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Introduction The Positive and Negative Syndrome Scale (PANSS) has been used as a universal instrument for clinical assessment of psychopathology in schizophrenia. Different studies have analyzed the factorial structure of this scale and have suggested a five-factor model: positive, negative, excited, depressive, and cognitive/disorganized factors. Two of the most used models are the Marder´s solution and the Wallwork´s one. Objectives The aim of this work was to study the correlations of the two cognitive factors (Marder and Wallwork) with a cognitive assessment performed with a standard cognitive battery, in a sample of patients with first psychotic episode of schizophrenia. Methods Seventy four patients with first psychotic episode of schizophrenia (26.9, SD:7.8 years old; 70.3% male) were included. The cognitive assessment was performed with the MATRICS Consensus Cognitive Battery (MCCB). The MCCB present seven cognitive domains: Speed of processing, Working memory, Attention/Vigilance, Verbal Learning, Visual Learning, Reasoning and Problem Solving, and Social cognition). Pearson correlations were performed between MCCB scores and Marder´s PANSS cognitive factor (P2, N5, G5, G10, G11, G13, G15) and Wallwork´s one (P2, N5, G11). Results Correlation between MCCB scores and cognitive factors of Marder and Wallwork can be seen in the table. Marder´s cognitive factor Wallwork´s cognitive factor Speed of processing r = -0.461; p

Purpose: Anti-programmed cell death 1 (PD1) is the first-choice treatment in patients with advanced cutaneous squamous cell carcinoma (cSCC), when curative options are unavailable. However, reliable biomarkers for patient selection are still lacking., Experimental Design: In this translational study, clinical annotations, tissue and liquid biopsies were acquired to investigate the association between sustained objective responses and transcriptional profiles, immune cell dynamics in tumor tissue and peripheral blood samples, as well as circulating cytokine levels., Results: First, we investigated the baseline characteristics of the immune landscape of cSCC biopsies. Gene Set Enrichment Analysis showed upregulation of interleukin (IL)2/STAT5 pathways and downregulation of Interferon signatures in non-responder patients compared with responders. Next, we studied the early changes induced by cemiplimab in tissue biopsies. Notably, after only three weeks, cemiplimab treatment induced an increase in B cells and CD8+ T cells in responders, whereas their abundance decreased in non-responder patients. Moreover, analyzing differentially expressed genes modulated early during treatment, compared with baseline biopsies, we found that IL1β and IL8 exhibited early downregulation in responder patients' tumor specimens. We assessed whether changes in the local tumor microenvironment were mirrored in peripheral blood. Similar to tissue findings, no changes were observed in the whole T regulatory (Treg) population, although PD1+ Tregs, which were downregulated in responder patients (vs T0), showed a rebound enrichment in non-responders after three cycles of cemiplimab. Finally, IL8 mirrored the tissue results, unlike IL1β, with early (T1) and then sustained (T3) downregulation of its levels in responder patients, while increased in non-responders., Conclusions: Taken together, these findings shed light on the significance of early transcriptomic and immune cell modulation in predicting responses to cemiplimab therapy. Additionally, our data suggest that IL8 levels in peripheral blood offer promising avenues for personalized treatment selection and response assessment in patients with cSCC receiving cemiplimab, while PD1+Tregs can be followed longitudinally to monitor response to therapy., Competing Interests: Competing interests: LF declares the following competing interests: Consultant and advisory board for Seagen, Amgen, BMS, MSD, Jansen and Pierre Fabre Pharma. RB declares the following competing interests: Consultant and advisory board for BMS, MSD, Pfizer, AstraZeneca, Lilly and Novartis. AS reports honoraria from Eli Lilly, MSD, and Janssen and travel support from Bristol-Myers Squibb and AstraZeneca. The remaining authors declare no competing interests., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Introduction: Relative or absolute safety of heated tobacco products (HTP) remains unknown, while independent literature suggests that these products do not favour tobacco control. We conducted a comprehensive systematic review and meta-analysis to evaluate HTP usage patterns and the effect of HTP use on conventional tobacco smoking (use transitions)., Methods: We used Pubmed/MEDLINE, Embase and the Cochrane Library to identify all articles published up to February 2022 on HTP use. For the present review, we included all representative cross-sectional studies dealing with HTP use, and all prospective cohort studies or cross-sectional studies on conventional tobacco smoking transitions due to HTP use. From 610 non-duplicate articles, 76 were eligible (71 cross-sectional and 5 prospective cohort studies)., Results: Compared with young adults, HTP use was less frequent among middle-aged (pooled odds ratio, OR=0.59; 95% confidence interval, CI: 0.48-0.74; number of studies, n=15) and older adults (OR=0.17; 95%-CI: 0.07-0.38; n=12). HTP use was more frequent among former (OR=2.73; 95%-CI: 1.03-7.25; n=6) and current smokers (OR=14.53; 95%-CI: 6.34-33.31; n=12). Overall, 68.3% of HTP users were dual users (n=26). Eight studies (including 5 cohorts) showed that HTP users were more likely than non-users to start conventional cigarette smoking (OR=6.31; 95%-CI: 4.13-9.65; n=2), whereas current cigarette smokers using HTPs were less likely to quit (OR=0.84; 95%-CI: 0.80-0.89; n=4)., Conclusions: We found that HTPs are specifically popular among young generations. More than two out of three HTP users are dual users. Prospective studies consistently show that in real life HTPs are not effective smoking cessation tools.

BCL11B is a Cys2-His2 zinc-finger (C2H2-ZnF) domain-containing, DNA-binding, transcription factor with established roles in the development of various organs and tissues, primarily the immune and nervous systems. BCL11B germline variants have been associated with a variety of developmental syndromes. However, genotype-phenotype correlations along with pathophysiologic mechanisms of selected variants mostly remain elusive. To dissect these, we performed genotype-phenotype correlations of 92 affected individuals harboring a pathogenic or likely pathogenic BCL11B variant, followed by immune phenotyping, analysis of chromatin immunoprecipitation DNA-sequencing data, dual-luciferase reporter assays, and molecular modeling. These integrative analyses enabled us to define three clinical subtypes of BCL11B-related disorders. It is likely that gene-disruptive BCL11B variants and missense variants affecting zinc-binding cysteine and histidine residues cause mild to moderate neurodevelopmental delay with increased propensity for behavioral and dental anomalies, allergies and asthma, and reduced type 2 innate lymphoid cells. Missense variants within C2H2-ZnF DNA-contacting α helices cause highly variable clinical presentations ranging from multisystem anomalies with demise in the first years of life to late-onset, hyperkinetic movement disorder with poor fine motor skills. Those not in direct DNA contact cause a milder phenotype through reduced, target-specific transcriptional activity. However, missense variants affecting C2H2-ZnFs, DNA binding, and "specificity residues" impair BCL11B transcriptional activity in a target-specific, dominant-negative manner along with aberrant regulation of alternative DNA targets, resulting in more severe and unpredictable clinical outcomes. Taken together, we suggest that the phenotypic severity and variability is largely dependent on the DNA-binding affinity and specificity of altered BCL11B proteins., Competing Interests: Declaration of interests Baylor College of Medicine (BCM) and Miraca Holdings Inc. have formed a joint venture with shared ownership and governance of the Baylor Genetics (BG), which performs clinical exome sequencing. J.R.L. has stock ownership in 23andMe, is a paid consultant for Genome International, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, genomic disorders, and bacterial genomic fingerprinting. A. Begtrup is an employee of and may hold stock in GeneDx, LLC., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Autism spectrum disorder (ASD) exhibits an ∼4:1 male-to-female sex bias and is characterized by early-onset impairment of social/communication skills, restricted interests, and stereotyped behaviors. Disruption of the Xp22.11 locus has been associated with ASD in males. This locus includes the three-exon PTCHD1, an adjacent multi-isoform long noncoding RNA (lncRNA) named PTCHD1-AS (spanning ∼1 Mb), and a poorly characterized single-exon RNA helicase named DDX53 that is intronic to PTCHD1-AS. While the relationship between PTCHD1/PTCHD1-AS and ASD is being studied, the role of DDX53 has not been comprehensively examined, in part because there is no apparent functional murine ortholog. Through clinical testing, here, we identified 8 males and 2 females with ASD from 8 unrelated families carrying rare, predicted damaging or loss-of-function variants in DDX53. Additionally, we identified a family consisting of a male proband and his affected mother with high-functioning autism, both harboring a gene deletion involving DDX53 and exons of the noncoding RNA PTCHD1-AS. Then, we examined databases, including the Autism Speaks MSSNG and Simons Foundation Autism Research Initiative, as well as population controls. We identified 26 additional individuals with ASD harboring 19 mostly maternally inherited, rare, damaging DDX53 variations, including two variants detected in families from the original clinical analysis. Our findings in humans support a direct link between DDX53 and ASD, which will be important in clinical genetic testing. These same autism-related findings, coupled with the observation that a functional orthologous gene is not found in mice, may also influence the design and interpretation of murine modeling of ASD., Competing Interests: Declaration of interests At the time of this study and its publication, S.W.S. served on the scientific advisory committee of Population Bio. Intellectual property from aspects of his research held at The Hospital for Sick Children are licensed to Athena Diagnostics and Population Bio. These relationships did not influence data interpretation or presentation during this study but are disclosed for potential future considerations. S.V.M. is an employee of GeneDx, LLC. H.F.P. is on the research advisory boards and speaker bureau for Takeda Pharmaceutical, AvroBio, Amicus Therapeutics, Sanofi, Alexion Therapeutics, Denali Therapeutics, and Acer Therapeutics., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Pediatric intestinal pseudo-obstruction (PIPO) is a rare congenital disorder of the enteric nervous system with distal colon aganglionosis potentially leading to intestinal obstruction. Recently, biallelic variants in KIF26A, encoding a crucial motor protein for the migration and differentiation of enteric neural crest cells, have been associated with a neurodevelopmental condition featuring cortical defects and PIPO-like features, though in absence of aganglionosis. So far, only 10 patients have been reported. In this study, we investigated three subjects with congenital hydrocephalus, neurodevelopmental impairment, and intestinal obstruction megacolon syndrome. Brain MRI revealed malformations within cortical dysplasia spectrum, including polymicrogyria and heterotopia. Pathology study of the intestine revealed aganglionosis and elevated acetylcholinesterase activity in parasympathetic nerve fibers. Through trio-exome sequencing (ES), we detected four novel biallelic KIF26A variants, including two missense changes (#1) and two distinct homozygous truncating variants in (#2 and #3). All variants are rare and predicted to be deleterious according to in silico tools. To characterize the impact of the missense variants, we performed 3D protein modeling using Alphafold3 and YASARA. Mutants exhibited increased energy scores compared to wild-type protein, supporting a significant structural destabilization of the protein. Our study expands the genotype and phenotype spectrum of the emerging KIF26A-related disorder., (© 2024 The Author(s). Clinical Genetics published by John Wiley & Sons Ltd.)

Background: We aimed to estimate real-world evidence of the prevalence rate of genetic developmental and epileptic encephalopathies (DEEs) in the Italian population over a 11-year period., Methods: Fifteen paediatric and adult tertiary Italian epilepsy centres participated in a survey related to 98 genes included in the molecular diagnostic workflows of most centres. We included patients with a clinical diagnosis of DEE, caused by a pathogenic or likely pathogenic variant in one of the selected genes, with a molecular diagnosis established between 2012 and 2022. These data were used as a proxy to estimate the prevalence rate of DEEs., Results: We included 1568 unique patients and found a mean incidence proportion of 2.6 patients for 100.000 inhabitants (SD=1.13) with consistent values across most Italian regions. The number of molecular diagnoses showed a continuing positive trend, resulting in more than a 10-fold increase between 2012 and 2022. The mean age at molecular diagnosis was 11.2 years (range 0-75). Pathogenic or likely pathogenic variants in genes with an autosomal dominant inheritance pattern occurred in 77% (n=1207) patients; 17% (n=271) in X-linked genes and 6% (n=90) in genes with autosomal recessive inheritance. The most frequently reported genes in the survey were SCN1A (16%), followed by KCNQ2 (5.6%) and SCN2A (5%)., Conclusion: Our study provides a large dataset of patients with monogenic DEE, from a European country. This is essential for informing decision-makers in drug development on the appropriateness of initiatives aimed at developing precision medicine therapies and is instrumental in implementing disease-specific registries and natural history studies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY. Published by BMJ Group.)

The revival of psilocybin in psychopharmacological research heralds a potential paradigm shift for treating mood and anxiety disorders, and other psychiatric conditions beyond the psychotic spectrum. This critical review evaluates current evidence on psilocybin's efficacy, juxtaposing potential benefits with the practical aspects of psychedelic-assisted psychotherapy (PAP) and the methodological constraints of existing research.An electronic literature search was conducted using PubMed/MEDLINE, selecting studies published up to December 2023 that explored the clinical use of psilocybin in mood and anxiety disorders, obsessive-compulsive disorder, post-traumatic stress disorder, and substance use disorder. Despite promising preliminary results suggesting psilocybin's efficacy in alleviating depression and anxiety, as well as obsessions, compulsions, and addictive behaviors, significant evidence gaps persist. These include evaluating the efficacy of psilocybin compared to standard antidepressants or anxiolytic molecules and identifying patient subpopulations that might benefit most from PAP. Concerns about psilocybin's safety, long-term efficacy, and optimal dosage remain unclear due to previous trials' limitations. Real-world implementation faces challenges, including infrastructural requirements, personnel training, and unresolved legal and ethical issues. This paper argues for further research to substantiate the evidence base, emphasizing the need for larger studies that overcome current methodological limitations and explore psilocybin's full therapeutic potential. While psilocybin holds promise for psychiatry, its successful translation from research to clinical practice demands more robust evidence on efficacy, safety, and methodological rigor. In addition, other factors, such as cultural stigma and legal/ethical issues, need to be successfully addressed to facilitate psilocybin's implementation in healthcare systems.

RAC3 encodes a small GTPase of the Rho family that plays a critical role in actin cytoskeleton remodeling and intracellular signaling regulation. Pathogenic variants in RAC3 , all of which reported thus far affect conserved residues within its functional domains, have been linked to neurodevelopmental disorders characterized by diverse phenotypic features, including structural brain anomalies and facial dysmorphism (NEDBAF). Recently, a novel de novo RAC3 variant (NM_005052.3): c.196C>T, p.R66W was identified in a prenatal case with fetal akinesia deformation sequence (a spectrum of conditions that interfere with the fetus's ability to move), and complex brain malformations featuring corpus callosum agenesis, diencephalosynapsis, kinked brainstem, and vermian hypoplasia. To investigate the mechanisms underlying the association between RAC3 deficiency and this unique, distinct clinical phenotype, we explored the pathophysiological significance of the p.R66W variant in brain development. Biochemical assays revealed a modest enhancement in intrinsic GDP/GTP exchange activity and an inhibitory effect on GTP hydrolysis. Transient expression studies in COS7 cells demonstrated that RAC3-R66W interacts with the downstream effectors PAK1, MLK2, and N-WASP but fails to activate SRF-, AP1-, and NFkB-mediated transcription. Additionally, overexpression of RAC3-R66W significantly impaired differentiation in primary cultured hippocampal neurons. Acute expression of RAC3-R66W in vivo by in utero electroporation resulted in impairments in cortical neuron migration and axonal elongation during corticogenesis. Collectively, these findings suggest that the p.R66W variant may function as an activated version in specific signaling pathways, leading to a distinctive and severe prenatal phenotype through variant-specific mechanisms.

Deficits in social cognition may impair emotional processing and facial emotional recognition (FER) in patients with bipolar disorder (BD) and schizophrenia. FER is generally explored using photographs or images of static faces that do not fully capture the complexity of real-life facial stimuli. To overcome this limitation, we developed a set of dynamic virtual faces depicting six basic emotions (i.e. happiness, sadness, anger, fear, disgust, and surprise) and a neutral expression suitable for presentation in immersive and nonimmersive virtual realities. This study presents preliminary findings on the differences in FER accuracy from a frontal view between immersive and nonimmersive virtual realities among patients experiencing a relapse of schizophrenia (n = 10), a manic phase of BD (n = 10), and a group of healthy controls (HCs) (n = 10). As a secondary objective, we compare the FER accuracy across these three groups. Patients with schizophrenia and BD showed similar accuracy in recognizing emotions in immersive and nonimmersive virtual reality settings. However, patients with schizophrenia exhibited lower FER accuracy than HCs in both settings. Individuals with BD showed intermediate accuracy between those with schizophrenia and HCs, although these differences were not statistically significant. Notably, recognition of negative emotions was significantly impaired in both groups of patients., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Severe neonatal inflammatory conditions in very preterm infants (VPT: <32 weeks gestational age, GA) are linked to adverse neurodevelopmental outcomes. Differences in white matter (WM) microstructure of the corpus callosum (CC) have been observed at age 6 in VPT children with a history of severe neonatal inflammation. The goal of this study was to determine whether these CC differences can be detected at term-equivalent age using diffusion MRI (dMRI), and whether neonatal inflammation is associated with altered WM in additional tracts implicated in the encephalopathy of prematurity., Methods: We conducted a retrospective study of VPT infants ( n = 152) born at 22-32 weeks GA, classified based on the presence (I+, n = 80) or absence (I-, n = 72) of severe neonatal inflammatory conditions (bronchopulmonary dysplasia, necrotizing enterocolitis, or culture-positive sepsis). Analysis of covariance (ANCOVA) assessed group differences in near-term dMRI mean fractional anisotropy (FA) and mean diffusivity (MD) across seven segments of the CC and the anterior thalamic radiation, arcuate fasciculus, cingulum, corticospinal tract, inferior longitudinal fasciculus, superior cerebellar peduncle, and uncinate fasciculus. Due to imbalance of GA in the full sample, secondary ANCOVA analyses were performed in a GA-matched subset ( n = 42) to further isolate the effect of inflammation., Results: FA was significantly lower in the I+ group compared to the I- group in the anterior frontal, posterior parietal, temporal, and occipital segments of the CC, and in the cingulum, inferior longitudinal fasciculus, and superior cerebellar peduncle. This general pattern persisted in the GA-matched subset, with significant differences in the anterior frontal and temporal CC segments., Conclusions: VPT infants with severe neonatal inflammation had lower FA in multiple white matter tracts, suggesting that inflammation-related alterations in WM development begin in the neonatal period. The observed differences detected using dMRI at term-equivalent age corroborate prior findings and may provide a window of opportunity for early identification of VPT infants at increased risk of poor neurodevelopmental outcomes., Competing Interests: Declaration of competing interest All individuals listed as authors meet authorship criteria, no persons have been omitted from the authorship list, all contributors and funding sources have been acknowledged, and authors have approved acknowledgment of their contributions. No authors have conflicts of interest nor have any financial interests to declare.

Legius syndrome, commonly referred to as SPRED1-related neurofibromatosis type 1-like syndrome, is a rare autosomal dominant disorder characterized by café-au-lait macules, freckling, lipomas, macrocephaly, and heterogeneous neurodevelopmental manifestations, including a different degree of learning difficulties. Although a partial clinical overlap exists with neurofibromatosis type 1 (NF1), Legius syndrome is distinguished by its genetic etiology and the absence of neurofibromas, indicating an inherent lack of tumor risk. The SPRED1 gene encodes the Sprouty-related protein with an EVH1 domain 1 (SPRED1), a negative regulator of the RAS-MAPK signaling pathway with a crucial role in cellular growth and development. Despite various genetic variants and genomic deletions associated with Legius syndrome, the full genetic spectrum of this condition remains elusive. In this study, we investigated the underlying genetic etiology in a cohort of patients presenting with typical manifestations of Legius syndrome using a custom Next Generation Sequencing (NGS) panel and Multiplex Ligation-Dependent Probe Amplification (MLPA) for NF1 and SPRED1. We identified 12 novel SPRED1 damaging variants segregating with the phenotype in all families. These rare variants affect conserved residues of the protein and are predicted damaging according to in silico tools. No clear genotype-phenotype correlations could be observed in the current cohort and previously reported patients, underscoring the heterogeneous genotype spectrum of this condition. Our findings expand the understanding of SPRED1 variants causing Legius syndrome and underscore the importance of comprehensively characterizing the genetic landscape of this disorder. Despite the absence of clear genotype-phenotype correlations, elucidating the genetic etiology of Legius syndrome is pertinent for facilitating accurate diagnosis, genetic counseling, and therapeutic interventions., (© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Pathogenic variants in the SETD5 gene cause a neurodevelopmental disorder characterized by intellectual disability, autism, and facial dysmorphisms, with incomplete penetrance. To date, no distinctive neurological, psychiatric, electroencephalographic, and neuroimaging features have been identified in this condition. We expand the clinical phenotype of SETD5-related disorder by describing 28 previously unreported patients, 26 carrying single nucleotide variants, and 2 with copy number variations involving SETD5 gene, focusing on neurological, psychiatric, EEG, and brain MRI data. In our cohort neurological symptoms include hypotonia (39.2 %), hyperkinetic movement disorders including stereotypies and chorea (21.4 %) and gait abnormalities ranging from tip-toe or unsteady walking and alterations of fine motor skills (35.7 %). Epilepsy was present in about 14 % of patients, including different types of seizures as epileptic spasms, focal motor, and non-motor seizures. Concerning the cognitive phenotype, intellectual disability or global developmental delay depending on age, ranging from mild to severe, was present in 75 % of cohort, 21.4 % exhibit borderline intellectual functioning while an individual has a normal intelligence quotient. Other psychiatric comorbidities include autism, ADHD, psychotic disorder and other internalizing and externalizing symptoms. Finally, we conduct a comprehensive review of the available literature, suggesting a possible genotype-phenotype correlation., Competing Interests: Declaration of competing interest All authors declare no conflict of interest., (Copyright © 2024 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Rigid spine syndrome is a rare childhood-onset myopathy characterised by slowly progressive or non-progressive scoliosis, neck and spine contractures, hypotonia, and respiratory insufficiency. Biallelic variants in SELENON account for most cases of rigid spine syndrome, however, the underlying genetic cause in some patients remains unexplained. We used exome and genome sequencing to investigate the genetic basis of rigid spine syndrome in patients without a genetic diagnosis. In five patients from four unrelated families, we identified biallelic variants in HMGCS1 (3-hydroxy-3-methylglutaryl-coenzyme A synthase). These included six missense variants and one frameshift variant distributed throughout HMGCS1. All patients presented with spinal rigidity primarily affecting the cervical and dorsolumbar regions, scoliosis, and respiratory insufficiency. Creatine kinase levels were variably elevated. The clinical course worsened with intercurrent disease or certain drugs in some patients; one patient died from respiratory failure following infection. Muscle biopsies revealed irregularities in oxidative enzyme staining with occasional internal nuclei and rimmed vacuoles. HMGCS1 encodes a critical enzyme of the mevalonate pathway and has not yet been associated with disease. Notably, biallelic hypomorphic variants in downstream enzymes including HMGCR and GGPS1 are associated with muscular dystrophy resembling our cohort's presentation. Analyses of recombinant human HMGCS1 protein and four variants (p.S447P, p.Q29L, p.M70T, p.C268S) showed that all mutants maintained their dimerization state. Three of the four mutants exhibited reduced thermal stability, and two mutants showed subtle changes in enzymatic activity compared to the wildtype. Hmgcs1 mutant zebrafish displayed severe early defects, including immobility at 2 days and death by day 3 post-fertilisation and were rescued by HMGCS1 mRNA. We demonstrate that the four variants tested (S447P, Q29L M70T, and C268S) have reduced function compared to wildtype HMGCS1 in zebrafish rescue assays. Additionally, we demonstrate the potential for mevalonic acid supplementation to reduce phenotypic severity in mutant zebrafish. Overall, our analyses suggest that these missense variants in HMGCS1 act through a hypomorphic mechanism. Here, we report an additional component of the mevalonate pathway associated with disease and suggest biallelic variants in HMGCS1 should be considered in patients presenting with an unresolved rigid spine myopathy phenotype. Additionally, we highlight mevalonoic acid supplementation as a potential treatment for patients with HMGCS1-related disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: To examine the relationship between inpatient skin-to-skin care rates and neurodevelopmental scores measured at 12 months in very preterm (VPT) infants., Study Design: From a retrospective review of medical records of 181 VPT infants (<32 weeks gestational age [GA] at birth), we derived skin-to-skin care rate, ie, total minutes of skin-to-skin care each infant received over the number of days of hospital stay. We used scores on the Capute Scales from routine follow-up assessments at 12 months to measure neurodevelopmental outcomes., Results: Families averaged approximately 17 minutes/day of skin-to-skin care (2 days/week, 70 minutes/session), although there was substantial variability. Variation in skin-to-skin rate was positively associated with outcomes at 12 months corrected age (r = 0.25, P < .001). Skin-to-skin rate significantly predicted 6.2% unique variance in 12-month neurodevelopmental outcomes, after adjusting for GA, socioeconomic status (SES), health acuity, and visitation frequency. A 20-minute increase in skin-to-skin care per day was associated with a 10-point increase (0.67 SDs) in neurodevelopmental outcomes at 12 months. GA and infant health acuity did not moderate these relations., Conclusion: VPT infants who experienced more skin-to-skin care during hospitalization demonstrated higher scores on 12-month neurodevelopmental assessments. Results provide evidence that skin-to-skin care confers extended benefits to VPT infants through the first year of life. Skin-to-skin care offers promise as a family-centered intervention designed to promote positive developmental outcomes in at-risk infants., Competing Interests: Declaration of Competing Interest This research work was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (K.E. Travis, PI: 5R00-HD84749; H.M. Feldman, PI: 2R01-HD069150) and the National Institute of Mental Health Postdoctoral Research Training in Child Psychiatry and Neurodevelopment (A. Reiss, PI: T32-MH019908)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Cariprazine (CAR), an antipsychotic with partial agonism at the D3 receptor and higher affinity than dopamine, has shown significant procognitive effects in preclinical animal studies. This study systematically reviews CAR's effects on cognitive measures in patients with schizophrenia and bipolar disorder., Methods: Two independent reviewers systematically searched PubMed, Web of Science, Scopus, and the Cochrane Library up to May 2024, following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Additional studies were found by hand searching the references of included studies. Eligible studies were randomized controlled trials (RCTs) in English that assessed CAR's effects on cognition in patients with schizophrenia or bipolar disorder. Quality was assessed using the Jadad scale., Results: Out of 139 reports, 5 studies (involving 6,104 patients with schizophrenia or bipolar disorder) were included. In schizophrenia, CAR showed better cognitive outcomes (mainly indirect measures) than placebo (PBO) in both early and late stages. It also outperformed risperidone and aripiprazole in attention-related cognitive tests. In bipolar disorder, CAR improved cognition compared to PBO (also using indirect measures). Most studies found the greatest cognitive benefits with low doses of CAR (1.5-3 mg/d)., Conclusions: CAR improved cognitive measures compared to PBO and other D2 antagonists or partial agonists in RCTs, especially in patients with greater baseline impairment. Thus, CAR may be a promising option for enhancing cognition in schizophrenic and bipolar patients; though, more trials using specific cognitive assessment tools are needed., Systematic Review Registration: PROSPERO CRD42023485028., (Copyright © 2024 President and Fellows of Harvard College.)

An increasing number of individuals with intellectual developmental disorder (IDD) and heterozygous variants in BCL11A are identified, yet our knowledge of manifestations and mutational spectrum is lacking. To address this, we performed detailed analysis of 42 individuals with BCL11A-related IDD (BCL11A-IDD, a.k.a. Dias-Logan syndrome) ascertained through an international collaborative network, and reviewed 35 additional previously reported patients. Analysis of 77 affected individuals identified 60 unique disease-causing variants (30 frameshift, 7 missense, 6 splice-site, 17 stop-gain) and 8 unique BCL11A microdeletions. We define the most prevalent features of BCL11A-IDD: IDD, postnatal-onset microcephaly, hypotonia, behavioral abnormalities, autism spectrum disorder, and persistence of fetal hemoglobin (HbF), and identify autonomic dysregulation as new feature. BCL11A-IDD is distinguished from 2p16 microdeletion syndrome, which has a higher incidence of congenital anomalies. Our results underscore BCL11A as an important transcription factor in human hindbrain development, identifying a previously underrecognized phenotype of a small brainstem with a reduced pons/medulla ratio. Genotype-phenotype correlation revealed an isoform-dependent trend in severity of truncating variants: those affecting all isoforms are associated with higher frequency of hypotonia, and those affecting the long (BCL11A-L) and extra-long (-XL) isoforms, sparing the short (-S), are associated with higher frequency of postnatal microcephaly. With the largest international cohort to date, this study highlights persistence of fetal hemoglobin as a consistent biomarker and hindbrain abnormalities as a common feature. It contributes significantly to our understanding of BCL11A-IDD through an extensive unbiased multi-center assessment, providing valuable insights for diagnosis, management and counselling, and into BCL11A's role in brain development., (© 2024. The Author(s).)

Through the use of an innovative method to identify original publications, we conducted a meta-analysis of all epidemiological studies evaluating the association between second-hand smoke (SHS) exposure and breast cancer risk among female non-smokers published in English up to October 2022. Pooled relative risks (RR) were obtained through the use of random-effects models. Dose-response relationships were derived using log-linear functions. Out of 73 identified eligible studies, 63 original articles were included in the meta-analysis. The pooled RR for breast cancer for overall exposure to SHS was 1.24 (95% confidence interval, CI, 1.15-1.34, number of articles, n = 52). Regarding the setting of exposure, RRs were 1.17 (95% CI 1.08-1.27, n = 37) for SHS exposure at home, 1.03 (95% CI 0.98-1.08, n = 15) at the workplace, 1.24 (95% CI 1.11-1.37, n = 16) at home or workplace, and 1.45 (95% CI 1.16-1.80, n = 13) for non-specified settings. The risk of breast cancer increased linearly with higher duration (RR 1.29; 95% CI 1.04-1.59 for 40 years of SHS exposure, n = 12), intensity (RR 1.38; 95% CI 1.14-1.67 for 20 cigarettes of SHS exposure per day, n = 6), and pack-years (RR 1.50; 95% CI 0.92-2.45 for 40 SHS pack-years, n = 6) of SHS exposure. This meta-analysis shows a statistically significant excess risk of breast cancer in women exposed to SHS., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Early speech experiences have been proposed to contribute to the development of brain structures involved in processing spoken language. However, previous research has been limited to correlational studies. Here, we conducted an RCT with preterm neonates to determine whether increased exposure to maternal speech during NICU hospitalization is causally linked to structural white matter maturation., Methods: We enrolled 46 preterm neonates (24-31 weeks gestational age). Participants were randomly assigned to receive increased (T: n=21) or routine (C: n=25) exposure to mother's speech. The T-group heard 10-minute audio recordings of their mothers reading a children's story two times/hour between 10pm-6am, increasing speech exposure by 2.67 hours/day. At near-term-equivalent age, we obtained two high-angular resolution diffusion MRI (scan 1 bvalue=700, scan 2 bvalue=1500) and quantitative T1 relaxometry scans. We assessed mean diffusivity (MD), pre-registered primary outcome ( NCT02847689 ), of the left and right arcuate fasciculus, tracts implicated in language processing. Secondary outcomes included fractional anisotropy (FA) and R1 (1/T1)., Findings: T- and C-groups were equivalent on medical and demographic variables. Compared to the C- group, the T-group demonstrated significantly lower MD in the left (scan 1: mean difference Δ = 0.11, 95% CI:0.03 - 0.19; scan 2: Δ = 0.13, 95% CI:0.04 - 0.21) but not right arcuate (scan 1: Δ = 0.06, 95% CI: -0.23 - 0.15; scan 2: Δ = 0.05, 95% CI:-0.05 - 0.13). The T-group also demonstrated significantly higher FA (scan 1: Δ = - 0.02, 95% CI:-0.04 - -0.00; scan 2: Δ = -0.03, 95% CI:-0.06 - -0.00) and R1 ( Δ = -0.02, 95% CI:-0.04 - -0.01) in the left but not right arcuate., Interpretation: Preterm neonates who experienced increased exposure to maternal speech during hospitalization demonstrated more mature microstructure of the left arcuate. Findings provide evidence for a causal link between speech experiences and brain development. Increasing speech exposure in the NICU may benefit preterm children., Research in Context Panel: Evidence before this study: Observational studies document the importance of early speech experience for language learning and brain development in term and preterm children. Children born preterm are at-risk for adverse language outcomes that have been attributed to alterations in brain development from limited exposure to speech in the neonatal intensive care unit (NICU). However, evidence that early speech experiences causally effect the development of brain structures relevant for language is lacking. Added value of this study: The Listening to Mom in NICU study is the first randomized controlled trial specifically designed to test the causal effects of maternal speech exposure on white matter brain development in neonates born preterm. This study demonstrates that speech experiences during neonatal development directly contribute to the maturation of the left arcuate fasciculus, a white matter tract implicated in language. Implications of all the available evidence: Study findings advance understandings for how early speech experiences contribute to neonatal brain development. This study also demonstrates that increasing exposure to speech via audio recordings among infants born preterm could serve as an inexpensive and scalable intervention to support recovery from alterations in brain development related to the NICU experience.

Identifying genetic risk factors for highly heterogeneous disorders like epilepsy remains challenging. Here, we present the largest whole-exome sequencing study of epilepsy to date, with >54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets, and four copy number variants at exome-wide significance. Genes encoding ion channels show strong association with multiple epilepsy subtypes, including epileptic encephalopathies, generalized and focal epilepsies, while most other gene discoveries are subtype-specific, highlighting distinct genetic contributions to different epilepsies. Combining results from rare single nucleotide/short indel-, copy number-, and common variants, we offer an expanded view of the genetic architecture of epilepsy, with growing evidence of convergence among different genetic risk loci on the same genes. Top candidate genes are enriched for roles in synaptic transmission and neuronal excitability, particularly postnatally and in the neocortex. We also identify shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our data can be accessed via an interactive browser, hopefully facilitating diagnostic efforts and accelerating the development of follow-up studies., Competing Interests: Competing Interests B.M.N is a member of the scientific advisory board at Deep Genomics and Neumora. No other authors have competing interests to declare

Translation elongation factor eEF1A2 constitutes the alpha subunit of the elongation factor-1 complex, responsible for the enzymatic binding of aminoacyl-tRNA to the ribosome. Since 2012, 21 pathogenic missense variants affecting EEF1A2 have been described in 42 individuals with a severe neurodevelopmental phenotype including epileptic encephalopathy and moderate to profound intellectual disability (ID), with neurological regression in some patients. Through international collaborative call, we collected 26 patients with EEF1A2 variants and compared them to the literature. Our cohort shows a significantly milder phenotype. 83% of the patients are walking (vs. 29% in the literature), and 84% of the patients have language skills (vs. 15%). Three of our patients do not have ID. Epilepsy is present in 63% (vs. 93%). Neurological examination shows a less severe phenotype with significantly less hypotonia (58% vs. 96%), and pyramidal signs (24% vs. 68%). Cognitive regression was noted in 4% (vs. 56% in the literature). Among individuals over 10 years, 56% disclosed neurocognitive regression, with a mean age of onset at 2 years. We describe 8 novel missense variants of EEF1A2. Modeling of the different amino-acid sites shows that the variants associated with a severe phenotype, and the majority of those associated with a moderate phenotype, cluster within the switch II region of the protein and thus may affect GTP exchange. In contrast, variants associated with milder phenotypes may impact secondary functions such as actin binding. We report the largest cohort of individuals with EEF1A2 variants thus far, allowing us to expand the phenotype spectrum and reveal genotype-phenotype correlations., (© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.)

Aggressive and violent behaviour is a challenging psychiatric emergency to manage, especially among vulnerable categories such as patients with Intellectual Developmental Disorder. Although there is some evidence that clozapine may be useful as an anti-violence compound, its use is limited by common metabolic complications. An adult patient presented with obesity, type II diabetes mellitus, compulsive food intake, severe Intellectual Developmental Disorder, and a treatment-resistant aggressive behaviour. Clozapine was administered resulting in reduced aggressive behaviour. Unexpectedly, a reduction in the food craving as well as a sustained improvement in both anthropometric parameters and glycemic control were observed during the clozapine treatment. Our case report, describes these findings for the first time, highlighting the need for more clinical research to investigate both the efficacy of clozapine in the Intellectual Developmental Disorder populations and its long-term effects with special regard to the metabolic outcomes in this type of patients., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. R. Rodriguez-Jimenez has been a consultant for, spoken in activities of, or received grants from: Instituto de Salud Carlos III, Fondo de Investigación Sanitaria (FIS), Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid Regional Government (S2010/ BMD-2422 AGES; S2017/BMD-3740), JanssenCilag, Lundbeck, Otsuka, Pfizer, Ferrer, Juste, Takeda, Exeltis, Casen-Recordati, Angelini, Rovi.

Vacuolar-type ATPase (v-ATPase) is a multimeric protein complex that regulates H + transport across membranes and intra-cellular organelle acidification. Catabolic processes, such as endocytic degradation and autophagy, strictly rely on v-ATPase-dependent luminal acidification in lysosomes. The v-ATPase complex is expressed at high levels in the brain and its impairment triggers neuronal dysfunction and neurodegeneration. Due to their post-mitotic nature and highly specialized function and morphology, neurons display a unique vulnerability to lysosomal dyshomeostasis. Alterations in genes encoding subunits composing v-ATPase or v-ATPase-related proteins impair brain development and synaptic function in animal models and underlie genetic diseases in humans, such as encephalopathies, epilepsy, as well as neurodevelopmental, and degenerative disorders. This review presents the genetic and functional evidence linking v-ATPase subunits and accessory proteins to various brain disorders, from early-onset developmental epileptic encephalopathy to neurodegenerative diseases. We highlight the latest emerging therapeutic strategies aimed at mitigating lysosomal defects associated with v-ATPase dysfunction.

Structural variants (SVs), including large deletions, duplications, inversions, translocations, and more complex events have the potential to disrupt gene function resulting in rare disease. Nevertheless, current pipelines and clinical decision support systems for exome sequencing (ES) tend to focus on small alterations such as single nucleotide variants (SNVs) and insertions-deletions shorter than 50 base pairs (indels). Additionally, detection and interpretation of large copy-number variants (CNVs) are frequently performed. However, detection of other types of SVs in ES data is hampered by the difficulty of identifying breakpoints in off-target (intergenic or intronic) regions, which makes robust identification of SVs challenging. In this paper, we demonstrate the utility of SV calling in ES resulting in a diagnostic yield of 0.4% (23 out of 5825 probands) for a large cohort of unsolved patients collected by the Solve-RD consortium. Remarkably, 8 out of 23 pathogenic SV were not found by comprehensive read-depth-based CNV analysis, resulting in a 0.13% increased diagnostic value., (© 2024. The Author(s).)