Project description:The defining features of acute respiratory distress syndrome (ARDS) are an excessive inflammatory respiratory response associated with high morbidity and mortality. Treatment consists mainly of measures to avoid worsening lung injury and cannot reverse the underlying pathophysiological process. New pharmacological agents have shown promising results in preclinical studies; however, they have not been successfully translated to patients with ARDS. The lack of effective therapeutic interventions has resulted in a recent interest in strategies to prevent ARDS with treatments delivering medications directly to the lungs by inhalation and nebulization, hopefully minimizing systemic adverse events. We analyzed the effect of different aerosolized drugs such as bronchodilators, corticosteroids, pulmonary vasodilators, anticoagulants, mucolytics and surfactant. New therapeutic strategies and ongoing trials using carbon monoxide (CO) and AP301 peptide are also briefly reviewed.
Project description:Humans harbour large quantities of microbes, including bacteria, fungi, viruses and archaea, in the gut. Patients with liver disease exhibit changes in the intestinal microbiota and gut barrier dysfunction. Preclinical models demonstrate the importance of the gut microbiota in the pathogenesis of various liver diseases. In this review, we discuss how manipulation of the gut microbiota can be used as a novel treatment approach for liver disease. We summarise current data on untargeted approaches, including probiotics and faecal microbiota transplantation, and precision microbiome-centered therapies, including engineered bacteria, postbiotics and phages, for the treatment of liver diseases.
Project description:As the number of confirmed cases and resulting death toll of the COVID-19 pandemic continue to increase around the globe - especially with the emergence of new mutations of the SARS-CoV-2 virus in addition to the known alpha, beta, gamma, delta and omicron variants - tremendous efforts continue to be dedicated to the development of interventive therapeutics to mitigate infective symptoms or post-viral sequelae in individuals for which vaccines are not accessible, viable or effective in the prevention of illness. Many of these investigations aim to target the associated acute respiratory distress syndrome, or ARDS, which induces damage to lung epithelia and other physiologic systems and is associated with progression in severe cases. Recently, stem cell-based therapies have demonstrated preliminary efficacy against ARDS based on a number of preclinical and preliminary human safety studies, and based on promising outcomes are now being evaluated in phase II clinical trials for ARDS. A number of candidate stem cell therapies have been found to exhibit low immunogenicity, coupled with inherent tropism to injury sites. In recent studies, these have demonstrated the ability to modulate suppression of pro-inflammatory cytokine signals such as those characterizing COVID-19-associated ARDS. Present translational studies are aiming to optimize the safety, efficacy and delivery to fully validate stem cell-based strategies targeting COVID-19 associated ARDS for viable clinical application.
Project description:BackgroundThe recent pandemic highlights the essential nature of optimizing the use of invasive mechanical ventilation (IMV) in complex critical care settings. This review of reviews maps evidence-based practices (EBPs) that are associated with better outcomes among adult patients with acute respiratory failure or ARDS on the continuum of care, from intubation to liberation.Research questionWhat EPBs are recommended to reduce the duration of IMV and mortality rate among patients with acute respiratory failure/ARDS?Study design and methodsWe identified an initial set of reports that links EBPs to mortality rates and/or duration of IMV. We conducted a review of reviews, focusing on preappraised guidelines, meta-analyses, and systematic reviews. We searched Scopus, CINAHL, and PubMed from January 2016 to January 2019 for additional evidence that has not yet been incorporated into current guidelines.ResultsOur initial search produced 61 publications that contained 42 EBPs. We excluded 42 manuscripts during the data extraction process, primarily because they were not associated with improved patient outcomes. The remaining 19 preappraised guidelines, meta-analyses, and systematic reviews met our full inclusion criteria and spanned the continuum of IMV care from intubation to liberation. These contained 20 EBPs, a majority of which were supported with moderate levels of evidence. Of these, six EBPs focused on intubation and escalation of care, such as ventilator management and synchrony; ten EBPs reduced complications associated with IMV, which included spontaneous awakening and breathing trials and early mobility protocols; and four EBPs promoted timely extubation and postextubation recovery.InterpretationThis review describes EBPs that are associated with fewer ventilator days and/or lower mortality rates among patients who received IMV for acute respiratory failure/ARDS. Many of these EBPs are connected across the care continuum, which indicates the need to promote and assess effective implementation jointly, rather than individually.
Project description:We performed single cell RNAseq of liver cells in acute liver failure model in mice with different microbiome states to unravel cellular changes in the disease and the impact of gut microbiota on the physiology in this disease.
Project description:Acute respiratory failure occurs in up to half of patients with haematological malignancies and 15% of those with solid tumours or solid organ transplantation. Mortality remains high. Factors associated with mortality include a need for invasive mechanical ventilation, organ dysfunction, older age, frailty or poor performance status, delayed intensive care unit admission, and acute respiratory failure due to an invasive fungal infection or unknown cause. In addition to appropriate antibacterial therapy, initial clinical management aims to restore oxygenation and predict the most probable cause based on variables related to the underlying disease, acute respiratory failure characteristics, and radiographic findings. The cause of acute respiratory failure must then be confirmed using the most efficient, least invasive, and safest diagnostic tests. In patients with acute respiratory failure of undetermined cause, a standardised diagnostic investigation should be done immediately at admission before deciding whether to perform more invasive diagnostic procedures or to start empirical treatments. Collaborative and multidisciplinary clinical and research networks are crucial to improve our understanding of disease pathogenesis and causation and to develop less invasive diagnostic strategies and more targeted treatment options.
Project description:Heart failure has reached epidemic proportions with the advances in cardiovascular therapies for ischemic heart diseases and the progressive aging of the world population. Efficient pharmacological therapies are available for treating heart failure, but unfortunately, even with optimized therapy, prognosis is often poor. Their last therapeutic option is, therefore, a heart transplantation with limited organ supply and complications related to immunosuppression. In this setting, cell therapies have emerged as an alternative. Many clinical trials have now been performed using different cell types and injection routes. In this perspective, we will analyze the results of such trials and discuss future perspectives for cell therapies as an efficacious treatment of heart failure.
Project description:BackgroundEmergency general surgery (EGS) operations are associated with substantial risk of morbidity including postoperative respiratory failure (PRF). While existing risk models are not widely utilized and rely on traditional statistical methods, application of machine learning (ML) in prediction of PRF following EGS remains unexplored.ObjectiveThe present study aimed to develop ML-based prediction models for respiratory failure following EGS and compare their performance to traditional regression models using a nationally-representative cohort.MethodsNon-elective hospitalizations for EGS (appendectomy, cholecystectomy, repair of perforated ulcer, large or small bowel resection, lysis of adhesions) were identified in the 2016-18 Nationwide Readmissions Database. Factors associated with PRF were identified using ML techniques and logistic regression. The performance of XGBoost and logistic regression was evaluated using the receiver operating characteristic curve and coefficient of determination (R2). The impact of PRF on mortality, length of stay (LOS) and hospitalization costs was secondarily assessed using generalized linear models.ResultsOf 1,003,703 hospitalizations, 8.8% developed PRF. The XGBoost model exhibited slightly superior discrimination compared to logistic regression (0.900, 95% CI 0.899-0.901 vs 0.894, 95% CI 0.862-0.896). Compared to logistic regression, XGBoost demonstrated excellent calibration across all risk levels (R2: 0.998 vs 0.962). Congestive heart failure, neurologic disorders, and coagulopathy were significantly associated with increased risk of PRF. After risk-adjustment, PRF was associated with 10-fold greater odds (95% confidence interval (CI) 9.8-11.1) of mortality and incremental increases in LOS by 3.1 days (95% CI 3.0-3.2) and $11,900 (95% CI 11,600-12,300) in costs.ConclusionsLogistic regression and XGBoost perform similarly in overall classification of PRF risk. However, due to superior calibration at extremes of risk, ML-based models may prove more useful in the clinical setting, where probabilities rather than classifications are desired.