Association of Candidate Gene Polymorphisms With Chronic Kidney Disease: Results of a Case-Control Analysis in the Nefrona Cohort

Chronic kidney disease (CKD) is a major risk factor for end-stage renal disease, cardiovascular disease and premature death. Despite classical clinical risk factors for CKD and some genetic risk factors have been identified, the residual risk observed in prediction models is still high. Therefore, new risk factors need to be identified in order to better predict the risk of CKD in the population. Here, we analyzed the genetic association of 79 SNPs of proteins associated with mineral metabolism disturbances with CKD in a cohort that includes 2, 445 CKD cases and 559 controls. Genotyping was performed with matrix assisted laser desorption ionizationtime of flight mass spectrometry. We used logistic regression models considering different genetic inheritance models to assess the association of the SNPs with the prevalence of CKD, adjusting for known risk factors. Eight SNPs (rs1126616, rs35068180, rs2238135, rs1800247, rs385564, rs4236, rs2248359, and rs1564858) were associated with CKD even after adjusting by sex, age and race. A model containing five of these SNPs (rs1126616, rs35068180, rs1800247, rs4236, and rs2248359), diabetes and hypertension showed better performance than models considering only clinical risk factors, significantly increasing the area under the curve of the model without polymorphisms. Furthermore, one of the SNPs (the rs2248359) showed an interaction with hypertension, being the risk genotype affecting only hypertensive patients. We conclude that 5 SNPs related to proteins implicated in mineral metabolism disturbances (Osteopontin, osteocalcin, matrix gla protein, matrix metalloprotease 3 and 24 hydroxylase) are associated to an increased risk of suffering CKD

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

BLOOM: A 176B-Parameter Open-Access Multilingual Language Model

Large language models (LLMs) have been shown to be able to perform new tasks based on a few demonstrations or natural language instructions. While these capabilities have led to widespread adoption, most LLMs are developed by resource-rich organizations and are frequently kept from the public. As a step towards democratizing this powerful technology, we present BLOOM, a 176B-parameter open-access language model designed and built thanks to a collaboration of hundreds of researchers. BLOOM is a decoder-only Transformer language model that was trained on the ROOTS corpus, a dataset comprising hundreds of sources in 46 natural and 13 programming languages (59 in total). We find that BLOOM achieves competitive performance on a wide variety of benchmarks, with stronger results after undergoing multitask prompted finetuning. To facilitate future research and applications using LLMs, we publicly release our models and code under the Responsible AI License

Differential clinical characteristics and prognosis of intraventricular conduction defects in patients with chronic heart failure

Intraventricular conduction defects (IVCDs) can impair prognosis of heart failure (HF), but their specific impact is not well established. This study aimed to analyse the clinical profile and outcomes of HF patients with LBBB, right bundle branch block (RBBB), left anterior fascicular block (LAFB), and no IVCDs. Clinical variables and outcomes after a median follow-up of 21 months were analysed in 1762 patients with chronic HF and LBBB (n = 532), RBBB (n = 134), LAFB (n = 154), and no IVCDs (n = 942). LBBB was associated with more marked LV dilation, depressed LVEF, and mitral valve regurgitation. Patients with RBBB presented overt signs of congestive HF and depressed right ventricular motion. The LAFB group presented intermediate clinical characteristics, and patients with no IVCDs were more often women with less enlarged left ventricles and less depressed LVEF. Death occurred in 332 patients (interannual mortality = 10.8%): cardiovascular in 257, extravascular in 61, and of unknown origin in 14 patients. Cardiac death occurred in 230 (pump failure in 171 and sudden death in 59). An adjusted Cox model showed higher risk of cardiac death and pump failure death in the LBBB and RBBB than in the LAFB and the no IVCD groups. LBBB and RBBB are associated with different clinical profiles and both are independent predictors of increased risk of cardiac death in patients with HF. A more favourable prognosis was observed in patients with LAFB and in those free of IVCDs. Further research in HF patients with RBBB is warranted

Serum phosphate is associated with increased risk of bone fragility fractures in hemodialysis patients

COSMOS is sponsored by the Bone and Mineral Research Unit (Hospital Universitario Central de Asturias), SAFIM (Sociedad Asturiana Fomento Investigaciones Óseas), the European Renal Association. This study has been funded by Instituto de Salud Carlos III (ISCIII), the ISCIII Retic REDinREN (RD06/0016/1013, RD12/0021/0023 and RD16/0009/0017), the ISCIII Red de Investigación Cooperativa Orientada a Resultados en Salud RICORS2040 (RD21/0005/0001 and RD21/0005/0019, Next Generation EU; Recovery, Transformation and Resilience Plan), the ISCIII (ICI14/00107, PI17/00384 and PI20/00633, co-funded by the European Union), Plan Estatal de I + D + I 2013-2016, Plan de Ciencia, Tecnología e Innovación 2013-2017 y 2018-2022 del Principado de Asturias (GRUPIN14-028, IDI-2018-000152, IDI/2021/000080), Fundación Renal Íñigo Álvarez de Toledo (FRIAT) and the Spanish Society of Nephrology (Estudio Estratégico de la SEN). Logistics (meetings, secretarial help, printing of materials, development of website for data entry, etc.) have been financially supported by an unrestricted grant from AMGEN Europe and Fundación Renal Íñigo Álvarez de Toledo (FRIAT).BACKGROUND: Bone fragility fractures are associated with high morbidity and mortality. This study analysed the association between the current biochemical parameters of CKD-MBD and bone fragility fractures in the COSMOS project. METHODS: COSMOS is a 3-year, multicentre, open cohort, prospective, observational study carried out in 6797 hemodialysis patients (227 centres from 20 European countries). The association of bone fragility fractures (outcome) with serum calcium, phosphate and PTH (exposure), was assessed using Standard Cox proportional hazards regression and Cox proportional hazards regression for recurrent events. Additional analyses were performed considering all-cause mortality as a competitive event for bone fragility fracture occurrence. Multivariable models were used in all strategies, with the fully adjusted model including a total of 24 variables. RESULTS: During a median follow-up of 24 months 252 (4%) patients experienced at least one bone fragility fracture (incident bone fragility fracture rate 28.5 per 1000 patient-years). In the fractured and non-fractured patients, the percentage of men was 43.7% and 61.4%, mean age 68.1 and 63.8 years and a haemodialysis vintage of 55.9 and 38.3 months respectively. Baseline serum phosphate > 6.1 mg/dL (reference value 4.3-6.1 mg/dL) was significantly associated with a higher bone fragility fracture risk in both regression models (HR: 1.53[95%CI: 1.10-2.13] and HR: 1.44[95%CI: 1.02-2.05]. The significant association persisted after competitive risk analysis (subHR: 1.42[95%CI: 1.02-1.98]) but the finding was not confirmed when serum phosphate was considered as a continuous variable. Baseline serum calcium showed no association with bone fragility fracture risk in any regression model. Baseline serum PTH > 800 pg/mL was significantly associated with a higher bone fragility fracture risk in both regression models, but the association disappeared after a competitive risk analysis. CONCLUSIONS: Hyperphosphatemia was independently and consistently associated with an increased bone fracture risk, suggesting serum phosphate could be a novel risk factor for bone fractures in hemodialysis patients.publishersversionepub_ahead_of_prin

The Talavera Manifesto for Quantum Software Engineering and Programming

This paper presents the Talavera Manifesto for quantum software engineering and programming. This manifesto collects some principles and commitments about the quantum software engineering and programming field, as well as some calls for action. This is the result of the discussion and different viewpoints of academia and industry practitioners who joined at the first International Workshop on QuANtum SoftWare Engineering & pRogramming (QANSWER)

The Talavera Manifesto for Quantum Software Engineering and Programming

This paper presents the Talavera Manifesto for quantum software engineering and programming. This manifesto collects some principles and commitments about the quantum software engineering and programming field, as well as some calls for action. This is the result of the discussion and different viewpoints of academia and industry practitioners who joined at the first International Workshop on QuANtum SoftWare Engineering & pRogramming (QANSWER)

Transparencia, combate a la corrupción y Gobierno Abierto: La experiencia de México

La mayoría de las encuestas hacia las elecciones presidenciales en México de 2018 coinciden: el tema que más lastima a los mexicanos del Siglo XXI es la corrupción y la impunidad, junto con la seguridad ciudadana y económica. La promesa de una menor corrupción que acompañó nuestras transiciones, tanto a nivel federal como en las entidades federativas, no se ha cumplido, afectando nuestra confianza en el régimen democrático como el más efectivo para tener mejor calidad de vida. Este libro da cuenta de ello y con la creación del Sistema Nacional Anticorrupción, publicado en el Diario Oficial de la Federación el 25 de mayo de 2015, se abre un espacio para el trabajo colaborativo y de incidencia con las distintas organizaciones que integran el colectivo CIMTRA; para promover a partir de la transparencia las acciones contra la corrupción en los gobiernos. En la medida que las instituciones y los ciudadanos asumamos la corresponsabilidad que tenemos en la construcción de ciudadanía, y respeto a los derechos fundamentales de los ciudadanos se logrará controlar el ejercicio de los poderes públicos y se resignificará la política como el mejor espacio para el mejoramiento de nuestro país