Heart rate fragmentation and brain MRI markers of small vessel disease in MESA.

INTRODUCTION: Heart rate (HR) fragmentation indices quantify breakdown of HR regulation and are associated with atrial fibrillation and cognitive impairment. Their association with brain magnetic resonance imaging (MRI) markers of small vessel disease is unexplored. METHODS: In 606 stroke-free participants of the Multi-Ethnic Study of Atherosclerosis (mean age 67), HR fragmentation indices including percentage of inflection points (PIP) were derived from sleep study recordings. We examined PIP in relation to white matter hyperintensity (WMH) volume, total white matter fractional anisotropy (FA), and microbleeds from 3-Tesla brain MRI completed 7 years later. RESULTS: In adjusted analyses, higher PIP was associated with greater WMH volume (14% per standard deviation [SD], 95% confidence interval [CI]: 2, 27%, P = 0.02) and lower WM FA (-0.09 SD per SD, 95% CI: -0.16, -0.01, P = 0.03). DISCUSSION: HR fragmentation was associated with small vessel disease. HR fragmentation can be measured automatically from ambulatory electrocardiogram devices and may be useful as a biomarker of vascular brain injury.

Individuals with type 2 diabetes have higher density of small intestinal neurotensin-expressing cells.

Neurotensin (NT) is a gastro-intestinal hormone involved in several pathways that regulate energy and glucose homeostasis. NT was hypothesized to act in synergy with incretin hormones to potentiate its anti-diabetic effects. Additionally, circulating NT levels were shown to rise after bariatric surgery-induced weight loss. Knowledge of NT-secreting cells distribution along the small intestine and its variation according to diabetes status could provide insights on NT role in mediating type 2 diabetes (T2D) improvement after bariatric surgery. So, our aims were to characterize NT-expressing cell distribution along the human small intestine and to compare the relative density of NT-expressing cells in the small intestine of individuals with and without T2D undergoing bariatric surgery for obesity treatment. Autopsy-derived small intestine fragments (n = 30) were obtained at every 20 cm along the entire intestinal length. Additionally, jejunum biopsies (n = 29) were obtained during elective gastric bypass interventions from patients with (n = 10) or without T2D (n = 18). NT-expressing cells were identified by immunohistochemistry and quantified via computerized morphometric analysis. NT-expressing cell density increased along the human small intestine. NT-expressing cell density was significantly higher from 200 cm distal to the duodenojejunal flexure onward, as well as in subjects with T2D when compared to those without T2D. NT-expressing cell density increases along the human small gut, and a higher density is found in individuals with T2D. This finding suggests a potential role for NT in the mechanisms of disease and T2D improvement observed after bariatric surgery.

Chitosan 3D scaffolds with resolvin D1 for vertebral arthrodesis: a pilot study.

PURPOSE: Over the last years, the number of vertebral arthrodesis has been steadily increasing. The use of iliac crest bone autograft remains the "gold standard" for bone graft substitute in these procedures. However, this solution has some side effects, such as the problem of donor site morbidity indicating that there is a real need for adequate alternatives. This pilot study aimed to evaluate the usefulness of chitosan (Ch) porous 3D scaffolds incorporated with resolvin D1 (RvD1) as an alternative implant to iliac bone autograft. METHODS: We have performed bilateral posterolateral lumbar vertebral arthrodesis in a rat animal model. Three experimental groups were used: (i) non-operated animals; (ii) animals implanted with Ch scaffolds incorporated with RvD1 and (iii) animals implanted with iliac bone autograft. RESULTS: The collagenous fibrous capsule formed around the Ch scaffolds with RvD1 is less dense when compared with the iliac bone autograft, suggesting an important anti-inflammatory effect of RvD1. Additionally, new bone formation was observed in the Ch scaffolds with RvD1. CONCLUSION: These results demonstrate the potential of these scaffolds for bone tissue repair applications.

Regular Voluntary Running is Associated with Increased Tumor Vascularization and Immune Cell Infiltration and Decreased Tumor Growth in Mice.

Tumors present dysfunctional vasculature that limits blood perfusion and hinders immune cells delivery. We aimed to investigate if regular voluntary running promotes tumor vascular remodelling, improves intratumoral immune cells infiltration and inhibits tumor growth. Tumors were induced in C57BL/6 male mice (n=28) by subcutaneous inoculation in the dorsal region with a suspension of RM1 cells (1.5×105 cells/500 µL PBS) and randomly allocated into two groups: sedentary (n=14) and voluntarily exercised on a wheel (n=14). Seven mice from each group were sacrificed 14 and 28 days after cells' inoculation to evaluate tumor weight, microvessel density, vessels' lumen regularity and the intratumoral quantity of NKG2D receptors, CD4+and CD8+T cells, by immunohistochemistry. The statistical inference was done through a two-way ANOVA. Exercised mice developed smaller tumors at 14 (0.17±0.1 g vs. 0.48±0.2 g, p<0.05) and 28 (0.92±0.7 g vs. 2.09±1.3 g, p<0.05) days, with higher microvessel density (21.20±3.2 vs. 15.86±4.0 vessels/field, p<0.05), more regular vessels' lumen (1.06±0.2 vs. 1.43±0.2, p<0.05), and higher CD8+T cells (464.95±48.0 vs. 364.70±49.4 cells/mm2, p<0.01), after 28 days. NKG2D expression was higher in exercised mice at 14 (263.27±25.8 cells/mm2, p<0.05) and 28 (295.06±56.2 cells/mm2, p<0.001) days. Regular voluntary running modulates tumor vasculature, increases immune cells infiltration and attenuates tumor growth, in mice.

Visceral Adipose Tissue Bioenergetics Varies According to Individuals' Obesity Class.

Obesity is associated with complex adipose tissue energy metabolism remodeling. Whether AT metabolic reprogramming differs according to body mass index (BMI) and across different obesity classes is unknown. This study's purpose was to evaluate and compare bioenergetics and energy substrate preference of visceral adipose tissue (VAT) pertaining to individuals with obesity class 2 and class 3. VAT obtained from patients with obesity (n = 15) class 2 (n = 7; BMI 37.53 ± 0.58 kg/m2) or class 3 (n = 8; BMI 47.79 ± 1.52 kg/m2) was used to assess oxygen consumption rate (OCR) bioenergetics and mitochondrial substrate preferences. VAT of patients with obesity class 3 presented significantly higher non-mitochondrial oxygen consumption (p < 0.05). In VAT of patients with obesity class 2, inhibition of pyruvate and glutamine metabolism significantly decreased maximal respiration and spare respiratory capacity (p < 0.05), while pyruvate and fatty acid metabolism inhibition, which renders glutamine the only available substrate, increased the proton leak with a protective role against oxidative stress (p < 0.05). In conclusion, VAT bioenergetics of patients with obesity class 2 depicts a greater dependence on glucose/pyruvate and glutamine metabolism, suggesting that patients within this BMI range are more likely to be responsive to interventions based on energetic substrate modulation for obesity treatment.

Method to quantify the impact of sleep on cardiac neuroautonomic functionality: application to the prediction of cardiovascular events in the Multi-Ethnic Study of Atherosclerosis.

We introduce the concept of cardiac neuroautonomic renewability and a method for its quantification. This concept refers to the involuntary nervous system's capacity to improve cardiac control in response to restorative interventions, such as sleep. We used the change in heart rate fragmentation (ΔHRF), before sleep onset compared with after sleep termination, to quantify the restorative effects of sleep. We hypothesized that the ability to improve cardiac neuroautonomic functionality would diminish with age and be associated with lower risk of major adverse cardiovascular events (MACE). We analyzed the ECG channel of polysomnographic recordings from an ancillary investigation of the Multi-Ethnic Study of Atherosclerosis (MESA). In a cohort of 659 participants (mean ± SD age, 69.7 ± 8.8; 42% male), HRF was significantly (P < 0.001) lower after sleep (before: 74 ± 12%, after: 67 ± 13%). Furthermore, the magnitude of the decrease significantly (P < 0.001) diminished with cross-sectional age. In addition, a larger reduction in HRF following sleep (i.e., higher ΔHRF) was associated with lower risk of MACE, independent of traditional cardiovascular risk factors and current measures of sleep quality. Specifically, over a mean follow-up period of 6.4 ± 1.6 yr, in which 60 participants had their first MACE, a one-SD (12%) increase in ΔHRF was associated with a 36% (95% CI: 12%-53%) decrease in the risk of MACE. The results demonstrate the restorative impact of sleep on heart rate control. As such they support the concept of cardiac neuroautonomic renewability and the utility of ΔHRF for its quantification.

Maternal vaccination against group B Streptococcus glyceraldehyde-3-phosphate dehydrogenase leads to gut dysbiosis in the offspring.

Group B Streptococcus (GBS) remains a major neonatal life-threatening pathogen. We initially identified glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a promising vaccine candidate against GBS. Since GAPDH is highly conserved, we investigate whether GBS GAPDH maternal vaccination interferes with the intestinal colonization of the offspring and the development of its mucosal immune system and central nervous system. An altered gut microbiome with increased Proteobacteria is observed in pups born from vaccinated dams during early life. These pups present decreased relative expression of IL-1ß, IL-17A, RegIIIγ and MUC2 in the distal colon. They also display increased CD11b, F4/80 and MHC class II expression on microglia in early life and marked reduction of Ly6C+ cells and neutrophils. Importantly, male mice born from vaccinated mothers present behavioral abnormalities during adulthood, including decreased exploratory behavior, a subtle anxious-like phenotype and global alterations in spatial learning and memory strategies, and higher sensitivity to a stressful stimulus. Our study highlights the danger of using ubiquitous antigens in maternal human vaccines against neonatal pathogens.

Ang-Tie Angiogenic Pathway Is Distinctively Expressed in Benign and Malignant Adrenocortical Tumors.

The differential diagnosis between adrenocortical adenomas (ACAs) and adrenocortical carcinomas (ACCs) relies on unspecific clinical, imaging and histological features, and, so far, no single molecular biomarker has proved to improve diagnostic accuracy. Similarly, prognostic factors have an insufficient capacity to predict the heterogeneity of ACC clinical outcomes, which consequently lead to inadequate treatment strategies. Angiogenesis is a biological process regulated by multiple signaling pathways, including VEGF and the Ang-Tie pathway. Many studies have stressed the importance of angiogenesis in cancer development and metastasis. In the present study, we evaluated the expression of VEGF and Ang-Tie pathway mediators in adrenocortical tumors (ACTs), with the ultimate goal of assessing whether these molecules could be useful biomarkers to improve diagnostic accuracy and/or prognosis prediction in ACC. The expression of the proteins involved in angiogenesis, namely CD34, VEGF, VEGF-R2, Ang1, Ang2, Tie1 and Tie2, was assessed by immunohistochemistry in ACC (n = 22), ACA with Cushing syndrome (n = 8) and non-functioning ACA (n = 13). ACC presented a significantly higher Ang1 and Ang2 expression when compared to ACA. Tie1 expression was higher in ACC with venous invasion and in patients with shorter overall survival. In conclusion, although none of these biomarkers showed to be useful for ACT diagnosis, the Ang-Tie pathway is active in ACT and may play a role in regulating ACT angiogenesis.

Fragmented sinoatrial dynamics in the prediction of atrial fibrillation: the Multi-Ethnic Study of Atherosclerosis.

Heart rate fragmentation (HRF), a marker of abnormal sinoatrial dynamics, was shown to be associated with incident cardiovascular events in the Multi-Ethnic Study of Atherosclerosis (MESA). Here, we test the hypothesis that HRF is also associated with incident atrial fibrillation (AF) in the MESA cohort of participants who underwent in-home polysomnography (PSG) and in two high-risk subgroups: those ≥70 yr taking antihypertensive medication and those with serum concentrations of NH2-terminal prohormone B-type natriuretic peptide (NT-proBNP) >125 pg/ml (top quartile). Heart rate time series (n = 1,858) derived from the ECG channel of the PSG were analyzed using newly developed HRF metrics, traditional heart rate variability (HRV) indices and two widely used nonlinear measures. Eighty-three participants developed AF over a mean follow-up period of 3.83 ± 0.87 yr. A one-standard deviation increase in HRF was associated with a 31% (95% CI: 3-66%) increase in risk of incident AF, in Cox models adjusted for age, height, NT-proBNP, and frequent premature supraventricular complexes. Furthermore, HRF added value to the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE)-AF models. Traditional HRV and nonlinear indices were not significantly associated with incident AF. In the two high-risk subgroups defined above, HRF was also significantly associated with incident AF in unadjusted and adjusted models. These findings support the translational utility of HRF metrics for short-term (∼4-yr) prediction of AF. In addition, they support broadening the concept of atrial remodeling to include electrodynamical remodeling, a term used to refer to pathophysiological alterations in sinus interbeat interval dynamics.NEW & NOTEWORTHY This study is the first demonstration that heart rate fragmentation (HRF), a marker of anomalous sinoatrial dynamics, is an independent predictor of atrial fibrillation (AF). Traditional measures of heart rate variability and two widely used nonlinear measures were not associated with incident AF in the Multi-Ethnic Study of Atherosclerosis. Fragmentation measures added value to the strongest contemporary predictors of AF, including ECG-derived parameters, coronary calcification score, serum concentrations of NH2-terminal prohormone B-type natriuretic peptide, and supraventricular ectopy. The computational algorithms for quantification of HRF could be readily incorporated into wearable ECG monitoring devices.

Comparison of Invasive and Noninvasive Blood Pressure Measurements for Assessing Signal Complexity and Surgical Risk in Cardiac Surgical Patients.

BACKGROUND: Continuous arterial blood pressure (ABP) is typically recorded by placement of an intraarterial catheter. Recently, noninvasive ABP monitors have been shown to be comparable in accuracy to invasive measurements. In a previous study, we showed that the fluctuations in beat-to-beat ABP measurements were not random variations but had a complex dynamical structure, and that ABP dynamical complexity was inversely associated with surgical risk estimated using the Society of Thoracic Surgeons (STS) index. Dynamical complexity is a mathematical construct that reflects the capacity of a physiological system to adapt to stimuli. The objectives of present study were to: (1) determine whether noninvasive beat-to-beat ABP measurements also exhibit a complex temporal structure; (2) compare the complexity of noninvasive versus invasive ABP time series; and (3) quantify the relationship between the complexity of noninvasive ABP time series and the STS risk scores. METHODS: Fifteen adult patients undergoing coronary artery bypass graft, valve, or combined coronary artery bypass graft/valve surgery were enrolled in this observational study. Preoperative ABP waveforms were simultaneously recorded for ≥15 minutes using a radial artery catheter (invasive) and a continuous noninvasive arterial pressure monitor. Beat-to-beat systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), and mean arterial pressure (MAP) time series were extracted from the continuous waveforms. Complexity was assessed using the multiscale entropy method. The Wilcoxon signed-rank test was used to compare the mean ranks of indices derived from invasive versus noninvasive ABP time series. Spearman correlation coefficients were used to quantify the relationship between invasive and noninvasive indices. Linear regression analysis was used to quantify the association between each of the complexity indices and the STS risk scores. RESULTS: Beat-to-beat fluctuations in noninvasive ABP measurements were not random but complex; however, their degree of complexity was lower than that of fluctuations in invasively obtained ABP signals (SBP: 7.05 vs 8.66, P < .001; DBP: 7.40 vs 8.41, P < .001; PP: 6.83 vs 8.82, P < .001; and MAP: 7.17 vs 8.68, P < .005). Invasive and noninvasive indices for MSEΣ·slope showed good correlation (rs) (0.53 for SBP, 0.79 for DBP, 0.42 for PP, 0.60 for MAP). The complexity of noninvasive ABP time series (-0.70 [-1.28 to -0.11]; P = .023 for DBP), like that of invasive time series (-0.94 [-1.52 to -0.35]; P = .004 for DBP), was inversely associated with estimated surgical risk in patients undergoing cardiovascular operations. CONCLUSIONS: Our results support the use of noninvasive ABP monitoring in computations of complexity-based indices that correlate with estimated surgical risk.

MAPK/ERK pathway inhibition is a promising treatment target for adrenocortical tumors.

Unraveling molecular mechanisms that regulate tumor development and proliferation is of the utmost importance in the quest to decrease the high mortality rate of adrenocortical carcinomas (ACC). Our aim was to evaluate the role of two of the mitogen-activated protein kinase (MAPK) signaling pathways (extracellular signal-regulated protein kinases [ERKs 1/2] and p38) in the adrenocortical tumorigenesis, as well as the therapeutic potential of MAPK/ERK inhibition. ERKs 1/2 and p38 activation were evaluated in incidentalomas (INC; n = 10), benign Cushing's syndrome (BCS; n = 12), malignant Cushing's syndrome (MCS; n = 6) and normal adrenal glands (NAG; 8). ACC cell line (H295R) was used to evaluate the ability of PD184352 (0.1, 1, and 10 µM), a specific MEK-MAPK-ERK pathway inhibitor, to modulate cell proliferation, viability, metabolism, and steroidogenesis. ERKs 1/2 activation was significantly higher in MCS (2.83 ± 0.17) compared with NAG (1.00 ± 0.19 "arbitrary units"), INC (1.20 ± 0.13) and BCS (2.09 ± 0.09). Phospho-p38 expression was absent in all the MCS analyzed. MAPK/ERK kinase (MEK) inhibition with PD184352 significantly decreased proliferation as well as steroidogenesis and also increased the redox state of the H295R cells. This data suggests that MEK-MAPK-ERK signaling has a role in adrenocortical tumorigenesis that could be potentially used as a diagnostic marker for malignancy and targeted treatment in ACC.

Heart rate fragmentation: using cardiac pacemaker dynamics to probe the pace of biological aging.

This perspectives article discusses the use of a novel set of dynamical biomarkers in the assessment of biological versus chronological age. The basis for this development is a recently delineated property of altered sinoatrial pacemaker-neuroautonomic function, termed heart rate fragmentation (HRF). Fragmented rhythms manifest as an increase in the density of changes in heart rate acceleration sign, not mechanistically explicable by physiological cardiac vagal tone modulation. We reported that HRF increased monotonically with cross-sectional age and that HRF measures, but not conventional heart rate variability metrics, were significantly associated with major incident cardiovascular events in the Multi-Ethnic Study of Atherosclerosis (MESA). Furthermore, HRF measures added value to both Framingham and MESA cardiovascular risk indices. Here, we propose that interventions that fundamentally slow or reverse the pace of biological aging, via system-wide effects, should be associated with a decrease in the degree of HRF and possibly with a reemergence of the nonfragmented ("fluent") patterns associated with more youthful heart rate dynamics.

Complexity of preoperative blood pressure dynamics: possible utility in cardiac surgical risk assessment.

Complexity measures are intended to assess the cardiovascular system's capacity to respond to stressors. We sought to determine if decreased BP complexity is associated with increased estimated risk as obtained from two standard instruments: the Society of Thoracic Surgeons' (STS) Risk of Mortality and Morbidity Index and the European System for Cardiac Operative Risk Evaluation Score (EuroSCORE II). In this observational cohort study, preoperative systolic, diastolic, mean (MAP) and pulse pressure (PP) time series were derived in 147 patients undergoing cardiac surgery. The complexity of the fluctuations of these four variables was quantified using multiscale entropy (MSE) analysis. In addition, the traditional time series measures, mean and standard deviation (SD) were also computed. The relationships between time series measures and the risk indices (after logarithmic transformation) were then assessed using nonparametric (Spearman correlation, rs) and linear regression methods. A one standard deviation change in the complexity of systolic, diastolic and MAP time series was negatively associated (p < 0.05) with the STS and EuroSCORE indices in both unadjusted (21-34%) and models adjusted for age, gender and SD of the BP time series (15-31%). The mean and SD of BP time series were not significantly associated with the risk index except for a positive association with the SD of the diastolic BP. Lower preoperative BP complexity was associated with a higher estimated risk of adverse cardiovascular outcomes and may provide a novel approach to assessing cardiovascular risk. Future studies are needed to determine whether dynamical risk indices can improve current risk prediction tools.

Differential GIP/GLP-1 intestinal cell distribution in diabetics' yields distinctive rearrangements depending on Roux-en-Y biliopancreatic limb length.

As incretins are known to play an important role in type 2 diabetics (T2D) improvement observed after Roux-en-Y gastric bypass (RYGB), our aim was to assess whether increasing the length of RYGB biliopancreatic limb in T2D would modify the incretin staining cell density found after the gastric outlet. Small intestine biopsies (n = 38) were harvested during RYGB at two different distances from the duodenal angle; either 60-90 cm (n = 28), from non-diabetic (n = 18) patients, and T2D (n = 10), or 200 cm (n = 10) from T2D. GIP and GLP-1 staining cells were identified by immunohistochemistry and GLP-1/GIP co-staining cells by immunofluorescence. Incretin staining cell density at the proximal small intestine of T2D and non-diabetic individuals was similar. At 200 cm, T2D patients depicted a significantly lower GIP staining cell density (0.181 ± 0.016 vs 0.266 ± 0.033, P = 0.038) with a similar GLP-1 staining cell density when compared to the proximal gut. GIP/GLP-1 co-staining cells was similar in all studied groups. In T2D patients, the incretin staining cells density in the distal intestine is significantly different from the proximal gut. Thus, a longer RYGB biliopancreatic limb produces a distinctive incretin cell pattern at the gastro-enteric anastomosis that can result in different endocrine profiles.

Generalized Multiscale Entropy Analysis: Application to Quantifying the Complex Volatility of Human Heartbeat Time Series.

We introduce a generalization of multiscale entropy (MSE) analysis. The method is termed MSE n , where the subscript denotes the moment used to coarse-grain a time series. MSE µ , described previously, uses the mean value (first moment). Here, we focus on [Formula: see text], which uses the second moment, i.e., the variance. [Formula: see text] quantifies the dynamics of the volatility (variance) of a signal over multiple time scales. We use the method to analyze the structure of heartbeat time series. We find that the dynamics of the volatility of heartbeat time series obtained from healthy young subjects is highly complex. Furthermore, we find that the multiscale complexity of the volatility, not only the multiscale complexity of the mean heart rate, degrades with aging and pathology. The "bursty" behavior of the dynamics may be related to intermittency in energy and information flows, as part of multiscale cycles of activation and recovery. Generalized MSE may also be useful in quantifying the dynamical properties of other physiologic and of non-physiologic time series.

Dynamical density delay maps: simple, new method for visualising the behaviour of complex systems.

BACKGROUND: Physiologic signals, such as cardiac interbeat intervals, exhibit complex fluctuations. However, capturing important dynamical properties, including nonstationarities may not be feasible from conventional time series graphical representations. METHODS: We introduce a simple-to-implement visualisation method, termed dynamical density delay mapping ("D3-Map" technique) that provides an animated representation of a system's dynamics. The method is based on a generalization of conventional two-dimensional (2D) Poincaré plots, which are scatter plots where each data point, x(n), in a time series is plotted against the adjacent one, x(n + 1). First, we divide the original time series, x(n) (n = 1,…, N), into a sequence of segments (windows). Next, for each segment, a three-dimensional (3D) Poincaré surface plot of x(n), x(n + 1), h[x(n),x(n + 1)] is generated, in which the third dimension, h, represents the relative frequency of occurrence of each (x(n),x(n + 1)) point. This 3D Poincaré surface is then chromatised by mapping the relative frequency h values onto a colour scheme. We also generate a colourised 2D contour plot from each time series segment using the same colourmap scheme as for the 3D Poincaré surface. Finally, the original time series graph, the colourised 3D Poincaré surface plot, and its projection as a colourised 2D contour map for each segment, are animated to create the full "D3-Map." RESULTS: We first exemplify the D3-Map method using the cardiac interbeat interval time series from a healthy subject during sleeping hours. The animations uncover complex dynamical changes, such as transitions between states, and the relative amount of time the system spends in each state. We also illustrate the utility of the method in detecting hidden temporal patterns in the heart rate dynamics of a patient with atrial fibrillation. The videos, as well as the source code, are made publicly available. CONCLUSIONS: Animations based on density delay maps provide a new way of visualising dynamical properties of complex systems not apparent in time series graphs or standard Poincaré plot representations. Trainees in a variety of fields may find the animations useful as illustrations of fundamental but challenging concepts, such as nonstationarity and multistability. For investigators, the method may facilitate data exploration.

Dynamical glucometry: use of multiscale entropy analysis in diabetes.

Diabetes mellitus (DM) is one of the world's most prevalent medical conditions. Contemporary management focuses on lowering mean blood glucose values toward a normal range, but largely ignores the dynamics of glucose fluctuations. We probed analyte time series obtained from continuous glucose monitor (CGM) sensors. We show that the fluctuations in CGM values sampled every 5 min are not uncorrelated noise. Next, using multiscale entropy analysis, we quantified the complexity of the temporal structure of the CGM time series from a group of elderly subjects with type 2 DM and age-matched controls. We further probed the structure of these CGM time series using detrended fluctuation analysis. Our findings indicate that the dynamics of glucose fluctuations from control subjects are more complex than those of subjects with type 2 DM over time scales ranging from about 5 min to 5 h. These findings support consideration of a new framework, dynamical glucometry, to guide mechanistic research and to help assess and compare therapeutic interventions, which should enhance complexity of glucose fluctuations and not just lower mean and variance of blood glucose levels.

Blood pressure fragmentation as a new measure of blood pressure variability: association with predictors of cardiac surgery outcomes.

Background: Fluctuations in beat-to-beat blood pressure variability (BPV) encode untapped information of clinical utility. A need exists for developing new methods to quantify the dynamical properties of these fluctuations beyond their mean and variance. Objectives: Introduction of a new beat-to-beat BPV measure, termed blood pressure fragmentation (BPF), and testing of whether increased preoperative BPF is associated with (i) older age; (ii) higher cardiac surgical risk, assessed using the Society of Thoracic Surgeons' (STS) Risk of Morbidity and Mortality index and the European System for Cardiac Operative Risk Evaluation Score (EuroSCORE II); and (iii) longer ICU length of stay (LOS) following cardiac surgery. The secondary objective was to use standard BPV measures, specifically, mean, SD, coefficient of variation (CV), average real variability (ARV), as well a short-term scaling index, the detrended fluctuation analysis (DFA) ⍺1 exponent, in the same type of analyses to compare the results with those obtained using BPF. Methods: Consecutive sample of 497 adult patients (72% male; age, median [inter-quartile range]: 67 [59-75] years) undergoing cardiac surgery with cardiopulmonary bypass. Fragmentation, standard BPV and DFA ⍺1 measures were derived from preoperative systolic blood pressure (SBP) time series obtained from radial artery recordings. Results: Increased preoperative systolic BPF was associated with older age, higher STS Risk of Morbidity and Mortality and EuroSCORE II values, and longer ICU LOS in all models. Specifically, a one-SD increase in systolic BPF (9%) was associated with a 26% (13%-40%) higher likelihood of longer ICU LOS (>2 days). Among the other measures, only ARV and DFA ⍺1 tended to be associated with longer ICU LOS. However, the associations did not reach significance in the most adjusted models. Conclusion: Preoperative BPF was significantly associated with preoperative predictors of cardiac surgical outcomes as well as with ICU LOS. Our findings encourage future studies of preoperative BPF for assessment of health status and risk stratification of surgical and non-surgical patients.

Collagen-depletion strategies in dentin as alternatives to the hybrid layer concept and their effect on bond strength: a systematic review.

Strategies aiming to improve the longevity of resin-dentin adhesive interface developed so far have only been able to retard the problem. Different approaches are thus needed. The objective of this review was to determine whether the use of collagen-depletion strategies after acid-etching procedures may improve the bond strength of resin-based materials to dentin. A systematic review was planned following 2021 PRISMA statement guidelines, with a search strategy performed in five electronic databases: PubMed/Medline, Scopus, EMBASE, SciELO and IADR Abstract Archive (last search: 17/01/2022). Inclusion criteria encompassed studies which evaluated a collagen-depletion strategy in acid-etched human dentin and tensile/shear bond strength tests. Risk of bias assessment was carried out by two reviewers, working independently on an adapted five-domain risk of bias (RoB) checklist for laboratory studies. Results were synthesized qualitatively, as a meta-analysis was not possible due to limited number of studies and their RoB. A total of eight studies were eligible for inclusion in the systematic review after inclusion/exclusion criteria application. Out of these, two evaluated the effect of using NaOCl followed by an antioxidant, and the remaining six evaluated different enzymatic treatments (bromelain, chondroitinase ABC, papain, and trypsin). None of the studies reported a decrease of bond strength when a collagen-depletion strategy was used, in comparison to traditional hybrid layers (control). All enzymatic treatment studies which respected the inclusion criteria improved the bond strength to dentin. Some specific collagen-depletion strategies seem to play a favorable role in improving immediate bond strengths to dentin. Further research with sound methodology is required to consolidate these findings, since limitations in RoB and a low number of studies were found. The assessment of further proteolytic agents and long-term outcomes is also required.

In vivo cyclic induction of the FOXM1 transcription factor delays natural and progeroid aging phenotypes and extends healthspan.

The FOXM1 transcription factor exhibits pleiotropic C-terminal transcriptional and N-terminal non-transcriptional functions in various biological processes critical for cellular homeostasis. We previously found that FOXM1 repression during cellular aging underlies the senescence phenotypes, which were vastly restored by overexpressing transcriptionally active FOXM1. Yet, it remains unknown whether increased expression of FOXM1 can delay organismal aging. Here, we show that in vivo cyclic induction of an N-terminal truncated FOXM1 transgene on progeroid and naturally aged mice offsets aging-associated repression of full-length endogenous Foxm1, reinstating both transcriptional and non-transcriptional functions. This translated into mitigation of several cellular aging hallmarks, as well as molecular and histopathological progeroid features of the short-lived Hutchison-Gilford progeria mouse model, significantly extending its lifespan. FOXM1 transgene induction also reinstated endogenous Foxm1 levels in naturally aged mice, delaying aging phenotypes while extending their lifespan. Thus, we disclose that FOXM1 genetic rewiring can delay senescence-associated progeroid and natural aging pathologies.