Matching study design to prescribing intention: The prevalent new-user design for studying abuse-deterrent formulations of opioids.

PURPOSE: In drug studies, research designs requiring no prior exposure to certain drug classes may restrict important populations. Since abuse-deterrent formulations (ADF) of opioids are routinely prescribed after other opioids, choice of study design, identification of appropriate comparators, and addressing confounding by "indication" are important considerations in ADF post-marketing studies. METHODS: In a retrospective cohort study using claims data (2006-2018) from a North Carolina private insurer [NC claims] and Merative MarketScan [MarketScan], we identified patients (18-64 years old) initiating ADF or non-ADF extended-release/long-acting (ER/LA) opioids. We compared patient characteristics and described opioid treatment history between treatment groups, classifying patients as traditional (no opioid claims during prior six-month washout period) or prevalent new users. RESULTS: We identified 8415 (NC claims) and 147 978 (MarketScan) ADF, and 10 114 (NC claims) and 232 028 (MarketScan) non-ADF ER/LA opioid initiators. Most had prior opioid exposure (ranging 64%-74%), and key clinical differences included higher prevalence of recent acute or chronic pain and surgery among patients initiating ADFs compared to non-ADF ER/LA initiators. Concurrent immediate-release opioid prescriptions at initiation were more common in prevalent new users than traditional new users. CONCLUSIONS: Careful consideration of the study design, comparator choice, and confounding by "indication" is crucial when examining ADF opioid use-related outcomes.

Medicare Medication Therapy Management: beneficiary characteristics and utilization patterns in a national CMS Medicare fee-for-service sample (2013-2016).

BACKGROUND: The Medicare Medication Therapy Management (MTM) program has been available to eligible Medicare Part D beneficiaries since 2006, but research regarding program utilization and characterization is limited. OBJECTIVE: To describe enrollee and MTM program characteristics in a national sample of Medicare fee-for-service (FFS) beneficiaries (2013-2016). METHODS: Using a 5% random sample of Medicare FFS beneficiaries, we conducted a descriptive time series analysis to examine annual MTM enrollment and describe the type of MTM criteria at enrollment (Center for Medicare and Medicaid Services [CMS] vs. expanded). We investigated the offer of Comprehensive Medication Review (CMR) along with CMR receipt status, and delivery characteristics, as well as frequencies of Target Medication Reviews (TMR). RESULT: Beneficiaries who met CMS enrollment criteria, compared to those eligible under expanded criteria, were significantly older, more likely to be of white race, more likely to be female, and had a significantly higher number of comorbidities. Of those meeting CMS criteria, the proportion receiving TMR increased from 95% in 2013 to 98.1% in 2016, and over 97% were offered a CMR. Although the proportion of beneficiaries offered a CMR was stable over the study period, the proportion who received a CMR increased from 17% in 2013 to 35.4% in 2016. Telephone CMR delivery was the most common method used (87.8% to 89.1% of CMRs over the study period). Over 95% of the CMRs were delivered by a pharmacist. CONCLUSION: During the years 2013-2016, enrollment in the MTM program increased, as did the proportion of enrollees receiving TMRs and CMRs. However, uptake remained low and the main factors driving participation remain unclear. Significant differences in demographic characteristics between beneficiaries enrolled under the CMS MTM enrollment criteria and the expanded criteria suggest the need to further investigate the optimal provision of such programs.

Patterns and Trends in Continuous Glucose Monitoring Utilization Among Commercially Insured Individuals With Type 1 Diabetes: 2010-2013 to 2016-2019.

Prior studies suggest that only ∼30% of patients with type 1 diabetes use continuous glucose monitoring (CGM), but most studies to date focused on children and young adults seen by endocrinologists or in academic centers. This study examined national trends in CGM utilization among commercially insured children and adults with type 1 diabetes. Overall, CGM utilization was 20.12% in 2010-2013 and 49.78% in 2016-2019, reflecting a 2.5-fold increase in utilization within a period of <10 years. Identifying populations with low CGM use is a necessary first step in developing targeted interventions to increase CGM uptake.

Prescribing Characteristics of Octreotide Immediate-Release and Long-Acting Release in Patients with Neuroendocrine Tumors.

BACKGROUND: Treatment recommendations for patients with neuroendocrine tumors (NETs) include the use of octreotide long-acting release (LAR) for long-term therapy and immediate-release (IR) as rescue therapy to control the breakthrough symptoms of carcinoid syndrome (CS). High doses of LAR are commonly used in clinical practice. This study aimed to evaluate the real-world utilization of LAR and preceding IR use at the prescription and patient levels. METHODS: We used an administrative claims database (2009-2018) containing privately insured enrollees. We calculated the normalized LAR dose from pharmacy claims and the initial mean IR daily dose at the prescription level. At the patient level, we conducted a retrospective cohort study that included patients continuously enrolled with ≥1 pharmacy claim of LAR and evaluated the frequency and the clinical reason for dose escalation of LAR. The definition of the above-label maximum dose of LAR was ≥30 mg/4 weeks. RESULTS: Nineteen percent of LAR prescriptions had an above-label maximum dose. Only 7% of LAR prescriptions had preceding IR use. There were 386 patients with NETs or CS vs. 570 with an unknown diagnosis. Comparing patients with NETs or CS to those with an unknown diagnosis, 22.3% vs. 11.0 % experienced dose escalations and 29.0% vs. 26.6% had IR use before dose escalation, respectively. LAR dose escalation occurred in 50.9% vs. 39.2% for symptom control, 12.3% vs. 7.1% for tumor progression control, and 16.6% vs. 6.0% for both reasons in NETs/CS and unknown groups, respectively. CONCLUSION: Octreotide LAR dosing above the label-maximum dose is common and IR rescue dosing appears to be underutilized.

Gabapentin utilization among older adults with different cognitive statuses enrolled in the National Alzheimer's Coordinating Center (2006-2019).

This study aimed to examine gabapentin utilization trends among older adults with different cognitive statuses and investigate concurrent medication use of potentially inappropriate medications. Data were extracted from the National Alzheimer's Coordinating Center Uniform Data Set (2006-2019). We estimated the yearly prevalence of gabapentin use, both overall and within subgroups defined by cognitive status (normal, mild cognitive impairment and dementia) and demographics (age and sex) for participants aged 65+. Additionally, we assessed the prevalence of concurrent use of gabapentin with opioids, combined opioids and benzodiazepine, antidepressant and antipsychotic. From 35 205 eligible older adults (mean age [SD]: 75.7 [7.0]; male: 43.1%), gabapentin use increased from 2006 to 2019 in both overall and every participant subgroup. About 10%-30% of gabapentin users reported to concurrently use opioids, and the concurrent use of gabapentin, opioid and benzodiazepine was up to 7.5% throughout the study period. The frequency of concurrent use with antipsychotics or antidepressants was higher in participants with dementia than those with normal cognition or those who were mildly cognitively impaired. Given increasing use among older adults, rigorous studies are needed to examine the safety of gabapentin in this population.

Acceptability of patient-centered, multi-disciplinary medication therapy management recommendations: results from the INCREASE randomized study.

BACKGROUND: Polypharmacy and inappropriate medications may be a modifiable risk factor for Alzheimer's Disease and Related Dementias (ADRD). Medication therapy management (MTM) interventions may mitigate medication-induced cognitive dysfunction and delay onset of symptomatic impairment. The objective of the current study is to describe an MTM protocol for a patient-centered team intervention (pharmacist and non-pharmacist clinician) in a randomized controlled trial (RCT) directed at delaying the symptomatic onset of ADRD. METHODS: Community dwelling adults 65 + years, non-demented, using ≥ 1 potentially inappropriate medications (PIM) were enrolled in an RCT to evaluate the effect of an MTM intervention on improving medication appropriateness and cognition (NCT02849639). The MTM intervention involved a three-step process: (1) pharmacist identified potential medication-related problems (MRPs) and made initial recommendations for prescribed and over-the-counter medications, vitamins, and supplements; (2) study team reviewed all initial recommendations together with the participants, allowing for revisions prior to the finalized recommendations; (3) participant responses to final recommendations were recorded. Here, we describe initial recommendations, changes during team engagement, and participant responses to final recommendations. RESULTS: Among the 90 participants, a mean 6.7 ± 3.6 MRPs per participant were reported. Of the 259 initial MTM recommendations made for the treatment group participants (N = 46), 40% percent underwent revisions in the second step. Participants reported willingness to adopt 46% of final recommendations and expressed need for additional primary care input in response to 38% of final recommendations. Willingness to adopt final recommendations was highest when therapeutic switches were offered and/or with anticholinergic medications. CONCLUSION: The evaluation of modifications to MTM recommendations demonstrated that pharmacists' initial MTM recommendations often changed following the participation in the multidisciplinary decision-making process that incorporated patient preferences. The team was encouraged to see a correlation between engaging patients and a positive overall response towards participant acceptance of final MTM recommendations. TRIAL REGISTRATION: Study registration number: clinicaltrial.gov NCT02849639 registered on 29/07/2016.

An evaluation of injurious falls and Fall-Risk-Increasing-Drug (FRID) prescribing in ambulatory care in older adults.

BACKGROUND: Falls are a major public health problem affecting millions of older adults each year. Little is known about FRID prescribing behaviors after injurious falls occur. The primary objective of this study was to investigate whether an injurious fall is associated with being prescribed a new FRID. METHODS: We conducted a cross-sectional analysis using data from the National Ambulatory Medical Care Survey (2016). We included visits from patients age ≥ 65 years and classified visits based on presence of an injurious fall. The outcome of interest was prescription of new FRID between those with and without an injurious fall. Multivariable logistic regression weighted for sampling and adjusted for demographics, health history and other medications was used. Age and Alzheimer's disease were examined as potential effect measure modifiers. Odds ratios and 95% confidence intervals were reported. Bayes factor upper bounds were also reported to quantify whether the data were better predicted by the null hypothesis or the alternative hypothesis. RESULTS: The sample included 239,016,482 ambulatory care visits. 5,095,734 (2.1%) of the visits were related to an injurious fall. An injurious fall was associated with a non-statistically significant increase in odds of at least one new FRID prescription: adjusted OR = 1.6 (95% CI 0.6, 4.0). However, there was non-statistically significant evidence that the association depended on patient age, with OR = 2.6 (95% CI 0.9, 7.4) for ages 65-74 versus OR = 0.4 (95% CI 0.1, 1.6) for ages ≥ 75. In addition to age, Alzheimer's disease was also identified as a statistically significant effect measure modifier, but stratum specific estimates were not determined due to small sample sizes. CONCLUSIONS: Ambulatory care visits involving an injurious fall showed a non-statistically significant increase in odds of generating a new FRID prescription, but this association may depend on age.

Internet-Based Cognitive Behavioral Therapy for Insomnia in Appalachian Women: A Pilot Study.

OBJECTIVE/BACKGROUND: Appalachian women are disproportionately affected by insufficient sleep but live in a healthcare shortage area with prevalent prescription drug abuse. A self-administered, non-pharmacologic intervention such as Internet-based cognitive behavioral therapy for insomnia (CBT-I) may be ideal in this population, but psycho-social characteristics (e.g., high depression rates) and cultural norms (e.g., suspicion of technology) necessitate a pilot study. We evaluated the effectiveness of Sleep Healthy Using the Internet (SHUTi) on insomnia severity, sleep quality, perceived stress, depression symptoms, and sleep aid use in Appalachian women ages 45 +. PARTICIPANTS: Forty-six women enrolled; 38 completed the six-week intervention in 2018 (mean age 55 years). METHODS: We employed a single group, pre/post-test, mixed-methods design. Participants completed an online survey and a qualitative interview pre- and post-intervention. Quantitative data were analyzed using one-way repeated measures ANOVA or generalized estimating equations. Interviews were qualitatively analyzed using a multi-stage coding process. RESULTS: Positive and statistically significant (p < .01) improvements were observed on mean scores for the Insomnia Severity Index (15.1 to 6.5), the Pittsburgh Sleep Quality Index (12.1 to 8.5), the Perceived Stress Scale (20 to 14.6), and the Center for Epidemiologic Studies Depression Scale Revised (9.8 to 5.2). The odds of reporting sleep medication use post-intervention were significantly lower than pre-intervention (OR 0.28 [95% CI 0.11-0.74]). Interviews highlighted most and least helpful intervention components and suggested that participants benefitted from SHUTi. CONCLUSIONS: Internet-based CBT-I may be a useful, non-pharmacologic treatment that reduces insomnia severity, perceived stress, depression symptoms, and sleep aid use in middle-aged Appalachian women.

Outcomes after diagnosis of mild cognitive impairment in a large autopsy series.

OBJECTIVE: To determine clinical and neuropathological outcomes following a clinical diagnosis of mild cognitive impairment (MCI). METHODS: Data were drawn from a large autopsy series (N = 1,337) of individuals followed longitudinally from normal or MCI status to death, derived from 4 Alzheimer Disease (AD) Centers in the United States. RESULTS: Mean follow-up was 7.9 years. Of the 874 individuals ever diagnosed with MCI, final clinical diagnoses were varied: 39.2% died with an MCI diagnosis, 46.8% with a dementia diagnosis, and 13.9% with a diagnosis of intact cognition. The latter group had pathological features resembling those with a final clinical diagnosis of MCI. In terms of non-AD pathologies, both primary age-related tauopathy (p < 0.05) and brain arteriolosclerosis pathology (p < 0.001) were more severe in MCI than cognitively intact controls. Among the group that remained MCI until death, mixed AD neuropathologic changes (ADNC; ≥1 comorbid pathology) were more frequent than "pure" ADNC pathology (55% vs 22%); suspected non-Alzheimer pathology comprised the remaining 22% of cases. A majority (74%) of subjects who died with MCI were without "high"-level ADNC, Lewy body disease, or hippocampal sclerosis pathologies; this group was enriched in cerebrovascular pathologies. Subjects who died with dementia and were without severe neurodegenerative pathologies tended to have cerebrovascular pathology and carry the MCI diagnosis for a longer interval. INTERPRETATION: MCI diagnosis usually was associated with comorbid neuropathologies; less than one-quarter of MCI cases showed "pure" AD at autopsy. Ann Neurol 2017;81:549-559.

Longitudinal associations between different dementia diagnoses and medication use jointly accounting for dropout.

ABSTRACTBackground:Longitudinal studies of older adults are characterized by high dropout rates, multimorbid conditions, and multiple medication use, especially proximal to death. We studied the association between multiple medication use and incident dementia diagnoses including Alzheimer's disease (AD), vascular dementia (VD), and Lewy-body dementia (LBD), simultaneously accounting for dropout. METHODS: Using the National Alzheimer's Coordinating Center data with three years of follow-up, a set of covariate-adjusted models that ignore dropout was fit to complete-case data, and to the whole-cohort data. Additionally, covariate-adjusted joint models with shared random effects accounting for dropout were fit to the whole-cohort data. Multiple medication use was defined as polypharmacy (⩾ five medications), hyperpolypharmacy (⩾ ten medications), and total number of medications. RESULTS: Incident diagnoses were 2,032 for AD, 135 for VD, and 139 for LBD. Percentages of dropout at the end of follow-up were as follows: 71.8% for AD, 81.5% for VD, and 77.7% for LBD. The odds ratio (OR) estimate for hyperpolypharmacy among those with LBD versus AD was 2.19 (0.78, 6.15) when estimated using complete-case data and 3.00 (1.66, 5.40) using whole-cohort data. The OR reduced to 1.41 (0.76, 2.64) when estimated from the joint model accounting for dropout. The OR for polypharmacy using complete-case data differed from the estimates using whole-cohort data. The OR for dementia diagnoses on total number of medications was similar, but non-significant when estimated using complete-case data. CONCLUSION: Reasons for dropout should be investigated and appropriate statistical methods should be applied to reduce bias in longitudinal studies among high-risk dementia cohorts.

An investigation of factors predicting the type of bladder antimuscarinics initiated in Medicare nursing homes residents.

BACKGROUND: To examine factors predicting type of bladder antimuscarinics (BAM) initiated in nursing home (NH) residents. METHODS: Incident BAM initiators following NH admission were identified by constructing a retrospective cohort from Medicare files and Minimum Data Set (MDS). Participants included all residents 65 years and older admitted in Medicare-certified NH between January 1, 2007 and December 31, 2008 who were prescribed BAM and had continuous Medicare (Part A, B, and D) enrollment. Patient characteristics, medications, and comorbidities were derived from Medicare enrollment and claims. NH characteristics and health status were derived from MDS assessments. The outcome was defined as type of BAM initiated after admission (selective, non-selective extended release, non-selective immediate release). Multinomial logistic regression using generalized estimating equation methodology determined which factors predicted the type of BAM initiated. RESULTS: Twelve thousand eight hundred ninety-nine NH residents initiating BAM therapy were identified; 13.38% of new users were prescribed selective BAM, 45.56% non-selective extended release, and 41.07% non-selective immediate release medications. In both sexes, significant predictors of BAM included region of nursing home, body mass index, cognitive performance score, frailty measures, activities of daily living, and measures of bladder continence. In women, history of fracture and fall-related injuries were significant predictors of type of BAM use, while race and indicators of balance were significant predictors of type of BAM use in men. Non-pharmacological continence management strategies were not predictive of type of BAM initiation. CONCLUSIONS: Several factors are important in predicting type of BAM initiation in both women and men, but other factors are sex-specific. Some observed factors predicting the type of BAM initiated, such as other medications use, body mass index, or provider-related factors are potentially modifiable and could be used in targeted interventions to help optimize BAM use in this population. TRIAL REGISTRATION: Not applicable.

Evaluating the incident user design in the HIV population: incident use versus naive?

INTRODUCTION: The incident user design is the preferred study design in comparative effectiveness (CER) research. Usually, 180-365 days of exposure free time is adequate to remove biases associated with inclusion of prevalent users. In HIV research, the use of antiretrovirals (ARVs) at any time in the past may influence future treatment choices and CER results; thus, identifying naive as opposed to incident users is of importance. We examined misclassification of antiretroviral naive status based on Medicaid administrative data through linkage to the UNC CFAR HIV Clinical Cohort (UCHCC). METHODS: We identified Medicaid patients with incident exposure to common first-line ARV regimens between 2002 and 2008 that were also patients enrolled in the UCHCC. We calculated the proportion of antiretroviral naive patients based on the UCHCC, among patients identified as having incident exposure in Medicaid and examined factors associated with being antiretroviral naive in both data sources using logistic regression to generate prevalence odds ratios and associated 95% confidence intervals. RESULTS: Of the 3500 Medicaid patients with incident antiretroviral (ARV) exposure, 1344 were also enrolled in the UCHCC. In this sample, 34% were antiretroviral naive at the time of first exposure in the Medicaid data based on the UCHCC. In multivariable models, higher CD4 cell counts and log HIV RNA values were associated with being antiretroviral naive in both data sources. CONCLUSIONS: Administrative data are an important source of information related to HIV treatment. As the construction of a durable and long-lasting HIV treatment plan involves knowledge of current and past antiretroviral therapy, augmentation of this data with comprehensive clinical cohort information is necessary.

The Association of Gabapentin Initiation with Cognitive and Behavioral Changes in Older Adults with Cognitive Impairment: A Retrospective Cohort Study.

BACKGROUND: Although gabapentin has been increasingly prescribed to older adults, the relation between gabapentin initiation and longer-term neurocognitive changes is not well understood. Thus, this study aimed to examine the association of gabapentin initiation with cognitive and motor function decline in older adult participants with cognitive impairment. METHODS: A retrospective cohort study was conducted using the National Alzheimer's Coordinating Center Uniform Data Set (2005-March 2023). Participants with cognitive impairment at the visit of gabapentin initiation (i.e., index visit) were included. Using the incidence density sampling method, up to nine non-users were randomly selected for each initiator. Cognitive decline over 1 year was defined as any increase in Clinical Dementia Rating global score (CDR®GLOB) or a 1-point increase in CDR® sum of boxes (CDR®SB). Functional status decline over 1 year was defined as at least a 3-point increase in the Functional Activities Questionnaire (FAQ) sum or a 0.3-point increase of mean of FAQ. Motoric decline over 1 year was defined as new clinician reports of gait disorder, falls, and slowness. To mitigate confounding and selection bias, joint stabilized inverse probability of treatment weights and censoring weights were used. Analyses compared index with index + 1 and index + 2 visits. RESULTS: For the study of cognitive and functional status decline, we included 505 initiators (mean age [SD] 78.8 [7.4]; male = 45%) and 4545 non-users (79.2 [7.6]; 50.1%). For the study of motor decline, we included 353 initiators (78.3 [7.2]; 42.8%) and 3177 non-users (78.5 [7.4]; 48.1%). Gabapentin initiation was not statistically associated with decline on CDR®GLOB, CDR®SB, FAQ sum, or mean FAQ at the index + 1 or index + 2 visits. However, gabapentin initiation was significantly associated with increased odds of new falls at the index + 2 visit (odds ratio [95% confidence interval] 2.5 [1.3, 4.6]). CONCLUSIONS: Over 1 or 2 years of follow-up, gabapentin initiation was not associated with decline in cognitive or functional status but was associated with increased odds of falling among research participants with cognitive impairment.

Higher First 30-Day Dose of Buprenorphine for Opioid Use Disorder Treatment Is Associated With Decreased Mortality.

OBJECTIVE: Buprenorphine is a medication for opioid use disorder that reduces mortality. This study aims to investigate the less well-understood relationship between the dose in the early stages of treatment and the subsequent risk of death. METHODS: We used Kentucky prescription monitoring data to identify adult Kentucky residents initiating transmucosal buprenorphine medication for opioid use disorder (January 2017 to November 2019). Average daily buprenorphine dose for days covered in the first 30 days of treatment was categorized as ≤8 mg, >8 to ≤16 mg, and >16 mg. Patients were followed for 365 days after the first 30 days of buprenorphine treatment. Endpoints were opioid-involved overdose death and death from other causes. Causes and dates of death were obtained using Kentucky death certificate records. Associations were evaluated using multivariable Fine and Gray models adjusting for patient baseline characteristics. RESULTS: In the cohort of 49,857 patients, there were 227 opioid-involved overdose deaths and 459 deaths from other causes. Compared with ≤8 mg, the adjusted subdistribution hazard ratio (aSHR) of opioid-involved overdose death decreased by 55% (aSHR, 0.45; 95% confidence interval [CI], 0.34-0.60) and 64% (aSHR, 0.36; 95% CI, 0.25-0.52) for patients receiving doses of >8 to ≤16 mg and >16 mg, respectively. The incidence of death from other causes was lower in patients receiving >8 to ≤16 mg (aSHR, 0.78; 95% CI, 0.62-0.98) and >16 mg (aSHR, 0.62; 95% CI, 0.47-0.80) versus ≤8 mg dose. CONCLUSIONS: Higher first 30-day buprenorphine doses were associated with reduced opioid-involved overdose death and death from other causes, supporting benefit of higher dosing in reducing mortality.

Improvement in Post-traumatic Stress Symptoms Following an Internet-based Cognitive-Behavioral Intervention for Insomnia: An Open Trial among Rural Appalachian Women.

Appalachian women face significant health disparities and have limited access to health care. Mental health conditions and treatment-seeking are stigmatized in Appalachian communities. Appalachian women may benefit from web-based interventions targeting less stigmatized health complaints (e.g., insomnia), while simultaneously yielding benefit in associated mental health conditions including symptoms of post-traumatic stress disorder (PTSD). In this study, 37 trauma-exposed adult women aged 45 and older from rural Appalachian Kentucky completed a six-session online self-administered cognitive behavioral therapy for insomnia (CBT-I) intervention and completed measures of PTSD symptoms, insomnia, and depression at pre- and post-treatment. Participants reported a significant reduction in PTSD symptoms from pre- to post-intervention, and this remained significant after adjusting for severity of insomnia and depression pre-treatment. Pending replication in a randomized controlled trial, web-based CBT-I may offer an adjunctive mental health treatment option that circumvents cultural stigmas and reduces PTSD symptoms for trauma-exposed Appalachian women.

Urinary Incontinence in a Community-Based Autopsy Cohort Is Associated with Limbic Predominant Age-Related TDP-43 Encephalopathy Neuropathologic Changes.

BACKGROUND: Dementia and urinary incontinence (UI) are etiologically complex clinical syndromes. Dementia and UI often occur in the same individuals, but underlying factors connecting them are incompletely understood. OBJECTIVE: Query data from a community-based autopsy series to assess pathologies that underlie UI. METHODS: Included research subjects came to autopsy from the University of Kentucky Alzheimer's Disease Research Center longitudinal cohort. A total of 368 research volunteers met inclusion criteria for this cross-sectional study. The average age at death was 85.3 years and the average number of annual clinic visits was 5.2 visits. Statistical models were run to evaluate which pathologies were associated with UI. Data included pathologies scored according to conventional stage-based systems, and these studies were complemented by quantitative digital neuropathology. RESULTS: Dementia was diagnosed at the final clinical visit in 208 (56.7% of the sample) and UI was documented in 156 (42.7%). UI was associated with depression and dementia (both p < 0.001). More women than men had a history of UI (p < 0.04), and women with UI had had more biological children than those without UI (p < 0.005). Participants with limbic predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC) were more likely to have UI than those without LATE-NC (p < 0.001). The presence of LATE-NC (Stage > 1) was associated with UI with or without severe Alzheimer's disease neuropathologic changes and/or Lewy body pathology. CONCLUSION: In this community-based autopsy cohort, multiple factors were associated with UI, but the neuropathologic change most robustly associated with UI was LATE-NC.

Overactive Bladder and Cognitive Impairment: The American Urogynecologic Society and Pelvic Floor Disorders Research Foundation State-of-the-Science Conference Summary Report.

IMPORTANCE: Overactive bladder (OAB) is prevalent in older adults in whom management is complicated by comorbidities and greater vulnerability to the cognitive effects of antimuscarinic medications. OBJECTIVES: The aim of this study is to provide a comprehensive evidence-based summary of the 2021 State-of-the-Science (SOS) conference and a multidisciplinary expert literature review on OAB and cognitive impairment. STUDY DESIGN: The American Urogynecologic Society and the Pelvic Floor Disorders Research Foundation convened a 3-day collaborative conference. Experts from multidisciplinary fields examined cognitive function, higher neural control of the OAB patient, risk factors for cognitive impairment in older patients, cognitive effects of antimuscarinic medications for OAB treatment, OAB phenotyping, conservative and advanced OAB therapies, and the need for a multidisciplinary approach to person-centered treatment. Translational topics included the blood-brain barrier, purine metabolome, mechanotransduction, and gene therapy for OAB targets. RESULTS: Research surrounding OAB treatment efficacy in cognitively impaired individuals is limited. Short- and long-term outcomes regarding antimuscarinic effects on cognition are mixed; however, greater anticholinergic burden and duration of use influence risk. Oxybutynin is most consistently associated with negative cognitive effects in short-term, prospective studies. Although data are limited, beta-adrenergic agonists do not appear to confer the same cognitive risk. CONCLUSIONS: The 2021 SOS summary report provides a comprehensive review of the fundamental, translational, and clinical research on OAB with emphasis on cognitive impairment risks to antimuscarinic medications. Duration of use and antimuscarinic type, specifically oxybutynin when examining OAB treatments, appears to have the most cognitive impact; however, conclusions are limited by the primarily cognitively intact population studied. Given current evidence, it appears prudent to minimize anticholinergic burden by emphasizing nonantimuscarinic therapeutic regimens in the older population and/or those with cognitive impairment.

Prognostic Factors of COVID-19: An Umbrella Review Endorsed by the International Society for Pharmacoepidemiology.

During the coronavirus disease 2019 (COVID-19) pandemic, the urgency for updated evidence to inform public health and clinical care placed systematic literature reviews (SLRs) at the cornerstone of research. We aimed to summarize evidence on prognostic factors for COVID-19 outcomes through published SLRs and to critically assess quality elements in the findings' interpretation. An umbrella review was conducted via electronic databases from January 2020 to April 2022. All SLRs (and meta-analyses) in English were considered. Data screening and extraction were conducted by two independent reviewers. AMSTAR 2 tool was used to assess SLR quality. The study was registered with PROSPERO (CRD4202232576). Out of 4,564 publications, 171 SLRs were included of which 3 were umbrella reviews. Our primary analysis included 35 SLRs published in 2022, which incorporated studies since the beginning of the pandemic. Consistent findings showed that, for adults, older age, obesity, heart disease, diabetes, and cancer were more strongly predictive of risk of hospitalization, intensive care unit admission, and mortality due to COVID-19. Male sex was associated with higher risk of short-term adverse outcomes, but female sex was associated with higher risk of long COVID. For children, socioeconomic determinants that may unravel COVID-19 disparities were rarely reported. This review highlights key prognostic factors of COVID-19, which can help clinicians and health officers identify high-risk groups for optimal care. Findings can also help optimize confounding adjustment and patient phenotyping in comparative effectiveness research. A living SLR approach may facilitate dissemination of new findings. This paper is endorsed by the International Society for Pharmacoepidemiology.

Validation of tablet-based evaluation of color fundus images.

PURPOSE: To compare diabetic retinopathy (DR) referral recommendations made by viewing fundus images using a tablet computer with those made using a standard desktop display. METHODS: A tablet computer (iPad) and a desktop computer with a high-definition color display were compared. For each platform, 2 retinal specialists independently rated 1,200 color fundus images from patients at risk for DR using an annotation program Truthseeker. The specialists determined whether each image had referable DR and also how urgently each patient should be referred for medical examination. Graders viewed and rated the randomly presented images independently and were masked to their ratings on the alternative platform. Tablet-based and desktop display-based referral ratings were compared using cross-platform intraobserver kappa as the primary outcome measure. Additionally, interobserver kappa, sensitivity, specificity, and area under the receiver operating characteristic were determined. RESULTS: A high level of cross-platform intraobserver agreement was found for the DR referral ratings between the platforms (κ = 0.778) and for the 2 graders (κ = 0.812). Interobserver agreement was similar for the 2 platforms (κ = 0.544 and κ = 0.625 for tablet and desktop, respectively). The tablet-based ratings achieved a sensitivity of 0.848, a specificity of 0.987, and an area under the receiver operating characteristic of 0.950 compared with desktop display-based ratings. CONCLUSION: In this pilot study, tablet-based rating of color fundus images for subjects at risk for DR was consistent with desktop display-based rating. These results indicate that tablet computers can be reliably used for clinical evaluation of fundus images for DR.

The association of gabapentin initiation and neurocognitive changes in older adults with normal cognition.

Background: Gabapentin is increasingly prescribed to older adults, which raises concerns about its potential to cause neurocognitive changes. Therefore, we aimed to examine the association of gabapentin use with neurocognitive changes (i.e., cognitive decline, functional status decline, and motor function change) in older adults. Methods: We conducted a retrospective cohort study using the National Alzheimer's Coordinating Center Uniform Data Set (UDS; September 2005-March 2021 data freeze). From the eligible sample (≥age 65 years), we identified cognitively normal new-users of gabapentin and the visit they initiated gabapentin (i.e., index visit). Initiators were matched to randomly selected nonusers on year of UDS enrollment and visit number from enrollment to index. Cognitive decline was defined as any increase in the Clinical Dementia Rating global score (CDRGLOB) and as a 1-point increase in CDR sum of boxes (CDR-SB). Functional status decline was defined as a 3-point increase in the sum of the Functional Activities Questionnaire (FAQ) and as 0.3-point increase in mean FAQ. Decline in motor function was defined as new clinician reports of gait disorder, falls, and slowness. To mitigate confounding and selection bias, we used joint stabilized inverse probability of treatment weights and stabilized inverse probability of censoring weights. All analyses were conducted comparing index to index+1 and index+2 visits. Results: From the eligible UDS participants (N = 23,059), we included 480 initiators (mean age [SD]: 78.7 [6.9]; male 34.4%); 4,320 nonusers (78.3 [7.0]; 34.4%). Gabapentin initiation was significantly associated with cognitive/functional status decline: worsening CDRGLOB at index+1 visit (odds ratio [95% confidence interval]: 1.55 [1.07, 2.25]); CDR-SB at index+1 visit (1.94 [1.22, 3.09]); and mean of FAQ at index+2 visit (1.78 [1.12, 2.83]). After excluding initiators with extant motor dysfunction (n = 21), we identified 459 initiators (78.7 [6.9]; 34.0%) and 4,131 nonusers (78.2 [6.9]; 34.7%); in this sample, gabapentin initiation was associated with increased falls at the index+2 visit (2.51 [1.19, 5.31]). Conclusion: Gabapentin initiation was significantly associated with deleterious neurocognitive changes among older adults with initially normal cognition. Further studies are needed to examine the risk/benefit of prescribing gabapentin in older adults.