Identification of a pathogenic mutation in ARPP21 in patients with amyotrophic lateral sclerosis.

BACKGROUND AND OBJECTIVE: Between 5% and 10% of amyotrophic lateral sclerosis (ALS) cases have a family history of the disease, 30% of which do not have an identifiable underlying genetic cause after a comprehensive study of the known ALS-related genes. Based on a significantly increased incidence of ALS in a small geographical region from Spain, the aim of this work was to identify novel ALS-related genes in ALS cases with negative genetic testing. METHODS: We detected an increased incidence of both sporadic and, especially, familial ALS cases in a small region from Spain compared with available demographic and epidemiological data. We performed whole genome sequencing in a group of 12 patients with ALS (5 of them familial) from this unique area. We expanded the study to include affected family members and additional cases from a wider surrounding region. RESULTS: We identified a shared missense mutation (c.1586C>T; p.Pro529Leu) in the cyclic AMP regulated phosphoprotein 21 (ARPP21) gene that encodes an RNA-binding protein, in a total of 10 patients with ALS from 7 unrelated families. No mutations were found in other ALS-causing genes. CONCLUSIONS: While previous studies have dismissed a causal role of ARPP21 in ALS, our results strongly support ARPP21 as a novel ALS-causing gene.

Prognostic Relevance of Preoperative Immune, Inflammatory, and Nutritional Biomarkers in Patients Undergoing Gastrectomy for Resectable Gastric Adenocarcinoma: An Observational Multicentre Study.

Background: The aim of this study was to evaluate different preoperative immune, inflammatory, and nutritional scores and their best cut-off values as predictors of poorer overall survival (OS) and disease-free survival (DFS) in patients who underwent curative gastric cancer resection. Methods: This was a retrospective observational multicentre study based on data of the Spanish EURECCA Esophagogastric Cancer Registry. Time-dependent Youden index and log-rank test were used to obtain the best cut-offs of 18 preoperative biomarkers for OS and DFS. An adjusted Cox model with variables selected by bootstrapping was used to identify the best preoperative biomarkers, which were also analysed for every TNM stage. Results: High neutrophil-to-lymphocyte ratio (NLR), high monocyte systemic inflammation index (moSII), and low prognostic nutritional index (PNI) were identified as independent predictors of poor outcome: NLR > 5.91 (HR:1.73; 95%CI [1.23-2.43]), moSII >2027.12 (HR:2.26; 95%CI [1.36-3.78]), and PNI >40.31 (HR:0.75; 95%CI [0.58-0.96]) for 5-year OS and NLR > 6.81 (HR:1.75; 95%CI [1.24-2.45]), moSII > 2027.12 (HR:2.46; 95%CI [1.49-4.04]), and PNI > 40.31 (HR:0.77; 95%CI [0.60,0.97]) for 5-year DFS. These outcomes were maintained in the whole cohort for NLR and moSII (p < 0.05) but not in stage II and for PNI in all tumoral stages. The associations of NLR-PNI and moSII-PNI were also a relevant prognostic factor for OS. Conclusions: High NLR, high moSII (for stages I and III), and low PNI (regardless of tumour stage) were the most promising preoperative biomarkers to predict poor OS and DFS in gastric cancer patients treated with curative intent.

Isolation and Visualization of Plant Stress Granule-Associated Components via On-Beads Digestion and Co-localization Analysis.

Stress granules (SGs) are conserved cytoplasmic biomolecular condensates mainly formed by proteins and RNA molecules assembled by liquid-liquid phase separation. Isolation of SGs components has been a major challenge in the field due to the dynamic and transient nature of stress granule shells. Here, we describe the methodology for the isolation and visualization of SGs proteins from Arabidopsis thaliana plants using a scaffold component as the target. The protocol consists of the first immunoprecipitation of GFP-tagged scaffold protein, followed by an on-beads enzymatic digestion and previous mass spectrometry identification. Finally, the localization of selected SGs candidates is visualized in Nicotiana benthamiana mesophyll protoplasts.

Sexual dimorphism in colorectal cancer: molecular mechanisms and treatment strategies.

INTRODUCTION: Sexual dimorphism significantly influences cancer incidence and prognosis. Notably, females exhibit a lower risk and favorable prognosis for non-reproductive cancers compared to males, a pattern observable beyond the scope of risk behaviors such as alcohol consumption and smoking. Colorectal cancer, ranking third in global prevalence and second in mortality, disproportionately affects men. Sex steroid hormones, particularly estrogens and androgens, play crucial roles in cancer progression, considering epidemiological in vivo and in vitro, in general estrogens imparting a protective effect in females and androgens correlating with an increasing risk of colorectal cancer development. MAIN BODY: The hormonal impact on immune response is mediated by receptor interactions, resulting in heightened inflammation, modulation of NF-kB, and fostering an environment conducive to cancer progression and metastasis. These molecules also influence the enteric nervous system, that is a pivotal in neuromodulator release and intestinal neuron stimulation, also contributes to cancer development, as evidenced by nerve infiltration into tumors. Microbiota diversity further intersects with immune, hormonal, and neural mechanisms, influencing colorectal cancer dynamics. A comprehensive understanding of hormonal influences on colorectal cancer progression, coupled with the complex interplay between immune responses, microbiota diversity and neurotransmitter imbalances, underpins the development of more targeted and effective therapies. CONCLUSIONS: Estrogens mitigate colorectal cancer risk by modulating anti-tumor immune responses, enhancing microbial diversity, and curbing the pro-tumor actions of the sympathetic and enteric nervous systems. Conversely, androgens escalate tumor growth by dampening anti-tumor immune activity, reducing microbial diversity, and facilitating the release of tumor-promoting factors by the nervous system. These findings hold significant potential for the strategic purposing of drugs to fine-tune the extensive impacts of sex hormones within the tumor microenvironment, promising advancements in colorectal cancer therapies.

Emerging variants, unique phenotypes, and transcriptomic signatures: an integrated study of COASY-associated diseases.

OBJECTIVE: COASY, the gene encoding the bifunctional enzyme CoA synthase, which catalyzes the last two reactions of cellular de novo coenzyme A (CoA) biosynthesis, has been linked to two exceedingly rare autosomal recessive disorders, such as COASY protein-associated neurodegeneration (CoPAN), a form of neurodegeneration with brain iron accumulation (NBIA), and pontocerebellar hypoplasia type 12 (PCH12). We aimed to expand the phenotypic spectrum and gain insights into the pathogenesis of COASY-related disorders. METHODS: Patients were identified through targeted or exome sequencing. To unravel the molecular mechanisms of disease, RNA sequencing, bioenergetic analysis, and quantification of critical proteins were performed on fibroblasts. RESULTS: We identified five new individuals harboring novel COASY variants. While one case exhibited classical CoPAN features, the others displayed atypical symptoms such as deafness, language and autism spectrum disorders, brain atrophy, and microcephaly. All patients experienced epilepsy, highlighting its potential frequency in COASY-related disorders. Fibroblast transcriptomic profiling unveiled dysregulated expression in genes associated with mitochondrial respiration, responses to oxidative stress, transmembrane transport, various cellular signaling pathways, and protein translation, modification, and trafficking. Bioenergetic analysis revealed impaired mitochondrial oxygen consumption in COASY fibroblasts. Despite comparable total CoA levels to control cells, the amounts of mitochondrial 4'-phosphopantetheinylated proteins were significantly reduced in COASY patients. INTERPRETATION: These results not only extend the clinical phenotype associated with COASY variants but also suggest a continuum between CoPAN and PCH12. The intricate interplay of altered cellular processes and signaling pathways provides valuable insights for further research into the pathogenesis of COASY-associated diseases.

Mitochondrial DNA: Inherent Complexities Relevant to Genetic Analyses.

Mitochondrial DNA (mtDNA) exhibits distinct characteristics distinguishing it from the nuclear genome, necessitating specific analytical methods in genetic studies. This comprehensive review explores the complex role of mtDNA in a variety of genetic studies, including genome-wide, epigenome-wide, and phenome-wide association studies, with a focus on its implications for human traits and diseases. Here, we discuss the structure and gene-encoding properties of mtDNA, along with the influence of environmental factors and epigenetic modifications on its function and variability. Particularly significant are the challenges posed by mtDNA's high mutation rate, heteroplasmy, and copy number variations, and their impact on disease susceptibility and population genetic analyses. The review also highlights recent advances in methodological approaches that enhance our understanding of mtDNA associations, advocating for refined genetic research techniques that accommodate its complexities. By providing a comprehensive overview of the intricacies of mtDNA, this paper underscores the need for an integrated approach to genetic studies that considers the unique properties of mitochondrial genetics. Our findings aim to inform future research and encourage the development of innovative methodologies to better interpret the broad implications of mtDNA in human health and disease.

Unraveling the Properties of Phage Display Fab Libraries and Their Use in the Selection of Gliadin-Specific Probes by Applying High-Throughput Nanopore Sequencing.

Directed evolution is a pivotal strategy for new antibody discovery, which allowed the generation of high-affinity Fabs against gliadin from two antibody libraries in our previous studies. One of the libraries was exclusively derived from celiac patients' mRNA (immune library) while the other was obtained through a protein engineering approach (semi-immune library). Recent advances in high-throughput DNA sequencing techniques are revolutionizing research across genomics, epigenomics, and transcriptomics. In the present work, an Oxford Nanopore in-lab sequencing device was used to comprehensively characterize the composition of the constructed libraries, both at the beginning and throughout the phage-mediated selection processes against gliadin. A customized analysis pipeline was used to select high-quality reads, annotate chain distribution, perform sequence analysis, and conduct statistical comparisons between the different selection rounds. Some immunological attributes of the most representative phage variants after the selection process were also determined. Sequencing results revealed the successful transfer of the celiac immune response features to the immune library and the antibodies derived from it, suggesting the crucial role of these features in guiding the selection of high-affinity recombinant Fabs against gliadin. In summary, high-throughput DNA sequencing has improved our understanding of the selection processes aimed at generating molecular binders against gliadin.

Exploring Gluten Assessment in Marketed Products through a Sandwich ELISA Methodology Based on Novel Recombinant Antibodies.

This study presents the development of a sandwich ELISA method for gluten detection in foods, using recombinant Fab antibody fragments against gliadin. The Fabs were chemically biotinylated and immobilized on streptavidin-coated plates as capture antibodies, while alkaline phosphatase-conjugated Fabs were used as detection antibodies. Four different gliadin-binding Fabs were tested and the Fab pair Fab8E-4 and Fab-C showed the best compatibility. An indirect sandwich immunoassay, using unmodified Fab8E-4 for capture and Fab-C as the detection antibody, achieved a detection limit of 26 ng/mL of gliadin, corresponding to 10 mg/kg of gluten in foods. No cross-reactivity was observed against 60 gluten-free species commonly used in the food industry. Analysis of 50 commercial products demonstrated consistent results compared to the standard method for gluten detection. The complete lack of cross-reactivity of the developed immunoassay with oat products potentially provides an advantage over other gluten detection systems.

Application of Machine Learning Techniques for the Diagnosis of Obstructive Sleep Apnea/Hypopnea Syndrome.

Obstructive sleep apnea/hypopnea syndrome (OSAHS) is a condition linked to severe cardiovascular and neuropsychological consequences, characterized by recurrent episodes of partial or complete upper airway obstruction during sleep, leading to compromised ventilation, hypoxemia, and micro-arousals. Polysomnography (PSG) serves as the gold standard for confirming OSAHS, yet its extended duration, high cost, and limited availability pose significant challenges. In this paper, we employ a range of machine learning techniques, including Neural Networks, Decision Trees, Random Forests, and Extra Trees, for OSAHS diagnosis. This approach aims to achieve a diagnostic process that is not only more accessible but also more efficient. The dataset utilized in this study consists of records from 601 adults assessed between 2014 and 2016 at a specialized sleep medical center in Colombia. This research underscores the efficacy of ensemble methods, specifically Random Forests and Extra Trees, achieving an area under the Receiver Operating Characteristic (ROC) curve of 89.2% and 89.6%, respectively. Additionally, a web application has been devised, integrating the optimal model, empowering qualified medical practitioners to make informed decisions through patient registration, an input of 18 variables, and the utilization of the Random Forests model for OSAHS screening.

Application of ecotoxicological tools to evaluate the quality status of mangroves under restoration in the Yucatán Peninsula, Mexico.

Ecotoxicological tools, namely biomarkers and bioassays, may provide insights on the ecological quality status of mangroves under restoration. We investigated how 1) physicochemical parameters and water bioassays using Artemia franciscana; and 2) quantification of sublethal (osmoregulatory capacity, biochemical, and oxidative stress) and individual biomarkers (density, length-weight relationship [LWR], parasitic prevalence) in the sentinel fiddler crab Minuca rapax, can improve restoration indicators in mangroves from the Yucatán Peninsula, Southern Gulf of Mexico. We showed that water quality was improved with restoration, but still presented toxicity. Regarding sublethal biomarkers, M rapax from restored areas lower osmotic regulatory capacity, higher oxidative stress, and showed lipid peroxidation. As to the individual biomarkers, the density, LWR, and the prevalence of parasites in M. rapax was higher in restored areas. The use of bioassays/biomarkers were useful as early warning indicators to better assess the health of mangroves under restoration.

Diagnosing Alzheimer's disease: Which dementia screening test to use in elderly Puerto Ricans with mild cognitive impairment and early Alzheimer's disease?

Typically, Alzheimer's disease (AD) diagnosis is not made at its earliest period, for instance, at mild cognitive impairment (MCI) and early AD (E-AD). Our study aims to demonstrate a correlation between the screening tools, including the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Clinical Dementia Rating (CDR), and the biological biomarkers in the cerebrospinal fluid (CSF) amyloid beta 1-42 (Aß42), phosphorylated tau (p-tau) proteins and total tau (t-tau)/Aß42 ratio in Puerto Ricans > 55 years old with MCI and E-AD. We evaluated 30 participants, including demographics, memory scales, and CSF biomarkers. Twenty-eight CSF biomarkers (Aß42, p-tau protein, and t-tau/Aß42 ratio) were analyzed using the Meso Scale Discovery Platform (MSD). Associations between memory scales (MoCA, MMSE, CDR) and CSF markers were performed using Spearman rho correlation. Our study revealed a statistical association favoring a direct relationship between MMSE and MoCA with t-tau/Aß42 ratio in CSF (P = 0.022, P = 0.035, respectively). We found a trend toward significance with an inverse relationship with MMSE and Aß42 (P = 0.069) and a direct relationship with MMSE and p-tau (P = 0.098). MMSE and MoCA screening tests were identified with a statistically significant association with the CSF biomarkers, specifically t-tau/Aß42 ratio, in elderly Puerto Ricans with MCI and E-AD. Puerto Ricans > 55 years old with MCI and E-AD could be screened confidently with MMSE and MoCA for a higher likelihood of earlier detection and, thus, initiation of disease-modifying treatment and prompt non-pharmacological interventions.

Comprehensive study reveals phenotypic heterogeneity in Klebsiella pneumoniae species complex isolates.

Here, we conducted a comprehensive analysis of 356 Klebsiella pneumoniae species complex (KpSC) isolates that were classified as classical (cl), presumptive hypervirulent (p-hv) and hypermucoviscous-like (hmv-like). Overall, K. pneumoniae (82.3%), K. variicola (2.5%) and K. quasipneumoniae (2.5%) were identified. These isolates comprised 321 cl-KpSC, 7 p-hv-KpSC and 18 hmv-like-KpSC. A large proportion of cl-KpSC isolates were extended-spectrum-ß-lactamases (ESBLs)-producers (64.4%) and 3.4% of isolates were colistin-resistant carrying carbapenemase and ESBL genes. All p-hv-KpSC showed an antibiotic susceptible phenotype and hmv-like isolates were found to be ESBL-producers (8/18). Assays for capsule production and capsule-dependent virulence phenotypes and whole-genome sequencing (WGS) were performed in a subset of isolates. Capsule amount differed in all p-hv strains and hmv-like produced higher capsule amounts than cl strains; these variations had important implications in phagocytosis and virulence. Murine sepsis model showed that most cl strains were nonlethal and the hmv-like caused 100% mortality with 3 × 108 CFUs. Unexpectedly, 3/7 (42.9%) of p-hv strains required 108 CFUs to cause 100% mortality (atypical hypervirulent), and 4/7 (57.1%) strains were considered truly hypervirulent (hv). Genomic analyses confirmed the diverse population, including isolates belonging to hv clonal groups (CG) CG23, CG86, CG380 and CG25 (this corresponded to the ST3999 a novel hv clone) and MDR clones such as CG258 and CG147 (ST392) among others. We noted that the hmv-like and hv-ST3999 isolates showed a close phylogenetic relationship with cl-MDR K. pneumoniae. The information collected here is important to understand the evolution of clinically important phenotypes such as hypervirulent and ESBL-producing-hypermucoviscous-like amongst the KpSC in Mexican healthcare settings. Likewise, this study shows that mgrB inactivation is the main mechanism of colistin resistance in K. pneumoniae isolates from Mexico.

Clinical practice guidelines for the diagnosis and management of Charcot-Marie-Tooth disease.

INTRODUCTION: Charcot-Marie-Tooth disease (CMT) is classified according to neurophysiological and histological findings, the inheritance pattern, and the underlying genetic defect. The objective of these guidelines is to offer recommendations for the diagnosis, prognosis, follow-up, and treatment of this disease in Spain. MATERIAL AND METHODS: These consensus guidelines were developed through collaboration by a multidisciplinary panel encompassing a broad group of experts on the subject, including neurologists, paediatric neurologists, geneticists, physiatrists, and orthopaedic surgeons. RECOMMENDATIONS: The diagnosis of CMT is clinical, with patients usually presenting a common or classical phenotype. Clinical assessment should be followed by an appropriate neurophysiological study; specific recommendations are established for the parameters that should be included. Genetic diagnosis should be approached sequentially; once PMP22 duplication has been ruled out, if appropriate, a next-generation sequencing study should be considered, taking into account the limitations of the available techniques. To date, no pharmacological disease-modifying treatment is available, but symptomatic management, guided by a multidiciplinary team, is important, as is proper rehabilitation and orthopaedic management. The latter should be initiated early to identify and improve the patient's functional deficits, and should include individualised exercise guidelines, orthotic adaptation, and assessment of conservative surgeries such as tendon transfer. The follow-up of patients with CMT is exclusively clinical, and ancillary testing is not necessary in routine clinical practice.

Predicting major adverse cardiovascular events after orthotopic liver transplantation using a supervised machine learning model: A cohort study.

BACKGROUND: Liver transplant (LT) patients have become older and sicker. The rate of post-LT major adverse cardiovascular events (MACE) has increased, and this in turn raises 30-d post-LT mortality. Noninvasive cardiac stress testing loses accuracy when applied to pre-LT cirrhotic patients. AIM: To assess the feasibility and accuracy of a machine learning model used to predict post-LT MACE in a regional cohort. METHODS: This retrospective cohort study involved 575 LT patients from a Southern Brazilian academic center. We developed a predictive model for post-LT MACE (defined as a composite outcome of stroke, new-onset heart failure, severe arrhythmia, and myocardial infarction) using the extreme gradient boosting (XGBoost) machine learning model. We addressed missing data (below 20%) for relevant variables using the k-nearest neighbor imputation method, calculating the mean from the ten nearest neighbors for each case. The modeling dataset included 83 features, encompassing patient and laboratory data, cirrhosis complications, and pre-LT cardiac assessments. Model performance was assessed using the area under the receiver operating characteristic curve (AUROC). We also employed Shapley additive explanations (SHAP) to interpret feature impacts. The dataset was split into training (75%) and testing (25%) sets. Calibration was evaluated using the Brier score. We followed Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis guidelines for reporting. Scikit-learn and SHAP in Python 3 were used for all analyses. The supplementary material includes code for model development and a user-friendly online MACE prediction calculator. RESULTS: Of the 537 included patients, 23 (4.46%) developed in-hospital MACE, with a mean age at transplantation of 52.9 years. The majority, 66.1%, were male. The XGBoost model achieved an impressive AUROC of 0.89 during the training stage. This model exhibited accuracy, precision, recall, and F1-score values of 0.84, 0.85, 0.80, and 0.79, respectively. Calibration, as assessed by the Brier score, indicated excellent model calibration with a score of 0.07. Furthermore, SHAP values highlighted the significance of certain variables in predicting postoperative MACE, with negative noninvasive cardiac stress testing, use of nonselective beta-blockers, direct bilirubin levels, blood type O, and dynamic alterations on myocardial perfusion scintigraphy being the most influential factors at the cohort-wide level. These results highlight the predictive capability of our XGBoost model in assessing the risk of post-LT MACE, making it a valuable tool for clinical practice. CONCLUSION: Our study successfully assessed the feasibility and accuracy of the XGBoost machine learning model in predicting post-LT MACE, using both cardiovascular and hepatic variables. The model demonstrated impressive performance, aligning with literature findings, and exhibited excellent calibration. Notably, our cautious approach to prevent overfitting and data leakage suggests the stability of results when applied to prospective data, reinforcing the model's value as a reliable tool for predicting post-LT MACE in clinical practice.

Salinity and sedimentation rate influences on the community structure of polychaetes associated with two sympatric congeneric oyster species.

This study focused on spatial-temporal variations in the composition and structure of polychaete communities associated with two coexisting oyster species in a southern Gulf of Mexico coastal lagoon, showed that Crassostrea rhizophorae hosted 23 polychaete species and C. virginica only four. The observed variability was mainly explained by differences in salinity and sedimentation rate, two factors that also influenced the host species distribution. The highest values of richness and diversity occurred at C. rhizophorae sites during the rainy season, coinciding with increased salinity and a decrease in sedimentation rate. The shell-borer species Nereis garwoodi and Polydora websteri occurred in both oysters, but showing higher frequencies in C. virginica during the Nortes season (i.e., the cold fronts season). Our results underscore the contrasting diversity of associated polychaetes with two coexisting oyster species and emphasize the need for considering additional environmental parameters to allow better understanding of the factors that are driving the structure of these communities.

Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations.

Multiple sclerosis (MS) is a neuro-inflammatory and neurodegenerative disease that is most prevalent in Northern Europe. Although it is known that inherited risk for MS is located within or in close proximity to immune-related genes, it is unknown when, where and how this genetic risk originated1. Here, by using a large ancient genome dataset from the Mesolithic period to the Bronze Age2, along with new Medieval and post-Medieval genomes, we show that the genetic risk for MS rose among pastoralists from the Pontic steppe and was brought into Europe by the Yamnaya-related migration approximately 5,000 years ago. We further show that these MS-associated immunogenetic variants underwent positive selection both within the steppe population and later in Europe, probably driven by pathogenic challenges coinciding with changes in diet, lifestyle and population density. This study highlights the critical importance of the Neolithic period and Bronze Age as determinants of modern immune responses and their subsequent effect on the risk of developing MS in a changing environment.

In your CORT: Corticosterone and its receptors in the brain underlie mate choosiness in female Cope's gray treefrogs (Hyla chrysoscelis).

Selecting an attractive mate can involve trade-offs related to investment in sampling effort. Glucocorticoids like corticosterone (CORT) are involved in resolving energetic trade-offs. However, CORT is rarely studied in the context of mate choice, despite its elevated levels during reproductive readiness and the energetic transitions that characterize reproduction. Few systems are as well suited as anuran amphibians to evaluate how females resolve energetic trade-offs during mate choice. Phonotaxis tests provide a robust bioassay of mate choice that permit the precise measurement of inter-individual variation in traits such as choosiness-the willingness to pursue the most attractive mate despite costs. In Cope's gray treefrogs (Hyla chrysoscelis), females exhibit remarkable variation in circulating CORT as well as choosiness during mate choice, and a moderate dose of exogenous CORT rapidly (<1 h) and reliably induce large increases in choosiness. Here we measured the expression of glucocorticoid (GR) and mineralocorticoid (MR) receptors in the brains of females previously treated with exogenous CORT and tested for mate choosiness. We report a large decrease in GR expression in the hindbrain and midbrain of females that were treated with the moderate dosage of CORT-the same treatment group that exhibited a dramatic increase in choosiness following CORT treatment. This association, however, does not appear to be causal, as only forebrain GR levels, which are not affected by CORT injection, are positively associated with variation in choosiness. No strong effects were found for MR. We discuss these findings and suggest future studies to test the influence of glucocorticoids on mate choice.

Inherited SCN1A missense mutation in a Dravet Syndrome family: Neuropathological correlation, family screening and implications for adult carriers.

INTRODUCTION: Neuropathological findings in Dravet Syndrome (DS) are scarce, especially in adult patients, and often do not have a genetic confirmation. Additionally, the missense SCN1A pathogenic variant found has only been described as de novo mutation in previous literature. METHODS: We describe the clinical and genetic findings of a family (including three sisters and his father), using Sanger sequencing in the three sisters and in postmortem brain tissue in the father. The present study also shows the neuropathological findings of the father. RESULTS: Despite the presence of long term drug resistant epilepsy, starting with febrile seizures between 6 and 12 months of age, and intellectual disability (ID), the three sisters were diagnosed with DS in adulthood, identifying a missense SCN1A pathogenic variant in exon 20, previously described as de novo -p.Gly1332Glu (c .3995 G>A). The oldest sister had the most severe phenotype, with severe ID and wheel chair dependency, passing away at 52. The other two sisters had a moderate phenotype, being at the present seizure free, but with significant comorbidities, such as crouch gait and parkinsonism. Several relatives from the paternal path (including the father) presented epilepsy, but without ID. The father was diagnosed with Alzheimer´s Disease (AD) at 60, and because he donated his brain, the same variant was confirmed in postmortem study. Neither the MRI nor the histopathology showed specific morphological changes for DS, consistent with previous studies. CONCLUSIONS: This work supports the need to review the clinical and genetic spectra of DS in adults with epilepsy and unknown ID. The clinical consequences of this syndrome seem to have a functional rather than a structural basis, supported by the absence of specific neuropathological findings.

Performance of eight predictive models for hepatocellular carcinoma recurrence after liver transplantation: A comparative study.

INTRODUCTION AND OBJECTIVES: Liver transplantation is the optimal treatment for patients with early hepatocellular carcinoma and cirrhosis. However, hepatocellular carcinoma recurs in approximately 15 % of individuals. This study aimed to assess the efficacy of predictive models for hepatocellular carcinoma recurrence after liver transplantation. PATIENTS AND METHODS: This retrospective study included 381 patients with HCC and evaluated the performance of the following models: R3-AFP score, alpha-fetoprotein (AFP) model, University of California, Los Angeles (UCLA) nomogram, Pre-Model of Recurrence after Liver Transplantation (MORAL), Post-MORAL, and Combo MORAL models, Risk Estimation of Tumor Recurrence (RETREAT) model and Platelet to Lymphocyte Ratio (PLR) model. RESULTS: The R3-AFP score, UCLA nomogram, AFP model, RETREAT, Combo MORAL, and Post-MORAL models exhibited comparable AUROCs, ranging from 0.785 to 0.733. The AUROCs for the R3-AFP model and AFP model were superior to those of the Pre-MORAL and PLR models. The UCLA nomogram, RETREAT score, Combo MORAL model, and Post-MORAL model performed similarly to the first two models, but were only superior to the PLR model. CONCLUSIONS: The R3-AFP model, UCLA nomogram, AFP model, RETREAT, Combo MORAL, and Post-MORAL models demonstrated a moderate predictive capacity for hepatocellular carcinoma recurrence following transplantation. No significant differences were observed among these models in their ability to predict recurrence.