Improving Clinical Prediction of Bipolar Spectrum Disorders in Youth.

This report evaluates whether classification tree algorithms (CTA) may improve the identification of individuals at risk for bipolar spectrum disorders (BPSD). Analyses used the Longitudinal Assessment of Manic Symptoms (LAMS) cohort (629 youth, 148 with BPSD and 481 without BPSD). Parent ratings of mania symptoms, stressful life events, parenting stress, and parental history of mania were included as risk factors. Comparable overall accuracy was observed for CTA (75.4%) relative to logistic regression (77.6%). However, CTA showed increased sensitivity (0.28 vs. 0.18) at the expense of slightly decreased specificity and positive predictive power. The advantage of CTA algorithms for clinical decision making is demonstrated by the combinations of predictors most useful for altering the probability of BPSD. The 24% sample probability of BPSD was substantially decreased in youth with low screening and baseline parent ratings of mania, negative parental history of mania, and low levels of stressful life events (2%). High screening plus high baseline parent-rated mania nearly doubled the BPSD probability (46%). Future work will benefit from examining additional, powerful predictors, such as alternative data sources (e.g., clinician ratings, neurocognitive test data); these may increase the clinical utility of CTA models further

Factors Influencing Mental Health Service Utilization by Children with Serious Emotional and Behavioral Disturbance: Results from the LAMS Study

The official published article is available online at http://doi.org/10.1176/appi.ps.62.6.650.OBJECTIVE: To describe service utilization of a cohort of children with emotional and behavioral disorders who visited outpatient mental health clinics in four Midwest cities. METHOD: Data come from the Longitudinal Assessment of Manic Symptoms (LAMS) Study. 707 youth (ages 6–12 years) and their parents completed diagnostic assessments, demographic information and an assessment of mental health service utilization. Analyses examined the relationship of demographics, diagnoses, impairment, and comorbidity to the type and level of services utilized. RESULTS: Service utilization is multimodal with half of the youth receiving both outpatient and school services during their lifetime. Non-need factors including age, sex, race, and insurance, were related to types of services used. Youth diagnosed with a bipolar spectrum disorder had higher utilization of inpatient services and two or more services at one time compared to youth diagnosed with depressive or disruptive disorders. More than half of youth diagnosed with bipolar or depressive disorders had received both medication and therapy during their lifetime whereas for youth diagnosed with a disruptive disorder therapy only was more common. Impairment and comorbidity were not related to service utilization. CONCLUSIONS: Use of mental health services for children begins at a very young age and occurs in multiple service sectors. Type of service use is related to insurance and race/ethnicity, underscoring the need for research on treatment disparities. Contrary to findings from results based on administrative data, medication alone was infrequent. However, the reasonably low use of combination therapy suggests that clinicians and families need to be educated on the effectiveness of multimodal treatment

Stability of Satellite Planes in M31 II: Effects of the Dark Subhalo Population

The planar arrangement of nearly half the satellite galaxies of M31 has been a source of mystery and speculation since it was discovered. With a growing number of other host galaxies showing these satellite galaxy planes, their stability and longevity have become central to the debate on whether the presence of satellite planes are a natural consequence of prevailing cosmological models, or represent a challenge. Given the dependence of their stability on host halo shape, we look into how a galaxy plane's dark matter environment influences its longevity. An increased number of dark matter subhalos results in increased interactions that hasten the deterioration of an already-formed plane of satellite galaxies in spherical dark halos. The role of total dark matter mass fraction held in subhalos in dispersing a plane of galaxies present non trivial effects on plane longevity as well. But any misalignments of plane inclines to major axes of flattened dark matter halos lead to their lifetimes being reduced to < 3 Gyrs. Distributing > 40% of total dark mass in subhalos in the overall dark matter distribution results in a plane of satellite galaxies that is prone to change through the 5 Gyr integration time period.Comment: 11 pages, 9 figures, accepted to MNRAS September 22 201

Altered development of white matter in youth at high familial risk for bipolar disorder: a diffusion tensor imaging study

Objective: To study white matter (WM) development in youth at high familial risk for bipolar disorder (BD). WM alterations are reported in youth and adults with BD. WM undergoes important maturational changes in adolescence. Age-related changes in WM microstructure using diffusion tensor imaging with tract-based spatial statistics in healthy offspring having a parent with BD were compared with those in healthy controls. Method: A total of 45 offspring participated, including 20 healthy offspring with a parent diagnosed with BD (HBO) and 25 healthy control offspring of healthy parents (CONT). All were free of medical and psychiatric disorders. Mean fractional anisotropy (FA), radial diffusivity (RD), and longitudinal diffusivity were examined using whole-brain analyses, co-varying for age. Results: Group-by-age interactions showed a linear increase in FA and a linear decrease in RD in CONT in the left corpus callosum and right inferior longitudinal fasciculus. In HBO, there was a linear decrease in FA and an increase in RD with age in the left corpus callosum and no relation between FA or RD and age in the right inferior longitudinal fasciculus. Curve fitting confirmed linear and showed nonlinear relations between FA and RD and age in these regions in CONT and HBO. Conclusions: This is the first study to examine WM in healthy offspring at high familial risk for BD. Results from this cross-sectional study suggest altered development of WM in HBO compared with CONT in the corpus callosum and temporal associative tracts, which may represent vulnerability markers for future BD and other psychiatric disorders in HBO. J. Am. Acad. Child Adolesc. Psychiatry, J. Am. Acad. Child Adolesc. Psychiatry, 2010; 49(12):1249 -1259. Key words: bipolar disorder, familial risk, white matter, diffusion tensor imaging, neurodevelopment B ipolar disorder (BD) is a serious psychiatric illness affecting 1% to 3% of the adult population and remains a leading cause of morbidity, functional impairment, and completed suicide. 1 BD is characterized by difficulties in the regulation of emotions and behavior, as indicated by episodes of mania and depression. BD is highly heritable: the risk of BD is much greater in first-degree relatives of individuals diagnosed with BD. 2,3 Recent evidence has indicated that offspring of parents with BD are at increased risk for BD and other psychiatric disorders, including BD spectrum disorder, anxiety, and depression disorders. 2 Although genetic and environmental factors and their interactions are important in the development of BD, abnormalities of brain structure and function that most likely mediate these effects have yet to be elucidated. Converging evidence from epidemiologic, genetic, and neuroimaging studies has suggested that abnormalities in the development of white matter (WM) may play an important role in the neuropathophysiology of BD

High RBM3 expression in prostate cancer independently predicts a reduced risk of biochemical recurrence and disease progression

<p>Abstract</p> <p>Background</p> <p>High expression of the RNA-binding protein RBM3 has previously been found to be associated with good prognosis in breast cancer, ovarian cancer, malignant melanoma and colorectal cancer. The aim of this study was to examine the prognostic impact of immunohistochemical RBM3 expression in prostate cancer.</p> <p>Findings</p> <p>Immunohistochemical RBM3 expression was examined in a tissue microarray with malignant and benign prostatic specimens from 88 patients treated with radical prostatectomy for localized disease. While rarely expressed in benign prostate gland epithelium, RBM3 was found to be up-regulated in prostate intraepithelial neoplasia and present in various fractions and intensities in invasive prostate cancer. High nuclear RBM3 expression was significantly associated with a prolonged time to biochemical recurrence (BCR) (HR 0.56, 95% CI: 0.34-0.93, <it>p </it>= 0.024) and clinical progression (HR 0.09, 95% CI: 0.01-0.71, <it>p = </it>0.021). These associations remained significant in multivariate analysis, adjusted for preoperative PSA level in blood, pathological Gleason score and presence or absence of extracapsular extension, seminal vesicle invasion and positive surgical margin (HR 0.41, 95% CI: 0.19-0.89, <it>p </it>= 0.024 for BCR and HR 0.06, 95% CI: 0.01-0.50, <it>p = </it>0.009 for clinical progression).</p> <p>Conclusion</p> <p>Our results demonstrate that high nuclear expression of RBM3 in prostate cancer is associated with a prolonged time to disease progression and, thus, a potential biomarker of favourable prognosis. The value of RBM3 for prognostication, treatment stratification and follow-up of prostate cancer patients should be further validated in larger studies.</p

Effects of comorbid anxiety disorders on the longitudinal course of pediatric bipolar disorders

OBJECTIVE: To examine the longitudinal effects of comorbid anxiety disorders in youth with bipolar spectrum disorder (BP). METHOD: As part of the Course and Outcome of Bipolar Youth study, 413 youth, who were 7 through 17 years or age and who met criteria for DSM-IV BP-I (n = 244), BP-II (n = 28), and operationally defined bipolar disorder not otherwise specified (BP-NOS) (n = 141) were included. Subjects were followed on average 5 years using the Longitudinal Interval Follow-up Evaluation. Effects of anxiety on the time to mood recovery and recurrence and percentage of time with syndromal and subsyndromal mood symptomatology during the follow-up period were analyzed. RESULTS: At intake and during the follow-up, 62% of youth with BP met criteria for at least 1 anxiety disorder. About 50% of the BP youth with anxiety had ≥2 anxiety disorders. Compared to BP youth without anxiety, those with anxiety had significantly more depressive recurrences and significantly longer median time to recovery. The effects of anxiety on recovery disappeared when the severity of depression at intake was taken into account. After adjusting for confounding factors, BP youth with anxiety, particularly those with ≥2 anxiety disorders, spent significantly less follow-up time asymptomatic and more time with syndromal mixed/cycling and subsyndromal depressive symptomatology compared to those without anxiety. CONCLUSIONS: Anxiety disorders are common and adversely affect the course of BP in youth, as characterized by more mood recurrences, longer time to recovery, less time euthymic, and more time in mixed/cycling and depressive episodes. Prompt recognition and the development of treatments for BP youth with anxiety are warranted

Pediatric bipolar disorder and ADHD: Family history comparison in the LAMS clinical sample

Transgenerational association of bipolar spectrum disorder (BPSD) and attention deficit/hyperactivity disorder (ADHD) has been reported, but inconclusively

Disruptive mood dysregulation disorder and bipolar disorder not otherwise specified:fraternal or identical twins?

Objective: The purpose of this study was to examine similarities and differences between disruptive mood dysregulation disorder (DMDD) and bipolar disorder not otherwise specified (BP-NOS) in baseline sociodemographic and clinical characteristics and 36 month course of irritability in children 6–12.9 years of age. Methods: A total of 140 children with DMDD and 77 children with BP-NOS from the Longitudinal Assessment of Manic Symptoms cohort were assessed at baseline, then reassessed every 6 months for 36 months. Results: Groups were similar on most sociodemographic and baseline clinical variables other than most unfiltered (i.e., interviewer-rated regardless of occurrence during a mood episode) Young Mania Rating Scale (YMRS) and parent-reported General Behavior Inventory-10 Item Mania (PGBI-10M) items. Children with DMDD received lower scores on every item (including irritability) except impaired insight; differences were significant except for sexual interest and disruptiveaggressive behavior. Children with DMDD received lower scores on eight of 10 PGBI-10M items, the other two items rated irritability. Youth with DMDD were significantly less likely to have a biological parent with a bipolar diagnosis than were youth with BP-NOS. Children with DMDD were more likely to be male and older than children with BP-NOS, both small effect sizes, but had nearly double the rate of disruptive behavior disorders (large effect). Caregiver ratings of irritability based on the Child and Adolescent Symptom Inventory-4R (CASI-4R) were comparable at baseline; theDMDD group had a small but significantly steeper decline in scores over 36 months relative to the BP-NOS group (b=-0.24, SE = 0.12, 95% CI -0.48 to -0.0004). Trajectories for both groups were fairly stable, in the midrange of possible scores. Conclusions: In a sample selected for elevated symptoms of mania, twice as many children were diagnosed withDMDD than with BP-NOS. Children with DMDD and BP-NOS are similar on most characteristics other than manic symptoms, per se, and parental history of bipolar disorder. Chronic irritability is common in both groups. Comprehensive evaluations are needed to diagnose appropriately. Clinicians should not assume that chronic irritability leads exclusively to a DMDD diagnosis

Clinical impairment in premanifest and early Huntington's disease is associated with regionally specific atrophy.

TRACK-HD is a multicentre longitudinal observational study investigating the use of clinical assessments and 3-Tesla magnetic resonance imaging as potential biomarkers for future therapeutic trials in Huntington's disease (HD). The cross-sectional data from this large well-characterized dataset provide the opportunity to improve our knowledge of how the underlying neuropathology of HD may contribute to the clinical manifestations of the disease across the spectrum of premanifest (PreHD) and early HD. Two hundred and thirty nine gene-positive subjects (120 PreHD and 119 early HD) from the TRACK-HD study were included. Using voxel-based morphometry (VBM), grey and white matter volumes were correlated with performance in four domains: quantitative motor (tongue force, metronome tapping, and gait); oculomotor [anti-saccade error rate (ASE)]; cognition (negative emotion recognition, spot the change and the University of Pennsylvania smell identification test) and neuropsychiatric measures (apathy, affect and irritability). After adjusting for estimated disease severity, regionally specific associations between structural loss and task performance were found (familywise error corrected, P < 0.05); impairment in tongue force, metronome tapping and ASE were all associated with striatal loss. Additionally, tongue force deficits and ASE were associated with volume reduction in the occipital lobe. Impaired recognition of negative emotions was associated with volumetric reductions in the precuneus and cuneus. Our study reveals specific associations between atrophy and decline in a range of clinical modalities, demonstrating the utility of VBM correlation analysis for investigating these relationships in HD

The immunopeptidome from a genomic perspective:Establishing the noncanonical landscape of MHC class I–associated peptides

G.B., D.B., K.W., A.P., R.F., T.R.H., S.K., and J.A.A. received support from Fundacja na rzecz Nauki Polskiej (FNP) (grant ID: MAB/3/2017). D.R.G. received support from Genome Canada & Genome BC (grant ID: 264PRO). D.J.H. received support from NuCana plc (grant ID: SMD0-ZIUN05). H.A. received support from Swedish Cancer Foundation (grant ID: 211709). H.G. received support from United Kingdom Research and Innovation (UKRI) (grant ID: EP/S02431X/1). C.P. received support from Fundação para a Ciência e a Tecnologia (FCT) through LASIGE Research Unit (grant ID: UIDB/00408/2020 and UIDP/00408/2020). A.L. F.M.Z., C.P., A.R., A.P., and J.A.A. received support from European Union’s Horizon 2020 research and innovation programme (grant ID: 101017453). C.B. received support from Agence Nationale de la Recherche (ANR) through GRAL LabEX (grant ID: ANR-10-LABX-49-01) and CBH-EUR-GS 32 (grant ID: ANR-17-EURE0003). S.N.S. received support from Cancer Research UK (CRUK) and the Chief Scientist's Office of Scotland (CSO): Experimental Cancer Medicine Centre (ECMC) (grant ID: ECMCQQR-2022/100017). A.L. received support from Chief Scientist's Office of Scotland (CSO) NRS Career Researcher Fellowship. R.O.N. received support from CRUK Cambridge Centre Thoracic Cancer Programme (grant ID: CTRQQR-2021\100012).Tumor antigens can emerge through multiple mechanisms, including translation of non-coding genomic regions. This non-canonical category of antigens has recently gained attention; however, our understanding of how they recur within and between cancer types is still in its infancy. Therefore, we developed a proteogenomic pipeline based on deep learning de novo mass spectrometry to enable the discovery of non-canonical MHC-associated peptides (ncMAPs) from non-coding regions. Considering that the emergence of tumor antigens can also involve post-translational modifications, we included an open search component in our pipeline. Leveraging the wealth of mass spectrometry-based immunopeptidomics, we analyzed 26 MHC class I immunopeptidomic studies of 9 different cancer types. We validated the de novo identified ncMAPs, along with the most abundant post-translational modifications, using spectral matching and controlled their false discovery rate (FDR) to 1%. Interestingly, the non-canonical presentation appeared to be 5 times enriched for the A03 HLA supertype, with a projected population coverage of 54.85%. Here, we reveal an atlas of 8,601 ncMAPs with varying levels of cancer selectivity and suggest 17 cancer-selective ncMAPs as attractive targets according to a stringent cutoff. In summary, the combination of the open-source pipeline and the atlas of ncMAPs reported herein could facilitate the identification and screening of ncMAPs as targeting agents for T-cell therapies or vaccine development.Publisher PDFPeer reviewe