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Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of genetic neuropathies, with more than 90 associated genes. While the majority of individuals with genetic diagnosis have demyelinating CMT, a significant proportion of individuals with axonal CMT remain genetically unsolved. Aminoacyl-tRNA synthetases (aaRS) have been implicated in various neurological disorders, including CMT. Here, we hypothesize that hypomorphic variations of DARS2 , which encodes the mitochondrial aspartyl-tRNA synthetase, are associated with axonal CMT. We investigated four individuals from two unrelated families with axonal CMT. We conducted clinical assessments, genetic testing, and functional studies in fibroblasts from two affected individuals. Two pairs of siblings, now adults, presented with progressive distal muscle weakness with onset during childhood, absent lower limb reflexes and normal cognitive function. Brain MRI scans showed no abnormalities. Electrophysiological studies revealed positive waves and fibrillations and was consistent with a diagnosis of axonal motor and sensory neuropathy. Genetic testing identified compound heterozygous variants in DARS2 in both families (c.713C>T; p.Ser238Phe and c.1006C>T; p.Arg336Cys in Family 1; and c.74del; p.Ile25Thrfs*38 and c.1006C>T; p.Arg336Cys in Family 2). The four individuals share the variant DARS2 : c.1006C>T, p.Arg336Cys, located in the insertion subdomain of DARS2, where very few variants have been previously reported. In Family 1, this variant is in trans with another missense variant (c.713C>T; p.Ser238Phe) located in the dimerization domain of DARS2, which is an essential region for the correct functionality of the protein, as in other aaRS. In Family 2, it is combined with a truncating variant. Functional analyses in fibroblasts revealed reduced DARS2 protein levels and altered mitochondrial localization. Additionally, we observed a decrease in both mitochondrial mass and fragmentation, consistent with a disrupted mitochondrial network morphology, suggesting the involvement of DARS2 in the disease pathophysiology. The identification of fully penetrant variants (p.Ser238Phe and p.Ile25Thrfs*38) combined with a hypomorphic variant (p.Arg336Cys) expands the phenotypic spectrum of DARS2-related disorders, establishing a novel association between DARS2 and axonal CMT. The combination of penetrant variants and hypomorphic variants distinguishes these cases from previously reported with DARS2-related leukoencephalopathy. We propose that the genotypic combination of a hypomorphic and a penetrating allele for DARS2 explains the symptoms in these two families with a pure axonal CMT. These findings underscore the importance of mitochondrial aspartyl-tRNA synthetase in peripheral nerve function and highlight potential targets for therapeutic intervention in CMT. [ABSTRACT FROM AUTHOR]

Next-generation sequencing has enhanced the rate of genetic diagnosis in neuromuscular diseases. Nevertheless, half of the patients remain without a molecular diagnosis. One factor that can impede the acquisition of a genetic diagnosis is the presence of mosaicism: the coexistence of at least two different genetic cell populations within an organism. We present two cases of neuromuscular pediatric patients in which a phenotype-driven analysis guided the careful interrogation of candidate genes. Patient A showed a phenotype of congenital myopathy (CM). Trio genome sequencing detected a heterozygous likely pathogenic variant in RYR1 (c.14566G>A; p.Ala4856Thr), inherited from his unaffected mother. It was considered the potential existence of a missing second variant in trans in the proband, but also hypothesized that the variant might be mosaic in the mother. The comparison between alternative allele frequencies (AAF) showed that, while the affected child had an AAF of 0.60, the mother had an AAF of only 0.23. A quantification through ddPCR from blood-derived DNA revealed a 17% of the alternative allele in the mother's sample, whereas in the individual's sample, 49% was observed. Patient B was born with congenital hip dislocation, hypotonia and distal hyperlaxity. Upon clinical examination of the parents, it was detected a left hemicorporal hypotrophy and hand retractions in the father. A neuromuscular gene panel in patient B and his father was inconclusive. RNAseq performed on the muscle sample of the father revealed an exon 9 skipping of COL6A1 in 15% of the transcripts. In genome sequencing it was detected an exon 9 deletion of COL6A1 in 10% of the reads in the father and 50% in patient B (p.Gly269_Pro286del), which was validated through a custom MLPA. Our study highlights the importance of phenotype-driven analysis and careful interrogation of the likely relevant genes and variants and illustrates the genetic mosaicism as a possible explanation behind genetically unsolved affected individuals. [ABSTRACT FROM AUTHOR]

Congenital myasthenic syndromes (CMS) are a group of inherited neuromuscular junction (NMJ) disorders arising from gene variants encoding diverse NMJ proteins. Recently, the VAMP1 gene, responsible for encoding the vesicle-associated membrane protein 1 (VAMP1), has been associated with CMS. This study presents a characterization of five new individuals with VAMP1-related CMS, providing insights into the phenotype. The individuals with VAMP1-related CMS exhibited early disease onset, presenting symptoms prenatally or during the neonatal period, alongside severe respiratory involvement and feeding difficulties. Generalized weakness at birth was a common feature, and none of the individuals achieved independent walking ability. Notably, all cases exhibited scoliosis. The clinical course remained stable, without typical exacerbations seen in other CMS types. The response to anticholinesterase inhibitors and salbutamol was only partial, but the addition of 3,4-diaminopyridine (3,4-DAP) led to significant and substantial improvements, suggesting therapeutic benefits of 3,4-DAP for managing VAMP1-related CMS symptoms. Noteworthy is the identification of the VAMP1 (NM_014231.5): c.340delA; p.(Ile114SerfsTer72) as a founder variant in the Iberian Peninsula and Latin America. This study contributes valuable insights into VAMP1-related CMS, emphasizing its early onset, arthrogryposis, facial and generalized weakness, respiratory involvement, and feeding difficulties. Furthermore, the potential efficacy of 3,4-DAP as a useful therapeutic option warrants further exploration. The findings have implications for clinical management and genetic counseling in affected individuals. Additional research is necessary to elucidate the long-term outcomes of VAMP1-related CMS. [ABSTRACT FROM AUTHOR]

CHKB gene encodes choline kinase enzyme that catalyses the first step in membrane phospholipid phosphatidylcholine synthesis. Mutations in the CHKB gene lead to a muscular dystrophy, which has a characteristic histopathological pattern showing peripheral megamitochondria distribution, which has become the guide for histological diagnosis. However, megamitochondria is not exclusive to CHKB patients, and there are other histological features that go along this muscular dystrophy. A review of histological characteristics from muscles of 3 patient and fibroblasts of one of them with CHKB mutations was performed, to establish a detailed histological and morphological description of other guide signs beyond megamitochondria. Mitochondria, lipid, peroxisome, autophagosome and CHKB immunopathological studies were performed in genetically confirmed CHKB patients, control muscular biopsies and fibroblast culture. Imaging and 3D studies were performed using a TCS SP8 confocal microscope. Muscle biopsy of the 3 cases showed typical distribution of megamitochondria at fibre periphery with normal respiratory chain activity. Fibroblasts did not show megamitochondria, but minor changes were observed in mitochondria network. An increase in number and size of lipid droplets were observed. p62 aggregates were visible both in muscle and fibroblasts. No colocalization between lipid droplets and p62 was identified. Peroxisome signal was reduced in muscle as well as in fibroblasts. A decreased signal in CHKB immunofluorescence was appreciated in patient fibroblasts but not in muscle. The presence of megamitochondria and its distribution in muscle biopsies from CHKB patients continues to be the guiding sign in histopathological diagnosis. These changes are not so evident in fibroblasts. CHKB patients have alterations in lipid metabolism due to a disability in fatty acids metabolism, evidenced by an increase in the number and size of lipid droplets. These patients present the autophagy pathway activated. [ABSTRACT FROM AUTHOR]

Cognitive remediation therapy (CRT) demonstrates potential in enhancing cognitive function in schizophrenia (SZ), though the identification of molecular biomarkers remains challenging. The Neuritin-1 gene (NRN1) emerges as a promising candidate gene due to its association with SZ, cognitive performance and response to neurotherapeutic treatments. We aimed to investigate whether NRN1 genetic variability and methylation changes following CRT are related to cognitive improvements. Twenty-five SZ patients were randomly assigned to CRT or treatment-as-usual (TAU) groups, with cognitive function and NRN1 methylation assessed pre- and post-intervention using the MATRICS Consensus Cognitive Battery and EpiTYPER. Besides, eleven NRN1 polymorphisms were genotyped. Methylation changes (Δm = post - pre) were analyzed via sparse Partial Least Square Discriminant Analysis (sPLS-DA) to identify latent components (LCs) distinguishing CRT from TAU. To further explore methylation patterns of these LCs, CpG units were grouped into two subsets, yielding Δm means for those with increased and decreased methylation. Cognitive changes (Δcog = post - pre) were used to identify CRT improvers (CRT-I, Δcog ≥ 1), and the association between methylation changes and cognitive improvements post-therapy was also tested. We identified two LCs that differentiated CRT from TAU with a classification error rate of 0.28. The main component, LC1, included 25 CpG units. The subsets of CpG units with increased and decreased post-therapy methylation differed significantly between the two treatment arms, suggesting that differences were not merely data-driven but reflected meaningful biological variation. Additionally, CpG units linked to therapy were also associated with cognitive improvement, with LC1 and the subset of CpG units showing increased methylation post-therapy distinguishing CRT-I from the rest of the patients across multiple cognitive domains. Furthermore, the effect of LC1 on speed processing improvement after CRT was enhanced by considering the NRN1-rs9405890 polymorphism. Notably, these CpG units, particularly those with increased methylation after CRT, overlapped with key gene regulatory elements. Our model, integrating genetics and epigenetics, boosts the understanding of CRT response variability and highlights this multi-level approach as a promising strategy for identifying potential NRN1-related biomarkers of CRT effects, though further studies with larger samples are needed., Competing Interests: Declaration of competing interest Declaration of competing interest Rafael Penadés has received honoraria/travel support (unrelated to the present work) from Angelini. The rest of the authors reported no biomedical financial interests or potential conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Women are known to have twice as much lifetime prevalence of post-traumatic stress disorder (PTSD) as men do. It has been reported that the risk genotype (CC) of a single nucleotide polymorphism (SNP) (rs2267735) in the pituitary adenylate cyclase-activating polypeptide (PACAP-PAC1R) system is associated with PTSD risk and altered fear conditioning and fear extinction in women. Surprisingly, no previous work has studied the effect of this SNP on fear conditioning, extinction, or generalization in non-traumatized/low trauma load women. Here, two separate groups of women underwent either a two-day fear conditioning and fear extinction paradigm, or a one-day fear conditioning and fear generalization paradigm. Results showed no significant differences between genotypes in conditioned stimulus discrimination, during fear acquisition, extinction, or generalization. These findings suggest that the previously reported fear processing impairments in traumatized CC women are not a consequence of this genotype alone, but likely dependent on the interaction between this genetic risk and the exposure to traumatic stressors., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest, (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

Individuals with monoallelic pathogenic variants in the histone lysine methyltransferase DOT1L display global developmental delay and varying congenital anomalies. However, the impact of monoallelic loss of DOT1L remains unclear. Here, we present a largely female cohort of 11 individuals with DOT1L variants with developmental delays and dysmorphic facial features. We found that DOT1L variants include missense variants clustered in the catalytic domain, frameshift, and stop-gain variants. We demonstrate that specific variants cause loss of methyltransferase activity and therefore sought to define the effects of decreased DOT1L function. Using RNA-sequencing of cultured neurons and single nucleus RNA-sequencing of mouse cortical tissue, we found that partial Dot1l depletion causes sex-specific transcriptional responses and disrupts transcription of synaptic genes. Further, Dot1l loss alters neuron branching and expression of synaptic proteins. Lastly using zebrafish and mouse models, we found behavioral disruptions that include sex-specific deficits in mice. Overall, we define how DOT1L loss leads to neurological dysfunction by demonstrating that partial Dot1l loss impacts transcription, neuron morphology, and behavior across multiple models and systems., Competing Interests: Competing interests: KV has received honoraria as an advisory board member, travel expenses and speaker fees from Biogen, Santhera, Orchard, ITF and Novartis, outside the submitted work. JLM is an employee of and may own stock in GeneDx, LLC. All other authors declare they have no competing interests.

To date, there have been scarcely any published studies dedicated to developing instruments with sufficient guarantees of accuracy, validity, and reliability for the assessment of heritage learning in digital contexts. Furthermore, very few such studies on this subject have employed the network analysis methodology. The present study seeks to address these research gaps by applying network analysis methodology to the responses of 1323 participants concerning 49 items grouped into seven dimensions constituting the Heritage Learning Sequence (knowing, understanding, respecting, valuing, caring, enjoying, and transmitting). Network estimation was conducted using the Gaussian Graphical Model with regularization, ensuring both the accuracy of the network and the stability of centrality indices. The results indicate that satisfactory values have been achieved in both the network structure and in terms of predictability, replicability, and sensitivity. Finally, the invariance of the network structure among groups (male/female and random subsamples) has been demonstrated. These findings offer promising avenues for further research on heritage learning assessment using the network analysis methodology., Competing Interests: 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., (© 2024 Published by Elsevier Ltd.)

Objective: Biallelic titin truncating variants (TTNtv) have been associated with a wide phenotypic spectrum, ranging from complex prenatal muscle diseases with dysmorphic features to adult-onset limb-girdle muscular dystrophy, with or without cardiac involvement. Given the size and complexity of TTN, reaching an unequivocal molecular diagnosis and precise disease prognosis remains challenging., Methods: In this case series, 12 unpublished cases and one already published case with biallelic TTNtv were collected from multiple international medical centers between November 2022 and September 2023. TTN mutations were detected through exome or genome sequencing. Information about familial and personal clinical history was collected in a standardized form. RNA-sequencing and analysis of TTN exon usage were performed on an internal sample cohort including postnatal skeletal muscles, fetal skeletal muscles, postnatal heart muscles, and fetal heart muscles. In addition, publicly available RNA-sequencing data was retrieved from ENCODE., Results: We generated new RNA-seq data on TTN exons and identified genotype-phenotype correlations with prognostic implications for each titinopathy patient (whether worsening or improving in prenatal and postnatal life) using percentage spliced in (PSI) data for the involved exons. Interestingly, thanks to exon usage, we were also able to rule out a titinopathy diagnosis in one prenatal case., Interpretation: This study demonstrates that exon usage provides valuable insights for a more exhaustive clinical interpretation of TTNtv; additionally, it may serve as a model for implementing personalized medicine in many other genetic diseases, since most genes undergo alternative splicing., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Establishing a molecular diagnosis remains challenging in half of individuals with childhood-onset neuromuscular diseases (NMDs) despite exome sequencing. This study evaluates the diagnostic utility of combining genomic approaches in undiagnosed NMD patients. We performed deep phenotyping of 58 individuals with unsolved childhood-onset NMDs that have previously undergone inconclusive exome studies. Genomic approaches included trio genome sequencing and RNASeq. Genetic diagnoses were reached in 23 out of 58 individuals (40%). Twenty-one individuals carried causal single nucleotide variants (SNVs) or small insertions and deletions, while 2 carried pathogenic structural variants (SVs). Genomic sequencing identified pathogenic variants in coding regions or at the splice site in 17 out of 21 resolved cases, while RNA sequencing was additionally required for the diagnosis of 4 cases. Reasons for previous diagnostic failures included low coverage in exonic regions harboring the second pathogenic variant and involvement of genes that were not yet linked to human diseases at the time of the first NGS analysis. In summary, our systematic genetic analysis, integrating deep phenotyping, trio genome sequencing and RNASeq, proved effective in diagnosing unsolved childhood-onset NMDs. This approach holds promise for similar cohorts, offering potential improvements in diagnostic rates and clinical management of individuals with NMDs., Competing Interests: Competing interests: The authors declare no competing interests. Ethical approval: Data were collected and analyzed following the ethics guidelines of Hospital Sant Joan de Déu (PIC 98-20). The family provided written informed consent for the study., (© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.)

Evidence suggests a remarkable shared genetic susceptibility between psychiatric disorders. However, sex-dependent differences have been less studied. We explored the contribution of schizophrenia (SCZ), bipolar disorder (BD) and major depressive disorder (MDD) polygenic scores (PGSs) on the risk for psychotic disorders and whether sex-dependent differences exist (CIBERSAM sample: 1826 patients and 1372 controls). All PGSs were significantly associated with psychosis. Sex-stratified analyses showed that the variance explained in psychotic disorders risk was significantly higher in males than in females for all PGSs. Our results confirm the shared genetic architecture across psychotic disorders and demonstrate sex-dependent differences in the vulnerability to psychotic disorders., Competing Interests: Author disclosures CA has been a consultant to or has received honoraria or grants from Abbot, Acadia, Angelini, Biogen, Boehringer, Gedeon Richter, Janssen Cilag, Lundbeck, Medscape, Menarini, Minerva, Otsuka, Pfizer, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion, Takeda and Teva. JB received consulting fees from Takeda as members of the Advisory Board. JB received research grants and served as consultant, advisor, or speaker within the last 3 years for: AB-Biotics, Acadia Pharmaceuticals, Alkermes, Angelini, Ambrosetti-Angelini, Biogen, Casen Recordati, D&A Pharma, Exeltis, Gilead, Indivior, GW Pharmaceuticals, Janssen-Cilag, Jazz Pharmaceuticals, Lundbeck, Otsuka, Pfizer, Roche, Sage Therapeutics, Servier, Shire, Takeda. In addition, JB received research funding from the Spanish Ministry of Economy and Competitiveness—Centro de Investigación Biomedica en Red area de Salud Mental (CIBERSAM), and Instituto de Salud Carlos III, Spanish Ministry of Health. AG-P has received grants and served as consultant, advisor or CME speaker for the following entities: Janssen-Cilag, Lundbeck, Otsuka, Alter, Angelini, Novartis, Rovi, Takeda, the Spanish Ministry of Science and Innovation (CIBERSAM), the Ministry of Science (Carlos III Institute), the Basque Government, and the European Framework Program of Research. The rest of the authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Background: Congenital myasthenic syndromes (CMS) are a group of inherited neuromuscular junction (NMJ) disorders arising from gene variants encoding diverse NMJ proteins. Recently, the VAMP1 gene, responsible for encoding the vesicle-associated membrane protein 1 (VAMP1), has been associated with CMS., Methods: This study presents a characterization of five new individuals with VAMP1-related CMS, providing insights into the phenotype., Results: The individuals with VAMP1-related CMS exhibited early disease onset, presenting symptoms prenatally or during the neonatal period, alongside severe respiratory involvement and feeding difficulties. Generalized weakness at birth was a common feature, and none of the individuals achieved independent walking ability. Notably, all cases exhibited scoliosis. The clinical course remained stable, without typical exacerbations seen in other CMS types. The response to anticholinesterase inhibitors and salbutamol was only partial, but the addition of 3,4-diaminopyridine (3,4-DAP) led to significant and substantial improvements, suggesting therapeutic benefits of 3,4-DAP for managing VAMP1-related CMS symptoms. Noteworthy is the identification of the VAMP1 (NM_014231.5): c.340delA; p.Ile114SerfsTer72 as a founder variant in the Iberian Peninsula and Latin America., Conclusions: This study contributes valuable insights into VAMP1-related CMS, emphasizing their early onset, arthrogryposis, facial and generalized weakness, respiratory involvement, and feeding difficulties. Furthermore, the potential efficacy of 3,4-DAP as a useful therapeutic option warrants further exploration. The findings have implications for clinical management and genetic counseling in affected individuals. Additional research is necessary to elucidate the long-term outcomes of VAMP1-related CMS., 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 Elsevier Inc. All rights reserved.)

Lithium (Li) is the first-line treatment for bipolar disorder (BD) even though only 30 % of BD patients are considered excellent responders. The mechanisms by which Li exerts its action are not clearly understood, but it has been suggested that specific epigenetic mechanisms, such as methylation processes, may play a role. In this regard, DNA methylation patterns can be used to estimate epigenetic age (EpiAge), which is accelerated in BD patients and reversed by Li treatment. Our first aim was to compare the DNA methylation profile in peripheral blood between BD patients categorized as excellent responders to Li (Ex-Rp) and non-responders (N-Rp). Secondly, EpiAge was estimated to detect differential age acceleration between the two groups. A total of 130 differentially methylated positions (DMPs) and 16 differentially methylated regions (DMRs) between Ex-Rp (n = 26) and N-Rp (n = 37) were identified (FDR adjusted p-value < 0.05). We found 122 genes mapping the DMPs and DMRs, nine of which (HOXB6, HOXB3, HOXB-AS3, TENM2, CACNA1B, ANK3, EEF2K, CYP1A1, and SORCS2) had previously been linked to Li response. We found genes related to the GSK3β pathway to be highly represented. Using FUMA, we found enrichment in Gene Ontology Cell Component for the synapse. Gene network analysis highlighted functions related to the cell cycle, nervous system development and function, and gene expression. No significant differences in age acceleration were found between Ex-Rp and N-Rp for any of the epigenetic clocks analysed. Our findings indicate that a specific methylation pattern could determine the response to Li in BD patients. We also found that a significant portion of the differentially methylated genes are closely associated with the GSK3β pathway, reinforcing the role of this system in Li response. Future longitudinal studies with larger samples will help to elucidate the epigenetic mechanisms underlying Li response., Competing Interests: Declaration of competing interest AGP has received CME-related honoraria, or consulting fees unrelated to the present work from Angelini, Janssen-Cilag, Casen Recordati, Rovi, LCN and Lundbeck. EV has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, AbbVie, Adamed, Angelini, Biogen, Biohaven, Boehringer-Ingelheim, Celon Pharma, Compass, Dainippon Sumitomo Pharma, Ethypharm, Ferrer, Gedeon Richter, GH Research, Glaxo-Smith Kline, HMNC, Idorsia, Janssen, Lundbeck, Medincell, Merck, Novartis, Orion Corporation, Organon, Otsuka, Roche, Rovi, Sage, Sanofi-Aventis, Sunovion, Takeda, and Viatris, outside the submitted work. The rest of authors have nothing to disclose., (Copyright © 2024. Published by Elsevier B.V.)

Postcombustion CO 2 capture by calcium looping using circulating fluidized bed technology, CFB-CaL, is evolving to tackle industrial sectors that are difficult to decarbonize. In addition to the known advantages of CFB-CaL (i.e., retrofittability and competitive energy efficiencies and cost), the fuel flexibility by using renewable biomass in the oxy-fired CFB calciner and the possibility to reach extremely high CO 2 capture efficiencies in the carbonator are demonstrated in this paper. Results from the latest experimental campaigns in the TRL7 CFB-CaL pilot of the La Pereda are reported, treating over 2000 N m 3 /h of flue gases in the carbonator with a firing capacity of biomass pellets up to 2 MW th in the oxy-fired calciner. A new strategy to reach high CO 2 capture efficiencies (above 99% in some cases) in the carbonator has been tested. This involves decoupling the carbonator in two temperature zones by cooling the solids-lean top region to below 550 °C and ensuring that a sufficient flow of active CaO reaches such a region., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Background: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N = 2064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II., Results: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism., Conclusions: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II., (© 2024. The Author(s).)

The expression of Neuritin-1 (NRN1), a neurotrophic factor crucial for neurodevelopment and synaptic plasticity, is enhanced by the Brain Derived Neurotrophic Factor (BDNF). Although the receptor of NRN1 remains unclear, it is suggested that NRN1's activation of the insulin receptor (IR) pathway promotes the transcription of the calcium voltage-gated channel subunit alpha1 C (CACNA1C). These three genes have been independently associated with schizophrenia (SZ) risk, symptomatology, and brain differences. However, research on how they synergistically modulate these phenotypes is scarce. We aimed to study whether the genetic epistasis between these genes affects the risk and clinical presentation of the disorder via its effect on brain structure. First, we tested the epistatic effect of NRN1 and BDNF or CACNA1C on (i) the risk for SZ, (ii) clinical symptoms severity and functionality (onset, PANSS, CGI and GAF), and (iii) brain cortical structure (thickness, surface area and volume measures estimated using FreeSurfer) in a sample of 86 SZ patients and 89 healthy subjects. Second, we explored whether those brain clusters influenced by epistatic effects mediate the clinical profiles. Although we did not find a direct epistatic impact on the risk, our data unveiled significant effects on the disorder's clinical presentation. Specifically, the NRN1-rs10484320 x BDNF-rs6265 interplay influenced PANSS general psychopathology, and the NRN1-rs4960155 x CACNA1C-rs1006737 interaction affected GAF scores. Moreover, several interactions between NRN1 SNPs and BDNF-rs6265 significantly influenced the surface area and cortical volume of the frontal, parietal, and temporal brain regions within patients. The NRN1-rs10484320 x BDNF-rs6265 epistasis in the left lateral orbitofrontal cortex fully mediated the effect on PANSS general psychopathology. Our study not only adds clinical significance to the well-described molecular relationship between NRN1 and BDNF but also underscores the utility of deconstructing SZ into biologically validated brain-imaging markers to explore their mediation role in the path from genetics to complex clinical manifestation., (© 2024. The Author(s).)

Objective: Duchenne and Becker muscular dystrophies (DMD and BMD) are dystrophinopathies caused by variants in DMD gene, resulting in reduced or absent dystrophin. These conditions, characterized by muscle weakness, also manifest central nervous system (CNS) comorbidities due to dystrophin expression in the CNS. Prior studies have indicated a higher prevalence of epilepsy in individuals with dystrophinopathy compared to the general population. Our research aimed to investigate epilepsy prevalence in dystrophinopathies and characterize associated electroencephalograms (EEGs) and seizures., Methods: We reviewed 416 individuals with dystrophinopathy, followed up at three centers between 2010 and 2023, to investigate the lifetime epilepsy prevalence and characterize EEGs and seizures in those individuals diagnosed with epilepsy. Associations between epilepsy and type of dystrophinopathy, genotype, and cognitive involvement were studied., Results: Our study revealed a higher epilepsy prevalence than the general population (1.4%; 95% confidence interval: 0.7-3.2%), but notably lower than previously reported in smaller dystrophinopathy cohorts. No significant differences were found in epilepsy prevalence between DMD and BMD or based on underlying genotypes. Cognitive impairment was not found to be linked to higher epilepsy rates. The most prevalent epilepsy types in dystrophinopathies resembled those observed in the broader pediatric population, with most individuals effectively controlled through monotherapy., Interpretation: The actual epilepsy prevalence in dystrophinopathies may be markedly lower than previously estimated, possibly half or even less. Our study provides valuable insights into the epilepsy landscape in individuals with dystrophinopathy, impacting medical care, especially for those with concurrent epilepsy., (© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Although cognitive remediation therapy (CRT) produces cognitive benefits in schizophrenia, we do not yet understand whether molecular changes are associated with this cognitive improvement. A gene central to synaptic plasticity, the BDNF, has been proposed as one potential route. This study assesses whether BDNF methylation changes following CRT-produced cognitive improvement are detected. A randomized and controlled trial was performed with two groups (CRT, n = 40; TAU: Treatment as Usual, n = 20) on a sample of participants with schizophrenia. CRT was delivered by trained therapists using a web-based computerized program. Mixed Models, where the interaction of treatment (CRT, TAU) by time (T0: 0 weeks, T1: 16 weeks) was the main effect were used. Then, we tested the association between the treatment and methylation changes in three CpG islands of the BDNF gene. CRT group showed significant improvements in some cognitive domains. Between-groups differential changes in 5 CpG units over time were found, 4 in island 1 (CpG1.2, CpG1.7, CpG1.10, CpG1.17) and 1 in island 3 (CpG3.2). CRT group showed increases in methylation in CpG1.2, CpG1.7 and decreases in pG1.10, CpG1.17, and CpG3.2. Differences in the degree of methylation were associated with changes in Speed of Processing, Working Memory, and Verbal Learning within the CRT group. Those findings provide new data on the relationship between cognitive improvement and changes in peripheral methylation levels of BDNF gene, a key factor involved in neuroplasticity regulation. Trial Registration: NCT04278027., Competing Interests: Declaration of competing interest Rafael Penadés has received honoraria/travel support (unrelated to the present work) from Angelini. C Garcia-Rizo has served as consultant, advisor or received honoraria/travel support (unrelated to the present work) from Adamed, Angelini, Casen-Recordati, Janssen-Cilag, Lundbeck, Otsuka and Newron. The rest of the authors reported no biomedical financial interests or potential conflicts of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Introduction: The intricate nature of certain diseases necessitates complex medication regimens, utilization including high-cost medications, and continual vigilance to avoid potential complications. To address these exigencies, numerous healthcare institutions have instituted multidisciplinary management teams, exemplified in pharmaceutical care through Comprehensive Medication Management (CMM) programs. These programs oversee diverse facets such as patient education, medication adherence promotion, clinical monitoring, dose adjustments, and scrutiny of prescribed drug therapies. Given the emphasized significance, it is relevant to possess evidence to continue endorsing these initiatives from management positions within health centers, and it is for this reason that this study aims to evaluate the clinical and economic benefits provided by a CMM program within a private hospital in Latin America, by analyzing the effects of clinical interventions., Methods: A retrospective examination was conducted involving documented pharmaceutical interventions in an outpatient setting from January 2019 to September 2022. To assess the interventions' repercussions, a retrospective analysis was undertaken. The collated data included patients' basic characteristics, a comprehensive pharmacist-generated description of interventions, potential associated complications, and avoided medical services. Multiple clinical projections, which were endorsed by internal medicine physicians, were developed to explore potential scenarios in the absence of pharmaceutical care. These projections were associated with conceivable complications, aligned with the most plausible circumstances. Subsequently, utilizing the average cost of healthcare within a private hospital in Latin America, the cumulative savings were quantified. These savings were then attributed to the intrinsic advantages offered by pharmaceutical care., Results: The study discloses demographic trends among patients within distinct age groups in the CMM program. Rheumatology predominated as the main referral source, and interventions centering on monitoring emerged as the pivotal drug-related concern. This encompassed a collaborative approach, involving interdisciplinary efforts toward patient education and critical parameter monitoring. Of the total 347 pharmaceutical interventions, 66.3% ( N  = 230) specialty office visits, 14.1% ( N  = 49) general practitioner consultations, 12.4% ( N  = 43) hospitalizations, and 7.2% ( N  = 25) ER visits were avoided. The economic analysis underscores cost savings ensuing from pharmaceutical interventions, amounting to a cumulative 603,792.82 USD. Extrapolating these findings to a patient cohort of 400 enrolled in the pharmaceutical care program approximates per-patient savings of 361.47 USD., Conclusion: This study reveals the significant clinical and economic benefits of CMM programs, led by multidisciplinary pharmaceutical professionals. The findings provide compelling evidence for hospital management to consider promoting such programs, drawing from the patient-centered care model in the United States applicable to Latin America., Competing Interests: 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., (© 2024 The Authors. Published by Elsevier Inc.)

It is common for some participants in self-report surveys to be careless, inattentive, or lacking in effort. Data quality can be severely compromised by responses that are not based on item content (non-content-based [nCB] responses), leading to strong biases in the results of data analysis and misinterpretation of individual scores. In this study, we propose a specification of factor mixture analysis (FMA) to detect nCB responses. We investigated the usefulness and effectiveness of the FMA model in detecting nCB responses using both simulated data (Study 1) and real data (Study 2). In the first study, FMA showed reasonably robust sensitivity (.60 to .86) and excellent specificity (.96 to .99) on mixed-worded scales, suggesting that FMA had superior properties as a screening tool under different sample conditions. However, FMA performance was poor on scales composed of only positive items because of the difficulty in distinguishing acquiescent patterns from valid responses representing high levels of the trait. In Study 2 (real data), FMA detected a minority of cases (6.5%) with highly anomalous response patterns. Removing these cases resulted in a large increase in the fit of the unidimensional model and a substantial reduction in spurious multidimensionality., (© 2023. The Author(s).)

The assessment of heritage learning in digital environments lacks instruments that measure it with sufficient guarantees of accuracy, validity, and reliability. This study attempts to fill this gap by developing an instrument that has shown solid metric qualities. The process of design and calibration of a scale applied to 1,454 participants between 19 and 63 years of age is presented in this article. Exploratory factor analysis (Exploratory Structural Equation Modeling ESEM) and Item Response Theory models (Graded Response Model GRM) were used. Sufficient evidence of both reliability and validity based on content and internal structure was obtained. Invariance of scores as a function of gender and age of participants has also been demonstrated. The discrimination parameters of the items have been found to be high, and the test information curves have shown that the subscales measure with sufficient precision wide ranges of the respective latent variables. The instrument presents wide possibilities of application to various areas of Heritage Education (e.g., design of programs in HE, definition and planning of teaching objectives, evaluation of programs, etc., in virtual environments)., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Fontal et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Depression during pregnancy is a common complication that can negatively affect fetal health and birth outcomes. Cortisol is believed to be a key mediator of this association. Although pregnancy entails a natural increase in cortisol levels, preclinical depression could alter its circadian rhythm, producing excessively high overall diurnal cortisol levels that might be harmful for the fetus and future offspring development., Objectives: Using a prospective longitudinal design, we aimed to study (i) trimestral cortisol circadian rhythm and its overall levels throughout pregnancy in healthy women, (ii) the extent to which maternal depressive symptoms influence both cortisol rhythmicity and overall levels, and (iii) the possible adverse consequences of elevated maternal cortisol on the offspring's weight and gestational age at birth., Study Design: 112 healthy pregnant women from the general Spanish population were recruited before their first pregnancy. To assess cortisol circadian rhythm, participants provided four saliva samples at each trimester of pregnancy (at awakening, 30 min after awakening, before lunch and before going to bed). Overall cortisol levels were calculated with AUCg approximation. Depressive symptoms were evaluated in each trimester and defined according to EPDS cut-off values (1st trimester, EPDS ≥ 11; 2nd and 3rd trimesters, EPDS ≥ 10). At birth, the risk for low weight, prematurity and weight birth percentile was retrieved for 100 infants. Mixed models and simple effects were employed to study changes of maternal cortisol circadian rhythm and overall levels throughout pregnancy and the possible influence of maternal depressive symptoms. Finally, logistic regressions were performed to assess the associations between maternal overall cortisol levels in each trimester of pregnancy and birth anthropometrics., Results: Although overall diurnal cortisol levels increase throughout pregnancy, cortisol circadian rhythm is preserved in all trimesters [1st (F(3110)= 92.565, p < .001), 2nd (F(3,85)= 46.828, p < .001) and 3rd (F(3,90)= 65.555, p < .001)]. However, women with depressive symptoms showed a flattened cortisol circadian pattern only during the second trimester, characterized by a blunted awakening peak and reduced evening decline (F(3,85)= 4.136, p = .009), but not during the first (F(3,11)= 1.676, p = .176) or the third (F(3,90)= 1.089, p = .358) trimesters. Additionally, they did not show a cortisol increase from second to third trimester (p = .636). Finally, higher maternal cortisol levels in second and third trimesters seemed to be associated with increased risk of prematurity (adjusted OR -0.371, 95% CI 0.490-0.972, p = .034) and low birth weight percentile (adjusted OR -0.612, 95% CI 0.348-0.846, p = .007) respectively., Conclusion: Maternal cortisol levels increased throughout pregnancy, although cortisol circadian rhythm was preserved in all trimesters of pregnancy. However, prenatal depressive symptoms were associated with flattened maternal cortisol circadian rhythm in mid-pregnancy. Therefore, it seems that women with depressive symptoms tended to increase less gradually their cortisol levels from mid to late pregnancy. Finally, higher maternal cortisol levels in mid and late-pregnancy seem to be associated with poorer birth anthropometrics Early detection of depressive symptoms in general population could help to prevent putative obstetrical and birth adverse outcomes., Competing Interests: Declaration of Competing Interest Authors do not have any conflict of interest regarding the publication of this manuscript., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD., (© 2024. The Author(s).)