Human neural crest cells display molecular and phenotypic hallmarks of stem cells

The fields of both developmental and stem cell biology explore how functionally distinct cell types arise from a self-renewing founder population. Multipotent, proliferative human neural crest cells (hNCC) develop toward the end of the first month of pregnancy. It is assumed that most differentiate after migrating throughout the organism, although in animal models neural crest stem cells reportedly persist in postnatal tissues. Molecular pathways leading over time from an invasive mesenchyme to differentiated progeny such as the dorsal root ganglion, the maxillary bone or the adrenal medulla are altered in many congenital diseases. To identify additional components of such pathways, we derived and maintained self-renewing hNCC lines from pharyngulas. We show that, unlike their animal counterparts, hNCC are able to self-renew ex vivo under feeder-free conditions. While cross species comparisons showed extensive overlap between human, mouse and avian NCC transcriptomes, some molecular cascades are only active in the human cells, correlating with phenotypic differences. Furthermore, we found that the global hNCC molecular profile is highly similar to that of pluripotent embryonic stem cells when compared with other stem cell populations or hNCC derivatives. The pluripotency markers NANOG, POU5F1 and SOX2 are also expressed by hNCC, and a small subset of transcripts can unambiguously identify hNCC among other cell types. The hNCC molecular profile is thus both unique and globally characteristic of uncommitted stem cells

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Contribution de l'analyse du signal vocal à la détection de l'état de somnolence et du niveau de charge mentale

Operational requirements of aircraft pilots may cause drowsiness and inadequate mental load levels (i.e., too low or too high) during flights. Sleep debts and circadian disruptions linked to various factors (e.g., long working periods, irregular work schedules, etc.) require pilots to challenge their biological limits. Moreover, pilots' mental workload exhibits strong fluctuations during flights: higher during critical phases (i.e., takeoff and landing), it becomes very low during cruising phases. When the mental load becomes too high or, conversely, too low, performance decreases and flight errors may manifest. Implementation of detection methods of drowsiness and mental load levels in near real time is a major challenge for monitoring and controlling flight activity. The aim of this thesis is therefore to determine if the human voice can serve to detect on one hand the drowsiness and on the other hand the mental load level of an individual. In a first study, the voice of participants was recorded during a reading task before and after a night of total sleep deprivation (TSD). Drowsiness variations linked to TSD were assessed using self-evaluative and electrophysiological measures (ElectroEncephaloGraphy [EEG] and Evoked Potentials [EPs]). Results showed significant variations after the TSD in many acoustic features related to: (a) the amplitude of the glottal pulses (amplitude modulation frequency), (b) the shape of the acoustic wave (Euclidean length of the signal and its associated features) and (3) the spectrum of the vowel signal (harmonic-to-noise ratio, second formant frequency, skewness, spectral center of gravity, energy differences, spectral tilt and Mel-frequency cepstral coefficients). Most spectral features showed different sensitivity to sleep deprivation depending on the vowel type. Significant correlations were found between several acoustic features and several objective indicators (EEG and PEs) of drowsiness. In a second study, voices were recorded during a task featuring word-list recall. The difficulty of the task was manipulated by varying the number of words in each list (i.e., between one and seven, corresponding to seven mental load conditions). Evoked pupillary response - known to be a useful proxy of mental load - was recorded simultaneously with speech to attest variations in mental load level during the experimental task. Results showed that classical features (fundamental frequency and its standard deviation, shimmer, number of periods and harmonic-to-noise ratio) and original features (amplitude modulation frequency and short-term variation in digital amplitude length) were particularly sensitive to variations in mental load. Variations in these acoustic features were correlated to those of the pupil size. Results suggest that the acoustic features of the human voice identified during these experiments could represent relevant indicators for the detection of drowsiness and mental load levels of an individual. Findings open up many research and applications perspectives in the field of transport safety, particularly in the aeronautical sector.Les exigences opérationnelles du métier de pilote sont susceptibles d'engendrer de la somnolence et des niveaux de charge mentale inadéquats (i.e., trop faible ou trop élevé) au cours des vols. Les dettes de sommeil et les perturbations circadiennes liées à divers facteurs (e.g., longues périodes de services, horaires de travail irrégulier, etc.) demandent aux pilotes de repousser sans cesse leurs limites biologiques. Par ailleurs, la charge de travail mental des pilotes présente de fortes variations au cours d'un vol : élevée au cours des phases critiques (i.e., décollage et atterrissage), elle devient très réduite pendant les phases de croisière. Lorsque la charge mentale devient trop élevée ou, à l'inverse, trop faible, les performances se dégradent et des erreurs de pilotage peuvent apparaître. La mise en oeuvre de méthodes de détection de l'état de somnolence et du niveau de charge mentale en temps quasi réel est un défi majeur pour le suivi et le contrôle de l'activité de pilotage. L'objectif de la thèse est de déterminer si la voix humaine peut permettre de détecter d'une part, l'état de somnolence et d'autre part, le niveau de charge mentale d'un individu. Dans une première étude, la voix de participants a été enregistrée lors d'une tâche de lecture avant et après une nuit de privation totale de sommeil (PTS). Les variations de l'état de somnolence consécutives à la PTS ont été évaluées au moyen de mesures auto-évaluatives et électrophysiologiques (ÉlectroEncéphaloGraphie [EEG] et Potentiels Évoqués [PEs]). Les résultats ont montré une variation significative après la PTS de plusieurs paramètres acoustiques liés : (a) à l'amplitude des impulsions glottiques (fréquence de modulation d'amplitude), (b) à la forme du signal acoustique (longueur euclidienne du signal et ses caractéristiques associées) et (c) au spectre du signal des voyelles (rapport harmonique sur bruit, fréquence du second formant, coefficient d'asymétrie, centre de gravité spectral, différences d'énergie, pente spectrale et coefficients cepstraux à échelle Mel). La plupart des caractéristiques spectrales ont montré une sensibilité différente à la privation de sommeil en fonction du type de voyelles. Des corrélations significatives ont été mises en évidence entre plusieurs paramètres acoustiques et plusieurs indicateurs objectifs (EEG et PEs) de l'état de somnolence. Dans une seconde étude, le signal vocal a été enregistré durant une tâche de rappel de listes de mots. La difficulté de la tâche était manipulée en faisant varier le nombre de mots dans chaque liste (i.e., entre un et sept, correspondant à sept conditions de charge mentale). Le diamètre pupillaire - qui est un indicateur objectif pertinent du niveau de charge mentale - a été mesuré simultanément avec l'enregistrement de la voix afin d'attester de la variation du niveau de charge mentale durant la tâche expérimentale. Les résultats ont montré que des paramètres acoustiques classiques (fréquence fondamentale et son écart type, shimmer, nombre de périodes et rapport harmonique sur bruit) et originaux (fréquence de modulation d'amplitude et variations à court-terme de la longueur euclidienne du signal) ont été particulièrement sensibles aux variations de la charge mentale. Les variations de ces paramètres acoustiques étaient corrélées à celles du diamètre pupillaire. L'ensemble des résultats suggère que les paramètres acoustiques de la voix humaine identifiés lors des expérimentations pourraient représenter des indicateurs pertinents pour la détection de l'état de somnolence et du niveau de charge mentale d'un individu. Les résultats ouvrent de nombreuses perspectives de recherche et d'applications dans le domaine de la sécurité des transports, notamment dans le secteur aéronautique

Contribution of the analysis of speech signal to the detection of drowsiness and mental load level

Les exigences opérationnelles du métier de pilote sont susceptibles d'engendrer de la somnolence et des niveaux de charge mentale inadéquats (i.e., trop faible ou trop élevé) au cours des vols. Les dettes de sommeil et les perturbations circadiennes liées à divers facteurs (e.g., longues périodes de services, horaires de travail irrégulier, etc.) demandent aux pilotes de repousser sans cesse leurs limites biologiques. Par ailleurs, la charge de travail mental des pilotes présente de fortes variations au cours d'un vol : élevée au cours des phases critiques (i.e., décollage et atterrissage), elle devient très réduite pendant les phases de croisière. Lorsque la charge mentale devient trop élevée ou, à l'inverse, trop faible, les performances se dégradent et des erreurs de pilotage peuvent apparaître. La mise en oeuvre de méthodes de détection de l'état de somnolence et du niveau de charge mentale en temps quasi réel est un défi majeur pour le suivi et le contrôle de l'activité de pilotage. L'objectif de la thèse est de déterminer si la voix humaine peut permettre de détecter d'une part, l'état de somnolence et d'autre part, le niveau de charge mentale d'un individu. Dans une première étude, la voix de participants a été enregistrée lors d'une tâche de lecture avant et après une nuit de privation totale de sommeil (PTS). Les variations de l'état de somnolence consécutives à la PTS ont été évaluées au moyen de mesures auto-évaluatives et électrophysiologiques (ÉlectroEncéphaloGraphie [EEG] et Potentiels Évoqués [PEs]). Les résultats ont montré une variation significative après la PTS de plusieurs paramètres acoustiques liés : (a) à l'amplitude des impulsions glottiques (fréquence de modulation d'amplitude), (b) à la forme du signal acoustique (longueur euclidienne du signal et ses caractéristiques associées) et (c) au spectre du signal des voyelles (rapport harmonique sur bruit, fréquence du second formant, coefficient d'asymétrie, centre de gravité spectral, différences d'énergie, pente spectrale et coefficients cepstraux à échelle Mel). La plupart des caractéristiques spectrales ont montré une sensibilité différente à la privation de sommeil en fonction du type de voyelles. Des corrélations significatives ont été mises en évidence entre plusieurs paramètres acoustiques et plusieurs indicateurs objectifs (EEG et PEs) de l'état de somnolence. Dans une seconde étude, le signal vocal a été enregistré durant une tâche de rappel de listes de mots. La difficulté de la tâche était manipulée en faisant varier le nombre de mots dans chaque liste (i.e., entre un et sept, correspondant à sept conditions de charge mentale). Le diamètre pupillaire - qui est un indicateur objectif pertinent du niveau de charge mentale - a été mesuré simultanément avec l'enregistrement de la voix afin d'attester de la variation du niveau de charge mentale durant la tâche expérimentale. Les résultats ont montré que des paramètres acoustiques classiques (fréquence fondamentale et son écart type, shimmer, nombre de périodes et rapport harmonique sur bruit) et originaux (fréquence de modulation d'amplitude et variations à court-terme de la longueur euclidienne du signal) ont été particulièrement sensibles aux variations de la charge mentale. Les variations de ces paramètres acoustiques étaient corrélées à celles du diamètre pupillaire. L'ensemble des résultats suggère que les paramètres acoustiques de la voix humaine identifiés lors des expérimentations pourraient représenter des indicateurs pertinents pour la détection de l'état de somnolence et du niveau de charge mentale d'un individu. Les résultats ouvrent de nombreuses perspectives de recherche et d'applications dans le domaine de la sécurité des transports, notamment dans le secteur aéronautique.Operational requirements of aircraft pilots may cause drowsiness and inadequate mental load levels (i.e., too low or too high) during flights. Sleep debts and circadian disruptions linked to various factors (e.g., long working periods, irregular work schedules, etc.) require pilots to challenge their biological limits. Moreover, pilots' mental workload exhibits strong fluctuations during flights: higher during critical phases (i.e., takeoff and landing), it becomes very low during cruising phases. When the mental load becomes too high or, conversely, too low, performance decreases and flight errors may manifest. Implementation of detection methods of drowsiness and mental load levels in near real time is a major challenge for monitoring and controlling flight activity. The aim of this thesis is therefore to determine if the human voice can serve to detect on one hand the drowsiness and on the other hand the mental load level of an individual. In a first study, the voice of participants was recorded during a reading task before and after a night of total sleep deprivation (TSD). Drowsiness variations linked to TSD were assessed using self-evaluative and electrophysiological measures (ElectroEncephaloGraphy [EEG] and Evoked Potentials [EPs]). Results showed significant variations after the TSD in many acoustic features related to: (a) the amplitude of the glottal pulses (amplitude modulation frequency), (b) the shape of the acoustic wave (Euclidean length of the signal and its associated features) and (3) the spectrum of the vowel signal (harmonic-to-noise ratio, second formant frequency, skewness, spectral center of gravity, energy differences, spectral tilt and Mel-frequency cepstral coefficients). Most spectral features showed different sensitivity to sleep deprivation depending on the vowel type. Significant correlations were found between several acoustic features and several objective indicators (EEG and PEs) of drowsiness. In a second study, voices were recorded during a task featuring word-list recall. The difficulty of the task was manipulated by varying the number of words in each list (i.e., between one and seven, corresponding to seven mental load conditions). Evoked pupillary response - known to be a useful proxy of mental load - was recorded simultaneously with speech to attest variations in mental load level during the experimental task. Results showed that classical features (fundamental frequency and its standard deviation, shimmer, number of periods and harmonic-to-noise ratio) and original features (amplitude modulation frequency and short-term variation in digital amplitude length) were particularly sensitive to variations in mental load. Variations in these acoustic features were correlated to those of the pupil size. Results suggest that the acoustic features of the human voice identified during these experiments could represent relevant indicators for the detection of drowsiness and mental load levels of an individual. Findings open up many research and applications perspectives in the field of transport safety, particularly in the aeronautical sector

An analysis of the noise schedule for score-based generative models

Score-based generative models (SGMs) aim at estimating a target data distribution by learning score functions using only noise-perturbed samples from the target. Recent literature has focused extensively on assessing the error between the target and estimated distributions, gauging the generative quality through the Kullback-Leibler (KL) divergence and Wasserstein distances. All existing results have been obtained so far for time-homogeneous speed of the noise schedule. Under mild assumptions on the data distribution, we establish an upper bound for the KL divergence between the target and the estimated distributions, explicitly depending on any time-dependent noise schedule. Assuming that the score is Lipschitz continuous, we provide an improved error bound in Wasserstein distance, taking advantage of favourable underlying contraction mechanisms. We also propose an algorithm to automatically tune the noise schedule using the proposed upper bound. We illustrate empirically the performance of the noise schedule optimization in comparison to standard choices in the literature

Relationship between PET metabolism and SEEG epileptogenicity in focal lesional epilepsy

International audiencePurpose: This study aims to evaluate the performance of 18 F-FDG PET for distinguishing the epileptogenic zone (EZ) from propagation and non-involved zones at brain area level, as defined using stereo-EEG, in patients with pharmacoresistant epilepsy due to malformations of cortical development (MCD). Additionally, we seek to determine the relationship between 18 F-FDG-PET data and post-surgical seizure outcome. Methods: Thirty-eight patients with MCD were explored with 18 F-FDG PET and stereo-EEG. We compared PET metabolism of each patient to a control-population of healthy subjects. Based on MRI and SEEG, we separated 4 distinct zones at individual level: lesional, epileptogenic non-lesional, propagation, and non-involved. Then, we analysed: 1) difference of PET metabolism within these four distinct zones; 2) performance of PET in defining the EZ within the SEEG-sampled areas; 3) relation between extension of PET hypometabolism and post-surgical seizure outcome. Results: We found: 1) a gradient of PET hypometabolism from non-involved to propagation, then to epileptogenic and lesional zones (p<0.001); 2) good performance of PET in defining the EZ (AUC of ROC curve = 0.82); 3) poorer post-surgical prognosis associated with PET hypometabolism extension beyond SEEG sampling (p=0.024). Conclusion: 18 F-FDG-PET has good accuracy in determining EZ in patients with MCD even if the hypometabolism is not limited to the EZ. Furthermore, hypometabolic extension is unfavourably associated with post-surgical prognosis