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Abstract Study Objectives To examine associations between positive airway pressure (PAP) therapy, adherence and incident diagnoses of Alzheimer’s disease (AD), mild cognitive impairment (MCI), and dementia not otherwise specified (DNOS) in older adults. Methods This retrospective study utilized Medicare 5% fee-for-service claims data of 53,321 beneficiaries, aged 65 and older, with an obstructive sleep apnea (OSA) diagnosis prior to 2011. Study participants were evaluated using ICD-9 codes for neurocognitive syndromes (AD [n = 1,057], DNOS [n = 378], and MCI [n = 443]) that were newly identified between 2011 and 2013. PAP treatment was defined as the presence of at least one durable medical equipment (Healthcare Common Procedure Coding System [HCPCS]) code for PAP supplies. PAP adherence was defined as at least two HCPCS codes for PAP equipment, separated by at least 1 month. Logistic regression models, adjusted for demographic and health characteristics, were used to estimate associations between PAP treatment or adherence and new AD, DNOS, and MCI diagnoses. Results In this sample of Medicare beneficiaries with OSA, 59% were men, 90% were non-Hispanic whites and 62% were younger than 75 years. The majority (78%) of beneficiaries with OSA were prescribed PAP (treated), and 74% showed evidence of adherent PAP use. In adjusted models, PAP treatment was associated with lower odds of incident diagnoses of AD and DNOS (odds ratio [OR] = 0.78, 95% confidence interval [95% CI]: 0.69 to 0.89; and OR = 0.69, 95% CI: 0.55 to 0.85). Lower odds of MCI, approaching statistical significance, were also observed among PAP users (OR = 0.82, 95% CI: 0.66 to 1.02). PAP adherence was associated with lower odds of incident diagnoses of AD (OR = 0.65, 95% CI: 0.56 to 0.76). Conclusions PAP treatment and adherence are independently associated with lower odds of incident AD diagnoses in older adults. Results suggest that treatment of OSA may reduce the risk of subsequent dementia.

Randomized clinical trials (RCTs) are conducted to guide clinicians' selection of therapies for individual patients. Currently, RCTs in critical care often report an overall mean effect and selected individual subgroups. Yet work in other fields suggests that such reporting practices can be improved. Specifically, this Critical Care Perspective reviews recent work on so-called \"heterogeneity of treatment effect\" (HTE) by baseline risk and extends that work to examine its applicability to trials of acute respiratory failure and severe sepsis. Because patients in RCTs in critical care medicine-and patients in intensive care units-have wide variability in their risk of death, these patients will have wide variability in the absolute benefit that they can derive from a given therapy. If the side effects of the therapy are not perfectly collinear with the treatment benefits, this will result in HTE, where different patients experience quite different expected benefits of a therapy. We use simulations of RCTs to demonstrate that such HTE could result in apparent paradoxes, including: (1) positive trials of therapies that are beneficial overall but consistently harm or have little benefit to low-risk patients who met enrollment criteria, and (2) overall negative trials of therapies that still consistently benefit high-risk patients. We further show that these results persist even in the presence of causes of death unmodified by the treatment under study. These results have implications for reporting and analyzing RCT data, both to better understand how our therapies work and to improve the bedside applicability of RCTs. We suggest a plan for measurement in future RCTs in the critically ill.

Sex differences in dementia risk are unclear, but some studies have found greater risk for women. To determine associations between sex and cognitive decline in order to better understand sex differences in dementia risk. This cohort study used pooled analysis of individual participant data from 5 cohort studies for years 1971 to 2017: Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, and Northern Manhattan Study. Linear mixed-effects models were used to estimate changes in each continuous cognitive outcome over time by sex. Data analysis was completed from March 2019 to October 2020. Sex. The primary outcome was change in global cognition. Secondary outcomes were change in memory and executive function. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition. Among 34 349 participants, 26 088 who self-reported Black or White race, were free of stroke and dementia, and had covariate data at or before the first cognitive assessment were included for analysis. Median (interquartile range) follow-up was 7.9 (5.3-20.5) years. There were 11 775 (44.7%) men (median [interquartile range] age, 58 [51-66] years at first cognitive assessment; 2229 [18.9%] Black) and 14 313 women (median [interquartile range] age, 58 [51-67] years at first cognitive assessment; 3636 [25.4%] Black). Women had significantly higher baseline performance than men in global cognition (2.20 points higher; 95% CI, 2.04 to 2.35 points; P < .001), executive function (2.13 points higher; 95% CI, 1.98 to 2.29 points; P < .001), and memory (1.89 points higher; 95% CI, 1.72 to 2.06 points; P < .001). Compared with men, women had significantly faster declines in global cognition (-0.07 points/y faster; 95% CI, -0.08 to -0.05 points/y; P < .001) and executive function (-0.06 points/y faster; 95% CI, -0.07 to -0.05 points/y; P < .001). Men and women had similar declines in memory (-0.004 points/y faster; 95% CI, -0.023 to 0.014; P = .61). The results of this cohort study suggest that women may have greater cognitive reserve but faster cognitive decline than men, which could contribute to sex differences in late-life dementia.

[This corrects the article DOI: 10.1371/journal.pone.0282658.].

Epilepsy is a common, serious condition. Fortunately, seizure risk decreases with increasing seizure-free time on antiseizure medications (ASMs). Eventually, patients may consider whether to stop ASMs, which requires weighing treatment benefit versus burden. We developed a questionnaire to quantify patient preferences relevant to ASM decision-making. Respondents rated how concerning they would finding relevant items (e.g., seizure risks, side effects, cost) on a Visual Analogue Scale (VAS, 0–100) and then repeatedly chose the most and least concerning item from subsets (best-worst scaling, BWS). We pretested with neurologists, then recruited adults with epilepsy who were seizure-free at least one year. Primary outcomes were recruitment rate, and qualitative and Likert-based feedback. Secondary outcomes included VAS ratings and best-minus-worst scores. Thirty-one of 60 (52%) contacted patients completed the study. Most patients felt VAS questions were clear (28; 90%), easy to use (27; 87%), and assessed preferences well (25; 83%). Corresponding results for BWS questions were 27 (87%), 29 (97%), and 23 (77%). Physicians suggested adding a ‘warmup’ question showing a completed example and simplifying terminology. Patients suggested ways to clarify instructions. Cost, inconvenience of taking medication, and laboratory monitoring were the least concerning items. Cognitive side effects and a 50% seizure risk in the next year were the most concerning items. Twelve (39%) of patients made at least one ‘inconsistent choice’ for example ranking a higher seizure risk as lower concern compared with a lower seizure risk, though ‘inconsistent choices’ represented only 3% of all question blocks. Our recruitment rate was favorable, most patients agreed the survey was clear, and we describe areas for improvement. ‘Inconsistent’ responses may lead us to collapse seizure probability items into a single ‘seizure’ category. Evidence regarding how patients weigh benefits and harms may inform care and guideline development.

Background Although the efficacy of tissue plasminogen activator (tPA) for acute ischemic stroke is well established, rates of tPA use remain low. For clinicians, advocates, and policy-makers seeking to increase tPA treatment rates, it is important to understand what interventions exist and their relative effectiveness. Methods We searched PubMed and EMBASE to identify all studies published between 1995 and January 8, 2015 documenting interventions to increase the use of tPA with broadly inclusive criteria. The principal summary measure was the percentage change in rate of tPA administration. Random effects meta-analytic models were built to summarize the effect of intervention compared to control overall and for intervention characteristics. Results The search yielded 1457 results of which 25 met eligibility criteria. We identified 14 pre-post studies, ten randomized controlled trials, and one quasi-experiment. Included studies targeted their interventions at emergency medical services (EMS) ( n  = 14), telemedicine ( n  = 6), and public education ( n  = 6). In a random effects model, tPA administration was significantly higher in the intervention arm across all studies limiting enrollment to ischemic stroke patients ( n  = 16) with a risk ratio (RR) of 1.80 (95% confidence interval [CI], 1.45–2.22). A trend towards increased tPA administration was observed for all intervention approaches: risk ratio of 1.73 (95% CI, 1.44–2.09) for EMS, 1.58 (95% CI, 0.72–3.47) for telemedicine, and 1.89 (95% CI, 0.77–4.65) for public education, the latter not restricted to ischemic stroke patients. Conclusions Interventions to increase tPA use appear to have considerable effectiveness. Our findings support the use of such interventions to improve stroke outcomes.

Background Regular medical follow-up after stroke is important to reduce the risk of post-stroke complications and hospital readmission. Little is known about the factors associated with stroke survivors not maintaining regular medical follow-up. We sought to quantify the prevalence and predictors of stroke survivors not maintaining regular medical follow-up over time. Methods We conducted a retrospective cohort study of stroke survivors in the National Health and Aging Trends Study (2011–2018), a national longitudinal sample of United States Medicare beneficiaries. Our primary outcome was not maintaining regular medical follow-up. We performed a cox regression to estimate predictors of not maintaining regular medical follow-up. Results There were 1330 stroke survivors included, 150 of whom (11.3%) did not maintain regular medical follow-up. Stroke survivor characteristics associated with not maintaining regular medical follow-up included not having restrictions in social activities (HR 0.64, 95% CI 0.41, 1.01 for having restrictions in social activities compared to not having restrictions in social activities), greater limitations in self-care activities (HR 1.13, 95% CI 1.03, 1.23), and probable dementia (HR 2.23, 95% CI 1.42, 3.49 compared to no dementia). Conclusions The majority of stroke survivors maintain regular medical follow-up over time. Strategies to retain stroke survivors in regular medical follow-up should be directed towards stroke survivors who do not have restrictions in social activity participation, those with greater limitations in self-care activities, and those with probable dementia.

ObjectiveOptic neuritis (ON) is an acute focal inflammation of the optic nerve routinely treated with glucocorticoids. We aimed to compare adverse events (AE) among glucocorticoid-treated and untreated patients in the real world to guide clinical decision making about treatment tradeoffs.DesignRetrospective, longitudinal cohort study.SettingClaims study from a large, private insurer in the USA (2005–2019).ParticipantsAdults≥18 years old with ≥1 ICD9/10 ON diagnosis with an evaluation/management visit code, and ≥6 months continuous enrolment prior to and following ON diagnosis.InterventionGlucocorticoid prescription exposure.Primary and secondary outcome measuresPrimary outcome was any AE within 90 days of glucocorticoid prescription. Secondary outcome was AE assessment by severity. Generalised estimating equations with logit link assessed relationships between glucocorticoid prescription and AEs. High-dimensional propensity score analyses accounted for potential confounding (eg, sociodemographics and comorbidities). Sensitivity analyses restricted the cohort to high-dose prescriptions (≥100 mg prednisone equivalent, injection/infusion), AEs within 30 days, highly specific ON definition and traditional propensity score match.ResultsOf the 14 311 people with 17 404 ON claims, 66.3% were women (n=9481), predominantly White (78.2%; n=9940), with median age (IQR)=48 (37,60) years. Within 90 days of the claim, 15.7% (n=2733/17 404) were prescribed glucocorticoids. The median (IQR) prescription duration=10 (6,20) days. Any and severe AEs were higher among patients prescribed glucocorticoids versus none (any AEs: n=437/2733 (16.0%) vs n=1784/14 671 (12.2%), adjusted OR 1.33 (95% CI: 1.18 to 1.50); severe AEs: n=72/2733 (2.6%) vs n=273/14 671 (1.9%), adjusted OR 1.82 (95% CI: 1.37 to 2.35)). Sensitivity analyses were similar.ConclusionsReal-world glucocorticoid prescriptions among ON patients were short-term, associated with a 30% relative increase in potentially serious AEs captured within healthcare encounters, including those not previously observed, such as VTE. These results can inform treatment decisions, particularly for ON patients likely to experience only marginal benefits.

Background The evaluation and management of acute vertigo presentations is challenging for both patients and physicians. Benign paroxysmal positional vertigo (BPPV), acute unilateral vestibulopathy (e.g., vestibular neuritis), and stroke are priority diagnostic considerations in this circumstance. Existing evidence can be used to guide the diagnosis and treatment, however high value care opportunities—such as the Dix-Hallpike test (DHT), canalith repositioning maneuver (CRM), and gaze stabilization exercises (GSE)—are often underused, while neuroimaging studies are often overused. Methods This trial contains a health system focused stepped wedge intervention and an embedded individually patient randomized clinical trial. The study will start with a 6-month pre-intervention period. This will be followed by staggered intervention at the engaged EDs in 11 waves and then an approximately 6-month post-intervention period. Concurrently, patients will be recruited before and after the physician level intervention is implemented at each ED. Enrolled participants will complete baseline survey and then be randomized individually, stratified by sex, age, and medical center, to the intervention or control arm patient materials using central computerized randomization. The intervention arm will be sent intervention materials and the control arm will be sent the hospital’s standard post-discharge materials. The primary outcome of the physician-based part of the trial is use of evidence-based care practices during the index ED visit. The primary outcome of the patient focused part of the trial is the dizziness handicap index over 4 weeks. Discussion The DIZZTINCT-2 trial addresses key areas of uncertainty in how to improve the care of emergency department patients with acute vertigo. In addition, follow up data on how much and how fast patients improved was needed. DIZZTINCT-2 will address these key knowledge gaps efficiently. Trial registration Clinicaltrials.gov NCT05634902. Registered on November 2022.

Background Carotid endarterectomy (CEA) is routinely performed for asymptomatic carotid stenosis, yet its average net benefit is small. Risk stratification may identify high risk patients that would clearly benefit from treatment. Methods Retrospective cohort study using data from the Asymptomatic Carotid Atherosclerosis Study (ACAS). Risk factors for poor outcomes were included in backward and forward selection procedures to develop baseline risk models estimating the risk of non-perioperative ipsilateral stroke/TIA. Baseline risk was estimated for all ACAS participants and externally validated using data from the Atherosclerosis Risk in Communities (ARIC) study. Baseline risk was then included in a treatment risk model that explored the interaction of baseline risk and treatment status (CEA vs. medical management) on the patient-centered outcome of any stroke or death, including peri-operative events. Results Three baseline risk factors (BMI, creatinine and degree of contralateral stenosis) were selected into our baseline risk model (c-statistic 0.59 [95% CI 0.54–0.65]). The model stratified absolute risk between the lowest and highest risk quintiles (5.1% vs. 12.5%). External validation in ARIC found similar predictiveness (c-statistic 0.58 [0.49–0.67]), but poor calibration across the risk spectrum. In the treatment risk model, CEA was superior to medical management across the spectrum of baseline risk and the magnitude of the treatment effect varied widely between the lowest and highest absolute risk quintiles (3.2% vs. 10.7%). Conclusion Even modestly predictive risk stratification tools have the potential to meaningfully influence clinical decision making in asymptomatic carotid disease. However, our ACAS model requires target population recalibration prior to clinical application.