Impact of a family support intervention on hospitalization costs and hospital readmissions among ICU patients at high risk of death or severe functional impairment.

BACKGROUND: Patients with advanced critical illness often receive more intensive treatment than they would choose for themselves, which contributes to high health care costs near the end of life. The purpose of this study was to determine whether a family support intervention delivered by the interprofessional ICU team decreases hospitalization costs and hospital readmissions among critically ill patients at high risk of death or severe functional impairment. RESULTS: We examined index hospitalization costs as well as post-discharge utilization of acute care hospitals, rehabilitation and skilled nursing facilities, and hospice services for the PARTNER trial, a multicenter, stepped-wedge, cluster randomized trial of an interprofessional ICU family support intervention. We determined patients' total controllable and direct variable costs using a computerized accounting system. We determined post-discharge resource utilization (as defined above) by structured telephone interview at 6-month follow-up. We used multiple variable regression modelling to compare outcomes between groups. Compared to usual care, the PARTNER intervention resulted in significantly lower total controllable costs (geometric mean: $26,529 vs $32,105; log-linear coefficient: - 0.30; 95% CI - 0.49, - 0.11) and direct variable costs ($3912 vs $6034; - 0.33; 95% CI - 0.56, - 0.10). A larger cost reduction occurred for decedents ($20,304 vs. $26,610; - 0.66; 95% CI - 1.01, - 0.31) compared to survivors ($31,353 vs. $35,015; - 0.15; 95% CI - 0.35,0.05). A lower proportion in the intervention arm were re-admitted to an acute care hospital (34.9% vs 45.1%; 0.66; 95% CI 0.56, 0.77) or skilled nursing facility (25.3% vs 31.6%; 0.63; 95% CI 0.47, 0.84). CONCLUSIONS: A family support intervention delivered by the interprofessional ICU team significantly decreased index hospitalization costs and readmission rates over 6-month follow-up. Trial registration Trial registration number: NCT01844492.

Association of plasma biomarkers of Alzheimer's disease and related disorders with cognition and cognitive decline: The MYHAT population-based study.

INTRODUCTION: Plasma biomarkers of Alzheimer's disease and related dementias predict global cognitive performance and decline over time; it remains unclear how they associate with changes in different dementia syndromes affecting distinct cognitive domains. METHODS: In a prospective study with repeated assessments of a randomly selected population-based cohort (n = 787, median age 73), we evaluated performance and decline in different cognitive domains over up to 8 years in relation to plasma concentrations of amyloid beta 42/40 (Aß42/40) ratio, phosphorylated tau181 (p-tau181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). RESULTS: Cross-sectionally, memory showed the strongest associations with p-tau181, and attention, executive, and visuospatial functions with NfL. Longitudinally, memory decline was distinguishable with all biomarker profiles dichotomized according to data-driven cutoffs, most efficiently with Aß42/40. GFAP and Aß42/40 were the best discriminators of decline patterns in language and visuospatial functions, respectively. DISCUSSION: These relatively non-invasive tests may be beneficial for clinical screening after replication in other populations and validation through neuroimaging or cerebrospinal fluid analysis. HIGHLIGHTS: We performed a prospective study with up to 8 years of repeated domain-specific cognitive assessments and baseline plasma Alzheimer's disease and related dementias biomarker measurements in a randomly selected population-based cohort. We considered distinct growth curves of trajectories of different cognitive domains and survival bias induced by missing data by adding quadratic time and applying joint modeling technique. Cross-sectionally, memory showed the strongest associations with plasma phosphorylated tau181, while attention, executive, and visuospatial functions were most strongly associated with neurofilament light chain. Longitudinally, memory and visuospatial declines were most efficiently distinguished by dichotomized amyloid beta 42/40 profile among all plasma biomarkers, while language was by dichotomized glial fibrillary acidic protein. These relatively non-invasive tests may be beneficial for clinical screening; however, they will need replication in other populations and validation through neuroimaging and/or cerebrospinal fluid assessments.

Ethnoracial Identity and Cognitive Impairment: A Community Study.

BACKGROUND: Identifying potentially modifiable risk factors associated with MCI in different ethnoracial groups could reduce MCI burden and health inequity in the population. METHODS: Among 2845 adults aged 65+ years, we investigated potential risk exposures including education, physical and mental health, lifestyle, and sensory function, and their cross-sectional associations with MCI. We compared proportions of exposures between Black and White participants and explored relationships among race, MCI, and exposures. Logistic regression modeled MCI as a function of each exposure in the overall sample adjusting for age, sex, educational level, and race, and investigating race*exposure interactions. RESULTS: Compared with White participants, Black participants had greater odds of MCI (OR 1.53; 95% CI, 1.13 to 2.06) and were more likely to report depressive symptoms, diabetes, and stroke, to have high blood pressure and BMI, and to be APOE - 4 carriers. Exposures associated with higher odds of MCI were diabetes, stroke, lifetime smoking, sleep disturbances, social isolation, loneliness, depression and anxiety symptoms, and vision and hearing loss. There were no significant interactions between race and any exposure. CONCLUSIONS: Black participants had 53% higher odds of MCI adjusting for age, sex, and education. The same exposures were associated with MCI in Black and White participants.

Metformin for sepsis-associated AKI: a protocol for the Randomized Clinical Trial of the Safety and FeasibiLity of Metformin as a Treatment for sepsis-associated AKI (LiMiT AKI).

INTRODUCTION: Acute kidney injury (AKI) is a common complication of sepsis associated with increased risk of death. Preclinical data and observational human studies suggest that activation of AMP-activated protein kinase, an ubiquitous master regulator of energy that can limit mitochondrial injury, with metformin may protect against sepsis-associated AKI (SA-AKI) and mortality. The Randomized Clinical Trial of the Safety and FeasibiLity of Metformin as a Treatment for sepsis-associated AKI (LiMiT AKI) aims to evaluate the safety and feasibility of enteral metformin in patients with sepsis at risk of developing SA-AKI. METHODS AND ANALYSIS: Blind, randomised, placebo-controlled clinical trial in a single-centre, quaternary teaching hospital in the USA. We will enrol adult patients (18 years of age or older) within 48 hours of meeting Sepsis-3 criteria, admitted to intensive care unit, with oral or enteral access. Patients will be randomised 1:1:1 to low-dose metformin (500 mg two times per day), high-dose metformin (1000 mg two times per day) or placebo for 5 days. Primary safety outcome will be the proportion of metformin-associated serious adverse events. Feasibility assessment will be based on acceptability by patients and clinicians, and by enrolment rate. ETHICS AND DISSEMINATION: This study has been approved by the Institutional Review Board. All patients or surrogates will provide written consent prior to enrolment and any study intervention. Metformin is a widely available, inexpensive medication with a long track record for safety, which if effective would be accessible and easy to deploy. We describe the study methods using the Standard Protocol Items for Randomized Trials framework and discuss key design features and methodological decisions. LiMiT AKI will investigate the feasibility and safety of metformin in critically ill patients with sepsis at risk of SA-AKI, in preparation for a future large-scale efficacy study. Main results will be published as soon as available after final analysis. TRIAL REGISTRATION NUMBER: NCT05900284.

Identification of a hyperinflammatory sepsis phenotype using protein biomarker and clinical data in the ProCESS randomized trial.

Sepsis is a heterogeneous syndrome and phenotypes have been proposed using clinical data. Less is known about the contribution of protein biomarkers to clinical sepsis phenotypes and their importance for treatment effects in randomized trials of resuscitation. The objective is to use both clinical and biomarker data in the Protocol-Based Care for Early Septic Shock (ProCESS) randomized trial to determine sepsis phenotypes and to test for heterogeneity of treatment effect by phenotype comparing usual care to protocolized early, goal-directed therapy(EGDT). In this secondary analysis of a subset of patients with biomarker sampling in the ProCESS trial (n = 543), we identified sepsis phenotypes prior to randomization using latent class analysis of 20 clinical and biomarker variables. Logistic regression was used to test for interaction between phenotype and treatment arm for 60-day inpatient mortality. Among 543 patients with severe sepsis or septic shock in the ProCESS trial, a 2-class model best fit the data (p = 0.01). Phenotype 1 (n = 66, 12%) had increased IL-6, ICAM, and total bilirubin and decreased platelets compared to phenotype 2 (n = 477, 88%, p < 0.01 for all). Phenotype 1 had greater 60-day inpatient mortality compared to Phenotype 2 (41% vs 16%; p < 0.01). Treatment with EGDT was associated with worse 60-day inpatient mortality compared to usual care (58% vs. 23%) in Phenotype 1 only (p-value for interaction = 0.05). The 60-day inpatient mortality was similar comparing EGDT to usual care in Phenotype 2 (16% vs. 17%). We identified 2 sepsis phenotypes using latent class analysis of clinical and protein biomarker data at randomization in the ProCESS trial. Phenotype 1 had increased inflammation, organ dysfunction and worse clinical outcomes compared to phenotype 2. Response to EGDT versus usual care differed by phenotype.

Using a theory-based, customized video game as an educational tool to improve physicians' trauma triage decisions: study protocol for a randomized cluster trial.

BACKGROUND: Transfer of severely injured patients to trauma centers, either directly from the field or after evaluation at non-trauma centers, reduces preventable morbidity and mortality. Failure to transfer these patients appropriately (i.e., under-triage) remains common, and occurs in part because physicians at non-trauma centers make diagnostic errors when evaluating the severity of patients' injuries. We developed Night Shift, a theory-based adventure video game, to recalibrate physician heuristics (intuitive judgments) in trauma triage and established its efficacy in the laboratory. We plan a type 1 hybrid effectiveness-implementation trial to determine whether the game changes physician triage decisions in real-life and hypothesize that it will reduce the proportion of patients under-triaged. METHODS: We will recruit 800 physicians who work in the emergency departments (EDs) of non-trauma centers in the US and will randomize them to the game (intervention) or to usual education and training (control). We will ask those in the intervention group to play Night Shift for 2 h within 2 weeks of enrollment and again for 20 min at quarterly intervals. Those in the control group will receive only usual education (i.e., nothing supplemental). We will then assess physicians' triage practices for older, severely injured adults in the 1-year following enrollment, using Medicare claims, and will compare under-triage (primary outcome), 30-day mortality and re-admissions, functional independence, and over-triage between the two groups. We will evaluate contextual factors influencing reach, adoption, implementation, and maintenance with interviews of a subset of trial participants (n = 20) and of other key decision makers (e.g., patients, first responders, administrators [n = 100]). DISCUSSION: The results of the trial will inform future efforts to improve the implementation of clinical practice guidelines in trauma triage and will provide deeper understanding of effective strategies to reduce diagnostic errors during time-sensitive decision making. TRIAL REGISTRATION: ClinicalTrials.gov; NCT06063434 . Registered 26 September 2023.

Bayesian response adaptive randomization design with a composite endpoint of mortality and morbidity.

Allocating patients to treatment arms during a trial based on the observed responses accumulated up to the decision point, and sequential adaptation of this allocation, could minimize the expected number of failures or maximize total benefits to patients. In this study, we developed a Bayesian response-adaptive randomization (RAR) design targeting the endpoint of organ support-free days (OSFD) for patients admitted to the intensive care units. The OSFD is a mixture of mortality and morbidity assessed by the number of days of free of organ support within a predetermined post-randomization time-window. In the past, researchers treated OSFD as an ordinal outcome variable where the lowest category is death. We propose a novel RAR design for a composite endpoint of mortality and morbidity, for example, OSFD, by using a Bayesian mixture model with a Markov chain Monte Carlo sampling to estimate the posterior probability distribution of OSFD and determine treatment allocation ratios at each interim. Simulations were conducted to compare the performance of our proposed design under various randomization rules and different alpha spending functions. The results show that our RAR design using Bayesian inference allocated more patients to the better performing arm(s) compared to other existing adaptive rules while assuring adequate power and type I error rate control across a range of plausible clinical scenarios.

Benzodiazepine use and risk of incident MCI and dementia in a community sample.

OBJECTIVES: Older adults commonly take benzodiazepines (BZDs) that may have long-term adverse cognitive effects. We investigated whether BZD use was related to developing mild cognitive impairment (MCI) or dementia in cognitively normal older adults in the community. SETTING/PARTICIPANTS: A population-based cohort (n = 1959) of adults aged 65 and over, recruited from communities of low socioeconomic status. MEASUREMENTS: BZD use, Clinical Dementia Rating (CDR), anxiety symptoms, depression symptoms, sleep difficulties, and APOE genotype. DESIGN: We examined time from study entry to MCI (CDR = 0.5) and time from study entry to dementia (CDR ≥ 1) in participants who were cognitively normal at baseline (CDR = 0). We used survival analysis (Cox model), adjusted for age, sex, education, sleep, anxiety, and depression. For all the models, we included an interaction term between BZD use and APOE*4. RESULTS: Taking BZDs was significantly associated with higher risk of developing MCI, but not of developing dementia. The effect was not affected by APOE genotype. CONCLUSIONS: In a population-based sample of cognitively normal older adults, BZD use is associated with developing MCI, but not dementia. BZD use may be a potentially modifiable risk factor for MCI.

Persistence of pulmonary hypertension in patients undergoing ventricular assist devices and orthotopic heart transplantation.

Pulmonary hypertension (PH) is common in advanced heart failure and often improves quickly after left ventricular assist device (VAD) implantation or orthotopic heart transplantation (OHT), but long-term effects and outcomes are not well-described. This study evaluated PH persistence after VAD as destination therapy (VAD-DT), bridge to transplant (VAD-OHT), or OHT-alone. The study constituted a retrospective review of patients who underwent VAD-DT (n = 164), VAD-OHT (n = 111), or OHT-alone (n = 138) at a single tertiary-care center. Right heart catheterization (RHC) data was collected pre-, post-intervention (VAD and/or OHT), and 1-year from final intervention (latest-RHC) to evaluate the longitudinal hemodynamic course of right ventricular function and pulmonary vasculature. PH (Group II and Group I) definitions were adapted from expert guidelines. All groups showed significant improvements in mean pulmonary artery pressure (mPAP), pulmonary artery wedge pressure (PAWP), cardiac output, and pulmonary vascular resistance (PVR) at each RHC with greatest improvement at post-intervention RHC (post-VAD or post-OHT). PH was reduced from 98% to 26% in VAD-OHT, 92%-49% in VAD-DT, and 76%-28% in OHT-alone from preintervention to latest-RHC. At latest-RHC mPAP remained elevated in all groups despite normalization of PAWP and PVR. VAD-supported patients exhibited suppressed pulmonary artery pulsatility index (PaPi < 3.7) with improvement only posttransplant at latest-RHC. Posttransplant patients with PH at latest-RHC (n = 60) exhibited lower survival (HR: 2.1 [95% CI: 1.3-3.4], p < 0.001). Despite an overall significant improvement in pulmonary pressures and PH proportion, a notable subset of patients exhibited PH post-intervention. Post-intervention PH was associated with lower posttransplant survival.

Weighted Lottery to Equitably Allocate Scarce Supply of COVID-19 Monoclonal Antibody.

Importance: Equitable allocation of scarce medications is an important health policy goal. There are few data about attempts to achieve equitable allocation in the community setting. Objective: To describe the development and use of a weighted lottery to allocate a scarce supply of tixagevimab with cilgavimab as preexposure prophylaxis to COVID-19 for immunocompromised individuals and examine whether this promoted equitable allocation to disadvantaged populations. Design, Setting, and Participants: This quality improvement study analyzed a weighted lottery process from December 8, 2021, to February 23, 2022, that assigned twice the odds of drug allocation of 450 tixagevimab with cilgavimab doses to individuals residing in highly disadvantaged neighborhoods according to the US Area Deprivation Index (ADI) in a 35-hospital system in Pennsylvania, New York, and Maryland. In all, 10 834 individuals were eligible for the lottery. Weighted lottery results were compared with 10 000 simulated unweighted lotteries in the same cohort performed after drug allocation occurred. Main Outcomes: Proportion of individuals from disadvantaged neighborhoods and Black individuals who were allocated and received tixagevimab with cilgavimab. Results: Of the 10 834 eligible individuals, 1800 (16.6%) were from disadvantaged neighborhoods and 767 (7.1%) were Black. Mean (SD) age was 62.9 (18.8) years, and 5471 (50.5%) were women. A higher proportion of individuals from disadvantaged neighborhoods was allocated the drug in the ADI-weighted lottery compared with the unweighted lottery (29.1% vs 16.6%; P < .001). The proportion of Black individuals allocated the drug was greater in the weighted lottery (9.1% vs 7.1%; P < .001). Among the 450 individuals allocated tixagevimab with cilgavimab in the ADI-weighted lottery, similar proportions of individuals from disadvantaged neighborhoods accepted the allocation and received the drug compared with those from other neighborhoods (27.5% vs 27.9%; P = .93). However, Black individuals allocated the drug were less likely to receive it compared with White individuals (3 of 41 [7.3%] vs 118 of 402 [29.4%]; P = .003). Conclusions and Relevance: The findings of this quality improvement study suggest an ADI-weighted lottery process to allocate scarce resources is feasible in a large health system and resulted in more drug allocation to and receipt of drug by individuals who reside in disadvantaged neighborhoods. Although the ADI-weighted lottery also resulted in more drug allocation to Black individuals compared with an unweighted process, they were less likely to accept allocation and receive it compared with White individuals. Further strategies are needed to ensure that Black individuals receive scarce medications allocated.

Restrictive versus Liberal Rate of Extracorporeal Volume Removal Evaluation in Acute Kidney Injury (RELIEVE-AKI): a pilot clinical trial protocol.

INTRODUCTION: Observational studies have linked slower and faster net ultrafiltration (UFNET) rates during kidney replacement therapy (KRT) with mortality in critically ill patients with acute kidney injury (AKI) and fluid overload. To inform the design of a larger randomised trial of patient-centered outcomes, we conduct a feasibility study to examine restrictive and liberal approaches to UFNET during continuous KRT (CKRT). METHODS AND ANALYSIS: This study is an investigator-initiated, unblinded, 2-arm, comparative-effectiveness, stepped-wedged, cluster randomised trial among 112 critically ill patients with AKI treated with CKRT in 10 intensive care units (ICUs) across 2 hospital systems. In the first 6 months, all ICUs started with a liberal UFNET rate strategy. Thereafter, one ICU is randomised to the restrictive UFNET rate strategy every 2 months. In the liberal group, the UFNET rate is maintained between 2.0 and 5.0 mL/kg/hour; in the restrictive group, the UFNET rate is maintained between 0.5 and 1.5 mL/kg/hour. The three coprimary feasibility outcomes are (1) between-group separation in mean delivered UFNET rates; (2) protocol adherence; and (3) patient recruitment rate. Secondary outcomes include daily and cumulative fluid balance, KRT and mechanical ventilation duration, organ failure-free days, ICU and hospital length of stay, hospital mortality and KRT dependence at hospital discharge. Safety endpoints include haemodynamics, electrolyte imbalance, CKRT circuit issues, organ dysfunction related to fluid overload, secondary infections and thrombotic and haematological complications. ETHICS AND DISSEMINATION: The University of Pittsburgh Human Research Protection Office approved the study, and an independent Data and Safety Monitoring Board monitors the study. A grant from the United States National Institute of Diabetes and Digestive and Kidney Diseases sponsors the study. The trial results will be submitted for publication in peer-reviewed journals and presented at scientific conferences. TRIAL REGISTRATION NUMBER: This trial has been prospectively registered with clinicaltrials.gov (NCT05306964). Protocol version identifier and date: 1.5; 13 June 2023.

Social Isolation and Loneliness in a Population Study of Cognitive Impairment: The MYHAT Study.

In this study, we examined associations of social isolation and loneliness with cognitive impairment among older adults from a Rust Belt region in Southwest Pennsylvania. We used data from the population-based Monongahela-Youghiogheny Healthy Aging Team (MYHAT) study. We found that (a) 11 items combined into two reliable composites of social isolation and loneliness; (b) unique to this study, providing unpaid help to others was an indicator of reduced social isolation; (c) social isolation and loneliness were positively associated with cognitive impairment; and (d) these associations were appreciably attenuated by general health and physical functional status and depressive symptoms, respectively. We concluded that social isolation and loneliness are differentially associated with older adults' cognitive health, and that their effects might operate through separate pathways. Approaches to address social isolation and loneliness should consider the community context and its implications for older adults' cognitive health.

Trends in Use of Medication to Treat Opioid Use Disorder During the COVID-19 Pandemic in 10 State Medicaid Programs.

Importance: Federal and state agencies granted temporary regulatory waivers to prevent disruptions in access to medication for opioid use disorder (MOUD) during the COVID-19 pandemic, including expanding access to telehealth for MOUD. Little is known about changes in MOUD receipt and initiation among Medicaid enrollees during the pandemic. Objectives: To examine changes in receipt of any MOUD, initiation of MOUD (in-person vs telehealth), and the proportion of days covered (PDC) with MOUD after initiation from before to after declaration of the COVID-19 public health emergency (PHE). Design, Setting, and Participants: This serial cross-sectional study included Medicaid enrollees aged 18 to 64 years in 10 states from May 2019 through December 2020. Analyses were conducted from January through March 2022. Exposures: Ten months before the COVID-19 PHE (May 2019 through February 2020) vs 10 months after the PHE was declared (March through December 2020). Main Outcomes and Measures: Primary outcomes included receipt of any MOUD and outpatient initiation of MOUD via prescriptions and office- or facility-based administrations. Secondary outcomes included in-person vs telehealth MOUD initiation and PDC with MOUD after initiation. Results: Among a total of 8 167 497 Medicaid enrollees before the PHE and 8 181 144 after the PHE, 58.6% were female in both periods and most enrollees were aged 21 to 34 years (40.1% before the PHE; 40.7% after the PHE). Monthly rates of MOUD initiation, representing 7% to 10% of all MOUD receipt, decreased immediately after the PHE primarily due to reductions in in-person initiations (from 231.3 per 100 000 enrollees in March 2020 to 171.8 per 100 000 enrollees in April 2020) that were partially offset by increases in telehealth initiations (from 5.6 per 100 000 enrollees in March 2020 to 21.1 per 100 000 enrollees in April 2020). Mean monthly PDC with MOUD in the 90 days after initiation decreased after the PHE (from 64.5% in March 2020 to 59.5% in September 2020). In adjusted analyses, there was no immediate change (odds ratio [OR], 1.01; 95% CI, 1.00-1.01) or change in the trend (OR, 1.00; 95% CI, 1.00-1.01) in the likelihood of receipt of any MOUD after the PHE compared with before the PHE. There was an immediate decrease in the likelihood of outpatient MOUD initiation (OR, 0.90; 95% CI, 0.85-0.96) and no change in the trend in the likelihood of outpatient MOUD initiation (OR, 0.99; 95% CI, 0.98-1.00) after the PHE compared with before the PHE. Conclusions and Relevance: In this cross-sectional study of Medicaid enrollees, the likelihood of receipt of any MOUD was stable from May 2019 through December 2020 despite concerns about potential COVID-19 pandemic-related disruptions in care. However, immediately after the PHE was declared, there was a reduction in overall MOUD initiations, including a reduction in in-person MOUD initiations that was only partially offset by increased use of telehealth.

The quantity and quality of cardiovascular fat at mid-life and future cognitive performance among women: The SWAN cardiovascular fat ancillary study.

INTRODUCTION: Cardiovascular fat is a novel risk factor that may link to dementia. Fat volume and radiodensity are measurements of fat quantity and quality, respectively. Importantly, high fat radiodensity could indicate healthy or adverse metabolic processes. METHODS: The associations of cardiovascular fat (including epicardial, paracardial, and thoracic perivascular adipose tissue [PVAT]) quantity and quality assessed at mean age of 51 with subsequent cognitive performance measured repeatedly over 16 years of follow-up were examined using mixed models among 531 women. RESULTS: Higher thoracic PVAT volume was associated with a higher future episodic memory (ß[standard error (SE)] = 0.08 [0.04], P = 0.033), while higher thoracic PVAT radiodensity with lower future episodic (ß[SE] = -0.06 [0.03], P = 0.045) and working (ß[SE] = -0.24 [0.08], P = 0.003) memories. The latter association is prominent at higher volume of thoracic PVAT. DISCUSSION: Mid-life thoracic PVAT may have a distinct contribution to future cognition possibly due to its distinct adipose tissue type (brown fat) and anatomical proximity to the brain circulation. HIGHLIGHTS: Higher mid-life thoracic perivascular adipose tissue (thoracic PVAT) volume is related to a better future episodic memory in women. Higher mid-life thoracic PVAT radiodensity is related to worse future working and episodic memories. Negative association of high thoracic PVAT radiodensity with working memory is prominent at higher thoracic PVAT volume. Mid-life thoracic PVAT is linked to future memory loss, an early sign of Alzheimer's disease. Mid-life women's epicardial and paracardial fat are not related to future cognition.

Social connections and risk of incident mild cognitive impairment, dementia, and mortality in 13 longitudinal cohort studies of ageing.

INTRODUCTION: Previous meta-analyses have linked social connections and mild cognitive impairment, dementia, and mortality. However, these used aggregate data from North America and Europe and examined a limited number of social connection markers. METHODS: We used individual participant data (N = 39271, Mage  = 70.67 (40-102), 58.86% female, Meducation  = 8.43 years, Mfollow-up  = 3.22 years) from 13 longitudinal ageing studies. A two-stage meta-analysis of Cox regression models examined the association between social connection markers with our primary outcomes. RESULTS: We found associations between good social connections structure and quality and lower risk of incident mild cognitive impairment (MCI); between social structure and function and lower risk of incident dementia and mortality. Only in Asian cohorts, being married/in a relationship was associated with reduced risk of dementia, and having a confidante was associated with reduced risk of dementia and mortality. DISCUSSION: Different aspects of social connections - structure, function, and quality - are associated with benefits for healthy aging internationally. HIGHLIGHTS: Social connection structure (being married/in a relationship, weekly community group engagement, weekly family/friend interactions) and quality (never lonely) were associated with lower risk of incident MCI. Social connection structure (monthly/weekly friend/family interactions) and function (having a confidante) were associated with lower risk of incident dementia. Social connection structure (living with others, yearly/monthly/weekly community group engagement) and function (having a confidante) were associated with lower risk of mortality. Evidence from 13 longitudinal cohort studies of ageing indicates that social connections are important targets for reducing risk of incident MCI, incident dementia, and mortality. Only in Asian cohorts, being married/in a relationship was associated with reduced risk of dementia, and having a confidante was associated with reduced risk of dementia and mortality.

Use of residential opioid use disorder treatment among Medicaid enrollees in nine states.

INTRODUCTION: Residential treatment is a key component of the opioid use disorder care continuum, but research has not measured well the differences in its use across states at the enrollee level. METHODS: This cross-sectional observational study used Medicaid claims data from nine states to document the prevalence of residential treatment for opioid use disorder and to describe the characteristics of patients receiving care. For each patient characteristic, chi-square and t-tests tested for differences in the distribution between individuals who did and did not receive residential care. RESULTS: Among 491,071 Medicaid enrollees with opioid use disorder, 7.5 % were treated in residential facilities in 2019, though this number ranged widely (0.3-14.6 %) across states. Residential patients were more likely to be younger, non-Hispanic White, male, and living in an urban area. Although residential patients were less likely than those without residential care to be eligible for Medicaid through disability, diagnoses for comorbid conditions were more frequently observed among residential patients. CONCLUSIONS: Results from this large, multi-state study add context to the ongoing national conversation around opioid use disorder treatment and policy, providing a baseline for future work.

It goes both ways: The relationship between anxiety and mild cognitive impairment.

OBJECTIVE: To investigate the relationship between anxiety and mild cognitive impairment (MCI), and whether it is mediated by perceived stress, at the population level. METHOD AND DESIGN: In a longitudinal study of 368 adults aged 65+ from a population-based cohort, we annually assessed anxiety symptoms (GAD-7), perceived stress (PSS-4), and ratings on the Clinical Dementia Rating (CDR®), where CDR = 0.5 was operationalized as MCI. Examining data from three consecutive assessment waves, we first determined the associations between anxiety at the first wave with MCI at the third wave, and vice versa. We then used mediation analyses to determine whether the pathways in both directions were mediated by perceived stress at the second wave, adjusting for demographics and other relevant covariates. RESULTS: We confirmed significant bidirectional longitudinal associations between anxiety and MCI. Perceived stress was detected as a significant mediator for both pathways between anxiety and MCI, explaining 37.1% of the total effect (TE) of anxiety on incident MCI while conversely explaining 27.1% of the TE of MCI on anxiety. CONCLUSIONS: A bidirectional relationship with a 2-year lag between anxiety and MCI was mediated through perceived stress. Clinicians should be sensitive both to potential consequent anxiety when patients present with cognitive impairment, and to potential incipient MCI when the presenting complaint is anxiety. Managing stress may help mitigate adverse outcomes.

Plasma biomarkers identify older adults at risk of Alzheimer's disease and related dementias in a real-world population-based cohort.

INTRODUCTION: Plasma biomarkers-cost effective, non-invasive indicators of Alzheimer's disease (AD) and related disorders (ADRD)-have largely been studied in clinical research settings. Here, we examined plasma biomarker profiles and their associated factors in a population-based cohort to determine whether they could identify an at-risk group, independently of brain and cerebrospinal fluid biomarkers. METHODS: We measured plasma phosphorylated tau181 (p-tau181), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and amyloid beta (Aß)42/40 ratio in 847 participants from a population-based cohort in southwestern Pennsylvania. RESULTS: K-medoids clustering identified two distinct plasma Aß42/40 modes, further categorizable into three biomarker profile groups: normal, uncertain, and abnormal. In different groups, plasma p-tau181, NfL, and GFAP were inversely correlated with Aß42/40, Clinical Dementia Rating, and memory composite score, with the strongest associations in the abnormal group. DISCUSSION: Abnormal plasma Aß42/40 ratio identified older adult groups with lower memory scores, higher dementia risks, and higher ADRD biomarker levels, with potential implications for population screening. HIGHLIGHTS: Population-based plasma biomarker studies are lacking, particularly in cohorts without cerebrospinal fluid or neuroimaging data. In the Monongahela-Youghiogheny Healthy Aging Team study (n = 847), plasma biomarkers associated with worse memory and Clinical Dementia Rating (CDR), apolipoprotein E ε4, and greater age. Plasma amyloid beta (Aß)42/40 ratio levels allowed clustering participants into abnormal, uncertain, and normal groups. Plasma Aß42/40 correlated differently with neurofilament light chain, glial fibrillary acidic protein, phosphorylated tau181, memory composite, and CDR in each group. Plasma biomarkers can enable relatively affordable and non-invasive community screening for evidence of Alzheimer's disease and related disorders pathophysiology.

Heterogeneous Treatment Effects of Therapeutic-Dose Heparin in Patients Hospitalized for COVID-19.

Importance: Randomized clinical trials (RCTs) of therapeutic-dose heparin in patients hospitalized with COVID-19 produced conflicting results, possibly due to heterogeneity of treatment effect (HTE) across individuals. Better understanding of HTE could facilitate individualized clinical decision-making. Objective: To evaluate HTE of therapeutic-dose heparin for patients hospitalized for COVID-19 and to compare approaches to assessing HTE. Design, Setting, and Participants: Exploratory analysis of a multiplatform adaptive RCT of therapeutic-dose heparin vs usual care pharmacologic thromboprophylaxis in 3320 patients hospitalized for COVID-19 enrolled in North America, South America, Europe, Asia, and Australia between April 2020 and January 2021. Heterogeneity of treatment effect was assessed 3 ways: using (1) conventional subgroup analyses of baseline characteristics, (2) a multivariable outcome prediction model (risk-based approach), and (3) a multivariable causal forest model (effect-based approach). Analyses primarily used bayesian statistics, consistent with the original trial. Exposures: Participants were randomized to therapeutic-dose heparin or usual care pharmacologic thromboprophylaxis. Main Outcomes and Measures: Organ support-free days, assigning a value of -1 to those who died in the hospital and the number of days free of cardiovascular or respiratory organ support up to day 21 for those who survived to hospital discharge; and hospital survival. Results: Baseline demographic characteristics were similar between patients randomized to therapeutic-dose heparin or usual care (median age, 60 years; 38% female; 32% known non-White race; 45% Hispanic). In the overall multiplatform RCT population, therapeutic-dose heparin was not associated with an increase in organ support-free days (median value for the posterior distribution of the OR, 1.05; 95% credible interval, 0.91-1.22). In conventional subgroup analyses, the effect of therapeutic-dose heparin on organ support-free days differed between patients requiring organ support at baseline or not (median OR, 0.85 vs 1.30; posterior probability of difference in OR, 99.8%), between females and males (median OR, 0.87 vs 1.16; posterior probability of difference in OR, 96.4%), and between patients with lower body mass index (BMI <30) vs higher BMI groups (BMI ≥30; posterior probability of difference in ORs >90% for all comparisons). In risk-based analysis, patients at lowest risk of poor outcome had the highest propensity for benefit from heparin (lowest risk decile: posterior probability of OR >1, 92%) while those at highest risk were most likely to be harmed (highest risk decile: posterior probability of OR <1, 87%). In effect-based analysis, a subset of patients identified at high risk of harm (P = .05 for difference in treatment effect) tended to have high BMI and were more likely to require organ support at baseline. Conclusions and Relevance: Among patients hospitalized for COVID-19, the effect of therapeutic-dose heparin was heterogeneous. In all 3 approaches to assessing HTE, heparin was more likely to be beneficial in those who were less severely ill at presentation or had lower BMI and more likely to be harmful in sicker patients and those with higher BMI. The findings illustrate the importance of considering HTE in the design and analysis of RCTs. Trial Registration: ClinicalTrials.gov Identifiers: NCT02735707, NCT04505774, NCT04359277, NCT04372589.