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Background: Coronavirus disease 2019 (COVID-19) pandemic continues to escalate intensively worldwide. Massive studies on general populations with SARS-CoV-2 infection have revealed that pre-existing comorbidities were a major risk factor for the poor prognosis of COVID-19. Notably, 49–75% of COVID-19 patients had no comorbidities, but this cohort would also progress to severe COVID-19 or even death. However, risk factors contributing to disease progression and death in patients without chronic comorbidities are largely unknown; thus, specific clinical interventions for those patients are challenging. Methods: A multicenter, retrospective study based on 4806 COVID-19 patients without chronic comorbidities was performed to identify potential risk factors contributing to COVID-19 progression and death using LASSO and a stepwise logistic regression model. Results: Among 4806 patients without pre-existing comorbidities, the proportions with severe progression and mortality were 34.29% and 2.10%, respectively. The median age was 47.00 years [interquartile range, 36.00–56.00], and 2162 (44.99%) were men. Among 51 clinical parameters on admission, age ≥ 47, oxygen saturation < 95%, increased lactate dehydrogenase, neutrophil count, direct bilirubin, creatine phosphokinase, blood urea nitrogen levels, dyspnea, increased blood glucose and prothrombin time levels were associated with COVID-19 mortality in the entire cohort. Of the 3647 patients diagnosed with non-severe COVID-19 on admission, 489(13.41%) progressed to severe disease. The risk factors associated with COVID-19 progression from non-severe to severe illness were increased procalcitonin levels, SpO2 < 95%, age ≥ 47, increased LDH, activated partial thromboplastin time levels, decreased high-density lipoprotein cholesterol levels, dyspnea and increased D-dimer levels. Conclusions: COVID-19 patients without pre-existing chronic comorbidities have specific traits and disease patterns. COVID-19 accompanied by severe bacterial infections, as indicated by increased procalcitonin levels, was highly associated with disease progression from non-severe to severe. Aging, impaired respiratory function, coagulation dysfunction, tissue injury, and lipid metabolism dysregulation were also associated with disease progression. Once factors for multi-organ damage were elevated and glucose increased at admission, these findings indicated a higher risk for mortality. This study provides information that helps to predict COVID-19 prognosis specifically in patients without chronic comorbidities.

COVID-19, caused by SARS-CoV-2, is a highly infectious disease, and clinical laboratory detection has played important roles in its diagnosis and in evaluating progression of the disease. Nucleic acid amplification testing or gene sequencing can serve as pathogenic evidence of COVID-19 diagnosing for clinically suspected cases, and dynamic monitoring of specific antibodies (IgM, IgA, and IgG) is an effective complement for false-negative detection of SARS-CoV-2 nucleic acid. Antigen tests to identify SARS-CoV-2 are recommended in the first week of infection, which is associated with high viral loads. Additionally, many clinical laboratory indicators are abnormal as the disease evolves. For example, from moderate to severe and critical cases, leukocytes, neutrophils, and the neutrophil-lymphocyte ratio increase; conversely, lymphocytes decrease progressively but are over activated. LDH, AST, ALT, CK, high-sensitivity troponin I, and urea also increase progressively, and increased D-dimer is an indicator of severe disease and an independent risk factor for death. Severe infection leads to aggravation of inflammation. Inflammatory biomarkers and cytokines, such as CRP, SAA, ferritin, IL-6, and TNF-α, increase gradually. High-risk COVID-19 patients with severe disease, such as the elderly and those with underlying diseases (cardiovascular disease, diabetes, chronic respiratory disease, hypertension, obesity, and cancer), should be monitored dynamically, which will be helpful as an early warning of serious diseases.

COVID-19 patients have presented with a wide range of neurological disorders, among which stroke is the most devastating. We have reviewed current studies, case series, and case reports with a focus on COVID-19 patients complicated with stroke, and presented the current understanding of stroke in this patient population. As evidenced by increased D-dimer, fibrinogen, factor VIII and von Willebrand factor, SARS-CoV-2 infection induces coagulopathy, disrupts endothelial function, and promotes hypercoagulative state. Collectively, it predisposes patients to cerebrovascular events. Additionally, due to the unprecedented strain on the healthcare system, stroke care has been inevitably compromised. The underlying mechanism between COVID-19 and stroke warrants further study, so does the development of an effective therapeutic or preventive intervention.

Background and Aims The evolution and clinical significance of abnormal liver chemistries and the impact of hepatitis B infection on outcome in patients with COVID-19 is not well characterized. This study aimed to explore these issues. Methods This large retrospective cohort study included 2073 patients with COVID-19 having definite outcomes in Wuhan, China. Longitudinal liver function tests were conducted and determined their associated factors and death risk by multivariate regression analyses. A prognostic nomogram was formulated to predict the survival of patients with COVID-19. The characteristics of liver abnormalities and outcomes of patients with COVID-19 with and without hepatitis B were compared after 1:3 propensity score matching. Results Of the 2073 patients, 1282 (61.8%) had abnormal liver chemistries during hospitalization, and 297 (14.3%) had a liver injury. The mean levels of AST and D-Bil increased early after symptom onset in deceased patients and showed disparity compared with that in discharged patients throughout the clinical course of the disease. Abnormal admission AST (adjusted hazard ratio [HR]: 1.39, 95%CI: 1.04-1.86, P=0.027) and D-Bil (adjusted HR: 1.66, 95%CI: 1.22-2.26, P=0.001) levels were independent risk factors for mortality due to COVID-19. A nomogram was established based on the results of multivariate analysis and showed sufficient discriminatory power and good consistency between the prediction and the observation. HBV infection in patients did not increase the risk of COVID-19-associated poor outcomes. Conclusions Abnormal AST and D-Bil levels at admission were independent predictors of COVID-19 mortality. Therefore, monitoring liver chemistries, especially AST and D-Bil levels, in hospitalized patients with COVID-19, is necessary., Graphical abstract, Highlights 1. Levels of AST and D-Bil elevated early after the symptom onset in deceased patients and showed disparity compared with that in discharged patients throughout the clinical course of COVID-19. 2. Abnormal admission AST and D-Bil levels at admission were independent predictors of COVID-19 mortality. 3. A novel nomogram was built based on admission AST and D-Bil levels as well as other baseline characteristics to predict the in-hospital mortality of COVID-19. 4. Hepatitis B infection was not found to be associated with the risk of lethal outcome in patients with COVID-19., Lay Summary The AST and D-Bil levels increased early after symptom initiation in deceased patients of COVID-19 and showed disparity compared with that in discharged patients throughout the clinical course of the disease. Abnormal AST and D-Bil levels at admission were independent predictors for COVID-19 mortality. HBV infection in patients did not increase the risk of COVID-19-associated poor outcomes.

OBJECTIVES: Coronavirus disease 2019 (COVID-19) is a novel infectious disease, with significant morbidity and mortality. This meta-analysis is to evaluate the prevalence of disseminated intravascular coagulation (DIC) in COVID-19 patients and to determine the association of DIC with the severity and prognosis of COVID-19. METHODS: We searched the PubMed, EMBASE, and China National Knowledge Infrastructure (CNKI) database until August 12, 2020. The meta-analysis was performed using Stata 16.0 software. RESULTS: 14 studies were included in our meta-analysis. The pooled analysis revealed that the incidence of COVID-19 patients developing DIC was 3% (95%: 1%-5%, P

Highlights • Non-severe COVID-19 patients have abnormal laboratory investigations. • Patients with prolonged pretreatment APTT have a longer isolation length. • Patients with elevated eosinophils after treatment have a shorter isolation length. • A nomogram could help to predict isolation probability at 11-, 16- and 21-day., Background Majority coronavirus disease 2019 (COVID-19) patients are classified as mild and moderate (non-severe) diseases. We aim to develop a model to predict isolation length for non-severe patients. Methods Among 188 non-severe patients, 96 patients were enrolled as training cohort to identify factors associated with isolation length via Cox regression model and develop a nomogram. Other 92 patients formed as validation cohort to validate nomogram. Concordance index (C-index), area under the curve (AUC) and calibration curves were used to evaluated nomogram. Results Increasing absolute eosinophil count (AEC) after admission was correlated with shorter isolation length (P = 0.02). Baseline activated partial thromboplastin time (APTT) > 30 s was correlated with longer isolation length (P = 0.03). A nomogram to predict isolation probability at 11-, 16- and 21-day was developed and validated. The C-indices of training and validation cohort were 0.604 and 0.682 respectively. Both cohorts showed a good discriminative ability (AUC, 11-day: 0.646 vs 0.730; 16-day: 0.663 vs 0.750; 21-day: 0.711 vs 0.783; respectively) and calibration power. Conclusions Baseline APTT and dynamic change of AEC were two significant factors associated with isolation length of non-severe patients. Nomogram could predict isolation probability for each patient to estimate appropriate quarantine length.

Graphical abstract, Metabolic profiling in COVID-19 patients has been associated with disease severity, but there is no report on sex-specific metabolic changes in discharged survivors. Herein we used an integrated approach of LC-MS-and GC-MS-based untargeted metabolomics to analyze plasma metabolic characteristics in men and women with non-severe COVID-19 at both acute period and 30 days after discharge. The results demonstrate that metabolic alterations in plasma of COVID-19 patients during the recovery and rehabilitation process were presented in a sex specific manner. Overall, the levels of most metabolites were increased in COVID-19 patients after the cure relative to acute period. The major plasma metabolic changes were identified including fatty acids in men and glycerophosphocholines and carbohydrates in women. In addition, we found that women had shorter length of hospitalization than men and metabolic characteristics may contribute to predict the duration from positive to negative in non-severe COVID-19 patients. Collectively, this study shed light on sex-specific metabolic shifts in non-severe COVID-19 patients during the recovery process, suggesting a sex bias in prognostic and therapeutic evaluations based on metabolic profiling.

When Belgium's COVID-19 outbreak began in March of 2020, our neurosurgical department followed the protocol of most surgical departments in the world and postponed elective surgery. However, patients with tumor-like brain lesions requiring urgent surgery still received treatment as usual, in order to ensure ongoing neuro-oncological care. From a series of 31 patients admitted for brain surgery, three were confirmed as infected by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)., info:eu-repo/semantics/published

Highlights • Clinical signs are not useful for detecting DVT in critically ill COVID-19 patients • DVT occurs despite full dose anticoagulation in critically ill COVID-19 patients • Severe COVID-19 patients present a high prevalence of bilateral DVT

A 54-year-old woman with a mechanical mitral valve replacement presented with recurrent admissions for pneumonia and pulmonary edema. Multimodality imaging revealed mobile masses on the prosthesis and discrepant point of care and inpatient international normalized ratio levels owing to antiphospholipid antibody cross-reactivity on the outpatient assay. The prosthetic valve thromboses resolved with therapeutic anticoagulation. (Level of Difficulty: Beginner.), Graphical abstract, A 54-year-old woman with a mechanical MVR presented with recurrent admissions for pneumonia and pulmonary edema. Multimodality imaging revealed…

Liver fibrosis induces intrahepatic microcirculation disorder and hypoxic stress. Hypoxic stress has the potential for an increase in the possibility of more liver fibrosis and carcinogenesis. Liver biopsy is a standard method that evaluates of intrahepatic hypoxia, however, is invasive and has a risk of bleeding as a complication. Here, we investigated the hypoxia reactive gene expressions in peripheral blood mononuclear cells (PBMC) from chronic liver disease patients to evaluate intrahepatic hypoxia in a non-invasive manner. The subjects enrolled for this study were composed of 20 healthy volunteers (HV) and 48 patients with chronic liver disease (CLD). CLD patients contained 24 patients with chronic hepatitis（CH）and 24 patients with liver cirrhosis (LC). PBMC were isolated from heparinized peripheral blood samples. We measured the transcriptional expression of hypoxia reactive genes and inflammatory cytokines by quantitative RT-PCR. mRNA expression of adrenomedullin (AM), vascular endothelial growth factor A (VEGFA) superoxide dismutase (SOD), glutathione peroxidase (GPx) (p, Highlights • The hypoxia reactive genes in PBMC were elevated in patients with chronic liver disease. •Angiogenic genes were upregulated and correlated with liver fibrosis in patients with chronic liver disease. •Adrenomedullin mRNA expression in PBMC was correlated with liver function. •mRNA expression of adrenomedullin in PBMC could be the biomarker of intrahepatic hypoxia.

The recognition of the rare but serious and potentially lethal complication of vaccine induced thrombotic thrombocytopenia (VITT) raised concerns regarding the safety of COVID-19 vaccines and led to the reconsideration of vaccination strategies in many countries. Following the description of VITT among recipients of adenoviral vector ChAdOx1 vaccine, a review of similar cases after Ad26.COV2·S vaccination gave rise to the question whether this entity may constitute a potential class effect of all adenoviral vector vaccines. Most cases are females, typically younger than 60 years who present shortly (range: 5-30 days) following vaccination with thrombocytopenia and thrombotic manifestations, occasionally in multiple sites. Following initial incertitude, concrete recommendations to guide the diagnosis (clinical suspicion, initial laboratory screening, PF4-polyanion-antibody ELISA) and management of VITT (non-heparin anticoagulants, corticosteroids, intravenous immunoglobulin) have been issued. The mechanisms behind this rare syndrome are currently a subject of active research and include the following: 1) production of PF4-polyanion autoantibodies; 2) adenoviral vector entry in megacaryocytes and subsequent expression of spike protein on platelet surface; 3) direct platelet and endothelial cell binding and activation by the adenoviral vector; 4) activation of endothelial and inflammatory cells by the PF4-polyanion autoantibodies; 5) the presence of an inflammatory co-signal; and 6) the abundance of circulating soluble spike protein variants following vaccination. Apart from the analysis of potential underlying mechanisms, this review aims to synopsize the clinical and epidemiologic features of VITT, to present the current evidence-based recommendations on diagnostic and therapeutic work-up of VITT and to discuss new dilemmas and perspectives that emerged after the description of this entity.

Background COVID-19 is diagnosed using RT-PCR assays of samples from nasal and oropharyngeal swabs. People with negative RT-PCR often presented with clinical manifestations of COVID-19. The data on such patients are lacking. The present study aims to characterize the patients who were suspected COVID-19 cases and tested negative in RT-PCR compared to patients who had been tested RT-PCR positive. Methods This is a retrospective, observational study of adult suspected and confirmed patients of COVID-19 admitted to King Saud University Medical City, Riyadh, Saudi Arabia, from 1st March 2020 until 30th November 2020. Laboratory confirmation is done through nasal/pharyngeal swab specimens, tested positive in RT-PCR assay. Patients with initial negative RT-PCR test results were assessed again within 48−72 h to avoid false-negative results. Patient data were extracted from the electronic medical files of each included patient using a predesigned case report form. Results The study included 488 (80.93%) patients with RT-PCR swab results positive, and 115 (19.07%) patients who were negative. Respiratory rate and diastolic blood pressure were higher among the swab-positive cases. More number of swab-negative patients had comorbidities such as coronary heart disease, chronic kidney disease, and carcinoma. Fever, cough, and shortness of breath were reported higher among the swab-positive cases. ALT and AST, and LDH levels were found higher among RT-PCR-positive patients. Serum creatinine, blood urea nitrogen and troponin were more elevated in RT-PCR-negative patients. Antibiotics, anticoagulants, and corticosteroids were used more by swab-positive patients. Significantly higher number of RT-PCR-positive patients required proning, high-flow nasal cannula, non-invasive mechanical ventilation, and invasive mechanical ventilation. Acute cardiac ischemia and death were found to be similar among the patients. However, deaths occurred significantly earlier among the swab-positive cases when compared to the swab-negative group. Conclusion Distinctive symptoms and markers of COVID-19 are more frequent among patients who had RT-PCR-positive results.

Background The combination of visceral leishmaniasis (VL) and macrophage activation syndrome (MAS) makes the diagnosis difficult due to their similar clinical presentation, with a poor prognosis especially since the treatment is still poorly codified. We report the case of a 17-month-old female patient from Berkane, presenting for a 3 months history of anarchic fever with anemic syndrome made up of pallor and hemorrhagic syndrome made up of epistaxis. Physical examination revealed a temperature of 39 ° C, lower limbsedema, paleness of skin and mucous membranes, gingival petechiae, bleached hair, and hepatosplenomegaly. Case presentation The complete blood count showed pancytopenia with deep aregenerative normochromic normocytic anemia at 3 g/dL, leukocytes were at 4860/mm 3 with neutropenia at 680/mm 3 and thrombocytopenia at 12.000/mm3, the blood smear was without abnormality. These anomalies were associated with a hypoalbunemia, hypertriglyceridemia, hyperferritinemia, lactate dehydrogenase (LDH) level was at 337 IU/L, low prothrombin time (PT) at 56 % and fibrinogen level at 1 g/L. The direct Coombs test was positive. Examination of the myelogram revealed the presence of leishmania bodies and figures of hemophagocytosis. A diagnosis of visceral leishmaniasis associated with MAS was made. The patient was put on liposomal amphotericin B and corticosteroid therapy with good clinical and biological evolution and good therapeutic tolerance. Conclusion The association of VL and MAS remains rare and should be evoked even in non-endemic areas since late diagnosis worsens the prognosis and may even be responsible for the death of patients despite an aggressive treatment.

BACKGROUND Dyslipidemia induces platelet hyperactivation and hyper-aggregation, which are linked to thrombosis. Anthocyanins could inhibit platelet function in vitro and in mice fed high-fat diets with their effects on platelet function in subjects with dyslipidemia remained unknown. This study aimed to investigate the effects of different doses of anthocyanins on platelet function in individuals with dyslipidemia. METHODS A double-blind, randomized, controlled trial was conducted. Ninety-three individuals who were initially diagnosed with dyslipidemia were randomly assigned to placebo or 40, 80, 160 or 320 mg/day anthocyanin groups. The supplementations were anthocyanin capsules (Medox, Norway). Platelet aggregation by light aggregometry of platelet-rich plasma, P-selectin, activated GPⅡbⅢa, reactive oxygen species (ROS), and mitochondrial membrane potential were tested at baseline, 6 weeks and 12 weeks. FINDINGS Compared to placebo group, anthocyanins at 80 mg/day for 12 weeks reduced collagen-induced platelet aggregation (-3.39±2.36%) and activated GPⅡbⅢa (-8.25±2.45%) (P

Graphical abstract, Highlights • Ursolic acid was administered at a dose of 100, 300 or 1000 mg/kg/day. • No Ursolic acid related effects were found after administrating orally for 90 days. • The no observed adverse effect level is likely to be higher than 1000 mg/kg/day., Background Ursolic acid (UA) has been used in alternative medicine for decades, and there has been a great interest in its medicinal properties. Despite this increased interest, a detailed long-term toxicity study has not been performed. The objective of this study was to determine the long-term toxic effect of UA on clinical chemistry, haematology, coagulation, pathology/morphology, behaviour and motor skills in rats. Methods A solution was made by dissolving UA in a mixture of 0.1% Tween 80 and 0.5% hydroxypropyl methylcellulose in Milli-Q Water. The control group received the vehicle, and the test groups received a dose up to 1000 mg/kg/day via oral gavage. The solution was administered to both male and female (Han-Wistar) rats for 90 consecutive days. Results UA did not cause any deaths, abnormal body weights or abnormal pathology at all test doses. In addition to that, no toxicological changes were observed in behaviour, neurotoxicity, coagulation, haematology or clinical chemistry that are related to the administration of UA. Conclusion This study indicates that oral dosing of UA for 90 consecutive days does not lead to toxic effects at any of the doses. Therefore, the NOAEL for UA is likely to be higher than 1000 mg/kg/day.

Cardiovascular diseases prevail among modern societies and underdeveloped countries, and a high mortality rate has also been reported by the World Health Organization affecting millions of people worldwide. Hyperactive platelets are the major culprits in thrombotic disorders. A group of drugs is available to deal with such platelet-related disorders; however, sometimes, side effects and complications caused by these drugs outweigh their benefits. Ginseng and its nutraceuticals have been reported to reduce the impact of thrombotic conditions and improve cardiovascular health by antiplatelet mechanisms. This review provides (1) a comprehensive insight into the available pharmacological options from ginseng and ginsenosides (saponin and nonsaponin fractions) for platelet-originated cardiovascular disorders; (2) a discussion on the impact of specific functional groups on the modulation of platelet functions and how structural modifications among ginsenosides affect platelet activation, which may further provide a basis for drug design, optimization, and the development of ginsenoside scaffolds as pharmacological antiplatelet agents; (3) an insight into the synergistic effects of ginsenosides on platelet functions; and (4) a perspective on future research and the development of ginseng and ginsenosides as super nutraceuticals. Keywords: Antiplatelet, Ginsenosides, Nutraceutical, Structural modification, Synergism

This work was supported by the the University of Tours (to IDP and FDG), the University of Montpellier (to SD and EC), the Deutsche Forschungsgemeinschaft (to RTS), the Wellcome Trust project grant 093228 (to TKS) and the Campus France/DAAD PHC PROCOPE 24931RE (to RTS and EC). The funding source has no involvement in the conduct of the research and preparation of the article. Glycosylphosphatidylinositols (GPIs) are glycolipids described as toxins of protozoan parasites due to their inflammatory properties in mammalian hosts characterized by the production of interleukin (IL)-1, IL-12 and tumor necrosis factor (TNF)-α. In the present work, we studied the cytokines produced by antigen presenting cells in response to ten different GPI species extracted from Babesia divergens, responsible for babesiosis. Interestingly, B. divergens GPIs induced the production of anti-inflammatory cytokines (IL-2, IL-5) and of the regulatory cytokine IL-10 by macrophages and dendritic cells. In contrast to all protozoan GPIs studied until now, GPIs from B. divergens did not stimulate the production of TNF-α and IL-12, leading to a unique Th1/Th2 profile. Analysis of the carbohydrate composition of the B. divergens GPIs indicated that the di-mannose structure was different from the evolutionary conserved tri-mannose structure, which might explain the particular cytokine profile they induce. Expression of major histocompatibility complex (MHC) molecules on dendritic cells and apoptosis of mouse peritoneal cells were also analysed. B. divergens GPIs did not change expression of MHC class I, but decreased expression of MHC class II at the cell surface, while GPIs slightly increased the percentages of apoptotic cells. During pathogenesis of babesiosis, the inflammation-coagulation auto-amplification loop can lead to thrombosis and the effect of GPIs on coagulation parameters was investigated. Incubation of B. divergens GPIs with rat plasma ex vivo led to increase of fibrinogen levels and to prolonged activated partial thromboplastin time, suggesting a direct modulation of the extrinsic coagulation pathway by GPIs. Publisher PDF

Introduction Amyotrophic lateral sclerosis (ALS) is an intractable and incurable neurological disease. It is a progressive disease characterized by muscle atrophy and weakness caused by selective vulnerability of upper and lower motor neurons. In disease research, it has been common to use mouse models carrying mutations in responsible genes for familial ALS as pathological models of ALS. However, there is no model that has reproduced the actual conditions of human spinal cord pathology. Thus, we developed a method of producing human spinal motor neurons using human induced pluripotent stem cells (iPSCs) and an innovative experimental technique for drug screening. As a result, ropinirole hydrochloride was eventually discovered after considering such results as its preferable transitivity in the brain and tolerability, including possible adverse reactions. Therefore, we explore the safety, tolerability and efficacy of ropinirole hydrochloride as an ALS treatment in this clinical trial. Methods The ROPALS trial is a single-center double-blind randomized parallel group-controlled trial of the safety, tolerability, and efficacy of the ropinirole hydrochloride extended-release tablet (Requip CR) at 2- to 16-mg doses in patients with ALS. Twenty patients will be recruited for the active drug group (fifteen patients) and placebo group (five patients). All patients will be able to receive the standard ALS treatment of riluzole if not changed the dosage during this trial. The primary outcome will be safety and tolerability at 24 weeks, defined from the date of randomization. Secondary outcome will be the efficacy, including any change in the ALS Functional Rating Scale-Revised (ALSFRS-R), change in the Combined Assessment of Function and Survival (CAFS), and the composite endpoint as a sum of Z-transformed scores on various clinical items. Notably, we will perform an explorative search for a drug effect evaluation using the patient-derived iPSCs to prove this trial concept. Eligible patients will have El Escorial Possible, clinically possible and laboratory-supported, clinically probable, or clinically definite amyotrophic lateral sclerosis with disease duration less than 60 months (inclusive), an ALSFRS-R score ≥2 points on all items and age from 20 to 80 years. Conclusion Patient recruitment began in December 2018 and the last patient is expected to complete the trial protocol in November 2020. Trial registration Current controlled trials UMIN000034954 and JMA-IIA00397 Protocol version version 1.6 (Date; 5/Apr/2019)., Highlights • ALS is a progressive neurodegenerative disease caused by selective vulnerability of upper and lower motor neurons. • ALS patients have no radical treatment. • The ROPALS trial reveals the safety, tolerability, and efficacy of the ropinirole hydrochloride in patients with ALS. • This trial is the pioneering clinical trial for ALS based on iPSCs-drug discovery in Japan.

Introduction One of the relatively rare hemostatic disorders is coagulation factors' deficiency, where a single factor or multiple factors can be deficient. All hereditary coagulation factors' deficiencies are autosomal recessive, so they can manifest in both genders, but Hemophilia A and B are X-linked disorders. Therefore, females can rarely be affected. This paper reports the first case of simultaneous coagulation factors’ deficiencies of FVIII and FXI in a female. Case presentation A 17-year-old female came to the office due to prolonged epistaxis, with a history of severe menstrual bleeding and frequent episodes of epistaxis. In her familial history, a brother complained of epistaxis episodes. Bleeding time and prothrombin time were normal but activated partial thromboplastin time was increased. Von Willebrand disease was excluded, and she was diagnosed with hemophilia A and C. Discussion Females can be affected with X-linked disorders such as hemophilia A and B in some rare cases: a carrier mother and affected father, skewed X chromosome inactivation, Turner syndrome, inhibiting antibodies (acquired hemophilia), or a sporadic mutation on the most activated X chromosome. On the other hand, Hemophilia C is an autosomal recessive disease. Treatment of such cases is a challenge, and the recombinant coagulation factors are the treat-of-choice. Conclusion Although Von Willebrand disease is the most common hereditary bleeding disorder in females, other rare diseases could be suspected such as Hemophilia. X-linked Hemophilia should be kept in mind as a differential diagnosis in any female patient suffering from hemorrhage., Highlights • This study is the first case of both Hemophilia A and C in a female. • Females can be affected with X-linked disorders such as hemophilia A in rare cases. • Treatment of combined Coagulation factors' deficiencies is a challenge.

Visual Abstract, Highlights • An appropriate dose of RIV to inhibit the activity of factor Xa significantly suppressed the atherosclerotic area in the aorta of HFD-fed ApoE–/– mice. • Macrophage autophagy induced by 7KC administration was suppressed by the presence of factor Xa, resulting in the acceleration of inflammasome formation through the PAR2-mediated pathway. • The administration of CQ, an autophagy inhibitor, to HFD-fed ApoE–/–/PAR2 knockout bigenic mice significantly aggravated atherosclerosis in the aorta compared with untreated mice., Summary The authors showed a mechanism for attenuating atherosclerosis by directly administering an oral factor Xa inhibitor (ie, rivaroxaban [RIV]). The autophagy activity of macrophages was significantly suppressed by factor Xa and was alleviated by the administration of RIV. However, factor Xa failed to inhibit 7-ketocholesterol–induced autophagy and inflammasome activation in protease-activated receptor 2 (PAR2) knockout macrophages. The atherosclerotic area of apolipoprotein E knockout mice was significantly reduced by the genetic ablation of PAR2, which was partially reversed by chloroquine. Thus, the authors found that RIV attenuates atherogenesis by inhibiting the factor Xa–PAR2-mediated suppression of macrophage autophagy and abrogating inflammasome activity.

Multisystem inflammatory syndrome of children (MIS-C) continues to be a highly concerning diagnosis in those recently infected with SARS-CoV-2. The diagnosis of MIS-C cases will likely become even more challenging as vaccine uptake and natural immunity in previously infected persons leads to lower circulating rates of SARS-CoV-2 infection and will make cases sporadic. Febrile children presenting with cardiac dysfunction, symptoms overlapping Kawasaki disease or significant gastrointestinal complaints warrant a thorough screen in emergency departments, urgent care centers, and outpatient pediatric or family medicine practices. An increased index of suspicion and discussion regarding higher level of care (transferring to pediatric tertiary care centers or to intensive care) continues to be recommended. Herein we outline a broad approach with a multidisciplinary team for those meeting the case definition and believe such an approach is crucial for successful outcomes.

The aim of this study was to evaluate hyperferritinemia could be a predicting factor of mortality in hospitalized patients with coronavirus disease-2019 (COVID-19).A total of 100 hospitalized patients with COVID-19 in intensive care unit (ICU) were enrolled and classified into moderate (The amount of ferritin was significantly higher in critical group compared with moderate and severe groups. The median of ferritin concentration was about three times higher in death group than survival group (1722.25 μg/L vs. 501.90 μg/L,The ferritin measured at admission may serve as an independent factor for predicting in-hospital mortality in patients with COVID-19 in ICU.El objetivo de este estudio fue evaluar si la hiperferritinemia podría ser un factor predictivo de la mortalidad en pacientes hospitalizados con enfermedad por coronavirus de 2019 (COVID-19).Se incluyó un total de 100 pacientes hospitalizados con COVID-19 en la unidad de cuidados intensivos (UCI), clasificándose como grupos moderado (n = 17), grave (n = 40) y crítico (n = 43). Se recopiló la información clínica y de laboratorio, comparándose los niveles de ferritina entre los diferentes grupos. Se evaluó la asociación entre ferritina y mortalidad mediante un análisis de regresión logística. Además, se evaluó la eficacia del valor predictivo utilizando la curva ROCLa cantidad de ferritina fue significativamente superior en el grupo de pacientes críticos en comparación con el grupo de pacientes graves. La media de concentración de ferritina fue cerca de 3 veces superior en el grupo de muerte que en el grupo de supervivientes (1.722,25 μg/L vs. 501,90 μg/L, El valor de ferritina medido durante el ingreso puede servir de factor independiente para prevenir la mortalidad intrahospitalaria en los pacientes de COVID-19 en la UCI.

Highlights • Heparin, used clinically over 80 years, has shown potential for COVID-19 treatment. • The evidence and possible mechanisms of heparin for COVID-19 treatment are discussed. • The prospect of heparin therapy for COVID-19 is presented in this review., The pandemic coronavirus disease 2019 (COVID-19), caused by the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is rapidly spreading globally. Clinical observations found that systemic symptoms caused by SARS-CoV-2 infection are attenuated when using the anticoagulant agent heparin, indicating that heparin may play other roles in managing COVID-19, in addition to prevention of pulmonary thrombosis. Several biochemical studies show strong binding of heparin and heparin-like molecules to the Spike protein, which resulted in inhibition of viral infection to cells. The clinical observations and in vitro studies argue for a potential multiple-targeting effects of heparin. However, adverse effects of heparin administration and some of the challenges using heparin therapy for SARS-CoV-2 infection need to be considered. This review discusses the pharmacological mechanisms of heparin regarding its anticoagulant, anti-inflammatory and direct antiviral activities, providing current evidence concerning the effectiveness and safety of heparin therapy for this major public health emergency.

Background Despite an impressive effort in clinical research, no standard therapeutic approach for coronavirus disease 2019 (COVID-19) patients has been established, highlighting the need to identify early biomarkers for predicting disease progression and new therapeutic interventions for patient management. The present study aimed to evaluate the involvement of the human endogenous retrovirus -W envelope (HERV-W ENV) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection considering recent findings that HERVs are activated in response to infectious agents and lead to various immunopathological effects. We analysed HERV-W ENV expression in blood cells of COVID-19 patients in correlation with clinical characteristics and have discussed its potential role in the outcome of the disease. Methods We analysed HERV-W ENV expression in blood samples of COVID-19 patients and healthy donors by flow cytometry and quantitative reverse transcriptase PCR analysis, and evaluated its correlation with clinical signs, inflammatory markers, cytokine expression, and disease progression. Findings HERV-W ENV was highly expressed in the leukocytes of COVID-19 patients but not in those of healthy donors. Its expression correlated with the markers of T-cell differentiation and exhaustion and blood cytokine levels. The percentage of HERV-W ENV-positive lymphocytes correlated with inflammatory markers and pneumonia severity in COVID-19 patients. Notably, HERV-W ENV expression reflects the respiratory outcome of patients during hospitalization. Interpretation Given the known immuno- and neuro-pathogenicity of HERV-W ENV protein, it could promote certain pathogenic features of COVID-19 and therefore serve as a biomarker to predict clinical progression of disease and open to further studies for therapeutic intervention. Funding Information available at the end of the manuscript.

Background Venous thromboembolism (VTE) is a frequent complication in critically ill patients with coronavirus disease 2019 (COVID-19) and is associated with mortality. Early diagnosis and treatment of VTE is warranted. Objective To develop a prediction model for VTE in critically ill COVID-19 patients. Patients and methods In this retrospective cohort study, 127 adult patients with confirmed COVID-19 infection admitted to the intensive care unit of two teaching hospitals were included. VTE was diagnosed with either ultrasound or computed tomography scan. Univariate receiver operating characteristic (ROC) curves were constructed for Positive End Expiratory Pressure, PaO2/FiO2 ratio, platelet count, international normalized ratio, activated partial thromboplastin time as well as levels of fibrinogen, antithrombin, D-dimer and C-reactive protein (CRP). Multivariate analysis was done using binary linear regression. Results Variables associated with VTE in both univariate and multivariate analysis were D-dimer and CRP with an area under the curve (AUC) of 0.64, P = 0.023 and 0.75, P = 0.045, respectively. Variables indicating hypoxemia were not predictive. The ROC curve of D-dimer and CRP combined had an AUC of 0.83, P 15 in combination with a CRP > 280 was 98%. The negative predictive value of D-dimer was low. Conclusion Elevated CRP and D-dimer have a high positive predictive value for VTE in critically ill COVID-19 patients. We developed a prediction table with these biomarkers that can aid clinicians in the timing of imaging in patients with suspected VTE., Highlights • Venous thromboembolisms are a frequently observed complication of COVID-19. • Markers of oxygenation are not predictive of venous thromboembolism. • Elevated C-reactive protein and D-dimer have the potential to predict venous thromboembolism. • We created a prediction tool based on elevations in both CRP and D-dimer to optimize time of imaging.

Dear Sirs Accumulating evidence indicates an association between 2019-nCoV pneumonia and disseminated intravascular coagulation (DIC) [1,2]. Although some controversy exists about the extent of DIC in COVID-19 [3], DIC was indicated to be a strong predictor of mortality in patients developing pneumonia with this virus [1,2,4]. The pathophysiology of infection associated-DIC is complex and multifactorial, involving interplay between cellular and plasmatic elements of the hemostatic system and components of the innate immune response to the infecting pathogen [4,5]. In this letter, we report on the viscoelastic properties of clots formed by COVID-19 patients. Using a novel method to assess clot formation a fibrinolysis shut down was observed. This finding has not been reported yet in COVID-19 infection and suggests that fibrinolysis system significantly contributes to the procoagulatory status in COVID-19 patients and might represent a therapeutic target.

Graphical abstract, The coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), appears with a wide spectrum of mild-to-critical clinical complications. Many clinical and experimental findings suggest the role of inflammatory mechanisms in the immunopathology of COVID-19. Hence, cellular and molecular mediators of the immune system can be potential targets for predicting, monitoring, and treating the progressive complications of COVID-19. In this review, we assess the latest cellular and molecular data on the immunopathology of COVID-19 according to the pathological evidence (e.g., mucus and surfactants), dysregulations of pro- and anti-inflammatory mediators (e.g., cytokines and chemokines), and impairments of innate and acquired immune system functions (e.g., mononuclear cells, neutrophils and antibodies). Furthermore, we determine the significance of immune biomarkers for predicting, monitoring, and treating the progressive complications of COVID-19. We also discuss the clinical importance of recent immune biomarkers in COVID-19, and at the end of each section, recent clinical trials in immune biomarkers for COVID-19 are mentioned.

Coronavirus disease 2019 (COVID-19), a new type and rapidly spread viral pneumonia, is now producing an outbreak of pandemic proportions. The clinical features and laboratory results of different age groups are different due to the general susceptibility of the disease. The laboratory findings of COVID-19 in pregnant women are also conflicting. Para-clinical investigations including laboratory tests and radiologic findings play an important role in early diagnosis and treatment monitoring of COVID-19. The majority of previous reports on the COVID-19 laboratory results were based on data from the general population and limited information is available based on age difference and pregnancy status. This review aimed to describe the COVID-19 laboratory findings in neonates, children, adults, elderly and pregnant women altogether for the first time. The most attracting and reliable markers of COVID-19 in patients were: normal C-reactive protein (CRP) and very different and conflicting laboratory results regardless of clinical symptoms in neonates, normal or temporary elevated CRP, conflicting WBC count results and procalcitonin elevation in children, lymphopenia and elevated lactate dehydrogenase (LDH) in adult patients, lymphopenia and elevated CRP and LDH in the elderly people and high CRP, leukocytosis and elevated neutrophil ratio in pregnant women., Highlights The most attracting and reliable markers of COVID-19 in patients were as follows:•Normal C-reactive protein (CRP) and very different and conflicting laboratory results regardless of clinical symptoms in neonates•Normal or temporary elevated CRP, conflicting WBC count results and procalcitonin elevation in children•Lymphopenia and elevated lactate dehydrogenase (LDH) in adult patients•Lymphopenia and elevated CRP and LDH in the elderly people and high CRP•Leukocytosis and elevated neutrophil ratio in pregnant women.

Delonix regia (Bojer ex Hook.) Raf., Cassia fistula L. and Lagerstroemia speciosa L. are three ornamental plants that produce colorful flowers. The present study aimed to evaluate the phytochemicals and bioactivities of methanolic extracts of flowers from Delonix regia (DrFME), Cassia fistula (CfFME), and Lagerstroemia speciosa (LsFME). The presence of ten different chemical classes in varying degrees was confirmed while qualitatively screened. During quantitative determination, LsFME possesses the highest amount of total phenolic (418.0 mg/g), flavonoid (50.8 mg/g), and tannin (256.3 mg/g) contents. The extracts showed excellent antioxidant capacity in a concentration-dependent manner with the lowest IC50 value (41.51 μg/mL) displayed by LsFME. LsFME paralyzed the experimental worms at 2.95 min and killed at 3.96 min. DrFME was found to be more effective in thrombolytic (35.5% clot lysis) and anticoagulant activities. Negligible hemolytic activity (IC50 > 200 μg/mL) found for all extracts which suggest their less potential toxicity. The in vivo experiments revealed that the CfFME has the highest analgesic (64.34% pain inhibition) activity while LsFME has the highest antidiarrheal (70.27% inhibition) and antihyperglycemic (46.94% inhibition) activities at 400 mg/kg of body weight doses. This study has shown the presence of phytochemicals and potential bioactivities which indicates the possibility of these flowers to be used as a source of phytochemicals as well as safe and effective natural medicine., Highlights • Krisnachura (Delonix regia), Sonalu (Cassia fistula), and Jarul (Lagerstroemia speciosa) are colorful flower producing ornamental plants grown in Bangladesh. • The flowers of these plants are rich in phytochemicals and exhibit antioxidant, anthelmintic, thrombolytic, anticoagulant, analgesic, antidiarrheal and antihyperglycemic activities as determined by in vitro and in vivo methods. • The flowers can be used as a source of safe and effective natural medicine.

Graphical abstract, Introduction Cisplatin (CDDP) nephrotoxicity is one of the most significant complications limiting its use in cancer therapy. Objectives This study investigated the pivotal role played by thrombin in CDDP-mediated nephrotoxicity. This work also aimed to clarify the possible preventive effect of Dabigatran (Dab), a direct thrombin inhibitor, on CDDP nephrotoxicity. Methods Animals were grouped as follow; normal control group, CDDP nephrotoxicity group, CDDP + Dab 15, and CDDP + Dab 25 groups. Four days following CDDP administration, blood and urine samples were collected to evaluate renal function. Moreover, tissue samples were collected from the kidney to determine apoptosis markers, oxidative stress and histopathological evaluation. An immunofluorescence analysis of tissue factor (TF), thrombin, protease-activated receptor-2 (PAR2), fibrin, pERK1/2 and P53 proteins expression was also performed. Results Thrombin, pERK, cleaved caspase-3, and oxidative stress markers were significantly elevated in CDDP-treated group. However, pretreatment of animals with either low or high doses of Dab significantly improved kidney function and decreased oxidative stress and apoptotic markers. Conclusion We conclude that thrombin is an important factor in the pathogenesis of CDDP kidney toxicity via activation of ERK1/2, P53 and caspase-3 pathway, which can be effectively blocked by Dab.

Background & Aims Hypothermic oxygenated machine perfusion (HOPE) is a promising technique for providing oxygen to the liver during graft preservation; however, because of associated logistical constraints, addition of an oxygen transporter to static cold-storage solutions (SCS) might be easier. M101 is marine worm haemoglobin that has been shown to improve kidney preservation in the clinic when added to SCS. This study evaluated the effects of the addition of M101 to SCS on the quality of pig liver graft preservation. Methods Pig liver grafts were preserved using SCS, HOPE, or SCS+M101, and the liver functions were compared during cold preservation and after orthotopic allotransplantation (OLT) in pigs. Results During preservation of the liver grafts, mitochondrial function, ATP synthesis, antioxidant capacities, and hepatocyte architecture were better preserved, and free radical production, antioxidant activities, and inflammatory mediators were lower, with HOPE or SCS+M101 than with SCS alone. However, after 1 h of preservation, liver functions with HOPE were superior to those with SCS+M101. After 6 h of preservation and OLT, blood levels of aspartate and alanine aminotransferases and lactate dehydrogenase increased with a peak effect at Day 1 post-transplant; values were similar with HOPE and SCS+M101, and were significantly lower than those in the SCS group. At Days 1 and 3, tumor necrosis factor α levels remained lower with HOPE and SCS+M101 vs. SCS. At Day 7, liver cell necrosis and inflammation were less marked in both oxygenated groups. Conclusions When added to SCS, M101 effectively oxygenates liver grafts during preservation, preventing post-transplant injury; although graft performances are below those achieved with HOPE. Lay summary When transported between donors and recipients, even cold-stored liver grafts need oxygen to maintain their viability. To provide them with oxygen, we added a marine worm super haemoglobin (M101) to the cold-storage solution UWCS. Using a pig liver transplant model, we revealed that livers cold stored with UWCS+M101 showed improved oxygenation compared with simple cold-storage solutions, but did not reach the oxygenation level achieved with machine perfusion., Graphical abstract, Highlights • During cold storage, liver grafts lack oxygen. • Addition of the marine worm haemoglobin M101 provides oxygen during cold storage. • ATP synthesis and antioxidant activities are preserved by M101. • Reperfusion damage is reduced by M101.

Graphical abstract, Highlights • Hypercoagulability can be a deadly complication in patients with severe Covid-19. • Patients with elevated D-dimer received compassionate use of antiplatelet therapy. • Tirofiban, clopidogrel and acetylsalicylic acid provided acute oxygenation improvement. • Reduced alveolar-arterial gradient favoured a reduction in respiratory assistance. • Randomized trials on Covid-19-related thrombophilia are urgently needed., Patients affected by severe coronavirus induced disease-2019 (Covid-19) often experience hypoxemia due to alveolar involvement and endothelial dysfunction, which leads to the formation of micro thrombi in the pulmonary capillary vessels. Both hypoxemia and a prothrombotic diathesis have been associated with more severe disease and increased risk of death. To date, specific indications to treat this condition are lacking. This was a single center, investigator initiated, compassionate use, proof of concept, case control, phase IIb study (NCT04368377) conducted in the Intermediate Respiratory Care Unit of L. Sacco University Hospital in Milano, Italy. Our objective was to explore the effects of the administration of anti-platelet therapy on arterial oxygenation and clinical outcomes in patients with severe Covid-19 with hypercoagulability. We enrolled five consecutive patients with laboratory confirmed SARS-CoV-2 infection, severe respiratory failure requiring helmet continuous positive airway pressure (CPAP), bilateral pulmonary infiltrates and a pro-thrombotic state identified as a D-dimer > 3 times the upper limit of normal. Five patients matched for age, D-dimer value and SOFA score formed the control group. Beyond standard of care, treated patients received 25 µg/Kg/body weight tirofiban as bolus infusion, followed by a continuous infusion of 0.15 µg/Kg/body weight per minute for 48 hours. Before tirofiban, patients received acetylsalicylic acid 250 mg infusion and oral clopidogrel 300 mg; both were continued at a dose of 75 mg daily for 30 days. Fondaparinux2.5 mg/day sub-cutaneous was given for the duration of the hospital stay. All controls were receiving prophylactic or therapeutic dose heparin, according to local standard operating procedures. Treated patients consistently experienced a mean (SD) reduction in A-a O2 gradient of -32.6 mmHg (61.9, P = 0.154), -52.4 mmHg (59.4, P = 0.016) and -151.1 mmHg (56.6, P = 0.011; P = 0.047 vs. controls) at 24, 48 hours and 7 days after treatment. PaO2/FiO2 ratio increased by 52 mmHg (50, P = 0.172), 64 mmHg (47, P = 0.040) and 112 mmHg (51, P = 0.036) after 24, 48 hours and 7 days, respectively. All patients but one were successfully weaned from CPAP after 3 days. This was not true for the control group. No major adverse events were observed. Antiplatelet therapy might be effective in improving the ventilation/perfusion ratio in Covid-19 patients with severe respiratory failure. The effects might be sustained by the prevention and interference on forming clots in lung capillary vessels and by modulating megakaryocytes’ function and platelet adhesion. Randomized clinical trials are urgently needed to confirm these results.

Coronavirus Disease 2019 (COVID-19) is complicated by significant coagulopathy, that manifests in the form of both pulmonary artery microthromboses and systemic venous thromboembolism (VTE) leading to excess mortality. Dysregulated innate immune response in the lung due to viral-entry mediated angiotensin-I-converting enzyme 2 (ACE2) receptor downregulation causes endothelial injury in the pulmonary vasculature, inflammatory cytokine release, increased thrombin generation and impaired fibrinolysis. The inflammatory disease process, immobilization with prolonged hospital stay, hypoxia due to extensive lung injury and pre-existing comorbidities can contribute to thromboembolic episodes (TE). The observed risk for TE in COVID-19 is high despite anticoagulation, particularly in intensive care unit (ICU) patients. A high level of clinical suspicion, lower threshold for diagnostic imaging and aggressive early and extended thromboprophylaxis is indicated. The available evidence on the optimal strategies to prevent, diagnose, and treat VTE in patients with COVID-19 is heterogenous, but rapidly evolving. We propose an evidence-based, risk-stratified protocol in approaching the risk of TE episodes in COVID-19 patients.

A 12-year-old female with SARS-CoV-2 infection presented as phlegmasia cerulea dolens with venous gangrene.. Emergent mechanical thrombectomy was complicated by a massive pulmonary embolism and cardiac arrest for which extracorporeal cardiopulmonary resuscitation and therapeutic hypothermia were employed. Staged-ultrasound assisted catheter directed thrombolysis was employed for treatment of bilateral pulmonary emboli and the extensive lower extremity deep vein thrombosis while the patient received extracorporeal membrane oxygenation support. We highlight the need for heightened suspicion for occult SARS-CoV-2 infection among children presenting with unusual thrombotic complications.

Background Emerging evidence shows that severe COVID-19 can be complicated by a significant coagulopathy, that likely manifests in the form of both microthrombosis and venous thromboembolism (VTE). This recognition has led to the urgent need for practical guidance regarding prevention, diagnosis, and treatment of VTE. Methods A group of approved panelists developed key clinical questions by using the PICO (population, intervention, comparator, and outcome) format that addressed urgent clinical questions regarding the prevention, diagnosis and treatment of venous thromboembolism in patients with COVID-19. MEDLINE (via PubMed or Ovid), Embase and Cochrane Controlled Register of Trials were systematically searched for relevant literature and references were screened for inclusion. Validated evaluation tools were used to grade the level of evidence to support each recommendation. When evidence did not exist, guidance was developed based on consensus using the modified Delphi process. Results The systematic review and critical analysis of the literature based on13 PICO questions resulted in 22 statements. Very little evidence exists in the COVID-19 population. The panel thus used expert consensus and existing evidence-based guidelines to craft the guidance statements. Conclusions The evidence on the optimal strategies to prevent, diagnose, and treat venous thromboembolism in patients with COVID-19 is sparse, but rapidly evolving.

Background and aims Coronavirus disease (COVID-19) is a major worldwide threat for healthy individuals as well as for patients with comorbidities, but its impact on patients with cirrhosis is currently unknown. This study aimed at evaluating the impact of COVID-19 on the clinical outcome of these patients. Methods In this multicenter retrospective study, cirrhotic patients with confirmed Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection were enrolled between 1st and 31th March 2020. Clinical and biochemical data at COVID-19 and at the last outpatient visit were obtained through review of medical records. Results Fifty cirrhotic patients with confirmed SARS-CoV-2 infection were enrolled (age 67 years, 70% men, 38% virus-related, 52% previously compensated cirrhosis). At diagnosis, 64% of patients presented fever, 42% shortness of breath/polypnea, 22% encephalopathy, 96% needed hospitalization or prolonged an ongoing one. Respiratory-support was necessary in 71%, 52% received antivirals, 80% heparin. Serum albumin significantly decreased, while bilirubin, creatinine and prothrombin time significantly increased at COVID-19 diagnosis compared to last available data. The proportion of patients with MELD≥15 increased from 13% to 26% (p=0.037), acute-on-chronic liver failure and and de novo acute liver injury occurred in 14 (28%) and 10 patients, respectively. Seventeen patients died after a median of 10 (4-13) days from COVID-19 diagnosis, with a 30-day-mortality rate of 34%. Severity of lung and liver (according to CLIF-C, CLIF-OF and MELD scores) diseases independently predicted mortality. Mortality was significantly higher in hospitalized cirrhotics with COVID-19 than in those hospitalized for bacterial infections. Conclusion COVID-19 is associated with liver function deterioration and elevated mortality in cirrhotic patients., Graphical abstract, Highlights − Fifty cirrhotic patients with SARS-CoV-2 infection were studied: 64% presented with fever, 42% shortness of breath/polypnea, 22% encephalopathy; respiratory-support was necessary in 71%. − The 30-day mortality was 34% (95% CI 23-49), higher in those patients with moderate/severe respiratory failure and in those who had a more deteriorated liver function, as indicated by the increased MELD and CLIF-OF scores at COVID-19 diagnosis. − The 30-days mortality rate was higher in cirrhotics with COVID-19 than in cirrhotics with bacterial infection and in COVID-19 patients without cirrhosis − No major adverse events related to the thromboprophylaxis with heparin given to 80% of patients and treatments used to tackle the coronavirus infection.

Background Crucial roles of hematologic and immunologic responses in progression of COVID-19 remains largely unclear. Objective We sought to address the dynamic changes of hematologic and immunologic biomarkers and their associations with severity and outcomes of the disease. Methods A retrospective study including 548 COVID-19 patients with clarified outcome (discharged or deceased) from a national cohort in China was performed. Cross-sectional and longitudinal variations were compared and the associations with different severity and outcomes were analyzed. Results On admission, the counts of lymphocytes, T cell subsets, eosinophils and platelets decreased markedly, especially in severe/critical and fatal patients. Increased neutrophil count and neutrophils-to-lymphocytes ratio were predominant in severe/critical cases or non-survivors. During hospitalization, eosinophils, lymphocytes and platelets were shown an increasing trend in survivors, but maintained lower levels or dropped significantly afterwards in non-survivors. Non-survivors kept high level or showed an upward trend for neutrophils, IL-6, procalcitonin, D-dimer, amyloid A protein and C-reactive protein, which were kept stable or shown downward trend in survivors. Positive correlation between CD8+ T cell and lymphocytes count was found in survivors but not in non-survivors. A multivariate Cox regression model suggested that restored levels of lymphocytes, eosinophils and platelets could serve as the predictors for the recovery, while progressive increases in neutrophils, basophils and IL-6 were associated with fatal outcome. Conclusions Hematologic and immunologic impairment showed a significantly different profile between survivors and non-survivors in COVID-19 patients with different severity. The longitudinal variations of these biomarkers could serve to predict recovery or fatal outcome., Graphical abstract

Background & Aims Fontan-associated liver disease (FALD) has emerged as an important morbidity following surgical palliation of single ventricle congenital heart disease. In this study, non-invasive biomarkers that may be associated with severity of FALD were explored. Methods A retrospective cohort of paediatric patients post-Fontan who underwent liver biopsy at a high volume at a paediatric congenital heart disease centre was reviewed. Results Among 106 patients, 66% were male and 69% were Hispanic. The mean age was 14.4 ± 3.5 years, and biopsy was performed 10.8 ± 3.6 years post-Fontan. The mean BMI was 20.8 ± 5 kg/m2, with 27.4% meeting obesity criteria. Bridging fibrosis was observed in 35% of patients, and 10.4% of all patients had superimposed steatosis. Bridging fibrosis was associated with lower platelet counts (168.3 ± 58.4 vs. 203.9 ± 65.8 K/μl for congestive hepatic fibrosis score [CHFS] 0–2b, p = 0.009), higher bilirubin (1.7 ± 2.2 vs. 0.9 ± 0.7 mg/dl, p = 0.0090), higher aspartate aminotransferase-to-platelet ratio index [APRI] and fibrosis-4 [FIB-4] scores (APRI: 0.5 ± 0.3 vs. 0.4 ± 0.1, p, Graphical abstract, Highlights • FALD is universal within 10 years post-Fontan, with 35% of patients having bridging fibrosis. • Of our adolescent patient population, 10% had concomitant hepatic steatosis, which was associated with obesity. • Regression modelling demonstrates that temporal changes in platelet counts correlate with severity of fibrosis in FALD. • AST-to-platelet ratio index and FIB-4 scores correlate with bridging fibrosis with a high specificity. • Bridging fibrosis in FALD is associated with worse survival.

Introduction and Objectives In many studies, varying degrees of liver damage have been reported in more than half of the COVID-19 patients. The aim of this study is to determine the effect of liver biochemical parameters abnormality on mortality in critical COVID-19 patients who have been followed in the ICU since the beginning of the pandemic process. Materials and Methods In this study 533 critical patients who admitted to the ICU due to COVID-19 were included. The patients were divided into three groups according to their ALT, AST, and total bilirubin levels at their admission to the ICU. Group 1 was formed of patients with normal liver biochemical parameters values; Group 2 was formed of patients with liver biochemical parameters abnormality; Group 3 was formed of patients with liver injury. Results 353 (66.2%) of all patients died. Neutrophil, aPTT, CRP, LDH, CK, ALT, AST, bilirubin, procalcitonin and ferritin values in Group 2 and Group 3 were found to be statistically significantly higher than Group 1. It was detected that the days of stay in ICU of the patients in Group 1 was statistically significantly longer than others group. It was found that the patients in Groups 2 and 3 had higher total, 7-day, and 28-day mortality rates than expected. Conclusions The study showed that liver disfunction was associated with higher mortality and shorter ICU occupation time.