Christianson syndrome across the lifespan: genetic mutations and longitudinal study in children, adolescents, and adults.

OBJECTIVES: Mutations in the X-linked endosomal Na+/H+ exchanger 6 (NHE6) cause Christianson syndrome (CS). Here, in the largest study to date, we examine genetic diversity and clinical progression in CS into adulthood. METHOD: Data were collected as part of the International Christianson Syndrome and NHE6 (SLC9A6) Gene Network Study. 44 individuals with 31 unique NHE6 mutations, age 2-32 years, were followed prospectively, herein reporting baseline, 1 year follow-up and retrospective natural history. RESULTS: We present data on the CS phenotype with regard to physical growth and adaptive and motor regression across the lifespan including information on mortality. Longitudinal data on body weight and height were examined using a linear mixed model. The rate of growth across development was slow and resulted in prominently decreased age-normed height and weight by adulthood. Adaptive functioning was longitudinally examined; a majority of adult participants (18+ years) lost gross and fine motor skills over a 1 year follow-up. Previously defined core diagnostic criteria for CS (present in>85%)-namely non-verbal status, intellectual disability, epilepsy, postnatal microcephaly, ataxia, hyperkinesia-were universally present in age 6-16; however, an additional core feature of high pain tolerance was added (present in 91%). While neurologic examinations were consistent with cerebellar dysfunction, importantly, a majority of individuals (>50% older than 10) also had corticospinal tract abnormalities. Three participants died during the period of the study. CONCLUSIONS: In this large and longitudinal study of CS, we begin to define the trajectory of symptoms and the adult phenotype thereby identifying critical targets for treatment.

Validating the Fluctuating Mental Status Evaluation in Neurocritically Ill Patients With Acute Stroke.

OBJECTIVES: Neurocritically ill patients are at high risk for developing delirium, which can worsen the long-term outcomes of this vulnerable population. However, existing delirium assessment tools do not account for neurologic deficits that often interfere with conventional testing and are therefore unreliable in neurocritically ill patients. We aimed to determine the accuracy and predictive validity of the Fluctuating Mental Status Evaluation (FMSE), a novel delirium screening tool developed specifically for neurocritically ill patients. DESIGN: Prospective validation study. SETTING: Neurocritical care unit at an academic medical center. PATIENTS: One hundred thirty-nine neurocritically ill stroke patients (mean age, 63.9 [sd, 15.9], median National Institutes of Health Stroke Scale score 11 [interquartile range, 2-17]). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Expert raters performed daily Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition-based delirium assessments, while paired FMSE assessments were performed by trained clinicians. We analyzed 717 total noncomatose days of paired assessments, of which 52% (n = 373) were rated by experts as days with delirium; 53% of subjects were delirious during one or more days. Compared with expert ratings, the overall accuracy of the FMSE was high (area under the curve [AUC], 0.85; 95% CI, 0.82-0.87). FMSE scores greater than or equal to 1 had 86% sensitivity and 74% specificity on a per-assessment basis, while scores greater than or equal to 2 had 70% sensitivity and 88% specificity. Accuracy remained high in patients with aphasia (FMSE ≥ 1: 82% sensitivity, 64% specificity; FMSE ≥ 2: 64% sensitivity, 84% specificity) and those with decreased arousal (FMSE ≥ 1: 87% sensitivity, 77% specificity; FMSE ≥ 2: 71% sensitivity, 90% specificity). Positive FMSE assessments also had excellent accuracy when predicting functional outcomes at discharge (AUC, 0.86 [95% CI, 0.79-0.93]) and 3 months (AUC, 0.85 [95% CI, 0.78-0.92]). CONCLUSIONS: In this validation study, we found that the FMSE was an accurate delirium screening tool in neurocritically ill stroke patients. FMSE scores greater than or equal to 1 indicate "possible" delirium and should be used when prioritizing sensitivity, whereas scores greater than or equal to 2 indicate "probable" delirium and should be used when prioritizing specificity.

Factor structure of the Harmonized Cognitive Assessment Protocol neuropsychological battery in the Health and Retirement Study.

OBJECTIVE: The Harmonized Cognitive Assessment Protocol (HCAP) describes an assessment battery and a family of population-representative studies measuring neuropsychological performance. We describe the factorial structure of the HCAP battery in the US Health and Retirement Study (HRS). METHOD: The HCAP battery was compiled from existing measures by a cross-disciplinary and international panel of researchers. The HCAP battery was used in the 2016 wave of the HRS. We used factor analysis methods to assess and refine a theoretically driven single and multiple domain factor structure for tests included in the HCAP battery among 3,347 participants with evaluable performance data. RESULTS: For the eight domains of cognitive functioning identified (orientation, memory [immediate, delayed, and recognition], set shifting, attention/speed, language/fluency, and visuospatial), all single factor models fit reasonably well, although four of these domains had either 2 or 3 indicators where fit must be perfect and is not informative. Multidimensional models suggested the eight-domain model was overly complex. A five-domain model (orientation, memory delayed and recognition, executive functioning, language/fluency, visuospatial) was identified as a reasonable model for summarizing performance in this sample (standardized root mean square residual = 0.05, root mean square error of approximation = 0.05, confirmatory fit index = 0.94). CONCLUSIONS: The HCAP battery conforms adequately to a multidimensional structure of neuropsychological performance. The derived measurement models can be used to operationalize notions of neurocognitive impairment, and as a starting point for prioritizing pre-statistical harmonization and evaluating configural invariance in cross-national research.

Psychometric and adherence considerations for high-frequency, smartphone-based cognitive screening protocols in older adults.

OBJECTIVE: The psychometric rigor of unsupervised, smartphone-based assessments and factors that impact remote protocol engagement is critical to evaluate prior to the use of such methods in clinical contexts. We evaluated the validity of a high-frequency, smartphone-based cognitive assessment protocol, including examining convergence and divergence with standard cognitive tests, and investigating factors that may impact adherence and performance (i.e., time of day and anticipated receipt of feedback vs. no feedback). METHODS: Cognitively unimpaired participants (N = 120, Mage = 68.8, 68.3% female, 87% White, Meducation = 16.5 years) completed 8 consecutive days of the Mobile Monitoring of Cognitive Change (M2C2), a mobile app-based testing platform, with brief morning, afternoon, and evening sessions. Tasks included measures of working memory, processing speed, and episodic memory. Traditional neuropsychological assessments included measures from the Preclinical Alzheimer's Cognitive Composite battery. RESULTS: Findings showed overall high compliance (89.3%) across M2C2 sessions. Average compliance by time of day ranged from 90.2% for morning sessions, to 77.9% for afternoon sessions, and 84.4% for evening sessions. There was evidence of faster reaction time and among participants who expected to receive performance feedback. We observed excellent convergent and divergent validity in our comparison of M2C2 tasks and traditional neuropsychological assessments. CONCLUSIONS: This study supports the validity and reliability of self-administered, high-frequency cognitive assessment via smartphones in older adults. Insights into factors affecting adherence, performance, and protocol implementation are discussed.

Biomarkers of neurodegeneration and neural injury as potential predictors for delirium.

OBJECTIVES: Determine if biomarkers of Alzheimer's disease and neural injury may play a role in the prediction of delirium risk. METHODS: In a cohort of older adults who underwent elective surgery, delirium case-no delirium control pairs (N = 70, or 35 matched pairs) were matched by age, sex and vascular comorbidities. Biomarkers from CSF and plasma samples collected prior to surgery, including amyloid beta (Aß)42 , Aß40 , total (t)-Tau, phosphorylated (p)-Tau181 , neurofilament-light (NfL), and glial fibrillary acid protein (GFAP) were measured in cerebrospinal fluid (CSF) and plasma using sandwich enzyme-linked immunosorbent assays (ELISAs) or ultrasensitive single molecule array (Simoa) immunoassays. RESULTS: Plasma GFAP correlated significantly with CSF GFAP and both plasma and CSF GFAP values were nearly two-fold higher in delirium cases. The median paired difference between delirium case and control without delirium for plasma GFAP was not significant (p = 0.074) but higher levels were associated with a greater risk for delirium (odds ratio 1.52, 95% confidence interval 0.85, 2.72 per standard deviation increase in plasma GFAP concentration) in this small study. No matched pair differences or associations with delirium were observed for NfL, p-Tau 181, Aß40 and Aß42 . CONCLUSIONS: These preliminary findings suggest that plasma GFAP, a marker of astroglial activation, may be worth further investigation as a predictive risk marker for delirium.

Comparative Safety Analysis of Oral Antipsychotics for In-Hospital Adverse Clinical Events in Older Adults After Major Surgery : A Nationwide Cohort Study.

BACKGROUND: Antipsychotics are commonly used to manage postoperative delirium. Recent studies reported that haloperidol use has declined, and atypical antipsychotic use has increased over time. OBJECTIVE: To compare the risk for in-hospital adverse events associated with oral haloperidol, olanzapine, quetiapine, and risperidone in older patients after major surgery. DESIGN: Retrospective cohort study. SETTING: U.S. hospitals in the Premier Healthcare Database. PATIENTS: 17 115 patients aged 65 years and older without psychiatric disorders who were prescribed an oral antipsychotic drug after major surgery from 2009 to 2018. INTERVENTIONS: Haloperidol (≤4 mg on the day of initiation), olanzapine (≤10 mg), quetiapine (≤150 mg), and risperidone (≤4 mg). MEASUREMENTS: The risk ratios (RRs) for in-hospital death, cardiac arrhythmia events, pneumonia, and stroke or transient ischemic attack (TIA) were estimated after propensity score overlap weighting. RESULTS: The weighted population had a mean age of 79.6 years, was 60.5% female, and had in-hospital death of 3.1%. Among the 4 antipsychotics, quetiapine was the most prescribed (53.0% of total exposure). There was no statistically significant difference in the risk for in-hospital death among patients treated with haloperidol (3.7%, reference group), olanzapine (2.8%; RR, 0.74 [95% CI, 0.42 to 1.27]), quetiapine (2.6%; RR, 0.70 [CI, 0.47 to 1.04]), and risperidone (3.3%; RR, 0.90 [CI, 0.53 to 1.41]). The risk for nonfatal clinical events ranged from 2.0% to 2.6% for a cardiac arrhythmia event, 4.2% to 4.6% for pneumonia, and 0.6% to 1.2% for stroke or TIA, with no statistically significant differences by treatment group. LIMITATION: Residual confounding by delirium severity; lack of untreated group; restriction to oral low-to-moderate dose treatment. CONCLUSION: These results suggest that atypical antipsychotics and haloperidol have similar rates of in-hospital adverse clinical events in older patients with postoperative delirium who receive an oral low-to-moderate dose antipsychotic drug. PRIMARY FUNDING SOURCE: National Institute on Aging.

Development and assessment of analytic methods to improve the measurement of cognition in longitudinal studies of aging through the use of substudies with comprehensive neuropsychological testing.

INTRODUCTION: The Health and Retirement Study International Partner Surveys (HRS IPS) have rich longitudinal data, but the brevity of cognitive batteries is a limitation. METHODS: We used data from a substudy of the English Longitudinal Study of Ageing (ELSA) administering detailed cognitive assessments with the Harmonized Cognitive Assessment Protocol (ELSA-HCAP) (N = 1273) to inform approaches for estimating cognition in ELSA (N = 11,213). We compared two novel approaches: confirmatory factor analysis (CFA)- and regression-based prediction. RESULTS: Compared to estimates from the full HCAP battery, estimated cognitive functioning derived using regression models or CFA had high correlations (regression: r = 0.85 [95% confidence interval [CI]: 0.83 to 0.87]; CFA: r = 0.83 [95% CI: 0.81 to 0.85]) and reasonable mean squared error (regression: 0.25 [0.22 to 0.27]; CFA: 0.29 [0.26 to 0.32]) in held-out data. The use of additional items from waves 7 to 9 improved performance. DISCUSSION: Both approaches are recommended for future research; the similarity in approaches may be due to the brevity of available cognitive assessments in ELSA. HIGHLIGHTS: Estimates of cognitive functioning informed by English Longitudinal Study of Ageing-Harmonized Cognitive Assessment Protocol (ELSA-HCAP) data had an adequate performance. Standard errors were smaller for associations with example risks when using measures informed by ELSA-HCAP. Performance was better when including additional cognitive measures available in waves 7 to 9. Conceptual advantages to the confirmatory factor analysis (CFA) approach were not important in practice due to the brevity of the ELSA cognitive battery.

Lifetime occupational skill and later-life cognitive function among older adults in the United States, Mexico, India, and South Africa.

INTRODUCTION: We conducted a cross-national comparison of the association between main lifetime occupational skills and later-life cognitive function across four economically and socially distinct countries. METHODS: Data were from population-based studies of aging and their Harmonized Cognitive Assessment Protocols (HCAPs) in the US, South Africa, India, and Mexico (N = 10,037; Age range: 50 to 105 years; 2016 to 2020). Main lifetime occupational skill was classified according to the International Standard Classification of Occupations. Weighted, adjusted regression models estimated pooled and country-specific associations between main lifetime occupational skill and later-life general cognitive function in men and women. RESULTS: We observed positive gradients between occupational skill and later-life cognitive function for men and women in the US and Mexico, a positive gradient for women but not men in India, and no association for men or women in South Africa. DISCUSSION: Main lifetime occupations may be a source of later-life cognitive reserve, with cross-national heterogeneity in this association. HIGHLIGHTS: No studies have examined cross-national differences in the association of occupational skill with cognition. We used data from Harmonized Cognitive Assessment Protocols in the US, Mexico, India, and South Africa. The association of occupational skill with cognitive function varies by country and gender.

Cross-national comparisons of later-life cognitive function using data from the Harmonized Cognitive Assessment Protocol (HCAP): Considerations and recommended best practices.

The Harmonized Cognitive Assessment Protocol (HCAP) is a major innovation that provides, for the first time, harmonized data for cross-national comparisons of later-life cognitive functions that are sensitive to linguistic, cultural, and educational differences across countries. However, cognitive function does not lend itself to direct comparison across diverse populations without careful consideration of the best practices for such comparisons. This perspective discusses theoretical and methodological considerations and offers a set of recommended best practices for conducting cross-national comparisons of risk factor associations using HCAP data. Because existing and planned HCAP studies provide cognition data representing an estimated 75% of the global population ≥65 years of age, these recommended best practices will support high-quality comparative analyses of cognitive aging around the world. The principles described in this perspective are applicable to any researcher aiming to integrate or compare harmonized data on cognitive outcomes and their risk and protective factors across diverse populations.

Association of Loneliness With Change in Physical and Emotional Health of Older Adults During the COVID-19 Shutdown.

OBJECTIVES: To examine factors influencing loneliness and the effect of loneliness on physical and emotional health, in the context of the COVID-19 pandemic. DESIGN: Prospective, observational cohort. SETTING: Community-dwelling participants. PARTICIPANTS: Older adults (n = 238) enrolled in a longitudinal study. MEASUREMENTS: Interviews were completed July-December 2020. Loneliness was measured with the UCLA 3-item loneliness scale. Data including age, marriage, education, cognitive functioning, functional impairment, vision or hearing impairment, depression, anxiety, medical comorbidity, social network size, technology use, and activity engagement were collected. Health outcomes included self-rated health, and physical and mental composites from the 12-item Short Form Survey. Physical function was measured by a PROMIS-scaled composite score. RESULTS: Thirty-nine (16.4%) participants reported loneliness. Vulnerability factors for loneliness included age (RR = 1.08, 95% CI 1.02-1.14); impairment with instrumental activities of daily living (RR = 2.08, 95% CI 1.14-3.80); vision impairment (RR = 2.09, 95% CI 1.10-3.97); depression (RR = 1.34, 95% CI 1.25-1.43); and anxiety (RR = 1.92, 95% CI 1.55-2.39). Significant resilience factors included high cognitive functioning (RR = 0.88, 95% CI 0.83-0.94); large social network size (RR = 0.92, 95% CI 0.88-0.96); technology use (RR = 0.81, 95% CI 0.73-0.90); and social and physical activity engagement (RR = 0.91, 95% CI 0.85-0.98). Interaction analyses showed that larger social network size moderated the effect of loneliness on physical function (protective interaction effect, RR = 0.64, 95% CI 0.15-1.13, p <.01), and activity engagement moderated the effect of loneliness on mental health (protective interaction effect, RR = 0.65, 95% CI 0.25-1.05, p <.001). CONCLUSIONS: Resilience factors may mitigate the adverse health outcomes associated with loneliness. Interventions to enhance resilience may help to diminish the detrimental effects of loneliness and hold great importance for vulnerable older adults.

Linear linking for related traits (LLRT): A novel method for the harmonization of cognitive domains with no or few common items.

Harmonization means to make data comparable. Recent efforts to generate comparable data on cognitive performance of older adults from many different countries around the world have presented challenges for direct comparison. Neuropsychological instruments vary in many respects, including language, administration techniques and cultural differences, which all present important obstacles to assumptions regarding the presence of linking items. Item response theory (IRT) methods have been previously used to harmonize cross-national data on cognition, but these methods rely on linking items to establish the shared metric. We introduce an alternative approach for linking cognitive performance across two (or more) groups when the fielded assessments contain no items that can be reasonably considered linking items: Linear Linking for Related Traits (LLRT). We demonstrate this methodological approach in a sample from a single United States study split by educational attainment, and in two sets of cross-national comparisons (United States to England, and United States to India). All data were collected as part of the Harmonized Cognitive Assessment Protocol (HCAP) and are publicly available. Our method relies upon strong assumptions, and we offer suggestions for how the method can be extended to relax those assumptions in future work.

Patterns and Persistence of Perioperative Plasma and Cerebrospinal Fluid Neuroinflammatory Protein Biomarkers After Elective Orthopedic Surgery Using SOMAscan.

BACKGROUND: The neuroinflammatory response to surgery can be characterized by peripheral acute plasma protein changes in blood, but corresponding, persisting alterations in cerebrospinal fluid (CSF) proteins remain mostly unknown. Using the SOMAscan assay, we define acute and longer-term proteome changes associated with surgery in plasma and CSF. We hypothesized that biological pathways identified by these proteins would be in the categories of neuroinflammation and neuronal function and define neuroinflammatory proteome changes associated with surgery in older patients. METHODS: SOMAscan analyzed 1305 proteins in blood plasma (n = 14) and CSF (n = 15) samples from older patients enrolled in the Role of Inflammation after Surgery for Elders (RISE) study undergoing elective hip and knee replacement surgery with spinal anesthesia. Systems biology analysis identified biological pathways enriched among the surgery-associated differentially expressed proteins in plasma and CSF. RESULTS: Comparison of postoperative day 1 (POD1) to preoperative (PREOP) plasma protein levels identified 343 proteins with postsurgical changes ( P < .05; absolute value of the fold change [|FC|] > 1.2). Comparing postoperative 1-month (PO1MO) plasma and CSF with PREOP identified 67 proteins in plasma and 79 proteins in CSF with altered levels ( P < .05; |FC| > 1.2). In plasma, 21 proteins, primarily linked to immune response and inflammation, were similarly changed at POD1 and PO1MO. Comparison of plasma to CSF at PO1MO identified 8 shared proteins. Comparison of plasma at POD1 to CSF at PO1MO identified a larger number, 15 proteins in common, most of which are regulated by interleukin-6 (IL-6) or transforming growth factor beta-1 (TGFB1) and linked to the inflammatory response. Of the 79 CSF PO1MO-specific proteins, many are involved in neuronal function and neuroinflammation. CONCLUSIONS: SOMAscan can characterize both short- and long-term surgery-induced protein alterations in plasma and CSF. Acute plasma protein changes at POD1 parallel changes in PO1MO CSF and suggest 15 potential biomarkers for longer-term neuroinflammation that warrant further investigation.

A Pilot Study of the Fluctuating Mental Status Evaluation: A Novel Delirium Screening Tool for Neurocritical Care Patients.

BACKGROUND: Delirium occurs frequently in patients with stroke and neurocritical illness but is often underrecognized. We developed a novel delirium screening tool designed specifically for neurocritical care patients called the fluctuating mental status evaluation (FMSE) and aimed to test its usability and accuracy in a representative cohort of patients with intracerebral hemorrhage (ICH). METHODS: We performed a single-center prospective study in a pilot cohort of patients with ICH who had daily delirium assessments throughout their admission. Reference-standard expert ratings were performed each afternoon using criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and were derived from bedside assessments and clinical data from the preceding 24 h. Paired FMSE assessments were performed by patients' clinical nurses after receiving brief one-on-one training from research staff. Nursing assessments were aggregated over 24-h periods (including day and night shifts), and accuracy of the FMSE was analyzed in patients who were not comatose to determine optimal scoring thresholds. RESULTS: We enrolled 40 patients with ICH (mean age 71.1 ± 12.2, 55% male, median National Institutes of Health Stroke Scale score 16.5 [interquartile range 12-20]), of whom 85% (n = 34) experienced delirium during their hospitalization. Of 308 total coma-free days with paired assessments, 208 (68%) were rated by experts as days with delirium. Compared with expert ratings, FMSE scores ≥ 1 had 86% sensitivity and 73% specificity on a per-day basis, whereas FMSE scores ≥ 2 had 68% sensitivity and 82% specificity. Accuracy remained high in patients with aphasia (FMSE scores ≥ 1: 83% sensitivity, 77% specificity; FMSE scores ≥ 2: 68% sensitivity, 85% specificity) and decreased arousal (FMSE scores ≥ 1: 80% sensitivity, 100% specificity; FMSE scores ≥ 2: 73% sensitivity, 100% specificity). CONCLUSIONS: In this pilot study, the FMSE achieved a high sensitivity and specificity in detecting delirium. Follow-up validation studies in a larger more diverse cohort of neurocritical care patients will use score cutoffs of ≥ 1 as "possible" delirium and ≥ 2 as "probable" delirium.

One-year Medicare costs associated with delirium in older hospitalized patients with and without Alzheimer's disease dementia and related disorders.

INTRODUCTION: One-year health-care costs associated with delirium in older hospitalized patients with and without Alzheimer's disease and related dementias (ADRD) have not been examined previously. METHODS: Medicare costs were determined prospectively at discharge, and at 30, 90, and 365 days in a cohort (n = 311) of older adults after hospital admission. RESULTS: Seventy-six (24%) patients had ADRD and were more likely to develop delirium (51% vs. 24%, P < 0.001) and die within 1 year (38% vs. 21%, P = 0.002). In ADRD patients with versus without delirium, adjusted mean difference in costs associated with delirium were $34,828; most of the excess costs were incurred between 90 and 365 days (P = 0.03). In non-ADRD patients, delirium was associated with increased costs at all timepoints. Excess costs associated with delirium in ADRD patients increased progressively over 1 year, whereas in non-ADRD patients the increase was consistent across time periods. DISCUSSION: Our findings highlight the complexity of health-care costs for ADRD patients who develop delirium, a potentially preventable source of expenditures. HIGHLIGHTS: Novel examination of health-care costs of delirium in persons with and without Alzheimer's disease and related dementias (ADRD). Increased 1-year costs of $34,828 in ADRD patients with delirium (vs. without). Increased costs for delirium in ADRD occur later during the 365-day study period. For ADRD patients, cost differences between those with and without delirium increased over 1 year. For non-ADRD patients, the parallel cost differences were consistent over time.

Parental Education and Delirium Risk after Surgery in Older Adults.

OBJECTIVES: Efforts to conceptualize risk factors for postoperative delirium in older adults have focused on the time proximate to the episode, but how early-life exposures influence delirium risk is poorly understood. METHODS: An observational cohort of 547 patients aged 70+undergoing major non-cardiac surgery at two academic medical centers in Boston. Demographic characteristics, cognition, parental education, health, and participation in cognitively stimulating activities were assessed prior to surgery. Delirium incidence and severity were measured daily during hospitalization. RESULTS: Higher paternal education was associated with significantly lower incidence of delirium (X2(1, N =547)=8.35, p <.001; odds ratio OR=.93, 95% CI, .87 to .98) and inversely associated with delirium severity (r(545)=-.13, p <.001). Higher maternal education was associated with lower delirium incidence but did not reach statistical significance. The effect of paternal education on delirium incidence was independent of the patient's education, estimated premorbid intelligence, medical comorbidities, neighborhood disadvantage, and participation in cognitively stimulating activities (X2(2, N =547)=31.22, p <.001). CONCLUSIONS: Examining early-life exposures may yield unique insights into the risks and pathogenesis of delirium. CLINICAL IMPLICATIONS: Evaluating long-term factors that increase vulnerability to delirium may improve our ability to calculate risk. It may guide clinical decision-making and inform pre- and post-operative recommendations.

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.

Harmonization of Four Delirium Instruments: Creating Crosswalks and the Delirium Item-Bank (DEL-IB).

OBJECTIVES: Over 30 instruments are in current, active use for delirium identification. In a recent systematic review, we recommended 4 commonly used and well-validated instruments for clinical and research use. The goal of this study is to harmonize the four instruments on the same metric using modern methods in psychometrics. DESIGN: Secondary data analysis from 3 studies, and a simulation study based on the observed data. SETTING: Hospitalized (non-ICU) adults over 65 years old in the United States, Ireland, and Belgium. PARTICIPANTS: The total sample comprised 600 participants, contributing 1,623 assessments. MEASUREMENTS: Confusion Assessment Method (long-form and short-form), Delirium Observation Screening Scale, Delirium Rating Scale-Revised-98 (DRS-R-98) (total and severity scores), and Memorial Delirium Assessment Scale. RESULTS: Using item response theory, we linked scores across instruments, placing all four instruments and their separate scorings on the same metric (the propensity to delirium). Kappa statistics comparing agreement in delirium identification among the instruments ranged from 0.37 to 0.75, with the highest agreement between the DRS-R-98 total score and MDAS. After linking scores, we created a harmonized item bank, called the Delirium Item Bank (DEL-IB), consisting of 50 items. The DEL-IB allowed us to create six crosswalks, to allow scores to be translated across instruments. CONCLUSIONS: With our results, individual instrument scores can be directly compared to aid in clinical decision-making, and quantitatively combined in meta-analyses.

Delirium Item Bank: Utilization to Evaluate and Create Delirium Instruments.

INTRODUCTION: The large number of heterogeneous instruments in active use for identification of delirium prevents direct comparison of studies and the ability to combine results. In a recent systematic review we performed, we recommended four commonly used and well-validated instruments and subsequently harmonized them using advanced psychometric methods to develop an item bank, the Delirium Item Bank (DEL-IB). The goal of the present study was to find optimal cut-points on four existing instruments and to demonstrate use of the DEL-IB to create new instruments. METHODS: We used a secondary analysis and simulation study based on data from three previous studies of hospitalized older adults (age 65+ years) in the USA, Ireland, and Belgium. The combined dataset included 600 participants, contributing 1,623 delirium assessments, and an overall incidence of delirium of about 22%. The measurements included the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition diagnostic criteria for delirium, Confusion Assessment Method (long form and short form), Delirium Observation Screening Scale, Delirium Rating Scale-Revised-98 (total and severity scores), and Memorial Delirium Assessment Scale (MDAS). RESULTS: We identified different cut-points for each existing instrument to optimize sensitivity or specificity, and compared instrument performance at each cut-point to the author-defined cut-point. For instance, the cut-point on the MDAS that maximizes both sensitivity and specificity was at a sum score of 6 yielding 89% sensitivity and 79% specificity. We then created four new example instruments (two short forms and two long forms) and evaluated their performance characteristics. In the first example short form instrument, the cut-point that maximizes sensitivity and specificity was at a sum score of 3 yielding 90% sensitivity, 81% specificity, 30% positive predictive value, and 99% negative predictive value. DISCUSSION/CONCLUSION: We used the DEL-IB to better understand the psychometric performance of widely used delirium identification instruments and scorings, and also demonstrated its use to create new instruments. Ultimately, we hope that the DEL-IB might be used to create optimized delirium identification instruments and to spur the development of a unified approach to identify delirium.

Socio-Cognitive Behavioral Therapy for Latinx Adolescent with Suicidal Behaviors: A Pilot Randomized Trial.

Evidence-based treatment for Latinx/Hispanic (L/H) with suicidal behaviors (SB) is scarce. This study evaluated the acceptability and preliminary efficacy of a socio-cognitive-behavioral therapy protocol for SB (SCBT-SB) with L/H adolescents and the feasibility of conducting a randomized controlled trial (RCT) of SCBT-SB compared to treatment-as-usual (TAU). A pilot RCT was conducted with 46 L/H teens. The target outcomes included suicidal ideation (SI), suicide attempts (SAs), and depressive/internalizing symptoms. Results indicated that the SCBT-SB was acceptable and an RCT with diverse L/H families is feasible to implement. Within group analyses showed reductions over time for each group in SI and depressive/internalizing symptoms. Intent-to-treat between-group analyses showed a medium effect for the SCBT-SB at the twelve-month follow-up for depressive/internalizing symptoms and a large effect for SA. Although results must be interpreted cautiously given the small sample size, outcomes suggest that SCBT-SB may be a promising psychosocial treatment for depressive/internalizing symptoms, and SAs in L/H youth.

Quantifying Lifecourse Drivers of International Migration: A Cross-national Analysis of Mexico and the United States.

BACKGROUND: Evaluating the long-term health consequences of migration requires longitudinal data on migrants and non-migrants to facilitate adjustment for time-varying confounder-mediators of the effect of migration on health. METHODS: We merged harmonized data on subjects aged 50+ from the US-based Health and Retirement Study (HRS) and the Mexican Health and Aging Study (MHAS). Our exposed group includes MHAS-return migrants (n = 1555) and HRS Mexican-born migrants (n = 924). Our unexposed group includes MHAS-never migrants (n = 16,954). We constructed a lifecourse data set from birth (age 0) until either age at migration to the United States or age at study entry. To account for confounding via inverse probability of treatment weights (IPTW), we modeled the probability of migration at each year of life using time-varying pre-migration characteristics. We then evaluated the effect of migration on mortality hazard estimated with and without IPTW. RESULTS: Mexico to the United States migration was predicted by time-varying factors that occurred before migration. Using measured covariates at time of enrollment to account for selective migration, we estimated that, for women, migrating reduces mortality risk by 13%, although this estimate was imprecise and results were compatible with either large protective or deleterious associations (hazard ratio [HR] =0.87, 95% confidence interval [CI]: 0.60, 1.27). When instead using IPTWs, the estimated effect on mortality was similarly imprecise (HR = 0.98, 95% CI: 0.77, 1.25). The relationship among men was similarly uncertain in both models. CONCLUSIONS: Although time-varying social factors predicted migration, IPTW weighting did not affect our estimates. Larger samples are needed to precisely estimate the health effects of migration.