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The majority of university curricula for health professionals does not incorporate courses on human nutrition and its links with human and planetary health. This primarily applies to medical and pharmacy students, who have important counselling roles and are at the forefront of public health. To address this important issue, EIT Food recently launched an online course on nutrition, health, and sustainability. Learners were able to provide feedback on the course through an end-of-course survey and social interaction on the FutureLearn platform. The course was very well attended worldwide and received positive feedback from learners. A total of 3,858 students enrolled in the program, from >20 countries. Learners reported inadequate training on nutrition in their own curriculum and indicated they would use key insights from the course to inform their own practice. This report provides insights from the course, which could be used as guidance for future initiatives., This EIT Food activity has received funding from the European Institute of Innovation and Technology (EIT), a body of the European Union, under Horizon Europe, the EU Framework Programme for Research and Innovation.

Objectives: The KNee OsteoArthritis Prediction (KNOAP2020) challenge was organized to objectively compare methods for the prediction of incident symptomatic radiographic knee osteoarthritis within 78 months on a test set with blinded ground truth. Design: The challenge participants were free to use any available data sources to train their models. A test set of 423 knees from the Prevention of Knee Osteoarthritis in Overweight Females (PROOF) study consisting of magnetic resonance imaging (MRI) and X-ray image data along with clinical risk factors at baseline was made available to all challenge participants. The ground truth outcomes, i.e., which knees developed incident symptomatic radiographic knee osteoarthritis (according to the combined ACR criteria) within 78 months, were not provided to the participants. To assess the performance of the submitted models, we used the area under the receiver operating characteristic curve (ROCAUC) and balanced accuracy (BACC). Results: Seven teams submitted 23 entries in total. A majority of the algorithms were trained on data from the Osteoarthritis Initiative. The model with the highest ROCAUC (0.64 (95% confidence interval (CI): 0.57–0.70)) used deep learning to extract information from X-ray images combined with clinical variables. The model with the highest BACC (0.59 (95% CI: 0.52–0.65)) ensembled three different models that used automatically extracted X-ray and MRI features along with clinical variables. Conclusions: The KNOAP2020 challenge established a benchmark for predicting incident symptomatic radiographic knee osteoarthritis. Accurate prediction of incident symptomatic radiographic knee osteoarthritis is a complex and still unsolved problem requiring additional investigation.

Aim: There are two types of intestinal volvulus: midgut (MGV) and segmental (SV). Patients with different types of intestinal volvulus are often included in the same case series, which may affect the perception of how severe "intestinal volvuli" are. We aimed to compare both types of intestinal volvulus. Methods: This is a retrospective observational study including all patients with MGV and SV up to 28 days of life admitted to a tertiary hospital in Spain over a 20-year-period (1999-2019). A comparison between groups and a logistic regression model for mortality were done. Results: We identified 32 patients: 23 MGV and 9 SV. Malrotation was exclusive of MGV. Prenatal diagnosis, cystic fibrosis, and intestinal resection were significantly more frequent in SV. Surgery was performed at a significantly lower age in SV. The mortality observed in acute MGV with intestinal compromise (41.7%) is four times higher than the mortality of SV (11.1%). The overall mortality of all MGV patients (21.7%) is almost twice that of SV. Mortality was best predicted by the presence of hemodynamic instability (OR 27.5 95% CI 2.50-302.17; p = 0.007). Conclusion: SV and MGV have a different clinical presentation. Hemodynamic instability is the major risk factor for death.

Ingestión; Imanes; Urgencias de pediatría Ingestion; Magnets; Paediatric emergencies Ingestió; Imants; Urgències de pediatria Introduction The ingestion of magnetic objects can cause complications in children, and there are no epidemiological or clinical data on the subject in Spain. Objectives To determine the incidence, epidemiological characteristics and management of magnet ingestion in paediatric emergency departments in Spain. Material and methods Prospective observational multicentre study conducted over a 3-year period. The study universe consisted of patients aged less than 14 years. Results The incidence was 4.8 cases per 100 000 emergency care episodes. Of the 72 patients included (mean age, 7.2 years), 54% were male. Seven percent had neuropsychiatric disorders. Sixty-one percent of the magnets were spherical and 69% came from toys. The size was variable, most frequently between 5 and 10 mm (50%), and ranging from 3 to 30 mm. Eighty-six percent of patients were asymptomatic. The most frequent symptom was abdominal pain. Eighty-three percent of the patients sought medical care within 6 h of ingestion and 92% within 24 h. Thirty-one percent of the cases were of multiple ingestion. Endoscopy was required for extraction in 15% of cases, a proportion that rose to 36% in the group of cases of multiple ingestion. None of the patients required surgery. We did not observe any gastrointestinal complications of magnet ingestion. Conclusions The ingestion of multiple magnets is less frequent than single magnet ingestion, and we did not observe any complications despite the lower frequency of procedures compared to other studies. Introducción Las ingestas de objetos imantados pueden presentar complicaciones en el niño, no existiendo datos epidemiológicos ni clínicos en España. Objetivos Conocer la incidencia de ingesta de objetos imantados en los Servicios de Urgencias Pediátricos Españoles, sus características epidemiológicas y su manejo. Material y métodos Estudio observacional prospectivo multicéntrico realizado durante 3 años. Población de referencia menores de 14 años. Resultados La incidencia fue de 4,8/100.000 urgencias. De los 72 pacientes incluidos (edad media de 7,2 años), el 54% fueron varones. El 7% presentaron antecedentes neuropsiquiátricos. El 61% de los imanes fueron esféricos y el 69% procedían de juguetes. El tamaño fue variable con un predominio de los imanes entre 5 y 10 mm (50%). El 86% fueron asintomáticos. El síntoma más frecuente fue el dolor abdominal. El 83% de los pacientes consultaron en menos de 6 horas y el 92% en las primeras 24 horas. El 31% fueron ingestas múltiples. El 15% precisó intervención endoscópica, cifra que ascendió al 36% en los casos de ingestas múltiples. No se realizó ninguna intervención quirúrgica. No se observó ninguna complicación gastrointestinal secundaria. Conclusiones Las ingestas de imanes múltiples son menos frecuentes que las simples y en este estudio no se han observado complicaciones a pesar de que las intervenciones realizadas han sido menores que en otros estudios. The study was funded through the 2016 annual grant of the Research Network of the Sociedad Española de Urgencias de Pediatría (RiSEUP-SPERG), for an amount of euro4000.

ObjectiveTo evaluate trends in respiratory care practices and bronchopulmonary dysplasia (BPD) among very preterm infants born in Spain between 2010 and 2019.Study designThis was a retrospective cohort study of data obtained from a national population-based database (SEN1500 network). Changes in respiratory care and BPD-free survival of infants with gestational age (GA) of 230–316 weeks and ResultsA total of 17 952 infants were included. In the second period, infants were less frequently intubated in the delivery room and during neonatal intensive care unit stay. This corresponded with an increase in use of non-invasive ventilation techniques. There were no significant differences between the periods in BPD-free survival or survival without moderate-to-severe BPD. After adjusting for covariates, the RR for the change per year was significant for the following variables: never intubated (RR 1.03, 95% CI 1.02 to 1.04); intubation in the delivery room (RR 0.98, 95% CI 0.97 to 0.99); use of nasal intermittent positive pressure ventilation (RR 1.08, 95% CI 1.05 to 1.11); and BPD-free survival (only in the group with the lowest GA; RR 0.98, 95% CI 0.97 to 0.99).ConclusionOur findings reveal significant changes in respiratory care practices between 2009 and 2019. Despite an increase in use of non-invasive respiratory strategies, BPD-free survival did not improve and even worsened in the group with the lowest GA (230–256).

Autophagy is a process in which parts of the eukaryotic cell are selectively degraded in the lysosome. The materials to be catabolized are first surrounded by a double-membrane structure, the autophagosome. Autophagosome generation is a complex event, in which many proteins are involved. Among the latter, yeast Atg8 or its mammalian orthologues are essential in autophagosome membrane elongation, shaping and closure. A subfamily of the human Atg8 orthologues is formed by the proteins LC3A, LC3B, and LC3C. Previous studies suggest that, at variance with the other two, LC3C does not participate in cardiolipin-mediated mitophagy. The present study was devoted to exploring the binding of LC3C to lipid vesicles, bilayers and monolayers, and the ensuing protein-dependent perturbing effects, in the absence of the mitochondrial lipid cardiolipin. All Atg8 orthologues are covalently bound to a phospholipid prior to their involvement in autophagosome elongation. In our case, a mutant in the C-terminal amino acid, LC3C G126C, together with the use of a maleimide-derivatized phosphatidyl ethanolamine, ensured LC3C lipidation, up to 100% under certain conditions. Ultracentrifugation, surface pressure measurements, spectroscopic and cryo-electron microscopic techniques revealed that lipidated LC3C induced vesicle aggregation (5-fold faster in sonicated than in large unilamellar vesicles) and inter-vesicular lipid mixing (up to 82%), including inner-monolayer lipid mixing (up to 32%), consistent with in vitro partial vesicle fusion. LC3C was also able to cause the release of 80–90% vesicular aqueous contents. The data support the idea that LC3C would be able to help in autophagosome elongation/fusion in autophagy phenomena., This work was supported in part by the Spanish Ministerio de Ciencia e Innovación (MCI), Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) (grant No. PGC2018-099857-B-I00), by the Basque Government1 (grants No. IT1625-22 and IT1270-19), by Fundación Ramón Areces (CIVP20A6619), by Fundación Biofísica Bizkaia, and by the Basque Excellence Research Centre (BERC) program of the Basque Government. M.N.I. and Y.V. were recipients of pre-doctoral FPU fellowships from the Spanish Ministry of Science, Innovation and Universities (FPU16/05873, FPU18/00799). U.B. thanks the University of the Basque Country for a pre-doctoral contract. A.E. was a post-doctoral scientist supported by the Basque Government and by Ministerio de Ciencia e Innovación.

Purpose The composition of the subchondral bone marrow and cartilage endplate (CEP) could affect intervertebral disc health by influencing vertebral perfusion and nutrient diffusion. However, the relative contributions of these factors to disc degeneration in patients with chronic low back pain (cLBP) have not been quantified. The goal of this study was to use compositional biomarkers derived from quantitative MRI to establish how CEP composition (surrogate for permeability) and vertebral bone marrow fat fraction (BMFF, surrogate for perfusion) relate to disc degeneration. Methods MRI data from 60 patients with cLBP were included in this prospective observational study (28 female, 32 male; age = 40.0 ± 11.9 years, 19–65 [mean ± SD, min–max]). Ultra-short echo-time MRI was used to calculate CEP T2* relaxation times (reflecting biochemical composition), water-fat MRI was used to calculate vertebral BMFF, and T1ρ MRI was used to calculate T1ρ relaxation times in the nucleus pulposus (NP T1ρ, reflecting proteoglycan content and degenerative grade). Univariate linear regression was used to assess the independent effects of CEP T2* and vertebral BMFF on NP T1ρ. Mixed effects multivariable linear regression accounting for age, sex, and BMI was used to assess the combined relationship between variables. Results CEP T2* and vertebral BMFF were independently associated with NP T1ρ (p = 0.003 and 0.0001, respectively). After adjusting for age, sex, and BMI, NP T1ρ remained significantly associated with CEP T2* (p = 0.0001) but not vertebral BMFF (p = 0.43). Conclusion Poor CEP composition plays a significant role in disc degeneration severity and can affect disc health both with and without deficits in vertebral perfusion.

Introduction: Lung ultrasound (LUS) is useful for respiratory management in very preterm infants (VPI), but little is known about the echographic patterns in bronchopulmonary dysplasia (BPD), the relation between the image findings, and the severity of the disease and its long-term outcomes. We aimed to describe LUS patterns in BPD and analyze the accuracy of LUS to predict the need for respiratory support at 36 weeks postmenstrual age (PMA) in VPI. Methods: Preterm infants ≤30.6 weeks of gestational age were recruited. LUS was performed at admission, at 7th, and 28th day of life (DOL) with a standardized protocol (6 zones: anterior, lateral, and posterior fields). Clinical data, respiratory outcomes, and image findings were recorded. Results: Eighty-nine patients were studied. Infants with BPD had significantly higher LUS score at admission, at 7th, and 28th DOL. Patients with BPD exhibited more consolidations and pleural line abnormalities at 7th and 28th DOL than those without BPD (p < 0.001), regardless of the definition used for BPD. LUS at 7th DOL predicted NICHD 2001-BPD with R2 = 0.522; AUC = 0.87 (0.79–0.94), p < 0.001, and Jensen 2019-BPD with R2 = 0.315 (AUC = 0.80 [0.70–0.90], p < 0.001). A model including mechanical ventilation >5 days, oxygen therapy for 7 days and LUS score at 7th DOL accurately predicted the need for respiratory support at 36 weeks PMA (R2 = 0.655, p < 0.001) with an AUC = 0.90 (0.84–0.97), p < 0.001. Conclusion: LUS score, pleural line abnormalities, and consolidations can be useful to diagnose BPD in VPI and to predict its severity after the first week of life.

Many studies have validated cartilage thickness as a biomarker for knee osteoarthritis (OA); however, few studies investigate beyond cross-sectional observations or comparisons across two timepoints. By characterizing the trajectory of cartilage thickness changes over 8 years in healthy individuals from the OA initiative data set, this study discovers associations between the dynamics of cartilage changes and OA incidence. A fully automated cartilage segmentation and thickness measurement method were developed and validated against manual measurements: mean absolute error = 0.11-0.14 mm (n = 4129 knees) and automatic reproducibility = 0.04-0.07 mm (n = 316 knees). The mean thickness for the medial and lateral tibia (MT, LT), central weight-bearing medial and lateral femur (cMF, cLF), and patella (P) cartilage compartments were quantified for 1453 knees at seven timepoints. Trajectory subgroups were defined per cartilage compartment such as stable, thinning to thickening, accelerated thickening, plateaued thickening, thickening to thinning, accelerated thinning, or plateaued thinning. For tibiofemoral compartments, the stable (22%-36%) and plateaued thinning (22%-37%) trajectories were the most common, with an average initial velocity (μm/month), acceleration (μm/month2 ) for the plateaued thinning trajectories LT: -2.66, 0.0326; MT: -2.49, 0.0365; cMF: -3.51, 0.0509; and cLF: -2.68, 0.041. In the patella compartment, the plateaued thinning (35%) and thickening to thinning (24%) trajectories were the most common, with an average initial velocity, acceleration for each -4.17, 0.0424; 1.95, -0.0835. Knees with nonstable trajectories had higher adjusted odds of OA incidence than stable trajectories: accelerated thickening, accelerated thinning, and plateaued thinning trajectories of the MT had adjusted odds ratio (OR) of 18.9, 5.48, and 1.47, respectively; in the cMF, adjusted OR of 8.55, 10.1, and 2.61, respectively.

Background Birth before term is a stressful experience for parents because of the unexpected delivery or admission to the neonatal intensive care unit. Objective This research aimed to evaluate the impact of the early PT intervention on preterm infants' parents' experiences, and also to obtain knowledge about parents' experiences and perceived difficulties during preterm infants' care. Methods This qualitative study is based on the methods of phenomenology. In the first phase, open interviews were developed to allow researchers to immerse themselves in the context of the study and refine the questions for the semi-structured interviews. Data collected from the semi-structured interviews were analyzed through content analysis. Results The results were summarized around three themes: 1) parental competence; 2) difficulties during preterm infants' care; and 3) coping strategies. Each theme was divided into two sub-themes. Conclusion Mothers and fathers of preterm infants experienced difficulties when caring for their babies. Parents that received the early physiotherapy intervention felt empowered to take care of their babies and to enhance infants' development. These parents were more capable of developing coping strategies after the intervention. Parents that did not receive the early physiotherapy intervention expressed difficulties when caring for their preterm babies.

Background: Abnormal cholesterol metabolism changes the neuronal membrane and may promote amyloidogenesis. Oxysterols in cerebrospinal fluid (CSF) are related to Alzheimer's disease (AD) biomarkers in mild cognitive impairment and dementia. Cholesterol turnover is important for axonal and white matter (WM) microstructure maintenance. Objective: We aim to demonstrate that the association of oxysterols, AD biomarkers, and WM microstructure occurs early in asymptomatic individuals. Methods: We studied the association of inter-individual variability of CSF 24-hydroxycholesterol (24-OHC), 27-hydroxycholesterol (27-OHC), 7-ketocholesterol (7-KC), 7 beta-hydroxycholesterol (7 beta-OHC), amyloid-beta(42) (A beta(42)), total-tau (t-tau), phosphorylated-tau (p-tau), neurofilament (NfL), and WM microstructure using diffusion tensor imaging, generalized linear models and moderation/mediation analyses in 153 healthy adults. Results: Higher 7-KC levels were related to lower A beta(42), indicative of greater AD pathology (p = 0.041). Higher 7-KC levels were related to lower fractional anisotropy (FA) and higher mean (MD), axial (AxD), and radial (RD) diffusivity. 7-KC modulated the association between AxD and NfL in the corpus callosum splenium (B = 39.39, p = 0.017), genu (B = 68.64, p = 0.000), and fornix (B = 10.97, p = 0.000). Lower A beta(42) levels were associated to lower FA and higher MD, AxD, and RD in the fornix, corpus callosum, inferior longitudinal fasciculus, and hippocampus. The association between AxD and A beta(42) was moderated by 7K-C (p = 0.048). Conclusion: This study adds clinical evidence to support the role of 7K-C on axonal integrity and the involvement of cholesterol metabolism in the A beta(42) generation process.

Introduction: Extreme prematurity is associated with high mortality rates. The probability of death at different points in time is a priority for professionals and parents, and needs to be established on an individual basis. The aim of this study is to carry out a systematic review of predictive models of mortality in premature infants that have been published recently. Methods: A double search was performed for article published in PubMed on models predicting mortality in premature neonates. The population studied were premature neonates with a gestational age of ≤30 weeks and/or a weight at birth of ≤1500 g. Works published with new models from June 2010 to July 2019 after a systematic review by Medlock (2011) were included. An assessment was made of the population, characteristics of the model, variables used, measurements of functioning, and validation. Results: Of the 7744 references (1st search) and 1435 (2nd search) found, 31 works were selected, with 8 new models finally being included. Five models (62.5%) were developed in North America and 2 (25%) in Europe. A sequential model (Ambalavanan) enables predictions of mortality to be made at birth, 7, 28 days of life, and 36 weeks post-menstrual. A multiple logistic regression analysis was performed on 87.5% of the models. The population discrimination was measured using odds ratio (75%) and the area under the curve (50%). “internal validation” had been carried out on 5 models. Three models can be accessed on-line. There are no predictive models validated in Spain. Conclusions: The making of decisions based on predictive models can lead to the care given to the premature infant being more individualised and with a better use of resources. Predictive models of mortality in premature neonates in Spain need to be developed. Resumen: Introducción: La prematuridad extrema se asocia a altas tasas de mortalidad. Para profesionales y familias, es prioritario establecer de forma individualizada las probabilidades de muerte en diferentes momentos. El objetivo de este estudio es efectuar una revisión sistemática de modelos predictivos de mortalidad en prematuros publicados recientemente. Métodos: Doble búsqueda de artículos publicados en PubMed sobre modelos predictivos de muerte en prematuros. Población estudiada: prematuros con edad gestacional ≤30 semanas o peso al nacer ≤1.500 g. Inclusión: trabajos publicados con nuevos modelos desde junio del 2010 hasta julio del 2019, tras revisión sistemática de Medlock (2011). Se valoran: población, características de modelos, variables utilizadas, medidas de funcionamiento y validación. Resultados: De 7.744 referencias (primera búsqueda) y 1.435 (segunda búsqueda), se seleccionaron 31 trabajos, incluyéndose al final 8 nuevos modelos. Cinco modelos (62,5%) se desarrollaron en América del Norte y 2 (25%) en Europa. Un modelo secuencial (Ambalavanan) permite realizar predicciones de muerte al nacer, 7, 28 días de vida y 36 semanas posmenstruales. Análisis de regresión logística múltiple en el 87,5% de modelos. La discriminación poblacional se midió por odds ratio (75%) y área bajo la curva (50%). La «validación» se ha realizado en 5 modelos (interna). Tres modelos disponen de acceso online. No hay modelos predictivos validados en España. Conclusiones: La toma de decisiones basada en modelos predictivos permite una mayor individualización de la atención dada a un niño prematuro y una mejor utilización de recursos. Es necesario desarrollar modelos de predicción de mortalidad en prematuros de España.

Mobilization regimes in pediatric patients at high risk for poor mobilization are not standardized across different institutions. We present a retrospective analysis of our experience with a high-dose granulocyte colony-stimulating factor (G-CSF) regime of 12 μg/Kg per body weight (BW) twice a day for 4 days used in high-risk patients.We report the results of all pediatric patients mobilized with high-dose G-CSF between January 1999 and February 2021 in our center. A successful mobilization was defined as a peripheral blood (PB) CD34Of the 262 patients included in the analysis, mobilization failure was found in 27 (10.3%). In a univariate analysis, this was associated with age, weight, baseline diagnosis, and having undergone a previous mobilization cycle, the latter being the only factor that remained significantly associated in a multivariate analysis (P = 0.03). The 54 patients (20.6%) did not reach the minimum required CD34Although most high-risk pediatric patients are successfully mobilized with the high-dose G-CSF regime, this approach does not salvage all of them and significantly increases the presence of AEs in comparison to standard-dose regimes.

Importance: One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design.Objective: To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates.Design, Setting, and Participants: This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria.Exposures: Alzheimer disease biomarkers detected on PET or in CSF.Main Outcomes and Measures: Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations.Results: Among the 19 097 participants (mean [SD] age, 69.1 [9.8] years; 10 148 women [53.1%]) included, 10 139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P = .04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P = .004), subjective cognitive decline (9%; 95% CI, 3%-15%; P = .005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P = .004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P = .18).Conclusions and Relevance: This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.

The objective of this paper is to analyze the association between the job placement results of graduates and the satisfaction that, retrospectively, they express about their university education. Despite the fact that, in Spain, 47.0% of the population aged 25 to 34 has a higher education degree, we have little knowledge of the determinants of university student satisfaction. In addition, most studies have focused on evaluating the university experience (teaching activity, study plans, counselling for students, or facilities) and very few of them have taken into account the influence of graduates’ labour market outcomes on their satisfaction. This issue is of particular interest in the Spanish case, considering the dysfunctional nature of the youth labor market, which has high rates of overqualification, excessive job turnover and high unemployment. The sources of statistical information used in this work include the first two editions of the "University Graduate Job Placement Survey", carried out by the Spanish National Institute of Statistics (INE) in 2014 and 2019. The methodology used in the empirical work is the propensity score matching estimator. The results of empirical analysis indicate that graduates’ job placement difficulties have a significant association with their dissatisfaction with their university experience. In particular, educational mismatch (horizontal and vertical) and, to a lesser extent, unemployment and low wages significantly increase the probability of graduates stating that, if they had to start over, they would not return to university or they would not study the same degree.

This article belongs to the Special Issue Coffee and Caffeine Consumption for Human Health., Coffee is one of the most popular beverages consumed worldwide. Roasted coffee is a complex mixture of thousands of bioactive compounds, and some of them have numerous potential health-promoting properties that have been extensively studied in the cardiovascular and central nervous systems, with relatively much less attention given to other body systems, such as the gastrointestinal tract and its particular connection with the brain, known as the brain–gut axis. This narrative review provides an overview of the effect of coffee brew; its by-products; and its components on the gastrointestinal mucosa (mainly involved in permeability, secretion, and proliferation), the neural and non-neural components of the gut wall responsible for its motor function, and the brain–gut axis. Despite in vitro, in vivo, and epidemiological studies having shown that coffee may exert multiple effects on the digestive tract, including antioxidant, anti-inflammatory, and antiproliferative effects on the mucosa, and pro-motility effects on the external muscle layers, much is still surprisingly unknown. Further studies are needed to understand the mechanisms of action of certain health-promoting properties of coffee on the gastrointestinal tract and to transfer this knowledge to the industry to develop functional foods to improve the gastrointestinal and brain–gut axis health., The project “Nuevos conocimientos para la sostenibilidad del sector cafetero” was funded by Consejo Superior de Investigaciones Científicas (CSIC) (201970E117); “Generación de nuevos ingredientes y alimentos beneficiosos dirigidos a condiciones de riesgo y al bienestar global de personas con cáncer colorrectal (TERÁTROFO, IDI-20190960)” and “Novel coffee by-product beverages for an optimal health of the brain-gut axis (COFFEE4BGA)” were funded by the Ministerio de Ciencia e Innovación (PID2019-111510RB-I00).

This review was written on behalf of the Iberoamerican AGE Group., The present review aims to give dietary recommendations to reduce the occurrence of the Maillard reaction in foods and in vivo to reduce the body’s advanced glycation/lipoxidation end products (AGE/ALE) pool. A healthy diet, food reformulation and good culinary practices may be feasible for achieving the goal. A varied diet rich in fresh vegetables and fruits, non-added sugar beverages containing inhibitors of the Maillard reaction, and foods prepared by steaming and poaching as culinary techniques is recommended. Intake of supplements and novel foods with low sugars, low fats, enriched in bioactive compounds from food and waste able to modulate carbohydrate metabolism and reduce body’s AGE/ALE pool is also recommended. In conclusion, the recommendations made for healthy eating by the Spanish Society of Community Nutrition (SENC) and Harvard University seem to be adequate to reduce dietary AGE/ALE, the body’s AGE/ALE pool and to achieve sustainable nutrition and health., The SUSCOFFEE (AGL 2014-57239-R) and ALIBIRD-CM (S2013/ABI-2728) projects funded the present review. The project ‘Nuevos conocimientos para la sostenibilidad del sector cafetero’ funded by CSIC (201970E117) also funded the present review.

Externalization of the phospholipid cardiolipin (CL) to the outer mitochondrial membrane has been proposed to act as a mitophagy trigger. CL would act as a signal for binding the LC3 macroautophagy/autophagy proteins. As yet, the behavior of the LC3-subfamily members has not been directly compared in a detailed way. In the present contribution, an analysis of LC3A, LC3B and LC3C interaction with CL-containing model membranes, and of their ability to translocate to mitochondria, is described. Binding of LC3A to CL was stronger than that of LC3B; both proteins showed a similar ability to colocalize with mitochondria upon induction of CL externalization in SH-SY5Y cells. Besides, the double silencing of LC3A and LC3B proteins was seen to decrease CCCP-induced mitophagy. Residues 14 and 18 located in the N-terminal region of LC3A were shown to be important for its recognition of damaged mitochondria during rotenone- or CCCP-induced mitophagy. Moreover, the in vitro results suggested a possible role of LC3A, but not of LC3B, in oxidized-CL recognition as a counterweight to excessive apoptosis activation. In the case of LC3C, even if this protein showed a stronger CL binding than LC3B or LC3A, the interaction was less specific, and colocalization of LC3C with mitochondria was not rotenone dependent. These results suggest that, at variance with LC3A, LC3C does not participate in cargo recognition during CL-mediated-mitophagy. The data support the notion that the various LC3-subfamily members might play different roles during autophagy initiation, identifying LC3A as a novel stakeholder in CL-mediated mitophagy., This work was supported in part by the Spanish Ministerio de Ciencia e Innovación (MCI), Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) (grant No. PGC2018-099857-B-I00), by the Basque Government (grants No. IT1625-22 and IT1270-19), by Fundación Ramón Areces (CIVP20A6619), by Fundación Biofísica Bizkaia and by the Basque Excellence Research Centre (BERC) program of the Basque Government. MI and YV were recipients of predoctoral FPU fellowships from the Spanish Ministry of Science Innovation and Universities (FPU16/05873, FPU18/00799), UB thanks the University of the Basque Country for a predoctoral contract, JHH was supported by a Postdoctoral Fellowship from the Basque Government.

This article belongs to the Special Issue Role of Nutraceuticals in Metabolic and Gastrointestinal Disorders., Cannabis sativa is an aromatic annual flowering plant with several botanical varieties, used for different purposes, like the production of fibers, the production of oil from the seeds, and especially for recreational or medical purposes. Phytocannabinoids (terpenophenolic compounds derived from the plant), include the well-known psychoactive cannabinoid Δ9 -tetrahydrocannabinol, and many non-psychoactive cannabinoids, like cannabidiol. The endocannabinoid system (ECS) comprises of endocannabinoid ligands, enzymes for synthesis and degradation of such ligands, and receptors. This system is widely distributed in the gastrointestinal tract, where phytocannabinoids exert potent effects, particularly under pathological (i.e., inflammatory) conditions. Herein, we will first look at the hemp plant as a possible source of new functional food ingredients and nutraceuticals that might be eventually useful to treat or even prevent gastrointestinal conditions. Subsequently, we will briefly describe the ECS and the general pharmacology of phytocannabinoids. Finally, we will revise the available data showing that non-psychoactive phytocannabinoids, particularly cannabidiol, may be useful to treat different disorders and diseases of the gastrointestinal tract. With the increasing interest in the development of functional foods for a healthy life, the non-psychoactive phytocannabinoids are hoped to find a place as nutraceuticals and food ingredients also for a healthy gastrointestinal tract function., This research was funded by CSIC, 201970E117.

Knee pain is the most common and debilitating symptom of knee osteoarthritis (OA). While there is a perceived association between OA imaging biomarkers and pain, there are weak or conflicting findings for this relationship. This study uses Deep Learning (DL) models to elucidate associations between bone shape, cartilage thickness and T2 relaxation times extracted from Magnetic Resonance Images (MRI) and chronic knee pain. Class Activation Maps (Grad-CAM) applied on the trained chronic pain DL models are used to evaluate the locations of features associated with presence and absence of pain. For the cartilage thickness biomarker, the presence of features sensitive for pain presence were generally located in the medial side, while the features specific for pain absence were generally located in the anterior lateral side. This suggests that the association of cartilage thickness and pain varies, requiring a more personalized averaging strategy. We propose a novel DL-guided definition for cartilage thickness spatial averaging based on Grad-CAM weights. We showed a significant improvement modeling chronic knee pain with the inclusion of the novel biomarker definition: likelihood ratio test p-values of 7.01 × 10–33 and 1.93 × 10–14 for DL-guided cartilage thickness averaging for the femur and tibia, respectively, compared to the cartilage thickness compartment averaging.

OCCUPATIONAL APPLICATIONS Worker well-being and overall system performance are important elements in the design of production lines. However, studies of industry practice show that current design tools are unable to consider concurrently both productivity aspects (e.g., line balancing and cycle time) and worker well-being related aspects (e.g., the risk of musculoskeletal disorders). Current practice also fails to account for anthropometric diversity in the workforce and does not use the potential of multi-objective simulation-based optimization techniques. Accordingly, a framework consisting of a workflow and a digital tool was designed to assist in the proactive design of workstations to accommodate worker well-being and productivity. This framework uses state-of-the-art optimization techniques to make it easier and quicker for designers to find successful workplace design solutions. A case study to demonstrate the framework is provided TECHNICAL ABSTRACT Rationale: Simulation technologies are used widely in industry as they enable efficient creation, testing, and optimization of the design of products and production systems in virtual worlds. Simulations of productivity and ergonomics help companies to find optimized solutions that maintain profitability, output, quality, and worker well-being. However, these two types of simulations are typically carried out using separate tools, by persons with different roles, with different objectives. Silo effects can result, leading to slow development processes and suboptimal solutions. Purpose: This research is related to the realization of a framework that enables the concurrent optimization of worker well-being and productivity. The framework demonstrates how digital human modeling can contribute to Ergonomics 4.0 and support a human factors centered approach in Industry 4.0. The framework also facilitates consideration of anthropometric diversity in the user group. Methods: Design and creation methodology was used to create a framework that was applied to a case study, formulated together with industry partners, to demonstrate the functionality of the noted framework. Results: The framework workflow has three parts: (1) Problem definition and creation of the optimization model; (2) Optimization process; and (3) Presentation and selection of results. The case study shows how the framework was used to find a workstation design optimized for both productivity and worker well-being for a diverse group of workers. Conclusions: The framework presented allows for multi-objective optimizations of both worker well-being and productivity and was successfully applied in a welding gun use case. CC BY 4.0CONTACT Aitor Iriondo Pascual aitor.iriondo.pascual@his.sePublished online: 09 Nov 2021This work has received support from ITEA3/Vinnova in the project Modular Simulation of Natural Human Motions (MOSIM), and from the Knowledge Foundation and the associated INFINIT research environment at the University of Skövde, within the Virtual Factories–Knowledge-Driven Optimization (VF-KDO) research profile and the Synergy Virtual Ergonomics (SVE) project, and from the participating organizations. This support is gratefully acknowledged.10.1080/24725838.2021.1997834

The spine is an articulated, 3D structure with 6 degrees of translational and rotational freedom. Clinical studies have shown spinal deformities are associated with pain and functional disability in both adult and pediatric populations. Clinical decision making relies on accurate characterization of the spinal deformity and monitoring of its progression over time. However, Cobb angle measurements are time-consuming, are limited by interobserver variability, and represent a simplified 2D view of a 3D structure. Instead, spine deformities can be described by 3D shape parameters, addressing the limitations of current measurement methods. To this end, we develop and validate a deep learning algorithm to automatically extract the vertebral midline (from the upper endplate of S1 to the lower endplate of C7) for frontal and lateral radiographs. Our results demonstrate robust performance across datasets and patient populations. Approximations of 3D spines are reconstructed from the unit normalized midline curves of 20,118 pairs of full spine radiographs belonging to 15,378 patients acquired at our institution between 2008 and 2020. The resulting 3D dataset is used to describe global imbalance parameters in the patient population and to build a statistical shape model to describe global spine shape variations in preoperative deformity patients via eight interpretable shape parameters. The developed method can identify patient subgroups with similar shape characteristics without relying on an existing shape classification system.

Hematogenous metastasis is initiated by a subset of circulating tumor cells (CTC) shed from primary or metastatic tumors into the blood circulation. Thus, CTCs provide a unique patient biopsy resource to decipher the cellular subpopulations that initiate metastasis and their molecular properties. However, one crucial question is whether CTCs derived and expanded ex vivo from patients recapitulate human metastatic disease in an animal model. Here, we show that CTC lines established from patients with breast cancer are capable of generating metastases in mice with a pattern recapitulating most major organs from corresponding patients. Genome-wide sequencing analyses of metastatic variants identified semaphorin 4D as a regulator of tumor cell transmigration through the blood–brain barrier and MYC as a crucial regulator for the adaptation of disseminated tumor cells to the activated brain microenvironment. These data provide the direct experimental evidence of the promising role of CTCs as a prognostic factor for site-specific metastasis. Significance: Interests abound in gaining new knowledge of the physiopathology of brain metastasis. In a direct metastatic tropism analysis, we demonstrated that ex vivo–cultured CTCs from 4 patients with breast cancer showed organotropism, revealing molecular features that allow a subset of CTCs to enter and grow in the brain. This article is highlighted in the In This Issue feature, p. 1

Introduction: Pulmonary atresia with intact ventricular septum and critical pulmonary stenosis in newborns encompasses a wide spectrum of disease, including cases with significant right ventricular hypoplasia and coronary artery to right ventricle fistulae, which may be considered a contraindication for decompression of the right ventricle. The aim of this study was to review the middle- and long-term outcomes of these patients over 20 years and identify differential factors between both groups, including patients with coronary artery fistulae. Patients and methods: We performed a descriptive retrospective study by identifying all patients that received a diagnosis of pulmonary atresia with intact ventricular septum and critical pulmonary stenosis between January 1996 and January 2018. We collected and analysed data regarding right ventricular morphology, surgical management, percutaneous intervention and medium- and long-term outcomes. Results: 51 patients were admitted. A total of 9 patients (17.6%) died during the followup. None of the deceased patients had coronary artery to right ventricle fistulae. The median length of followup in the 42 survivors was 107.81 months (±53.56).The functional class based on the latest revision of the New York Heart Association classification was 1.2 for the overall sample. Survivors of critical pulmonary stenosis had a functional class of 1.1, and survivors of pulmonary atresia with intact ventricular septum a functional class of 1.6. There were no differences based on the presence or absence of coronary artery to right ventricle fistulae. Conclusions: Coronary artery to right ventricle fistulae may not be a contraindication for biventricular strategy. Patients with critical pulmonary stenosis had better outcomes compared to patients with pulmonary atresia with intact ventricular septum. The aggressive strategy of opening the pulmonary valve early on was associated with a good overall survival and correlated to a good functional class. Resumen: Introducción: Los neonatos afectos de atresia pulmonar con tabique interventricular íntegro y estenosis pulmonar crítica representan un espectro amplio, incluyendo aquellos con hipoplasia significativa del ventrículo derecho. La presencia de fístulas arteriales coronarias a ventrículo derecho puede ser una contraindicación para la descompresión del ventrículo derecho. El principal objetivo del presente trabajo es analizar los resultados a corto y largo plazo durante 20 años de estos pacientes, e identificar los factores diferenciales entre ambos grupos incluyendo aquellos pacientes afectos por fístulas arteriales coronarias. Pacientes y métodos: Este un estudio retrospectivo donde se identificaron todos los pacientes diagnosticados de atresia pulmonar con septo interventricular íntegro y estenosis pulmonar crítica entre los meses de enero de 1996 y enero de 2018. Se recogieron y analizaron las características morfológicas del ventrículo derecho, el manejo quirúrgico, la intervención percutánea y la evolución a corto y a largo plazo. Resultados: Cincuenta y un pacientes fueron incluidos. Un total de 9 (17,6%) fallecieron durante el seguimiento. Ninguno de ellos presentaba fístulas arteriales coronarias a ventrículo derecho. La media de seguimiento de los restantes 42 supervivientes fue de 107,81 meses (±53,56).La clase funcional según la New York Heart Association en la revisión más reciente fue de 1,2. Los supervivientes del grupo de estenosis pulmonar crítica presentaban una clase funcional de 1,1 y los del grupo de atresia pulmonar con tabique interventricular íntegro de 1,6. No hubo diferencias entre los pacientes que presentaban fístulas arteriales coronarias a ventrículo derecho y los que no. Conclusiones: La presencia de fístulas arteriales coronarias a ventrículo derecho no es una contraindicación para la vía biventricular. Los pacientes con estenosis pulmonar crítica presentan una mejor evolución que los afectos de atresia pulmonar con tabique interventricular íntegro. La estrategia de apertura agresiva y precoz de la válvula pulmonar tiene una buena supervivencia global correlacionada con una buena clase funcional.

Objective: This paper describes the results of testing a multi-component psychological therapy that includes integrated psychological therapy (IPT), together with an adaptation of emotional managem...

The cerebrospinal fluid (CSF) lipidome is attracting increasing attention due to the importance of lipids in brain molecular signaling and their involvement in several neurological diseases. Different solvent systems have been used for the extraction of multiple lipid classes from CSF but no comparative study of the effectiveness of these protocols has been carried out. To optimize CSF lipid extraction for lipidomic measurements by untargeted ultra-high performance liquid chromatography - mass spectrometry, we evaluate and compare two sample preparation protocols, one involving protein precipitation with isopropanol (IPA) and other consisting of a liquid-liquid extraction with chloroform-methanol. For that purpose, human CSF from neurologically healthy and normolipidemic volunteers was used. The criteria established to compare these two methods were based on four critical aspects of sample preparation: simplicity, lipid coverage, reproducibility and recovery efficiencies. We found that both methods were highly reproducible techniques (>75% of the lipids with coefficient of variation (CV)

The efficacy and safety of the rapid intravenous rehydration (RIR) guidelines in children affected by dehydration secondary to acute gastroenteritis is supported by current scientific evidence, but there is also great variability in its use in clinical practice.To prepare a document with evidence-based recommendations about RIR in paediatric population.The project was developed based on GRADE methodology, according to the following work schedule: Working Group training; creation of a catalogue of questions about research and definition of «relevant outcomes»; score and selection criteria for each item; bibliographic review; scientific evidence evaluation and synthesis (GRADE); review, discussion and creation of recommendations. 10 clinical questions and 15 relevant outcomes were created (7 about efficacy and 8 about security).Sixteen recommendations were set up, from which we can highlight as the main ones: (1) RIR is safe for children affected by mild-moderate dehydration secondary to acute gastroenteritis, unless expressly contraindicated or acute severe comorbidity (strong recommendation and moderate evidence). (2) Its use is recommended in this situation when oral rehydration has failed or due to contraindication (strong and high). (3) Isotonic fluids are recommended (strong and high), suggesting saline fluid as the first option (light and low), supplemented by glucose (2.5%) in those patients showing normoglycemia and ketosis (strong and moderate). (4) A rhythm of 20 cc/kg/h is recommended (strong and high) during 1-4 h (strong and moderate).This document establishes consensus recommendations, based on the available scientific evidence, which could contribute to the standardisation of the use of RIR in our setting.

This research examines the form in which undergraduates use video cameras during videoconferencing class sessions in a Smart Classroom context and, more specifically, the reasons why a considerable number of students opt to turn off their cameras when videoconferencing during the sessions while others keep them on. The study was carried out in an institution that had previously switched from face-to-face teaching to an Emergency Remote Teaching solution, initially adopted in 2019–2020 to cope with the COVID-19 pandemic restrictions. Findings suggest that using cameras when videoconferencing is associated with increasing and enhancing the interaction between the student and the rest of the class, although not all students agreed with this conclusion. In addition, having the video cameras switched fomented socialization and improved the overall online learning experience for students. However, the surveyed students pointed out diverse negative elements, such as why they had to turn on their personal cameras, privacy concerns, and limitations derived from the available technology infrastructure, in addition to other factors such as distractions, anxiety, and cognitive load. This work discusses how these elements can influence the well-being and the user experience of the students, both positively and negatively.

The improvement of the nutritional quality of dairy foods has become a key strategy for reducing the risk of developing diet-related non-communicable diseases. In this context, we aimed to optimize the concentration of inulin in combination with 10 mg/mL of coffee-cascara extract in yogurt while considering their effect on appetite control, gastrointestinal wellbeing, and their effect on the sensory and technological properties of the product. For this purpose, we tested four coffee-cascara yogurt treatments in a blind cross-over nutritional trial with 45 healthy adults: a coffee-cascara yogurt without inulin (Y0) and coffee-cascara yogurts containing 3% (Y3), 7% (Y7), and 13% (Y13) of inulin. The ratings on sensory acceptance, satiety, gastrointestinal tolerance, and stool frequency were measured. Surveys were carried out digitally in each participant&rsquo, s cellphone. Yogurt pH, titratable acidity, syneresis, and instrumental texture were analyzed. Inulin addition increased the yogurt&rsquo, s firmness and consistency. Y13 achieved significantly higher overall acceptance, texture, and taste scores than Y0 (p &lt, 0.05). Y3 presented similar gastrointestinal tolerance to Y0. However, 7% and 13% of inulin produced significant (p &lt, 0.05) bloating and flatulence when compared to Y0. The appetite ratings were not significantly affected by the acute intake of the different yogurts. Overall, Y3 was identified as the formulation that maximized nutritional wellbeing, reaching a &ldquo, source of fiber&rdquo, nutritional claim, without compromising its technological and sensory properties.

AIM: To develop and validate a feasible predictive model for early surfactant treatment in very preterm infants (VPI) admitted with respiratory distress syndrome (RDS). METHODS: Preterm infants less than 32 weeks of gestation with RDS and stabilized with noninvasive ventilation in delivery room were recruited (January 2018-April 2020). Clinical data, chest X-ray (CXR) score, respiratory support, oxygen saturation/fraction of inspired oxygen ratio (SF ratio), lung ultrasound (LUS) score, and diaphragmatic thickening fraction (DTF) were recorded at 60-120 min of life. Oxygen threshold for surfactant administration was fraction of inspired oxygen more than 30%; ultrasound findings were blinded. Logistic regression models using a stepwise selection of variables were developed in the derivation cohort. Coefficients from these models were applied to the validation cohort and a diagnostic performance was calculated. RESULTS: A total of 144 VPI with a mean gestational age of 28.7 ± 2.2 weeks were included (94 into the derivation cohort, 50 into the validation cohort); 37 required surfactant treatment (25.7%). Gestational age, SF ratio, LUS score, CXR score, and Silverman score were related to surfactant administration (R(2) = .823). Predictors included in the final model for surfactant administration were SF ratio and LUS score (R(2) = .783) with an area under the receiver operating characteristic (AUC) = 0.97 (95% confidence interval [CI]: 0.93-1.00) in the derivation cohort and an AUC = 0.95 (95% CI: 0.85-0.99) in the validation cohort. By applying our predictive model, 26 patients (70.2%) would have been treated with surfactant earlier than 2 h of life. CONCLUSION: The predictive model showed a high diagnostic performance and could be of value to optimize early respiratory management in VPI with RDS.

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 middle-income 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

Circulating tumor cells (CTC) can be isolated via a minimally invasive blood draw and are considered a “liquid biopsy” of their originating solid tumors. CTCs contain a small subset of metastatic precursors that can form metastases in secondary organs and provide a resource to identify mechanisms underlying metastasis-initiating properties. Despite technological advancements that allow for highly sensitive approaches of detection and isolation, CTCs are very rare and often present as single cells, posing an extreme challenge for ex vivo expansion after isolation. Here, using previously established patient-derived CTC lines, we performed a small-molecule drug screen to identify compounds that can improve ex vivo culture efficiency for single CTCs. We found that N-acetyl-L-cysteine (NAC) and other antioxidants can promote ex vivo expansion of single CTCs, by reducing oxidative and other stress particularly at the initial stage of single-cell expansion. RNA-seq analysis of growing clones and nongrowing clones confirmed the effect by NAC, but also indicates that NAC-induced decrease in oxidative stress is insufficient for promoting proliferation of a subset of cells with predominant senescent features. Despite the challenge in expanding all CTCs, NAC treatment led to establishment of single CTC clones that have similar tumorigenic features. Implications: Through a small molecule screen and validation study, we found that NAC could improve the success of ex vivo expansion of single CTCs by mitigating the initial stress, with the potential to facilitate the investigation of functional heterogeneity in CTCs.

Objective To compare length of stay (LOS) in neonatal care for babies born extremely preterm admitted to networks participating in the International Network for Evaluating Outcomes of Neonates (iNeo). Study design Data were extracted for babies admitted from 2014 to 2016 and born at 24 to 28 weeks of gestational age (n = 28 204). Median LOS was calculated for each network for babies who survived and those who died while in neonatal care. A linear regression model was used to investigate differences in LOS between networks after adjusting for gestational age, birth weight z score, sex, and multiplicity. A sensitivity analysis was conducted for babies who were discharged home directly. Results Observed median LOS for babies who survived was longest in Japan (107 days); this result persisted after adjustment (20.7 days more than reference, 95% CI 19.3-22.1). Finland had the shortest adjusted LOS (−4.8 days less than reference, 95% CI –7.3 to −2.3). For each week's increase in gestational age at birth, LOS decreased by 12.1 days (95% CI –12.3 to −11.9). Multiplicity and male sex predicted mean increases in LOS of 2.6 (95% CI 2.0-3.2) and 2.1 (95% CI 1.6-2.6) days, respectively. Conclusions We identified between-network differences in LOS of up to 3 weeks for babies born extremely preterm. Some of these may be partly explained by differences in mortality, but unexplained variations also may be related to differences in clinical care practices and healthcare systems between countries.

Dislipidemia is a risk factor for cognitive impairment. We studied the association between interindividual variability of plasma lipids and white matter (WM) microstructure, using diffusion tensor imaging (DTI) in 273 healthy adults. Special focus was placed on 7 regions of interest (ROI) which are structural components of cognitive neurocircuitry. We also investigated the effect of plasma lipids on cerebrospinal fluid (CSF) neurofilament light chain (NfL), an axonal degeneration marker. Low density lipoprotein (LDL) and triglyceride (TG) levels showed a negative association with axial diffusivity (AxD) in multiple regions. High density lipoproteins (HDL) showed a positive correlation. The association was independent of Apolipoprotein E (APOE) genotype, blood pressure or use of statins. LDL moderated the relation between NfL and AxD in the body of the corpus callosum (p = 0.041), right cingulum gyrus (p = 0.041), right fornix/stria terminalis (p = 0.025) and right superior longitudinal fasciculus (p = 0.020) and TG in the right inferior longitudinal fasciculus (p = 0.004) and left fornix/stria terminalis (p = 0.001). We conclude that plasma lipids are associated to WM microstructural changes and axonal degeneration and might represent a risk factor in the transition from healthy aging to disease.

While the central nervous system is considered an immunoprivileged site and brain tumors display immunosuppressive features, both innate and adaptive immune responses affect glioblastoma (GBM) growth and treatment resistance. However, the impact of the major immune cell population in gliomas, represented by glioma‐associated microglia/macrophages (GAMs), on patients’ clinical course is still unclear. Thus, we aimed at assessing the immunohistochemical expression of selected microglia and macrophage markers in 344 gliomas (including gliomas from WHO grade I–IV). Furthermore, we analyzed a cohort of 241 IDH1R132H‐non‐mutant GBM patients for association of GAM subtypes and patient overall survival. Phenotypical properties of GAMs, isolated from high‐grade astrocytomas by CD11b‐based magnetic cell sorting, were analyzed by immunocytochemistry, mRNA microarray, qRT‐PCR and bioinformatic analyses. A higher amount of CD68‐, CD163‐ and CD206‐positive GAMs in the vital tumor core was associated with beneficial patient survival. The mRNA expression profile of GAMs displayed an upregulation of factors that are considered as pro‐inflammatory M1 (eg, CCL2, CCL3L3, CCL4, PTGS2) and anti‐inflammatory M2 polarization markers (eg, MRC1, LGMN, CD163, IL10, MSR1), the latter rather being associated with phagocytic functions in the GBM microenvironment. In summary, we present evidence that human GBMs contain mixed M1/M2‐like polarized GAMs and that the levels of different GAM subpopulations in the tumor core are positively associated with overall survival of patients with IDH1R132H‐non‐mutant GBMs.

PURPOSE The LUME-Lung 1 study has brought consistent evidence of the effective use of nintedanib in lung adenocarcinoma as a second line of treatment; however, differences among ethnicities have been found in some studies. METHODS This was a retrospective review among 21 medical centers of 150 patients with a confirmed diagnosis of lung adenocarcinoma, included in a compassionate use program of nintedanib from March 2014 to September 2015. The current study aimed to analyze the effectiveness of nintedanib in combination with docetaxel in the Mexican population, using progression-free survival rate and the best objective response to treatment by RECIST 1.1 as a surrogate of effectiveness. In addition, we examined the toxicity profile of our study population as a secondary end point. RESULTS After exclusion criteria, only 99 patients met the criteria for enrollment in the current study. From the total study population, 53 patients (53.5%) were male and 46 (46.5%) were female, with an average age of 60 years and stage IV as the most prevalent clinical stage at the beginning of the compassionate use program. A total of 48 patients (48.5%) had partial response; 26 (26.3%), stable disease; 4 (4%), complete response; and 16 (16.2%), progression; and 5 (5%) were nonevaluable. We found a median progression-free survival of 5 months (95% CI, 4.3 to 5.7 months). The most common grade 3 or 4 adverse reactions were fatigue (14%) and diarrhea (13%). CONCLUSION Nintedanib, as part of a chemotherapy regimen, is an effective option with an acceptable toxicity profile for advanced lung adenocarcinoma after first-line treatment progression.

Background Very preterm infants are at high risk of death or severe morbidity. The objective was to determine the significance of severe congenital heart defects ( CHDs ) for these risks. Methods and Results This cohort study included infants from 10 countries born from 2007–2015 at 24 to 31 weeks’ gestation with birth weights CHDs were defined by International Classification of Diseases, Ninth Revision ( ICD‐9 ) and Tenth ( ICD‐10 ) codes and categorized as those compromising systemic output, causing sustained cyanosis, or resulting in congestive heart failure. The primary outcome was in‐hospital mortality. Secondary outcomes were neonatal brain injury, necrotizing enterocolitis, bronchopulmonary dysplasia, and retinopathy of prematurity. Adjusted and propensity score–matched odds ratios ( ORs ) were calculated. Analyses were stratified by type of CHD , gestational age, and network. A total of 609 (0.77%) infants had severe CHD and 76 371 without any malformation served as controls. The mean gestational age and birth weight were 27.8 weeks and 1018 g, respectively. The mortality rate was 18.6% in infants with CHD and 8.9% in controls (propensity score–matched OR , 2.30; 95% CI , 1.61–3.27). Severe CHD was not associated with neonatal brain injury, necrotizing enterocolitis, or retinopathy of prematurity, whereas the OR for bronchopulmonary dysplasia increased. Mortality was higher in all types, with the highest propensity score–matched OR (4.96; 95% CI, 2.11–11.7) for CHD causing congestive heart failure. While mortality did not differ between groups at OR for mortality in infants with CHD increased to 10.9 (95% CI, 5.76–20.70) at 31 weeks’ gestational age. Rates of CHD and mortality differed significantly between networks. Conclusions Severe CHD is associated with significantly increased mortality in very preterm infants.

Importance Inadequate management of elevated blood pressure is a significant contributing factor to maternal deaths. The role of blood pressure self-monitoring in pregnancy in improving clinical outcomes for the pregnant individual and infant is unclear. Objective To evaluate the effect of blood pressure self-monitoring, compared with usual care alone, on blood pressure control and other related maternal and infant outcomes, in individuals with pregnancy hypertension. Design, Setting, and Participants Unblinded, randomized clinical trial that recruited between November 2018 and September 2019 in 15 hospital maternity units in England. Individuals with chronic hypertension (enrolled up to 37 weeks’ gestation) or with gestational hypertension (enrolled between 20 and 37 weeks’ gestation). Final follow-up was in May 2020. Interventions Participants were randomized to either blood pressure self-monitoring using a validated monitor and a secure telemonitoring system in addition to usual care (n = 430) or to usual care alone (n = 420). Usual care comprised blood pressure measured by health care professionals at regular antenatal clinics. Main Outcomes and Measures The primary maternal outcome was the difference in mean systolic blood pressure recorded by health care professionals between randomization and birth. Results Among 454 participants with chronic hypertension (mean age, 36 years; mean gestation at entry, 20 weeks) and 396 with gestational hypertension (mean age, 34 years; mean gestation at entry, 33 weeks) who were randomized, primary outcome data were available from 444 (97.8%) and 377 (95.2%), respectively. In the chronic hypertension cohort, there was no statistically significant difference in mean systolic blood pressure for the self-monitoring groups vs the usual care group (133.8 mm Hg vs 133.6 mm Hg, respectively; adjusted mean difference, 0.03 mm Hg [95% CI, −1.73 to 1.79]). In the gestational hypertension cohort, there was also no significant difference in mean systolic blood pressure (137.6 mm Hg compared with 137.2 mm Hg; adjusted mean difference, −0.03 mm Hg [95% CI, −2.29 to 2.24]). There were 8 serious adverse events in the self-monitoring group (4 in each cohort) and 3 in the usual care group (2 in the chronic hypertension cohort and 1 in the gestational hypertension cohort). Conclusions and Relevance Among pregnant individuals with chronic or gestational hypertension, blood pressure self-monitoring with telemonitoring, compared with usual care, did not lead to significantly improved clinic-based blood pressure control. Trial Registration ClinicalTrials.gov Identifier: NCT03334149

Background There is evidence that delivery room resuscitation of very preterm infants often deviates from internationally recommended guidelines. There were no published data in Spain regarding the quality of neonatal resuscitation. Therefore, we decided to evaluate resuscitation team adherence to neonatal resuscitation guidelines after birth in very preterm infants. Methods We conducted an observational study. We video recorded resuscitations of preterm infants

Introduction The methanol (MeOH) leaf extracts of the species Faramea bahiensis, F. hyacinthina and F. truncata (Rubiaceae) have previously shown in vitro non-cytotoxic and anti-dengue virus serotype 2 (DENV2) activities in human hepatocarcinoma cell lineage (HepG2). Chemical studies have led to the isolation of major flavonoids, but quite complex fractions of phenolic compounds still remain. Objective To complete the study of phenolic compounds in the leaves and to access the presence of these compounds in the stems of these Faramea spp. by online high-performance liquid chromatography-diode array detector-electrospray ionisation tandem mass spectrometry (HPLC-DAD-ESI-MS/MS), as well as to evaluate the in vitro cytotoxic and anti-DENV2 activities of their MeOH stem extracts. Methodology The identification was performed by comparing retention times, UV and mass spectra with those of available standards and by using the mechanisms and fragmentation patterns established in previous studies. The effects of the extracts in DENV2 infected HepG2 cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The virus titer was quantified by plaque assay. Results The study led to the characterisation of 31 phenolic compounds including flavonoid O- and C-glycosides, phenolic acids and one coumarin. The stem extracts from F. hyacinthina and F. bahiensis presented a similar bioactivity to those of their leaves but a loss of cytoprotective activity of F. bahiensis and a higher cytotoxicity of F. truncata were observed. Conclusions This research allowed a detailed phenolic composition of three bioactive Faramea species to be achieved, thus contributing to the study of this genus and providing valuable information for further phytotherapeutic applications.

ObjectiveTo investigate the cognitive profile of healthy individuals with increased Cardiovascular Risk Factors, Aging and Dementia (CAIDE) dementia risk score and to explore whether this association is related to vascular burden and CSF biomarkers of amyloidosis and neurodegeneration.MethodCognitively normal participants (mean age 57.6 years) from the Gipuzkoa Alzheimer Project study were classified as having high risk (HR; n = 82) or low risk (LR; n = 293) for dementia according to a CAIDE score cutoff of 9. Cognitive composites were compared between groups. We explored using generalized linear models the role of APOE genotype, MRI white matter hyperintensities (WMH), and CSF (n = 218) levels of β-amyloid1-42 (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) in the association between CAIDE score and cognition.ResultsHR participants obtained lower scores on executive function (EF) (p = 0.001) and visual perception and construction (VPC) (p < 0.001) composites. EF composite was associated with CAIDE score × p-tau (p = 0.001), CAIDE score × t-tau (p = 0.001), and WMH (p = 0.003). VPC composite was associated with APOE (p = 0.001), Aβ1–42 (p = 0.004), the interaction APOE × Aβ1–42 (p = 0.003), and WMH (p = 0.004). Performance on global memory was associated with Aβ1–42 (p = 0.006), APOE (p = 0.008), and their interaction (p = 0.006). Analyses were adjusted for age, education, sex, premorbid intelligence, and stress.ConclusionHealthy participants at increased dementia risk based on CAIDE scores show lower performance in EF and VPC. This difference is related to APOE, WMH, and Alzheimer biomarkers.

Triple-negative breast cancer (TNBC) is a highly metastatic subtype of breast cancer that has limited therapeutic options. Thus, developing novel treatments for metastatic TNBC is an urgent need. Here, we show that nanoparticle-mediated delivery of transforming growth factor-β1-activated kinase-1 (TAK1) inhibitor 5Z-7-Oxozeaenol can inhibit TNBC lung metastasis in most animals tested. P38 is a central signal downstream of TAK1 in TNBC cells in TAK1-mediated response to multiple cytokines. Following co-culturing with macrophages or fibroblasts, TNBC cells express interleukin-1 (IL1) or tumor necrosis factor-α (TNFα), respectively. Compared to TAK1 inhibition, suppressing IL1 signaling with recombinant IL1 receptor antagonist (IL1RA) is less efficient in reducing lung metastasis, possibly due to the additional TAK1 signals coming from distinct stromal cells. Together, these observations suggest that TAK1 may play a central role in promoting TNBC cell adaptation to the lung microenvironment by facilitating positive feedback signaling mediated by P38. Approaches targeting the key TAK1-P38 signal could offer a novel means for suppressing TNBC lung metastasis., Therapeutic options for triple-negative breast cancer (TNBC) metastasis are limited. Here they show nanoparticle-mediated delivery of TAK1 inhibitor 5Z-7-Oxozeaenol to inhibit TNBC lung metastasis in mice, and that TAK1 might promote TNBC cell adaptation in lung microenvironment by positive feedback mediated by P38 signaling.

Functional status measures are important patient-centered indicators of inpatient rehabilitation facility (IRF) quality of care. We developed a risk-adjusted self-care functional status measure for the IRF Quality Reporting Program. This paper describes the development and performance of the measure's risk-adjustment model.Our sample included IRF Medicare fee-for-service patients from the Centers for MedicareMedicaid Services' 2008-2010 Post-Acute Care Payment Reform Demonstration. Data sources included the Continuity Assessment Record and Evaluation Item Set, IRF-Patient Assessment Instrument, and Medicare claims. Self-care scores were based on 7 Continuity Assessment Record and Evaluation items. The model was developed using discharge self-care score as the dependent variable, and generalized linear modeling with generalized estimation equation to account for patient characteristics and clustering within IRFs. Patient demographics, clinical characteristics at IRF admission, and clinical characteristics related to the recent hospitalization were tested as risk adjusters.A total of 4769 patient stays from 38 IRFs were included. Approximately 57% of the sample was female; 38.4%, 75-84 years; and 31.0%, 65-74 years. The final model, containing 77 risk adjusters, explained 53.7% of variance in discharge self-care scores (P0.0001). Admission self-care function was the strongest predictor, followed by admission cognitive function and IRF primary diagnosis group. The range of expected and observed scores overlapped very well, with little bias across the range of predicted self-care functioning.Our risk-adjustment model demonstrated strong validity for predicting discharge self-care scores. Although the model needs validation with national data, it represents an important first step in evaluation of IRF functional outcomes.

Objective Predictive models for preterm infant mortality have been developed internationally, albeit not valid for all populations. This study aimed to develop and validate different mortality predictive models, using Spanish data, to be applicable to centers with similar morbidity and mortality. Methods Infants born alive, admitted to NICU (BW30 days of life, respectively. During validation, models 1 and 2 showed moderate concordance, whilst that of model 3 was good. Conclusion Using dynamic models to predict individual mortality can improve outcome estimations. Development of models in the prenatal period, first 24 hours, and during hospital admission, cover key stages of mortality prediction in preterm infants. All phases of this study were supported by an “Instituto de Salud Carlos III” grant (PI16/00748). The authors have no financial relationships relevant to this article to disclose.

Circulating tumor cells (CTCs) shed from solid tumors can serve as a minimally invasive liquid biopsy for monitoring disease progression. Because CTCs are rare and heterogeneous, their biological properties need to be investigated at the single cell level, which requires efficient ways to isolate and analyze live single CTCs. Current methods for CTC isolation and identification are either performed on fixed and stained cells or need multiple procedures to isolate pure live CTCs. Here, we used the AccuCyte-RareCyte system to develop a Protocol for Integrated Capture and Retrieval of Ultra-pure single live CTCs using Negative and positive selection (PIC&RUN). The positive selection module of PIC&RUN identifies CTCs based on detection of cancer surface markers and exclusion of immune markers. Combined with a two-step cell picking protocol to retrieve ultrapure single CTCs, the positive selection module is compatible for downstream single cell transcriptomic analysis. The negative selection module of PIC&RUN identifies CTCs based on a live cell dye and the absence of immune markers, allowing retrieval of viable CTCs that are suitable for ex vivo culture. This new assay combines the CTC capture and retrieval in one integrated platform, providing a valuable tool for downstream live CTC analyses.