Chikungunya virus (CHIKV) emerged in the Caribbean island of Saint-Martin in December 2013. Weimplemented a hospital-based surveillance system to detect and describe CHIKV cases including severe ...forms of theinfection and deaths in the islands of Martinique and Guadeloupe. A case was defined as a patient with a CHIKV laboratoryconfirmation cared for in a public hospital for chikungunya for at least 24 hours, and a severe CHIKV case was defined as aCHIKV case presenting one or more organ failures. Sociodemographic, clinical, and laboratory data were collected andcases classified into severe or nonsevere based on medical records. From December 2013 to January 2015, a total of1,836 hospitalized cases were identified. Rate of hospital admissions for CHIKV infection was 60 per 10,000 suspectedclinical CHIKV cases and severity accounted for 12 per 10,000. A total of 74 deaths related to CHIKV infection occurred.Infants and elderly people were more frequently hospitalized compared with others and severity was more frequentlyreported in elderly subjects and subjects with underlying health condition. Fifteen neonatal infections consecutive tomother-to-child transmission were diagnosed, seven of which were severe. The most vulnerable groups of the population,such as the elderly, infants, individuals with comorbidities, and pregnant women, should remain the main targets of publichealth priorities.
Le recueil de gravures des Evangelicae historiae imagines paraît en 1593, puis deux ans plus tard, toujours à Anvers, accompagné d’un vaste ensemble de méditations rapportées à ces gravures et ...signées du nom de Hieronimus Natalis, mort quinze ans plus tôt et qui avait été l’un des plus proches collaborateurs d’Ignace de Loyola, fondateur de la Compagnie de Jésus en 1540. Ces images, produites pour la majorité d’entre elles par les plus célèbres graveurs sur cuivre de leur temps, les frères Wierix, avaient connu une très lente et tumultueuse genèse depuis le début des années 1560. Leur conception finale révèle l’extrême complexité de leurs enjeux théologiques, exégétiques et esthétiques. Sommet de l’image religieuse et de l’exégèse du récit évangélique dans cette fin du XVIe siècle, les Imagines et les Adnotationes et Meditationes deviendront pour les deux siècles suivants un parangon adapté et transformé de mille manières. Reconstruites ici pour la première fois dans la totalité de sa trajectoire, la genèse, la structure et la postérité de ce recueil de gravures lettrées, légendées et glosées rend compte du destin de l’image dans le monde du catholicisme post-tridentin, de l’Europe au Mexique et au Pérou, à la Chine et au Japon.
In this paper, we report on the possibility of using particle-based Monte Carlo (MC) techniques to incorporate all relevant quantum effects in the simulation of semiconductor nanotransistors. ...Starting from the conventional MC approach within the semiclassical Boltzmann approximation, we develop a multisubband description of transport to include quantization in ultrathin-body devices. This technique is then extended to the particle simulation of quantum transport within the Wigner formulation. This new simulator includes all expected quantum effects in nanotransistors and all relevant scattering mechanisms, which are taken into account the same way as in Boltzmann simulation. This paper is illustrated by analyzing the device operation and performance of multigate nanotransistors in a convenient range of channel lengths and thicknesses to separate the influence of all relevant effects: Significant quantization effects occur for thickness smaller than 5 nm and wave-mechanical-transport effects manifest themselves for channel length smaller than 10 nm. We also show that scattering mechanisms still have an important influence in nanoscaled double-gate transistors, both in the intrinsic part of the channel and in the resistive lateral extensions.
Developmental and epileptic encephalopathies (DEE) refer to a heterogeneous group of devastating neurodevelopmental disorders. Variants in KCNB1 have been recently reported in patients with ...early‐onset DEE. KCNB1 encodes the α subunit of the delayed rectifier voltage‐dependent potassium channel Kv2.1. We review the 37 previously reported patients carrying 29 distinct KCNB1 variants and significantly expand the mutational spectrum describing 18 novel variants from 27 unreported patients. Most variants occur de novo and mainly consist of missense variants located on the voltage sensor and the pore domain of Kv2.1. We also report the first inherited variant (p.Arg583*). KCNB1‐related encephalopathies encompass a wide spectrum of neurodevelopmental disorders with predominant language difficulties and behavioral impairment. Eighty‐five percent of patients developed epilepsies with variable syndromes and prognosis. Truncating variants in the C‐terminal domain are associated with a less‐severe epileptic phenotype. Overall, this report provides an up‐to‐date review of the mutational and clinical spectrum of KCNB1, strengthening its place as a causal gene in DEEs and emphasizing the need for further functional studies to unravel the underlying mechanisms.
KCNB1 encodes the α subunit of the delayed rectifier voltage‐dependent potassium channel Kv2.1. In this mutation update, we provide an up‐to‐date review of the mutational and clinical spectrum of the KCNB1 encephalopathy and report 18 novel variants.
Radiation therapy (RT) is used for the treatment of sacral chordoma, in combination with surgery or alone for unresected tumours, to improve local control (LC) and potentially overall survival (OS). ...The purpose of the present study was to evaluate efficacy and toxicity of proton therapy (PT), and/or intensity modulated radiation therapy (IMRT), particularly Tomotherapy, for sacral chordoma treatment.
Material: Between November 2005 and June 2018, 41 consecutive patients who were not included in clinical trials, received sacral chordoma radiation treatment in Institut Curie with Tomotherapy alone in 13 patients, and combined PT and Tomotherapy boost (Proton - Tomo) in 28 patients. RT was delivered as the exclusive local treatment in 11 patients, and as a post-operative complementary treatment in 30 patients.
After a median follow-up of 46 months (range, 0-125 months), eight local relapses were observed, and seven patients developed distant metastasis (particularly bone and lung). The 2- and 5- year local relapse rates were 11.4% CI (0.65-22.2%) and 29% (10.5-47.4%), respectively.
Over the follow-up period, ten patients died (24.4%). The estimated 2- and 5-year OS rates were 91.4% CI (82.5-100%) and 74.5% (59.4-93.5%), respectively. Fibrosis, cauda equina syndrome, and pain were the most common late toxicities. The comparison between Tomotherapy alone and Proton - Tomo revealed that acute and late cystitis were significantly more frequent in the Tomotherapy group: SHR = 0.12 IC95% (0.01-0.90 p = .04), as well as late proctitis. A dosimetric comparison confirmed the interest of PT to spare rectum and bladder in this context.
RT remains essential to improve local control in sacral chordoma. The combination of proton and photon seems to improve organ at risk sparing, resulting in a decreased rate of reported late toxicities.
The prevalence of neurological involvement in patients with a deletion of or a variant in the HNF1B gene remains discussed. The aim of this study was to investigate the neuropsychological outcomes in ...a large cohort of children carrying either a HNF1B whole-gene deletion or a disease-associated variant, revealed by the presence of kidney anomalies. The neuropsychological development-based on school level-of 223 children included in this prospective cohort was studied. Data from 180 children were available for analysis. Patients mean age was 9.6 years, with 39.9% of girls. Among these patients, 119 carried a HNF1B deletion and 61 a disease-associated variant. In the school-aged population, 12.7 and 3.6% of patients carrying a HNF1B deletion and a disease-associated variant had special educational needs, respectively. Therefore, the presence of a HNF1B deletion increases the risk to present with a neuropsychiatric involvement when compared with the general population. On the other hand, almost 90% of patients carrying a HNF1B disease-associated variant or deletion have a normal schooling in a general educational environment. Even if these findings do not predict the risk of neuropsychiatric disease at adulthood, most patients diagnosed secondary to kidney anomalies do not show a neurological outcome severe enough to impede standard schooling at elementary school. These results should be taken into account in prenatal counseling.
Summary
Objective
To present the baseline data of the international TuberOus SClerosis registry to increase disease Awareness (TOSCA) with emphasis on the characteristics of epilepsies associated ...with tuberous sclerosis complex (TSC).
Methods
Retrospective and prospective patients’ data on all aspects of TSC were collected from multiple countries worldwide. Epilepsy variables included seizure type, age at onset, type of treatment, and treatment outcomes and association with genotype, seizures control, and intellectual disability. As for noninterventional registries, the study protocol did not specify any particular clinical instruments, laboratory investigations, or intervention. Evaluations included those required for diagnosis and management following local best practice.
Results
Epilepsy was reported in 83.6% of patients (1852/2216) at baseline; 38.9% presented with infantile spasms and 67.5% with focal seizures. The mean age at diagnosis of infantile spasms was 0.4 year (median <1 year; range <1‐30 years) and at diagnosis of focal seizures was 2.7 years (median 1 year; range <1‐66 years). A total of 1469 patients (79.3%) were diagnosed with epilepsy <2 years. The rate of infantile spasms was higher in patients with a TSC2 mutation than in patients with a TSC1 mutation (47.3% vs 23%). ɣ‐aminobutyric acid (GABA)ergic drugs were the most common treatment modality for both infantile spasms (78.7%) and focal seizures (65.5%). Infantile spasms and focal seizures were controlled in 76.3% and 58.2% of patients, respectively. Control of seizures was associated with lower rates of intellectual disability in both groups.
Significance
This registry reports the largest international cohort of patients with TSC. Findings confirmed the typical onset pattern of infantile spasms and other focal seizures in the first 2 years of life, and the high rates of infantile spasms in patients with TSC2 mutation. Our results underscored the occurrence of focal seizures at all ages, including an onset that preceded emergence of infantile spasms. Seizure control was shown to be associated with lower rates of intellectual disability but did not preclude the presence of intellectual disability.
Cet ouvrage collectif naît d’abord d’un contexte. À une époque où les crises s’enchaînent au point de paraître permanentes, les législations d’urgence et les mesures dérogatoires connaissent une ...expansion telle que l’exception semble devenir la règle. Pourtant, le concept même d’état d’exception ne va pas de soi et alimente, dans le champ académique, de nombreux débats. Ne masque-t-il pas, derrière le sentiment partagé de quitter un monde politique et constitutionnel stabilisé, des situations juridiques très différentes ? Ce faisant, ne nous rend-il pas, paradoxalement, impuissants à penser le monde qui vient ? Les textes rassemblés ici proposent d’élargir ces réflexions en les réinscrivant dans une perspective historique longue. Ils présentent un vaste répertoire des formes historiques de « l’exceptionnalité », depuis l’institution romaine de la dictature jusqu’à l’état d’urgence contemporain, en tenant compte des normes et des pratiques juridico-politiques, mais aussi des concepts qui leur ont été associés. Au fil d’un dialogue entre histoire et philosophie, l’ouvrage s’ouvre à d’autres disciplines et aux réflexions transversales qui ont accompagné ces concepts. Il interroge la manière dont des termes « dictature » ou « état d’exception » circulent et se modifient, en laissant émerger des questions récurrentes, notamment autour du rapport du droit et du politique à l’histoire et au temps.
High-throughput screening of Tranzyme Pharma's proprietary macrocycle library using the aequorin Ca2+-bioluminescence assay against the human ghrelin receptor (GRLN) led to the discovery of novel ...agonists against this G-protein coupled receptor. Early hits such as 1 (Ki=86 nM, EC50=134 nM) though potent in vitro displayed poor pharmacokinetic properties that required optimization. While such macrocycles are not fully rule-of-five compliant, principally due to their molecular weight and clogP, optimization of their pharmacokinetic properties proved feasible largely through conformational rigidification. Extensive SAR led to the identification of 2 (Ki=16 nM, EC50=29 nM), also known as ulimorelin or TZP-101, which has progressed to phase III human clinical trials for the treatment of postoperative ileus. X-ray structure and detailed NMR studies indicated a rigid peptidomimetic portion in 2 that is best defined as a nonideal type-I' β-turn. Compound 2 is 24% orally bioavailable in both rats and monkeys. Despite its potency, in vitro and in gastric emptying studies, 2 did not induce growth hormone (GH) release in rats, thus demarcating the GH versus GI pharmacology of GRLN.
MDH2 encodes mitochondrial malate dehydrogenase (MDH), which is essential for the conversion of malate to oxaloacetate as part of the proper functioning of the Krebs cycle. We report bi-allelic ...pathogenic mutations in MDH2 in three unrelated subjects presenting with early-onset generalized hypotonia, psychomotor delay, refractory epilepsy, and elevated lactate in the blood and cerebrospinal fluid. Functional studies in fibroblasts from affected subjects showed both an apparently complete loss of MDH2 levels and MDH2 enzymatic activity close to null. Metabolomics analyses demonstrated a significant concomitant accumulation of the MDH substrate, malate, and fumarate, its immediate precursor in the Krebs cycle, in affected subjects’ fibroblasts. Lentiviral complementation with wild-type MDH2 cDNA restored MDH2 levels and mitochondrial MDH activity. Additionally, introduction of the three missense mutations from the affected subjects into Saccharomyces cerevisiae provided functional evidence to support their pathogenicity. Disruption of the Krebs cycle is a hallmark of cancer, and MDH2 has been recently identified as a novel pheochromocytoma and paraganglioma susceptibility gene. We show that loss-of-function mutations in MDH2 are also associated with severe neurological clinical presentations in children.
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