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.

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.

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.

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.

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.

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.

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.

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.

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.

Investigating a Commercial Functional Adhesive with 12-MDPB and Reactive Filler to Strengthen the Adhesive Interface in Eroded Dentin.

To compare the adhesive interface of eroded dentin formed by a functional dental adhesive and a gold standard strategy, by testing microtensile bond strength (µTBS), hardness/elastic modulus. Permanent sound human molars were randomly allocated to four experimental groups, all subject to artificial erosion (0.05 M citric acid; 3× daily, 5 days). Groups included control Clearfil SE Bond 2 (CFSE), and experimental group Clearfil SE Protect (CFP), at two different time points-immediate (24 h) and long term (3 months-3 M). Samples were sectioned into microspecimens for µTBS (n = 8) and into 2-mm thick slabs for nanoindentation assays (n = 3). Groups CFSE_3M and CFP_3M were stored in artificial saliva. Statistical analysis included two-way ANOVA for µTBS data, while hardness/modulus results were analyzed using Kruskal-Wallis H Test (significance level of 5%; SPSS v.27.0). Although no significant differences were found between mean µTBS values, for different adhesives and time points (p > 0.05), a positive trend, with µTBS rising in the CFP_3M group, was observed. Regarding hardness, no significant differences were seen in the hybrid layer, considering the two variables (p > 0.05), while the reduced elastic modulus rose in CFP_3M when compared to 24 h. Thus, CFP shows similar mechanical and adhesive performance to CFSE in eroded dentin, although it may comprise promising long-term results. This is advantageous in eroded substrates due to their increased enzymatic activity and need for remineralization.

Prediction of Cognitive Decline Using Heart Rate Fragmentation Analysis: The Multi-Ethnic Study of Atherosclerosis.

Background: Heart rate fragmentation (HRF), a new non-invasive metric quantifying cardiac neuroautonomic function, is associated with increasing age and cardiovascular disease. Since these are risk factors for cognitive decline and dementia, in the Multi-Ethnic Study of Atherosclerosis (MESA), we investigated whether disrupted cardiac neuroautonomic function, evidenced by increased HRF, would be associated with worse cognitive function assessed concurrently and at a later examination, and with greater cognitive decline. Methods: HRF was derived from the ECG channel of the polysomnographic recordings obtained in an ancillary study (n = 1,897) conducted in conjunction with MESA exam 5 (2010-2012). Cognitive function was assessed at exam 5 and 6.4 ± 0.5 years later at exam 6 (2016-2018) with tests of global cognitive performance (the Cognitive Abilities Screening Instrument, CASI), processing speed (Digit Symbol Coding, DSC) and working memory (Digit Span). Multivariable regression models were used to quantify the associations between HRF indices and cognitive scores. Results: The participants' mean age was 68 ± 9 years (54% female). Higher HRF at baseline was independently associated with lower cognitive scores at both exams 5 and 6. Specifically, in cross-sectional analyses, a one-standard deviation (SD) (13.7%) increase in HRF was associated with a 0.51 (95% CI: 0.17-0.86) points reduction in CASI and a 1.12 (0.34-1.90) points reduction in DSC. Quantitatively similar effects were obtained in longitudinal analyses. A one-SD increase in HRF was associated with a 0.44 (0.03-0.86) and a 1.04 (0.28-1.81) points reduction in CASI and DSC from exams 5 to 6, respectively. HRF added predictive value to the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE-APOE-ε4) risk score and to models adjusted for serum concentration of NT-proBNP, an analyte associated with cognitive impairment and dementia. Conclusion: Increased HRF assessed during sleep was independently associated with diminished cognitive performance (concurrent and future) and with greater cognitive decline. These findings lend support to the links between cardiac neuroautonomic regulation and cognitive function. As a non-invasive, repeatable and inexpensive probe, HRF technology may be useful in monitoring cognitive status, predicting risk of dementia and assessing therapeutic interventions.

Mineralocorticoid Receptor Antagonists Eplerenone and Spironolactone Modify Adrenal Cortex Morphology and Physiology.

Mineralocorticoid receptor antagonists (MRAs) are a class of anti-hypertensive drugs that act by blocking aldosterone action. The aim of this study was to evaluate whether the MRAs spironolactone and eplerenone influence adrenal cortical physiology and morphology. Spontaneous hypertensive rats (SHR, n = 18) and normotensive rats (WKY, n = 18) were randomly exposed to a daily dose of spironolactone (n = 6), eplerenone (n = 6), or no drug (n = 6) over 28 days. After that, aldosterone, corticosterone, and 11-deoxycorticosterone plasma concentrations were quantified. Adrenal glands were subjected to morphological analysis to assess lipid droplets content, capsular width, cell proliferation, and steroidogenic proteins expression. The adrenal cortex in untreated SHR showed higher lipid droplet content as than in WKY. In SHR, MRA treatment was associated with higher circulating aldosterone levels and Ki-67 expression in aldosterone-secreting cells. In WKY, the only difference observed after MRA spironolactone treatment was a narrower capsule. There was no difference in abundance of steroidogenic enzyme between groups. In conclusion, MRAs modify adrenal gland function and morphology in SHR. The effects observed within the adrenal glomerulosa with aldosterone-secreting cell proliferation and higher circulating aldosterone levels suggests that MRA treatment provokes activation of the renin angiotensin system. The prognostic value of hyperaldosteronism secondary to MRAs blockade requires further investigation.

Regular Voluntary Running Inhibits Androgen-Independent Prostate Cancer Growth in Mice.

INTRODUCTION: Benefits of regular physical exercise were demonstrated as preventive and coadjuvant nonpharmacological anticancer therapy. However, the role of exercise in modulating prostate cancer behavior has yet to be established. METHODS: Prostate tumors were induced in C57BL/6 male mice (n = 28) by subcutaneous inoculation of a suspension of murine androgen-independent RM1 cells (1.5 × 105 cells/500 µL phosphate-buffered saline) in the dorsal region. Mice were randomly allocated into 2 study groups: sedentary tumor-induced (n = 14) and exercised tumor-induced (n = 14). Exercise consisted of voluntary running in wheeled cages. Mice (n = 7 per group) were sacrificed either 14 or 28 days after cell inoculation to evaluate tumor weight and percentage of area occupied by immunohistochemistry stained cells for Ki-67 and TdT-mediated dUTP-biotin nick end labeling, used as surrogate markers of cell proliferation and apoptosis, respectively. RESULTS: Compared with sedentary tumor-induced mice, the tumors developed by exercised tumor-induced mice were significantly smaller at 14 days (0.17 [0.12] g vs 0.48 [0.24] g, P < .05) and at 28 days (0.92 [0.73] g vs 2.09 [1.31] g, P < .05), with smaller Ki-67 and greater TdT-mediated dUTP-biotin nick end-labeling stained areas (P < .05). CONCLUSION: These results suggest that regular voluntary running inhibits prostate cancer cell growth by reducing cell proliferation and enhancing apoptosis.

Analysis of laboratory adhesion studies in eroded enamel and dentin: a scoping review.

AIM: To summarize and report laboratory studies of adhesion in eroded substrates, which used bond strength as an outcome measure. To determine the strategies available to overcome bonding difficulties, the quality and consistency of the methodology and to find evidence gaps. MATERIALS AND METHODS: The present review followed PRISMA-ScR guidelines. A search was conducted on PubMed/Medline, Scopus and EMBASE (Ovid) databases to identify published peer-reviewed papers (2010-2020). For final qualitative synthesis, 29 articles were selected which respected the inclusion criteria. Data charting was carried out, independently, by two reviewers and quality assessment of the articles was performed. RESULTS: The primary studies included fall into four major categories: comparison of restorative materials and application modes, enzymatic inhibitors, surface pretreatments or remineralization strategies. Most studies found evaluated dentin (76%), while 17% evaluated enamel, and 7% evaluated both substrates. The majority of the studies reported an effective intervention (83%). Bond strength to eroded dentin is significantly reduced, while in enamel erosion is beneficial. The bond strength to eroded dentin is material-dependent and favored in systems containing 10-MDP. Great disparities among the erosion models used were found, with citric acid in different concentrations being the preferred method, although standardization is lacking. CONCLUSIONS: Adhesives containing 10-MDP show beneficial results in eroded dentin, and surface preparation methods should be considered. Studies which evaluated adhesion to eroded enamel/dentin show high heterogeneity in what concerns aims and methodology. Strategies that focus on remineralizing dentin and strategies to protect bond longevity in this substrate require further research.

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.

Incomplete Pattern of Steroidogenic Protein Expression in Functioning Adrenocortical Carcinomas.

Autonomous steroid secretion is a common feature of adrenocortical carcinomas (ACC), although not always clinically evident owing to inefficient steroidogenesis with increased release of steroid precursors. Our study aim was to analyze the expression profile of four key proteins involved in the steroidogenesis cascade, in different adrenocortical tumors. Expression of proteins involved in steroidogenesis, namely steroidogenic acute regulatory protein (StAR), 11ß-hydroxylase (CYP11B1), aldosterone synthase (CYP11B2) and 17α-hydroxylase (CYP17A1), were analyzed by immunohistochemistry in ACC (n = 14), adenomas presenting with Cushing's syndrome (ACAc) (n = 11) and clinically non-functioning adenomas (ACAn) (n = 15). A percentage of the stained area for each protein was analyzed using ImageJ software for computerized morphometric quantification. CYP11B1, StAR and CYP17A1 expression were significantly lower in ACC when compared to ACAc. In addition, ACC presented co-staining cells for CYP11B1 and CYP11B2. CYP11B1 was the steroidogenic enzyme with the most discriminative power to distinguish ACC from ACAc, with a sensitivity of 100%, specificity of 92%, and an expression higher than 4.44%, indicating the presence of a cortisol secreting adenoma. ACC depicts an incomplete pattern of steroidogenic protein expression, with decreased CYP11B1 and CYP17A1, which could explain the predominant secretion of steroid precursors.

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.