Publications

The issue of failed weaning is a critical concern in the intensive care unit (ICU) setting. This scenario occurs when a patient experiences difficulty maintaining spontaneous breathing and ensuring a patent airway within the first 48 hours after the withdrawal of mechanical ventilation. Approximately 20% of ICU patients experience this phenomenon, which has severe repercussions on their health. It also has a substantial impact on clinical evolution and mortality, which can increase by 25% to 50%. To address this issue, we propose a medical support system that uses a convolutional neural network (CNN) to assess a patient's suitability for disconnection from a mechanical ventilator after a spontaneous breathing test (SBT). During SBT, respiratory flow and electrocardiographic activity were recorded and after processed using time-frequency analysis (TFA) techniques. Two CNN architectures were evaluated in this study: one based on ResNet50, with parameters tuned using a Bayesian optimization algorithm, and another CNN designed from scratch, with its structure also adapted using a Bayesian optimization algorithm. The WEANDB database was used to train and evaluate both models. The results showed remarkable performance, with an average accuracy 98 +/- 1.8% when using CNN from scratch. This model has significant implications for the ICU because it provides a reliable tool to enhance patient care by assisting clinicians in making timely and accurate decisions regarding weaning. This can potentially reduce the adverse outcomes associated with failed weaning events.

JTD Keywords: Bayesian optimization algorithm (boa, Continuous wavelet transform (cwt), Convolutional, Extubation, Failur, Intensive-care-unit, Neural network (cnn) from scratch, Respiratory-distress-syndrome, Time-frequency analysis (tfa), Weaning

Surface electromyography (sEMG) can be used to measure the electrical activity of the respiratory muscles. The possible applications of sEMG span from patients suffering from acute respiratory failure to patients receiving chronic home mechanical ventilation, to evaluate muscle function, titrate ventilatory support and guide treatment. However, sEMG is mainly used as a monitoring tool for research and its use in clinical practice is still limited-in part due to a lack of standardization and transparent reporting. During this round table meeting, recommendations on data acquisition, processing, interpretation, and potential clinical applications of respiratory sEMG were discussed. This paper informs the clinical researcher interested in respiratory muscle monitoring about the current state of the art on sEMG, knowledge gaps and potential future applications for patients with respiratory failure.

JTD Keywords: Acute respiratory failure, Artificial ventilation, Asthmatic-children, Breathing muscle, Clinical monitoring, Clinical practice, Clinical research, Consensus development, Data interpretation, Disease exacerbation, Drive, Electrode positioning, Electrode removal, Electromyography, Force, Home care, Human, Human diaphragm, Humans, Information processing, Inspiratory muscle training, Inspiratory muscles, Intensive care unit, Knowledge gap, Long term care, Mechanical ventilation, Medical procedures, Muscle contraction, Muscle fatigue, Muscle function, Muscle training, Muscle, skeletal, Muscle-activity, Noninvasive ventilation, Patient monitoring, Patient-ventilator asynchrony, Physiology, Prognosis, Quality of life, Reporting and data system, Respiratory failure, Respiratory muscles, Review, Severe exacerbations, Signal processing, Skeletal muscle, Standardization, Surface electromyography, Time factor

A large portion of the elderly population are affected by cardiovascular diseases. Early prognosis of cardiomyopathies remains a challenge. The aim of this study was to classify cardiomyopathy patients by their etiology based on significant indexes extracted from the characterization of the baroreflex mechanism in function of the influence of the cardio-respiratory activity over the blood pressure. Forty-one cardiomyopathy patients (CMP) classified as ischemic (ICM-24 patients) and dilated (DCM-17 patients) were considered. In addition, thirty-nine control (CON) subjects were used as reference. The beat-to-beat (BBI) time series, from the electrocardiographic (ECG) signal, the systolic (SBP), and diastolic (DBP) time series, from the blood pressure signal (BP), and the respiratory time (TT), from the respiratory flow (RF) signal, were extracted. The three-dimensional representation of the cardiorespiratory and vascular activities was characterized geometrically, by fitting a polygon that contains 95% of data, and by statistical descriptive indices. DCM patients presented specific patterns in the respiratory response to decreasing blood pressure activity. ICM patients presented more stable cardiorespiratory activity in comparison with DCM patients. In general, CMP shown limited ability to regulate changes in blood pressure. In addition, patients also shown a limited ability of their cardiac and respiratory systems response to regulate incremental changes of the vascular variability and a lower heart rate variability. The best classifiers were used to build support vector machine models. The optimal model to classify ICM versus DCM patients achieved 92.7% accuracy, 94.1% sensitivity, and 91.7% specificity. When comparing CMP patients and CON subjects, the best model achieved 86.2% accuracy, 82.9% sensitivity, and 89.7% specificity. When comparing ICM patients and CON subjects, the best model achieved 88.9% accuracy, 87.5% sensitivity, and 89.7% specificity. When comparing DCM patients and CON subjects, the best model achieved 87.5% accuracy, 76.5% sensitivity, and 92.3% specificity. In conclusion, this study introduced a new method for the classification of patients by their etiology based on new indices from the analysis of the baroreflex mechanism.Copyright © 2023 Rodriguez, Schulz, Voss, Herrera, Benito and Giraldo.

JTD Keywords: abnormalities, blood pressure variability, cardio-respiratory variability, dilated cardiomyopathy, disease, heart-failure secondary, ischemic cardiomyopathy, ischemic-dilated cardiomyopathy, morphology-relative change, Baroreflex activity, Blood pressure variability, Cardio-respiratory variability, Cheyne-stokes respiration, Ischemic-dilated cardiomyopathy, Morphology-relative change

Liver cirrhosis is the end stage of all chronic liver diseases and contributes significantly to overall mortality of 2% globally. The age-standardized mortality from liver cirrhosis in Europe is between 10 and 20% and can be explained by not only the development of liver cancer but also the acute deterioration in the patient's overall condition. The development of complications including accumulation of fluid in the abdomen (ascites), bleeding in the gastrointestinal tract (variceal bleeding), bacterial infections, or a decrease in brain function (hepatic encephalopathy) define an acute decompensation that requires therapy and often leads to acute-on-chronic liver failure (ACLF) by different precipitating events. However, due to its complexity and organ-spanning nature, the pathogenesis of ACLF is poorly understood, and the common underlying mechanisms leading to the development of organ dysfunction or failure in ACLF are still elusive. Apart from general intensive care interventions, there are no specific therapy options for ACLF. Liver transplantation is often not possible in these patients due to contraindications and a lack of prioritization. In this review, we describe the framework of the ACLF-I project consortium funded by the Hessian Ministry of Higher Education, Research and the Arts (HMWK) based on existing findings and will provide answers to these open questions.

JTD Keywords: 12/15-lipoxygenase, combination, inflammation, interleukin-22, metabolism, mortality, organ failure, portal-hypertension, receptor, regeneration, systemic inflammation, systems medicine, translational hepatology, Decompensated cirrhosis, Organ failure, Systemic inflammation, Systems medicine, Translational hepatology

In situ tissue engineering strategies are a promising approach to activate the endogenous regenerative potential of the cardiac tissue helping the heart to heal itself after an injury. However, the current use of complex reprogramming vectors for the activation of reparative pathways challenges the easy translation of these therapies into the clinic. Here, we evaluated the response of mouse neonatal and human induced pluripotent stem cell-derived cardiomyocytes to the presence of exogenous lactate, thus mimicking the metabolic environment of the fetal heart. An increase in cardiomyocyte cell cycle activity was observed in the presence of lactate, as determined through Ki67 and Aurora-B kinase. Gene expression and RNA-sequencing data revealed that cardiomyocytes incubated with lactate showed upregulation of BMP10, LIN28 or TCIM in tandem with downregulation of GRIK1 or DGKK among others. Lactate also demonstrated a capability to modulate the production of inflammatory cytokines on cardiac fibroblasts, reducing the production of Fas, Fraktalkine or IL-12p40, while stimulating IL-13 and SDF1a. In addition, the generation of a lactate-rich environment improved ex vivo neonatal heart culture, by affecting the contractile activity and sarcomeric structures and inhibiting epicardial cell spreading. Our results also suggested a common link between the effect of lactate and the activation of hypoxia signaling pathways. These findings support a novel use of lactate in cardiac tissue engineering, modulating the metabolic environment of the heart and thus paving the way to the development of lactate-releasing platforms for in situ cardiac regeneration.Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.

JTD Keywords: cardiac regeneration, cardiac tissue engineering, cell cycle, failure, growth, heart regeneration, induced pluripotent stem cells, ischemia, lactate, metabolic environment, metabolism, mouse, proliferation, repair, Bone morphogenetic protein-10, Cardiac tissue engineering, Cardiomyocytes, Cell cycle, Induced pluripotent stem cells, Lactate, Metabolic environment

Albumin has been used primarily as a plasma expander, since it leads to an increase in the circulating blood volume. Current generally recommended indications for albumin therapy in cirrhotic patients are the prevention of circulatory dysfunction after large-volume paracentesis, the prevention of hepatorenal syndrome (HRS) in patients with spontaneous bacterial peritonitis (SBP), and the management of HRS in combination with vasoconstrictors. Yet, new indications for albumin have been tested in the recent years and are outlined in this short review.New data show that albumin both supports the circulation and reduces systemic inflammation. In addition, to its oncotic function, it acts as an antioxidant, radical scavenger, and immune modulator. These nononcotic properties explain why long-term albumin administration in patients with decompensated cirrhosis may be useful in the prevention of associated complications (acute-on-chronic liver failure, infections). New data show that long-term albumin therapy in patients with cirrhosis and ascites improves survival, prevents complications, simplifies ascites management, and lowers hospitalization rates. The so-called disease-modifying effects of long-term albumin therapy may have a favorable effect on the course of the disease. Nevertheless, the optimal dosage and administration intervals have not yet been finally defined.Albumin therapy is effective in the indications already recommended by the guidelines. A possible extension of the indication for albumin administration in non-SBP infections and as long-term therapy is promising, but should be confirmed by further studies.Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

JTD Keywords: ascites, failure, hepatorenal syndrome, hospitalized-patients, hypothesis, infections, portal hypertension, spontaneous bacterial peritonitis, systemic inflammation, Acute-on-chronic liver failure, Human serum-albumin

The association between sarcopenia and prognosis in patients with cirrhosis remains to be determined. In this study, we aimed to quantify the association between sarcopenia and the risk of mortality in patients with cirrhosis, by sex, underlying liver disease etiology, and severity of hepatic dysfunction.PubMed, Web of Science, EMBASE, and major scientific conference sessions were searched without language restriction through 13 January 2021 with additional manual search of bibliographies of relevant articles. Cohort studies of ?100 patients with cirrhosis and ?12 months of follow-up that evaluated the association between sarcopenia, muscle mass and the risk of mortality were included.22 studies with 6965 patients with cirrhosis were included. The pooled prevalence of sarcopenia in patients with cirrhosis was 37.5% overall (95% CI 32.4%-42.8%), higher in male patients, patients with alcohol associated liver disease (ALD), patients with CTP grade C, and when sarcopenia was defined in patients by lumbar 3- skeletal muscle index (L3-SMI). Sarcopenia was associated with the increased risk of mortality in patients with cirrhosis (adjusted-hazard ratio [aHR] 2.30, 95% CI 2.01-2.63), with similar findings in sensitivity analysis of cirrhosis patients without HCC (aHR 2.35, 95% CI 1.95-2.83) and in subgroup analysis by sex, liver disease etiology, and severity of hepatic dysfunction. The association between quantitative muscle mass index and mortality further supports the poor prognosis for patients with sarcopenia (aHR 0.95, 95% CI 0.93-0.98). There was no significant heterogeneity in all analyses.Sarcopenia was highly and independently associated with higher risk of mortality in patients with cirrhosis.The prevalence of sarcopenia and its association with death in patients with cirrhosis remain unclear. This meta-analysis indicated that sarcopenia affected about one-third of patients with cirrhosis and up to 50% in patients with ALD or Child's class C cirrhosis. Sarcopenia was independently associated with about 2-fold higher risk of mortality in patients with cirrhosis. The mortality rate increased with greater severity or longer period of having sarcopenia. Increasing awareness about the importance of sarcopenia in patients with cirrhosis among stakeholders must be prioritized.Copyright © 2021. Published by Elsevier B.V.

JTD Keywords: alcohol associated liver disease, alcohol-associated liver disease, cirrhosis, failure, frailty, impact, list, mass, model, mortality, prognosis, prognostic value, sarcopenia, severe muscle depletion, skeletal muscle index, Alcohol-associated liver disease, Cirrhosis, Liver-transplant candidates, Prognosis, Sarcopenia, Skeletal muscle index

In clinical practice, when a patient is undergoing mechanical ventilation, it is important to identify the optimal moment for extubation, minimizing the risk of failure. However, this prediction remains a challenge in the clinical process. In this work, we propose a new protocol to study the extubation process, including the electromyographic diaphragm signal (diaEMG) recorded through 5-channels with surface electrodes around the diaphragm muscle. First channel corresponds to the electrode on the right. A total of 40 patients in process of withdrawal of mechanical ventilation, undergoing spontaneous breathing tests (SBT), were studied. According to the outcome of the SBT, the patients were classified into two groups: successful (SG: 19 patients) and failure (FG: 21 patients) groups. Parameters extracted from the envelope of each channel of diaEMG in time and frequency domain were studied. After analyzing all channels, the second presented maximum differences when comparing the two groups of patients, with parameters related to root mean square (p = 0.005), moving average (p = 0.001), and upward slope (p = 0.017). The third channel also presented maximum differences in parameters as the time between maximum peak (p = 0.004), and the skewness (p = 0.027). These results suggest that diaphragm EMG signal could contribute to increase the knowledge of the behaviour of respiratory system in these patients and improve the extubation process.Clinical Relevance - This establishes the characterization of success and failure patients in the extubation process. © 2021 IEEE.

JTD Keywords: classification, recognition, Airway extubation, Artificial ventilation, Clinical practices, Clinical process, Diaphragm, Diaphragm muscle, Diaphragms, Electrodes, Electromyographic, Extubation, Frequency domain analysis, Human, Humans, Maximum differences, Mechanical ventilation, New protocol, Respiration, artificial, Respiratory system, Risk of failure, Spontaneous breathing, Surface electrode, Surface emg signals, Thorax, Ventilation, Ventilator weaning

Background & Aims: MicroRNAs (miRNAs) circulate in several body fluids and can be useful biomarkers. The aim of this study was to identify blood-circulating miRNAs associated with cirrhosis progression and acute-on-chronic liver failure (ACLF). Methods: Using high-throughput screening of 754 miRNAs, serum samples from 45 patients with compensated cirrhosis, decompensated cirrhosis, or ACLF were compared with those from healthy individuals (n = 15). miRNA levels were correlated with clinical parameters, organ failure, and disease progression and outcome. Dysregulated miRNAs were evaluated in portal and hepatic vein samples (n = 33), liver tissues (n = 17), and peripheral blood mononuclear cells (PBMCs) (n = 16). Results: miRNA screening analysis revealed that circulating miRNAs are dysregulated in cirrhosis progression, with 51 miRNAs being differentially expressed among all groups of patients. Unsupervised clustering and principal component analysis indicated that the main differences in miRNA expression occurred at decompensation, showing similar levels in patients with decompensated cirrhosis and those with ACLF. Of 43 selected miRNAs examined for differences among groups, 10 were differentially expressed according to disease progression. Moreover, 20 circulating miRNAs were correlated with model for end-stage liver disease and Child-Pugh scores. Notably, 11 dysregulated miRNAs were associated with kidney or liver failure, encephalopathy, bacterial infection, and poor outcomes. The most severely dysregulated miRNAs (i.e. miR-146a5p, miR-26a-5p, and miR-191-5p) were further evaluated in portal and hepatic vein blood and liver tissue, but showed no differences. However, PBMCs from patients with cirrhosis showed significant downregulation of miR-26 and miR-146a, suggesting a extrahepatic origin of some circulating miRNAs. Conclusions: This study is a repository of circulating miRNA data following cirrhosis progression and ACLF. Circulating miRNAs were profoundly dysregulated during the progression of chronic liver disease, were associated with failure of several organs and could have prognostic utility. Lay summary: Circulating miRNAs are small molecules in the blood that can be used to identify or predict a clinical condition. Our study aimed to identify miRNAs for use as biomarkers in patients with cirrhosis or acute-on-chronic liver failure. Several miRNAs were found to be dysregulated during the progression of disease, and some were also related to organ failure and disease-related outcomes. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL).

JTD Keywords: aclf, acute-on-chronic liver failure, alt, alanine aminotransferase, ast, aspartate aminotransferase, biomarkers, chronic liver disease, cxcl10, c-x-c motif chemokine ligand 10, ef clif, european foundation for the study of chronic liver failure, foxo, forkhead box o, inr, international normalised ratio, ldh, lactate dehydrogenase, liver decompensation, mapk, mitogen-activated protein kinase, meld, model for end-stage liver disease, nash, non-alcoholic steatohepatitis, non-coding rnas, pbmcs, peripheral blood mononuclear cells, pca, principal component analysis, tgf, transforming growth factor, tips, transjugular intrahepatic portosystemic shunt, Biomarkers, Chronic liver disease, Expression, Liver decompensation, Markers, Mir-146a, Non-coding rnas, Qpcr, quantitative pcr

Background & Aims: Acute-on-chronic liver failure (ACLF) is characterized by high short-term mortality and systemic inflammation (SI). Recently, different cardiodynamic states were shown to independently predict outcomes in cirrhosis. The relationship between cardiodynamic states, SI, and portal hypertension and their impact on ACLF development remains unclear. The aim of this study was therefore to evaluate the interplay of cardiodynamic state and SI on fatal ACLF development in cirrhosis. Results: At inclusion, hemodynamic measures including cardiac index (CI) and hepatic venous pressure gradient of 208 patients were measured. Patients were followed prospectively for fatal ACLF development (primary endpoint). SI was assessed by proinflammatory markers such as interleukins (ILs) 6 and 8 and soluble IL-33 receptor (sIL-33R). Patients were divided according to CI (<3.2; 3.2-4.2; >4.2 L/min/m2) in hypo- (n = 84), normo- (n = 69) and hyperdynamic group (n = 55). After a median follow-up of 3 years, the highest risk of fatal ACLF was seen in hyperdynamic (35%) and hypodynamic patients (25%) compared with normodynamic (14%) (P = .011). Hyperdynamic patients showed the highest rate of SI. The detectable level of IL-6 was an independent predictor of fatal ACLF development. Conclusions: Cirrhotic patients with hyperdynamic and hypodynamic circulation have a higher risk of fatal ACLF. Therefore, the cardiodynamic state is strongly associated with SI, which is an independent predictor of development of fatal ACLF.

JTD Keywords: Acute-on-chronic liver failure, Circulation, Cirrhosis, Hemodynamic, Inflammation

Background & Aims: The relationship between acute-on-chronic liver failure (ACLF) and acute variceal bleeding (AVB) is poorly understood. Specifically, the prevalence and prognosis of ACLF in the context of AVB is unclear, while the role of transjugular intrahepatic portosystemic shunt (TIPS) in the management in patients with ACLF has not been described to date. Methods: A multicenter, international, observational study was conducted in 2,138 patients from 34 centers between 2011 and 2015. ACLF was defined and graded according to the EASL-CLIF consortium definition. Placement of pre-emptive TIPS (pTIPS) was based on individual center policy. Patients were followed-up for 1 year, until death or liver transplantation. Cox regression and competing risk models (Gray's test) were used to identify independent predictors of rebleeding or mortality. Results: At admission, 380/2,138 (17.8%) patients had ACLF according to EASL-CLIF criteria (grade 1: 38.7%; grade 2: 39.2%; grade 3: 22.1%). The 42-day rebleeding (19% vs. 10%; p <0.001) and mortality (47% vs. 10%; p <0.001) rates were higher in patients with ACLF and increased with ACLF grades. Of note, the presence of ACLF was independently associated with rebleeding and mortality. pTIPS placement improved survival in patients with ACLF at 42 days and 1 year. This effect was also observed in propensity score matching analysis of 66 patients with ACLF, of whom 44 received pTIPs and 22 did not. Conclusions: This large multicenter international real-life study identified ACLF at admission as an independent predictor of rebleeding and mortality in patients with AVB. Moreover, pTIPS was associated with improved survival in patients with ACLF and AVB. Lay summary: Acute variceal bleeding is a deadly complication of liver cirrhosis that results from severe portal hypertension. This study demonstrates that the presence of acute-on-chronic liver failure (ACLF) is the strongest predictor of mortality in patients with acute variceal bleeding. Importantly, patients with ACLF and acute variceal (re)bleeding benefit from pre-emptive (early) placement of a transjugular intrahepatic portosystemic shunt.

JTD Keywords: Acute variceal bleeding, Acute-on-chronic liver failure, Cirrhosis, Rebleeding

Background & Aims: Spontaneous portosystemic shunts (SPSS) frequently develop in liver cirrhosis. Recent data suggested that the presence of a single large SPSS is associated with complications, especially overt hepatic encephalopathy (oHE). However, the presence of >1 SPSS is common. This study evaluates the impact of total cross-sectional SPSS area (TSA) on outcomes in patients with liver cirrhosis. Methods: In this retrospective international multicentric study, CT scans of 908 cirrhotic patients with SPSS were evaluated for TSA. Clinical and laboratory data were recorded. Each detected SPSS radius was measured and TSA calculated. One-year survival was the primary endpoint and acute decompensation (oHE, variceal bleeding, ascites) was the secondary endpoint. Results: A total of 301 patients (169 male) were included in the training cohort. Thirty percent of all patients presented with >1 SPSS. A TSA cut-off of 83 mm2 was used to classify patients with small or large TSA (S-/L-TSA). Patients with L-TSA presented with higher model for end-stage liver disease score (11 vs. 14) and more commonly had a history of oHE (12% vs. 21%, p <0.05). During follow-up, patients with L-TSA experienced more oHE episodes (33% vs. 47%, p <0.05) and had lower 1-year survival than those with S-TSA (84% vs. 69%, p <0.001). Multivariate analysis identified L-TSA (hazard ratio 1.66; 95% CI 1.02–2.70, p <0.05) as an independent predictor of mortality. An independent multicentric validation cohort of 607 patients confirmed that patients with L-TSA had lower 1-year survival (77% vs. 64%, p <0.001) and more oHE development (35% vs. 49%, p <0.001) than those with S-TSA. Conclusion: This study suggests that TSA >83 mm2 increases the risk for oHE and mortality in patients with cirrhosis. Our results support the clinical use of TSA/SPSS for risk stratification and decision-making in the management of patients with cirrhosis. Lay summary: The prevalence of spontaneous portosystemic shunts (SPSS) is higher in patients with more advanced chronic liver disease. The presence of more than 1 SPSS is common in advanced chronic liver disease and is associated with the development of hepatic encephalopathy. This study shows that total cross-sectional SPSS area (rather than diameter of the single largest SPSS) predicts survival in patients with advanced chronic liver disease. Our results support the clinical use of total cross-sectional SPSS area for risk stratification and decision-making in the management of SPSS.

JTD Keywords: ACLF, Acute decompensation, Acute-on-chronic liver failure, Ascites, Cirrhosis, Computed tomography, Hepatic encephalopathy, Liver, Portal hypertension, Spontaneous portosystemic shunt, SPSS, TIPS

Background & Aims: Remodelling of extracellular matrix is crucial in progressive liver fibrosis. Collagen type III desposition has been shown in acute decompensation. Extratracellular matrix is compiled of deposition of various components. The role of basement membrane collagen type IV in advanced cirrhosis and acute decompensation is unclear and investigated in this study. Methods: Patients with decompensated cirrhosis from the prospective NEPTUN cohort (ClinicalTrials.gov Identifier: NCT03628807), who underwent transjugular intrahepatic portosystemic shunt procedure were included. Clinical and laboratory parameters, PRO-C4 and C4M levels were measured in blood samples from portal and hepatic veins just before transjugular intrahepatic portosystemic shunt placement. Results: Levels of C4M and PRO-C4 are significantly lower in patients with massive ascites and impaired renal sodium excretion. C4M and PRO-C4 show gender-specific profiles with significantly lower levels in females compared to males. Females with higher C4M levels show higher mortality. By contrast, males with higher C4M levels show lower mortality. In multivariate Cox regression analysis, C4M is an independent predictor of survival in female patients. Conclusion: This study shows that markers of collagen type IV remodelling do not accumulate in severe renal dysfunction. Although collagen type IV degradation markers derive from the liver, portal venous C4M levels are relevant for survival. Moreover, it demonstrates that circulating C4M shows gender-specific profiles, which can independently predict survival in female patients with decompensated cirrhosis.

JTD Keywords: ACLF, Acute decompensation, Acute-on-chronic liver failure, Cirrhosis, Collagen type IV, Extracellular matrix remodelling, Gender, Liver, Portal hypertension, Transjugular intrahepatic portosystemic shunt

Background: Patients with acutely decompensated cirrhosis (AD) may or may not develop acute-on-chronic liver failure (ACLF). ACLF is characterized by high-grade systemic inflammation, organ failures (OF) and high short-term mortality. Although patients with AD cirrhosis exhibit distinct clinical phenotypes at baseline, they have low short-term mortality, unless ACLF develops during follow-up. Because little is known about the association of profile of systemic inflammation with clinical phenotypes of patients with AD cirrhosis, we aimed to investigate a battery of markers of systemic inflammation in these patients. Methods: Upon hospital admission baseline plasma levels of 15 markers (cytokines, chemokines, and oxidized albumin) were measured in 40 healthy controls, 39 compensated cirrhosis, 342 AD cirrhosis, and 161 ACLF. According to EASL-CLIF criteria, AD cirrhosis was divided into three distinct clinical phenotypes (AD-1: Creatinine<1.5, no HE, no OF; AD-2: creatinine 1.5–2, and or HE grade I/II, no OF; AD-3: Creatinine<1.5, no HE, non-renal OF). Results: Most markers were slightly abnormal in compensated cirrhosis, but markedly increased in AD. Patients with ACLF exhibited the largest number of abnormal markers, indicating “full-blown” systemic inflammation (all markers). AD-patients exhibited distinct systemic inflammation profiles across three different clinical phenotypes. In each phenotype, activation of systemic inflammation was only partial (30% of the markers). Mortality related to each clinical AD-phenotype was significantly lower than mortality associated with ACLF (p < 0.0001 by gray test). Among AD-patients baseline systemic inflammation (especially IL-8, IL-6, IL-1ra, HNA2 independently associated) was more intense in those who had poor 28-day outcomes (ACLF, death) than those who did not experience these outcomes. Conclusions: Although AD-patients exhibit distinct profiles of systemic inflammation depending on their clinical phenotypes, all these patients have only partial activation of systemic inflammation. However, those with the most extended baseline systemic inflammation had the highest the risk of ACLF development and death.

JTD Keywords: ACLF, Acute decompensation, Cirrhosis, Organ dysfunction, Organ failure, Signature

Background: Acquired dysfunctional immunity in cirrhosis predisposes patients to frequent bacterial infections, especially spontaneous bacterial peritonitis (SBP), leading to systemic inflammation that is associated with poor outcome. But systemic inflammation can also be found in the absence of a confirmed infection. Detection of bacterial DNA has been investigated as a marker of SBP and as a predictor of prognosis. Data is, however, contradictory. Here we investigated whether levels of IL-6 and IL-8 putatively produced by myeloid cells in ascites are associated with systemic inflammation and whether inflammation depends on the presence of specific bacterial DNA. Methods and Materials: We enrolled 33 patients with decompensated liver cirrhosis from whom we collected paired samples of blood and ascites. IL-6 and IL-8 were measured in serum samples of all patients using ELISA. In a subset of 10 representative patients, bacterial DNA was extracted from ascites and whole blood, followed by 16S rRNA gene amplicon sequencing. Results: There were significantly higher levels of IL-6 in ascites fluid compared to blood samples in all patients. Interestingly, IL-6 levels in blood correlated tightly with disease severity and surrogates of systemic inflammation, while IL-6 levels in ascites did not. Moreover, patients with higher blood CRP levels showed greater SBP prevalence compared to patients with lower levels, despite similar positive culture results. Bacterial richness was also significantly higher in ascites compared to the corresponding patient blood. We identified differences in microbial composition and diversity between ascites and blood, but no tight relationship with surrogates of systemic inflammation could be observed. Discussion: In decompensated cirrhosis, markers of systemic inflammation and microbiota composition seem to be dysregulated in ascites and blood. While a relationship between systemic inflammation and microbiota composition seems to exist in blood, this is not the case for ascites in our hands. These data may suggest compartmentalization of the immune response and interaction of the latter with the microbiota especially in the blood compartment.

JTD Keywords: Acute-on-chronic liver failure, Ascites, Cirrhosis, Cytokines, Microbiome, Myeloid cells, Systemic inflammation

Breathing pattern as periodic breathing (PB) in chronic heart failure (CHF) is associated with poor prognosis and high mortality risk. This work investigates the significance of a number of time domain parameters for characterizing respiratory flow cycle morphology in patients with CHF. Thus, our primary goal is to detect PB pattern and identify patients at higher risk. In addition, differences in respiratory flow cycle morphology between CHF patients (with and without PB) and healthy subjects are studied. Differences between these parameters are assessed by investigating the following three classification issues: CHF patients with PB versus with non-periodic breathing (nPB), CHF patients (both PB and nPB) versus healthy subjects, and nPB patients versus healthy subjects. Twenty-six CHF patients (8/18 with PB/nPB) and 35 healthy subjects are studied. The results show that the maximal expiratory flow interval is shorter and with lower dispersion in CHF patients than in healthy subjects. The flow slopes are much steeper in CHF patients, especially for PB. Both inspiration and expiration durations are reduced in CHF patients, mostly for PB. Using the classification and regression tree technique, the most discriminant parameters are selected. For signals shorter than 1 min, the time domain parameters produce better results than the spectral parameters, with accuracies for each classification of 82/78, 89/85, and 91/89 %, respectively. It is concluded that morphologic analysis in the time domain is useful, especially when short signals are analyzed.

JTD Keywords: Chronic heart failure, Ensemble average, Periodic and non-periodic breathing, Respiratory pattern

Patients with Chronic Heart Failure (CHF) often develop oscillatory breathing patterns. This work proposes the characterization of respiratory pattern by Wavelet Transform (WT) technique to identify Periodic Breathing pattern (PB) and Non-Periodic Breathing pattern (nPB) through the respiratory flow signal. A total of 62 subjects were analyzed: 27 CHF patients and 35 healthy subjects. Respiratory time series were extracted, and statistical methods were applied to obtain the most relevant information to classify patients. Support Vector Machine (SVM) were applied using forward selection technique to discriminate patients, considering four kernel functions. Differences between these parameters are assessed by investigating the following four classification issues: healthy subjects versus CHF patients, PB versus nPB patients, PB patients versus healthy subjects, and nPB patients versus healthy subjects. The results are presented in terms of average accuracy for each kernel function, and comparison groups.

JTD Keywords: Chronic heart failure, Forward selection, Non-periodic breathing, Periodic breathing, Support vector machine

Assessment of the dynamic interactions between cardiovascular signals can provide valuable information that improves the understanding of cardiovascular control. Heart rate variability (HRV) analysis is known to provide information about the autonomic heart rate modulation mechanism. Using the HRV signal, we aimed to obtain parameters for classifying patients with and without chronic heart failure (CHF), and with periodic breathing (PB), non-periodic breathing (nPB), and Cheyne-Stokes respiration (CSR) patterns. An electrocardiogram (ECG) and a respiratory flow signal were recorded in 36 elderly patients: 18 patients with CHF and 18 patients without CHF. According to the clinical criteria, the patients were classified into the follow groups: 19 patients with nPB pattern, 7 with PB pattern, 4 with Cheyne-Stokes respiration (CSR), and 6 non-classified patients (problems with respiratory signal). From the HRV signal, parameters in the time and frequency domain were calculated. Frequency domain parameters were the most discriminant in comparisons of patients with and without CHF: P_Tot (p = 0.02), P_LF (p = 0.022) and fp_HF (p = 0.021). For the comparison of the nPB vs. CSR patients groups, the best parameters were RMSSD (p = 0.028) and SDSD (p = 0.028). Therefore, the parameters appear to be suitable for enhanced diagnosis of decompensated CHF patients and the possibility of developed periodic breathing and a CSR pattern.

JTD Keywords: cardiovascular system, diseases, electrocardiography, frequency-domain analysis, geriatrics, medical signal processing, patient diagnosis, pneumodynamics, signal classification, Cheyne-Stokes respiration patterns, ECG, autonomic heart rate modulation mechanism, cardiovascular control, cardiovascular signals, chronic heart failure, decompensated CHF patients, dynamic interaction assessment, elderly patients, electrocardiogram, enhanced diagnosis, frequency domain parameters, heart rate variability analysis, patient classification, periodic breathing, respiratory flow signal recording, Electrocardiography, Frequency modulation, Frequency-domain analysis, Heart rate variability, Senior citizens, Standards

Some of the most common clinical problems in elderly patients are related to diseases of the cardiac and respiratory systems. Elderly patients often have altered breathing patterns, such as periodic breathing (PB) and Cheyne-Stokes respiration (CSR), which may coincide with chronic heart failure. In this study, we used the envelope of the respiratory flow signal to characterize respiratory patterns in elderly patients. To study different breathing patterns in the same patient, the signals were segmented into windows of 5 min. In oscillatory breathing patterns, frequency and time-frequency parameters that characterize the discriminant band were evaluated to identify periodic and non-periodic breathing (PB and nPB). In order to evaluate the accuracy of this characterization, we used a feature selection process, followed by linear discriminant analysis. 22 elderly patients (7 patients with PB and 15 with nPB pattern) were studied. The following classification problems were analyzed: patients with either PB (with and without apnea) or nPB patterns, and patients with CSR versus PB, CSR versus nPB and PB versus nPB patterns. The results showed 81.8% accuracy in the comparisons of nPB and PB patients, using the power of the modulation peak. For the segmented signal, the power of the modulation peak, the frequency variability and the interquartile ranges provided the best results with 84.8% accuracy, for classifying nPB and PB patients.

JTD Keywords: cardiovascular system, diseases, feature extraction, geriatrics, medical signal processing, oscillations, pneumodynamics, signal classification, time-frequency analysis, Cheyne-Stokes respiration, apnea, cardiac systems, chronic heart failure, classification problems, discriminant band, diseases, elderly patients, feature selection process, frequency variability, interquartile ranges, linear discriminant analysis, nonperiodic breathing, oscillatory breathing pattern, periodic breathing, respiratory How signal, respiratory systems, signal segmentation, time 5 min, time-frequency parameters, Accuracy, Aging, Frequency modulation, Heart, Senior citizens, Time-frequency analysis

High altitude periodic breathing (PB) shares some common pathophysiologic aspects with sleep apnea, Cheyne-Stokes respiration and PB in heart failure patients. Methods that allow quantifying instabilities of respiratory control provide valuable insights in physiologic mechanisms and help to identify therapeutic targets. Under the hypothesis that high altitude PB appears even during physical activity and can be identified in comparison to visual analysis in conditions of low SNR, this study aims to identify PB by characterizing the respiratory pattern through the respiratory volume signal. A number of spectral parameters are extracted from the power spectral density (PSD) of the volume signal, derived from respiratory inductive plethysmography and evaluated through a linear discriminant analysis. A dataset of 34 healthy mountaineers ascending to Mt. Muztagh Ata, China (7,546 m) visually labeled as PB and non periodic breathing (nPB) is analyzed. All climbing periods within all the ascents are considered (total climbing periods: 371 nPB and 40 PB). The best crossvalidated result classifying PB and nPB is obtained with Pm (power of the modulation frequency band) and R (ratio between modulation and respiration power) with an accuracy of 80.3% and area under the receiver operating characteristic curve of 84.5%. Comparing the subjects from 1_st and 2_nd ascents (at the same altitudes but the latter more acclimatized) the effect of acclimatization is evaluated. SaO₂ and periodic breathing cycles significantly increased with acclimatization (p-value <; 0.05). Higher Pm and higher respiratory frequencies are observed at lower SaO₂, through a significant negative correlation (p-value <; 0.01). Higher Pm is observed at climbing periods visually labeled as PB with >; 5 periodic breathing cycles through a significant positive correlation (p-value <; 0.01). Our data demonstrate that quantification of the respiratory volum- signal using spectral analysis is suitable to identify effects of hypobaric hypoxia on control of breathing.

JTD Keywords: Frequency domain analysis, Frequency modulation, Heart, Sleep apnea, Ventilation, Visualization, Cardiology, Medical disorders, Medical signal processing, Plethysmography, Pneumodynamics, Sensitivity analysis, Sleep, Spectral analysis, Cheyne-Stokes respiration, Climbing periods, Dataset, Heart failure patients, High altitude PB, High altitude periodic breathing, Hypobaric hypoxia, Linear discriminant analysis, Pathophysiologic aspects, Physical activity, Physiologic mechanisms, Power spectral density, Receiver operating characteristic curve, Respiratory control, Respiratory frequency, Respiratory inductive plethysmography, Respiratory pattern, Respiratory volume signal, Sleep apnea, Spectral analysis, Spectral parameters

This study proposes a method for the characterization of respiratory patterns in chronic heart failure (CHF) patients with periodic breathing (PB) and nonperiodic breathing (nPB), using the flow signal. Autoregressive modeling of the envelope of the respiratory flow signal is the starting point for the pattern characterization. Spectral parameters extracted from the discriminant frequency band (DB) are used to characterize the respiratory patterns. For each classification problem, the most discriminant parameter subset is selected using the leave-one-out cross-validation technique. The power in the right DB provides an accuracy of 84.6% when classifying PB vs. nPB patterns in CHF patients, whereas the power of the DB provides an accuracy of 85.5% when classifying the whole group of CHF patients vs. healthy subjects, and 85.2% when classifying nPB patients vs. healthy subjects.

JTD Keywords: Chronic heart failure, AR modeling, Respiratory pattern, Discriminant band, Periodic and nonperiodic breathing

A correntropy-based technique is proposed for the characterization and classification of respiratory flow signals in chronic heart failure (CHF) patients with periodic or nonperiodic breathing (PB or nPB, respectively) and healthy subjects. The correntropy is a recently introduced, generalized correlation measure whose properties lend themselves to the definition of a correntropy-based spectral density (CSD). Using this technique, both respiratory and modulation frequencies can be reliably detected at their original positions in the spectrum without prior demodulation of the flow signal. Single-parameter classification of respiratory patterns is investigated for three different parameters extracted from the respiratory and modulation frequency bands of the CSD, and one parameter defined by the correntropy mean. The results show that the ratio between the powers in the modulation and respiratory frequency bands provides the best result when classifying CHF patients with either PB or nPB, yielding an accuracy of 88.9%. The correntropy mean offers excellent performance when classifying CHF patients versus healthy subjects, yielding an accuracy of 95.2% and discriminating nPB patients from healthy subjects with an accuracy of 94.4%.

JTD Keywords: Autoregressive (AR) modeling, Chronic heart failure (CHF), Correntropy spectral density (CSD), Linear classification, Periodic breathing (PB)

In this study we propose the correntropy function as a discriminative measure for detecting nonlinearities in the respiratory pattern of chronic heart failure (CHF) patients with periodic or nonperiodic breathing pattern (PB or nPB, respectively). The complexity seems to be reduced in CHF patients with higher risk level. Correntropy reflects information on both, statistical distribution and temporal structure of the underlying dataset. It is a suitable measure due to its capability to preserve nonlinear information. The null hypothesis considered is that the analyzed data is generated by a Gaussian linear stochastic process. Correntropy is used in a statistical test to reject the null hypothesis through surrogate data methods. Various parameters, derived from the correntropy and correntropy spectral density (CSD) to characterize the respiratory pattern, presented no significant differences when extracted from the iteratively refined amplitude adjusted Fourier transform (IAAFT) surrogate data. The ratio between the powers in the modulation and respiratory frequency bands R was significantly different in nPB patients, but not in PB patients, which reflects a higher presence of nonlinearities in nPB patients than in PB patients.

JTD Keywords: Practical, Theoretical or Mathematical, Experimental/cardiology diseases, Fourier transforms, Medical signal processing, Pattern classification, Pneumodynamics, Spectral analysis, Statistical analysis, Stochastic processes/ correntropy based nonlinearity test, Chronic heart failure, Correntropy function, Respiratory pattern nonlinearities, CHF patients, Nonperiodic breathing pattern, Dataset statistical distribution, Dataset temporal structure, Nonlinear information, Null hypothesis, Gaussian linear stochastic process, Statistical test, Correntropy spectral density, Iteratively refined amplitude adjusted Fourier transform, Surrogate data, Periodic breathing pattern

The cytoskeleton is a complex polymer network that regulates the structural stability of living cells. Although the cytoskeleton plays a key role in many important cell functions, the mechanisms that regulate its mechanical behaviour are poorly understood. Potential mechanisms include the entropic elasticity of cytoskeletal filaments, glassy-like inelastic rearrangements of cross-linking proteins and the activity of contractile molecular motors that sets the tensional stress (prestress) borne by the cytoskeleton filaments. The contribution of these mechanisms can be assessed by studying how cell mechanics depends on temperature. The aim of this work was to elucidate the effect of temperature on cell mechanics using atomic force microscopy. We measured the complex shear modulus (G*) of human alveolar epithelial cells over a wide frequency range (0.1-25.6 Hz) at different temperatures (13-37 degrees C). In addition, we probed cell prestress by mapping the contractile forces that cells exert on the substrate by means of traction microscopy. To assess the role of actomyosin contraction in the temperature-induced changes in G* and cell prestress, we inhibited the Rho kinase pathway of the myosin light chain phosphorylation with Y-27632. Our results show that with increasing temperature, cells become stiffer and more solid-like. Cell prestress also increases with temperature. Inhibiting actomyosin contraction attenuated the temperature dependence of G* and prestress. We conclude that the dependence of cell mechanics with temperature is dominated by the contractile activity of molecular motors.

JTD Keywords: Membrane Stress Failure, Frog Skeletal-Muscle, Extracellular-Matrix, Glass-Transition, Energy Landscape, Actin-Filaments, Living Cell, Single, Traction, Cytoskeleton