Comparative safety and cardiovascular effectiveness of sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists in nursing homes.

AIM: Studies examining the safety and effectiveness of sodium-glucose cotransporter-2 inhibitors (SGLT2is) versus glucagon-like peptide-1 receptor agonists (GLP-1RAs) among community-dwelling adults may not generalize to nursing home (NH) residents, who are typically older and more multimorbid. We compared the safety and cardiovascular effectiveness of SGLT2is and GLP-1RAs among US NH residents. MATERIALS AND METHODS: Eligible individuals were aged ≥66 years with type 2 diabetes mellitus and initiated an SGLT2i or GLP-1RA in an NH between 2013 and 2018. Safety outcomes included fall-related injuries, hypoglycaemia, diabetic ketoacidosis (DKA), urinary tract infection or genital infection, and acute kidney injury in the year following treatment initiation. Cardiovascular effectiveness outcomes included death, major adverse cardiovascular events and hospitalization for heart failure. Per-protocol adjusted hazard ratios (HR) were calculated using stabilized inverse probability of treatment and censoring weighted cause-specific hazard regression models accounting for 127 covariates. RESULTS: The study population included 7710 residents (31.08% SGLT2i, 68.92% GLP-1RA). Compared with GLP-1RA initiators, SGLT2i initiators had higher rates of DKA (HR 1.95, 95% confidence limits 1.27, 2.99) and death (HR 1.18, 95% confidence limits 1.02, 1.36). Rates of urinary tract infection or genital infection, acute kidney injury, major adverse cardiovascular events, and heart failure were also elevated, while rates of fall-related injuries and hypoglycaemia were reduced, but all estimates were imprecise and highly compatible with no difference. CONCLUSIONS: SGLT2is do not have superior, and may have inferior, effectiveness compared with GLP-1RAs for cardiovascular and mortality outcomes in NH residents. Residents initiating SGLT2is should be monitored closely for DKA.

Anticholinergic and sedative medication use in older patients with cognitive concerns.

BACKGROUND: Anticholinergic (AC) and sedative medications are a risk factor for cognitive impairment. This study sought to characterize AC and sedative use in older patients seen for outpatient neuropsychological evaluation and evaluate their associations with different cognitive domains. We hypothesized that AC and sedative use would be associated with worse attention/processing speed (AP), executive functioning (EF), and memory. METHODS: We conducted a cross-sectional chart review of 392 patients (mean [M] age = 72 ± 7.7 years, range = 54-91). Medications were characterized by number of AC medications (≥1 on the Anticholinergic Cognitive Burden Scale [ACB]), number of sedative medications, and polypharmacy (≥5 daily medications). Demographically adjusted composites were calculated for AP, EF, and memory. Bivariate Pearson correlations assessed relationships between medication use and cognition. Multivariate linear regressions evaluated significant medication-cognition associations, controlling for total medications, medical comorbidities, and estimated premorbid cognitive functioning. RESULTS: Polypharmacy was common (80%; n = 314). Most patients (70%; n = 275) used ≥1 sedative medications (range = 0-9). Over half (63%; n = 248) used ≥1 AC drugs (range = 0-7), yet ACB scores were ≤2 in 74% of patients. Sedative use was negatively correlated with AP (r = -0.134, p = 0.008) and EF (r = -0.105, p = 0.04). ACB scores were negatively correlated with AP (r = -0.106, p = 0.037). Sedatives and a priori covariates significantly predicted AP performance (R2 = 0.127, p < 0.001); using more sedative medications was uniquely associated with worse AP (ß = -0.426, p = 0.049). No significant associations were found with memory. CONCLUSION: AC and sedative medications and polypharmacy were prevalent in this sample of older patients. Though both drug classes had negative relationships with AP and EF, sedatives had a particularly negative association with AP. Contrary to our hypotheses, memory was not associated with medication use; however, anticholinergic burden was low within the sample, and AP and EF deficits may masquerade as memory problems.

Use of Diabetes Medications before and after a Heart Failure-Related Hospitalization among Nursing Home Residents.

OBJECTIVES: Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) offer cardiovascular benefits, whereas thiazolidinediones (TZDs) and sulfonylureas (SUs) increase cardiovascular risk. The objective of this study was to describe the use of SGLT-2is, GLP-1RAs, TZDs, and SUs before and after a heart failure (HF)-related hospitalization in nursing home (NH) residents with type 2 diabetes (T2D). DESIGN: This was a cohort study using a 20% sample of Medicare claims linked with Minimum Data Set resident assessments. SETTING AND PARTICIPANTS: The study population was long-stay NH residents with T2D and an HF-related hospitalization between January 1, 2013, and August 31, 2018. For individuals with multiple HF hospitalizations, 1 hospitalization was randomly selected. METHODS: We ascertained diabetes medications using Medicare Part D claims during the 120 days before and after hospital discharge (or skilled nursing facility discharge, where applicable). We calculated (1) the proportion of study participants who received a medication class of interest during pre- and posthospitalization periods; (2) the proportion of continuous users; and (3) the proportion of posthospitalization users who were new users. RESULTS: A total of 12,990 NH residents with T2D and an HF-related hospitalization were included (mean age 78 years, 66% female, 19% Black). Before hospitalization, 1.5% received TZDs, 14.1% received SUs, 1.2% received GLP-1RAs, and 0.3% received SGLT-2is. Among prehospitalization users of TZDs, SUs, GLP-1RAs, and SGLT-2is, 49%, 62%, 60%, and 40% continued the medications, respectively. Among posthospitalization users of TZDs, SUs, GLP-1RAs, and SGLT-2is, 37%, 10%, 28%, and 11%, respectively, were new users. CONCLUSIONS: Among NH residents with hospitalized HF, GLP-1RAs and SGLT-2is were seldom used. TZDs and SUs were still used by many residents with T2D after HF hospitalizations. IMPLEMENTATIONS: Barriers may exist in the use of newer diabetes medications to prevent heart failure in NH residents with T2D, which warrants further studies in older adults with multimorbidity.

Benefits and Harms of Standard Versus Reduced-Dose Direct Oral Anticoagulant Therapy for Older Adults With Multiple Morbidities and Atrial Fibrillation.

Background Dose reduction of direct oral anticoagulant (DOAC) medications is inconsistently applied to older adults with multiple morbidities, potentially due to perceived harms and unknown benefits of standard dosing. Methods and Results Using 2013 to 2017 US Medicare claims linked to Minimum Data Set records, we conducted a retrospective cohort study. We identified DOAC initiators (apixaban, dabigatran, rivaroxaban) aged ≥65 years with nonvalvular atrial fibrillation residing in a nursing home. We estimated inverse-probability of treatment weights for DOAC dose using propensity scores. We examined safety (hospitalization for major bleeding) and effectiveness outcomes (all-cause mortality, thrombosis [myocardial infarction, stroke, systemic embolism, venous thromboembolism]). We estimated hazard ratios (HRs) and 95% CIs using cause-specific hazard-regression models. Of 21 878 DOAC initiators, 48% received reduced dosing. The mean age of residents was 82.0 years, 66% were female, and 31% had moderate/severe cognitive impairment. After estimating inverse-probability of treatment weights, standard dosing was associated with a higher rate of bleeding (HR, 1.18 [95% CI, 1.03-1.37]; 9.4 versus 8.0 events per 100 person-years). Standard-dose therapy was associated with the highest rates of bleeding among those aged >80 years (9.1 versus 6.7 events per 100 person-years) and with a body mass index <30 kg/m2 (9.4 versus 7.4 events per 100 person-years). There was no association of dosing with mortality (HR, 0.99 [95% CI, 0.96-1.06]) or thrombotic events (HR, 1.16 [95% CI, 0.96-1.41]). Conclusions In this nationwide study of nursing home residents with nonvalvular atrial fibrillation, we found a higher rate of bleeding and little difference in effectiveness of standard versus reduced-dose DOAC treatment. Our results support the use of reduced-dose DOACs for many older adults with multiple morbidities.

The Burden and Treatment of Chronic Constipation Among US Nursing Home Residents.

OBJECTIVE: To evaluate the burden of chronic constipation (CC) and the use of drugs to treat constipation (DTC) in 2 complementary data sources. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: US nursing home residents aged ≥65 years with CC. METHODS: We conducted 2 retrospective cohort studies in parallel using (1) 2016 electronic health record (EHR) data from 126 nursing homes and (2) 2014-2016 Medicare claims, each linked with the Minimum Data Set (MDS). CC was defined as (1) the MDS constipation indicator and/or (2) chronic DTC use. We described the prevalence and incidence rate of CC and the use of DTC. RESULTS: In the EHR cohort, we identified 25,739 residents (71.8%) with CC during 2016. Among residents with prevalent CC, 37% received a DTC, with an average duration of use of 19 days per resident-month during follow-up. The most frequently prescribed DTC classes included osmotic (22.6%), stimulant (20.9%), and emollient (17.9%) laxatives. In the Medicare cohort, a total of 245,578 residents (37.5%) had CC. Among residents with prevalent CC, 59% received a DTC and slightly more than half (55%) were prescribed an osmotic laxative. Duration of use was shorter (10 days per resident-month) in the Medicare (vs EHR) cohort. CONCLUSIONS AND IMPLICATIONS: The burden of CC is high among nursing home residents. The differences in the estimates between the EHR and Medicare data confirm the importance of using secondary data sources that include over-the-counter drugs and other treatments unobservable in Medicare Part D claims to assess the burden of CC and DTC use in this population.

Federal Nursing Home Policies on Antipsychotics had Similar Impacts by Race and Ethnicity for Residents With Dementia.

OBJECTIVES: Federal initiatives have been successful in reducing antipsychotic exposure in nursing home residents with dementia. We assessed if these initiatives were implemented equally across racial and ethnic minority groups. DESIGN: Retrospective, cross-sectional trends study. SETTING AND PARTICIPANTS: National long-stay nursing home residents with dementia from 2011 to 2017. METHODS: We examined trends in psychotropic drug class exposures from the Minimum Data Set assessments for non-Hispanic Black (NHB), Hispanic, and non-Hispanic White (NHW) residents using interrupted time-series analyses with age-sex standardized quarterly outcomes and time points to denote the National Partnership (2012) and Five Star Rating changes (2015). RESULTS: Initially, antipsychotic (33.0%) and sedative (6.8%) exposure was highest for Hispanic residents; antidepressant (59.8%) and anxiolytic (23.4%) exposure was highest for NHW residents; NHB residents had the lowest use of each. Antipsychotic use dropped at the time of the Partnership (ß = -0.8807, P = .0023) and the slope declined further after the Partnership (ß = -0.6611, P < .0001) for NHW. In comparison to NHW, the level and slope changes for NHB and Hispanics were not significantly different. The Five Star Rating change did not impact the level of antipsychotic use (ß = 0.027, P = .9467), but the slope changed to indicate a slowed rate of decline (ß = 0.1317, P = .4075) for NHW. As to the other psychotropic drug classes, there were few significant differences between trends seen in the racial and ethnic subgroups. The following exceptions were noted: antidepressant use decreased at a faster rate for NHB residents post-Partnership (ß = -0.1485, P = .0371), and after the Five Star Rating change, NHB residents (ß = -0.0428, P = .0312) and Hispanic residents (ß = -0.0834, P < .0001) saw antidepressant use decrease faster than NHW. Sedative use in slope post-Partnership period (ß = -0.086, P = .0275) and post-Five Star Rating (ß = -0.0775, P < .0001) declined faster among Hispanic residents. CONCLUSIONS AND IMPLICATIONS: We found little evidence of clinically meaningful differences in changes to 4 classes of psychotropic medication use among racial and ethnic minority nursing home residents with dementia following 2 major federal initiatives.

Development and validation of the fall-related injury risk in nursing homes (INJURE-NH) prediction tool.

BACKGROUND: Existing models to predict fall-related injuries (FRI) in nursing homes (NH) focus on hip fractures, yet hip fractures comprise less than half of all FRIs. We developed and validated a series of models to predict the absolute risk of FRIs in NH residents. METHODS: Retrospective cohort study of long-stay US NH residents (≥100 days in the same facility) between January 1, 2016 and December 31, 2017 (n = 733,427) using Medicare claims and Minimum Data Set v3.0 clinical assessments. Predictors of FRIs were selected through LASSO logistic regression in a 2/3 random derivation sample and tested in a 1/3 validation sample. Sub-distribution hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated for 6-month and 2-year follow-up. Discrimination was evaluated via C-statistic, and calibration compared the predicted rate of FRI to the observed rate. To develop a parsimonious clinical tool, we calculated a score using the five strongest predictors in the Fine-Gray model. Model performance was repeated in the validation sample. RESULTS: Mean (Q1, Q3) age was 85.0 (77.5, 90.6) years and 69.6% were women. Within 2 years of follow-up, 43,976 (6.0%) residents experienced ≥1 FRI. Seventy predictors were included in the model. The discrimination of the 2-year prediction model was good (C-index = 0.70), and the calibration was excellent. Calibration and discrimination of the 6-month model were similar (C-index = 0.71). In the clinical tool to predict 2-year risk, the five characteristics included independence in activities of daily living (ADLs) (HR 2.27; 95% CI 2.14-2.41) and a history of non-hip fracture (HR 2.02; 95% CI 1.94-2.12). Performance results were similar in the validation sample. CONCLUSIONS: We developed and validated a series of risk prediction models that can identify NH residents at greatest risk for FRI. In NH, these models should help target preventive strategies.

State Variation in Antipsychotic Use Among Assisted Living Residents With Dementia.

OBJECTIVES: More than two-thirds of assisted living (AL) residents have dementia or cognitive impairment and antipsychotics are commonly prescribed for behavioral disturbances. As AL communities are regulated by state-level policies, which vary significantly regarding the care for people with dementia, we examined how antipsychotic prescribing varied across states among AL residents with dementia. DESIGN: This was an observational study using 20% sample of national Medicare data in 2017. SETTING AND PARTICIPANTS: The study cohort included Medicare beneficiaries with dementia aged 65 years or older who resided in larger (≥25-bed) ALs in 2017. METHODS: The study outcome was the percentage of eligible AL person-months in which antipsychotics were prescribed for each state. We used a random intercept linear regression model to shrink estimates toward the overall mean use of antipsychotics addressing unstable estimates due to small sample sizes in some states. RESULTS: A total of 20,867 AL residents with dementia were included in the analysis, contributing to 194,718 person-months of observation. On average, AL residents with dementia were prescribed antipsychotics during 12.6% of their person-months. This rate varied significantly by state, with a low of 7.8% (95% CI 5.9%-10.3%) for Hawaii to a high of 20.5% (95% CI 16.4%-25.3%) for Wyoming. CONCLUSIONS AND IMPLICATIONS: We observed significant state variation in the prescribing of antipsychotics among AL residents with dementia using national data. These variations may reflect differences in state regulations regarding the care for AL residents with dementia and suggest the need for further investigation to ensure high quality of care.

Integrated postoperative care model for older colorectal surgery patients improves outcomes and reduces healthcare costs.

BACKGROUND: Older surgical patients have an increased risk for postoperative complications, driving up healthcare costs. We determined if postoperative co-management of older surgery patients is associated with postoperative outcomes and hospital costs. METHODS: Retrospective data were collected for patients ≥70 years old undergoing colorectal surgery at a community teaching hospital. Patient outcomes were compared between those receiving postoperative surgery co-management care through the Optimization of Senior Care and Recovery (OSCAR) program and controls who received standard of care. Main outcome measures were postoperative complications and hospital charges, 30-day readmission rate, length of stay (LOS), and transfer to intensive care during hospitalization. Multivariable linear regression was used to model total charge and multivariable logistic regression to model complications, adjusted for multiple variables (e.g., age, sex, race, body mass index, Charlson Comorbidity Index [CCI], American Society of Anesthesiologists score, surgery duration). RESULTS: All 187 patients in the OSCAR and control groups had a similar mean CCI score of 2.7 (p = 0.95). Compared to the control group, OSCAR recipients experienced less postoperative delirium (17% vs. 8%; p = 0.05), cardiac arrhythmia (12% vs. 3%; p = 0.03), and clinical worsening requiring transfer to intensive care (20% vs. 6%; p < 0.005). OSCAR group patients had a shorter mean LOS among high-risk patients (CCI ≥3) (-1.8 days; p = 0.09) and those ≥80 years old (-2.3 days; p = 0.07) compared to the control group. Mean total hospital charge was $10,297 less per patient in the OSCAR group (p = 0.01), with $17,832 less per patient with CCI ≥3 (p = 0.01), than the control group. CONCLUSIONS: A co-management care approach after colorectal surgery in older patients improves outcomes and decreases costs, with the most benefit going to the oldest patients and those with higher comorbidity scores.

Psychotropic medication prescribing in assisted living and nursing home residents with dementia after the National Partnership.

BACKGROUND: The Centers for Medicare & Medicaid Services implemented the National Partnership to Improve Dementia Care in Nursing Homes (the Partnership) to decrease antipsychotic use and improve care for nursing home (NH) residents with dementia. We determined whether the extent of antipsychotic and other psychotropic medication prescribing in AL residents with dementia mirrored that of long-stay NH (LSNH) residents after the Partnership. METHODS: Using a 20% sample of fee-for-service Medicare beneficiaries with Part D, we conducted a retrospective cohort study including AL and LSNH residents with dementia. The monthly prevalence of psychotropic medication prescribing (antipsychotics, antidepressants, anxiolytics/sedative-hypnotics, anticonvulsants/mood stabilizers, benzodiazepines, and antidementia medications) was examined. We used an interrupted time-series analysis to compare medication prescribing before (July 1, 2010-March 31, 2012) and after (April 1, 2012-December 31, 2017) the Partnership in both settings. RESULTS: We identified 107,931 beneficiaries with ≥1 month as an AL resident and 323,766 beneficiaries with ≥1 month as a LSNH resident with dementia, including 1,923,867 person-months and 4,984,405 person-months, respectively. Antipsychotic prescribing declined over the study period in both settings. After the launch of the Partnership, the rate of decline in antipsychotic prescribing slowed in AL residents with dementia (slope change = 0.03 [95% CLs: 0.02, 0.04]) while the rate of decline in antipsychotic prescribing increased in LSNH residents with dementia (slope change = -0.12 [95% CLs: -0.16, -0.08]). Antidepressants were the most prevalent medication prescribed, anticonvulsant/mood stabilizer prescribing increased, and anxiolytic/sedative-hypnotic and antidementia medication prescribing declined. CONCLUSIONS: The federal Partnership to reduce antipsychotic prescribing in NH residents did not appear to affect antipsychotic prescribing in AL residents with dementia. Given the increase in the prescribing of mood stabilizers/anticonvulsants that occurred after the launch of the Partnership, monitoring may be warranted for all psychotropic medications in AL and NH settings.

Discontinuation of beta-blockers among nursing home residents at end of life.

BACKGROUND: Given limited life expectancy of nursing home (NH) residents, harms of continuing beta-blockers (BBs) may outweigh clinical benefits. Our objective was to describe beta-blocker discontinuation for NH residents during the last year of life, and identify characteristics associated with earlier discontinuation. METHODS: This was a retrospective cohort study that included all long-stay residents in fee-for-service Medicare who died in 2016 and were prescribed oral BBs 1 year before death. Beta-blocker discontinuation was defined as a gap in medication on hand for ≥45 days per Medicare Part D claims, measured from the last date drug was on hand. Comorbidities were obtained from Chronic Condition Warehouse, and other characteristics from the Minimum Data Set. Kaplan-Meier curves were used to describe time to first discontinuation. Findings were stratified by cardiac diagnoses, perceived life expectancy of <6 months, or elevated mortality index. RESULTS: Eighty-eight thousand two hundred and eighty-four residents were prescribed ≥1 daily BB 12 months before death. Mean age was 84.1 years and 69.2% were female. Of these, 60,573 residents (68.6%) remained on a BB in the last 45 days of life, and 57,880 residents (65.6%) had ≥1 cardiac diagnosis. Only 5239 residents (5.9%) had elevated mortality index, whereas 16,798 residents (19.0%) had perceived poor prognosis. In the last year of life, there was no difference in beta-blocker discontinuation pattern between residents with and without cardiac diagnoses. Residents with perceived poor prognosis and elevated mortality index discontinued BBs earlier. For example, mean time until discontinuation among residents with poor perceived prognosis was 245 versus 279 days in residents without such prognosis (p < 0.0001). CONCLUSIONS: BBs are commonly prescribed to NH residents in the final year of life. Overall, discontinuation occurs earlier in residents for whom clinicians perceive limited life expectancy, suggesting that improved prognostication may offer an important opportunity to reduce polypharmacy toward end of life.

Identification of Fall-Related Injuries in Nursing Home Residents Using Administrative Claims Data.

BACKGROUND: Fall-related injuries (FRIs) are a leading cause of morbidity, mortality, and costs among nursing home (NH) residents. Carefully defining FRIs in administrative data is essential for improving injury-reduction efforts. We developed a series of novel claims-based algorithms for identifying FRIs in long-stay NH residents. METHODS: This is a retrospective cohort of residents of NH residing there for at least 100 days who were continuously enrolled in Medicare Parts A and B in 2016. FRIs were identified using 4 claims-based case-qualifying (CQ) definitions (Inpatient [CQ1], Outpatient and Provider with Procedure [CQ2], Outpatient and Provider with Fall [CQ3], or Inpatient or Outpatient and Provider with Fall [CQ4]). Correlation was calculated using phi correlation coefficients. RESULTS: Of 153 220 residents (mean [SD] age 81.2 [12.1], 68.0% female), we identified 10 104 with at least one FRI according to one or more CQ definition. Among 2 950 residents with hip fractures, 1 852 (62.8%) were identified by all algorithms. Algorithm CQ4 (n = 326-2 775) identified more FRIs across all injuries while CQ1 identified less (n = 21-2 320). CQ2 identified more intracranial bleeds (1 028 vs 448) than CQ1. For nonfracture categories, few FRIs were identified using CQ1 (n = 20-488). Of the 2 320 residents with hip fractures identified by CQ1, 2 145 (92.5%) had external cause of injury codes. All algorithms were strongly correlated, with phi coefficients ranging from 0.82 to 0.99. CONCLUSIONS: Claims-based algorithms applied to outpatient and provider claims identify more nonfracture FRIs. When identifying risk factors, stakeholders should select the algorithm(s) suitable for the FRI and study purpose.

Impact of Delirium on Outcomes After Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Delirium portends worse outcomes after intracerebral hemorrhage (ICH), but it is unclear if symptom resolution or postacute care intensity may mitigate its impact. We aimed to explore differences in outcome associated with delirium resolution before hospital discharge, as well as the potential mediating role of postacute discharge site. METHODS: We performed a single-center cohort study on consecutive ICH patients over 2 years. Delirium was diagnosed according to DSM-5 criteria and further classified as persistent or resolved based on delirium status at hospital discharge. We determined the impact of delirium on unfavorable 3-month outcome (modified Rankin Scale score, 4-6) using logistic regression models adjusted for established ICH predictors, then used mediation analysis to examine the indirect effect of delirium via postacute discharge site. RESULTS: Of 590 patients (mean age 70.5±15.5 years, 52% male, 83% White), 59% (n=348) developed delirium during hospitalization. Older age and higher ICH severity were delirium risk factors, but only younger age predicted delirium resolution, which occurred in 75% (161/215) of ICH survivors who had delirium. Delirium was strongly associated with unfavorable outcome, but patients with persistent delirium fared worse (adjusted odds ratio [OR], 7.3 [95% CI, 3.3-16.3]) than those whose delirium resolved (adjusted OR, 3.1 [95% CI, 1.8-5.5]). Patients with delirium were less likely to be discharged to inpatient rehabilitation than skilled nursing facilities (adjusted OR, 0.31 [95% CI, 0.17-0.59]), and postacute care site partially mediated the relationship between delirium and functional outcome in ICH survivors, leading to a 25% reduction in the effect of delirium (without mediator: adjusted OR, 3.0 [95% CI, 1.7-5.6]; with mediator: adjusted OR, 2.3 [95% CI, 1.2-4.3]). CONCLUSIONS: Acute delirium resolves in most patients with ICH by hospital discharge, which was associated with better outcomes than in patients with persistent delirium. The impact of delirium on outcomes may be further mitigated by postacute rehabilitation.

Novel blood test for early biomarkers of preeclampsia and Alzheimer's disease.

A non-invasive and sensitive blood test has long been a goal for early stage disease diagnosis and treatment for Alzheimer's disease (AD) and other proteinopathy diseases. We previously reported that preeclampsia (PE), a severe pregnancy complication, is another proteinopathy disorder with impaired autophagy. We hypothesized that induced autophagy deficiency would promote accumulation of pathologic protein aggregates. Here, we describe a novel, sensitive assay that detects serum protein aggregates from patients with PE (n = 33 early onset and 33 late onset) and gestational age-matched controls (n = 77) as well as AD in both dementia and prodromal mild cognitive impairment (MCI, n = 24) stages with age-matched controls (n = 19). The assay employs exposure of genetically engineered, autophagy-deficient human trophoblasts (ADTs) to serum from patients. The aggregated protein complexes and their individual components, including transthyretin, amyloid ß-42, α-synuclein, and phosphorylated tau231, can be detected and quantified by co-staining with ProteoStat, a rotor dye with affinity to aggregated proteins, and respective antibodies. Detection of protein aggregates in ADTs was not dependent on transcriptional upregulation of these biomarkers. The ROC curve analysis validated the robustness of the assay for its specificity and sensitivity (PE; AUC: 1, CI: 0.949-1.00; AD; AUC: 0.986, CI: 0.832-1.00). In conclusion, we have developed a novel, noninvasive diagnostic and predictive assay for AD, MCI and PE.

Common biomarkers of physiologic stress and associations with delirium in patients with intracerebral hemorrhage.

PURPOSE: To examine associations between physiologic stress and delirium in the setting of a direct neurologic injury. MATERIALS AND METHODS: We obtained initial neutrophil-to-lymphocyte ratio (NLR), glucose, and troponin in consecutive non-comatose patients with non-traumatic intracerebral hemorrhage (ICH) over 1 year, then used multivariable regression models to determine associations between each biomarker and incident delirium. Delirium diagnoses were established using DSM-5-based methods, with exploratory analyses further categorizing delirium as first occurring <24 h ("early-onset") or > 24 h after presentation ("later-onset"). RESULTS: Of 284 patients, delirium occurred in 55% (early-onset: 39% [n = 111]; later-onset: 16% [n = 46]). Patients with delirium had higher NLR (mean 9.0 ± 10.4 vs. 6.4 ± 5.5; p = 0.01), glucose (mean 146.5 ± 59.6 vs. 129.9 ± 41.4 mg/dL; p = 0.008), and a higher frequency of elevated troponin (>0.05 ng/mL; 21% vs. 10%, p = 0.02). In adjusted models, elevated NLR (highest quartile: OR 3.4 [95% CI 1.5-7.8]), glucose (>180 mg/dL: OR 3.1 [95% CI 1.1-8.2]), and troponin (OR 3.0 [95% CI 1.2-7.2]) were each associated with delirium, but only initial NLR was specifically associated with later-onset delirium and with delirium in non-mechanically ventilated patients. CONCLUSIONS: Stress-related biomarkers corresponding to multiple organ systems are associated with ICH-related delirium. Early NLR elevation may also predict delayed-onset delirium, potentially implicating systemic inflammation as a contributory delirium mechanism.

Trends in antipsychotic prescribing among long-term care residents receiving hospice care.

IMPORTANCE: The Centers for Medicare & Medicaid Services' (CMS) National Partnership to Improve Dementia Care in Nursing Homes ("CMS National Partnership") focuses on reducing antipsychotic prescribing to long-term care residents. Hospice enrollment is not an exclusionary condition for the antipsychotic quality measure reported by CMS. It is unclear how prescribing in hospice may have been impacted by the initiative. OBJECTIVE: Estimate the association of the CMS National Partnership with trends in antipsychotic prescribing among long-term care residents in hospice. DESIGN: Interrupted time-series analysis of a 100% Minimum Data Set sample with linked hospice claims from 2011 to 2017. SETTING: Long-term care nursing facilities. PARTICIPANTS: Older adults ≥65 residing in long-term care (n = 3,741,379) and limited to those enrolled in hospice (n = 821,610). MAIN OUTCOME: Quarterly prevalence of antipsychotic and other psychotropic (antianxiety, hypnotic, antidepressant) use among long-term care residents; overall and among residents with dementia, stratified by hospice enrollment. RESULTS: From 2011 to 2017, parallel declines in antipsychotic prescribing were observed among long-term care residents enrolled and not enrolled in hospice (hospice: decline from 26.8% to 18.7%; non-hospice: decline from 23.0% to 14.4%). Following the 2012 CMS National Partnership, quarterly rates of antipsychotic prescribing declined significantly for both residents enrolled and not enrolled in hospice care. Declines in antipsychotic prescribing were greater for residents with dementia, with similar rates among residents enrolled and not enrolled in hospice. Among residents with dementia enrolled in hospice, use of other psychotropic medication classes including antianxiety, antidepressant, and hypnotic use remained relatively stable over time. CONCLUSIONS AND RELEVANCE: Declines in antipsychotic prescribing during the CMS National Partnership occurred among long-term care residents in hospice, where use may be deemed clinically appropriate. Nursing homes are an important location for the provision of dementia end-of-life care and the drivers of potentially unintended reductions in antipsychotic use merits further investigation.

Pilot study of an Alzheimer's disease risk assessment program in a primary care setting.

INTRODUCTION: The goal of this study was to pilot a referral-based cognitive screening and genetic testing program for Alzheimer's disease (AD) risk assessment in a primary care setting. METHODS: Primary care providers (PCPs; N = 6) referred patients (N = 94; M = 63 years) to the Rhode Island Alzheimer's Disease Prevention Registry for apolipoprotein E (APOE) genotyping and cognitive screening. PCPs disclosed test results to patients and counseled them about risk factor modification. RESULTS: Compared to the Registry as a whole, participants were younger, more likely to be non-White, and had lower cognitive screening scores. Mild cognitive impairment participants correctly reported a higher perceived risk of developing AD. Patients who recalled being counseled about modifiable risk factors were more likely to report positive health behavior changes. DISCUSSION: A referral-based program for cognitive and genetic AD risk assessment in a primary care setting is feasible, acceptable to patients, and yielded a more demographically diverse sample than an AD prevention registry.

Peripheral Markers of Vascular Endothelial Dysfunction Show Independent but Additive Relationships with Brain-Based Biomarkers in Association with Functional Impairment in Alzheimer's Disease.

BACKGROUND: Cerebrovascular dysfunction confers risk for functional decline in Alzheimer's disease (AD), yet the clinical interplay of these two pathogenic processes is not well understood. OBJECTIVE: We utilized Alzheimer's Disease Neuroimaging Initiative (ADNI) data to examine associations between peripherally derived soluble cell adhesion molecules (CAMs) and clinical diagnostic indicators of AD. METHODS: Using generalized linear regression models, we examined cross-sectional relationships of soluble plasma vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-Selectin to baseline diagnosis and functional impairment (clinical dementia rating sum-of-boxes, CDR-SB) in the ADNI cohort (n = 112 AD, n = 396 mild cognitive impairment (MCI), n = 58 cognitively normal). We further analyzed associations of these biomarkers with brain-based AD biomarkers in a subset with available cerebrospinal fluid (CSF) data (n = 351). p-values derived from main effects and interaction terms from the linear regressions were used to assess the relationship between independent and dependent variables for significance (significance level was set at 0.05 a priori for all analysis). RESULTS: Higher mean VCAM-1 (p = 0.0026) and ICAM-1 (p = 0.0189) levels were found in AD versus MCI groups; however, not in MCI versus cognitively normal groups. Only VCAM-1 was linked with CDR-SB scores (p = 0.0157), and APOE ɛ4 genotype modified this effect. We observed independent, additive associations when VCAM-1 and CSF amyloid-ß (Aß42), total tau, phosphorylated tau (P-tau), or P-tau/Aß42 (all < p = 0.01) were combined in a CDR-SB model; ICAM-1 showed a similar pattern, but to a lesser extent. CONCLUSION: Our findings indicate independent associations of plasma-based vascular biomarkers and CSF biomarkers with AD-related clinical impairment.