Synergistic effect of chronic kidney disease, neuropathy, and retinopathy on all-cause mortality in type 1 and type 2 diabetes: a 21-year longitudinal study.

BACKGROUND: The prognostic value of common and frequently associated diabetic microvascular complications (MVC), namely chronic kidney disease (CKD), cardiac autonomic neuropathy (CAN), peripheral neuropathy (DPN), and retinopathy (DR), is well established. However, the impact of their different combinations on long-term mortality has not been adequately assessed. METHODS: We retrospectively analyzed 21-year longitudinal data from 303 patients with long-standing type 1 (T1D) or type 2 diabetes (T2D), who were thoroughly characterized at baseline for the presence of MVC using 99mTc-DTPA dynamic renal scintigraphy, overnight urine collection, cardiovascular autonomic tests, monofilament testing, and dilated fundus oculi examination. RESULTS: After a 5,244 person-years follow-up, a total of 133 (43.9%) deaths occurred. The presence of CKD and CAN, regardless of other MVC, increased the adjusted all-cause mortality risk by 117% (HR 2.17 [1.45-3.26]) and 54% (HR 1.54 [1.01-2.36]), respectively. Concomitant CKD&CAN at baseline were associated with the highest mortality risk (HR 5.08 [2.52-10.26]), followed by CKD&DR (HR 2.95 [1.63-5.32]), and CAN&DR (HR 2.07 [1.11-3.85]). Compared with patients free from MVC, the mortality risk was only numerically higher in those with any isolated MVC (HR 1.52 [0.87-2.67]), while increased by 203% (HR 3.03 [1.62-5.68]) and 692% (HR 7.92 [2.93-21.37]) in patients with two and three concomitant MVC, respectively. CONCLUSIONS: Our study demonstrates the long-term, synergistic, negative effects of single and concomitant diabetic MVC on all-cause mortality, which should encourage comprehensive screenings for MCV in both T1D and T2D to improve risk stratification and treatment.

Prognostic value of 24-hour ambulatory blood pressure patterns in diabetes: A 21-year longitudinal study.

AIMS: To establish the long-term prognostic value of abnormal circadian blood pressure (BP) patterns in diabetes. MATERIALS AND METHODS: We retrospectively examined a cohort of 349 outpatients with diabetes who were screened for microvascular complications and followed up for 21 years. Dipping, nondipping and reverse-dipping status were defined based on 24-hour ambulatory BP monitoring (ABPM) as ≥10% reduction, <10% reduction, and any increase in average nighttime versus daytime systolic BP (SBP), respectively. RESULTS: After 6251 person-years of follow-up (median [range] follow-up 21.0 [1.1-22.0] years, 52% women, age 57.1 ± 11.9 years, 81.4% type 2 diabetes and 18.6% type 1 diabetes), a total of 136 deaths (39%) occurred. Compared with dippers, the nondippers and reverse dippers showed progressively higher prevalence of chronic kidney disease (CKD), cardiac autonomic neuropathy (CAN) and postural hypotension. Reverse dippers showed a 13.4% (2.5-year) reduction in mean overall survival and a twofold increased risk of all-cause mortality after adjustment for traditional risk factors (hazard ratio 2.2 [95% confidence interval 1.3-3.8]). Each 1% decrease in nighttime versus daytime SBP ratio was independently associated with a 4% reduction in 20-year mortality risk. CONCLUSIONS: In patients with diabetes, reverse dipping is associated with a higher prevalence of CKD and CAN and more than doubled the adjusted risk of all-cause mortality over a 21-year observation.

Learning prevalent patterns of co-morbidities in multichronic patients using population-based healthcare data.

The prevalence of longstanding chronic diseases has increased worldwide, along with the average age of the population. As a result, an increasing number of people is affected by two or more chronic conditions simultaneously, and healthcare systems are facing the challenge of treating multimorbid patients effectively. Current therapeutic strategies are suited to manage each chronic condition separately, without considering the whole clinical condition of the patient. This approach may lead to suboptimal clinical outcomes and system inefficiencies (e.g. redundant diagnostic tests and inadequate drug prescriptions). We develop a novel methodology based on the joint implementation of data reduction and clustering algorithms to identify patterns of chronic diseases that are likely to co-occur in multichronic patients. We analyse data from a large adult population of multichronic patients living in Tuscany (Italy) in 2019 which was stratified by sex and age classes. Results demonstrate that (i) cardio-metabolic, endocrine, and neuro-degenerative diseases represent a stable pattern of multimorbidity, and (ii) disease prevalence and clustering vary across ages and between women and men. Identifying the most common multichronic profiles can help tailor medical protocols to patients' needs and reduce costs. Furthermore, analysing temporal patterns of disease can refine risk predictions for evolutive chronic conditions.

Circadian heart rate fluctuations predict cardiovascular and all-cause mortality in type 2 and type 1 diabetes: a 21-year retrospective longitudinal study.

BACKGROUND: Circadian heart rate (HR) fluctuations are associated with cardiovascular health. We examined their relationship with microvascular disease and long-term survival in patients with diabetes. METHODS: In this secondary analysis from the CHAMP1ON cohort of 497 adults with metabolic disease, 349 participants who had type 1 or type 2 diabetes, baseline 24h ambulatory blood pressure and HR monitoring (ABPM), and survival data over a 21-year observational follow-up were included. Clinical features, microvascular complications, and mortality rates were examined in participants with low circadian HR fluctuations (24h-HR SD below the median of 30.4) and blunted nocturnal HR dip (<10%). RESULTS: Low 24h-HR SD and blunted nocturnal HR dip were associated with an adverse cardiometabolic risk profile and 12-23% higher prevalence of cardiac autonomic neuropathy and nephropathy. After 6,251 person-years follow-up (21.0 [14.0-21.0] years), a total of 136 (39%) deaths occurred, of which 100 (68%) of cardiovascular cause. The low 24h-HR SD group had a higher risk for both cardiovascular (adjusted hazard ratio [aHR] 2.00, 95%CI 1.30-3.08, p=0.002) and all-cause mortality (aHR 1.61, 95%CI 1.13-2.29, p=0.009), compared with high 24h-HR SD. Similarly, patients with blunted nocturnal HR dip had a higher risk for cardiovascular (aHR 1.63, 95%CI 1.08-2.46, p=0.019) and all-cause mortality (aHR 1.69, 95%CI 1.20-2.38, p=0.003), compared with those with preserved nocturnal HR dip. CONCLUSIONS: Impaired circadian HR fluctuations are associated with microvascular disease and long-term cardiovascular and all-cause mortality in diabetes. ABPM-derived HR measures may provide a widely available and inexpensive risk stratification tool in this high-risk population.

Circadian heart rate (HR) fluctuations are associated with cardiovascular health. We examined their relationship with microvascular disease and long-term survival in patients with diabetes. Impaired HR fluctuations measured by 24h ambulatory blood pressure and HR monitoring (ABPM) were associated with an adverse cardiometabolic risk profile, higher prevalence of cardiac autonomic neuropathy and nephropathy, and higher risk for cardiovascular and all-cause mortality over a 21-year follow-up. ABPM-derived HR measures may provide a cost-effective risk stratification tool in this high-risk population.

An Immune-Related Gene Expression Signature Predicts Benefit from Adding Atezolizumab to FOLFOXIRI plus Bevacizumab in Metastatic Colorectal Cancer.

PURPOSE: AtezoTRIBE phase II randomized study demonstrated that adding atezolizumab to first-line FOLFOXIRI (5-fluorouracil, oxaliplatin, irinotecan) plus bevacizumab prolongs progression-free survival (PFS) of patients with metastatic colorectal cancer (mCRC), with a modest benefit among proficient mismatch repair (pMMR). DetermaIO is an immune-related 27-gene expression signature able to predict benefit from immune checkpoint inhibition in triple-negative breast cancer. In this analysis of AtezoTRIBE, we investigated the predictive impact of DetermaIO in mCRC. EXPERIMENTAL DESIGN: Patients with mCRC unselected for MMR status were randomly assigned (1:2) to FOLFOXIRI plus bevacizumab (control arm) or the same regimen with atezolizumab (atezolizumab arm). qRT-PCR by DetermaIO was performed on RNA purified from pretreatment tumors of 132 (61%) of 218 enrolled patients. A binary result (IOpos vs. IOneg) adopting the preestablished DetermaIO cut-off point (0.09) was obtained, and an exploratory optimized cut-off point (IOOPT) was computed in the overall population and in pMMR subgroup (IOOPTpos vs. IOOPTneg). RESULTS: DetermaIO was successfully determined in 122 (92%) cases, and 23 (27%) tumors were IOpos. IOpos tumors achieved higher PFS benefit from atezolizumab arm than IOneg (HR: 0.39 vs. 0.83; Pinteraction = 0.066). In pMMR tumors (N = 110), a similar trend was observed (HR: 0.47 vs. 0.93; Pinteraction = 0.139). In the overall population, with the computed IOOPT cut-off point (0.277), 16 (13%) tumors were IOOPTpos and they derived higher PFS benefit from atezolizumab than IOOPTneg (HR: 0.10 vs. 0.85, Pinteraction = 0.004). Similar results were found in the pMMR subgroup. CONCLUSIONS: DetermaIO may be useful to predict benefit of adding atezolizumab to first-line FOLFOXIRI plus bevacizumab in mCRC. The exploratory IOOPT cut-off point should be validated in independent mCRC cohorts.

Soluble CD40 receptor is a biomarker of the burden of carotid artery atherosclerosis in subjects at high cardiovascular risk.

BACKGROUND AND AIMS: The severity of the atherosclerotic burden is hardly quantifiable in subjects at high cardiovascular (CV) risk under intensive pharmacological therapy. Several molecules have been proposed as circulating biomarkers of atherosclerosis, but none has emerged as clinically meaningful. METHODS: Circulating proteins involved in inflammation, plaque remodeling, smooth muscle cell migration, apoptosis and endothelial activity were measured by Proximity Extension Assay in the SUMMIT study cohort (n = 1500), including patients with type 2 diabetes (66%) and established CV disease (50%), who underwent ultrasound assessment of carotid atherosclerosis with total plaque area quantification. RESULTS: In patients with evidence of carotid artery atherosclerosis (n = 1174), seven biomarkers were identified as the more closely related to atherosclerosis extension. Compared with a multivariable model including major traditional CV risk factors, the percentage gain of explained variability in total plaque area was the greatest (33%) after inclusion of CD40 receptor (CD40R) ligand, followed by PDGF (30%), CD40R (26%), EGF (22%), CXCL1 (15%), HBEGF and MMP-17 (both 11%). The relationship of total plaque area with CD40R, PDGF was hyperbolic. In the whole study cohort, including subjects without carotid plaques, CD40R was the strongest predictor of the presence and extension of carotid atherosclerosis. Subjects in the third CD40R tertile had a more than two-fold greater atherosclerotic burden compared with lower CD40R tertiles, despite an only marginally higher load of CV risk factors. CONCLUSIONS: CD40R stands among an extended set of plausible atherosclerosis-related biomarkers as the most powerful predictor of carotid atherosclerosis burden in a high CV risk cohort.

Female Sex and Angiotensin-Converting Enzyme (ACE) Insertion/Deletion Polymorphism Amplify the Effects of Adiposity on Blood Pressure.

The pathophysiological link between adiposity and blood pressure is not completely understood, and evidence suggests an influence of sex and genetic determinants. We aimed to identify the relationship between adiposity and blood pressure, independent of a robust set of lifestyle and metabolic factors, and to examine the modulating role of sex and Angiotensin-Converting Enzyme (ACE) insertion/deletion (I/D) polymorphisms. In the Relationship Between Insulin Sensitivity and Cardiovascular Disease (RISC) study cohort, 1211 normotensive individuals, aged 30 to 60 years and followed-up after 3.3 years, were characterized for lifestyle and metabolic factors, body composition, and ACE genotype. Body mass index (BMI) and waist circumference (WC) were independently associated with mean arterial pressure, with a stronger relationship in women than men (BMI: r=0.40 versus 0.30; WC: r=0.40 versus 0.30, both P<0.01) and in individuals with the ID and II ACE genotypes in both sexes (P<0.01). The associations of BMI and WC with mean arterial pressure were independent of age, sex, lifestyle, and metabolic variables (standardized regression coefficient=0.17 and 0.18 for BMI and WC, respectively) and showed a significant interaction with the ACE genotype only in women (P=0.03). A 5 cm larger WC at baseline increased the risk of developing hypertension at follow-up only in women (odds ratio, 1.56 [95% CI, 1.15-2.10], P=0.004) and in II genotype carriers (odds ratio, 1.87 [95% CI, 1.09-3.20], P=0.023). The hypertensive effect of adiposity is more pronounced in women and in people carrying the II variant of the ACE genotype, a marker of salt sensitivity.

Adoption of Improved Reprocessing Decreased Microbiological Non-Compliance for Bronchoscopes.

BACKGROUND: In the past few decades, the inadequate reprocessing of bronchoscopes has been associated with several serious outbreaks caused by multidrug-resistant microorganisms. In this study we evaluated the improvement in the quality of reprocessing in a Bronchoscopy Unit (BU), after the introduction of a new procedure. METHODS: In 2019, observational and clinical audits were conducted in the BU. After the introduction of an improved procedure in 2020, a microbiological surveillance plan was implemented in 2021. RESULTS: In 2019, 13 of 22 bronchoscopes (59%) resulted as non-compliant, 18% as high concern organisms (HCO) and 36.4% as high microbial count (≥100 CFU/all channels) and HCO. The most frequent microorganisms were Staphylococcus aureus (38.5%) and NDM-producing Klebsiella pneumoniae (15.4%). The bronchoscopes were stored inside their transport cases, which in some cases were found to be contaminated by the same strains isolated on the bronchoscopes (Enterobacter gergoviae and Vibrio alginolyticus). In 2021, all 31 bronchoscopes were sampled at least three times and 13/99 (13.1%) resulted as non-compliant, mostly K. pneumoniae (4.04%). Contamination level increases weakly in bronchoscopes in use for more than 14 years (R = 0.32). CONCLUSIONS: The adoption of an improved reprocessing procedure decreased the non-compliance of bronchoscopes, increasing the quality of the process and patient safety.

Glutamate-Serine-Glycine Index: A Novel Potential Biomarker in Pediatric Non-Alcoholic Fatty Liver Disease.

Preliminary evidence suggests that the glutamate-serine-glycine (GSG) index, which combines three amino acids involved in glutathione synthesis, may be used as a potential biomarker of non-alcoholic fatty liver disease (NAFLD). We investigated whether the GSG index is associated with NAFLD in youth, independent of other risk factors. Intrahepatic fat content (HFF%) and abdominal fat distribution were measured by magnetic resonance imaging (MRI) in a multiethnic cohort of obese adolescents, including Caucasians, African Americans, and Hispanics. NAFLD was defined as HFF% ≥ 5.5%. Plasma amino acids were measured by mass spectrometry. The GSG index was calculated as glutamate/(serine + glycine). The GSG index was higher in NAFLD patients (p = 0.03) and positively correlated with HFF% (r = 0.26, p = 0.02), alanine aminotransferase (r = 0.39, p = 0.0006), and aspartate aminotransferase (r = 0.26, p = 0.03). Adolescents with a high GSG index had a twofold higher prevalence of NAFLD than those with a low GSG index, despite similar adiposity, abdominal fat distribution, and liver insulin resistance. NAFLD prevalence remained significantly different between groups after adjustment for age, sex, race/ethnicity, and body mass index (OR 3.07, 95% confidence interval 1.09-8.61, p = 0.03). This study demonstrates the ability of the GSG index to detect NAFLD in at-risk pediatric populations with different genetically determined susceptibilities to intrahepatic fat accumulation, independent of traditional risk factors.

Evaluation of Microbial Adhesion and Biofilm Formation on Nano-Structured and Nano-Coated Ortho-Prosthetic Materials by a Dynamic Model.

The bio-engineering technologies of medical devices through nano-structuring and coating was recently proposed to improve biocompatibility and to reduce microbial adhesion in the prevention of implantable device-related infections. Our aim was to evaluate the ability of new nano-structured and coated materials to prevent the adhesion and biofilm formation, according to the American Standard Test Method ASTM-E2647-13. The materials composition was determined by X-ray Fluorescence and Laser Induced Breakdown Spectroscopy. Silver release was evaluated by Inductively Coupled Plasma Mass Spectrometry analysis. The gene expression levels of the Quorum Sensing Las and Rhl system were evaluated by the ΔΔCt method. The Log bacterial density (Log CFU/cm2) on TiAl6V4 was 4.41 ± 0.76 and 4.63 ± 1.01 on TiAl6V4-AgNPs compared to 2.57 ± 0.70 on CoCr and 2.73 ± 0.61 on CoCr-AgNPs (P < 0.0001, A.N.O.V.A.- one way test). The silver release was found to be equal to 17.8 ± 0.2 µg/L after the batch phase and 1.3 ± 0.1 µg/L during continuous flow. The rhlR gene resulted in a 2.70-fold increased expression in biofilm growth on the silver nanoparticles (AgNPs) coating. In conclusion, CoCr showed a greater ability to reduce microbial adhesion, independently of the AgNPs coating. The silver release resulted in promoting the up-regulation of the Rhl system. Further investigation should be conducted to optimize the effectiveness of the coating.