Direct-Acting Oral Anticoagulants and Antiseizure Medications for Atrial Fibrillation and Epilepsy and Risk of Thromboembolic Events.

Importance: Direct-acting oral anticoagulants (DOACs) are commonly prescribed with antiseizure medications (ASMs) due to concurrency of and the association between atrial fibrillation (AF) and epilepsy. However, enzyme-inducing (EI) ASMs may reduce absorption and accelerate metabolism of DOACs, potentially lowering DOAC levels and elevating thromboembolism risk. Objective: To assess the rates of thromboembolic and major bleeding events in adults with AF and epilepsy dispensed DOACs and EI ASMs vs DOACs with non-EI ASMs. Design, Setting, and Participants: This active-comparator, new-user cohort study included US health care data from the Clinformatics Data Mart database from October 2010 to September 2021 for a nationally representative population of adults with AF and epilepsy. Exposure: Evaluations included episodes of contiguous coadministration of DOACs for AF with EI ASMs (exposed) or non-EI ASMs (referent) for epilepsy. Main Outcomes and Measures: Thromboembolic events (primary outcome) and major bleeding events (secondary outcome) were identified based on a series of validated, diagnosis-based coding algorithms. Data-adaptive, high-dimensional propensity score matching was used to control for observed confounders and proxies for unobserved confounders. Adjusted hazard ratios (AHRs) were estimated using Cox proportional hazards regression models with robust variance estimators to account for clustering within matched pairs. Results: This study included 14 078 episodes (median age, 74 [IQR, 67-81]; 52.4% female) and 14 158 episodes (median age, 74 [IQR, 67-81]; 52.4% female) of incident DOAC and ASM use that met eligibility criteria for assessment of thromboembolic and major bleeding outcomes, respectively. Incidence was 88.5 per 1000 person-years for thromboembolic events and 68.3 per 1000 person-years for bleeding events. Compared with use of non-EI ASMs, use of EI ASMs with DOACs was not associated with a difference in risk of thromboembolic events (AHR, 1.10; 95% CI, 0.82-1.46) but was associated with a reduction in risk of major bleeding events (AHR, 0.63; 95% CI, 0.44-0.89). Conclusions and Relevance: In this cohort study, EI ASMs were not associated with alteration in DOAC efficacy. Further research is needed on the reduction in bleeding risk associated with EI ASMs, as this may suggest that pharmacokinetic interactions are associated with lowering DOAC levels without negating therapeutic effects.

Interaction between visual impairment and genetic risk of dementia and psychosis in older adults.

BACKGROUND: Visual impairment (VI) is associated with dementia and other neuropsychiatric outcomes, but previous studies have not considered genetic sources of confounding or effect modification. METHODS: We analysed data from the Health and Retirement Study, an ongoing nationally representative survey of older US adults, a subset of whom underwent genetic testing from 2006 to 2012 (n = 13 465). Using discrete time proportional hazards models and generalised estimating equations, we measured the association between VI and dementia, depression and hallucinations adjusting for demographics and comorbidities, ancestry-specific principal components and polygenic risk scores (PRS) for Alzheimer's disease, major depressive disorder or schizophrenia. Effect modification was assessed using VI-PRS interaction terms and stratified analyses. RESULTS: VI was associated with dementia, depression and hallucinations after adjusting polygenic risk and other confounders. There was no VI-PRS interaction for dementia or depression. However, the association between VI and hallucinations varied by genetic risk of schizophrenia. Within the bottom four quintiles of schizophrenia PRS, VI was not associated with hallucinations among White (OR 1.16, 95% CI: 0.87-1.55) or Black participants (OR 0.96, 95% CI: 0.49-1.89). In contrast, VI was strongly associated with hallucinations among White (OR 2.08, 95% CI: 1.17-3.71) and Black (OR 10.63, 95% CI: 1.74-65.03) participants in the top quintile of schizophrenia PRS. CONCLUSIONS: The association between VI and neuropsychiatric outcomes is not explained by shared genetic risk factors, and there is a significant interaction between VI and polygenic risk of hallucinations in older adults.

Application of high-dimensional propensity score methods to the National Health and Aging Trends Study.

BACKGROUND: High-dimensional propensity scoring (HDPS) is a method for empirically identifying potential confounders within large healthcare databases such as administrative claims data. However, this method has not yet been applied to large national health surveys such as the National Health and Aging Trends Study (NHATS), an ongoing nationally representative survey of older adults in the U.S and important resource in gerontology research. METHODS: In this Research Practice article, we present an overview of HDPS and describe the specific data transformation steps and analytic considerations needed to apply it to national health surveys. We applied HDPS within NHATS to investigate the association between self-reported visual difficulty and incident dementia, comparing HDPS to conventional confounder selection methods. RESULTS: Among 7,207 dementia-free NHATS wave 1 respondents, 528 (7.3%) had self-reported visual difficulty. In an unadjusted discrete time proportional hazards model accounting for the complex survey design of NHATS, self-reported visual difficulty was strongly associated with incident dementia (OR 2.34, 95% CI: 1.95-2.81). After adjustment for standard investigator-selected covariates via inverse probability weighting, the magnitude of this association decreased, but evidence of an association remained (OR 1.44, 95% CI: 1.11-1.85). Adding 75 HDPS-prioritized variables to the investigator-selected propensity score model resulted in further attenuation of the association between visual impairment and dementia (OR 0.94, 95% CI: 0.70-1.23). CONCLUSIONS: HDPS can be successfully applied to national health surveys such as NHATS and may improve confounder adjustment. We hope developing this framework will encourage future consideration of HDPS in this setting.

Thinking Three-Dimensionally: A Self- and Externally-Controlled Approach to Screening for Drug-Drug-Drug Interactions Among High-Risk Populations.

The global rise in polypharmacy has increased both the necessity and complexity of drug-drug interaction (DDI) assessments, given the growing potential for interactions involving more than two drugs. Leveraging large-scale healthcare claims data, we piloted a semi-automated, high-throughput case-crossover-based approach for drug-drug-drug interaction (3DI) screening. Cases were direct-acting oral anticoagulant (DOAC) users with either a major bleeding event during ongoing dispensings for potentially interacting, enzyme-inhibiting antihypertensive drugs (AHDs) (Study 1), or a thromboembolic event during ongoing dispensings for potentially interacting, enzyme-inducing antiseizure medications (ASMs) (Study 2). 3DI detection was based on screening for additional drug exposures that served as acute outcome triggers. To mitigate direct effects and confounding by concomitant drugs, self-controlled estimates were adjusted using negative cases (external "control" DOAC users with the same outcomes but co-dispensings for non-interacting AHDs or ASMs). Signal thresholds were set based on P-values and false discovery rate q-values to address multiple comparisons. Study 1: 285 drugs were examined among 3,306 episodes. Self-controlled assessments with q-value thresholds yielded 9 3DI signals (cases) and 40 DDI signals (negative cases). External adjustment generated 10 3DI signals from the P-value threshold and no signals from the q-value threshold. Study 2: 126 drugs were examined among 604 episodes. Assessments with P-value thresholds yielded 3 3DI and 26 DDI signals following self-control, as well as 4 3DI signals following adjustment. No 3DI signals met the q-value threshold. The presented self- and externally-controlled approach aimed to advance paradigms for real-world higher order drug interaction screening among high-susceptibility populations with pre-existent DDI risk.

Genetic and phenotypic characterization of Parkinson's disease at the clinic-wide level.

Observational studies in Parkinson's disease (PD) deeply characterize relatively small numbers of participants. The Molecular Integration in Neurological Diagnosis Initiative seeks to characterize molecular and clinical features of every PD patient at the University of Pennsylvania (UPenn). The objectives of this study are to determine the feasibility of genetic characterization in PD and assess clinical features by sex and GBA1/LRRK2 status on a clinic-wide scale. All PD patients with clinical visits at the UPenn PD Center between 9/2018 and 12/2022 were eligible. Blood or saliva were collected, and a clinical questionnaire administered. Genotyping at 14 GBA1 and 8 LRRK2 variants was performed. PD symptoms were compared by sex and gene groups. 2063 patients were approached and 1,689 (82%) were enrolled, with 374 (18%) declining to participate. 608 (36%) females were enrolled, 159 (9%) carried a GBA1 variant, and 44 (3%) carried a LRRK2 variant. Compared with males, females across gene groups more frequently reported dystonia (53% vs 46%, p = 0.01) and anxiety (64% vs 55%, p < 0.01), but less frequently reported cognitive impairment (10% vs 49%, p < 0.01) and vivid dreaming (53% vs 60%, p = 0.01). GBA1 variant carriers more frequently reported anxiety (67% vs 57%, p = 0.04) and depression (62% vs 46%, p < 0.01) than non-carriers; LRRK2 variant carriers did not differ from non-carriers. We report feasibility for near-clinic-wide enrollment and characterization of individuals with PD during clinical visits at a high-volume academic center. Clinical symptoms differ by sex and GBA1, but not LRRK2, status.

Self-reported Visual Difficulty, Age-related Eye Disease, and Neuropsychiatric Outcomes in Older Adults.

PURPOSE: Self-reported visual difficulty is consistently associated with dementia and other neuropsychiatric outcomes, but studies of specific age-related eye diseases have yielded conflicting results. METHODS: We conducted a retrospective cohort study using data from The National Health and Aging Trends Study, an ongoing nationally representative survey of older U.S. adults (n = 10,089). All subjects are screened for self-reported visual difficulty annually. Using linked Medicare claims data, we identified subjects with age-related macular degeneration (AMD), primary open-angle glaucoma (POAG), diabetic retinopathy, and cataract. For each condition, controls with complete Medicare eligibility and at least one eye care encounter were selected. We used semiparametric discrete time proportional hazards models to measure associations with incident dementia, and generalized estimating equations to examine longitudinal associations with depression, anxiety, and hallucinations, adjusting for baseline demographics and time-varying comorbidities. RESULTS: Self-reported visual difficulty was associated with dementia (HR 1.16, 95% CI: 1.00-1.34), depression (OR 1.14, 95% CI: 1.04-1.26), anxiety (OR 1.17, 95% CI: 1.06-1.29), and hallucinations (OR 1.54, 95% CI: 1.29-1.84). Diabetic retinopathy was associated with depression (OR 1.31, 95% CI: 1.05-1.64), and cataracts were associated with a lower risk of depression (OR 0.84, 95% CI: 0.74-0.95) and anxiety (OR 0.86, 95% CI: 0.75-0.99). There were no other associations between age-related eye disease and neuropsychiatric outcomes. CONCLUSION: Self-reported visual difficulty is associated with dementia and other neuropsychiatric outcomes to a greater degree than age-related eye disease. These findings highlight the distinction between self-reported vision and clinically diagnosed eye disease with regard to health outcomes in older adults.

Nationwide emergency department visits for pediatric traumatic spinal cord injury in the United States, 2016-2020.

Introduction: Traumatic spinal cord injury (tSCI) is a debilitating neurological condition resulting in lifelong disability for many individuals. The primary objectives of our study were to describe national trends in incident emergency department (ED) visits for tSCI among children (less than 21 years) in the United States, and to determine the proportion of visits that resulted in immediate hospitalization each year, including stratified by age and sex. Secondary objectives were to examine associations between select characteristics and hospitalization following tSCI, as well as to assess sports-related tSCIs over time, including by individual sport and geographic region. Methods: We used the Healthcare Cost and Utilization Project Nationwide Emergency Department Sample to identify ED visits among children between January 2016 and December 2020 for incident tSCI. Diagnosis codes were used to identify tSCI and sports-related injury etiologies. Census Bureau data were used to approximate annual rates of pediatric ED visits for tSCI per 100,000 children. Unconditional logistic regression modeling assessed whether select factors were associated with hospital admission. Results: We found that the annual ED visit rate for tSCI remained relatively stable between 2016 and 2020, with approximately 2,200 new all-cause pediatric ED visits for tSCI annually. Roughly 70% of ED visits for tSCI resulted in hospitalization; most ED visits for tSCI were by older children (15-20 years) and males, who were also more often admitted to the hospital. Notable secondary findings included: (a) compared with older children (15-20 years), younger children (10-14 years) were less likely to be hospitalized immediately following an ED visit for tSCI; (b) patient sex and race were not associated with hospital admission; and (c) American tackle football was the leading cause of sports-related ED visits for tSCI among children. Our findings also suggest that the proportion of sports-related tSCI ED visits may have increased in recent years. Discussion: Future research should further examine trends in the underlying etiologies of pediatric tSCI, while assessing the effectiveness of new and existing interventions aimed at tSCI prevention.

Unique characteristics of end-of-life hospitalizations in Parkinson disease.

Introduction: Persons with Parkinson disease (PD) are hospitalized at higher rates, have longer lengths of stay, and are more likely to die in the hospital than age-matched peers. Although prior studies have compared inpatient outcomes between persons with and without PD, little is known about inpatient outcomes across the PD trajectory, or whether hospitalizations occurring in the last 6 months of life differ from earlier hospitalizations. Methods: This cross-sectional study compared Medicare Part A and B beneficiaries aged 65 and older with a qualifying PD diagnosis who were hospitalized in 2017: decedents who died between 7/1/2017 and 12/31/2017 from all causes and were hospitalized at least once in their last 6 months of life, and non-decedents who were hospitalized between 1/1/2017 and 6/30/2017 and lived 6 or more months after discharge. End-of-life (EoL) hospitalizations were defined as those occurring in the last 6 months of life. Descriptive analyses compared patient-level variables (e.g., demographics, comorbidities, treatment intensity) and encounter-level variables (e.g., length of stay, total charges) between groups. Multivariable logistic regression models also compared rates of intensive care unit (ICU) admission and 30-day readmission between hospitalized decedents and hospitalized non-decedents, adjusting for age, sex, race/ethnicity, rural residence, and Charlson Comorbidity Index Score. Results: Of 26,492 Medicare decedents with PD, 16,187 (61.1%) were hospitalized in their last 6 months of life. Of 347,512 non-decedents with PD, 62,851 (18.1%) were hospitalized in a 6-month period. Hospitalized decedents were slightly older than hospitalized non-decedents (82.3 [SD 7.40] vs. 79.5 [SD 7.54] years) and had significantly more comorbidities. Compared to non-EoL hospitalizations, EoL hospitalizations were slightly longer (5 [IQR 3-9] vs. 4 [IQR 3-7] days) and more expensive based on total charges per admission ($36,323 [IQR 20,091-69,048] vs. $32,309 [IQR 18,789-57,756]). In covariate-adjusted regression models using hospitalized non-decedents as the reference group, hospitalized decedents were more likely to experience an ICU admission (AOR 2.36; CI 2.28-2.45) and 30-day readmission (AOR 2.43; CI 2.34-2.54). Discussion: Hospitalizations occurring in the last 6 months of life among persons with PD in the United States are longer, more costly, and more resource intensive than earlier hospitalizations and may stem from medical comorbidities. Once hospitalized, ICU admission and 30-day readmission may aid in prognostication and serve as markers of transition to the EoL period.

Health equity integrated epilepsy care and research: A narrative review.

BACKGROUND: With the unanimous approval of the Intersectoral Global Action Plan on epilepsy and other neurological disorders by the World Health Organization in May 2022, there are strong imperatives to work towards equitable neurological care. AIMS: Using epilepsy as an entry point to other neurologic conditions, we discuss disparities faced by marginalized groups including racial/ethnic minorities, Americans living in rural communities, and Americans with low socioeconomic status. MATERIALS AND METHODS: The National Institute on Minority Health Disparities Research Framework (NIMHD) was used to conduct a narrative review through a health equity lens to create an adapted framework for epilepsy and propose approaches to working towards equitable epilepsy and neurological care. RESULTS: In this narrative review, we identified priority populations (racial and ethnic minority, rural-residing, and low socioeconomic status persons with epilepsy) and outcomes (likelihood to see a neurologist, be prescribed antiseizure medications, undergo epilepsy surgery, and be hospitalized) to explore disparities in epilepsy and guide our focused literature search using PubMed. In an adapted NIMHD framework, we examined individual, interpersonal, community, and societal level contributors to health disparities across five domains: (1) behavioral, (2) physical/built environment, (3) sociocultural, (4) environment, and (5) healthcare system. We take a health equity approach to propose initiatives that target modifiable factors that impact disparities and advocate for sustainable change for priority populations. DISCUSSION: To improve equity, healthcare providers and relevant societal stakeholders can advocate for improved care coordination, referrals for epilepsy surgery, access to care, health informatics interventions, and education (i.e., to providers, patients, and communities). More broadly, stakeholders can advocate for reforms in medical education, and in the American health insurance landscape. CONCLUSIONS: Equitable healthcare should be a priority in neurological care.

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

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

Potentially inappropriate medications in older adults with Parkinson disease before and after hospitalization for injury.

BACKGROUND: Parkinson disease (PD) patients are at increased risk of serious injury, such as fall-related fractures. Prescription medications are a modifiable factor for injury risk. OBJECTIVES: To determine the extent to which a serious injury requiring hospitalization affects prescribing of potentially inappropriate medications (PIMs) among older adults with PD. METHODS: We conducted a quasi-experimental difference-in-difference (DID) study using 2013-2017 Medicare data. The cohort consisted of beneficiaries with PD hospitalized for injury versus for other reasons. PIMs were classified into PD and injury-relevant categories (CNS-active PIMs, PD motor symptom PIMs, PD non-motor symptom PIMs, PIMs that reduce bone mineral density). We estimated mean standardized daily doses (SDDs) of medications within each PIM category before and at 3, 6, and 12 months after hospitalization. We used generalized linear regression models to compare changes in mean SDDs for each PIM category between the injury and non-injury group at each timepoint, adjusting for biological, clinical and social determinants of health variables. RESULTS: Both groups discontinued PIMs and/or reduced PIM doses after hospitalization. There were no between-group differences in mean SDD changes, after covariate adjustment, for any PIM category, except for the CNS-active PIMs category at 3 months (DID p-value = 0.00) and for the category of PIMs that reduce bone mineral density at all timepoints (DID p-values = 0.02, 0.04, 0.02 at 3, 6, and 12 months). CONCLUSIONS: Similar patterns of PIM among persons with PD after hospitalization for serious injury versus for other reasons may represent a missed opportunity to deprescribe high-risk medications during care transitions.

Adjusting for Underrepresentation Reveals Widespread Underestimation of Parkinson's Disease Symptom Burden.

BACKGROUND: Clinical research is limited by underrepresentation, but the impact of underrepresentation on patient-reported outcomes in Parkinson's disease (PD) is unknown. OBJECTIVES: To produce nationwide estimates of non-motor symptom (NMS) prevalence and PD-related quality of life (QOL) limitations while accounting for underrepresentation. METHODS: We performed a cross-sectional analysis of data from the Fox Insight (FI) study, an ongoing prospective longitudinal study of persons with self-reported PD. Using epidemiologic literature and United States (US) Census Bureau, Medicare, and National Health and Aging Trends Study data, we simulated a "virtual census" of the PD population. To compare the PD census to the FI cohort, we used logistic regression to model the odds of study participation and calculate predicted probabilities of participation for inverse probability weighting. RESULTS: There are an estimated 849,488 persons living with PD in the US. Compared to 22,465 eligible FI participants, non-participants are more likely to be older, female, and non-White; live in rural regions; have more severe PD; and have lower levels of education. When these predictors were incorporated into a multivariable regression model, predicted probability of participation was much higher for FI participants than non-participants, indicating a significant difference in the underlying populations (propensity score distance 2.62). Estimates of NMS prevalence and QOL limitation were greater when analyzed using inverse probability of participation weighting compared to unweighted means and frequencies. CONCLUSIONS: PD-related morbidity may be underestimated because of underrepresentation, and inverse probability of participation weighting can be used to give greater weight to underrepresented groups and produce more generalizable estimates. © 2023 International Parkinson and Movement Disorder Society.

Sociodemographic and Geographic Disparities in End-of-Life Health Care Intensity Among Medicare Beneficiaries With Parkinson Disease.

Background and Objective: Current studies of end-of-life care in Parkinson disease (PD) do not focus on diverse patient samples or provide national views of end-of-life resource utilization. We determined sociodemographic and geographic differences in end-of-life inpatient care intensity among persons with PD in the United States (US). Methods: This retrospective cohort study included Medicare Part A and Part B beneficiaries 65 years and older with a qualifying PD diagnosis who died between January 1, 2017, and December 31, 2017. Medicare Advantage beneficiaries and those with atypical or secondary parkinsonism were excluded. Primary outcomes included rates of hospitalization, intensive care unit (ICU) admission, in-hospital death, and hospice discharge in the last 6 months of life. Descriptive analyses and multivariable logistic regression models compared differences in end-of-life resource utilization and treatment intensity. Adjusted models included demographic and geographic variables, Charlson Comorbidity Index score, and Social Deprivation Index score. The national distribution of primary outcomes was mapped and compared by hospital referral region using Moran I. Results: Of 400,791 Medicare beneficiaries with PD in 2017, 53,279 (13.3%) died. Of decedents, 33,107 (62.1%) were hospitalized in the last 6 months of life. In covariate-adjusted regression models using White male decedents as the reference category, odds of hospitalization was greater for Asian (AOR 1.38; CI 1.11-1.71) and Black (AOR 1.23; CI 1.08-1.39) male decedents and lower for White female decedents (AOR 0.80; CI 0.76-0.83). ICU admissions were less likely in female decedents and more likely in Asian, Black, and Hispanic decedents. Odds of in-hospital death was greater among Asian (AOR 2.49, CI 2.10-2.96), Black (AOR 1.11, CI 1.00-1.24), Hispanic (AOR 1.59; CI 1.33-1.91), and Native American (AOR 1.49; CI 1.05-2.10) decedents. Asian and Hispanic male decedents were less likely to be discharged to hospice. In geographical analyses, rural-dwelling decedents had lower odds of ICU admission (AOR 0.77; CI 0.73-0.81) and hospice discharge (AOR 0.69; CI 0.65-0.73) than urban-dwelling decedents. Nonrandom clusters of primary outcomes were observed across the US, with highest rates of hospitalization in the South and Midwest (Moran I = 0.134; p < 0.001). Discussion: Most persons with PD in the US are hospitalized in the last 6 months of life, and treatment intensity varies by sex, race, ethnicity, and geographic location. These group differences emphasize the importance of exploring end-of-life care preferences, service availability, and care quality among diverse populations with PD and may inform new approaches to advance care planning.

Racial and Ethnic Disparities in Parkinson Disease: A Call to Action.

Health disparities are pervasive in the United States. In the field of Parkinson disease (PD), profound racial and ethnic disparities exist in diagnosis, treatment, and research participation, leading to differential health outcomes and lack of generalizable research data. Racial and ethnic disparities not only limit our understanding of this complex heterogeneous disorder but also hamper our ability to provide new evidence-based care for America's most vulnerable populations. In this report, we summarize findings from our comprehensive white paper for the Michael J. Fox Foundation that reviews the current state of knowledge on racial and ethnic disparities in PD care in the following areas: epidemiology, etiology, phenotype and diagnosis, treatment, and research. We also identify knowledge gaps and necessary policy changes to ensure equitable, high-value care for all persons with PD. These strategies are designed to help identify and reduce health disparities among persons with PD and may serve as a model for other neurologic diseases.

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

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

Dopamine agonists and risk of lung cancer in patients with restless legs syndrome.

PURPOSE: To examine the association between long-term use of dopamine agonists (DAs) and the risk of lung cancer in patients with restless legs syndrome (RLS). METHODS: We conducted a retrospective cohort study using Optum Clinformatics® database. We included adults ≥40 years diagnosed with RLS during the study period (1/2006-12/2016). Follow-up started with the first RLS diagnosis and ended on the earliest of: incident diagnosis of lung cancer, end of enrollment in the database or end of the study period. The exposure of interest was cumulative duration of DAs use, measured in a time-varying manner. We constructed a multivariable Cox regression model to estimate HRs and 95% CIs for the association between lung cancer and cumulative durations of DA use, adjusting for potential confounding variables. RESULTS: We identified 295 042 patients with a diagnosis of RLS. The mean age of the cohort was 62.9; 66.6% were women and 82.3% were white. The prevalence of any DA exposure was 40.3%. Compared to the reference group (no use and ≤1 year), the crude HRs for lung cancer were 1.16 (95% CI 0.99-1.36) and 1.14 (95% CI 0.86-1.51) for 1-3 years and >3 years of cumulative DA use, respectively. The adjusted HR for lung cancer was 1.05 (95% CI 0.88-1.25) for 1-3 years and 1.02 (95% CI 0.76-1.37) for >3 years of cumulative DA use, respectively. CONCLUSIONS: At typical doses for the clinical management of RLS, long-term DA use was not associated with risk of lung cancer.

Nationwide trends in emergency department utilisation for acute retinal ischaemia in the USA, 2011-2018.

BACKGROUND: Guidelines recommend urgent evaluation for transient monocular vision loss (TMVL) and retinal artery occlusion (RAO), but emergency department (ED) utilisation for these conditions is unknown. METHODS: We performed a retrospective longitudinal cross-sectional analysis of the Nationwide Emergency Department Sample (2011-2018), a database of all ED visits from a representative 20% sample of US hospital-based EDs. We identified patients aged 40 and older with a primary diagnosis of TMVL or RAO and calculated the weighted number of total visits and admission rate by year. We used joinpoint regression to analyse time trends and logistic regression to measure differences according to demographic characteristics and comorbidities. RESULTS: There were an estimated 2451 ED visits for TMVL and 2472 for RAO annually in the USA from 2011 to 2018. Approximately 36% of TMVL and 51% of RAO patients were admitted. The admission rate decreased by an average of 4.9% per year for TMVL (95% CI -7.5% to -2.3%) and 2.2% per year for RAO (95% CI -4.1% to -0.4%), but the total number of ED visits did not change significantly over time. Elixhauser Comorbidity Index and hyperlipidaemia were associated with increased odds of hospital admission for both TMVL and RAO. There were also differences in admission rate by insurance payer and hospital region. CONCLUSION: Of the estimated 48 000 patients with TMVL or RAO annually in the USA, few are evaluated in the ED, and admission rates are less than for transient ischaemic attack or ischaemic stroke and are decreasing over time.

Seasonal Variation in Neurologic Hospitalizations in the United States.

OBJECTIVE: Certain neurologic diseases have been noted to vary by season, and this is important for understanding disease mechanisms and risk factors, but seasonality has not been systematically examined across the spectrum of neurologic disease, and methodologic guidance is also lacking. METHODS: Using nationally representative data from the National Inpatient Sample, a stratified 20% sample of all non-federal acute care hospitalizations in the United States, we calculated the monthly rate of hospitalization for 14 neurologic diseases from 2016 to 2018. For each disease, we assessed seasonality of hospitalization using chi-squared, Edward, and Walter-Elwood tests and seasonal time series regression models. Statistical tests were adjusted for multiple hypothesis testing using Bonferroni correction. RESULTS: Meningitis, encephalitis, ischemic stroke, intracerebral hemorrhage, Guillain-Barre syndrome, and multiple sclerosis had statistically significant seasonality according to multiple methods of testing. Subarachnoid hemorrhage, status epilepticus, myasthenia gravis, and epilepsy had significant seasonality according to Edwards and Walter-Elwood tests but not chi-square tests. Seasonal time series regression illustrated seasonal variation in all 14 diseases of interest, but statistical testing for seasonality within these models using the Kruskal-Wallis test only achieved statistical significance for meningitis. INTERPRETATION: Seasonal variation is present across the spectrum of acute neurologic disease, including some conditions for which seasonality has not previously been described, and can be examined using multiple different methods. ANN NEUROL 2023;93:743-751.

Functional Impairment in Individuals With Prodromal or Unrecognized Parkinson Disease.

Importance: Daily functioning in individuals with prodromal Parkinson disease requires more detailed description. Objective: To evaluate whether functional limitations exist in individuals with Parkinson disease prior to diagnosis compared with the general population. Design, Setting, and Participants: This case-control study used Medicare-linked data from the National Health and Aging Trends Study (NHATS), a longitudinal survey in the US, for a random subsample of Medicare beneficiaries aged 65 years or older, with Black and older individuals oversampled by design. Patients with incident Parkinson disease were defined as having 2 or more Medicare diagnoses from January 2011 to December 2017, with Medicare eligibility 2 or more consecutive years prior to the first diagnosis. Controls were defined as individuals with Medicare eligibility at a baseline year and 2 or more years prior, with no Parkinson disease diagnosis. Analyses were conducted from November 2021 to June 2022. Exposures: Responses to survey questions addressing dexterity, eating, mobility, mood, pain, sleep, speech, strength, and vision. Main Outcome and Measures: Associations between survey responses and Parkinson disease diagnosis in the first year of diagnosis (baseline) and up to 3 years prior to diagnosis (ie, during the prodromal phase) were examined using logistic regression. Results: A total of 6674 participants were included. The participant numbers and case prevalence each year varied from 3492 to 5049 and from 700 to 1180 per 100 000 population, respectively. The median age groups were 75 to 79 years and 80 to 84 years, and the percentage of females varied from 48.21% (27 of 56 cases) to 59.98% (2079 of 3466 controls) across all years, with similar proportions among cases and controls. Individuals with prodromal Parkinson disease were less likely to report being able to walk 6 blocks (odds ratio [OR], 0.34; 95% CI, 0.15-0.82), stand independently from a kneeling position (OR, 0.30; 95% CI, 0.11-0.85), or lift a heavy object above one's head (OR, 0.36; 95% CI, 0.15-0.87) and were more likely to report imbalance (OR, 2.77; 95% CI, 1.24-6.20) 3 years prior to diagnosis. Conclusions and Relevance: The findings suggest that individuals with prodromal or unrecognized Parkinson disease may have greater impairment in activities involving mobility and strength up to 3 years prior to diagnosis compared with the general population. Identification of prodromal disease may facilitate earlier intervention to improve function.