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Background: Observational studies using real-world data (RWD) can address gaps in knowledge on deprescribing medications but are subject to methodological issues. Limited data exist on the methods employed to use RWD to measure the effects of deprescribing., Objective: To describe methodological approaches used in observational studies of deprescribing medications in older adults., Method: We conducted a systematic review in Medline for observational studies published in English (01/01/2000-09/14/2023) that examined the health effects of medication deprescribing in older adults. We described study characteristics and methods, focusing on the operationalization of deprescribing as an exposure and potential time-related biases., Results: Forty-five studies were included, representing a variety of drug classes (e.g., statins, aspirin, bisphosphonates) and diseases. Most studies adequately addressed potential time-related biases. The definition of deprescribing was not clearly defined in 12 studies. There was heterogeneity regarding the minimum duration of time that qualified as deprescribing, even within a drug class; fewer than one-third of studies provided a justification for these definitions., Conclusion: Observational studies are common to examine the effects of deprescribing; however, there were inconsistencies in measuring deprescribing and a lack of transparency in reporting. There is a need for minimum sufficient reporting criteria for observational studies on deprescribing., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Objective: We sought to compare patient outcomes between carbapenem-resistant Enterobacterales (CRE) and carbapenem-susceptible Enterobacterales (CSE) infections at our academic medical center., Design: We conducted a retrospective cohort study of adult patients with a positive culture of E. coli, E. cloacae, K. aerogenes, K. oxytoca, and/or K. pneumoniae admitted at UK HealthCare (January 1, 2010-December 31, 2019). Based on the type of pathogen on the date of the first culture (index date), patients were included in the CRE (i.e., exposed) group, or the CSE (comparator) group. Exclusion criteria were age < 18 years old, pregnancy, endocarditis, osteomyelitis, necrotizing fasciitis, or cystic fibrosis. We evaluated the impact of CRE vs CSE on a composite outcome of 30-day of all-cause mortality or discharge to hospice using Kaplan-Meier survival curves and Cox proportional hazard regression with inverse probability of treatment weights (IPTW)., Results: Of 17,839 hospitalized patients, 128 and 6,953 patients were included in the CRE and CSE groups, respectively. Baseline differences existed in sex-assigned-at-birth, admission source, time-to-index culture, and infection type/severity. Most CRE index cultures observed (76%) only exhibited resistance to ertapenem. IPTW-adjusted HR [95% CI] of composite outcome was 0.99 [0.65, 1.51] after 30 days. Follow-up analysis in patients with carbapenem-non-susceptible Enterobacterales bloodstream infections on index yielded an HR of 1.38 [0.85, 2.24]., Conclusions: Risk of composite outcome was not estimated to differ between patients with CRE and CSE in the overall analysis. Although follow-up analysis identified an increased risk, we cannot statistically distinguish this from a null effect., Competing Interests: None., (© The Author(s) 2024.)

Background: Ischemic stroke is a leading cause of death and disability. Society guidelines recommend pharmacotherapies for secondary stroke prevention. However, the role of sex differences in prescription and adherence to guideline-directed medical therapies (GDMT) after ischemic stroke remains understudied. The aim of this study was to examine sex differences in prescription and adherence to GDMT at 1-year after ischemic stroke in a cohort of commercially insured patients. Methods: Using the Truven Health MarketScan database from 2016-2020, we identified patients admitted with ischemic stroke. GDMT was defined as any statin, antihypertensive, and anticoagulant prescription within 30-days after discharge. Medication adherence was estimated using the proportion of days covered (PDC) at 1-year. PDC <0.80 was used to define non-adherence. A multivariable model adjusting for covariates was performed to identify the factors associated with non-adherence at 1-year. This analysis was restricted to new users of GDMT. Results: Among 155220 patients admitted with acute ischemic stroke during the study period, 15,919 met the inclusion criteria. The mean age was 55.7 years, and 7,701 (48.3%) were women. Women were less likely prescribed statins (58.0% vs 71.8%), and antihypertensives (27.7% vs 41.8%). In this subset of patients with atrial flutter/fibrillation, women were also less likely prescribed anticoagulants (41.2% vs 45.0%). Women were more likely to be non-adherent (i.e., PDC <0.80) to statins (47.3% vs 41.6%, P<0.0001), antihypertensives (33.3% vs 32.2%, P=0.005), and the combination of both (49.6% vs 45.0%, P=0.003). On multivariable analysis, women were likely to be non-adherent to GDMT at 1-year (odds ratio 1.23, 95% confidence interval 1.08-1.41). Conclusions: In this real-world analysis of commercially insured patients with ischemic stroke, women were less likely initiated on GDMT within 30 days after discharge. Women were more likely to be non-adherent to statins and antihypertensive agents at 1-year. Future efforts and novel interventions are needed to understand the reasons and minimize these disparities.

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 to 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 (TMRs)., 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 to 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., Competing Interests: Disclosure The author declares no conflicts of interest or financial interests in any product or service mentioned in this article., (Copyright © 2024 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Abuse-deterrent formulations of opioid analgesics (ADFs) were introduced to reduce opioid-related harms among pain patients, but post-marketing study results have been mixed. However, these studies may be subject to bias from selection criteria, comparator choice, and potential confounding by "indication," highlighting the need for thorough study design considerations. In a sample of privately insured patients prescribed ADF or non-ADF extended-release/long-acting (ER/LA) opioids in North Carolina, we implemented a version of the prevalent new-user design to evaluate the relationship between ADFs and opioid use disorder (OUD, n=235) and opioid overdose (n=18) through six months of follow-up using inverse probability-weighted cumulative incidence functions and Fine-Gray models. The weighted hazard [HRw] of opioid overdose among patients initiating ADFs was 0.87 (95% CI: 0.23, 3.24) times as high as among patients who initiated, restarted, or continued non-ADF ER/LA opioids. We observed a short-term benefit of ADFs for incident OUD (HRw=0.58; 95% CI: 0.35, 0.93) compared to non-ADF ER/LA opioids in the first six weeks of follow-up, but this benefit disappeared later in follow-up (HRw=1.30; 0.86, 1.95). In summary, our findings add to the expanding body of evidence that there is no clear long-term reduction in harm from ADF opioids among patients in outpatient use., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

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., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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., Competing Interests: No potential conflicts of interest relevant to this article were reported., (©2024 by the American Diabetes Association.)

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., (© 2024 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

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., (Copyright © 2024 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

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., (© 2023 The Authors. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics.)

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., (© The Author(s) 2023. Published by Oxford University Press.)

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., (© 2023. The Author(s).)

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., (© 2022 British Pharmacological Society.)

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., Competing Interests: K.L.D. is a speaker (Education): Pacira, Inc. J.Z. received grant funding from Medtronic. A.W. is consultant and research support for Essity Hygiene & Health. Speaker bureau for Urovant Sciences. Research support for Pfizer Corp. C.E.DB. is part of the American Geriatric Society Beers Criteria Revision Panel. M.F.A.'s spouse is from Johnson & Johnson Corporate and received grant funding from National Institute on Aging, Alzheimer's Association, Tamara Harris Foundation. M.A. is part of MAB, Renovia, Inc. H.H.L. received grant funding from NIH, Medtronic: Interstim registry study, Neurspera: DSMB, Astella: Consultant, Ironwood, Biohaven, MicrogenDx: Consultant, V.W.S. received grant funding from NICHD. The remaining authors have declared that there are no conflicts of interest., (Copyright © 2023 American Urogynecologic Society. All rights reserved.)

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.

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.

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Oh, Moga, Fardo and Abner.)

As the scientific research community along with healthcare professionals and decision makers around the world fight tirelessly against the coronavirus disease 2019 (COVID-19) pandemic, the need for comparative effectiveness research (CER) on preventive and therapeutic interventions for COVID-19 is immense. Randomized controlled trials markedly under-represent the frail and complex patients seen in routine care, and they do not typically have data on long-term treatment effects. The increasing availability of electronic health records (EHRs) for clinical research offers the opportunity to generate timely real-world evidence reflective of routine care for optimal management of COVID-19. However, there are many potential threats to the validity of CER based on EHR data that are not originally generated for research purposes. To ensure unbiased and robust results, we need high-quality healthcare databases, rigorous study designs, and proper implementation of appropriate statistical methods. We aimed to describe opportunities and challenges in EHR-based CER for COVID-19-related questions and to introduce best practices in pharmacoepidemiology to minimize potential biases. We structured our discussion into the following topics: (1) study population identification based on exposure status; (2) ascertainment of outcomes; (3) common biases and potential solutions; and (iv) data operational challenges specific to COVID-19 CER using EHRs. We provide structured guidance for the proper conduct and appraisal of drug and vaccine effectiveness and safety research using EHR data for the pandemic. This paper is endorsed by the International Society for Pharmacoepidemiology (ISPE)., (© 2022 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Purpose: Developing effective deprescribing interventions relies on understanding attitudes, beliefs, and communication challenges of those involved in the deprescribing decision-making process, including the patient, the primary care clinician, and the pharmacist. The objective of this study was to assess patients' beliefs and attitudes and identify facilitators of and barriers to deprescribing., Methods: As part of a larger study, we recruited patients ⩾18 years of age taking ⩾3 chronic medications. Participants were recruited from retail pharmacies associated with the University of Kentucky HealthCare system. They completed an electronic survey that included demographic information, questions about communication with their primary care clinician and pharmacists, and the revised Patients' Attitudes Toward Deprescribing (rPATD) questionnaire., Results: Our analyses included 103 participants ( n  = 65 identified as female and n  = 74 as White/Caucasian) with a mean age of 50.4 years [standard deviation (SD) = 15.5]. Participants reported taking an average of 8.4 daily medications (SD = 6.1). Most participants reported effective communication with clinicians and pharmacists (66.9%) and expressed willingness to stop one of their medications if their clinician said it was possible (83.5%). Predictors of willingness to accept deprescribing were older age [odds ratio (OR) = 2.99, 95% confidence interval (CI) = 1.45-6.2], college/graduate degree (OR = 55.25, 95% CI = 5.74-531.4), perceiving medications as less appropriate (OR = 8.99, 95% CI = 1.1-73.62), and perceived effectiveness of communication with the clinician or pharmacist (OR = 4.56, 95% CI = 0.85-24.35)., Conclusion: Adults taking ⩾3 chronic medications expressed high willingness to accept deprescribing of medications when their doctor said it was possible. Targeted strategies to facilitate communication within the patient-primary care clinician-pharmacist triad that consider patient characteristics such as age and education level may be necessary ingredients for developing successful deprescribing interventions., Plain Language Summary: Are patients willing to accept stopping medications? Sometimes, medicines that a patient takes regularly become inappropriate. In other words, the risks of adverse effects might be greater than a medicine's potential benefits. The decision to stop such medicines should involve the patient and consider their preferences. We surveyed a group of patients taking multiple medicines to see how they felt about having those medicines stopped. We also asked patients whether and how much they talk to their primary care clinician and pharmacists about their medicines. To qualify for this study, patients had to be at least 18 years old and to take three or more medicines daily; they also needed to speak English. Participants provided demographic information and answered questions about their medicines, their communication with primary care clinicians and pharmacists, and their feelings about having one or more of their medicines stopped. We recruited 107 people and were able to use responses from 103 of them. Their average age was 50 years; 65 of them identified as female, and 75 identified as White/Caucasian. Most of our participants mentioned having conversations with primary care clinicians and pharmacists and said they would be willing to stop a medication if their clinician said it was possible. Older participants, those with more years of education, those who thought their medications might lead to side effects, and those who communicated with their clinician or pharmacists were more willing to have one of their medicines stopped.Our results indicate that patient characteristics and communication with clinicians and pharmacists are factors to consider when designing interventions to reduce the use of inappropriate medicines., Competing Interests: Competing interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Introduction: High-quality randomised controlled trials (RCTs) provide the most reliable evidence on the comparative efficacy of new medicines. However, non-randomised studies (NRS) are increasingly recognised as a source of insights into the real-world performance of novel therapeutic products, particularly when traditional RCTs are impractical or lack generalisability. This means there is a growing need for synthesising evidence from RCTs and NRS in healthcare decision making, particularly given recent developments such as innovative study designs, digital technologies and linked databases across countries. Crucially, however, no formal framework exists to guide the integration of these data types., Objectives and Methods: To address this gap, we used a mixed methods approach (review of existing guidance, methodological papers, Delphi survey) to develop guidance for researchers and healthcare decision-makers on when and how to best combine evidence from NRS and RCTs to improve transparency and build confidence in the resulting summary effect estimates., Results: Our framework comprises seven steps on guiding the integration and interpretation of evidence from NRS and RCTs and we offer recommendations on the most appropriate statistical approaches based on three main analytical scenarios in healthcare decision making (specifically, 'high-bar evidence' when RCTs are the preferred source of evidence, 'medium,' and 'low' when NRS is the main source of inference)., Conclusion: Our framework augments existing guidance on assessing the quality of NRS and their compatibility with RCTs for evidence synthesis, while also highlighting potential challenges in implementing it. This manuscript received endorsement from the International Society for Pharmacoepidemiology., Competing Interests: Competing interests: We have read and understood BMJ Evidence-Based Medicine policy on declaration of interests and declare the following interests: GS is employed by Visible Analytics, Ltd; DB is employed by Takeda; ARZ holds a grant from Sanofi Pasteur (direct to institution); MP owns stocks from Merck, Sanofi, and Johnson & Johnson; MG is employed by GSK; and TD is an advisor to pharma industry., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2022. The Author(s).)

Background: Cognitive reserve has been hypothesized as a mechanism to explain differences in individual risk for symptomatic expression of Alzheimer's Disease (AD). Inappropriate medications may diminish cognitive reserve, precipitating the transition from preclinical AD (pAD) to a symptomatic state. To date, there is limited data on the potential impact of medication optimization as a potential tool for slowing the symptomatic expression of AD., Objectives: (1) To test the efficacy of a medication therapy management intervention designed to bolster cognitive reserve in community-dwelling older adults without dementia. (2) To evaluate the efficacy of intervention by baseline pAD status., Design: A 1-year randomized controlled trial was conducted in community-dwelling older adults without dementia. Randomization was stratified by amyloid β positron emission tomography levels., Setting: Community-based, Lexington, Kentucky., Participants: Adults 65 years or older with no evidence of dementia and reporting at least one potentially inappropriate medication as listed in the Beers 2015 criteria were recruited. The study aimed to enroll 90 participants based on the a priori sample size calculation., Intervention: Medication therapy management versus standard of care., Measurements: Primary outcomes were: (1) one-year changes in the Medication Appropriateness Index; (2) one-year changes in Trail Making Test B under scopolamine challenge., Results: The medication therapy management intervention resulted in significant improvement in Medication Appropriateness Index scores. Overall, there was no beneficial effect of the medication therapy management on Trail Making Test B scores, however stratified analysis demonstrated improvement in Trail Making Test B challenged scores associated with the medication therapy management for those with elevated amyloid β positron emission tomography levels consistent with pAD., Conclusions: Medication therapy management can reduce inappropriate medication use in older adults at risk for AD. Our study indicated beneficial cognitive effects in those with preclinical Alzheimer's Disease. No statistically significant effects were evident in the study group as a whole, or in those without preclinical cerebral amyloidosis. Further work designed to improve the effectiveness of the medication therapy management approach and defining other preclinical pathologic states that may benefit from medication optimization are readily achievable goals for promoting improved cognitive health and potentially delaying the onset of symptomatic AD.

Background: With the older adult population in the USA increasing, so is the population of those with Alzheimer's disease and related dementias (ADRD). Older adults are vulnerable to the effects of potentially inappropriate medications as established by the Beers Criteria; however, some medications continue to be prescribed against recommendations., Objectives: Our objectives were to describe potentially inappropriate medication (PIM) use linked to cognitive impairment or decline (referred to as Cog-PIM) in older adults with and without ADRD and to investigate whether the odds of Cog-PIM report differ by ADRD status in ambulatory care (i.e., outpatient care) in the USA., Methods: A cross-sectional analysis was performed using a nationally representative sample of non-perioperative, office-based ambulatory care visits by adults aged ≥ 65 years in 2016 (n = 218,182,131). Data were collected from the National Ambulatory Medical Care Survey. Cog-PIMs were identified as defined in the 2015 Beers Criteria recommendations for medications that may be potentially inappropriate in older adults with cognitive impairment or dementia. ADRD status was determined by clinician report using free text, the ADRD flag, or the presence of a diagnosis code indicating dementia. Multivariable logistic regressions were used to estimate the odds of Cog-PIM use overall and by medication class., Results: In 2016, 2.1% (n = 4,651,563) of outpatient visits were made by older adults with ADRD, 33.2% of which reported at least one Cog-PIM. Anticholinergic Cog-PIMs were noted in 20.5% of ADRD visits compared with 8.1% of non-ADRD visits. Antipsychotic PIMs were noted in 15.5% of ADRD visits compared with 0.8% of non-ADRD visits. Benzodiazepine and non-benzodiazepine receptor agonist hypnotic (Z drug) Cog-PIMs were reported in 10.9% of ADRD visits and 10.7% of non-ADRD visits. ADRD status was a significant predictor of Cog-PIM report overall (adjusted odds ratio [aOR] 2.74 [95% confidence interval {CI} 1.20-6.27]) and for anticholinergics and antipsychotics specifically (aOR 3.35 [95% CI 1.24-9.03] and aOR 22.80 [95% CI 5.80-89.50], respectively)., Conclusion: This study demonstrated a high prevalence of Cog-PIM use and increased odds of Cog-PIM use in older adults with ADRD. Future work should investigate opportunities in the ambulatory care setting for safer prescribing and de-escalation of Cog-PIMs., (© 2021. The Author(s).)

Introduction: Mitigating the burden of unnecessary polypharmacy or multiple medication use in people living with dementia has been recognized as a key priority internationally. One approach to reducing inappropriate polypharmacy is through medication withdrawal or deprescribing. Area covered: Non-systematic searches of key databases including PubMed, Embase, and Google Scholar were conducted from inception to 28 February 2021 for articles that assessed the safety and/or efficacy of deprescribing in older adults living with dementia. Personal reference libraries were also utilized. Information on current clinical trials was found in clinicaltrial.gov. Expert Opinion:  There is limited direct evidence to inform deprescribing in older adults with dementia specifically. This review identified nineteen studies that have assessed the impact of deprescribing interventions to reduce inappropriate polypharmacy or direct deprescribing of specific medications. However, the current evidence is limited in scope as most studies focused on medication-related outcomes (e.g. discontinuation of high-risk medications) rather than patient-centered outcomes in individuals living with dementia. Furthermore, most studies focused on addressing inappropriate polypharmacy in older adults with dementia living in long-term care facilities, and interventions did not involve the person and their carer. Further evidence on the impact of deprescribing in this population across clinical settings is needed.

Background: There is currently insufficient data describing how new medications are provided to older adult ambulatory patients with dementia in the United States (US)., Objectives: To describe characteristics of ambulatory care visits for adults ≥65 years old and investigate differences in prescribing of new medications between patients with and without dementia., Methods: We conducted a population-based cross-sectional study using the 2016 National Ambulatory Medical Care Survey (NAMCS) in the US. Non-perioperative ambulatory care visits of patients ≥65 years old with sampling weights were used to provide national estimates of visits. Baseline characteristics were compared between visits for patients with and without dementia using Pearson's chi square or Student's t- tests. We used multivariable logistic regression to estimate the odds of receiving a new medication., Results: 218,182,131 non-perioperative ambulatory care visits of patients ≥65 years old were included, 2.1% of which were for patients with dementia; these patients were older on average and had more comorbidities and higher ambulatory care utilization than those without dementia. New medications were provided at 26.3% of visits for patients with dementia. After adjusting for confounders, there was no statistically significant difference in odds of a new medication being provided between visits for patients with and without dementia (odds ratio [OR], 0.555; 95% confidence interval [CI], 0.183-1.678). Differences were seen in the provision of cholinesterase inhibitors, antipsychotics, and central nervous system agents at visits for patients with dementia ( p  = 0.0011, <0.0001, and 0.0011 respectively)., Conclusion: While fewer visits for patients with dementia provided new medications compared to patients without dementia, after adjusting for confounders no significant difference were identified. Significant differences were seen in the classes of new medications provided. Further investigation is needed to evaluate new medication usage and the utility of pharmacists in the care of patients with dementia at an outpatient setting., Competing Interests: The authors declare no relevant conflicts of interest or financial relationships., (© 2021 The Authors.)

The factors associated with chronic opioid therapy (COT) in patients with HIV is understudied. Using Medicaid data (2002-2009), this retrospective cohort study examines COT in beneficiaries with HIV who initiated standard combination anti-retroviral therapy (cART). We used generalized estimating equations on logistic regression models with backward selection to identify significant predictors of COT initiation. COT was initiated among 1014 out of 9615 beneficiaries with HIV (male: 10.4%; female: 10.7%). Those with older age, any malignancy, Hepatitis C infection, back pain, arthritis, neuropathy pain, substance use disorder, polypharmacy, (use of) benzodiazepines, gabapentinoids, antidepressants, and prior opioid therapies were positively associated with COT. In sex-stratified analyses, multiple predictors were shared between male and female beneficiaries; however, chronic obstructive pulmonary disease, liver disease, any malignancy, and antipsychotic therapy were unique to female beneficiaries. Comorbidities and polypharmacy were important predictors of COT in Medicaid beneficiaries with HIV who initiated cART., (© 2021. The Author(s).)

Potentially inappropriate anticholinergic medications (including over-the-counter products), polypharmacy, and the existence of communication barriers among members of the interprofessional team frequently contribute to clinical complexity in older adults. We present the case of a frail 86-year old female from the perspective of a community pharmacist managing outpatient medications and transitions of care. CD's past medical history is significant for dementia, multiple falls, recurrent urinary tract infections, depression, cardiac arrhythmia, macular degeneration, chronic pain, depression, and cerebrovascular disease., Competing Interests: LE is affiliated to 2PRO2RX LLC Pharmacy Consulting Services. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Elliott, Eckmann and Moga.)

Objective: To develop a mentor-supervised, interprofessional, geriatric telemedicine experiential education project in response to the COVID-19 pandemic., Method: Medical and pharmacy students collaborated via remote consultations to address the coexistence of multimorbidity and polypharmacy in geriatric patients. In-depth interviews of students and patients as well as Likert scale-based telephonic survey were performed for a comprehensive evaluation of the project's significance., Results: To date, 49 consultations have been conducted. Remote consultations performed by medical and pharmacy students working collaboratively were beneficial for both students, participants., Conclusions and Practice Implications: This experimental education project provided students with authentic challenges while simultaneously delivering care to the older adults who are susceptible to disruption of care associated with the pandemic. Further development and expanded implementation of such approaches may be a post-pandemic practice to provide more accessible care for senior patients while incorporating interprofessional education.

Objective: To determine whether assessment tools for non-randomised studies (NRS) address critical elements that influence the validity of NRS findings for comparative safety and effectiveness of medications., Design: Systematic review and Delphi survey., Data Sources: We searched PubMed, Embase, Google, bibliographies of reviews and websites of influential organisations from inception to November 2019. In parallel, we conducted a Delphi survey among the International Society for Pharmacoepidemiology Comparative Effectiveness Research Special Interest Group to identify key methodological challenges for NRS of medications. We created a framework consisting of the reported methodological challenges to evaluate the selected NRS tools., Study Selection: Checklists or scales assessing NRS., Data Extraction: Two reviewers extracted general information and content data related to the prespecified framework., Results: Of 44 tools reviewed, 48% (n=21) assess multiple NRS designs, while other tools specifically addressed case-control (n=12, 27%) or cohort studies (n=11, 25%) only. Response rate to the Delphi survey was 73% (35 out of 48 content experts), and a consensus was reached in only two rounds. Most tools evaluated methods for selecting study participants (n=43, 98%), although only one addressed selection bias due to depletion of susceptibles (2%). Many tools addressed the measurement of exposure and outcome (n=40, 91%), and measurement and control for confounders (n=40, 91%). Most tools have at least one item/question on design-specific sources of bias (n=40, 91%), but only a few investigate reverse causation (n=8, 18%), detection bias (n=4, 9%), time-related bias (n=3, 7%), lack of new-user design (n=2, 5%) or active comparator design (n=0). Few tools address the appropriateness of statistical analyses (n=15, 34%), methods for assessing internal (n=15, 34%) or external validity (n=11, 25%) and statistical uncertainty in the findings (n=21, 48%). None of the reviewed tools investigated all the methodological domains and subdomains., Conclusions: The acknowledgement of major design-specific sources of bias (eg, lack of new-user design, lack of active comparator design, time-related bias, depletion of susceptibles, reverse causation) and statistical assessment of internal and external validity is currently not sufficiently addressed in most of the existing tools. These critical elements should be integrated to systematically investigate the validity of NRS on comparative safety and effectiveness of medications. SYSTEMATIC REVIEW PROTOCOL AND REGISTRATION: https://osf.io/es65q., Competing Interests: Competing interests: DB is an employee of Takeda. ARZ has received salary support from Sanofi Pasteur through a grant to Brown University unrelated to the current work. TD provides consulting services via Smart Data Analysis and Statistics. GS discloses being employed by Visible Analytics Ltd., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Sufficient sleep is critical for health in older adults, but prescription sleep aids are associated with numerous health risks (e.g., cognitive impairment and falls). We examine usage prevalence of two medication categories-sedative hypnotics (SH) and medications commonly used for insomnia (MCUFI)-among adults aged 45+ in the National Alzheimer's Coordinating Center data set. Analyzing the visits conducted between September 2005 and June 2018, we determine the factors associated with SH and MCUFI use, including sociodemographic, health, independence, and cognitive statuses. Usage rates were 9% for MCUFI ( N = 3,279) and 4% for SH ( N = 1,382). Multivariable logistic regression identified White race, higher education, younger age, depression, and sedative polypharmacy as factors associated with prescription sleep aid use. We conclude that sleep medication usage rates among older adults, higher likelihood of sedative medication polypharmacy, and higher likelihood of MCUFI use among adults with cognitive impairment are findings of concern and may warrant clinical intervention.

Background: Patients' attitudes toward deprescribing are crucial to understand before developing interventions, but no such data exists in the medically underserved, health disparities population of rural Appalachian United States., Objective(s): Assess Appalachian women's openness to deprescribing medications and determine if polypharmacy influenced their attitudes toward deprescribing., Methods: Before and after a cognitive behavioral therapy intervention, middle-aged Appalachian women self-reported medication use and completed the revised Patients' Attitudes Toward Deprescribing Questionnaire (rPATD). Responses were described, stratified by presence of polypharmacy., Results: 30 women completed the rPATD pre- and post-intervention (mean [SD] age 55.8 [6.6] years; 96.7% white). Those with polypharmacy (n = 16) had higher burden and involvement scores (median 2.8 vs 2.0, p = 0.01; 4.9 vs 4.6, p = 0.06), and lower appropriateness scores (3.4 vs 3.9, p = 0.04). Burden, concerns about stopping, and involvement factor scores were similar before and after the intervention (p = 0.08, 0.86, and 0.41 respectively). ≥90% of participants were satisfied with their current medications yet would be willing to stop one or more., Conclusions: Middle-aged women in rural Appalachian United States are open to deprescribing; polypharmacy is associated with lower belief in the appropriateness of medications. Larger studies are needed to inform future deprescribing interventions for this and other similarly disadvantaged populations., (Copyright © 2020. Published by Elsevier Inc.)

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.

Background: Older adults are especially susceptible to adverse effects of inappropriate medication therapy, and anticholinergic medications are common culprits for cognitive dysfunction due to their action on the central nervous system. Medication therapy management (MTM) interventions can aid in deprescribing and reducing inappropriate medication use in older adults. However, there is sparse literature on the long-term sustainability of these interventions., Objectives: To (a) investigate whether the deprescribing of anticholinergic medications during an 8-week randomized controlled trial (RCT) of a targeted MTM intervention is sustained at 1-year postintervention follow-up and (b) compare anticholinergic utilization trends in the study population with a large sample of similar individuals not exposed to the intervention., Methods: Participants in the targeted MTM (tMTM) RCT had normal cognition or mild cognitive impairment and were recruited from enrollees in a longitudinal study at the University of Kentucky Alzheimer's Disease Center (ADC) and thus have pertinent medical information gathered approximately annually. In this posttrial observational follow-up, sustainability of the anticholinergic deprescribing intervention was assessed in participants in the RCT, and anticholinergic medication use trends were described from the RCT baseline (which occurred immediately following an ADC visit) to the next annual visit in all participants. Mean change in anticholinergic burden from RCT baseline to the next annual visit was estimated using analysis of covariance, and participants were compared with 2 external samples. Anticholinergic burden was measured using the Anticholinergic Drug Scale (ADS). The odds of decreasing baseline anticholinergic burden and number of total and strong anticholinergic medications at the follow-up study time point was assessed using logistic regression., Results: Of the deprescribing changes made during the initial RCT, 50% were sustained after 1 year. Participants in the tMTM trial reported decreases in the use of anticholinergic antihistamines and bladder agents (-6.5 and -4.4%, respectively), but there was no change in the use of anticholinergic agents targeted at the central nervous system. While the anticholinergic burden of RCT participants decreased over 1 year (adjusted mean ADS change [95% CI] = -0.33 [-0.72, 0.07]), it was not different than the change observed in 2 external samples at the trial center (-0.20 [-0.42, 0.02]) and nationally (-0.33 [-0.39, -0.26]). There were no statistically significant differences between trial participants and external samples in the odds of decreasing anticholinergic burden nor in decreasing the number of total, or strongly anticholinergic, medications at the 1-year follow-up., Conclusions: This study demonstrates that the sustainability of deprescribing is limited to the period of intervention, rather than affording lasting effects even over periods as short as 1 year, which was demonstrated not only in the small group of RCT participants but also by comparison with external groups. Future work should extend the duration of intervention and follow-up periods for MTM interventions to allow further insights regarding the sustainability of deprescribing efforts in older adults., Disclosures: The original trial was supported by a pilot study award from the University of Kentucky Center for Clinical and Translational Sciences (UL1TR000117). Additional support for this study was provided by the National Institutes of Health/National Institute on Aging (R01 AG054130). Jicha reports contract research for Esai, Biohaven, Alltech, Suven, Novartis, and Lilly. The other authors have nothing to disclose.

Background: The course of Alzheimer's disease (AD) includes a 10-20-year preclinical period with progressive accumulation of amyloid β (Aβ) plaques and neurofibrillary tangles in the absence of symptomatic cognitive or functional decline. The duration of this preclinical stage in part depends on the rate of pathologic progression, which is offset by compensatory mechanisms, referred to as cognitive reserve (CR). Comorbid medical conditions, psychosocial stressors, and inappropriate medication use may lower CR, hastening the onset of symptomatic AD. Here, we describe a randomized controlled trial (RCT) designed to test the efficacy of a medication therapy management (MTM) intervention to reduce inappropriate medication use, bolster cognitive reserve, and ultimately delay symptomatic AD., Methods/design: Our study aims to enroll 90 non-demented community-dwelling adults ≥ 65 years of age. Participants will undergo positron emission tomography (PET) scans, measuring Aβ levels using standardized uptake value ratios (SUVr). Participants will be randomly assigned to MTM intervention or control, stratified by Aβ levels, and followed for 12 months via in-person and telephone visits. Outcomes of interest include: (1) medication appropriateness (measured with the Medication Appropriateness Index (MAI)); (2) scores from Trail Making Test B (TMTB), Montreal Cognitive Assessment (MoCA), and California Verbal Learning Test (CVLT); (3) perceived health status (measured with the SF-36). We will also evaluate pre- to post-intervention change in: (1) use of inappropriate medications as measured by MAI; 2) CR Change Score (CRCS), defined as the difference in scopolamine-challenged vs unchallenged cognitive scores at baseline and follow-up. Baseline Aβ SUVr will be used to examine the relative impact of preclinical AD (pAD) pathology on CRCS, as well as the interplay of amyloid burden with inappropriate medication use., Discussion: This manuscript describes the protocol of INCREASE ("INtervention for Cognitive Reserve Enhancement in delaying the onset of Alzheimer's Symptomatic Expression"): a randomized controlled trial that investigates the impact of deprescribing inappropriate medications and optimizing medication regimens on potentially delaying the onset of symptomatic AD and AD-related dementias., Trial Registration: ClinicalTrials.gov, NCT02849639. Registered on 29 July 2016.

Background: Nearly 70% of Americans with cardiovascular disease use statins, which have documented bleeding effects independent of their cholesterol-lowering activities. However, the literature is conflicting regarding the association between statin use and gastrointestinal hemorrhage., Objectives: The aim of this study was to investigate the risk of gastrointestinal hemorrhage in statin users., Methods: In this retrospective cohort study, data from the Truven Health MarketScan ® Research Database (2009-2015) were used to investigate the risk of gastrointestinal hemorrhage amongst statin users aged 30-65 years at the initial prescription claim. Statin users and a group of negative controls (i.e. other chronic medication users) were followed until first gastrointestinal hemorrhage event (both inpatient and outpatient, as well as restricted to inpatient), and were censored at treatment discontinuation, disenrollment from coverage, or the end of the study period., Results: Statin users had an elevated risk of gastrointestinal hemorrhage, which was especially apparent in the first year of treatment (1-year adjusted hazard ratio 1.19; 95% confidence interval (CI) 1.15-1.23). The risk of gastrointestinal hemorrhage leading to hospitalization was even higher (1-year adjusted hazard ratio 1.38; 95% CI 1.30-1.69). High-intensity statin users had a greater rate of gastrointestinal hemorrhage than moderate-intensity users (incidence rates per 1000 subject-years 22.2 (95% CI 21.9-22.8) vs. 21.5 (95% CI 21.3-21.8), respectively)., Conclusions: In a population of commercially insured subjects aged 30-65 years, statin users had a higher risk for gastrointestinal hemorrhage than other chronic medication users. These findings are important when treating patients at a high risk for bleeding events.

Background: Given the controversy around the effectiveness of opioid treatment for chronic pain and the lack of detailed guidance for prescribing opioids in older adults, the objectives of this study were to estimate the trajectories and predictors of opioid use in older adults., Methods: Data were extracted from the National Alzheimer's Coordinating Center (2005-2017). Group-based trajectory modeling was used to identify the patterns of opioid use (any or strong) among participants age 65+. We used multivariable logistic regression with backward selection to evaluate demographics and comorbidities as potential predictors of trajectory membership., Results: Among 13,059 participants, four trajectories were identified for the use of both any opioids and strong opioids (minimal-users, incident chronic-users, discontinuing-users, and prevalent chronic-users). For any opioids, female sex (adjusted odds ratio = 1.23; 95% confidence interval = 1.03-1.46), black vs. white (1.47; 1.18-1.82), year of education (0.96; 0.94-0.99), type of residence (independent group vs. private: 1.77; 1.38-2.26, care facility vs. private: 1.89; 1.20-2.97), hypertension (1.44; 1.20-1.72), cardiovascular disease (1.30; 1.09-1.55), urinary incontinence (1.45; 1.19-1.78), dementia (0.73; 0.57-0.92), number of medications (1 to 4 vs. none: 0.48; 0.36-0.64, 5 or more vs. none: 0.67; 0.50-0.88), and antidepressant agent (1.38; 1.14-1.67) were associated with incident chronic-use vs. non-use. For strong opioids, female sex (1.27; 1.04-1.56), type of residence (independent group vs. private: 1.90; 1.43-2.53, care facility vs. private: 2.37; 1.44-3.90), current smoking (1.68; 1.09-2.60), hypertension (1.49; 1.21-1.83), urinary incontinence (1.45; 1.14-1.84), dementia (0.73; 0.55-0.97), number of medications (1 to 4 vs. none: 0.46; 0.32-0.65, 5 or more vs. none: 0.59; 0.42-0.83), and antidepressant agent (1.55; 1.24-1.93) were associated with incident chronic-use vs. non-use., Conclusion: Given that chronic opioid use was more prevalent in participants who were more vulnerable (i.e., older age, with multiple comorbidities, and polypharmacy), further studies should evaluate the safety and efficacy of using opioids in this population., Competing Interests: The authors have declared that no competing interests exist.

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.

Background: Use of potentially inappropriate medications (PIM) among people with dementia is common. We assessed the patterns of medication use from 1-year before dementia diagnosis, to 1-year after dementia diagnosis, compared with patterns of medication use in people without dementia., Methods: We conducted longitudinal study using the National Alzheimer's Coordinating Center data. Adults aged 65 years and older newly diagnosed with dementia (n = 2,418) during 2005-2015 were year, age, and sex matched 1:1 with controls. Generalized estimating equation models weighted for missingness and adjusted for 15 participant characteristics were fit., Results: Among participants with dementia, number of medications reported 1-year prediagnosis was 8% lower than at diagnosis year (p < .0001) and 11% higher 1-year postdiagnosis compared with year of diagnosis (p < .0001). Among participants with dementia, the odds of PIM exposure, assessed using the 2015 Beers Criteria, was 17% lower 1-year prediagnosis (p < .0001) and 17% higher 1-year postdiagnosis (p = .006) compared with year of diagnosis. Among controls, there were approximately 6% more medications reported between consecutive years (p < .0001 each comparison) and the odds of PIM exposure increased 11% between consecutive years (p = .006 and p = .047). At each annual follow-up, participants with dementia had lower odds of PIM exposure than their controls (prediagnosis p < .0001, at diagnosis p = .0007, postdiagnosis p = .03, respectively). There were no differences in exposure to anticholinergic medications., Conclusions: Number of medications and PIM use increased annually for participants with and without dementia. Persistent challenge of increasing PIM use in this group of older adults is of major concern and warrants interventions to minimize such prescribing.

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.

Dementia represents one of the most important and growing public health issues facing society today. Primary care clinics serve a crucial role as the first line of defense in the recognition and treatment of dementia. Increased awareness and treatment of risk factors for dementia are important for lessening disease burden in the population. Diagnostic workup should include screening for medical and nondegenerative causes of cognitive impairment that may be remedial. Treatment approaches should include multimodal approaches to address cognitive decline and behavioral/psychiatric symptoms of dementia in an effort to maximize quality of life for both patients and caregivers., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The complexity of medication therapy in older adults with multiple comorbidities often leads to inappropriate prescribing. Drugs with anticholinergic properties are of particular interest because many are not recognized for this property; their use may lead to increased anticholinergic burden resulting in significant health risks, as well as negatively impacting cognition. Medication therapy management (MTM) interventions showed promise in addressing inappropriate medication use, but the effectiveness of targeted multidisciplinary team interventions addressing anticholinergic medications in older populations is yet to be determined., Methods: We conducted an 8-week, parallel-arm, randomized trial to evaluate whether a targeted patient-centered pharmacist-physician team MTM intervention ("targeted MTM intervention") reduced the use of inappropriate anticholinergic medications in older patients enrolled in a longitudinal cohort at University of Kentucky's Alzheimer's Disease Center. Study outcomes included changes in the medication appropriateness index (MAI) targeting anticholinergic medications and in the anticholinergic drug scale (ADS) score from baseline to the end of study., Results: Between October 1, 2014 and September 30, 2015 we enrolled and randomized 50 participants taking at least one medication with anticholinergic properties. Of these, 35 (70%) were women, 45 (90%) were white, and 33 (66%) were cognitively intact (clinical dementia rating [CDR] = 0); mean age was 77.7 ± 6.6 years. At baseline, the mean MAI was 12.6 ± 6.3; 25 (50%) of the participants used two or more anticholinergics, and the mean ADS score was 2.8 ± 1.6. After randomization, although no statistically significant difference was noted between groups, we identified a potentially meaningful imbalance as the intervention group had more participants with intact cognition, and thus included CDR in all of the analyses. The targeted MTM intervention resulted in statistically significant CDR adjusted differences between groups with regard to improved MAI (change score of 3.6 (1.1) for the MTM group as compared with 1.0 (0.9) for the control group, p = 0.04) and ADS (change score of 1.0 (0.3) for the MTM group as compared with 0.2 (0.3) for the control group, p = 0.03)., Conclusions: Our targeted MTM intervention resulted in improvement in anticholinergic medication appropriateness and reduced the use of inappropriate anticholinergic medications in older patients. Our results show promise in an area of great importance to ensure optimum outcomes for medications used in older adults., Trial Registration: ClinicalTrials.gov NCT02172612 . Registered 20 June 2014.

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., (© 2017 American Neurological Association.)

Introduction: The evidence on the impact of bladder antimuscarinics initiation on cognitive function in older adults is inconsistent., Methods: A retrospective analysis of data from the National Alzheimer's Coordinating Center (NACC) on enrollees 65 years and older evaluated the association between antimuscarinic initiation and cognitive decline. We defined decline from baseline (yes/no) for cognitive assessments included in the NACC Uniform Data Set 2.0 battery. New users were matched on year of enrollment and time in the cohort to randomly selected nonusers. Analyses were conducted using inverse probability of treatment weights based on baseline propensity scores., Results: Our analyses included 698 new users and 7037 nonusers. The odds ratio (OR) and 95% confidence interval for cognitive decline in users as compared to nonusers was 1.4 (1.19-1.65) for Mini-Mental State Examination (MMSE), and 1.21 (1.03-1.42) for Clinical Dementia Rating; in addition, the odds of decline were 20% higher in users compared to nonusers for semantic memory/language and executive function. The effect estimate for MMSE was 1.94 (1.3-2.91) for those with mild cognitive impairment, 1.26 (0.99-1.62) in those with normal cognition, and 1.44 (1.04-1.99) in those with dementia at baseline., Discussion: Our results show that antimuscarinic initiation is associated with cognitive decline and raise questions about their use, especially in those with impaired cognition.

Aims: Given the high prevalence of psychotropic medication use in people with dementia and the potential for different prescribing practices in men and women, our study aimed to investigate sex differences in psychotropic medication use in older adults with Alzheimer's disease (AD) living in the US and Finland., Methods: We used data collected between 2005 and 2011 as part of the National Alzheimer's Coordinating Center (NACC) in the US, and Medication use and Alzheimer's disease (MEDALZ) cohorts in Finland. We evaluated psychotropic medication use (antidepressant, antipsychotic, anxiolytic, sedative, or hypnotic) in participants aged 65 years or older. We employed multivariable logistic regression adjusted for demographics, co-morbidities, and other medications to estimate the magnitude of the association (adjusted odds ratio [aOR] with 95% confidence intervals [CIs]) according to sex., Results: We included 1099 NACC participants (502 [45.68%] men, 597 [54.32%] women), and 67,049 participants from the MEDALZ cohort (22,961 [34.24%] men, 44,088 [65.75%] women). Women were more likely than men to use psychotropic medications: US, 46.2% vs. 33.1%, p < 0.001; Finland, 45.3% vs. 36.1%, p < 0.001; aOR was 2.06 (95% CI 1.58-2.70) in the US cohort and 1.38 (95% CI 1.33-1.43) in the Finnish cohort. Similarly, of the different psychotropic medications, women were more likely to use antidepressants (aOR-US: 2.16 [1.44-3.25], Finland: 1.52 [1.45-1.58]) and anxiolytics (aOR-US: 2.16 [1.83-3.96], Finland: 1.17 [1.13-1.23]) than men., Conclusion: Older women with AD are more likely to use psychotropic medications than older men, regardless of study population and country. Approaches to mitigate psychotropic medication use need to consider different prescribing habits observed in older women vs. men with AD., Competing Interests: DM, AMT, QW, GJ and DG declare no conflicts of interest.