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Pulmonary fibrosis (PF) is a chronic, progressive, fibrotic interstitial disease of the lung with poor prognosis and without effective treatment currently. Data from previous coronavirus infections, such as the Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome, as well as current clinical evidence from the Coronavirus disease 2019 (COVID-19), support that SARS-CoV-2 infection may lead to PF, seriously impacting patient prognosis and quality of life. Therefore, effective prevention and treatment of PF will improve patient prognosis and reduce the overall social and economic burdens. Stem cells, especially mesenchymal stem cells (MSCs) have many great advantages, including migration to damaged lung tissue and secretion of various paracrine factors, thereby regulating the permeability of endothelial and epithelial cells, reducing inflammatory response, promoting tissue repair and inhibiting bacterial growth. Clinical trials of MSCs for the treatment of acute lung injury, PF and severe and critically ill COVID-19 are ongoing. The purpose of this study is to systematically review preclinical studies, explored the effectiveness of MSCs in the treatment of bleomycin (BLM)-induced pulmonary fibrosis and analyze the potential mechanism, combined with clinical trials of current MSCs for idiopathic pulmonary fibrosis (IPF) and COVID-19, so as to provide support for clinical research and transformation of MSCs. Searching PubMed and Embase (− 2021.4) identified a total of 36 preclinical studies of MSCs as treatment of BLM-induced acute lung injury and PF in rodent models. Most of the studies showed the MSCs treatment to reduce BLM-induced lung tissue inflammatory response, inflammatory cell infiltration, inflammatory cytokine expression, extracellular matrix production and collagen deposition, and to improve Ashcroft score. The results of present studies indicate that MSCs may serve as a potential therapeutic modality for the treatment of PF, including viral-induced PF and IPF.

Similar to two other lethal coronaviruses, SARS‐CoV and MERS‐CoV, SARS‐CoV‐2 induces excessive and aberrant host immune responses that are always accompanied by cytokine storms (CS) and subsequent ALI or even ARDS, resulting in multiple organ failure and death. 2 Even in patients who were treated in intensive care units for CS, persistent inflammation led to serious sequelae of lung fibrosis, causing lung dysfunction and reduced quality of life. 3 Although corticosteroid given to reverse catabolism in critical illness decreased the mortality after SARS and MERS infection, the clinical application of corticosteroid has been restricted in COVID‐19, considering its delay in virus clearance and complications in survivors. To alleviate acute respiratory disease and reverse pulmonary fibrosis in intensive‐care SARS‐CoV‐2‐infected patients, three curative properties of MSCs have emerged (Figure 1): (a) directly inducing the apoptosis of activated T cells to relieve the aberrant and excessive immune responses, (b) homing toward specific injuries of lung to maintain homeostasis as well as promote regeneration, and (c) releasing cytokines to diminish inflammation and extracellular vesicles (EVs) to stimulate tissue reparation. 1 Notably, it has been proved that MSC‐released cytokines can potently inhibit neutrophil intravasation and enhance the differentiation of macrophages. 5,6 Moreover, these MSC‐released EVs can deliver microRNA, mRNA, DNA, proteins, and metabolites into host cells in specific injuries of the lung to promote lung repair as well as regeneration and restore lung function. 1 1 FIGURE. Potential mechanism of MSCs in the treatment of severe COVID‐19 As the continuing epidemic threat of SARS‐CoV‐2 to global health and the fast‐growing number of fatalities, advancing new therapeutic development becomes central or primary to minimize the death and sequelae from SARS‐CoV‐2 infection. [...]MSCs should be considered as a potential treatment for these critical patients.

Correspondence to Prof. Mindie H Nguyen, Stanford University Medical Center; Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, CA 94305, USA; mindiehn@stanford.edu ; Prof. Fanpu Ji, Department of Infectious Diseases, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China; jifanpu1979@163.com We read with interest the article by Dufour et al.1 The authors were to be commended for their comprehensive review on the presentations, pathophysiology and prognosis of COVID-19 in patients with chronic liver disease. Notably, the authors included data from multicentre and nationwide cohort studies to suggest decompensated cirrhosis as an independent risk factor for severe COVID-19 and death.1–6 However, while excess death from COVID-19 among patients with cirrhosis is important, the non-COVID-19-related excess death is integral in considering the degree of care disruption and delayed presentation, especially for those before 65 years of age. [...]using the CDC WONDER website of the US National Vital Statistic System, which includes over 99% of deaths annually, we evaluated the percentage of excess years of potential life loss (YPLL) among individuals with cirrhosis during the pandemic and how much of these excess YPLL were directly versus indirectly related to COVID-19. ALD, alcohol-associated liver disease; HBV, hepatitis B virus infection; HCV, hepatitis C virus infection; NAFLD, non-alcoholic fatty liver disease; YPLL, years of potential life lost. [...]returning to normal’ of healthcare access and reception should be the goal for all stakeholders.

Background: Despite its significant health burden, there is a lack of national-level temporal patterns in gastrointestinal bleeding (GIB) mortality. Objectives: To comprehensively decipher the annual and monthly trend of GIB-related mortality in the United States. Design: Cross-sectional study. Methods: We analyzed the National Vital Statistic System database, which documents more than 99% of the annual deaths in the United States for GIB-related deaths from January 2010 to May 2023. Annual and monthly age-standardized mortality rates were estimated and categorized by age, sex, and bleeding site. Joinpoint regression was performed for trend analysis. Prediction modeling was conducted to determine the GIB-associated excess mortality. Results: A total of 529,094 and 210,641 GIB-associated deaths occurred before and after 2020, respectively. Following a stably decreasing trend between 2010 and 2019, there was an excess mortality rate during the pandemic which peaked in 2021. The monthly mortality trend showed spikes corresponding to the outbreak of variants. Importantly, excess GIB-related mortality resolved in 2023, with the convergence of predicted and observed mortality rates. Subgroup analysis showed that young males (aged 19–44 years) were affected the most during the pandemic, with excess mortality rates of 35.80%, 52.77%, and 31.46% in 2020, 2021, and 2022, respectively. While the increasing trend of upper GIB was accentuated during the pandemic, lower GIB showed a reversal of the pre-pandemic decreasing trend. Conclusion: Our findings demonstrate the trend of GIB-related mortality, underscoring an increased excess death during the pandemic followed by a resolution in 2023. We identify subpopulations vulnerable to the pandemic. Plain language summary Increased gastrointestinal bleeding-related mortality during the COVID-19 pandemic Why was the study done? While the COVID-19 pandemic has incurred substantial gastrointestinal (GI)-related excess mortality, the detailed temporal trends throughout the pandemic’s duration remain unclear. What did the researchers do? Using a nationwide mortality database, we identified deaths related to GI bleeding that occurred between January 2010 and May 2023. What did the researchers find? A total of 529,094 and 210,641 GI bleeding-associated deaths occurred before and during the pandemic, respectively. The annual excess mortality rate peaked in 2021 and declined in 2022. The monthly mortality trend showed spikes corresponding to the outbreak of new variants. Importantly, excess GI bleeding-related mortality resolved in 2023, with the convergence of predicted and observed mortality rates. Subgroup analysis showed that young males (aged 19-44 years) were affected the most during the pandemic, with excess mortality rates of 35.80%, 52.77%, and 31.46% in 2020, 2021, and 2022, respectively. While the increasing trend of upper GI bleeding was accentuated during the pandemic, lower GI bleeding showed a reversal of the pre-pandemic decreasing trend. What do the findings mean? Our findings demonstrate the resolution of excess GI bleeding-related mortality in 2023 and identify subpopulations vulnerable to the pandemic. It has implications for policymakers in addressing the current pandemic and preparing for future pandemics.

Our aim was to evaluate the impact of race/ethnicity on cirrhosis-related premature death during the COVID-19 pandemic. We obtained cirrhosis-related death data (n = 872,965, January 1, 2012-December 31, 2021) from the US National Vital Statistic System to calculate age-standardized mortality rates and years of potential life lost (YPLL) for premature death aged 25-64 years. Significant racial/ethnic disparity in cirrhosis-related age-standardized mortality rates was noted prepandemic but widened during the pandemic, with the highest excess YPLL for the non-Hispanic American Indian/American Native (2020: 41.0%; 2021: 68.8%) followed by other minority groups (28.7%-45.1%), and the non-Hispanic White the lowest (2020: 20.7%; 2021: 31.6%). COVID-19 constituted >30% of the excess YPLLs for Hispanic and non-Hispanic American Indian/American Native in 2020, compared with 11.1% for non-Hispanic White. Ethnic minorities with cirrhosis experienced a disproportionate excess death and YPLLs in 2020-2021.

Background Since December 14, 2020, New York City (NYC) has started the first batch of COVID-19 vaccines. However, the shortage of vaccines is currently an inevitable problem. Therefore, optimizing the age-specific COVID-19 vaccination is an important issue that needs to be addressed as a priority. Objective Combined with the reported COVID-19 data in NYC, this study aimed to construct a mathematical model with five age groups to estimate the impact of age-specific vaccination on reducing the prevalence of COVID-19. Methods We proposed an age-structured mathematical model and estimated the unknown parameters based on the method of Markov Chain Monte Carlo (MCMC). We also calibrated our model by using three different types of reported COVID-19 data in NYC. Moreover, we evaluated the reduced cumulative number of deaths and new infections with different vaccine allocation strategies. Results Compared with the current vaccination strategy in NYC, if we gradually increased the vaccination coverage rate for only one age groups from March 1, 2021 such that the vaccination coverage rate would reach to 40% by June 1, 2021, then as of June 1, 2021, the cumulative deaths in the 75–100 age group would be reduced the most, about 72 fewer deaths per increased 100,000 vaccinated individuals, and the cumulative new infections in the 0–17 age group would be reduced the most, about 21,591 fewer new infections per increased 100,000 vaccinated individuals. If we gradually increased the vaccination coverage rate for two age groups from March 1, 2021 such that the vaccination coverage rate would reach to 40% by June 1, 2021, then as of June 1, 2021, the cumulative deaths in the 65–100 age group would be reduced the most, about 36 fewer deaths per increased 100,000 vaccinated individuals, and the cumulative new infections in the 0–44 age group would be reduced the most, about 17,515 fewer new infections per increased 100,000 vaccinated individuals. In addition, if we had an additional 100,000 doses of vaccine for 0–17 and 75–100 age groups as of June 1, 2021, then the allocation of 80% to the 0–17 age group and 20% to the 75–100 age group would reduce the maximum numbers of new infections and deaths simultaneously in NYC. Conclusions The COVID-19 burden including deaths and new infections would decrease with increasing vaccination coverage rate. Priority vaccination to the elderly and adolescents would minimize both deaths and new infections.

Background/Aims: Nonalcoholic fatty liver disease (NAFLD) is associated with a multitude of adverse outcomes. We aimed to estimate the pooled incidence of NAFLD-related adverse events. Methods: We performed a systematic review and meta-analysis of cohort studies of adults with NAFLD to evaluate the pooled incidence of adverse events. Results: 19,406 articles were screened, 409 full-text articles reviewed, and 79 eligible studies (1,377,466 persons) were included. Mean age was 51.47 years and body mass index 28.90 kg/m2. Baseline comorbidities included metabolic syndrome (41.73%), cardiovascular disease (CVD) (16.83%), cirrhosis (21.97%), and nonalcoholic steatohepatitis (NASH) (58.85%). Incidence rate per 1,000 person-years for mortality included: all-cause (14.6), CVD-related (4.53), non-liver cancer-related (4.53), and liver-related (3.10). Incidence for liver-related events included overall (24.3), fibrosis progression (49.0), cirrhosis (10.9), liver transplant (12.0), and hepatocellular carcinoma (HCC) (3.39). Incidence for non-liver events included metabolic syndrome (25.4), hypertension (25.8), dyslipidemia (26.4), diabetes (19.0), CVD (24.77), renal impairment (30.3), depression/anxiety (29.1), and non-liver cancer (10.5). Biopsy-proven NASH had higher incidence of HCC (P=0.043) compared to non-NASH. Higher rates of CVD and mortality were observed in North America and Europe, hypertension and non-liver cancer in North America, and HCC in Western Pacific/Southeast Asia (P<0.05). No significant differences were observed by sex. Time-period analyses showed decreasing rates of cardiovascular and non-liver cancer mortality and increasing rates of decompensated cirrhosis (P<0.05). Conclusions: People with NAFLD have high incidence of liver and non-liver adverse clinical events, varying by NASH, geographic region, and time-period, but not sex. KCI Citation Count: 33

Background: Acute variceal bleeding (AVB), a life-threatening complication of liver cirrhosis, can be effectively treated by endoscopy, but there is a risk of early rebleeding after endoscopic variceal treatment (EVT). Thrombocytopenia is the most common hemostatic abnormality in liver cirrhosis. However, it is still unclear about whether thrombocytopenia increases the failure of EVT in cirrhotic patients with AVB. Objectives: We investigated the association between thrombocytopenia and the failure of EVT in cirrhotic patients with AVB. Design: International multicenter, retrospective study. Methods: Overall, 2467 cirrhotic patients with acute gastrointestinal bleeding who were enrolled into an international multicenter study between September 30, 2020 and June 30, 2023 were retrospectively screened. Thrombocytopenia was defined as platelet count below 150 × 109/L and further classified as mild (100 × 109/L–150 × 109/L), moderate (50 × 109/L–100 × 109/L), and severe (<50 × 109/L). A 1:1 propensity score matching (PSM) analysis was performed. Five-day failure to control bleeding was evaluated. Results: Overall, 1079 patients were included, of whom 923 (85.5%) had thrombocytopenia, including mild (n = 241), moderate (n = 445), and severe (n = 237) thrombocytopenia. PSM analysis demonstrated that the rate of 5-day failure to control bleeding was not significantly different between patients with and without thrombocytopenia (mild: (12/153) 7.8% vs (7/153) 4.6%, p = 0.236; moderate: (9/155) 5.8% vs (7/155) 4.5%, p = 0.608; or severe: (5/132) 3.8% vs (7/132) 5.3%, p = 0.555). Conclusion: Thrombocytopenia may not influence the efficacy of EVT in cirrhotic patients with AVB. Graphical abstract Plain language summary Effect of decreased platelet count on the failure to control bleeding after endoscopic therapy in cirrhotic patients presenting with hematemesis or melena Why was the study done? Patients with cirrhosis who have hematemesis or melena are usually treated by endoscopy. However, in some patients, endoscopic therapy cannot completely control bleeding. Notably, cirrhotic patients may experience varying degrees of decreased platelet count, which may be associated with increased risk of bleeding. Until now, it is still unclear about whether decreased platelet count is associated with the failure to control bleeding after endoscopic therapy. What did the researchers do? Cirrhotic patients with acute gastrointestinal bleeding from an international multicenter database were screened. We adjusted confounding factors that may potentially influence the efficacy of endoscopic therapy to further clarify the effect of decreased platelet count on the failure of endoscopic therapy. What did the researchers find? Overall, 1079 patients were included, of whom 923 had decreased platelet count. Among them, platelet count was mildly, moderately, and severely decreased in 241, 445, and 237 patients, respectively. After eliminating the confounding factors, the incidence of failure of endoscopic therapy was not significantly different between patients with and without decreased platelet count. What do the findings mean? Decreased platelet count may not influence the efficacy of endoscopic therapy in cirrhotic patients presenting with hematemesis or melena.

Background/Aims: Prediction of short-term mortality in patients with acute-on-chronic liver failure (ACLF) admitted to the intensive care unit (ICU) may enhance effective management.Methods: To develop, explain, and validate a predictive machine learning (ML) model for short-term mortality in patients with ACLF with two or more organ failures (OFs). Utilizing a large ICU cohort with detailed clinical information, we identified ACLF patients with two or more OFs according to the EASL-CLIF and NACSELD definitions. ML model was developed for each definition to predict 30-day mortality. The Shapley value was estimated to explain the models. Validation and calibration of these models were performed.Results: Of 5,994 patients with cirrhosis admitted to ICU, 1,511 met NACSELD criteria, and 1,692 met EASL-CLIF grade II or higher criteria. The CatBoost ACLF (CBA) model had the greatest accuracy in the NACSELD cohort (area under curve [AUC] of 0.87), while the Random Forest ACLF (RFA) model performed best in the EASL-CLIF cohort (AUC of 0.83). Both models showed robust calibration. The models were explained by SHAP score analysis, yielding a rank list, and the top twelve predictors were selected. Both simplified models demonstrated similar performance (CBA model: AUC 0.89, RFA model: AUC 0.81) and significantly outperformed contemporary scoring systems, including CLIF-C ACLF and MELD 3.0. The models were validated in both internal and external cohorts. A simple-to-use online tool was created to predict mortality rates.Conclusions: We presented explainable, well-validated, and calibrated predictive models for ACLF patients with two or more OFs, which outperformed existing predictive scores.