El recién nacido con encefalopatía hipóxico-isquémica perinatal en la era de la hipotermia terapéutica

The research work carried out is aimed at knowing relevant and novel aspects of the newborn (RN) with moderate-severe hypoxic-ischemic encephalopathy (HIE) who receives treatment with hypothermia (HT). The thesis has been structured in three main objectives whose justification and main results are:1. Evolution of the incidence of HIE, severity and mortality in the era of HT. Multicenter cross-sectional study of RNs ≥ 35 weeks of gestational age diagnosed with moderate-severe HIE in the first 6 h of life in a large region of Spain between 2011 and 2019 to detect trend changes over time in annual incidence, degree of neurological and multisystem involvement and neonatal death caused by HIE.The annual incidence rate of moderate to severe HIE was 0.84 (95% confidence interval (CI) 0.7–0.97) per 1,000 births, with no trend changes over time (p = 0.8), although the proportion of severe cases showed an average annual decrease of 0.86 points (95% CI 0.75 to 0.98). There were 102 (70%) RN diagnosed with moderate HIE and 44 (30%) with severe HIE. HT was offered at 139/146 (95%) RN. Lower clinical and/or electrical seizures were observed with a trend ranging from 56 to 28% (p = 0.006). Mortality decreased but without statistical significance (p = 0.4) and the severity of systemic damage remained unchanged (p = 0.3). Obstetric characteristics remained similar, while over time higher perinatal pH (p = 0.03) and Apgar (p = 0.05) values were found with less need for resuscitation (p = 0.07). 2. Challenges in the implementation of HT. We lack population data in Spain on the application of HT. The objective was to examine adherence to management standards during HT of RNs with HIE. An observational cohort study was conducted, multicenter from the beginning of HT (2010) in a Spanish region, until 2019.We included 133 patients, 72% with moderate HIE and the rest with severe HIE. The accessibility to HT in this Spanish region is very satisfactory. The precocity in reaching the target temperature and the implementation of therapy agree with the established standards. There are aspects of improvement in the application of the treatment such as a) reducing the differences in the age at which the target temperature is reached; b) in those with severe HIE, implement the study of MRI and biomarkers of harm in the time interval of decision-making on care redirection; (c) reduce the use of aminoglycosides; and d) improve the integration of the family in the care of RN with EHI in HT.3. Use of functional echocardiography (EcoFn) in the care of RN with HIE during treatment with HT. To know the reality of the use of this tool in the integral management of the RN with EHI that receives HT, a national cross-sectional study was carried out in Spain in 2015 through a questionnaire sent to the 57 level III units that offered HT. Almost half of the hospitals report not having professionals with experience in echocardiography, with knowledge of EcoFn clearly insufficient in 50% of the centers. 77% of the centers do not perform EcoFn as part of the study of factors that may contribute to influencing the evolution of neurological injury, and none took into account the Information of the EcoFn in the prognosis of death or disability in the long term.El trabajo de investigación realizado está dirigido a conocer aspectos relevantes y novedosos del recién nacido (RN) con encefalopatía hipóxico-isquémica (EHI) moderada-grave que recibe tratamiento con hipotermia (HT). La tesis se ha estructurado en tres objetivos principales cuya justificación y principales resultados son: 1. Evolución de la incidencia de la EHI, gravedad y mortalidad en la era de la HT. Estudio transversal multicéntrico de los RN ≥ 35 semanas de edad gestacional diagnosticados de EHI moderada-grave en las primeras 6 h de vida en una extensa región de España entre los años 2011 y 2019 para detectar cambios de tendencia a lo largo del tiempo en la incidencia anual, el grado de compromiso neurológico, multisistémico y en la muerte neonatal causada por EHI. La tasa de incidencia anual de EHI de moderada a grave fue de 0,84 (intervalo de confianza [IC] del 95 %: 0,7–0,97) por 1.000 nacimientos, sin cambios de tendencia en el tiempo (p = 0,8), aunque la proporción de casos graves mostraron una disminución anual promedio de 0,86 puntos (IC del 95%: 0,75 a 0,98). Hubo 102 (70%) RN diagnosticados de EHI moderada y 44 (30%) de EHI grave. Se ofreció HT a 139/146 (95%) RN. Se observaron menores convulsiones clínicas y/o eléctricas con una tendencia que varía del 56 al 28% (p = 0,006). La mortalidad disminuyó pero sin significación estadística (p = 0,4) y la gravedad del daño sistémico permaneció sin cambios (p = 0,3). Las características obstétricas se mantuvieron similares, mientras que con el tiempo se encontraron valores de pH perinatal (p = 0,03) y Apgar (p = 0,05) más altos con menor necesidad de reanimación (p = 0,07). 2. Desafíos en la implementación de la HT. Carecemos de datos poblacionales en España sobre la aplicación de la HT. El objetivo fue examinar la adherencia a los estándares de manejo durante la HT de los RN con EHI. Se realizó un estudio observacional de cohortes, multicéntrico desde el inicio de la HT (2010) en una región española, hasta el año 2019. Se incluyeron 133 pacientes, el 72% con EHI moderada y el resto con EHI grave. La accesibilidad a la HT en esta región española es muy satisfactoria. La precocidad en alcanzar la temperatura diana y la implementación de la terapia concuerdan con los estándares establecidos. Existen aspectos de mejora en la aplicación del tratamiento como son a) reducir las diferencias en la edad a la que se alcanza la temperatura diana; b) en aquellos con EHI grave, implementar el estudio de RM y de biomarcadores de daño en el intervalo temporal de la toma de decisiones sobre redirección del cuidado; c) reducir la utilización de aminoglucósidos; y d) mejorar la integración de la familia en los cuidados del RN con EHI en HT. 3. Utilización de la ecocardiografía funcional (EcoFn) en la asistencia al RN con EHI durante el tratamiento con HT. Para conocer la realidad del uso de esta herramienta en el manejo integral del RN con EHI que recibe HT, se realizó en España en 2015 un estudio transversal nacional mediante un cuestionario enviado a las 57 unidades de nivel III que ofertaban HT. Casi la mitad de los hospitales refieren no contar con profesionales con experiencia en ecocardiografía, con conocimiento de la EcoFn claramente insuficiente en el 50% de los centros. El 77% de los centros no realizan EcoFn como parte del estudio de factores que pueden contribuir a influir en la evolución de la lesión neurológica, y ninguno tuvo en cuenta la información de la EcoFn en el pronóstico de muerte o discapacidad a largo plazo.Escuela de DoctoradoDoctorado en Investigación en Ciencias de la Salu

Incidence of encephalopathy and comorbidity in infants with perinatal asphyxia: a comparative prospective cohort study

BackgroundPrograms that aim to improve the detection hypoxic-ischemic encephalopathy (HIE) should establish which neonates suffering from perinatal asphyxia need to be monitored within the first 6 h of life.MethodAn observational prospective cohort study of infants with gestational age ≥35 weeks, and above 1,800g, were included according to their arterial cord pH value (ApH): ≤7.00 vs. 7.01–7.10. Data was collected including obstetrical history, as well as neonatal comorbidities, including the presence of HIE, that happened within 6 h of life. A standardized neurological exam was performed at discharge.ResultsThere were 9,537 births; 176 infants with ApH 7.01–7.10 and 117 infants with ApH ≤7.00. All 9 cases with moderate-to-severe HIE occurred among infants with ApH ≤7.00. The incidence of global and moderate-severe HIE was 3/1,000 and 1/1,000 births, respectively. Outcome at discharge (abnormal exam or death) showed an OR 12.03 (95% CI 1.53, 94.96) in infants with ApH ≤7.00 compared to ApH 7.01–7.10 cohort. Ventilation support was 5.1 times (95% CI 2.87, 9.03) more likely to be needed by those with cord ApH ≤7.00 compared to those with ApH 7.01–7.10, as well as hypoglycemia (37% vs. 25%; p = 0.026). In 55%, hypoglycemia occurred despite oral and/or intravenous glucose administration had been already initiated.ConclusionsCord pH 7.00 might be a safe pH cut-off point when developing protocols to monitor infants born with acidemia in order to identify infants with moderate or severe HIE early on. There is non-negligible comorbidity in the ApH ≤7.00 cohort, but also in the 7.01–7.10 cohort

Observation of the Rare Decay of the η Meson to Four Muons

A search for the rare η→μ+μ−μ+μ− double-Dalitz decay is performed using a sample of proton-proton collisions, collected by the CMS experiment at the CERN LHC with high-rate muon triggers during 2017 and 2018 and corresponding to an integrated luminosity of 101  fb−1. A signal having a statistical significance well in excess of 5 standard deviations is observed. Using the η→μ+μ− decay as normalization, the branching fraction B(η→μ+μ−μ+μ−)=[5.0±0.8(stat)±0.7(syst)±0.7(B2μ)]×10−9 is measured, where the last term is the uncertainty in the normalization channel branching fraction. This work achieves an improved precision of over 5 orders of magnitude compared to previous results, leading to the first measurement of this branching fraction, which is found to agree with theoretical predictions

Search for new physics in multijet events with at least one photon and large missing transverse momentum in proton-proton collisions at 13 TeV

A search for new physics in final states consisting of at least one photon, multiple jets, and large missing transverse momentum is presented, using proton-proton collision events at a center-of-mass energy of 13 TeV. The data correspond to an integrated luminosity of 137 fb−1, recorded by the CMS experiment at the CERN LHC from 2016 to 2018. The events are divided into mutually exclusive bins characterized by the missing transverse momentum, the number of jets, the number of b-tagged jets, and jets consistent with the presence of hadronically decaying W, Z, or Higgs bosons. The observed data are found to be consistent with the prediction from standard model processes. The results are interpreted in the context of simplified models of pair production of supersymmetric particles via strong and electroweak interactions. Depending on the details of the signal models, gluinos and squarks of masses up to 2.35 and 1.43 TeV, respectively, and electroweakinos of masses up to 1.23 TeV are excluded at 95% confidence level

First measurement of the top quark pair production cross section in proton-proton collisions at s \sqrt{s} = 13.6 TeV

The first measurement of the top quark pair (tt¯) production cross section in proton-proton collisions at s√ = 13.6 TeV is presented. Data recorded with the CMS detector at the CERN LHC in Summer 2022, corresponding to an integrated luminosity of 1.21 fb−1, are analyzed. Events are selected with one or two charged leptons (electrons or muons) and additional jets. A maximum likelihood fit is performed in event categories defined by the number and flavors of the leptons, the number of jets, and the number of jets identified as originating from b quarks. An inclusive tt¯ production cross section of 881 ± 23 (stat + syst) ± 20 (lumi) pb is measured, in agreement with the standard model prediction of 924+32−40 pb

Measurements of inclusive and differential cross sections for the Higgs boson production and decay to four-leptons in proton-proton collisions at s \sqrt{s} = 13 TeV

Measurements of the inclusive and differential fiducial cross sections for the Higgs boson production in the H → ZZ → 4ℓ (ℓ = e, μ) decay channel are presented. The results are obtained from the analysis of proton-proton collision data recorded by the CMS experiment at the CERN LHC at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 138 fb−1. The measured inclusive fiducial cross section is 2.73 ± 0.26 fb, in agreement with the standard model expectation of 2.86 ± 0.1 fb. Differential cross sections are measured as a function of several kinematic observables sensitive to the Higgs boson production and decay to four leptons. A set of double-differential measurements is also performed, yielding a comprehensive characterization of the four leptons final state. Constraints on the Higgs boson trilinear coupling and on the bottom and charm quark coupling modifiers are derived from its transverse momentum distribution. All results are consistent with theoretical predictions from the standard model

Search for Scalar Leptoquarks Produced via τ-Lepton-Quark Scattering in pppp Collisions at s=13TeV\sqrt{s}=13 TeV

The first search for scalar leptoquarks produced in τ-lepton–quark collisions is presented. It is based on a set of proton-proton collision data recorded with the CMS detector at the LHC at a center-of-mass energy of 13 TeV corresponding to an integrated luminosity of 138  fb$^{−1}$. The reconstructed final state consists of a jet, significant missing transverse momentum, and a τ lepton reconstructed through its hadronic or leptonic decays. Limits are set on the product of the leptoquark production cross section and branching fraction and interpreted as exclusions in the plane of the leptoquark mass and the leptoquark-τ-quark coupling strength

Motor, cognitive and behavioural outcomes after neonatal hypoxic-ischaemic encephalopathy

Introduction: The current neurodevelopmental status of patients with neonatal hypoxic-ischaemic encephalopathy (HIE) in Spain is unknown. Recent European studies highlight a shift of severe pathology towards mild motor disorders and emotional problems. The aim of this study was to analyse neurodevelopmental outcomes in a cohort of neonates with HIE at age 3 years. Patients and method: Multicentre observational study of neonates born at 35 or more weeks of gestation with moderate to severe HIE in 2011–2013 in 12 hospitals in a large Spanish region (91 217 m2), with the recruitment extended through 2017 in the coordinating hospital. We analysed the findings of neonatal neuroimaging and neurodevelopmental test scores at 3 years (Bayley-III, Peabody Picture Vocabulary Test and Child Behavior Checklist). The sample included 79 controls with no history of perinatal asphyxia. Results: Sixty-three patients were recruited, of whom 5 (7.9%) were excluded due to other pathology and 14 (24%) died. Of the 44 survivors, 42 (95.5%) were evaluated. Of these 42, 10 (24%) had adverse outcomes (visual or hearing impairment, epilepsy, cerebral palsy or developmental delay). Other detected problems were minor neurological signs in 6 of the 42 (14%) and a higher incidence of emotional problems compared to controls: introversion (10.5% vs. 1.3%), anxiety (34.2% vs. 11.7%) and depression (28.9% vs. 7.8%) (P < .05). The severity of the lesions on neuroimaging was significantly higher in patients with motor impairment (P = .004) or who died or had an adverse outcome (P = .027). Conclusion: In addition to classical sequelae, the followup of patients with neonatal HIE should include the diagnosis and treatment of minor motor disorders and social and emotional problems. Resumen: Introducción: El neurodesarrollo actual de pacientes con encefalopatía hipóxico-isquémica (EHI) neonatal en España se desconoce. Recientes estudios europeos destacan el desplazamiento de la patología grave hacia trastornos motores leves y problemas emocionales. El objetivo de este estudio fue analizar el estado neuroevolutivo integral a los 3 años de una cohorte de neonatos con EHI. Pacientes y métodos: Estudio observacional multicéntrico de neonatos ≥35 semanas de edad gestacional con EHI moderada-grave nacidos entre 2011–2013 en 12 hospitales de una extensa región española (91.217 m2) y ampliado hasta 2017 en el hospital coordinador. Se evaluaron los estudios de neuroimagen neonatal y del neurodesarrollo a los 3 años mediante Bayley-III, Peabody Picture Vocabulary Test y Child Behaviour Checklist. Se incluyeron 79 controles sin asfixia perinatal. Resultados: Se reclutaron 63 pacientes de los cuales 5/63 (7,9%) se excluyeron por presentar otra patología; 14/58 (24%) fallecieron. De los 44 supervivientes, 42/44 (95,5%) fueron evaluados. De ellos; 10/42 (24%) presentaron evolución adversa (alteraciones visuales o auditivas, epilepsia, parálisis cerebral o retraso del desarrollo). Adicionalmente se detectaron otras alteraciones: trastorno motor mínimo en 6/42 (14%) y más problemas de introversión (10,5% vs. 1,3%), ansiedad (34,2% vs. 11,7%) y depresión (28,9% vs. 7,8%) que los controles (p < 0,05). La gravedad de las lesiones en neuroimagen fue significativamente mayor en pacientes con trastorno motor (p = 0,004) y muerte o evolución adversa (p = 0,027) Conclusiones: Además de las secuelas clásicas, el seguimiento de los pacientes con EHI neonatal debería incluir el diagnóstico y manejo de trastornos motores mínimos y problemas emocionales