Coste-efectividad del implante percutáneo de válvula aórtica con SAPIEN 3 en pacientes con bajo riesgo de mortalidad quirúrgica en España

España; Prótesis valvular cardiaca; Coste-efectividadSpain; Prosthetic heart valve; Cost-effectiveness analisyEspanya; Pròtesis valvular cardíaca; Cost-efectivitatIntroduction and objectives: Transcatheter aortic valve implantation (TAVI) was first introduced in 2007 as an alternative to open heart surgery to treat patients with severe symptomatic aortic stenosis (sSAS) with various indication expansions since that date. Recently, the PARTNER 3 study (Placement of aortic transcatheter valve) demonstrated clinical benefits with TAVI with the SAPIEN 3 valve vs surgical aortic valve replacement (SAVR) in selected low surgical mortality risk patients. We reviewed data from the PARTNER 3 and economic data from Spain to assess the cost-effectiveness ratio of TAVI vs SAVR in patients with sSAS and low surgical mortality risk. Methods: A 2-stage model was used to estimate direct healthcare costs and health-related quality of life data regarding TAVI with the SAPIEN 3 valve and SAVR. Early adverse events associated with TAVI from the PARTNER 3 were fed into a Markov model that captured longer-term outcomes after TAVI or SAVR. Results: TAVI with SAPIEN 3 improved quality-adjusted life years per patient (+ 1.00) with an increase in costs vs SAVR (€6971 per patient). This meant an incremental cost-effectiveness ratio/quality-adjusted life year of €6952 per patient. The results were robust with TAVI with the SAPIEN 3 valve remaining cost-effective across several sensitivity analyses. Conclusions: TAVI with the SAPIEN 3 valve is cost effective compared to SAVR in patients with sSAS and low surgical mortality risk. These findings can inform policymakers to facilitate policy development in Spain on intervention selection in this patient population.Introducción y objetivos: El implante percutáneo de válvula aórtica (TAVI) se introdujo en 2007 como una alternativa a la cirugía a corazón abierto para tratar a pacientes con estenosis aórtica grave sintomática, y desde entonces han aumentado las indicaciones autorizadas. Recientemente, el Placement of Aortic Transcatheter Valve Study (PARTNER) 3 ha demostrado beneficios clínicos con el TAVI con la válvula SAPIEN 3 frente al reemplazo quirúrgico de válvula aórtica (RVAo) en pacientes seleccionados con bajo riesgo de mortalidad quirúrgica. Utilizando los datos del PARTNER 3 junto con datos económicos de España, se evaluó la relación coste-efectividad del TAVI en comparación con el RVAo en pacientes con estenosis aórtica grave sintomática con bajo riesgo de mortalidad quirúrgica. Métodos: Se utilizó un modelo en dos etapas para estimar los costes directos sanitarios y los datos de calidad de vida relacionados con la salud para TAVI con la válvula SAPIEN 3 y RVAo. Los eventos adversos tempranos relacionados con TAVI del PARTNER 3 se incluyeron en un modelo de Markov, que capturó los resultados a más largo plazo tras TAVI o RVAo. Resultados: El TAVI con SAPIEN 3 mejoró los años de vida ajustados por calidad por paciente (+1,00), con un aumento en el coste frente al RVAo de 6.971 € por paciente. Esto representó una ratio coste-efectividad incremental por año de vida ganado ajustado por calidad de 6.952€ por paciente. Los resultados fueron robustos en los diversos análisis de sensibilidad realizados, en los que el TAVI con SAPIEN 3 se mantiene como una opción coste-efectiva. Conclusiones: El TAVI con SAPIEN 3 es coste-efectivo en comparación con el RVAo en pacientes con estenosis aórtica grave sintomática con bajo riesgo de mortalidad quirúrgica. Estos resultados pueden informar a los decisores políticos en España para facilitar el desarrollo de políticas sobre la selección de opciones terapéuticas en esta población de pacientes. Palabras clave: España. Implante percutáneo de válvula aórtica. Cirugía cardiaca. Prótesis valvular cardiaca. Reemplazo quirúrgico de válvula aórtica. Análisis coste-beneficio. Análisis coste-efectividad. Estenosis aórtica. Bajo riesgo.Edwards Lifesciences SA, Switzerland provided funding for the economic assessment and was involved in the analysis as well as in the drafting of this manuscript

Loose ends: almost one in five human genes still have unresolved coding status

Seventeen years after the sequencing of the human genome, the human proteome is still under revision. One in eight of the 22 210 coding genes listed by the Ensembl/GENCODE, RefSeq and UniProtKB reference databases are annotated differently across the three sets. We have carried out an in-depth investigation on the 2764 genes classified as coding by one or more sets of manual curators and not coding by others. Data from large-scale genetic variation analyses suggests that most are not under protein-like purifying selection and so are unlikely to code for functional proteins. A further 1470 genes annotated as coding in all three reference sets have characteristics that are typical of non-coding genes or pseudogenes. These potential non-coding genes also appear to be undergoing neutral evolution and have considerably less supporting transcript and protein evidence than other coding genes. We believe that the three reference databases currently overestimate the number of human coding genes by at least 2000, complicating and adding noise to large-scale biomedical experiments. Determining which potential non-coding genes do not code for proteins is a difficult but vitally important task since the human reference proteome is a fundamental pillar of most basic research and supports almost all large-scale biomedical projects.National Institutes of Health [2 U41 HG007234 to I.J., L.M., J.M.R. and M.L.T., R01 HG004037 to I.J.]. Funding for open access charge: NIH [2 U41 HG007234].S

Analysis of variants in the HCN4 gene and in three single nucleotide polymorphisms of the CYP3A4 gene for association with ivabradine reduction in heart rate: A preliminary report

Background: Ivabradine, a selective bradycardic drug, inhibits the If. In patients with heart failure (HF), ivabradine reduces the risk of rehospitalization and mortality. The average heart rate (HR) reduction is 8–10 beats, although clinical trials reveal interindividual variability. The aim of the study is to identify variants associated with HR reduction produced by ivabradine in genes involved in the drug metabolism (CYP3A4) or related to the drug target (HCN4). Methods: In an exploratory cohort (n = 11), patients started on ivabradine were genotyped and the HR reduction was studied. Results: The mean HR reduction after the treatment was 18.10 ± 12.26 bpm. The HR reduction was ≥ 15 bpm in 3 patients and > 5 and < 15 bpm in 7 patients. Four synonymous variants, L12L, L520L, P852P, and P1200P, were detected in the HCN4 gene (frequency = 0.045, 0.045, and 0.681, respectively). Moreover, the CYP3A4*1F and CYP3A4*1B were found in one patient each and CYP3A4*1G was presented in 3 patients. Conclusions: This is the first study using an exploratory pharmacogenetic approach that attempts to explain interindividual variability in ivabradine HR reduction. However, more research must be undertaken in order to determine the role of variants in HCN4 and CYP3A4 genes in response to ivabradine

Comprehensive Quantification of the Modified Proteome Reveals Oxidative Heart Damage in Mitochondrial Heteroplasmy

Post-translational modifications hugely increase the functional diversity of proteomes. Recent algorithms based on ultratolerant database searching are forging a path to unbiased analysis of peptide modifications by shotgun mass spectrometry. However, these approaches identify only one-half of the modified forms potentially detectable and do not map the modified residue. Moreover, tools for the quantitative analysis of peptide modifications are currently lacking. Here, we present a suite of algorithms that allows comprehensive identification of detectable modifications, pinpoints the modified residues, and enables their quantitative analysis through an integrated statistical model. These developments were used to characterize the impact of mitochondrial heteroplasmy on the proteome and on the modified peptidome in several tissues from 12-week-old mice. Our results reveal that heteroplasmy mainly affects cardiac tissue, inducing oxidative damage to proteins of the oxidative phosphorylation system, and provide a molecular mechanism explaining the structural and functional alterations produced in heart mitochondria.We thank Simon Bartlett (CNIC) for English editing. This study was supported by competitive grants from the Spanish Ministry of Economy and Competitiveness (MINECO) (BIO2015-67580-P) through the Carlos III Institute of Health-Fondo de Investigacion Sanitaria (PRB2, IPT13/0001-ISCIII-SGEFI/FEDER; ProteoRed), by Fundacion La Marato TV3, and by FP7-PEOPLE-2013-ITN ``Next-Generation Training in Cardiovascular Research and Innovation-Cardionext.'' N.B. is a FP7-PEOPLE-2013-ITN-Cardionext Fellow. The CNIC is supported by the MINECO and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO Award SEV-2015-0505).S

SQANTI : extensive characterization of long-read transcript sequences for quality control in full-length transcriptome identification and quantification

High-throughput sequencing of full-length transcripts using long reads has paved the way for the discovery of thousands of novel transcripts, even in well-annotated mammalian species. The advances in sequencing technology have created a need for studies and tools that can characterize these novel variants. Here, we present SQANTI, an automated pipeline for the classification of long-read transcripts that can assess the quality of data and the preprocessing pipeline using 47 unique descriptors. We apply SQANTI to a neuronal mouse transcriptome using Pacific Biosciences (PacBio) long reads and illustrate how the tool is effective in characterizing and describing the composition of the full-length transcriptome. We perform extensive evaluation of ToFU PacBio transcripts by PCR to reveal that an important number of the novel transcripts are technical artifacts of the sequencing approach and that SQANTI quality descriptors can be used to engineer a filtering strategy to remove them. Most novel transcripts in this curated transcriptome are novel combinations of existing splice sites, resulting more frequently in novel ORFs than novel UTRs, and are enriched in both general metabolic and neural-specific functions. We show that these new transcripts have a major impact in the correct quantification of transcript levels by state-of-the-art short-read-based quantification algorithms. By comparing our iso-transcriptome with public proteomics databases, we find that alternative isoforms are elusive to proteogenomics detection. SQANTI allows the user to maximize the analytical outcome of long-read technologies by providing the tools to deliver quality-evaluated and curated full-length transcriptomes

Multicenter study of lumen-apposing metal stents with or without pigtail in endoscopic ultrasound-guided biliary drainage for malignant obstruction - BAMPI TRIAL: an open-label, randomized controlled trial protocol

Background It is unclear whether the insertion of an axis-orienting double-pigtail plastic stent (DPS) through biliary lumen-apposing meal stent (LAMS) in EUS-guided choledochoduodenostomy (CDS) improves the stent patency. The aim of this study is to determine whether this technical variant offers a clinical benefit in EUS-guided biliary drainage (BD) for the management of distal malignant biliary obstruction. Methods/design This is a multicenter open-label, randomized controlled trial with two parallel groups. Eighty-four patients with malignant biliary obstruction will undergo EUS-BD (CDS type) using LAMS in 7 tertiary hospitals in Spain and will be randomized to the LAMS and LAMS plus DPS groups. The primary endpoint is the rate of recurrent biliary obstruction, as a stent dysfunction parameter, detected during follow-up. Secondary endpoints: technical and clinical success (reduction in bilirubin > 50% within 14 days of stent placement), safety, and others (number of reinterventions, time to biliary obstruction, prognostic factors, survival rate). Discussion The BAMPI trial has been designed to determine whether the addition of a coaxial axis-orienting DPS through LAMS is superior to LAMS alone to prevent stent dysfunction

Surgical treatment for colorectal cancer: Analysis of the influence of an enhanced recovery programme on long-term oncological outcomes-a study protocol for a prospective, multicentre, observational cohort study

Introduction The evidence currently available from enhanced recovery after surgery (ERAS) programmes concerns their benefits in the immediate postoperative period, but there is still very little evidence as to whether their correct implementation benefits patients in the long term. The working hypothesis here is that, due to the lower response to surgical aggression and lower rates of postoperative complications, ERAS protocols can reduce colorectal cancer-related mortality. The main objective of this study is to analyse the impact of an ERAS programme for colorectal cancer on 5-year survival. As secondary objectives, we propose to analyse the weight of each of the predefined items in the oncological results as well as the quality of life. Methods and analysis A multicentre prospective cohort study was conducted in patients older than 18 years of age who are scheduled to undergo surgery for colorectal cancer. The study involved 12 hospitals with an implemented enhanced recovery protocol according to the guidelines published by the Spanish National Health Service. The intervention group includes patients with a minimum implementation level of 70%, and the control group includes those who fail to reach this level. Compliance will be studied using 18 key performance indicators, and the results will be analysed using cancer survival indicators, including overall survival, cancer-specific survival and relapse-free survival. The time to recurrence, perioperative morbidity and mortality, hospital stay and quality of life will also be studied, the latter using the validated EuroQol Five questionnaire. The propensity index method will be used to create comparable treatment and control groups, and a multivariate regression will be used to study each variable. The Kaplan-Meier estimator will be used to estimate survival and the log-rank test to make comparisons. A p value of less than 0.05 (two-tailed) will be considered to be significant. Ethics and dissemination Ethical approval for this study was obtained from the Aragon Ethical Committee (C.P.-C.I. PI20/086) on 4 March 2020. The findings of this study will be submitted to peer-reviewed journals (BMJ Open, JAMA Surgery, Annals of Surgery, British Journal of Surgery). Abstracts will be submitted to relevant national and international meetings.The present research study was awarded a Ministerio de Ciencia e Innovación health research project grant (PI19/00291) from the Carlos III Institute of the Spanish National Health Service as part of the 2019 call for Strategic Action in Health

Investigación en Matemáticas, Economía, Ciencias Sociales y Agronomía

Cada trabajo del libro incluye conclusiones para los interesados en las temáticas aludidas y en ellos nos enteramos de aspectos como los siguientes: - El mayor incremento del precio de los insumos como el maíz, sorgo y en menor medida desperdicio de pan, en relación con el menor crecimiento del precio del ganado en pie, dará como consecuencia un desabasto de carne bovina. - El agua es un recurso primordial en las zonas áridas y semiáridas de México, en tanto que su aporte limita la producción de la agricultura. En este estudio se observó que el precio real del agua es muy bajo en relación a otras zonas agrícolas del mundo. - Hoy en día en el país se consumen alrededor de 718 mil barriles diarios de gasolinas, un aproximado de 113.7 millones de litros, una cantidad tan grande que nuestro país se ve en la necesidad de importar cerca del 39 % de las gasolinas que consumimos. - Los jaliscienses radicados en Estados Unidos tienen una mayor capacidad de financiamiento del bienestar en la entidad, que el propio gobierno de ese estado. - México continuará basando sus finanzas públicas y su política de desarrollo económico en la extracción de combustibles fósiles (petróleo). Este modelo acelerará el deterioro y agotamiento de los recursos naturales. -La importancia de la agricultura orgánica radica en que retoma los tres ámbitos de la sustentabilidad; el ámbito ambiental, el económico y el social. - Es fundamental motivar la organización de los productores de haba para que ellos puedan captar una mayor proporción de los altos márgenes de precios que los consumidores están dispuestos a pagar. - Las condiciones del clima afectan a la producción agraria. Debido al fenómeno de cambio climático, es necesario contar con herramientas informáticas que proporcionen información climatológica para poder tomar medidas preventivas a favor de una mayor cantidad y calidad de producción. La herramienta de software permite la consulta del clima por localidades evitando la necesidad de contar con una estación meteorológica

Risk factors for developing ventilator-associated lower respiratory tract infection in patients with severe COVID-19:a multinational, multicentre study, prospective, observational study

Around one-third of patients diagnosed with COVID-19 develop a severe illness that requires admission to the Intensive Care Unit (ICU). In clinical practice, clinicians have learned that patients admitted to the ICU due to severe COVID-19 frequently develop ventilator-associated lower respiratory tract infections (VA-LRTI). This study aims to describe the clinical characteristics, the factors associated with VA-LRTI, and its impact on clinical outcomes in patients with severe COVID-19. This was a multicentre, observational cohort study conducted in ten countries in Latin America and Europe. We included patients with confirmed rtPCR for SARS-CoV-2 requiring ICU admission and endotracheal intubation. Only patients with a microbiological and clinical diagnosis of VA-LRTI were included. Multivariate Logistic regression analyses and Random Forest were conducted to determine the risk factors for VA-LRTI and its clinical impact in patients with severe COVID-19. In our study cohort of 3287 patients, VA-LRTI was diagnosed in 28.8% [948/3287]. The cumulative incidence of ventilator-associated pneumonia (VAP) was 18.6% [610/3287], followed by ventilator-associated tracheobronchitis (VAT) 10.3% [338/3287]. A total of 1252 bacteria species were isolated. The most frequently isolated pathogens were Pseudomonas aeruginosa (21.2% [266/1252]), followed by Klebsiella pneumoniae (19.1% [239/1252]) and Staphylococcus aureus (15.5% [194/1,252]). The factors independently associated with the development of VA-LRTI were prolonged stay under invasive mechanical ventilation, AKI during ICU stay, and the number of comorbidities. Regarding the clinical impact of VA-LRTI, patients with VAP had an increased risk of hospital mortality (OR [95% CI] of 1.81 [1.40-2.34]), while VAT was not associated with increased hospital mortality (OR [95% CI] of 1.34 [0.98-1.83]). VA-LRTI, often with difficult-to-treat bacteria, is frequent in patients admitted to the ICU due to severe COVID-19 and is associated with worse clinical outcomes, including higher mortality. Identifying risk factors for VA-LRTI might allow the early patient diagnosis to improve clinical outcomes. Trial registration: This is a prospective observational study; therefore, no health care interventions were applied to participants, and trial registration is not applicable