Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients

In order to characterize the genetic architecture of epilepsy in a pediatric population from the Iberian Peninsula (including the Canary Islands), we conducted targeted exome sequencing of 246 patients with infantile-onset seizures with or without neurodevelopmental delay. We detected 107 variants in 48 different genes, which were implicated in neuronal excitability, neurodevelopment, synaptic transmission, and metabolic pathways. In 104 cases (42%) we detected variant(s) that we classified as pathogenic or likely pathogenic. Of the 48 mutated genes, 32 were dominant, 8 recessive and 8 X-linked. Of the patients for whom family studies could be performed and in whom pathogenic variants were identified in dominant or X-linked genes, 82% carried de novo mutations. The involvement of small copy number variations (CNVs) is 9%. The use of progressively updated custom panels with high mean vertical coverage enabled establishment of a definitive diagnosis in a large proportion of cases (42%) and detection of CNVs (even duplications) with high fidelity. In 10.5% of patients we detected associations that are pending confirmation via functional and/or familial studies. Our findings had important consequences for the clinical management of the probands, since a large proportion of the cohort had been clinically misdiagnosed, and their families were subsequently able to avail of genetic counseling. In some cases, a more appropriate treatment was selected for the patient in question, or an inappropriate treatment discontinued. Our findings suggest the existence of modifier genes that may explain the incomplete penetrance of some epilepsy-related genes. We discuss possible reasons for non-diagnosis and future research directions. Further studies will be required to uncover the roles of structural variants, epimutations, and oligogenic inheritance in epilepsy, thereby providing a more complete molecular picture of this disease. In summary, given the broad phenotypic spectrum of most epilepsy-related genes, efficient genomic tools like the targeted exome sequencing panel described here are essential for early diagnosis and treatment, and should be implemented as first-tier diagnostic tools for children with epilepsy without a clear etiologic basis

Assessment of nutritional risk among in-school adolescents from Cantabria

Seminario “Promoción de hábitos saludables en adolescentes desde el ámbito educativo”.Objetivo: Evaluar el riesgo nutricional, por edad y sexo, que presentan los adolescentes escolarizados en la Comunidad Autónoma de Cantabria. Sujetos: Se realizó un estudio transversal, analizando una muestra de 1101 adolescentes, de los que 51,6% eran varones y 48,4% fueron mujeres de edades comprendidas entre los 10 y los 17 años, escolarizados en centros de enseñanza pública, mediante el cuestionario Krece Plus. Resultados: Se observa un elevado porcentaje de ado- lescentes que presentan un riesgo nutricional elevado (35%). Los varones presentan un riesgo nutricional alto en un porcentaje ligeramente superior a las mujeres (37,8 % vs 32,1%). Además, el riesgo nutricional alto sufre un notable incremento a medida que la edad de los jóvenes aumenta. Se aprecian diferencias estadísticamente signi- ficativas tanto en los grupos de edad de los varones (p = 0,024), de las mujeres (p < 0,001) como en el grupo global (p = 0,001). En los tres casos, la distribución del riego nutricional en los grupos de menor edad es muy similar (entre 35,2 y 35,8% en los h , entre 27,9 y 29,7% en las m , y entre 31,7 y 32,7% en el grupo total). Mientras que en el grupo de mayor edad estos valores prácticamente se duplican (57,1% en los h , 69,0% en las m , y 62,2 % en el grupo total). Conclusión: Los resultados obtenidos muestran una realidad preocupante debido, principalmente, al elevado porcentaje de adolescentes que presentan un riesgo nutri- cional elevado. Siendo los varones y los adolescentes de mayor edad los sectores en los que este riesgo nutricional elevado es superior.Objective: To analyse nutritional risk, by age and sex, among primary and secondary education adolescents from Cantabria. Methodology: a cross-sectional study was carried out, analysing a sample of 1101 adolescents: 568 (51.6%) were men and 533 (48.4%) were women, aged 12 to 17, attending 16 different primary and secondary education centres in Cantabria, by means of a Krece Plus questionnaire. Results: A high percentage of adolescents with a high nutritional risk (35%) can be observed. Men show a high nutritional risk slightly higher than women (37.8% h vs 32.1% m ). Moreover, the high nutritional risk expe riences a notable increase as young people get older. Significant statistical differences can be seen both in male and female groups, and as a global group. In all three cases, the nutritional risk distribution in the youngest group is very similar (35.2-35.8% in h , 27.9-29.7% in m , 31.7-32.7% in the global group); whereas in elder adolescents, those values are practically doubled (57.1% in h , 69.0% in m , y 62.2% in the global group). Conclusions: Results are alarming mainly given the high percentage of adolescents with a high nutritional risk. Men and older adolescents are the groups in which high nutritional risk is more evident

Prácticas alimentarias de los adolescentes de Cantabria

Objetivo. Analizar determinadas prácticas alimentarias en adolescentes escolarizados en centros de educación pública de Cantabria, participantes en el Proyecto "Promoción de Hábitos Saludables en Adolescentes desde el Ámbito Educativo". Sujetos. Se realizó un estudio transversal, analizando una muestra de 1.101 adolescentes: 568 (51,6%) varones y 533 (48,4%) mujeres, de edades comprendidas entre los 10 y los 17 años, escolarizados en dieciséis centros de enseñanza primaria y secundaria, mediante un cuestionario autocumplimentado. Resultados. Los adolescentes suelen realizar entre cuatro (41,5%) y cinco (31,6%) ingestas diarias. Durante los días de colegio, el 34% emplea entre diez y quince minutos en desayunar, y entre 30 y 35 minutos en comer (33,5%) y cenar (23%). Un elevado porcentaje (49,4%) de adolescentes desayunaba en soledad durante los días lectivos. Las principales ingestas alimenticias se realizan en el hogar. Las bebidas no alcohólicas (53,6%) y los dulces (42%) son los principales destinos de su dinero de bolsillo. En la casi totalidad de los hogares, es la madre la que se encarga de la compra de los alimentos, de la preparación de las comidas y de decidir tanto el almuerzo como la merienda. La pizza (72,6%) y las patatas fritas (70,8%) son los alimentos considerados más ricos entre los analizados, mientras que el perrito caliente (49,4%) y la hamburguesa (48,5%) son considerados como los menos sanos. El 58,6% de los encuestados cena viendo la televisión. Conclusión. En el estudio del comportamiento alimentario es necesario analizar la influencia de otros factores que, en muchas ocasiones, están detrás de las recomendaciones dietéticas y que casi siempre son ignorados. Prácticas alimentarias como las analizadas en el presente estudio, permiten, cuando estas se desarrollan de forma adecuada, una mejora sustancial en la salud alimentaria y nutricional de las personas

Systemic and Local Hypoxia Synergize Through HIF1 to Compromise the Mitochondrial Metabolism of Alzheimer's Disease Microglia

Microglial cells are key contributors to Alzheimer’s disease (AD), constituting the first cellular line against Aß plaques. Local hypoxia and hypoperfusion, which are typically present in peripheral inflammatory foci, are also common in the AD brain. We describe here that Aß deposits are hypoxic and hypoperfused and that Aß plaque-associated microglia (AßAM) are characterized by the expression of hypoxia-inducible factor 1 (HIF1)-regulated genes. Notably, AßAM simultaneously upregulate the expression of genes involved in anaerobic glycolysis and oxidative mitochondrial metabolism, show elongated mitochondria surrounded by rough endoplasmic reticulum, and blunt the HIF1-mediated exclusion of pyruvate from the mitochondria through the pyruvate dehydrogenase kinase 1 (PDK1). Overstabilization of HIF1 –by genetic (von Hippel-Lindau deficient microglia) or systemic hypoxia (an AD risk factor)– induces PDK1 in microglia and reduces microglial clustering in AD mouse models. The human AD brain exhibits increased HIF1 activity and a hypoxic brain area shows reduced microglial clustering. The loss of the microglial barrier associates with augmented Aß neuropathology both in the chronic hypoxia AD mouse model and the human AD brain. Thus, the synergy between local and systemic AD risk factors converges with genetic susceptibility to cause microglial dysfunction.Peer reviewe

Hypoxia compromises the mitochondrial metabolism of Alzheimer’s disease microglia via HIF1

Genetic Alzheimer’s disease (AD) risk factors associate with reduced defensive amyloid β plaque-associated microglia (AβAM), but the contribution of modifiable AD risk factors to microglial dysfunction is unknown. In AD mouse models, we observe concomitant activation of the hypoxia-inducible factor 1 (HIF1) pathway and transcription of mitochondrial-related genes in AβAM, and elongation of mitochondria, a cellular response to maintain aerobic respiration under low nutrient and oxygen conditions. Overactivation of HIF1 induces microglial quiescence in cellulo, with lower mitochondrial respiration and proliferation. In vivo, overstabilization of HIF1, either genetically or by exposure to systemic hypoxia, reduces AβAM clustering and proliferation and increases Aβ neuropathology. In the human AD hippocampus, upregulation of HIF1α and HIF1 target genes correlates with reduced Aβ plaque microglial coverage and an increase of Aβ plaque-associated neuropathology. Thus, hypoxia (a modifiable AD risk factor) hijacks microglial mitochondrial metabolism and converges with genetic susceptibility to cause AD microglial dysfunction.R.M.-D. was the recipient of a Sara Borrell fellowship from Instituto de Salud Carlos III (ISCIII) (CD09/0007). N.L.-U., C.O.-d.S.L., C.R.-M. and M.I.A.-V. were the recipients of FPU fellowships from Spanish Ministry of Education, Culture and Sport (FPU14/02115, AP2010‐1598, FPU16/02050 and FPU15/02898, respectively). A.H.-G. was the recipient of an FPI fellowship from the Spanish Ministry of Education, Culture and Sport (BES-2010-033886). This work was supported by grants from the Spanish MINEICO, ISCIII and FEDER (European Union) (SAF2012‐33816, SAF2015‐64111‐R, SAF2017-90794-REDT and PIE13/0004 to A.P.); by the Regional Government of Andalusia co-funded by CEC and FEDER funds (European Union) (‘Proyectos de Excelencia’; P12‐CTS‐2138 and P12‐CTS‐2232 to A.P.); by the ‘Ayuda de Biomedicina 2018’, Fundación Domingo Martínez (to A.P.) ; by the ISCIII of Spain, co-financed by FEDER funds (European Union) through grants PI18/01556 (to J.V.) and PI18/01557 (to A. Gutierrez); by Junta de Andalucía, co-financed by FEDER funds (grants UMA18-FEDERJA-211 (to A. Gutierrez) and US‐1262734 (to J.V.)); and by Spanish MINEICO (BFU2016-76872-R and BES-2011-047721 to E.B.).Peer reviewe

Amyloid‐β impairs the phagocytosis of dystrophic synapses by astrocytes in Alzheimer's disease

Reactive astrocytes and dystrophic neurites, most aberrant presynaptic elements, are found surrounding amyloid‐β plaques in Alzheimer's disease (AD). We have previously shown that reactive astrocytes enwrap, phagocytose, and degrade dystrophic synapses in the hippocampus of APP mice and AD patients, but affecting less than 7% of dystrophic neurites, suggesting reduced phagocytic capacity of astrocytes in AD. Here, we aimed to gain insight into the underlying mechanisms by analyzing the capacity of primary astrocyte cultures to phagocytose and degrade isolated synapses (synaptoneurosomes, SNs) from APP (containing dystrophic synapses and amyloid‐β peptides), Tau (containing AT8‐ and AT100‐positive phosphorylated Tau) and WT (controls) mice. We found highly reduced phagocytic and degradative capacity of SNs‐APP, but not AT8/AT100‐positive SNs‐Tau, as compared with SNs‐WT. The reduced astrocyte phagocytic capacity was verified in hippocampus from 12‐month‐old APP mice, since only 1.60 ± 3.81% of peri‐plaque astrocytes presented phagocytic structures. This low phagocytic capacity did not depend on microglia‐mediated astrocyte reactivity, because removal of microglia from the primary astrocyte cultures abrogated the expression of microglia‐dependent genes in astrocytes, but did not affect the phagocytic impairment induced by oligomeric amyloid‐β alone. Taken together, our data suggest that amyloid‐β, but not hyperphosphorylated Tau, directly impairs the capacity of astrocytes to clear the pathological accumulation of oligomeric amyloid‐β, as well as of peri‐plaque dystrophic synapses containing amyloid‐β, perhaps by reducing the expression of phagocytosis receptors such as Mertk and Megf10, thus increasing neuronal damage in AD. Therefore, the potentiation or recovery of astrocytic phagocytosis may be a novel therapeutic avenue in AD.Research funding: Centro de Invesitgacion Biomedica en Red Enfermedades Neurodegenetativas (CIBERNED). Grant Numbers: CB06/05/0094, CB06/05/1116; Instituto de Salud Carlos III co‐financed by FEDER funds from European Union. Grant Numbers: PI18/01556, PI18/01557; Junta de Andalucia Consejería de Economía y Conocimiento co‐financed by Programa Operativo FEDER 2014‐2020. Grant Numbers: PY18‐RT‐2233, UMA18‐FEDERJA‐211, US‐1262734; La Marató‐TV3 Foundation. Grant Numbers: 20141430, 20141431, 20141432

Safety of hospital discharge before return of bowel function after elective colorectal surgery

Background: Ileus is common after colorectal surgery and is associated with an increased risk of postoperative complications. Identifying features of normal bowel recovery and the appropriateness for hospital discharge is challenging. This study explored the safety of hospital discharge before the return of bowel function.Methods: A prospective, multicentre cohort study was undertaken across an international collaborative network. Adult patients undergoing elective colorectal resection between January and April 2018 were included. The main outcome of interest was readmission to hospital within 30 days of surgery. The impact of discharge timing according to the return of bowel function was explored using multivariable regression analysis. Other outcomes were postoperative complications within 30 days of surgery, measured using the Clavien-Dindo classification system.Results: A total of 3288 patients were included in the analysis, of whom 301 (9.2 per cent) were discharged before the return of bowel function. The median duration of hospital stay for patients discharged before and after return of bowel function was 5 (i.q.r. 4-7) and 7 (6-8) days respectively (P &lt; 0.001). There were no significant differences in rates of readmission between these groups (6.6 versus 8.0 per cent; P = 0.499), and this remained the case after multivariable adjustment for baseline differences (odds ratio 0.90, 95 per cent c.i. 0.55 to 1.46; P = 0.659). Rates of postoperative complications were also similar in those discharged before versus after return of bowel function (minor: 34.7 versus 39.5 per cent; major 3.3 versus 3.4 per cent; P = 0.110).Conclusion: Discharge before return of bowel function after elective colorectal surgery appears to be safe in appropriately selected patients

Timing of nasogastric tube insertion and the risk of postoperative pneumonia: an international, prospective cohort study

Aim: Aspiration is a common cause of pneumonia in patients with postoperative ileus. Insertion of a nasogastric tube (NGT) is often performed, but this can be distressing. The aim of this study was to determine whether the timing of NGT insertion after surgery (before versus after vomiting) was associated with reduced rates of pneumonia in patients undergoing elective colorectal surgery. Method: This was a preplanned secondary analysis of a multicentre, prospective cohort study. Patients undergoing elective colorectal surgery between January 2018 and April 2018 were eligible. Those receiving a NGT were divided into three groups, based on the timing of the insertion: routine NGT (inserted at the time of surgery), prophylactic NGT (inserted after surgery but before vomiting) and reactive NGT (inserted after surgery and after vomiting). The primary outcome was the development of pneumonia within 30 days of surgery, which was compared between the prophylactic and reactive NGT groups using multivariable regression analysis. Results: A total of 4715 patients were included in the analysis and 1536 (32.6%) received a NGT. These were classified as routine in 926 (60.3%), reactive in 461 (30.0%) and prophylactic in 149 (9.7%). Two hundred patients (4.2%) developed pneumonia (no NGT 2.7%; routine NGT 5.2%; reactive NGT 10.6%; prophylactic NGT 11.4%). After adjustment for confounding factors, no significant difference in pneumonia rates was detected between the prophylactic and reactive NGT groups (odds ratio 1.03, 95% CI 0.56–1.87, P = 0.932). Conclusion: In patients who required the insertion of a NGT after surgery, prophylactic insertion was not associated with fewer cases of pneumonia within 30 days of surgery compared with reactive insertion