L- Arginine (2-Amino-5-guanidinovaleric acid, L-Arg) is a semi-essential amino acid that is mainly produced within the urea cycle. It acts as a key precursor in the synthesis of proteins, urea, creatine, prolamines (including putrescine, spermine, and spermidine), proline, and nitric oxide (NO). WhenL-Arg is metabolized, it produces NO, glutamate, and prolamines, which all play important regulatory roles in various physiological functions. In addition to its metabolic roles,L-Arg significantly influences immune responses, especially in the context of inflammation and autoimmune diseases. It affects the activity of immune cells by modulating T-cell function, the polarization of macrophages, and the release of cytokines. Importantly,L-Arg plays a dual role in immune regulation, functioning as both an immunostimulatory and immunosuppressive agent depending on the specific cellular and biochemical environments. This review examines the immunopharmacological mechanisms of L-Arg, emphasizing its involvement in inflammatory responses and its potential therapeutic uses in autoimmune conditions like rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease. By influencing the pathways of nitric oxide synthase (NOS) and arginase (ARG), L-Arg helps maintain immune balance and contributes to the pathophysiology of diseases. Gaining a better understanding of the pharmacological effects of L-Arg on immune regulation could yield new perspectives on targeted treatments for immune-related diseases. Exploring its impact on immune signaling and metabolic pathways may result in novel therapeutic approaches for chronic inflammatory and autoimmune disorders.

Inflammatory disorders and endothelial dysfunction are prevalent in patients with chronic kidney disease (CKD). Thrombomodulin (TM) possesses both anticoagulant and anti-inflammatory properties. This study aimed to investigate the association between TM levels and the severity of CKD.

This cross-sectional study included two cohorts of patients with CKD from the General Hospital of the Chinese People's Liberation Army. Patients with CKD were categorized into high and low TM groups based on the upper plasma TM reference value. The laboratory indices of patients were compared. Simultaneously, a correlation analysis was performed to identify the association between the TM and each parameter. Patients were categorized into two groups based on eGFR: preserved renal function (eGFR ≥ 60 mL/min/1.73 m²) and significantly impaired renal function (eGFR < 60 mL/min/1.73 m²). Logistic regression analysis and receiver operating characteristic (ROC) curves were used for analysis.

A total of 33 patients with CKD were included in the discovery cohort, and 150 were included in the validation cohort. In the discovery cohort, creatinine (P = 0.0028) and urea nitrogen (P = 0.0011) were significantly higher in the high TM group compared to the low TM group, whereas eGFR (P = 0.0005) was lower. In the validation cohort, high TM group exhibited significantly higher creatinine (P < 0.001), urea nitrogen (P < 0.001), and 24-hour proteinuria levels (P < 0.001) compared to the low TM group, while eGFR (P < 0.001) was lower. Merging the discovery and validation cohorts revealed significant positive correlations between TM and IL-2, TNF-α, vWF (Act), vWF (Ag), serum creatinine, urea nitrogen, and 24-hour proteinuria, while eGFR was negatively correlated with TM (P < 0.001). After adjusting for confounders, TM (adjusted odds ratio = 1.31; 95% CI: 1.10-1.57; P = 0.003) was independently and significantly correlated with CKD severity. Using a TM threshold of > 14.55 TU/ml derived from ROC analysis for severity stratification, the AUC was 0.7739 (95% CI: 0.71-0.84) in differentiating CKD severity stages.

Serum TM levels demonstrated a significant correlation with CKD severity, suggesting its potential as a biomarker with clinical utility for CKD staging.

Not applicable.

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.

Increasing long-term observations suggest that coronavirus disease 2019 (COVID-19) vasculopathy may persist even 1.5 years after the acute phase, potentially accelerating the development of atherosclerotic cardiovascular diseases. This study systematically reviewed the variability of brachial flow-mediated dilation (FMD) and carotid-femoral pulse wave velocity (cfPWV) from the acute phase of COVID-19 through 16 months of follow-up (F/U). Databases including PubMed, Web of Science, MEDLINE, and Embase were screened for a meta-analysis without language or date restrictions (PROSPERO reference CRD42025642888, last search conducted on 1 February 2025). The quality of the included studies was assessed using the Newcastle-Ottawa Quality Scale. We considered all studies (interventional pre-post studies, prospective observational studies, prospective randomized, and non-randomized trials) that assessed FMD or cfPWV in adults (aged ≥ 18 years) with or after laboratory-confirmed COVID-19 compared with non-COVID-19 controls or that assessed changes in these parameters during the F/U. Twenty-one studies reported differences in FMD, and 18 studies examined cfPWV between COVID-19 patients and control groups during various stages: acute/subacute COVID-19 (≤30 days from disease onset), early (>30-90 days), mid-term (>90-180 days), late (>180-270 days), and very late (>270 days) post-COVID-19 recovery. Six studies assessed variability in FMD, while nine did so for cfPWV during the F/U. Data from 14 FMD studies (627 cases and 694 controls) and 15 cfPWV studies (578 cases and 703 controls) were included in our meta-analysis. FMD showed a significant decrease compared to controls during the acute/subacute phase (standardized mean difference [SMD]= -2.02, p < 0.001), with partial improvements noted from the acute/subacute phase to early recovery (SMD = 0.95, p < 0.001) and from early to mid-term recovery (SMD = 0.92, p = 0.006). Normalization compared to controls was observed in late recovery (SMD = 0.12, p = 0.69). In contrast, cfPWV values, which were higher than controls in the acute/subacute phase (SMD = 1.27, p < 0.001), remained elevated throughout the F/U, with no significant changes except for a decrease from mid-term to very late recovery (SMD= -0.39, p < 0.001). In the very late recovery, cfPWV values remained higher than those of controls (SMD = 0.45, p = 0.010). In the manuscript, we discuss how various factors, including the severity of acute COVID-19, the persistence of long-term COVID-19 syndrome, and the patient's initial vascular age, depending on metrics age and cardiovascular risk factors, influenced the time and degree of FMD and cfPWV improvement.

Neuroimaging studies have indicated that altered cerebral blood flow (CBF) was associated with the long-term symptoms of postacute sequelae of SARS-CoV-2 infection (PASC), also known as "long COVID". COVID-19 and long COVID were found to be strongly associated with host gene expression. Nevertheless, the relationships between altered CBF, clinical symptoms, and gene expression in the central nervous system (CNS) remain unclear in individuals with long COVID. This study aimed to explore the genetic mechanisms of CBF abnormalities in individuals with long COVID by transcriptomic-neuroimaging spatial association. Lower CBF in the left frontal-temporal gyrus was associated with higher fatigue and worse cognition in individuals with long COVID. This CBF pattern was spatially associated with the expression of 2,178 genes, which were enriched in the molecular functions and biological pathways of COVID-19. Our study suggested that lower CBF is associated with persistent clinical symptoms in long COVID individuals, possibly as a consequence of the complex interactions among multiple COVID-19-related genes, which contributes to our understanding of the impact of adverse CNS outcomes and the trajectory of development to long COVID.

Characterizing the paradigm and impact of long COVID is crucial for addressing this worldwide health challenge. This study aimed to investigate the prevalence of long COVID one year after primary Omicron infection and characterize differences in long-term health consequence between participants with persistent long COVID and those who fully recovered.

This a community-based cross-sectional study conducted from December 2023 to March 2024 at the China-Japan Friendship Hospital and 16 administrative districts in Beijing. 12,789 participants infected with Omicron between December 2022 and January 2023 were recruited through stratified multistage random sampling and included in the final analysis. Of them, 376 participants with persistent long COVID and 229 without long COVID were matched for further physical examinations. The primary outcome was the prevalence of long COVID one year after infection. Secondary outcomes included muscle strength, exercise capacity, health-related quality of life (HRQoL), mental health, work status, laboratory tests, and examinations.

Among 12,789 participants (media [IQR] age, 48.4 [37.3 to 61.4] years; 7817 females [61.1%]), 995 of them (7.8%) experienced long COVID within one year, with 651 (5.1%) having persistent symptoms. Fatigue (598/995 [60.1%]) and post-exertional malaise (367/995 [36.9%]) were the most common symptoms. Brain fog had the lowest resolution proportion as 4.2% within one year. The odds of long COVID increased with reinfections (odds ratios for one reinfection 2.592 [95% CI: 2.188 to 3.061]; two or more: 6.171 [3.227 to 11.557]; all p < 0.001). Participants with persistent long COVID had markedly lower muscle strength (upper-limb: 26.9 ± 12.4 vs. 29.1 ± 14.5 Kg; lower-limb: 40.0 [27.0 to 62.0] vs. 43.0 [28.0 to 59.0] s), worse exercise capacity and poorer HRQoL, and meaningful difference in laboratory tests results compared to those without long COVID. They also exhibited significantly higher proportions of abnormal lung function (FEV1 %pred<80%: 13.0% vs. 2.0%; DLco %pred<80%: 32.7% vs. 19.9%) and lung imaging abnormalities (23.5% vs. 13.6%).

The considerable health burden of long COVID and the progression of neurological symptoms following Omicron infection warrant close monitoring. Utilizing professional questionnaires and developing reliable diagnostic tools are necessary for improving diagnosis and treatment of long COVID.

This work was supported by Beijing Research Center for Respiratory Infectious Diseases (BJRID2024-012), Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2022-I2M-CoV19-005/CIFMS 2021-I2M-1-048), the National Natural Science Foundation of China (82241056/82200114/82200009), the New Cornerstone Science Foundation.

The long-term health impacts of COVID-19, including post-acute sequelae of SARS-CoV-2, remain insufficiently explored, especially concerning pre-existing cardiovascular risk factors in older adults. This study examines the association between these risk factors and post-acute sequelae of SARS-CoV-2 in this population.

A retrospective study of Brazilian adults aged = 60 years assessed the persistence of post-acute sequelae of SARS-CoV-2 three months after infection in 2020. Cardiovascular risk factors (obesity, smoking, high blood pressure, diabetes mellitus, hypercholesterolemia, and chronic kidney disease) were analyzed in relation to sequelae and adjusting for sociodemographic variables. Data were obtained from the Department of Epidemiological Surveillance in Roraima, Brazil.

Of the 1,322 participants (55% female; mean age 70.4 years, SD = 7.87), 61.7% (95% CI: 59.1-63.9) reported at least one post-acute sequelae of SARS-CoV-2 at the three-month follow-up. The likelihood of post-acute sequelae of SARS-CoV-2 was significantly higher in participants with diabetes mellitus (OR = 4.39; 95% CI: 3.42-5.66), tobacco use (OR = 3.93; 95% CI: 2.47-6.23), hypertension (OR = 3.62; 95% CI: 2.73-4.78), or hypercholesterolemia (OR = 3.58; 95% CI: 2.80-4.59). Chronic kidney disease (OR = 2.28; 95% CI: 1.59-3.25) and obesity (OR = 1.83; 95% CI: 1.28-2.61) were less strongly associated.

Pre-existing cardiovascular risk factors are linked to a higher likelihood of long-term COVID-19 sequelae in adults aged = 60 years old. Preventing and managing these factors are crucial for reducing the long-term effects of COVID-19, particularly during a pandemic.

Neurodegenerative diseases (NDs) and Long COVID represent critical and growing global health challenges, characterized by complex pathophysiological mechanisms including neuronal deterioration, protein misfolding, and persistent neuroinflammation. The emergence of innovative therapeutic approaches, such as whole-body hyperthermia (WBH), offers promising potential to modulate underlying pathophysiological mechanisms in NDs and related conditions like Long COVID. WBH, particularly in fever-range, enhances mitochondrial function, induces heat shock proteins (HSPs), and modulates neuroinflammation-benefits that pharmacological treatments often struggle to replicate. HSPs such as HSP70 and HSP90 play pivotal roles in protein folding, aggregation prevention, and cellular protection, directly targeting pathological processes seen in NDs like Alzheimer's, Parkinson's, and Huntington's disease. Preliminary findings also suggest WBH's potential to alleviate neurological symptoms in Long COVID, where persistent neuroinflammation and serotonin dysregulation are prominent. Despite the absence of robust clinical trials, the therapeutic implications of WBH extend to immune modulation and the restoration of disrupted physiological pathways. However, the dual nature of hyperthermia's effects-balancing pro-inflammatory and anti-inflammatory responses-emphasizes the need for dose-controlled applications and stringent patient monitoring to minimize risks in vulnerable populations. While WBH shows potential interest, significant challenges remain. These include individual variability in response, limited accessibility to advanced hyperthermia technologies, and the need for standardized clinical protocols. Future research must focus on targeted clinical trials, biomarker identification, and personalized treatment strategies to optimize WBH's efficacy in NDs and Long COVID. The integration of WBH into therapeutic paradigms could mark a transformative step in addressing these complex conditions.

The emergence of SARS-CoV-2 has precipitated a global pandemic with substantial long-term health implications, including the condition known as post-acute sequelae of SARS-CoV-2 infection (PASC), commonly referred to as Long COVID. PASC is marked by persistent symptoms such as fatigue, neurological issues, and autonomic dysfunction that persist for months beyond the acute phase of COVID-19. This review examines the potential role of herpesvirus reactivation, specifically Epstein-Barr virus (EBV) and cytomegalovirus (CMV), in the pathogenesis of PASC. Elevated antibody titers and specific T cell responses suggest recent herpesvirus reactivation in some PASC patients, although viremia is not consistently detected. SARS-CoV-2 exhibits endothelial trophism, directly affecting the vascular endothelium and contributing to microvascular pathologies. These pathologies are significant in PASC, where microvascular dysfunction may underlie various chronic symptoms. Similarly, herpesviruses like CMV also exhibit endothelial trophism, which may exacerbate endothelial damage when reactivated. Evidence suggests that EBV and CMV reactivation could indirectly contribute to the immune dysregulation, immunosenescence, and autoimmune responses observed in PASC. Additionally, EBV may play a role in the genesis of neurological symptoms through creating mitochondrial dysfunction, though direct confirmation remains elusive. The reviewed evidence suggests that while herpesviruses may not play a direct role in the pathogenesis of PASC, their potential indirect effects, especially in the context of endothelial involvement, warrant further investigation.

Long COVID (also known as post-acute sequelae of SARS-CoV-2 infection [PASC] or post-COVID syndrome) is characterized by persistent symptoms that extend beyond the acute phase of SARS-CoV-2 infection, affecting approximately 10% to over 30% of those infected. It presents a significant clinical challenge, notably due to pronounced neurocognitive symptoms such as brain fog. The mechanisms underlying these effects are multifactorial, with mounting evidence pointing to a central role of cerebromicrovascular dysfunction. This review investigates key pathophysiological mechanisms contributing to cerebrovascular dysfunction in long COVID and their impacts on brain health. We discuss how endothelial tropism of SARS-CoV-2 and direct vascular infection trigger endothelial dysfunction, impaired neurovascular coupling, and blood-brain barrier disruption, resulting in compromised cerebral perfusion. Furthermore, the infection appears to induce mitochondrial dysfunction, enhancing oxidative stress and inflammation within cerebral endothelial cells. Autoantibody formation following infection also potentially exacerbates neurovascular injury, contributing to chronic vascular inflammation and ongoing blood-brain barrier compromise. These factors collectively contribute to the emergence of white matter hyperintensities, promote amyloid pathology, and may accelerate neurodegenerative processes, including Alzheimer's disease. This review also emphasizes the critical role of advanced imaging techniques in assessing cerebromicrovascular health and the need for targeted interventions to address these cerebrovascular complications. A deeper understanding of the cerebrovascular mechanisms of long COVID is essential to advance targeted treatments and mitigate its long-term neurocognitive consequences.

The aging population in Europe faces a substantial burden from dementia, with vascular cognitive impairment and dementia (VCID) being a preventable cause. Atrial fibrillation (AF), a common cardiac arrhythmia, increases the risk of VCID through mechanisms such as thromboembolism, cerebral hypoperfusion, and inflammation. This review explores the epidemiology, pathophysiology, and preventive strategies for AF-related VCID. Epidemiological data indicate that AF prevalence rises with age, affecting up to 12% of individuals over 80. Neuroimaging studies reveal chronic brain changes in AF patients, including strokes, lacunar strokes, white matter hyperintensities (WMHs), and cerebral microbleeds (CMHs), while cognitive assessments show impairments in memory, executive function, and attention. The COVID-19 pandemic has exacerbated the underdiagnosis of AF, leading to an increase in undiagnosed strokes and cognitive impairment. Many elderly individuals did not seek medical care due to fear of exposure, resulting in delayed diagnoses. Additionally, reduced family supervision during the pandemic contributed to missed opportunities for early detection of AF and related complications. Emerging evidence suggests that long COVID may also elevate the risk of AF, further complicating the management of this condition. This review underscores the importance of early detection and comprehensive management of AF to mitigate cognitive decline. Preventive measures, including public awareness campaigns, patient education, and the use of smart devices for early detection, are crucial. Anticoagulation therapy, rate and rhythm control, and addressing comorbid conditions are essential therapeutic strategies. Recognizing and addressing the cardiovascular and cognitive impacts of AF, especially in the context of the COVID-19 pandemic, is essential for advancing public health.

Endocan has been scarcely explored in COVID-19, especially regarding its modulation by veno-venous extracorporeal membrane oxygenation (VV-ECMO), hypertension or previous renin-angiotensin-aldosterone system (RAAS) inhibitors treatment. We compared endocan and other endotheliitis markers in hospitalized COVID-19 patients and assessed their modulation by VV-ECMO, hypertension and previous RAAS inhibitors treatment.

Serum endocan, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin were measured in "severe" (n = 27), "critically ill" (n = 17) and "critically ill on VV-ECMO" (n = 17) COVID-19 patients at admission, days 3-4, 5-8 and weekly thereafter, and in controls (n = 23) at a single time point.

Admission endocan and VCAM-1 were increased in all patients, but "critically ill on VV-ECMO" patients had higher endocan and E-Selectin. Endocan remained elevated throughout hospitalization in all groups. "Severe" and "critically ill" hypertensive patients or previously treated with RAAS inhibitors had higher endocan and/or VCAM-1, but in VV-ECMO patients the raised endocan values seemed unrelated with these factors. Among all COVID-19 hypertensive patients, those with previous RAAS inhibitors treatment had higher endocan.

In our study, endocan stands out as the best marker of endotheliitis in hospitalized COVID-19 patients, being upregulated by VV-ECMO support, hypertension and previous RAAS inhibitor treatment.

Background: The lingering effects of SARS-CoV-2 infection, collectively known as post-COVID syndrome (PCS), affect a significant proportion of recovered patients, manifesting as persistent symptoms like fatigue, cognitive dysfunction, and exercise intolerance. Increasing evidence suggests that endothelial dysfunction and coagulation abnormalities play a central role in PCS pathophysiology. This study investigates hypercoagulability and endothelial dysfunction in PCS through thrombin generation and the von Willebrand factor (VWF)/ADAMTS13 axis. Methods: Plasma samples from 97 PCS patients recruited since October 2020 by the clinical research unit of the Brugmann University Hospital were analyzed. A thrombin generation test was performed on a St-Genesia® analyzer (Stago) using the Thromboscreen kit; VWF antigen was determined on a CS-2500 analyzer (Siemens); and ADAMTS-13 activity was determined using an ELISA kit (Technozym®) on an ElX808 plate reader. Results: Thrombin generation testing revealed elevated thrombin production in PCS patients, particularly when thrombomodulin was included. Although most PCS patients showed normalized VWF/ADAMTS13 ratios, 11.3% exhibited elevated ratios (≥1.5), associated with advanced age. Conclusions: Patients with PCS show a consistent pattern of prolonged thrombo-inflammatory dysregulation, highlighted by elevated in vitro thrombin generation and the persistence of abnormal VWF/ADAMTS-13 ratios in a subset of patients.

To identify the early predictors of a self-reported persistence of long COVID syndrome (LCS) at 12 months after hospitalisation and to propose the prognostic model of its development.

A combined cross-sectional and prospective observational study.

A tertiary care hospital.

221 patients hospitalised for COVID-19 who have undergone comprehensive clinical, sonographic and survey-based evaluation predischarge and at 1 month with subsequent 12-month follow-up. The final cohort included 166 patients who had completed the final visit at 12 months.

A self-reported persistence of LCS at 12 months after discharge.

Self-reported LCS was detected in 76% of participants at 3 months and in 43% at 12 months after discharge. Patients who reported incomplete recovery at 1 year were characterised by a higher burden of comorbidities (Charlson index of 0.69±0.96 vs 0.31±0.51, p=0.001) and residual pulmonary consolidations (1.56±1.78 vs 0.98±1.56, p=0.034), worse blood pressure (BP) control (systolic BP of 138.1±16.2 vs 132.2±15.8 mm Hg, p=0.041), renal (estimated glomerular filtration rate of 59.5±14.7 vs 69.8±20.7 mL/min/1.73 m2, p=0.007) and endothelial function (flow-mediated dilation of the brachial artery of 10.4±5.4 vs 12.4±5.6%, p=0.048), higher in-hospital levels of liver enzymes (alanine aminotransferase (ALT) of 76.3±60.8 vs 46.3±25.3 IU/L, p=0.002) and erythrocyte sedimentation rate (ESR) (34.3±12.1 vs 28.3±12.6 mm/h, p=0.008), slightly higher indices of ventricular longitudinal function (left ventricular (LV) global longitudinal strain (GLS) of 18.0±2.4 vs 17.0±2.3%, p=0011) and higher levels of Hospital Anxiety and Depression Scale anxiety (7.3±4.2 vs 5.6±3.8, p=0.011) and depression scores (6.4±3.9 vs 4.9±4.3, p=0.022) and EFTER-COVID study physical symptoms score (12.3±3.8 vs 9.2±4.2, p<0.001). At 1 month postdischarge, the persisting differences included marginally higher LV GLS, mitral E/e' ratio and significantly higher levels of both resting and exertional physical symptoms versus patients who reported complete recovery. Logistic regression and machine learning-based binary classification models have been developed to predict the persistence of LCS symptoms at 12 months after discharge.

Compared with post-COVID-19 patients who have completely recovered by 12 months after hospital discharge, those who have subsequently developed 'very long' COVID were characterised by a variety of more pronounced residual predischarge abnormalities that had mostly subsided by 1 month, except for steady differences in the physical symptoms levels. A simple artificial neural networks-based binary classification model using peak ESR, creatinine, ALT and weight loss during the acute phase, predischarge 6-minute walk distance and complex survey-based symptoms assessment as inputs has shown a 92% accuracy with an area under receiver-operator characteristic curve 0.931 in prediction of LCS symptoms persistence at 12 months.

In the present study, we provide evidence on the potential mechanisms involved in the residual pulmonary impairment described in long COVID syndrome. Data highlight that lung damage is significantly associated with a proinflammatory platelet phenotype, characterized mainly by the formation of platelet-leukocyte aggregates. In ex vivo experiments, long COVID plasma reproduces the platelet activation observed in vivo and highlights low-grade inflammation as a potential underpinning mechanism, exploiting a synergistic activity between C-reactive protein and subthreshold concentrations of interleukin-6. The platelet-activated phenotype is blunted by anti-inflammatory and antiplatelet drugs, suggesting a potential therapeutic option in this clinical setting.

Persistent elevation of biomarkers associated with endothelial dysfunction in convalescent COVID-19 patients has been linked to an increased risk of long-term cardiovascular complications, including long COVID syndrome. Sulodexide, known for its vascular endothelial affinity, has demonstrated pleiotropic protective properties. This study aims to evaluate the impact of sulodexide on serum levels of endothelial dysfunction biomarkers in patients during the convalescent phase of COVID-19.

We conducted a double-blind, single-center, randomized, placebo-controlled trial in Mexico, comparing sulodexide (250 LRU orally, twice daily) with placebo over 8 weeks in adult patients during early COVID-19 convalescence. Differences in serum biomarkers between the groups were analyzed using repeated measures and post hoc tests, with Thrombomodulin (TM) as the primary endpoint.

Among 206 analyzed patients (103 in each group), at week 8, the sulodexide group exhibited significantly lower mean levels of Thrombomodulin (TM) (25.2 ± 7.9 ng/mL vs 29.9 ± 14.7 ng/mL, P = .03), von Willebrand Factor (vWF) (232 ± 131 U/dL vs 266 ± 122 U/dL, P = .02) and Interleukin-6 (IL-6) (12.5 ± 13.2 pg/mL vs 16.2 ± 16.5 pg/mL, P = .03) compared to the placebo group. D-dimer and C reactive protein (CRP) in the sulodexide group were also lowered. No significant differences were observed for P-selectin, fibrinogen, VCAM-1, or ICAM-1 levels.

Patients in the convalescent phase of COVID-19 who received sulodexide for eight weeks showed a reduction in TM, vWF, D-dimer, CRP, and IL-6 serum levels compared to placebo. These findings suggest a potential protective effect of sulodexide against thromboinflammation and endothelial damage.

The complex link between COVID-19 and immunometabolic diseases demonstrates the important interaction between metabolic dysfunction and immunological response during viral infections. Severe COVID-19, defined by a hyperinflammatory state, is greatly impacted by underlying chronic illnesses aggravating the cytokine storm caused by increased levels of Pro-inflammatory cytokines. Metabolic reprogramming, including increased glycolysis and altered mitochondrial function, promotes viral replication and stimulates inflammatory cytokine production, contributing to illness severity. Mitochondrial metabolism abnormalities, strongly linked to various systemic illnesses, worsen metabolic dysfunction during and after the pandemic, increasing cardiovascular consequences. Long COVID-19, defined by chronic inflammation and immune dysregulation, poses continuous problems, highlighting the need for comprehensive therapy solutions that address both immunological and metabolic aspects. Understanding these relationships shows promise for effectively managing COVID-19 and its long-term repercussions, which is the focus of this review paper.

Significant progress has been made in treating Coronavirus disease (COVID) - an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). An ominous turn in the pandemic is the evolving public health crisis emanating from persistent SARS-CoV-2 infection and its associated long-term impact. Long COVID or post-COVID syndrome describes protean symptoms that persist at least 3 months after the onset of acute illness and last for at least 2 months in individuals with a history of confirmed SARS-CoV-2 infection. Long COVID has become a public health concern. Millions of infected individuals are now facing chronic multi-organ failures, including neuropsychiatric, cardiovascular, pulmonary, and kidney complications. In general, the cause of long COVID syndrome is unclear but factors such as prolonged activation of immune responses, and viral persistence triggering transcription dysregulation of genes associated with normal thrombotic disease may play a role in cardiovascular complications. Although inflammatory biomarkers are reported in other disorders, it remains unclear whether similar biomarkers are associated with cardiovascular manifestations following COVID. Medications such as sulodexide directed at glycocalyx and coagulation have demonstrated benefits for long COVID in smaller studies. Here, we describe the outcomes of the symposium on the underlying cardiovascular mechanisms of the long COVID.

Since it first appeared, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has had a significant and lasting negative impact on the health and economies of millions of individuals all over the globe. At the level of individual health too, many patients are not recovering fully and experiencing a long-term condition now commonly termed 'long-COVID'. Long-COVID is a collection of symptoms which must last more than 12 weeks following initial COVID infection, and which cannot be adequately explained by alternate diagnoses. The neurological and psychosocial impact of long-COVID is itself now a global health crisis and therefore preventing, diagnosing, and managing these patients is of paramount importance. This review focuses primarily on: neurological functioning deficits; mental health impacts; long-term mood problems; and associated psychosocial issues, among patients suffering from long-COVID with an eye towards the neurological basis of these symptoms. A concise account of the clinical relevance of the neurological and psychosocial impacts of long-COVID, the effects on long-term morbidity, and varied approaches in managing patients with significant chronic neurological symptoms and conditions was extracted from the literature, analysed and reported. A comprehensive account of plausible pathophysiological mechanisms involved in the development of long-COVID, its management, and future research needs have been discussed.

Hypercoagulation is central to the pathogenesis of acute and post-acute COVID-19. This prospective observational study explored whether rotational thromboelastometry (ROTEM), a method that unveils coagulation status, predicts outcomes of hospitalized patients with COVID-19 pneumonia. We investigated 62 patients using ROTEM that was conducted at enrollment, clinical deterioration, discharge and follow-up visits 1 and 3 months post-discharge. A hypercoagulable ROTEM was more common at clinical deterioration than at enrollment and the levels of hypercoagulable ROTEM indices correlated with the clinical severity score. Hypercoagulable ROTEM at enrollment was not associated with in-hospital death. Patients with hypercoagulable ROTEM at enrollment, discharge and 1 month post-discharge had an increased risk of persistent symptoms 1 and 3 months after discharge. Patients with hypercoagulable ROTEM at enrollment, discharge, and 1 month after discharge were more likely to have lung diffusion capacity (DLco) impairment 3 months after discharge. High levels of hypercoagulable ROTEM indices were associated with the increased risk of persistent symptoms at later stages of the disease. In a multivariate analysis, (i) hypercoagulable ROTEM at discharge and female gender were linked to the presence of symptoms at one month post-discharge, (ii) hypercoagulable ROTEM at one month after discharge was linked to the presence of symptoms at three months post-discharge, (iii) hypercoagulable ROTEM at enrollment and at discharge and female gender were linked to the presence of impaired DLco at three months post-discharge. Excessive coagulation may contribute to long-COVID pathogenesis and ROTEM findings during hospitalization may predict post-acute-COVID-19 sequelae in patients with COVID-19-related pneumonia.

The thrombo-inflammatory response and outcomes of community-acquired pneumonia (CAP) due to various organisms (non-COVID-19 CAP) versus CAP due to a single virus, SARS-CoV-2 (i.e., COVID-19) may differ.

Adults hospitalized with non-COVID-19 CAP (December 1, 2021-June 15, 2023) or COVID-19 (March 2, 2020-June 15, 2023) in Canada. We compared non-COVID-19 CAP and COVID-19 baseline, thrombo-inflammatory response, and mortality. We measured plasma cytokine and coagulation factor levels in a sample of patients, did hierarchical clustering, and compared cytokine and coagulation factor levels.

In 2,485 patients (non-COVID-19 CAP, n = 719; COVID-19 patients, n = 2,157), non-COVID-19 CAP patients had significantly lower 28-day mortality (CAP vs. COVID-19 waves 1 and 2; 10% vs. 18% and 16%, respectively), intensive care unit admission (CAP vs. all waves; 15% vs. 39%, 37%, 33%, and 24%, respectively), invasive ventilation (CAP vs. waves 1, 2, and 3 patients; 11% vs. 25%, 20%, and 16%), vasopressor use (CAP 12% vs. 23%, 21%, and 18%), and renal replacement therapy use (CAP 3% vs. Omicron 7%). Complexity of hierarchical clustering aligned directly with mortality: COVID-19 wave 1 and 2 patients had six clusters at admission and higher mortality than non-COVID-19 CAP and Omicron that had three clusters at admission. Pooling all COVID-19 waves increased complexity with seven clusters on admission.

Complex thrombo-inflammatory responses aligned with mortality of CAP. At a fundamental level, the human thrombo-inflammatory response to a brand new virus was "confused" whereas humans had eons of time to develop a more concise efficient thrombo-inflammatory host response to CAP.

Post-COVID-19 condition (PCC) is emerging as a common and debilitating condition with few treatment options.

To assess the effectiveness of a brief outpatient rehabilitation program based on a cognitive and behavioral approach for patients with PCC.

Patients with mild to moderate PCC were randomized 1:1 to an established transdiagnostic rehabilitation program or care as usual at a single referral center recruiting from the region of the South-Eastern Norway Regional Health Authority. Participants were followed up after treatment completion and 12 months after enrollment using participant-reported outcome measures. Data were collected from February 22, 2022, until April 15, 2024. Intention-to-treat analysis was performed.

The program consisted of 2 to 8 outpatient encounters with approximately 2 to 6 weeks between each encounter. The intervention was theoretically grounded in the cognitive activation theory of stress, and physicians and physiotherapists were trained in cognitive and behavioral approaches with targeted negative stimuli and response outcome expectancies being particularly important.

Participant-reported physical function assessed by the Short-Form Health Survey 36 Physical Function Subscale (SF-36-PFS) served as the primary outcome. Secondary outcome measures were the remaining subscales of the SF-36, return to work self-efficacy and symptom scores on fatigue, postexertional malaise, breathlessness, cognitive difficulties, sleep problems, anxiety and depression symptoms, and smell and taste abnormalities. Safety measures included primary health care contacts; hospital admissions; initiation of pharmacologic and/or nonpharmacologic therapy; occurrence of novel disease, illness, or other health problems; worsening of selected key symptoms; working abilities; and thoughts of suicide.

A total of 473 patients with mild to moderate PCC were assessed for eligibility (n = 364 physician referred; n = 109 self-referred); 314 were included (225 females [72%]; mean [SD] age, 43 [12] years) and 231 completed the primary end point evaluation. The SF-36-PFS scores improved statistically and clinically significantly in the intervention group (score difference between groups, 9.2; 95% CI, 4.3-14.2; P < .001; Cohen d = 0.43; intention-to-treat analysis). The effect was sustained over time. Most secondary and safety measures favored the intervention.

In this randomized clinical trial, a brief outpatient rehabilitation program with a cognitive and behavioral approach in patients with PCC was effective and safe. This trial adds to the evidence supporting such interventions in routine clinical care. Future research should investigate which elements of this approach are the most effective and identify subgroups for which the current treatment is most relevant.

ClinicalTrials.gov Identifier: NCT05196451.

Since widespread vaccination against COVID-19, the development of effective antiviral drugs, and the decreasing number of patients with COVID-19 in intensive care, the risk from SARS-CoV-2 infection appears less threatening. However, studies show that a significant number of patients suffer from long-term sequelae, even months after SARS-CoV-2 infection. The so-called post-COVID syndrome (PCS) often presents a diagnostic and treatment challenge for physicians. This study protocol describes the "All Eyes on PCS" study, which aims to investigate the retinal microvasculature in PCS patients and COVID-19-recovered patients to provide new insights into the pathophysiology of PCS. "All Eyes on PCS" is a prospective, case-control study with the primary objective of detecting endothelial dysfunction (ED) in patients with PCS. Therefore, we intend to recruit patients with PCS, fully SARS-CoV-2-infection-recovered (CR) participants, and SARS-CoV-2-infection-naïve (CN) participants. Baseline measurements will include: (1) patient-specific characteristics, (2) biochemistry, (3) retinal vessel analysis (RVA), (4) survey questionnaires as patient-reported outcomes measurements (PROMs), (5) optical coherence tomography (OCT), OCT angiography (OCTA), and adaptive optics (AO), (6) blood pressure recordings, (7) handgrip strength test. After 6 months, baseline measurements will be repeated in the PCS cohort, and after 1 year, a telephone query will be conducted to assess residual symptoms and treatment needs. The aim of this study is to gain insight into the pathophysiology of PCS and to provide an objective biomarker for diagnosis and treatment, while also creating a comprehensive clinical database of PCS patients.ClinicalTrials.gov Identifier: NCT05635552; Date: 2.12.2022.

Long COVID, also known as PASC (post-acute sequelae of SARS-CoV-2), is a complex infection-associated chronic condition affecting tens of millions of people worldwide. Many aspects of this condition are incompletely understood. Among them is how this condition may manifest itself in older adults and how it might impact the older population. Here, we briefly review the current understanding of PASC in the adult population and examine what is known on its features with aging. Finally, we outline the major gaps and areas for research most germane to older adults.

There is increasing evidence that COVID-19 induces endothelial dysfunction that may precede thrombotic and cardiovascular complications. The aim of this study is to evaluate endothelial function using peripheral arterial tonometry (EndoPAT). The primary endpoint is the hyperemic vascular response index (LnRHI) at two months post-discharge. Secondary endpoints include the LnRHI during hospitalization and at six-month follow-up, the proportion of patients with endothelial dysfunction (LnRHI ≤ 0.51), and the incidence of thrombotic events, cardiovascular complications, and mortality during the follow-up period. The study included 23 COVID-19 patients and 22 COVID-19-negative, matched controls. The patients exhibited a significant reduction in the LnRHI at two months post-discharge compared to the controls (median = 0.55 [IQR: 0.49-0.68] vs. median = 0.70 [IQR: 0.62-0.83]; p = 0.012). The difference in the LnRHI between patients and controls was evident from hospitalization and persisted at two and six months without significant temporal changes. The proportion of COVID-19 patients with endothelial dysfunction (LnRHI ≤ 0.51) was 61% during hospitalization and 55% at six months. There was no significant difference in thrombotic or cardiovascular events, nor in mortality. This study demonstrates that COVID-19 adversely affects endothelial function, as evidenced by a reduction in the hyperemic vascular response index, and endothelial dysfunction may also persist.

COVID-19 infectious is still a widely prevalent disease today. Although most patients with COVID-19 infection are mild. Some patients still develop to post-COVID-19 conditions, significantly increasing the perioperative cardiovascular risks. To better assess and prevent the perioperative cardiovascular risks of patients with COVID-19 infection, the safety and effectiveness of clinical practice can be improved through comprehensive measures, such as medical history collection, detection of symptoms and signs, application of auxiliary examinations, selection of scales and related rehabilitation treatment.

The rapid global spread of a new coronavirus disease known as COVID-19 has led to a significant increase in mortality rates, resulting in an unprecedented worldwide pandemic.

The impact of COVID-19, particularly its long-term effects, has also had a profound effect on the health and well-being of individuals.Metabolic syndrome increases the risk of heart and brain diseases, presenting a significant danger to human well-being.

The prognosis of long COVID and the progression of metabolic syndrome interact with each other, but there is currently a lack of systematic reports.In this paper, the pathogenesis, related treatment and prognosis of long COVID and metabolic syndrome are systematically reviewed.

Long COVID, a type of post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PASC) defined by medically unexplained symptoms following infection with SARS-CoV-2, is a newly recognized infection-associated chronic condition that causes disability in some people. Substantial progress has been made in defining its epidemiology, biology, and pathophysiology. However, there is no cure for the tens of millions of people believed to be experiencing long COVID, and industry engagement in developing therapeutics has been limited. Here, we review the current state of knowledge regarding the biology and pathophysiology of long COVID, focusing on how the proposed mechanisms explain the physiology of the syndrome and how they provide a rationale for the implementation of a broad experimental medicine and clinical trials agenda. Progress toward preventing and curing long COVID and other infection-associated chronic conditions will require deep and sustained investment by funders and industry.

COVID-19 posed a major challenge to the healthcare system and resources worldwide. The popularization of vaccines and the adoption of numerous prevention and control measures enabled the gradual end of the COVID-19 pandemic. However, successive occurrence of autoimmune diseases in patients with COVID-19 cannot be overlooked. Long COVID has been the major focus of research due to the long duration of different symptoms and the variety of systems involved. Autoimmunity may play a crucial role in the pathogenesis of long COVID. Here, we reviewed several autoimmune disorders occurring after COVID-19 infection and the pathogenesis of long COVID.

Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) infection can cause feared consequences, such as affecting microcirculatory activity. The combined use of HRV analysis, genetic algorithms, and machine learning classifiers can be helpful in better understanding the characteristics of microcirculation that are mainly affected by COVID-19 infection.

This study aimed to verify the presence of microcirculation alterations in patients with COVID-19 infection, performing Heart Rate Variability (HRV) parameters analysis extracted from PhotoPlethysmoGraphy (PPG) signals. The dataset included 97 subjects divided into two groups: healthy (50 subjects) and patients affected by mild-severity COVID-19 (47 subjects). A total of 26 parameters were extracted by the HRV analysis and were investigated using genetic algorithms with three different subject selection methods and five different machine learning classifiers.

Three parameters: meanRR, alpha1, and sd2/sd1 were considered significant, combining the results obtained by the genetic algorithm. Finally, machine learning classifications were performed by training classifiers with only those three features. The best result was achieved by the binary Decision Tree classifier, achieving accuracy of 82%, specificity (or precision) of 86%, and sensitivity of 79%.

The study's results highlight the ability to use HRV parameters extraction from PPG signals, combined with genetic algorithms and machine learning classifiers, to determine which features are most helpful in discriminating between healthy and mild-severity COVID-19-affected subjects.

For many years, it has been known that von Willebrand factor (VWF) interacts with factor VIII, collagen, and platelets. In addition, the key roles played by VWF in regulating normal hemostasis have been well defined. However, accumulating recent evidence has shown that VWF can interact with a diverse array of other novel ligands. To date, over 60 different binding partners have been described, with interactions mapped to specific VWF domains in some cases. Although the biological significance of these VWF-binding interactions has not been fully elucidated, recent studies have identified some of these novel ligands as regulators of various aspects of VWF biology, including biosynthesis, proteolysis, and clearance. Conversely, VWF binding has been shown to directly affect the functional properties for some of its ligands. In keeping with those observations, exciting new roles for VWF in regulating a series of nonhemostatic biological functions have also emerged. These include inflammation, wound healing, angiogenesis, and bone metabolism. Finally, recent evidence supports the hypothesis that the nonhemostatic functions of VWF directly contribute to pathogenic mechanisms in a variety of diverse diseases including sepsis, malaria, sickle cell disease, and liver disease. In this manuscript, we review the accumulating data regarding novel ligand interactions for VWF and critically assess how these interactions may affect cellular biology. In addition, we consider the evidence that nonhemostatic VWF functions may contribute to the pathogenesis of human diseases beyond thrombosis and bleeding.

The 2019 coronavirus disease (COVID-19), triggered by the severe acute respiratory syndrome coronavirus (SARS-CoV-2), has seen numerous individuals undergo and recover from it, drawing extensive attention to their health conditions. Extensive studies indicate that even after surpassing the acute phase of infection, patients continue to experience persistent symptoms such as fatigue, pain, depression, weakening, and anosmia. COVID-19 appears not to have concluded but rather to persist long-term in certain individuals, termed as "long COVID." This represents a heterogeneous ailment involving multiple organ systems, with a perceived complex and still elusive pathogenesis. Among patients with long COVID, observations reveal immune dysregulation, coagulation impairments, and microbial dysbiosis, considered potential mechanisms explaining sustained adverse outcomes post COVID-19. Based on the multifactorial nature, varied symptoms, and heterogeneity of long COVID, we have summarized several categories of current therapeutic approaches. Furthermore, the symptoms of long COVID resemble those of other viral illnesses, suggesting that existing knowledge may offer novel insights into long-term COVID implications. Here, we provide an overview of existing literature associated with long COVID and summarize potential mechanisms, treatment modalities, and other analogous conditions. Lastly, we underscore the inadequacies in long COVID treatment approaches and emphasize the significance of conducting further research and clinical trials.

Data are limited on the impact of commencing antiplatelet therapy on von Willebrand Factor Antigen (VWF:Ag) or von Willebrand Factor propeptide (VWFpp) levels and ADAMTS13 activity, and their relationship with platelet reactivity following TIA/ischaemic stroke. In this pilot, observational study, VWF:Ag and VWFpp levels and ADAMTS13 activity were quantified in 48 patients ≤4 weeks of TIA/ischaemic stroke (baseline), and 14 days (14d) and 90 days (90d) after commencing aspirin, clopidogrel or aspirin+dipyridamole. Platelet reactivity was assessed at moderately-high shear stress (PFA-100® Collagen-Epinephrine / Collagen-ADP / INNOVANCE PFA P2Y assays), and low shear stress (VerifyNow® Aspirin / P2Y12, and Multiplate® Aspirin / ADP assays). VWF:Ag levels decreased and VWFpp/VWF:Ag ratio increased between baseline and 14d and 90d in the overall population (P ≤ 0.03). In the clopidogrel subgroup, VWF:Ag levels decreased and VWFpp/VWF:Ag ratio increased between baseline and 14d and 90d (P ≤ 0.01), with an increase in ADAMTS13 activity between baseline vs. 90d (P ≤ 0.03). In the aspirin+dipyridamole subgroup, there was an inverse relationship between VWF:Ag and VWFpp levels with both PFA-100 C-ADP and INNOVANCE PFA P2Y closure times (CTs) at baseline (P ≤ 0.02), with PFA-100 C-ADP, INNOVANCE PFA P2Y and C-EPI CTs at 14d (P ≤ 0.05), and between VWF:Ag levels and PFA-100 INNOVANCE PFA P2Y CTs at 90d (P = 0.03). There was a positive relationship between ADAMTS13 activity and PFA-100 C-ADP CTs at baseline (R2 = 0.254; P = 0.04). Commencing/altering antiplatelet therapy, mainly attributed to commencing clopidogrel in this study, was associated with decreasing endothelial activation following TIA/ischaemic stroke. These data enhance our understanding of the impact of VWF:Ag and VWFpp especially on ex-vivo platelet reactivity status at high shear stress after TIA/ischaemic stroke.