Clonal Hematopoiesis and Inflammation in the VasculaturE (CHIVE): a prospective, longitudinal cohort and biorepository.

Clonal hematopoiesis (CH) is an age-associated phenomenon leading to increased risk of both hematologic malignancy and non-malignant organ dysfunction. Increasingly available genetic testing has made incidental discovery of CH clinically common, yet evidence-based guidelines and effective management strategies to prevent adverse CH health outcomes are lacking. To address this gap, the prospective CHIVE registry and biorepository was created to identify and monitor individuals at risk, support multidisciplinary CH clinics, and to refine standards of practice for CH risk mitigation. Data from the first 181 patients enrolled in this registry recapitulate the molecular epidemiology of CH from biobank scale retrospective studies, with DNMT3A, TET2, ASXL1, and TP53 as the most commonly mutated genes. CH patients had higher rates of end organ dysfunction, in particular chronic kidney disease (p=0.001). Among patients with CH, variant allele frequency was independently associated with presence of cytopenias (p=0.008) and progression to hematologic malignancy (p=0.010), while other common high-risk CH clone features were not clear. Notably, accumulation of multiple distinct high-risk clone features was also associated with cytopenias (p=0.013) and hematologic malignancy progression (p=0.004), supporting a recently published CH risk score. Surprisingly, ~30% of patients enrolled in CHIVE from CH clinics were adjudicated as not having CHIP, highlighting the need for molecular standards and purpose-built assays in this field. Maintenance of this well-annotated cohort and continued expansion of CHIVE to multiple institutions is underway and will be critical to understand how to thoughtfully care for this patient population.

Cost-Effective and Scalable Clonal Hematopoiesis Assay Provides Insight into Clonal Dynamics.

Clonal hematopoiesis of indeterminate potential (CHIP) is a common age-related phenomenon in which hematopoietic stem cells acquire mutations in a select set of genes commonly mutated in myeloid neoplasia which then expand clonally. Current sequencing assays to detect CHIP mutations are not optimized for the detection of these variants and can be cost-prohibitive when applied to large cohorts or to serial sequencing. In this study, an affordable (approximately US $8 per sample), accurate, and scalable sequencing assay for CHIP is introduced and validated. The efficacy of the assay was demonstrated by identifying CHIP mutations in a cohort of 456 individuals with DNA collected at multiple time points in Vanderbilt University's biobank and quantifying clonal expansion rates over time. A total of 101 individuals with CHIP/clonal cytopenia of undetermined significance were identified, and individual-level clonal expansion rate was calculated using the variant allele fraction at both time points. Differences in clonal expansion rate by driver gene were observed, but there was also significant individual-level heterogeneity, emphasizing the multifactorial nature of clonal expansion. Additionally, the study explores mutation co-occurrence and clonal competition between multiple driver mutations.

Multiomic Profiling of Human Clonal Hematopoiesis Reveals Genotype and Cell-Specific Inflammatory Pathway Activation.

Clonal hematopoiesis (CH) is an age-associated phenomenon that increases risk for hematologic malignancy and cardiovascular disease. CH is thought to enhance disease risk through inflammation in the peripheral blood1. Here, we profile peripheral blood gene expression in 66,968 single cells from a cohort of 17 CH patients and 7 controls. Using a novel mitochondrial DNA barcoding approach, we were able to identify and separately compare mutant TET2 and DNMT3A cells to non-mutant counterparts. We discovered the vast majority of mutated cells were in the myeloid compartment. Additionally, patients harboring DNMT3A and TET2 CH mutations possessed a pro-inflammatory profile in CD14+ monocytes through previously unrecognized pathways such as galectin and macrophage Inhibitory Factor (MIF). We also found that T cells from CH patients, though mostly un-mutated, had decreased expression of GTPase of the immunity associated protein (GIMAP) genes, which are critical to T cell development, suggesting that CH impairs T cell function.

Cost-effective and scalable clonal hematopoiesis assay provides insight into clonal dynamics.

Clonal hematopoiesis of indeterminate potential (CHIP) is a common age-related phenomenon that occurs when hematopoietic stem cells acquire mutations in a select set of genes commonly mutated in myeloid neoplasia which then expand clonally. Current sequencing assays to detect CHIP are not optimized for the detection of these variants and can be cost-prohibitive when applied to large cohorts or serial sequencing. Here, we present and validate a CHIP targeted sequencing assay that is affordable (∼$8/sample), accurate and highly scalable. To demonstrate the utility of this assay, we detected CHIP in a cohort of 456 individuals with DNA collected at multiple timepoints in the Vanderbilt BioVU biobank and quantified clonal expansion rates over time. A total of 101 individuals with CHIP were identified, and individual-level clonal expansion rate was calculated using the variant allele fraction (VAF) at both timepoints. Differences in clonal expansion rate by driver gene were observed, but there was also significant individual-level heterogeneity, emphasizing the multifactorial nature of clonal expansion. We further describe the mutation co-occurrence and clonal competition between multiple driver mutations.

Chapitre 8. Mexique : Comment un pays catholique approuve-t-il l'avortement ?

In a first part, this article shows the characteristics of Mexican society and their opinion on abortion. The second part develops the legal evolution of the decriminalization of abortion in Mexico and with the data, gives elements that can answer the main question.

Categorización y revisión de reevaluaciones en tomografía computada en una unidad de telerradiología de urgencia / Categorization and review of reevaluations in computed tomography in an emergency teleradiology unit

INTRODUCCIÓN La telerradiología se basa en el despliegue de radiólogos a distancia para evaluar estudios de dicha especialidad. Actualmente hay evidencia limitada sobre las tasas de error de evaluaciones en telerradiología. Este estudio corresponde a una revisión de las discrepancias entre los informes preliminares y finales de tomografía computada (TC) de una unidad de urgencia telerradiológica. OBJETIVO Determinar las discrepancias de las reevaluaciones (addendum) en los informes radiológicos de TC en una unidad de telerradiología de urgencia. MATERIALES Y MÉTODOS La recolección de datos se planificó a modo de tabla de cotejo, en la cual se tabularon casos de reevaluaciones de urgencia desde el mes de enero hasta mayo del año 2021, en base a la categorización Agrawal. RESULTADOS De una total de 111.599, 836 informes presentaron addendum, que corresponden al 0,74% del total informado, La categoría Agrawal 0 agrupó la mayor cantidad de casos y los exámenes de TC especialidad de cuerpo se encuentran los segmentos con mayores requerimientos de reevaluación. Discusión: Los valores obtenidos permiten establecer una baja incidencia de reevaluaciones y de la gravedad de estas, apuntando a errores asociados a canales de comunicación, redacción y elaboración de informes con especial énfasis en estudios TC Tórax y Abdomen/Pelvis. CONCLUSIÓN El porcentaje de cumplimiento de un 99,26% de exactitud en los informes permite concluir la alta confiabilidad y la calidad del servicio de telerradiología de la empresa en cuestión durante el periodo evaluado y el empleo de medidas correctivas basadas en organización, gestión e instrumentalización tecnológica

Enteric mesenchymal cells support the growth of postnatal enteric neural stem cells.

Interplay between embryonic enteric neural stem cells (ENSCs) and enteric mesenchymal cells (EMCs) in the embryonic gut is essential for normal development of the enteric nervous system. Disruption of these interactions underlies the pathogenesis of intestinal aganglionosis in Hirschsprung disease (HSCR). ENSC therapy has been proposed as a possible treatment for HSCR, but whether the survival and development of postnatal-derived ENSCs similarly rely on signals from the mesenchymal environment is unknown and has important implications for developing protocols to expand ENSCs for cell transplantation therapy. Enteric neural crest-derived cells (ENCDCs) and EMCs were cultured from the small intestine of Wnt1-Rosa26-tdTomato mice. EMCs promoted the expansion of ENCDCs 9.5-fold by inducing ENSC properties, including expression of Nes, Sox10, Sox2, and Ngfr. EMCs enhanced the neurosphere-forming ability of ENCDCs, and this persisted after withdrawal of the EMCs. These effects were mediated by paracrine factors and several ligands known to support neural stem cells were identified in EMCs. Using the optimized expansion procedures, neurospheres were generated from small intestine of the Ednrb-/- mouse model of HSCR. These ENSCs had similar proliferative and migratory capacity to Ednrb+/+ ENSCs, albeit neurospheres contained fewer neurons. ENSCs derived from Ednrb-/- mice generated functional neurons with similar calcium responses to Ednrb+/+ ENSCs and survived after transplantation into the aganglionic colon of Ednrb-/- recipients. EMCs act as supporting cells to ENSCs postnatally via an array of synergistically acting paracrine signaling factors. These properties can be leveraged to expand autologous ENSCs from patients with HSCR mutations for therapeutic application.

[Difficulties of the negotiation process of the Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the application of biology and medicine (and a call for its adhesion)]. / Dificultades del proceso de negociación de la Convención para la Protección de los Derechos Humanos y la Dignidad del Ser Humano con respecto a las aplicaciones de la Biología y la Medicina (y un llamado a su adhesión).

Making an attempt to frame the controversial topic of bioethics within international law and with the aim of watching over the society, the Council of Europe elaborated the Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the application of biology and medicine. The instrument, which came into force 12 years ago, is opened to all countries but only 29 states have ratified it. This legal document represents the base of a universal legislation on the subject. The present article examines the origin of the Convention, its process and evolution. It analyses the intense debates with regard to the human dignity, the freedom of science, the beginning of life, among others; equally it explores the interests at stake within the convention, whether political, moral, scientific, and economic, at the moment of its draft and in the present. Finally, the article analyses the possibility of the adoption of the Convention by the Mexican government. It concludes on the effectiveness of the international law of bioethics, and calls for the need that the Convention be used as a base for universal legislation.