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Wildfires represent a critical environmental and social challenge, with long-term implications for human health, ecosystems, and infrastructure. This complex issue is exacerbated by various factors, including socioeconomic changes, unsustainable practices in agro-forestry land management, and the intensification of extreme weather events. The complexity of fire management in Italy necessitates effective governance mechanisms and planning tools at both regional and national levels. This study looks at successful prevention strategies, such as prescribed burning and proactive land management, while also addressing existing governance challenges, such as coordination among relevant institutions and the need for stronger regulatory frameworks. In addition to providing insights into the current state of fire governance and proposing practical solutions, we suggest that more resilient and sustainable fire management practices, already successfully implemented in some regions, should be adopted nationwide in Italy.

Concrete is a prominent construction material globally, owing to its reputed attributes such as robustness, endurance, optimal functionality, and adaptability. Formulating concrete mixtures poses a formidable challenge, mainly when introducing novel materials and additives and evaluating diverse design resistances. Recent methodologies for projecting concrete performance in fundamental aspects, including compressive strength, flexural strength, tensile strength, and durability (encompassing homogeneity, porosity, and internal structure), exist. However, actual approaches need more diversity in the materials and properties considered in their analyses.This dataset outlines the outcomes of an extensive 10-year laboratory investigation into concrete materials involving mechanical tests and non-destructive assessments within a comprehensive dataset denoted as ConcreteXAI. This dataset encompasses evaluations of mechanical performances and non-destructive tests. ConcreteXAI integrates a spectrum of analyzed mixtures comprising twelve distinct concrete formulations incorporating diverse additives and aggregate types. The dataset encompasses 18,480 data points, establishing itself as a cutting-edge resource for concrete analysis.ConcreteXAI acknowledges the influence of artificial intelligence techniques in various science fields. Emphatically, deep learning emerges as a precise methodology for analyzing and constructing predictive models. ConcreteXAI is designed to seamlessly integrate with deep learning models, enabling direct application of these models to predict or estimate desired attributes. Consequently, this dataset offers a resourceful avenue for researchers to develop high-quality prediction models for both mechanical and non-destructive tests on concrete elements, employing advanced deep learning techniques.

This study takes a unique approach, using satellite remote sensing to analyze the land surface temperature (LST) in seven coastal cities located at latitudes between 18° and 22° and longitudes between 106° and 91°. The methodology consists of obtaining the LST on two selected days, one in July 2019 and one in July 2020, to determine how the temperature was modified by the atypical mobility caused by Coronavirus Disease 2019 (COVID-19) and social distancing. Using these data, we determine the representative surface temperature that tended to rise (RHST) and the representative surface temperature that tended to decrease (RLST), depending on the affected area. This approach allows us to comprehensively compare how mobility modified the four variables studied: territorial extension, population, types of soil (paving), and vegetation. We concluded that, among the factors analyzed, the types of paving and vegetation were those that generated a more significant decrease in temperature; the variables of territorial extension and the number of inhabitants had a smaller impact. This study paves the way for a discussion of the significant influence of mobility on the behavior of the LST.

This study takes a unique approach, using satellite remote sensing to analyze the land surface temperature (LST) in seven coastal cities located at latitudes between 18° and 22° and longitudes between 106° and 91°. The methodology consists of obtaining the LST on two selected days, one in July 2019 and one in July 2020, to determine how the temperature was modified by the atypical mobility caused by Coronavirus Disease 2019 (COVID-19) and social distancing. Using these data, we determine the representative surface temperature that tended to rise (RHST) and the representative surface temperature that tended to decrease (RLST), depending on the affected area. This approach allows us to comprehensively compare how mobility modified the four variables studied: territorial extension, population, types of soil (paving), and vegetation. We concluded that, among the factors analyzed, the types of paving and vegetation were those that generated a more significant decrease in temperature; the variables of territorial extension and the number of inhabitants had a smaller impact. This study paves the way for a discussion of the significant influence of mobility on the behavior of the LST. [ABSTRACT FROM AUTHOR]

The design of flexible road pavements is a complex process as a result of the multiple variables that influence and interact in the models that allow the design of each layer. In recent years, a particular interest has been raised to ensure that climate is considered in pavement design due to temperature and precipitation that influence the deterioration of pavements, impacting their service life. This paper presents a critical review of flexible pavement design methods, from the first ones based on experience, such as empirical methods, to the most recent ones on mechanical–empirical methodologies, where, based on different principles, they determine the thicknesses of the layers that integrate the structure of a pavement to identify how these methods have included climate variables within their methodology. Through this review, it was identified that temperature is incorporated in the dynamic modulus of the asphalt mix, and precipitation and moisture are incorporated through the resilient modulus in the granular layers (base, subbase, and foundation soil or subgrade courses). As a result, it was identified that the most holistic way of integrating climate is through the Enhanced Integrated Climatic Model (EICM) from the Mechanistic–Empirical Pavement Design Guide (MEPDG). In many cases, climate is incorporated through parameters whose behavior is associated with temperature and precipitation but does not use the data of these climate variables directly from the project site. The practical incorporation of climate into design methods allows an increase in the certainty of results, ensuring additional climate-resilient pavement structures and increasing their durability and sustainability during their service life. [ABSTRACT FROM AUTHOR]

Background: In atrial fibrillation (AF) management, understanding left atrial (LA) substrate is crucial. While both electroanatomical mapping (EAM) and late gadolinium enhancement MRI (LGE-MRI) are accepted methods for assessing the atrial substrate and are associated with ablation outcome, recent findings have highlighted discrepancies between low voltage areas (LVAs) in EAM and LGE-areas., Objective: Explore the relationship between LGE regions and unipolar and bipolar-LVAs utilizing multipolar high-density (HD) mapping., Methods: 20 patients scheduled for AF ablation underwent pre-ablation LGE-MRI. LA segmentation was conducted using a deep learning approach, which subsequently generated a 3D mesh integrating the LGE data. HD-EAM was performed in sinus rhythm for each patient. The EAM map and LGE-MRI mesh were co-registered. LVAs were defined using voltage cut-offs of 0.5mV for bipolar and 2.5mV for unipolar. Correspondence between LGE-areas and LVAs in the LA was analyzed using confusion matrices and performance metrics., Results: A considerable 87.3% of LGE regions overlapped with unipolar-LVAs, compared to only 16.2% overlap observed with bipolar-LVAs. Across all performance metrics, unipolar-LVAs outperformed bipolar-LVAs in identifying LGE-areas [precision (78.6% vs. 61.1%); sensitivity (87.3% vs. 16.2%); F1 score (81.3% vs. 26.0%); accuracy (74.0% vs. 35.3%)]., Conclusion: Our findings demonstrate that unipolar-LVAs highly correlate with LGE regions. These findings support the integration of unipolar mapping alongside bipolar mapping into clinical practice. This would offer a nuanced approach to diagnose and manage atrial fibrillation by revealing critical insights into the complex architecture of the atrial substrate., (Copyright © 2024. Published by Elsevier Inc.)

Global prevalence rates for transgender individuals vary with estimates ranging from 0.3% to 1%, translating to a potential global population of 24.3 million to 81 million. It is estimated that one in two people will develop cancer in their lifetime. Gender-affirming hormone therapy (GAHT) is a common medical intervention for transgender and non-binary individuals. GAHT requires careful consideration for concurrent medical care due to potential drug interactions and physiological changes. A multi-disciplinary team with expertise in transgender health, oncology and pharmacy met to develop a document summarizing current knowledge on the topic for practical use. The team included trans and non-binary authors who shaped the document's language and focus. The document gives a status update on the current understanding of GAHT and how this may intersect with the safe prescribing of systemic anti-cancer therapies (SACT). The document underwent multiple review stages including internal review, review by the British Oncology Pharmacy Association (BOPA) EDI Subcommittee and, finally, BOPA Executive Committee review and final approval. Key recommendations of this document include the use of inclusive and effective communication, vigilant monitoring of kidney function and cardiovascular health, and considerations for hormone receptor-positive cancers. The document also recognizes the multidisciplinary nature of transgender healthcare and where this relates to social prescribing., (© 2024 British Pharmacological Society.)

Objective: Rare and complex epilepsies encompass a diverse range of disorders characterized by seizures. We aimed to establish a consensus on key issues related to these conditions through collaboration among experienced neurologists, neuropediatricians, and patient advocacy representatives., Methods: Employing a modified Delphi method, a scientific board comprising 20 physicians and 4 patient advocacy representatives synthesized existing literature with their expertise to formulate statements on contentious topics. A final 32-member expert panel, representing diverse regions of Italy, validated these statements through a two-round voting process, with consensus defined as an average score ≥7., Results: Sixteen statements reached a consensus, emphasizing the necessity for epidemiological studies to ascertain the true prevalence of rare epilepsies. Etiology emerged as a crucial factor influencing therapeutic strategies and outcome prediction, with particular concern regarding prolonged and tonic-clonic seizures. The importance of early implementation of specific drugs and non-pharmacological interventions in the treatment algorithm for developmental and epileptic encephalopathies (DEEs) was underscored. Multidisciplinary care involving experts with diverse skills was deemed essential, emphasizing non-seizure outcomes in adolescence and adulthood., Significance: This national consensus underscores the imperative for personalized, comprehensive, and multidisciplinary management of rare epilepsies/DEEs. It advocates for increased research, particularly in epidemiology and therapeutic approaches, to inform clinical decision-making and healthcare policies, ultimately enhancing patients' outcomes., Plain Language Summary: The modified Delphi method is broadly used to evaluate debated topics. In this work, we sought the consensus on integrated and social care in epilepsy management. Both representatives of high-level epilepsy centers and patients' caregivers were directly involved., (© 2024 The Author(s). Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Challenges drive the state-of-the-art of automated medical image analysis. The quantity of public training data that they provide can limit the performance of their solutions. Public access to the training methodology for these solutions remains absent. This study implements the Type Three (T3) challenge format, which allows for training solutions on private data and guarantees reusable training methodologies. With T3, challenge organizers train a codebase provided by the participants on sequestered training data. T3 was implemented in the STOIC2021 challenge, with the goal of predicting from a computed tomography (CT) scan whether subjects had a severe COVID-19 infection, defined as intubation or death within one month. STOIC2021 consisted of a Qualification phase, where participants developed challenge solutions using 2000 publicly available CT scans, and a Final phase, where participants submitted their training methodologies with which solutions were trained on CT scans of 9724 subjects. The organizers successfully trained six of the eight Final phase submissions. The submitted codebases for training and running inference were released publicly. The winning solution obtained an area under the receiver operating characteristic curve for discerning between severe and non-severe COVID-19 of 0.815. The Final phase solutions of all finalists improved upon their Qualification phase solutions., 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 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: This study was undertaken to assess the effectiveness/tolerability of adjunctive cenobamate, variations in the load of concomitant antiseizure medications (ASMs) and predictors of clinical response in people with focal epilepsy., Methods: This was a retrospective study at 21 centers participating in the Italian Expanded Access Program. Effectiveness outcomes included retention and responder rates (≥50% and 100% reduction in baseline seizure frequency). Tolerability/safety outcomes included the rate of treatment discontinuation due to adverse events (AEs) and their incidence. Total drug load was quantified as the number of concomitant ASMs and total defined daily dose (DDD). Concomitant ASMs were also classified according to their mechanism of action and pharmacokinetic interactions to perform explorative subgroup analyses., Results: A total of 236 subjects with a median age of 38 (Q 1 -Q 3 = 27-49) years were included. At 12 months, cenobamate retention rate was 78.8% and responders were 57.5%. The seizure freedom rates during the preceding 3 months were 9.8%, 12.2%, 16.3%, and 14.0% at 3, 6, 9, and 12 months. A higher percentage of responders was observed among subjects treated with clobazam, although the difference was not statistically significant. A total of 223 AEs were recorded in 133 of 236 participants, leading to cenobamate discontinuation in 8.5% cases. At 12 months, a reduction of one or two concomitant ASMs occurred in 42.6% and 4.3% of the subjects. The median total DDD of all concomitant ASMs decreased from 3.34 (Q 1 -Q 3  = 2.50-4.47) at baseline to 2.50 (Q 1 -Q 3  = 1.67-3.50) at 12 months (p < .001, median percentage reduction = 22.2%). The highest rates of cotreatment withdrawal and reductions in the DDD were observed for sodium channel blockers and γ-aminobutyric acidergic modulators (above all for those linked to pharmacokinetic interactions), and perampanel., Significance: Adjunctive cenobamate was associated with a reduction in seizure frequency and in the burden of concomitant ASMs in adults with difficult-to-treat focal epilepsy. The type of ASM associated did not influence effectiveness except for a favorable trend with clobazam., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

This article delves into the intricate relationship between oral health, quality of life, and behavioral characteristics in individuals with autism spectrum disorder (ASD). Background/Objectives: Autism has been associated with various challenges, and this study seeks to elucidate the impact of ASD on oral health outcomes and overall well-being. The research focuses on assessing overall oral health by evaluating various parameters, such as the condition of lips, tongue, gums and tissues, natural teeth, dentures, oral hygiene, and dental pain in individuals with ASD. Additionally, the study explores the influence of age, sex, and certain variables, like basic daily living skills on oral health practices, aiming to identify potential correlations between these factors and oral health outcomes. Methods: We employed standardized instruments to quantitatively measure and analyze the impact of oral health status on the overall quality of life experienced by individuals with ASD. Results: The study found a statistically significant positive association between oral health, measured by the Oral Health Assessment Tool (OHAT), and quality of life, as indicated by EuroQol 5-Dimensions Youth version (EQ-5D-Y) total scores (β = 0.13045, p = 0.00271). This suggests that better oral health is linked to higher quality of life. When adjusting for age and sex in a multiple linear regression model, the association remained significant but with a slightly reduced effect size (β = 0.10536, p = 0.0167). Age also showed a marginally significant positive association with quality-of-life scores. ANOVA results indicated that participants with advanced oral health status reported significantly higher quality-of-life scores than those with poorer oral health ( p = 0.00246). The study also found that intelligence quotient (IQ) does not substantially influence dental health status, while the "Autonomy" subscale of the EQ-5D-Y is positively related to the OHAT. Conclusions: Unhealthy oral conditions significantly impact the overall quality of life in individuals with ASD. Therefore, it is crucial to include regular dental assessments and treatments in therapeutic protocols for patients with ASD.

Hypoxic-ischemic brain damage presents a significant neurological challenge, often manifesting during the perinatal period. Specifically, periventricular leukomalacia (PVL) is emerging as a notable contributor to cerebral palsy and intellectual disabilities. It compromises cerebral microcirculation, resulting in insufficient oxygen or blood flow to the periventricular region of the brain. As widely documented, these pathological conditions can be caused by several factors encompassing preterm birth (4-5% of the total cases), as well single cotwin abortion and genetic variants such as those associated with GTPase pathways. Whole exome sequencing (WES) analysis identified a de novo causative variant within the pleckstrin homology domain-containing family G member 1 ( PLEKHG1 ) gene in a patient presenting with PVL. The PLEKHG1 gene is ubiquitously expressed, showing high expression patterns in brain tissues. PLEKHG1 is part of a family of Rho guanine nucleotide exchange factors, and the protein is essential for cell division control protein 42 (CDC42) activation in the GTPase pathway. CDC42 is a key small GTPase of the Rho-subfamily, regulating various cellular functions such as cell morphology, migration, endocytosis, and cell cycle progression. The molecular mechanism involving PLEKHG1 and CDC42 has an intriguing role in the reorientation of cells in the vascular endothelium, thus suggesting that disruption responses to mechanical stress in endothelial cells may be involved in the formation of white matter lesions. Significantly, CDC42 association with white matter abnormalities is underscored by its MIM phenotype number. In contrast, although PLEKHG1 has been recently associated with patients showing white matter hyperintensities, it currently lacks a MIM phenotype number. Additionally, in silico analyses classified the identified variant as pathogenic. Although the patient was born prematurely and subsequently to dichorionic gestation, during which its cotwin died, we suggest that the variant described can strongly contribute to PVL. The aim of the current study is to establish a plausible association between the PLEKHG1 gene and PVL.

CDKL5 deficiency disorder (CDD) is a complex clinical condition resulting from non-functional or absent CDKL5 protein, a serine-threonine kinase pivotal for neural maturation and synaptogenesis. The disorder manifests primarily as developmental epileptic encephalopathy, with associated neurological phenotypes, such as hypotonia, movement disorders, visual impairment, and gastrointestinal issues. Its prevalence is estimated at 1 in 40,000-60,000 live births, and it is more prevalent in females due to the lethality of germline mutations in males during fetal development. This Italian multi-center observational study focused on 34 patients with CDKL5-related epileptic encephalopathy, aiming to enhance the understanding of the clinical and molecular aspects of CDD. The study, conducted across 14 pediatric neurology tertiary care centers in Italy, covered various aspects, including phenotypic presentations, seizure types, EEG patterns, treatments, neuroimaging findings, severity of psychomotor delay, and variant-phenotype correlations. The results highlighted the heterogeneity of seizure patterns, with hypermotor-tonic-spasms sequence seizures (HTSS) noted in 17.6% of patients. The study revealed a lack of clear genotype-phenotype correlation within the cohort. The presence of HTSS or HTSS-like at onset resulted a negative prognostic factor for the presence of daily seizures at long-term follow-up in CDD patients. Despite extensive polypharmacotherapy, including medications such as valproic acid, clobazam, cannabidiol, and others, sustained seizure freedom proved elusive, affirming the inherent drug-resistant nature of CDD. The findings underscored the need for further research to explore response rates to different treatments and the potential role of non-pharmacological interventions in managing this challenging disorder., (© 2024. The Author(s).)

E3 ubiquitin protein ligase encoded by ARIH2 gene catalyses the ubiquitination of target proteins and plays a crucial role in posttranslational modifications across various cellular processes. As prior documented, mutations in genes involved in the ubiquitination process are often associated with autism spectrum disorder (ASD) and/or intellectual disability (ID). In the current study, a de novo heterozygous mutation was identified in the splicing intronic region adjacent to the last exon of the ARIH2 gene using whole exome sequencing (WES). We hypothesize that this mutation, found in an ASD/ID patient, disrupts the protein Ariadne domain which is involved in the autoinhibition of ARIH2 enzyme. Predictive analyses elucidated the implications of the novel mutation in the splicing process and confirmed its autosomal dominant inheritance model. Nevertheless, we cannot exclude the possibility that other genetic factors, undetectable by WES, such as mutations in non-coding regions and polygenic risk in inter-allelic complementation, may contribute to the patient's phenotype. This work aims to suggest potential relationship between the detected mutation in ARIH2 gene and both ASD and ID, even though functional studies combined with new sequencing approaches will be necessary to validate this hypothesis., (© 2024. The Author(s).)

SRY-box transcription factor ( SOX ) genes, a recently discovered gene family, play crucial roles in the regulation of neuronal stem cell proliferation and glial differentiation during nervous system development and neurogenesis. Whole exome sequencing (WES) in patients presenting with generalized epilepsy, intellectual disability, and childhood emotional behavioral disorder, uncovered a de novo variation within SOX12 gene. Notably, this gene has never been associated with neurodevelopmental disorders. No variants in known genes linked with the patient's symptoms have been detected by the WES Trio analysis. To date, any MIM phenotype number associated with intellectual developmental disorder has not been assigned for SOX12 . In contrast, both SOX4 and SOX11 genes within the same C group ( SoxC ) of the Sox gene family have been associated with neurodevelopmental disorders. The variant identified in the patient here described was situated within the critical high-mobility group (HMG) functional site of the SOX12 protein. This domain, in the Sox protein family, is essential for DNA binding and bending, as well as being responsible for transcriptional activation or repression during the early stages of gene expression. Sequence alignment within SoxC ( SOX12 , SOX4 and SOX11 ) revealed a high conservation rate of the HMG region. The in silico predictive analysis described this novel variant as likely pathogenic. Furthermore, the mutated protein structure predictions unveiled notable changes with potential deleterious effects on the protein structure. The aim of this study is to establish a correlation between the SOX12 gene and the symptoms diagnosed in the patient.

Background and Aims: Peroral endoscopic myotomy (POEM) is a standard treatment option for achalasia patients. Treatment response varies due to factors such as achalasia type, degree of dilatation, pressure and distensibility indices. We present an innovative approach for treatment response prediction based on an automatic three-dimensional (3-D) reconstruction of the tubular oesophagus (TE) and the lower oesophageal sphincter (LES) in patients undergoing POEM for achalasia., Methods: A software was developed, integrating data from high-resolution manometry, timed barium oesophagogram and endoscopic images to automatically generate 3-D reconstructions of the TE and LES. Novel normative indices for TE (volume×pressure) and LES (volume/pressure) were automatically integrated, facilitating pre-POEM and post-POEM comparisons. Treatment response was evaluated by changes in volumetric and pressure indices for the TE and the LES before as well as 3 and 12 months after POEM. In addition, these values were compared with normal value indices of non-achalasia patients., Results: 50 treatment-naive achalasia patients were enrolled prospectively. The mean TE index decreased significantly (p<0.0001) and the mean LES index increased significantly 3 months post-POEM (p<0.0001). In the 12-month follow-up, no further significant change of value indices between 3 and 12 months post-POEM was seen. 3 months post-POEM mean LES index approached the mean LES of the healthy control group (p=0.077)., Conclusion: 3-D reconstruction provides an interactive, dynamic visualisation of the oesophagus, serving as a comprehensive tool for evaluating treatment response. It may contribute to refining our approach to achalasia treatment and optimising treatment outcomes., Trial Registration Number: 22-0149., Competing Interests: Competing interests: HM: Olympus, Satisfai (Grants); Dr. Falk Pharma, Olympus, Norgine, IPSEN, medupdate, Erbe (Speakers fee); Olympus, Ambu, Boston Scientific, Covidien, Takeda (Consultation fees). AE: Olympus Medical, FujiFilm, Pentax, Ambu, Falk Pharma and Medtronic (Lecture fees). SN: Falk Pharma, Pfizer and Sanofi (Lecture fees)., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Autism is a common neurodevelopmental condition with a complex genetic aetiology that includes contributions from monogenic and polygenic factors. Many autistic people have unmet healthcare needs that could be served by genomics-informed research and clinical trials. The primary aim of the European Autism GEnomics Registry (EAGER) is to establish a registry of participants with a diagnosis of autism or an associated rare genetic condition who have undergone whole-genome sequencing. The registry can facilitate recruitment for future clinical trials and research studies, based on genetic, clinical and phenotypic profiles, as well as participant preferences. The secondary aim of EAGER is to investigate the association between mental and physical health characteristics and participants' genetic profiles., Methods and Analysis: EAGER is a European multisite cohort study and registry and is part of the AIMS-2-TRIALS consortium. EAGER was developed with input from the AIMS-2-TRIALS Autism Representatives and representatives from the rare genetic conditions community. 1500 participants with a diagnosis of autism or an associated rare genetic condition will be recruited at 13 sites across 8 countries. Participants will be given a blood or saliva sample for whole-genome sequencing and answer a series of online questionnaires. Participants may also consent to the study to access pre-existing clinical data. Participants will be added to the EAGER registry and data will be shared externally through established AIMS-2-TRIALS mechanisms., Ethics and Dissemination: To date, EAGER has received full ethical approval for 11 out of the 13 sites in the UK (REC 23/SC/0022), Germany (S-375/2023), Portugal (CE-085/2023), Spain (HCB/2023/0038, PIC-164-22), Sweden (Dnr 2023-06737-01), Ireland (230907) and Italy (CET&#95;62/2023, CEL-IRCCS OASI/24-01-2024/EM01, EM 2024-13/1032 EAGER). Findings will be disseminated via scientific publications and conferences but also beyond to participants and the wider community (eg, the AIMS-2-TRIALS website, stakeholder meetings, newsletters)., Competing Interests: Competing interests: In the past 3 years, TC has served as a paid consultant to F. Hoffmann-La Roche and Servier and has received royalties from Sage Publications and Guilford Publications. DGMM has received funding for a PhD studentship from Compass, and for consulting from Jaguar Therapeutics and Hoffman Le Roche. GM receives funding for an investigator-initiated study from Compass Pathways; no financial or other conflict of interest with the present study. SB discloses that he has in the last 3 years acted as an author, consultant, or lecturer for Medice, Roche and Linus Biotechnology. SB receives royalties for textbooks and diagnostic tools from Hogrefe, UTB, Ernst Reinhardt, Kohlhammer, and Liber, and is a partner at NeuroSupportSolutions International AB. CC is a full-time employee of Genentech and owns stocks or RSUs in Roche Holdings. MA is the UK chief investigator for a trial sponsored by Roche (a phase II, randomised, double-blind, placebo-controlled, parallel group study to evaluate the safety, efficacy and pharmacodynamics of 52 weeks of treatment with basmasanil in participants aged 2–14 years old with dup15q syndrome followed by a 2-year optional open-label extension). LB served on an advisory board to Kingdom therapeutics in 2022., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Fibromyalgia (FM), a chronic disease with a high incidence in women, poses a significant challenge for diagnosis and treatment, especially due to the absence of specific biomarkers and the multifaceted nature of its symptoms, which range from neuromuscular pain to mood disorders and intestinal dysbiosis. While diagnosis currently relies on rheumatological clinical evaluations and treatment options mainly focus on symptom management, FM seems to have possible links with systemic metabolic dysfunctions with a common inflammatory root. In this context, a new therapeutic avenue emerges: could a therapeutic nutritional approach be the missing piece of the puzzle? Indeed, diet therapies employed particularly for metabolic syndromes proved recently to be efficacious for correcting systemic dysmetabolism and a high number of chronic inflammation conditions. In particular, the very-low-calorie ketogenic diet (VLCKD) demonstrated therapeutic benefits in many disorders. In the present study, we aimed to investigate the specific effects of two dietary interventions, namely the oloproteic VLCKD and the low-glycemic insulinemic (LOGI) diet, on two groups of female FM patients (FM1 and FM2) over a 45-day period. Utilizing clinical and laboratory tests, as well as non-invasive NMR metabolomic analysis of serum, urine, and saliva samples, we sought to uncover how these dietary regimens impact the metabolic dysfunctions associated with FM.

Background: Carotid near-occlusion (CNO) represents an anatomical-functional condition characterized by severe (more than 90%) internal carotid artery stenosis which can lead to a distal lumen diameter greater or less than 2 mm. CNO can be divided into a less severe subgroup (without lumen full collapse: diameter >2 mm) and a more severe subgroup (with lumen full collapse: diameter <2 mm). The decision for revascularization is still highly debated in Literature. The aim of the present multicenter retrospective study is to analyze the incidence of perioperative (30 days) and follow-up complications in 2 groups of patients with or without distal internal carotid lumen full collapse., Methods: Between January 2011 and March 2023, in 5 Vascular Surgery Units, 67 patients (49 male, 73% and 18 females, 27%) with CNO underwent carotid endarterectomy: 28 (41.7%) with lumen diameter <2 mm and 39 (58.3%) with diameter >2 mm. 19 patients were symptomatic and 48 asymptomatic. The outcomes considered for comparative analysis were: perioperative neurological and cardiac complications, carotid restenosis or occlusion at follow-up. Both groups were homogeneous in terms of risk factors, morphological features and pharmacological treatments., Results: In the group with lumen <2 mm, 3 perioperative major events (10.7%) occurred (1 ischemic stroke, 1 hemorrhagic stroke, 1 myocardial infarction) and 2 (7.1%) at follow-up (average 11 ± 14.5 months; 1 asymptomatic carotid occlusion, 1 hemodynamic restenosis treated with stenting). No event was recorded in the group with lumen >2 mm., Conclusions: According to our results CNO patients show different complication risk according to the presence or not of distal lumen collapse. The later seems to play a significant role in perioperative and follow-up complication rate. These results therefore support a surgical treatment only in patients with CNO without lumen full collapse., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Our study aimed to evaluate the effectiveness of corticosteroids on seizure control in drug-resistant epilepsies (DREs). Our primary goal was to assess the response to steroids for various underlying etiologies, interictal electroencephalographic (EEG) patterns and electroclinical seizure descriptions. Our second goal was to compare steroid responsiveness to different treatment protocols., Methods: This is a retrospective multicentre cohort study conducted according to the STROBE guidelines (Strengthening the Reporting of Observational Studies in Epidemiology). The following data were collected for each patient: epilepsy etiology, interictal EEG pattern, seizure types and type of steroid treatment protocol administered., Results: Thirty patients with DRE were included in the study. After 6 months of therapy, 62.7 % of patients experienced reduced seizure frequency by 50 %, and 6.6 % of patients experienced complete seizure cessation. Findings associated with favourable response to steroids included structural/lesional etiology of epilepsy, immune/infectious etiology and focal interictal abnormalities on EEG. Comparing four different steroid treatment protocols, the most effective for seizure control was treatment with methylprednisolone at the dose of 30 mg/kg/day administered for 3 days, leading to greater than 50 % seizure reduction at 6 months in 85.7 % of patients. Treatment with dexamethasone 6 mg/day for 5 days decreased seizure frequency in 71.4 % of patients. Hydrocortisone 10 mg/kg administered for 3 months showed a good response to treatment in 71 %., Conclusions: In our study, two-thirds of patients with DRE experienced a significant seizure reduction following treatment with steroids. We suggest considering steroids as a potential therapeutic option in children with epilepsy not responding to conventional antiseizure medicines (ASM)., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier Ltd.)

Objectives: Because bloodstream infection and venous catheter (or cannula) bloodstream infection are associated with high morbidity and cost, early identification and treatment are important. Isothermal microcalorimetry can detect microbial growth using thermal power (heat flow), essentially in real time. The aim of this study was to examine the potential of this technique in clinical practice., Methods: Thermal power of wild-type bacteria (Escherichia coli, Staphylococcus epidermidis, Klebsiella pneumoniae, and Enterococcus faecium) isolated from blood cultures of adult inpatients receiving parenteral nutrition in routine clinical practice was measured at 37°C every 10s using a Thermometric 2277 instrument. Temporal patterns of heat flow were used to detect the presence of bacteria, differentiate between them, and test their antibiotic sensitivity. Within and between batch reproducibility (% coefficient of variation [%CV]) was also established., Results: Isothermal microcalorimetry always correctly detected the absence or presence of wild-type bacteria. Thermograms differed distinctly between species. Key thermographic features, such as peak heights, timing of peak heights, and interval between peak heights, were highly reproducible within each species (within-batch %CV usually about ≤1%, although between-batch %CV was usually higher). The antibiotic sensitivities (tested only for S. epidermidis and K. pneumoniae) confirmed the results obtained from the hospital laboratory., Conclusions: Isothermal microcalorimetry is a promising and highly reproducible real-time measurement technique with potential application to the investigation, species identification, and targeted antibiotic treatment of bloodstream infection and venous catheter (or cannula) bloodstream infection., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Peter David Austin reports financial support was provided by National Institute for Health and Care Research., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Physics-based deep learning frameworks have shown to be effective in accurately modeling the dynamics of complex physical systems with generalization capability across problem inputs. However, time-independent problems pose the challenge of requiring long-range exchange of information across the computational domain for obtaining accurate predictions. In the context of graph neural networks (GNNs), this calls for deeper networks, which, in turn, may compromise or slow down the training process. In this work, we present two GNN architectures to overcome this challenge-the edge augmented GNN and the multi-GNN. We show that both these networks perform significantly better than baseline methods, such as MeshGraphNets, when applied to time-independent solid mechanics problems. Furthermore, the proposed architectures generalize well to unseen domains, boundary conditions, and materials. Here, the treatment of variable domains is facilitated by a novel coordinate transformation that enables rotation and translation invariance. By broadening the range of problems that neural operators based on graph neural networks can tackle, this paper provides the groundwork for their application to complex scientific and industrial settings., (© 2024. The Author(s).)

We compute the sphaleron rate of N&#95;{f}=2+1 QCD at the physical point for a range of temperatures 200  MeV≲T≲600  MeV. We adopt a strategy recently applied in the quenched case, based on the extraction of the rate via a modified version of the Backus-Gilbert method from finite-lattice-spacing and finite-smoothing-radius Euclidean topological charge density correlators. The physical sphaleron rate is finally computed by performing a continuum limit at fixed physical smoothing radius, followed by a zero-smoothing extrapolation. Dynamical fermions were discretized using the staggered formulation, which is known to yield large lattice artifacts for the topological susceptibility. However, we find them to be rather mild for the sphaleron rate.

Ion channelopathies result from impaired ion channel protein function, due to mutations affecting ion transport across cell membranes. Over 40 diseases, including neuropathy, pain, migraine, epilepsy, and ataxia, are associated with ion channelopathies, impacting electrically excitable tissues and significantly affecting skeletal muscle. Gene mutations affecting transmembrane ionic flow are strongly linked to skeletal muscle disorders, particularly myopathies, disrupting muscle excitability and contraction. Electromyography (EMG) analysis performed on a patient who complained of weakness and fatigue revealed the presence of primary muscular damage, suggesting an early-stage myopathy. Whole exome sequencing (WES) did not detect potentially causative variants in known myopathy-associated genes but revealed a novel homozygous deletion of the P2RX6 gene likely disrupting protein function. The P2RX6 gene, predominantly expressed in skeletal muscle, is an ATP-gated ion channel receptor belonging to the purinergic receptors (P2RX) family. In addition, STRING pathways suggested a correlation with more proteins having a plausible role in myopathy. No previous studies have reported the implication of this gene in myopathy. Further studies are needed on patients with a defective ion channel pathway, and the use of in vitro functional assays in suppressing P2RX6 gene expression will be required to validate its functional role.

Developmental and epileptic encephalopathies (DEE) are severe neurodevelopmental disorders characterized by recurrent, usually early-onset, epileptic seizures accompanied by developmental impairment often related to both underlying genetic etiology and abnormal epileptiform activity. Today, next-generation sequencing technologies (NGS) allow us to sequence large portions of DNA quickly and with low costs. The aim of this study is to evaluate the use of whole-exome sequencing (WES) as a first-line molecular genetic test in a sample of subjects with DEEs characterized by early-onset drug-resistant epilepsies, associated with global developmental delay and/or intellectual disability (ID). We performed 82 WESs, identifying 35 pathogenic variants with a detection rate of 43%. The identified variants were highlighted on 29 different genes including, 3 new candidate genes ( KCNC2 , STXBP6 , DHRS9 ) for DEEs never identified before. In total, 23 out of 35 (66%) de novo variants were identified. The most frequently identified type of inheritance was autosomal dominant de novo (60%) followed by autosomal recessive in homozygosity (17%) and heterozygosity (11%), autosomal dominant inherited from parental mosaicism (6%) and X-linked dominant de novo (6%). The most frequent mutations identified were missense (75%) followed by frameshift deletions (16%), frameshift duplications (5%), and splicing mutations (3%). Considering the results obtained in the present study we support the use of WES as a form of first-line molecular genetic testing in DEEs.

Objective: Malnutrition and obesity are complex burdensome challenges in pediatric chronic kidney disease (CKD) management that can adversely affect growth, disease progression, wellbeing, and response to treatment. Total energy expenditure (TEE) and energy requirements in children are essential for growth outcomes but are poorly defined, leaving clinical practice varied and insecure. The aims of this study were to explore a practical approach to guide prescribed nutritional interventions, using measurements of TEE, physical activity energy expenditure (PAEE), and their relationship to kidney function., Design and Methods: In a cross-sectional prospective age-matched and sex-matched controlled study, 18 children with CKD (6-17 years, mean stage 3) and 20 healthy, age-matched, and gender-matched controls were studied. TEE and PAEE were measured using basal metabolic rate (BMR), activity diaries and doubly labeled water (healthy subjects). Results were related to estimated glomerular filtration rate (eGFR). The main outcome measure was TEE measured by different methods (factorial, doubly labeled water, and a novel device)., Results: Total energy expenditure and PAEE with or without adjustments for age, gender, weight, and height did not differ between the groups and was not related to eGFR. TEE ranged from 1927 ± 91 to 2330 ± 73 kcal/d; 95 ± 5 to 109 ± 5% estimated average requirement (EAR), physical activity level (PAL) 1.52 ± 0.01 to 1.71 ± 0.17, and PAEE 24 to 34% EAR. Comparisons between DLW and alternative methods in healthy children did not differ significantly, except for 2 (factorial methods and a fixed PAL; and the novel device)., Conclusion: In clinical practice, structured approaches using supportive evidence (weight, height, BMI sds), predictive BMR or TEE values and simple questions on activity, are sufficient for most children with CKD as a starting energy prescription., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate peri-operative outcomes in patients on chronic aspirin therapy undergoing percutaneous nephrolithotomy (PCNL), with and without discontinuation of aspirin. Anti-coagulation and anti-platelet therapy are contraindications for PCNL per American Urological Association guidelines due to bleeding risk. However, there is potentially increased cardiovascular risk with peri-procedural aspirin withdrawal., Methods: Patients on chronic aspirin undergoing PCNL between January 2014 and May 2019 were retrospectively reviewed and stratified by continued or discontinued aspirin >5 days preoperatively. Hematologic complications, transfusions, and thrombotic complications were assessed with logistic regression model., Results: Three hundred twenty-five patients on chronic aspirin therapy underwent PCNL-85 continued and 240 discontinued aspirin. There were no significant differences in hemoglobin change, estimated blood loss, transfusions, creatinine change, thrombotic complications, 30-days re-admissions, complications, or 30-day emergency department visits. Patients who continued aspirin had longer length of stay (1.6 vs 1.9 days, P = .03). American Society of Anesthesiologists (ASA) score of 3 (OR 3.2, P = .02, 95% confidence intervals (CI) [1.2-8.4]), ASA score of 4 (OR 4.0, P = .02, 95% CI [1.2-13.1]), Black race, and previous smoking (OR 2.1, P = .02, 95% CI [1.1-3.9]) was associated with continued aspirin. Body mass index ≥30 was associated with aspirin discontinuation (OR 0.9, P = .004, 95% CI [0.9-1.0]). Increased postoperative hematologic complications were associated with additional anticoagulation medication (OR 2.9, P = .04, 95% CI [1.0-4.4])., Conclusion: Continued aspirin use did not increase in postoperative complications in patients undergoing PCNL. Patients who are on additional anticoagulation medication are at risk of hematologic complications., Competing Interests: Declaration of Competing Interest Smita De: consultant to Boston Scientific and Noah Medical. All other authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Wilson disease (WD) is caused by mutations in the ATP7B gene that encodes a copper (Cu) transporting ATPase whose trafficking from the Golgi to endo-lysosomal compartments drives sequestration of excess Cu and its further excretion from hepatocytes into the bile. Loss of ATP7B function leads to toxic Cu overload in the liver and subsequently in the brain, causing fatal hepatic and neurological abnormalities. The limitations of existing WD therapies call for the development of new therapeutic approaches, which require an amenable animal model system for screening and validation of drugs and molecular targets. To achieve this objective, we generated a mutant Caenorhabditis elegans strain with a substitution of a conserved histidine (H828Q) in the ATP7B ortholog cua-1 corresponding to the most common ATP7B variant (H1069Q) that causes WD. cua-1 mutant animals exhibited very poor resistance to Cu compared to the wild-type strain. This manifested in a strong delay in larval development, a shorter lifespan, impaired motility, oxidative stress pathway activation, and mitochondrial damage. In addition, morphological analysis revealed several neuronal abnormalities in cua-1 mutant animals exposed to Cu. Further investigation suggested that mutant CUA-1 is retained and degraded in the endoplasmic reticulum, similarly to human ATP7B-H1069Q. As a consequence, the mutant protein does not allow animals to counteract Cu toxicity. Notably, pharmacological correctors of ATP7B-H1069Q reduced Cu toxicity in cua-1 mutants indicating that similar pathogenic molecular pathways might be activated by the H/Q substitution and, therefore, targeted for rescue of ATP7B/CUA-1 function. Taken together, our findings suggest that the newly generated cua-1 mutant strain represents an excellent model for Cu toxicity studies in WD., (© 2023 The Authors. Traffic published by John Wiley & Sons Ltd.)

Objectives: Although melatonin (MLT) is the molecule most used by pediatricians for sleep problems, scarce evidence exists on its use in healthy pediatric population. The objective of this study was to describe MLT use by Italian pediatricians in healthy children with chronic insomnia., Study Design: A cross-sectional open survey was administered to Italian pediatricians, between June and November 2022, collecting information about their use of MLT in healthy children: age range of patients, dosages used, time of administration, duration of treatment, association with other treatments, perceived efficacy, and side effects. Data were reported as frequencies with their respective 95% confidence intervals. Chi-square statistics assessed significant differences between pediatricians who had training in pediatric sleep and those who did not., Results: Among 428 respondents, 97.4% of pediatricians used MLT; 87.3% of them prescribed MLT in children aged 1-2 years, 62.1% in 2-5 years and 42.5% in 10-18 years. 84.9% of them suggested to take MLT 30 min before bedtime. 37.9% indicated to continue treatment for one month, 30.2% for 2-3 months. 74.1% of pediatricians usually prescribed MLT 1 mg/day. The most frequent treatment associated with MLT was sleep hygiene (85.4%). Almost all pediatricians found MLT effective in reducing difficulties falling asleep. Only 3.2% of them reported mild side effects., Conclusions: MLT is widely prescribed by Italian pediatricians, but no consensus exists about its use in typically developing children. There is a need for clear guidelines to optimize the use of MLT in healthy children., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article to disclose., (© 2023 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.)