Filadelfia

This study aimed to assess the performance of the Nelli seizure monitoring system in detecting and classifying seizures during sleep or while at rest in bed in patients with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS). We conducted a non-interventional, single-center feasibility study from August 2023 to March 2024, involving 20 patients aged ≥2 years diagnosed with DS or LGS. Participants used Nelli for home-based seizure monitoring during sleep or while at rest in bed for 4 weeks. Seizures were detected and classified by Nelli, and results were compared to epileptologist reviews and seizure diaries. Of 20 enrolled patients, 14 (70%) who experienced seizures at rest were included in the analyses. Among them, Nelli detected 368 seizures, with an accuracy of 97.8%, as confirmed by independent reviewers. Eight seizures (2.2%) detected by Nelli were false positives, identified as part of a single seizure episode. Of the 14 patients, only 35.7% reported experiencing seizures in their diaries, and only 26.1% of the seizures were documented. Seizure durations ranged from 6 to 396 s, with considerable variation. Nelli demonstrated high accuracy in seizure classification (Gwet agreement coefficient [AC1] = .81-1.00) in nine of 14 cases. However, in three of 14 patients, moderate accuracy (AC1 = .41-.60) was observed due to challenges in classifying seizures in patients with high seizure frequency or suboptimal device positioning. The average classification accuracy of Nelli for tonic-clonic seizures was .99 (150/152 seizures), tonic seizures .55 (102/186), clonic seizures 1.00 (3/3), focal motor seizures .89 (16/18), and myoclonic seizures 1.00 (1/1). Nelli demonstrated high sensitivity and classification accuracy for detecting and categorizing seizures in bed in patients with DS and LGS, outperforming seizure diaries and providing a reliable tool for seizure monitoring in home settings.

Excitatory amino acid transporter 2 (EAAT2) is the predominant glutamate transporter and a key mediator of excitatory neurotransmission in the human brain. Here we present a cohort of 18 individuals harbouring 13 different SLC1A2 variants, who all present with neurodevelopmental impairment with variable symptoms and disease severities, and we delineate the impact of these variants on EAAT2 function. The consequences of nine novel missense SLC1A2 variants for expression, transport and anion channel properties of EAAT2 expressed in mammalian cells were characterized by confocal microscopy, enzyme-linked immunosorbent and [3H]-D-aspartate uptake assays, and electrophysiological recordings. Ten of the 13 SLC1A2 variants mediated significant changes to EAAT2 expression and/or function. These molecular phenotypes were classified into three categories: overall loss-of-function (F249Sfs∗17, A432D, A439V, c.1421+1G>C), mild gain-of-anion-channel function (I276S, G360A), and mixed loss-of-transport/gain-of-anion-channel function (G82R, L85R, L85P, P289R). In contrast, L37P, H542R and I546T did not mediate significant changes to EAAT2 expression or function. Although specific clinical outcomes in individuals carrying variants within each category varied somewhat, the three categories overall translated into distinct clinical phenotypes in terms of phenotypic traits and severity. The observed associations between functional effects and clinical phenotypes produced by these variants offer valuable insights for future predictions of progression and severity of SLC1A2-associated neurodevelopmental disorders. Furthermore, these associations between variant-induced changes in EAAT2 function and phenotypic traits could assist in tailoring personalized treatments of these disorders. This work was funded by the German Ministry of Education and Research and by the Lundbeck Foundation.

ObjectivesDravet syndrome is a developmental and epileptic encephalopathy characterized by early onset epilepsy with multiple seizure types often intractable to treatment. Randomized clinical trials have demonstrated how treatment with fenfluramine significantly reduces seizure frequency in patients with Dravet syndrome. The study aims to (1) describe the efficacy and tolerability of fenfluramine in a Danish cohort of patients with Dravet syndrome; and (2) evaluate whether treatment with fenfluramine reduces epilepsy‐related hospital contacts administrated by pediatricians or epilepsy‐trained nurses.MethodsA retrospective registry‐based cohort study at the Danish Epilepsy Centre, Filadelfia, Dianalund, Denmark, enrolled 30 pediatric patients with Dravet syndrome treated with fenfluramine between 2017 and 2023.ResultsThirty patients with Dravet syndrome (aged 3–21 years, 12 females) with a verified pathogenic SCN1A variant were included. They were treated with fenfluramine at a mean duration of 29 months with a mean maintenance dose of 0.5 mg/kg/day. The number of patient‐years on treatment was 75 years. At last follow‐up, 6 patients had discontinued treatment due to lack of efficacy or adverse effects. In the remaining 24 patients, generalized tonic–clonic seizures were reduced by ≥30% in 83%, by ≥50% in 67%, and by 100% in 25%. Additionally, 71% of the patients were reduced in concomitant anti‐seizure medication, and 75% experienced a reduction (mean reduction at 52%, range 11%–94%) in epilepsy‐related hospital contacts from baseline to the end of the treatment period.SignificanceTreatment with fenfluramine effectively reduced seizure frequency and concomitant antiseizure medication in patients with Dravet syndrome. Furthermore, a decrease in epilepsy‐related contacts by 80% was observed over 6 years of treatment, which may indicate cost‐effective benefits.Plain Language SummaryPatients with Dravet syndrome suffer from severe epileptic seizures that are difficult to treat with medication. Earlier, treatment with fenfluramine (an anti‐seizure medication) has been documented to decrease the total number of seizures in patients with Dravet syndrome. This publication summarizes the experiences with fenfluramine in children with Dravet syndrome at the Danish Epilepsy Centre, Filadelfia, Dianalund, Denmark. Our publication also illustrates that treatment with fenfluramine may reduce the patients' number of yearly contacts with doctors and nurses specialized in epilepsy treatment, which may indicate cost‐effectiveness.

O jejum intermitente, caracterizado por períodos de jejum intercalados com uma janela de alimentação, tem se apresentado como uma estratégia alimentar cada vez mais utilizada, seja por seus benefícios no controle e manutenção do peso corporal, como também no controle efetivo da patogênese de diversas doenças, principalmente nas doenças de cunho inflamatório. Nesse contexto, uma ampla gama de estudos tem surgido afim de comprovar tais benefícios, bem como analisar marcadores inflamatórios em indivíduos que praticam o jejum. A partir disso, foi realizada uma revisão com estudos datados nos últimos dez anos, com o intuito de analisar e revisar as evidências científicas disponíveis relativas ao impacto do Jejum intermitente em marcadores pró inflamatórios em humanos, de modo a contribuir para estimativas mais estáveis dos efeitos do Jejum Intermitente.

ABSTRACTSCN2Agene disorders cover a wide range of medical conditions, from epileptic encephalopathies to neurodevelopmental disorders. The variants of these disorders, studied through electrophysiology, show complex behaviors that go beyond simple classification as either gain or loss of function. In our study, we simulated the biophysical effects of variants (R937C,V208E,S1336Y, andR853Q) to understand their impact. Our findings reveal that all these variants negatively affect the structural stability of the gene, withR937Cbeing the most unstable. Specifically,R937Cdisrupts important charged interactions affecting sodium ion flow, whileS1336Yintroduces a new interaction that impacts the channel’s inactivation gate. Conversely, the variantsV208EandR853Q, which are located in the voltage-sensing domains, have opposite effects:R853Qincreases compactness and interaction, whereasV208Eshows a decrease. Our computer-based method offers a scalable way to gain crucial insights into how genetic variants influence channel dysfunction and contribute to neurodevelopmental disorders.AUTHOR SUMMARYDespite numerous advancements in computational methods for predicting variant pathogenicity in theSCN2Agene, understanding the precise biophysical molecular mechanisms associated with each variant at the atomic level remains a challenge. Presently, variants are predominantly categorized as either gain or loss of function, often overlooking critical structural details associated with these variants. This study focuses on elucidating the molecular mechanisms linked to the four most commonSCN2Avariants using all-atom molecular dynamics simulations, employing three replicas for each system. Our findings offer insights into the potential mechanisms underlying these four variants, thereby providing explanations for the observed electrophysiological outcomes. This investigation significantly contributes to enhancing our comprehension of howSCN2Avariants manifest in various diseases. It underscores the importance of unraveling the biophysical properties underlying potential disease mechanisms, which could potentially enhance diagnostic and therapeutic strategies for patients afflicted withSCN2A-related disorders.

Pierwsze czasopismo polskojęzyczne na półkuli zachodniej „Echo z Polski” powstało w Nowym Jorku w 1863 r. Także nad Hudsonem ujrzało światło dzienne pierwsze polonijne pismo humorystyczne w USA. Był to tygodnik „Osa”, założony przez Juliana Czupkę w roku 1886. Żywot „Osy” trwał ledwie kilka miesięcy, lecz po jej upadku pojawiły się w innych miastach kolejne „wesołe gazetki”: „Bocian”, „Kukuryku”, „Śmiech”, „Zabawny Kuryerek”, „Kikier”. Artykuł przedstawia zarys dziejów pierwszych sześciu pism humorystyczno-satyrycznych, które bawiły polskich czytelników w USA w XIX stuleciu, oraz sylwetki wybranych redaktorów.

O transplante hepático é uma alternativa terapêutica para pacientes com doença hepática terminal. No Brasil, existem 27 centros habilitados para realizar esse procedimento, sendo apenas um na região norte, localizado em Belém-PA. O perfil dos pacientes submetidos ao transplante hepático é pouco conhecido, assim como os fatores associados à sobrevida e à qualidade de vida desses pacientes. O transplante hepático é uma alternativa terapêutica para pacientes com doença hepática terminal. No Brasil, existem 27 centros habilitados para realizar esse procedimento, sendo apenas um na região norte, localizado em Belém-PA. O perfil dos pacientes submetidos ao transplante hepático é pouco conhecido, assim como os fatores associados à sobrevida e à qualidade de vida desses pacientes.

La incorporación de herramientas digitales lleva años haciendo la gestión de recursos humanos más accesible para las pequeñas y medianas empresas. Hoy, con la incorporación de la inteligencia artificial, el valor aportado por estás herramientas crece exponencialmente. Ante diversos desafíos de crecimiento y estructura, una pequeña empresa de arquitectura, ubicada en la ciudad de La Plata (Argentina), decide acudir a la herramienta digital de gestión de recursos humanos llamada Nawaiam. Tal metodología, basada en la gamificación, permite obtener de forma rápida y sencilla los perfiles de conducta de los empleados así como también la evaluación de sus competencias. Por medio del uso de Nawaiam, se establece como objetivo, definir el grado de compatibilidad de los perfiles de los empleados actuales de la entidad con las competencias requeridas en sus puestos de trabajo,

Patients with end-stage kidney disease may require creation of an arteriovenous fistula in order to receive hemodialysis treatment. The creation may result in several complications, including carpal tunnel syndrome. Early diagnosis and treatment are essential to relieve symptoms, prevent permanent nerve damage, and improve quality of life. However, the sensory and motor disturbances resembling carpal tunnel syndrome could be related to other etiologies than external compression of the median nerve underneath the transverse ligament. This case report presents eight patients with a radiocephalic arteriovenous fistula, who all had symptoms of carpal tunnel syndrome. Ultrasonographic examination showed a segmental intraneural hypervascularization of a large vessel inside the median nerve proximal to the wrist and arteriovenous fistula anastomosis with garland-like course as well as multiple flow velocities. The neurophysiological findings showed a significant decreased velocity in the ipsilateral forearm to the arteriovenous fistula.