Cognition in older age bipolar disorder: An analysis of archival data across the globe.

BACKGROUND: Cognitive deficits in bipolar disorder (BD) impact functioning and are main contributors to disability in older age BD (OABD). We investigated the difference between OABD and age-comparable healthy comparison (HC) participants and, among those with BD, the associations between age, global cognitive performance, symptom severity and functioning using a large, cross-sectional, archival dataset harmonized from 7 international OABD studies. METHODS: Data from the Global Aging and Geriatric Experiments in Bipolar Disorder (GAGE-BD) database, spanning various standardized measures of cognition, functioning and clinical characteristics, were analyzed. The sample included 662 euthymic to mildly symptomatic participants aged minimum 50years (509 BD, 153 HC), able to undergo extensive cognitive testing. Linear mixed models estimated associations between diagnosis and global cognitive performance (g-score, harmonized across studies), and within OABD between g-score and severity of mania and depressive symptoms, duration of illness and lithium use and of global functioning. RESULTS: After adjustment for study cohort, age, gender and employment status, there was no significant difference in g-score between OABD and HC, while a significant interaction emerged between employment status and diagnostic group (better global cognition associated with working) in BD. Within OABD, better g-scores were associated with fewer manic symptoms, higher education and better functioning. LIMITATIONS: Cross-sectional design and loss of granularity due to harmonization. CONCLUSION: More research is needed to understand heterogenous longitudinal patterns of cognitive change in BD and understand whether particular cognitive domains might be affected in OABD in order to develop new therapeutic efforts for cognitive dysfunction OABD.

Bipolar symptoms, somatic burden and functioning in older-age bipolar disorder: A replication study from the global aging & geriatric experiments in bipolar disorder database (GAGE-BD) project.

OBJECTIVES: The Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD) project pools archival datasets on older age bipolar disorder (OABD). An initial Wave 1 (W1; n = 1369) analysis found both manic and depressive symptoms reduced among older patients. To replicate this finding, we gathered an independent Wave 2 (W2; n = 1232, mean ± standard deviation age 47.2 ± 13.5, 65% women, 49% aged over 50) dataset. DESIGN/METHODS: Using mixed models with random effects for cohort, we examined associations between BD symptoms, somatic burden and age and the contribution of these to functioning in W2 and the combined W1 + W2 sample (n = 2601). RESULTS: Compared to W1, the W2 sample was younger (p < 0.001), less educated (p < 0.001), more symptomatic (p < 0.001), lower functioning (p < 0.001) and had fewer somatic conditions (p < 0.001). In the full W2, older individuals had reduced manic symptom severity, but age was not associated with depression severity. Age was not associated with functioning in W2. More severe BD symptoms (mania p ≤ 0.001, depression p ≤ 0.001) were associated with worse functioning. Older age was significantly associated with higher somatic burden in the W2 and the W1 + W2 samples, but this burden was not associated with poorer functioning. CONCLUSIONS: In a large, independent sample, older age was associated with less severe mania and more somatic burden (consistent with previous findings), but there was no association of depression with age (different from previous findings). Similar to previous findings, worse BD symptom severity was associated with worse functioning, emphasizing the need for symptom relief in OABD to promote better functioning.

Sociodemographic and clinical characteristics of people with oldest older age bipolar disorder in a global sample: Results from the global aging and geriatric experiments in bipolar disorder project.

OBJECTS: Studies of older age bipolar disorder (OABD) have mostly focused on "younger old" individuals. Little is known about the oldest OABD (OOABD) individuals aged ≥70 years old. The Global Aging and Geriatric Experiments in Bipolar Disorder (GAGE-BD) project provides an opportunity to evaluate the OOABD group to understand their characteristics compared to younger groups. METHODS: We conducted cross-sectional analyses of the GAGE-BD database, an integrated, harmonized dataset from 19 international studies. We compared the sociodemographic and clinical characteristics of those aged <50 (YABD, n = 184), 50-69 (OABD, n = 881), and ≥70 (OOABD, n = 304). To standardize the comparisons between age categories and all characteristics, we used multinomial logistic regression models with age category as the dependent variable, with each characteristic as the independent variable, and clustering of standard errors to account for the correlation between observations from each of the studies. RESULTS: OOABD and OABD had lower severity of manic symptoms (Mean YMRS = 3.3, 3.8 respectively) than YABD (YMRS = 7.6), and lower depressive symptoms (% of absent = 65.4%, and 59.5% respectively) than YABD (18.3%). OOABD and OABD had higher physical burden than YABD, especially in the cardiovascular domain (prevalence = 65% in OOABD, 41% in OABD and 17% in YABD); OOABD had the highest prevalence (56%) in the musculoskeletal domain (significantly differed from 39% in OABD and 31% in YABD which didn't differ from each other). Overall, OOABD had significant cumulative physical burden in numbers of domains (mean = 4) compared to both OABD (mean = 2) and YABD (mean = 1). OOABD had the lowest rates of suicidal thoughts (10%), which significantly differed from YABD (26%) though didn't differ from OABD (21%). Functional status was higher in both OOABD (GAF = 63) and OABD (GAF = 64), though only OABD had significantly higher function than YABD (GAF = 59). CONCLUSIONS: OOABD have unique features, suggesting that (1) OOABD individuals may be easier to manage psychiatrically, but require more attention to comorbid physical conditions; (2) OOABD is a survivor cohort associated with resilience despite high medical burden, warranting both qualitative and quantitative methods to better understand how to advance clinical care and ways to age successfully with BD.

Sex Differences Among Older Adults With Bipolar Disorder: Results From the Global Aging & Geriatric Experiments in Bipolar Disorder (GAGE-BD) Project.

OBJECTIVE: Sex-specific research in adult bipolar disorder (BD) is sparse and even more so among those with older age bipolar disorder (OABD). Knowledge about sex differences across the bipolar lifespan is urgently needed to target and improve treatment. To address this gap, the current study examined sex differences in the domains of clinical presentation, general functioning, and mood symptoms among individuals with OABD. METHODS: This Global Aging & Geriatric Experiments in Bipolar Disorder (GAGE-BD) study used data from 19 international studies including BD patients aged ≥50 years (N = 1,185: 645 women, 540 men).A comparison of mood symptoms between women and men was conducted initially using two-tailed t tests and then accounting for systematic differences between the contributing cohorts by performing generalized linear mixed models (GLMMs). Associations between sex and other clinical characteristics were examined using GLMM including: age, BD subtype, rapid cycling, psychiatric hospitalization, lifetime psychiatric comorbidity, and physical health comorbidity, with study cohort as a random intercept. RESULTS: Regarding depressive mood symptoms, women had higher scores on anxiety and hypochondriasis items. Female sex was associated with more psychiatric hospitalizations and male sex with lifetime substance abuse disorders. CONCLUSION: Our findings show important clinical sex differences and provide support that older age women experience a more severe course of BD, with higher rates of psychiatric hospitalization. The reasons for this may be biological, psychological, or social. These differences as well as underlying mechanisms should be a focus for healthcare professionals and need to be studied further.

Demographic and clinical associations to employment status in older-age bipolar disorder: Analysis from the GAGE-BD database project.

OBJECTIVE: The current literature on employment in older adults with bipolar disorder (OABD) is limited. Using the Global Aging and Geriatric Experiments in Bipolar Disorder Database (GAGE-BD), we examined the relationship of occupational status in OABD to other demographic and clinical characteristics. METHODS: Seven hundred and thirty-eight participants from 11 international samples with data on educational level and occupational status were included. Employment status was dichotomized as employed versus unemployed. Generalized linear mixed models with random intercepts for the study cohort were used to examine the relationship between baseline characteristics and employment. Predictors in the models included baseline demographics, education, psychiatric symptom severity, psychiatric comorbidity, somatic comorbidity, and prior psychiatric hospitalizations. RESULTS: In the sample, 23.6% (n = 174) were employed, while 76.4% were unemployed (n = 564). In multivariable logistic regression models, less education, older age, a history of both anxiety and substance/alcohol use disorders, more prior psychiatric hospitalizations, and higher levels of BD depression severity were associated with greater odds of unemployment. In the subsample of individuals less than 65 years of age, findings were similar. No significant association between manic symptoms, gender, age of onset, or employment status was observed. CONCLUSION: Results suggest an association between educational level, age, psychiatric severity and comorbidity in relation to employment in OABD. Implications include the need for management of psychiatric symptoms and comorbidity across the lifespan, as well as improving educational access for people with BD and skills training or other support for those with work-life breaks to re-enter employment and optimize the overall outcome.

Bipolar I and bipolar II subtypes in older age: Results from the Global Aging and Geriatric Experiments in Bipolar Disorder (GAGE-BD) project.

OBJECTIVES: The distinction between bipolar I disorder (BD-I) and bipolar II disorder (BD-II) has been a topic of long-lasting debate. This study examined differences between BD-I and BD-II in a large, global sample of OABD, focusing on general functioning, cognition and somatic burden as these domains are often affected in OABD. METHODS: Cross-sectional analyses were conducted with data from the Global Aging and Geriatric Experiments in Bipolar Disorder (GAGE-BD) database. The sample included 963 participants aged ≥50 years (714 BD-I, 249 BD-II). Sociodemographic and clinical factors were compared between BD subtypes including adjustment for study cohort. Multivariable analyses were conducted with generalized linear mixed models (GLMMs) and estimated associations between BD subtype and (1) general functioning (GAF), (2) cognitive performance (g-score) and (3) somatic burden, with study cohort as random intercept. RESULTS: After adjustment for study cohort, BD-II patients more often had a late onset ≥50 years (p = 0.008) and more current severe depression (p = 0.041). BD-I patients were more likely to have a history of psychiatric hospitalization (p < 0.001) and current use of anti-psychotics (p = 0.003). Multivariable analyses showed that BD subtype was not related to GAF, cognitive g-score or somatic burden. CONCLUSION: BD-I and BD-II patients did not differ in terms of general functioning, cognitive impairment or somatic burden. Some clinical differences were observed between the groups, which could be the consequence of diagnostic definitions. The distinction between BD-I and BD-II is not the best way to subtype OABD patients. Future research should investigate other disease specifiers in this population.

Clinical correlates of late-onset versus early-onset bipolar disorder in a global sample of older adults.

OBJECTIVES: Late-onset bipolar disorder (LOBD) represents a significant subgroup of bipolar disorder (BD). However, knowledge for this group is mostly extrapolated from small studies in subjects with early/mixed age of illness onset. In this global sample of older adults with BD (OABD: ≥50 years old) we aim to characterize the sociodemographic and clinical presentation of LOBD (≥40 years at BD onset) compared to early-onset BD (EOBD: <40 years at BD onset). METHODS: The Global Aging and Geriatric Experiments in Bipolar Disorder consortium provided international data on 437 older age bipolar disorder participants. We compared LOBD versus EOBD on depression, mania, functionality, and physical comorbidities. Exploratory analyses were performed on participants with BD onset ≥50 years old. RESULTS: LOBD (n = 105) did not differ from EOBD (n = 332) on depression, mania, global functioning, nor employment status (p > 0.05). Late-onset bipolar disorder was associated with higher endocrine comorbidities (odds ratio = 1.48, [95%CI = 1.0,12.1], p = 0.03). This difference did not remain significant when subjects with BD onset ≥50 years old were analyzed. LIMITATIONS: This study is limited by the retrospective nature of the variable age of onset and the differences in evaluation methods across studies (partially overcame by harmonization processes). CONCLUSION: The present analysis is in favor of the hypothesis that LOBD might represent a similar clinical phenotype as classic EOBD with respect to core BD symptomatology, functionality, and comorbid physical conditions. Large-scale global collaboration to improve our understanding of BD across the lifespan is needed.

Mobile survey engagement by older adults is high during multiple phases of the COVID-19 pandemic and is predicted by baseline and structural factors.

Digital surveys, such as mobile phone ecological momentary assessment (EMA), bear the potential to assess and target individual wellbeing in a personalized, real-time approach and allow for interaction in situations when in-person contact is not possible, such as during the coronavirus pandemic. While the use of digital technology might especially benefit research in older adults who find themselves in circumstances of reduced mobility, little is known about their barriers to adherence. We investigated baseline and structural factors that predict study withdrawal and adherence from daily smartphone EMA self-report surveys in the StayWELL Study. The StayWELL study is a longitudinal, observational study on the relationship between social restrictions during the coronavirus pandemic and mental well-being in 95 community-dwelling older aged adults (67-87 years) who were participants in a randomized clinical trial using EMA. Withdrawal was associated with less research staff changes and less likely in participants that reached the study mid-point. No baseline characteristics predicted withdrawal. Main reasons for withdrawal were communication issues, i.e. staff not being able to contact participants. We found an adherence rate of 82% and no fatigue effects. Adherence was predicted by education status, study participation duration, reaching the study midpoint and time between study start and enrollment. COVID infections or supporting people in the household was not related to adherence. To conclude, it is feasible to conduct an EMA study in older people without impacting engagement during a pandemic. Furthermore, personal characteristics and smartphone operating system (Android vs. iOS) used did not relate to engagement, allowing for a broad distribution of digital health technologies. Our study adds information on single predictive variables relevant for adherence and withdrawal from EMA smartphone surveys in older people that can inform the design of future digital EMA research to maximize engagement and reliability of study results.

Peripheral inflammation levels associated with degree of advanced brain aging in schizophrenia.

Brain structural abnormalities have been demonstrated in schizophrenia (SZ); these resemble those seen in typical aging, but are seen at younger ages. Furthermore, SZ is associated with accelerated global brain aging, as measured by brain structure-based brain predicted age difference (Brain-PAD). High heterogeneity exists in the degree of brain abnormalities in SZ, and individual differences may be related to levels of peripheral inflammation and may relate to cognitive deficits and negative symptoms. The goal of our study was to investigate the relationship between brain aging, peripheral inflammation, and symptoms of SZ. We hypothesized older brain-PAD in SZ vs. healthy comparison (HC) participants, as well as positive relationships of brain-PAD with peripheral inflammation markers and symptoms in SZ. We analyzed data from two cross-sectional studies in SZ (n = 26; M/F: 21/5) and HC (n = 28; 20/8) (22-64 years). Brain-PAD was calculated using a previously validated Gaussian process regression model applied to raw T1-weighted MRI data. Plasma levels of inflammatory biomarkers (CRP, Eotaxin, Fractalkine, IP10, IL6, IL10, ICAM1, IFNγ, MCP1, MIP1ß, SAA, TNFα, VEGF, VCAM1) and cognitive and negative symptoms were assessed. We observed a higher brain-PAD in SZ vs. HC, and advanced brain age relative to chronological age was related to higher peripheral levels of TNFα in the overall group and in the SZ group; other inflammatory markers were not related to brain-PAD. Within the SZ group, we observed no association between cognitive or negative symptoms and brain-PAD. These results support our hypothesis of advanced brain aging in SZ. Furthermore, our findings on the relationship of the pro-inflammatory cytokine TNFα with higher brain-PAD of SZ are relevant to explain heterogeneity of brain ages in SZ, but we did not find strong evidence for cognitive or negative symptom relationships with brain-PAD.

Comparing continuous and harmonized measures of depression severity in older adults with bipolar disorder: Relationship to functioning.

OBJECTIVE: Harmonizing different depression severity scales often requires creation of categorical variables that may decrease the sensitivity of the measure. Our aim was to compare the associations between categorical and continuous and harmonized measures of depression and global functioning in a large dataset of older age patients with bipolar disorder (OABD). METHOD: In the Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD) the 17-item Hamilton Depression scale (HAM-D), Montgomery Asberg Depression Rating Scale (MADRS) or the Center for Epidemiological Studies Depression scales (CES-D) was used to assess current depressive symptoms, while the Global Assessment of Functioning (GAF) assessed functional status. Data were harmonized from 8 OABD studies (n = 582). In each subsample, the relationship of depression severity as a continuous and categorical measure was compared to GAF. In the total sample, harmonized ordinal depression categories were compared to GAF. RESULTS: Effect size and variance explained by the model for the categorical measure in the total sample was higher than both the categorical and continuous measure in the CES-D subsample, higher than the categorical but lower than the continuous measure in the HAM-D subsample, and lower than both the categorical and continuous measures in the MADRS subsample. LIMITATIONS: All included studies have different inclusion and exclusion criteria, study designs, and differ in aspects of sociodemographic variables. CONCLUSIONS: Associations were only slightly larger for the continuous vs categorical measures of depression scales. Harmonizing different depression scales into ordinal categories for analyses is feasible without losing statistical power.

Demographic and clinical characteristics of lithium-treated older adults with bipolar disorder.

OBJECTIVES: There is limited information on the characteristics of older adults with bipolar disorder (OABD) treated with lithium, along with safety concerns about its use by older adults. The aim of the present study is to describe the demographic and clinical characteristics of OABD receiving lithium therapy, using data from the Global Ageing & Geriatric Experiments in Bipolar Disorder (GAGE-BD). EXPERIMENTAL PROCEDURES: Cross-sectional analysis of the GAGE-BD dataset to determine differences and similarities between lithium users and non-users. We analysed data from 986 participants aged 50 years or older (mean age 63.5 years; 57.5% females) from 12 study sites. Two subgroups ('Lithium'; 'Non-lithium') were defined according to the current prescription of lithium. We compared several outcomes between these groups, controlling for age, gender, and study site. RESULTS: OABD treated with lithium had lower scores on depression rating scales and were less likely to be categorised as with moderate or severe depression. There was a lower proportion of lithium users than non-users among those with evidence of rapid cycling and non-bipolar psychiatric diagnoses. Assessment of global cognitive state and functionality indicated better performance among lithium users. The current use of antipsychotics was less frequent among lithium users, who also reported fewer cardiovascular comorbidities than non-users. CONCLUSION: We found several potentially relevant differences in the clinical profile of OABD treated with lithium compared with those treated with other mood stabilisers. However, the interpretation of the present results must take into account the methodological limitations inherent to the cross-sectional approach and data harmonisation.

Demographic and Clinical Characteristics of Antipsychotic Drug-Treated Older Adults with Bipolar Disorder from the Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD).

Objectives: Antipsychotic drugs (APS) are widely used to treat patients with bipolar disorder (BD), but there is limited information in older-age bipolar disorder (OABD). This analysis of the Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD) investigated characteristics of OABD patients prescribed APS vs. those not prescribed APS. Experimental Design: The observational analysis used baseline, cross-sectional data from 16 international studies for adults aged ≥ 50 years with BD comprising 1,007 individuals with mean age 63.2 years (SD = 9.0), 57.4% women, and mean age of onset 31.6 years (SD = 15.0). The dependent variable was current APS treatment status. The independent variables included demographic and clinical variables, and a random effect for study, that were included in generalized mixed models. Principal Observations: 46.6% of individuals (n = 469) were using APS. The multivariate model results suggest that those treated with APS were younger (p = 0.01), less likely to be employed (p < 0.001), had more psychiatric hospitalizations (p = 0.009) and were less likely to be on lithium (p < 0.001). Of individuals on APS, only 6.6% of those (n = 27) were on first-generation antipsychotics (FGAs) and experienced a greater burden of psychiatric hospitalizations (p = 0.012). Conclusions: APS are widely prescribed in OABD, observed in nearly half of this sample with great variation across sites. Individuals with OABD on APS have more severe illness, more frequent hospitalizations and are more often unemployed vs. those not on APS. Future studies need to examine longitudinal outcomes in OABD prescribed APS to characterize underlying causal relationships.

Symptom Severity Mixity in Older-Age Bipolar Disorder: Analyses From the Global Aging and Geriatric Experiments in Bipolar Disorder Database (GAGE-BD).

OBJECTIVE: Some individuals with bipolar disorder (BD) experience manic and depressive symptoms concurrently, but data are limited on symptom mixity in older age bipolar disorder (OABD). Using the Global Aging & Geriatric Experiments in Bipolar Disorder Database, we characterized mixity in OABD and associations with everyday function. METHODS: The sample (n = 805), from 12 international studies, included cases with both mania and depression severity ratings at a single timepoint. Four mixity groups were created: asymptomatic (A), mixed (Mix), depressed only (Dep), and manic only (Man). Generalized linear mixed models used mixity group as the predictor variable; cohort was included as a random intercept. Everyday function was assessed with the Global Assessment of Functioning score. RESULTS: Group proportions were Mix (69.6%; n = 560), followed by Dep (18.4%; n = 148), then A (7.8%; n = 63), then Man (4.2%; n= 34); levels of depression and mania were similar in Mix compared to Dep and Man, respectively. Everyday function was lowest in Mix, highest in A, and intermediate in Man and Dep. Within Mix, severity of depression was the main driver of worse functioning. Groups differed in years of education, with A higher than all others, but did not differ by age, gender, employment status, BD subtype, or age of onset. CONCLUSIONS: Mixed features predominate in a cross-sectional, global OABD sample and are associated with worse everyday function. Among those with mixed symptoms, functional status relates strongly to current depression severity. Future studies should include cognitive and other biological variables as well as longitudinal designs to allow for evaluation of causal effects.

Physical Health Burden Among Older Men and Women With Bipolar Disorder: Results From the Gage-Bd Collaboration.

OBJECTIVES: To compare the prevalence of physical morbidities among men and women with older adult bipolar disorder (OABD), and men with and without OABD. METHODS: Cross-sectional analysis of the collaborative Global Aging & Geriatric Experiments in Bipolar Disorder (GAGE-BD) database and non-OABD data from the Health in Men Study. OABD defined as bipolar disorder among adults aged greater than or equal to 50 years. Outcomes of interest were diseases affecting the cardiovascular, respiratory, gastrointestinal, renal, musculoskeletal and endocrinological systems. RESULTS: We examined 1407 participants with OABD aged 50-95 years, of whom 787 were women. More women than men showed evidence of morbidities affecting the respiratory, gastrointestinal, musculoskeletal and endocrinological systems. More men with than without OABD showed evidence of cardiovascular, renal and endocrinological diseases. CONCLUSION: GAGE-BD data showed that physical morbidities affect more women than men with OABD, and more men with than without OABD. The underlying reasons for these differences require clarification.

Bipolar symptoms, somatic burden, and functioning in older-age bipolar disorder: Analyses from the Global Aging & Geriatric Experiments in Bipolar Disorder Database project.

OBJECTIVE: Literature on older-age bipolar disorder (OABD) is limited. This first-ever analysis of the Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD) investigated associations among age, BD symptoms, comorbidity, and functioning. METHODS: This analysis used harmonized, baseline, cross-sectional data from 19 international studies (N = 1377). Standardized measures included the Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), and Global Assessment of Functioning (GAF). RESULTS: Mean sample age was 60.8 years (standard deviation [SD] 12.2 years), 55% female, 72% BD I. Mood symptom severity was low: mean total YMRS score of 4.3 (SD 5.4) and moderate-to-severe depression in only 22%. Controlled for sample effects, both manic and depressive symptom severity appeared lower among older individuals (p's < 0.0001). The negative relationship between older age and symptom severity was similar across sexes, but was stronger among those with lower education levels. GAF was mildly impaired (mean =62.0, SD = 13.3) and somatic burden was high (mean =2.42, SD = 1.97). Comorbidity burden was not associated with GAF. However, higher depressive (p < 0.0001) and manic (p < 0.0001) symptoms were associated with lower GAF, most strongly among older individuals. CONCLUSIONS: Findings suggest an attenuation of BD symptoms in OABD, despite extensive somatic burden. Depressive symptom severity was strongly associated with worse functioning in older individuals, underscoring the need for effective treatments of BD depression in older people. This international collaboration lays a path for the development of a better understanding of aging in BD.

Correlates of poor sleep based upon wrist actigraphy data in bipolar disorder.

BACKGROUND: Wrist-worn actigraphy can objectively measure sleep, and has advantages over self-report, particularly for people with Bipolar Disorder (BD) for whom self-reports might be influenced by affect. Clinically useful data reduction approaches are needed to explore these complex data. METHODS: We created a composite score of sleep metrics in BD based on 51 BD and 80 healthy comparison (HC) participants. Subjects wore an actigraph for up to 14 consecutive 24-h periods, and we assessed total sleep time (TST), wake after sleep onset (WASO), percent sleep (PS), and number of awakenings (NA). We focused on participants who had at least 5 nights of actigraphy data. We computed z-scores for within-person means of sleep measures for BD subjects versus HCs, which were averaged to create a composite measure. We correlated this composite with participant characteristics, and used LASSO regression to identify sleep measures best explaining variability in identified correlates. RESULTS: Sleep measures and the composite did not differ between BDs and HCs; however, there was considerable variability in z-scores among those with BD. In BDs, the composite score was higher in women (t(49) = 2.28, p = 0.027) and those who were employed (t(34) = 2.34, p = 0.025), and positively correlated with medication load (r = 0.41, p = 0.003) while negatively correlated with Young Mania Rating Scale (YMRS; r = -0.35, p = 0.030). In LASSO regression, TST and NA best explained medication load while PS best explained employment and YMRS. CONCLUSION: While a composite score of sleep metrics may provide useful information about sleep quality globally, our findings suggest that selection of theory-driven sleep measures may be more clinically meaningful.

Modular Chimeric Antigen Receptor Systems for Universal CAR T Cell Retargeting.

The engineering of T cells through expression of chimeric antigen receptors (CARs) against tumor-associated antigens (TAAs) has shown significant potential for use as an anti-cancer therapeutic. The development of strategies for flexible and modular CAR T systems is accelerating, allowing for multiple antigen targeting, precise programming, and adaptable solutions in the field of cellular immunotherapy. Moving beyond the fixed antigen specificity of traditional CAR T systems, the modular CAR T technology splits the T cell signaling domains and the targeting elements through use of a switch molecule. The activity of CAR T cells depends on the presence of the switch, offering dose-titratable response and precise control over CAR T cells. In this review, we summarize developments in universal or modular CAR T strategies that expand on current CAR T systems and open the door for more customizable T cell activity.

Next-generation sequencing-guided identification and reconstruction of antibody CDR combinations from phage selection outputs.

Next-generation sequencing (NGS) technologies have been employed in several phage display platforms for analyzing natural and synthetic antibody sequences and for identifying and reconstructing single-chain variable fragments (scFv) and antigen-binding fragments (Fab) not found by conventional ELISA screens. In this work, we developed an NGS-assisted antibody discovery platform by integrating phage-displayed, single-framework, synthetic Fab libraries. Due to limitations in attainable read and amplicon lengths, NGS analysis of Fab libraries and selection outputs is usually restricted to either VH or VL. Since this information alone is not sufficient for high-throughput reconstruction of Fabs, we developed a rapid and simple method for linking and sequencing all diversified CDRs in phage Fab pools. Our method resulted in a reliable and straightforward platform for converting NGS information into Fab clones. We used our NGS-assisted Fab reconstruction method to recover low-frequency rare clones from phage selection outputs. While previous studies chose rare clones for rescue based on their relative frequencies in sequencing outputs, we chose rare clones for reconstruction from less-frequent CDRH3 lengths. In some cases, reconstructed rare clones (frequency ∼0.1%) showed higher affinity and better specificity than high-frequency top clones identified by Sanger sequencing, highlighting the significance of NGS-based approaches in synthetic antibody discovery.