Potential limitations in COVID-19 machine learning due to data source variability: A case study in the nCov2019 dataset

[EN] Objective: The lack of representative coronavirus disease 2019 (COVID-19) data is a bottleneck for reliable and generalizable machine learning. Data sharing is insufficient without data quality, in which source variability plays an important role. We showcase and discuss potential biases from data source variability for COVID-19 machine learning. Materials and Methods: We used the publicly available nCov2019 dataset, including patient-level data from several countries. We aimed to the discovery and classification of severity subgroups using symptoms and comorbidities. Results: Cases from the 2 countries with the highest prevalence were divided into separate subgroups with distinct severity manifestations. This variability can reduce the representativeness of training data with respect the model target populations and increase model complexity at risk of overfitting. Conclusions: Data source variability is a potential contributor to bias in distributed research networks. We call for systematic assessment and reporting of data source variability and data quality in COVID-19 data sharing, as key information for reliable and generalizable machine learning.This work was supported by Universitat Politecnica de Valencia contract no. UPV-SUB.2-1302 and FONDO SUPERA COVID-19 by CRUE-Santander Bank grant "Severity Subgroup Discovery and Classification on COVID-19 Real World Data through Machine Learning and Data Quality assessment (SUBCOVERWD-19)."Sáez Silvestre, C.; Romero, N.; Conejero, JA.; Garcia-Gomez, JM. (2021). Potential limitations in COVID-19 machine learning due to data source variability: A case study in the nCov2019 dataset. Journal of the American Medical Informatics Association. 28(2):360-364. https://doi.org/10.1093/jamia/ocaa25836036428

Subphenotyping of Mexican Patients With COVID-19 at Preadmission To Anticipate Severity Stratification: Age-Sex Unbiased Meta-Clustering Technique

[EN] Background: The COVID-19 pandemic has led to an unprecedented global health care challenge for both medical institutions and researchers. Recognizing different COVID-19 subphenotypes-the division of populations of patients into more meaningful subgroups driven by clinical features-and their severity characterization may assist clinicians during the clinical course, the vaccination process, research efforts, the surveillance system, and the allocation of limited resources. Objective: We aimed to discover age-sex unbiased COVID-19 patient subphenotypes based on easily available phenotypical data before admission, such as pre-existing comorbidities, lifestyle habits, and demographic features, to study the potential early severity stratification capabilities of the discovered subgroups through characterizing their severity patterns, including prognostic, intensive care unit (ICU), and morbimortality outcomes. Methods: We used the Mexican Government COVID-19 open data, including 778,692 SARS-CoV-2 population-based patient-level data as of September 2020. We applied a meta-clustering technique that consists of a 2-stage clustering approach combining dimensionality reduction (ie, principal components analysis and multiple correspondence analysis) and hierarchical clustering using the Ward minimum variance method with Euclidean squared distance. Results: In the independent age-sex clustering analyses, 56 clusters supported 11 clinically distinguishable meta-clusters (MCs). MCs 1-3 showed high recovery rates (90.27%-95.22%), including healthy patients of all ages, children with comorbidities and priority in receiving medical resources (ie, higher rates of hospitalization, intubation, and ICU admission) compared with other adult subgroups that have similar conditions, and young obese smokers. MCs 4-5 showed moderate recovery rates (81.30%-82.81%), including patients with hypertension or diabetes of all ages and obese patients with pneumonia, hypertension, and diabetes. MCs 6-11 showed low recovery rates (53.96%-66.94%), including immunosuppressed patients with high comorbidity rates, patients with chronic kidney disease with a poor survival length and probability of recovery, older smokers with chronic obstructive pulmonary disease, older adults with severe diabetes and hypertension, and the oldest obese smokers with chronic obstructive pulmonary disease and mild cardiovascular disease. Group outcomes conformed to the recent literature on dedicated age-sex groups. Mexican states and several types of clinical institutions showed relevant heterogeneity regarding severity, potentially linked to socioeconomic or health inequalities. Conclusions: The proposed 2-stage cluster analysis methodology produced a discriminative characterization of the sample and explainability over age and sex. These results can potentially help in understanding the clinical patient and their stratification for automated early triage before further tests and laboratory results are available and even in locations where additional tests are not available or to help decide resource allocation among vulnerable subgroups such as to prioritize vaccination or treatments.We sincerely thank the different types of clinical institutions and the Mexican government, which made a huge effort to make these data publicly available. We also thank the clinicians and epidemiologists from the Servicios de Salud de Nayarit for the useful discussions on specific aspects of the medical attention to hospitalized patients and the reporting of epidemiological data processes related to COVID-19. Furthermore, we would also like to thank Francisco Tomas Garcia Ruiz for his valuable help in data visualization design. This work was supported by Universitat Politecnica de Valencia contract no. UPV-SUB.2-1302 and FONDO SUPERA COVID-19 by CRUE-Santander Bank grant: "Severity Subgroup Discovery and Classification on COVID-19 Real World Data through Machine Learning and Data Quality assessment (SUBCOVERWD-19) ." The authors thank the Institute for Information and Communication Technologies (ITACA) at the Universitat Politecnica de Valencia for its support in the publication of this manuscript.Zhou, L.; Romero-Garcia, N.; Martínez-Miranda, J.; Conejero, JA.; Garcia-Gomez, JM.; Sáez Silvestre, C. (2022). Subphenotyping of Mexican Patients With COVID-19 at Preadmission To Anticipate Severity Stratification: Age-Sex Unbiased Meta-Clustering Technique. JMIR Public Health and Surveillance. 8(3):1-21. https://doi.org/10.2196/300321218

Análisis del efecto intraarticular de células madre mesenquimales autólogas y alogénicas en caballos

El caballo, además de ser paciente dada su relevante importancia económica en los países desarrollados, es un animal modelo para el desarrollo de tratamientos para diferentes patologías en la especie humana Durante los últimos años, el uso de células madre, como opción terapéutica, en lesiones osteoarticulares equinas, ha aumentado de forma exponencial. El principal objetivo de este estudio prospectivo es conocer la seguridad (existencia o no de posibles efectos adversos) de la aplicación de células madre mesenquimales obtenidas de la médula ósea (BM-MSC) autólogas y alogénicas en articulaciones equinas sanas, como paso previo a su posible uso terapéutico en patologías articulares. Se utilizaron 6 caballos adultos sanos (3 machos enteros y 3 hembras) de los cuales se han aislado, cultivado, diferenciado, caracterizado y criopreservado MSC provenientes de la 5ª y 6ª esternebras. La realización del estudio constó de tres experimentos: En el primer experimento se comparó y evaluó el grado de inflamación que produce la inoculación intraarticular de BM-MSC autólogas frente a Ringer Lactato (RL) como control en la articulación contralateral, inoculadas en la articulación tarsocrural. El segundo experimento que comparó y evaluó el grado de inflamación que produce la inoculación intraarticular de una mezcla de BM-MSC alogénicas frente al RL, en la articulación carporadial. En el tercer experimento se comparó y evaluó el grado de inflamación que produce una segunda inoculación intraarticular de una mezcla de BM-MSC alogénicas frente al RL en la misma articulación carporadial. En todos los experimentos, previo al implante intraarticular (0 horas), y posteriormente a las 24, 48, 72 horas, 5 y 10 días se realizaron las siguientes determinaciones clínicas y analíticas: examen visual, examen de cojera estático y dinámico (incluyendo tests de flexión), medición del perímetro de las articulaciones a estudio, medición de la temperatura de la piel sobre los recesos sinoviales, evaluación ecográfica de la articulación, medición del espesor de la membrana sinovial y de la profundidad de líquido sinovial, así como artrocentesis para la obtención de líquido sinovial para determinar el recuento leucocitario total y el recuento de neutrófilos, realizar una evaluación citológica y medir la concentración de proteínas totales. Los resultados de este trabajo muestran que la inoculación intraarticular de MSC equinas, independientemente de su origen (autólogas o alogénicas) produce una reacción inflamatoria transitoria que se normaliza en 10 días sin necesidad de tratamiento alguno. Esta inflamación pasajera es, en la mayoría de los animales, difícilmente detectable a nivel clínico, pero sí que es muy marcada en los parámetros laboratoriales (proteínas totales y recuento leucocitario y de neutrófilos)

Small extracellular vesicles from young adipose-derived stem cells prevent frailty, improve health span, and decrease epigenetic age in old mice.

Aging is associated with an increased risk of frailty, disability, and mortality. Strategies to delay the degenerative changes associated with aging and frailty are particularly interesting. We treated old animals with small extracellular vesicles (sEVs) derived from adipose mesenchymal stem cells (ADSCs) of young animals, and we found an improvement in several parameters usually altered with aging, such as motor coordination, grip strength, fatigue resistance, fur regeneration, and renal function, as well as an important decrease in frailty. ADSC-sEVs induced proregenerative effects and a decrease in oxidative stress, inflammation, and senescence markers in muscle and kidney. Moreover, predicted epigenetic age was lower in tissues of old mice treated with ADSC-sEVs and their metabolome changed to a youth-like pattern. Last, we gained some insight into the microRNAs contained in sEVs that might be responsible for the observed effects. We propose that young sEV treatment can promote healthy aging

Status and recommendations of technological and data-driven innovations in cancer care:Focus group study

Background: The status of the data-driven management of cancer care as well as the challenges, opportunities, and recommendations aimed at accelerating the rate of progress in this field are topics of great interest. Two international workshops, one conducted in June 2019 in Cordoba, Spain, and one in October 2019 in Athens, Greece, were organized by four Horizon 2020 (H2020) European Union (EU)-funded projects: BOUNCE, CATCH ITN, DESIREE, and MyPal. The issues covered included patient engagement, knowledge and data-driven decision support systems, patient journey, rehabilitation, personalized diagnosis, trust, assessment of guidelines, and interoperability of information and communication technology (ICT) platforms. A series of recommendations was provided as the complex landscape of data-driven technical innovation in cancer care was portrayed. Objective: This study aims to provide information on the current state of the art of technology and data-driven innovations for the management of cancer care through the work of four EU H2020-funded projects. Methods: Two international workshops on ICT in the management of cancer care were held, and several topics were identified through discussion among the participants. A focus group was formulated after the second workshop, in which the status of technological and data-driven cancer management as well as the challenges, opportunities, and recommendations in this area were collected and analyzed. Results: Technical and data-driven innovations provide promising tools for the management of cancer care. However, several challenges must be successfully addressed, such as patient engagement, interoperability of ICT-based systems, knowledge management, and trust. This paper analyzes these challenges, which can be opportunities for further research and practical implementation and can provide practical recommendations for future work. Conclusions: Technology and data-driven innovations are becoming an integral part of cancer care management. In this process, specific challenges need to be addressed, such as increasing trust and engaging the whole stakeholder ecosystem, to fully benefit from these innovations

Running title: Non-toxic broad anti-tumor activity of an EGFR×4-1BB bispecific trimerbod

32 p.-4 fig.Purpose: The induction of 4-1BB signaling by agonistic antibodies can drive the activation and proliferation of effector T cells and thereby enhance a T-cell–mediated antitumor response. Systemic administration of anti-4-1BB–agonistic IgGs, although effective preclinically, has not advanced in clinical development due to their severe hepatotoxicity.Experimental Design: Here, we generated a humanized EGFR-specific 4-1BB-agonistic trimerbody, which replaces the IgG Fc region with a human collagen homotrimerization domain. It was characterized by structural analysis and in vitro functional studies. We also assessed pharmacokinetics, antitumor efficacy, and toxicity in vivo.Results: In the presence of a T-cell receptor signal, the trimerbody provided potent T-cell costimulation that was strictly dependent on 4-1BB hyperclustering at the point of contact with a tumor antigen-displaying cell surface. It exhibits significant antitumor activity in vivo, without hepatotoxicity, in a wide range of human tumors including colorectal and breast cancer cell-derived xenografts, and non–small cell lung cancer patient-derived xenografts associated with increased tumor-infiltrating CD8+ T cells. The combination of the trimerbody with a PD-L1 blocker led to increased IFNγ secretion in vitro and resulted in tumor regression in humanized mice bearing aggressive triple-negative breast cancer.Conclusions: These results demonstrate the nontoxic broad antitumor activity of humanized Fc-free tumor-specific 4-1BB-agonistic trimerbodies and their synergy with checkpoint blockers, which may provide a way to elicit responses in most patients with cancer while avoiding Fc-mediated adverse reactions.This work was supported by grants from the European Union [IACT Project (602262), H2020-iNEXT (1676)]; the Spanish Ministry of Science, Innovation and Universities and the Spanish Ministry of Economy and Competitiveness (SAF2017-89437-P, CTQ2017-83810-R, RTC-2016-5118-1, RTC-2017-5944-1), partially supported by the European Regional Development Fund; the Carlos III Health Institute (PI16/00357), co-founded by the Plan Nacional de Investigación and the European Union; the CRIS Cancer Foundation (FCRIS-IFI-2018); and the Spanish Association Against Cancer (AECC, 19084). C. Domínguez-Alonso was supported by a predoctoral fellowship from the Spanish Ministry of Science, Innovation and Universities (PRE2018-083445). M. Zonca was supported by the Torres Quevedo Program from the Spanish Ministry of Economy and Competitiveness, co-founded by the European Social Fund (PTQ-16-08340).Peer reviewe

The Double-Edged Role of Extracellular Vesicles in the Hallmarks of Aging

The exponential growth in the elderly population and their associated socioeconomic burden have recently brought aging research into the spotlight. To integrate current knowledge and guide potential interventions, nine biochemical pathways are summarized under the term hallmarks of aging. These hallmarks are deeply inter-related and act together to drive the aging process. Altered intercellular communication is particularly relevant since it explains how damage at the cellular level translates into age-related loss of function at the organismal level. As the main effectors of intercellular communication, extracellular vesicles (EVs) might play a key role in the aggravation or mitigation of the hallmarks of aging. This review aims to summarize this role and to provide context for the multiple emerging EV-based gerotherapeutic strategies that are currently under study

Efecto del tratamiento con vesículas extracelulares de células madre de tejido adiposo de ratones jóvenes sobre parámetros de envejecimiento y longevidad en ratones de edad avanzada

Introducción El envejecimiento es un proceso universal y progresivo de deterioro de las funciones orgánicas del individuo. La alteración en la comunicación intercelular es un sello del envejecimiento, junto con la senescencia y la disfunción mitocondrial. Las vesículas extracelulares (EVs), partículas que median la comunicación intercelular, han demostrado tener un papel en la regulación del envejecimiento. Recientemente, la terapia con células madre ha sido reemplazada por la terapia basada en EVs, que podría replicar sus efectos beneficiosos por un mecanismo paracrino. Objetivos Nuestro grupo ha demostrado que las EVs de células madre mesenquimales de tejido adiposo (ADSCs) de ratones jóvenes mejoran parámetros relacionados con el envejecimiento, incluyendo pruebas físicas y regeneración tisular. Nuestro objetivo general es evaluar el impacto de las EVs de ratón joven sobre distintos sellos del envejecimiento en ratones viejos. Los objetivos específicos incluyen estudiar sus efectos sobre la senescencia celular, función mitocondrial, composición muscular, metaboloma y longevidad de los ratones viejos. Material y Métodos Se utilizaron ratones C57BL/6J jóvenes (4-6 meses) y viejos (22-24 meses). Se aislaron ADSCs de los panículos adiposos inguinales de ratones jóvenes y se cultivaron en una cabina de hipoxia. Las EVs se aislaron del medio de cultivo mediante ultracentrifugación diferencial. Los ratones viejos recibieron dos dosis de EVs intravenosas separadas por una semana. Para estudios de supervivencia, se repitió el tratamiento mensualmente. Los análisis incluyeron estudios de función mitocondrial, composición muscular, metaboloma plasmático y biodistribución de EVs. Resultados y Discusión En un modelo in vitro con mioblastos senescentes tratados con Palbociclib, las EVs de ADSCs de ratones jóvenes mitigaron la senescencia. La reducción de interleucinas proinflamatorias y la ausencia de apoptosis sugiere un mecanismo senomórfico, que fue replicado con los análogos de miRNAs contenidos en las EVs. Las EVs de ADSCs de ratón joven mejoraron la composición del músculo esquelético en ratones viejos, aumentando las fibras tipo IIA y reduciendo el depósito lipídico. La respirometría de alta resolución mostró un incremento en la respiración mitocondrial acompañado de un aumento en la expresión de enzimas antioxidantes, lo que sugiere protección frente al estrés oxidativo. El perfil metabolómico plasmático de los ratones viejos tratados con EVs se asemejó al de los ratones jóvenes, con un aumento de aminoácidos como la valina y el triptófano. El análisis de Kaplan Meier mostró un aumento significativo en la longevidad de las hembras tratadas con EVs. Conclusiones Las EVs de ADSCs de individuos jóvenes muestran potencial para mejorar varios procesos que definen el envejecimiento celular, incluyendo la senescencia y la disfunción mitocondrial. Estos efectos se traducen en cambios en el metaboloma y un aumento en la longevidad en ratones hembras

Intranasal Insulin Administration to Prevent Delayed Neurocognitive Recovery and Postoperative Neurocognitive Disorder: A Narrative Review

Delayed neurocognitive recovery and postoperative neurocognitive disorders are major complications of surgery, hospitalization, and anesthesia that are receiving increasing attention. Their incidence is reported to be 10–80% after cardiac surgery and 10–26% after non-cardiac surgery. Some of the risk factors include advanced age, level of education, history of diabetes mellitus, malnutrition, perioperative hyperglycemia, depth of anesthesia, blood pressure fluctuation during surgery, chronic respiratory diseases, etc. Scientific evidence suggests a causal association between anesthesia and delayed neurocognitive recovery or postoperative neurocognitive disorders, and various pathophysiological mechanisms have been proposed: mitochondrial dysfunction, neuroinflammation, increase in tau protein phosphorylation, accumulation of amyloid-β protein, etc. Insulin receptors in the central nervous system have a non-metabolic role and act through a neuromodulator-like action, while an interaction between anesthetics and central nervous system insulin receptors might contribute to anesthesia-induced delayed neurocognitive recovery or postoperative neurocognitive disorders. Acute or chronic intranasal insulin administration, which has no influence on the blood glucose concentration, appears to improve working memory, verbal fluency, attention, recognition of objects, etc., in animal models, cognitively healthy humans, and memory-impaired patients by restoring the insulin receptor signaling pathway, attenuating anesthesia-induced tau protein hyperphosphorylation, etc. The aim of this review is to report preclinical and clinical evidence of the implication of intranasal insulin for preventing changes in the brain molecular pattern and/or neurobehavioral impairment, which influence anesthesia-induced delayed neurocognitive recovery or postoperative neurocognitive disorders

Intranasal Insulin Administration to Prevent Delayed Neurocognitive Recovery and Postoperative Neurocognitive Disorder: A Narrative Review

Delayed neurocognitive recovery and postoperative neurocognitive disorders are major complications of surgery, hospitalization, and anesthesia that are receiving increasing attention. Their incidence is reported to be 10-80% after cardiac surgery and 10-26% after non-cardiac surgery. Some of the risk factors include advanced age, level of education, history of diabetes mellitus, malnutrition, perioperative hyperglycemia, depth of anesthesia, blood pressure fluctuation during surgery, chronic respiratory diseases, etc. Scientific evidence suggests a causal association between anesthesia and delayed neurocognitive recovery or postoperative neurocognitive disorders, and various pathophysiological mechanisms have been proposed: mitochondrial dysfunction, neuroinflammation, increase in tau protein phosphorylation, accumulation of amyloid-β protein, etc. Insulin receptors in the central nervous system have a non-metabolic role and act through a neuromodulator-like action, while an interaction between anesthetics and central nervous system insulin receptors might contribute to anesthesia-induced delayed neurocognitive recovery or postoperative neurocognitive disorders. Acute or chronic intranasal insulin administration, which has no influence on the blood glucose concentration, appears to improve working memory, verbal fluency, attention, recognition of objects, etc., in animal models, cognitively healthy humans, and memory-impaired patients by restoring the insulin receptor signaling pathway, attenuating anesthesia-induced tau protein hyperphosphorylation, etc. The aim of this review is to report preclinical and clinical evidence of the implication of intranasal insulin for preventing changes in the brain molecular pattern and/or neurobehavioral impairment, which influence anesthesia-induced delayed neurocognitive recovery or postoperative neurocognitive disorders