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Resumen: Introducción: Se cumple ahora más de una década del inicio de la hipotermia terapéutica (HT) en España, la única intervención neuroprotectora que ha venido a ser práctica estándar en el tratamiento de la encefalopatía hipóxico-isquémica perinatal (EHI). El objetivo de este artículo es ofrecer un panorama actual y presentar las controversias surgidas alrededor de la aplicación de esta terapia. Desarrollo: En esta década se ha implantado con éxito la HT en la gran mayoría de los hospitales terciarios de España y más del 85% de los recién nacidos con EHI moderada-grave reciben esta terapia. Entre los aspectos que pueden mejorar la eficacia de la HT están su inicio precoz dentro de las primeras 6 h de vida y el control de factores comórbidos asociados a la asfixia perinatal. En los pacientes con EHI moderada el inicio después de las 6 h parece mantener cierta eficacia neuroprotectora. Una duración de la HT mayor de 72 horas o un enfriamiento más profundo no ofrecen mayor eficacia neuroprotectora y aumentan el riesgo de efectos adversos. Aspectos no bien aclarados aún son la sedación durante la HT y la aplicación de esta intervención a los neonatos con EHI leve y en otros escenarios. La información pronóstica y su marco temporal es uno de los aspectos más desafiantes. Conclusiones: La HT es universal en países con recursos económicos, aunque existen puntos de controversia no resueltos. Si bien es un tratamiento generalizado en nuestro país, falta disponer de dispositivos para el traslado de estos pacientes y su centralización. Abstract: Introduction: More than a decade has passed since therapeutic hypothermia (TH) was introduced in Spain; this is the only neuroprotective intervention that has become standard practice in the treatment of perinatal hypoxic-ischaemic encephalopathy (HIE). This article aims to provide a current picture of the technique and to address the controversies surrounding its use. Development: In the last 10 years, TH has been successfully implemented in the vast majority of tertiary hospitals in Spain, and more than 85% of newborns with moderate or severe HIE currently receive the treatment. The factors that can improve the efficacy of TH include early treatment onset (first 6 hours of life) and the control of comorbid factors associated with perinatal asphyxia. In patients with moderate HIE, treatment onset after 6 hours seems to have some neuroprotective efficacy. TH duration longer than 72 hours or deeper hypothermia do not offer greater neuroprotective efficacy, but instead increase the risk of adverse effects. Unclarified aspects are the sedation of patients during TH, the application of the treatment in infants with mild HIE, and its application in other scenarios. Prognostic information and time frame are one of the most challenging aspects. Conclusions: TH is universal in countries with sufficient economic resources, although certain unresolved controversies remain. While the treatment is widespread in Spain, there is a need for cooling devices for the transfer of these patients and their centralisation.

Introduction: There is not much information about the care of infants with hypoxic-ischaemic encephalopathy (HIE) treated with therapeutic hypothermia (TH) in Spain. This includes whether protocols are routinely used, the type of neuro-monitoring performed, and how information on the neurological prognosis is presented to families. The answers to these would allow to detect and implement areas of improvement. Method: A cross-sectional analysis was performed on the responses to structured questionnaires sent to all the Spanish neonatal units that were performing TH in June 2015. Questions were divided into 5 sections: (1) the availability of protocols and technological resources, (2) the use of neuro-monitoring tools, (3) the knowledge and training of the professionals; (4) the prognostic information given to the parents; and (5) the discharge report and the follow-up plan. Results: Most centres (95%) use servo controlled whole-body cooling methods and have specific management protocols. Sedation is used in 70% of centres, and in 68% of them the onset of enteral feeding is delayed until the end of the cooling period. Amplitude-integrated electroencephalography monitoring is used in more than 80% of the centres, although only in 50% are nurses able to interpret it. Cerebral oxygen saturation is not often monitored (16%). As regards diagnostic-prognostic studies, neuroimaging is universal, but brain damage biomarkers are hardly used (29%). Prognostic information is offered within the first 72 posnatal hours in 21% of the centres, and is given without the presence of the nurse in 70% of the centres. Follow-up is performed by a neuro-paediatrician (84%), with an uneven duration between centres. Conclusions: The care of infants with HIE treated with TH in Spain is generally adequate, although there are areas for improvement in neuromonitoring, sedation, prognostic information, teamwork, and duration of follow-up. Resumen: Introducción: Apenas conocemos cómo es la asistencia de los recién nacidos (RN) con encefalopatía hipóxico-isquémica (EHI) en hipotermia terapéutica (HT), especialmente si existen protocolos asistenciales, la neuromonitorización que se realiza o cómo es la aproximación al pronóstico neurológico. Este conocimiento permite detectar e implementar áreas de mejora asistencial. Método: Estudio transversal de los 57 hospitales españoles que realizaban HT en 2015, mediante cuestionario sobre: 1) la disponibilidad de protocolos y de recursos tecnológicos; 2) el uso de herramientas de neuromonitorización; 3) los conocimientos de los profesionales; 4) la información pronóstica que se da los padres, y 5) el informe al alta y del plan de seguimiento. Resultados: El 95% utiliza enfriamiento corporal-total servocontrolado y dispone de protocolos específicos de actuación. El 70% utiliza sedación y el 68% deja al paciente a dieta absoluta. La monitorización con electroencefalografía integrada por amplitud se utiliza en más del 80% de los centros, aunque solo en el 50% la enfermera es capaz de interpretarlo. La saturación de oxígeno cerebral es escasamente monitorizada (16%). Entre los estudios diagnóstico-pronósticos, la neuroimagen es universal, pero los neurobiomarcadores apenas se utilizan (29%). Solo el 21% ofrece información pronóstica antes de las 72 h de vida; sin presencia de la enfermera en el 70%. El seguimiento lo realiza el neuropediatra (84%), con una duración desigual entre centros. Conclusiones: La asistencia del RN con EHI en España es adecuada, con áreas de mejora en: neuromonitorización, sedación, marco temporal de la información pronóstica, trabajo en equipo y estandarización de la duración del seguimiento.

Resumen: Introducción: Apenas conocemos cómo es la asistencia de los recién nacidos (RN) con encefalopatía hipóxico-isquémica (EHI) en hipotermia terapéutica (HT), especialmente si existen protocolos asistenciales, la neuromonitorización que se realiza o cómo es la aproximación al pronóstico neurológico. Este conocimiento permite detectar e implementar áreas de mejora asistencial. Método: Estudio transversal de los 57 hospitales españoles que realizaban HT en 2015, mediante cuestionario sobre: 1) la disponibilidad de protocolos y de recursos tecnológicos; 2) el uso de herramientas de neuromonitorización; 3) los conocimientos de los profesionales; 4) la información pronóstica que se da los padres, y 5) el informe al alta y del plan de seguimiento. Resultados: El 95% utiliza enfriamiento corporal-total servocontrolado y dispone de protocolos específicos de actuación. El 70% utiliza sedación y el 68% deja al paciente a dieta absoluta. La monitorización con electroencefalografía integrada por amplitud se utiliza en más del 80% de los centros, aunque solo en el 50% la enfermera es capaz de interpretarlo. La saturación de oxígeno cerebral es escasamente monitorizada (16%). Entre los estudios diagnóstico-pronósticos, la neuroimagen es universal, pero los neurobiomarcadores apenas se utilizan (29%). Solo el 21% ofrece información pronóstica antes de las 72 h de vida; sin presencia de la enfermera en el 70%. El seguimiento lo realiza el neuropediatra (84%), con una duración desigual entre centros. Conclusiones: La asistencia del RN con EHI en España es adecuada, con áreas de mejora en: neuromonitorización, sedación, marco temporal de la información pronóstica, trabajo en equipo y estandarización de la duración del seguimiento. Abstract: Introduction: There is not much information about the care of infants with hypoxic-ischaemic encephalopathy (HIE) treated with therapeutic hypothermia (TH) in Spain. This includes whether protocols are routinely used, the type of neuro-monitoring performed, and how information on the neurological prognosis is presented to families. The answers to these would allow to detect and implement areas of improvement. Method: A cross-sectional analysis was performed on the responses to structured questionnaires sent to all the Spanish neonatal units that were performing TH in June 2015. Questions were divided into 5 sections: 1) the availability of protocols and technological resources, 2) the use of neuro-monitoring tools, 3) the knowledge and training of the professionals; 4) the prognostic information given to the parents; and 5) the discharge report and the follow-up plan. Results: Most centres (95%) use servo controlled whole-body cooling methods and have specific management protocols. Sedation is used in 70% of centres, and in 68% of them the onset of enteral feeding is delayed until the end of the cooling period. Amplitude-integrated electroencephalography monitoring is used in more than 80% of the centres, although only in 50% are nurses able to interpret it. Cerebral oxygen saturation is not often monitored (16%). As regards diagnostic-prognostic studies, neuroimaging is universal, but brain damage biomarkers are hardly used (29%). Prognostic information is offered within the first 72 posnatal hours in 21% of the centres, and is given without the presence of the nurse in 70% of the centres. Follow-up is performed by a neuro-paediatrician (84%), with an uneven duration between centres. Conclusions: The care of infants with HIE treated with TH in Spain is generally adequate, although there are areas for improvement in neuromonitoring, sedation, prognostic information, teamwork, and duration of follow-up.

Introduction: The process of care and assistance from birth to the starting of therapeutic hypothermia (TH) is crucial in order to improve its effectiveness and prevent the worsening of hypoxic-ischaemic injury. Methods: A national cross-sectional study carried out in 2015 by use of a questionnaire sent to all level III units on the care of the newborn ≥ 35 weeks gestation within the first hours of life after a perinatal asphyxia event. According to clinical practice guidelines, the quality of care was compared between the hospitals that carried out or did not carry out TH, and according to the level of care. Results: A total of 89/90 hospitals participated, of which 57/90 performed TH. They all used resuscitation protocols and turned off the radiant warmer after stabilisation. All of them performed glucose and blood gas analysis, monitored the central temperature, put the newborn on a diet, and performed at least two examinations for the diagnosis of hypoxic-ischaemic encephalopathy. Greater than one-third (35%) of hospitals did not have amplitude-integrated electroencephalogram, and 6/57 were TH-hospitals. The quality of care among hospitals with and without TH was similar, childbirth being better in those that performed TH, and those with a higher level of care. Level IIIc hospitals had higher scores than the others. The TH-hospitals mentioned not always having neonatologists with experience in neurological assessment and interpretation of amplitude-integrated electroencephalogram (25%), or in brain ultrasound (62%). Conclusions: In response to the recommendations of the asphyxiated newborn, there is a proper national health care standard with differences according to the level of care and whether TH is offered. More amplitude-integrated electroencephalogram devices are necessary, as well as more neonatologists trained in the evaluations that will be required by the newborn with hypoxic-ischaemic encephalopathy. Resumen: Introducción: El proceso asistencial hasta el inicio de la hipotermia terapéutica (HT) es crucial para mejorar su efectividad y prevenir el agravamiento del daño hipóxico-isquémico. Método: Estudio transversal nacional realizado en 2015 mediante cuestionario a todas las unidades nivel iii sobre la asistencia al recién nacido (RN) con asfixia perinatal en las primeras horas de vida. Se comparó la calidad asistencial entre los hospitales que realizaban o no HT y según el nivel asistencial, de acuerdo a las guías de práctica clínica. Resultados: Participaron 89/90 hospitales, 57/90 realizaban HT. Todos utilizaban protocolos de reanimación y apagaban la cuna tras estabilización. Fue universal realizar medición de glucemia y gasometría, monitorizar la temperatura, dejar al RN a dieta y realizar al menos 2 exploraciones para el diagnóstico de encefalopatía hipóxico-isquémica. El 35% no disponía de electroencefalograma integrado por amplitud; 6/57 eran hospitales que realizaban HT. La calidad asistencial entre los hospitales con/sin HT fue similar, siendo mejor la del parto en los que hacían HT, y la de aquellos con mayor nivel asistencial. El 25% de aquellos que realizaban HT no tenían neonatólogos con experiencia en la exploración neurológica o en la interpretación del electroencefalograma integrado por amplitud; ni en la realización de ecografía cerebral en el 62%. Conclusiones: Atendiendo a las recomendaciones del RN asfíctico, existe un adecuado estándar asistencial nacional, con diferencias según el nivel asistencial y si realizan o no hipotermia. Son necesarios más equipos de electroencefalograma integrado por amplitud y formación de los neonatólogos en las evaluaciones que requerirá el RN con encefalopatía hipóxico-isquémica.

Abstract We present a detailed study of the production of dark matter in the form of a sterile neutrino via freeze-in from decays of heavy right-handed neutrinos. Our treatment accounts for thermal effects in the effective couplings, generated via neutrino mixing, of the new heavy neutrinos with the Standard Model gauge and Higgs bosons and can be applied to several low-energy fermion seesaw scenarios featuring heavy neutrinos in thermal equilibrium with the primordial plasma. We find that the production of dark matter is not as suppressed as to what is found when considering only Standard Model gauge interactions. Our study shows that the freeze-in dark matter production could be efficient.

ABSTRACT: Objectives: Little is known regarding outcomes and optimal therapeutic regimens of infections caused by Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) resistant to ceftazidime/avibactam (CZA) and susceptible to meropenem (MEM). Although susceptible to MEM in vitro, the possibility of developing MEM resistance overtime is a concern. We describe the clinical characteristics of patients with colonization/infection due to KPC variants with a focus on the in vitro activity of fosfomycin (FOS)-containing combinations. Methods: Patients with colonization/infection due to a KPC variant were included. Fosfomycin susceptibility was performed by agar dilution method. Synergistic activity of FOS-based combinations was evaluated by gradient strip-agar diffusion method. The emergence of in vitro MEM resistance was also tested. Results: Eleven patients were included: eight with infection [four with ventilator-associated pneumonia and four with bloodstream infections] and three with colonization. Previous therapy with CZA was administered to all patients (with a mean cumulative duration of 23 days). All subjects with infection received meropenem, in monotherapy (n = 4) or with amikacin (n = 2) or fosfomycin (n = 2), and achieved clinical cure. A new CZA-susceptible and MEM-resistant KPC-Kp strain was subsequently isolated in three patients (27.3%). Meropenem/vaborbactam (MVB) showed high in vitro activity, while FOS+MEM combination was synergistic in 40% of cases. In vitro resistance to MEM was observed with maintenance of CZA resistance. Conclusions: Detection of KPC variants may occur within the same patient, especially if CZA has been previously administered. Although clinical success has been obtained with carbapenems, the emergence of MEM resistance is a concern. Fosfomycin plus meropenem is synergistic and may be a valuable combination option for KPC variants, while MVB may be considered in monotherapy. The detection of KPC variants in an endemic setting for KPC-Kp represents a worryingly emerging condition. The optimal therapeutic approach is still unknown and the development of meropenem resistance is of concern, which may lead to therapeutic failure in clinical practice. In these cases, the addition of fosfomycin to meropenem, or a more potent antibiotic, such as meropenem/vaborbactam, may be valuable therapeutic options.

Colovesical fistula (CVF) is an abnormal connection between the colon and the urinary bladder. Faecaluria, reported in 40–70% of cases, is virtually pathognomonic for CVF. During the 5th day of recovery in an 84 years old subject, the passage of cloudy, malodorous urine with visible debris was observed. According to the pathognomonic character of faecaluria, the sample was signed to the laboratory for biochemical and microbiological investigation, able to define the type and origin of materials. Following clinical requirements, both biochemical pathways and instrumental procedures able to confirm or exclude the presence of faecal components in urine were considered. No biochemical compound or component addressing faecal compounds in urine results available between laboratory tests. The brown powder component of the pellet was identified as Keratin, with 90% overlapping with the reference spectrum of the compound. FT-IR analysis on urine pellet can be proposed as a simple, non-invasive, and fast method to improve the diagnostic course of CVF.

Introduction The Coronavirus pandemic has been causing a significant psychological impact on the population, showing symptoms such as anxiety, depression, post-traumatic stress disorder, among others. In addition, health professionals, who are on the front line, need to act promptly seeking unceasingly to save lives, predisposing to psychosocial events due to the risk of contamination, family distance and frustration in relation to death. Objectives To analyze the profile of the psychosocial care performed in workers of a Brazilian university hospital who sought care to control the anxiety-stress resulting from the pandemic Methods Cross-sectional observational study, using a questionnaire to survey psychosocial demands and evaluate the care of workers who sought assistance in this service (n=61). As a dependent variable, the sector of action was stipulated and as independent the sex, age and the demands that justified the need for assistance. The data were analyzed by Pearson’s correlation with 5% of significance through the statistical software SPSS. Results There was a statistic difference between the groups in the variables age and psychosocial interventions for anxiety and stress management. The most part of the sample was composed of health professionals, women, with an average of 33 years old, motivated, technically prepared, scared and not overloaded. Conclusions Psychosocial care to health professionals for the management of anxiety and depression is indispensable either during or after the pandemic by seeking Mental Health interventions to minimize the suffering of these workers.

Introduction Nursing work requires technical, scientific competence, knowledge, skill and emotional control over practice, considering that care presents risk situations, physical and emotional stress, responsibilities with people’s lives, coping with fears and suffering. All this situation in which the professional is exposed can lead to the occurrence of psychological wear, high stress and anxiety, this is conceptualized as a vague and unpleasant feeling of fear, apprehension, with characteristics of tension or discomfort derived from anticipating danger, something unknown or strange. Objectives To identify the prevalence and factors associated with anxiety among nursing professionals who work coping with COVID-19 in a Brazilian regional university hospital. Methods Cross-sectional observational study, with sociodemographic questionnaire and anxiety measurement scale (HAD), with 88 nursing professionals. The data were analyzed using absolute and relative frequency, using the software StatisticalPackage for the Social Sciences. Results There was a prevalence of anxiety (48.9%), with the majority of the sample consisting of women, over 40 years old, married or in a stable relationship, white, with higher education or postgraduate education, with income above R $ 3,000.00, tendered, with a work regime of 40 hours per week and time in the hospital from 1 to 5 years. Conclusions The impact should be considered on Nursing Mental Health caused by COVID-19 and intervene with coping strategies to minimize anxiety.

Chikungunya is an arboviral disease transmitted by Aedes mosquitoes. The disease typically consists of an acute illness characterised by fever, rash, and incapacitating arthralgia, that can persist for months. Chikungunya virus, a member of the genus Alphavirus, has recently caused a large outbreak on islands in the Indian Ocean and on the Indian subcontinent. The ongoing outbreak has involved more than 1.5 million patients, including travellers who have visited these areas. We describe our casistic of six travellers with Chikungunya arthropathy. All patients experienced fever and rash of short term during a travel in areas of epidemicity. All patients had peripheral poliarthralgias, which duration was >2 months in 4 cases (66%) and >6 months in 1 case (16%).

Background/aims: The impact of chronic hepatitis C (HCV) virus infection on atherosclerosis is controversial. In this pilot clinical study, we examined whether HCV patients significantly differed in markers of subclinical atherosclerosis compared to patients with alcohol-related chronic liver disease. Methods: We enrolled 21 consecutive adult patients with HCV and 11 patients with alcohol-related chronic liver disease after detoxification from alcohol. Common carotid intima-media thickness (CIMT) and brachial artery flow mediated vasodilation (FMD) by ultrasonography and carotid-femoral pulse wave velocity (cf-PWV) by applanation tonometry were measured in all participants by a single trained operator, who was blind to clinical features of participants. Results: Compared with those with alcohol-related liver disease, patients with HCV had markedly lower FMD (4.57±1.50 vs. 9.84±3.60%, p

Ambient Particulate Matter (PM) has been shown to be associated with cardiopulmonary diseases and lung cancer. Several groups of investigators have shown that the size of the airborne particles and their surface area determine the potential to elicit inflammatory injury and other mechanisms of adverse cellular effects. Because traffic is an important source of PM, it seems obvious that physicochemical characterization of vehicles exhaust emission has an important impact on both quantitative and qualitative aspects of ambient PM. In the present study the exhaust emissions of 8 vehicles of different categories were analyzed to attempt to differentiate them. For such purpose the particulate was collected on SPME fibers exposed to the exhaust emission for 150 s. The particulate was first characterized by micro-Raman spectroscopy and then subjected to Fast Gas Chromatography-Mass Spectrometry analyses for the chemical identification of the Polycyclic Aromatic Hydrocarbons (PAHs) compounds, the organic fraction of particulate matter in air pollution with a major role in the toxicity, notably via its effects on inflammation. Both the particle count and the PAHs compositional data were assembled to be interpreted by Principal Components Analysis. This multivariate analysis grouped the data according mainly to the naphthalene amount, as well as the volume concentration of the particles smaller than 0.5 μm, suggesting that the different exhaust emissions could be easily differentiated. With this new methodology, future research should aim at establishing a mechanism of formation during internal engine combustion processes in order to obtain a clearer picture of the inflammatory and carcinogenic mechanisms of PM in the lungs.

Background: Brain injury and poor neurodevelopment have been consistently reported in infants and adults born before term. These changes occur, at least in part, prenatally and are associated with intra-amniotic inflammation. The pattern of brain changes has been partially documented by magnetic resonance imaging but not by neurosonography along with amniotic fluid brain injury biomarkers., Objective: This study aimed to evaluate the prenatal features of brain remodeling and injury in fetuses from patients with preterm labor with intact membranes or preterm premature rupture of membranes and to investigate the potential influence of intra-amniotic inflammation as a risk mediator., Study Design: In this prospective cohort study, fetal brain remodeling and injury were evaluated using neurosonography and amniocentesis in singleton pregnant patients with preterm labor with intact membranes or preterm premature rupture of membranes between 24.0 and 34.0 weeks of gestation, with (n=41) and without (n=54) intra-amniotic inflammation. The controls for neurosonography were outpatient pregnant patients without preterm labor or preterm premature rupture of membranes matched 2:1 by gestational age at ultrasound. Amniotic fluid controls were patients with an amniocentesis performed for indications other than preterm labor or preterm premature rupture of membranes without brain or genetic defects whose amniotic fluid was collected in our biobank for research purposes matched by gestational age at amniocentesis. The group with intra-amniotic inflammation included those with intra-amniotic infection (microbial invasion of the amniotic cavity and intra-amniotic inflammation) and those with sterile inflammation. Microbial invasion of the amniotic cavity was defined as a positive amniotic fluid culture and/or positive 16S ribosomal RNA gene. Inflammation was defined by amniotic fluid interleukin 6 concentrations of >13.4 ng/mL in preterm labor and >1.43 ng/mL in preterm premature rupture of membranes. Neurosonography included the evaluation of brain structure biometric parameters and cortical development. Neuron-specific enolase, protein S100B, and glial fibrillary acidic protein were selected as amniotic fluid brain injury biomarkers. Data were adjusted for cephalic biometrics, fetal growth percentile, fetal sex, noncephalic presentation, and preterm premature rupture of membranes at admission., Results: Fetuses from mothers with preterm labor with intact membranes or preterm premature rupture of membranes showed signs of brain remodeling and injury. First, they had a smaller cerebellum. Thus, in the intra-amniotic inflammation, non-intra-amniotic inflammation, and control groups, the transcerebellar diameter measurements were 32.7 mm (interquartile range, 29.8-37.6), 35.3 mm (interquartile range, 31.2-39.6), and 35.0 mm (interquartile range, 31.3-38.3), respectively (P=.019), and the vermian height measurements were 16.9 mm (interquartile range, 15.5-19.6), 17.2 mm (interquartile range, 16.0-18.9), and 17.1 mm (interquartile range, 15.7-19.0), respectively (P=.041). Second, they presented a lower corpus callosum area (0.72 mm 2 [interquartile range, 0.59-0.81], 0.71 mm 2 [interquartile range, 0.63-0.82], and 0.78 mm 2 [interquartile range, 0.71-0.91], respectively; P=.006). Third, they showed delayed cortical maturation (the Sylvian fissure depth-to-biparietal diameter ratios were 0.14 [interquartile range, 0.12-0.16], 0.14 [interquartile range, 0.13-0.16], and 0.16 [interquartile range, 0.15-0.17], respectively [P<.001], and the right parieto-occipital sulci depth ratios were 0.09 [interquartile range, 0.07-0.12], 0.11 [interquartile range, 0.09-0.14], and 0.11 [interquartile range, 0.09-0.14], respectively [P=.012]). Finally, regarding amniotic fluid brain injury biomarkers, fetuses from mothers with preterm labor with intact membranes or preterm premature rupture of membranes had higher concentrations of neuron-specific enolase (11,804.6 pg/mL [interquartile range, 6213.4-21,098.8], 8397.7 pg/mL [interquartile range, 3682.1-17,398.3], and 2393.7 pg/mL [interquartile range, 1717.1-3209.3], respectively; P<.001), protein S100B (2030.6 pg/mL [interquartile range, 993.0-4883.5], 1070.3 pg/mL [interquartile range, 365.1-1463.2], and 74.8 pg/mL [interquartile range, 44.7-93.7], respectively; P<.001), and glial fibrillary acidic protein (1.01 ng/mL [interquartile range, 0.54-3.88], 0.965 ng/mL [interquartile range, 0.59-2.07], and 0.24 mg/mL [interquartile range, 0.20-0.28], respectively; P=.002)., Conclusion: Fetuses with preterm labor with intact membranes or preterm premature rupture of membranes had prenatal signs of brain remodeling and injury at the time of clinical presentation. These changes were more pronounced in fetuses with intra-amniotic inflammation., (Copyright © 2024. Published by Elsevier Inc.)

Background: It has been suggested that a 30-50 % lithium dose reduction or lithium discontinuation 24-48 h before delivery could minimize neonatal complications. We investigated the maternal lithemia changes around delivery after a brief discontinuation, the placental transfer of lithium at delivery, and the association between neonatal lithemia at delivery and acute neonatal outcomes., Methods: A retrospective observational cohort study was conducted in a teaching hospital (November/2006-December/2018). Data was extracted from the medical records. We included psychopathologically stable women, with a singleton pregnancy, treated with lithium in late pregnancy, with at least one maternal and neonatal lithemia at delivery. Lithium was discontinued 12 h before a scheduled caesarean section or induction, or at admission day to hospital birth; and restarted 6-12 h post., Results: Sixty-six mother-infant pairs were included, and 226 maternal and 66 neonatal lithemias were obtained. We found slight maternal lithemia fluctuations close to 0.20 mEq/L, and early postpartum relapse of 6 %. The mean (SD) umbilical cord/mother intrapartum lithemia ratio was 1.10 (0.17). Fifty-six percent of neonates presented transient acute complications. Neonatal hypotonia was the most frequent outcome (N = 15). Mean lithemia were 0.178 mEq/L higher in those with hypotonia than in those without (p = 0.028)., Limitations: It is a retrospective cohort of a moderate sample size of healthy uncomplicated pregnancies and results cannot be generalized to all pregnant treated with lithium., Conclusions: Lithium transfers completely across the placenta. A brief predelivery lithium discontinuation was associated with slight maternal lithemia fluctuations. Neonates exposed intrautero to lithium present frequent but transient acute effects., Competing Interests: Declaration of competing interest EV has received grants and served as a consultant, advisor or CME speaker for the following entities: AB-Biotics, Abbott, Allergan, Angelini, AstraZeneca, Biogen, Biohaven, Bristol-Myers Squibb, Celon, Compass, Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, Glaxo-Smith-Kline, HMNC, Idorsia, Janssen, Lundbeck, Medincell, Merck, Novartis, Orion, Otsuka, Pfizer, Roche, SAGE, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, Viatris, the Brain and Behaviour Foundation, the Spanish Ministry of Science and Innovation (CIBERSAM), the EU Horizon 2020 and the Stanley Medical Research Institute. Other authors declare no financial interests or potential conflicts of interest regarding the authorship and publication of this article., (Copyright © 2024. Published by Elsevier B.V.)

Background: Perinatal mortality remains high in low- and middle-income countries. Accurate assessment of fetal gestational age is crucial to distinguish between prematurity and intrauterine growth restriction, 2 conditions commonly associated with perinatal mortality that require different preventive strategies and management. Ultrasound measurements of the cerebellum have been shown to be accurate in assessing gestational age during pregnancy, but their postmortem performance has not yet been evaluated., Objective: We aimed to explore the feasibility and validity of gestational age estimation in fetal and perinatal deaths by ultrasound measurements of the cerebellum., Study Design: This is an observational cross-sectional study. Between August 2020 and November 2022 postmortem cerebellar ultrasound measurements were conducted in a tertiary referral hospital in Barcelona, Spain. Extrauterine assessment included transcerebellar diameter, cerebellar vermis height, and cerebellar vermis length. Moreover, intrauterine ultrasound and autopsy direct cerebellar assessments were undertaken in a subset of cases. A total of 137 fetal and perinatal deaths [63 (46.0%) fetal deaths, 69 (50.4%) stillbirths, and 5 (3.6%) neonates] were included. First, we correlated different types of transcerebellar diameter measurements between them (intrauterine, extrauterine, and autopsy-based). Then, we evaluated the relationship between the extrauterine cerebellar ultrasound measurements and gestational age, and their performance across trimesters of gestation and in different central nervous system abnormalities., Results: Gestational age ranged from 15.2 to 40.6 weeks. High correlation was observed between extrauterine, intrauterine, and autopsy transcerebellar measurements (P<.001) and between all extrauterine cerebellar measurements and gestational age (P<.001). Extrauterine transcerebellar diameter was identified as the strongest predictor of gestational age (coefficient of determination=0.88; P<.001), and its accuracy was not affected by the trimester of gestation, intrauterine growth restriction, or central nervous system alterations., Conclusion: This study shows the feasibility and accuracy of postmortem gestational age evaluation by extrauterine ultrasound measurements of the cerebellum, especially of transcerebellar diameter. Implementation of this method as part of postmortem assessment could improve cause of death attribution, especially in resource-constrained settings., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

It is estimated that 96% of infants with hypoxic-ischaemic encephalopathy (HIE) are born in resource-limited settings with no capacity to provide the standard of care that has been established for nearly 15 years in high-resource countries, which includes therapeutic hypothermia (TH), continuous electroencephalographic monitoring and magnetic resonance imaging (MRI) in addition to close vital signs and haemodynamic monitoring. This situation does not seem to be changing; however, even with these limitations, currently available knowledge can help improve the care of HIE patients in resource-limited settings. The purpose of this systematic review was to provide, under the term "HIE Code", evidence-based recommendations for feasible care practices to optimise the care of infants with HIE and potentially help reduce the risks associated with comorbidity and improve neurodevelopmental outcomes. The content of the HIE code was grouped under 9 headings: (1) prevention of HIE, (2) resuscitation, (3) first 6h post birth, (4) identification and grading of encephalopathy, (5) seizure management, (6) other therapeutic interventions, (7) multiple organ dysfunction, (8) diagnostic tests and (9) family care., (Copyright © 2024 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Despite the numerous studies in favor of breastfeeding for its benefits in cognition and mental health, the long-term effects of breastfeeding on brain structure are still largely unknown. Our main objective was to study the relationship between breastfeeding duration and cerebral gray matter volumes. We also explored the potential mediatory role of brain volumes on behavior., Methods: We analyzed 7,860 magnetic resonance images of children 9-11 years of age from the Adolescent Brain Cognitive Development (ABCD) dataset in order to study the relationship between breastfeeding duration and cerebral gray matter volumes. We also obtained several behavioral data (cognition, behavioral problems, prodromal psychotic experiences, prosociality, impulsivity) to explore the potential mediatory role of brain volumes on behavior., Results: In the 7,860 children analyzed (median age = 9 years and 11 months; 49.9% female), whole-brain voxel-based morphometry analyses revealed an association mainly between breastfeeding duration and larger bilateral volumes of the pars orbitalis and the lateral orbitofrontal cortex. In particular, the association with the left pars orbitalis and the left lateral orbitofrontal cortex proved to be very robust to the addition of potentially confounding covariates, random selection of siblings, and splitting the sample in two. The volume of the left pars orbitalis and the left lateral orbitofrontal cortex appeared to mediate the relationship between breastfeeding duration and the negative urgency dimension of the UPPS-P Impulsive Behavior Scale. Global gray matter volumes were also significant mediators for behavioral problems as measured with the Child Behavior Checklist., Conclusions: Our findings suggest that breastfeeding is a relevant factor in the proper development of the brain, particularly for the pars orbitalis and lateral orbitofrontal cortex regions. This, in turn, may impact impulsive personality and mental health in early puberty., (© 2023 Association for Child and Adolescent Mental Health.)

Background: Massive infarction in adults is a devastating entity characterized by signs of extreme swelling of the brain's parenchyma. We explored whether a similar entity exists in neonates, which we call massive neonatal arterial ischemic stroke (M-NAIS), and assess its potential clinical implications., Methods: Prospective multicenter cohort study comprising 48 neonates with gestational age ≥35 weeks with middle cerebral artery (MCA) NAIS was performed. Diagnosis with magnetic resonance imaging (MRI) was performed within the first three days after symptom onset. The presence of signs of a space-occupying mass, such as brain midline shift and/or ventricular and/or extra-axial space collapse, was recorded. The volume of the infarct and brain midline shift were determined with semiautomatic procedures. Neurodevelopment was assessed at age 24 months., Results: Fifteen (31%) neonates presented MRI signs of a space-occupying mass effect and were considered to have an M-NAIS. The relative volume (infarct volume/total brain volume) of the infarct was on average significantly greater in the M-NAIS subgroup (29% vs 4.9%, P < 0.001). Patients with M-NAIS consistently presented lesions involving the M1 arterial territory of the MCA and showed more apneic and tonic seizures, which had an earlier onset and lasted longer. Moderate to severe adverse neurodevelopmental outcomes were present in most M-NAIS cases (79% vs 6%, P < 0.001)., Conclusions: M-NAIS appears to be a distinctive subtype of neonatal infarction, defined by characteristic neuroimaging signs. Neonates with M-NAIS frequently present a moderate to severe adverse outcome. Early M-NAIS identification would allow for prompt, specific rehabilitation interventions and would provide more accurate prognostic information to families., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: More than a decade has passed since therapeutic hypothermia (TH) was introduced in Spain; this is the only neuroprotective intervention that has become standard practice in the treatment of perinatal hypoxic-ischaemic encephalopathy (HIE). This article aims to provide a current picture of the technique and to address the controversies surrounding its use., Development: In the last 10 years, TH has been successfully implemented in the vast majority of tertiary hospitals in Spain, and more than 85% of newborns with moderate or severe HIE currently receive the treatment. The factors that can improve the efficacy of TH include early treatment onset (first 6 h of life) and the control of comorbid factors associated with perinatal asphyxia. In patients with moderate HIE, treatment onset after 6 h seems to have some neuroprotective efficacy. TH duration longer than 72 h or deeper hypothermia do not offer greater neuroprotective efficacy, but instead increase the risk of adverse effects. Controversy persists around the sedation of patients during TH, the application of the treatment in infants with mild HIE, and its application in other scenarios. Prognostic information and time frame are one of the most challenging aspects., Conclusions: TH is universal in countries with sufficient economic resources, although certain unresolved controversies remain. While the treatment is widespread in Spain, there is a need for devices for the transfer of these patients and their centralisation., (Copyright © 2020 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.)

Objective: This study aims to predict perinatal death or severe sequelae in isolated small-for-gestational-age fetuses, diagnosed at a periviable gestational age, based on ultrasound and Doppler parameters at diagnosis., Design: Observational study., Setting: A tertiary perinatal centre., Population: A cohort of singleton non-malformed fetuses suspected to be small for gestational age (estimated fetal weight, EFW, <10th centile) diagnosed at 22.0-25.6 weeks of gestation. The following parameters were recorded at diagnosis: severe smallness (<3rd centile); absent or reversed end-diastolic velocity in umbilical artery; abnormal middle cerebral artery Doppler; abnormal cerebroplacental ratio; abnormal uterine artery Doppler; and absent or reversed end-diastolic velocity in the ductus venosus., Methods: Logistic regression analysis., Main Outcome Measures: Predictive performance of EFW and Doppler parameters for short-term adverse outcome of perinatal morbimortality and composite serious adverse outcomes (death, neurological impairment or severe bronchopulmonary dysplasia)., Results: A total of 155 pregnancies were included. There were 13 (8.4%) intrauterine and 11 (7.7%) neonatal deaths. A short-term adverse perinatal outcome occurred in 40 (25.8%) pregnancies. There were 31 (20%) cases of serious adverse outcomes. For the prediction of serious adverse outcomes, the combination of absent or reversed end-diastolic velocity in the umbilical artery and impaired middle cerebral artery detected by Doppler evaluation achieved a detection rate of 87%, with a false-positive rate of 14% (accuracy 86%)., Conclusion: In periviable isolated small-for-gestational-age fetuses, a Doppler evaluation of the umbilical and fetal brain circulation can accurately predict short-term adverse perinatal complications and serious adverse outcomes., (© 2022 John Wiley & Sons Ltd.)

Objective: In contrast to motor impairments, the association between lesion location and cognitive or language deficits in patients with neonatal arterial ischaemic stroke remains largely unknown. We conducted a voxel-based lesion-symptom mapping cross-sectional study aiming to reveal neonatal arterial stroke location correlates of language, motor and cognitive outcomes at 2 years of age., Design: Prospective observational multicentre study., Setting: Six paediatric university hospitals in Spain., Participants: We included 53 patients who had a neonatal arterial ischaemic stroke with neonatal MRI and who were followed up till 2 years of age., Main Outcome Measures: We analysed five dichotomous clinical variables: speech therapy (defined as the need for speech therapy as established by therapists), gross motor function impairment, and the language, motor and cognitive Bayley scales. All the analyses were controlled for total lesion volume., Results: We found that three of the clinical variables analysed significantly correlated with neonatal stroke location. Speech therapy was associated with lesions located mainly at the left supramarginal gyrus (p=0.007), gross motor function impairment correlated with lesions at the left external capsule (p=0.044) and cognitive impairment was associated with frontal lesions, particularly located at the left inferior and middle frontal gyri (p=0.012)., Conclusions: The identification of these susceptible brain areas will allow for more precise prediction of neurological impairments on the basis of neonatal brain MRI., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To develop and test the Neonatal Encephalopathy-Rating Scale (NE-RS), a new rating scale to grade the severity of neonatal encephalopathy (NE) within the first 6 hours after birth., Study Design: A 3-phase process was conducted: (1) design of a comprehensive scale that would be specific, sensitive, brief, and unsophisticated; (2) evaluation in a cohort of infants with neonatal encephalopathy and healthy controls; and (3) validation with brain magnetic resonance imaging findings and outcome at 2 years of age., Results: We evaluated the NE-RS in 54 infants with NE and 28 healthy infants. The NE-RS had excellent internal consistency (Cronbach alpha coefficient: 0.93 [95% CI 0.86-0.94]) and reliability (intraclass correlation coefficient in the NE cohort 0.996 [95% CI 0.993-0.998; P < .001]). Alertness, posture, motor response, and spontaneous activity were the top discriminators for degrees of NE. The cut-off value for mild vs moderate NE was 8 points (area under the curve [AUC] 0.99, 95% CI 0.85-1.00) and for moderate vs severe NE, 30 points (AUC 0.93, 95% CI 0.81-0.99). The NE-RS was significantly correlated with the magnetic resonance imaging score (Spearman Rho 0.77, P < .001) and discriminated infants who had an adverse outcome (AUC 0.91, 95% CI 0.83-0.99, sensitivity 0.82, specificity 0.81, positive predictive value 0.87, negative predictive value 0.74)., Conclusions: The NE-RS is reliable and performs well in reflecting the severity of NE within the first 6 hours after birth. This tool could be useful when assessing clinical criteria for therapeutic hypothermia in NE., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: The aim of the study was to assess the diagnostic yield of 2 different next-generation sequencing (NGS) approaches: gene panel and "solo" clinical exome sequencing (solo-CES), in fetuses with structural anomalies and normal chromosomal microarray analysis (CMA), in the absence of a known familial mutation., Methodology: Gene panels encompassing from 2 to 140 genes, were applied mainly in persistent nuchal fold/fetal hydrops and in large hyperechogenic kidneys. Solo-CES, which entails sequencing the fetus alone and only interpreting the Online Mendelian Inheritance in Man genes, was performed in multisystem or recurrent structural anomalies., Results: During the study period (2015-2020), 153 NGS studies were performed in 148 structurally abnormal fetuses with a normal CMA. The overall diagnostic yield accounted for 35% (53/153) of samples and 36% (53/148) of the fetuses. Diagnostic yield with the gene panels was 31% (15/49), similar to 37% (38/104) in solo-CES., Conclusions: A monogenic disease was established as the underlying cause in 35% of selected fetal structural anomalies by gene panels and solo-CES., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

Background: We aimed to assess whether a gene expression assay provided insights for understanding the heterogeneity among newborns affected by neonatal encephalopathy (NE)., Methods: Analysis by RT-qPCR of the mRNA expression of candidate genes in whole blood from controls (n = 34) and NE (n = 24) patients at <6, 12, 24, 48, 72 and 96 h of life, followed by determination of differences in gene expression between conditions and correlation with clinical variables., Results: During the first 4 days of life, MMP9, PPARG, IL8, HSPA1A and TLR8 were more expressed and CCR5 less expressed in NE patients compared to controls. MMP9 and PPARG increased and CCR5 decreased in moderate/severe NE patients compared to mild. At 6-12 h of life, increased IL8 correlated with severe NE and death, decreased CCR5 correlated with chorioamnionitis and increased HSPA1A correlated with expanded multiorgan dysfunction, severe NE and female sex., Conclusions: MMP9, PPARG and CCR5 mRNA expression within first days of life correlates with the severity of NE. At 6-12 h, IL8 and HSPA1A are good reporters of clinical variables in NE patients. HSPA1A may have a role in the sexual dimorphism observed in NE. CCR5 is potentially involved in the link between severe NE and chorioamnionitis.

Objectives: To investigate whether cerebrospinal fluid levels of neuron-specific enolase (CSF-NSE) during the first 72 hours correlate with other tools used to assess ongoing brain damage, including clinical grading of hypoxic-ischemic encephalopathy (HIE), abnormal patterns in amplitude integrated electroencephalography (aEEG), and magnetic resonance imaging (MRI), as well as with the neurodevelopmental outcomes at two years of age., Material and Methods: Prospective observational study performed in two hospitals between 2009 and 2011. Forty-three infants diagnosed with HIE within 6 hours of life were included. HIE was severe in 20 infants, moderate in 12, and mild in 11. Infants with moderate-to-severe HIE received whole-body cooling. Both the HIE cohort and a control group of 59 infants with suspected infection underwent measurement of CSF-NSE concentrations at between 12 and 72 hours after birth. aEEG monitoring was started at admission and brain MRI was performed within the first 2 weeks. Neurodevelopment was assessed at 24 months., Results: The HIE group showed higher levels of CSF-NSE than the control group: median 70 ng/ml (29; 205) vs 10.6 ng/ml (7.7; 12.9); p <0.001. Median levels of CSF-NSE in infants with severe, moderate, and mild HIE were 220.5 ng/ml (120.5; 368.8), 45.5 ng/ml (26, 75.3), and 26 ng/ml (18, 33), respectively. CSF-NSE levels correlated were significantly higher in infants with seizures, abnormal aEEG, or abnormal MRI, compared to those without abnormalities. Infants with an adverse outcome showed higher CSF-NSE levels than those with normal findings (p<0.001), and the most accurate CSF-NSE cutoff level for predicting adverse outcome in the whole cohort was 108 ng/ml and 50ng/ml in surviving infants., Conclusions: In the era of hypothermia, CSF-NSE concentrations provides valuable information as a clinical surrogate of the severity of hypoxic-ischemic brain damage, and this information may be predictive of abnormal outcome at two years of age., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Data regarding neonatal arterial ischemic stroke (NAIS) topography are still sparse and inaccurate. Despite the importance of locating NAIS to predict the long-term outcome of neonates, a map of arterial territories is not yet available. Our aim was therefore to generate the first three-dimensional map of arterial territories of the neonatal brain (ATNB) and test its usefulness., Methods: Three-dimensional time-of-flight magnetic resonance angiography images were acquired from four neonates without NAIS. Arteries were semi-automatically segmented to build a symmetric arterial template. This allowed us to delineate the volumetric extension of each arterial territory, giving rise to the ATNB map, which is publicly available. Its applicability was tested on a sample of 34 neonates with NAIS., Results: After applying the ATNB map to the neonatal sample, the posterior trunk of the middle cerebral artery, followed by its anterior trunk, were identified as the most affected arterial territories. When comparing the results obtained employing the map with the original diagnoses made during the standard clinical evaluation of NAIS, major diagnostic errors were found in 18% of cases., Conclusion: The ATNB map has been proven useful to precisely identify the arterial territories affected by an NAIS, as well as to increase the accuracy of clinical diagnoses.

Objective: To correlate neuron-specific enolase (NSE) levels in cerebrospinal fluid (CSF) in neonate infants with symptomatic neonatal arterial ischaemic stroke (NAIS) with the arterial distribution of infarct, infarct volume and outcome., Design: Prospective observational multicentre cohort., Setting: Three paediatric university hospitals in Spain., Subjects: Thirty-eight neonates with more than 35 weeks' gestational age between 2006 and 2016 were studied. They were diagnosed with NAIS by MRI. They underwent a lumbar puncture to measure CSF-NSE concentrations within 96 hours after the onset of symptoms. Sixty-seven neonates admitted with suspected infections served as controls. We used a classification based on the arterial distribution, and the lesions were segmented with ITK-Snap software to determine their volume. Neurodevelopment was assessed at 24 months using the Bayley-III, Gross Motor Function Classification System and Bimanual Fine Motor Function., Results: CSF-NSE levels were higher in patients with symptomatic NAIS when compared with controls. Neonates with multifocal NAIS and with NAIS located in middle cerebral artery (MCA)-M1 arterial territory showed higher CSF-NSE levels when compared with cases with MCA-M2-M3-M4 territories (p<0.001). A significant correlation was found between CSF-NSE and relative infarction volume (r s =0.597; p<0.001). CSF-NSE values were higher in those infants with symptomatic NAIS with adverse outcome compared with infants with good development (p=0.020). Infants with CSF-NSE values above 55 ng/mL had an OR of adverse outcome of 6.48 (95% CI 1.48 to 28.33)., Conclusions: CSF-NSE is a potential early prognostic biomarker after an NAIS due to the relation between volume, topology and neurodevelopment at 2 years of age., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Magnetic resonance imaging is the gold standard technique in establishing the diagnosis of neonatal arterial ischemic stroke (NAIS). The diagnostic value of cranial ultrasound scanning in this clinical context is controversial. We aimed to assess the current sensitivity of the cranial ultrasound scan (CUS) in detecting NAIS, as this issue has not been well described in the literature. Newborns with NAIS diagnosed by magnetic resonance imaging between 2010 and 2016 were included. All CUSs were blindly analyzed retrospectively by a neonatologist expert in neuroimaging and compared with the findings of non-expert evaluators recorded on medical charts immediately after performing the evaluation. The overall sensitivity of CUS in detecting an imaging finding suggestive of NAIS was 87% (95% confidence interval (CI): 79%-95%) for an expert evaluator, but declined to 72% (61%-83%) when performed by a non-expert evaluator (p 0.002). Sensitivity was 83% and 61% in the first 24 h and 86% and 66% at 24-48 h for expert and non-expert evaluators, respectively (p < 0.05). CUS has higher sensitivity than previously reported in the detection of a NAIS, for both expert and non-expert evaluators. These findings may be explained by the advanced technology of new ultrasound equipment. Expertise in performing CUS is useful, particularly in the first 48 h after clinical debut., (Copyright © 2018. Published by Elsevier Inc.)