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The increasing interest in distributed energy resources (DER) challenges electricity distribution grids to host the required distributed generation (DG) capacities and the expected load increase from electrification. However, a large-scale estimation of costs for integrating DER into low, medium, and high voltage distribution networks has yet to be addressed. This paper contributes a model for the large-scale estimation of the impact of distributed generation, electric vehicles and heat pumps on network reinforcement requirements. The model allocates future DER geographically to 8000 Spanish peninsular municipalities. The large-scale model considers low, medium and high voltage distribution grids. The resulting distribution grid investment is determined via individualised reinforcement costs for each of the 47 peninsular Spanish provinces, distinguishing between urban, semi-urban, rural concentrated and rural dispersed configurations of distribution networks. A 2030 case study shows that the geographical allocation of DG is not aligned with the allocation of load electrification, leading to total investment requirements of 2627 MEUR. This finding points out that distribution system operators covering different parts of the territory are likely to face a variety of challenges that are not aligned across the territories, requiring regulation to account for a variation of distribution grid expansion requirements for the energy transition.

Duchenne muscular dystrophy (DMD) is an X‐linked disorder characterized by progressive muscle weakness due to the absence of functional dystrophin. DMD patients also develop dilated cardiomyopathy (DCM). We have previously shown that DMD (mdx) mice and a canine DMD model (GRMD) exhibit abnormal intracellular calcium (Ca2+) cycling related to early‐stage pathological remodelling of the ryanodine receptor intracellular calcium release channel (RyR2) on the sarcoplasmic reticulum (SR) contributing to age‐dependent DCM. Here, we used hiPSC‐CMs from DMD patients selected by Speckle‐tracking echocardiography and canine DMD cardiac biopsies to assess key early‐stage Duchenne DCM features. Dystrophin deficiency was associated with RyR2 remodelling and SR Ca2+leak (RyR2 Po of 0.03 ± 0.01 for HC vs. 0.16 ± 0.01 for DMD, P< 0.01), which led to early‐stage defects including senescence. We observed higher levels of senescence markers including p15 (2.03 ± 0.75 for HC vs. 13.67 ± 5.49 for DMD, P< 0.05) and p16 (1.86 ± 0.83 for HC vs. 10.71 ± 3.00 for DMD, P< 0.01) in DMD hiPSC‐CMs and in the canine DMD model. The fibrosis was increased in DMD hiPSC‐CMs. We observed cardiac hypocontractility in DMD hiPSC‐CMs. Stabilizing RyR2 pharmacologically by S107 prevented most of these pathological features, including the rescue of the contraction amplitude (1.65 ± 0.06 μm for DMD vs. 2.26 ± 0.08 μm for DMD + S107, P< 0.01). These data were confirmed by proteomic analyses, in particular ECM remodelling and fibrosis. We identified key cellular damages that are established earlier than cardiac clinical pathology in DMD patients, with major perturbation of the cardiac ECC. Our results demonstrated that cardiac fibrosis and premature senescence are induced by RyR2 mediated SR Ca2+leak in DMD cardiomyocytes. We revealed that RyR2 is an early biomarker of DMD‐associated cardiac damages in DMD patients. The progressive and later DCM onset could be linked with the RyR2‐mediated increased fibrosis and premature senescence, eventually causing cell death and further cardiac fibrosis in a vicious cycle leading to further hypocontractility as a major feature of DCM. The present study provides a novel understanding of the pathophysiological mechanisms of the DMD‐induced DCM. By targeting RyR2 channels, it provides a potential pharmacological treatment.

IMPORTANCE: Cerebral amyloid angiopathy (CAA) is a common cause of spontaneous intracerebral hemorrhage in older patients. Although other types of intracranial hemorrhage can occur in conjunction with CAA-related intracerebral hemorrhage, the association between CAA and other subtypes of intracranial hemorrhage, particularly in the absence of intracerebral hemorrhage, remains poorly understood. OBJECTIVE: To determine whether CAA is an independent risk factor for isolated nontraumatic subdural hemorrhage (SDH). DESIGN, SETTING, AND PARTICIPANTS: A population-based cohort study was performed using a 2-stage analysis of prospectively collected data in the UK Biobank cohort (discovery phase, 2006-2022) and the All of Us Research Program cohort (replication phase, 2018-2022). Participants included those who contributed at least 1 year of data while they were older than 50 years, in accordance with the diagnostic criteria for CAA. Participants with prevalent intracranial hemorrhage were excluded. Data were analyzed from October 2022 to October 2023. EXPOSURE: A diagnosis of CAA, identified using the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnosis code. MAIN OUTCOMES AND MEASURES: The outcome was an isolated nontraumatic SDH, identified using ICD-10-CM codes. Two identical analyses were performed separately in the 2 cohorts. First, the risk of SDH in patients with and without CAA was assessed using Cox proportional hazards models, adjusting for demographic characteristics, cardiovascular comorbidities, and antithrombotic medication use. Second, multivariable logistic regression was used to study the association between CAA and SDH. RESULTS: The final analytical sample comprised 487 223 of the total 502 480 individuals in the UK Biobank cohort and 158 008 of the total 372 082 individuals in the All of Us cohort. Among the 487 223 participants in the discovery phase of the UK Biobank, the mean (SD) age was 56.5 (8.1) years, and 264 195 (54.2%) were female. There were 649 cases of incident SDH. Of the 126 participants diagnosed with CAA, 3 (2.4%) developed SDH. In adjusted Cox regression analyses, participants with CAA had an increased risk of having an SDH compared with those without CAA (hazard ratio [HR], 8.0; 95% CI, 2.6-24.8). Multivariable logistic regression analysis yielded higher odds of SDH among participants with CAA (odds ratio [OR], 7.6; 95% CI, 1.8-20.4). Among the 158 008 participants in the All of Us cohort, the mean (SD) age was 63.0 (9.5) years, and 89 639 (56.7%) were female. The findings were replicated in All of Us, in which 52 participants had CAA and 320 had an SDH. All of Us participants with CAA had an increased risk of having an SDH compared with those without CAA (HR, 4.9; 95% CI, 1.2-19.8). In adjusted multivariable logistic regression analysis, CAA was associated with higher odds of SDH (OR, 5.2; 95% CI, 0.8-17.6). CONCLUSIONS AND RELEVANCE: In 2 large, heterogeneous cohorts, CAA was associated with increased risk of SDH. These findings suggest that CAA may be a novel risk factor for isolated nontraumatic SDH.

PurposeIn this study, we describe the phenotype and genotype of the largest cohort of patients with Joubert syndrome (JS) carrying pathogenic variants on one of the most frequent causative genes, CC2D2A.MethodsWe selected 53 patients with pathogenic variants on CC2D2A, compiled and analysed their clinical, neuroimaging and genetic information and compared it to previous literature.ResultsDevelopmental delay (motor and language) was nearly constant but patients had normal intellectual efficiency in 74% of cases (20/27 patients) and 68% followed mainstream schooling despite learning difficulties. Epilepsy was found in only 13% of cases. Only three patients had kidney cysts, only three had genuine retinal dystrophy and no subject had liver fibrosis or polydactyly. Brain MRIs showed typical signs of JS with rare additional features. Genotype–phenotype correlation findings demonstrate a homozygous truncating variant p.Arg950* linked to a more severe phenotype.ConclusionThis study contradicts previous literature stating an association between CC2D2A-related JS and ventriculomegaly. Our study implies that CC2D2A-related JS is linked to positive neurodevelopmental outcome and low rate of other organ defects except for homozygous pathogenic variant p.Arg950*. This information will help modulate patient follow-up and provide families with accurate genetic counselling.

Provision of firm capacity will become a challenge in power systems dominated by renewable generation. This paper analyzes the competitiveness and role of battery storage, six types of pumped-hydro storage, open cycle gas turbine (OCGT), and demand response (DR) technologies in providing the firm capacity required to guarantee the security of supply in a real-size power system such as the Spanish one in horizon 2030. The paper contributes with detailed and realistic modeling of the DR capabilities. Demand is disaggregated by sector and activities and projected towards 2030, applying a growth rate by activity. The load flexibility constraints are considered to ensure the validity of the results. A generation operation planning and expansion model, SPLODER, is conveniently upgraded to properly represent the different storage alternatives addressed in the paper. The results highlight the importance of considering demand response for evaluating long-term firm capacity requirements, showing a non-negligible impact on the investment decisions on the amount of firm capacity required in the system and the optimal shares of wind and solar PV renewable generation. Results also show the dominance of cost-competitiveness of pumped hydro and OCGTs over batteries. Additionally, capacity payments are required to support firm capacity providers’ investments.

At operational level, fossil fuel phase-out and high shares of non-dispatchable renewable energy resources (RES) will challenge the system operator’s (SO) ability to balance generation, and the demand at any time. The variability of RES output ranges from one hour to a season, and critical events such as low supply and high demand might occur more frequently and for more extended periods. When evaluating the role of Energy Storage Systems (ESSs) in this context, the need for a long time scope to capture the different RES variabilities must be reconciled with the need for modeling the hourly chronology. This paper presents a medium-term operation planning model, addressing both the energy dispatch and the balancing services. This study shows that representing the combined chronological variability of demand and RES production is essential to properly assess the roles of different kinds of ESSs in the future 2030 electricity mix. Otherwise, it would not be possible to appropriately capture the frequency, depth, and length of events for which ESSs are activated. The analysis also highlights the importance of considering balancing services, given the significant contribution of batteries to the reserve market. Finally, the results show that batteries and Pumped Storage Hydro (PSH) have different roles in the Spanish electricity system with a high renewable penetration. While PSH is mainly used to provide energy during critical periods, batteries mostly provide balancing services.

ABSTRACTIntroductionThanks to the emergence of new therapeutics, prognosis and outcome of breast cancer patients (any subtype) have improved significantly. This raises the issue of the interactions and side effects related to the use of multiple drugs. Thus, to decide on a treatment, the optimal benefit risk-ratio should be carefully watched as toxicities such as cardiac ones effect on long-term survival. Indeed, nowadays in France, cardiovascular diseases rank first as causes of death in women.Areas coveredThis non-exhaustive review aims to report the currently available data on cardiac side effects caused by the use of emerging drugs in breast cancer, in localized or metastatic diseases alike. We will focus on HER2-inhibitors, cyclin-dependent-kinase 4/6 and PARP inhibitors, chemotherapy and immunotherapy, before discussing the means of prevention.Expert opinionAlthough this issue has largely been studied, the recent emergence of new drugs emphasizes the necessity for oncologists to adapt their practice to a multidisciplinary model that includes cardio-oncology.

Despite the increasing interest in applying composts as soil amendments worldwide, there is a lack of knowledge on short-term effects of compost amendments on soil structural and hydraulic properties. Our goal was to study the effect of compost and vermicompost-based soil amendments on soil structure, soil water retention characteristics, aggregate stability and plant water use efficiency compared to that of mineral fertilizers and food-waste digestate and examine if these effects are evident within a short time after application. We set up a pot experiment with spring wheat using a sandy and a loamy soil receiving either mineral fertilizer (MF); dewatered digestate from anaerobic digestion of food waste (DG), vermicomposted digestate (VC_DG); sewage sludge-based compost (C_SS) and sewage sludge-based vermicompost (VC_SS). We then monitored and calculated the soil water balance components (irrigation, outflow, evaporation, transpiration, and soil water content). At harvest, we measured shoot biomass, soil texture, bulk density, water retention characteristics and aggregate stability. The irrigation use efficiency (IE) and the plant water use efficiency (WUE) were calculated for each treatment by dividing the transpiration and the dry shoot biomass with the amount of water used for irrigation, respectively. For the sandy soil, we used X-Ray computed tomography to visualise the pore system after applying organic amendments and to derive metrics of the pore-network such as its fractal dimension, imaged macroporosity and critical pore diameter. X-Ray tomography indicated that composting and vermicomposting resulted in more complex and diverse porous system and increased soil macroporosity. The increased fractal dimensions also indicated that compost and vermicompost can contribute to structure formation and stabilization within a short time after their application. Despite the small application rate and short incubation time, the application of organic amendments to the two different soil types resulted in improved soil water holding capacity and water use efficiency. Composting and vermicomposting appeared to have the best effect at reducing the irrigation demand and evaporation losses and increasing the water use efficiency of the plant, likely through their effect on soil structure and the pore-size distribution.

ABSTRACTCell invasion is associated with numerous patho-physiologic states including cell development and metastatic dissemination. This process couples the activation of cell motility with the capacity to degrade the extracellular matrix, thereby permitting cells to pass through basal membranes. Invasion is sustained by the actions of invadosomes, an ensemble of subcellular structures with high functional homology. Invadosomes are 3D acto-adhesive structures that can also mediate local extracellular matrix degradation through the controlled delivery of proteases. Intracellular RHO GTPases play a central role in the regulation of invadosomes where their complex interplay regulates multiple invadosome functions. This review aims to provide an overview of the synergistic activities of the small GTPases in invadosome biology. This broad-based review also reinforces the importance of the spatiotemporal regulation of small GTPases and the impact of this process on invadosome dynamics.

En 1868, Duchenne de Boulogne décrivait cliniquement une maladie évolutive responsable d’une dystrophie musculaire qui porte aujourd’hui son nom, sans pour autant en comprendre l’origine. Il y a maintenant 30 ans des travaux de recherches menés par une équipe dirigée par le professeur LM. Kunkel (Boston, USA) sur cette dystrophie musculaire permettait d’identifier le gène DMD. La protéine résultante était alors baptisée : la dystrophine. Depuis les revues de mise à jour des connaissances acquises ont été très nombreuses sur ce sujet. Où en est-on en 2017 ? Cet article propose de faire le point sur la dystrophine et son environnement musculaire, les pathologies qui résultent d’une altération directe et/ou indirecte de la dystrophine ainsi que sur les perspectives expérimentales du traitement d’un déficit en dystrophine.

Early infantile epileptic encephalopathy (EIEE) is a heterogeneous group of severe forms of age-related developmental and epileptic encephalopathies with onset during the first weeks or months of life. The interictal electroencephalogram (EEG) shows a “suppression burst” (SB) pattern. The prognosis is usually poor and most children die within the first two years or survive with very severe intellectual disabilities. EIEE type 3 is caused by variants affecting function, in SLC25A22, which is also responsible for epilepsy of infancy with migrating focal seizures (EIMFS). We report a family with a less severe phenotype of EIEE type 3. We performed exome sequencing and identified two unreported variants in SLC25A22in the compound heterozygous state: NM_024698.4: c.[813_814delTG];[818 G>A] (p.[Ala272Glnfs*144];[Arg273Lys]). Functional studies in cultured skin fibroblasts from a patient showed that glutamate oxidation was strongly defective, based on a literature review. We clustered the 18 published patients (including those from this family) into three groups according to the severity of the SLC25A22-related disorders. In an attempt to identify genotype–phenotype correlations, we compared the variants according to the location depending on the protein domains. We observed that patients with two variants located in helical transmembrane domains presented a severe phenotype, whereas patients with at least one variant outside helical transmembrane domains presented a milder phenotype. These data are suggestive of a continuum of disorders related to SLC25A22that could be called SLC25A22-related disorders. This might be a first clue to enable geneticists to outline a prognosis based on genetic molecular data regarding the SLC25A22gene.

Batch distillation is a commonly used unit operation in specialty chemicals. In order to maximize profitability and improve separations using a batch distillation column, optimal reflux operation can be used. The mathematical and numerical complexities of the optimal control problem get worse when uncertainty is present in the formulation. However, in the specialty chemical industry, thermodynamic properties of not all chemical components of a mixture to be separated are known. In reality, these components are treated as missing components and their composition is merged with known components. These uncertainties in the problem formulation can result in suboptimal solutions. In this work, we are providing a new approach to solve this problem. We use Ito processes and stochastic maximum principle for the formulation of the resulting stochastic optimal control problem. This algorithm is implemented in the MultiBatchDS batch distillation process simulator. Finally, a numerical case study derived from a real-world batch distillation separation problem encountered at Firmenich is presented to show the scope and application of the proposed approach.

ABSTRACTThe accurate evaluation of electrical energy demanded by a CNC toolpath during a machining process is essential to determine its efficiency. Actually, the dynamic behavior of cutting forces seems to be neglected by investigators despite its influence on the consumed cutting energy during a face milling operation. This paper aims to investigate the effect of dynamic behavior of the machining system in order to take into account the dynamic response of the cutting forces on the axis feed power prediction. A dynamic cutting power model is developed in order to predict the consumed cutting energy. A parametric study is performed in order to show the impact of cutting conditions on the consumed energy values. The numerical results are compared to experimental ones.

Prognosis of Duchenne muscular dystrophy (DMD) is related to cardiac dysfunction. Speckle-tracking echocardiographic (STE) imaging is emerging as a noninvasive functional biomarker to consider in the early detection of DMD-related cardiomyopathy. However, STE analysis has not been assessed in a prospectively controlled study, especially in presymptomatic children with DMD, and no study has used STE analysis in all three displacements (longitudinal, radial, and circumferential) and for both ventricles.

Background: Predicting functional impairment after intracerebral hemorrhage (ICH) provides valuable information for planning of patient care and rehabilitation strategies. Current prognostic tools are limited in making long term predictions and require multiple expert-defined inputs and interpretation that make their clinical implementation challenging. This study aimed to predict long term functional impairment of ICH patients from admission non-contrast CT scans, leveraging deep learning models in a survival analysis framework.Methods: We used the admission non-contrast CT scans from 882 patients from the Massachusetts General Hospital ICH Study for training, hyperparameter optimization, and model selection, and 146 patients from the Yale New Haven ICH Study for external validation of a deep learning model predicting functional outcome. Disability (modified Rankin scale [mRS] > 2), severe disability (mRS > 4), and dependent living status were assessed via telephone interviews after 6, 12, and 24 months. The prediction methods were evaluated by the c-index and compared with ICH score and FUNC score.Results: Using non-contrast CT, our deep learning model achieved higher prediction accuracy of post-ICH dependent living, disability, and severe disability by 6, 12, and 24 months (c-index 0.742 [95% CI –0.700 to 0.778], 0.712 [95% CI –0.674 to 0.752], 0.779 [95% CI –0.733 to 0.832] respectively) compared with the ICH score (c-index 0.673 [95% CI –0.662 to 0.688], 0.647 [95% CI –0.637 to 0.661] and 0.697 [95% CI –0.675 to 0.717]) and FUNC score (c-index 0.701 [95% CI– 0.698 to 0.723], 0.668 [95% CI –0.657 to 0.680] and 0.727 [95% CI –0.708 to 0.753]). In the external independent Yale-ICH cohort, similar performance metrics were obtained for disability and severe disability (c-index 0.725 [95% CI –0.673 to 0.781] and 0.747 [95% CI –0.676 to 0.807], respectively). Similar AUC of predicting each outcome at 6 months, 1 and 2 years after ICH was achieved compared with ICH score and FUNC score.Conclusion: We developed a generalizable deep learning model to predict onset of dependent living and disability after ICH, which could help to guide treatment decisions, advise relatives in the acute setting, optimize rehabilitation strategies, and anticipate long-term care needs.

L’inactivité physique constitue la 4ecause mortalité dans le monde [1]. Pourtant, l’Activité Physique (AP), pratiquée de manière régulière, permet de prévenir l’apparition des maladies chroniques et d’en réduire les complications [2]. C’est dans ce contexte qu’en 2017, un décret relatif au sport sur ordonnance a vu le jour en France [3]. Ce dernier donne la possibilité au médecin traitant de prescrire une Activité Physique Adaptée (APA) aux patients atteints d’une ALD. Le Masseur-Kinésithérapeute (MK) et l’Enseignant en APA (EAPA) sont les principaux intervenants habilités à dispenser cette APA. L’objectif de cette étude est d’établir un état des lieux de cette pratique dans la profession des MK.

Chaotropes such as urea can break the structure of water, weakening the hydrophobic effect and reducing aggregation. Here, we investigated how the addition of urea affects the transfer of ions and cationic dyes across the interface between immiscible electrolyte solutions,  both water-1,2-dichloroethane and water-trifluorotoluene. For most cations, their half-wave potential of transfer shifted toward more negative values, indicating that it is easier to transfer these ions from the aqueous phase with urea to the organic phase, showing that the addition of urea decreases the solvation of ions in the aqueous phase. However, the half-wave potentials for a series of cationic phenothiazine dyes shifted toward more positive potentials, indicating improved solvation in urea solution. The effect of urea was investigated also by differential capacitance and electrocapillary curves, as well as by molecular dynamics simulations. Finally, electrochemistry at liquid–liquid interfaces allows determination of the transfer energies of ions between water and aqueous solutions of urea via a thermodynamic cycle.

Myopathies and muscular dystrophies (M-MDs) are genetically heterogeneous diseases, with >100 identified genes, including the giant and complex titin (TTN) and nebulin (NEB) genes. Next-generation sequencing technology revolutionized M-MD diagnosis and revealed high frequency of TTNand NEBvariants. We developed a next-generation sequencing diagnostic strategy targeted to the coding sequences of 135 M-MD genes. Comparison of two targeted capture technologies (SeqCap EZ Choice library capture kit and Nextera Rapid Capture Custom Enrichment kit) and of two whole-exome sequencing kits (SureSelect V5 and TruSeq RapidExome capture) revealed best coverage with the SeqCap EZ Choice protocol. A marked decrease in coverage was observed with the other kits, affecting mostly the first exons of genes and the repeated regions of TTNand NEB. Bioinformatics analysis strategy was fine-tuned to achieve optimal detection of variants, including small insertions/deletions (INDELs) and copy number variants (CNVs). Analysis of a cohort of 128 patients allowed the detection of 52 substitutions, 13 INDELs (including a trinucleotide repeat expansion), and 3 CNVs. Two INDELs were localized in the repeated regions of NEB, suggesting that these mutations may be frequent but underestimated. A large deletion was also identified in TTNthat is, to our knowledge, the first published CNV in this gene.

Dans un contexte de réflexion internationale sur les systèmes alimentaires, de valorisation des connaissances autochtones et de reconnaissance de l’étude des « faits alimentaires » comme discipline, cette étude met l’accent sur la diversité de l’alimentation traditionnelle au Cameroun et notamment sur la place du safou (Dacryodes edulis). Viade nombreux verbatims extraits de discussions dirigées, le safou apparaît comme un fruit aux vertus nutritionnelles et sensorielles appréciées, un fruit social, un fruit moyen de subsistance, un fruit emblématique d’une alimentation traditionnelle riche d’atouts pour faire face à la transition nutritionnelle.

It is noteworthy that thirty three years of efforts in corticotropin releasing factor (CRF) research by academia and the pharmaceutical industry resulted in several thousand papers and patents, yet little progress has been made to identify and market diagnostic or therapeutic CRF peptides and small molecule ligands. We document the potential relevance of CRF peptide antagonists to reinvigorate stress/anxiety affected “anatomy systems” in order to boost their efficacy.

Experiments in the ATALANTE facility can lead to high activity samples (for example the dissolution of hulls and spent fuels), essentially coming from the presence of 137Cs. Usually, these samples are handled in a shielded cell. The removal of this radionuclide from the sample would make it possible to handle it in glove boxes without having to perform an important dilution in the shielded cells beforehand. It would allow to analyze samples using techniques usually implemented in glove boxes (such as ICP, α spectrometry …) and to reach lower detection and quantification limits. To do so, a separation by extraction chromatography using a Triskem AMP-PAN column was developed. A cesium decontamination factor higher than 5×104and detection limits improvement up to a factor 100 were obtained.