In-and-out Technique: An In-house Efficient Predictive Hole Fabrication Workflow.

Virtual surgical planning (VSP) and three-dimensional (3D) printing can increase precision and reduce surgical time in craniofacial reconstruction. However, the elevated cost and manufacturing time of outsourced workflows is increasing the development of in-house solutions. One of the main challenges in in-house workflows is to create cutting guides that hold plate position information. This is due to the fact that hospitals usually lack the infrastructure required to design and 3D print custom-made plates. Including plate-positioning information in resection guides is especially relevant in complex reconstructions and when tumor extension limits plate placement before resection. Current in-house workflows revolve around the idea of 3D scanning the bent plate's shape and to fuse it with the VSP. The goal of this article is to share our technique to transfer plate position information to resection guides. Our protocol uses a 3D model of the reconstruction as an intermediate step to transfer the plate position of a bent stock reconstruction plate to cutting guides. Two patients who required mandibular reconstruction with fibula flap are presented to illustrate the technique. This workflow requires a 3D-printed model of the desired outcome, cutting guides, and a stock plate. Results were satisfactory in terms of cutting location and angulation, plate adaptation and condylar position. This technique allows for a simple, safe, cheap, and quick alternative to add reconstruction plate information to cutting guides.

Life cycle assessment of a LiFePO4 cylindrical battery.

Reduction of the environmental impact, energy efficiency and optimization of material resources are basic aspects in the design and sizing of a battery. The objective of this study was to identify and characterize the environmental impact associated with the life cycle of a 7.47 Wh 18,650 cylindrical single-cell LiFePO4 battery. Life cycle assessment (LCA), the SimaPro 9.1 software package, the Ecoinvent 3.5 database and the ReCiPe 2016 impact assessment method were used for this purpose. Environmental impacts were modelled and quantified using the dual midpoint-endpoint approach and the "cradle-to-gate" model. The results showed the electrodes to be the battery components with the highest environmental impact (41.36% of the total), with the negative electrode being the most unfavourable (29.8 mPt). The ageing, calibration and testing process (53.97 mPt) accounts for 97.21% of the total impact associated with the production process's consumption of energy, and 41.20% of the total impact associated with the battery. This new knowledge will allow a more detailed view of the environmental impact of cylindrical cell LiFePO4 batteries, favouring the identification of critical points to enhance their sustainable production.

Prostate Cancer and the Mevalonate Pathway.

Antineoplastic therapies for prostate cancer (PCa) have traditionally centered around the androgen receptor (AR) pathway, which has demonstrated a significant role in oncogenesis. Nevertheless, it is becoming progressively apparent that therapeutic strategies must diversify their focus due to the emergence of resistance mechanisms that the tumor employs when subjected to monomolecular treatments. This review illustrates how the dysregulation of the lipid metabolic pathway constitutes a survival strategy adopted by tumors to evade eradication efforts. Integrating this aspect into oncological management could prove valuable in combating PCa.

Comparative Effects of Two High-Intensity Intermittent Training Programs on Sub-Elite Male Basketball Referees' Fitness Levels.

This study aimed to compare the effects of an 8-week short-term training program, comprising repeated sprints or running-based high-intensity intermittent training (HIIT), on the aerobic fitness and repeated sprint ability (RSA) performance of sub-elite basketball referees. Twenty male referees participated in supervised training sessions twice a week. They were randomly assigned to either the RSA-based group (RSAG) or the running-based HIIT group (HIITG). The RSAG conducted 3-4 sets of 8 × 20-m all-out sprints, while the HIITG performed 2-3 sets of 6 × 20-s runs at 90% of their maximal velocity achieved in the 30-15 intermittent fitness test (30-15IFT). Referees underwent a graded exercise test on a treadmill, the 30-15IFT, and an RSA test before and after the training program. Both groups showed significant improvement (~3%) in the fastest (22.6 ± 1.4 vs. 23.4 ± 1.7 and 22.0 ±1.9 vs. 22.4 ± 1.7 km·h-1 in RSAG and HIITG, respectively) and mean (21.5 ± 1.2 vs. 22.4 ± 1.4 and 21.3 ± 1.8 vs. 21.7 ± 1.6 km·h-1 in RSAG and HIITG, respectively) sprint velocity of the RSA test (p < 0.05). Moreover, positive changes (p < 0.05) were observed in the 30-15IFT maximal velocity (18.6 ± 1.1 vs. 19.3 ± 1.0 and 19.4 ± 0.9 vs. 20.5 ± 0.9 km·h-1 in RSAG and HIITG, respectively). In conclusion, an 8-week training intervention using either RSA or running-based HIIT led to similar improvements in referees' RSA performance and specific aerobic fitness measures. These findings could assist in devising tailored training programs for basketball referees.

Readaptación funcional basada en ejercicio físico terapéutico en pacientes con COVID persistente (RECOVER) / Functional rehabilitation based on therapeutic exercise training in patients with postacute COVID syndrome (RECOVER)

Introduction and objectives Postacute COVID syndrome (PACS) is common after acute SARS-CoV-2 infection. One of the most frequent and disabling symptoms is exercise intolerance (EI). Recent evidence suggests that EI in PACS has a peripheral (metabolic-neuromuscular) origin, suggesting that exercise training may be an effective treatment. The aim of this study was to assess the role a therapeutic physical exercise program (TPEP) in PACS with EI. Method This single-center, open-label, randomized clinical trial compared an exercise training program (intervention group) with regular physical activity recommendations (control group) in patients with PACS and EI. The intervention group underwent an 8-week TPEP. The primary endpoint was improvement in functional capacity, assessed as the change in peak VO2. Results We included 50 participants with PACS (73% women, mean age 47±7.1 years). The intervention group showed a 15% improvement in peak VO2 (peak VO2 pre- and postintervention: 25.5±7.7mL/kg/min and 29.3±4.7 mL/kg/min; P <.001) and a 13.2% improvement in predicted values (92.1±14.3% and 108.4±13.4%; P <.001). No significant changes in VO2 values were observed in the control group. Unlike the control group, the intervention group also showed improvements in all secondary outcomes: quality of life scales, muscle power, maximum inspiratory power, metabolic flexibility, and body fat percentage. Conclusions The program improved functional capacity in patients with PACS and EI (AU)

Introducción y objetivos El síndrome de COVID persistente (SCP) es frecuente tras la infección aguda por SARS-CoV-2, y la intolerancia al ejercicio (IE) uno de los síntomas más frecuentes y limitantes. La evidencia reciente indica que el origen de los síntomas es periférico (muscular), por lo que el ejercicio físico podría ser un tratamiento eficaz. Este estudio evalúa la eficacia de un programa de ejercicio físico terapéutico (PEFT) en la mejora de la capacidad funcional de los pacientes con SCP e IE. Métodos Estudio aleatorizado, unicéntrico, controlado y abierto que compara un PEFT (grupo de intervención) con recomendaciones de actividad física estándar (grupo de control) en pacientes con SCP con IE. El grupo de intervención recibió 8 semanas de PEFT. El objetivo principal fue el cambio en la capacidad funcional medido mediante el consumo pico de oxígeno (VO2 pico). Resultados Se incluyó a un total de 50 pacientes con SCP (el 73% mujeres; media de edad, 47±7,1 años). El grupo de intervención presentó una mejora en el VO2 pico del 15% (VO2 pico inicial y final: 25,5±7,7 y 29,3±4,7ml/kg/min; p <0,001) y del 13,2% en valores del %VO2 máximo predicho (el 92,1±14,3% y el 108,4±13,4%; p <0,001), sin cambios significativos en el grupo de control. Todos los objetivos secundarios también mejoraron exclusivamente en el grupo de intervención: escalas de calidad de vida, potencia muscular desarrollada, potencia inspiratoria máxima, flexibilidad metabólica y porcentaje de grasa corporal. Conclusiones El PEFT mejora la capacidad funcional de los pacientes con SCP e IE (AU)

Is there a preferred platinum and fluoropyrimidine regimen for advanced HER2-negative esophagogastric adenocarcinoma? Insights from 1293 patients in AGAMENON-SEOM registry.

BACKGROUND: The optimal chemotherapy backbone for HER2-negative advanced esophagogastric cancer, either in combination with targeted therapies or as a comparator in clinical trials, is uncertain. The subtle yet crucial differences in platinum-based regimens' safety and synergy with combination treatments need consideration. METHODS: We analyzed cases from the AGAMENON-SEOM Spanish registry of HER2-negative advanced esophagogastric adenocarcinoma treated with platinum and fluoropyrimidine from 2008 to 2021. This study focused exclusively on patients receiving one of the four regimens: FOLFOX (5-FU and oxaliplatin), CAPOX (capecitabine and oxaliplatin), CP (capecitabine and cisplatin) and FP (5-FU and cisplatin). The aim was to determine the most effective and tolerable platinum and fluoropyrimidine-based chemotherapy regimen and to identify any prognostic factors. RESULTS: Among 1293 patients, 36% received either FOLFOX (n = 468) or CAPOX (n = 466), 20% CP (n = 252), and 8% FP (n = 107). FOLFOX significantly increased PFS (progression free survival) compared to CP, with a hazard ratio of 0.73 (95% CI 0.58-0.92, p = 0.009). The duration of treatment was similar across all groups. Survival outcomes among regimens were similar, but analysis revealed worse ECOG-PS (Eastern Cooperative Oncology Group-Performance Status), > 2 metastatic sites, bone metastases, hypoalbuminemia, higher NLR (neutrophil-to-lymphocyte ratio), and CP regimen as predictors of poor PFS. Fatigue was common in all treatments, with the highest incidence in FOLFOX (77%), followed by FP (72%), CAPOX (68%), and CP (60%). Other notable toxicities included neuropathy (FOLFOX 69%, CAPOX 62%), neutropenia (FOLFOX 52%, FP 55%), hand-foot syndrome in CP (46%), and thromboembolic events (FP 12%, CP 11%). CONCLUSIONS: FOLFOX shown better PFS than CP. Adverse effects varied: neuropathy was more common with oxaliplatin, while thromboembolism was more frequent with cisplatin.

Digital Microscopy Augmented by Artificial Intelligence to Interpret Bone Marrow Samples for Hematological Diseases.

Analysis of bone marrow aspirates (BMAs) is an essential step in the diagnosis of hematological disorders. This analysis is usually performed based on a visual examination of samples under a conventional optical microscope, which involves a labor-intensive process, limited by clinical experience and subject to high observer variability. In this work, we present a comprehensive digital microscopy system that enables BMA analysis for cell type counting and differentiation in an efficient and objective manner. This system not only provides an accessible and simple method to digitize, store, and analyze BMA samples remotely but is also supported by an Artificial Intelligence (AI) pipeline that accelerates the differential cell counting process and reduces interobserver variability. It has been designed to integrate AI algorithms with the daily clinical routine and can be used in any regular hospital workflow.

ARGEN SHOCK: Mortality related to the use of Swan Ganz and to the hemodynamic pattern found in patients with AMICS.

The Swan Ganz Catheter (SGC) allows us to diagnose different types of cardiogenic shock (CS). OBJECTIVES: 1) Determine the frequency of use of SGC, 2) Analyze the clinical characteristics and mortality according to its use and 3) Analyze the prevalence, clinical characteristics and mortality according to the type of Shock. METHODS: The 114 patients (p) from the ARGEN SHOCK registry were analyzed. A "classic" pattern was defined as PCP > 15 mm Hg, CI < 2.2 L/min/ m2, SVR > 1,200 dynes × sec × cm-5. A "vasoplegic/mixed" pattern was defined when p did not meet the classic definition. CS due to right ventricle (RV) was excluded. RESULTS: SGC was used in 35 % (n:37). There were no differences in clinical characteristics according to SGC use, but those with SGC were more likely to receive dobutamine, levosimendan, and intra aortic balloon pump (IABP). Mortality was similar (59.4 % vs 61.3 %). The pattern was "classic" in 70.2 %. There were no differences in clinical characteristics according to the type of pattern or the drugs used. Mortality was 54 % in patients with the classic pattern and 73 % with the mixed/vasoplegic pattern, but the difference did not reach statistical significance (p:0.23). CONCLUSIONS: SGC is used in one third of patients with CS. Its use does not imply differences in the drugs used or in mortality. Most patients have a classic hemodynamic pattern. There are no differences in mortality or in the type of vasoactive agents used according to the CS pattern found.

Cómo estimar la composición corporal en la enfermedad de Huntington. Estudio transversal y observacional con bioimpedancia de múltiples frecuencias / How to estimate body composition in Huntington’s disease. A cross-sectional, observational study using multiple frequencies bioimpedance

Introducción La enfermedad de Huntington (EH) es un trastorno raro neurodegenerativo. La información fiable del estado nutricional, especialmente de la composición corporal, es crítica en clínica y en investigación. La facilidad de aplicación y portabilidad del análisis de la bioimpedancia de múltiples frecuencias (mfBIA) la convierten en una herramienta atractiva para medirla, pero se desconoce su precisión en la EH. Objetivo Evaluar la precisión del mfBIA frente a la absorciometría dual de rayos X (DEXA) en la EH. Pacientes y métodos Estudio transversal, observacional y unicéntrico. La EH se midió con la subescala motora de la escala unificada de valoración de la EH y con la capacidad funcional total. La composición corporal se valoró según la masa libre de grasa (MLG), la masa grasa (MG), el índice de masa libre de grasa (IMLG) y el índice de masa grasa (IMG). Se utilizó el coeficiente de correlación intraclase con intervalos de confianza al 95% y estimaciones de sesgo mediante gráficos de Bland-Altman. Resultados Se incluyó a 16 pacientes, siete hombres y nueve mujeres, con edad media de 58,5 (32-68) años, capacidad funcional total de 10 (3-13) y escala unificada de valoración de la EH de 31 (7-85). La fiabilidad era alta entre el mfBIA y la DEXA para el IMLG en hombres, 0,88 (intervalo de confianza al 95%: 0,17-0,98), y mujeres, 0,9 (intervalo de confianza al 95%: 0,61-0,98); y para el IMG en hombres, 0,97 (intervalo de confianza al 95%: 0,83-0,99), y mujeres, 0,91 (intervalo de confianza al 95%: 0,68-0,98). El mfBIA sobreestimó ligeramente la MLG, la MG, el IMG y el IMLG en los hombres, pero subestimó el IMLG en las mujeres. Conclusiones El mfBIA es un método fácil de usar, seguro, no invasivo y preciso para medir la composición corporal y el estado nutricional en pacientes con EH leve-moderada. (AU)

INTRODUCTION Huntington´s disease (HD) is a rare neurodegenerative disorder. Reliable information about nutritional status, especially body composition from individuals with HD is critical for clinical care and research. The ease of application and portability of multiple frequencies bioelectrical impedance analysis (mfBIA) make it an attractive tool for measuring body composition, but its accuracy in HD is unknown. AIM To evaluate the accuracy of mfBIA vs. Dual X-ray absorptiometry (DEXA) in HD. PATIENTS AND METHODS Cross-sectional, observational, and single-center study. HD severity was measured using motor subscale of the unified Huntington´s disease rating scale (m-UHDRS) and the total functional capacity (TFC). Body composition was measured in terms of fat-free mass (FFM), fat mass (FM), fat-free mass index (FFMI), and fat mass index (FMI). Using Bland-Altman plots, we analyzed reliability between DEXA and mfBIA using the Intraclass Correlation Coefficient with 95% confidence intervals (CI) and bias estimates for all. RESULTS We included 16 patients with HD, 7 men, and 9 women, median age of 58.5 (32;68) years, TFC: 10 (3;13), and m-UHDRS: 31 (7;85). The reliability between mfBIA and DEXA were high for FFMI in men: 0.88 (95% CI 0.17-0.98), and women: 0.90 (95% CI 0.61- 0.98); for FMI, men: 0.97 (95% CI 0.83-0.99), and women: 0.91 (95% CI 0.68-0.98). Compared to DEXA, mfBIA slightly overestimated FFM, FM, FMI and FFMI in men and underestimated FFMI in women. CONCLUSIONS mfBIA is an easy-to-use, safe, non-invasive, accurate method for measuring body composition and nutritional status in patients with mild-moderate HD. (AU)

Validation of ActiGraph and Fitbit in the assessment of energy expenditure in Huntington's disease.

BACKGROUND: Consumer and research activity monitors have become popular because of their ability to quantify energy expenditure (EE) in free-living conditions. However, the accuracy of activity trackers in determining EE in people with Huntington's Disease (HD) is unknown. RESEARCH QUESTION: Can the ActiGraph wGT3X-B or the Fitbit Charge 4 accurately measure energy expenditure during physical activity, in people with HD compared to Indirect Calorimetry (IC) (Medisoft Ergo Card)? METHODS: We conducted a cross-sectional, observational study with fourteen participants with mild-moderate HD (mean age 55.7 ± 11.4 years). All participants wore an ActiGraph and Fitbit during an incremental test, running on a treadmill at 3.2 km/h and 5.2 km/h for three minutes at each speed. We analysed and compared the accuracy of EE estimates obtained by Fitbit and ActiGraph against the EE estimates obtained by a metabolic cart, using with Intra-class correlation (ICC), Bland-Altman analysis and correlation tests. RESULTS: A significant correlation and a moderate reliability was found between ActiGraph and IC for the incremental test (r = 0.667)(ICC=0.633). There was a significant correlation between Fitbit and IC during the incremental test (r = 0.701), but the reliability was poor at all tested speeds in the treadmill walk. Fitbit significantly overestimated EE, and ActiGraph underestimated EE compared to IC, but ActiGraph estimates were more accurate than Fitbit in all tests. SIGNIFICANCE: Compared to IC, Fitbit Charge 4 and ActiGraph wGT3X-BT have reduced accuracy in estimating EE at slower walking speeds. These findings highlight the need for population-specific algorithms and validation of activity trackers.

Sumoylation in astrocytes induces changes in the proteome of the derived small extracellular vesicles which change protein synthesis and dendrite morphology in target neurons.

Emerging evidence highlights the relevance of the protein post-translational modification by SUMO (Small Ubiquitin-like Modifier) in the central nervous system for modulating cognition and plasticity in health and disease. In these processes, astrocyte-to-neuron crosstalk mediated by extracellular vesicles (EVs) plays a yet poorly understood role. Small EVs (sEVs), including microvesicles and exosomes, contain a molecular cargo of lipids, proteins, and nucleic acids that define their biological effect on target cells. Here, we investigated whether SUMOylation globally impacts the sEV protein cargo. For this, sEVs were isolated from primary cultures of astrocytes by ultracentrifugation or using a commercial sEV isolation kit. SUMO levels were regulated: 1) via plasmids that over-express SUMO, or 2) via experimental conditions that increase SUMOylation, i.e., by using the stress hormone corticosterone, or 3) via the SUMOylation inhibitor 2-D08 (2',3',4'-trihydroxy-flavone, 2-(2,3,4-Trihydroxyphenyl)-4H-1-Benzopyran-4-one). Corticosterone and 2-D08 had opposing effects on the number of sEVs and on their protein cargo. Proteomic analysis showed that increased SUMOylation in corticosterone-treated or plasmid-transfected astrocytes increased the presence of proteins related to cell division, transcription, and protein translation in the derived sEVs. When sEVs derived from corticosterone-treated astrocytes were transferred to neurons to assess their impact on protein synthesis using the fluorescence non-canonical amino acid tagging assay (FUNCAT), we detected an increase in protein synthesis, while sEVs from 2-D08-treated astrocytes had no effect. Our results show that SUMO conjugation plays an important role in the modulation of the proteome of astrocyte-derived sEVs with a potential functional impact on neurons.

A New Set of in Silico Tools to Support the Interpretation of ATM Missense Variants Using Graphical Analysis.

Establishing the pathogenic nature of variants in ATM, a gene associated with breast cancer and other hereditary cancers, is crucial for providing patients with adequate care. Unfortunately, achieving good variant classification is still difficult. To address this challenge, we extended the range of in silico tools with a series of graphical tools devised for the analysis of computational evidence by health care professionals. We propose a family of fast and easy-to-use graphical representations in which the impact of a variant is considered relative to other pathogenic and benign variants. To illustrate their value, the representations are applied to three problems in variant interpretation. The assessment of computational pathogenicity predictions showed that the graphics provide an intuitive view of prediction reliability, complementing and extending conventional numerical reliability indexes. When applied to variant of unknown significance populations, the representations shed light on the nature of these variants and can be used to prioritize variants of unknown significance for further studies. In a third application, the graphics were used to compare the two versions of the ATM-adapted American College of Medical Genetics and Genomics and Association for Molecular Pathology guidelines, obtaining valuable information on their relative virtues and weaknesses. Finally, a server [ATMision (ATM missense in silico interpretation online)] was generated for users to apply these representations in their variant interpretation problems, to check the ATM-adapted guidelines' criteria for computational evidence on their variant(s) and access different sources of information.

The formulation and in vitro evaluation of WS Biotin, a novel encapsulated form of D-Biotin with improved water solubility for hair and skin treatment applications.

OBJECTIVE: To develop and evaluate the efficacy of WS Biotin, a novel water-soluble form of D-Biotin, for cosmetic use. METHODS: A new encapsulated form of D-Biotin was developed with the purpose of improving the water solubility of biotin. This novel form of encapsulated biotin was characterized by its physicochemical properties: particle size, D-Biotin content and solubility in water. Also, proliferation and gene expression in vitro tests in cell culture were performed to evaluate its effectiveness in promoting hair growth, an ELISA test was conducted for hair keratinization and skin lightening property was tested by analysing the intracellular melanin content. RESULTS: The developed WS Biotin microcapsules exhibit a particle size range of 2-30 µm with D-Biotin content of ~50% (w/w). The water solubility of WS Biotin was found to be 20-fold greater than free biotin. The obtained in vitro results indicated that WS Biotin enhances the expression of hair-related keratins in hair follicle keratinocytes, as well as the expression of hair growth-promoting genes in dermal papilla cells. Moreover, the melanin content in UVA-exposed epidermal melanocytes was reduced upon exposure to WS Biotin. CONCLUSION: In this work, a novel form of encapsulated biotin, WS Biotin, was developed in order to improve the water solubility of free biotin and was found to be effective for cosmetic use in both hair and skin applications.

OBJECTIF: Développer et évaluer l'efficacité de la WS Biotin, une nouvelle forme hydrosoluble de D-biotine, à usage cosmétique. MÉTHODES: Une nouveau format gélules de D-biotine a été développé dans le but d'améliorer la propriété d'hydrosolubilité de la biotine. Ce nouveau format de gélules de biotine a été caractérisé pour ses propriétés physicochimiques : taille des particules, teneur en D-biotine et solubilité dans l'eau. En outre, des tests in vitro de prolifération et d'expression génique en culture cellulaire ont été réalisés pour évaluer son efficacité à favoriser la croissance des cheveux, un test ELISA a été réalisé pour la kératinisation des cheveux et la propriété d'éclaircissement de la peau a été testée en analysant la teneur en mélanine intracellulaire. RÉSULTATS: Les microgélules de WS Biotin développées présentent une plage de tailles de particules de 2 à 30 micromètres avec une teneur en biotine D d'environ 50 % (p/p). L'hydrosolubilité de WS Biotin s'est avérée 20 fois plus élevée que celle de la biotine libre. Les résultats in vitro obtenus ont indiqué que WS Biotin améliorait l'expression des kératines capillaires dans les kératinocytes des follicules pileux, ainsi que l'expression des gènes favorisant la croissance dans les cellules papillaires dermiques. En outre, la teneur en mélanine dans les mélanocytes épidermiques exposés aux UVA a été réduite lors de l'exposition à WS Biotin. CONCLUSION: Dans ce travail, une nouvelle forme de biotine en gélule, WS Biotin, a été développée afin d'améliorer l'hydrosolubilité de la biotine libre et s'est avérée efficace pour une utilisation cosmétique dans les applications capillaires et cutanées.

Functional rehabilitation based on therapeutic exercise training in patients with postacute COVID syndrome (RECOVER).

INTRODUCTION AND OBJECTIVES: Postacute COVID syndrome (PACS) is common after acute SARS-CoV-2 infection. One of the most frequent and disabling symptoms is exercise intolerance (EI). Recent evidence suggests that EI in PACS has a peripheral (metabolic-neuromuscular) origin, suggesting that exercise training may be an effective treatment. The aim of this study was to assess the role a therapeutic physical exercise program (TPEP) in PACS with EI. METHODS: This single-center, open-label, randomized clinical trial compared an exercise training program (intervention group) with regular physical activity recommendations (control group) in patients with PACS and EI. The intervention group underwent an 8-week TPEP. The primary endpoint was improvement in functional capacity, assessed as the change in peak VO2. RESULTS: We included 50 participants with PACS (73% women, mean age 47±7.1 years). The intervention group showed a 15% improvement in peak VO2 (peak VO2 pre- and postintervention: 25.5±7.7mL/kg/min and 29.3±4.7 mL/kg/min; P <.001) and a 13.2% improvement in predicted values (92.1±14.3% and 108.4±13.4%; P <.001). No significant changes in VO2 values were observed in the control group. Unlike the control group, the intervention group also showed improvements in all secondary outcomes: quality of life scales, muscle power, maximum inspiratory power, metabolic flexibility, and body fat percentage. CONCLUSIONS: The program improved functional capacity in patients with PACS and EI.

Developmental epileptic encephalopathy in DLG4-related synaptopathy.

OBJECTIVE: The postsynaptic density protein of excitatory neurons PSD-95 is encoded by discs large MAGUK scaffold protein 4 (DLG4), de novo pathogenic variants of which lead to DLG4-related synaptopathy. The major clinical features are developmental delay, intellectual disability (ID), hypotonia, sleep disturbances, movement disorders, and epilepsy. Even though epilepsy is present in 50% of the individuals, it has not been investigated in detail. We describe here the phenotypic spectrum of epilepsy and associated comorbidities in patients with DLG4-related synaptopathy. METHODS: We included 35 individuals with a DLG4 variant and epilepsy as part of a multicenter study. The DLG4 variants were detected by the referring laboratories. The degree of ID, hypotonia, developmental delay, and motor disturbances were evaluated by the referring clinician. Data on awake and sleep electroencephalography (EEG) and/or video-polygraphy and brain magnetic resonance imaging were collected. Antiseizure medication response was retrospectively assessed by the referring clinician. RESULTS: A large variety of seizure types was reported, although focal seizures were the most common. Encephalopathy related to status epilepticus during slow-wave sleep (ESES)/developmental epileptic encephalopathy with spike-wave activation during sleep (DEE-SWAS) was diagnosed in >25% of the individuals. All but one individual presented with neurodevelopmental delay. Regression in verbal and/or motor domains was observed in all individuals who suffered from ESES/DEE-SWAS, as well as some who did not. We could not identify a clear genotype-phenotype relationship even between individuals with the same DLG4 variants. SIGNIFICANCE: Our study shows that a subgroup of individuals with DLG4-related synaptopathy have DEE, and approximately one fourth of them have ESES/DEE-SWAS. Our study confirms DEE as part of the DLG4-related phenotypic spectrum. Occurrence of ESES/DEE-SWAS in DLG4-related synaptopathy requires proper investigation with sleep EEG.

Expanding the clinical and molecular spectrum of FOXG1- and ZBTB18-associated neurodevelopmental disorders.

Introduction The zinc finger BTB domain-containing protein ZBTB18 binds to FOXG1 to form a transcriptional repressive complex involved in neuronal differentiation. Disruption of the components of this complex results in chromosome 1q43-q44 deletion syndrome/intellectual developmental disorder 22 or in FOXG1 syndrome. Case presentation This study reports on five patients with cognitive and behavioral impairment, seizures, microcephaly, and/or congenital brain abnormalities. Whole exome sequencing identified deleterious ZBTB18 variants in three patients and deleterious FOXG1 variants in the remaining patients. We have detected a missense variant within the BTB domain of ZBTB18 in two affected monozygotic twins. In addition, we observed agenesis of the septum pellucidum in a missense FOXG1 carrier with a severe FOXG1 syndrome. Conclusion Although the ZBTB18 zinc finger domains harbor the majority of known deleterious variants, we report a novel de novo rare missense variant within the BTB domain. The agenesis of the septum pellucidum observed in a missense FOXG1 carrier could be considered as a novel clinical feature associated with FOXG1 syndrome. The severe FOXG1 syndrome in this patient contrasts with the milder phenotype expected for a missense. Genetic or environmental factors may explain this phenotypic variability in FOXG1 syndrome.