Search

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: 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.

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).)

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).)

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: 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.)

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.)

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.

Introduction: There is a significant need for disease-modifying therapies to treat and prevent dementia, including Alzheimer's disease. Availability of real-world observational information and new analytic techniques to analyze large volumes of data can provide a path to aid drug discovery., Methods: Using a self-controlled study design, we examined the association between 2181 medications and incidence of dementia across four US insurance claims databases. Medications associated with ≥50% reduction in risk of dementia in ≥2 databases were examined., Results: A total of 117,015,066 individuals were included in the analysis. Seventeen medications met our threshold criteria for a potential protective effect on dementia and fell into five classes: catecholamine modulators, anticonvulsants, antibiotics/antivirals, anticoagulants, and a miscellaneous group., Discussion: The biological pathways of the medications identified in this analysis may be targets for further research and may aid in discovering novel therapeutic approaches to treat dementia. These data show association not causality., (© 2019 The Authors.)

Background: Parkinson's disease is a disorder growing in prevalence, disability, and deaths. Healthcare databases provide a 'real-world' perspective for millions of individuals. We envisioned helping accelerate drug discovery by using these databases., Objectives: The objectives of this study were to assess the association of marketed medications with the risk of parkinsonism in four US claims databases and to evaluate the consistency of the association of β-adrenoreceptor modulation with parkinsonism., Methods: The study was conducted using a self-controlled cohort design in which subjects served as their own control. The time from treatment initiation until discontinuation or end of observation was the exposed period and a similar time preceding medication was the unexposed period. Medications were studied at ingredient and class level. The incidence rate ratio (IRR) and combined IRR were calculated., Results: We assessed 2181 drugs and 117,015,066 people. Diphenhydramine, isradipine, methylphenidate, armodafinil, and modafinil were associated with reduced risk for parkinsonism in at least two databases. Armodafinil, modafinil, methylphenidate, and the β-agonist albuterol were associated with a 56%, 54%, 39%, and 17% reduction in the risk of having parkinsonism, respectively. Isradipine results were heterogeneous and no significant association was found. Propranolol was associated with a 32% increased risk, the only β-adrenoceptor antagonist (β-blocker) associated with an increased risk., Conclusions: Armodafinil, modafinil, and methylphenidate were associated with a decreased risk of parkinsonism, as were β-agonists. Of the β-blockers, only propranolol was associated with increased risk. Healthcare database analyses that incorporate scientific rigor provide insight and direction for drug discovery efforts. These findings show association not causality; however, they offer considerable support to the association between β-adrenergic receptor modulation and risk of Parkinson's disease.

Introduction: Complex or personalized insulin regimens challenge traditional adherence measures. Our objective was to develop an improved basal insulin (BI) adherence measure using both patient-reported and administrative claims data, resulting in a more complete measure., Methods: Patients' self-reported BI utilization over the previous 12 months was linked with their claims data for the same period. Hybrid medication possession ratio (MPR) was derived by calculating expected days of insulin supply [total dispensed insulin units from claims over 12 months divided by self-reported total daily dose (TDD)]. The hybrid MPR was compared against traditional claims-based MPR, adjusted claims-based MPR, and patient-reported MPR. For all MPR measures, the adherence threshold was ≥ 0.8. A logistic model was used to predict non-adherence per hybrid MPR. The predicted model-based MPR was compared with existing measures in a larger cohort., Results: The study sample consisted of 296 patients. TDD derived from claims was higher than self-reported TDD [77.9 (71.8) vs. 57.7 (38.3)], implying average dispensed insulin would last longer than claims-based days supply. Correspondingly, hybrid and MPRs adjusted for package size (56% and 71%, respectively) were higher than claims-based MPR (50%). Age, total claims-based days supply, retinopathy, adjusted MPR-based adherence, and non-insulin injectable use were key predictors of hybrid MPR-based adherence. Applying the claims-based prediction model to a larger cohort to test validity showed high correlations with predicted and adjusted MPR-based adherence., Conclusions: Traditional claims-based MPR underestimated adherence while adjusted MPR overestimated adherence when self-reported total daily dose was taken as benchmark insulin dose. The predicted model may help identify patients with poor basal insulin adherence. More research is needed to further confirm the findings., Funding: Eli Lilly and Company, Indianapolis, IN, USA.

Introduction: To describe treatment patterns in newly diagnosed rheumatoid arthritis (RA) patients in a large, nationally representative managed-care database., Methods: Newly diagnosed RA patients were identified from 07/01/2006-08/31/2014. Patients had ≥ 1 RA diagnosis by a rheumatologist, or ≥ 2 non-rheumatologist RA diagnoses ≥ 30 days apart, or RA diagnosis followed by a disease-modifying antirheumatic drug (DMARD) prescription fill within 1 year. Patients were ≥ 18 years old at index (earliest date fulfilling diagnostic criteria) and had ≥ 6 and 12 months of pre- and post-index health plan enrollment, respectively. Patterns of DMARD treatment, including conventional synthetic DMARDs (csDMARD), tumor necrosis factor inhibitors (TNFi), non-TNFi, and Janus kinase inhibitors (JAKi), were captured during follow-up., Results: Of the 63,101 RA patients identified, 73% were female; mean age was 57 years. During an average of 3.5 ± 2.1 years of follow-up, 45% of patients never received a DMARD, 52% received a csDMARD (94 ± 298 mean ± SD days from index), 16% a TNFi (315 ± 448 days), 4% a non-TNFi (757 ± 660 days), and < 1% a JAKi. Among DMARD recipients, the most common treatment patterns were: receiving csDMARDs only (68%), adding a TNFi as second-line therapy after initiation of a csDMARD (12%), and receiving only a TNFi (6%) during follow-up. Among those not on DMARDs, the all-cause usage of an opioid was 56% and 19% had chronic opioid use (≥ 180 days supplied)., Conclusions: Despite American College of Rheumatology recommendations for DMARD treatment of RA, nearly half of newly diagnosed RA patients received no DMARD therapy during follow-up. These data identify a treatment gap in RA management., Funding: Eli Lilly & Company.

This study examined the association between the price of healthier food relative to unhealthy food and type 2 diabetes prevalence, incidence and insulin resistance (IR). Data came from the Multi-Ethnic Study of Atherosclerosis exam 5 administered 2010-2012 (exam 4, five years prior, was used only for diabetes incidence) and supermarket food/beverage prices derived from Information Resources Inc. For each individual, average price of a selection of healthier foods, unhealthy foods and their ratio was computed for supermarkets within 3miles of the person's residential address. Diabetes status was confirmed at each exam and IR was assessed via the homeostasis model assessment index. Multivariable-adjusted logistic, modified Poisson and linear regression models were used to model diabetes prevalence, incidence and IR, respectively as a function of price and covariates; 2353 to 3408 participants were included in analyses (depending on the outcome). A higher ratio of healthy-to-unhealthy neighborhood food price was associated with greater IR (4.8% higher HOMA-IR score for each standard deviation higher price ratio [95% CI -0.2% to 10.1%]) after adjusting for region, age, gender, race/ethnicity, family history of diabetes, income/wealth index, education, smoking status, physical activity, and neighborhood socioeconomic status. No association with diabetes incidence (relative risk=1.11, 95% CI 0.85 to 1.44) or prevalence (odds ratio=0.95, 95% CI 0.81 to 1.11) was observed. Higher neighborhood prices of healthier food relative to unhealthy food were positively associated with IR, but not with either diabetes outcome. This study provides new insight into the relationship between food prices with IR and diabetes., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Few studies have examined associations of geographically proximal cigarette prices with within-person changes in smoking outcomes or assessed interactions between cigarette prices and smoking bans., Methods: We linked neighborhood cigarette prices (inflation-adjusted) at chain supermarkets and drug stores and bar/restaurant smoking ban policies to cohort participants (632 smokers from the Multi-Ethnic Study of Atherosclerosis, 2001-2012, baseline mean age 58 years) using geocoded retailer and participant addresses. We used fixed-effects models to investigate associations of within-person changes in price and ban exposures with within-person changes in five smoking outcomes: current smoking, heavy (≥10 cigarettes) smoking, cessation, relapse, and intensity (average number of cigarettes smoked per day, natural log transformed). We assessed intensity associations among all smokers, and heavy (≥10 cigarettes per day) and light (<10) baseline smokers. Finally, we tested interactions between cigarette price and bans., Results: A $1 increase in price was associated with a 3% reduction in risk of current smoking (adjusted risk ratio [aRR]: 0.97; 95% confidence interval [CI] = 0.93, 1.0), a 7% reduction in risk of heavy smoking (aRR: 0.93; CI = 0.87, 0.99), a 20% increase in risk of smoking cessation (aRR: 1.2; CI = 0.99, 1.4), and a 35% reduction in the average number of cigarettes smoked per day by heavy baseline smokers (ratio of geometric means: 0.65; CI = 0.45, 0.93). We found no association between smoking bans and outcomes, and no evidence that price effects were modified by the presence of bans., Conclusions: Results underscore the importance of local prices, but not hospitality smoking bans, in influencing older adults' smoking behaviors.

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<0.001), indicating a 22% reduction in risk of COPD exacerbation associated with initiation of BFC versus tiotropium. A post hoc sensitivity analysis found similar effects in those who had a prior asthma diagnosis (HR =0.72 [0.61, 0.86]) and those who did not (HR =0.83 [0.72, 0.96]). BFC initiation was associated with lower COPD-related health care resource utilization and costs ($4,084 per patient-year compared with $5,656 for tiotropium patients, P<0.001)., Conclusion: In COPD patients new to controller therapies, initiating treatment with BFC was associated with improvements in health and economic outcomes compared with tiotropium.

Objectives: To evaluate treatment patterns, healthcare resource utilization, and costs among patients within a large managed care population chronically using opioids for non-cancer pain., Study Design: Retrospective cohort study., Methods: Patients aged ≥18 years with ≥1 prescription initiating opioids between January 1, 2007, and December 31, 2011, who also had 12 months of continuous pre-index health plan enrollment, were identified. Patients with pre-index opioid use or cancer diagnosis were excluded. Opioid exposure was stratified by treatment duration-short-term (30-182 days) versus chronic (≥183 days)-and by index opioid type (weak vs strong)., Results: A total of 2.9 million patients initiating opioids were identified, of which 257,602 had at least 30 days of continuous use and were included in the study. The mean age was 51 years and 52% were female. Overall, 239,998 (93%) patients had short-term opioid use, and 17,604 (7%) had chronic use; 215,424 (84%) initiated treatment with a weak opioid, and 44,712 (17%) with a strong opioid. The specialty most associated with the use of less potent opioids was general/family practice (28%), and for more potent opioids it was surgery (22%). Large increases in health-care utilization were reported between the pre-index and first 6-month post initiation periods for chronic users. Utilization rates decreased after the first 6 months but never reverted to baseline levels. Costs mirrored utilization trends, more than doubling between baseline and the first 6 months of treatment for pharmacy ($2029 vs $4331) and all-cause medical ($11,430 vs $27,365). Costs declined after the first 6 months of opioid use but remained above pre-index levels., Conclusions: These results demonstrated that healthcare resource utilization and costs increased during the first 6 months following clinical scenarios that necessitated opioid initiation and subsequently declined, suggesting the need to monitor patients beyond the acute care period.