Challenges in the application of non-servocontrolled therapeutic hypothermia during neonatal transport in Catalonia

Transporte neonatal; Encefalopatía hipoxico-isquémica; HipotermiaTransport neonatal; Encefalopatia hipoxico-isquèmica; HipotèrmiaNeonatal transport; Hypoxic-ischemic encephalopathy; HypothermiaIntroducción La hipotermia terapéutica (HTT) es el único tratamiento que ha demostrado aumentar la posibilidad de supervivencia libre de secuelas en los recién nacidos (RNs) afectos de encefalopatía hipóxico-isquémica (EHI), recomendándose iniciarla lo antes posible. Lo más frecuente es que los pacientes tributarios de HTT no nazcan en los centros de referencia (CR) .requiriendo ser transportados. Métodos Estudio observacional descriptivo prospectivo de RNs con EHI moderada-grave trasladados en hipotermia terapéutica no servo-controlada por los dos equipos de transporte neonatal y pediátrico terrestres de Cataluña (abril 2018-noviembre 2019). Resultados 51 pacientes. Mediana de tiempo de estabilización 68 minutos (p25-75, 45 – 85 min), traslado 30 minutos (p25-75, 15 – 45 min). Media de edad a la llegada al CR 4 horas y 18 minutos (DE 96 min). Medidas terapéuticas adoptadas: apagar la incubadora 43 (84,3%), bolsas de hielo 11 (21,6%) y ambas 11 (21,5%) pacientes. Se consiguió la temperatura rectal (TR) diana en 19 (37,3%) pacientes. No hubo diferencias en el sobre-enfriamiento según las medidas usadas para la aplicación de la HTT no servo-controlada (HTTnc). La duración del traslado no se relacionó con diferencias en la estabilización de la temperatura ni en la consecución de la temperatura objetivo. Conclusiones La monitorización de la TR en el centro emisor es un pilar fundamental en la estabilización del paciente y la aplicación de la HTTnc. Existe una clara área de mejora en la eficacia de la HTTnc durante el transporte. La HTT servo-controlada sería una opción para poder ofrecer las mismas posibilidades terapéuticas a los RNs extramuros de los CR.Introduction Therapeutic hypothermia (TH) improves survival and neurological prognosis in hypoxic-ischemic encephalopathic (HIE) babies, being better the sooner TH is implemented. HIE babies are born more frequently in a non-cooling centre and need to be referred. Methods Prospective-observational study (April 18–November 19). Newborns (≥34 weeks of gestational age (GA) and >1800 g) with moderate/severe HIE on non-servocontrolled therapeutic hypothermia by the two neonatal transport teams in Catalonia. Results 51 newborns. The median stabilisation and transport time were 68 min (p25–75, 45–85 min) and 30 min (p25–75, 15–45 min), respectively. The mean age at arrival at the receiving unit was 4 h and 18 min (SD 96.6). The incubator was set off in 43 (84%), iced-packs 11 (21.5%) and both (11, 21.5%). Target temperature was reached in 19 (37.3%) babies. There was no differences in the overcooling in relation to the measures applied. The transport duration was not related with temperature stabilisation or target temperature reachiness. Conclusions Rectal temperature monitorisation is compulsory for the stabilisation and the application of non-servocontrolled hypothermia during transport. There is still time for improving in the administration of this treatment during transport. Servo-controlled hypothermia would be a better alternative to improve the management of HIE babies

Consensus of catalan hospitals for the management of apparent life - threatening events

Fonament. No existeixen documents de consens universalment acceptats sobre quin ha de ser el maneig de l'Episodi Aparentment Letal (EAL). Com a conseqüència, existeix una gran variabilitat en el seu abordatge. Objectiu. El Grup de Treball de la Mort Sobtada Infantil (GMSI) de la Societat Catalana de Pediatria es proposa consensuar amb els hospitals catalans un algoritme d'actuació. Mètode. El GMSI elabora un algoritme d'abordatge de l'EAL que no inclou els nounats ingressats en Unitats Neonatals. Participen professionals de diferents subespecialitats pediàtriques que formen part del grup. L'algoritme es basa en una revisió de la literatura i en el consens dels integrants del GMSI. Es contempla l'actuació a Urgències, els criteris d'ingrés i la indicació de proves complementàries. Es remet el mes de juliol del 2015 a 48 responsables de 40 hospitals catalans perquè el valorin. Resultats. Es reben 21 respostes, que corresponen a 17 hospitals. Fins a 5 responsables accepten l'algoritme mentre que 16 fan comentaris o proposen modificacions. Totes les respostes són valorades pel GMSI i es realitzen canvis en l'algoritme. Conclusions. El GMSI aporta un algoritme de consens entre els diferents hospitals catalans que permetrà homogeneïtzar l'abordatge dels pacients amb EAL

Advancing in Schaaf-Yang syndrome pathophysiology: from bedside to subcellular analyses of truncated MAGEL2

Background Schaaf-Yang syndrome (SYS) is caused by truncating mutations in MAGEL2, mapping to the Prader-Willi region (15q11-q13), with an observed phenotype partially overlapping that of Prader-Willi syndrome. MAGEL2 plays a role in retrograde transport and protein recycling regulation. Our aim is to contribute to the characterisation of SYS pathophysiology at clinical, genetic and molecular levels. Methods We performed an extensive phenotypic and mutational revision of previously reported patients with SYS. We analysed the secretion levels of amyloid-β 1-40 peptide (Aβ1-40) and performed targeted metabolomic and transcriptomic profiles in fibroblasts of patients with SYS (n=7) compared with controls (n=11). We also transfected cell lines with vectors encoding wild- type (WT) or mutated MAGEL2 to assess stability and subcellular localisation of the truncated protein. Results Functional studies show significantly decreased levels of secreted Aβ1-40 and intracellular glutamine in SYS fibroblasts compared with WT. We also identified 132 differentially expressed genes, including non-coding RNAs (ncRNAs) such as HOTAIR, and many of them related to developmental processes and mitotic mechanisms. The truncated form of MAGEL2 displayed a stability similar to the WT but it was significantly switched to the nucleus, compared with a mainly cytoplasmic distribution of the WT MAGEL2. Based on the updated knowledge, we offer guidelines for the clinical management of patients with SYS. Conclusion A truncated MAGEL2 protein is stable and localises mainly in the nucleus, where it might exert a pathogenic neomorphic effect. Aβ1-40 secretion levels and HOTAIR mRNA levels might be promising biomarkers for SYS. Our findings may improve SYS understanding and clinical management

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Consensus of catalan hospitals for the management of apparent life - threatening events

Fonament. No existeixen documents de consens universalment acceptats sobre quin ha de ser el maneig de l'Episodi Aparentment Letal (EAL). Com a conseqüència, existeix una gran variabilitat en el seu abordatge. Objectiu. El Grup de Treball de la Mort Sobtada Infantil (GMSI) de la Societat Catalana de Pediatria es proposa consensuar amb els hospitals catalans un algoritme d'actuació. Mètode. El GMSI elabora un algoritme d'abordatge de l'EAL que no inclou els nounats ingressats en Unitats Neonatals. Participen professionals de diferents subespecialitats pediàtriques que formen part del grup. L'algoritme es basa en una revisió de la literatura i en el consens dels integrants del GMSI. Es contempla l'actuació a Urgències, els criteris d'ingrés i la indicació de proves complementàries. Es remet el mes de juliol del 2015 a 48 responsables de 40 hospitals catalans perquè el valorin. Resultats. Es reben 21 respostes, que corresponen a 17 hospitals. Fins a 5 responsables accepten l'algoritme mentre que 16 fan comentaris o proposen modificacions. Totes les respostes són valorades pel GMSI i es realitzen canvis en l'algoritme. Conclusions. El GMSI aporta un algoritme de consens entre els diferents hospitals catalans que permetrà homogeneïtzar l'abordatge dels pacients amb EAL

Challenges in the application of non-servocontrolled therapeutic hypothermia during neonatal transport in Catalonia

Transporte neonatal; Encefalopatía hipoxico-isquémica; HipotermiaTransport neonatal; Encefalopatia hipoxico-isquèmica; HipotèrmiaNeonatal transport; Hypoxic-ischemic encephalopathy; HypothermiaIntroduction Therapeutic hypothermia (TH) improves survival and neurological prognosis in hypoxic-ischemic encephalopathic (HIE) babies, being better the sooner TH is implemented. HIE babies are born more frequently in a non-cooling centre and need to be referred. Methods Prospective-observational study (April 18 2018 – November 19 2019). Newborns (≥34 weeks of gestational age (GA) and >1800 g) with moderate/severe HIE on non-servocontrolled therapeutic hypothermia by the two neonatal transport teams in Catalonia. Results 51 newborns. The median stabilisation and transport time were 68 min (p25–75, 45–85 min) and 30 min (p25–75, 15–45 min), respectively. The mean age at arrival at the receiving unit was 4 h and 18 min (SD 96.6). The incubator was set off in 43 (84%), iced-packs 11 (21.5%) and both (11, 21.5%). Target temperature was reached in 19 (37.3%) babies. There were no differences in the overcooling in relation to the measures applied. The transport duration was not related with temperature stabilisation or target temperature reachiness. Conclusions Rectal temperature monitorisation is compulsory for the stabilisation and the application of non-servocontrolled hypothermia during transport. There is still time for improving in the administration of this treatment during transport. Servo-controlled hypothermia would be a better alternative to improve the management of HIE babies.Introducción La hipotermia terapéutica (HTT) es el único tratamiento que ha demostrado aumentar la posibilidad de supervivencia libre de secuelas en los recién nacidos (RNs) afectos de encefalopatía hipóxico-isquémica (EHI), recomendándose iniciarla lo antes posible. Lo más frecuente es que los pacientes tributarios de HTT no nazcan en los centros de referencia (CR), requiriendo ser transportados. Métodos Estudio observacional descriptivo prospectivo de RNs con EHI moderada-grave trasladados en hipotermia terapéutica no servo-controlada por los dos equipos de transporte neonatal y pediátrico terrestres de Cataluña (abril 2018-noviembre 2019). Resultados 51 pacientes. Mediana de tiempo de estabilización 68 minutos (p25-75, 45 – 85 min), traslado 30 minutos (p25-75, 15 – 45 min). Media de edad a la llegada al CR 4 horas y 18 minutos (DE 96 min). Medidas terapéuticas adoptadas: apagar la incubadora 43 (84,3%), bolsas de hielo 11 (21,6%) y ambas 11 (21,5%) pacientes. Se consiguió la temperatura rectal (TR) diana en 19 (37,3%) pacientes. No hubo diferencias en el sobre-enfriamiento según las medidas usadas para la aplicación de la HTT no servo-controlada (HTTnc). La duración del traslado no se relacionó con diferencias en la estabilización de la temperatura ni en la consecución de la temperatura objetivo. Conclusiones La monitorización de la TR en el centro emisor es un pilar fundamental en la estabilización del paciente y la aplicación de la HTTnc. Existe una clara área de mejora en la eficacia de la HTTnc durante el transporte. La HTT servo-controlada sería una opción para poder ofrecer las mismas posibilidades terapéuticas a los RNs extramuros de los CR

The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies

International audienceSignificance There is growing evidence that preexisting autoantibodies neutralizing type I interferons (IFNs) are strong determinants of life-threatening COVID-19 pneumonia. It is important to estimate their quantitative impact on COVID-19 mortality upon SARS-CoV-2 infection, by age and sex, as both the prevalence of these autoantibodies and the risk of COVID-19 death increase with age and are higher in men. Using an unvaccinated sample of 1,261 deceased patients and 34,159 individuals from the general population, we found that autoantibodies against type I IFNs strongly increased the SARS-CoV-2 infection fatality rate at all ages, in both men and women. Autoantibodies against type I IFNs are strong and common predictors of life-threatening COVID-19. Testing for these autoantibodies should be considered in the general population

The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies

International audienceSignificance There is growing evidence that preexisting autoantibodies neutralizing type I interferons (IFNs) are strong determinants of life-threatening COVID-19 pneumonia. It is important to estimate their quantitative impact on COVID-19 mortality upon SARS-CoV-2 infection, by age and sex, as both the prevalence of these autoantibodies and the risk of COVID-19 death increase with age and are higher in men. Using an unvaccinated sample of 1,261 deceased patients and 34,159 individuals from the general population, we found that autoantibodies against type I IFNs strongly increased the SARS-CoV-2 infection fatality rate at all ages, in both men and women. Autoantibodies against type I IFNs are strong and common predictors of life-threatening COVID-19. Testing for these autoantibodies should be considered in the general population

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in similar to 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1x10(-4)) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1x10(-4)). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4x10(-3)), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7x10(-8)). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10(-5)).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old