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Blanco-Almazan, D., Groenendaal, W., Lozano-Garcia, M., Estrada-Petrocelli, L., Lijnen, L., Smeets, C., Ruttens, D., Catthoor, F., Jané, R., (2021). Combining bioimpedance and myographic signals for the assessment of COPD during loaded breathing IEEE Transactions on Biomedical Engineering 68, (1), 298-307

Chronic Obstructive Pulmonary Disease (COPD) is one of the most common chronic conditions. The current assessment of COPD requires a maximal maneuver during a spirometry test to quantify airflow limitations of patients. Other less invasive measurements such as thoracic bioimpedance and myographic signals have been studied as an alternative to classical methods as they provide information about respiration. Particularly, strong correlations have been shown between thoracic bioimpedance and respiratory volume. The main objective of this study is to investigate bioimpedance and its combination with myographic parameters in COPD patients to assess the applicability in respiratory disease monitoring. We measured bioimpedance, surface electromyography and surface mechanomyography in forty-three COPD patients during an incremental inspiratory threshold loading protocol. We introduced two novel features that can be used to assess COPD condition derived from the variation of bioimpedance and the electrical and mechanical activity during each respiratory cycle. These features demonstrate significant differences between mild and severe patients, indicating a lower inspiratory contribution of the inspiratory muscles to global respiratory ventilation in the severest COPD patients. In conclusion, the combination of bioimpedance and myographic signals provides useful indices to noninvasively assess the breathing of COPD patients.

Keywords: Bioimpedance, Chronic obstructive pulmonary disease, Inspiratory threshold protocol, Myographic signals, Wearables

Blanco-Fernandez, B., Castaño, O., Mateos-Timoneda, M. A., Engel, E., Pérez-Amodio, S., (2021). Nanotechnology approaches in chronic wound healing Advances in Wound Care Ahead of Print

Significance: The incidence of chronic wounds is increasing due to our aging population and the augment of people afflicted with diabetes. With the extended knowledge on the biological mechanisms underlying these diseases, there is a novel influx of medical technologies into the conventional wound care market. Recent Advances: Several nanotechnologies have been developed demonstrating unique characteristics that address specific problems related to wound repair mechanisms. In this review, we focus on the most recently developed nanotechnology-based therapeutic agents and evaluate the efficacy of each treatment in in vivo diabetic models of chronic wound healing. Critical Issues: Despite the development of potential biomaterials and nanotechnology-based applications for wound healing, this scientific knowledge is not translated into an increase of commercially available wound healing products containing nanomaterials. Future Directions: Further studies are critical to provide insights into how scientific evidences from nanotechnology-based therapies can be applied in the clinical setting.

Keywords: Diabetes, Chronic, Wound healing, Nanoparticles, Nanofibers, Liposomes

Dhillon, Poonam, Park, Jihwan, Hurtado del Pozo, Carmen, Li, Lingzhi, Doke, Tomohito, Huang, Shizheng, Zhao, Juanjuan, Kang, Hyun Mi, Shrestra, Rojesh, Balzer, Michael S., Chatterjee, Shatakshee, Prado, Patricia, Han, Seung Yub, Liu, Hongbo, Sheng, Xin, Dierickx, Pieterjan, Batmanov, Kirill, Romero, Juan P., Prósper, Felipe, Li, Mingyao, Pei, Liming, Kim, Junhyong, Montserrat, Nuria, Susztak, Katalin, (2021). The nuclear receptor ESRRA protects from kidney disease by coupling metabolism and differentiation Cell Metabolism 33, (2), 379-394.E8

Kidney disease is poorly understood because of the organ’s cellular diversity. We used single-cell RNA sequencing not only in resolving differences in injured kidney tissue cellular composition but also in cell-type-specific gene expression in mouse models of kidney disease. This analysis highlighted major changes in cellular diversity in kidney disease, which markedly impacted whole-kidney transcriptomics outputs. Cell-type-specific differential expression analysis identified proximal tubule (PT) cells as the key vulnerable cell type. Through unbiased cell trajectory analyses, we show that PT cell differentiation is altered in kidney disease. Metabolism (fatty acid oxidation and oxidative phosphorylation) in PT cells showed the strongest and most reproducible association with PT cell differentiation and disease. Coupling of cell differentiation and the metabolism was established by nuclear receptors (estrogen-related receptor alpha [ESRRA] and peroxisomal proliferation-activated receptor alpha [PPARA]) that directly control metabolic and PT-cell-specific gene expression in mice and patient samples while protecting from kidney disease in the mouse model.

Keywords: Single-cell RNA sequencing, Single-cell ATAC sequencing, Kidney, Fibrosis, Organoids, Fatty-acid oxidation, PPARA, ESRRA, Proximal tubule cells, Chronic kidney disease

Perez-Amodio, S., Rubio, N., Vila, Olaia F., Navarro-Requena, C., Castaño, O., Sanchez-Ferrero, A., Marti-Muñoz, J., Alsina-Giber, M., Blanco, J., Engel, E., (2021). Polymeric composite dressings containing calcium-releasing nanoparticles accelerate wound healing in diabetic mice Advances in Wound Care Ahead of Print

Objective: Wound healing is a complex process that involves the interaction between different cell types and bioactive factors. Impaired wound healing is characterized by a loss in synchronization of these interactions, resulting in nonhealing chronic wounds. Chronic wounds are a socioeconomic burden, one of the most prominent clinical manifestations of diabetes, however, they lack satisfactory treatment options. The objective of this study was to develop polymeric composites that deliver ions having wound healing properties and evaluate its performance using a pressure ulcer model in diabetic mice. Approach: To develop a polymeric composite wound dressing containing ion-releasing nanoparticles for chronic wound healing. This composite was chemically and physically characterized and evaluated using a pressure ulcer wound model in diabetic (db/db) mice to explore their potential as novel wound dressing. Results: This dressing exhibits a controlled ion release and a good in vitro bioactivity. The polymeric composite dressing treatment stimulates angiogenesis, collagen synthesis, granulation tissue formation, and accelerates wound closure of ischemic wounds created in diabetic mice. In addition, the performance of the newly designed composite is remarkably better than a commercially available dressing frequently used for the treatment of low-exuding chronic wounds. Innovation: The developed nanoplatforms are cell- and growth factor free and control the host microenvironment resulting in enhanced wound healing. These nanoplatforms are available by cost-effective synthesis with a defined composition, offering an additional advantage in potential clinical application. Conclusion: Based on the obtained results, these polymeric composites offer an optimum approach for chronic wound healing without adding cells or external biological factors.

Keywords: Chronic wounds, Bioactive dressings, Diabetes, Angiogenesis

Praktiknjo, M., Monteiro, S., Grandt, J., Kimer, N., Madsen, J. L., Werge, M. P., William, P., Brol, M. J., Turco, L., Schierwagen, R., Chang, J., Klein, S., Uschner, F. E., Welsch, C., Moreau, R., Schepis, F., Bendtsen, F., Gluud, L. L., Møller, S., Trebicka, J., (2020). Cardiodynamic state is associated with systemic inflammation and fatal acute-on-chronic liver failure Liver International 40, (6), 1457-1466

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.

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

Del Mar Cendra, Maria, Torrents, Eduard, (2020). Differential adaptability between reference strains and clinical isolates of Pseudomonas aeruginosa into the lung epithelium intracellular lifestyle Virulence 11, (1), 862-876

Intracellular invasion is an advantageous mechanism used by pathogens to evade host defense and antimicrobial therapy. In patients, the intracellular microbial lifestyle can lead to infection persistence and recurrence, thus worsening outcomes. Lung infections caused by Pseudomonas aeruginosa, especially in cystic fibrosis (CF) patients, are often aggravated by intracellular invasion and persistence of the pathogen. Proliferation of the infectious species relies on a continuous deoxyribonucleotide (dNTP) supply, for which the ribonucleotide reductase enzyme (RNR) is the unique provider. The large genome plasticity of P. aeruginosa and its ability to rapidly adapt to different environments are challenges for studying the pathophysiology associated with this type of infection. Using different reference strains and clinical isolates of P. aeruginosa independently combined with alveolar (A549) and bronchial (16HBE14o- and CF-CFBE41o-) epithelial cells, we analyzed host–pathogen interactions and intracellular bacterial persistence with the aim of determining a cell type-directed infection promoted by the P. aeruginosa strains. The oscillations in cellular toxicity and oxygen consumption promoted by the intracellular persistence of the strains were also analyzed among the different infectious lung models. Significantly, we identified class II RNR as the enzyme that supplies dNTPs to intracellular P. aeruginosa. This discovery could contribute to the development of RNR-targeted strategies against the chronicity occurring in this type of lung infection. Overall our study demonstrates that the choice of bacterial strain is critical to properly study the type of infectious process with relevant translational outcomes.

Keywords: Pseudomonas aeruginosa, Intracellular persistence, Lung, Epithelial cells, Clinical isolates, Host-pathogen interactions, Intracellular lifestyle, Chronic infections, Cystic fibrosis, Ribonucleotide reductase

Calvo, Mireia, González, Rubèn, Seijas, Núria, Vela, Emili, Hernández, Carme, Batiste, Guillem, Miralles, Felip, Roca, Josep, Cano, Isaac, Jané, Raimon, (2020). Health outcomes from home hospitalization: Multisource predictive modeling Journal of Medical Internet Research 22, (10), e21367

Background: Home hospitalization is widely accepted as a cost-effective alternative to conventional hospitalization for selected patients. A recent analysis of the home hospitalization and early discharge (HH/ED) program at Hospital Clínic de Barcelona over a 10-year period demonstrated high levels of acceptance by patients and professionals, as well as health value-based generation at the provider and health-system levels. However, health risk assessment was identified as an unmet need with the potential to enhance clinical decision making. Objective: The objective of this study is to generate and assess predictive models of mortality and in-hospital admission at entry and at HH/ED discharge. Methods: Predictive modeling of mortality and in-hospital admission was done in 2 different scenarios: at entry into the HH/ED program and at discharge, from January 2009 to December 2015. Multisource predictive variables, including standard clinical data, patients’ functional features, and population health risk assessment, were considered. Results: We studied 1925 HH/ED patients by applying a random forest classifier, as it showed the best performance. Average results of the area under the receiver operating characteristic curve (AUROC; sensitivity/specificity) for the prediction of mortality were 0.88 (0.81/0.76) and 0.89 (0.81/0.81) at entry and at home hospitalization discharge, respectively; the AUROC (sensitivity/specificity) values for in-hospital admission were 0.71 (0.67/0.64) and 0.70 (0.71/0.61) at entry and at home hospitalization discharge, respectively. Conclusions: The results showed potential for feeding clinical decision support systems aimed at supporting health professionals for inclusion of candidates into the HH/ED program, and have the capacity to guide transitions toward community-based care at HH discharge.

Keywords: Home hospitalization, Health risk assessment, Predictive modeling, Chronic care, Integrated care, Modeling, Hospitalization, Health risk, Prediction, Mortality, Clinical decision support

Guixé-Muntet, Sergi, Ortega-Ribera, Martí, Wang, Cong, Selicean, Sonia, Andreu, Ion, Kechagia, Jenny Z., Fondevila, Constantino, Roca-Cusachs, Pere, Dufour, Jean-François, Bosch, Jaime, Berzigotti, Annalisa, Gracia-Sancho, Jordi, (2020). Nuclear deformation mediates liver cell mechanosensing in cirrhosis JHEP Reports 2, (5), 100145

Background & AimsLiver stiffness is increased in advanced chronic liver disease (ACLD) and accurately predicts prognosis in this population. Recent data suggest that extracellular matrix stiffness per se may modulate the phenotype of liver cells. We aimed at investigating the effect of matrix stiffness on the phenotype of liver cells of rats with cirrhosis, assessing its influence on their response to antifibrotic strategies and evaluating associated molecular mechanisms.

Keywords: Chronic liver disease, Hepatocyte, HSC, LSEC, Stiffness

Vodovotz, Y., Barnard, N., Hu, F. B., Jakicic, J., Lianov, L., Loveland, D., Buysse, D., Szigethy, E., Finkel, T., Sowa, G., Verschure, P., Williams, K., Sanchez, E., Dysinger, W., Maizes, V., Junker, C., Phillips, E., Katz, D., Drant, S., Jackson, R. J., Trasande, L., Woolf, S., Salive, M., South-Paul, J., States, S. L., Roth, L., Fraser, G., Stout, R., Parkinson, M. D., (2020). Prioritized research for the prevention, treatment, and reversal of chronic disease: recommendations from the lifestyle medicine research summit Frontiers in Medicine 7, 585744

Declining life expectancy and increasing all-cause mortality in the United States have been associated with unhealthy behaviors, socioecological factors, and preventable disease. A growing body of basic science, clinical research, and population health evidence points to the benefits of healthy behaviors, environments and policies to maintain health and prevent, treat, and reverse the root causes of common chronic diseases. Similarly, innovations in research methodologies, standards of evidence, emergence of unique study cohorts, and breakthroughs in data analytics and modeling create new possibilities for producing biomedical knowledge and clinical translation. To understand these advances and inform future directions research, The Lifestyle Medicine Research Summit was convened at the University of Pittsburgh on December 4–5, 2019. The Summit's goal was to review current status and define research priorities in the six core areas of lifestyle medicine: plant-predominant nutrition, physical activity, sleep, stress, addictive behaviors, and positive psychology/social connection. Forty invited subject matter experts (1) reviewed existing knowledge and gaps relating lifestyle behaviors to common chronic diseases, such as cardiovascular disease, diabetes, many cancers, inflammatory- and immune-related disorders and other conditions; and (2) discussed the potential for applying cutting-edge molecular, cellular, epigenetic and emerging science knowledge and computational methodologies, research designs, and study cohorts to accelerate clinical applications across all six domains of lifestyle medicine. Notably, federal health agencies, such as the Department of Defense and Veterans Administration have begun to adopt “whole-person health and performance” models that address these lifestyle and environmental root causes of chronic disease and associated morbidity, mortality, and cost. Recommendations strongly support leveraging emerging research methodologies, systems biology, and computational modeling in order to accelerate effective clinical and population solutions to improve health and reduce societal costs. New and alternative hierarchies of evidence are also be needed in order to assess the quality of evidence and develop evidence-based guidelines on lifestyle medicine. Children and underserved populations were identified as prioritized groups to study. The COVID-19 pandemic, which disproportionately impacts people with chronic diseases that are amenable to effective lifestyle medicine interventions, makes the Summit's findings and recommendations for future research particularly timely and relevant.

Keywords: Chronic disease, Epigenetics, In silico modeling, Inflammation, Lifestyle medicine, Nutrition, Physical activity, Research methodologies

Trebicka, J., Gu, W., Ibañez-Samaniego, L., Hernández-Gea, V., Pitarch, C., Garcia, E., Procopet, B., Giráldez, Á, Amitrano, L., Villanueva, C., Thabut, D., Silva-Junior, G., Martinez, J., Genescà , J., Bureau, C., Llop, E., Laleman, W., Palazon, J. M., Castellote, J., Rodrigues, S., Gluud, L., Ferreira, C. N., Barcelo, R., Cañete, N., Rodríguez, M., Ferlitsch, A., Mundi, J. L., Gronbaek, H., Hernández-Guerra, M., Sassatelli, R., Dell'Era, A., Senzolo, M., Abraldes, J. G., Romero-Gómez, M., Zipprich, A., Casas, M., Masnou, H., Primignani, M., Weiss, E., Catalina, M. V., Erasmus, H. P., Uschner, F. E., Schulz, M., Brol, M. J., Praktiknjo, M., Chang, J., Krag, A., Nevens, F., Calleja, J. L., Robic, M. A., Conejo, I., Albillos, A., Rudler, M., Alvarado, E., Guardascione, M. A., Tantau, M., Bosch, J., Torres, F., Pavesi, M., Garcia-Pagán, J. C., Jansen, C., Bañares, R., (2020). Rebleeding and mortality risk are increased by ACLF but reduced by pre-emptive TIPS Journal of Hepatology 73, (5), 1082-1091

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.

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

Praktiknjo, M., Simón-Talero, M., Römer, J., Roccarina, D., Martínez, J., Lampichler, K., Baiges, A., Low, G., Llop, E., Maurer, M. H., Zipprich, A., Triolo, M., Maleux, G., Fialla, A. D., Dam, C., Vidal-González, J., Majumdar, A., Picón, C., Toth, D., Darnell, A., Abraldes, J. G., López, M., Jansen, C., Chang, J., Schierwagen, R., Uschner, F., Kukuk, G., Meyer, C., Thomas, D., Wolter, K., Strassburg, C. P., Laleman, W., La Mura, V., Ripoll, C., Berzigotti, A., Calleja, J. L., Tandon, P., Hernandez-Gea, V., Reiberger, T., Albillos, A., Tsochatzis, E. A., Krag, A., Genescà , J., Trebicka, J., (2020). Total area of spontaneous portosystemic shunts independently predicts hepatic encephalopathy and mortality in liver cirrhosis Journal of Hepatology 72, (6), 1140-1150

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.

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

Rafols-de-Urquia, M., Estrada, L., Estevez-Piorno, J., Sarlabous, L., Jane, R., Torres, A., (2019). Evaluation of a wearable device to determine cardiorespiratory parameters from surface diaphragm electromyography IEEE Journal of Biomedical and Health Informatics 23, (5), 1964-1971

The use of wearable devices in clinical routines could reduce healthcare costs and improve the quality of assessment in patients with chronic respiratory diseases. The purpose of this study is to evaluate the capacity of a Shimmer3 wearable device to extract reliable cardiorespiratory parameters from surface diaphragm electromyography (EMGdi). Twenty healthy volunteers underwent an incremental load respiratory test whilst EMGdi was recorded with a Shimmer3 wearable device (EMGdiW). Simultaneously, a second EMGdi (EMGdiL), inspiratory mouth pressure (Pmouth) and lead-I electrocardiogram (ECG) were recorded via a standard wired laboratory acquisition system. Different cardiorespiratory parameters were extracted from both EMGdiW and EMGdiL signals: heart rate, respiratory rate, respiratory muscle activity and mean frequency of EMGdi signals. Alongside these, similar parameters were also extracted from reference signals (Pmouth and ECG). High correlations were found between the data extracted from the EMGdiW and the reference signal data: heart rate (R = 0.947), respiratory rate (R = 0.940), respiratory muscle activity (R = 0.877), and mean frequency (R = 0.895). Moreover, similar increments in EMGdiW and EMGdiL activity were observed when Pmouth was raised, enabling the study of respiratory muscle activation. In summary, the Shimmer3 device is a promising and cost-effective solution for the ambulatory monitoring of respiratory muscle function in chronic respiratory diseases.

Keywords: Cardiorespiratory monitoring, Chronic respiratory diseases, Fixed sample entropy, Non-invasive respiratory monitoring, Surface diaphragm electromyography, Wearable wireless device

Lehmann, J., Praktiknjo, M., Nielsen, M. J., Schierwagen, R., Meyer, C., Thomas, D., Violi, F., Strassburg, C. P., Bendtsen, F., Moller, S., Krag, A., Karsdal, M. A., Leeming, D. J., Trebicka, J., (2019). Collagen type IV remodelling gender-specifically predicts mortality in decompensated cirrhosis Liver International 39, (5), 885-893

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 ( 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.

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

Alvarez-Silva, C., Schierwagen, R., Pohlmann, A., Magdaleno, F., Uschner, F. E., Ryan, P., Vehreschild, M. J. G. T., Claria, J., Latz, E., Lelouvier, B., Arumugam, M., Trebicka, J., (2019). Compartmentalization of immune response and microbial translocation in decompensated cirrhosis Frontiers in Immunology 10, 69

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.

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

Blanco-Almazan, D., Groenendaal, W., Catthoor, F., Jane, R., (2019). Wearable bioimpedance measurement for respiratory monitoring during inspiratory loading IEEE Access 7, 89487-89496

Bioimpedance is an unobtrusive noninvasive technique to measure respiration and has a linear relation with volume during normal breathing. The objective of this paper was to assess this linear relation during inspiratory loading protocol and determine the best electrode configuration for bioimpedance measurement. The inspiratory load is a way to estimate inspiratory muscle function and has been widely used in studies of respiratory mechanics. Therefore, this protocol permitted us to evaluate bioimpedance performance under breathing pattern changes. We measured four electrode configurations of bioimpedance and airflow simultaneously in ten healthy subjects using a wearable device and a standard wired laboratory acquisition system, respectively. The subjects were asked to perform an incremental inspiratory threshold loading protocol during the measurements. The load values were selected to increase progressively until the 60% of the subject's maximal inspiratory pressure. The linear relation of the signals was assessed by Pearson correlation (r ) and the waveform agreement by the mean absolute percentage error (MAPE), both computed cycle by cycle. The results showed a median greater than 0.965 in r coefficients and lower than 11 % in the MAPE values for the entire population in all loads and configurations. Thus, a strong linear relation was found during all loaded breathing and configurations. However, one out of the four electrode configurations showed robust results in terms of agreement with volume during the highest load. In conclusion, bioimpedance measurement using a wearable device is a noninvasive and a comfortable alternative to classical methods for monitoring respiratory diseases in normal and restrictive breathing.

Keywords: Bioimpedance, Chronic respiratory diseases, Electrode configurations, Inspiratory threshold protocol, Wearable

Sarlabous, L., Estrada, L., Cerezo-Hernández, A., Leest, Sietske V. D., Torres, A., Jané, R., Duiverman, M., Garde, Ainara, (2019). Electromyography-based respiratory onset detection in COPD patients on non-invasive mechanical ventilation Entropy 21, (3), 258

To optimize long-term nocturnal non-invasive ventilation in patients with chronic obstructive pulmonary disease, surface diaphragm electromyography (EMGdi) might be helpful to detect patient-ventilator asynchrony. However, visual analysis is labor-intensive and EMGdi is heavily corrupted by electrocardiographic (ECG) activity. Therefore, we developed an automatic method to detect inspiratory onset from EMGdi envelope using fixed sample entropy (fSE) and a dynamic threshold based on kernel density estimation (KDE). Moreover, we combined fSE with adaptive filtering techniques to reduce ECG interference and improve onset detection. The performance of EMGdi envelopes extracted by applying fSE and fSE with adaptive filtering was compared to the root mean square (RMS)-based envelope provided by the EMG acquisition device. Automatic onset detection accuracy, using these three envelopes, was evaluated through the root mean square error (RMSE) between the automatic and mean visual onsets (made by two observers). The fSE-based method provided lower RMSE, which was reduced from 298 ms to 264 ms when combined with adaptive filtering, compared to 301 ms provided by the RMS-based method. The RMSE was negatively correlated with the proposed EMGdi quality indices. Following further validation, fSE with KDE, combined with adaptive filtering when dealing with low quality EMGdi, indicates promise for detecting the neural onset of respiratory drive.

Keywords: Fixed sample entropy, Adaptive filtering, Root mean square, Diaphragm electromyography, Non-invasive mechanical ventilation, Chronic obstructive pulmonary disease

Garde, A., Sörnmo, L., Laguna, P., Jané, R., Benito, S., Bayés-Genís, A., Giraldo, B. F., (2017). Assessment of respiratory flow cycle morphology in patients with chronic heart failure Medical and Biological Engineering and Computing , 55, (2), 245-255

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.

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

Rodríguez, J. C., Arizmendi, C. J., Forero, C. A., Lopez, S. K., Giraldo, B. F., (2017). Analysis of the respiratory flow signal for the diagnosis of patients with chronic heart failure using artificial intelligence techniques IFMBE Proceedings VII Latin American Congress on Biomedical Engineering (CLAIB 2016) , Springer (Santander, Colombia) 60, 46-49

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.

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

Correa, L.S., Giraldo, B., Correa, R., Arini, P.D., Laciar, E., (2014). Estudio de la pausa espiratoria en pacientes con enfermedades obstructivas en proceso de desconexión de la ventilación mecánica IFMBE Proceedings VI Latin American Congress on Biomedical Engineering (CLAIB 2014) , Springer (Paraná, Argentina) 49, 705-708

In this work, the flow signal Expiratory Pause (EP) temporal analysis is used in 18 patients with obstructive lung diseases going through spontaneous breathing trial at weaning process. The main objective was to identify the patients who were successfully disconnected (success group: 9 patients), and those who were not (failure and reintubated group: 9 patients). A variable selection stage was done by mean group comparison and step wise variable inclusion, leading to a 3 parameters set: EP time median; cycle time mean; and median absolute deviation of the EP maxima local number. Next, this set was used in a classifier based on linear discriminant analysis, which results in 17 patients (94.4%) correctly classified, with 88.9% of specificity (Sp) and 100% of sensitivity (Se). Finally, applying the leave-one-out cross validation method, results were 88.9% of correctly classified patients (Sp=77.8% and Se=100%). In conclusion, the proposed parameters showed a good performance and could be used to help therapists to wean patients with obstructive diseases.

Keywords: Chronic Obstructive Pulmonary Disease (COPD), Weaning, Mechanical ventilation, Expiratory pause

Giraldo, B. F., Tellez, J. P., Herrera, S., Benito, S., (2013). Analysis of heart rate variability in elderly patients with chronic heart failure during periodic breathing CinC 2013 Computing in Cardiology Conference (CinC) , IEEE (Zaragoza, Spain) , 991-994

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: PTot (p = 0.02), PLF (p = 0.022) and fpHF (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.

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

Giraldo, B. F., Tellez, J. P., Herrera, S., Benito, S., (2013). Study of the oscillatory breathing pattern in elderly patients Engineering in Medicine and Biology Society (EMBC) 35th Annual International Conference of the IEEE , IEEE (Osaka, Japan) , 5228-5231

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.

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

Garde, A., Sörnmo, L., Jané, R., Giraldo, B., (2010). Breathing pattern characterization in chronic heart failure patients using the respiratory flow signal Annals of Biomedical Engineering , 38, (12), 3572-3580

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.

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

Garde, A., Sörnmo, L., Jané, R., Giraldo, B. F., (2010). Correntropy-based spectral characterization of respiratory patterns in patients with chronic heart failure IEEE Transactions on Biomedical Engineering 57, (8), 1964-1972

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%.

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

Garde, A., Sörnmo, L., Jané, R., Giraldo, B. F., (2010). Correntropy-based nonlinearity test applied to patients with chronic heart failure Engineering in Medicine and Biology Society (EMBC) 32nd Annual International Conference of the IEEE , IEEE (Buenos Aires, Argentina) , 2399-2402

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.

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