Diagnosis of Genetic White Matter Disorders by Singleton Whole-Exome and Genome Sequencing Using Interactome-Driven Prioritization

Background and Objectives Genetic white matter disorders (GWMD) are of heterogeneous origin, with >100 causal genes identified to date. Classic targeted approaches achieve a molecular diagnosis in only half of all patients. We aimed to determine the clinical utility of singleton whole-exome sequencing and whole-genome sequencing (sWES-WGS) interpreted with a phenotype- and interactome-driven prioritization algorithm to diagnose GWMD while identifying novel phenotypes and candidate genes. Methods A case series of patients of all ages with undiagnosed GWMD despite extensive standard-of-care paraclinical studies were recruited between April 2017 and December 2019 in a collaborative study at the Bellvitge Biomedical Research Institute (IDIBELL) and neurology units of tertiary Spanish hospitals. We ran sWES and WGS and applied our interactome-prioritization algorithm based on the network expansion of a seed group of GWMD-related genes derived from the Human Phenotype Ontology terms of each patient. Results We evaluated 126 patients (101 children and 25 adults) with ages ranging from 1 month to 74 years. We obtained a first molecular diagnosis by singleton WES in 59% of cases, which increased to 68% after annual reanalysis, and reached 72% after WGS was performed in 16 of the remaining negative cases. We identified variants in 57 different genes among 91 diagnosed cases, with the most frequent being RNASEH2B, EIF2B5, POLR3A, and PLP1, and a dual diagnosis underlying complex phenotypes in 6 families, underscoring the importance of genomic analysis to solve these cases. We discovered 9 candidate genes causing novel diseases and propose additional putative novel candidate genes for yet-to-be discovered GWMD. Discussion Our strategy enables a high diagnostic yield and is a good alternative to trio WES/WGS for GWMD. It shortens the time to diagnosis compared to the classical targeted approach, thus optimizing appropriate management. Furthermore, the interactome-driven prioritization pipeline enables the discovery of novel disease-causing genes and phenotypes, and predicts novel putative candidate genes, shedding light on etiopathogenic mechanisms that are pivotal for myelin generation and maintenance

Association Between Preexisting Versus Newly Identified Atrial Fibrillation and Outcomes of Patients With Acute Pulmonary Embolism

Background Atrial fibrillation (AF) may exist before or occur early in the course of pulmonary embolism (PE). We determined the PE outcomes based on the presence and timing of AF. Methods and Results Using the data from a multicenter PE registry, we identified 3 groups: (1) those with preexisting AF, (2) patients with new AF within 2 days from acute PE (incident AF), and (3) patients without AF. We assessed the 90-day and 1-year risk of mortality and stroke in patients with AF, compared with those without AF (reference group). Among 16 497 patients with PE, 792 had preexisting AF. These patients had increased odds of 90-day all-cause (odds ratio [OR], 2.81; 95% CI, 2.33-3.38) and PE-related mortality (OR, 2.38; 95% CI, 1.37-4.14) and increased 1-year hazard for ischemic stroke (hazard ratio, 5.48; 95% CI, 3.10-9.69) compared with those without AF. After multivariable adjustment, preexisting AF was associated with significantly increased odds of all-cause mortality (OR, 1.91; 95% CI, 1.57-2.32) but not PE-related mortality (OR, 1.50; 95% CI, 0.85-2.66). Among 16 497 patients with PE, 445 developed new incident AF within 2 days of acute PE. Incident AF was associated with increased odds of 90-day all-cause (OR, 2.28; 95% CI, 1.75-2.97) and PE-related (OR, 3.64; 95% CI, 2.01-6.59) mortality but not stroke. Findings were similar in multivariable analyses. Conclusions In patients with acute symptomatic PE, both preexisting AF and incident AF predict adverse clinical outcomes. The type of adverse outcomes may differ depending on the timing of AF onset.info:eu-repo/semantics/publishedVersio

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Registro Preliminar de Macrohongos (Ascomycetes y Basidiomycetes) en el Bosque Húmedo Montano del Alto El Romeral (Municipio de Angelópolis, Departamento de Antioquia - Colombia) Preliminar Report of Macrofungi (Ascomycetes and Basidiomycetes) in the Romeral's Montain Humid Forest (Angelopolis, Antioquia - Colombia)

Los macrohongos desempeñan un papel importante en el ciclado de nutrientes, en especial en el del carbono, al participar activamente en los procesos de descomposición de la materia orgánica dentro de los bosques tropicales. El conocimiento de la diversidad de este grupo en Colombia está aún incompleto. Como contribución a este tema, se desarrolló durante cinco meses en cuatro hectáreas de un bosque húmedo montano del Departamento de Antioquia, el trabajo que reporta y describe un total de 40 especies de macrohongos (dos de ellas posiblemente nuevas para la ciencia) pertenecientes a 34 géneros y 18 familias, creciendo sobre diferentes tipos de sustrato. La familia Marasmiaceae fue la más diversa con cinco especies, seguida por Boletaceae, Polyporacea y Russulaceae con cuatro especies cada una. Hypholoma, Lactarius y Marasmius fueron los géneros más importantes con tres especies cada uno. Las especies de mayor ocurrencia fueron Auricularia delicata (Fr.) Henn., Xylaria polymorpha (Pers.) Grev. y Ganoderma applanatum (Pers.) Pat. La mayor cantidad de especies se registró creciendo sobre troncos caídos (19 especies) y la menor sobre hojarasca (seis especies).<br>Macrofungi play an important role in nutrient cycling. Especially, they are important drivers in the carbon cycling and in the organic matter decomposition process in tropical forests. In Colombia the knowledge on diversity of this group is still very poor. Through this work we intend to contribute to this knowledge. The macrofungi diversity was assessed on three different substrates on a 4 ha wet montane forest in the Antioquia province during five months. Forty species of macrofungi (two of them possible new species to science) belonging to 34 genera and 18 families were recorded. Marasmiaceae was the most diverse family with five species followed by Boletaceae, Polyporacea and Russulaceae with four species each one. Hypholoma, Lactarius and Marasmius were the most important genera with three species each one. Auricularia delicata (Fr.) Henn., Xylaria polymorpha (Pers.) Grev. y Ganoderma applanatum (Pers.) Pat. were the most frequently found species. The highest species numbers were growing on dead wood (19 species) and the lowest were recorded on litter (six species)

Registro preliminar de macrohongos (ascomycetes y basidiomycetes) en el bosque húmedo montano del alto el romeral (municipio de angelópolis, departamento de antioquia - colombia)

Los macrohongos desempeñan un papel importante en el ciclado de nutrientes, en especial en el del carbono, al participar activamente en los procesos de descomposición de la materia orgánica dentro de los bosques tropicales. El conocimiento de la diversidad de este grupo en Colombia está aún incompleto. Como contribución a este tema, se desarrolló durante cinco meses en cuatro hectáreas de un bosque húmedo montano del Departamento de Antioquia, el trabajo que reporta y describe un total de 40 especies de macrohongos (dos de ellas posiblemente nuevas para la ciencia) pertenecientes a 34 géneros y 18 familias, creciendo sobre diferentes tipos de sustrato. La familia Marasmiaceae fue la más diversa con cinco especies, seguida por Boletaceae, Polyporacea y Russulaceae con cuatro especies cada una. Hypholoma, Lactarius y Marasmius fueron los géneros más importantes con tres especies cada uno. Las especies de mayor ocurrencia fueron Auricularia delicata (Fr.) Henn., Xylaria polymorpha (Pers.) Grev. y Ganoderma applanatum (Pers.) Pat. La mayor cantidad de especies se registró creciendo sobre troncos caídos (19 especies) y la menor sobre hojarasca (seis especies)

Derecho de las Víctimas ¿Avance o Retroceso?

La víctima en estos momentos se enfrenta a una coexistencia de sistemas procesales, en donde su participación en cada uno resulta muy diferente debido a la naturaleza de cada uno de los procesos. En el primer sistema, la víctima adquiere la calidad de sujeto procesal constituyéndose en Parte Civil; mientrasque en el segundo, es considerado como un interviniente especial en el proceso. Este artículo nos presenta la participación de la víctima en cada uno de los sistemas, con el fin de permitirnos establecer cuál de los dos sistemas resulta más garantista.

Participación en el proceso de reconstrucción Integral del municipio de La Tebaida, Quindío

174 páginasCon este trabajo se pretende mostrar la labor desempeñada por los ingenieros voluntarios de la Escuela de Ingeniería de Antioquia y por la Corporación Antioquia Presente durante el proceso de reconstrucción del municipio de La Tebaida, haciendo una recopilación de las labores desempeñadas por ambas partes, las experiencias vividas y algunas recomendaciones. Se desarrollaron principalmente cuatro aspectos: vivienda, alojamientos temporales, impactos causados y una propuesta para actuar en caso de un evento sísmico, basados en la experiencia vivida. También se hizo un estudio de la historia del municipio y de los planes a desarrollar por el FOREC para su reconstrucción. Son muchos los resultados obtenidos con esta experiencia, tanto en el aspecto personal como profesional que tratan de plasmarse en este informe. Después de esta vivencia, sentimos un enorme compromiso con Colombia para construir un país mejor, no solo en su infraestructura física sino también fortalecido en el aspecto social.ABSTRACT: With this project we pretend to show the work that was made by a group of engineers that work in a volunteer way and by the Corporación Antioquia Presente during the reconstruction process of La Tebaida town. Here we compiled tasks, ¡¡ved experiences and sorne useful recomendations, ah based in the work made by the group of engineers and by La Corporación Antioquia Presente. There were developed mainly four topics: housing, temporary accommodation, caused impacts and a proposal to work when a seismic event take place, al¡ on the basis of the ¡¡ved experience. There is also a study of the town history and the plan tha the FOREC is going to develope for this reconstruction. There are lots of fruits that we obtained with this experience not only in the personal aspect but in the professional, this is what we want to show with this brief.. After this working time we feel a great obligation with our Colombia to build a better country not only in their phisicaly infraestructure but in their social aspect.PregradoIngeniero(a) Civi

Assessment of plasma chitotriosidase activity, CCL18/PARC concentration and NP-C suspicion index in the diagnosis of Niemann-Pick disease type C : A prospective observational study

Niemann-Pick disease type C (NP-C) is a rare, autosomal recessive neurodegenerative disease caused by mutations in either the NPC1 or NPC2 genes. The diagnosis of NP-C remains challenging due to the non-specific, heterogeneous nature of signs/symptoms. This study assessed the utility of plasma chitotriosidase (ChT) and Chemokine (C-C motif) ligand 18 (CCL18)/pulmonary and activation-regulated chemokine (PARC) in conjunction with the NP-C suspicion index (NP-C SI) for guiding confirmatory laboratory testing in patients with suspected NP-C. In a prospective observational cohort study, incorporating a retrospective determination of NP-C SI scores, two different diagnostic approaches were applied in two separate groups of unrelated patients from 51 Spanish medical centers (n = 118 in both groups). From Jan 2010 to Apr 2012 (Period 1), patients with ≥2 clinical signs/symptoms of NP-C were considered 'suspected NP-C' cases, and NPC1/NPC2 sequencing, plasma chitotriosidase (ChT), CCL18/PARC and sphingomyelinase levels were assessed. Based on findings in Period 1, plasma ChT and CCL18/PARC, and NP-C SI prediction scores were determined in a second group of patients between May 2012 and Apr 2014 (Period 2), and NPC1 and NPC2 were sequenced only in those with elevated ChT and/or elevated CCL18/PARC and/or NP-C SI ≥70. Filipin staining and 7-ketocholesterol (7-KC) measurements were performed in all patients with NP-C gene mutations, where possible. In total across Periods 1 and 2, 10/236 (4%) patients had a confirmed diagnosis o NP-C based on gene sequencing (5/118 [4.2%] in each Period): all of these patients had two causal NPC1 mutations. Single mutant NPC1 alleles were detected in 8/236 (3%) patients, overall. Positive filipin staining results comprised three classical and five variant biochemical phenotypes. No NPC2 mutations were detected. All patients with NPC1 mutations had high ChT activity, high CCL18/PARC concentrations and/or NP-C SI scores ≥70. Plasma 7-KC was higher than control cut-off values in all patients with two NPC1 mutations, and in the majority of patients with single mutations. Family studies identified three further NP-C patients. This approach may be very useful for laboratories that do not have mass spectrometry facilities and therefore, they cannot use other NP-C biomarkers for diagnosis

Diplomado en Servicios Públicos Domiciliarios

In the present work, addresses the contemporary view of the concept of domestic public services in Colombia, reviewing the public policies which make the rights of users effective, free competition, socio-environmental responsibility of companies providing public services, inclusion of the criterion of sustainability that is evidenced in aspects such as renewable energies and inclusion of management indicators of high environmental quality for companies providing the public service and finally the particularities of employment regimen in the context of privatization processes. Certainly, the management model for public utilities is in compliance with the regulatory guidelines redesigned in the 1990s and in turn is articulated with the model of sustainable development adopted in the Constitution, allowing the participation of both private capital and public capital for an optimal provision of the service, that responds to the basic principles of universality, low tariffs, continuity of service and efficiency. All of which gives rise to a series of specific legal relationships between the State and the companies that are governed by the concession contracts and by the state's regulatory authority, between the companies and their users, which is guided by uniform conditions contracts and between the companies and their workers with certain peculiarities in the employment regimen.En el presente trabajo aborda una visión contemporánea del concepto de los servicios públicos domiciliarios en Colombia, abordando las políticas públicas que hacen efectivos los derechos que de los usuarios, la libre competencia, la responsabilidad socio ambiental de las empresas prestadoras de servicios públicos, la inclusión del criterio de sostenibilidad que se evidencia en aspectos como energías renovables e inclusión de indicadores de gestión de alta calidad ambiental para las empresas prestadoras del servicio público y finalmente las particularidades de las relaciones laborales en el contexto de los procesos de privatización. Ciertamente, el modelo de gestión de los servicios públicos domiciliarios guarda observancia de las directrices regulatorias rediseñadas en los años noventa y a su vez se articula con el modelo de desarrollo sostenible adoptado en la Constitución Política, permitiendo la participación tanto de capital privado como por capital público para una óptima prestación del servicio que responda a los principios básicos de universalidad, continuidad en la prestación y eficiencia. Todo lo cual, da origen a una serie de relaciones jurídicas específicas entre el Estado con las empresas que se rige por los contratos de concesión y por la facultad regulatoria del Estado, ente las empresas y sus usuarios que se orienta por los contratos de condiciones uniformes y entre las empresas y sus trabajadores con ciertas particularidades en el régimen laboral