Preliminary Evaluation of 2 Patient-Centered Educational Animations About Kidney Transplant Complications.

BACKGROUND Fear of kidney transplant complications and incomplete information can lower transplant acceptance and preparedness. Our group developed 2 patient-centered educational animated videos on common kidney transplant complications to complement a previously developed video-based curriculum intended to promote kidney transplant access. MATERIAL AND METHODS We preliminarily evaluated the 2 animated educational videos at a single center using mixed methods. We conducted a before-and-after single group study with 22 patients after kidney transplantation to measure the videos' acceptability and feasibility to improve patient knowledge, understanding, and concerns of kidney transplant complications. Concurrently, we individually interviewed 12 patients before kidney transplantation about their perceptions of the 2 videos and analyzed the data thematically. RESULTS Knowledge of kidney transplant complications increased 10% (7.82 to 8.59, P=0.002) from before to after video viewing. Large effect size increases for knowledge were found for different strata of age, race, and health literacy. The mean total score for perceived understanding of kidney transplant complications increased after video exposure by 7% (mean 2.48 to 2.66, P=0.184). There was no change in kidney transplant concern scores from before to after video viewing (mean 1.70 to 1.70, P=1.00). After video viewing, all patients reported positive ratings on comfort watching, understanding, and engaging. Three themes of patient perceptions emerged: (1) messages received as intended, (2) felt informed, and (3) scared but not deterred. CONCLUSIONS Two animated educational videos about kidney transplant complications were well received and promise to positively impact individuals' knowledge and understanding, without raising excessive concerns.

Newspaper framing of motor vehicle crashes and road safety in Argentina.

The media plays a key role in shaping the public's perception of road safety. This study analyzes the newspaper coverage and framing of motor vehicle crashes (MVCs) and road safety in Argentina, South America. The content of 304 articles published by 15 newspapers in November 2020 was reviewed. The results show that episodically framed news stories (focused on a single event or incident) prevail over thematically framed articles. MVCs are presented primarily as 'police' events and tend to receive more coverage when fatalities are involved. There is limited information provided on contextual and risk factors, and road safety advice is rarely included. Speeding, infrastructure, alcohol and other human-related variables are the most cited risk factors. Very few articles mention the use of protective devices (seat-belt, helmet and child restraint system). Although motorcyclists represent 40% of RTC deaths in Argentina, only 20% of the news coverage was about them. News coverage was quite similar in national and regional newspapers. There is an opportunity for the media to help build a better road safety culture, but significant changes in news framing are required. Practical recommendations for editors, journalists and road safety practitioners are provided.

Genetics and Epigenetics in Obesity: What Do We Know so Far?

PURPOSE OF REVIEW: Enormous progress has been made in understanding the genetic architecture of obesity and the correlation of epigenetic marks with obesity and related traits. This review highlights current research and its challenges in genetics and epigenetics of obesity. RECENT FINDINGS: Recent progress in genetics of polygenic traits, particularly represented by genome-wide association studies, led to the discovery of hundreds of genetic variants associated with obesity, which allows constructing polygenic risk scores (PGS). In addition, epigenome-wide association studies helped identifying novel targets and methylation sites being important in the pathophysiology of obesity and which are essential for the generation of methylation risk scores (MRS). Despite their great potential for predicting the individual risk for obesity, the use of PGS and MRS remains challenging. Future research will likely discover more loci being involved in obesity, which will contribute to better understanding of the complex etiology of human obesity. The ultimate goal from a clinical perspective will be generating highly robust and accurate prediction scores allowing clinicians to predict obesity as well as individual responses to body weight loss-specific life-style interventions.

The effect of polyphenols on DNA methylation-assessed biological age attenuation: the DIRECT PLUS randomized controlled trial.

BACKGROUND: Epigenetic age is an estimator of biological age based on DNA methylation; its discrepancy from chronologic age warrants further investigation. We recently reported that greater polyphenol intake benefitted ectopic fats, brain function, and gut microbiota profile, corresponding with elevated urine polyphenols. The effect of polyphenol-rich dietary interventions on biological aging is yet to be determined. METHODS: We calculated different biological aging epigenetic clocks of different generations (Horvath2013, Hannum2013, Li2018, Horvath skin and blood2018, PhenoAge2018, PCGrimAge2022), their corresponding age and intrinsic age accelerations, and DunedinPACE, all based on DNA methylation (Illumina EPIC array; pre-specified secondary outcome) for 256 participants with abdominal obesity or dyslipidemia, before and after the 18-month DIRECT PLUS randomized controlled trial. Three interventions were assigned: healthy dietary guidelines, a Mediterranean (MED) diet, and a polyphenol-rich, low-red/processed meat Green-MED diet. Both MED groups consumed 28 g walnuts/day (+ 440 mg/day polyphenols). The Green-MED group consumed green tea (3-4 cups/day) and Mankai (Wolffia globosa strain) 500-ml green shake (+ 800 mg/day polyphenols). Adherence to the Green-MED diet was assessed by questionnaire and urine polyphenols metabolomics (high-performance liquid chromatography quadrupole time of flight). RESULTS: Baseline chronological age (51.3 ± 10.6 years) was significantly correlated with all methylation age (mAge) clocks with correlations ranging from 0.83 to 0.95; p < 2.2e - 16 for all. While all interventions did not differ in terms of changes between mAge clocks, greater Green-Med diet adherence was associated with a lower 18-month relative change (i.e., greater mAge attenuation) in Li and Hannum mAge (beta = - 0.41, p = 0.004 and beta = - 0.38, p = 0.03, respectively; multivariate models). Greater Li mAge attenuation (multivariate models adjusted for age, sex, baseline mAge, and weight loss) was mostly affected by higher intake of Mankai (beta = - 1.8; p = 0.061) and green tea (beta = - 1.57; p = 0.0016) and corresponded with elevated urine polyphenols: hydroxytyrosol, tyrosol, and urolithin C (p < 0.05 for all) and urolithin A (p = 0.08), highly common in green plants. Overall, participants undergoing either MED-style diet had ~ 8.9 months favorable difference between the observed and expected Li mAge at the end of the intervention (p = 0.02). CONCLUSIONS: This study showed that MED and green-MED diets with increased polyphenols intake, such as green tea and Mankai, are inversely associated with biological aging. To the best of our knowledge, this is the first clinical trial to indicate a potential link between polyphenol intake, urine polyphenols, and biological aging. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03020186.

Implication of DNA methylation during lifestyle mediated weight loss.

Over the past 50 years, the number of overweight/obese people increased significantly, making obesity a global public health challenge. Apart from rare monogenic forms, obesity is a multifactorial disease, most likely resulting from a concerted interaction of genetic, epigenetic and environmental factors. Although recent studies opened new avenues in elucidating the complex genetics behind obesity, the biological mechanisms contributing to individual's risk to become obese are not yet fully understood. Non-genetic factors such as eating behaviour or physical activity are strong contributing factors for the onset of obesity. These factors may interact with genetic predispositions most likely via epigenetic mechanisms. Epigenome-wide association studies or methylome-wide association studies are measuring DNA methylation at single CpGs across thousands of genes and capture associations to obesity phenotypes such as BMI. However, they only represent a snapshot in the complex biological network and cannot distinguish between causes and consequences. Intervention studies are therefore a suitable method to control for confounding factors and to avoid possible sources of bias. In particular, intervention studies documenting changes in obesity-associated epigenetic markers during lifestyle driven weight loss, make an important contribution to a better understanding of epigenetic reprogramming in obesity. To investigate the impact of lifestyle in obesity state specific DNA methylation, especially concerning the development of new strategies for prevention and individual therapy, we reviewed 19 most recent human intervention studies. In summary, this review highlights the huge potential of targeted interventions to alter disease-associated epigenetic patterns. However, there is an urgent need for further robust and larger studies to identify the specific DNA methylation biomarkers which influence obesity.

Implementation of the Canadian syncope pathway: a pilot non-randomized stepped wedge trial.

BACKGROUND: We developed the Canadian Syncope Pathway (CSP) based on the Canadian Syncope Risk Score (CSRS) to aid emergency department (ED) syncope management. This pilot implementation study assessed patient inclusion, length of transition period, as well as process measures (engagement, reach, adoption, and fidelity) to prepare for multicenter implementation. METHODS: A non-randomized stepped wedge trial at two hospitals was conducted over a 7-month period. After 2-3 months in the control condition, the hospitals crossed over in a stepwise fashion to the intervention condition. Study participants were ED and non-ED physicians, or their delegates, and patients (aged ≥ 18 years) with syncope. We aimed to analyze patient characteristics, ED management including disposition decision, and CSRS recommendations application for all eligible patients during the intervention period. Our targets were 95% inclusion rate, 70% adoption (proportion of physicians who applied the pathway), 60% reach (intervention applied to eligible patients) and 70% fidelity (appropriate recommendations application) for all eligible patients. Clinical Trials registration NCT04790058. RESULTS: 1002 eligible patients (mean age 56.6 years; 51.0% males) were included: 349 patients during the control and 653 patients during the intervention period. Physician engagement varied from 39.7% to 97.1% for presentation at meetings. Process measures for the first month and the end of the intervention were: adoption 70.7% (58/82) and 84.4% (103/122), reach 67.5% (108/160) and 55.0% (359/653), fidelity among patients with physician data form completion 86.3% (88/102) and 88.3% (294/333), versus fidelity among all eligible patients 83.8% (134/160) and 83.3% (544/653) respectively with no significant differences in fidelity at one month and the end of the intervention period. CONCLUSION: In this pilot study, we achieved all prespecified benchmarks for proceeding to the multicenter CSP implementation except reach. Our results indicate a 1-month transition period will be adequate though regular reminders will be needed during full-scale implementation.

RéSUMé: CONTEXTE: Nous avons mis au point la Canadian Syncope Pathway (CSP) basée sur le Canadian Syncope Risk Score (CSRS) pour aider les services d'urgence à gérer la syncope. Cette étude pilote de mise en œuvre a évalué l'inclusion des patients, la durée de la période de transition, ainsi que les mesures de processus (engagement, portée, adoption et fidélité) pour se préparer à la mise en œuvre multicentrique MéTHODES: Un essai par étapes non randomisé dans deux hôpitaux a été mené sur une période de 7 mois. Après 2 à 3 mois dans l'état de contrôle, les hôpitaux sont passés progressivement à l'état d'intervention. Les participants à l'étude étaient des médecins du service de l'urgence et non du service de l'urgence, ou leurs délégués, et des patients (âgés de 18 ans) atteints de syncope. Nous avons cherché à analyser les caractéristiques des patients, la prise en charge des urgences, y compris la décision de disposition, et l'application des recommandations du CSRS pour tous les patients admissibles pendant la période d'intervention. Nos cibles étaient le taux d'inclusion de 95 %, l'adoption de 70 % (proportion de médecins qui ont appliqué la voie), la portée de 60 % (intervention appliquée aux patients admissibles) et la fidélité de 70 % (application des recommandations appropriées) pour tous les patients admissibles. Enregistrement des essais cliniques NCT04790058. RéSULTATS: 1002 patients éligibles (âge moyen 56,6 ans; 51,0% d'hommes) ont été inclus : 349 patients pendant le contrôle et 653 patients pendant la période d'intervention. La participation des médecins variait de 39,7 % à 97,1 % pour la présentation aux réunions. Les mesures du processus pour le premier mois et la fin de l'intervention étaient les suivantes : adoption 70,7 % (58/82) et 84,4 % (103/122), atteinte de 67,5 % (108/160) et 55,0 % (359/653), fidélité chez les patients ayant rempli le formulaire de données médicales 86,3 % (88/102) et 88,3 % (294/333), versus fidélité chez tous les patients admissibles 83,8 % (134/160) et 83,3 % (544/653) respectivement, sans différence significative de fidélité à un mois et à la fin de la période d'intervention. CONCLUSION: Dans cette étude pilote, nous avons atteint tous les points de repère prédéterminés pour procéder à la mise en œuvre du PSC multicentrique, sauf la portée. Nos résultats indiquent qu'une période de transition d'un mois sera adéquate, bien que des rappels réguliers seront nécessaires pendant la mise en œuvre à grande échelle.

Activated protein C modulates T-cell metabolism and epigenetic FOXP3 induction via α-ketoglutarate.

A direct regulation of adaptive immunity by the coagulation protease activated protein C (aPC) has recently been established. Preincubation of T cells with aPC for 1 hour before transplantation increases FOXP3+ regulatory T cells (Tregs) and reduces acute graft-versus-host disease (aGVHD) in mice, but the underlying mechanism remains unknown. Because cellular metabolism modulates epigenetic gene regulation and plasticity in T cells, we hypothesized that aPC promotes FOXP3+ expression by altering T-cell metabolism. To this end, T-cell differentiation was assessed in vitro using mixed lymphocyte reaction or plate-bound α-CD3/CD28 stimulation, and ex vivo using T cells isolated from mice with aGVHD without and with aPC preincubation, or analyses of mice with high plasma aPC levels. In stimulated CD4+CD25- cells, aPC induces FOXP3 expression while reducing expression of T helper type 1 cell markers. Increased FOXP3 expression is associated with altered epigenetic markers (reduced 5-methylcytosine and H3K27me3) and reduced Foxp3 promoter methylation and activity. These changes are linked to metabolic quiescence, decreased glucose and glutamine uptake, decreased mitochondrial metabolism (reduced tricarboxylic acid metabolites and mitochondrial membrane potential), and decreased intracellular glutamine and α-ketoglutarate levels. In mice with high aPC plasma levels, T-cell subpopulations in the thymus are not altered, reflecting normal T-cell development, whereas FOXP3 expression in splenic T cells is reduced. Glutamine and α-ketoglutarate substitution reverse aPC-mediated FOXP3+ induction and abolish aPC-mediated suppression of allogeneic T-cell stimulation. These findings show that aPC modulates cellular metabolism in T cells, reducing glutamine and α-ketoglutarate levels, which results in altered epigenetic markers, Foxp3 promoter demethylation and induction of FOXP3 expression, thus favoring a Treg-like phenotype.

A polyphenol-rich green Mediterranean diet enhances epigenetic regulatory potential: the DIRECT PLUS randomized controlled trial.

BACKGROUND: The capacity of a polyphenol-enriched diet to modulate the epigenome in vivo is partly unknown. Given the beneficial metabolic effects of a Mediterranean (MED) diet enriched in polyphenols and reduced in red/processed meat (green-MED), as previously been proven by the 18-month DIRECT PLUS randomized controlled trial, we analyzed the effects of the green-MED diet on methylome and transcriptome levels to highlight molecular mechanisms underlying the observed metabolic improvements. METHODS: Our study included 260 participants (baseline BMI = 31.2 kg/m2, age = 5 years) of the DIRECT PLUS trial, initially randomized to one of the intervention arms: A. healthy dietary guidelines (HDG), B. MED (440 mg polyphenols additionally provided by walnuts), C. green-MED (1240 mg polyphenols additionally provided by walnuts, green tea, and Mankai: green duckweed shake). Blood methylome and transcriptome of all study subjects were analyzed at baseline and after completing the 18-month intervention using Illumina EPIC and RNA sequencing technologies. RESULTS: A total of 1573 differentially methylated regions (DMRs; false discovery rate (FDR) < 5 %) were found in the green-MED compared to the MED (177) and HDG (377) diet participants. This corresponded to 1753 differentially expressed genes (DEGs; FDR < 5 %) in the green-MED intervention compared to MED (7) and HDG (738). Consistently, the highest number (6 %) of epigenetic modulating genes was transcriptionally changed in subjects participating in the green-MED intervention. Weighted cluster network analysis relating transcriptional and phenotype changes among participants subjected to the green-MED intervention identified candidate genes associated with serum-folic acid change (all P < 1 × 10-3) and highlighted one module including the KIR3DS1 locus, being negatively associated with the polyphenol changes (e.g. P < 1 × 10-4), but positively associated with the MRI-assessed superficial subcutaneous adipose area-, weight- and waist circumference- 18-month change (all P < 0.05). Among others, this module included the DMR gene Cystathionine Beta-Synthase, playing a major role in homocysteine reduction. CONCLUSIONS: The green-MED high polyphenol diet, rich in green tea and Mankai, renders a high capacity to regulate an individual's epigenome. Our findings suggest epigenetic key drivers such as folate and green diet marker to mediate this capacity and indicate a direct effect of dietary polyphenols on the one­carbon metabolism.

Preliminary feasibility of animated video education designed to empower patients' referral to kidney transplantation.

BACKGROUND: Referral for kidney transplantation is influenced by patient education; digital technologies can enhance broad information accessibility. This single-group study tested the feasibility and acceptability of patient-centered self-directed educational animated videos to improve mediators of kidney transplant referral. METHODS: Community-based adults with chronic kidney disease stage ≥4 invited from a clinical registry or self-responding to flyers viewed eight sequential videos (19:36 min total duration) remotely on their own device. Change in kidney transplant knowledge, concerns, and confidence talking about kidney transplantation to doctors was assessed with self-report surveys before and immediately after viewing. Program feedback was assessed by survey and self-selected exit interview. RESULTS: Viewers of the video set (n = 50) demonstrated increases in mean kidney transplantation knowledge by +22%, confidence discussing with their doctor by +6%, and reductions in concerns by -2%. Knowledge results were consistent across age, race, and literacy level. Over 90% indicated positive ratings on understanding, engaging, and helpfulness. In post-study interviews viewers indicated the videos promoted confidence in obtaining a kidney transplant and none reported that the 19-min duration of the home education was too long. CONCLUSION: The animated video education is promising to improve diverse individuals' knowledge, concerns, and communication confidence about kidney transplantation and is highly acceptable.

Using Animated Videos to Increase Patient Knowledge: A Meta-Analytic Review.

This article meta-analyzed 21 studies that tested the effectiveness of animated videos in improving learning in clinical and nonclinical settings compared with standard education. Animation was defined as the use of moving objects that are typically drawn or simulated. Videos ranged from just over 2 min in duration to 16 min in duration in articles published from 2009 through 2020. Mayer's Cognitive Theory of Multimedia Learning provided the theoretical model to frame the current analyses. Findings indicated an overall positive effect (d = 0.35) for use of animation in improving viewers' learning across a variety of health and clinical contexts, including surgery and diabetes. Moderator analyses indicated learning effects were greater in patient samples and samples with a higher proportion of male participants. Study findings were discussed in terms of the theoretical and practical implications for health communication scholars and practitioners.

Patient perceptions by race of educational animations about living kidney donation made for a diverse population.

INTRODUCTION: This qualitative study sought to identify potential design and delivery alterations to inform cultural adaptation of educational animations about living donor kidney transplantation (LDKT)-previously developed for a diverse population-to better fit Black Americans' needs. METHODS: We conducted a secondary analysis of 88 transcripts derived from interviews and focus groups conducted with diverse target users (62 kidney failure patients, 36 prior/potential donors, and 11 care partners) to develop 12 animations about LDKT, named KidneyTIME. Statements were abstracted and coded pertaining to cognitive and communication barriers to LDKT, and the perceived value of using the videos to learn and share the information with social network members using content analysis. Incidence counts of each content code were also calculated to assess differences between Black and non-Black patients. RESULTS: Cognitive barrier codes included lack of knowledge, ambivalence, and concern for donor. Communication barrier codes included reluctance and difficulty talking about LDKT. Cognitive facilitating codes included attention-getting, efficient learning, manageable content, emotional impact, and new knowledge. Communication facilitating codes included delivery through many dissemination channels and broadly shareable. Compared to non-black patients (n = 33) Black patients (n = 29) more often stated concern for donor and reluctance/difficulty talking about LDKT as barriers, and less often stated efficient learning and manageable content as facilitators. CONCLUSION: Findings highlight the value of LDKT informational content that is visually appealing, digestible, non-threatening, and highly shareable. Heterogeneity may exist when considering access and intervention preferences in using KidneyTIME videos and highlight a potential for further cultural targeting or tailoring.

How the Covid-19 pandemic has drawn attention to the issue of active mobility and co-benefits in Latin American cities.

The Covid-19 pandemic has brought to the fore many issues that will impact public health for years to come -one such impact is on the nexus between transportation and health. Promoting safe, active transport is an activity that has many physical and mental health benefits. During lockdowns, many cities in Latin America imposed infrastructural and legislative changes in order to abide with public health and social mea-sures to reduce virus spread. These ranged from additional bike lanes to reduced speed limits or incentives to purchase bicycles. These cities showed reduced motorized transport, improved air quality and increased active transport, all of which have multiple health and equity benefits. As countries "build back better", promoting active transport offers the most value for investment and improves health and well-being while continuing to offer social distancing. Quantified case studies are needed to have a more comprehensive under-standing of the impact of active transport in various contexts.

Reversal of the renal hyperglycemic memory in diabetic kidney disease by targeting sustained tubular p21 expression.

A major obstacle in diabetes is the metabolic or hyperglycemic memory, which lacks specific therapies. Here we show that glucose-mediated changes in gene expression largely persist in diabetic kidney disease (DKD) despite reversing hyperglycemia. The senescence-associated cyclin-dependent kinase inhibitor p21 (Cdkn1a) was the top hit among genes persistently induced by hyperglycemia and was associated with induction of the p53-p21 pathway. Persistent p21 induction was confirmed in various animal models, human samples and in vitro models. Tubular and urinary p21-levels were associated with DKD severity and remained elevated despite improved blood glucose levels in humans. Mechanistically, sustained tubular p21 expression in DKD is linked to demethylation of its promoter and reduced DNMT1 expression. Two disease resolving agents, protease activated protein C (3K3A-aPC) and parmodulin-2, reversed sustained tubular p21 expression, tubular senescence, and DKD. Thus, p21-dependent tubular senescence is a pathway contributing to the hyperglycemic memory, which can be therapeutically targeted.

DNA methylation patterns reflect individual's lifestyle independent of obesity.

OBJECTIVE: Obesity is driven by modifiable lifestyle factors whose effects may be mediated by epigenetics. Therefore, we investigated lifestyle effects on blood DNA methylation in participants of the LIFE-Adult study, a well-characterised population-based cohort from Germany. RESEARCH DESIGN AND METHODS: Lifestyle scores (LS) based on diet, physical activity, smoking and alcohol intake were calculated in 4107 participants of the LIFE-Adult study. Fifty subjects with an extremely healthy lifestyle and 50 with an extremely unhealthy lifestyle (5th and 95th percentiles LS) were selected for genome-wide DNA methylation analysis in blood samples employing Illumina Infinium® Methylation EPIC BeadChip system technology. RESULTS: Differences in DNA methylation patterns between body mass index groups (<25 vs. >30 kg/m2 ) were rather marginal compared to inter-lifestyle differences (0 vs. 145 differentially methylated positions [DMPs]), which identified 4682 differentially methylated regions (DMRs; false discovery rate [FDR <5%) annotated to 4426 unique genes. A DMR annotated to the glutamine-fructose-6-phosphate transaminase 2 (GFPT2) locus showed the strongest hypomethylation (∼6.9%), and one annotated to glutamate rich 1 (ERICH1) showed the strongest hypermethylation (∼5.4%) in healthy compared to unhealthy lifestyle individuals. Intersection analysis showed that diet, physical activity, smoking and alcohol intake equally contributed to the observed differences, which affected, among others, pathways related to glutamatergic synapses (adj. p < .01) and axon guidance (adj. p < .05). We showed that methylation age correlates with chronological age and waist-to-hip ratio with lower DNA methylation age (DNAmAge) acceleration distances in participants with healthy lifestyles. Finally, two identified top DMPs for the alanyl aminopeptidase (ANPEP) locus also showed the strongest expression quantitative trait methylation in blood. CONCLUSIONS: DNA methylation patterns help discriminate individuals with a healthy versus unhealthy lifestyle, which may mask subtle methylation differences derived from obesity.

Changes in Circulating miR-375-3p and Improvements in Visceral and Hepatic Fat Contents in Response to Lifestyle Interventions: The CENTRAL Trial.

OBJECTIVE: To investigate whether changes in circulating levels of pancreatic islet-related miRNA-375 (miR-375) are related to improved visceral and intrahepatic fat accumulation. RESEARCH DESIGN AND METHODS: This study included adults with abdominal obesity from an 18-month weight loss lifestyle intervention trial. Circulating miR-375-3p was measured at baseline and 18 months. MRI was performed (n = 139) to assess 18-month changes in abdominal and intrahepatic fat depots. RESULTS: Circulating miR-375-3p was related to fasting insulin and insulin resistance in participants with prediabetes. After the interventions, there was a significant increase of miR-375-3p (P < 0.001). Greater increase in miR-375-3p was associated with greater reductions of visceral (P = 0.024) and deep subcutaneous (P < 0.001) adipose tissues and intrahepatic fat content (P = 0.012). CONCLUSIONS: Increases in circulating miR-375-3p were associated with visceral and intrahepatic fat reduction. Changes in circulating pancreatic islet-related miR-375-3p may be linked to improved diabetogenic fat depots during weight loss lifestyle interventions.

Changes in circulating microRNAs-99/100 and reductions of visceral and ectopic fat depots in response to lifestyle interventions: the CENTRAL trial.

BACKGROUND: MicroRNAs (miRNAs) are short noncoding RNAs and important posttranscriptional regulators of gene expression. Adipose tissue is a major source of circulating miRNAs; adipose-related circulating miRNAs may regulate body fat distribution and glucose metabolism. OBJECTIVES: We investigated how changes in adipose-related circulating microRNAs-99/100 (miR-99/100) in response to lifestyle interventions were associated with improved body fat distribution and reductions of diabetogenic ectopic fat depots among adults with abdominal obesity. METHODS: This study included adults with abdominal obesity from an 18-mo diet and physical activity intervention trial. Circulating miR-99a-5p, miR-99b-5p, and miR-100-5p were measured at baseline and 18 mo; changes in these miRNAs in response to the interventions were evaluated. The primary outcomes were changes in abdominal adipose tissue [visceral (VAT), deep subcutaneous (DSAT), and superficial subcutaneous (SSAT) adipose tissue; cm2] (n = 144). The secondary outcomes were changes in ectopic fat accumulation in the liver (n = 141) and pancreas (n = 143). RESULTS: Greater decreases in miR-100-5p were associated with more reductions of VAT (ß ± SE per 1-SD decrease: -9.63 ± 3.13 cm2; P = 0.0025), DSAT (ß ± SE: -5.48 ± 2.36 cm2; P = 0.0218), SSAT (ß ± SE: -4.64 ± 1.68 cm2; P = 0.0067), and intrahepatic fat percentage (ß ± SE: -1.54% ± 0.49%; P = 0.0023) after the interventions. Similarly, participants with greater decrease in miR-99a-5p had larger 18-mo reductions of VAT (ß ± SE: -10.12 ± 3.31 cm2 per 1-SD decrease; P = 0.0027) and intrahepatic fat percentage (ß ± SE: -1.28% ± 0.52%; P = 0.015). Further, decreases in circulating miR-99b-5p (ß ± SE: per 1-SD decrease: -0.44% ± 0.21%; P = 0.038) and miR-100-5p (ß ± SE: -0.50% ± 0.23%; P = 0.033) were associated with a decrease in pancreatic fat percentage, as well as improved glucose metabolism and insulin secretion at 18 mo. CONCLUSIONS: Decreases in circulating miR-99-5p/100-5p expression induced by lifestyle interventions were related to improved body fat distribution and ectopic fat accumulation. Our study suggests that changes in circulating adipose-related miR-99-5p/100-5p may be linked to reducing diabetogenic fat depots in patients with abdominal obesity.This trial was registered at clinicaltrials.gov as NCT01530724.

Kidney Transplant Outcomes after Prolonged Delayed Graft Function.

Background: The protracted recovery of renal function may be an actionable marker of post-transplant adverse events, but a paucity of data are available to determine if the duration of graft recovery serves to stratify risk. Materials and Methods: Single-center data of adult-isolated deceased-donor kidney transplant (KTX) recipients between 1 July 2015 and 31 December 2018 were stratified by delayed graft function (DGF) duration, defined as time to serum creatinine < 3.0 mg/dL. Results: Of 355 kidney transplants, the time to creatinine < 3.0 mg/dL was 0−3 days among 96 cases (DGF ≤ 3), 4−10 days among 85 cases (DGF4-10), 11−20 days among 93 cases (DGF11-20), and ≥21 days for 81 cases (DGF ≥ 21). DGF ≥ 21 recipients were significantly more likely to be male, non-sensitized, and receive kidneys from donors that were older, with donation after circulatory death, non-mandatory share, hypertensive, higher KDPI, higher terminal creatinine, and longer cold and warm ischemia time. On multivariate analysis, DGF ≥ 21 was associated with a 5.73-fold increased odds of 12-month eGFR < 40 mL/min compared to DGF ≤ 3. Lesser degrees of DGF had similar outcomes. Conclusions: Prolonged DGF lasting over 20 days signifies a substantially higher risk for reduced eGFR at 1 year compared to lesser degrees of DGF, thus serving as a threshold indicator of increased risk.

Circulating Levels of microRNA-122 and Hepatic Fat Change in Response to Weight-Loss Interventions: CENTRAL Trial.

PURPOSE: Little is known about the relations between changes in circulating microRNA-122 (miR-122) and liver fat in response to weight-loss interventions. We aimed to investigate the association between miR-122 and changes of hepatic fat content during 18-month diet and physical activity interventions. METHODS: The CENTRAL trial is an 18-month randomized, controlled trial among adults with abdominal obesity or dyslipidemia. Subjects were randomly assigned to a low-fat diet or a Mediterranean/low-carbohydrate diet. After 6 months of dietary intervention, each diet group was further randomized into added physical activity groups or no added physical activity groups for the following 12 months of intervention. The current study included 220 participants at baseline and 134 participants with repeated measurements on serum miR-122 and hepatic fat content over 18 months. RESULTS: Serum miR-122 significantly increased from baseline to 18 months, while no difference was observed across the 4 intervention groups. We found a significant association between miR-122 and hepatic fat content at baseline, as per unit increment in log-transformed miR-122 was associated with 3.79 higher hepatic fat content (P < 0.001). Furthermore, we found that higher elevations in miR-122 were associated with less reductions in hepatic fat percentage during 18-month interventions (ß = 1.56, P = 0.002). We also found a significant interaction between changes in miR-122 and baseline fasting plasma glucose with hepatic fat content changes in 18 months (P interaction = 0.02). CONCLUSIONS: Our data indicate that participants with higher elevation in serum miR-122 may benefit less in reduction of hepatic fat content in response to diet and physical activity interventions.

Genomic editing of metformin efficacy-associated genetic variants in SLC47A1 does not alter SLC47A1 expression.

Several pharmacogenetics studies have identified an association between a greater metformin-dependent reduction in HbA1c levels and the minor A allele at rs2289669 in intron 10 of SLC47A1, encoding multidrug and toxin extrusion 1 (MATE1), a presumed metformin transporter. It is currently unknown if the rs2289669 locus is a cis-eQTL, which would validate its role as predictor of metformin efficacy. We looked at association between common genetic variants in the SLC47A1 gene region and HbA1c reduction after metformin treatment using locus-wise meta-analysis from the MetGen consortium. CRISPR-Cas9 was applied to perform allele editing of, or genomic deletion around, rs2289669 and of the closely linked rs8065082 in HepG2 cells. The genome-edited cells were evaluated for SLC47A1 expression and splicing. None of the common variants including rs2289669 showed significant association with metformin response. Genomic editing of either rs2289669 or rs8065082 did not alter SLC47A1 expression or splicing. Experimental and in silico analyses show that the rs2289669-containing haploblock does not appear to carry genetic variants that could explain its previously reported association with metformin efficacy.

Multiomics reveal unique signatures of human epiploic adipose tissue related to systemic insulin resistance.

OBJECTIVE: Human white adipose tissue (AT) is a metabolically active organ with distinct depot-specific functions. Despite their locations close to the gastrointestinal tract, mesenteric AT and epiploic AT (epiAT) have only scarcely been investigated. Here, we aim to characterise these ATs in-depth and estimate their contribution to alterations in whole-body metabolism. DESIGN: Mesenteric, epiploic, omental and abdominal subcutaneous ATs were collected from 70 patients with obesity undergoing Roux-en-Y gastric bypass surgery. The metabolically well-characterised cohort included nine subjects with insulin sensitive (IS) obesity, whose AT samples were analysed in a multiomics approach, including methylome, transcriptome and proteome along with samples from subjects with insulin resistance (IR) matched for age, sex and body mass index (n=9). Findings implying differences between AT depots in these subgroups were validated in the entire cohort (n=70) by quantitative real-time PCR. RESULTS: While mesenteric AT exhibited signatures similar to those found in the omental depot, epiAT was distinct from all other studied fat depots. Multiomics allowed clear discrimination between the IS and IR states in all tissues. The highest discriminatory power between IS and IR was seen in epiAT, where profound differences in the regulation of developmental, metabolic and inflammatory pathways were observed. Gene expression levels of key molecules involved in AT function, metabolic homeostasis and inflammation revealed significant depot-specific differences with epiAT showing the highest expression levels. CONCLUSION: Multi-omics epiAT signatures reflect systemic IR and obesity subphenotypes distinct from other fat depots. Our data suggest a previously unrecognised role of human epiploic fat in the context of obesity, impaired insulin sensitivity and related diseases.