Impact of a Successful Percutaneous Mitral Paravalvular Leak Closure on Long-term Major Clinical Outcomes.

BACKGROUND: Percutaneous mitral paravalvular leak (PVL) closure techniques are an effective and safe alternative to surgical treatment, but data regarding long-term outcomes are scarce. We aim to describe the impact of successful percutaneous mitral PVL closure on long-term outcomes. METHODS: All consecutive patients in whom a first-attempt percutaneous mitral PVL closure was performed in a single tertiary centre between January 2010 and October 2021 were included. Clinical variables, procedural details, and procedural success were collected. Patients were classified based on procedural success, defined as no more than mild residual leak. All-cause mortality was the primary endpoint. Cardiovascular death and heart failure hospitalizations (HFHs) were key secondary endpoints. RESULTS: Ninety patients (median age 72.5 years [66.0-78.4]; median EuroSCORE-II 8.2 [5.3-12.46]) were included. Although reduction of at least 1 degree in PVL severity was achieved in 82 (91.1%), procedural success was achieved in 47 (52.2%). Chronic kidney disease, previous surgery for PVL, and the presence of multiple jets were independently associated with procedural failure. After a median follow-up of 3.2 (1.2-5.2) years, mortality rate was higher in the procedural failure group (27.3 per 100 patients-years) compared with the group with successful closure (8.2 per 100 patient-years). Procedural failure was associated with all-cause death (adjusted hazard ratio [aHR], 2.59; 95% confidence interval [CI], 1.41-4.78), cardiovascular death (aHR, 3.53; 95% CI, 1.67-7.49) and HFH (aHR, 3.27; 95% CI,1.72-6.20). CONCLUSIONS: A successful reduction in PVL to mild or absent is associated with improved rates of all-cause death, cardiovascular death, and HFHs.

Impact of the COVID-19 Pandemic on the Socioeconomic Inequalities in Mortality in Spanish Provinces.

BACKGROUND: Although many studies have assessed the socioeconomic inequalities caused by COVID-19 in several health outcomes, there are numerous issues that have been poorly addressed. For instance, have socioeconomic inequalities in mortality from COVID-19 increased? What impact has the pandemic had on inequalities in specific causes of mortality other than COVID-19? Are the inequalities in COVID-19 mortality different from other causes? In this paper we have attempted to answer these questions for the case of Spain. METHODS: We used a mixed longitudinal ecological design in which we observed mortality from 2005 to 2020 in the 54 provinces into which Spain is divided. We considered mortality from all causes, not excluding, and excluding mortality from COVID-19; and cause-specific mortality. We were interested in analysing the trend of the outcome variables according to inequality, controlling for both observed and unobserved confounders. RESULTS: Our main finding was that the increased risk of dying in 2020 was greater in the Spanish provinces with greater inequality. In addition, we have found that: (i) the pandemic has exacerbated socioeconomic inequalities in mortality, (ii) COVID-19 has led to gender differences in the variations in risk of dying (higher in the case of women) and (iii) only in cardiovascular diseases and Alzheimer did the increased risk of dying differ between the most and least unequal provinces. The increase in the risk of dying was different by gender (greater in women) for cardiovascular diseases and cancer. CONCLUSION: Our results can be used to help health authorities know where and in which population groups future pandemics will have the greatest impact and, therefore, be able to take appropriate measures to prevent such effects.

Transcriptomics of Hirschsprung disease patient-derived enteric neural crest cells reveals a role for oxidative phosphorylation.

Hirschsprung disease is characterized by the absence of enteric neurons caused by the defects of enteric neural crest cells, leading to intestinal obstruction. Here, using induced pluripotent stem cell-based models of Hirschsprung and single-cell transcriptomic analysis, we identify a gene set of 118 genes commonly dysregulated in all patient enteric neural crest cells, and suggest HDAC1 may be a key regulator of these genes. Furthermore, upregulation of RNA splicing mediators and enhanced alternative splicing events are associated with severe form of Hirschsprung. In particular, the higher inclusion rate of exon 9 in PTBP1 and the perturbed expression of a PTBP1-target, PKM, are significantly enriched in these patient cells, and associated with the defective oxidative phosphorylation and impaired neurogenesis. Hedgehog-induced oxidative phosphorylation significantly enhances the survival and differentiation capacity of patient cells. In sum, we define various factors associated with Hirschsprung pathogenesis and demonstrate the implications of oxidative phosphorylation in enteric neural crest development and HSCR pathogenesis.

Clinical and demographical characteristics in a cohort of MND patients treated with riluzole. Differences between tablets and oral suspension.

Objective: To describe the clinical and demographic characteristics of patients with MND treated with riluzole by comparing two dosage forms (oral suspension and tablets), as well as the impact on survival in patients with and without dysphagia according to the form of dosage.Methods: Retrospective and prospective cohort of patients diagnosed with MND at the multidisciplinary functional unit of Motor Neuron Disease in our center in the period between 1 of January 2011 and 31 of December 2020 (n = 742). A descriptive analysis (univariate and bivariate) was carried out and survival curves were estimated.Results: During the follow-up period, 402 males (54.18%) and 340 females (45.82%) were diagnosed with MND. Of these patients, 632 (97.23%) were being treated with 100mg riluzole: 282 (54.55%) patients took this in tablet form and 235 (45.45%) oral suspension. Riluzole in tablet form is taken more frequently by men than women, in younger age ranges, and mostly without dysphagia (78.31%). Also, it is the predominant dosage form for classic spinal ALS and respiratory phenotypes. Dosages via oral suspension are taken by patients in the older age ranges (over 64.8 years), mostly with dysphagia (53.67%) and more frequently with bulbar phenotypes such as classic bulbar ALS and PBP. Because of this, patients using oral suspension (most of them with dysphagia) had a poorer survival rate (at 90% CI) than patients using tablets (most of them without dysphagia).Conclusions: The most appropriate dosage form should be given according to the patient's needs at each stage of the disease and, furthermore, oral suspension could improve adherence to treatment because it avoids having to change from one form (tablet) to the other (suspension) when swallowing disorders appear.

Whole genome sequencing reveals epistasis effects within RET for Hirschsprung disease.

Common variants in RET and NRG1 have been associated with Hirschsprung disease (HSCR), a congenital disorder characterised by incomplete innervation of distal gut, in East Asian (EA) populations. However, the allelic effects so far identified do not fully explain its heritability, suggesting the presence of epistasis, where effect of one genetic variant differs depending on other (modifier) variants. Few instances of epistasis have been documented in complex diseases due to modelling complexity and data challenges. We proposed four epistasis models to comprehensively capture epistasis for HSCR between and within RET and NRG1 loci using whole genome sequencing (WGS) data in EA samples. 65 variants within the Topologically Associating Domain (TAD) of RET demonstrated significant epistasis with the lead enhancer variant (RET+3; rs2435357). These epistatic variants formed two linkage disequilibrium (LD) clusters represented by rs2506026 and rs2506028 that differed in minor allele frequency and the best-supported epistatic model. Intriguingly, rs2506028 is in high LD with one cis-regulatory variant (rs2506030) highlighted previously, suggesting that detected epistasis might be mediated through synergistic effects on transcription regulation of RET. Our findings demonstrated the advantages of WGS data for detecting epistasis, and support the presence of interactive effects of regulatory variants in RET for HSCR.

Multimorbidity and chronic co-prescription networks and potential interactions in adult patients with epilepsy: MorbiNet study.

OBJECTIVE: We constructed epilepsy multimorbidity networks to study associations with chronic conditions, and co-prescriptions and drug-disease networks to assess potential interactions. We conducted a population-based study in Catalonia, Spain, with electronic files of 3,135,948 adult patients with multimorbidity, 32,625 of them with epilepsy (active diagnosis any time during 2006-2017). We constructed epilepsy comorbidity networks using logistic regression models from odds ratio estimates adjusted by age, sex, and comorbidities with R software and generated trajectories to study the progression of epilepsy. We constructed drug-disease and co-prescription networks using mixed models with repeated measures adjusting by age, sex, and period with chronic prescription invoiced data. Comorbidity more frequently preceding epilepsy included cerebrovascular accident (OR: 3.59), congenital anomalies (2.18), and multiple sclerosis (1.33); and following epilepsy: dementia (1.91), personality disorder (1.59), alcohol abuse (1.22), and Parkinson (1.21). Mental retardation (13.08), neurological cancer (8.49), benign neoplasm (4.69), infections (3.14), and psychosis (1.58) might precede or not epilepsy. A common progression was to schizophrenia, dementia, and other neurological diseases (mainly cerebral palsy and other degenerative diseases of nervous system). Co-prescription associations with major-moderate potential interactions were 54% for carbamazepine, 61% phenytoin, 53% phenobarbital, and 32% valproate. Major potential interactions were with antipsychotic, anxiolytic, opioid, cardiovascular, and other anti-seizure medications (ASMs). The most frequent comorbidities of epilepsy were congenital, cerebrovascular, and neurological and psychiatric conditions. High comorbidity and co-prescription with potential interactions can increase the complexity of care of patients with epilepsy.

NGS4THAL, a One-Stop Molecular Diagnosis and Carrier Screening Tool for Thalassemia and Other Hemoglobinopathies by Next-Generation Sequencing.

Thalassemia is one of the most common genetic diseases and a major health threat worldwide. Accurate, efficient, and scalable analysis of next-generation sequencing (NGS) data is much needed for its molecular diagnosis and carrier screening. We developed NGS4THAL, a bioinformatics analysis pipeline analyzing NGS data to detect pathogenic variants for thalassemia and other hemoglobinopathies. NGS4THAL realigns ambiguously mapped NGS reads derived from the homologous Hb gene clusters for accurate detection of point mutations and small insertions/deletions. It uses a combination of complementary structural variant (SV) detection tools and an in-house database of control data containing specific SVs to achieve accurate detection of the complex SV types. Detected variants are matched with those in HbVar (A Database of Human Hemoglobin Variants and Thalassemia Mutations), allowing recognition of known pathogenic variants, including disease modifiers. Tested on simulation data, NGS4THAL achieved high sensitivity and specificity. For targeted NGS sequencing data from samples with laboratory-confirmed pathogenic Hb variants, it achieved 100% detection accuracy. Application of NGS4THAL on whole genome sequencing data from unrelated studies revealed thalassemia mutation carrier rates for Hong Kong Chinese and Northern Vietnamese that were consistent with previous reports. NGS4THAL is a highly accurate and efficient molecular diagnosis tool for thalassemia and other hemoglobinopathies based on tailored analysis of NGS data and may be scaled for population carrier screening.

PandemonCAT: Monitoring the COVID-19 Pandemic in Catalonia, Spain.

BACKGROUND: The principal objective of this paper is to introduce an online interactive application that helps in real-time monitoring of the COVID-19 pandemic in Catalonia, Spain (PandemonCAT). METHODS: This application is designed as a collection of user-friendly dashboards using open-source R software supported by the Shiny package. RESULTS: PandemonCAT reports accumulated weekly updates of COVID-19 dynamics in a geospatial interactive platform for individual basic health areas (ABSs) of Catalonia. It also shows on a georeferenced map the evolution of vaccination campaigns representing the share of population with either one or two shots of the vaccine, for populations of different age groups. In addition, the application reports information about environmental and socioeconomic variables and also provides an interactive interface to visualize monthly public mobility before, during, and after the lockdown phases. Finally, we report the smoothed standardized COVID-19 infected cases and mortality rates on maps of basic health areas ABSs and regions of Catalonia. These smoothed rates allow the user to explore geographic patterns in incidence and mortality rates. The visualization of the variables that could have some influence on the spatiotemporal dynamics of the pandemic is demonstrated. CONCLUSIONS: We believe the addition of these new dimensions, which is the key innovation of our project, will improve the current understanding of the spread and the impact of COVID-19 in the community. This application can be used as an open tool for consultation by the public of Catalonia and Spain in general. It could also have implications in facilitating the visualization of public health data, allowing timely interpretation due to the unpredictable nature of the pandemic.

Systemic inflammation and sympathetic activation in gestational diabetes mellitus with obstructive sleep apnea.

BACKGROUND: Although some evidence suggests an association between obstructive sleep apnea (OSA) and gestational diabetes mellitus (GDM), its consequences still remain largely unknown. We sought to determine whether OSA is associated with higher inflammation and sympathetic levels in GDM, and to relate them with insulin resistance and perinatal outcomes. METHODS: OSA was identified by polysomnography and defined as an apnea-hypopnea index of ≥ 5 h-1. Plasma cytokines (TNF-α, IL-1ß, IL-6, IL-8, IL-10), metanephrine, and normetanephrine were determined by immunoassays. RESULTS: We included 17 patients with GDM and OSA and 34 without OSA. Women with GDM and OSA had higher normetanephrine concentrations [81 IQR (59-134) vs. 68 (51-81) pg/mL]. No differences in the inflammatory profile were found, while IL-1ß was higher in patients with mean nocturnal oxyhemoglobin saturation ≤ 94%. We found positive correlations between increased sympathetic activation and IL-1ß, with obstructive apneas, while time in REM showed an inverse relationship with IL-1ß and metanephrine. Furthermore, IL-10 was inversely related with time in sleep stages 1-2, and with the arousal index, and it was positively related with time in slow-wave sleep. Significant correlations were also found between IL-1ß and insulin resistance. There were no significant differences in neonatal characteristics; however, we found inverse relationships between IL-10 and birth weight (BW), and percentile of BW. CONCLUSIONS: OSA increased sympathetic activity, and IL-1ß concentration was higher in patients with GDM with lower nocturnal oxygenation, all of which were related with obstructive events, and time in REM. Moreover, IL-1ß was related with insulin resistance, and IL-10 inversely correlated with neonatal BW.

Sequencing of a Chinese tetralogy of Fallot cohort reveals clustering mutations in myogenic heart progenitors.

Tetralogy of Fallot (TOF) is the most common cyanotic heart defect, yet the underlying genetic mechanisms remain poorly understood. Here, we performed whole-genome sequencing analysis on 146 nonsyndromic TOF parent-offspring trios of Chinese ethnicity. Comparison of de novo variants and recessive genotypes of this data set with data from a European cohort identified both overlapping and potentially novel gene loci and revealed differential functional enrichment between cohorts. To assess the impact of these mutations on early cardiac development, we integrated single-cell and spatial transcriptomics of early human heart development with our genetic findings. We discovered that the candidate gene expression was enriched in the myogenic progenitors of the cardiac outflow tract. Moreover, subsets of the candidate genes were found in specific gene coexpression modules along the cardiomyocyte differentiation trajectory. These integrative functional analyses help dissect the pathogenesis of TOF, revealing cellular hotspots in early heart development resulting in cardiac malformations.

Prenatal exposure to antibiotics and risk of childhood overweight or obesity: A systematic review and meta-analysis.

Infant antibiotic use has been modestly associated with childhood overweight, while evidence on prenatal exposures remains less clear. A systematic review and meta-analysis were conducted to examine associations between maternal antibiotic exposure and subsequent risk of childhood overweight/obesity. Publications were retrieved from PubMed and Web of Science databases up to December 2019. A random effects model was used to summarize risk estimates, overall, and by period and frequency of exposure. Ten observational studies were included in the narrative synthesis. We did not observe a clear pattern of association between prenatal antibiotic use and childhood overweight/obesity. There were suggestive associations for repeated exposures (≥3 courses) and those taking place during the second trimester of gestation, which were also pointed out in our meta-analysis (relative risk, RR2T = 1.15 (95% CI 1.04; 1.28, I2  = 18%), and RR3courses = 1.31 (95% CI 1.03; 1.67, I2  = 65%), respectively). In most studies, however, confounding by underlying infections cannot be ruled out. Overall, current data do not conclusively support the hypothesis that prenatal exposure to antibiotics is a risk factor for childhood obesity/overweight. Further studies, controlling for underlying infections and exploring the association according to frequency, period (both prenatal and intrapartum) and type of antibiotic, are needed to clarify this association.

Deviation from baseline mutation burden provides powerful and robust rare-variants association test for complex diseases.

Identifying rare variants that contribute to complex diseases is challenging because of the low statistical power in current tests comparing cases with controls. Here, we propose a novel and powerful rare variants association test based on the deviation of the observed mutation burden of a gene in cases from a baseline predicted by a weighted recursive truncated negative-binomial regression (RUNNER) on genomic features available from public data. Simulation studies show that RUNNER is substantially more powerful than state-of-the-art rare variant association tests and has reasonable type 1 error rates even for stratified populations or in small samples. Applied to real case-control data, RUNNER recapitulates known genes of Hirschsprung disease and Alzheimer's disease missed by current methods and detects promising new candidate genes for both disorders. In a case-only study, RUNNER successfully detected a known causal gene of amyotrophic lateral sclerosis. The present study provides a powerful and robust method to identify susceptibility genes with rare risk variants for complex diseases.

Methodological limitations in studies assessing the effects of environmental and socioeconomic variables on the spread of COVID-19: a systematic review.

BACKGROUND: While numerous studies have assessed the effects of environmental (meteorological variables and air pollutants) and socioeconomic variables on the spread of the COVID-19 pandemic, many of them, however, have significant methodological limitations and errors that could call their results into question. Our main objective in this paper is to assess the methodological limitations in studies that evaluated the effects of environmental and socioeconomic variables on the spread of COVID-19. MAIN BODY: We carried out a systematic review by conducting searches in the online databases PubMed, Web of Science and Scopus up to December 31, 2020. We first excluded those studies that did not deal with SAR-CoV-2 or COVID-19, preprints, comments, opinion or purely narrative papers, reviews and systematic literature reviews. Among the eligible full-text articles, we then excluded articles that were purely descriptive and those that did not include any type of regression model. We evaluated the risk of bias in six domains: confounding bias, control for population, control of spatial and/or temporal dependence, control of non-linearities, measurement errors and statistical model. Of the 5631 abstracts initially identified, we were left with 132 studies on which to carry out the qualitative synthesis. Of the 132 eligible studies, we evaluated 63.64% of the studies as high risk of bias, 19.70% as moderate risk of bias and 16.67% as low risk of bias. CONCLUSIONS: All the studies we have reviewed, to a greater or lesser extent, have methodological limitations. These limitations prevent conclusions being drawn concerning the effects environmental (meteorological and air pollutants) and socioeconomic variables have had on COVID-19 outcomes. However, we dare to argue that the effects of these variables, if they exist, would be indirect, based on their relationship with social contact. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12302-021-00550-7.

Los equipos de pediatría ante la obesidad infantil: un estudio cualitativo dentro del proyecto STOP / Paediatric teams in front of childhood obesity: a qualitative study within the STOP project

Introducción: Comprender los factores que influyen en el tratamiento del sobrepeso y la obesidad infantil es crucial para ofrecer el mejor apoyo a las familias y solucionar este grave problema de salud pública.Objetivo: Describir las actitudes y sentimientos del personal de pediatría al tratar con los padres el sobrepeso y la obesidad de sus hijos, explorando los facilitadores y las barreras percibidas, a fin de realizar una atención efectiva.Sujetos y método: Estudio cualitativo por cuestionarios individuales semiestructurados de personal pediátrico (pediatras y enfermeras pediatras; n=57; 68% mujeres) de centros de atención primaria y hospitales de la isla de Mallorca, sobre los que se aplicó un análisis temático.Resultados: Se identificaron 3 temas: «La actitud de los padres en la obesidad infantil» (subtemas «La conciencia de los padres», «Los padres piden ayuda»), «El personal pediátrico y la obesidad infantil» (subtemas «Aproximación al problema: la entrevista con los padres», «Buscando juntos la solución») y «Barreras del sistema» (subtemas «Mejorar el trabajo en equipo y la política de salud», «Participación familiar al abordar y estudiar la obesidad infantil»).Conclusiones: El personal pediátrico sabe tratar la obesidad infantil, pero demanda entrenamiento en motivación. La terapia de la obesidad infantil será efectiva cuando los padres/cuidadores reconocen el problema y establecen confianza con los equipos pediátricos. El sistema de salud aún es una barrera a la actividad del personal pediátrico. (AU)

Introduction: Understanding the underlying factors that influence the approach to overweight and obesity in children is basic to best support families searching a solution to this important public health problem.Objective: To assess attitudes and feelings of paediatric staff in addressing overweight and childhood obesity to parents, exploring perceived barriers and facilitators, for an effective care.Participants and method: Qualitative study by means of individual semi-structured questionnaires of paediatric staff (paediatricians and paediatrician nurses; n=57; 68% female) of primary health care centres and hospitals in Mallorca. Thematic analysis was done.Results: Three themes emerged from the data: «Parents’ attitude in childhood obesity» (sub-themes «The conscience of parents», «The parents ask for help»), «Paediatric staff and childhood obesity» (sub-themes «Approaching to the problem: The interview with parents», «Looking together for the solution»), and «System barriers» (sub-themes «Improving teamwork and health policy», «Family participation in addressing childhood obesity»).Conclusions: Paediatric staffs know how to treat childhood obesity, but demand training on motivation. Effectivity on therapy of childhood obesity will be obtained after parents/carers recognize the problem and establish a trustful relationship with paediatric staff. The health system is still a barrier to the activity of paediatric personnel. (AU)

Size matters: Large copy number losses in Hirschsprung disease patients reveal genes involved in enteric nervous system development.

Hirschsprung disease (HSCR) is a complex genetic disease characterized by absence of ganglia in the intestine. HSCR etiology can be explained by a unique combination of genetic alterations: rare coding variants, predisposing haplotypes and Copy Number Variation (CNV). Approximately 18% of patients have additional anatomical malformations or neurological symptoms (HSCR-AAM). Pinpointing the responsible culprits within a CNV is challenging as often many genes are affected. Therefore, we selected candidate genes based on gene enrichment strategies using mouse enteric nervous system transcriptomes and constraint metrics. Next, we used a zebrafish model to investigate whether loss of these genes affects enteric neuron development in vivo. This study included three groups of patients, two groups without coding variants in disease associated genes: HSCR-AAM and HSCR patients without associated anomalies (HSCR-isolated). The third group consisted of all HSCR patients in which a confirmed pathogenic rare coding variant was identified. We compared these patient groups to unaffected controls. Predisposing haplotypes were determined, confirming that every HSCR subgroup had increased contributions of predisposing haplotypes, but their contribution was highest in isolated HSCR patients without RET coding variants. CNV profiling proved that specifically HSCR-AAM patients had larger Copy Number (CN) losses. Gene enrichment strategies using mouse enteric nervous system transcriptomes and constraint metrics were used to determine plausible candidate genes located within CN losses. Validation in zebrafish using CRISPR/Cas9 targeting confirmed the contribution of UFD1L, TBX2, SLC8A1, and MAPK8 to ENS development. In addition, we revealed epistasis between reduced Ret and Gnl1 expression and between reduced Ret and Tubb5 expression in vivo. Rare large CN losses-often de novo-contribute to HSCR in HSCR-AAM patients. We proved the involvement of six genes in enteric nervous system development and Hirschsprung disease.

Impact of COVID-19 on the Health of the General and More Vulnerable Population and Its Determinants: Health Care and Social Survey-ESSOC, Study Protocol.

This manuscript describes the rationale and protocol of a real-world data (RWD) study entitled Health Care and Social Survey (ESSOC, Encuesta Sanitaria y Social). The study's objective is to determine the magnitude, characteristics, and evolution of the COVID-19 impact on overall health as well as the socioeconomic, psychosocial, behavioural, occupational, environmental, and clinical determinants of both the general and more vulnerable population. The study integrates observational data collected through a survey using a probabilistic, overlapping panel design, and data from clinical, epidemiological, demographic, and environmental registries. The data will be analysed using advanced statistical, sampling, and machine learning techniques. The study is based on several measurements obtained from three random samples of the Andalusian (Spain) population: general population aged 16 years and over, residents in disadvantaged areas, and people over the age of 55. Given the current characteristics of this pandemic and its future repercussions, this project will generate relevant information on a regular basis, commencing from the beginning of the State of Alarm. It will also establish institutional alliances of great social value, explore and apply powerful and novel methodologies, and produce large, integrated, high-quality and open-access databases. The information described here will be vital for health systems in order to design tailor-made interventions aimed at improving the health care, health, and quality of life of the populations most affected by the COVID-19 pandemic.