title stringlengths 1 1.19k | keywords stringlengths 0 668 | concept stringlengths 0 909 | paragraph stringlengths 0 61.8k | PMID stringlengths 10 11 |
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Outcome | death, ’ disease, cancer, CVD, Deaths, Death | CVD, CANCER, SECONDARY | The primary outcome of the study was all-cause mortality and secondary outcomes included CVD mortality, cancer mortality, and other-cause mortality. The SUN cohort keeps a close and permanent follow-up that provides continuously updated information about participants’ disease incidence and death. Deaths are reported by... | PMC10195723 |
Other covariates | Participants provided additional information at baseline on sociodemographic characteristics, medication use, personal and family history of medical conditions, and adherence to the Mediterranean diet (MedDiet) [ | PMC10195723 | ||
Statistical analysis | cancer, death | REGRESSION, CANCER, CVD | Baseline characteristics for all participants and OBS components were described according to OBS quartiles, expressed as means with standard deviations for numerical variables or percentages for categorical variables. Pearson product–moment correlation coefficients were calculated between dietary OBS components.Cox pro... | PMC10195723 |
Results | PMC10195723 | |||
Contribution of the individual components of the OBS | tachycardia, cardiovascular disease, aneurysm, cancer, stroke, diabetes, angina pectoris, atrial fibrillation, depression, hypertension, dyslipidemia | PULMONARY EMBOLISM, MYOCARDIAL INFARCTION, CARDIOVASCULAR DISEASE, ANEURYSM, CARDIOVASCULAR DISEASES, DEEP VEIN THROMBOSIS, CANCER, STROKE, RECRUITMENT, INTERMITTENT CLAUDICATION, CARDIAC INSUFFICIENCY, DIABETES, ATRIAL FIBRILLATION, EVENTS, HYPERTENSION, DYSLIPIDEMIA | After removing each of the OBS components one at a time and adjusting for the removed component using it as a covariate, the differences in mortality risk estimates remained significant and barely changed (a maximum difference of 2% with respect to the primary OBS analysis) (Fig. All-cause mortality hazard ratios (HRs)... | PMC10195723 |
Sensitivity analyses | Consistent with the primary analyses, all point estimates showed an inverse association between the OBS and risk of all-cause and cause-specific mortality for all the sensitivity analyses. Results remained similar in most scenarios, and in some models, the inverse association became stronger, suggesting a robust associ... | PMC10195723 | ||
Discussion | cancer | CVD, CANCER, OXIDATIVE STRESS, OXIDATIVE STRESS | We investigated the association of overall oxidative balance with all-cause, CVD, cancer, and other-cause mortality risk among nearly 20,000 middle-aged Spanish adults in a Mediterranean cohort. We used a novel holistic score based on 12 a priori selected dietary and non-dietary lifestyle pro- and antioxidants exposure... | PMC10195723 |
Conclusions | CVD | Our findings suggest that greater antioxidant balance status is associated to lower premature mortality, including CVD and cancer-related mortality. Individuals exposed to both antioxidant dietary and lifestyle exposures may potentially experience the lowest all-cause and cause-specific mortality risk. Moreover, the re... | PMC10195723 | |
Additional information | The findings of the study have been presented as a virtual oral presentation at the American Society for Nutrition meeting, NUTRITION 2021 LIVE ONLINE, and the presentation has been recognized as finalist for the American Society for Nutrition’s Emerging Leaders in Nutrition Science Abstract Recognition Award Program. | PMC10195723 | ||
Supplementary Information | Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 237 KB)Irene Talavera-Rodriguez and Cesar I. Fernandez-Lazaro have contributed equally to this work. | PMC10195723 | ||
Acknowledgements | More extensive acknowledgments are included in the online Additional File 1. | PMC10195723 | ||
Author contributions | ITR and CIFL contributed equally to this work. ITR, AHR, MAM and MRC participated in the design research; ITR, CIFL, and MRC conducted research; ITR, CIFL, and MRC analyzed data or performed statistical analysis; ITR, CIFL, MSH, MRC wrote the manuscript; AHR, CG, MSP, CFA, and MAM revised the manuscript and provided cr... | PMC10195723 | ||
Funding | Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. The SUN Project has received funding from the Spanish Government-Instituto de Salud Carlos III, and the European Regional Development Fund (FEDER) (RD 06/0045, CIBER-OBN, Grants PI10/02658, PI10/02293, PI13/00615, PI14/01668, PI14/0179... | PMC10195723 | ||
Data availability | Data described in the manuscript, code book, and analytic code will be made available upon request pending application and approval. | PMC10195723 | ||
Declarations | PMC10195723 | |||
Conflict of interest | The authors declare that there is no conflict of interest regarding the publication of this article. | PMC10195723 | ||
Ethical approval | The present study has been conducted in accordance with the Declaration of Helsinki, with the approval of the Institutional Review Board of the University of Navarra. | PMC10195723 | ||
Consent to participate | All participants provided informed consent by responding to the first questionnaire. | PMC10195723 | ||
Consent for publication | No applicable. | PMC10195723 | ||
References | PMC10195723 | |||
Methods | First, we analysed differential gene expression in six lymphoblastoid cell lines (LCLs) before and after incubation with busulfan. Second, we used WES data from 87 HSCT patients and estimated the association with SOS at the SNP and the gene levels. We then combined the results of the expression and the association anal... | PMC10075428 | ||
Results | After treatment of LCLs with busulfan, 1708 genes were significantly up-, and 1385 down-regulated. The combination of the expression experiment and the association analysis of WES data into a single test statistic revealed 35 genes associated with the outcome. These genes are involved in various biological functions an... | PMC10075428 | ||
Conclusions | RARE DISEASES | This novel data analysis pipeline integrates two independent omics datasets and increases statistical power for identifying genotype-phenotype associations. The analysis of the transcriptomics profile of cell lines treated with busulfan and WES data from HSCT patients allowed us to identify potential genetic contributo... | PMC10075428 | |
Trial registration | For the clinical dataset: Clinicaltrials.gov: | PMC10075428 | ||
Data Availability | Hepatic Sinusoidal Obstruction Syndrome | BLOOD | The data underlying the results presented in the study were included in a previously published article and its supplementary information files: Ansari M, Petrykey K, Rezgui MA, Del Vecchio V, Cortyl J, Ralph R-O et al. Genetic Susceptibility to Hepatic Sinusoidal Obstruction Syndrome in Pediatric Patients Undergoing He... | PMC10075428 |
1. Introduction | SINUSOIDAL OBSTRUCTION SYNDROME, COMPLICATIONS, COMPLICATION | Sinusoidal obstruction syndrome (SOS) of the liver is a serious, sometimes life-threatening complication of chemotherapies and hematopoietic stem cell transplantation (HSCT) [Various studies have reported germline genetic variants in association with SOS. Most of these studies have used a candidate gene approach. They ... | PMC10075428 | |
2. Materials and methods | PMC10075428 | |||
2.1. Design of the study | We developed a data analysis pipeline which includes the following steps:First, we performed a differential gene expression analysis of LCLs before and after | PMC10075428 | ||
Flowchart of the transcriptomic data analysis pipeline in 6 lymphoblastic cell lines with and without | Legend: BAM, Binary Alignment Map; DEG, differentially expressed genes; RNA, ribonucleic acid; SAM, Sequence Alignment Map; WES, whole-exome sequencing. | PMC10075428 | ||
2.2 Transcriptomic analysis of lymphoblastoid cell lines | We collected RNA sequencing data on LCLs (Coriell Cell Repository, Camden, NJ, USA) before and after exposure to busulfan. Briefly, we performed true-seq RNA-sequencing of mRNA extracted from six LCLs (GM7056, GM12239, GM12762, GM12057, GM12489, and GM12546) pre and post 48h of 100 μM busulfan treatment. The chosen con... | PMC10075428 | ||
2.3. Data filtering on WES genotype data | We used the unfiltered whole-exome sequencing data, of which analyses were published previously [ | PMC10075428 | ||
2.4. Tests of association of WES data with clinical outcome | Our clinical outcome SOS was defined using the modified Seattle criteria, as outlined in the description of the clinical dataset [We used the Versatile Gene-based Association Study-2 (VEGAS2) software [ | PMC10075428 | ||
2.5. Combined test of transcriptomic and WES data | We computed a gene-based score, and its associated p-value, by combining the results of the differential gene expression analysis (To assign equal weights to the 2 experiments into the combined statistic, we rescaled the p-values derived from the LCL expression analysis to have the same range as the p-values calculated... | PMC10075428 | ||
2.6. Over-representation analysis | The functional characterization of the genes that show a significant difference in expression in LCLs after treatment with busulfan was performed using an over-representation analysis (ORA). We used the Kyoto Encyclopedia of Genes and Genomes (KEGG) [ | PMC10075428 | ||
2.7. Polygenic risk scores | ∑We | REGRESSION | We computed polygenic risk scores (PRSs), for the cases and controls, as the sum of the number of risk alleles carried at each locus (∑We used for the estimations of the PRSs the SNPs with the p-value of the association test using the logistic regression model < 0.05, and located within the boundaries of the genes (inc... | PMC10075428 |
3. Results | PMC10075428 | |||
3.1. Transcriptomic analysis of lymphoblastoid cell lines | death, Death, necrosis | GRAFT-VERSUS-HOST DISEASE, DISEASE, ADHESION, NECROSIS | We identified 3093 genes that showed significant differential expression in the LCLs after Among the gene sets that were enriched in up-regulated genes, we found pathways involved in “Cell growth and death” (p53 signaling pathway, Apoptosis, Necroptosis; Regulation by c-FLIP, Caspase activation via Death Receptors in t... | PMC10075428 |
3.2. Data filtering on WES genotype data | We used the unfiltered whole-exome sequencing data from our previous publication [ | PMC10075428 | ||
3.3. Association tests in the clinical WES dataset | The analysis at the SNP level using a standard chi-squared test identified 60 variants associated with SOS after Benjamini and Hochberg (1995) step-up false discovery rate (FDR) control [At the gene-level, we identified 12 genes that reached significance after Benjamini and Hochberg FDR control | PMC10075428 | ||
3.4. Combined test, Over-representation analysis and polygenic risk score | We identified 35 genes that were found to be significant for the test which combined the results of the differential gene expression analysis in LCLs and the gene-based test for an association in the WES dataset after Bonferroni correction for multiple testing | PMC10075428 | ||
Graphical representation of the relationship between the p-values of the combined test (color coded), the lymphoblastoid cell line expression test (x-axis), and the whole-exome sequencing association test (y axis): We see that the majority of the genes that are associated with a significant combined test statistic show... | cancer, death | CANCER, HAND INFECTION | The functional characterization of these genes using the Reactome database identified 14 significantly enriched pathways The KEGG analysis identified 16 enriched pathways. These pathways were involved in “cell growth and death” (p53 signaling pathway, cellular senescence), “signaling molecules and interaction” (cytokin... | PMC10075428 |
Over representation analysis using CPDB.org incorporating 35 genes associated with sinusoidal obstruction syndrome identified through a combined test statistic. | The polygenic risk score computed using 209 SNPs from the 35 genes identified through combined expression and association analyses at the gene level showed a significantly different distribution between the cases and the controls (p-value = 8.506e-07; | PMC10075428 | ||
4. Discussion | death | ADVERSE EVENTS, INFLAMMATORY RESPONSE | In this study, we identified new potential genetic determinants of SOS at the SNP, gene, and pathway levels using a new multi-omics data analysis pipeline integrating data from two different experiments. We analyzed In the LCLs treated with busulfan, we found several upregulated pathways, which are mainly involved in t... | PMC10075428 |
Supporting information | PMC10075428 | |||
Clinical data of 87 patients included in this study (adapted from Ansari et al. BBMT, 2020, with permission). | (PDF)Click here for additional data file. | PMC10075428 | ||
Differential gene expression analysis in lymphoblastoid cell lines; sorted by expression change. | (PDF)Click here for additional data file. | PMC10075428 | ||
Over-representation analysis of differentially expressed genes in lymphoblastoid cell lines, sorted by strength of association. | (PDF)Click here for additional data file. | PMC10075428 | ||
List of SNPs that are found to be in significant association with VOD, after correction for multiple testing. | The SNPs are sorted by chromosome and position. Functional annotations of the variants were retrieved from ENSEMBL (Genome assembly: GRCh37.p13). The r2 column shows the r2 measure of linkage disequilibrium between each SNP and the following SNP in the table, in the CEU population from the 1,000 Genomes phase 3 data, a... | PMC10075428 | ||
Whole-exome sequencing association analysis of 57 individuals (11 cases with sinusoidal obstruction syndrome and 46 controls), genes with the strongest association, sorted by adjusted association metric. | (PDF)Click here for additional data file. | PMC10075428 | ||
Combined association analysis of differential gene expression in lymphoblastoid cell lines and whole-exome sequencing in 57 individuals; genes sorted by adjusted association metric. | (PDF)Click here for additional data file. | PMC10075428 | ||
Over-representation analysis of differentially expressed genes in a combined test statistic integrating differential expression data of lymphoblastoid cell lines after exposure to busulfan and a whole-exome association analysis. | (PDF)Click here for additional data file. | PMC10075428 | ||
Abbreviations | Acute lymphoblastic leukemiaConfidence intervalCentral nervous systemDeoxyribonucleic acidFalse discovery rateHematopoietic stem cell transplantationHardy–Weinberg equilibriumLymphoblastoid cell lineLinkage disequilibriumKyoto Encyclopedia of Genes and GenomesMinor allele frequencyOver-representation analysisPolygenic ... | PMC10075428 | ||
References | PMC10075428 | |||
Objectives | To develop and probe the first computerised decision-support tool to provide antidepressant treatment guidance to general practitioners (GPs) in UK primary care. | PMC9990646 | ||
Design | BLIND | A parallel group, cluster-randomised controlled feasibility trial, where individual participants were blind to treatment allocation. | PMC9990646 | |
Setting | South London NHS GP practices. | PMC9990646 | ||
Participants | depressive disorder, treatment-resistant | Ten practices and eighteen patients with treatment-resistant current major depressive disorder. | PMC9990646 | |
Interventions | Practices were randomised to two treatment arms: (a) treatment-as-usual, (b) computerised decision support tool. | PMC9990646 | ||
Results | ADVERSE EVENTS, RECRUITMENT | Ten GP practices participated in the trial, which was within our target range (8–20). However, practice and patient recruitment were slower than anticipated and only 18 of 86 intended patients were recruited. This was due to fewer than expected patients being eligible for the study, as well as disruption resulting from... | PMC9990646 | |
Conclusions | RECRUITMENT | Overall, feasibility was not shown in the current study and the following modifications would be needed to attempt to overcome the limitations found: (a) inclusion of patients who have only tried one Selective Serotonin Reuptake Inhibitor, rather than two, to improve recruitment and pragmatic relevance of the study; (b... | PMC9990646 | |
STRENGTHS AND LIMITATIONS OF THIS STUDY | The Antidepressant Advisor tool was incorporated into an existing general practitioner (GP) healthcare record system for ease of use by GPs.We were unable to recruit a sufficient number of participants to estimate effect sizes for future trials.The eligibility criteria for participants to have tried two antidepressants... | PMC9990646 | ||
Introduction | depression | The last 70 years have seen the development of a wide range of antidepressants. In UK primary care, three first-line antidepressants are primarily used for the treatment of depression (fluoxetine, sertraline and citalopram), all of which are Selective Serotonin Reuptake Inhibitors.One way to provide structured treatmen... | PMC9990646 | |
Study objectives | RECRUITMENT | Our objectives were to describe (a) the recruitment of GP practices and enrolment of patients, (b) baseline patient characteristics, (c) report the prespecified feasibility outcomes and (d) provide descriptive summaries of the chosen clinical outcomes. | PMC9990646 | |
Methods | PMC9990646 | |||
Design | The Antidepressant Advisor Study (ADeSS) was a feasibility cluster-randomised clinical trial of a computerised decision support system for antidepressant prescribing in UK primary care. The trial was randomised at the GP practice level, where GP practices formed the clusters. At each practice, a single GP could partici... | PMC9990646 | ||
Eligibility criteria | depressive syndrome | Inclusion criteria for GP practices were: (a) up to one GP/practice participating at any time; located within one of the study’s South East London areas; and (b) using EMIS electronic health record software. Inclusion criteria for patients in addition to being registered at one of the participating practices were: (a) ... | PMC9990646 | |
Recruitment of GP practices | RECRUITMENT | The GP practice recruitment period was from September 2018 until March 2020, when the study had to be stopped due to the COVID-19 pandemic. During this time, 70 GP practices in Lambeth were approached as well as several other practices in South East London. Of these, 20 (29%) were recruited into the study and randomise... | PMC9990646 | |
Recruitment of patients | Patients at participating GP practices were enrolled in three stages: first, a search was conducted (via EMIS) to identify potentially eligible patients from among those registered at each GP practice. Second, patients meeting initial screening criteria were sent a letter inviting them to participate in the study and a... | PMC9990646 | ||
Measures | PMC9990646 | |||
Feasibility outcomes | ADVERSE EVENT, RECRUITMENT, ADVERSE EVENT | The primary feasibility outcome was:The number and percentage of patients lost to follow-up.Secondary feasibility outcomes were:GP adherence to the algorithm for each completed patient rated by a trial clinician (0=none of recommended steps implemented; 1=less than 50% of recommended steps implemented; 2=50% or more of... | PMC9990646 | |
Primary clinical outcome measure | Depressive | Self-rated Quick Inventory of Depressive Symptomatology sum score (QIDS-SR16 | PMC9990646 | |
Secondary clinical outcome measures | Depressive, Anxiety, Montgomery-Asberg Depression | Depressive symptoms were assessed by the Montgomery-Asberg Depression Rating Scale (MADRSClinical Global Impression (CGI) scale,Generalised Anxiety Disorder-7Body mass index at follow-up assessment adjusting for baseline score. | PMC9990646 | |
Exploratory clinical outcome measures | app).Average | MEDICATION SIDE EFFECTS | Average score for medication side effects on Frequency, Intensity, Burden of Side Effects Rating (FIBSER)Average % of adherence to prescribed antidepressant medication (self-report via mobile app).Average Maudsley Modified Patient Health Questionnaire-9 (MM-PHQ-9) | PMC9990646 |
Health economic measures | psychiatric | Service use as determined on EMIS including psychiatric referrals and referrals to study psychiatrist, as well as time to psychiatric referral; also primary care consultation rates.Service use; self-reported using a modified version of the Adult Service Use Schedule.Quality of life using the EQ-5D-3LRefer to the publis... | PMC9990646 | |
Interventions | SIDE EFFECTS | ADeSS was a two-arm cluster-randomised study. GP practices were allocated either to the intervention arm (herein ‘Decision tool’) or the control arm (herein ‘treatment-as-usual’; TAU). In the Decision tool arm, patients received treatment from GPs who were using the computerised decision support tool. The tool assisted... | PMC9990646 | |
Statistical analyses | depression | REGRESSION | The primary feasibility outcome (#1, ‘Number of patients lost to follow-up’) was summarised with frequencies and percentages with exact 95% CIs (Clopper-Pearson methodSeveral continuous outcomes (#8–9; clinical outcomes #13–14, #16–17, #20) were analysed using linear regression models where the dependent variable was t... | PMC9990646 |
Patient and public involvement | The study was supported by service users which provide input to the study. We have scheduled regular meetings with our service users and one of our service user representatives has read our trial protocol publication and commented on it before submission. Due to the pandemic we have not been able to run wider public en... | PMC9990646 | ||
Results | SECONDARY | Results for study outcomes below are ordered conceptually rather than by importance or whether they were related to feasibility or explored clinical outcomes for future trials. For our health economic results showing the absence of secondary care use in our sample (see Supplementary Results and Supplementary Table A, B... | PMC9990646 | |
Patient enrolment and baseline characteristics | PMC9990646 | |||
Number of patients enrolled per month | Hypomania | Each practice enrolled between 0 and 4 patients during the enrolment period, a mean of one per month (95% Poisson CI 0.59 to 1.58). Consolidated Standards of Reporting Trials (CONSORT) flow diagram. A CONSORT diagram describing the participant flow and exclusion from prescreening to follow-up for the trial. GP, general... | PMC9990646 | |
GP-based outcomes | PMC9990646 | |||
Number of GP practices recruited per month | RECRUITMENT | When including all recruited GP practices, a total of 20 practices were recruited. A breakdown of GP recruitment by month is presented in Supplementary Table D. The mean number of practices recruited per month was 1.11 (95% Poisson CI 0.68 to 1.72). When including only GP practices that participated in the study (ie, e... | PMC9990646 | |
GP satisfaction with tool-assisted consultation flow and outcome | GPs in the Decision tool arm were invited to complete a satisfaction survey at the end of their time in the trial. There were five GP practices in the Decision tool arm, although only four of these practices saw at least one patient and the practice not having any eligible patients also did not return a GP satisfaction... | PMC9990646 | ||
GP adherence to the algorithm | Supplementary Table F presents, for each GP in the Decision tool arm, the number of patients in each adherence category (and percent, relative to total number of patients seen by the GP). These data present a mixed picture. While for 4/7 patients the algorithm was ‘Fully implemented’ by the GPs, for 3/7 patients GPs im... | PMC9990646 | ||
Loss to follow-up (primary feasibility outcome) | Only 1/18 (5.6%; 95% CI 0.1 to 27.3) participants failed to attend their follow-up interview at 15/18 weeks after baseline. The single patient not attending follow-up was in the TAU arm. In total, five patients had their follow-up interview outside the 15–18 weeks window because of difficulties contacting patients or s... | PMC9990646 | ||
Adverse events | nausea, tiredness | ADVERSE EVENTS | Most adverse events were attributable to expected antidepressant side effects, such as tiredness, loss of libido and nausea (see also Supplementary Table G). No SAEs were recorded during the trial. In total, there were eight mild AEs (affecting eight patients) and two moderate AEs (affecting one patient). There was an ... | PMC9990646 |
Score for medication side effects during follow-up | 5/18 patients were not using the mobile app and their weekly FIBSER scores were collected by telephone or email. FIBSER completion rates in the first week were good (83% overall), but this fell in subsequent weeks and around 20%–30% of patients completed FIBSER during the final weeks of the treatment period (Supplement... | PMC9990646 | ||
Patient adherence to treatment based on EMIS electronic prescribing records | Supplementary Table J presents the percentage of scheduled GP appointments that were attended by patients (including phone consultations) over the treatment period. This information was collected from EMIS records for 15/18 patients. One patient did not attend follow-up (and therefore, EMIS data were not extracted); tw... | PMC9990646 | ||
Adherence to prescribed antidepressant measured via mobile app | Uptake of the mobile app was low and some patients who initially agreed to use the app experienced technical difficulties (eg, unable to log in, missed notifications). Initial inspection of the data indicated that there were insufficient reports of daily adherence to summarise this outcome. Therefore, we report data co... | PMC9990646 | ||
GP practice effect on primary clinical outcome | The ICC for QIDS-SR16 at follow-up (among 17 patients at 9 practices) was 0.07, indicating that 7.3% of variance in patient scores was attributable to differences between GP practices, after taking into account treatment allocation and baseline score. However, the 95% bootstrap CIs ranged from <0.001 to 0.76, highlight... | PMC9990646 | ||
Discussion | depression, depressive symptoms | RECRUITMENT | This trial investigated the feasibility of a cluster-randomised design to study a novel computerised Antidepressant Advisor tool for UK primary care which was developed as part of this study. While the loss to follow-up rate (the primary feasibility outcome) was very low and the software implementation of our algorithm... | PMC9990646 |
Supplementary Material | PMC9990646 | |||
Reviewer comments | PMC9990646 | |||
Data availability statement | Data are available upon reasonable request. We have not obtained consent for sharing pseudonymised data and will therefore only be able to share fully anonymised data such as scores on standardised instruments via the King’s Open Research Data System ( | PMC9990646 | ||
Ethics statements | PMC9990646 | |||
Patient consent for publication | Not applicable. | PMC9990646 | ||
Ethics approval | This study involves human participants and was approved by London - Camberwell St Giles Research Ethics Committee, reference number: 17/LO/2074. Participants gave informed consent to participate in the study before taking part. | PMC9990646 | ||
References | PMC9990646 | |||
1. Introduction | CORONAVIRUS INFECTION | This research aimed to evaluate the effects of high-dose cholecalciferol (VDThe new coronavirus infection (COVID-19) is a global pandemic that has aggressively propagated worldwide [In this manner, vitamins D (VD) and C, in addition to zinc supplementations, are recommended by the Jordan Ministry of Health as a part of... | PMC10005440 | |
2. Materials and Methods | PMC10005440 |
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