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Risky decision-making is a common, heritable endophenotype seen across many psychiatric disorders. Its underlying genetic architecture is incompletely explored. We examined behavior in the Balloon Analogue Risk Task (BART), which tests risky decision-making, in two independent samples of European ancestry. One sample (n = 1138) comprised healthy participants and some psychiatric patients (53 schizophrenia, 42 bipolar disorder, 47 ADHD); the other (n = 911) excluded for recent treatment of various psychiatric disorders but not ADHD. Participants provided DNA and performed the BART, indexed by mean adjusted pumps. We constructed a polygenic risk score (PRS) for discovery in each dataset and tested it in the other as replication. Subsequently, a genome-wide MEGA-analysis, combining both samples, tested genetic correlation with risk-taking self-report in the UK Biobank sample and psychiatric phenotypes characterized by risk-taking (ADHD, Bipolar Disorder, Alcohol Use Disorder, prior cannabis use) in the Psychiatric Genomics Consortium. The PRS for BART performance in one dataset predicted task performance in the replication sample (r = 0.13, p = 0.000012, pFDR = 0.000052), as did the reciprocal analysis (r = 0.09, p = 0.0083, pFDR=0.04). Excluding participants with psychiatric diagnoses produced similar results. The MEGA-GWAS identified a single SNP (rs12023073; p = 3.24 × 10-8) near IGSF21, a protein involved in inhibitory brain synapses; replication samples are needed to validate this result. A PRS for self-reported cannabis use (p = 0.00047, pFDR = 0.0053), but not self-reported risk-taking or psychiatric disorder status, predicted behavior on the BART in our MEGA-GWAS sample. The findings reveal polygenic architecture of risky decision-making as measured by the BART and highlight its overlap with cannabis use.

Background: Although many endophenotypes for schizophrenia have been studied individually, few studies have examined the extent to which common neurocognitive and neurophysiological measures reflect shared versus unique endophenotypic factors. It may be possible to distill individual endophenotypes into composite measures that reflect dissociable, genetically informative elements. Methods: The first phase of the Consortium on the Genetics of Schizophrenia (COGS-1) is a multisite family study that collected neurocognitive and neurophysiological data between 2003 and 2008. For these analyses, participants included schizophrenia probands (n=. 83), their nonpsychotic siblings (n=. 151), and community comparison subjects (n=. 209) with complete data on a battery of 12 neurocognitive tests (assessing domains of working memory, declarative memory, vigilance, spatial ability, abstract reasoning, facial emotion processing, and motor speed) and 3 neurophysiological tasks reflecting inhibitory processing (P50 gating, prepulse inhibition and antisaccade tasks). Factor analyses were conducted on the measures for each subject group and across the entire sample. Heritability analyses of factors were performed using SOLAR. Results: Analyses yielded 5 distinct factors: 1) Episodic Memory, 2) Working Memory, 3) Perceptual Vigilance, 4) Visual Abstraction, and 5) Inhibitory Processing. Neurophysiological measures had low associations with these factors. The factor structure of endophenotypes was largely comparable across probands, siblings and controls. Significant heritability estimates for the factors ranged from 22% (Episodic Memory) to 39% (Visual Abstraction). Conclusions: Neurocognitive measures reflect a meaningful amount of shared variance whereas the neurophysiological measures reflect largely unique contributions as endophenotypes for schizophrenia. Composite endophenotype measures may inform our neurobiological and genetic understanding of schizophrenia.

We investigated the predictive power of morphological features in 224 autistic patients and 224 matched-pairs controls. To assess the relationship between the morphological features and autism, we used the receiver operator curves (ROC). In addition, we used recursive partitioning (RP) to determine a specific pattern of abnormalities that is characteristic for the difference between autistic children and typically developing controls. The present findings showed that morphological features are significantly increased in patients with autism. Using ROC and RP, some of the morphological measures also led to strong predictive accuracy. Facial asymmetry, multiple hair whorls and prominent forehead significantly differentiated patients with autism from controls. Future research on multivariable risk prediction models may benefit from the use of morphological features. (Contains 2 figures.)

Background: The increased use of the MATRICS Consensus Cognitive Battery (MCCB) to investigate cognitive dysfunctions in schizophrenia fostered interest in its sensitivity in the context of family studies. As various measures of the same cognitive domains may have different power to distinguish between unaffected relatives of patients and controls, the relative sensitivity of MCCB tests for relative–control differences has to be established. We compared MCCB scores of 852 outpatients with schizophrenia (SCZ) with those of 342 unaffected relatives (REL) and a normative Italian sample of 774 healthy subjects (HCS). We examined familial aggregation of cognitive impairment by investigating within-family prediction of MCCB scores based on probands’ scores. Methods: Multivariate analysis of variance was used to analyze group differences in adjusted MCCB scores. Weighted least-squares analysis was used to investigate whether probands’ MCCB scores predicted REL neurocognitive performance. Results: SCZ were significantly impaired on all MCCB domains. REL had intermediate scores between SCZ and HCS, showing a similar pattern of impairment, except for social cognition. Proband's scores significantly predicted REL MCCB scores on all domains except for visual learning. Conclusions: In a large sample of stable patients with schizophrenia, living in the community, and in their unaffected relatives, MCCB demonstrated sensitivity to cognitive deficits in both groups. Our findings of significant within-family prediction of MCCB scores might reflect disease-related genetic or environmental factors. [ABSTRACT FROM AUTHOR]

A correction to the article "Latent structure of cognition in schizophrenia: a confirmatory factor analysis of the MATRICS Consensus Cognitive Battery (MCCB)" is presented.

Background Although many studies have assessed cognitive functioning in first-episode schizophrenia (FESz), the pattern and severity of impairment across cognitive domains remain unclear. Moreover, few studies have directly compared the pattern of cognitive performance between FESz and chronic schizophrenia (CSz). In this study we examined the cognitive impairment profile in FESz using a standardized neurocognitive battery (MATRICS Consensus Cognitive Battery; MCCB). Methods MCCB data were compared from 105 FESz patients, 176 CSz patients and 300 non-psychiatric (NP) participants. Mixed model analysis evaluated group differences in MCCB profiles and relative strengths and weaknesses in the MCCB profiles of patients. Clinical implications of MCCB performance were also examined; we compared the proportion of participants from each group who exhibited clinically-significant global cognitive impairment based on the MCCB Overall Composite score. Results FESz and CSz showed impaired performance across all MCCB domains relative to NP. With the exception of relative preservation of working memory and social cognition in FESz, the MCCB domain scores were similar in FESz and CSz. The distribution of impairment on the Overall Composite score did not significantly differ between FESz and CSz; compared to NP, both patient groups were overrepresented in moderate and severe impairment categories. Conclusion The pattern, magnitude, and distribution of severity of impairment in FESz were similar to that observed in CSz. However, early in the illness, there may be relative sparing of working memory and social cognition. [ABSTRACT FROM AUTHOR]

Objective: This study examines the potential role of candidate genes in moderating treatment effects of methylphenidate (MPH) in attention-deficit/hyperactivity disorder (ADHD).Method: Eighty-two subjects with ADHD aged 6 to 17 years participated in a prospective, double-blind, placebo-controlled, multiple-dose, crossover titration trial of immediate release MPH three times daily. The subjects were assessed on a variety of parent and clinician ratings and a laboratory math test. Data reduction based on principal components analysis identified statistically derived efficacy and side effect outcomes.Results: Attention-deficit/hyperactivity disorder symptom response was predicted by polymorphisms at the serotonin transporter (SLC6A4) intron 2 VNTR (p = .01), with a suggested trend for catechol-O-methyltransferase (COMT) (p = .04). Gene × dose interactions were noted on math test outcomes for the dopamine D4 receptor (DRD4) promoter (p = .008), DRD4 exon 3 VNTR (p = .006), and SLC6A4 promoter insertion/deletion polymorphism (5HTTLPR) (p = .02). Irritability was predicted by COMT (p = .02). Vegetative symptoms were predicted by 5HTTLPR (p = .003). No significant effects were noted for the dopamine transporter (SLC6A3) or synaptosomal-associated protein 25 (SNAP25).Conclusions: This article confirms and expands previous studies suggesting that genes moderate ADHD treatment response. The ADHD outcomes are not unitary but reflect both behavioral and learning domains that are likely influenced by different genes. Future research should emphasize candidate gene and genome-wide association studies in larger samples, symptom reduction as well as side effects outcomes, and responses over full therapeutic dose ranges to assess differences in both gene and gene × dose interactive effects. [ABSTRACT FROM AUTHOR]

Background: A core feature of body dysmorphic disorder (BDD) is body image disturbance. Many with BDD misperceive and are dissatisfied with the sizes and shapes of body parts, but detailed quantification and analysis of this has not yet been performed. To address this gap, we applied Somatomap 3D, a digital avatar tool, to quantify body image disturbances by assessing body size estimation (BSE) accuracy and body dissatisfaction., Methods: Sixty-one adults (31 with BDD, 30 healthy controls) created avatars to reflect their perceived current body and ideal body by altering 23 body part sizes and lengths using Somatomap 3D. Physical measurements of corresponding body parts were recorded for comparison. BSE accuracy (current minus actual) and body dissatisfaction (ideal minus current) were compared between groups and in relation to BDD symptom severity using generalized estimating equations., Results: Individuals with BDD significantly over- and under-estimated certain body parts compared to healthy controls. Individuals with BDD overall desired significantly thinner body parts compared to healthy controls. Moreover, those with worse BSE accuracy had greater body dissatisfaction and poorer insight., Conclusion: In sum, this digital avatar tool revealed disturbances in body image in individuals with BDD that may have perceptual and cognitive/affective components., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to examine whether different aspects of women's cognitive function are associated with lower urinary tract symptoms (LUTS) and their impact., Methods: In 2010-2011, women aged 42 to 57 years in the Coronary Artery Risk Development in Young Adults study completed different tests of cognitive function, including the Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, and Stroop test. Two years later, data on LUTS and their impact were collected. LUTS/impact, a four-level composite variable ranging from bladder health to mild, moderate, and severe LUTS/impact, was regressed on each cognitive test separately, as well as a cognitive function composite variable. The analytic sample was composed of 1,021 women with complete data., Results: When adjusting for sociodemographic variables (age, race, education) and gynecologic/obstetric variables (parity, menopausal status, hysterectomy, hormonal use), better performance on the cognitive function composite and Digit Symbol Substitution Test were both associated with lower odds of membership to a more severe LUTS/impact category (odds ratio, 0.90 [95% confidence interval, 0.83-0.98] and 0.89 [95% confidence interval, 0.82-0.97], respectively). These associations became nonsignificant when additionally adjusting for mechanisms that might explain an association between cognitive function and LUTS/impact, including health behaviors and health conditions that may covary with cerebral and peripheral vascular health and cognitive function., Conclusions: In this sample of midlife adult women, a modest association was found between better cognitive function and lower likelihood of LUTS/impact. Longitudinal studies are needed to further investigate the association between cognitive function and LUTS/impact, as well as potential explanatory mechanisms, particularly as women age and cognitive function varies to a greater degree., Competing Interests: Financial disclosure/conflicts of interest: Cynthia S. Fok currently receives author royalties from UpToDate, currently serves as an NIH PLUS Consortium investigator and an NIH PLUS CARDIA investigator, and received a past consulting fee from UroCure in 2022. The other authors have nothing to disclose., (Copyright © 2024 by The Menopause Society.)

Social cognition-the complex mental ability to perceive social stimuli and negotiate the social environment-has emerged as an important cognitive ability needed for social functioning, everyday functioning, and quality of life. Deficits in social cognition have been well documented in those with severe mental illness including schizophrenia and depression, those along the autism spectrum, and those with other brain disorders where such deficits profoundly impact everyday life. Moreover, subtle deficits in social cognition have been observed in other clinical populations, especially those that may have compromised non-social cognition (i.e., fluid intelligence such as memory). Among people living with HIV (PLHIV), 44% experience cognitive impairment; likewise, social cognitive deficits in theory of mind, prosody, empathy, and emotional face recognition/perception are gradually being recognized. This systematic review and meta-analysis aim to summarize the current knowledge of social cognitive ability among PLHIV, identified by 14 studies focused on social cognition among PLHIV, and provides an objective consensus of the findings. In general, the literature suggests that PLHIV may be at-risk of developing subtle social cognitive deficits that may impact their everyday social functioning and quality of life. The causes of such social cognitive deficits remain unclear, but perhaps develop due to (1) HIV-related sequelae that are damaging the same neurological systems in which social cognition and non-social cognition are processed; (2) stress related to coping with HIV disease itself that overwhelms one's social cognitive resources; or (3) may have been present pre-morbidly, possibly contributing to an HIV infection. From this, a theoretical framework is proposed highlighting the relationships between social cognition, non-social cognition, and social everyday functioning., (© 2024. The Author(s).)

Objectives: To operationalize a new definition for bladder health, we examined the distribution and impact of lower urinary tract symptoms (LUTS), along with risk factors, among men in the Coronary Artery Risk Development in Young Adults (CARDIA) study., Methods: LUTS were defined by American Urologic Association Symptom Index (AUASI) scores and impact on quality of life (QoL). Separate questions assessed urinary incontinence (UI) and postvoid dribbling. We performed cluster analyses using AUASI scores, with and without urine incontinence and postvoid dribbling, and impact collected in 2010-11. We performed analyses to evaluate sociodemographic and cardiovascular risk factors between clusters., Results: Among CARDIA men (mean age: 50.0, SD = 3.6; range: 42-56 years) with complete LUTS data (n = 929), we identified and compared four clusters: men who reported no or very mild symptoms and no impact on well-being (bladder health, n = 696, 75%), men with moderate symptoms and moderate impact on well-being (moderate symptoms/impact, n = 84, 9%), men with high symptoms and high impact on well-being (severe symptoms/impact, n = 117, 13%), and a separate group that reported moderate symptoms and UI with a high impact on well-being (UI + moderate symptoms/severe impact, n = 32, 3%). Exploration of the groupings showed a large percentage of postvoid dribbling across groups (overall 69%). Sociodemographic and cardiovascular risk factors were not associated with symptom/impact groups., Conclusions: Bladder health clustered into four categories. A majority of middle-aged men in the community showed no or mild bladder symptoms without impact on QoL. Postvoid dribbling is pervasive but did not cluster with a specific LUTS or impact category., (© 2024 Wiley Periodicals LLC.)

Objectives: Lower urinary tract symptoms (LUTS) are common among employed women. An underexplored topic is whether characteristics of women's occupations may influence LUTS. The present study examined whether job strain and its individual components (psychological demands, decision latitude) were associated with greater LUTS and their impact and whether, compared to managerial and professional occupations, occupations characterized by manual labor, sales, service, nursing, and teaching were associated with greater LUTS and their impact., Methods: Coronary Artery Risk Development in Young Adults cohort study data were analyzed. Job strain and occupation were assessed in 1987-88 and 1995-96. In 2012-13, LUTS and their impact were assessed. LUTS/impact category (a composite variable ranging from bladder health to mild, moderate, and severe LUTS/impact) was regressed on job strain and occupation in separate analyses, adjusting for age, race, parity, education, and financial hardship (n = 1006)., Results: Job strain and its individual components were not associated with LUTS/impact. In comparison to managerial and professional occupations, service occupations in 1987-88 and 1995-96 were both associated with greater odds of LUTS/impact in proportional odds logistic regression analyses. Employment as a nurse, health assistant, or health aide in 1995-96 was associated with greater odds of any LUTS/impact versus bladder health. Support positions in 1987-88 and sales positions in 1995-96 were associated with greater odds of moderate or severe LUTS/impact versus bladder health or mild LUTS/impact., Conclusions: Future research should examine characteristics of workplaces that may promote or constrain bladder health (e.g., time and autonomy to void when desired, infrastructure to void)., (© 2023 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC.)

Background: A small number of cross-sectional studies have found that financial insecurity-a social determinant of health-is associated with lower urinary tract symptoms., Objective: This study aimed to examine (1) whether women in the Coronary Artery Risk Development in Young Adult Study with higher levels of financial strain, assessed at 7 time points across 25 years beginning in 1985-1986, were more likely to report lower urinary tract symptoms and impact after the 2010-2011 financial strain assessment and (2) whether healthcare access and comorbidities mediated potential associations., Study Design: This prospective cohort study recruited Black and White participants aged 18 to 30 years at baseline (1985-1986) from the populations of 4 US cities. The analytical sample was composed of women with complete data for analyses involving financial strain trajectories across 7 assessments (n=841) and mediation tests of data collected at 4 assessments (n=886). The outcome variable was previously developed through a cluster analysis of urinary incontinence severity, urinary incontinence impact, other lower urinary tract symptoms severity, and their impact in 2012-2013, which yielded 4 lower urinary tract symptoms and impact cluster categories: women with no symptom or very mild symptoms and no impact vs women with mild, moderate, or severe symptoms and impact. Financial strain was defined as finding it "very hard," "hard," or "somewhat hard" (vs "not very hard") to pay for the very basics, such as food, heating, and medical care. Using proportional odds logistic regression, cluster categories were regressed on the financial strain trajectory group, adjusting for age, race, education, and parity. For mediation analyses, separate financial strain variables (difficulty paying for the very basics, such as food and heating, and difficulty paying for medical care) were created by combining 1995-1996 and 2000-2001 values. Two healthcare access variables (difficulty receiving care and underutilization of care) and a single comorbidity index (smoking, physical inactivity, body mass index, hypertension, diabetes mellitus, and depressive symptoms) were created by combining 2005-2006 and 2010-2011 values. Regression analyses and structural equation modeling were used to test whether healthcare access and comorbidities mediated associations between financial strain and lower urinary tract symptoms and impact cluster categories., Results: In comparison to women who were consistently not financially strained, women who were consistently strained (odds ratio, 2.10; 95% confidence interval, 1.13-3.91), shifted into being strained (odds ratio, 2.00; 95% confidence interval, 1.29-3.10), or experienced >1 shift in strain (odds ratio, 1.99; 95% confidence interval, 1.46-2.71) had roughly twice the odds of reporting greater lower urinary tract symptoms and impact. Underutilization of healthcare and comorbidities mediated the association between difficulty paying for medical care and lower urinary tract symptoms and impact. In the structural equation model, difficulty paying for medical care and underutilization of care were associated (β=.31; P<.01), as was underutilization of care and greater lower urinary tract symptoms and impact (β=.09; P<.01). Moreover, difficulty paying for medical care and the comorbidity index were associated (β=.34; P<.01), as was the comorbidity index and greater lower urinary tract symptoms and impact (β=.24; P<.01). Collectively, these mediation pathways eliminated a direct association between difficulty paying for medical care and lower urinary tract symptoms and impact., Conclusion: Underutilization of healthcare and comorbidities explained an association between financial strain (difficulty paying for medical care) and lower urinary tract symptoms and impact. Research is needed to confirm the findings and examine other mechanisms that may further explain the association. Accumulated evidence may inform future policies and practices., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Electroconvulsive therapy (ECT) is effective for treatment-resistant depression and leads to short-term structural brain changes and decreases in the inflammatory response. However, little is known about how brain structure and inflammation relate to the heterogeneity of treatment response in the months following an index ECT course., Methods: A naturalistic six-month study following an index ECT course included 20 subjects with treatment-resistant depression. Upon conclusion of the index ECT course and again after six months, structural magnetic resonance imaging scans and peripheral inflammation measures [interleukin-6 (IL-6), IL-8, tumor necrosis factor (TNF- α ), and C-reactive protein] were obtained. Voxel-based morphometry processed with the CAT-12 Toolbox was used to estimate changes in gray matter volume., Results: Between the end of the index ECT course and the end of follow-up, we found four clusters of significant decreases in gray matter volume ( p < 0.01, FWE) and no regions of increased volume. Decreased HAM-D scores were significantly related only to reduced IL-8 level. Decreased volume in one cluster, which included the right insula and Brodmann's Area 22, was related to increased HAM-D scores over six months. IL-8 levels did not mediate or moderate the relationship between volumetric change and depression., Conclusions: Six months after an index ECT course, multiple regions of decreased gray matter volume were observed in a naturalistic setting. The independent relations between brain volume and inflammation to depressive symptoms suggest novel explanations of the heterogeneity of longer-term ECT treatment response.

Objective: This study examines whether discriminatory experiences are associated with lower urinary tract symptoms (LUTS) and their impact among 972 women in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort study, which recruited participants from 4 cities in the United States., Method: Exposure to discrimination was assessed 3 times (1992-93, 2000-01, 2010-11) and averaged across assessments. Participants separately reported whether they experienced discrimination on the basis of their gender, race or color, and socioeconomic position or social class. For each social identity, discrimination was assessed in 6-7 settings (e.g., when getting a job, medical care, or housing). At different time points, women who reported discriminatory experiences for a given social identity were asked how frequently the discrimination occurred and how stressful experience(s) were. Following the 2010-11 assessment, data on LUTS and their impact were collected. Women were classified into bladder health versus mild, moderate, or severe symptoms/impact clusters., Results: More Black than White women reported discriminatory experiences across all social identities and most settings. Perceived stress of discriminatory experiences did not differ between Black and White women. In analyses stratified by race and social identity, White women reported LUTS/impact with discriminatory experiences in more settings, more frequent discriminatory experiences across settings, and each additional social identity for which discrimination was experienced. Black women reported LUTS/impact with more frequent discriminatory experiences across settings. For Black women, greater perceived stress of both gender and race discrimination were associated with LUTS/impact. For White women, only greater perceived stress of race discrimination was associated with LUTS/impact., Conclusions: This is one of the first studies to examine discrimination in relation to LUTS/impact. Additional research is needed to better understand differences in how discriminatory experiences based on potentially intersecting identities may be related to bladder health among women., Competing Interests: Declaration of conflict of interest Sonya S. Brady: None. Andrés Arguedas: None. Jared D. Huling: None. Gerhard Hellemann: None. Cora E. Lewis: None. Cynthia S. Fok: None. Stephen K. Van Den Eeden: None. Alayne D. Markland: None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Clinical trials in autism spectrum disorder (ASD) often rely on clinician rating scales and parent surveys to measure autism-related features and social behaviors. To aid in the selection of these assessments for future clinical trials, the Autism Biomarkers Consortium for Clinical Trials (ABC-CT) directly compared eight common instruments with respect to acquisition rates, sensitivity to group differences, equivalence across demographic sub-groups, convergent validity, and stability over a 6-week period. The sample included 280 children diagnosed with ASD (65 girls) and 119 neurotypical children (36 girls) aged from 6 to 11 years. Full scale IQ for ASD ranged from 60 to 150 and for neurotypical ranged from 86 to 150. Instruments measured clinician global assessment and autism-related behaviors, social communication abilities, adaptive function, and social withdrawal behavior. For each instrument, we examined only the scales that measured social or communication functioning. Data acquisition rates were at least 97.5% at T1 and 95.7% at T2. All scales distinguished diagnostic groups. Some scales significantly differed by participant and/or family demographic characteristics. Within the ASD group, most clinical instruments exhibited weak (≥ |0.1|) to moderate (≥ |0.4|) intercorrelations. Short-term stability was moderate (ICC: 0.5-0.75) to excellent (ICC: >0.9) within the ASD group. Variations in the degree of stability may inform viability for different contexts of use, such as identifying clinical subgroups for trials versus serving as a modifiable clinical outcome. All instruments were evaluated in terms of their advantages and potential concerns for use in clinical trials., (© 2023 International Society for Autism Research and Wiley Periodicals LLC.)

Over 95% of children with sickle cell disease (SCD) survive into adulthood in the United States. However, early mortality remains a problem, especially in persons between the ages of 18 and 35. One possible explanation for the increased mortality rate in young adults is difficulties in engaging in care during the transition from a heavily contiguous pediatric healthcare model to a more self-reliant adult healthcare model. The goal of this study was to identify potential facilitators and barriers to a successful transfer in care from the pediatric to adult SCD program before the formation of a formal transition program. This is a retrospective cohort study of transition outcomes for 472 individuals with SCD (all genotypes) treated at the University of Alabama at Birmingham (UAB) sickle cell clinic (aged 18-24). The primary outcome was whether the patient continued care in (any) adult SCD program (defined as being seen at least once in an adult hematology/SCD clinic). One hundred eighty-eight (45%) transition age patients successfully transferred to adult care. Facilitators to successful transfer in care included being treated at the same hospital for both pediatric and adult programs, having the genotype HbSS, and/or receiving an SCD-modifying therapy at the time of transition (hydroxyurea and/or red cell transfusion therapy). Of primary interest, many of the patients who failed to transition to an adult clinic were lost to follow-up prior to 15 years of age. Importantly, these patients who had previously been labeled as "transition failures," were lost to follow-up long before the transition age. Early engagement is needed for this population., (© 2023 Wiley Periodicals LLC.)

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique involving administration of well-tolerated electrical current to the brain through scalp electrodes. TDCS may improve symptoms in neuropsychiatric disorders, but mixed results from recent clinical trials underscore the need to demonstrate that tDCS can modulate clinically relevant brain systems over time in patients. Here, we analyzed longitudinal structural MRI data from a randomized, double-blind, parallel-design clinical trial in depression (NCT03556124, N = 59) to investigate whether serial tDCS individually targeted to the left dorso-lateral prefrontal cortex (DLPFC) can induce neurostructural changes. Significant (FWEc p < 0.05) treatment-related gray matter changes were observed with active high-definition (HD) tDCS relative to sham tDCS within the left DLPFC stimulation target. No changes were observed with active conventional tDCS. A follow-up analysis within individual treatment groups revealed significant gray matter increases with active HD-tDCS in brain regions functionally connected with the stimulation target, including the bilateral DLPFC, bilateral posterior cingulate cortex, subgenual anterior cingulate cortex, and the right hippocampus, thalamus and left caudate brain regions. Integrity of blinding was verified, no significant differences in stimulation-related discomfort were observed between treatment groups, and tDCS treatments were not augmented by any other adjunct treatments. Overall, these results demonstrate that serial HD-tDCS leads to neurostructural changes at a predetermined brain target in depression and suggest that such plasticity effects may propagate over brain networks., (© 2023. The Author(s).)

Objective: Numerous candidate EEG biomarkers have been put forward for use in clinical research on autism spectrum disorder (ASD), but biomarker development has been hindered by limited attention to the psychometric properties of derived variables, inconsistent results across small studies, and variable methodology. The authors evaluated the basic psychometric properties of a battery of EEG assays for their potential suitability as biomarkers in clinical trials., Methods: This was a large, multisite, naturalistic study in 6- to 11-year-old children who either had an ASD diagnosis (N=280) or were typically developing (N=119). The authors evaluated an EEG battery composed of well-studied assays of resting-state activity, face perception (faces task), biological motion perception, and visual evoked potentials (VEPs). Biomarker psychometrics were evaluated in terms of acquisition rates, construct performance, and 6-week stability. Preliminary evaluation of use was explored through group discrimination and phenotypic correlations., Results: Three assays (resting state, faces task, and VEP) show promise in terms of acquisition rates and construct performance. Six-week stability values in the ASD group were moderate (intraclass correlations ≥0.66) for the faces task latency of the P1 and N170, the VEP amplitude of N1 and P1, and resting alpha power. Group discrimination and phenotype correlations were primarily observed for the faces task P1 and N170., Conclusions: In the context of a large-scale, rigorous evaluation of candidate EEG biomarkers for use in ASD clinical trials, neural response to faces emerged as a promising biomarker for continued evaluation. Resting-state activity and VEP yielded mixed results. The study's biological motion perception assay failed to display construct performance. The results provide information about EEG biomarker performance that is relevant for the next stage of biomarker development efforts focused on context of use.

Cardiopulmonary complications remain a leading cause of morbidity and mortality in sickle cell disease (SCD). The overall goals of this study were to evaluate the relationship between left ventricular hypertrophy (LVH) and laboratory markers of hemolysis and determine the association between LVH and SCD-specific therapies (hydroxyurea and chronic red cell transfusion). Data from the DISPLACE (Dissemination and Implementation of Stroke Prevention Looking at the Care Environment) study cohort was used. LVH was defined based on the left ventricular mass indexed to the body surface area as left ventricular mass index >103.0 g/m2 for males and >84.2 g/m2 for females. There were 1,409 children included in the analysis and 20.3% had LVH. Results of multivariable analysis of LVH showed baseline hemoglobin levels were associated with the lower odds of having LVH (odds ratio [OR]: 0.71, 95% confidence interval [CI]: 0.60- 0.84). The odds of LVH increases for every 1-year increase in age (OR: 1.07, 95% CI: 1.02-1.13). Similarly, the odds of LVH were lower among males than females (OR: 0.59, 95% CI: 0.38-0.93). The odds of LVH were higher among those on hydroxyurea compared to no therapy (OR: 1.83, 95% CI: 1.41-2.37). Overall results of the study showed that LVH occurs early in children with SCD and the risk increases with increasing age and with lower hemoglobin. Further, we found higher use of hydroxyurea among those with LVH, suggesting that the need for hydroxyurea conveys a risk of cardiovascular remodeling.

N-acetylcysteine (NAC) is a commonly used antioxidant that may have beneficial effects for schizophrenia. In this double-blind, randomized, placebo-controlled preliminary study, 40 patients with schizophrenia or schizoaffective disorder were randomized to receive 2400 mg NAC daily or placebo over eight weeks to examine the effects of NAC on prefrontal magnetic resonance spectroscopy levels of glutathione and glutamate. Secondary outcomes included negative symptoms, cognition, and plasma glutathione levels. We found that NAC treatment was associated with increased glutathione (statistically significant) and decreased glutamate (trend-level) compared with placebo in medial prefrontal cortex but not dorsolateral prefrontal cortex. We also observed a baseline association between medial prefrontal cortex levels of glutathione and plasma reduced / oxidized glutathione ratios. No treatment effects on symptoms or cognition were observed. Taken together, these findings indicate that treatment with N-acetylcysteine may increase medial prefrontal cortical levels of glutathione after eight weeks of treatment. These changes in cortical levels of glutathione may serve as an early biomarker of later clinical change and may underlie the cognitive and symptomatic improvements reported in longer-term treatment studies., (Published by Elsevier B.V.)

Background: Ketamine is a rapidly-acting antidepressant treatment with robust response rates. Previous studies have reported that serial ketamine therapy modulates resting state functional connectivity in several large-scale networks, though it remains unknown whether variations in brain structure, function, and connectivity impact subsequent treatment success. We used a data-driven approach to determine whether pretreatment multimodal neuroimaging measures predict changes along symptom dimensions of depression following serial ketamine infusion., Methods: Patients with depression ( n = 60) received structural, resting state functional, and diffusion MRI scans before treatment. Depressive symptoms were assessed using the 17-item Hamilton Depression Rating Scale (HDRS-17), the Inventory of Depressive Symptomatology (IDS-C), and the Rumination Response Scale (RRS) before and 24 h after patients received four (0.5 mg/kg) infusions of racemic ketamine over 2 weeks. Nineteen unaffected controls were assessed at similar timepoints. Random forest regression models predicted symptom changes using pretreatment multimodal neuroimaging and demographic measures., Results: Two HDRS-17 subscales, the HDRS-6 and core mood and anhedonia (CMA) symptoms, and the RRS: reflection (RRSR) scale were predicted significantly with 19, 27, and 1% variance explained, respectively. Increased right medial prefrontal cortex/anterior cingulate and posterior insula (PoI) and lower kurtosis of the superior longitudinal fasciculus predicted reduced HDRS-6 and CMA symptoms following treatment. RRSR change was predicted by global connectivity of the left posterior cingulate, left insula, and right superior parietal lobule., Conclusions: Our findings support that connectivity of the anterior default mode network and PoI may serve as potential biomarkers of antidepressant outcomes for core depressive symptoms.

Aims: We sought to identify person- and program-level factors distinguishing permanent supportive housing (PSH) residents with higher versus lower social integration; and higher versus lower instrumental functioning., Methods: Among 60 PSH residents at Los Angeles' VA, surveys and medical records captured person-level factors. Using a median split, we dichotomized participants with higher versus lower social integration; and higher versus lower instrumental functioning. Recursive partitioning (RP) identified variables that best-differentiated these subgroups. Interviews with 26 participants captured their perceptions on social integration and instrumental functioning., Results: Using RP, health-related quality of life, psychiatric symptoms and case management frequency best-differentiated the social integration subgroups. Few perceived that PSH affected social integration. RP did not yield a stable model to differentiate the instrumental functioning subgroups; participants perceived that PSH addressed most functional deficits., Conclusions: Services that enhance social integration may benefit PSH residents with poor health; existing services may adequately address instrumental functioning., (Published 2021. This article is a U.S. Government work and is in the public domain in the USA.)

Black Americans are overrepresented in Veteran and non-Veteran homeless populations. Community integration remains a problem for many Veterans after they obtain housing, and Black Veterans may encounter additional difficulties due to systemic racism. However, no prior study has specifically examined whether there are racial differences in community integration; similarly, no study has considered racial differences in psychosocial correlates of community integration in homeless Veterans. Knowledge of these factors could inform the development of culturally congruent rehabilitative interventions for Black Veterans. Semi-structured clinical interviews were administered to Black (N = 99) and White (N = 49) homeless Veterans to examine relations among psychiatric symptoms, motivation, and community integration domains (e.g., social integration, work productivity, and independent living). There were no significant racial differences in independent living or work productivity. Black Veterans had better social integration with family compared to White Veterans. In addition, psychiatric symptoms were more strongly correlated with social integration for Black than White Veterans. The association between motivation and work productivity was also stronger for Black Veterans. Recovery-oriented interventions could harness family connections and better target psychiatric symptoms to improve community integration for Black Veterans. Work productivity may improve from interventions aimed at enhancing motivation for Black Veterans., (Published by Elsevier B.V.)

Background: Little is known about the determinants of community integration (i.e. recovery) for individuals with a history of homelessness, yet such information is essential to develop targeted interventions., Methods: We recruited homeless Veterans with a history of psychotic disorders and evaluated four domains of correlates of community integration: perception, non-social cognition, social cognition, and motivation. Baseline assessments occurred after participants were engaged in supported housing services but before they received housing, and again after 12 months. Ninety-five homeless Veterans with a history of psychosis were assessed at baseline and 53 returned after 12 months. We examined both cross-sectional and longitudinal relationships with 12-month community integration., Results: The strongest longitudinal association was between a baseline motivational measure and social integration at 12 months. We also observed cross-sectional associations at baseline between motivational measures and community integration, including social, work, and independent living. Cross-lagged panel analyses did not suggest causal associations for the motivational measures. Correlations with perception and non-social cognition were weak. One social cognition measure showed a significant longitudinal correlation with independent living at 12 months that was significant for cross-lagged analysis, consistent with a causal relationship and potential treatment target., Conclusions: The relatively selective associations for motivational measures differ from what is typically seen in psychosis, in which all domains are associated with community integration. These findings are presented along with a partner paper (Study 2) to compare findings from this study to an independent sample without a history of psychotic disorders to evaluate the consistency in findings regarding community integration across projects.

Ischemic stroke is one of the most devastating complications of sickle cell anemia (SCA). Previous studies have shown that intracardiac shunting including patent foramen ovale (PFO) can be a potential risk factor for stroke in children with SCA. This study investigates the association between PFO and overt ischemic stroke in the DISPLACE (Dissemination and Implementation of Stroke Prevention Looking at the Care Environment) study cohort of 5,247 children with SCA of whom 1,414 had at least one clinical non-contrast transthoracic echocardiogram. Presence of PFO was taken from the clinical report. Further, we assessed the association between PFO and other clinical and hemolytic factors in children with SCA such as history of abnormal sickle stroke screen [elevated Transcranial Doppler ultrasound (TCD) velocity] and patient's baseline hemoglobin. In 642 children for whom all data were available, the adjusted odds ratio (OR) for overt stroke was higher in those with PFO but this was not statistically significant (OR: 1.49, 95% CI: 0.20-11.03, p = 0.6994). With an OR of 0.85, the study suggested less PFOs in those with abnormal TCD, but this was not statistically significant (95% CI: 0.17-4.25, p = 0.8463). Overall, the prevalence of PFO in this large sub study of non-contrast echocardiography amongst children with SCA is much lower than previous smaller studies using bubble contrast echocardiography. Overt stroke was non-statistically more common in children with SCA and PFO, but there was no evidence that PFO was more common in those with abnormal TCD, the most important pediatric sickle stroke screen., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Galadanci, Johnson, Carson, Hellemann, Howard and Kanter.)

Background: In an initial study (Study 1), we found that motivation predicted community integration (i.e. functional recovery) 12 months after receiving housing in formerly homeless Veterans with a psychotic disorder. The current study examined whether the same pattern would be found in a broader, more clinically diverse, homeless Veteran sample without psychosis., Methods: We examined four categories of variables as potential predictors of community integration in non-psychotic Veterans: perception, non-social cognition, social cognition, and motivation at baseline (after participants were engaged in a permanent supported housing program but before receiving housing) and a 12-month follow-up. A total of 82 Veterans had a baseline assessment and 41 returned for testing after 12 months., Results: The strongest longitudinal association was between an interview-based measure of motivation (the motivation and pleasure subscale from the Clinical Assessment Interview for Negative Symptoms) at baseline and measures of social integration at 12 months. In addition, cross-lagged panel analyses were consistent with a causal influence of general psychiatric symptoms at baseline driving social integration at 12 months, and reduced expressiveness at baseline driving independent living at 12 months, but there were no significant causal associations with measures of motivation., Conclusions: The findings from this study complement and reinforce those in Veterans with psychosis. Across these two studies, our findings suggest that motivational factors are associated at baseline and at 12 months and are particularly important for understanding and improving community integration in recently-housed Veterans across psychiatric diagnoses.

Depression symptom heterogeneity limits the identifiability of treatment-response biomarkers. Whether improvement along dimensions of depressive symptoms relates to separable neural networks remains poorly understood. We build on work describing three latent symptom dimensions within the 17-item Hamilton Depression Rating Scale (HDRS) and use data-driven methods to relate multivariate patterns of patient clinical, demographic, and brain structural changes over electroconvulsive therapy (ECT) to dimensional changes in depressive symptoms. We included 110 ECT patients from Global ECT-MRI Research Collaboration (GEMRIC) sites who underwent structural MRI and HDRS assessments before and after treatment. Cross validated random forest regression models predicted change along symptom dimensions. HDRS symptoms clustered into dimensions of somatic disturbances (SoD), core mood and anhedonia (CMA), and insomnia. The coefficient of determination between predicted and actual changes were 22%, 39%, and 39% (all p < .01) for SoD, CMA, and insomnia, respectively. CMA and insomnia change were predicted more accurately than HDRS-6 and HDRS-17 changes (p < .05). Pretreatment symptoms, body-mass index, and age were important predictors. Important imaging predictors included the right transverse temporal gyrus and left frontal pole for the SoD dimension; right transverse temporal gyrus and right rostral middle frontal gyrus for the CMA dimension; and right superior parietal lobule and left accumbens for the insomnia dimension. Our findings support that recovery along depressive symptom dimensions is predicted more accurately than HDRS total scores and are related to unique and overlapping patterns of clinical and demographic data and volumetric changes in brain regions related to depression and near ECT electrodes., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Lay Abstract: This is a study of the secondary effects of interventions for young children with autism on their parents. Specifically, we were interested in the impact on parent's sense of efficacy, or how confident and competent a parent feels about themselves as a parent. We tested three ideas: (1) that the style of the intervention, whether it was more or less structured and whether the parent had a more or less formal role, would impact a parent's sense of efficacy; (2) that the intensity of the intervention, how many hours per week the intervention was delivered, would impact parental efficacy; and (3) that the parent's level of stress prior to intervention would impact how intensity and style effected efficacy. We randomly assigned 87 children with autism, age 13-30 months, into one of four conditions: 15 versus 25 intervention hours crossed with two different styles of intervention. We used statistical tests to examine these ideas. We found that parental efficacy was related to intervention intensity but not style. Parents with higher stress at the beginning of a 1-year, home-based, comprehensive intervention program had a higher sense of parenting efficacy if their child received lower intensity intervention; parents with lower stress at baseline had a higher sense of efficacy if their child received higher intensity intervention. If a parent can emerge from the process of diagnosis and early intervention with an increased sense that they can make a difference in their child's life (i.e. increased sense of efficacy), it may set the stage for meeting the long-term demands of parenting a child with autism.

Introduction: In cross-sectional studies of depressed patients, relationships between depression and levels of IL-8 are inconsistent, and have not been examined in relation to sex. Given identified sex differences in longitudinal data, it is important to evaluate sex-specific cross-sectional relationships between IL-8 and depressive symptoms, which may explain some inconsistency in the extant literature. It is further unknown whether IL-8 levels may relate to specific symptom profiles among depressed patients, with or without regard to sex., Methods: Among 108 patients with treatment resistant depression (50 females), we evaluated cross-sectional relationships between IL-8 and depression severity, as measured by the Hamilton Depression Rating Scale [HAM-D] Score, and examined sex-specific relationships, as well as relationships with depressive symptom profiles. Other inflammatory markers (IL-6, IL-10, TNF-α, CRP) were also explored in relation to HAM-D., Results: Higher IL-8 was associated with lower total HAM-D score (standardized β = -0.19, p = 0.049). Sex-specific effects were identified (IL-8 x sex interaction: p = 0.03), in which higher IL-8 related to lower HAM-D score in females (standardized β = -0.41, p = 0.004, effect size (sr 2 ) = 0.17), but not males (standardized β = 0.02, p = 0.91). Among a subset of 94 patients (41 females) who had individual HAM-D items available, we evaluated relationships between IL-8 and HAM-D factor subscores. Across sexes, higher IL-8 was associated with lower anxiety/hypochondriasis subscores (standardized β = -0.31, p = 0.002; sex interaction: p = 0.99). Sex differences were identified for relationships between IL-8 and two other HAM-D factor subscores., Conclusions: IL-8 may be related to anxiety symptoms across sexes, but may have a sex-specific relationship with other depressive symptoms. Further evaluation of sex-specific relationships between IL-8, depression symptom profiles, treatment response, and potential neurobiological correlates, may inform mechanisms of depression pathophysiology and aid in development of precision medicine strategies., (Published by Elsevier Ltd.)

Electroconvulsive therapy (ECT) has been repeatedly linked to hippocampal plasticity. However, it remains unclear what role hippocampal plasticity plays in the antidepressant response to ECT. This magnetic resonance imaging (MRI) study tracks changes in separate hippocampal subregions and hippocampal networks in patients with depression (n = 44, 23 female) to determine their relationship, if any, with improvement after ECT. Voxelwise analyses were restricted to the hippocampus, amygdala, and parahippocampal cortex, and applied separately for responders and nonresponders to ECT. In analyses of arterial spin-labeled (ASL) MRI, nonresponders exhibited increased cerebral blood flow (CBF) in bilateral anterior hippocampus, while responders showed CBF increases in right middle and left posterior hippocampus. In analyses of gray matter volume (GMV) using T1-weighted MRI, GMV increased throughout bilateral hippocampus and surrounding tissue in nonresponders, while responders showed increased GMV in right anterior hippocampus only. Using CBF loci as seed regions, BOLD-fMRI data from healthy controls (n = 36, 19 female) identified spatially separable neurofunctional networks comprised of different brain regions. In graph theory analyses of these networks, functional connectivity within a hippocampus-thalamus-striatum network decreased only in responders after two treatments and after index. In sum, our results suggest that the location of ECT-related plasticity within the hippocampus may differ according to antidepressant outcome, and that larger amounts of hippocampal plasticity may not be conducive to positive antidepressant response. More focused targeting of hippocampal subregions and/or circuits may be a way to improve ECT outcome., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Ketamine is a highly effective antidepressant for patients with treatment-resistant major depressive disorder (MDD). Resting-state functional magnetic resonance imaging studies show disruptions of functional connectivity (FC) between limbic regions and resting-state networks (RSNs) in MDD, including the default mode network, central executive network (CEN), and salience network (SN). Here, we investigated whether serial ketamine treatments change FC between limbic structures and RSNs., Methods: Patients with MDD (n = 44) were scanned at baseline (time 1 [T1]) and 24 hours after the first (T2) and fourth (T3) infusions of ketamine. Healthy control subjects (n = 50) were scanned at baseline, with a subgroup (n = 17) being rescanned at 2 weeks. Limbic regions included the amygdala and hippocampus, and RSNs included the default mode network, CEN, and SN., Results: Ketamine increased right amygdala FC to the right CEN (p = .05), decreased amygdala FC to the left CEN (p = .005) at T2 versus T1 (p = .015), which then increased at T3 versus T2 (p = .002), and decreased left amygdala FC to the SN (p = .016). Decreased left amygdala to SN FC at T2 predicted improvements in anxiety at T3 (p = .006). Ketamine increased right hippocampus FC to the left CEN (p = .001), and this change at T2 predicted decreased anhedonia at T3 (p = .005)., Conclusions: Ketamine modulates FC between limbic regions and RSNs implicated in MDD. Increases in FC between limbic regions and the CEN suggest that ketamine may be involved in restoring top-down control of emotion processing. FC decreases between the left amygdala and SN suggest that ketamine may ameliorate MDD-related dysconnectivity in these circuits. Early FC changes between limbic regions and RSNs may be predictive of clinical improvements., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)