The aim of this study was to identity in silico the relationships among microRNAs (miRNAs) and genes encoding transcription factors, ubiquitylation, DNA methylation, and histone modifications in ...systemic lupus erythematosus (SLE). To identify miRNA dysregulation in SLE, we used miR2Disease and PhenomiR for information about miRNAs exhibiting differential regulation in disease and other biological processes, and HMDD for information about experimentally supported human miRNA-disease association data from genetics, epigenetics, circulating miRNAs, and miRNA-target interactions. This information was incorporated into the miRNA analysis. High-throughput sequencing revealed circulating miRNAs associated with kidney damage in patients with SLE. As the main finding of our in silico analysis of miRNAs differentially expressed in SLE and their interactions with disease-susceptibility genes, post-translational modifications, and transcription factors; we highlight 226 miRNAs associated with genes and processes. Moreover, we highlight that alterations of miRNAs such as hsa-miR-30a-5p, hsa-miR-16-5p, hsa-miR-142-5p, and hsa-miR-324-3p are most commonly associated with post-translational modifications. In addition, altered miRNAs that are most frequently associated with susceptibility-related genes are hsa-miR-16-5p, hsa-miR-374a-5p, hsa-miR-34a-5p, hsa-miR-31-5p, and hsa-miR-1-3p.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To define the relationship between chronic chikungunya post-viral arthritis disease severity, cytokine response and T cell subsets in order to identify potential targets for therapy.
Participants ...with chikungunya arthritis were recruited from Colombia from 2019-2021. Arthritis disease severity was quantified using the Disease Activity Score-28 and an Arthritis-Flare Questionnaire adapted for chikungunya arthritis. Plasma cytokine concentrations (interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, interferon-γ and tumor necrosis factor (TNF)) were measured using a Meso Scale Diagnostics assay. Peripheral blood T cell subsets were measured using flow cytometry.
Among participants with chikungunya arthritis (N = 158), IL-2 levels and frequency of regulatory T cells (Tregs) were low. Increased arthritis disease activity was associated with higher levels of inflammatory cytokines (IL-6, TNF and CRP) and immunoregulatory cytokine IL-10 (p<0.05). Increased arthritis flare activity was associated with higher Treg frequencies (p<0.05) without affecting T effector (Teff) frequencies, Treg/Teff ratios and Treg subsets. Finally, elevated levels of IL-2 were correlated with increased Treg frequency, percent Tregs out of CD4+ T cells, and Treg subsets expressing immunosuppressive markers, while also correlating with an increased percent Teff out of live lymphocytes (p<0.05).
Chikungunya arthritis is characterized by increased inflammatory cytokines and deficient IL-2 and Treg responses. Greater levels of IL-2 were associated with improved Treg numbers and immunosuppressive markers. Future research may consider targeting these pathways for therapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The complex physiology of eukaryotic cells is regulated through numerous mechanisms, including epigenetic changes and posttranslational modifications. The wide-ranging diversity of these mechanisms ...constitutes a way of dynamic regulation of the functionality of proteins, their activity, and their subcellular localization as well as modulation of the differential expression of genes in response to external and internal stimuli that allow an organism to respond or adapt to accordingly. However, alterations in these mechanisms have been evidenced in several autoimmune diseases, including systemic lupus erythematosus (SLE). The present review aims to provide an approach to the current knowledge of the implications of these mechanisms in SLE pathophysiology.
Dengue is endemic in many countries throughout the tropics and subtropics, and the disease causes substantial morbidity and health-care burdens in these regions. We previously compared antibody ...responses after one-dose, two-dose, or three-dose primary regimens with the only approved dengue vaccine CYD-TDV (Dengvaxia; Sanofi Pasteur, Lyon, France) in individuals aged 9 years and older with previous dengue exposure. In this study, we assessed the need for a CYD-TDV booster after these primary vaccination regimens.
In this randomised, controlled, phase 2, non-inferiority study, healthy individuals aged 9–50 years recruited from three sites in Colombia and three sites in the Philippines (excluding those with the usual contraindications to vaccinations) were randomly assigned 1:1:1 via a permuted block method with stratification by site and by age group using an independent voice response system to receive, at 6-month intervals, three doses of CYD-TDV (three-dose group), one dose of placebo followed by two doses of CYD-TDV (two-dose group), or two doses of placebo followed by one dose of CYD-TDV (one-dose group). Participants were also randomly assigned (1:1) to receive a CYD-TDV booster at 1 year or 2 years after the last primary dose. Each CYD-TDV dose was 0·5 mL and administered subcutaneously in the deltoid region of the upper arm. The investigators and sponsor, study staff interacting with the investigators, and participants and their parents or legally acceptable representatives were masked to group assignment. Neutralising antibodies were measured by 50% plaque reduction neutralisation testing, and geometric mean titres (GMTs) were calculated. Due to a change in study protocol, only participants who were dengue seropositive at baseline in the Colombian cohort received a booster vaccination. The primary outcome was to show non-inferiority of the booster dose administered at 1 year or 2 years after the two-dose and three-dose primary regimens; non-inferiority was shown if the lower limit of the two-sided adjusted 95% CI of the between-group (day 28 post-booster dose GMT from the three-dose or two-dose group vs day 28 GMT post-dose three of the three-dose primary regimen three-dose group) geometric mean ratio (GMR) was higher than 0·5 for each serotype. Non-inferiority of the 1-year or 2-year booster was shown if all four serotypes achieved non-inferiority. Safety was assessed among all participants who received the booster. This trial is registered with ClinicalTrials.gov, NCT02628444, and is closed to accrual.
Between May 2 and Sept 16, 2016, we recruited and enrolled 1050 individuals who received either vaccine or placebo. Of the 350, 348, and 352 individuals randomly assigned to three-dose, two-dose, and one-dose groups, respectively, 108, 115, and 115 from the Colombian cohort were dengue seropositive at baseline and received a booster; 55 and 53 in the three-dose group received a booster after 1 year and 2 years, respectively, as did 59 and 56 in the two-dose group, and 62 and 53 in the one-dose group. After the three-dose primary schedule, non-inferiority was shown for serotypes 2 (GMR 0·746; 95% CI 0·550–1·010) and 3 (1·040; 0·686–1·570) but not serotypes 1 (0·567; 0·399–0·805) and 4 (0·647; 0·434–0·963) for the 1-year booster, and again for serotypes 2 (0·871; 0·673–1·130) and 3 (1·150; 0·887–1·490) but not serotypes 1 (0·688; 0·479–0·989) and 4 (0·655; 0·471–0·911) for the 2-year booster. Similarly, after the two-dose primary schedule, non-inferiority was shown for serotypes 2 (0·809; 0·505–1·300) and 3 (1·19; 0·732–1·940) but not serotypes 1 (0·627; 0·342–1·150) and 4 (0·499; 0·331–0·754) for the 1-year booster, and for serotype 3 (0·911; 0·573–1·450) but not serotypes 1 (0·889; 0·462–1·710), 2 (0·677; 0·402–1·140), and 4 (0·702; 0·447–1·100) for the 2-year booster. Thus, non-inferiority of the 1-year or 2-year booster was not shown after the three-dose or two-dose primary vaccination regimen in dengue-seropositive participants. No safety concerns occurred with the 1-year or 2-year CYD-TDV booster.
CYD-TDV booster 1 year or 2 years after the two-dose or three-dose primary vaccination regimen does not elicit a consistent, meaningful booster effect against all dengue serotypes in participants who are seropositive for dengue at baseline.
Sanofi Pasteur.
For the Spanish translation of the abstract see Supplementary Materials section.
Three doses of the licensed tetravalent dengue vaccine CYD-TDV (Dengvaxia, Sanofi Pasteur, Lyon France) are immunogenic and effective against symptomatic dengue in individuals aged 9 years and older ...who are dengue seropositive. Previous trials have provided some evidence that antibody responses elicited after just one dose or two doses of CYD-TDV might be similar to those elicited after three doses. We compared antibody responses following one-dose, two-dose, and three-dose vaccination regimens in individuals who were dengue seropositive at baseline up to 1 year after the last injection.
In this randomised, controlled, phase 2, non-inferiority study (CYD65), healthy individuals aged 9–50 years were recruited from the community in three sites in Colombia and three sites in the Philippines. Participants were randomly assigned (1:1:1), using a permuted block method with stratification by site and age group, to receive, at 6-month intervals (on day 0, month 6, and month 12), three doses of CYD-TDV (three-dose group), one dose of placebo (on day 0) and two doses of CYD-TDV (at months 6 and 12; two-dose group), or two doses of placebo (on day 0 and month 6) and one dose of CYD-TDV (at month 12; one-dose group). Each dose of CYD-TDV was 0·5 mL, administered subcutaneously into the deltoid of the upper arm. Participants, study staff, investigators, and the funder were masked to group assignment. The co-primary endpoints were geometric mean titres (GMTs) of neutralising antibodies against each dengue virus serotype at 28 days and 1 year after the last vaccine injection. After a protocol amendment during the conduct of the study, the original co-primary objectives of non-inferiority of the one-dose and two-dose groups to the three-dose group were altered to include non-inferiority of the two-dose group to the three-dose group only, to be assessed in individuals who were dengue seropositive at baseline. Non-inferiority was shown if the lower limit of the 95% CI for the ratio of GMTs (GMR) at 28 days and 1 year between groups was more than 0·5 for each serotype. The analysis of the coprimary objectives was done in the per-protocol analysis dataset, which included all participants who had been vaccinated, had no protocol deviations, and had a valid serology test result for at least one dengue serotype at 28 days after the third injection. Safety was assessed throughout in all participants who received at least one injection of study drug, regardless of serostatus. This trial is registered with ClinicalTrials.gov, NCT02628444, and is closed to accrual.
Between May 2, 2016, and Sept 16, 2016, we recruited and enrolled 1050 individuals, of whom 1048 received at least one injection and 993 had at least one blood sample taken (full-analysis dataset; 333 in three-dose group, 328 in two-dose group, and 332 in one-dose group). 860 (86·6%) of 993 participants in the full-analysis dataset were dengue seropositive at baseline. Non-inferiority (two dose vs three dose) was shown for each serotype at both 28 days and 1 year among dengue-seropositive participants (number of participants assessed: 272 two-dose group, 265 three-dose group at 28 days; and 190 two-dose group, 185 three-dose group at 1 year). At 28 days after the last injection, neutralising antibody GMTs were 899 (95% CI 752–1075) in the two-dose group versus 822 (700–964) in the three dose group against dengue serotype 1 (GMR 1·09 95% CI 0·86–1·39); 869 (754–1002) versus 875 (770–995) against serotype 2 (GMR 0·99 0·82–1·20); 599 (524–685) versus 610 (535–694) against serotype 3 (GMR 0·98 0·82–1·18); and 510 (453–575) versus 531 (470–601) against serotype 4 (GMR 0·96 0·81–1·14). At year 1, GMTs had decreased but remained above baseline for all serotypes: 504 (95% CI 403–630) in the two-dose group versus 490 (398–604) in the three-dose group against serotype 1 (GMR 1·03 0·76–1·40); 737 (611–888) versus 821 (704–957) against serotype 2 (GMR 0·90 0·71–1·14); 437 (368–519) versus 477 (405–561) against serotype 3 (GMR 0·92 0·72–1·16); and 238 (205–277) versus 270 (235–310) against serotype 4 (GMR 0·88 0·72–1·09). Reactogenicity profiles were similar across treatment groups. Most unsolicited adverse events after any injection were non-serious and systemic in nature. During the study, 60 serious adverse events were reported in 58 participants (14 in three-dose group, 26 in two-dose group, 18 in one-dose group), mostly infection and infestations or injury, poisoning, and procedural complications. No serious adverse events of special interest or admissions to hospital for dengue occurred. Two deaths occurred, unrelated to study treatment.
A two-dose CYD-TDV regimen might be an alternative to the licensed three-dose regimen in individuals who are dengue seropositive at baseline and aged 9 years and older. Vaccination with a reduced number of doses could lead to improved vaccine compliance and coverage, especially in low-resource settings.
Sanofi Pasteur.
Abstract Introduction: This article describes the main differences between COVID-19-induced acute kidney injury (AKI-COVID19) in patients with previous normal renal function (AKI-NRF) and those with ...chronic kidney disease (AKI-CKD) treated in a high complexity clinic in Barranquilla (Colombia). Material and Methods: The patients included in this study (n: 572) were those with a positive diagnosis of COVID-19 confirmed by detection of a positive PCR for SARS-CoV-2. Of these patients, 188 developed AKI during their hospital stay. Patients’ epidemiological data, serum parameters, and clinical frailty status were recorded. Statistical analysis and comparison among AKI-NRF, AKI-CKD, and non-AKI patients were performed. Results: The incidence of COVID-19-induced AKI was 33%, with the majority classified as AKIN 1, 16% requiring renal replacement therapy, and AKI-COVID19 mortality of 68%. A significantly higher prevalence of hypertension, cardiac disease, and serum reactive C-protein and lower albumin values in AKI-CKD patients was recorded. Mortality rate, invasive ventilation requirement, and D-dimer levels were significantly higher in AKI-NRF patients: Conclusion: Different clinical patterns between AKI-NRF and AKI-CKD were documented.
Resumo Introdução: Este artigo descreve as principais diferenças entre a lesão renal aguda induzida por COVID-19 (LRA-COVID19) em pacientes com função renal normal prévia (LRA-FRN) e aqueles com doença renal crônica (LRA-DRC) atendidos em uma clínica de alta complexidade em Barranquilla (Colômbia). Material e Métodos: Os pacientes incluídos neste estudo (n: 572) foram aqueles com um diagnóstico positivo de COVID-19 confirmado pela detecção de PCR positivo para SARS-CoV-2. Destes pacientes, 188 desenvolveram LRA durante sua internação. Foram registrados os dados epidemiológicos, os parâmetros séricos e o estado de fragilidade clínica dos pacientes. Foram feitas a análise estatística e a comparação entre pacientes com LRA-FRN, LRA-DRC, e pacientes sem LRA. Resultados: A incidência de LRA induzida por COVID-19 foi de 33%, com a maioria classificada como AKIN 1, 16% exigindo terapia renal substitutiva, e a mortalidade por LRA-COVID19 foi de 68%. Foi registrada uma prevalência significativamente mais alta de hipertensão, doença cardíaca e proteína C reativa sérica e valores mais baixos de albumina em pacientes com LRA-DRC. A taxa de mortalidade, a necessidade de ventilação invasiva e os níveis de dímero-D foram significativamente mais altos em pacientes com LRA-FRN. Conclusão: Foram documentados padrões clínicos diferentes entre LRA-FRN e LRA-DRC.
Introduction
Atypical hemolytic uremic syndrome (aHUS) is a rare and genetically mediated systemic disease most often caused by uncontrolled and chronic complement activation that leads to systemic ...thrombotic microangiopathy, renal and extra-renal damage.
Materials and methods
This is descriptive, retrospective and multicenter study, which reports demographic, clinical, laboratory, and genetic characteristics, as well as their treatment response and outcome of 20 aHUS patients diagnosed between 2014 and 2018.
Results
Most patients were female adults (75%) and 30% were associated to pregnancy/postpartum, 15% to autoimmune disease, and 65% to infections. Gastrointestinal involvement (75%) was the most frequent extra-renal organ damage. Antenatal mortality and mortality rate were 5% and 10%, respectively. 25% of the patients progressed to end-stage renal disease. In 4/8 of patients treated within 1 week of presentation, eculizumab treatment restored multi-organ function after 4 weeks of treatment. CFH (37%) and CFI (25%) mutations were the most frequent.
Conclusion
This is the first series of aHUS cases of Colombian Caribbean region which reports the clinical and epidemiological characteristics of this condition in this region.
Introduction
Frailty is a multicausal syndrome characterized by a decrease in strength, resistance and physiological function, which makes the individual vulnerable and dependent, and increases ...his/her mortality. This syndrome is more prevalent among older individuals, and chronic kidney disease patients, particularly those on dialysis. Dialysis dose is currently standardized for hemodialysis (HD) patients regardless of their age and functional status. However, it has been postulated that the dialysis dose required in older patients, especially frail ones, should be lower, since it could increase their degree of frailty. Then, the purpose of this study was to evaluate if there would be a correlation between the dose of Kt/V and the degree of frailty in a population of adult patients on HD.
Materials and methods
A cross-sectional study with 82 patients on HD in Barranquilla (Colombia) and Lobos (Argentina) was conducted. Socio-demographic and laboratory data, as well as dialysis doses (Kt/V) were recorded and scales of fragility, physical activity, gait and grip strength were applied. Then these data were correlated by a Spearman’s correlation and a logistic regression.
Results
CFS, social isolation, physical activity,
gait speed,
and
prehensile strength tests
were outside the reference ranges in the studied group. No significant correlation was found between dialysis dose and all the above mentioned functional tests. However, a significant and inverse correlation between physical activity and CFS was documented (score − 1.41 (CI − 2.1 to − 0.7).
Conclusion
No significant correlation was documented between Kt/V value and different parameters of the frailty status, but this status correlated significantly and inversely with physical activity in this group. Frailty status in hemodialysis patients was significantly higher in older individuals, although young individuals were not exempt from it.
In this review, we were interested to identify the wide universe of enzymes associated with epigenetic modifications, whose gene expression is regulated by miRNAs with a high relative abundance in ...Crohn's disease (CD) affected tissues, with the aim to determine their impact in the pathogenesis and evolution of the disease.
We used HMDD and Bibliometrix R-package in order to identify the miRNAs overexpressed in CD. The identified enzymes associated with epigenetic mechanisms and post-translational modifications, regulated by miRNAs upregulated in CD, were analyzed using String v11 database.
We found 190 miRNAs with great abundance in patients with CD, of which 26 miRNAs regulate the gene expression of enzymes known to catalyze epigenetic modifications involved in essentials pathophysiological processes, such as chromatin architecture reorganization, immune response regulation including CD4+ T cells polarization, integrity of gut mucosa, gut microbiota composition and tumorigenesis.
The integrated analysis of miRNAs with a high relative abundance in patients with CD showed a combined and superimposed gene expression regulation of enzymes associated with relevant epigenetic mechanisms and that could explain, in part, the pathogenesis of CD.
In FIDELITY, finerenone improved cardiorenal outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes. This analysis explores the efficacy and safety of finerenone in Hispanic ...patients.
Post hoc analysis of the FIDELITY prespecified pooled analysis of the FIDELIO-DKD and FIGARO-DKD randomized control trials.
Patients with type 2 diabetes and CKD (urinary albumin-to-creatinine ratio UACR of≥30 to<300mg/g and estimated glomerular filtration rate eGFR of≥25-≤90mL/min/1.73m2, or UACR of≥300 to≤5,000 and eGFR of≥25mL/min/1.73m2) on optimized renin–angiotensin system blockade.
Finerenone or placebo.
Cardiovascular composite (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure); kidney composite (kidney failure, sustained ≥57% eGFR decline, or renal death); change in UACR.
Of 13,026 patients, 2,099 (16.1%) self-identified as Hispanic. Median follow-up was 3.0 years. The cardiovascular composite outcome occurred in 10.0% of Hispanic patients receiving Finerenone and in 12.3% of Hispanic patients receiving placebo (HR, 0.80; 95% CI, 0.62-1.04). This was consistent with non-Hispanic patients (HR, 0.87; 95% CI, 0.79-0.97; Pinteraction=0.59). The kidney composite outcome occurred in 6.5% and 6.6% of Hispanic patients with finerenone and placebo, respectively (HR, 0.94; 95% CI, 0.67-1.33). The risk reduction was consistent with that observed in non-Hispanic patients (HR, 0.75; 95% CI, 0.64-0.87; Pinteraction=0.22). Finerenone reduced UACR by 32% at month 4 in both Hispanic and non-Hispanic patients versus placebo (P<0.001 for both patient groups). The safety profile of finerenone and incidence of hyperkalemia was similar between Hispanic and non-Hispanic patient groups.
Small sample size, short follow-up time, and lower treatment adherence in the Hispanic population.
Overall, the efficacy and safety of finerenone were similar in Hispanic and non-Hispanic patients with CKD and type 2 diabetes.
Bayer AG
ClinicalTrials.gov identifier: NCT02540993, NCT02545049
Chronic kidney disease (CKD) in patients with type 2 diabetes occurs more frequently in Hispanic patients than in non-Hispanic patients, with a more rapid progression to kidney failure. Treatment with finerenone reduces the risk of having a kidney or heart event (such as starting dialysis or having a heart attack) in patients with CKD and type 2 diabetes. Because clinical trials that investigate treatments for CKD and type 2 diabetes have not included enough Hispanic patients, the benefits of treatments particularly for Hispanic patients are frequently unknown. This study explores the benefits of finerenone in Hispanic patients. Overall, the study shows that finerenone can provide kidney and heart benefits in Hispanic patients with CKD and type 2 diabetes, as it does in non-Hispanic patients.
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