Fat tissue quantity, waist circumference or waist-to-hip ratio in patients with chronic kidney disease: A systematic review and meta-analysis.

The BMI predicts mortality and cardiovascular disease (CVD) in the general population, while in patients with end-stage chronic kidney disease (CKD) a high BMI is associated with improved survival, a phenomenon referred to as the "obesity paradox". While BMI is easy to determine and helps to categorize patients, it does not differentiate between fat tissue, lean tissue and bone mass. As the BMI may be altered in CKD, e.g. by muscle wasting, we determined in this meta-analysis (i) the association of mortality with fat tissue quantity in CKD and (ii) the association of mortality with abdominal obesity (as measured by waist circumference (WC) or waist-to-hip ratio (WHR)) in CKD. We systematically reviewed databases for prospective or retrospective cohort studies. In eleven studies with 23,523 patients the association between mortality and high fat tissue quantity in CKD was calculated. The pooled hazard ratio (HR) for this association in the CKD group in the dialysis group 0.91 (CI 0.84- 0.98, p = 0.01) which is comparable to the HR for the association with BMI. The HR in patients without dialysis was 0.7 (95% CI 0.53- 0.93, p = 0.01), suggesting a better risk prediction of high fat tissue content with mortality as compared to higher BMI with mortality in patients with CKD without dialysis. Importantly, both BMI and fat tissue quantity in CKD are described by the "obesity paradox": the higher the fat tissue content or BMI, the lower the mortality risk. In thirteen studies with 55,175 patients the association between mortality and high WC or WHR in CKD (with or without dialysis) was calculated. We observed, that the HR in the WHR group was 1.31 (CI 1.08-1.58, p = 0.007), whereas the overall hazard ratio of both groups was 1.09 (CI 1.01-1.18, p = 0.03), indicating that a higher abdominal obesity as measured by WHR is associated with higher mortality in CKD. Our analysis suggests gender-specific differences, which need larger study numbers for validation. This meta-analysis confirms the obesity paradox in CKD using fat tissue quantity as measure and further shows that using abdominal obesity measurements in the routine in obese CKD patients might allow better risk assessment than using BMI or fat tissue quantity. Comparable to the overall population, here, the higher the WHR, the higher the mortality risk.

Clinical Trajectory and Risk Stratification for Heart Failure with Preserved Ejection Fraction in a Real-World Cohort of Patients with Suspected Coronary Artery Disease.

Background: Heart failure with preserved ejection fraction (HFpEF) is a widespread condition with significant morbidity and mortality. Its clinical heterogeneity may delay the diagnosis. Aim: To identify predictors of HFpEF-related hospitalizations in ambulatory patients presenting with elevated cardiovascular risk, suspected coronary artery diseases (CADs), and positive HFpEF screenings. Methods: Consecutive patients presenting with suspected CAD, enrolled in the observational LIFE-Heart study (2006-2014, NCT00497887), and meeting HFpEF criteria per the 2016 European Society of Cardiology (ESC) guidelines were categorized according to the presence of "overlapping conditions" potentially masking or contributing to their symptoms. Additional stratification using the H2FPEF score (<2: low risk, 2-5: intermediate risk, and ≥6 high risk) was performed. Follow-up for hospitalizations, reasons of hospitalization, and death spanned a median of 6 years. Results: Of 1054 patients (66 ± 10 years, 60% male, NT-pro-BNP 286, IQR 183-574 pg/mL), 53% had overlapping conditions, while 47% had "isolated HFpEF". The H2FPEF scores classified 23%, 57%, and 20% as low-, intermediate-, and high-risk, respectively, with consistent proportions across patients with and without overlapping conditions (p = 0.91). During the follow-up observational phase, 54% were rehospitalized, 22% experienced heart failure (HF) rehospitalizations, and 11% of patients died. Multivariable logistic regression revealed a high-risk H2FPEF category as an independent predictor of HF rehospitalization in the overall cohort (odds ratio: 3.4, CI: 2.4-4.9, p < 0.01) as well as in patients with and without overlapping conditions. Furthermore, a H2FPEF score ≥ 6 was independently associated with higher mortality rates (hazard ratio: 1.8, CI: 1.2-2.6, p < 0.01) in the Cox regression analysis. Conclusions: Ambulatory patients presenting for suspected CAD and meeting HFpEF screening criteria face elevated risks for rehospitalizations over six years. Regardless of concomitant diagnoses, quantifying cardiac damage with the H2FPEF score helps in risk-stratifying patients for HF hospitalization and mortality.

Applying Machine Learning to Blood Count Data Predicts Sepsis with ICU Admission.

BACKGROUND: Timely diagnosis is crucial for sepsis treatment. Current machine learning (ML) models suffer from high complexity and limited applicability. We therefore created an ML model using only complete blood count (CBC) diagnostics. METHODS: We collected non-intensive care unit (non-ICU) data from a German tertiary care centre (January 2014 to December 2021). Using patient age, sex, and CBC parameters (haemoglobin, platelets, mean corpuscular volume, white and red blood cells), we trained a boosted random forest, which predicts sepsis with ICU admission. Two external validations were conducted using data from another German tertiary care centre and the Medical Information Mart for Intensive Care IV database (MIMIC-IV). Using the subset of laboratory orders also including procalcitonin (PCT), an analogous model was trained with PCT as an additional feature. RESULTS: After exclusion, 1 381 358 laboratory requests (2016 from sepsis cases) were available. The CBC model shows an area under the receiver operating characteristic (AUROC) of 0.872 (95% CI, 0.857-0.887). External validations show AUROCs of 0.805 (95% CI, 0.787-0.824) for University Medicine Greifswald and 0.845 (95% CI, 0.837-0.852) for MIMIC-IV. The model including PCT revealed a significantly higher AUROC (0.857; 95% CI, 0.836-0.877) than PCT alone (0.790; 95% CI, 0.759-0.821; P < 0.001). CONCLUSIONS: Our results demonstrate that routine CBC results could significantly improve diagnosis of sepsis when combined with ML. The CBC model can facilitate early sepsis prediction in non-ICU patients with high robustness in external validations. Its implementation in clinical decision support systems has strong potential to provide an essential time advantage and increase patient safety.

Comparative Analysis of Acute Kidney Injury Models and Related Fibrogenic Responses: Convergence on Methylation Patterns Regulated by Cold Shock Protein.

BACKGROUND: Fibrosis is characterized by excessive extracellular matrix formation in solid organs, disrupting tissue architecture and function. The Y-box binding protein-1 (YB-1) regulates fibrosis-related genes (e.g., Col1a1, Mmp2, and Tgfß1) and contributes significantly to disease progression. This study aims to identify fibrogenic signatures and the underlying signaling pathways modulated by YB-1. METHODS: Transcriptomic changes associated with matrix gene patterns in human chronic kidney diseases and murine acute injury models were analyzed with a focus on known YB-1 targets. Ybx1-knockout mouse strains (Ybx1ΔRosaERT+TX and Ybx1ΔLysM) were subjected to various kidney injury models. Fibrosis patterns were characterized by histopathological staining, transcriptome analysis, qRT-PCR, methylation analysis, zymography, and Western blotting. RESULTS: Integrative transcriptomic analyses revealed that YB-1 is involved in several fibrogenic signatures related to the matrisome, the WNT, YAP/TAZ, and TGFß pathways, and regulates Klotho expression. Changes in the methylation status of the Klotho promoter by specific methyltransferases (DNMT) are linked to YB-1 expression, extending to other fibrogenic genes. Notably, kidney-resident cells play a significant role in YB-1-modulated fibrogenic signaling, whereas infiltrating myeloid immune cells have a minimal impact. CONCLUSIONS: YB-1 emerges as a master regulator of fibrogenesis, guiding DNMT1 to fibrosis-related genes. This highlights YB-1 as a potential target for epigenetic therapies interfering in this process.

Lipoprotein(a) serum concentrations in children in relation to body mass index, age and sex.

BACKGROUND: Lipoprotein(a) (Lp(a)) is an inherited risk factor for atherosclerotic cardiovascular disease (ASCVD). Limited data exist on Lp(a) values in children. We aimed to evaluate whether Lp(a) concentrations in youth are influenced by BMI. METHODS: 756 blood samples of 248 children with obesity and 264 matched healthy children aged 5 and 18 years, enrolled in the population-based LIFE Child (German civilization diseases cohort) study, were analyzed. Repeat measurements were available in 154 children (1-4 follow ups, ~1 year apart). RESULTS: The median Lp(a) concentration in the total cohort (n = 512) at first visit was 9.7 mg/dL (IQR 4.0-28.3). Lp(a) concentrations between 30-50 mg/dL were observed in 11.5%, while 12.5% exhibited Lp(a) ≧50 mg/dL. There was no association of Lp(a) with body mass index (BMI) (ß = 0.004, P = 0.49). Lp(a) levels did not correlate with age or sex, while Lp(a) was associated positively with low-density lipoprotein cholesterol (ß = 0.05, P < 0.0001). The Lp(a) risk category remained stable in 94% of all children in repeated measurements. CONCLUSIONS: The data showed no association of Lp(a) levels in children with BMI, age or sex. Measurement of Lp(a) in youth may be useful to identify children at increased lifetime risk for ASCVD. IMPACT: In youth, Lp(a) levels are not affected by age, sex and BMI. Lp(a) risk categories remain stable over time in repeated measurements in children. Measurement of Lp(a) in children may be useful as an additional factor to identify children at increased lifetime risk for ASCVD and for reverse family screening.

The role of endoplasmic reticulum-mitochondria-associated membranes in diabetic kidney disease.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide. The pathomechanisms of DKD are multifactorial, yet haemodynamic and metabolic changes in the early stages of the disease appear to predispose towards irreversible functional loss and histopathological changes. Recent studies highlight the importance of endoplasmic reticulum-mitochondria-associated membranes (ER-MAMs), structures conveying important cellular homeostatic and metabolic effects, in the pathology of DKD. Disruption of ER-MAM integrity in diabetic kidneys is associated with DKD progression, but the regulation of ER-MAMs and their pathogenic contribution remain largely unknown. Exploring the cell-specific components and dynamic changes of ER-MAMs in diabetic kidneys may lead to the identification of new approaches to detect and stratify diabetic patients with DKD. In addition, these insights may lead to novel therapeutic approaches to target and/or reverse disease progression. In this review, we discuss the association of ER-MAMs with key pathomechanisms driving DKD such as insulin resistance, dyslipidaemia, ER stress, and inflammasome activation and the importance of further exploration of ER-MAMs as diagnostic and therapeutic targets in DKD.

Glomerular-tubular crosstalk via cold shock Y-box binding protein-1 in the kidney.

Glomerular-tubular crosstalk within the kidney has been proposed, but the paracrine signals enabling this remain largely unknown. The cold-shock protein Y-box binding protein 1 (YBX1) is known to regulate inflammation and kidney diseases but its role in podocytes remains undetermined. Therefore, we analyzed mice with podocyte specific Ybx1 deletion (Ybx1ΔPod). Albuminuria was increased in unchallenged Ybx1ΔPod mice, which surprisingly was associated with reduced glomerular, but enhanced tubular damage. Tubular toll-like receptor 4 (TLR4) expression, node-like receptor protein 3 (NLRP3) inflammasome activation and kidney inflammatory cell infiltrates were all increased in Ybx1ΔPod mice. In vitro, extracellular YBX1 inhibited NLRP3 inflammasome activation in tubular cells. Co-immunoprecipitation, immunohistochemical analyses, microscale cell-free thermophoresis assays, and blunting of the YBX1-mediated TLR4-inhibition by a unique YBX1-derived decapeptide suggests a direct interaction of YBX1 and TLR4. Since YBX1 can be secreted upon post-translational acetylation, we hypothesized that YBX1 secreted from podocytes can inhibit TLR4 signaling in tubular cells. Indeed, mice expressing a non-secreted YBX1 variant specifically in podocytes (Ybx1PodK2A mice) phenocopied Ybx1ΔPod mice, demonstrating a tubular-protective effect of YBX1 secreted from podocytes. Lipopolysaccharide-induced tubular injury was aggravated in Ybx1ΔPod and Ybx1PodK2A mice, indicating a pathophysiological relevance of this glomerular-tubular crosstalk. Thus, our data show that YBX1 is physiologically secreted from podocytes, thereby negatively modulating sterile inflammation in the tubular compartment, apparently by binding to and inhibiting tubular TLR4 signaling. Hence, we have uncovered an YBX1-dependent molecular mechanism of glomerular-tubular crosstalk.

Telemedical Monitoring of Plantar Temperature in Diabetic Patients at Risk of Foot Ulcers.

BACKGROUND: The worldwide prevalence of diabetic foot ulcers (DFUs) among persons with diabetes is estimated at 6.3%, with an annual incidence of 9.1 to 26.1 million persons. The early detection of asymmetrical plantar temperature elevation, followed by reduction of weight-bearing on the affected foot, may be an effective mode of prevention. METHODS: Patients with diabetes and peripheral neuropathy (DFU risk groups 2/3) were monitored for plantar abnormalities with a telemedical system consisting of sole inserts with temperature sensors and photographic documentation. An open, prospective, randomized controlled trial was performed to determine whether this system prevented DFUs. The intervention and control groups were also trained in ulcer prevention and observed in follow-up at 6-month intervals for 24 months. RESULTS: 283 patients were recruited. In 85 137 observation days, DFUs arose in five patients in the control group (n = 143) and in no patient in the intervention group (n = 140). The primary outcome measure was the hazard ratio, which was calculated to be 0.015 (95% confidence interval [0; 19,717]; p = 0.25) after adjustment for age, sex, severity of neuropathy, and risk class. There were 239 alarms and 75 instructions to reduce weight-bearing on the foot. The subjects carried out the telemedical application on about 70% of the days of observation. Quality of life improved in both groups. CONCLUSION: The tele-health system used in this trial is practical and enables the early detection of morbidity. Likely explanations for the unexpectedly low ulceration rate in this trial (and, in turn, for the lack of statistical significance) include the availability of a training program and regular follow-up examinations to patients in both arms of the trial, along with lower mobility levels due to the COVID pandemic.

Tissue factor binds to and inhibits interferon-α receptor 1 signaling.

Tissue factor (TF), which is a member of the cytokine receptor family, promotes coagulation and coagulation-dependent inflammation. TF also exerts protective effects through unknown mechanisms. Here, we showed that TF bound to interferon-α receptor 1 (IFNAR1) and antagonized its signaling, preventing spontaneous sterile inflammation and maintaining immune homeostasis. Structural modeling and direct binding studies revealed binding of the TF C-terminal fibronectin III domain to IFNAR1, which restricted the expression of interferon-stimulated genes (ISGs). Podocyte-specific loss of TF in mice (PodΔF3) resulted in sterile renal inflammation, characterized by JAK/STAT signaling, proinflammatory cytokine expression, disrupted immune homeostasis, and glomerulopathy. Inhibiting IFNAR1 signaling or loss of Ifnar1 expression in podocytes attenuated these effects in PodΔF3 mice. As a heteromer, TF and IFNAR1 were both inactive, while dissociation of the TF-IFNAR1 heteromer promoted TF activity and IFNAR1 signaling. These data suggest that the TF-IFNAR1 heteromer is a molecular switch that controls thrombo-inflammation.

Evidence-based cutoffs for total and adjusted calcium: a major factor in detecting severe hypo- and hypercalcemia.

OBJECTIVES: Severe hypo- and hypercalcemia are common and urgent treatment is recommended. Free calcium (fCa) is the gold standard but needs blood gas tests with challenging preanalytics. Total calcium (tCa) and calculated adjusted calcium (aCa) are readily available, but their interpretation is hampered by identical tCa and aCa cutoffs, laborious local aCa calculation and difficult comparability of calcium biomarkers. METHODS: Laboratory results from University Medicine Leipzig were evaluated over a five-year period (236,274 patients). A local aCa equation was derived by linear least squares regression, the agreement between fCa, tCa and aCa assessed with Cohen's κ and decision thresholds derived by this indirect method. RESULTS: The local aCa equation was created from data of 9,756 patients, each with one paired measurement of tCa, fCa and albumin. Derived aCa cutoffs (1.95/3.15 mmol/L) differ markedly from derived tCa cutoffs (1.6/2.9 mmol/L) and severe hypo- and hypercalcemia can be more accurately assessed by aCa (κ=0.489, 0.812) than by tCa (κ=0.445, 0.744). Comparing our approach to standard care (tCa, literature cutoff), a total 3,250 of 3,680 (88.3 %) misclassified measurements were correctly classified when using aCa with evidence-based cutoffs. CONCLUSIONS: Optimized cutoffs for aCa and tCa hold great potential for improved patient care. Locally derived aCa equations differ mostly in the chosen mean normal calcium and provide minimal overall improvement, but entail a close examination of the used cutoffs before application.

Impact of anaemia and iron deficiency on outcomes in cardiogenic shock complicating acute myocardial infarction.

AIMS: Anaemia and iron deficiency (ID) are common comorbidities in cardiovascular patients and are associated with a poor clinical status, as well as a worse outcome in patients with heart failure and acute myocardial infarction (AMI). Nevertheless, data concerning the impact of anaemia and ID on clinical outcomes in patients with cardiogenic shock (CS) are scarce. This study aimed to assess the impact of anaemia and ID on clinical outcomes in patients with CS complicating AMI. METHODS AND RESULTS: The presence of anaemia (haemoglobin <13 g/dl in men and <12 g/dl in women) or ID (ferritin <100 ng/ml or transferrin saturation <20%) was determined in patients with CS due to AMI from the CULPRIT-SHOCK trial. Blood samples were collected in the catheterization laboratory during initial percutaneous coronary intervention. Clinical outcomes were compared in four groups of patients having neither anaemia nor ID, against patients with anaemia with or without ID and patients with ID only. A total of 427 CS patients were included in this analysis. Anaemia without ID was diagnosed in 93 (21.7%), anaemia with ID in 54 study participants (12.6%), ID without anaemia in 72 patients (16.8%), whereas in 208 patients neither anaemia nor ID was present (48.9%). CS patients with anaemia without ID were older (73 ± 10 years, p = 0.001), had more frequently a history of arterial hypertension (72.8%, p = 0.01), diabetes mellitus (47.8%, p = 0.001), as well as chronic kidney disease (14.1%, p = 0.004) compared to CS patients in other groups. Anaemic CS patients without ID presence were at higher risk to develop a composite from all-cause death or renal replacement therapy at 30-day follow-up (odds ratio [OR] 3.83, 95% confidence interval [CI] 2.23-6.62, p < 0.001) than CS patients without anaemia/ID. The presence of ID in CS patients, with and without concomitant anaemia, did not increase the risk for the primary outcome (OR 1.17, 95% CI 0.64-2.13, p = 0.64; and OR 1.01, 95% CI 0.59-1.73, p = 0.54; respectively) within 30 days of follow-up. In time-to-event Kaplan-Meier analysis, anaemic CS patients without ID had a significantly higher hazard ratio (HR) for the primary outcome (HR 2.11, 95% CI 1.52-2.89, p < 0.001), as well as for death from any cause (HR 1.90, 95% CI 1.36-2.65, p < 0.001) and renal replacement therapy during 30-day follow-up (HR 2.99, 95% CI 1.69-5.31, p < 0.001). CONCLUSION: Concomitant anaemia without ID presence in patients with CS at hospital presentation is associated with higher risk for death from any cause or renal replacement therapy and the individual components of this composite endpoint within 30 days after hospitalization. ID has no relevant impact on clinical outcomes in patients with CS.

The Challenge to Stabilize, Extract and Analyze Urinary Cell-Free DNA (ucfDNA) during Clinical Routine.

BACKGROUND: The "Liquid Biopsy" has become a powerful tool for cancer research during the last decade. Circulating cell-free DNA (cfDNA) that originates from tumors has emerged as one of the most promising analytes. In contrast to plasma-derived cfDNA, only a few studies have investigated urinary cfDNA. One reason might be rapid degradation and hence inadequate concentrations for downstream analysis. In this study, we examined the stability of cfDNA in urine using different methods of preservation under various storage conditions. METHODOLOGY: To mimic patient samples, a pool of healthy male and female urine donors was spiked with a synthetic cfDNA reference standard (fragment size 170 bp) containing the T790M mutation in the EGFR gene. Spiked samples were preserved with three different buffers and with no buffer over four different storage periods (0 h; 4 h; 12 h; 24 h) at room temperature vs. 4 °C. The preservatives used were Urinary Analyte Stabilizer (UAS, Novosanis, Wijnegem, Belgium), Urine Conditioning Buffer (UCB, Zymo, Freiburg, Germany) and a self-prepared buffer called "AlloU". CfDNA was extracted using the QIAamp MinElute ccfDNA Mini Kit (Qiagen, Hilden, Germany). CfDNA concentration was measured using the Qubit™ 4 fluorometer (Thermo Fisher Scientific, Waltham, MA, USA). Droplet digital PCR (ddPCR) was used for detection and quantification of the T790M mutation. RESULTS: Almost no spiked cfDNA was recoverable from samples with no preservation buffer and the T790M variant was not detectable in these samples. These findings indicate that cfDNA was degraded below the detection limit by urinary nucleases. Stabilizing buffers showed varying efficiency in preventing this degradation. The most effective stabilizing buffer under all storage conditions was the UAS, enabling adequate recovery of the T790M variant using ddPCR. CONCLUSION: From a technical point of view, stabilizing buffers and adequate storage conditions are a prerequisite for translation of urinary cfDNA diagnostics into clinical routine.

Long-term green-Mediterranean diet may favor fasting morning cortisol stress hormone; the DIRECT-PLUS clinical trial.

Background: Fasting morning cortisol (FMC) stress hormone levels, are suggested to reflect increased cardiometabolic risk. Acute response to weight loss diet could elevate FMC. Richer Polyphenols and lower carbohydrates diets could favor FMC levels. We aimed to explore the effect of long-term high polyphenol Mediterranean diet (green-MED) on FMC and its relation to metabolic health. Methods: We randomized 294 participants into one of three dietary interventions for 18-months: healthy dietary guidelines (HDG), Mediterranean (MED) diet, and Green-MED diet. Both MED diets were similarly hypocaloric and lower in carbohydrates and included walnuts (28 g/day). The high-polyphenols/low-meat Green-MED group further included green tea (3-4 cups/day) and a Wolffia-globosa Mankai plant 1-cup green shakeFMC was obtained between 07:00-07:30AM at baseline, six, and eighteen-months. Results: Participants (age=51.1years, 88% men) had a mean BMI of 31.3kg/m2, FMC=304.07nmol\L, and glycated-hemoglobin-A1c (HbA1c)=5.5%; 11% had type 2 diabetes and 38% were prediabetes. Baseline FMC was higher among men (308.6 ± 90.05nmol\L) than women (269.6± 83.9nmol\L;p=0.02). Higher baseline FMC was directly associated with age, dysglycemia, MRI-assessed visceral adiposity, fasting plasma glucose (FPG), high-sensitivity C-reactive-protein (hsCRP), testosterone, Progesterone and TSH levels (p ≤ 0.05 for all). The 18-month retention was 89%. After 6 months, there were no significant changes in FMC among all intervention groups. However, after 18-months, both MED groups significantly reduced FMC (MED=-1.6%[-21.45 nmol/L]; Green-MED=-1.8%[-26.67 nmol/L]; p<0.05 vs. baseline), as opposed to HDG dieters (+4%[-12 nmol/L], p=0.28 vs. baseline), whereas Green-MED diet FMC change was significant as compared to HDG diet group (p=0.048 multivariable models). Overall, 18-month decrease in FMC levels was associated with favorable changes in FPG, HbA1c, hsCRP, TSH, testosterone and MRI-assessed hepatosteatosis, and with unfavorable changes of HDLc (p<0.05 for all, weight loss adjusted, multivariable models). Conclusion: Long-term adherence to MED diets, and mainly green-MED/high polyphenols diet, may lower FMC, stress hormone, levels,. Lifestyle-induced FMC decrease may have potential benefits related to cardiometabolic health, irrespective of weight loss. Clinical trial registration: ClinicalTrials.gov, identifier NCT03020186.

Development, Design and Utilization of a CDSS for Refeeding Syndrome in Real Life Inpatient Care-A Feasibility Study.

BACKGROUND: The refeeding syndrome (RFS) is an oftentimes-unrecognized complication of reintroducing nutrition in malnourished patients that can lead to fatal cardiovascular failure. We hypothesized that a clinical decision support system (CDSS) can improve RFS recognition and management. METHODS: We developed an algorithm from current diagnostic criteria for RFS detection, tested the algorithm on a retrospective dataset and combined the final algorithm with therapy and referral recommendations in a knowledge-based CDSS. The CDSS integration into clinical practice was prospectively investigated for six months. RESULTS: The utilization of the RFS-CDSS lead to RFS diagnosis in 13 out of 21 detected cases (62%). It improved patient-related care and documentation, e.g., RFS-specific coding (E87.7), increased from once coded in 30 month in the retrospective cohort to four times in six months in the prospective cohort and doubled the rate of nutrition referrals in true positive patients (retrospective referrals in true positive patients 33% vs. prospective referrals in true positive patients 71%). CONCLUSION: CDSS-facilitated RFS diagnosis is possible and improves RFS recognition. This effect and its impact on patient-related outcomes needs to be further investigated in a large randomized-controlled trial.

An atlas of genome-wide gene expression and metabolite associations and possible mediation effects towards body mass index.

Investigating the cross talk of different omics layers is crucial to understand molecular pathomechanisms of metabolic diseases like obesity. Here, we present a large-scale association meta-analysis of genome-wide whole blood and peripheral blood mononuclear cell (PBMC) gene expressions profiled with Illumina HT12v4 microarrays and metabolite measurements from dried blood spots (DBS) characterized by targeted liquid chromatography tandem mass spectrometry (LC-MS/MS) in three large German cohort studies with up to 7706 samples. We found 37,295 associations comprising 72 amino acids (AA) and acylcarnitine (AC) metabolites (including ratios) and 8579 transcripts. We applied this catalogue of associations to investigate the impact of associating transcript-metabolite pairs on body mass index (BMI) as an example metabolic trait. This is achieved by conducting a comprehensive mediation analysis considering metabolites as mediators of gene expression effects and vice versa. We discovered large mediation networks comprising 27,023 potential mediation effects within 20,507 transcript-metabolite pairs. Resulting networks of highly connected (hub) transcripts and metabolites were leveraged to gain mechanistic insights into metabolic signaling pathways. In conclusion, here, we present the largest available multi-omics integration of genome-wide transcriptome data and metabolite data of amino acid and fatty acid metabolism and further leverage these findings to characterize potential mediation effects towards BMI proposing candidate mechanisms of obesity and related metabolic diseases. KEY MESSAGES: Thousands of associations of 72 amino acid and acylcarnitine metabolites and 8579 genes expand the knowledge of metabolome-transcriptome associations. A mediation analysis of effects on body mass index revealed large mediation networks of thousands of obesity-related gene-metabolite pairs. Highly connected, potentially mediating hub genes and metabolites enabled insight into obesity and related metabolic disease pathomechanisms.

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.

Genetic dissection of serum vaspin highlights its causal role in lipid metabolism.

OBJECTIVE: Vaspin (visceral adipose tissue derived serine protease inhibitor, SERPINA12) is associated with obesity-related metabolic traits, but its causative role is still elusive. The role of genetics in serum vaspin variability to establish its causal relationship with metabolically relevant traits was investigated. METHODS: A meta-analysis of genome-wide association studies for serum vaspin from six independent cohorts (N = 7446) was conducted. Potential functional variants of vaspin were included in Mendelian randomization (MR) analyses to assess possible causal pathways between vaspin and homeostasis model assessment and lipid traits. To further validate the MR analyses, data from Genotype-Tissue Expression (GTEx) were analyzed, db/db mice were treated with vaspin, and serum lipids were measured. RESULTS: A total of 468 genetic variants represented by five independent variants (rs7141073, rs1956709, rs4905216, rs61978267, rs73338689) within the vaspin locus were associated with serum vaspin (all p < 5×10-8 , explained variance 16.8%). MR analyses revealed causal relationships between serum vaspin and triglycerides, low-density lipoprotein, and total cholesterol. Gene expression correlation analyses suggested that genes, highly correlated with vaspin expression in adipose tissue, are enriched in lipid metabolic processes. Finally, in vivo vaspin treatment reduced serum triglycerides in obese db/db mice. CONCLUSIONS: The data show that serum vaspin is strongly determined by genetic variants within vaspin, which further highlight vaspin's causal role in lipid metabolism.

Excessive sodium chloride ingestion promotes inflammation and kidney fibrosis in aging mice.

In aging kidneys, a decline of function resulting from extracellular matrix (ECM) deposition and organ fibrosis is regarded as "physiological." Whether a direct link between high salt intake and fibrosis in aging kidney exists autonomously from arterial hypertension is unclear. This study explores kidney intrinsic changes (inflammation, ECM derangement) induced by a high-salt diet (HSD) in a murine model lacking arterial hypertension. The contribution of cold shock Y-box binding protein (YB-1) as a key orchestrator of organ fibrosis to the observed differences is determined by comparison with a knockout strain (Ybx1ΔRosaERT+TX). Comparisons of tissue from mice fed with normal-salt diet (NSD, standard chow) or high-salt diet (HSD, 4% NaCl in chow; 1% NaCl in water) for up to 16 mo revealed that with HSD tubular cell numbers decrease and tubulointerstitial scarring [periodic acid-Schiff (PAS), Masson's trichrome, Sirius red staining] prevails. In Ybx1ΔRosaERT+TX animals tubular cell damage, a loss of cell contacts with profound tubulointerstitial alterations, and tubular cell senescence was seen. A distinct tubulointerstitial distribution of fibrinogen, collagen type VI, and tenascin-C was detected under HSD, transcriptome analyses determined patterns of matrisome regulation. Temporal increase of immune cell infiltration was seen under HSD of wild type, but not Ybx1ΔRosaERT+TX animals. In vitro Ybx1ΔRosaERT+TX bone marrow-derived macrophages exhibited a defect in polarization (IL-4/IL-13) and abrogated response to sodium chloride. Taken together, HSD promotes progressive kidney fibrosis with premature cell aging, ECM deposition, and immune cell recruitment that is exacerbated in Ybx1ΔRosaERT+TX animals.NEW & NOTEWORTHY Short-term experimental studies link excessive sodium ingestion with extracellular matrix accumulation and inflammatory cell recruitment, yet long-term data are scarce. Our findings with a high-salt diet over 16 mo in aging mice pinpoints to a decisive tipping point after 12 mo with tubular stress response, skewed matrisome transcriptome, and immune cell infiltration. Cell senescence was aggravated in knockout animals for cold shock Y-box binding protein (YB-1), suggesting a novel protective protein function.