Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Oscilaciones lentas en la red cortical alterada: una caracterización de los modelos murinos 3xTg-AD, SAMP8 y Fmr1KO

[spa] A lo largo de esta tesis se han utilizado las oscilaciones lentas (SO), que emergen durante el sueño de onda lenta y bajo el efecto de ciertos tipos de anestesia, como paradigma para detectar alteraciones funcionales en la corteza de varios modelos murinos de la Enfermedad de Alzheimer (AD) y el Síndrome X Frágil (FXS), para monitorizar la progresión de su enfermedad, y para evaluar la efectividad de dos intervenciones terapéuticas. La caracterización detallada de los parámetros de las SO en varias áreas corticales de los modelos de la AD 3xTg-AD y SAMP8 mostró que dichos parámetros se alteran de manera muy similar en ambos modelos, de un modo que es consistente con una red cortical menos excitable en estos animales. Los parámetros de las SO registradas cerca de las placas de β-amiloide en el modelo APP/PS1 también se alteraron de un modo que sugiere una reducción de la excitabilidad de la neuronas que se encuentran a su alrededor. La realización de ocho semanas de ejercicio físico voluntario en los animales SAMP8 de 7 meses de edad no consiguió cancelar las diferencias que presentaban respecto a los animales control, pero atenuó los efectos de la edad sobre algunos parámetros de la oscilación lenta en ambos grupos, que después de hacer ejercicio presentaron valores más parecidos a los de los 5 meses de edad. Los cambios detectados en el modelo del FXS Fmr1KO fueron contrarios a los detectados en los modelos de la AD, y consistentes con una red cortical hiperexcitable, cambios que fueron revertidos por la subexpresión del receptor cannabinoide CB1, que restauró las diferencias que se habían encontrado entre los animales control y Fmr1KO no tratados. El trabajo realizado en esta tesis debe ser relevante para obtener un fenotipo de red en estos modelos animales, que puede ser contrastado con el que está presente en humanos, pero también puede aportar indicios sobre los mecanismos subyacentes a la actividad de red alterada, que podría estar contribuyendo a los déficits cognitivos característicos de la Enfermedad de Alzheimer y el Síndrome X Frágil.[eng] The slow oscillation (SO) is a rhythmic cortical pattern that emerges during slow-wave sleep and under the effect of certain types of anesthesia. In this Thesis, we used this pattern as a paradigm to 1) identify functional alterations in the cerebral cortex of several mouse models of Alzheimer’s disease (AD) and the Fragile X Syndrome (FXS), 2) to monitor the progression of these diseases, and 3) to evaluate the effectiveness of two therapeutic interventions. Slow oscillations were recorded in different cortical areas of these mouse models, and several parameters of this rhythmic pattern were quantified and compared between them and control groups. The parameters of the SO were similarly altered in 3xTg-AD and SAMP8 mouse models of AD, in a way that suggests a reduced excitability of the cortical network. In addition, these parameters were also altered in the vicinity of amyloid- β plaques in the APP/PS1 mouse model of AD, suggesting a reduced excitability of the neurons located around them. The realization of eight weeks of voluntary physical exercise on 7-month-old SAMP8 animals failed to cancel the differences between them and control animals, but attenuated the effects of aging on some parameters of the SO in both groups, showing similar values to those observed at 5 months of age. Changes in the SO parameters detected in Fmr1KO mouse model of FXS occurred in the opposite way to those detected in the AD mouse models, and were suggestive of a hyperexcitable cortical network. Those changes in the Fmr1KO mouse model were reverted by genetic partial blockade of CB1 cannabinoid receptors, which restored the differences between control and untreated Fmr1KO animals. The work conducted in this Thesis may be relevant to obtain a network phenotype in these animal models, which can be contrasted with that present in humans. Also, it provides clues about the mechanisms underlying the altered network activity, which could be contributing to the cognitive deficits present in the AD and FXS pathological conditions

Overexpression of Dyrk1A, a down syndrome candidate, decreases excitability and impairs gamma oscillations in the prefrontal cortex

The dual-specificity tyrosine phosphorylation-regulated kinase DYRK1A is a serine/threonine kinase involved in neuronal differentiation and synaptic plasticity and a major candidate of Down syndrome brain alterations and cognitive deficits. DYRK1A is strongly expressed in the cerebral cortex, and its overexpression leads to defective cortical pyramidal cell morphology, synaptic plasticity deficits, and altered excitation/inhibition balance. These previous observations, however, do not allow predicting how the behavior of the prefrontal cortex (PFC) network and the resulting properties of its emergent activity are affected. Here, we integrate functional, anatomical, and computational data describing the prefrontal network alterations in transgenic mice overexpressingDyrk1A(TgDyrk1A). Usingin vivoextracellular recordings, we show decreased firing rate and gamma frequency power in the prefrontal network of anesthetized and awakeTgDyrk1Amice. Immunohistochemical analysis identified a selective reduction of vesicular GABA transporter punctae on parvalbumin positive neurons, without changes in the number of cortical GABAergic neurons in the PFC ofTgDyrk1Amice, which suggests that selective disinhibition of parvalbumin interneurons would result in an overinhibited functional network. Using a conductance-based computational model, we quantitatively demonstrate that this alteration could explain the observed functional deficits including decreased gamma power and firing rate. Our results suggest that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of Down syndrome. SIGNIFICANCE STATEMENT:DYRK1Ais a major candidate gene in Down syndrome. Its overexpression results into altered cognitive abilities, explained by defective cortical microarchitecture and excitation/inhibition imbalance. An open question is how these deficits impact the functionality of the prefrontal cortex network. Combining functional, anatomical, and computational approaches, we identified decreased neuronal firing rate and deficits in gamma frequency in the prefrontal cortices of transgenic mice overexpressingDyrk1A We also identified a reduction of vesicular GABA transporter punctae specifically on parvalbumin positive interneurons. Using a conductance-based computational model, we demonstrate that this decreased inhibition on interneurons recapitulates the observed functional deficits, including decreased gamma power and firing rate. Our results suggest that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of Down syndrome.This work was supported by Foundation Jerome Lejeune Grant 937-SM2011B, Ministerio de Ciencia e Innovación Grants BFU2011-27094 and BFU2014-52467-R, and the EU PF7 FET CORTICONIC contract 600806 (M.V.S.-V.); Ministerio de Economia y Competitividad Grant FIS2012-37655 and the Institució Catalana de Recerca i Estudis Avançats Academia (J.G.O.); and the FRAXA Foundation, Fondation Jerome Lejeune Grant 937-SM2011B, Ministerio de Economia y Competitividad Grants SAF2013-49129-C2-1-R and “Centro de Excelencia Severo Ochoa 2013–2017” SEV-2012-0208, EU ERA-Net Neuron (FOOD for THOUGHT), Secretaria de Universidades e Investigación del Departamento de Economía y Conocimiento de la Generalidad de Cataluña Grant SGR 2014/1125, and CIBERER (Centro de Investigación Biomédica en Red de Enfermedades Raras) (M.D.)

Overexpression of Dyrk1A, a down syndrome candidate, decreases excitability and impairs gamma oscillations in the prefrontal cortex

The dual-specificity tyrosine phosphorylation-regulated kinase DYRK1A is a serine/threonine kinase involved in neuronal differentiation and synaptic plasticity and a major candidate of Down syndrome brain alterations and cognitive deficits. DYRK1A is strongly expressed in the cerebral cortex, and its overexpression leads to defective cortical pyramidal cell morphology, synaptic plasticity deficits, and altered excitation/inhibition balance. These previous observations, however, do not allow predicting how the behavior of the prefrontal cortex (PFC) network and the resulting properties of its emergent activity are affected. Here, we integrate functional, anatomical, and computational data describing the prefrontal network alterations in transgenic mice overexpressingDyrk1A(TgDyrk1A). Usingin vivoextracellular recordings, we show decreased firing rate and gamma frequency power in the prefrontal network of anesthetized and awakeTgDyrk1Amice. Immunohistochemical analysis identified a selective reduction of vesicular GABA transporter punctae on parvalbumin positive neurons, without changes in the number of cortical GABAergic neurons in the PFC ofTgDyrk1Amice, which suggests that selective disinhibition of parvalbumin interneurons would result in an overinhibited functional network. Using a conductance-based computational model, we quantitatively demonstrate that this alteration could explain the observed functional deficits including decreased gamma power and firing rate. Our results suggest that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of Down syndrome. SIGNIFICANCE STATEMENT:DYRK1Ais a major candidate gene in Down syndrome. Its overexpression results into altered cognitive abilities, explained by defective cortical microarchitecture and excitation/inhibition imbalance. An open question is how these deficits impact the functionality of the prefrontal cortex network. Combining functional, anatomical, and computational approaches, we identified decreased neuronal firing rate and deficits in gamma frequency in the prefrontal cortices of transgenic mice overexpressingDyrk1A We also identified a reduction of vesicular GABA transporter punctae specifically on parvalbumin positive interneurons. Using a conductance-based computational model, we demonstrate that this decreased inhibition on interneurons recapitulates the observed functional deficits, including decreased gamma power and firing rate. Our results suggest that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of Down syndrome.This work was supported by Foundation Jerome Lejeune Grant 937-SM2011B, Ministerio de Ciencia e Innovación Grants BFU2011-27094 and BFU2014-52467-R, and the EU PF7 FET CORTICONIC contract 600806 (M.V.S.-V.); Ministerio de Economia y Competitividad Grant FIS2012-37655 and the Institució Catalana de Recerca i Estudis Avançats Academia (J.G.O.); and the FRAXA Foundation, Fondation Jerome Lejeune Grant 937-SM2011B, Ministerio de Economia y Competitividad Grants SAF2013-49129-C2-1-R and “Centro de Excelencia Severo Ochoa 2013–2017” SEV-2012-0208, EU ERA-Net Neuron (FOOD for THOUGHT), Secretaria de Universidades e Investigación del Departamento de Economía y Conocimiento de la Generalidad de Cataluña Grant SGR 2014/1125, and CIBERER (Centro de Investigación Biomédica en Red de Enfermedades Raras) (M.D.)