50% reduction in risk for both depressive and bipolar disorders within two or more databases were evaluated as potential treatment targets., Results: Eight medications met our inclusion criteria, which fell into three treatment groups: drugs used in substance use disorders; drugs that affect the cholinergic system; and drugs used for the management of cardiovascular-related conditions., Limitations: This study was not designed to confirm a causal association nor inform current clinical practice. Instead, this research and the methods employed intended to be hypothesis generating and help uncover potential treatment pathways that could warrant further investigation., Conclusions: Several potential drug targets that could aid further research and discovery into novel treatments for depressive and bipolar disorders were identified., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: It is critical to assess who is being treated with a new marketed drug like esketamine to understand how it is used in the real-world setting and the effects of the medication., Methods: Retrospective analysis using two large U.S. health care databases that included commercially insured and Medicaid patients. Patients treated with esketamine were identified and their baseline characteristics described and compared with the baseline characteristics of patients with treatment resistant depression (TRD) and with patients undergoing transcranial magnetic stimulation (TMS). To quantify the differences, standardized mean differences were calculated., Results: In the commercially insured database, 418 patients were treated with esketamine and 830,047 patients were in the TRD group. Large differences in baseline characteristics were observed. Patients in the esketamine group were more likely to have severe depression, suicidal thoughts, and prior treatments with TMS or electroconvulsive therapy than the TRD control group. Patients in the esketamine group had more comorbid psychiatric conditions (anxiety disorder, posttraumatic stress disorders, substance use disorders) and higher exposure to antipsychotics, antiepileptics, hypnotics and sedatives. In terms of general health, patients in the esketamine group had many more outpatient visits, were more likely to have chronic pain and higher Charlson comorbidity scores, a predicator of mortality. Results were similar for both the Medicaid and TMS populations., Conclusion: Patients treated with esketamine have a higher burden of disease than other patients with TRD. In any real-world comparative effectiveness or safety study these differences need to be understood and accounted for to produce valid results., (© 2021 The Authors. Depression and Anxiety published by Wiley Periodicals LLC.)

Background: An important component of a systematic strategy for safety surveillance is prospective identification of anticipated serious adverse events (SAEs). Developing a structured approach to identify anticipated events and estimating their incidence can help align the safety strategy and the safety surveillance efforts., Methods: We developed a novel approach to identify anticipated events for a hypothetical randomized, double-blind, controlled trial in subjects with bipolar disorder using the adverse events reported in the placebo arm of trials from the ClinicalTrials.gov database. We searched the ClinicalTrials.gov database for all trials on bipolar depression with similar inclusion/exclusion criteria and study duration as our hypothetical study. The frequencies of anticipated events in placebo arms were abstracted from each trial and 95% confidence intervals (CI) were calculated using the Clopper-Pearson method. Meta-analysis with a random effects model was performed to obtain a summary estimate and 95% CI for the events identified in more than one trial., Results: A total of 129 clinical trials were initially identified, and 18 were ultimately selected as they met all the selection criteria. There were 69 unique anticipated SAEs identified, and 13 out of 69 were reported in at least 2 clinical trials. The top 5 anticipated SAEs for our study were: (1) hospitalization, psychiatric symptom (3.57%); (2) suicidal behavior, overdose (3.57%), (3) cholecystitis (2.86%); (4) fall (2.86%); (5) road traffic accident, injury (2.86%)., Conclusion: We successfully identified the anticipated events from registered trials that included a population similar to our trial. This method for identifying anticipated events could be applied to other disease areas.

Background: Observational data may inform novel drug development programs by identifying previously unappreciated, clinical benefits of existing drugs. Several preclinical and clinical studies have suggested emergent therapeutic utility of drugs acting on the N-methyl-D-aspartate (NMDA) receptor, a subtype of glutamate receptors, including the antidementia drug memantine., Methods: Using a self-controlled cohort study design, the association of exposure to the NMDA receptor antagonist memantine with the incidence of all observed disease outcomes in four US administrative claims databases, spanning from January 2000 through January 2019, was assessed. The databases used in this study were the IBM MarketScan ® Commercial Database (CCAE), the IBM MarketScan ® Multi-State Medicaid Database (MDCD), the IBM MarketScan ® Medicare Supplemental Database (MDCR), and the Optum ©  De-Identified Clinformatics ® Data Mart Database. Outcomes were defined according to the unique Systematized Nomenclature of Medicine-Clinical Terms (SNOMED CT) classification system codes and required a diagnosis on two or more distinct dates. Of 20,953 outcomes assessed, only those for which memantine was associated with a ≥ 50% reduction in risk in two or more databases were included. A meta-analysis with random effects was used to pool data across the databases., Results: Overall, 312,336 patients were exposed to memantine during the study. After removing conditions related to dementia and memory loss, 60 outcomes met the threshold criteria. Results fell into five disease categories: mental disorders, substance use disorders, pain, gastrointestinal and colon disorders, and demyelinating disease. The bulk of findings fell into the first two groups, with 28 outcomes related to mental disorders and 24 related to substance use disorders., Conclusion: The present results confirm that NMDA receptor antagonism may have broader therapeutic utility than previously recognized. Further observational and clinical research may be warranted to explore the therapeutic benefit of NMDA antagonists for the outcomes found in this study.

The SARS-CoV-2 3a protein is a putative ion channel implicated in virus life cycle and pathogenesis. We recently expressed, purified, and reconstituted 3a into lipid nanodiscs to solve its structure by cryo-EM to 2.1Å resolution. In this chapter, we describe methods we developed in order to facilitate the study of this protein in other laboratories. We emphasize factors that enabled rapid progression from gene sequence to reconstituted protein (3 weeks in the case of 3a) and provide general observations and tips for adapting these protocols to other membrane proteins of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To conduct a retrospective analysis of sequential cross-sectional data of opioid prescribing practices in patients with no prior history of opioid use., Methods: Individuals filling an oral opioid prescription who had 1 year of prior observation were identified from four different administrative claims databases for the period between January 1, 2002, and December 31, 2018: IBM MarketScan® Commercial Database (CCAE), Multi-State Medicaid Database (MDCD), Medicare Supplemental Database (MDCR), and Optum© De-Identified Clinformatics® Data Mart Database. Outcomes included incidence of new opioid use and characteristics of patients' first opioid prescription, including dispensed morphine milligram equivalent (MME) per day, total MME dispensed, total MME ≥300, and days' supply of prescription for ≤3 or ≥30 days., Results: There were 40,600,696 new opioid users identified. The incidence of new opioid use in the past 17 years ranged from 6% to 11% within the two commercially insured databases. Incidence decreased over time in MDCD and was consistently higher in MDCR. Total MME dispensed decreased in MDCD and increased in CCAE, with no major changes in the other databases. The proportion of patients receiving ≥30-day prescriptions decreased and the proportion of patients receiving ≤3-day prescriptions increased in MDCD, while ≥30-day prescriptions in the Optum database dramatically increased (low of 3.0% in 2003 to peak of 16.9% in 2017)., Conclusions: Opioid prescribing practices varied across different populations of insured individuals during the past 17 years. The most substantial changes in opioid prescriptions over time have occurred in MDCD, with reductions in use across multiple metrics., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Immunization is an important component of preventive healthcare services. By recognizing and understanding factors associated with suboptimal vaccination compliance, healthcare providers can better approach at-risk populations and target efforts at reinforcing the vital importance of immunizations. The objective of this study was to understand the factors associated with adherence, beliefs and behaviors of influenza, pneumococcal, and herpes zoster vaccines receipt among commercially insured adults. A cross-sectional survey of patients with medical and pharmacy benefits for a 24-month period between August 1, 2014 and July 31, 2016 who were eligible to receive at least one of three adult vaccines (influenza, pneumococcal, and herpes zoster) was completed. Patients were identified as eligible to receive a vaccine based on current guidelines from the CDC ACIP. Health plan members were identified from administrative claims data in the HealthCore Integrated Research DatabaseSM (HIRD). Among the participants, 11% were eligible and up-to-date on all three vaccines; 52% on some and 37% were not up-to-date on any of the three vaccines. Participants with a healthcare provider were more likely to be up-to-date on eligible vaccines: 79.9% for none, 91.3% for some, and 97.8% for all eligible vaccines. The composite Vaccine Myth Belief score was significantly associated with being up to date on eligible vaccines: 45.0%/12.8% for none, 12/5%/30.8% for some, and 8.9%/33.3% for those up-to-date on all eligible vaccines. Despite numerous interventions designed to increase vaccination rates among adults, compliance remains suboptimal. It is evident that patient and provider education is necessary to fill knowledge gaps and misunderstandings; however knowledge by itself is not sufficient to improve immunization practices. Our results highlight a population that could benefit from a multidisciplinary approach, including interventions at the individual and health system levels., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: KS, KJ, LP are employees of MSD, who may own stock and/or hold stock options in the Company. JJS, JV, HC, WY, DMK are or were at time of the study employees of HealthCore Inc., Wilmington, DE USA. Healthcore Inc. received funding from Merck & Co., Inc. for the execution of this study., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: Refilling an opioid prescription early is an important risk factor of prescription opioid abuse and misuse; we aimed to understand the scope of this behavior. This study was conducted to quantify the prevalence and distribution of early refills among patients prescribed opioids., Methods: We conducted a retrospective cohort study utilizing dispensed prescription records. Patients filling one or more prescription opioids were identified and followed for one year. Early refills were defined as having a second prescription filled ≥15% early relative to the days' supply of the previous prescription for the same opioid (according to the National Drug Code [NDC]). The distribution of the number of early refills and patient characteristics were assessed., Results: A total of 60.6 million patients met the study criteria; 28.8% had two or more opioid prescriptions for the same opioid during follow-up. Less than 3% of all patients receiving an opioid had an early refill. Approximately 10% of those with two or more opioid prescriptions for the same drug had an early refill. For patients with multiple fills (N = 1.5 million with extended-release long-acting [ER/LA] opioids; N = 17.1 million with immediate-release short-acting [IR/SA] opioids), early refills were more common among patients with an ER/LA opioid (18.5%) compared with an IR/SA opioid (8.7%). Three-quarters of patients with an early refill had only one (70.9% and 78.4% for ER/LA and IR/SA, respectively)., Conclusion: Refilling an opioid prescription with the same opioid early is an infrequent behavior within all opioid users, but more common in ER/LA users. Patients who refilled early tended to do so just once., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Academy of Pain Medicine.)

Background: The treatment landscape for multiple sclerosis (MS) is quickly evolving. Understanding real-world treatment patterns of patients is necessary to identifying potential gaps in care., Methods: Patients with incident MS were identified from a large national claims database during 1/1/2014-6/30/2019. Patients had ≥2 diagnoses for MS or an inpatient hospitalization with a primary diagnosis of MS. Patients were required to have enrollment in the database ≥1 year prior to and ≥ 1 year following their first MS diagnosis. Treatment sequences were captured for all available disease modifying therapies (DMTs) during all available follow-up. Presence of comorbid conditions were captured during the one year prior to and following (and including) the index date; absolute change in prevalence from the pre- to post-index periods was calculated., Results: We identified 5691 patients with incident MS. Common comorbidities included physical symptoms (e.g., pain, weakness, fatigue), mental health conditions (anxiety, depression), and cardiovascular/metabolic conditions (hypertension, hyperlipidemia, diabetes, obesity). Just 1994 (35.0%) of patients received a DMT at any time during follow-up. Of those receiving a DMT, 28.2% went on to receive a second line of therapy, 5.8% received a third, and just 0.9% went on to a fourth line. Use of more than one DMT concomitantly occurred in just 1.8% of all treated patients. Glatiramer and dimethyl fumarate were by far the most common first-line treatments received accounting for nearly 62% of patients receiving a DMT., Conclusion: Approximately two-thirds of patients newly diagnosed with MS did not receive a DMT and the disease is accompanied by a significant comorbid burden.

Background: Reports suggest low levels of cholesterol are associated with depression. However, results have not been replicated, the direction of the associations among types of cholesterol levels is not consistent, there is large study heterogeneity, and many studies have small samples., Objective: The objective of the study was to assess the association of cholesterol with depression., Methods: This is a cross-sectional study using the National Health and Nutrition Examination Survey (NHANES). The NHANES is a research program that collects health information from a representative U.S., Sample: We included subjects aged ≥18 years who responded to NHANES surveys from 2009 to 2015. Subjects were classified as having major depression if the Patient Health Questionnaire scores were ≥10. Exposures were total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglyceride levels. We considered the age, body mass index, gender, smoking, alcohol use, health status, and exposure to statins and antipsychotics as potential confounders. To assess the association of the exposures with depression, we used decision tree and logistic regression models., Results: A total of 19,527 subjects were analyzed, and 8% had depression. Subjects with depression were more likely to be women and smokers, and to have higher body mass index, poor health, higher levels of total cholesterol and triglycerides and lower levels of high-density lipoprotein cholesterol than subjects with no depression. After adjustment, low levels of total cholesterol (<129 mg/dL) were associated with decreased risk of depression compared with higher levels, OR = 0.64 and 95% CI (0.42-0.98)., Conclusion: This large population-based study found no association of low cholesterol or any other lower type of cholesterol levels with increased risk of depression. These findings are generalizable to the U.S., (Copyright © 2020 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Cation-chloride-cotransporters (CCCs) catalyze transport of Cl - with K + and/or Na + across cellular membranes. CCCs play roles in cellular volume regulation, neural development and function, audition, regulation of blood pressure, and renal function. CCCs are targets of clinically important drugs including loop diuretics and their disruption has been implicated in pathophysiology including epilepsy, hearing loss, and the genetic disorders Andermann, Gitelman, and Bartter syndromes. Here we present the structure of a CCC, the Mus musculus K + -Cl - cotransporter (KCC) KCC4, in lipid nanodiscs determined by cryo-EM. The structure, captured in an inside-open conformation, reveals the architecture of KCCs including an extracellular domain poised to regulate transport activity through an outer gate. We identify binding sites for substrate K + and Cl - ions, demonstrate the importance of key coordinating residues for transporter activity, and provide a structural explanation for varied substrate specificity and ion transport ratio among CCCs. These results provide mechanistic insight into the function and regulation of a physiologically important transporter family., Competing Interests: MR, DK, SB No competing interests declared, (© 2020, Reid et al.)

This study sought to: 1. determine the frequency of rehospitalization with diagnosis of suicidal ideation or suicide attempt (SI/SA) within a year and how often patients had multiple rehospitalizations; 2. identify the time period for which the risk of rehospitalization is highest; and 3. determine the characteristics of patients with multiple rehospitalizations. We conducted a retrospective cohort study of adults with depression using 4 US health claims databases. We defined hospitalization as an inpatient or emergency room visit with codes indicating a suicide attempt or suicidal thoughts using a validated algorithm. Rates of rehospitalization with SI or SA were analyzed together and separately, including multiple re-hospitalizations with SI/SA. Across all databases 121,065 patients were hospitalized with a diagnosis of SI/SA. Rates of rehospitalization within a year ranged from 7.96% to 11.24%. The risk of rehospitalization with SI/SA is highest during the first month. Nearly 50% of rehospitalizations occurred within 3 months after initial hospitalization. Patients with rehospitalization(s) had more anxiety disorders, sleep disorders and substance use disorders than patients without. Among patients with depression hospitalized for SI/SA, rehospitalization for SI/SA within a year is not uncommon. Risk of rehospitalization with a diagnosis of SI/SA is highest during the first month., Competing Interests: Declaration of Competing Interest All authors are employees of Janssen Research & Development, LLC and stockholders of Johnson & Johnson. No mention of any drugs in the manuscript., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Identifying the medical conditions that are associated with poor health is crucial to prioritize decisions for future research and organizing care. However, assessing the burden of disease in the general population is complex, lengthy, and expensive. Claims databases that include self-reported health status can be used to assess the impact of medical conditions on the health in a population., Objective: This study aimed to identify medical conditions that are highly predictive of poor health status using claims databases., Methods: To determine the medical conditions most highly predictive of poor health status, we used a retrospective cohort study using 2 US claims databases. Subjects were commercially insured patients. Health status was measured using a self-report health status response. All medical conditions were included in a least absolute shrinkage and selection operator regression model to assess which conditions were associated with poor versus excellent health., Results: A total of 1,186,871 subjects were included; 61.64% (731,587/1,186,871) reported having excellent or very good health. The leading medical conditions associated with poor health were cancer-related conditions, demyelinating disorders, diabetes, diabetic complications, psychiatric illnesses (mood disorders and schizophrenia), sleep disorders, seizures, male reproductive tract infections, chronic obstructive pulmonary disease, cardiomyopathy, dementia, and headaches., Conclusions: Understanding the impact of disease in a commercially insured population is critical to identify subjects who may be at risk for reduced productivity and job loss. Claims database studies can measure the impact of medical conditions on the health status in a population and to assess changes overtime and could limit the need to collect prospective collection of information, which is slow and expensive, to assess disease burden. Leading medical conditions associated with poor health in a commercially insured population were the ones associated with high burden of disease such as cancer-related conditions, demyelinating disorders, diabetes, diabetic complications, psychiatric illnesses (mood disorders and schizophrenia), infections, chronic obstructive pulmonary disease, cardiomyopathy, and dementia. However, sleep disorders, seizures, male reproductive tract infections, and headaches were also part of the leading medical conditions associated with poor health that had not been identified before as being associated with poor health and deserve more attention., (©M Soledad Cepeda, Jenna Reps, David M Kern, Paul Stang. Originally published in JMIR Public Health and Surveillance (http://publichealth.jmir.org), 08.01.2020.)

Background: Understanding how patients are treated in the real-world is vital to identifying potential gaps in care. We describe the current pharmacologic treatment patterns for the treatment of depression., Methods: Patients with depression were identified from four large national claims databases during 1/1/2014-1/31/2019. Patients had ≥2 diagnoses for depression or an inpatient hospitalization with a diagnosis of depression. Patients were required to have enrollment in the database ≥1 year prior to and 3 years following their first depression diagnosis. Treatment patterns were captured at the class level and included selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, other antidepressants, anxiolytics, hypnotics/sedatives, and antipsychotics. Treatment patterns were captured during all available follow-up., Results: We identified 269,668 patients diagnosed with depression. The proportion not receiving any pharmacological treatment during follow-up ranged from 29 to 52%. Of the treated, approximately half received ≥2 different classes of therapy, a quarter received ≥3 classes and more than 10% received 4 or more. SSRIs were the most common first-line treatment; however, many patients received an anxiolytic, hypnotic/sedative, or antipsychotic prior to any antidepressive treatment. Treatment with a combination of classes ranged from approximately 20% of first-line therapies to 40% of fourth-line., Conclusions: Many patients diagnosed with depression go untreated and many others receive a non-antidepressant medication class as their first treatment. More than half of patients received more than one type of treatment class during the study follow up, suggesting that the first treatment received may not be optimal for most patients.

Background : Among patients with chronic pain using long-term opioid therapy, the incidence of opioid abuse, addiction, overdose, and associated death are not well quantified. The range of estimates for these adverse outcomes varies drastically and may depend on how they are measured (i.e. study definitions of outcomes) and on patient characteristics and opioid-use factors (e.g. regimen, daily dose). Methods : Based on a review of the literature, the US Food and Drug Administration (FDA) required companies that manufacture and sell extended-release/long-acting (ER/LA) opioids conduct as a postmarketing requirement (PMR) a series of observational studies to estimate the rates of treatment-emergent misuse, abuse, addiction, overdose, and death using validated measures. The companies formed a consortium, the Opioid PMR Consortium (OPC), to conduct the studies. Results : The FDA initially requested four observational studies (a cohort study, a questionnaire validation study, a code validation study, and a doctor-shopping validation study), but in order to achieve the FDA's goals of the 4 studies, OPC and FDA agreed to 10 observational studies (a prospective cohort study, a retrospective database cohort study, three questionnaire validation studies, two code validation studies, and three doctor-shopping validation studies). The studies are continuing through 2020. Conclusions : A series of 10 observational studies was or are being conducted in response to the FDA's postmarketing requirement. All studies have been feasible to conduct, although a validated algorithm for measuring abuse and addiction in databases was not successful.