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Introduction: Decreasing rates of blood donation and close margins between blood supply and demand pose challenges in healthcare. Genetically engineered pig red blood cells (pRBCs) have been explored as alternatives to human RBCs for transfusion, and triple-gene knockout (TKO) modification improves the compatibility of pRBCs with human blood in vitro. In this study, we assessed the efficacy and risks of transfusing wild-type (WT)- and TKO-pRBCs into nonhuman primates (NHPs). Methods: Blood from O-type WT and TKO pigs was processed to produce pRBCs for transfusion, which were transfused or not into NHPs (n=4 per group: WT, TKO, and control) after 25% total blood volume withdrawal: their biological responses were compared. Hematological, biochemical, and immunological parameters were measured before, immediately after, and at intervals following transfusion. Two months later, a second transfusion was performed in three NHPs of the transfusion group. Results: Transfusion of both WT- and TKO-pRBCs significantly improved RBC counts, hematocrit, and hemoglobin levels up to the first day post-transfusion, compared to the controls. The transfusion groups showed instant complement activation and rapid elicitation of anti-pig antibodies, as well as elevated liver enzyme and bilirubin levels post-transfusion. Despite the higher agglutination titers with WT-pRBCs in the pre-transfusion crossmatch, the differences between the WT and TKO groups were not remarkable except for less impairment of liver function in the TKO group. After the second transfusion, more pronounced adverse responses without any hematological gain were observed. Conclusions: WT- and TKO-pRBC transfusions effectively increased hematologic parameters on the first day, with rapid clearance from circulation thereafter. However, pRBC transfusion triggers strong antibody responses, limiting the benefits of the pRBC transfusion and increasing the risk of adverse reactions.
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Transfusão de Eritrócitos , Eritrócitos , Técnicas de Inativação de Genes , Animais , Transfusão de Eritrócitos/efeitos adversos , Transfusão de Eritrócitos/métodos , Suínos , Eritrócitos/imunologia , Eritrócitos/metabolismo , Animais Geneticamente Modificados , Hemoglobinas/metabolismo , Galactosiltransferases/genética , Galactosiltransferases/deficiência , Hematócrito , Feminino , Masculino , PrimatasRESUMO
Background: Islet transplantation holds promise for treating selected type 1 diabetes mellitus patients, yet the scarcity of human donor organs impedes widespread adoption. Porcine islets, deemed a viable alternative, recently demonstrated successful longterm survival without zoonotic risks in a clinically relevant pig-to-non-human primate islet transplantation model. This success prompted the development of a clinical trial protocol for porcine islet xenotransplantation in humans. Methods: A single-center, open-label clinical trial initiated by the sponsor will assess the safety and efficacy of porcine islet transplantation for diabetes patients at Gachon Hospital. The protocol received approval from the Gachon Hospital Institutional Review Board (IRB) and the Korean Ministry of Food and Drug Safety (MFDS) under the Investigational New Drug (IND) process. Two diabetic patients, experiencing inadequate glycemic control despite intensive insulin treatment and frequent hypoglycemic unawareness, will be enrolled. Participants and their family members will engage in deliberation before xenotransplantation during the screening period. Each patient will receive islets isolated from designated pathogen-free pigs. Immunosuppressants and systemic infection prophylaxis will follow the program schedule. The primary endpoint is to confirm the safety of porcine islets in patients, and the secondary endpoint is to assess whether porcine islets can reduce insulin dose and the frequency of hypoglycemic unawareness. Conclusion: A clinical trial protocol adhering to global consensus guidelines for porcine islet xenotransplantation is presented, facilitating streamlined implementation of comparable human trials worldwide.
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BACKGROUND: Despite extensive findings on the hazardous impacts of environmental heat exposure, little is known about the effect on people with disabilities. This study aimed to estimate the association between environmental heat exposure and emergency department admissions for people with disabilities compared with people without disabilities. METHODS: In this nationwide, case-crossover study, we linked data on emergency department admissions (cases) for any cause in the warm season in South Korea from the Korean National Health Insurance Service (NHIS)-National Sample Cohort database (a nationally representative database of 1 million systematically sampled beneficiaries covering all ages) from Jan 1, 2002, to Dec 31, 2019, and short-term daily mean temperature exposure (measured via Google Earth Engine at a 9 km spatial grid, aggregated to district). We defined beneficiaries with disabilities as those who were registered as disabled in the NHIS; disabilities included in our study were physical disability, brain lesion disorders, blindness or vision loss, and deafness or hearing loss. Other types of disability were not included for confidentiality reasons. A time-stratified case-crossover design, in which participants served as their own control, was used with conditional logistic regression to estimate the association between heat and emergency department admissions in people with and without disabilities. FINDINGS: 23â792 emergency department admissions were recorded for 59â527 people with disabilities. Of these 23â792 admissions, 10â234 (43·0%) individuals were female and 13â558 (57·0%) were male. The odds ratio (OR) of emergency department admissions associated with heat (99th temperature percentile vs 75th percentile) was 1·15 (95% CI 1·07-1·24) in people with disabilities and 1·06 (1·04-1·09) in people without disabilities. The annual excess number of emergency department admissions attributable to heat per 100â000 persons-years was 27·81 admissions (95% CI 9·20-45·69) and excess medical costs were US$638â739·47 (95% CI 201â900·12-1â059â641·87) in people with disabilities; these values were more than four times that of the non-disabled population. People with brain lesion disorders, people with severe physical disabilities, female individuals, and those aged 65 years or older showed higher heat risks. The risks of emergency department admissions due to mental disorder (1·89, 95% CI 1·18-3·00) and respiratory diseases (1·34, 1·06-1·70) also showed higher heat risks than for the other two analysed causes of admission (cardiovascular and genitourinary diseases). INTERPRETATION: Heat was associated with increased risk of emergency department admissions for people with and without disabilities, but the risk appeared to be higher for those with disabilities. These results can inform policy makers when establishing action plans for people with disabilities. FUNDING: National Research Foundation of Korea, the South Korean Ministry of Environment, and the South Korean Ministry of Education.
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Pessoas com Deficiência , Doenças do Sistema Nervoso , Humanos , Masculino , Feminino , Estudos Cross-Over , Temperatura Alta , República da Coreia/epidemiologia , HospitaisRESUMO
Because there is a shortage of donor kidneys, researchers are exploring the possibility of using genetically modified pig kidneys for transplantation. Approaches involving knockout of carbohydrate genes or knockin of protective proteins have been attempted to determine the best gene modifications. In this study, we utilized GalT-/-;hCD39;hCD55 and GalT-/-;hCD39;hCD46;hCD55;thrombomodulin (TBM) pigs for transplantation in nonhuman primates (NHPs). The NHPs survived for 4 weeks after kidney transplantation (4 WAT) from the GalT-/-;hCD39;hCD55 pig and for 6 WAT from the GalT-/-;hCD39;hCD46;hCD55;TBM pig. However, messenger RNA (mRNA) sequencing and immunohistochemistry analysis revealed that the 6 WAT kidney exhibited more severe apoptosis, inflammation, loss of renal function, and renal fibrosis than the 4 WAT kidney. These results indicate that additional knockin of complement regulator (hCD46) and coagulation regulator (TBM) is not enough to prevent renal damage, suggesting that improved immune suppression is needed for more prolonged survival.
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Transplantes , Animais , Suínos , Animais Geneticamente Modificados , Transplante Heterólogo/métodos , Primatas , Rim , Rejeição de EnxertoRESUMO
Introduction: The global shortage of human blood for medical use has prompted the development of alternative blood sources. Nonhuman primates (NHPs) are commonly used owing to their physiological similarities to humans. The objective of the current study was to establish a controlled-blood-loss model in NHPs to explore their clinical and biological responses. Methods: Blood was sequentially withdrawn from 10 cynomolgus monkeys (10, 14, 18, 22, and 25% of the total blood volume); their vital signs were monitored, and blood parameters were serially analyzed. Humoral mediators in the blood were measured using flow cytometry and enzyme-linked immunosorbent assays. Results: In NHPs subjects to 25% blood loss and presenting with related clinical symptoms, the systolic blood pressure ratio on day 0 after bleeding was significantly lower than that of the animals from the other groups (median: 0.65 vs. 0.88, P = 0.0444). Red blood cell counts from day 0-14 and hematocrit levels from day 0-7 were markedly decreased relative to the baseline (P < 0.01). These parameters showed a direct correlation with the extent of blood loss. The levels of creatine phosphokinase, aspartate aminotransferase, and alanine aminotransferase exhibited increases in response to blood loss and had a stronger correlation with the hemoglobin ratio than the volume of blood loss. The levels of C3a and C4a, as well as interleukin (IL)-1α and IL-15, displayed a strong correlation, with no apparent association with blood loss. Conclusion: The findings of the present study showed that only NHPs with 25% blood loss exhibited clinical decompensation and significant systolic blood pressure reduction without fatalities, suggesting that this level of blood loss is suitable for evaluating blood transfusion efficacy or other treatments in NHP models. In addition, the ratio of hemoglobin may serve as a more dependable marker for predicting clinical status than the actual volume of blood loss. Thus, our study could serve as a basis for future xenotransfusion research and to predict biological responses to massive blood loss in humans where controlled experiments cannot be ethically performed.
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Hemorragia , Interleucina-1alfa , Humanos , Animais , Contagem de Eritrócitos , Aspartato Aminotransferases , Hemoglobinas , PrimatasRESUMO
Introducción: Los procesos de acreditación de la calidad de los programas de formación de médicos tienen importancia en cuanto al impulso que pueden dar a la formación de mejores profesionales. El reconocimiento de la calidad educativa de un determinado programa o carrera por parte de los organismos facultados, como la Agencia Nacional de Evaluación y Acreditación de la Educación Superior (ANEAES) es una garantía del cumplimiento de los criterios mínimos de calidad establecidos. Sin embargo, la calidad de un postgrado no solo es valorada por el cumplimiento de los criterios de calidad mínimos establecidos por los organismos encargados, sino por otros criterios como serían la percepción de los estudiantes, actuales y graduados sobre la calidad de la formación ofrecida por el mismo. Objetivos: El presente trabajo tiene como objetivo general estudiar la calidad de la formación en el Postgrado de Especialización en Pediatría Clínica de la FCM-UNA, a partir de las percepciones de sus estudiantes, actuales y graduados. Materiales y métodos: La metodología se enmarca en la tradición cualitativa de investigación social y en su instrumentación se incluye la realización de entrevistas semiestructuradas aplicadas a los estudiantes actuales (residentes) y graduados (egresados) del programa, así como el desarrollo, implementación y análisis de matrices, con la discusión de los resultados correspondientes a cada una de ellas. Resultados: Los resultados obtenidos muestran que la mayor parte de los estudiantes, actuales y egresados, del Postgrado de Especialización en Pediatría Clínica de la FCM UNA, perciben que la formación en este es de buena a mediana calidad. Los factores que inciden positivamente en la percepción de la calidad de la formación son: el ámbito de desarrollo del programa, el plan de estudios, las actividades académicas, la calidad de la composición y el desempeño del plantel docente, así como las relaciones interpersonales, tanto con los docentes como con sus pares; con algunas excepciones puntuales. La inclusión en el currículum de los aspectos relativos a la responsabilidad social universitaria también tuvo una incidencia positiva. Los factores que incidieron negativamente en la percepción de la calidad de la formación fueron: la carga horaria excesiva, el sistema de evaluación exigente, las falencias en la infraestructura y las tareas de asistencia social, en desmedro de la optimización del tiempo para la formación. En lo referente a la incidencia de la pandemia de COVID 19 en la calidad de la formación, las percepciones fueron dispares al interior de los casos de estudio que cursaron el postgrado durante la misma, con elementos negativos y llamativamente algunos elementos positivos. A la hora de sopesar en qué medida los factores positivos y negativos incidieron globalmente en la percepción de la calidad de la formación, se evidenció que, a pesar del reconocimiento de la existencia de varios factores negativos, los primeros primaron sobre los segundos. Esto hace que la mayoría de los estudiantes actuales y egresados manifiesten su satisfacción con el postgrado y los graduados con su desempeño autónomo al cumplir con sus expectativas. Conclusión: La mayor parte de los estudiantes, actuales y graduados del Postgrado de especialización en Pediatría Clínica de la FCM UNA, perciben que la formación en el mismo es de buena a mediana calidad, con aspectos a mejorar que son mencionados en las recomendaciones.
Introduction: The quality accreditation processes of medical training programs are important in terms of the boost they can give to the training of better professionals. Recognition of the educational quality of a certain program or career by authorized bodies, such as the National Agency for the Evaluation and Accreditation of Higher Education (ANEAES) is a guarantee of compliance with the minimum established quality criteria. However, the quality of a postgraduate course is not only assessed by compliance with the minimum quality criteria established by the bodies in charge, but by other criteria such as the perception of current and graduate students about the quality of the training offered by the same. Objectives: The general objective is to study the quality of training in the Postgraduate Specialization in Clinical Pediatrics of the FCM-UNA, based on the perceptions of its current and graduate students. Materials and methods: The methodology is part of the qualitative tradition of social research and its instrumentation includes semi-structured interviews applied to current students (residents) and graduates of the program, as well as the development, implementation and analysis of matrices, with the discussion of the results corresponding to each of them. Results: The results obtained show that most of the students, current and graduates, of the Postgraduate Specialization in Clinical Pediatrics of the FCM UNA, perceive that the training is of good to medium quality. Factors that positively affect the perception of the quality of training are: the scope of development of the program, the study plan, academic activities, quality of the composition and performance of the teaching staff, as well as interpersonal relationships, both with teachers and with their peers; with some specific exceptions. The inclusion in the curriculum of aspects related to university social responsibility also had a positive impact. Factors that negatively affected perception of the quality of training were: excessive workload, the demanding evaluation system, shortcomings in the infrastructure and the tasks of social service, to the detriment of time dedicated to optimizing training. Regarding the incidence of the COVID 19 pandemic on the quality of training, perceptions were uneven within the case studies that took the postgraduate course during it, with negative elements and strikingly some positive elements. When weighing up the extent to which the positive and negative factors had a global impact on the perception of the quality of training, it was shown that, despite the recognition of the existence of several negative factors, the former prevailed over the latter. This makes the majority of current students and graduates express their satisfaction with the postgraduate course and graduates with their autonomous performance in meeting their expectations. Conclusion: Most of the students, current and graduates of the Postgraduate specialization in Clinical Pediatrics of the FCM UNA, perceive that the training in it is of good to medium quality, with aspects to improve that are mentioned in the recommendations.