Peptide-like 3CLpro covalent binding inhibitors are the most effective antiviral drugs for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Their covalent warheads were designed based on the addition reaction activity of the aldehyde (ketone) carbonyl or its derivative structures. These addition reactions between the warheads and the thiol of the 3CLpro are reversible, and the resulting hemimonothioacetals are chemically unstable. Herein, after DFT calculation, we designed thiol ester warheads using the principle of ester exchange reaction. Then, the warhead fluorescence probe binding experiment suggested these adducts of thiol ester warheads and 3CLpro protein are more stable than the hemimonothioacetals mentioned earlier. Therefore, new 3CLpro inhibitors were subsequently designed through a structure-based drug design method employing those thiol ester warheads. Those 3CLpro inhibitors demonstrated potent 3CLpro inhibitory activities and anti-coronavirus HCoV-OC43 activities. Among them, B16 stands out as the most promising, demonstrating not only the strongest anti-coronavirus HCoV-OC43 activity but also being a moderate inhibitor of CYP3A4, suggesting that B16 does not require co-administration with ritonavir in the treatment of SARS-CoV-2 infection. This work demonstrates the significant potential of thiol esters as novel chemical warheads in designing covalent binding inhibitors for 3CLpro and beyond.

Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) initiated a global pandemic resulting in an estimated 775 million infections with over 7 million deaths, it has become evident that COVID-19 is not solely a pulmonary disease. Emerging evidence has shown that, in a subset of patients, certain symptoms - including chest pain, stroke, anosmia, dysgeusia, diarrhea and abdominal pain - all indicate a role of vascular, neurological and gastrointestinal (GI) pathology in the disease process. Many of these disease processes persist long after the acute disease has been resolved, resulting in 'long COVID' or post-acute sequelae of COVID-19 (PASC). The molecular mechanisms underlying the acute and systemic conditions associated with COVID-19 remain incompletely defined. Appropriate animal models provide a method of understanding underlying disease mechanisms at the system level through the study of disease progression, tissue pathology, immune system response to the pathogen and behavioral responses. However, very few studies have addressed PASC and whether existing models hold promise for studying this challenging problem. Here, we review the current literature on cardiovascular, neurological and GI pathobiology caused by COVID-19 in patients, along with established animal models of the acute disease manifestations and their prospects for use in PASC studies. Our aim is to provide guidance for the selection of appropriate models in order to recapitulate certain aspects of the disease to enhance the translatability of mechanistic studies.

Cardiac troponin I (cTnI) is a critical protein biomarker for heart attack diagnosis. This study presents a thorough analysis of a novel biosensing device utilizing molecularly imprinted polymer nanoparticles (nanoMIPs) for detecting cTnI in clinical patient serum samples post myocardial infarction. The methodology, based on the heat-transfer method approach, offers faster measurements times than the current gold standard and sample volumes equivalent to a single blood drop. Biomarker binding shows performance comparable to a high-sensitivity ELISA, accurately identifying patients with elevated cTnI levels (R2 = 0.893). The cTnI peak concentration time variations are attributed to heterogeneous serum complexes, with different troponin complex sizes potentially generating differing thermal insulation levels. Comparison with an established patient database demonstrates robust correlations between our cTnI concentrations and clinical parameters (R2 = 0.855). This underscores the potential of nanoMIP sensors for sensitive cTnI detection, providing insights into post-heart attack biomarker levels. Furthermore, our methodology presents the additional benefits of being low cost and portable enabling measurements at time and place of patients. Consequently, it holds the potential to become a vital part of the diagnostic pathway for heart attack treatment, ultimately reducing healthcare costs and improving patient outcomes.

While ambient air pollution has been associated with COVID-19 outcomes, the role of early-life exposure in childhood COVID-19 infection and sequelae remains unexplored.

To assess the associations between early-life exposure to ambient air pollutants during and childhood COVID-19 infection and sequelae.

This cross-sectional retrospective cohort study surveyed families with children aged 3-6 years in families across nine Chinese cities between December 2019 and May 2023. The primary outcomes were doctor-diagnosed childhood COVID-19 infection and sequelae. Individual exposure to PM2.5, PM2.5-10, PM10, SO2, NO2, CO, O3, and temperature were estimated.

Among 20,012 children from 60,036 participants, 5.81 % were diagnosed with COVID-19 infection, and 1.72 % had sequelae. Prenatal CO exposure was associated with higher infection risk (OR: 1.33; 95 % CI: 1.05-1.69 per IQR increase). SO2 exposure during the first trimester (OR: 3.02; 95 % CI: 1.20-7.61), second trimester (OR: 4.00; 95 % CI: 1.56-10.27) and third trimester (OR: 3.84; 95 % CI: 1.69-8.76) of pregnancy and the first year of life (OR: 8.43; 95 % CI: 1.80-39.48) was strongly associated with sequelae. Pre-existing allergies and coarser particulate matter (PM2.5-10 and PM10) amplified these associations. High relative humidity significantly increased the effect of exposure to NO2 during four-six months before pregnancy and the second trimester of pregnancy, as well as O3 exposure during the first year on childhood COVID-19 infection.

Early-life exposure to air pollutants and interactions with allergic conditions and coarser particles influence childhood COVID-19 risks.

To assess the impact of post-COVID clinics by examining the association between their early usage and downstream health care utilization.

In a case-control study spanning data from March 11, 2020 to June 1, 2023, patients with Long COVID were identified from a major health system using diagnosis codes. The Fast, Large-Scale Almost Matching Exactly algorithm was used to match patients who presented early to post-COVID clinics with patients with Long COVID who did not attend such clinics. Matching was performed on demographic characteristics, acute COVID severity, comorbidities, diagnosis date, and vaccination, to reduce confounders for the comparison of the health care utilization and mortality between cohorts.

When exactly matching on all 46 features, the algorithm yielded 2814 matched patients, of whom 692 (24.6%; 66.6% females; mean [SD] age, 48.8 [14.5] years) were seen in post-COVID clinics within the first 6 months and 2122 (75.4%; 64.1% females; mean [SD] age, 49.7 [15.2] years) who were not. The average treatment effect (95% CI) of early post-COVID clinic usage was -0.60 (-0.83 to -0.39) on inpatient visits, -0.19 (-0.26 to -0.11) on emergency department visits, 7.62 (6.96-8.56) on outpatient visits, -$3467 (-$6267 to -$754) on estimated costs, and -0.006 (-0.010 to -0.003) on mortality.

Early usage of post-COVID clinics by patients with Long COVID is associated with not only fewer downstream inpatient stays, emergency department visits, estimated costs, and reduced mortality within the first 6 months but also greater outpatient utilization. Results suggest early post-COVID clinic involvement shifts care to outpatient settings, potentially reducing costs and mortality.

NETosis, the process through which neutrophils release neutrophil extracellular traps (NETs), has emerged as a crucial mechanism in host defense and the pathogenesis of autoimmune responses. During the SARS-CoV-2 pandemic, this process received significant attention due to the central role of neutrophil recruitment and activation in infection control. However, elevated neutrophil levels and dysregulated NET formation have been linked to coagulopathy and endothelial damage, correlating with disease severity and poor prognosis in COVID-19. Moreover, it is known that SARS-CoV-2 can induce persistent low-grade systemic inflammation, known as long COVID, although the underlying causes remain unclear. It has been increasingly acknowledged that excessive NETosis and NET generation contribute to further pathophysiological abnormalities following SARS-CoV-2 infection. This review provides an updated overview of the role of NETosis in autoimmune diseases, but also the relationship between COVID-19 and long COVID with autoimmunity (e.g., latent and overt autoimmunity, molecular mimicry, epitope spreading) and NETosis (e.g., immune responses, NET markers). Finally, we discuss potential therapeutic strategies targeting dysregulated NETosis to mitigate the severe complications of COVID-19 and long COVID.

We aim to estimate impact and projection of the COVID-19 pandemic on the burden of stroke at global, regional, and national levels METHODS: Utilizing standardized GBD methodologies, we conducted a comprehensive analysis of the prevalence, incidence, mortality, and disability-adjusted life years (DALYs) associated with stroke across 204 countries and regions spanning the periods from 1990 to 2019, 2019 to 2021, and 1990 to 2021. Our study provides detailed estimates accompanied by corresponding 95% uncertainty intervals (UIs), stratified by age and sex. To elucidate the temporal trends in stroke burden, we calculated the Estimated Annual Percentage Change (EAPC). Additionally, we explored the relationship between stroke burden and sociodemographic index (SDI) levels. The DALYs attributable to various risk factors for stroke were also analyzed. The burden of stroke in the next 20 years was also predicted.

From 2019 to 2021, the age-standardized prevalence rates (ASPR), incidence rates (ASIR), mortality rates (ASMR), and DALYs rates for stroke remained stable, diverging from the declining trends observed from 1990 to 2019 and from 1990 to 2021 at global, regional, and national levels, as indicated by both percent change analysis and EAPC analysis. This pattern was similarly reflected in the global burden of intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH), and ischemic stroke (IS). The changes in the burden of stroke, ICH, and IS from 2019 to 2021 were consistent between males and females. Importantly, the impact of COVID-19 on stroke burden remains substantial, irrespective of variations in the SDI. The IS burden increased in the next 20 years, and more attention should be paid on the stroke burden in young people.

Throughout the COVID-19 pandemic, the burden of stroke exhibited a stable trajectory, in contrast to the declining trend observed from 1990 to 2019 and from 1990 to 2021. The increased burden was observed in IS and young people in the next 20 years. These observations highlight the disparities in stroke burden that exist across different levels of socioeconomic development. The longitudinal epidemiological data presented in this study provide valuable insights into the significant shifts brought about by the COVID-19 pandemic, offering crucial information for researchers, policymakers, healthcare professionals, and other stakeholders.

We conducted a multicenter, observational, 12-month follow-up study to identify the extended health burden of severe COVID-19 pneumonia by characterizing long-term sequelae of acute infection in participants previously enrolled in clinical trials for severe COVID-19 pneumonia requiring hospitalization. Overall, 134 (77.5%) of 173 participants completed the study. At 12 months, 51 (29.5%) participants reported cough, 60 (34.7%) reported dyspnea, 56 (32.4%) had residual lung texture abnormalities on high-resolution computed tomography scans, 26 (15.0%) had impaired forced vital capacity, 52 (30.1%) had cognitive impairment, and 77 (44.5%) reported fatigue. Disease severity during acute infection and age were associated with persistent lung texture abnormalities; history of hypertension was associated with higher prevalence of fatigue and more frequent dyspnea and cough; and age and obesity were associated with long-term cognitive impairment. Our findings underscore the long-term health burden of severe COVID-19 pneumonia, reinforcing the importance of regular monitoring in older persons and those with underlying illnesses.

Accumulating clinical evidence suggests an intricate relationship between severe COVID-19 and preexisting metabolic complications, which share some metabolic dysregulations, including hyperglycaemia, hyperinsulinaemia and hyperlipidaemia. However, the potential role of these metabolic risk factors in SARS-CoV-2 infection and entry factor expression remains unknown. Here we report the implication of hyperglycaemia in SARS-CoV-2 infection and therapy. Hyperglycaemia, instead of hyperinsulinaemia and hyperlipidaemia, can significantly induce the expression of SARS-CoV-2 entry factors (Ace2, Tmprss2, Tmprss4, Furin and Nrp1) in liver cells, but not in lung and pancreatic cells, which is attenuated by mTOR inhibition. Correspondingly, pathological glucose levels promote SARS-CoV-2 entry into cultured hepatocytes in pseudovirus cell systems. Conversely, representative glucose-lowering drugs (metformin, dapagliflozin, sitagliptin and exenatide) are able to diminish the enhancement of entry factor expression and SARS-CoV-2 infection in cultured hepatocytes under pathological glucose conditions. Intriguingly, SARS-CoV-2 entry factors are increased in the livers of nonalcoholic fatty liver disease and diabetes patients. These results define hyperglycaemia as a key susceptibility factor for hepatic SARS-CoV-2 infection, and provide insights into the clinical application of glucose-lowering therapies in COVID-19 patients under comorbid hyperglycaemia conditions.

COVID-19 is one of the most pressing public health issues worldwide. The sequelae of COVID-19 however remains unclear. We performed a systematic assessment of sequelae across all body systems, focusing on whether COVID-19 is associated with increased risk of hospitalization for various diseases.

In this cohort study, we examined 135 disorders in UK biobank (UKBB) (N = 412,096; age: 50-87). We also conducted analysis for new-onset and recurrent cases, and employed the prior event rate adjustment (PERR) approach to minimize effects of unmeasured confounders. Time-dependent effects were also tested.

Compared to individuals with no known COVID-19 history, those with severe COVID-19 (hospitalized) exhibited increased hazards of hospitalization due to multiple disorders (median follow-up = 261 days), including disorders of respiratory, cardiovascular, neurological, gastrointestinal, genitourinary, musculoskeletal systems, as well as injuries, infections and non-specific symptoms. Notably, severe COVID-19 was associated with increased hospitalization risks in 77 out of the 107 disease categories with ≥ 5 events in both groups. These results remained largely consistent in sensitivity analyses. Mild (non-hospitalized) COVID-19 was associated with increased risk of hospitalization for several disorders: aspiration pneumonitis, musculoskeletal pain and other general signs/symptoms. The risk of hospitalizations following infection was generally higher during the pre-vaccination era.

This study revealed increased risk of hospitalization from a wide variety of pulmonary and extra-pulmonary diseases after COVID-19, especially for severe infections. The findings may have important clinical implications, such as the need for closer monitoring and risk assessment of relevant sequelae, and allocating more resources toward prevention and treatment of such sequelae.

The COVID-19 pandemic disrupted healthcare systems and possibly impacted the management of heart failure (HF). This study examined the impact of the pandemic on HF hospitalization activities, outcomes, and costs in Victoria, Australia.

Data on HF hospitalizations were acquired from the Victorian Admitted Episodes Dataset. All consecutive patients hospitalized for HF in both public and private hospitals in Victoria between February 2019 and March 2021 were extracted using the International Statistical Classification of Diseases and Related Health Problems, 10th Revision, Australian Modification. Data were analysed using descriptive analysis and interrupted time series analysis. A total of 85 564 completed admissions were identified, of which 45 080 were hospitalized in the pre-COVID-19 period and 40 484 were hospitalized in the COVID-19 impacted period. A higher average cost per completed admission in the COVID-19 impacted period was observed, while average length of stay (LOS) was not different between the two periods. It was revealed that monthly total LOS and hospitalization activity cost across all HF admissions dropped at the beginning of the pandemic and continued to decrease until the end of the observation period. However, these changes were not statistically significant.

The impacts of COVID-19 on HF hospitalization activities and associated outcomes at the beginning of the pandemic appeared relatively small and were not sustained. Further studies using other data (i.e. linkage data) are required to understand if, or how, the pandemic impacted on HF management in Australia, especially in the long COVID-19 era.

Real-world data indicate that the management of low-density lipoprotein cholesterol (LDL-C) is suboptimal in clinical practice and that many patients fail to reach guideline-recommended LDL-C goals. This may be due in part to physician inertia with regard to prescribing appropriate lipid-lowering therapies or poor adherence to such therapies in real-world practice. Shared decision-making is a collaborative process in which patients and healthcare professionals work together to develop treatment plans and management strategies that consider an individual's values and preferences, as well as clinical evidence. In this commentary, two preventive cardiologists and a nurse practitioner working in US practice discuss their real-world experiences of shared decision-making as well as key benefits such as helping to tackle the negative impacts of medical misinformation to restore patients' trust in healthcare professionals. Other potential benefits of shared decision-making include increased adherence to therapy and greater trust between patients and healthcare professionals. Finally, the authors discuss proposed solutions for potential barriers to the implementation of shared decision-making, including the support of a multidisciplinary team, the provision of learning materials from trustworthy sources, and tailoring of discussions to the individual patient.

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.

It has been found that individuals with psychiatric illnesses are predisposed to an elevated risk of cardiovascular diseases (CVDs). Mood swing is a clinically relevant characteristic linked to psychiatric disorders. This study examined the possible relationship between genetically predicted mood swings and CVDs risk. In this mediation Mendelian randomization (MR) study, we compiled data from genome-wide association studies examining mood swings (n = 451,619) and 5 CVDs among Europeans, including coronary artery disease (CAD) (n = 547,261), major coronary heart disease events (MCEs) (n = 361,194), all-cause heart failure (AHF) (n = 218,208), atrial fibrillation (n = 1030,836), and stroke (n = 446,696). The inverse variance weighting method was considered the primary assessment approach in MR analysis, and several sensitivity analyses were performed to evaluate the reliability of the results. Furthermore, the mediating effect of lifestyle factors including smoking, alcohol intake, walking, and waist-hip ratio was explored by using a two-step MR. According to our MR analysis, mood swings were genetically associated with a higher risk of CAD (OR, 2.101; 95% CI, 1.200-3.679; P = .009), AHF (OR, 2.761; 95% CI, 1.312-5.810; P = .007), and MCE (OR, 1.048; 95% CI, 1.022-1.076; P < .001). In the two-step MR analysis, smoking may mediate the causal pathways from mood swings to CAD (27%), MCE (18%), and AHF (26%). Our MR study revealed a potential causal relationship between mood swings and CVDs, smoking may play an important role in it, highlighting the need for regulating mood stability and build a healthy lifestyle to prevent the onset of CVDs. However, due to the limitations of MR, further research is needed to confirm these associations and clarify the underlying mechanisms.

People with long COVID report prolonged, multisystem involvement and significant disability. This study aimed to determine long COVID prevalence and factors associated with it among US adults using nationally representative data.

This cross-sectional analysis utilized data from 2022 Behavioral Risk Factor Surveillance System survey, a nationally representative telephone survey conducted among noninstitutionalized adults aged ≥ 18 years residing in the United States. Age-adjusted prevalence of long COVID was calculated using weighted survey analysis. Poisson regression was employed to assess adjusted prevalence ratios (aPRs) associated with long COVID across various demographic, socioeconomic and health-related characteristics.

Among 390,233 participants, 120,178 reported COVID-19, with 25,582 experiencing long COVID. Age-adjusted prevalence of self-reported COVID-19 and long COVID were estimated at 34.1% (95% CI, 33.7-34.4%) and 7.2% (95% CI, 7.0-7.4%) as of 2022, respectively. Among adults reporting COVID-19, 20.9% (95% CI, 20.5-21.4%) had ever experienced long COVID. An inverted U-shaped association was observed between long COVID risk and age, with the highest prevalence (23.5%) in the 45-54 age group. Long COVID was more prevalent among women (aPR, 1.40 [95% CI, 1.34-1.47]), individuals without a spouse (aPR, 1.06 [95% CI, 1.00-1.13]), uninsured (aPR, 1.16 [95% CI, 1.06-1.27]), and those with a high school education (aPR, 1.17 [95% CI, 1.12-1.23]), cardiovascular disease (aPR, 1.17 [95% CI, 1.09-1.25]), depressive disorder (aPR, 1.41 [95% CI, 1.34-1.48]), chronic obstructive pulmonary disease (aPR, 1.33 [95% CI, 1.24-1.43]), asthma (aPR, 1.28 [95% CI, 1.21-1.35]), and kidney disease (aPR, 1.11 [95% CI, 1.01-1.21]). Long COVID was less prevalent among non-Hispanic Black (aPR, 0.87 [95% CI, 0.81-0.95]), students (aPR, 0.87 [95% CI, 0.76-0.99]) or retired individuals (aPR, 0.89 [95% CI, 0.82-0.98]), and those with household incomes ≥$100,000 (aPR, 0.85 [95% CI, 0.79-0.92]).

Long COVID affects 7.2% of US adults, with higher vulnerability among women, middle-aged individuals, White individuals, socioeconomically disadvantaged groups, and those with chronic conditions. These findings underscore the need for targeted public health strategies to address disparities in long COVID burden and support high-risk populations.

Cardiac aging involves progressive structural, functional, cellular, and molecular changes that impair heart function. This review explores key mechanisms, including oxidative stress, mitochondrial dysfunction, impaired autophagy, and chronic low-grade inflammation. Excess reactive oxygen species (ROS) damage heart muscle cells, contributing to fibrosis and cellular aging. Mitochondrial dysfunction reduces energy production and increases oxidative stress, accelerating cardiac decline. Impaired autophagy limits the removal of damaged proteins and organelles, while inflammation activates signaling molecules that drive tissue remodeling. Gender differences reveal estrogen's protective role in premenopausal women, with men showing greater susceptibility to heart muscle dysfunction and injury. After menopause, women lose this hormonal protection, increasing their risk of cardiovascular conditions. Ethnic disparities, particularly among underserved minority populations, emphasize how social factors such as access to care, environment, and chronic stress contribute to worsening cardiovascular outcomes. The coronavirus disease pandemic has introduced further challenges by increasing the incidence of heart damage through inflammation, blood clots, and long-term heart failure, especially in older adults with existing metabolic conditions like diabetes and high blood pressure. The virus's interaction with receptors on heart and blood vessel cells, along with a weakened immune response in older adults, intensifies cardiac aging. Emerging therapies include delivery of therapeutic extracellular vesicles, immune cell modulation, and treatments targeting mitochondria. In addition, lifestyle strategies such as regular physical activity, nutritional improvements, and stress reduction remain vital to maintaining cardiac health. Understanding how these biological and social factors intersect is critical to developing targeted strategies that promote healthy aging of the heart.

With the COVID-19 pandemic becoming endemic, vigilance for Long COVID-related cardiovascular issues remains essential, though their specific pathophysiology is largely unexplored.

Our study investigates the persistent cardiovascular symptoms observed in individuals long after contracting SARS-CoV-2, a condition commonly referred to as "Long COVID", which has significantly affected millions globally.

We meticulously describe the cardiovascular outcomes in five patients, encompassing a range of severe conditions such as sudden cardiac death during exercise, coronary atherosclerotic heart disease, palpitation, chest tightness, and acute myocarditis.

All five patients were diagnosed with myocarditis, confirmed through endomyocardial biopsy and histochemical staining, which identified inflammatory cell infiltration in their heart tissue. Crucially, electron microscopy revealed widespread mitochondrial vacuolations and the presence of myofilament degradation within the cardiomyocytes of these patients. These findings were mirrored in SARS-CoV-2-infected mice, suggesting a potential underlying cellular mechanism for the cardiac effects associated with Long COVID.

Our findings demonstrate a profound impact of SARS-CoV-2 on mitochondrial integrity, shedding light on the cardiovascular implications of Long COVID.

Cardiovascular complications are a hallmark of Post-Acute Sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection (PASC), yet the mechanisms driving persistent cardiac dysfunction remain poorly understood. Emerging evidence implicates mitochondrial dysfunction in immune cells as a key contributor. This study investigated whether CD14++ monocytes from long COVID patients exhibit bioenergetic impairment, mitochondrial DNA (mtDNA) damage, and defective oxidative stress adaptation, which may underlie cardiovascular symptoms in PASC. CD14++ monocytes were isolated from 14 long COVID patients with cardiovascular symptoms (e.g., dyspnea, angina) and 10 age-matched controls with similar cardiovascular risk profiles. Mitochondrial function was assessed using a Seahorse Agilent Analyzer under basal conditions and after oxidative stress induction with buthionine sulfoximine (BSO). Mitochondrial membrane potential was measured via Tetramethylrhodamine Ethyl Ester (TMRE) assay, mtDNA integrity via qPCR, and reactive oxygen species (ROS) dynamics via Fluorescence-Activated Cell Sorting (FACS). Parallel experiments exposed healthy monocytes to SARS-CoV-2 spike protein to evaluate direct viral effects. CD14++ monocytes from long COVID patients with cardiovascular symptoms (n = 14) exhibited profound mitochondrial dysfunction compared to age-matched controls (n = 10). Under oxidative stress induced by buthionine sulfoximine (BSO), long COVID monocytes failed to upregulate basal respiration (9.5 vs. 30.4 pmol/min in controls, p = 0.0043), showed a 65% reduction in maximal respiration (p = 0.4035, ns) and demonstrated a 70% loss of spare respiratory capacity (p = 0.4143, ns) with significantly impaired adaptation to BSO challenge (long COVID + BSO: 9.9 vs. control + BSO: 54 pmol/min, p = 0.0091). Proton leak, a protective mechanism against ROS overproduction, was blunted in long COVID monocytes (3-fold vs. 13-fold elevation in controls, p = 0.0294). Paradoxically, long COVID monocytes showed reduced ROS accumulation after BSO treatment (6% decrease vs. 1.2-fold increase in controls, p = 0.0015) and elevated mitochondrial membrane potential (157 vs. 113.7 TMRE fluorescence, p = 0.0179), which remained stable under oxidative stress. mtDNA analysis revealed severe depletion (80% reduction, p < 0.001) and region-specific damage, with 75% and 70% reductions in amplification efficiency for regions C and D (p < 0.05), respectively. In contrast, exposure of healthy monocytes to SARS-CoV-2 spike protein did not recapitulate these defects, with preserved basal respiration, ATP production, and spare respiratory capacity, though coupling efficiency under oxidative stress was reduced (p < 0.05). These findings suggest that mitochondrial dysfunction in long COVID syndrome arises from maladaptive host responses rather than direct viral toxicity, characterized by bioenergetic failure, impaired stress adaptation, and mitochondrial genomic instability. This study identifies persistent mitochondrial dysfunction in long COVID monocytes as a critical driver of cardiovascular complications in PASC. Key defects-bioenergetic failure, impaired stress adaptation and mtDNA damage-correlate with clinical symptoms like heart failure and exercise intolerance. The stable elevation of mitochondrial membrane potential and resistance to ROS induction suggest maladaptive remodeling of mitochondrial physiology. These findings position mitochondrial resilience as a therapeutic target, with potential strategies including antioxidants, mtDNA repair agents or metabolic modulators. The dissociation between spike protein exposure and mitochondrial dysfunction highlights the need to explore host-directed mechanisms in PASC pathophysiology. This work advances our understanding of long COVID cardiovascular sequelae and provides a foundation for biomarker development and targeted interventions to mitigate long-term morbidity.

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.

Background: The association between Coronavirus Disease-2019 (COVID-19) and new-onset cardiomyopathy (NOC) is unclear. Objectives: We aim to assess the incidence of NOC in hospitalized COVID-19 patients and its impact on short- and long-term survival. Methods: We retrospectively studied 2219 COVID-19 patients hospitalized between March 2020 and February 2022 who underwent an in-hospital echocardiogram. NOC was defined as a left-ventricular ejection fraction (LVEF) reduction of >10%, resulting in an LVEF of <54% for females and <52% for males. The 30-day and 1-year survival outcomes in patients without and with NOC were studied. Results: Among 25,943 hospitalized COVID-19 patients, 2219 met our inclusion criteria, with 209 (9.4%) having NOC. NOC patients were more likely to be male (56.1% vs. 68.4%, p = 0.001) and have chronic kidney disease (51.4% vs. 60.3%, p = 0.018). They had a higher 30-day mortality rate (29.1% vs. 32%, p = 0.033), but the 1-year survival rate was similar between the patients without and with NOC (36.9% vs. 41.6%, p = 0.12). Multivariable regression revealed that advanced age, admission to intensive care unit, mechanical ventilation, treatment with glucocorticoids, and treatment with vasopressors were associated with higher odds of 30-day mortality in NOC patients. Only 74 (35.4%) NOC patients had follow-up echocardiograms after discharge, of which 47 showed persistent cardiomyopathy. Conclusions: NOC can affect around 1 out of 10 hospitalized COVID-19 patients undergoing echocardiography. While NOC was associated with worse short-term survival, it did not impact the long-term mortality of these patients. Persistent LVEF deficits in some patients emphasize the need for improved outpatient follow-up to identify at-risk individuals and optimize treatment.

There is significant overlap in clinical features between multisystem inflammatory syndrome in children (MIS-C) and Kawasaki disease (KD). We sought to compare the prevalence, severity, and associated factors for coronary artery (CA) involvement.

From January 1, 2020 through January 31, 2023, 1191 patients with MIS-C and 554 patients contemporaneously diagnosed with KD were enrolled into the International Kawasaki Disease Registry. Demographic and clinical features, laboratory values, maximum Z score in any CA branch at any time point, and worst left ventricular ejection fraction, were compared between groups. Factors associated with CA aneurysms (maximum Z score in any CA branch +2.5 or greater) were determined separately for each diagnosis using multivariable logistic regression analyses. The prevalence of CA aneurysms was lower for MIS-C versus KD (16% versus 25%, respectively; P<0.001) and less severe by size category (1.2% with medium/large CA aneurysm versus 9.6%, respectively). Male sex and lower nadir hemoglobin levels were associated with greater odds of CA aneurysms for both groups. Additional associated factors for KD patients included age<6 months, fewer clinical KD criteria (more incomplete presentation), presentation with shock, and greater total days of fever. There were no additional associated factors for patients with MIS-C. Using exploratory splines, there was a trend of improvement in Z scores within 30 days of illness for both MIS-C and KD for CA involvement other than large aneurysms.

CA involvement for patients with MIS-C was less prevalent and milder in severity compared with contemporaneous patients with KD, with fewer associated factors, and a high prevalence of regression to a normal luminal dimension.

Despite the potential association between herpes zoster infection and cardiovascular events, limited studies have investigated the relationship between live zoster vaccination and cardiovascular outcomes. This large-scale, population-based cohort study with a long-term follow-up aimed to investigate the association between live zoster vaccination and the risk of various cardiovascular events.

Data on comprehensive information of individuals aged ≥50 years from South Korea (n = 2 207 784) were included from 1 January 2012, to 31 December 2021. National insurance information from the Korea Health Insurance Review and Assessment Service, the national health examination results from the Korean National Health Insurance Service, and the live zoster vaccination data from the Korea Disease Control and Prevention Agency were merged. The risk of incident cardiovascular outcomes after live zoster vaccination was assessed compared with unvaccinated individuals. The primary outcome was the risk of cardiovascular diseases based on International Classification of Diseases, Tenth Revision code diagnosis. In propensity score-based overlap weighted cohorts, Cox proportional hazard models were used to estimate hazard ratios (HRs) for overall and specific cardiovascular outcomes, while calculating restricted mean survival time (RMST) for each outcome. The observation period was from 1 January 2012, to 31 January 2024. Multiple stratification analyses were performed.

After applying propensity score-based overlap weighting, 1 271 922 individuals were included [mean age, 61.3 years (standard deviation, 3.4); 548 986 (43.2%) male; median follow-up time, 6.0 years] in overlap-weighted cohort. Live zoster vaccination was associated with lower risks of overall cardiovascular events [HR 0.77, 95% confidence interval (CI) 0.76-0.78], particularly major adverse cardiovascular events [0.74 (0.71-0.77)], heart failure [0.74 (0.70-0.77)], cerebrovascular disorders [0.76 (0.74-0.78)], ischaemic heart disease [0.78 (0.76-0.80)], thrombotic disorders [0.78 (0.74-0.83)], and dysrhythmia [0.79 (0.77-0.81)]. The RMST difference for overall cardiovascular events following live zoster vaccination was 95.14 days per decade (95% CI 94.99-95.30). The protective association persisted up to 8 years, with the greatest reduction observed 2-3 years post-vaccination. The decrease in cardiovascular disease risk was more pronounced among males, individuals aged <60 years, those with unhealthy lifestyle habits, and those from low-income households and rural residents.

These findings suggest that live zoster vaccination may be beneficial as a public health strategy with potential implications for cardiovascular disease burden in the general population. This strategy may help address health disparities and mortality linked to cardiovascular complications.

Significant progress has been made in our understanding of the acute and chronic clinical and radiological manifestations of coronavirus-19 (COVID-19). This article provides an updated review on pulmonary COVID-19, while highlighting the key imaging features that can identify and distinguish acute COVID-19 pneumonia and its chronic sequelae from other diseases.

Acute COVID-19 pneumonia typically presents with manifestations of organizing pneumonia on computed tomography (CT). In cases of severe disease, patients clinically progress to acute respiratory distress syndrome, which manifests as diffuse alveolar damage on CT. The most common chronic imaging finding is ground-glass opacities, which commonly resolves, as well as subpleural bands and reticulation. Pulmonary fibrosis is an overall rare complication of COVID-19, with characteristic features, including architectural distortion, and traction bronchiectasis.

Chest CT can be a helpful adjunct tool in both diagnosing and managing acute COVID-19 pneumonia and its chronic sequelae. It can identify high-risk cases and guide decision-making, particularly in cases of severe or complicated disease. Follow-up imaging can detect persistent lung abnormalities associated with long COVID and guide appropriate management.

Hypertension is a leading cause of cardiovascular disease and affects about 1.3 billion adults worldwide. Despite interventions, awareness and control remain suboptimal and might have worsened due to the COVID-19 pandemic. This population-based study examines 20-year trends in hypertension prevalence, awareness, treatment, and control in Geneva, Switzerland (2005-2023).

This is a year-trends population-based study (Bus Sante) ongoing in Geneva, Switzerland. Data collected in this study were between 2005 and 2023. Hypertension trends and prevalence were stratified by sex, age, education, and income. Multivariable regression models adjusted for sociodemographic and health factors identified determinants of outcomes.

Overall, 11,278 individuals participated. Hypertension prevalence decreased from 38.9 % to 35.2 %, with greater reductions in individuals with primary education (-6.1 %) and low income (-6.1 %). Awareness remained stable with time. Uncontrolled hypertension decreased (44.9 % to 42.2 %, p = 0.01), with improvements in lower socioeconomic groups, and individuals with diabetes. Older women were more likely to have untreated (+16.1 %) and uncontrolled hypertension, while younger men exhibited higher unawareness rates (57.7 %). Having a doctor visit in the past 12 months was not associated with increased awareness.

Hypertension prevalence and control improved overall, with reduced socioeconomic disparities. However, some groups remain at risk and primary care is essential for better screening, awareness, treatment, and control of hypertension.

Inflammation and thrombosis are traditionally considered two separate entities of acute host responses to barrier breaks. While inciting inflammatory responses is a prerequisite to fighting invading pathogens and subsequent restoration of tissue homeostasis, thrombus formation is a crucial step of the hemostatic response to prevent blood loss following vascular injury. Though originally designed to protect the host, excessive induction of either inflammatory signaling or thrombus formation and their reciprocal activation contribute to a plethora of disorders, including cardiovascular, autoimmune, and malignant diseases. In this state-of-the-art review, we summarize recent insights into the intricate interplay of inflammation and thrombosis. We focus on the protective aspects of immunothrombosis as well as evidence of detrimental sequelae of thromboinflammation, specifically regarding recent studies that elucidate its pathophysiology beyond coronavirus disease 2019 (COVID-19). We introduce recently identified molecular aspects of key cellular players like neutrophils, monocytes, and platelets that contribute to both immunothrombosis and thromboinflammation. Further, we describe the underlying mechanisms of activation involving circulating plasma proteins and immune complexes. We then illustrate how these factors skew the inflammatory state toward detrimental thromboinflammation across cardiovascular as well as septic and autoimmune inflammatory diseases. Finally, we discuss how the advent of new technologies and the integration with clinical data have been used to investigate the mechanisms and signaling cascades underlying immunothrombosis and thromboinflammation. This review highlights open questions that will need to be addressed by the field to translate our mechanistic understanding into clinically meaningful therapeutic targeting.

Pulmonary arterial hypertension (PAH) is a pathological condition in which pulmonary artery pressure is elevated which causes patients to die of right heart failure. Chronic intermittent hypobaric hypoxia (CIHH) represents a novel method of intermittently exposing subjects to a simulated plateau hypobaric hypoxia environment. This study investigates the potential preventive and protective effects of CIHH on PAH.

Male Sprague-Dawley rats were randomly divided into four groups: control group (Con), chronic intermittent hypobaric hypoxia group (CIHH), pulmonary arterial hypertension group (PAH), chronic intermittent hypobaric hypoxia + pulmonary arterial hypertension group (CIHH + PAH). To evaluate the effects of CIHH on PAH, a range of techniques was employed, including pulmonary hemodynamics, vascular reactivity assay, Western blot, RNA sequencing, HE staining and co-immunoprecipitation.

CIHH was demonstrated to reduce pulmonary artery constriction and enhance relaxation, reducing the mean pulmonary artery pressure in PAH rats. This is achieved through attenuating the CaM/eNOS (Calmodulin,CaM)protein interaction and increasing the CaV1/eNOS (Caveolin-1,CaV1) protein interaction, thereby preventing eNOS overactivation contribution to improving NO bioavailability in PAH rats.

CIHH prevents PAH by maintaining eNOS homeostasis in PAH rats.

Cardiovascular disease (CVD) is a leading cause of death worldwide, and infections often worsen the clinical condition of these patients. Respiratory infections, either bacterial or viral sources, are important causes of high morbidity and mortality in older adults. Beyond the burden of infection-related complications, they are also associated with non-infection-related complications such as cardiovascular (CV) events. For example, herpes zoster is associated with an increased risk of stroke and myocardial infarction. Vaccination is an effective preventive strategy for patients with CVD by reducing viral and bacterial infections, and minimizing systemic inflammatory responses to support plaque stability and reduce the likelihood of CV events in high-risk patients, thereby reducing the risks of CV and non-CV hospitalizations and mortality. Despite evidence on the effectiveness, safety, and benefits of vaccines and recommendations to vaccinate older patients and those with risk factors, vaccination rates remain sub-optimal in this population. The Taiwan Society of Cardiology and the Infectious Diseases Society of Taiwan recently appointed a task force to formulate a consensus on vaccinations for adults with high CV risk or CVD. Based on the most up-to-date information, the consensus provides current evidence-based important recommendations.

Patients with pre-existing Parkinson's disease (PD) face higher risks of severe acute COVID-19 outcomes than matched controls, but long-term post-COVID-19 outcomes remain largely unknown. This study investigated clinical outcomes up to 3.5 years post-infection in a Bronx inner-city PD population.

This retrospective study evaluated 3512 patients with PD in the Montefiore Health System (January 2016-July 2023), which serves a large diverse population and was an epicenter of the early COVID-19 pandemic and subsequent infection surges. Comparisons were made with PD patients without a positive SARS-CoV-2 test (defined by polymerase chain reaction test). Outcomes were post-index date all-cause mortality, major adverse cardiovascular events (MACE), altered mental status, fatigue, dyspnea, headache, psychosis, dementia, depression, anxiety, dysphagia, falls, and orthostatic hypotension. Changes in Levodopa prescriptions were also tabulated. Adjusted hazard ratios (aHR) were computed accounting for competing risks.

PD patients with COVID-19 had similar demographics but a higher prevalence of pre-existing comorbidities compared to PD patients without COVID-19. PD patients with COVID-19 had greater risk of mortality (aHR = 1.58 [95% CI: 1.03, 2.41]), MACE (aHR = 1.57 [1.19, 2.07]), dyspnea, fatigue, and fall compared to PD patients without COVID-19. Levodopa dose adjustment was higher post-infection in the COVID-19 cohort.

Among PD patients, COVID-19 was associated with a higher risk of adverse long-term outcomes. PD patients who survive COVID-19 may benefit from heightened clinical awareness and close follow-up. Findings highlight the need to improve post-COVID care for PD patients to mitigate disease progression and maintain quality of life.

Increased risks of death and hospitalisation for organ disorders after discharge for COVID-19 hospitalisation have been reported but their persistence is unknown.

We conducted a nationwide cohort study using the French claims database; subjects hospitalised for COVID-19 between 2020/01/01 and 2020/08/30 were followed up to 30-months and matched to controls from the general population (GP) not hospitalised for COVID-19 during this period. Outcomes were all-cause mortality and organ disorders-related hospitalisation identified using ICD-10 codes. Cumulative incidences were estimated using the Kaplan-Meier method. Incidence rate ratios (IRR) were estimated such as the adjusted sub-distribution hazard ratio on 6-month periods during the follow-up using Cox regressions.

63,990 COVID-19 subjects (mean age (SD) 65 years (18), 53.1% male) were matched to 319,891 controls. The weighted cumulative incidences of all-cause mortality and all-cause hospitalisation were 5,218/105 person-years (PY) [95%CI 5,127; 5,305] and 16,334/105 PY [16,162; 16,664] among COVID-19 subjects and 4,013/105 [3,960; 4,047] and 12,095/105 PY [12,024; 12,197] among controls, respectively. COVID-19 subjects were more likely to be hospitalised for cardiovascular (IRR 1.22 [1.15; 1.29]), psychiatric (IRR 1.41 [1.29; 1.53]), neurological (IRR 1.50 [1.41; 1.61]), and respiratory events (IRR 1.99 [1.87; 2.12]). The excess risk strongly decreased after the first 6 months for all outcomes but remained significantly increased up to 30-month for neurological, respiratory disorders, chronic renal failure and diabetes.

COVID-19 hospitalised subjects were at increased risk of death or hospitalisation for various organ disorders up to 30 months after discharge, reflecting the multi-organ consequences of the disease.

Heart failure (HF) is a growing public health concern, with an increasing incidence among younger populations. Traditionally, HF was considered a condition primarily affecting the elderly, but of late, emerging evidence hints at a rapidly rising HF incidence in youth in the past 2 decades. HF in youth has been linked to a complex interaction between emerging risk factors, such as metabolic syndrome, environmental exposures, genetic predispositions, and lifestyle behaviors. This review examines these evolving determinants, including substance abuse, autoimmune diseases, and the long-term cardiovascular effects of coronavirus disease 2019, which disproportionately affect younger individuals. Through a comprehensive analysis, the study highlights the importance of early detection, targeted prevention strategies, and multidisciplinary management approaches to address this alarming trend. Promoting awareness and integrating age-specific interventions could significantly reduce the burden of HF and improve long-term outcomes among younger populations.

The purpose of this study was to determine if the COVID-19 pandemic had differential effects on individuals with chemical intolerances (CI). CI is characterised by multisystem symptoms initiated by a one-time high dose or persistent low-dose exposure to environmental toxins including chemicals, foods and drugs. With an estimated 20% US prevalence, symptoms include fatigue, headache, weakness, rash, mood changes, musculoskeletal pain, gastrointestinal issues, difficulties with memory, concentration and respiratory problems, which are similar to COVID-19 and its sequelae.

A US population-based survey involving 7500 respondents was asked if they ever had COVID-19, what the severity was, and if they had long COVID-19. CI was assessed using the Quick Environmental Exposure and Sensitivity Inventory.

The Center for Disease Control estimates that over 24 million have been infected with COVID-19 in the USA with over 6 700 000 being hospitalised and over 1 174 000 deaths. Other industrialised countries show similar numbers.

Those in the High CI class reported a greater COVID-19 prevalence, symptom severity and long COVID-19 than in the medium and low CI groups (p<0.0001). These associations were independent of race, ethnicity, income, age and sex. However, there were significantly increased odds of COVID-19 severity among women and those over 45 years old. Asian individuals were least likely to have severe symptoms compared with white individuals (OR=0.53; 95% CI 0.35 to 0.79). Black/African American individuals reported a lower prevalence of COVID-19 than non-Hispanic whites. However, one interaction between CI and race was significant, African Americans with high CI reported greater odds (OR=2.2; 95% CI 1.15 to 3.16) of reporting COVID-19 prevalence. Furthermore, African American individuals had significantly greater odds of increased symptom severity.

Prior studies show higher risk for COVID-19 among older age groups, male sex, those with pre-existing comorbidities (eg, challenged immunities) and those from minoritised racial/ethnic groups. The results of this study suggest that those with CI be included in a high-risk group. Various risk subsets may exist and future investigations could identify different risk subsets. Understanding these subgroups would be helpful in mounting targeted prevention efforts.

Long COVID syndrome has had a major impact on million patients' lives worldwide. The cardiovascular system is an important aspect of this multifaceted disease that may manifest in many ways. We have hereby performed a narrative review in order to identify the extent of the cardiovascular manifestations of the Long COVID syndrome.

An in-depth systematic search of the literature has been conducted for this narrative review. The systematic search of PubMed and Cochrane databases yielded 3993 articles, of which 629 underwent full-text screening. A total of 78 studies were included in the final qualitative synthesis and data evaluation. The pathophysiology of the cardiovascular sequelae of Long COVID syndrome and the cardiac manifestations and complications of Long COVID syndrome are critically evaluated. In addition, potential cardiovascular risk factors are assessed, and preventive methods and treatment options are examined in this review.

This systematic review poignantly summarizes the evidence from the available literature regarding the cardiovascular manifestations of Long COVID syndrome and reviews potential mechanistic pathways, diagnostic approaches, preventive measures, and treatment options.

Infections, cancer, and trauma can cause life-threatening hyperinflammation. In the present study, using single-cell RNA sequencing of circulating immune cells, we found that the mammalian target of rapamycin (mTOR) pathway plays a critical role in myeloid cell regulation in COVID-19 patients. Previously, we developed an mTOR-inhibiting nanobiologic (mTORi-nanobiologic) that efficiently targets myeloid cells and their progenitors in the bone marrow. In vitro, we demonstrated that mTORi-nanobiologics potently inhibit infection-associated inflammation in human primary immune cells. Next, we investigated the in vivo effect of mTORi-nanobiologics in mouse models of hyperinflammation and acute respiratory distress syndrome. Using 18F-FDG uptake and flow cytometry readouts, we found mTORi-nanobiologic therapy to efficiently reduce hematopoietic organ metabolic activity and inflammation to levels comparable to those of healthy control animals. Together, we show that regulating myelopoiesis with mTORi-nanobiologics is a compelling therapeutic strategy to prevent deleterious organ inflammation in infection-related complications.