On the feasibility of collaborative green data center ecosystems

The increasing awareness of the impact of the IT sector on the environment, together with economic factors, have fueled many research efforts to reduce the energy expenditure of data centers. Recent work proposes to achieve additional energy savings by exploiting, in concert with customers, service workloads and to reduce data centers’ carbon footprints by adopting demand-response mechanisms between data centers and their energy providers. In this paper, we debate about the incentives that customers and data centers can have to adopt such measures and propose a new service type and pricing scheme that is economically attractive and technically realizable. Simulation results based on real measurements confirm that our scheme can achieve additional energy savings while preserving service performance and the interests of data centers and customers.Peer ReviewedPostprint (author's final draft

Loss of seryl-tRNA synthetase (SARS1) causes complex spastic paraplegia and cellular senescence

Genetic research; Nervous system diseases; PediatricsInvestigación genética; Enfermedades del sistema nervioso; PediatríaRecerca genètica; Malalties del sistema nerviós; PediatriaBackground Aminoacyl-tRNA synthetases (ARS) are key enzymes catalysing the first reactions in protein synthesis, with increasingly recognised pleiotropic roles in tumourgenesis, angiogenesis, immune response and lifespan. Germline mutations in several ARS genes have been associated with both recessive and dominant neurological diseases. Recently, patients affected with microcephaly, intellectual disability and ataxia harbouring biallelic variants in the seryl-tRNA synthetase encoded by seryl-tRNA synthetase 1 (SARS1) were reported. Methods We used exome sequencing to identify the causal variant in a patient affected by complex spastic paraplegia with ataxia, intellectual disability, developmental delay and seizures, but without microcephaly. Complementation and serylation assays using patient’s fibroblasts and an Saccharomyces cerevisiae model were performed to examine this variant’s pathogenicity. Results A de novo splice site deletion in SARS1 was identified in our patient, resulting in a 5-amino acid in-frame insertion near its active site. Complementation assays in S. cerevisiae and serylation assays in both yeast strains and patient fibroblasts proved a loss-of-function, dominant negative effect. Fibroblasts showed an abnormal cell shape, arrested division and increased beta-galactosidase staining along with a senescence-associated secretory phenotype (raised interleukin-6, p21, p16 and p53 levels). Conclusion We refine the phenotypic spectrum and modes of inheritance of a newly described, ultrarare neurodevelopmental disorder, while unveiling the role of SARS1 as a regulator of cell growth, division and senescence.This study was supported by grants from the Undiagnosed Rare Disease programme URD-Cat (SLT002/16/00174) from the Generalitat de Catalunya, the Center for Biomedical Research on Rare Diseases (CIBERER) (ACCI19-759), the ASL-HSP France and the Hesperia Foundation to AP. This study was also funded by the Instituto de Salud Carlos III and ‘Fondo Europeo de Desarrollo Regional (FEDER), Unión Europea, una manera de hacer Europa’ (FIS PI20/00758) to CC and ‘La Marató de TV3’ Foundation (202006-30) to CC and AP. This study was also funded by Instituto de Salud Carlos III (Sara Borrell programme, CD19/00221) to EV, the Spanish Ministerio de Economia, Industria y Competividad (Juan de la Cierva programme FJCI-2016-28811) to EV, and the Center for Biomedical Research on Rare Diseases (CIBERER) to MR and NL. This study was supported by the French National Programme Investissement d’Avenir administered by the ‘Agence National de la Recherche’ (ANR), ‘MitoCross’ Laboratory of Excellence (Labex), funded as ANR-10-IDEX-0002-02, the University of Strasbourg and CNRS (to HB, BS). The CERCA Programme/Generalitat de Catalunya provided institutional support. AP is member of the Undiagnosed Disease Network International (UDNI)

Health-related quality of life and the burden of prolonged seizures in noninstitutionalized children with epilepsy

OBJECTIVE: This study aimed to provide information on the burden of illness and health-related quality of life (HRQoL) in children with epilepsy who experience prolonged acute convulsive seizures (PACS) in the community setting, and to investigate factors that may predict poor HRQoL in this population. METHODS: Noninstitutionalized children (aged 3–16 years) who had experienced at least one PACS within the past year and had currently prescribed PACS rescue medication were enrolled in a cross-sectional study in Germany, Italy, Spain, and the United Kingdom (Practices in Emergency and Rescue medication For Epilepsy managed with Community-administered Therapy 3 [PERFECT-3]). Clinicians, parents/guardians, and patients completed web-based questionnaires regarding clinical characteristics, PACS frequency, and day-to-day impairment. Patients' HRQoL was rated by clinicians, parents/guardians, and patients themselves using the 5-dimension EuroQol questionnaire (EQ-5D) and summarized as a utility score. Potential predictors of poor HRQoL were tested in individual univariate generalized linear models and a global multivariable model. RESULTS: Enrolled children (N = 286) had experienced 1–400 PACS (median: 4) in the past year. Clinicians reported that 216/281 patients (76.9%) had learning disabilities of varying severity. Mean EQ-5D utility scores rated by clinicians (n = 279), parents (n = 277), and patients (n = 85) were 0.52 (standard deviation: 0.41), 0.51 (0.39), and 0.74 (0.29), respectively. Increasing PACS frequency, increasing severity of learning disability, and specialist school attendance were significantly associated with decreasing EQ-5D utility score. In the multivariable model, having learning disabilities was the best predictor of poor HRQoL. SIGNIFICANCE: Health-related quality of life was very poor in many children with epilepsy whose PACS were managed with rescue medication in the community, with learning disability being the most powerful predictor of patients' HRQoL. Mean EQ-5D utility scores were lower (worse) than published values for many other chronic disorders, indicating that optimal treatment should involve helping children and their families to manage learning disabilities and day-to-day impairments, in addition to preventing seizures

Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy

Hypomyelinating leukodystrophy; Inborn errors of metabolism; PhosphoinositolLeucodistrofia hipomielinizante; Errores innatos del metabolismo; FosfoinositolLeucodistròfia hipomielinizant; Errors innats del metabolisme; FosfoinositolPhosphoinositides are lipids that play a critical role in processes such as cellular signalling, ion channel activity and membrane trafficking. When mutated, several genes that encode proteins that participate in the metabolism of these lipids give rise to neurological or developmental phenotypes. PI4KA is a phosphoinositide kinase that is highly expressed in the brain and is essential for life. Here we used whole exome or genome sequencing to identify 10 unrelated patients harbouring biallelic variants in PI4KA that caused a spectrum of conditions ranging from severe global neurodevelopmental delay with hypomyelination and developmental brain abnormalities to pure spastic paraplegia. Some patients presented immunological deficits or genito-urinary abnormalities. Functional analyses by western blotting and immunofluorescence showed decreased PI4KA levels in the patients’ fibroblasts. Immunofluorescence and targeted lipidomics indicated that PI4KA activity was diminished in fibroblasts and peripheral blood mononuclear cells. In conclusion, we report a novel severe metabolic disorder caused by PI4KA malfunction, highlighting the importance of phosphoinositide signalling in human brain development and the myelin sheath.We thank the CERCA Program/Generalitat de Catalunya for institutional support. This study was supported by grants from the Hesperia Foundation, the Asociación Española contra las Leucodistrofias (ALE-ELA España), the Autonomous Government of Catalonia (SGR 2017SGR1206 and PERIS program URD-Cat SLT002/16/00174) and the Center for Biomedical Research on Rare Diseases (CIBERER) (ACCI19-759 to A.P.). This study was also funded by Fundació La Marató de TV3 (595/C/2020) as well as Instituto de Salud Carlos III (FIS PI20/00758 to C.C.) (co-funded by European Regional Development Fund. ERDF, a way to build Europe). This study was also funded by the Instituto de Salud Carlos III (Rio Hortega, CM18/00145 to V.V.; PFIS, FI18/00141 to L.P.; and Sara Borrell, CD19/00221 to E.V.), co-funded by European Social Fund. ESF investing in your future; the Ministerio de Ciencia e Innovación y Universidades (Juan de la Cierva, FJCI-2016-28811 to E.V.), and the Center for Biomedical Research on Rare Diseases (CIBERER to M.R.). Sequencing and analysis of Patient 5 were performed by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and were funded by the National Human Genome Research Institute, the National Eye Institute, the National Heart, Lung and Blood Institute grants UM1 HG008900 and R01 HG009141 and the Chan Zuckerberg Initiative to the Rare Genomes Project. This work was in part supported by the association ‘Connaître les Syndromes Cérébelleux’ (CSC). This research received funding specifically appointed to the Department of Medical Sciences from the Italian Ministry for Education, University and Research (Ministero dell’istruzione, dell’università e della ricerca-MIUR) under the programme ‘Dipartimenti di Eccellenza 2018-2022’ Project code D15D18000410001. Whole-exome sequencing was performed as part of the Autism Sequencing Consortium and was supported by the NIMH (MH111661). D.R.A. and A.P. are members of the Undiagnosed Disease Network International (UDNI)

Long term behavioural outcomes after paediatric convulsive status epilepticus: a population-based study:Behavioural outcomes after childhood CSE

AIM: To describe behavioural and psychiatric outcomes of children within 10 years of convulsive status epilepticus (CSE). METHOD: Children originally identified by the population-based North London Convulsive Status Epilepticus in Childhood Surveillance Study were followed-up between July 2009 and February 2013. They were grouped into epilepsy- and non-epilepsy-related CSE, and compared with population norms and healthy controls using the Strengths and Difficulties Questionnaire; the Autism Spectrum Screening Questionnaire; and the Swanson, Nolan, and Pelham questionnaire. Children who scored above recommended clinical cut-offs on any scale were invited for a neuropsychiatric assessment. Regression models were fitted to identify clinically relevant covariates associated with behavioural outcomes. RESULTS: At a mean follow-up of 8.1 years post-CSE, 28% of enrolled children were found to have a psychiatric disorder. Children with epilepsy-related CSE scored higher than norms on all scales and children with non-epilepsy-related CSE scored higher than norms on the Strengths and Difficulties Questionnaire and the Autism Spectrum Screening Questionnaire. Presence of seizures at baseline and recurrence of CSE was associated with worse outcomes in the group with epilepsy. Intellectual abilities were associated with behavioural outcomes in all participants. INTERPRETATION: A large proportion of children manifest behavioural issues 8 years after CSE. The present data highlight the need for behavioural screening in children with neurodevelopmental impairments post-CSE. What this paper adds Eight years post convulsive status epilepticus (CSE), 37% of parents report behavioural issues. Of enrolled children, 28% were found to have a Diagnostic and Statistical Manual mental disorder. Intellectual abilities are strongly associated with behavioural outcomes in children post-CSE

Effect of rescue medication on seizure duration in non-institutionalized children with epilepsy

OBJECTIVES: Characterize the real-world management of and outcomes for children with epilepsy receiving rescue medication for prolonged acute convulsive seizures (PACS) in the community. METHODS: PERFECT-3 (Practices in Emergency and Rescue medication For Epilepsy managed with Community-administered Therapy 3) was a European, retrospective observational study. Eligible patients were non-institutionalized children with epilepsy aged 3–16 years who had experienced ≥1 PACS in the past year and had ≥1 currently prescribed PACS rescue medication. Investigators provided clinical assessments and parents/guardians completed questionnaires. Statistical tests were post hoc; p values are descriptive. RESULTS: At enrollment (N = 286), most patients had prescriptions for diazepam (69.2%) and/or midazolam (55.9%); some had two (26.6%) or three (2.4%) prescribed rescue medications. Most patients experienced PACS despite regular anti-epilepsy medication. According to parents, the average duration of their child’s seizures without rescue medication was <5 minutes in 35.7% of patients, 5–<20 minutes in 42.6%, and ≥20 minutes in 21.7% (n = 258); with rescue medication seizure duration was <5 minutes in 69.4% of patients, 5–<20 minutes in 25.6%, and ≥20 minutes in 5.0%. Rescue medication use was significantly associated with average seizures lasting <5 minutes (χ2 = 58.8; p < 0.0001). At the time of their most recent PACS, 58.5–67.8% of children reportedly received rescue medication within 5 minutes of seizure onset, and 85.4–94.1% within 10 minutes. CONCLUSION: This study provides the first real-world data that rescue medications administered in the community reduce the duration of PACS in children with epilepsy. Study limitations including potential recall bias are acknowledged

Death within 8 years after childhood convulsive status epilepticus:a population-based study

The risk of long-term mortality and its predictors following convulsive status epilepticus in childhood are uncertain. We report mortality within 8 years after an episode of convulsive status epilepticus, and investigate its predictors from a paediatric, prospective, population-based study from north London, UK. In the current study, we followed-up a cohort previously ascertained during a surveillance study of convulsive status epilepticus in childhood. After determining the survival status of the cohort members, we defined cause of death as that listed on their death certificates. We estimated a standardized mortality ratio to compare mortality in our cohort with that expected in the reference population. Multivariable Cox regression analysis was used to investigate any association between the clinical and demographic factors at the time of status epilepticus and subsequent risk of death. The overall case fatality was 11% (95% confidence interval 7.5–16.2%); seven children died within 30 days of their episode of convulsive status epilepticus and 16 during follow-up. The overall mortality in our cohort was 46 times greater than expected in the reference population, and was predominantly due to higher mortality in children who had pre-existing clinically significant neurological impairments when they had their acute episode of convulsive status epilepticus. Children without prior neurological impairment who survived their acute episode of convulsive status epilepticus were not at a significantly increased risk of death during follow-up. There were no deaths in children following prolonged febrile convulsions and idiopathic convulsive status epilepticus. A quarter of deaths during follow-up were associated with intractable seizures/convulsive status epilepticus, and the rest died as a complication of their underlying medical condition. On regression analysis, presence of clinically significant neurological impairments prior to convulsive status epilepticus was the only independent risk factor for mortality. In conclusion, there is a high risk of death within 8 years following childhood convulsive status epilepticus but most deaths are not seizure related. Presence of pre-existing clinically significant neurological impairments at the time of convulsive status epilepticus is the main risk factor for mortality within 8 years after the acute episode. The attributable role of convulsive status epilepticus on mortality remains uncertain, but appears less than is generally perceived

Long-term prognosis after childhood status epilepticus: a prospective cohort study

Background: The prognosis of convulsive status epilepticus (CSE), a common childhood medical neurological emergency, is not well characterised. We aimed to investigate the long-term outcomes in a cohort of participants who previously had CSE. Methods: In this prospective study, we followed up a population-based childhood CSE cohort from north London, UK (the north London convulsive status epilepticus surveillance study cohort; NLSTEPSS). We collected data from structured clinical neurological assessment, neurocognitive assessment (Wechsler Abbreviated Scale of Intelligence), brain MRI, medical records, and structured interviews with participants and their parents to determine neurological outcomes, with adverse outcome defined as presence of one or more of epilepsy (active or in remission), motor disability, intellectual disability, or statement of special educational needs. We applied multiple imputation to address missing data and performed binary logistic regression analyses on complete-case and imputed datasets to investigate sociodemographic and CSE factors associated with adverse outcomes. Findings: Of 203 survivors (90% of inception cohort), 134 (66%) were assessed at a median follow-up of 8·9 years (IQR 8·2–9·5). The cumulative incidence of epilepsy was 24·7% (95% CI 16·2–35·6), with most (89%) emerging within 18 months after CSE. The cumulative incidence of epilepsy was lower in patients with prolonged febrile seizures (14·3%, 6·3–29·4) and survivors of acute symptomatic CSE (13·3%, 3·7–37·9) than in those of remote symptomatic CSE (45·5%, 21·3–72·0) and unclassified CSE (50·0%, 25·4–74·6). One participant (2·9%, 0·5–14·5) in the prolonged febrile seizures group developed temporal lobe epilepsy with mesial temporal sclerosis. The absence of fever at CSE was the only predictor of incident epilepsy (odds ratio [OR] 7·5, 95% CI 2·25–25·1). Motor and intellectual disability was seen predominantly in participants who had idiopathic and cryptogenic CSE (seven [36·8%, 95% CI 19·1–59·0] and 16 [84·2%, 62·4–94·5] of 19, respectively) and remote symptomatic CSE (33 [62·3%, 48·8–74·1] and 40 [75·5%, 62·4–85·1] of 53), and most of these participants had pre-existing disabilities. Pre-existing epilepsy was the only predictor of intellectual disability (OR 8·0, 95% CI 1·1–59·6). 51·5% (95% CI 43·1–59·8) of those followed up had a statement of special educational needs. Interpretation: Childhood CSE is associated with substantial long-term neurological morbidity, but primarily in those who have epilepsy, neurological abnormalities, or both before the episode of CSE. Survivors without neurological abnormalities before CSE have favourable outcomes

Herpes simplex virus encephalitis is a trigger of brain autoimmunity

In 5 prospectively diagnosed patients with relapsing post-herpes simplex encephalitis (HSE), N-methyl-D-aspartate receptor (NMDAR) antibodies were identified. Antibody synthesis started 1 to 4 weeks after HSE, preceding the neurological relapse. Three of 5 patients improved postimmunotherapy, 1 spontaneously, and 1 has started to improve. Two additional patients with NMDAR antibodies, 9 with unknown neuronal surface antibodies, and 1 with NMDAR and unknown antibodies, were identified during retrospective assessment of 34 HSE patients; the frequency of autoantibodies increased over time (serum, p=0.004; cerebrospinal fluid, p=0.04). The 3 retrospectively identified NMDAR antibody-positive patients also had evidence of relapsing post-HSE. Overall, these findings indicate that HSE triggers NMDAR antibodies and potentially other brain autoimmunity