Association between early echocardiography screening of low systemic blood flow and intraventricular hemorrhage in preterm infants: a multicenter cohort study.

OBJECTIVE: To determine whether early echocardiography screening of low systemic blood flow reduces intraventricular hemorrhage in preterm infants. STUDY DESIGN: Prospective multicenter study in preterm infants below 33 weeks of gestational age at nine neonatal units. Five units performed early echocardiography screening for low systemic blood flow and guided clinical management (exposure group) and 4 units did not (control group). Our main outcome was ≥grade II intraventricular hemorrhage or death within the first 7 days of life. The main analysis used the inverse probability of treatment weighting. RESULTS: Three hundred and thirty-two preterm infants (131 in the exposure group and 201 in the control group) were included. Exposure to early echocardiography screening was associated with a significant reduction in ≥grade II intraventricular hemorrhage or early death [odds ratio 0.285 (95% CI: 0.133-0.611); p = 0.001]. CONCLUSIONS: Early echocardiography screening for low systemic blood flow may reduce the incidence of intraventricular hemorrhage in preterm infants.

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

Background: Programs 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. Method: An 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. Results: There 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. Conclusions: Cord 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.

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.

Desarrollo motor, cognitivo y conductual tras encefalopatía hipóxico-isquémica neonatal / Motor, cognitive and behavioural outcomes after neonatal hypoxic-ischaemic encephalopathy

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 3años 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 y 2013 en 12 hospitales de una extensa región española (91.217m2) y ampliado hasta 2017 en el hospital coordinador. Se evaluaron los estudios de neuroimagen neonatal y del neurodesarrollo a los 3años 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, y 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 [PC] o retraso del desarrollo). Adicionalmente se detectaron otras alteraciones: trastorno motor mínimo (TMM) 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 (PC o TMM) (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 el manejo de trastornos motores mínimos y problemas emocionales.(AU)

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 3years. 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 (91,217m2), with the recruitment extended through 2017 in the coordinating hospital. We analysed the findings of neonatal neuroimaging and neurodevelopmental test scores at 3years (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 follow-up of patients with neonatal HIE should include the diagnosis and treatment of minor motor disorders and social and emotional problems.(AU)

8-Amide and 8-carbamate substitution patterns as modulators of 7-hydroxy-4-methylcoumarin's antidepressant profile: Synthesis, biological evaluation and docking studies.

Psychiatric and neurological disorders affect millions of people worldwide. Currently available treatments may help to improve symptoms, but they cannot cure the diseases. Therefore, there is an urgent need for potent and safe therapeutic solutions. 8-Amide and 8-carbamatecoumarins were synthetized and evaluated as human monoamine oxidase A and B (hMAO-A and hMAO-B) inhibitors. Comparison between both scaffolds has been established, and we hypothesized that the introduction of different substituents can modulate hMAO activity and selectivity. N-(7-Hydroxy-4-methylcoumarin-8-yl)-4-methylbenzamide (9) and ethyl N-(7-hydroxy-4-methylcoumarin-8-yl)carbamate (20) proved to be the most active and selective hMAO-A inhibitors (IC50 = 15.0 nM and IC50 = 22.0 nM, respectively), being compound 9 an irreversible hMAO-A inhibitor twenty-four times more active in vitro than moclobemide, a drug used in the treatment of depression and anxiety. Based on PAMPA assay results, both compounds proved to be good candidates to cross the blood-brain barrier. In addition, these compounds showed non-significant cytotoxicity on neuronal viability assays. Also, the best compound proved to have a t1/2 of 6.84 min, an intrinsic clearance of 195.63 µL min-1 mg-1 protein, and to be chemically stable at pH 3.0, 7.4 and 10.0. Docking studies were performed to better understand the binding affinities and selectivity profiles for both hMAO isoforms. Finally, theoretical drug-like properties calculations corroborate the potential of both scaffolds on the search for new therapeutic solutions for psychiatric disorders as depression.

Adherencia a los estándares en el tratamiento con hipotermia del recién nacido con encefalopatía hipóxico-isquémica / Adherence to hypothermia guidelines in newborns with hypoxic-ischemic encephalopathy

Introducción: No disponemos de datos poblacionales en España sobre la aplicación de la hipotermia terapéutica (HT). El objetivo fue examinar la adherencia a los estándares de manejo durante la HT de los recién nacidos (RN) con encefalopatía hipóxico-isquémica (EHI). Método: Estudio observacional de cohortes, multicéntrico desde el inicio de la HT (2010) en una región extensa española, hasta el año 2019. Resultados: Se incluyeron 133 pacientes, el 72% con EHI moderada y el resto con EHI grave. En el 84% se inició hipotermia pasiva en paritorio. La HT activa comenzó a las 5h de vida (RIC: 3,3-6,3), si bien, la temperatura diana central (33-34°C) se alcanzó a una edad de 3,5h (1;6). Los nacidos extramuros iniciaron la HT activa 3,3h de media más tarde que los intramuros, pero sin diferencias en la edad a la que se alcanzó la temperatura diana. El 96% recibió sedoanalgesia. El 100% fue monitorizado con electroencefalografía integrada por amplitud y el 59% con oximetría cerebral. La RM se realizó en el 94% con EHI moderada vs. el 65% con grave; p<0,001. Se determinó enolasa neuronal-específica en LCR en el 42% de los pacientes. La duración media del recalentamiento fue de 10h (RIC: 8-12), sin diferencias según el grado de EHI (p=0,57). Conclusiones: La aplicación de la HT cumplió satisfactoriamente con los estándares. No obstante, se detectaron aspectos de la atención mejorables. Auditar la atención al recién nacido con EHI es crucial para conseguir programas con una alta calidad asistencial en cada región. (AU)

Introduction: We do not have population data in Spain on the application of therapeutic hypothermia (TH). The objective was to examine adherence to management standards during TH of infants with hypoxic-ischemic encephalopathy (HIE). Method: Multicenter observational cohort study from the beginning of TH (year 2010) in 5 hospitals in a Spanish region, until year 2019. Results: 133 patients were recruited, 72% diagnosed with moderate HIE and the rest of them with severe HIE. In 84% of infants, passive hypothermia was started at birth. Active TH was started at a median age of 5hours of life (IQR: 3.3-6.3), although the central targeted temperature (33-34°C) was reached at a median age of 3.5hours (IQR: 1-6). Those born extramural, initiated active TH 3.3hours on average later than those born intramural, but without differences in the age at which the targeted temperature was reached. Sedoanalgesia was used in 97%. The 100% were monitored with amplitude-integrated EEG and 59% with cerebral oxymetry. MRI was performed in 94% with moderate HIE vs. 65% with severe; P<.001. Neuron-specific enolase in cerebrospinal fluid was determined in 42%. The average duration of rewarming was median 10hours (IQR: 8-12), with no differences depending on the degree of HIE (P=.57). Conclusions: The implementation of TH successfully met the standards. However, aspects of care that could be improved were detected. Auditing newborn care with HIE is crucial to achieving programs with a high quality of care in each region. (AU)

Adherence to hypothermia guidelines in newborns with hypoxic-ischemic encephalopathy.

INTRODUCTION: We do not have population data in Spain on the application of therapeutic hypothermia (TH). The objective was to examine adherence to management standards during TH of infants with hypoxic-ischemic encephalopathy (HIE). METHOD: Multicenter observational cohort study from the beginning of TH (year 2010) in 5 hospitals in a Spanish region, until year 2019. RESULTS: 133 patients were recruited, 72% diagnosed with moderate HIE and the rest of them with severe HIE. In 84% of infants, passive hypothermia was started at birth. Active TH was started at a median age of 5 h of life (IQR 3.3; 6.3), although the central targeted temperature (33-34 °C) was reached at a median age of 3.5 h (IQR 1; 6). Those born extramural, initiated active TH 3.3 h on average later than those born intramural, but without differences in the age at which the targeted temperature was reached. Sedoanalgesia was used in 97%. 100% were monitored with amplitude-integrated EEG and 59% with cerebral oxymetry. MRI was performed in 94% with moderate HIE vs. 65% with severe; P < .001. Neuron-specific enolase in cerebrospinal fluid was determined in 42%. The average duration of rewarming was median 10 h (IQR 8; 12), with no differences depending on the degree of HIE (P = .57). CONCLUSIONS: The implementation of TH successfully met the standards. However, aspects of care that could be improved were detected. Auditing newborn care with HIE is crucial to achieving programs with a high quality of care in each region.

Inter-observer reliability for amplitude-integrated electroencephalography in the newborn with perinatal asphyxia.

INTRODUCTION: Amplitude integrated electroencephalography (aEEG) is a tool widely used for neuromonitoring in the critical neonate. In the patient with perinatal asphyxia, its interpretation is key to identifying candidates for therapeutic hypothermia, detecting subclinical seizures and providing pronostic information. Our aim was to analyze the concordance in the interpretation of aEEG among neonatologists with different levels of experience. MATERIAL AND METHODS: Unicenter retrospective study of newborns ≥ 35 weeks with perinatal asphyxia included consecutively over a two-year period and monitored with aEEG for at least 6 h. The bedside neonatologist interpreted aEEG regarding background pattern, sleep-wake cycling, and seizures. The aEEG tracings were blindly reviewed by two neonatologists with different experience. The aEEG tracings were divided into periods of 0-3 h and 3-6 h of life, and the concordance (Cohen Kappa coefficient, k), between the two examiners and that of their consensus with the bedside neonatologist, was analyzed. RESULTS: Seventy-five newborns were included, 5 of them were not aEEG-monitored. 132 tracings were analyzed with a very good concordance between the two examiners in the three characteristics of the aEEG. The k for the bedside neonatologist was very good for background pattern (k = 0.93), moderate (k = 0.52) for sleep-wake cycling, and weak (k = 0.32) for seizures. CONCLUSIONS: This study supports that background pattern is easily interpreted compared to sleep-wake cycling or crisis, improving when targeted training on aEEG is received.

Concordancia interobservador del electroencefalograma integrado por amplitud en el neonato con asfixia perinatal / Inter-observer reliability for amplitude-integrated EEG in the newborn with perinatal asphyxia

Introducción: La electroencefalografía integrada por amplitud (aEEG) es una herramienta utilizada en la neuromonitorización del neonato crítico. En el paciente con asfixia perinatal, su interpretación es clave para identificar a los candidatos a hipotermia terapéutica, detectar crisis subclínicas y aportar información pronóstica. Nuestro objetivo fue analizar la concordancia en la interpretación del aEEG entre neonatólogos con distinto nivel de experiencia. Material y métodos: Estudio retrospectivo unicéntrico de los recién nacidos ≥ 35 semanas con asfixia perinatal incluidos consecutivamente durante un periodo de dos años y monitorizados con aEEG durante al menos 6 horas. El médico de guardia interpretó el aEEG respecto al trazado de base, los ciclos vigilia-sueño y las crisis. Los aEEG fueron revisados de forma ciega por dos neonatólogas con distinta experiencia. Se analizó la concordancia (coeficiente Kappa de Cohen, k) de los aEEG divididos en periodos de 0-3 horas y 3-6 horas de vida, entre ambas y la de su consenso con el médico de guardia. Resultados: Se incluyeron 75 neonatos, 5 de ellos no se monitorizaron. Se analizaron 132 trazados con una concordancia muy buena entre las dos examinadoras en las tres características del aEEG. El k respecto al médico de guardia fue muy bueno para el trazado de base (k=0,93), moderado (k=0,52) para los ciclos vigilia-sueño y débil (k=0,32) para las crisis. Conclusiones: Este estudio apoya una mayor facilidad para interpretar adecuadamente el trazado de base frente a los ciclos vigilia-sueño o las crisis, mejorando cuando se recibe una formación dirigida en el aEEG. (AU)

Introduction: Amplitude integrated electroencephalography (aEEG) is a widely tool used for neuromonitoring in the critical neonate. In the patient with perinatal asphyxia, its interpretation is key to identifying candidates for therapeutic hypothermia, detecting subclinical seizures and providing pronostic information. Our aim was to analyze the concordance in the interpretation of aEEG among neonatologists with different level of experience. Material and methods: Unicenter retrospective study of newborns ≥35 weeks with perinatal asphyxia included consecutively over a two-year period and monitored with aEEG for at least 6h. The bedside neonatologist interpreted aEEG regarding background pattern, sleep-wake cycling, and seizures. The aEEG tracings were blindly reviewed by two neonatologists with different experience. The aEEG tracings were divided into periods of 0–3h and 3-6h of life, and the concordance (Cohen Kappa coefficient, k), between the two examiners and that of their consensus with the bedside neonatologist, was analyzed. Results: Seventy-five newborns were included, 5 of them were not aEEG-monitored. 132 tracings were analyzed with a very good concordance between the two examiners in the three characteristics of the aEEG. The k for the bedside neonatologist was very good for background pattern (k=0.93), moderate (k=0.52) for sleep-wake cycling, and weak (k=0.32) for seizures. Conclusions: This study supports that background pattern is easily interpreted compared to sleep-wake cycling or crisis, improving when targeted training on aEEG is received. (AU)

Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A1 Antagonists.

We herein document a large collection of 108 2-amino-4,6-disubstituted-pyrimidine derivatives as potent, structurally simple, and highly selective A1AR ligands. The most attractive ligands were confirmed as antagonists of the canonical cyclic adenosine monophosphate pathway, and some pharmacokinetic parameters were preliminarilly evaluated. The library, built through a reliable and efficient three-component reaction, comprehensively explored the chemical space allowing the identification of the most prominent features of the structure-activity and structure-selectivity relationships around this scaffold. These included the influence on the selectivity profile of the aromatic residues at positions R4 and R6 of the pyrimidine core but most importantly the prominent role to the unprecedented A1AR selectivity profile exerted by the methyl group introduced at the exocyclic amino group. The structure-activity relationship trends on both A1 and A2AARs were conveniently interpreted with rigorous free energy perturbation simulations, which started from the receptor-driven docking model that guided the design of these series.

[Adherence to hypothermia guidelines in newborns with hypoxic-ischemic encephalopathy]. / Adherencia a los estándares en el tratamiento con hipotermia del recién nacido con encefalopatía hipóxico-isquémica.

INTRODUCTION: We do not have population data in Spain on the application of therapeutic hypothermia (TH). The objective was to examine adherence to management standards during TH of infants with hypoxic-ischemic encephalopathy (HIE). METHOD: Multicenter observational cohort study from the beginning of TH (year 2010) in 5 hospitals in a Spanish region, until year 2019. RESULTS: 133 patients were recruited, 72% diagnosed with moderate HIE and the rest of them with severe HIE. In 84% of infants, passive hypothermia was started at birth. Active TH was started at a median age of 5hours of life (IQR: 3.3-6.3), although the central targeted temperature (33-34°C) was reached at a median age of 3.5hours (IQR: 1-6). Those born extramural, initiated active TH 3.3hours on average later than those born intramural, but without differences in the age at which the targeted temperature was reached. Sedoanalgesia was used in 97%. The 100% were monitored with amplitude-integrated EEG and 59% with cerebral oxymetry. MRI was performed in 94% with moderate HIE vs. 65% with severe; P<.001. Neuron-specific enolase in cerebrospinal fluid was determined in 42%. The average duration of rewarming was median 10hours (IQR: 8-12), with no differences depending on the degree of HIE (P=.57). CONCLUSIONS: The implementation of TH successfully met the standards. However, aspects of care that could be improved were detected. Auditing newborn care with HIE is crucial to achieving programs with a high quality of care in each region.

Temporal Trends in the Severity and Mortality of Neonatal Hypoxic-Ischemic Encephalopathy in the Era of Hypothermia.

INTRODUCTION: There is a paucity of studies examining temporal trends in the incidence and mortality of moderate-to-severe hypoxic-ischemic encephalopathy (HIE) during the last decade of therapeutic hypothermia (TH). METHODS: Multicenter cross-sectional study of all infants ≥35 weeks gestational age diagnosed with moderate-to-severe HIE within 6 h of birth in an extensive region of Spain between 2011 and 2019, in order to detect trend changes over time in the (1) annual incidence, (2) severity of neurological and systemic organ involvement, and (3) neonatal death from HIE. RESULTS: Annual incidence rate of moderate-to-severe HIE was 0.84 (95% confidence interval [CI] 0.7-0.97) per 1,000 births, without trend changes over time (p = 0.8), although the proportion of severe HIE infants showed an average annual decline of 0.86 points (95% CI 0.75-0.98). There were 102 (70%) infants diagnosed with moderate HIE and 44 (30%) with severe HIE. TH was offered to 139/146 (95%) infants. Infants with clinical and/or electrical seizures showed a decreasing trend from 56 to 28% (p = 0.006). Mortality showed a nonstatistically significant decline (p = 0.4), and the severity of systemic damage showed no changes (p = 0.3). Obstetric characteristics remained unchanged, while higher perinatal pH values (p = 0.03) and Apgar scores (p = 0.05), and less need for resuscitation (p = 0.07), were found over time. CONCLUSION: The annual incidence of moderate-to-severe HIE has stabilized at around 1 per 1,000 births, with a temporal trend toward a decrease in severe HIE infants and a slight decline of mortality. No association was found between temporal trends and changes in perinatal/obstetric characteristics over time.

[Inter-observer reliability for amplitude-integrated EEG in the newborn with perinatal asphyxia]. / Concordancia interobservador del electroencefalograma integrado por amplitud en el neonato con asfixia perinatal.

INTRODUCTION: Amplitude integrated electroencephalography (aEEG) is a widely tool used for neuromonitoring in the critical neonate. In the patient with perinatal asphyxia, its interpretation is key to identifying candidates for therapeutic hypothermia, detecting subclinical seizures and providing pronostic information. Our aim was to analyze the concordance in the interpretation of aEEG among neonatologists with different level of experience. MATERIAL AND METHODS: Unicenter retrospective study of newborns ≥35 weeks with perinatal asphyxia included consecutively over a two-year period and monitored with aEEG for at least 6h. The bedside neonatologist interpreted aEEG regarding background pattern, sleep-wake cycling, and seizures. The aEEG tracings were blindly reviewed by two neonatologists with different experience. The aEEG tracings were divided into periods of 0-3h and 3-6h of life, and the concordance (Cohen Kappa coefficient, k), between the two examiners and that of their consensus with the bedside neonatologist, was analyzed. RESULTS: Seventy-five newborns were included, 5 of them were not aEEG-monitored. 132 tracings were analyzed with a very good concordance between the two examiners in the three characteristics of the aEEG. The k for the bedside neonatologist was very good for background pattern (k=0.93), moderate (k=0.52) for sleep-wake cycling, and weak (k=0.32) for seizures. CONCLUSIONS: This study supports that background pattern is easily interpreted compared to sleep-wake cycling or crisis, improving when targeted training on aEEG is received.

Usefulness of video recordings for validating neonatal encephalopathy exams: a population-based cohort study.

OBJECTIVE: To determine the usefulness of video recordings for validating neonatal encephalopathy (NE) exams. DESIGN: Population-based prospective cohort study. NE was assessed and recorded at 1, 3 and 5 hours after birth by the attending physician. Recordings were reviewed blindly after the recruitment period by two specialists. Outcome was assessed at 36 months of age. SETTING: Twelve intensive care units in Spain. PATIENTS: Infants of ≥35 weeks' gestational age with perinatal asphyxia. MAIN OUTCOMES MEASURES: Weighted kappa to measure disagreement between the two specialists and between the attending physician and the specialists' classification agreed on by consensus. Regression models to test the association of disagreement on NE assessment and outcome. RESULTS: Of the 32 325 liveborn infants, 217 met the inclusion criteria. Video-recordings were not available for 43 infants (20%). Weighted kappa statistic was 0.74 (95% CI 0.67 to 0.81) between the specialists and the attending physicians. Disagreement occurred in 93 of the 417 (22%) videos, specifically in 39 (14%), 43 (47%), 11 (34%) and 0 exams categorised as no, mild, moderate and severe NE, respectively. According to the specialist consensus assessment, there was disagreement on the therapeutic hypothermia decision in 10 infants.When there was consensus among the specialists assessing a more severe NE degree compared with the attending physicians in 170 infants, those infants had lower cognitive scores with a median of -5.33 points (95% CI -9.85 to -8.16; p=0.02). CONCLUSIONS: This study supports the feasibility and benefit of using video recordings to identify NE in infants with perinatal asphyxia.

Lack of Variability in Cerebral Oximetry Tendency in Infants with Severe Hypoxic-Ischemic Encephalopathy Under Hypothermia.

Cerebral oximetry using near-infrared spectroscopy (NIRS) provides continuous, noninvasive assessment of the degree of hemoglobin saturation of the brain tissue. Previous studies suggest that high values of regional cerebral tissue oxygen saturation (rScO2) during the first days in neonates with significant hypoxic-ischemic encephalopathy (HIE) are correlated with an adverse neurological outcome. However, the results are not consistent among the studies. To examine the correlation of rScO2 values and their variability over time with HIE severity, amplitude integrated electroencephalography (aEEG) background and seizure activity, neuron-specific enolase levels in cerebrospinal fluid, magnetic resonance imaging (MRI) findings, and neurological outcome. Retrospective study that included all consecutive infants with moderate-to-severe HIE born at ≥35 weeks gestational age admitted between January 2011 and December 2014. NIRS monitoring was initiated at admission and maintained during therapeutic hypothermia up to 12 hours after rewarming. To analyze rScO2, different periods (0-6, 6-24, 24-48, 48-72, and 72-100 hours of life) and three ranges (<55%, 55-90%, >90%) were considered. Variability in each patient was considered ≤5% when changes in rScO2 values in all periods were ≤5%. Twenty-three newborns were included. Infants who suffered from severe HIE, seizures, abnormal aEEG background, altered MRI or death, and abnormal outcome had rScO2 values >90% and with less variability (≤5%). rScO2 values >90% and a lack of variability over time in infants with HIE during cooling provide useful information about the severity of neurological status.

Computer-aided design of multi-target ligands at A1R, A2AR and PDE10A, key proteins in neurodegenerative diseases.

Compounds designed to display polypharmacology may have utility in treating complex diseases, where activity at multiple targets is required to produce a clinical effect. In particular, suitable compounds may be useful in treating neurodegenerative diseases by promoting neuronal survival in a synergistic manner via their multi-target activity at the adenosine A1 and A2A receptors (A1R and A2AR) and phosphodiesterase 10A (PDE10A), which modulate intracellular cAMP levels. Hence, in this work we describe a computational method for the design of synthetically feasible ligands that bind to A1 and A2A receptors and inhibit phosphodiesterase 10A (PDE10A), involving a retrosynthetic approach employing in silico target prediction and docking, which may be generally applicable to multi-target compound design at several target classes. This approach has identified 2-aminopyridine-3-carbonitriles as the first multi-target ligands at A1R, A2AR and PDE10A, by showing agreement between the ligand and structure based predictions at these targets. The series were synthesized via an efficient one-pot scheme and validated pharmacologically as A1R/A2AR-PDE10A ligands, with IC50 values of 2.4-10.0 µM at PDE10A and Ki values of 34-294 nM at A1R and/or A2AR. Furthermore, selectivity profiling of the synthesized 2-amino-pyridin-3-carbonitriles against other subtypes of both protein families showed that the multi-target ligand 8 exhibited a minimum of twofold selectivity over all tested off-targets. In addition, both compounds 8 and 16 exhibited the desired multi-target profile, which could be considered for further functional efficacy assessment, analog modification for the improvement of selectivity towards A1R, A2AR and PDE10A collectively, and evaluation of their potential synergy in modulating cAMP levels.

Three-component assembly of structurally diverse 2-aminopyrimidine-5-carbonitriles.

An expedient route for the synthesis of libraries of diversely decorated 2-aminopyrimidine-5-carbonitriles is reported. This approach is based on a three-component reaction followed by spontaneous aromatization.

Effect of phosphodiesterase 7 (PDE7) inhibitors in experimental autoimmune encephalomyelitis mice. Discovery of a new chemically diverse family of compounds.

Phosphodiesterase (PDE) 7 is involved in proinflammatory processes, being widely expressed both on lymphocytes and on certain brain regions. Specific inhibitors of PDE7 have been recently reported as potential new drugs for the treatment of neurological disorders because of their ability to increase intracellular levels of cAMP and thus to modulate the inflammatory process, as a neuroprotective well-established strategy. Multiple sclerosis is an unmet disease in which pathologies on the immune system, T-cells, and specific neural cells are involved simultaneously. Therefore, PDE7 inhibitors able to interfere with all these targets may represent an innovative therapy for this pathology. Here, we report a new chemically diverse family of heterocyclic PDE7 inhibitors, discovered and optimized by using molecular modeling studies, able to increase cAMP levels in cells, decrease inflammatory activation on primary neural cultures, and also attenuate the clinical symptoms in the experimental autoimmune encephalomyelitis (EAE) mouse model. These results led us to propose the use of PDE7 inhibitors as innovative therapeutic agents for the treatment of multiple sclerosis.

Neuroprotective efficacy of quinazoline type phosphodiesterase 7 inhibitors in cellular cultures and experimental stroke model.

A simple and efficient synthetic method for the preparation of quinazoline type phosphodiesterase 7 (PDE7) inhibitors, based on microwave irradiation, has been developed. The use of this methodology improved yields and reaction times, providing a scalable procedure. These compounds are pharmacologically interesting because of their in vivo efficacy both in spinal cord injury and Parkinson's disease models, as shown in previous studies from our group. Herein we describe for the first time that administration of one of the PDE7 inhibitors here optimized, 3-phenyl-2,4-dithioxo-1,2,3,4-tetrahydroquinazoline (compound 5), ameliorated brain damage and improved behavioral outcome in a permanent middle cerebral artery occlusion (pMCAO) stroke model. Furthermore, we demonstrate that these PDE7 inhibitors are potent anti-inflammatory as well as neuroprotective agents in primary cultures of neural cells. These results led us to propose PDE7 inhibitors as a new class of therapeutic agents for neuroprotection.