Prescribed psychostimulants and other pro-cognitive medications in bipolar disorder: A systematic review and meta-analysis of recurrence of manic symptoms.

OBJECTIVES: Clinicians are often hesitant to prescribe psychostimulants in bipolar disorder (BD) due to concerns of inducing (hypo)mania, despite limited published evidence on associations between prescribed psychostimulant use and recurrence of mood episodes in BD. The current systematic review and meta-analysis evaluated the emergence of (hypo)manic symptoms in patients with BD receiving prescribed psychostimulants or other pro-cognitive medications in euthymic or depressive states. METHODS: A systematic search was performed of MEDLINE, Embase, and PsychINFO from inception to April 5, 2023 and search of Clinicaltrials.gov and Clinicaltrialsregister.eu for unpublished data. References of included studies were hand-searched. Randomized trials and prospective longitudinal studies that evaluated psychostimulants and non-stimulant medications recommended for the treatment of ADHD by the Canadian ADHD practice guidelines were included. The review was reported in line with PRISMA guidelines and was preregistered on PROSPERO (CRD42022358588). RESULTS: After screening 414 unique records, we included 27 studies, of which five reported data that was quantitatively synthesized (n = 1653). The use of psychostimulants in BD was not associated with increased scores on the Young Mania Rating Scale in patients who were in a euthymic or depressed state (SMD IV -0.17; 95% CI, -0.40 to 0.06) compared to placebo. There was a high degree of study-level heterogeneity (I2 = 80%). A qualitative synthesis of studies revealed a limited risk of medication-induced manic symptoms. CONCLUSIONS: Our review provides preliminary evidence to suggest psychostimulants and non-stimulant ADHD medications have a limited risk of precipitating (hypo)mania symptoms. More extensive studies evaluating the safety and efficacy of these medications are warranted.

CIViCdb 2022: evolution of an open-access cancer variant interpretation knowledgebase.

CIViC (Clinical Interpretation of Variants in Cancer; civicdb.org) is a crowd-sourced, public domain knowledgebase composed of literature-derived evidence characterizing the clinical utility of cancer variants. As clinical sequencing becomes more prevalent in cancer management, the need for cancer variant interpretation has grown beyond the capability of any single institution. CIViC contains peer-reviewed, published literature curated and expertly-moderated into structured data units (Evidence Items) that can be accessed globally and in real time, reducing barriers to clinical variant knowledge sharing. We have extended CIViC's functionality to support emergent variant interpretation guidelines, increase interoperability with other variant resources, and promote widespread dissemination of structured curated data. To support the full breadth of variant interpretation from basic to translational, including integration of somatic and germline variant knowledge and inference of drug response, we have enabled curation of three new Evidence Types (Predisposing, Oncogenic and Functional). The growing CIViC knowledgebase has over 300 contributors and distributes clinically-relevant cancer variant data currently representing >3200 variants in >470 genes from >3100 publications.

Large scale genotype- and phenotype-driven machine learning in Von Hippel-Lindau disease.

Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome where individuals are predisposed to tumor development in the brain, adrenal gland, kidney, and other organs. It is caused by pathogenic variants in the VHL tumor suppressor gene. Standardized disease information has been difficult to collect due to the rarity and diversity of VHL patients. Over 4100 unique articles published until October 2019 were screened for germline genotype-phenotype data. Patient data were translated into standardized descriptions using Human Genome Variation Society gene variant nomenclature and Human Phenotype Ontology terms and has been manually curated into an open-access knowledgebase called Clinical Interpretation of Variants in Cancer. In total, 634 unique VHL variants, 2882 patients, and 1991 families from 427 papers were captured. We identified relationship trends between phenotype and genotype data using classic statistical methods and spectral clustering unsupervised learning. Our analyses reveal earlier onset of pheochromocytoma/paraganglioma and retinal angiomas, phenotype co-occurrences and genotype-phenotype correlations including hotspots. It confirms existing VHL associations and can be used to identify new patterns and associations in VHL disease. Our database serves as an aggregate knowledge translation tool to facilitate sharing information about the pathogenicity of VHL variants.

Signatures of natural selection and ethnic-specific prevalence of NPC1 pathogenic mutations contributing to obesity and Niemann-Pick disease type C1.

While homozygous pathogenic mutations in the NPC1 gene cause Niemann-Pick type C1 disease, heterozygous mutations cause highly-penetrant obesity. We aimed to investigate the prevalence of NPC1 mutations and their signatures of natural selection in 122,678 exome sequenced participants from six ethnic groups in the Genome Aggregation Database. Pathogenic missense coding mutations were identified by in silico tools and the ClinVar database. Signatures of natural selection were assessed by the probability of NPC1 being loss-of-function mutation intolerant and Z-scores of observed/expected synonymous and non-synonymous mutation ratios. There was no evidence of negative selection observed for synonymous, non-synonymous and loss-of-function mutations. However, there were significant ethnic differences in the prevalence of heterozygous pathogenic NPC1 mutations ranging from 0.56% in Ashkenazi Jewish to 3.26% in African/African Americans (5.8-fold difference). Four homozygous carriers of pathogenic NPC1 mutations were also identified, belonging to the South Asian population. In conclusion, NPC1 mutations are consistent with a model of balanced selection, where heterozygotes and homozygotes have higher and lower reproductive fitness, respectively. Therefore, NPC1 heterozygous mutations may account for a substantial and ethnic-dependent percentage of obesity in the general population, while NPC1 homozygous mutations may be frequent in the South Asian populations and warrants more investigation.

Childhood and adolescent mental health of NICU graduates: an observational study.

OBJECTIVE: To investigate the mental health of children and adolescents admitted to neonatal intensive/special care units (NICUs) in infancy. METHODS: This cross-sectional study used a provincially representative cohort from the 2014 Ontario Child Health Study. Parents provided data on psychiatric disorders using the MINI International Neuropsychiatric Interview for Children and Adolescents in 3141 children aged 4-11 years (NICU n=389; control n=2752) and in 2379 children aged 12-17 years (NICU n=298; control n=2081). Additionally, 2235 adolescents aged 12-17 years completed the interview themselves (NICU n=285; control n=1950). Odds of psychiatric disorder were compared in those admitted and controls. RESULTS: Based on parent reports, NICU graduates aged 4-11 years had increased adjusted ORs (95% CI) of 1.78 (1.39 to 2.28) for any psychiatric disorder, with a marginal prevalence of 32.4% in NICU participants and 27.6% in controls. At this age, NICU graduates also had increased ORs of 1.74 (1.25 to 2.40) for psychiatric comorbidity, 1.48 (1.04 to 2.11) for oppositional defiant disorder, 1.61 (1.19 to 2.19) for attention-deficit hyperactivity disorder, 4.11 (2.33 to 7.25) for separation anxiety disorder and 2.13 (1.37 to 3.31) for specific phobia. At 12-17 years, 40.5% and 30.5% of NICU graduates and 30.6% and 17.9% of controls had any psychiatric disorder as reported by parents and self-report, respectively. Parents and adolescents, respectively, reported increased adjusted ORs (95% CI) of 1.63 (1.18 to 2.26) and 1.55 (1.13 to 2.11) for any disorder, 1.64 (1.06 to 2.54) and 1.74 (1.11 to 2.73) for psychiatric comorbidity, and 1.89 (1.22 to 2.93) and 3.17 (2.03 to 4.95) for oppositional defiant disorder. CONCLUSIONS: NICU graduates are at increased risk for psychiatric disorders during childhood and adolescence.

Comprehensive characterization of a Canadian cohort of von Hippel-Lindau disease patients.

Von Hippel-Lindau disease (VHL) is a heritable condition caused by pathogenic variants in VHL and is characterized by benign and malignant lesions in the central nervous system (CNS) and abdominal viscera. Due to its variable expressivity, existing efforts to collate VHL patient data do not adequately capture all VHL manifestations. We developed a comprehensive and standardized VHL database in the web-based application, REDCap, that thoroughly captures all VHL manifestation data. As an initial trial, information from 86 VHL patients from the University Health Network/Hospital for Sick Children was populated into the database. Analysis of this cohort showed missense variants occurring with the greatest frequency, with all variants localizing to the α- or ß-domains of VHL. The most prevalent manifestations were central nervous system (CNS), renal, and retinal neoplasms, which were associated with frameshift variants and large deletions. We observed greater age-related penetrance for CNS hemangioblastomas with truncating variants compared to missense, while the reverse was true for pheochromocytomas. We demonstrate the utility of a comprehensive VHL database, which supports the standardized collection of clinical and genetic data specific to this patient population. Importantly, we expect that its web-based design will facilitate broader international collaboration and lead to a better understanding of VHL.

Childhood Motor Coordination and Adult Affective Experience Among Extremely Low Birth Weight Survivors.

Poor motor coordination in childhood has been associated in adulthood with more negative affect, less positive affect, and an increased risk of psychopathology. While survivors of extremely low birth weight (ELBW; < 1,000 grams) are more likely to manifest poor motor coordination than people born at normal birth weight (NBW; > 2,500 g), they have had better mental health outcomes than those with NBW who have motor difficulties. How emotion is experienced is an important risk factor for mental illness; yet, little is known about the affective experience of survivors of ELBW who also have poor motor coordination. In this longitudinal study, we examined interactions between birth weight status and childhood motor coordination on affective experience among 88 ELBW and 89 NBW participants. We first assessed childhood motor coordination at eight years of age, using the Bruininks-Oseretsky Test of Motor Proficiency, and we later gathered self-report data regarding affective style, using the Positive and Negative Affect Scedule and the Affective Styles Questionnaire, when these participants were 30-35 years of age. We found a statistically significant interaction between motor coordination and birth weight status. As motor coordination worsened among ELBW survivors, positive affect increased, while we observed the opposite trend in NBW participants (p < 0.05). There was no interaction for negative affect. Positive affect may contribute to previous findings of better relative adult mental health among ELBW survivors with poor childhood motor coordination. Strategies aimed at optimizing positive affect may be fruitful for optimizing mental health outcomes among preterm survivors and others with reduced motor proficiency.