Real-world data are needed to inform clinical practice with regards to anticoagulation treatment for persons with venous thromboembolism (VTE).

To identify the type and duration of antithrombotic treatment in persons with VTE. Anticoagulation dosage and persistence/adherence were among the secondary objectives.

A multicenter, observational, prospective study conducted in Greek adults with VTE with two on-site visits -baseline and at three months- and a telephone follow-up at 6 months.

A total of 600 eligible persons were enrolled. The index event was 'PE only' in 50%, 'DVT only' in 40%, and 'DVT+PE' in 10%. Risk factors were categorized as temporary major (21%), temporary minor (37%), and persistent (43%), with active cancer present in 18% of patients. All VTE patients received anticoagulants: 73% received oral anticoagulants (72% DOACs, 1% VKAs) and 70% received parenteral anticoagulants. Treatment was oral only in 30%, parenteral only in 27%, and both in 43%. The most common DOAC was apixaban (47%). Extended anticoagulation (>6 months) was administered to 41% with only 9% (18/198) of those on DOACs receiving a reduced dose. Persistent risk factors predicted extended anticoagulation, while diabetes, COVID-19, and temporary minor risk factors did not. Adherence/persistence rates were similar between DOAC and non-DOAC-treated patients.

VTE was mainly treated with a combination of parenteral and oral anticoagulants. DOACs, primarily apixaban, were the most common oral treatments. Forty percent of patients received extended anticoagulation, mostly at standard dosages. Adherence and persistence rates were high for both DOAC and non-DOAC treatments.

Coronavirus disease 2019 (COVID-19), a viral respiratory illness caused by severe acute respiratory disease coronavirus 2 (SARS-COV-2), has caused in the last 5 years a global pandemic of unprecedented scale in the modern era. Other than the typical respiratory symptoms, patients suffering from moderate to severe COVID-19 are at risk of developing a peculiar systemic coagulopathy, known as COVID-19-associated coagulopathy. In addition to a predominantly hypercoagulable state, COVID-19 patients may experience hemorrhagic complications triggered by the viral infection. The current knowledge on the underlying molecular mechanisms, the laboratory and clinical characteristics of coagulation abnormalities associated with COVID-19, along with their management, will be summarized in this narrative review.

Microangiopathy is a major complication of SARS-CoV-2 infection and contributes to the acute and chronic complications of the disease1. Endotheliopathy and dysregulated blood coagulation are prominent in COVID-19 and are considered to be major causes of microvascular obstruction1,2. Here we demonstrate extensive endothelial cell (EC) death in the microvasculature of COVID-19 organs. Notably, EC death was not associated with fibrin formation or platelet deposition, but was linked to microvascular red blood cell (RBC) haemolysis. Importantly, this RBC microangiopathy was associated with ischaemia-reperfusion injury, and was prominent in the microvasculature of humans with myocardial infarction, gut ischaemia, stroke, and septic and cardiogenic shock. Mechanistically, ischaemia induced MLKL-dependent EC necroptosis and complement-dependent RBC haemolysis. Deposition of haemolysed RBC membranes at sites of EC death resulted in the development of a previously unrecognized haemostatic mechanism preventing microvascular bleeding. Exaggeration of this haemolytic response promoted RBC aggregation and microvascular obstruction. Genetic deletion of Mlkl from ECs decreased RBC haemolysis, microvascular obstruction and reduced ischaemic organ injury. Our studies demonstrate the existence of a RBC haemostatic mechanism induced by dying ECs, functioning independently of platelets and fibrin. Therapeutic targeting of this haemolytic process may reduce microvascular obstruction in COVID-19, and other major human diseases associated with organ ischaemia.

Cerebral small vessel disease (CSVD) refers to a group of pathological syndromes that affect the brain's microcirculation. These conditions involve damage to small arteries, arterioles, capillaries, venules, and small veins. Cerebrovascular risk factors, immunosenescence, and inflammatory responses contribute to the pathogenesis of cerebral small vessel disease. The global impact of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has drawn significant attention to chronic inflammation caused by infections. Research into the mechanisms by which infections induce CSVD has made continual advancements. It is imperative to reassess the importance of managing infections and the chronic inflammatory phase that follows, highlighting their critical role in the pathogenesis. Our focus encompasses SARS-CoV-2, Human Immunodeficiency Virus (HIV), Hepatitis C Virus (HCV), Zika Virus(ZIKV), Treponema pallidum, as well as the microbial communities within the gut and oral cavity. These pathogen infections and chronic inflammation can contribute to CSVD through mechanisms such as neuroinflammation, blood-brain barrier disruption, microthrombosis, and endothelial cell damage, thereby promoting the occurrence and progression of the disease. This highlights the need for detailed mechanistic research on CSVD associated with these pathogens. Furthermore, we hope that in the future, we will be able to devise targeted prevention and treatment strategies for CSVD based on the unique characteristics of the pathogenic mechanisms associated with various infections.

Monoclonal gammopathy-associated capillary leak syndrome (MG-CLS) is a rare condition characterized by recurrent episodes of hypovolemic shock caused by a sudden increase in capillary permeability. The COVID-19 pandemic has been associated with a rise in MG-CLS episodes and increased mortality. We aimed to explore the association between MG-CLS and SARS-CoV-2 infection. We conducted a multicenter retrospective observational study involving MG-CLS patients who were admitted to the intensive care unit (ICU). The primary endpoint was 28-day mortality according to whether SARS-CoV-2 was identified as a trigger.

The study included 84 patients (44% women) with a median age of 55 years [IQR 46-62], accounting for 127 ICU admissions. Most patients (88%) had monoclonal gammopathy, predominantly with an IgG heavy chain (98%). A trigger was identified in 63% of cases, primarily suspected or confirmed viral infections, including 26 episodes of SARS-CoV-2 infection. Within 28 days of ICU admission, 32% of patients died. Episodes triggered by SARS-CoV-2 were associated with a higher need for mechanical ventilation (69% vs. 38%, p = 0.004), renal replacement therapy (54% vs. 31%, p = 0.03), and increased 28-day mortality (42% vs. 17%, p = 0.005). Multivariable analysis revealed that SARS-CoV-2 infection was independently associated with 28-day mortality (OR 4.67 [1.08-20.1], p = 0.04). The use of intravenous immunoglobulins did not improve 28-day survival.

In this large cohort of MG-CLS episodes requiring ICU admission, SARS-CoV-2as a trigger was associated with significantly higher 28-day mortality compared to other triggers. Further research is essential to elucidate the specific mechanisms by which SARS-CoV-2 impacts MG-CLS patients.

Cognitive dysfunction represents one of the most persistent and disabling features of Long COVID, yet its molecular underpinnings remain incompletely understood. This narrative review synthesizes current evidence on the pathophysiological mechanisms linking SARS-CoV-2 infection to long-term neurocognitive sequelae. Key processes include persistent neuroinflammation, blood-brain barrier (BBB) disruption, endothelial dysfunction, immune dysregulation, and neuroendocrine imbalance. Microglial activation and cytokine release (e.g., IL-6, TNF-α) promote synaptic dysfunction and neuronal injury, while activation of inflammasomes such as NLRP3 amplifies CNS inflammation. Vascular abnormalities, including microthrombosis and BBB leakage, facilitate the infiltration of peripheral immune cells and neurotoxic mediators. Hypothalamic-pituitary-adrenal axis dysfunction and reduced vagal tone further exacerbate systemic inflammation and autonomic imbalance. Biomarkers such as GFAP, NFL, IL-6, and S100B have been associated with both neuroinflammation and cognitive symptoms. Notably, transcriptomic signatures in Long COVID overlap with those observed in Alzheimer's disease, highlighting shared pathways involving tau dysregulation, oxidative stress, and glial reactivity. Understanding these mechanisms is critical for identifying at-risk individuals and developing targeted therapeutic strategies. This review underscores the need for longitudinal research and integrative biomarker analysis to elucidate the molecular trajectory of cognitive impairment in Long COVID.

The formation of neutrophil extracellular traps (NETs) is a novel way for neutrophils to perform organismal protective functions essential for protecting the host against infections. Nevertheless, an increasing amount of data shows that uncontrolled or excessive formation of NETs in the body leads to inflammation and thrombosis. Many serious human diseases, such as sepsis, stroke, cancer, and autoimmune diseases, are associated with thrombosis, and inhibiting its formation is essential to prevent the development of many inflammatory and thrombotic diseases. With deeper research, it has been found that there is a complex interaction between NETs and platelets: platelets activate neutrophils to form NETs, while NET components enhance platelet aggregation and activation. This self-perpetuating vicious cycle between them mediates pathological processes such as inflammation, coagulation, and thrombosis. A deeper comprehension of the underlying molecular mechanisms between them promises to be a new target for thrombotic diseases. In this review, we concentrate on a summary of NET formation and its mechanisms of action. Providing a thorough summary of how neutrophils are activated by platelets to form NETs, how NETs cause platelet activation, and how this close interaction during inflammatory events affects the course of the disease, with the aim of providing fresh targets and ideas for thrombotic disease clinical prevention and therapy.

Splanchnic vein thrombosis (SVT) is a heterogeneous group of disorders affecting the portal, mesenteric, splenic, and hepatic veins. While frequently associated with liver cirrhosis and malignancy, SVT also occurs in non-cirrhotic, non-neoplastic patients. This narrative review evaluates the epidemiology and risk factors for SVT in this population. The prevalence and incidence of SVT in non-cirrhotic, non-neoplastic patients remain incompletely characterized, with estimates varying widely across studies. The clinical significance of SVT relates to potential complications, including intestinal ischemia, portal hypertension, and a possible underlying systemic disorder. Risk factors for SVT can be categorized into local abdominal conditions, thrombophilias, and systemic disorders. Local factors include inflammatory bowel disease, pancreatitis, abdominal surgery, and trauma. Thrombophilias, both inherited and acquired, are significant contributors to SVT risk. Systemic conditions associated with SVT include autoimmune disorders, pregnancy, hematological diseases, and infections. The complex interplay of these risk factors highlights the need for a comprehensive evaluation of SVT patients. Early recognition and management of these conditions can prevent potentially life-threatening complications and guide decisions regarding anticoagulation and long-term follow-up.

The aim of the present clinical consensus statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases is to review the current knowledge on the epidemiology, pathogenesis, diagnosis, therapy, and outcomes of myocardial and pericardial complications of coronavirus disease 2019 (COVID-19) and vaccination in order to improve the awareness and clinical confidence on the management of patients with these complications. The risk of myopericardial complications is especially higher within 1 month of COVID-19 disease and vaccination. Forms related to the disease are generally more common and severe than those related to vaccination. Even if vaccination against COVID-19 increases myocarditis risk, this risk is lower in vaccinated than non-vaccinated COVID-19 individuals, supporting the vaccine use. Overall, COVID-19 related complications, especially myocarditis, are relatively rare.

Neutrophil extrusion of neutrophil extracellular traps (NETs) in a process called NETosis provides immune defense against extracellular bacteria. It has been observed that bacteria are capable of activating neutrophils to release NETs that subsequently kill them or at least prevent their local spread within host tissue. However, existing studies have mainly focused on the isolated function of NETs, with less attention given to their anti-bacterial mechanisms through interactions with other immune cell populations. The net effect of these complex intercellular interactions, which may act additively, synergistically, or antagonistically, is a critical determinant in the outcomes of host-pathogen interactions. This review summarizes the mechanisms underlying classic NET formation and their crosstalk with the immune system, offering novel insights aimed at balancing the anti-microbial function with their potential inflammatory risks.

Thrombotic diseases remain the major cause of death and disability worldwide, and the contribution of inflammation is increasingly recognized. Thromboinflammation has been identified as a key pathomechanism, but an unsupervised map of immune-cell states, trajectories, and intercommunication at a single-cell level has been lacking. Here, we reveal innate leukocyte substates with prominent thrombolytic properties by employing single-cell omics measures on human stroke thrombi. Using in vivo and in vitro thrombosis models, we propose a pro-resolving monocyte-neutrophil axis, combining two properties: (1) NR4A1hi non-classical monocytes acquire a thrombolytic and neutrophil-chemoattractive phenotype, and (2) blood neutrophils are thereby continuously recruited to established thrombi through CXCL8-CXCR1 and CXCR2 and adopt a hypoxia-induced thrombus-resolving urokinase receptor (PLAUR)+ phenotype. This immunothrombolytic axis results in thrombus resolution. Together, with this immune landscape of thrombosis, we provide a valuable resource and introduce the concept of "immunothrombolysis" with broad mechanistic and translational implications at the crossroad of inflammation and thrombosis.

Coronavirus disease 2019 (COVID-19) presents with various symptoms, and some patients develop post-COVID-19 condition (PCC). Vitamin D has shown therapeutic potential in COVID-19 and may offer benefits for PCC. The aim of this study was to evaluate the differences associated with two supplementation strategies (bolus and daily) on interleukin-6 (IL-6) levels, glutathione peroxidase (GPx) activity, and clinical outcomes in PCC patients, regardless of whether target 25 (OH) D levels reached the ideal range. We conducted a self-controlled study in which 54 participants with PCC were supplemented with vitamin D3 (n = 28 bolus and n = 26 daily) for 2 months. Blood samples were collected to measure IL-6 levels and GPx activity using spectrophotometric methods. The Hospital Anxiety and Depression Scale (HADS) was used to assess mental function. Both bolus and daily vitamin D supplementation were significantly associated with increased GPx activity and decreased IL-6 levels. Daily supplementation was additionally associated with a significant reduction in anxiety and depression scores. However, neither regimen was associated with improvements in cough, dyspnea, or fatigue. These findings suggest a potential association between vitamin D supplementation and improvements in antioxidant and neuropsychiatric parameters in PCC, possibly mediated by its immunomodulatory and antioxidant properties. Further placebo-controlled trials are warranted to determine whether these observed associations reflect causal relationships.

COVID-19 is a disease that affects people globally. Beyond affecting the respiratory system, COVID-19 patients are at an elevated risk for both venous and arterial thrombosis. This heightened risk contributes to an increased probability of acute complications, including acute myocardial infarction (AMI) and acute ischemic stroke (AIS). Given the unclear relationship between COVID-19, AMI, and AIS, it is crucial to gain a deeper understanding of their associations and potential molecular mechanisms. This study aims to utilize bioinformatics to analyze gene expression data, identify potential therapeutic targets and biomarkers, and explore the role of immune cells in the disease.

This study employed three Gene Expression Omnibus (GEO) datasets for analysis, which included data on COVID-19, AMI and AIS. We performed enrichment analysis on the co-DEGs for these three diseases to clarify gene pathways and functions, and also examined the relationship between co-DEGs and immune infiltration. Machine learning techniques and protein-protein interaction networks (PPI) were used to identify hub genes within the co-DEGs. Finally, we employed a dual validation strategy integrating independent GEO datasets and in vitro experiments with human blood samples to comprehensively assess the reliability of our experimental findings.

We identified 88 co-DEGs associated with COVID-19, AMI and AIS. Enrichment analysis results indicated that co-DEGs were significantly enriched in immune inflammatory responses related to leukocytes and neutrophils. Immune infiltration analysis revealed significant differences in immune cell populations between the disease group and the normal group. Finally, genes selected through machine learning methods included: CLEC4E, S100A12, and IL1R2. Based on the PPI network, the top ten most influential DEGs were identified as MMP9, TLR2, TLR4, ITGAM, S100A12, FCGR1A, CD163, FCER1G, FPR2, and CLEC4D. The integration of the protein-protein interaction (PPI) network with machine learning techniques facilitated the identification of S100A12 as a potential common biomarker for early diagnosis and a therapeutic target for all three diseases. Ultimately, validation of S100A12 showed that it was consistent with our experimental results, confirming its reliability as a biomarker. Moreover, it demonstrated good diagnostic performance for the three diseases.

We employed bioinformatics methods and machine learning to investigate common diagnostic biomarkers and immune infiltration characteristics of COVID-19, AMI and AIS. Functional and pathway analyses indicated that the co-DEGs were primarily enriched in immune inflammatory responses related to leukocytes and neutrophils. Through two machine learning approaches and the PPI network, and subsequent validation and evaluation, we identified S100A12 as a potential common therapeutic target and biomarker related to immune response that may influence these three diseases.

This study explored the relationship between the concentrations of homoarginine and arginine and between homoarginine concentration and laboratory parameters in coronavirus disease 2019 (COVID-19) patients with different severity to demonstrate the role of homoarginine in the progress of COVID-19. The laboratory-confirmed COVID-19 patients were included from Peking University Third Hospital during December 2022 to January 2023. Serum, urine, and stool samples were collected from the patients and detected by liquid chromatography-mass spectrometry. Totally 46 patients were recruited, including 18 in the mild group, 19 in the severe group, and 9 fatal. The concentration of homoarginine was positively correlated with the concentration of arginine in serum (r = 0.50), urine (r = 0.55), and stool samples (r = 0.39), respectively (all P < 0.001). The serum concentration and urine concentration of homoarginine were lower in severe patients than in mild patients (both P < 0.05). 13 indicators reflecting immunity and coagulation, including but not limited to T cell, white blood cell, natural killer cell, interleukin 6 (IL-6), and IL-8, had statistically significant correlations with both disease severity and the homoarginine concentration. Patients with hypertension were significantly associated with the decreased serum homoarginine (odds ratio 10.905, 95% confidence interval 1.454 - 137.144). Our results suggest that the homoarginine plays a role in the progress of COVID-19, which may be achieved by influencing arginine metabolism.

Severe COVID-19 disease is accompanied by high plasma levels of proinflammatory, prothrombotic NETs, and NET-inducing cytokine IL-18. We found that both, IL-18 and NETs, are elevated in men with severe disease, but not in women of the same category. Our findings warrant further investigation of sex-related differences in SARS-CoV-2 infection.

SARS-CoV-2 induces acute non-specific endothelial/microvascular alterations that have been identified by nailfold videocapillaroscopy (NVC). Details on NVC abnormalities in long covid (LC) patients (pts) are unknown.

LC pts without and with systemic sclerosis (non-SSc-LC and SSc-LC), recovered COVID-19 (RC) pts that did not develop LC and healthy matched control subjects (CNT) that underwent NVC examinations were evaluated in a multicentre national study from the Capillaroscopy and Microcirculation in Rheumatic Diseases Study Group of the Italian Society of Rheumatology. Retrospective collection was performed for demographic data, course of SARS-CoV-2 infection, comorbidities, concomitant drugs. NVC alterations were quantified by validated scores. Pre-COVID-19 and post-COVID-19 microvascular status was analysed by NVC.

62 non-SSc-LC pts (49 female/13 male, 51±16 years old), 24 SSc-LC pts (21 female/3 male, 59±17 years old), 23 RC pts (18 female/5 male, 51±18 years old) and 84 CNT (68 female/16 male, 52±12 years old) were analysed. Non-SSc-LC pts showed significantly more dilated capillaries (p<0.01, p multivariate<0.01), microhaemorrhages (p=0.01, p multivariate<0.05), abnormal shapes (p<0.05, p multivariate<0.05) than CNT and of note, lower mean capillary number per linear millimetre (p<0.01, p multivariate<0.01) than both RC pts and CTN (p<0.01, p multivariate<0.05).Of highest interest, 16 non-SSc-LC pts showed statistically significantly more dilated capillaries (p<0.05) and microhaemorrhages (p<0.05) in NVC examinations after COVID-19, compared with pre-COVID-19 status.Similarly, SSc-LC pts (24) showed significantly lower capillary density (p=0.01) and more dilated capillaries (p<0.01) in NVC examinations after COVID-19, compared with pre-COVID-19 status.

LC pts show more microvascular alterations at NVC as compared with RC patients and CNT, which may contribute to the pathogenesis of persistent organ/systems dysfunction.

Acute surgical abdomen is characterized by intense, sudden abdominal pain due to intra-abdominal conditions requiring prompt surgical intervention. The coronavirus disease 2019 (COVID-19) pandemic has led to various complications related to the disease's complex pathophysiological mechanisms, hence the hypothesis of COVID-19-induced acute abdominal surgical pathologies. The connection between acute surgical abdomen and COVID-19 involves two primary mechanisms. First, there is the presence of angiotensin-converting enzyme 2 (ACE2) receptors in multiple abdominal organs. This facilitates the cytokine storm through direct viral injury and inflammation. Second, the hypercoagulable state induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) increases the thrombotic risk within abdominal vessels, which can subsequently lead to ischemia. ACE2 receptors are notably expressed in the gastric, duodenal, and rectal epithelium, with SARS-CoV-2 viral RNA and nucleocapsid proteins detected in these tissues. The inflammatory response results in significant endothelial damage, activating coagulation pathways that cause monocellular infiltration, lymphocytic inflammation, and uncontrolled coagulation. These findings highlight the need for further research to clarify how COVID-19 leads to acute abdominal pathologies. Understanding these mechanisms is vital for improving clinical management and patient outcomes during future health crises and in the aftermath of the pandemic.

We investigated whether baseline levels of biomarkers related to endotheliopathy, thromboinflammation, and fibrosis were associated with clinical outcomes in hospitalized COVID-19 patients. We analyzed the associations between baseline levels of 21 biomarkers and time to hospital discharge and change in NEWS-2 score in patients from DisCoVeRy trial. We fitted multivariate models adjusted for baseline ISARIC 4C score, disease severity, D-dimer values, and treatment regimen. Between March 22 and June 29, 2020, 603 participants were randomized; 454 had a sample collected at baseline and analyzed. The backward selection of multivariate models showed that higher baseline levels of soluble suppressor of tumorigenicity 2 (sST2) and nucleosomes were statistically associated with a lower chance of hospital discharge before day 29 (sST2: aHR 0.24, 95% CI [0.15-0.38], p < 10-9; nucleosomes: aHR 0.62, 95% CI [0.48-0.81], p < 10-3). Likewise, higher levels of baseline sST2 were statistically associated with lower changes in the NEWS-2 score between baseline and day 15 (adjusted beta 4.47, 95% CI [2.65-6.28], p < 10-5). Moreover, we evaluated sST2 involvement in a confirmation cohort (SARCODO study, 103 patients) and found that elevated baseline sST2 levels were significantly associated with lower rates of hospital discharge before day 29 and a higher model performance (AUC at day 29 of 92%) compared to models without sST2. sST2 emerged as an independent predictor of clinical outcomes in two large cohort of hospitalized COVID-19 patients, warranting further investigation to elucidate its role in disease progression and potential as a therapeutic target.

Understanding the interplay among clinical variables-such as demographics, symptoms, and laboratory results-and their relationships with disease outcomes is critical for advancing diagnostics and understanding mechanisms in complex diseases. Existing methods fail to capture indirect or directional relationships, while existing Bayesian network learning methods are computationally expensive and only infer general associations without focusing on disease outcomes. Here we introduce random walk- and genetic algorithm-based network inference (RAMEN), a method for Bayesian network inference that uses absorbing random walks to prioritize outcome-relevant variables and a genetic algorithm for efficient network refinement. Applied to COVID-19 (Biobanque québécoise de la COVID-19), intensive care unit (ICU) septicemia (MIMIC-III), and COPD (CanCOLD) datasets, RAMEN reconstructs networks linking clinical markers to disease outcomes, such as elevated lactate levels in ICU patients. RAMEN demonstrates advantages in computational efficiency and scalability compared to existing methods. By modeling outcome-specific relationships, RAMEN provides a robust tool for uncovering critical disease mechanisms, advancing diagnostics, and enabling personalized treatment strategies.

Cytokine storm (CS) is a severe systemic inflammatory syndrome characterized by the excessive activation of immune cells and a significant increase in circulating levels of cytokines. This pathological process is implicated in the development of life-threatening conditions such as fulminant myocarditis (FM), acute respiratory distress syndrome (ARDS), primary or secondary hemophagocytic lymphohistiocytosis (HLH), cytokine release syndrome (CRS) associated with chimeric antigen receptor-modified T (CAR-T) therapy, and grade III to IV acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. The significant involvement of the JAK-STAT pathway, Toll-like receptors, neutrophil extracellular traps, NLRP3 inflammasome, and other signaling pathways has been recognized in the pathogenesis of CS. Therapies targeting these pathways have been developed or are currently being investigated. While novel drugs have demonstrated promising therapeutic efficacy in mitigating CS, the overall mortality rate of CS resulting from underlying diseases remains high. In the clinical setting, the management of CS typically necessitates a multidisciplinary team strategy encompassing the removal of abnormal inflammatory or immune system activation, the preservation of vital organ function, the treatment of the underlying disease, and the provision of life supportive therapy. This review provides a comprehensive overview of the key signaling pathways and associated cytokines implicated in CS, elucidates the impact of dysregulated immune cell activation, and delineates the resultant organ injury associated with CS. In addition, we offer insights and current literature on the management of CS in cases of FM, ARDS, systemic inflammatory response syndrome, treatment-induced CRS, HLH, and other related conditions.

In December 2019, the novel SARS-CoV-2 triggered a global pneumonia outbreak, leading to millions of deaths worldwide. A subset of survivors faces increased morbidity and mortality, particularly due to subacute lung injury evolving to chronic fibrosing interstitial lung disease. While nintedanib, a tyrosine-kinase inhibitor, shows promise in treating progressive fibrotic lung disease, limited randomised trial data exists for post-COVID-19-induced lung injury. We hypothesise that treatment with nintedanib may attenuate advancement to the fibrotic stages, offering a potential avenue for improving outcomes in this specific patient subset.

We describe the design of a multicentre, randomised, double-blind, placebo-controlled trial involving approximately 170 patients with subacute lung injury secondary to COVID-19, who required respiratory support with oxygen supplementation. Patients are randomised by site and disease phenotype (fibrotic vs non-fibrotic) in a 1:1 ratio to either oral nintedanib or placebo. Patients will be followed for 180 days. The primary endpoint is to assess change from baseline in forced vital capacity (FVC, mL) at 180 days. Secondary objectives include change in FVC (mL) at 90 days; diffusing capacity of carbon monoxide (% of predicted) and 6-min walk test (feet) at 180 days; and mortality at 90 and 180 days. Qualitative and quantitative changes in high-resolution computerised tomography (HRCT), change in patient-reported outcome measures (PROMs) and safety endpoints will also be assessed. Analysis will be performed according to the intention-to-treat principle.

The study is conducted in accordance with the Good Clinical Practices as outlined by the Food and Drug Administration and the Declaration of Helsinki 2008. This study received approval from participating sites' Institutional Review Boards and committees, including The Ethics Committee of the Medical Board at the Mount Sinai Hospital (ID: HS#20-01166). The Independent Oversight Committee oversees study conduct, data and patient safety for the duration of the study investigation. The trial details presented align with the trial protocol V.8. (April 2022). Results will be presented at national and international conferences, published in a peer-reviewed journal and disseminated to patients, funders and researchers on data analysis completion.

NCT04619680. First posted 6 November 2020.

Therapeutic plasma exchange (TPE) is the primary intervention for treating symptomatic hyperviscosity from hypergammaglobulinemia, yet its efficacy for treating hyperviscosity related to hyperfibrinogenemia is unclear.

Define the safety and efficacy of TPE for critically ill COVID-19 patients with elevated blood viscosity from hyperfibrinogenemia.

We performed a prospective randomized controlled trial in critically ill COVID-19 patients in a single US healthcare system. Patients with hyperfibrinogenemia (>800 mg/dL) or elevated plasma viscosity (2.3-3.5 centipoise [cP]) were randomized to receive TPE on 2 consecutive days or continued standard of care (SOC).

Twenty participants were enrolled, with 10 receiving TPE and 10 receiving SOC alone. Mean (±SEM) plasma viscosity decreased significantly from 2.35 cP (±0.12) to 1.61 cP (±0.03) in the TPE group and was unchanged in the SOC group (2.47 cP [±0.11] to 2.47 cP [±0.15]). Mean fibrinogen decreased from 934.0 mg/dL (±25.1) to 359.1 mg/dL (±22.5) after TPE vs from 859.6 mg/dL (±57.6) to 807.3 mg/dL (±63.1) in SOC. There was no significant difference in 28-day all-cause mortality between groups, with 2 deaths in the TPE cohort and 5 deaths in the SOC cohort (P = .13). No serious safety events related to TPE were reported. TPE significantly decreased biomarkers of inflammation (erythrocyte sedimentation rate and C-reactive protein) and endothelial activation (von Willebrand factor and factor VIII) but not hemostatic activation (prothrombin fragment 1.2, thrombin-antithrombin complex, and fibrin monomer) or immunoglobulin (IgG and IgM) levels.

TPE is safe and effective for normalizing elevated blood viscosity from hyperfibrinogenemia in COVID-19 patients. Additional studies are needed to determine the impact of TPE on overall patient outcomes, including in those with non-COVID-19 conditions associated with hyperfibrinogenemia.

Portal vein thrombosis (PVT) is commonly encountered in patients with cirrhosis, challenging our understanding of its development, particularly the ambiguous contribution of inflammation. This study utilized Mendelian randomization (MR) to explore the causal impact of circulating inflammatory markers on PVT.Employing a two-sample MR framework, we merged genome-wide association study (GWAS) meta-analysis findings of 91 inflammation-associated proteins with independent PVT data from the FinnGen consortium's R10 release. A replication analysis was performed using a distinct GWAS dataset from the UK Biobank. Inverse variance weighting, MR-Egger regression, weighted median estimator, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier were used for analysis, supplemented by multivariable MR (MVMR) to adjust for cirrhosis effects.Findings indicate a significant inverse association between the genetically inferred concentration of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and PVT risk, evidenced by an odds ratio (OR) of 0.37 (95% confidence interval [CI]: 0.21-0.67; p = 9.2 × 10-4; adjusted for multiple testing p = 0.084). This association was corroborated in the replication phase (OR = 0.39, 95% CI: 0.17-0.93; p = 0.03) and through MVMR analysis (OR = 0.34, 95% CI: 0.15-0.79; p = 0.012). Sensitivity analyses disclosed no evidence of heterogeneity or pleiotropy.Our investigation emphasizes the 4E-BP1 as a protective factor against PVT, underscoring its potential relevance in understanding PVT pathogenesis and its implications for diagnosis and therapy.

Long coronavirus disease 2019 (COVID-19)-a postacute consequence of severe acute respiratory syndrome coronavirus 2 infection-manifests with a broad spectrum of relapsing and remitting or persistent symptoms as well as varied levels of organ damage, which may be asymptomatic or present as acute events such as heart attacks or strokes and recurrent infections, hinting at complex underlying pathogenic mechanisms. Central to these symptoms is vascular dysfunction rooted in thrombotic endothelialitis. We review the scientific evidence that widespread endothelial dysfunction (ED) leads to chronic symptomatology. We briefly examine the molecular pathways contributing to endothelial pathology and provide a detailed analysis of how these cellular processes underpin the clinical picture. Noninvasive diagnostic techniques, such as flow-mediated dilation and peripheral arterial tonometry, are evaluated for their utility in identifying ED. We then explore mechanistic, cellular-targeted therapeutic interventions for their potential in treating ED. Overall, we emphasize the critical role of cellular health in managing Long COVID and highlight the need for early intervention to prevent long-term vascular and cellular dysfunction.

Acute respiratory distress syndrome (ARDS) is a life-threatening pulmonary condition with significant mortality, largely due to a lack of therapeutic interventions grounded in its molecular pathophysiology. Immune checkpoint regulators, such as the V-domain Ig Suppressor of T cell Activation (VISTA), may provide novel immunotherapeutic strategies for ARDS by modulating the immune response, a concept extensively explored in cancer and autoimmune diseases. Investigating VISTA in the context of ARDS could unveil new therapeutic avenues.

We used a mouse model of indirect ARDS by subjecting C57BL/6J mice to hemorrhage followed by cecal ligation and puncture. Systemic and localized inflammatory conditions were assessed using samples from blood, lung, and peritoneal fluid. Lung pathology was quantified by scoring hematoxylin and eosin-stained sections. Flow cytometry, enzyme-linked immunosorbent assay, and reverse transcription-polymerase chain reaction analyses concentrated on macrophages, neutrophils, endothelial cells, and epithelial cells to elucidate VISTA expression patterns.

Hemorrhage or cecal ligation and puncture-treated mice exhibited hallmark symptoms of indirect ARDS, including elevated levels of inflammatory cytokines and chemokines. Notably, VISTA expression was substantially upregulated on various cell types, including blood monocytes, lung macrophages, and both circulating and lung-infiltrating neutrophils, as well as on pulmonary epithelial cells and endothelial cells.

Our model replicates critical inflammatory and physiologic changes leading to ARDS, with the elevated expression of VISTA on immune and parenchymal cells suggesting its central involvement in lung injury. The findings propose VISTA as both a potential biomarker for lung damage and as a promising target for ARDS therapy.

Severe pneumonia, frequently accompanied by cytokine storms, stands as a perilous respiratory condition with alarmingly high mortality rates. Tetrastigma hemsleyanum polysaccharide (THP), a pivotal constituent derived from Tetrastigma hemsleyanum Diels et Gilg (TH), has demonstrated efficacy in treating lung inflammation. However, its precise efficacy and underlying mechanisms in the context of severe pneumonia remain elusive. Our research aims to elucidate THP's protective effects in a "two-hit" severe pneumonia model. Our observations indicate that THP administration markedly shields the lungs from injury, reduces pulmonary apoptosis, balances the formation of immune thrombus and alleviates oxidative stress in pneumonia-induced mice. Furthermore, THP significantly decreases the levels of pro-inflammatory cytokines, suggesting its robust anti-inflammatory capabilities. Notably, THP also plays a crucial role in normalizing gut microbiota imbalance, which is vital in the pathogenesis of severe pneumonia. Metabolomic analysis further validates THP's restorative effects on plasma metabolites, indicating its involvement in regulating energy metabolism and immune homeostasis. Mechanistically, THP targets the TLR4/NF-κB signaling pathway, a core mediator of inflammation, thereby dampening the inflammatory cascade. In summary, our findings underscore that THP, through its multifaceted actions targeting inflammation, oxidative stress, immune thrombus formation, gut microbiota regulation, and metabolic modulation, emerges as a promising therapeutic approach for severe pneumonia. This study provides invaluable insights into the potential applications of natural polysaccharides in treating severe pneumonia and highlights the significance of the TLR4/NF-κB pathway in the disease's progression.