Activity-Dependent Degradation of the Nascentome by the Neuronal Membrane Proteasome.

Activity-dependent changes in neuronal function require coordinated regulation of the protein synthesis and protein degradation machinery to maintain protein homeostasis, critical for proper neuronal function. However, the biochemical evidence for this balance and coordination is largely lacking. Leveraging our recent discovery of a neuronal-specific 20S membrane proteasome complex (NMP), we began exploring how neuronal activity regulates its function. Here, we found that the NMP degrades exclusively a large fraction of ribosome-associated nascent polypeptides that are being newly synthesized during neuronal stimulation. Using deep-coverage and global mass spectrometry, we identified the nascent protein substrates of the NMP, which included products encoding immediate-early genes, such as c-Fos and Npas4. Intriguingly, we found that turnover of nascent polypeptides and not full-length proteins through the NMP occurred independent of canonical ubiquitylation pathways. We propose that these findings generally define a neuronal activity-induced protein homeostasis program of coordinated protein synthesis and degradation through the NMP.

Neuronal membrane proteasomes regulate neuronal circuit activity in vivo and are required for learning-induced behavioral plasticity.

Protein degradation is critical for brain function through processes that remain incompletely understood. Here, we investigated the in vivo function of the 20S neuronal membrane proteasome (NMP) in the brain of Xenopus laevis tadpoles. With biochemistry, immunohistochemistry, and electron microscopy, we demonstrated that NMPs are conserved in the tadpole brain and preferentially degrade neuronal activity-induced newly synthesized proteins in vivo. Using in vivo calcium imaging in the optic tectum, we showed that acute NMP inhibition rapidly increased spontaneous neuronal activity, resulting in hypersynchronization across tectal neurons. At the circuit level, inhibiting NMPs abolished learning-dependent improvement in visuomotor behavior in live animals and caused a significant deterioration in basal behavioral performance following visual training with enhanced visual experience. Our data provide in vivo characterization of NMP functions in the vertebrate nervous system and suggest that NMP-mediated degradation of activity-induced nascent proteins may serve as a homeostatic modulatory mechanism in neurons that is critical for regulating neuronal activity and experience-dependent circuit plasticity.

EphB-mediated degradation of the RhoA GEF Ephexin5 relieves a developmental brake on excitatory synapse formation.

The mechanisms that promote excitatory synapse formation and maturation have been extensively studied. However, the molecular events that limit excitatory synapse development so that synapses form at the right time and place and in the correct numbers are less well understood. We have identified a RhoA guanine nucleotide exchange factor, Ephexin5, which negatively regulates excitatory synapse development until EphrinB binding to the EphB receptor tyrosine kinase triggers Ephexin5 phosphorylation, ubiquitination, and degradation. The degradation of Ephexin5 promotes EphB-dependent excitatory synapse development and is mediated by Ube3A, a ubiquitin ligase that is mutated in the human cognitive disorder Angelman syndrome and duplicated in some forms of Autism Spectrum Disorders (ASDs). These findings suggest that aberrant EphB/Ephexin5 signaling during the development of synapses may contribute to the abnormal cognitive function that occurs in Angelman syndrome and, possibly, ASDs.

Orthogonal approaches required to measure proteasome composition and activity in mammalian brain tissue.

Proteasomes are large macromolecular complexes with multiple distinct catalytic activities that are each vital to human brain health and disease. Despite their importance, standardized approaches to investigate proteasomes have not been universally adapted. Here, we describe pitfalls and define straightforward orthogonal biochemical approaches essential to measure and understand changes in proteasome composition and activity in the mammalian central nervous system. Through our experimentation in the mammalian brain, we determined an abundance of catalytically active proteasomes exist with and without a 19S cap(s), the regulatory particle essential for ubiquitin-dependent degradation. Moreover, we learned that in-cell measurements using activity-based probes (ABPs) are more sensitive in determining the available activity of the 20S proteasome without the 19S cap and in measuring individual catalytic subunit activities of each ß subunit within all neuronal proteasomes. Subsequently, applying these tools to human brain samples, we were surprised to find that post-mortem tissue retained little to no 19S-capped proteasome, regardless of age, sex, or disease state. In comparing brain tissues (parahippocampal gyrus) from patients with Alzheimer's disease (AD) and unaffected individuals, the available 20S proteasome activity was significantly elevated in severe cases of AD, an observation not previously noted. Taken together, our study establishes standardized approaches for the comprehensive investigation of proteasomes in mammalian brain tissue, and we reveal new insight into brain proteasome biology.

Non-benzodiazepine Hypnotics and Police-Reported Motor Vehicle Crash Risk among Older Adults: A Sequential Target Trial Emulation.

Non-benzodiazepine hypnotics ( "Z-drugs") are prescribed for insomnia, but might increase risk of motor vehicle crash (MVC) among older adults through prolonged drowsiness and delayed reaction times. We estimated the effect of initiating Z-drug treatment on the 12-week risk of MVC in a sequential target trial emulation. After linking New Jersey driver licensing and police-reported MVC data to Medicare claims, we emulated a new target trial each week (July 1, 2007 - October 7, 2017) in which Medicare fee-for-service beneficiaries were classified as Z-drug-treated or untreated at baseline and followed for an MVC. We used inverse probability of treatment and censoring weighted pooled logistic regression models to estimate risk ratios (RR) and risk differences with 95% bootstrap confidence limits (CLs). There were 257,554 person-trials, of which 103,371 were Z-drug-treated and 154,183 untreated, giving rise to 976 and 1,249 MVCs, respectively. The intention-to-treat RR was 1.06 (95%CLs 0.95, 1.16). For the per-protocol estimand, there were 800 MVCs and 1,241 MVCs among treated and untreated person-trials, respectively, suggesting a reduced MVC risk (RR 0.83 [95%CLs 0.74, 0.92]) with sustained Z-drug treatment. Z-drugs should be prescribed to older patients judiciously but not withheld entirely over concerns about MVC risk.

Integrated psychological care services within seizure settings: Key components and implementation factors among example services in four ILAE regions: A report by the ILAE Psychiatry Commission.

Mental health comorbidities are prevalent and problematic in patients with seizures but often suboptimally managed. To address common gaps in care, the Integrated Mental Health Care Pathways Task Force of the International League Against Epilepsy (ILAE) Psychiatry Commission was tasked with providing education and guidance on the integration of mental health management (e.g., screening, referral, treatment) into routine seizure care. This report aims to describe a variety of established services in this area, with a specific focus on psychological care models. Services were identified by members of the ILAE Psychiatry Commission and authors of psychological intervention trials in epilepsy. A total of eight services met inclusion criteria and agreed to be showcased. They include three pediatric and five adult services located across four distinct ILAE regions (Europe, North America, Africa, Asia Oceania). The report describes the core operations, known outcomes, and implementation factors (i.e., barriers and facilitators) of these services. The report concludes with a set of practical tips for building successful psychological care services within seizure settings, including the importance of having local champions, clearly defining the scope of the service, and establishing sustainable funding models. The breadth of exemplars demonstrates how models tailored to the local environment and resources can be implemented. This report is an initial step to disseminate information regarding integrated mental health care within seizure care settings. Future work is needed to systematically examine both psychological and pharmacological care models and to further establish the evidence base in this area, especially around clinical impact, and cost-effectiveness.

Medication self-management in predominantly African American and Caribbean American people with epilepsy: The role of medication beliefs and epilepsy knowledge.

INTRODUCTION: Suboptimal medication adherence is common in people with epilepsy (PWE) and disproportionally prevalent among racially/ethnically diverse patients. Understanding reasons and risks of suboptimal adherence is critical to developing interventions that reduce negative health outcomes. This cross-sectional study characterized common barriers to medication self-management, prevalence of negative medication beliefs, and gaps in epilepsy knowledge among predominantly African American and Caribbean American PWE and examined their interrelationships. MATERIALS AND METHODS: Sixty-three PWE (Age = 42.1 ± 13.2; 60% female; 79% Black; 19% Hispanic/Latino) completed validated self-report questionnaires about medication self-management, medication beliefs, and epilepsy knowledge. Correlations and t-tests examined interrelationships. RESULTS: Four barriers to medication self-management were common, including not taking antiseizure medications at the same time every day, forgetting doses, not planning refills before running out, and spreading out doses when running low. More than half the sample believed medications were overused by prescribers. Nearly one-third believed medications were harmful, and nearly a quarter believed their antiseizure medications were minimally necessary with almost half reporting elevated concerns about negative consequences of antiseizure medications. Poorer medication self-management was associated with stronger beliefs that medications in general are harmful/overused by prescribers. Individuals who were "accepting" of their antiseizure medications (i.e., high perceived necessity, low concerns) were less likely to spread out time between doses when running low compared to non-accepting counterparts. Knowledge gaps related to the cause of seizures/epilepsy, chronicity of epilepsy treatment, and seizure semiology/diagnosis were common. Nevertheless, epilepsy knowledge was unrelated to medication self-management and medication beliefs. CONCLUSIONS: In these PWE, the most prevalent reasons for suboptimal medication self-management were behaviorally mediated and potentially modifiable. Negative medication beliefs and misconceptions about epilepsy and its treatment were common. Results further suggest that interventions addressing negative medication beliefs will be more effective than knowledge-based psychoeducation alone to improve medication self-management in this patient population.

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.

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.

Healthy Lifestyle Behaviors and Viewpoints Among Members of an Alzheimer Prevention Registry.

BACKGROUND: Research on Alzheimer disease and related dementias is increasingly focused on preventative strategies to target modifiable risk factors (eg, exercise, diet, cognitive stimulation) to reduce risk of cognitive decline, though it remains difficult for adults to adopt and maintain these behaviors on their own. METHODS/PARTICIPANTS: In this survey study, we examined knowledge about modifiable risk factors for dementia, engagement in healthy lifestyle behaviors, and associated barriers/facilitators in an Alzheimer disease prevention registry of at-risk, cognitively normal adults (n=135: 77% female; 96% Caucasian and non-Hispanic; mean age=66.1; 79% with family history of dementia; 46% with subjective memory decline). RESULTS: Participants reported high levels of engagement in exercise (mean 3.4 d/wk), a healthy diet (60% with a healthy/balanced diet), and cognitive stimulation (52% engaging in cognitive stimulation 3 to 7 d/wk), and most (56% to 57%) reported moderate to high knowledge about dementia and modifiable risk factors. Family history of dementia was associated with greater knowledge of risk factors for dementia (P=0.017), but not with knowledge of lifestyle recommendations to reduce risk (P=0.85). Most participants (63%) reported a preference for walking/running over other types of aerobic exercise. On average, participants reported that they would be willing to increase healthy lifestyle behaviors to achieve "moderate" risk reduction for dementia (∼21% to 23%, on a scale from 0% to 40%, reflecting mildly to substantially reduced risk). CONCLUSION: Results broaden our understanding of current habits and willingness to engage in healthy lifestyle behaviors, which may inform individualized lifestyle interventions and/or design of prevention trials, particularly among at-risk adults with subjective or mild cognitive concerns, who may be especially motivated and able to engage in lifestyle interventions, to optimize brain health and reduce risk of cognitive decline.

Distance From Home to Motor Vehicle Crash Location: Implications for License Restrictions Among Medically-At-Risk Older Drivers.

In 30 states, licensing agencies can restrict the distance from home that "medically-at-risk" drivers are permitted to drive. However, where older drivers crash relative to their home or how distance to crash varies by medical condition is unknown. Using geocoded crash locations and residential addresses linked to Medicare claims, we describe how the relationship between distance from home to crash varies by driver characteristics. We find that a majority of crashes occur within a few miles from home with little variation across driver demographics or medical conditions. Thus, distance restrictions may not reduce crash rates among older adults, and the tradeoff between safety and mobility warrants consideration.

Amelogenin phosphorylation regulates tooth enamel formation by stabilizing a transient amorphous mineral precursor.

Dental enamel comprises interwoven arrays of extremely long and narrow crystals of carbonated hydroxyapatite called enamel rods. Amelogenin (AMELX) is the predominant extracellular enamel matrix protein and plays an essential role in enamel formation (amelogenesis). Previously, we have demonstrated that full-length AMELX forms higher-order supramolecular assemblies that regulate ordered mineralization in vitro, as observed in enamel rods. Phosphorylation of the sole AMELX phosphorylation site (Ser-16) in vitro greatly enhances its capacity to stabilize amorphous calcium phosphate (ACP), the first mineral phase formed in developing enamel, and prevents apatitic crystal formation. To test our hypothesis that AMELX phosphorylation is critical for amelogenesis, we generated and characterized a hemizygous knockin (KI) mouse model with a phosphorylation-defective Ser-16 to Ala-16 substitution in AMELX. Using EM analysis, we demonstrate that in the absence of phosphorylated AMELX, KI enamel lacks enamel rods, the hallmark component of mammalian enamel, and, unlike WT enamel, appears to be composed of less organized arrays of shorter crystals oriented normal to the dentinoenamel junction. KI enamel also exhibited hypoplasia and numerous surface defects, whereas heterozygous enamel displayed highly variable mosaic structures with both KI and WT features. Importantly, ACP-to-apatitic crystal transformation occurred significantly faster in KI enamel. Secretory KI ameloblasts also lacked Tomes' processes, consistent with the absence of enamel rods, and underwent progressive cell pathology throughout enamel development. In conclusion, AMELX phosphorylation plays critical mechanistic roles in regulating ACP-phase transformation and enamel crystal growth, and in maintaining ameloblast integrity and function during amelogenesis.

Deconstructing Poststroke Delirium in a Prospective Cohort of Patients With Intracerebral Hemorrhage.

OBJECTIVES: Poststroke delirium may be underdiagnosed due to the challenges of disentangling delirium symptoms from underlying neurologic deficits. We aimed to determine the prevalence of individual delirium features and the frequency with which they could not be assessed in patients with intracerebral hemorrhage. DESIGN: Prospective observational cohort study. SETTING: Neurocritical Care and Stroke Units at a university hospital. PATIENTS: Consecutive patients with intracerebral hemorrhage from February 2018 to May 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: An attending neurointensivist performed 257 total daily assessments for delirium on 60 patients (mean age 68.0 [SD 18.4], 62% male, median intracerebral hemorrhage score 1.5 [interquartile range 1-2], delirium prevalence 57% [n = 34]). Each assessment included the Confusion Assessment Method for the ICU, Intensive Care Delirium Screening Checklist, a focused bedside cognitive examination, chart review, and nurse interview. We characterized individual symptom prevalence and established delirium diagnoses using Diagnostic and Statistical Manual of Mental Disorders, fifth edition criteria, then compared performance of the Confusion Assessment Method for the ICU and Intensive Care Delirium Screening Checklist against reference-standard expert diagnosis. Symptom fluctuation (61% of all assessments), psychomotor changes (46%), sleep-wake disturbances (46%), and impaired arousal (37%) had the highest prevalence and were never rated "unable to assess," while inattention (36%), disorientation (27%), and disorganized thinking (18%) were also common but were often rated 'unable to assess' (32%, 43%, and 44% of assessments, respectively), most frequently due to aphasia (32% of patients). Including nonverbal assessments of attention decreased the frequency of 'unable to assess' ratings to 11%. Since the Intensive Care Delirium Screening Checklist may be positive without the presence of symptoms that require verbal assessment, it was more accurate (sensitivity = 77%, specificity = 97%, area under the receiver operating characteristic curve, 0.87) than the Confusion Assessment Method for the ICU (sensitivity = 41%, specificity = 88%, area under the receiver operating characteristic curve, 0.64). CONCLUSIONS: Delirium is common after intracerebral hemorrhage, but severe neurologic deficits may confound its assessment and lead to underdiagnosis. The Intensive Care Delirium Screening Checklist's inclusion of nonverbal features may make it more accurate than the Confusion Assessment Method for the ICU in patients with neurologic deficits, but novel tools designed for such patients may be warranted.

Current recommendations on the selection of measures for well-being.

Measures of well-being have proliferated over the past decades. Very little guidance has been available as to which measures to use in what contexts. This paper provides a series of recommendations, based on the present state of knowledge and the existing measures available, of what measures might be preferred in which contexts. The recommendations came out of an interdisciplinary workshop on the measurement of well-being. The recommendations are shaped around the number of items that can be included in a survey, and also based on the differing potential contexts and purposes of data collection such as, for example, government surveys, or multi-use cohort studies, or studies specifically about psychological well-being. The recommendations are not intended to be definitive, but to stimulate discussion and refinement, and to provide guidance to those relatively new to the study of well-being.

The association between Extraversion and well-being is limited to one facet.

OBJECTIVE: Mõttus argues that effects should not be attributed to traits if they are driven by particular facets or items. We apply this reasoning to investigate the relationship between facets and items of Extraversion and well-being. METHOD: We analyzed five cross-sectional datasets (total N = 1,879), with facet- and item-level correlations and SEM. RESULTS: We found that the correlation between the energy level facet and well-being was solely responsible for the association between Extraversion and well-being. Neither sociability nor assertiveness were uniquely related to well-being when energy level was included as a predictor. Thus, the correlations between well-being and sociability and between well-being and assertiveness can be almost fully explained by these constructs' relationships with energy level. CONCLUSIONS: We conclude that the link between Extraversion and well-being should be attributed to the energy level facet rather than generalized to the trait level.

Anxiety disorders in predominantly African American and Caribbean American adults with intractable epilepsy: The role of perceived epilepsy stigma.

INTRODUCTION: Anxiety disproportionately affects people with epilepsy (PWE) and leads to poor outcomes. Yet, risk factors are not well understood especially among underserved groups. This cross-sectional study aimed to identify epilepsy-specific predictors of anxiety disorders in predominantly African American and Caribbean American PWE. MATERIALS AND METHODS: The prevalence of anxiety disorders was established via diagnostic interview (Mini-International Neuropsychiatric Interview (MINI)). We identified the extent to which aspects of seizure burden (seizure frequency, seizure severity, convulsive vs. nonconvulsive seizures), seizure worry, and perceived epilepsy stigma were associated with anxiety disorder diagnosis. Finally, logistic regression assessed the overall and independent contributions of significant risk factors. RESULTS: There were 60 participants (62% women, 52% African American, 27% Caribbean American, 20% Hispanic/Latino) with an average of 2 seizures per month. Nearly half of the sample (43%) had ≥1 anxiety disorder, with 62% of affected individuals qualifying for agoraphobia. Those with anxiety disorders tended to have convulsive seizures (p = 0.037) and endorsed greater seizure worry (p = 0.012), more general symptoms of anxiety (p = 0.005), and worse perceived epilepsy stigma (p = 0.003). Logistic regression accounted for 28% to 37.6% of the variance in anxiety disorder diagnostic status and correctly classified 73% of cases; however, only perceived epilepsy stigma made a unique contribution. CONCLUSIONS: Anxiety disorders were prevalent in these predominantly African American and Caribbean American PWE. Epilepsy-specific risk factors included convulsive seizures, seizure worry, and perceived epilepsy stigma. Interventions aimed at treating anxiety disorders in diverse PWE may especially benefit from targeting stigma beliefs.

Anticholinergic/sedative drug burden predicts worse memory acquisition in older racially/ethnically diverse patients with type 2 diabetes mellitus.

OBJECTIVE: Anticholinergic/sedative drug use, measured by the Drug Burden Index (DBI), is linked to cognitive impairment in older adults. Yet, studies on the DBI's association with neuropsychological functioning are lacking, especially in underserved groups at increased risk of cognitive impairment. We examined cross-sectional relationships between total DBI (DBIT ) and an age-adjusted analogue (Adj DBIT ) with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) in diverse adults with type 2 diabetes mellitus (T2DM). Based on results of a prior study, we anticipated higher DBIs would be associated with worse memory at older ages. METHODS: One hundred five adults with T2DM (age = 57 ± 9 years, 65% female, 62% Black, 27% Hispanic/Latino, HbA1c = 7.8 ± 1.8) participated. Although memory outcomes were normally distributed, DBIT values were positively skewed. Spearman correlations assessed their bivariate relationships with RBANS. Adjusting for comorbidities, polypharmacy, HbA1c , and education, we tested the moderating effect of age on DBI-RBANS associations at mean ±1 standard deviations of age. RESULTS: One third of the participants endorsed current sedative/anticholinergic use. Mean DBIT was 0.385, and mean Adj DBIT was 0.393 (ranges = 0.00-4.22). Drug burden negatively correlated with RBANS Immediate Memory (DBIT rs = -0.237, P = .013; Adj DBIT rs = -0.239, P = .014) but no other indices. There was a significant DBI*Age interaction; the negative effect of drug burden on Immediate Memory was significant for ages greater than or equal to 55 years old. CONCLUSIONS: Sedative/anticholinergic drug exposure was prevalent in these diverse T2DM patients. Adjusting for covariates, greater drug burden was associated with worse memory acquisition among older adults only. Prospective studies should examine these relationships over time and assess whether dementia biomarkers affect the interaction.

A New Measure of Life Satisfaction: The Riverside Life Satisfaction Scale.

The Satisfaction With Life Scale (Diener, Emmons, Larsen, & Griffin, 1985) has been the dominant measure of life satisfaction since its creation more than 30 years ago. We sought to develop an improved measure that includes indirect indicators of life satisfaction (e.g., wishing to change one's life) to increase the bandwidth of the measure and account for acquiescence bias. In 3 studies, we developed a 6-item measure of life satisfaction, the Riverside Life Satisfaction Scale, and obtained reliability and validity evidence. Importantly, the Riverside Life Satisfaction Scale retained the high internal consistency, test-retest stability, and unidimensionality of the Satisfaction With Life Scale. In addition, the Riverside Life Satisfaction Scale correlated with other well-being measures, Big Five personality traits, values, and demographic information in expected ways. Although the Riverside Life Satisfaction Scale correlated highly with the Satisfaction With Life Scale, we believe it improves the Satisfaction With Life Scale by appropriately increasing construct breadth and reducing the potential for bias.

Perceived epilepsy stigma mediates relationships between personality and social well-being in a diverse epilepsy population.

INTRODUCTION: Perceived epilepsy stigma and reduced social well-being are prevalent sources of distress in people with epilepsy (PWE). Yet, research on patient-level correlates of these difficulties is lacking, especially among underserved groups. MATERIALS AND METHODS: Racially/ethnically diverse adults with intractable seizures (N=60, 62% female; 79% Black, 20% Hispanic/Latino, 8% White) completed validated measures of personality (NEO Five Factor Inventory, NEO-FFI-3), perceived epilepsy stigma (Epilepsy Stigma Scale, ESS), and quality of life (Quality of Life Inventory in Epilepsy, QOLIE-89). Controlling for covariates, ordinary least-squares (OLS) regression evaluated the total, direct, and indirect effects of NEO-FFI-3 neuroticism and extraversion scores on epilepsy-related social well-being (i.e., combination of QOLIE-89 social isolation and work/driving/social function subscales, α=0.87), mediated through perceived stigma. RESULTS: In separate models, higher levels of neuroticism (N) and lower levels of extraversion (E) were significantly and independently associated with greater perceived stigma (N path a=0.71, p=0.005; E path a=-1.10, p<0.005). Stigma, in turn, was significantly and independently associated with poorer social well-being (N path b=0.23, p<0.001; E path b=-0.23, p<0.001). Bias-corrected bootstrap confidence intervals (CIs) showed that neuroticism and extraversion were indirectly associated with social well-being through their respective associations with perceived stigma (N path ab=-0.16, 95% CIs [-0.347, -0.044]; E path ab=0.25, 95% CIs [0.076, 0.493]). CONCLUSION: Higher neuroticism and lower extraversion covaried with stigma beliefs, and these may be markers of poor social outcomes in PWE. Mediation models suggest that targeting epilepsy stigma beliefs may be a particularly useful component to incorporate when developing interventions aimed at promoting social well-being in diverse PWE.