Study protocol of a randomized controlled trial to assess safety of teleconsultation compared with face-to-face consultation: the ECASeT study

BackgroundThe use of remote consultation modalities has exponentially grown in the past few years, particularly since the onset of the COVID-19 pandemic. Although a huge body of the literature has described the use of phone (tele) and video consultations, very few of the studies correspond to randomized controlled trials, and none of them has assessed the safety of these consultation modalities as the primary objective. The primary objective of this trial was to assess the safety of remote consultations (both video and teleconsultation) in the follow-up of patients in the hospital setting.MethodsMulticenter, randomized controlled trial being conducted in four centers of an administrative healthcare area in Catalonia (North-East Spain). Participants will be screened from all individuals, irrespective of age and sex, who require follow-up in outpatient consultations of any of the departments involved in the study. Eligibility criteria have been established based on the local guidelines for screening patients for remote consultation. Participants will be randomly allocated into one of the two study arms: conventional face-to-face consultation (control) and remote consultation, either teleconsultation or video consultation (intervention). Routine follow-up visits will be scheduled at a frequency determined by the physician based on the diagnostic and therapy of the baseline disease (the one triggering enrollment). The primary outcome will be the number of adverse reactions and complications related to the baseline disease. Secondary outcomes will include non-scheduled visits and hospitalizations, as well as usability features of remote consultations. All data will either be recorded in an electronic clinical report form or retrieved from local electronic health records. Based on the complications and adverse reaction rates reported in the literature, we established a target sample size of 1068 participants per arm. Recruitment started in May 2022 and is expected to end in May 2024.DiscussionThe scarcity of precedents on the assessment of remote consultation modalities using randomized controlled designs challenges making design decisions, including recruitment, selection criteria, and outcome definition, which are discussed in the manuscript.Trial registrationNCT05094180. The items of the WHO checklist for trial registration are available in Additional file 1. Registered on 24 November 2021

Regulatory sites for splicing in human basal ganglia are enriched for disease-relevant information

Genome-wide association studies have generated an increasing number of common genetic variants associated with neurological and psychiatric disease risk. An improved understanding of the genetic control of gene expression in human brain is vital considering this is the likely modus operandum for many causal variants. However, human brain sampling complexities limit the explanatory power of brain-related expression quantitative trait loci (eQTL) and allele-specific expression (ASE) signals. We address this, using paired genomic and transcriptomic data from putamen and substantia nigra from 117 human brains, interrogating regulation at different RNA processing stages and uncovering novel transcripts. We identify disease-relevant regulatory loci, find that splicing eQTLs are enriched for regulatory information of neuron-specific genes, that ASEs provide cell-specific regulatory information with evidence for cellular specificity, and that incomplete annotation of the brain transcriptome limits interpretation of risk loci for neuropsychiatric disease. This resource of regulatory data is accessible through our web server, http://braineacv2.inf.um.es/

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Background Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. Methods We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. Findings Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16–36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10−7). Interpretation These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data. Funding The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources)

Identification of candidate Parkinson disease genes by integrating genome-wide association study, expression, and epigenetic data sets

Importance Substantial genome-wide association study (GWAS) work in Parkinson disease (PD) has led to the discovery of an increasing number of loci shown reliably to be associated with increased risk of disease. Improved understanding of the underlying genes and mechanisms at these loci will be key to understanding the pathogenesis of PD. Objective To investigate what genes and genomic processes underlie the risk of sporadic PD. Design and Setting This genetic association study used the bioinformatic tools Coloc and transcriptome-wide association study (TWAS) to integrate PD case-control GWAS data published in 2017 with expression data (from Braineac, the Genotype-Tissue Expression [GTEx], and CommonMind) and methylation data (derived from UK Parkinson brain samples) to uncover putative gene expression and splicing mechanisms associated with PD GWAS signals. Candidate genes were further characterized using cell-type specificity, weighted gene coexpression networks, and weighted protein-protein interaction networks. Main Outcomes and Measures It was hypothesized a priori that some genes underlying PD loci would alter PD risk through changes to expression, splicing, or methylation. Candidate genes are presented whose change in expression, splicing, or methylation are associated with risk of PD as well as the functional pathways and cell types in which these genes have an important role. Results Gene-level analysis of expression revealed 5 genes (WDR6 [OMIM 606031], CD38 [OMIM 107270], GPNMB [OMIM 604368], RAB29 [OMIM 603949], and TMEM163 [OMIM 618978]) that replicated using both Coloc and TWAS analyses in both the GTEx and Braineac expression data sets. A further 6 genes (ZRANB3 [OMIM 615655], PCGF3 [OMIM 617543], NEK1 [OMIM 604588], NUPL2 [NCBI 11097], GALC [OMIM 606890], and CTSB [OMIM 116810]) showed evidence of disease-associated splicing effects. Cell-type specificity analysis revealed that gene expression was overall more prevalent in glial cell types compared with neurons. The weighted gene coexpression performed on the GTEx data set showed that NUPL2 is a key gene in 3 modules implicated in catabolic processes associated with protein ubiquitination and in the ubiquitin-dependent protein catabolic process in the nucleus accumbens, caudate, and putamen. TMEM163 and ZRANB3 were both important in modules in the frontal cortex and caudate, respectively, indicating regulation of signaling and cell communication. Protein interactor analysis and simulations using random networks demonstrated that the candidate genes interact significantly more with known mendelian PD and parkinsonism proteins than would be expected by chance. Conclusions and Relevance Together, these results suggest that several candidate genes and pathways are associated with the findings observed in PD GWAS studies

Impact of the controlling nutritional status (CONUT) score on perioperative morbidity and oncological outcomes in patients with bladder cancer treated with radical cystectomy

Introduction and objectives: To evaluate the impact of the Controlling Nutritional Status (CONUT) score on perioperative morbidity and oncological outcomes of bladder cancer (BC) patients treated with radical cystectomy (RC). Materials and methods: We retrospectively analyzed a multi-institutional cohort of 347 patients treated with RC for clinical-localized BC between 2005 and 2019. The CONUT-score was defined as an algorithm including serum albumin, total lymphocyte count, and cholesterol. Multivariable logistic regression analyses were performed to evaluate the ability of the CONUT-score to predict any-grade complications, major complications and 30 days readmission. Multivariable Cox' regression models were performed to evaluate the prognostic effect of the CONUT-score on recurrence-free survival (RFS), overall survival (OS), and cancer-specific survival (CSS). Results: A cut-off value to discriminate between low and high CONUT-score was determined by calculating the receiver operating characteristic (ROC) curve. The area under the curve was 0.72 hence high CONUT-score was defined as ≥3 points. Overall, 112 (32.3%) patients had a high CONUT. At multivariable logistic regression analyses, high CONUT was associated with any-grade complications (OR 3.58, P = 0.001), major complications (OR 2.56, P = 0.003) and 30 days readmission (OR 2.39, P = 0.01). On multivariable Cox' regression analyses, high CONUT remained associated with worse RFS (HR 2.57, P < 0.001), OS (HR 2.37, P < 0.001) and CSS (HR 3.52, P < 0.001). Conclusions: Poor nutritional status measured by the CONUT-score is independently associated with a poorer postoperative course after RC and is predictive of worse RFS, OS, and CSS. This simple index could serve as a comprehensive personalized risk-stratification tool identifying patients who may benefit from an intensified regimen of supportive cares

Study protocol of a randomized controlled trial to assess safety of teleconsultation compared with face-to-face consultation: the ECASeT study

Abstract Background The use of remote consultation modalities has exponentially grown in the past few years, particularly since the onset of the COVID-19 pandemic. Although a huge body of the literature has described the use of phone (tele) and video consultations, very few of the studies correspond to randomized controlled trials, and none of them has assessed the safety of these consultation modalities as the primary objective. The primary objective of this trial was to assess the safety of remote consultations (both video and teleconsultation) in the follow-up of patients in the hospital setting. Methods Multicenter, randomized controlled trial being conducted in four centers of an administrative healthcare area in Catalonia (North-East Spain). Participants will be screened from all individuals, irrespective of age and sex, who require follow-up in outpatient consultations of any of the departments involved in the study. Eligibility criteria have been established based on the local guidelines for screening patients for remote consultation. Participants will be randomly allocated into one of the two study arms: conventional face-to-face consultation (control) and remote consultation, either teleconsultation or video consultation (intervention). Routine follow-up visits will be scheduled at a frequency determined by the physician based on the diagnostic and therapy of the baseline disease (the one triggering enrollment). The primary outcome will be the number of adverse reactions and complications related to the baseline disease. Secondary outcomes will include non-scheduled visits and hospitalizations, as well as usability features of remote consultations. All data will either be recorded in an electronic clinical report form or retrieved from local electronic health records. Based on the complications and adverse reaction rates reported in the literature, we established a target sample size of 1068 participants per arm. Recruitment started in May 2022 and is expected to end in May 2024. Discussion The scarcity of precedents on the assessment of remote consultation modalities using randomized controlled designs challenges making design decisions, including recruitment, selection criteria, and outcome definition, which are discussed in the manuscript. Trial registration NCT05094180. The items of the WHO checklist for trial registration are available in Additional file 1. Registered on 24 November 2021

The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population‐Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight

The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases. To perform the largest PD genome-wide association study restricted to a single country. We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations, and burden analyses. We identified a novel population-specific genome-wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome-wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence by two-sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls. Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain. © 2019 International Parkinson and Movement Disorder Society