Cytotoxicity and Chemotaxonomic Significance of Saponins from Wild and Cultured Asparagus Shoots.

The shoots of Asparagus L. are consumed worldwide, although most species belonging to this genus have a restricted range, and several taxa remain unstudied. In this work, a total of four taxa from different locations were scrutinized and compared with cultivated A. officinalis. All shoots were screened for saponins via LC-MS, and in vitro antiproliferative activities against the HT-29 colorectal cancer cell line were assessed via the MTT assay. The total saponins (TS) contained in the crude extracts ranged from 710.0 (A. officinalis) to 1258.6 mg/100 g dw (A. acutifolius). The richness of the compounds detected in this work stands out; a total of 47 saponins have been detected and quantified in the edible parts (shoots) of five taxa of Asparagus. The structure of all the saponins found present skeletons of the furostane and spirostane type. In turn, the structures with a furostane skeleton are divided into unsaturated and dioxygenated types, both in the 20-22 position. The sum of dioscin and derivatives varied largely among the studied taxa, reaching the following percentages of TS: 27.11 (A. officinalis), 18.96 (A. aphyllus), 5.37 (A. acutifolius), and 0.59 (A. albus); while in A. horridus, this compound remains undetected. Aspachiosde A, D, and M varied largely among samples, while a total of seven aspaspirostanosides were characterized in the analyzed species. The hierarchical cluster analysis of the saponin profiles clearly separated the various taxa and demonstrated that the taxonomic position is more important than the place from which the samples were acquired. Thus, saponin profiles have chemotaxonomic significance in Asparagus taxa. The MTT assay showed dose- and time-dependent inhibitory effects of all saponins extracts on HT-29 cancer cells, and the strongest cell growth inhibition was exercised by A. albus and A. acutifolius (GI50 of 125 and 175 µg/mL). This work constitutes a whole approach to evaluating the saponins from the shoots of different Asparagus taxa and provides arguments for using them as functional foods.

Behaviour Hallmarks in Alzheimer's Disease 5xFAD Mouse Model.

The 5xFAD transgenic mouse model widely used in Alzheimer's disease (AD) research recapitulates many AD-related phenotypes with a relatively early onset and aggressive age-dependent progression. Besides developing amyloid peptide deposits alongside neuroinflammation by the age of 2 months, as well as exhibiting neuronal decline by the age of 4 months that intensifies by the age of 9 months, these mice manifest a broad spectrum of behavioural impairments. In this review, we present the extensive repertoire of behavioural dysfunctions in 5xFAD mice, organised into four categories: motor skills, sensory function, learning and memory abilities, and neuropsychiatric-like symptoms. The motor problems, associated with agility and reflex movements, as well as balance and coordination, and skeletal muscle function, typically arise by the time mice reach 9 months of age. The sensory function (such as taste, smell, hearing, and vision) starts to deteriorate when amyloid peptide buildups and neuroinflammation spread into related anatomical structures. The cognitive functions, encompassing learning and memory abilities, such as visual recognition, associative, spatial working, reference learning, and memory show signs of decline from 4 to 6 months of age. Concerning neuropsychiatric-like symptoms, comprising apathy, anxiety and depression, and the willingness for exploratory behaviour, it is believed that motivational changes emerge by approximately 6 months of age. Unfortunately, numerous studies from different laboratories are often contradictory on the conclusions drawn and the identification of onset age, making preclinical studies in rodent models not easily translatable to humans. This variability is likely due to a range of factors associated with animals themselves, housing and husbandry conditions, and experimental settings. In the forthcoming studies, greater clarity in experimental details when conducting behavioural testing in 5xFAD transgenic mice could minimise the inconsistencies and could ensure the reliability and the reproducibility of the results.

Association of High-Density Lipoprotein Parameters and Risk of Heart Failure: A Multicohort Analysis.

BACKGROUND: High-density lipoprotein (HDL) is commonly characterized by its cholesterol concentration (HDL-C) and inverse association with atherosclerotic cardiovascular disease. OBJECTIVES: The authors sought to evaluate the association of HDL particle concentration (HDL-P), HDL particle size (HDL-size), HDL-C, and cholesterol content per particle (HDL-C/HDL-P) with risk of overall heart failure (HF) and subtypes. METHODS: Participants from the Atherosclerosis Risk In Communities Study, Dallas Heart Study, Multi-Ethnic Study of Atherosclerosis, and Prevention of Renal and Vascular End-stage Disease studies without HF history were included. Associations of HDL-P, HDL-size, HDL-C, and HDL-C/HDL-P with risk of overall HF, HF with reduced and preserved ejection fraction were assessed using adjusted Cox models. RESULTS: Among 16,925 participants (53.5% women; 21.8% Black), there were 612 incident HF events (3.6%) (HF with reduced ejection fraction, 309 [50.5%]; HF preserved ejection fraction, 303 [49.5%]) over median follow-up of 11.4 years. In adjusted models, higher HDL-P was significantly associated with lower HF risk (HR of highest vs lowest tertile of HDL-P: 0.76 [95% CI: 0.62-0.93]). Larger HDL-size was significantly associated with higher overall HF risk (HR of largest vs smallest tertile of HDL-size: 1.27 [95% CI: 1.03-1.58]). HF risk associated with HDL-P and HDL-size was similar for HF subtypes. In adjusted analyses, there was no significant association between HDL-C and HF risk. Higher HDL-C/HDL-P was significantly associated with higher overall HF risk (HR of highest vs lowest tertile of HDL-C/HDL-P: 1.29 [95% CI: 1.04-1.60]). CONCLUSIONS: Higher HDL-P was associated with a lower risk of HF. In contrast, larger HDL-size was associated with higher risk of HF and there was no significant association observed between HDL-C and HF risk after accounting for cardiovascular risk factors.

Major alteration of Lung Microbiome and the Host Reaction in critically ill COVID-19 Patients with high viral load.

Background: Patients with COVID-19 under invasive mechanical ventilation are at higher risk of developing ventilator-associated pneumonia (VAP), associated with increased healthcare costs, and unfavorable prognosis. The underlying mechanisms of this phenomenon have not been thoroughly dissected. Therefore, this study attempted to bridge this gap by performing a lung microbiota analysis and evaluating the host immune responses that could drive the development of VAP. Materials and methods: In this prospective cohort study, mechanically ventilated patients with confirmed SARS-CoV-2 infection were enrolled. Nasal swabs (NS), endotracheal aspirates (ETA), and blood samples were collected initially within 12 hours of intubation and again at 72 hours post-intubation. Plasma samples underwent cytokine and metabolomic analyses, while NS and ETA samples were sequenced for lung microbiome examination. The cohort was categorized based on the development of VAP. Data analysis was conducted using RStudio version 4.3.1. Results: In a study of 36 COVID-19 patients on mechanical ventilation, significant differences were found in the nasal and pulmonary microbiome, notably in Staphylococcus and Enterobacteriaceae, linked to VAP. Patients with VAP showed a higher SARS-CoV-2 viral load, elevated neutralizing antibodies, and reduced inflammatory cytokines, including IFN-δ, IL-1ß, IL-12p70, IL-18, IL-6, TNF-α, and CCL4. Metabolomic analysis revealed changes in 22 metabolites in non-VAP patients and 27 in VAP patients, highlighting D-Maltose-Lactose, Histidinyl-Glycine, and various phosphatidylcholines, indicating a metabolic predisposition to VAP. Conclusions: This study reveals a critical link between respiratory microbiome alterations and ventilator-associated pneumonia in COVID-19 patients, with elevated SARS-CoV-2 levels and metabolic changes, providing novel insights into the underlying mechanisms of VAP with potential management and prevention implications.

Insights on the Use of Transgenic Mice Models in Alzheimer's Disease Research.

Alzheimer's disease (AD), the leading cause of dementia, presents a significant global health challenge with no known cure to date. Central to our understanding of AD pathogenesis is the ß-amyloid cascade hypothesis, which underlies drug research and discovery efforts. Despite extensive studies, no animal models of AD have completely validated this hypothesis. Effective AD models are essential for accurately replicating key pathological features of the disease, notably the formation of ß-amyloid plaques and neurofibrillary tangles. These pathological markers are primarily driven by mutations in the amyloid precursor protein (APP) and presenilin 1 (PS1) genes in familial AD (FAD) and by tau protein mutations for the tangle pathology. Transgenic mice models have been instrumental in AD research, heavily relying on the overexpression of mutated APP genes to simulate disease conditions. However, these models do not entirely replicate the human condition of AD. This review aims to provide a comprehensive evaluation of the historical and ongoing research efforts in AD, particularly through the use of transgenic mice models. It is focused on the benefits gathered from these transgenic mice models in understanding ß-amyloid toxicity and the broader biological underpinnings of AD. Additionally, the review critically assesses the application of these models in the preclinical testing of new therapeutic interventions, highlighting the gap between animal models and human clinical realities. This analysis underscores the need for refinement in AD research methodologies to bridge this gap and enhance the translational value of preclinical studies.

Triglyceride/HDL cholesterol ratio and lipoprotein insulin resistance Score: Associations with subclinical atherosclerosis and incident cardiovascular disease.

BACKGROUND: The triglyceride/HDL cholesterol (TG/HDL-C) ratio and the Lipoprotein Insulin Resistance (LP-IR) score are lipid markers of insulin resistance. Their associations with carotid intima media thickness (cIMT; subclinical atherosclerosis) and incident cardiovascular disease (CVD) have not been thoroughly investigated. METHODS: In a cross-sectional cohort (89 subjects without type 2 diabetes (T2D) and 81 subjects with T2D we determined cIMT (ultrasound), homeostasis model assessment of insulin resistance (HOMA-IR) and the TG/HDL-C ratio. The LP-IR score, based on 6 lipoprotein characteristics determined by nuclear magnetic resonance spectroscopy, was measured in 123 participants. A prospective study was carried out among 6232 participants (Prevention of REnal and Vascular ENd-stage Disease study). RESULTS: Cross-sectionally, the adjusted associations of HOMA-IR, the TG/HDL-C ratio and the LP-IR score with cIMT were approximately similar (standardized ß = 0.34 (95 % CI 0.19-0.48), 0.24 (95 % CI 0.09-039) and 0.41 (95 % CI 0.23--0.59), respectively). Prospectively, 507 new cases of CVD were observed after a median follow-up of 8.2 (interquartile range 7.5-8.8) years. HOMA-IR, the TG/HDL-C ratio and LP-IR were each associated with incident CVD independent of potential confounders (HR 1.12, 95 % CI 1.02-1.24;1.22, 95 % CI 1.11-1.35 and 1.15. 95 % CI 1.01-1.31, respectively). The association of the TG/HDL-C ratio with incident CVD was somewhat stronger than that of HOMA-IR. CONCLUSION: Lipoprotein-based markers of insulin resistance are at least as strongly associated with subclinical atherosclerosis and clinical atherosclerosis development as HOMA-IR, obviating the need to measure insulin to determine the impact of insulin resistance. For practical purposes, the easily obtainable TG/HDL-C ratio may suffice.

Wild Asparagus Shoots Constitute a Healthy Source of Bioactive Compounds.

Wild Asparagus shoots are consumed worldwide, although most species remain understudied. In this work, a total of four wild Asparagus species were collected from different locations and analyzed compared with farmed A. officinalis. Shoots were screened for (i) phenolic compounds by HPLC-DAD and LC-MS; (ii) total phenolic acids and total flavonoid content by the Folin-Ciocalteu and aluminum chloride methods; (iii) vitamin C by HPLC-DAD; (iv) antioxidant activity by the DPPH and ABTS•+ methods; and (v) the in vitro antiproliferative activities against HT-29 colorectal cancer cells by the MTT assay. Phenolics ranged from 107.5 (A. aphyllus) to 605.4 mg/100 g dry weight (dw) (A. horridus). Vitamin C ranged from 15.8 (A. acutifolius) to 22.7 mg/100 g fresh weight (fw) (A. officinalis). The antioxidant activity was similar in all species, standing out in A. officinalis with 5.94 (DPPH) and 4.64 (ABTS) mmol TE/100 g dw. Among phenolics, rutin reached the highest values (574 mg/100 g dw in A. officinalis), followed by quercetin, nicotiflorin, asterin, and narcissin. The MTT assay revealed the inhibitory effects of ethanol extracts against HT-29 cancer cells, highlighting the cell growth inhibition exercised by A. albus (300 µg/mL after 72 h exposure to cells). This work improves knowledge on the phytochemicals and bioactivities of the shoots of wild Asparagus species and confirms their suitability for use as functional foods.

High plasma levels of betaine, a trimethylamine N-Oxide-related metabolite, are associated with the severity of cirrhosis.

BACKGROUND AND AIMS: The gut microbiome-related metabolites betaine and trimethylamine N-oxide (TMAO) affect major health issues. In cirrhosis, betaine metabolism may be diminished because of impaired hepatic betaine homocysteine methyltransferase activity, whereas TMAO generation from trimethylamine may be altered because of impaired hepatic flavin monooxygenase expression. Here, we determined plasma betaine and TMAO levels in patients with end-stage liver disease and assessed their relationships with liver disease severity. METHODS: Plasma betaine and TMAO concentrations were measured by nuclear magnetic resonance spectroscopy in 129 cirrhotic patients (TransplantLines cohort study; NCT03272841) and compared with levels from 4837 participants of the PREVEND cohort study. Disease severity was assessed by Child-Pugh-Turcotte (CPT) classification and Model for End-stage Liver Disease (MELD) score. RESULTS: Plasma betaine was on average 60% higher (p < .001), whereas TMAO was not significantly lower in cirrhotic patients vs. PREVEND population (p = .44). After liver transplantation (n = 13), betaine decreased (p = .017; p = .36 vs. PREVEND population), whereas TMAO levels tended to increase (p = .085) to higher levels than in the PREVEND population (p = .003). Betaine levels were positively associated with the CPT stage and MELD score (both p < .001). The association with the MELD score remained in the fully adjusted analysis (p < .001). The association of TMAO with the MELD score did not reach significance (p = .11). Neither betaine nor TMAO levels were associated with mortality on the waiting list for liver transplantation (adjusted p = .78 and p = .44, respectively). CONCLUSION: Plasma betaine levels are elevated in cirrhotic patients in parallel with disease severity and decrease after liver transplantation.

Fatty acid profiling in the genus Pinus in relation to its chemotaxonomy and nutritional or pharmaceutical properties.

To develop and utilize the oil of Pinus seeds and explore natural resources rich in pinolenic acid (PNLA), twenty-one Pinus taxa were evaluated in a search of Δ5-unsaturated polymethylene-interrupted fatty acids (Δ5-UPIFA)-rich oils. While the fatty acid (FA) composition was determined by GC-FID and GC-MS, NMR of crude oils proved to be a fast method for establishing the ratio between Δ5-UPIFA and total FA. For all analyzed taxa, both the geographical origin and the concentration of total FA in the seeds are provided. PNLA and sciadonic acids occurred in all samples, while taxoleic and bishomopinolenic acids were present in most taxa. PNLA reached a maximum of 28.3% of total FA in P. mugo, and P. koraiensis showed the highest total FA amount (66.8 g/100 g seeds). The previously unanalyzed taxon P. ponderosa var. scopulorum can be considered a new PNLA source (17.1%). Principal Component Analysis showed that the similarities in FA profiles allow the grouping of the various taxa within Pinus subsections and confirmed the differential metabolic activities of Δ5 and Δ9 desaturase enzymes. This study showed that several underutilized Pinus taxa could be developed into renewable woody oil species, and their seeds could be used as raw materials for Δ5-UPIFA-rich oils extraction.

Quantification of glycated hemoglobin and glucose in vivo using Raman spectroscopy and artificial neural networks.

Undiagnosed type 2 diabetes (T2D) remains a major public health concern. The global estimation of undiagnosed diabetes is about 46%, being this situation more critical in developing countries. Therefore, we proposed a non-invasive method to quantify glycated hemoglobin (HbA1c) and glucose in vivo. We developed a technique based on Raman spectroscopy, RReliefF as a feature selection method, and regression based on feed-forward artificial neural networks (FFNN). The spectra were obtained from the forearm, wrist, and index finger of 46 individuals. The use of FFNN allowed us to achieve an error in the predictive model of 0.69% for HbA1c and 30.12 mg/dL for glucose. Patients were classified according to HbA1c values into three categories: healthy, prediabetes, and T2D. The proposed method obtained a specificity and sensitivity of 87.50% and 80.77%, respectively. This work demonstrates the benefit of using artificial neural networks and feature selection techniques to enhance Raman spectra processing to determine glycated hemoglobin and glucose in patients with undiagnosed T2D.

A soft robotic sleeve mimicking the haemodynamics and biomechanics of left ventricular pressure overload and aortic stenosis.

Preclinical models of aortic stenosis can induce left ventricular pressure overload and coarsely control the severity of aortic constriction. However, they do not recapitulate the haemodynamics and flow patterns associated with the disease. Here we report the development of a customizable soft robotic aortic sleeve that can mimic the haemodynamics and biomechanics of aortic stenosis. By allowing for the adjustment of actuation patterns and blood-flow dynamics, the robotic sleeve recapitulates clinically relevant haemodynamics in a porcine model of aortic stenosis, as we show via in vivo echocardiography and catheterization studies, and a combination of in vitro and computational analyses. Using in vivo and in vitro magnetic resonance imaging, we also quantified the four-dimensional blood-flow velocity profiles associated with the disease and with bicommissural and unicommissural defects re-created by the robotic sleeve. The design of the sleeve, which can be adjusted on the basis of computed tomography data, allows for the design of patient-specific devices that may guide clinical decisions and improve the management and treatment of patients with aortic stenosis.

Adherence to literature search reporting guidelines in leading rheumatology journals' systematic reviews: umbrella review protocol.

Literature searches are important components of systematic reviews. They are not only informative of the retrieval process, but they also set the data to be analyzed and influence additional components of systematic reviews. Despite the available guidelines, several studies have shown that the quality of reporting in systematic reviews is deficient in several medical fields. Systematic reviews may not comply completely with those guidelines despite explicitly stating they do. This protocol intends to answer to what extent systematic reviews published in rheumatology journals have complied with the PRISMA's search strategy guidelines published in 2009. The objective of the study is to analyze the compliance with the PRISMA (2009) search strategy guidelines among systematic reviews published in leading rheumatology journals. Inclusion criteria for this umbrella review protocol are systematic reviews (with or without meta-analyses) that mention having followed the PRISMA statement (2009) in their methods section, and published in journals listed in the Rheumatology category of the Journal of Citations Report 2020. Exclusion criteria are articles published before 2009; retraction letters, notes, expressions of concern; systematic reviews using PRISMA 2020. Databases to be consulted are Web of Science, PubMed and Scopus, from inception to present. Data summaries will be presented in graphs, figures, tables and network maps. A narrative synthesis will be described. This protocol complies with guidelines such as PRISMA 2020, PRISMA-A, PRISMA-P, PRISMA-S, PRESS, and JBI Manual for evidence synthesis, as long as it is suitable for umbrella review protocols. Articles in any language will be considered.

Commencement of flash glucose monitoring is associated with a decreased rate of depressive disorders among persons with diabetes (FLARE-NL7).

INTRODUCTION: Depressive disorders are more common among persons with diabetes, as compared with persons without diabetes. The burden of glucose management is known to associate with depressive symptoms. This study aims to assess the effects of commencement of FreeStyle Libre flash glucose monitoring (FSL-FGM) on the mental health status of persons with diabetes. RESEARCH DESIGN AND METHODS: Post-hoc analysis of data from a 1-year prospective nationwide FSL-FGM registry. Participants who used FSL-FGM for 12 months and completed the 12-Item Short Form Health Survey version 2 (SF-12v2) questionnaires at baseline, 6 and 12 months were included. An SF-12v2 Mental Component Score (MCS) of ≤45 was used as a cut-off to discriminate between persons with and without a depressive disorder. RESULTS: A total of 674 patients were included with a mean age of 48.2 (±15.8) years, 51.2% men, 78.2% type 1 diabetes and baseline HbA1c 62.8 (±13.4) mmol/mol (7.9±1.2%). At baseline, 235 (34.9%) persons had an SF-12 MCS ≤45 while after 6 and 12 months these numbers decreased: 202 (30.0%, p<0.01) and 173 (25.7%, p<0.01). Overall, MCS improved from 48.5 at baseline to 50.7 after 6 months and 51.3 after 12 months. In multivariable regression analysis, age and MCS at baseline were associated with improvement of MCS after 12 months of FSL-FGM use. CONCLUSIONS: This analysis suggests that use of FSL-FGM is associated with a decreased rate of depressive disorders among persons with diabetes. Future studies are needed to corroborate these findings.

Muscle mass and estimates of renal function: a longitudinal cohort study.

BACKGROUND: Creatinine is the most widely used test to estimate the glomerular filtration rate (GFR), but muscle mass as key determinant of creatinine next to renal function may confound such estimates. We explored effects of 24-h height-indexed creatinine excretion rate (CER index) on GFR estimated with creatinine (eGFRCr ), muscle mass-independent cystatin C (eGFRCys ), and the combination of creatinine and cystatin C (eGFRCr-Cys ) and predicted probabilities of discordant classification given age, sex, and CER index. METHODS: We included 8076 adults enrolled in the PREVEND study. Discordant classification was defined as not having eGFRCr  <60 mL/min per 1.73 m2 when eGFRCys was <60 mL/min/1.73 m2 . Baseline effects of age and sex on CER index were quantified with linear models using generalized least squares. Baseline effects of CER index on eGFR were quantified with quantile regression and logistic regression. Effects of annual changes in CER index on trajectories of eGFR were quantified with linear mixed-effects models. Missing observations in covariates were multiply imputed. RESULTS: Mean (SD) CER index was 8.0 (1.7) and 6.1 (1.3) mmol/24 h per meter in male and female participants, respectively (Pdifference  < 0.001). In male participants, baseline CER index increased until 45 years of age followed by a gradual decrease, whereas a gradual decrease across the entire range of age was observed in female participants. For a 70-year-old male participant with low muscle mass (CER index of 2 mmol/24 h per meter), predicted baseline eGFRCr and eGFRCys disagreed by 24.7 mL/min/1.73 m2 (and 30.1 mL/min/1.73 m2 when creatinine was not corrected for race). Percentages (95% CI) of discordant classification in male and female participants aged 60 years and older with low muscle mass were 18.5% (14.8-22.1%) and 15.2% (11.4-18.5%), respectively. For a 70-year-old male participant who lost muscle during follow-up, eGFRCr and eGFRCys disagreed by 1.5, 5.0, 8.5, and 12.0 mL/min/1.73 m2 (and 6.7, 10.7, 13.5, and 15.9 mL/min/1.73 m2 when creatinine was not corrected for race) at baseline, 5 years, 10 years, and 15 years of follow-up, respectively. CONCLUSIONS: Low muscle mass may cause considerable overestimation of single measurements of eGFRCr . Muscle wasting may cause spurious overestimation of repeatedly measured eGFRCr . Implementing muscle mass-independent markers for estimating renal function, like cystatin C as superior alternative to creatinine, is crucial to accurately assess renal function in settings of low muscle mass or muscle wasting. This would also eliminate the negative consequences of current race-based approaches.

Profoundly Disturbed Lipoproteins in Cirrhotic Patients: Role of Lipoprotein-Z, a Hepatotoxic LDL-like Lipoprotein.

Detailed information regarding lipoprotein concentrations and subfractions in cirrhotic patients before and after orthotopic liver transplantation (OLT) is lacking. Lipoprotein-Z (LP-Z) is a recently characterised abnormal, hepatotoxic free cholesterol-rich low-density lipoprotein (LDL)-like lipoprotein. We determined the lipoprotein profiles, including LP-Z, in cirrhotic patients and OLT recipients and assessed the prognostic significance of LP-Z on the OLT waiting list. We performed analyses in cirrhotic transplant candidates and non-cirrhotic OLT recipients. A population-based cohort was used as reference. The setting was a University hospital. Lipoprotein particle concentrations and subfractions were measured by nuclear magnetic resonance spectroscopy. In the cirrhotic patients (N = 130), most measures of triglyceride-rich lipoproteins (TRL), LDL, and high-density lipoproteins (HDL) were much lower compared to the OLT recipients (N = 372) and controls (N = 6027) (p < 0.01). In the OLT recipients, many lipoprotein variables were modestly lower, but HDL-cholesterol, triglycerides, and TRL and HDL size were greater vs. the control population. LP-Z was measurable in 40 cirrhotic patients and 3 OLT recipients (30.8% vs. 0.8%, p < 0.001). The cirrhotic patients with measurable LP-Z levels had profoundly lower HDL-cholesterol and particle concentrations (p < 0.001), and worse Child Pugh Turcotte classifications and MELD scores. The presence of LP-Z (adjusted for age, sex, and MELD score) predicted worse survival in cirrhotic patients (HR per 1 LnSD increment: 1.11, 95%CI 1.03−1.19, p = 0.003). In conclusion, cirrhotic patients have considerably lower plasma concentrations of all major lipoprotein classes with changes in lipoprotein subfraction distribution. After OLT, these lipoprotein abnormalities are in part reversed. LP-Z is associated with cirrhosis. Its presence may translate in disturbed HDL metabolism and worse survival.

Mahalanobis distance, a novel statistical proxy of homeostasis loss is longitudinally associated with risk of type 2 diabetes.

BACKGROUND: The potential role of individual plasma biomarkers in the pathogenesis of type 2 diabetes (T2D) has been broadly studied, but the impact of biomarkers interaction remains underexplored. Recently, the Mahalanobis distance (MD) of plasma biomarkers has been proposed as a proxy of physiological dysregulation. Here we aimed to investigate whether the MD calculated from circulating biomarkers is prospectively associated with development of T2D. METHODS: We calculated the MD of the Principal Components (PCs) integrating the information of 32 circulating biomarkers (comprising inflammation, glycemic, lipid, microbiome and one-carbon metabolism) measured in 6247 participants of the PREVEND study without T2D at baseline. Cox proportional-hazards regression analyses were performed to study the association of MD with T2D development. FINDINGS: After a median follow-up of 7·3 years, 312 subjects developed T2D. The overall MD (mean (SD)) was higher in subjects who developed T2D compared to those who did not: 35·65 (26·67) and 30.75 (27·57), respectively (P = 0·002). The highest hazard ratio (HR) was obtained using the MD calculated from the first 31 PCs (per 1 log-unit increment) (1·72 (95% CI 1·42,2·07), P < 0·001). Such associations remained after the adjustment for age, sex, plasma glucose, parental history of T2D, lipids, blood pressure medication, and BMI (HRadj 1·37 (95% CI 1·11,1·70), P = 0·004). INTERPRETATION: Our results are in line with the premise that MD represents an estimate of homeostasis loss. This study suggests that MD is able to provide information about physiological dysregulation also in the pathogenesis of T2D. FUNDING: The Dutch Kidney Foundation (Grant E.033).

Long-term outcome of early steroid withdrawal in pediatric renal transplantation.

BACKGROUND: Steroid use in renal transplant is related to multiple adverse effects. Long-term effects of early withdrawal steroids in pediatric renal transplant were assessed. METHODS: Renal transplant children with low immunological risk treated on basiliximab, tacrolimus, and mycophenolate with steroid withdrawal or steroid control were evaluated between 2003 and 2019. Clinical variables, treatment adherence, acute rejection, graft loss, and death were analyzed through hazard ratios, and Kaplan-Meier and multivariate analyses. RESULTS: The study included 152 patients, 71.1% steroid withdrawal, mean follow-up 8.5 years, 64.5% structural abnormalities, and 81.6% deceased donor. At 12 years of transplant, event-free survival analysis for graft loss or death showed no significant difference between steroid withdrawal and control steroid treatment (85.9% vs. 80.4%, p = .36) nor in acute rejection at 10 years (18.5% vs. 20.5%, p = .78) or in donor-specific antibody appearance (19.6% vs. 21.4%, p = .98). Delta height Z-score was increased in the steroid withdrawal group (p < .01). The main predictor of graft loss or death was non-adherence to treatment (p = .001; OR: 17.5 [3.3-90.9]). CONCLUSIONS: Steroid withdrawal therapy was effective and safe for low-risk pediatric renal transplant in long-term evaluation. Non-adherence was the main predictor of graft loss or death.

Triglyceride-rich lipoprotein and LDL particle subfractions and their association with incident type 2 diabetes: the PREVEND study.

BACKGROUND: Triglyceride-rich lipoproteins particles (TRLP) and low density lipoprotein particles (LDLP) vary in size. Their association with ß-cell function is not well described. We determined associations of TRLP and LDLP subfractions with ß-cell function, estimated as HOMA-ß, and evaluated their associations with incident T2D in the general population. METHODS: We included 4818 subjects of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study without T2D at baseline. TRLP and LDLP subfraction concentrations and their average sizes were measured using the LP4 algorithm of the Vantera nuclear magnetic resonance platform. HOMA-IR was used as measure of insulin resistance. HOMA-ß was used as a proxy of ß-cell function. RESULTS: In subjects without T2D at baseline, very large TRLP, and LDL size were inversely associated with HOMA-ß, whereas large TRLP were positively associated with HOMA-ß when taking account of HOMA-IR. During a median follow-up of 7.3 years, 263 participants developed T2D. In multivariable-adjusted Cox regression models, higher concentrations of total, very large, large, and very small TRLP (reflecting remnants lipoproteins) and greater TRL size were associated with an increased T2D risk after adjustment for relevant covariates, including age, sex, BMI, HDL-C, HOMA-ß, and HOMA-IR. On the contrary, higher concentrations of large LDLP and greater LDL size were associated with a lower risk of developing T2D. CONCLUSIONS: Specific TRL and LDL particle characteristics are associated with ß-cell function taking account of HOMA-IR. Moreover, TRL and LDL particle characteristics are differently associated with incident T2D, even when taking account of HOMA-ß and HOMA-IR.

A metabolomic index based on lipoprotein subfractions and branched chain amino acids is associated with incident hypertension.

OBJECTIVE: The present study aims to evaluate the performance of the Diabetes Risk Index (DRI), a metabolomic index based on lipoprotein particles and branched chain amino acids, on the incidence of newly developed hypertension in a large community dwelling cohort. METHODS: The DRI was calculated by combining 6 lipoprotein parameters [sizes of very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL), concentrations of large VLDL, small LDL, and large HDL particles], and the concentrations of valine and leucine. DRI scores were estimated in 4169 participants from the PREVEND prospective cohort. Cox proportional hazards regression was used to evaluate the association of DRI scores with incident hypertension. RESULTS: During a median follow-up of 8.6 years, 924 new hypertension cases were ascertained. In analyses adjusted for age and sex, there was a significant association between DRI and incident hypertension with a hazard ratio (HR) per 1 SD increase of 1.45 (95% CI 1.36,1.54; p < 0.001). After additional adjustment for traditional risk factors, the HR remained significant (HRadj 1.21, 95% CI 1.10, 1.33, p <0.001). Likewise, subjects in the top quartile of DRI presented with a higher risk of hypertension (HRadj 1.64, 95% CI 1.28, 2.10, p <0.001). Furthermore, the net reclassification improvement assessment improved after the addition of DRI to a traditional risk model (p <0.001), allowing proper reclassification of 34% of the participants. CONCLUSION: Higher DRI scores were associated with an increased risk of incident hypertension. Such association was independent of traditional clinical risk factors for hypertension.