Impact of viral hepatitis therapy in multiple myeloma and other monoclonal gammopathies linked to hepatitis B or C viruses.

Subsets of multiple myeloma (MM) and monoclonal gammopathies of undetermined significance (MGUS) present with a monoclonal immunoglobulin specific for hepatitis C virus (HCV), thus are presumably HCV-driven, and antiviral treatment can lead to the disappearance of antigen stimulation and improved control of clonal plasma cells. Here we studied the role of hepatitis B virus (HBV) in the pathogenesis of MGUS and MM in 45 HBV-infected patients with monoclonal gammopathy. We analyzed the specificity of recognition of the monoclonal immunoglobulin of these patients and validated the efficacy of antiviral treatment (AVT). For 18 of 45 (40%) HBV-infected patients, the target of the monoclonal immunoglobulin was identified: the most frequent target was HBV (n=11), followed by other infectious pathogens (n=6) and glucosylsphingosine (n=1). Two patients whose monoclonal immunoglobulin targeted HBV (HBx and HBcAg), implying that their gammopathy was HBV-driven, received AVT and the gammopathy did not progress. AVT efficacy was then investigated in a large cohort of HBV-infected MM patients (n=1367) who received or did not receive anti-HBV treatments and compared to a cohort of HCV-infected MM patients (n=1220). AVT significantly improved patient probability of overall survival (P=0.016 for the HBV-positive cohort, P=0.005 for the HCV-positive cohort). Altogether, MGUS and MM disease can be HBV- or HCV-driven in infected patients, and the study demonstrates the importance of AVT in such patients.

Mortality, Functional Status, and Quality of Life after 5 Years of Patients Admitted to Critical Care for Spontaneous Intracerebral Hemorrhage.

BACKGROUND: The objective of this study was to assess long-term outcome in patients with spontaneous intracerebral hemorrhage admitted to the intensive care unit. METHODS: Mortality and Glasgow Outcome Scale, Barthel Index, and 5-level EQ-5D version (EQ-5D-5L) scores were analyzed in a multicenter cohort study of three Spanish hospitals (336 patients). Mortality was also analyzed in the Medical Information Mart for Intensive Care III (MIMIC-III) database. RESULTS: The median (25th percentile-75th percentile) age was 62 (50-70) years, the median Glasgow Coma Score was 7 (4-11) points, and the median Acute Physiology and Chronic Health disease Classification System II (APACHE-II) score was 21 (15-26) points. Hospital mortality was 54.17%, mortality at 90 days was 56%, mortality at 1 year was 59.2%, and mortality at 5 years was 66.4%. In the Glasgow Outcome Scale, a normal or disabled self-sufficient situation was recorded in 21.5% of patients at 6 months, in 25.5% of patients after 1 year, and in 22.1% of patients after 5 years of follow-up (4.5% missing). The Barthel Index score of survivors improved over time: 50 (25-80) points at 6 months, 70 (35-95) points at 1 year, and 90 (40-100) points at 5 years (p < 0.001). Quality of life evaluated with the EQ-5D-5L at 1 year and 5 years indicated that greater than 50% of patients had no problems or slight problems in all items (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). In the MIMIC-III study (N = 1354), hospital mortality was 31.83% and was 40.5% at 90 days and 56.2% after 5 years. CONCLUSIONS: In patients admitted to the intensive care unit with a diagnosis of nontraumatic intracerebral hemorrhage, hospital mortality up to 90 days after admission is very high. Between 90 days and 5 years after admission, mortality is not high. A large percentage of survivors presented a significant deficit in quality of life and functional status, although with progressive improvement over time. Five years after the hemorrhagic stroke, a survival of 30% was observed, with a good functional status seen in 20% of patients who had been admitted to the hospital.

Outcome of video-assisted thoracoscopic treatment of idiopathic chylothorax in 15 cats.

OBJECTIVE: To evaluate the outcomes and complications of video-assisted thoracoscopic (VATS) treatment of chylothorax in cats. STUDY DESIGN: Multi-institutional retrospective study. ANIMALS: Fifteen client-owned cats. METHODS: The medical records of cats undergoing thoracoscopic thoracic duct ligation (TDL) for treatment of idiopathic chylothorax were reviewed. Cats undergoing additional procedures including thoracoscopic pericardectomy and/or laparoscopic cisterna chyli ablation (CCA)_were included. Follow up was obtained through communication with the referring veterinarian or owner. RESULTS: All cats underwent thoracoscopic TDL. Thirteen cats underwent simultaneous pericardectomy and two cats underwent laparoscopic CCA without pericardectomy. Conversion from a thoracoscopic to open approach was necessary in 2/15 (13%) of thoracic duct ligations and 1/11 (9%) of pericardectomies. The most common postoperative complication was persistent pleural effusion in five cats (33%). Four of 15 cats (27%) died or were euthanized prior to hospital discharge following surgery. Recurrence of effusion occurred in 1/7 (14%) of cats that sustained resolution of the effusion at the time of surgery with a median follow up of 8 months. The overall mortality attributed to chylothorax was 47%. CONCLUSION: Thoracoscopic treatment of idiopathic chylothorax resulted in a low incidence of intraoperative complications or conversion in the study population; however, mortality related to feline idiopathic chylothorax remained high. CLINICAL SIGNIFICANCE: While VATS treatment of idiopathic chylothorax is technically feasible, further consideration of the underlying pathology and current treatment algorithm is needed to improve outcomes as this remains a frustrating disease to treat in the feline population.

Inflammasome activation mediated by oxidised low-density lipoprotein in patients with sleep apnoea and early subclinical atherosclerosis.

BACKGROUND: Atherosclerosis is a common comorbidity of obstructive sleep apnoea (OSA) patients, caused by the interaction of dyslipidaemia and systemic inflammation. The OSA pro-inflammatory response is mediated by NLRP3 inflammasome activation, which requires a priming signal mediated by intermittent hypoxia (IH) and an activation signal provided by soluble stimulus present in plasma. Our objectives were to study oxidised low-density lipoprotein (oxLDL) expression in OSA patients with or without early subclinical atherosclerosis (eSA) as well as its contribution to NLRP3 activation and tissue factor (TF) release. METHODS: We analysed oxLDL, key components of the NLRP3 inflammasome cascade and TF in plasma and monocytes from OSA patients and non-apnoeic subjects, with or without eSA as determined by increased carotid intima-media thickness without the appearance of atherosclerotic plaques. The oxLDL contribution to NLRP3 inflammasome activation was assessed using in vitro models. RESULTS: High levels of oxLDL were identified in plasma from OSA patients, particularly in those with eSA, as well as an overexpression of NLRP3 cascade components and TF. Furthermore, in vitro models showed that both oxLDL and plasma from OSA patients with eSA act synergistically with IH as a priming and activation signal of NLRP3 that enhances the inflammatory response, pyroptosis and TF release. CONCLUSIONS: OSA patients with eSA exhibit NLRP3 activation by IH and the presence of oxLDL capable of releasing TF, constituting a pathway for the interaction between dyslipidaemia and systemic inflammation in the development of atherosclerotic lesions.

Multi-Omics Analysis of Circulating Exosomes in Adherent Long-Term Treated OSA Patients.

Obstructive sleep apnea (OSA) is a highly prevalent chronic disease affecting nearly a billion people globally and increasing the risk of multi-organ morbidity and overall mortality. However, the mechanisms underlying such adverse outcomes remain incompletely delineated. Extracellular vesicles (exosomes) are secreted by most cells, are involved in both proximal and long-distance intercellular communication, and contribute toward homeostasis under physiological conditions. A multi-omics integrative assessment of plasma-derived exosomes from adult OSA patients prior to and after 1-year adherent CPAP treatment is lacking. We conducted multi-omic integrative assessments of plasma-derived exosomes from adult OSA patients prior to and following 1-year adherent CPAP treatment to identify potential specific disease candidates. Fasting morning plasma exosomes isolated from 12 adult patients with polysomnographically-diagnosed OSA were analyzed before and after 12 months of adherent CPAP therapy (mean ≥ 6 h/night) (OSAT). Exosomes were characterized by flow cytometry, transmission electron microscopy, and nanoparticle tracking analysis. Endothelial cell barrier integrity, wound healing, and tube formation were also performed. Multi-omics analysis for exosome cargos was integrated. Exosomes derived from OSAT improved endothelial permeability and dysfunction as well as significant improvement in tube formation compared with OSA. Multi-omic approaches for OSA circulating exosomes included lipidomic, proteomic, and small RNA (miRNAs) assessments. We found 30 differentially expressed proteins (DEPs), 72 lipids (DELs), and 13 miRNAs (DEMs). We found that the cholesterol metabolism (has04979) pathway is associated with lipid classes in OSA patients. Among the 12 subjects of OSA and OSAT, seven subjects had complete comprehensive exosome cargo information including lipids, proteins, and miRNAs. Multi-omic approaches identify potential signature biomarkers in plasma exosomes that are responsive to adherent OSA treatment. These differentially expressed molecules may also play a mechanistic role in OSA-induced morbidities and their reversibility. Our data suggest that a multi-omic integrative approach might be useful in understanding how exosomes function, their origin, and their potential clinical relevance, all of which merit future exploration in the context of relevant phenotypic variance. Developing an integrated molecular classification should lead to improved diagnostic classification, risk stratification, and patient management of OSA by assigning molecular disease-specific therapies.

SMAD4 Expression in Monocytes as a Potential Biomarker for Atherosclerosis Risk in Patients with Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) patients are at special risk of suffering atherosclerosis, leading to major cardiovascular diseases. Notably, the transforming growth factor (TGF-ß) plays a crucial role in the development and progression of atherosclerosis. In this context, the central regulator of TGF-ß pathway, SMAD4 (small mother against decapentaplegic homolog 4), has been previously reported to be augmented in OSA patients, which levels were even higher in patients with concomitant cardiometabolic diseases. Here, we analyzed soluble and intracellular SMAD4 levels in plasma and monocytes from OSA patients and non-apneic subjects, with or without early subclinical atherosclerosis (eSA). In addition, we used in vitro and ex vivo models to explore the mechanisms underlying SMAD4 upregulation and release. Our study confirmed elevated sSMAD4 levels in OSA patients and identified that its levels were even higher in those OSA patients with eSA. Moreover, we demonstrated that SMAD4 is overexpressed in OSA monocytes and that intermittent hypoxia contributes to SMAD4 upregulation and release in a process mediated by NLRP3. In conclusion, this study highlights the potential role of sSMAD4 as a biomarker for atherosclerosis risk in OSA patients and provides new insights into the mechanisms underlying its upregulation and release to the extracellular space.

Laparoscopic extra-abdominal transfascial suturing technique for diaphragmatic rupture repair in a cat.

OBJECTIVE: To describe the technique, complications, and outcome of the laparoscopic extra-abdominal transfascial suturing method for diaphragmatic rupture repair in a cat. STUDY DESIGN: Case report. ANIMALS: A 10 year old, female domestic shorthair cat. METHODS: An acute traumatic diaphragmatic rupture was diagnosed in a cat. Following initial stabilization, 3-port laparoscopic surgery was performed. After the laparoscopic reduction of herniating organs, a circumferential diaphragmatic tear was diagnosed, which was repaired using a multiple extra-abdominal transfascial suture technique. The total surgical time was 50 min with no intraoperative complications encountered. RESULTS: The successful procedure was confirmed by normalization of chest radiography, clinical signs, and blood gas analysis in the perioperative and postoperative periods. Mild skin irritation occurred 3 weeks after surgery but was resolved following the removal of sutures. The cat recovered well without major complications; the final reexamination was performed 3 months postoperatively. CONCLUSION: The laparoscopic extra-abdominal transfascial suturing technique appears to be a feasible, and effective technique for feline diaphragmatic circumferential rupture repair. This technique may be an alternative option to intracorporeal suturing for diaphragmatic rupture treatment in the cat.

Laparoscopic resection of pancreatic masses in 12 dogs.

OBJECTIVE: To describe the surgical management and outcome of dogs undergoing laparoscopic pancreatic mass resection (LPMR). STUDY DESIGN: Retrospective study. ANIMALS: Twelve client-owned dogs. METHODS: Data collected from medical records of dogs that underwent LPMR between 2012 and 2023 included signalment, clinical signs, mass location within pancreas, preoperative diagnostic imaging, laparoscopic approach, number of portals and device type used for LPMR, operating time, complications and clinical outcome. RESULTS: Pancreatic tumors were located in the left lobe (7), in the right lobe (4) and in the body of the pancreas (1). A 3- or 4-port technique was used in nine and three dogs, respectively. LPMR was performed with the Ligasure in nine dogs, a harmonic scalpel in two dogs and an endoscopic stapler in one dog. The procedure was performed successfully, with no conversion to open laparotomy, in all cases with a median operating time of 69 min. Postoperative complications occurred in four dogs, which resolved with medical treatments. All dogs survived the surgical procedure, were discharged from the hospital and alive a minimum of 90 days postoperatively. The final follow-up time ranged between 105 and 245 days (median 147). Histopathological diagnosis included insulinoma (9) and pancreatic carcinoma (3). CONCLUSION: LPMR was performed successfully using a 3- or 4-port technique and was associated with a low complication rate and a good clinical outcome. CLINICAL SIGNIFICANCE: LPMR may be considered as an alternative to open celiotomy in dogs, particularly for small tumors located in the distal aspect of the pancreatic lobes.

Cluster analysis and forecasting of viruses incidence growth curves: Application to SARS-CoV-2.

The sanitary emergency caused by COVID-19 has compromised countries and generated a worldwide health and economic crisis. To provide support to the countries' responses, numerous lines of research have been developed. The spotlight was put on effectively and rapidly diagnosing and predicting the evolution of the pandemic, one of the most challenging problems of the past months. This work contributes to the existing literature by developing a two-step methodology to analyze the transmission rate, designing models applied to territories with similar pandemic behavior characteristics. Virus transmission is considered as bacterial growth curves to understand the spread of the virus and to make predictions about its future evolution. Hence, an analytical clustering procedure is first applied to create groups of locations where the virus transmission rate behaved similarly in the different outbreaks. A curve decomposition process based on an iterative polynomial process is then applied, obtaining meaningful forecasting features. Information of the territories belonging to the same cluster is merged to build models capable of simultaneously predicting the 14-day incidence in several locations using Evolutionary Artificial Neural Networks. The methodology is applied to Andalusia (Spain), although it is applicable to any region across the world. Individual models trained for a specific territory are carried out for comparison purposes. The results demonstrate that this methodology achieves statistically similar, or even better, performance for most of the locations. In addition to being extremely competitive, the main advantage of the proposal lies in its complexity cost reduction. The total number of parameters to be estimated is reduced up to 93.51% for the short term and 93.31% for the mid-term forecasting, respectively. Moreover, the number of required models is reduced by 73.53% and 58.82% for the short- and mid-term forecasting horizons.

Soluble RAGE in COPD, with or without coexisting obstructive sleep apnoea.

BACKGROUND: Hypoxia can reduce the levels of soluble receptor for advanced glycation end-products (sRAGE), a new anti-inflammatory biomarker of COPD. We assessed sRAGE in patients with hypoxia-related diseases such as COPD, OSA and OSA-COPD overlap. METHODS: Plasma levels of sRAGE were measured in 317 subjects at baseline (57 heathy nonsmokers [HNS], 84 healthy smokers [HS], 79 OSA, 62 COPD and 35 OSA-COPD overlap patients) and in 294 subjects after one year of follow-up (50 HNS, 74 HS, 77 OSA, 60 COPD and 33 overlap). RESULTS: After adjusting for age, sex, smoking status and body mass index, sRAGE levels showed a reduction in OSA (- 12.5%, p = 0.005), COPD (- 14.8%, p < 0.001) and OSA-COPD overlap (- 12.3%, p = 0.02) compared with HNS. There were no differences when comparing sRAGE plasma levels between overlap patients and those with OSA or COPD alone. At follow-up, sRAGE levels did not change significantly in healthy subjects, COPD and OSA or OSA-COPD overlap nontreated with continuous positive airway pressure (CPAP). Moreover, in patients with OSA and OSA-COPD overlap who were treated with CPAP, sRAGE increased significantly. CONCLUSIONS: The levels of sRAGE are reduced in COPD and OSA. Treatment with CPAP appears to improve sRAGE levels in patients with OSA who also had COPD.

Hospitalization characteristics and outcomes of patients with cancer and COVID-19 at a comprehensive cancer center.

PURPOSE: Several studies have confirmed increased mortality among patients with both COVID-19 and cancer. It remains important to continue to report observations of morbidity and mortality from COVID-19 in this vulnerable population. The purpose of this study is to describe the hospitalization characteristics and outcomes of patients with both cancer and COVID-19 admitted to our comprehensive cancer center. METHODS: This was a descriptive study of the first COVID-19-related hospitalization among adult patients with cancer admitted to our institution. Descriptive statistics were used to summarize patient demographics, clinical as well as hospitalization characteristics. Overall survival (OS) was estimated using the Kaplan-Meier method. RESULTS: A total of 212 patients were included in our cohort with a mean age of 59 years. Fifty-four percent of patients had history of solid tumor malignancy and 46% had hematologic malignancies. Eighty-five percent of our cohort had active malignancy. The mean length of stay (LOS) for hospitalization was 11.2 days (median LOS of 6 days). Twenty-five percent had severe disease and 10.8% died during their initial hospitalization. Those who had severe disease had worse survival at the end of the observation period. CONCLUSIONS: COVID-19 among cancer patients causes significant morbidity and mortality as well as repeat hospitalizations. Continued study of COVID-19 in this vulnerable population is essential in order to better inform evolving treatment algorithms, public health policies, and infection control protocols, especially for institutions caring for patients with cancer.

Laparoscopic portosystemic shunt attenuation in 20 dogs (2018-2021).

OBJECTIVE: To describe the technique, complications, and outcome of laparoscopic portosystemic shunt attenuation (LPSSA) in dogs. STUDY DESIGN: Retrospective study. ANIMALS: Twenty client-owned dogs. METHODS: Medical records were searched for dogs with a single congenital extrahepatic portosystemic shunt (CEPSS) that was treated with LPSSA. Signalment, clinical signs, CEPSS location, diagnostic imaging, laparoscopic approach, operative technique, complications, and clinical outcome were reviewed. RESULTS: Fourteen dogs with CEPSS located in the epiploic foramen had a right (13/14) or left (1/14) paramedian approach. In 6 dogs a CEPSS was not located in the epiploic foramen, and a left paramedian approach was used. A 3 or 4-port technique was used in 7 and 13 dogs, respectively. A thin film band was used for CEPSS attenuation in all dogs. The median operating time for LPSSA was 62 min (range 27-98 min). Intraoperative complications requiring conversion to an open technique occurred in 5 dogs. Mild perioperative self-limiting portal hypertension occurred in 3 dogs, while severe portal hypertension with surgical revision occurred in 1 case. The complications were resolved, and all dogs had a good outcome. CONCLUSION: Laparoscopic portosystemic shunt attenuation can be performed in dogs, in particular for a CEPSS located in the epiploic foramen using a right paramedian approach. For CEPSS not located in the epiploic foramen, a left paramedian approach is recommended. Conversion to open celiotomy was required in around a third of cases. CLINICAL SIGNIFICANCE: Laparoscopic attenuation of CEPSSs can be performed in dogs and has a good clinical outcome, particularly for CEPSS located in the epiploic foramen.

COVID-19 contagion forecasting framework based on curve decomposition and evolutionary artificial neural networks: A case study in Andalusia, Spain.

Many types of research have been carried out with the aim of combating the COVID-19 pandemic since the first outbreak was detected in Wuhan, China. Anticipating the evolution of an outbreak helps to devise suitable economic, social and health care strategies to mitigate the effects of the virus. For this reason, predicting the SARS-CoV-2 transmission rate has become one of the most important and challenging problems of the past months. In this paper, we apply a two-stage mid and long-term forecasting framework to the epidemic situation in eight districts of Andalusia, Spain. First, an analytical procedure is performed iteratively to fit polynomial curves to the cumulative curve of contagions. Then, the extracted information is used for estimating the parameters and structure of an evolutionary artificial neural network with hybrid architectures (i.e., with different basis functions for the hidden nodes) while considering single and simultaneous time horizon estimations. The results obtained demonstrate that including polynomial information extracted during the training stage significantly improves the mid- and long-term estimations in seven of the eight considered districts. The increase in average accuracy (for the joint mid- and long-term horizon forecasts) is 37.61% and 35.53% when considering the single and simultaneous forecast approaches, respectively.

Protective role of mindfulness, self-compassion and psychological flexibility on the burnout subtypes among psychology and nursing undergraduate students.

AIMS: To explore the relationship between mindfulness, self-compassion and psychological flexibility, and the burnout subtypes in university students of the Psychology and Nursing degrees, and to analyse possible risk factors for developing burnout among socio-demographic and studies-related characteristics. DESIGN: Cross-sectional study conducted on a sample of 644 undergraduate students of Nursing and Psychology from two Spanish universities. METHODS: The study was conducted between December 2015 and May 2016. Bivariate Pearson's correlations were computed to analyse the association between mindfulness facets, self-compassion and psychological flexibility, and levels of burnout. Multivariate linear regression models and bivariate and multivariate binary logistic regressions were also computed. RESULTS: The three subtypes of burnout presented significant correlations with psychological flexibility, self-compassion and some mindfulness facets. Psychological flexibility, self-compassion and the mindfulness facets of observing and acting with awareness were significantly associated to burnout. Among the risk factors, 'year of study' was the only variable to show significantly higher risk for every burnout subtype. CONCLUSION: The significant associations found between mindfulness, self-compassion, psychological flexibility and burnout levels underline the need of including these variables as therapeutic targets when addressing the burnout syndrome in university students. IMPACT: Undergraduate students, especially those of health sciences, often experience burnout. This study delves into the protective role of some psychological variables: mindfulness, self-compassion and psychological flexibility. These should be considered as potentially protective skills for developing burnout, and therefore, undergraduate students could be trained on these abilities to face their studies and their future profession to prevent experiencing burnout syndrome.

The Mystery of Red Blood Cells Extracellular Vesicles in Sleep Apnea with Metabolic Dysfunction.

Sleep is very important for overall health and quality of life, while sleep disorder has been associated with several human diseases, namely cardiovascular, metabolic, cognitive, and cancer-related alterations. Obstructive sleep apnea (OSA) is the most common respiratory sleep-disordered breathing, which is caused by the recurrent collapse of the upper airway during sleep. OSA has emerged as a major public health problem and increasing evidence suggests that untreated OSA can lead to the development of various diseases including neurodegenerative diseases. In addition, OSA may lead to decreased blood oxygenation and fragmentation of the sleep cycle. The formation of free radicals or reactive oxygen species (ROS) can emerge and react with nitric oxide (NO) to produce peroxynitrite, thereby diminishing the bioavailability of NO. Hypoxia, the hallmark of OSA, refers to a decline of tissue oxygen saturation and affects several types of cells, playing cell-to-cell communication a vital role in the outcome of this interplay. Red blood cells (RBCs) are considered transporters of oxygen and nutrients to the tissues, and these RBCs are important interorgan communication systems with additional functions, including participation in the control of systemic NO metabolism, redox regulation, blood rheology, and viscosity. RBCs have been shown to induce endothelial dysfunction and increase cardiac injury. The mechanistic links between changes of RBC functional properties and cardiovascular are largely unknown. Extracellular vesicles (EVs) are secreted by most cell types and released in biological fluids both under physiological and pathological conditions. EVs are involved in intercellular communication by transferring complex cargoes including proteins, lipids, and nucleic acids from donor cells to recipient cells. Advancing our knowledge about mechanisms of RBC-EVs formation and their pathophysiological relevance may help to shed light on circulating EVs and to translate their application to clinical practice. We will focus on the potential use of RBC-EVs as valuable diagnostic and prognostic biomarkers and state-specific cargoes, and possibilities as therapeutic vehicles for drug and gene delivery. The use of RBC-EVs as a precision medicine for the diagnosis and treatment of the patient with sleep disorder will improve the prognosis and the quality of life in patients with cardiovascular disease (CVD).

Extracellular Vesicles from Airway Secretions: New Insights in Lung Diseases.

Lung diseases (LD) are one of the most common causes of death worldwide. Although it is known that chronic airway inflammation and excessive tissue repair are processes associated with LD such as asthma, chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis (IPF), their specific pathways remain unclear. Extracellular vesicles (EVs) are heterogeneous nanoscale membrane vesicles with an important role in cell-to-cell communication. EVs are present in general biofluids as plasma or urine but also in secretions of the airway as bronchoalveolar lavage fluid (BALF), induced sputum (IS), nasal lavage (NL) or pharyngeal lavage. Alterations of airway EV cargo could be crucial for understanding LD. Airway EVs have shown a role in the pathogenesis of some LD such as eosinophil increase in asthma, the promotion of lung cancer in vitro models in COPD and as biomarkers to distinguishing IPF in patients with diffuse lung diseases. In addition, they also have a promising future as therapeutics for LD. In this review, we focus on the importance of airway secretions in LD, the pivotal role of EVs from those secretions on their pathophysiology and their potential for biomarker discovery.

Cell-Selective Altered Cargo Properties of Extracellular Vesicles Following In Vitro Exposures to Intermittent Hypoxia.

Intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), is associated with cardiovascular and metabolic dysfunction. However, the mechanisms underlying these morbidities remain poorly delineated. Extracellular vesicles (EVs) mediate intercellular communications, play pivotal roles in a multitude of physiological and pathological processes, and could mediate IH-induced cellular effects. Here, the effects of IH on human primary cells and the release of EVs were examined. Microvascular endothelial cells (HMVEC-d), THP1 monocytes, THP1 macrophages M0, THP1 macrophages M1, THP1 macrophages M2, pre-adipocytes, and differentiated adipocytes (HAd) were exposed to either room air (RA) or IH for 24 h. Secreted EVs were isolated and characterized using transmission electron microscopy, nanoparticle tracking analysis, and Western blotting. The effects of each of the cell-derived EVs on endothelial cell (EC) monolayer barrier integrity, on naïve THP1 macrophage polarity, and on adipocyte insulin sensitivity were also evaluated. IH did not alter EVs cell quantal release, but IH-EVs derived from HMVEC-d (p < 0.01), THP1 M0 (p < 0.01) and HAd (p < 0.05) significantly disrupted HMVEC-d monolayer integrity, particularly after H2O2 pre-conditioning. IH-EVs from HMVEC-d and THP1 M0 elicited M2-polarity changes did not alter insulin sensitivity responses. IH induces cell-selective changes in EVs cargo, which primarily seem to target the emergence of endothelial dysfunction. Thus, changes in EVs cargo from selected cell sources in vivo may play causal roles in some of the adverse outcomes associated with OSA.

Cerebrospinal Fluid and Plasma Small Extracellular Vesicles and miRNAs as Biomarkers for Prion Diseases.

Diagnosis of transmissible spongiform encephalopathies (TSEs), or prion diseases, is based on the detection of proteinase K (PK)-resistant PrPSc in post-mortem tissues as indication of infection and disease. Since PrPSc detection is not considered a reliable method for in vivo diagnosis in most TSEs, it is of crucial importance to identify an alternative source of biomarkers to provide useful alternatives for current diagnostic methodology. Ovine scrapie is the prototype of TSEs and has been known for a long time. Using this natural model of TSE, we investigated the presence of PrPSc in exosomes derived from plasma and cerebrospinal fluid (CSF) by protein misfolding cyclic amplification (PMCA) and the levels of candidate microRNAs (miRNAs) by quantitative PCR (qPCR). Significant scrapie-associated increase was found for miR-21-5p in plasma-derived but not in CSF-derived exosomes. However, miR-342-3p, miR-146a-5p, miR-128-3p and miR-21-5p displayed higher levels in total CSF from scrapie-infected sheep. The analysis of overexpressed miRNAs in this biofluid, together with plasma exosomal miR-21-5p, could help in scrapie diagnosis once the presence of the disease is suspected. In addition, we found the presence of PrPSc in most CSF-derived exosomes from clinically affected sheep, which may facilitate in vivo diagnosis of prion diseases, at least during the clinical stage.

Epigenetics dysfunction in morbid obesity with or without obstructive sleep apnoea: the EPIMOOSA study.

BACKGROUND: Obstructive sleep apnoea (OSA) and morbid obesity (MO), defined by a body mass index ≥35 kg/m2, are two closely related conditions. Recent studies suggest that circulating microRNA (miRNA) plays a potential role in the physiopathology of both conditions. To date, circulating miRNA expression has been studied separately in both conditions, but never jointly. The primary treatment of OSA is continuous positive airway pressure (CPAP), whereas bariatric surgery (BS) is the treatment of choice for MO. We have thus initiated the Epigenetics modification in Morbid Obesity and Obstructive Sleep Apnoea (EPIMOOSA) study (ClinicalTrials.gov identifier: NCT03995836). METHODS/DESIGN: EPIMOOSA is a prospective non-interventional cohort study aiming to recruit 45 MO patients who are candidates for BS. Three groups will be formed: MO without OSA, MO with OSA without CPAP and MO with OSA and CPAP. All of them will be followed up in 4 visits: baseline, 6 months prior to BS and 3, 6 and 12 months post-BS. At baseline, OSA status will be assessed by home sleep polygraphy (HSP), and CPAP will be adopted according to national guidelines. A specific standardized questionnaire (including medical conditions and AOS-related symptoms) and anthropometrical examination will be performed at each visit. Blood samples will be obtained at each visit for immediate standard biochemistry, haematology and inflammatory cytokines. For bio-banking, serum, plasma, and circulating exosomes will also be obtained. Twenty-four hours of blood pressure and electrocardiogram (ECG) Holter monitoring will be performed at all visits. A new HSP will be performed at the last visit. Finally, the three groups will be sex- and age- matched with participants in the EPIOSA study, an ongoing study aimed at understanding epigenetic changes in non-obese OSA patients. DISCUSSION: EPIMOOSA will evaluate changes in circulating miRNA in MO with or without OSA for the first time. In addition, EPIMOOSA will be able to elucidate the influence of OSA in MO patients and how specific and combined treatments alter miRNA expression.

Improvement of quality of life (QOL) between 1 and 3-4 years after traumatic brain injury (TBI) in ICU patients.

BACKGROUND: Evaluation of changes in quality of life (QOL) in ICU patients several years after traumatic brain injury (TBI) is not well documented. METHODS: A prospective cohort study was conducted in all patients with TBI admitted between 2004 and 2008 to the ICU of Regional Hospital of Malaga (Spain). Functional status was evaluated by Glasgow Outcome Scale (GOS) and QOL by PAECC (Project for the Epidemiologic Analysis of Critical Care patients) questionnaire between 0 (normal QOL) to 29 points (worst QOL). RESULTS: A total of 531 patients. Median(Quartile1,Quartile 3) age: 35 (22, 56) years. After 3-4 years, 175 died (33%). Survivor QOL was deteriorated (median total PAECC score: 5 (0, 11) points) although 75.76% of patients who survived showed good functional situation (GOS normal or mild dysfunction). An improvement in QOL scores between 1 and 3-4 years was observed (median PAECC score differences between 3-4 years and 1 year: - 1(- 4, 0) points). QOL score improved during this interval of time: 62.6% of patients. Change in QOL was related by multivariate analysis to admission cranial-computed tomography scan (Marshall's classification), age, and Injury Severity Score (ISS), with the biggest improvement seen in younger patients and with more severe ISS. Basic physiological activities were maintained in the majority of patients. Subjective aspects and working activities improved between 1 and 3-4 years but with a high proportion still impaired in these items after 3-4 years. CONCLUSIONS: ICU patients with TBI after 1 year show improvement in QOL between 1 and 3-4 years, with the biggest improvement in QOL seen in younger patients and in those with more severe ISS.