Deep learning-based radiomics techniques have the potential to aid specialists and physicians in performing decision-making in COVID-19 scenarios. Specifically, a Deep Learning (DL) ensemble model is employed to classify medical images when addressing the diagnosis during the classification tasks for COVID-19 using chest X-ray images. It also provides feasible and reliable visual explicability concerning the results to support decision-making.

Our DEELE-Rad approach integrates DL and Machine Learning (ML) techniques. We use deep learning models to extract deep radiomics features and evaluate its performance regarding end-to-end classifiers. We avoid successive radiomics approach steps by employing these models with transfer learning techniques from ImageNet, such as VGG16, ResNet50V2, and DenseNet201 architectures. We extract 100 and 500 deep radiomics features from each DL model. We also placed these features into well-established ML classifiers and applied automatic parameter tuning and a cross-validation strategy. Besides, we exploit insights into the decision-making behavior by applying a visual explanation method.

Experimental evaluation on our proposed approach achieved 89.97% AUC when using 500 deep radiomics features from the DenseNet201 end-to-end classifier. Besides, our ensemble DEELE-Rad method improves the results up to 96.19% AUC for the 500 dimensions. To outperform, ML DEELE-Rad reached the best results with an Accuracy of 98.39% and 99.19% AUC for the same setup. Our visual assessment employs additional possibilities for specialists and physicians to decision-making.

The results reflect that the DEELE-Rad approach provides robustness and confidence to the images' analysis. Our approach can benefit healthcare specialists when employed at clinical routines and respective decision-making procedures. For reproducibility, our code is available at https://github.com/usmarcv/deele-rad.

Apium graveolens L. (celery) is a dietary vegetable with anti-inflammatory properties. It has the potential to treat acute lung injury (ALI) caused by COVID-19 or other diseases.

To investigate the effects of Apium graveolens water extract (AGWE) on ALI in human lung A-549 cells induced by lipopolysaccharide (LPS).

A-549 cells were treated with AGWE for 24 h and then stimulated with 10 μg/mL LPS for another 24 h. The effects of AGWE on cell viability, the inflammatory response, oxidative stress, and apoptosis and their regulatory factors, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and NLR family pyrin domain containing 3 (NLRP3) inflammasome signaling activation were analyzed.

Treatment with 5-50 μg/mL AGWE reversed the decrease in cell viability caused by LPS (p < 0.05). AGWE can reduce interleukin (IL)-1β, IL-6, IL-18, and TNF-α levels; their EC50 values are 61.4, 65.7, 37.8, and 79.7 μg/mL, respectively. AGWE can reduce reactive oxygen species and thiobarbituric acid reactive substances in A-549 cells induced by LPS. AGWE also reduced the levels of apoptosis (EC50 of 74.8 μg/mL) and its regulators (Bid; Caspase-9, -8, and -3; Bax) and increased the levels of the mitochondrial membrane potential in A-549 cells induced by LPS. AGWE can also decrease the protein levels of NLRP3 and Caspase-1 and the activation of NF-κB signaling in A-549 cells induced by LPS.

These results show that 10 and 50 μg/mL AGWE can reduce the acute inflammation induced by LPS by reducing NF-κB and NLRP3 inflammasome signaling and mitochondria-dependent apoptosis pathways.

INO-4800 represents a DNA-based vaccine encoding the spike protein of SARS-CoV-2. This phase 2 trial evaluated the immunogenicity and safety of INO-4800 as a primary vaccination series in adults. We conducted a randomized, observer-blind, placebo-controlled phase 2 trial of intradermal injection of INO-4800 in both healthy adults and elderly individuals. Eligible participants from each age group were enrolled and randomly assigned in a 3:3:2 ratio to receive two doses of INO-4800 (1.0 mg or 2.0 mg) or placebo, followed by electroporation on day 0 and day 28. The primary immunogenicity endpoints focused on determining the geometric mean titers (GMTs) of spike-binding antibodies and live SARS-CoV-2 neutralizing antibody at day 30 after the second dose. The primary endpoint for safety was the occurrence of adverse events within 30 days after vaccination. A total of 781 volunteers were recruited and screened for eligibility, with 320 eligible young adults (≥18 to <60 years old) and 320 elderly (≥60 to ≤85 years old) were randomly assigned to receive the low-dose (1.0 mg, n = 120) or high-dose (2.0 mg, n = 120) INO-4800, or placebo (n = 80). Notably, both dose groups exhibited significant increases in spike-binding antibodies at day 30 after the second dose, with GMTs of 1609.3 (95% CI: 1385.5-1869.3) for the low-dose group and 3016.7 (95% CI: 2577.4-3530.8) for the high-dose group. Additionally, both dose groups induced neutralizing antibodies against live SARS-CoV-2, with GMTs of 4.7 (95% CI: 4.2-5.3) and 6.6 (95% CI: 5.9-7.4) at day 30 after the second dose. The incidence of adverse events within 30 days after vaccination was slightly higher in the high-dose group (115 [47.9%]) than that in the low-dose group (105 [43.8%]) (p = .0060). All adverse reactions were grade 1 or 2, primarily occurring within 14 days after vaccination. No vaccine-related serious adverse events were reported. The COVID-19 DNA vaccine INO-4800 at two doses (1.0 mg or 2.0 mg) showed an acceptable safety profile and modest immunogenicity, with the high-dose slightly more immunogenic than the low-dose.Clinical Trials Registration: www.chictr.org.cn, identifier is ChiCTR2000040146.

The elderly population, who have increased susceptibility to severe outcomes, have been particularly impacted by the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), leading to a global health crisis. However, definitive parameters or mechanisms underlying the severity of COVID-19 in elderly people remain unclear. Thus, this study seeks to elucidate the mechanism behind the increased vulnerability of elderly individuals to severe COVID-19. We employed an aged mouse model with a mouse-adapted SARS-CoV-2 strain to mimic the severe symptoms observed in elderly patients with COVID-19. Comprehensive analyses of the whole lung were performed using transcriptome and proteome sequencing, comparing data from aged and young mice. For transcriptome analysis, bulk RNA sequencing was conducted using an Illumina sequencing platform. Proteomic analysis was performed using mass spectrometry following protein extraction, digestion, and peptide labelling. We analysed the transcriptome and proteome profiles of young and aged mice and discovered that aged mice exhibited elevated baseline levels of inflammation and tissue damage repair. After SARS-CoV-2 infection, aged mice showed increased antiviral and inflammatory responses; however, these responses were weaker than those in young mice, with significant complement and coagulation cascade responses. In summary, our study demonstrates that the increased vulnerability of the elderly to severe COVID-19 may be attributed to an attenuated antiviral response and the overactivation of complement and coagulation cascades. Future research on antiviral and inflammatory responses is likely to yield treatments that reduce the severity of viral respiratory diseases in the elderly.

Patients with severe coronavirus disease 2019 (COVID-19) have been reported to show hypoxia without displaying typical clinical signs or symptoms, called "happy hypoxia." To explore the potential of happy hypoxia as a distinctive symptom of COVID-19, we compared vital signs in the triage phase between patients with and without COVID-19.

We retrospectively identified emergency patients with and without COVID-19 admitted to Rakuwakai Marutamachi Hospital, Kyoto, Japan, between January 2021 and December 2021.

317 patients were analyzed. Multivariate logistic regression analysis, including all vital signs, demonstrated that the respiratory rate was not statistically associated with COVID-19 (odds ratio, 0.94, p = 0.058), suggesting that happy hypoxia may not be a distinct hallmark of COVID-19.

Persistent respiratory symptoms and impaired gas exchange are common in patients recovering from COVID-19 pneumonia. The Lung Diffusing Capacity for Carbon Monoxide (DLCO) and Carbon Monoxide Transfer Coefficient (KCO) do not adequately distinguish alveolar membrane dysfunction from vascular abnormalities. This study aimed to characterize persistent diffusion impairment in post-ICU patients with prior SARS-CoV-2 pneumonia and reduced DLCO.

After hospital discharge, patients underwent spirometry, DLCO measurement, and a 6-minute walking test every six months. If DLCO remained impaired at 18-24 months, a combined Lung Diffusing Capacity for Nitric Oxide (DLNO) and DLCO assessment was performed to differentiate alveolar-capillary membrane (DmCO) and pulmonary capillary blood volume (Vc) alterations.

Among 20 patients with persistent DLCO reduction, 3 had an obstructive ventilatory pattern, 6 had restriction, and 12 had low KCO. In restrictive cases, KCO was reduced but remained within normal limits without compensation. The DLNO/DLCO ratio exceeded 113.5% predicted in all patients. DmCO was impaired in 7 patients, while Vc was reduced in 16.

Both DLCO determinants were affected, with vascular impairment predominating. Vc reduction was present in most patients, with mean values below the lower limit of normality, whereas DmCO was less affected and often normal. The elevated DLNO/DLCO ratio suggests that persistent DLCO reduction is primarily driven by prolonged pulmonary capillary circulation dysfunction rather than alveolar membrane alterations, highlighting the vascular component as the primary site of long-term impairment.

Assuming a homogeneous population, we employ a deterministic model based on first principles of probability to explore dynamics of an epidemic controlled by isolation alone, quarantine alone, and the two together. We develop explicit closed-form equations for key metrics of control performance: cumulative fraction of population infected over the course of the epidemic (final size), maximum fraction infected at any one time, and epidemic duration. We derive an analytical solution for final size of an epidemic controlled by isolation, when final size is small, and develop empirical relations for the other cases. We frame equations in terms of reproduction numbers, measures of intervention effort and initial conditions. We model both strength and speed of interventions, assume second order gamma distributions for intervention waiting times and employ non-time-invariant equations for quarantine. We also account for quarantine of unexposed, susceptible individuals and for imperfect intervention.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can have a serious course with many complications, especially in immunocompromised individuals. In such persons, other latent virus infections may contribute to disease pathology, in particular viruses which infect immune cells such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV).

In this study, serology-based assays were conducted to analyse antibody responses to SARS-CoV-2 spike protein (SP), EBV Epstein-Barr nuclear antigen (EBNA)-1 and CMV phosphoprotein (pp)52 in naturally SARS-CoV-2-infected individuals, non-infected healthy controls (HCs) and vaccinated healthy controls (VHCs) to identify an association between SARS-CoV-2 antibodies and EBV and CMV antibodies in order to determine whether latent EBV and CMV infected individuals are more prone to become infected with SARS-CoV-2. Moreover, SARS-CoV-2, EBV, and CMV antibody responses were characterized in serum from patients with relapsing-remitting multiple sclerosis (RRMS), a chronic inflammatory disease strongly associated with EBV infections, to determine whether the serologic virus antibody profile varies in immunocompromised RRMS individuals upon SARS-CoV-2 vaccinations compared to VHCs.

Significantly elevated SP IgG, IgM and IgA levels were identified in SARS-CoV-2-infected immunocompetent individuals when compared to non-infected HCs. However, no correlation was found to serum antibodies between SARS-CoV-2, EBV, and CMV in individuals infected with SARS-CoV-2 and in VHCs, suggesting that latent infections with neither EBV nor CMV associates to SARS-CoV-2 infection. Moreover, no significant difference in SP IgG, IgA and IgM levels was observed between vaccinated RRMS patients and VHCs, indicating that the immune system of immune deficient RRMS patients and VHCs respond identical to SARS-CoV-2 vaccinations.

Collectively, SARS-CoV-2 SP antibody levels reflect the vaccination and infection history and do not associate with EBV and CMV serostatus.

In severe COVID-19 patients, excessive inflammation can lead to multiorgan dysfunction. Current anti-inflammatory treatments like glucocorticoids partially improve the outcomes, while immune systems are compromised. We have identified that SARS-CoV-2-infected obese mice were a good model of the cytokine storm seen in COVID-19. Here, we revealed that iguratimod (IGU), an approved agent for rheumatoid arthritis, improved survival by attenuating inflammation with minimal immune suppression. In this study, C57BL/6 mice were fed a high-fat diet (HFD) or a normal-fat diet (NFD) for ten weeks before being infected with a mouse-adapted SARS-CoV-2. IGU significantly improved survival rates and reduced lung inflammation in HFD-fed mice, with minimal impact on interferon-induced genes and viral load. Meanwhile, dexamethasone (DEX) did not improve survival, while it suppressed various immune reactions with different mechanisms to IGU. Interestingly, IGU-treated mice had fewer SARS-CoV-2 positive cells in the lung, although viral replication was comparable to the control mice. Neither IGU nor DEX inhibited the SARS-CoV-2 infection in Vero-E6 cells, unlike the antiviral agent, remdesivir. Of note, IGU was effective prophylactically and therapeutically in HFD mice, and showed beneficial effects in NFD-fed mice with a lethal dose exposure of SARS-CoV-2. We demonstrated that IGU could be a promising treatment for severe COVID-19, especially in obese patients, by fine-tuning inflammation without compromising antiviral immunity. This study supports the possibility of drug repositioning for IGU COVID-19 beyond autoimmune diseases.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is an enveloped RNA virus that caused the Coronavirus Disease 2019 (COVID-19) pandemic. The SARS-CoV-2 Spike glycoprotein binds to angiotensin converting enzyme 2 (ACE2) on host cells to facilitate viral entry. However, the presence of SARS-CoV-2 in nearly all human organs - including those with little or no ACE2 expression - suggests the involvement of alternative receptors. Recent studies have identified several cellular proteins and molecules that influence SARS-CoV-2 entry through ACE2-dependent, ACE2-independent, or inhibitory mechanisms. In this review, we explore how these alternative receptors were identified, their expression patterns and roles in viral entry, and their impact on SARS-CoV-2 infection. Additionally, we discuss therapeutic strategies aimed at disrupting these virus-receptor interactions to mitigate COVID-19 pathogenesis.

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.

Anticoagulants have an important role in the prevention of cardiovascular disorders. Costus speciosus (Costaceae) is a medicinal herb used to treat COVID-19-induced thrombosis. The purpose of this study was to assess the anticoagulant activity of various C. speciosus aqueous (CSAE), ethanol (SCEE), and methanol (CSME) extracts in vivo and in vitro utilizing thrombin time (TT), activated partial thromboplastin time (aPTT), and prothrombin time (PT). Different concentrations of the three extracts were used to evaluate the anticoagulation effects in vitro. In the in vivo assay, male Sprague Dawley rats were used to test the CSME as in vivo anticoagulants. Three groups of rats included the control group and the groups that received CSME daily at a low (200 mg/kg) or high dose (400 mg/kg b.w) for 2 weeks. The molecular docking of the major bioactive constituents of the methanolic extract against the binding site of the thrombin inhibitor complex was evaluated. The HPLC detected 13, 10 and 11 polyphenols in the methanolic, ethanolic and aqueous extracts, respectively. The in vitro results showed that all the studied extracts had anticoagulant activity and increased aPTT, TT, and PT time. The in vivo experiment supported the in vitro results and demonstrated that CSME greatly prolonged the anticoagulant characteristics when compared to the negative control. Both findings suggested that these extracts have significant anticoagulant activity, with CSME being more effective and potentially useful in pharmaceutical applications as a natural anticoagulant medication.

In recent years, the role of the intestinal microbiota in regulating host health and immune balance has attracted widespread attention. This study provides an in-depth analysis of the close relationship between the intestinal microbiota and respiratory system diseases, with a focus on three common respiratory virus infections, including respiratory syncytial virus (RSV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and influenza virus. The research indicates that during RSV infection, there is a significant decrease in intestinal microbial diversity, suggesting the impact of the virus on the intestinal ecosystem. In SARS-CoV-2 infection, there are evident alterations in the intestinal microbiota, which are positively correlated with the severity of the disease. Similarly, influenza virus infection is associated with dysbiosis of the intestinal microbiota, and studies have shown that the application of specific probiotics exhibits beneficial effects against influenza virus infection. Further research indicates that the intestinal microbiota exerts a wide and profound impact on the occurrence and development of respiratory system diseases through various mechanisms, including modulation of the immune system and production of short-chain fatty acids (SCFAs). This article comprehensively analyzes these research advances, providing new perspectives and potential strategies for the prevention and treatment of future respiratory system diseases. This study not only deepens our understanding of the relationship between the intestinal microbiota and respiratory system diseases but also offers valuable insights for further exploring the role of host-microbiota interactions in the development of diseases.

Ferritin, an iron storage protein, is crucial for maintaining iron metabolism balance throughout the body and serves as a key biomarker for evaluating the body's iron reserves. Reduced ferritin levels typically indicate iron deficiency, whereas elevated ferritin levels indicate an acute inflammatory response in infectious diseases. Recent research has established a significant link between elevated ferritin levels and disease severity and prognosis. The concept of hyperferritinemic syndrome has underscored ferritin's role as a pathogenic mediator. During infections, ferritin not only serves as a biomarker of inflammation but also exerts pro-inflammatory functions, which is a key factor in perpetuating the vicious pathogenic cycle. This review offers a comprehensive exploration of ferritin, covering its structural characteristics, regulatory mechanisms, and how diverse pathogens modulate ferritin. Understanding its pivotal role in infectious diseases is essential for identifying novel therapeutic prospects and enhancing disease management and prevention.

COVID-19 manifests with a wide range of severities, from asymptomatic to critical conditions. Immunological profiles in patients positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may serve as early indicators of disease severity, aiding in prioritizing patient care.

Archived patient plasma samples were retrieved from the Molecular Lab Bio-repository, ensuring equal representation of males, females, and various disease severities. Socio-demographic and disease severity data were obtained from patient health records. Levels of pro-inflammatory cytokines (interferon-gamma [IFN-γ], tumor necrosis factor-alpha [TNF-α], interleukin-2 [IL-2], and interleukin-17 [IL-17]) and anti-inflammatory cytokines (interleukin-4 [IL-4], interleukin-6 [IL-6], and interleukin-10 [IL-10]) were measured using the BD FACSCalibur flow cytometer. Data analysis involved comparing cytokine levels across different disease severities, with demographic data expressed as means ± standard deviation (SD). Statistical significance was set at P ≤ 0.05.

The mean ages for males and females were 49.6 ± 22.7 and 48.4 ± 23.7, respectively. Mean ages for disease severity categories were 33 ± 19 (asymptomatic), 45.2 ± 21.5 (moderate), 56.8 ± 18.7 (severe), and 61.95 ± 22 (critical). Comorbidities were present in 25 % of patients, with cardiovascular disease (41 %) and pulmonary disease (31 %) being the most common. Predominant symptoms in critical patients included dyspnea (63 %) and myalgia (60 %), while rhinorrhea (46.2 %) and chest pain (45.7 %) were common in severe cases. Gastrointestinal symptoms were observed only in severe and critical groups. Levels of the pro-inflammatory cytokines (IFN-γ, TNF-α, and IL-17) increased linearly with disease severity. Among anti-inflammatory cytokines, IL-6 and IL-10 levels also rose significantly with increasing severity.

Levels of TNF-α, IL-17, and IL-6 correlated with disease severity and may serve as prognostic biomarkers. Advanced age and underlying comorbidities were independently associated with higher disease severity.

The COVID-19 disease has spread rapidly across the world within just six months, affecting 169 million people and causing 3.5 million deaths globally (2021). The most affected countries include the USA, Brazil, India, and several European countries such as the UK and Russia. Healthcare professionals face new challenges in finding better ways to manage patients and save lives. In this regard, more comprehensive research is needed, including genomic and proteomic studies, personalized medicines and the design of suitable treatments. However, finding novel molecular entities (NME) using a standard or de novo strategy to drug development is a time-consuming and costly process. Another alternate strategy is discovering new therapeutic uses for old/existing/available medications, known as drug repurposing. There are a variety of computational repurposing methodologies, and some of them have been used to counter the coronavirus disease pandemic of 2019 (COVID-19). This review article compiles recently published data on the origin, transmission, pathogenesis, diagnosis, and management of the coronavirus by drug repurposing and vaccine development approach. We have attempted to screen probable drugs in clinical trials by using literature survey. This systematic review aims to create priorities for future research of drugs repurposed and vaccine development for COVID-19.

The epidemiological patterns of respiratory tract infections (RTIs) have experienced substantial changes due to the influence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with a particular focus on acute respiratory infections (ARIs). Challenges in early diagnosis, inadequate triage strategies, and the inappropriate use of antimicrobials or antivirals have compounded the difficulties in accurately diagnosing and managing ARIs in the post-pandemic context. This study aimed to investigate the efficacy of fever clinics equipped with nucleic acid testing capabilities in the precise triage of ARIs. In a cohort of 604 individuals presenting with symptoms of ARIs, we utilized real-time reverse transcription polymerase chain reaction (RT-PCR) technology available in the fever clinic to perform nucleic acid testing for SARS-CoV-2, influenza A virus (Flu A), influenza B virus (Flu B), respiratory syncytial virus, adenovirus, human rhinovirus, and Mycoplasma pneumoniae. Subsequently, statistical methods were employed to analyze the distribution and types of ARIs associated with these pathogens. In fever clinics, most patients presenting with respiratory pathogen infections were diagnosed with non-SARS-CoV-2 respiratory pathogens, with a higher incidence noted among pediatric patients compared to adults. In contrast, SARS-CoV-2 primarily affected the adult population and was linked to more severe clinical outcomes. Consequently, the swift triage of patients exhibiting ARI symptoms in a fever clinic equipped with nucleic acid testing enables the rapid identification and precise treatment of pathogens. This approach alleviates patient discomfort and enhances the efficiency of healthcare resource utilization.

The emergence of coronavirus disease 2019 (COVID-19) has triggered research into its impact on male reproductive health. However, studies exploring the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on semen quality in infertile men remain limited. Herein, we enrolled 781 male infertile patients who recovered from COVID-19 and analyzed their semen and blood samples collected at different time points. We found that SARS-CoV-2 RNA was undetectable in semen samples. Compared with pre-COVID-19 status, total sperm count, sperm concentration, vitality, motility, and percentage of sperm cells with normal morphology decreased significantly in the first month post-COVID-19. However, these alterations were reversed in the third month. Furthermore, seminal plasma samples exhibited reduced proinflammatory cytokine levels and notable changes in amino acid, nucleic acid, and carbohydrate metabolism by the third month compared with those in the first month. By contrast, no significant alterations in reproductive hormone levels were found. Vitality, progressive motility, and total motility negatively correlated with body temperature when it was above 38°C. In conclusion, semen quality initially decreases post-COVID-19 but reverses after approximately 3 months, with a decline related to inflammatory and fever. These findings may provide guidance to infertile male patients who need assisted reproductive technology.

Traditional Chinese medicine has been recognized for its significant role in treating acute lung injury (ALI) due to its distinct therapeutic advantages. Liang-Ge-San (LGS), a formulation from the ancient "Taiping Huimin Hejiju Fang", is believed to possess beneficial effects for treating ALI. However, LGS's precise mechanisms and efficacy in addressing viral ALI remain inadequately explored.

To evaluate LGS's therapeutic effects and underlying mechanisms in treating viral-induced ALI.

The protective effects of LGS were examined in a Polyinosinic-polycytidylic acid [Poly(I:C)]-induced ALI model using real-time quantitative PCR, enzyme-linked immunosorbent assay, and histopathological analysis. A bioinformatics approach combined with network pharmacology was utilized to ascertain the key targets of LGS in viral pneumonia. The pharmacodynamic mechanisms of LGS in viral ALI were further validated through immunofluorescence, overexpression, short hairpin RNA, chromatin immunoprecipitation, and target agonist assays.

LGS administration resulted in a reduction of IL-1β, IL-6, and TNF-α levels, along with a decrease in macrophage infiltration, pulmonary damage, and pneumonedema following the Poly(I:C) challenge. Bioinformatics and network pharmacology analyses suggested that Farnesyl X receptor (FXR) and angiotensin converting enzyme 2 (ACE2) are potential therapeutic targets for LGS in viral pneumonia. Further experiments revealed that LGS suppressed the expression of FXR, ACE2, and NF-κB-p65 in Poly(I:C)-infected cells. Notably, overexpression of FXR counteracted the repressive effects of LGS, while ACE2 expression remained unchanged in FXR-knockdown RAW264.7 cells upon treatment with Poly(I:C) or LGS. Additionally, LGS inhibited the interaction between FXR and ACE2 transcriptional promoters. In vivo, LGS attenuated the Poly(I:C)-induced upregulation of FXR, ACE2, IL-1β, IL-6, and TNF-α in ALI zebrafish and mice models, effects that could be reversed by chenodeoxycholic acid (CDCA), an FXR agonist. Moreover, LGS markedly alleviated weight loss, improved survival rates, reduced lung index, diminished viral load, and inhibited lung pathological changes in H1N1-PR8-induced ALI mice. IL-1β, IL-6, TNF-α, INF-γ, FXR, ACE2, small heterodimer partner, and NF-κB-p65 levels were markedly reduced by LGS, with these effects being reversed by CDCA.

This investigation provides the first evidence that FXR/ACE2 signaling is pivotal in acute respiratory viral infections, while LGS demonstrates antiviral activity against viral-induced ALI. LGS inhibits ACE2 expression induced by viral infection via FXR inhibition and modulates the cytokine storm, thus alleviating viral ALI. These findings suggest that LGS may be a promising treatment strategy for treating viral ALI.

It is understood that microvascular dysfunction plays a key role in the pathogenesis of SARS-CoV-2 coronavirus disease (COVID-19). The aim of this study was to evaluate the usefulness of an automated, quantitative nailfold capillaroscopy system in identifying microvascular changes in those confirmed with or having had COVID-19.

Ninety-seven participants were enrolled into this study and grouped as follows: 52 participants with acute COVID-19 (further grouped by disease severity) and 45 participants with convalescent COVID-19 (further grouped into long COVID i.e. symptoms beyond 12 weeks, and fully recovered). Nailfold capillaroscopy images were obtained from the bilateral ring fingers using a Dino-Lite CapillaryScope 200 Pro, a small USB handheld microscope. Images were assessed quantitatively using bespoke automated measurement software and the number of haemorrhages noted for each participant.

Capillaries were predominantly 'normal' in appearance with narrow capillary loops and evenly distributed, but with an increased number of haemorrhages (40 % in the convalescent group and 17 % in the acute group, p = 0.007). There was no statistically significant difference in the mean width of capillaries (20.9-21.8 μm) or vessel density (9.6-9.9 caps/mm; acute and convalescent group, respectively).

This study has demonstrated the feasibility of nailfold capillaroscopy at the critical care bedside. Capillary structure appeared normal across all groups of individuals affected by COVID-19. Although the small differences in the microvasculature in recovered patients compared to in acutely unwell patients may suggest delayed structural change due to COVID-19, these differences are unlikely to be clinically relevant. Longitudinal studies would be required to explore this in more detail.

After the COVID-19 pandemic, nonhuman primate (NHP) models, which are necessary for the rapid development of vaccines and new medical therapies, have become important in studies on infectious diseases because of their genetic, metabolic, and immunological similarities to humans. Our group has long been using NHP models in studies on infectious diseases including H1N1 influenza pandemic and COVID-19. Despite limitations such as the limited number of animals and the husbandry requirements, NHP models have contributed to the prediction of the pathogenicity of emerging viruses and the evaluation of the efficacy of vaccines and therapeutics due to the similarity of NHP models to humans before starting clinical trials to select good candidates of vaccines and drugs. In this review, the findings obtained in NHP infectious disease models of influenza and COVID-19 are summarized to clarify the benefits of NHP models for studies on infectious diseases. We believe that this review will support future research in exploring new perspectives for the development of vaccines and therapies targeting influenza, COVID-19, and infectious diseases in future pandemics.

The COVID-19 pandemic is a great burden worldwide, but its impact on patients with genitourinary cancer (GUC) is poorly characterized. This study aimed to characterize the clinical features and evolution of GUC patients affected by COVID-19 in Spain.

SOGUG-COVID-19 was an observational ambispective non-interventional study that recruited patients with SARS-CoV-2 infection who had been treated for GUC in 32 Spanish hospitals. Data were collected from patients' medical records in a short period of time, coinciding with the first waves of COVID-19, when the mortality was also higher in the general population.

From November 2020 to April 2021, 408 patients were enrolled in the study. The median age was 70 years, and 357 patients (87.5%) were male. Most frequent Cancer Origin was: prostate (40.7%), urothelial (31.4%) and kidney (22.1%). Most patients (71.3%) were diagnosed at the metastatic stage, and 33.3% had poorly differentiated histology. Anticancer treatment during the infection was reported in 58.3% of patients, and 21.3% had received immunotherapy prior to or concurrent with the infection. The most frequent COVID-19 symptoms were pyrexia (49.0%), cough (38.2%) and dyspnea (31.9%). Median age was higher for patients with pneumonia (p < 0.001), patchy infiltrates (p = 0.005), ICU admission (p < 0.001) and death (p < 0.001). Tumor stage was associated with complications (p = 0.006). The fatality rate was 19.9% and the 6-month COVID-19-specific survival rate was 79.7%.

Patients with genitourinary cancers seem exceptionally vulnerable to COVID-19 regardless of tumor type or anticancer therapy. Age and tumor stage were the only identified risk factors for severe COVID-19.

Novel therapeutic approaches are needed to treat respiratory infections due to the rising antimicrobial resistance and the lack of effective antiviral therapies. A promising avenue to overcome treatment failure is to develop strategies that target the host immune response rather than the pathogen itself. Granulocyte-macrophage colony-stimulating factor (GM-CSF) plays a critical role in controlling homeostasis in lungs, alveolar macrophages being the most sensitive cells to GM-CSF signaling. In this review, we discuss the importance of GM-CSF secretion for lung homeostasis and its alteration during respiratory infections. We also present the pre-clinical evidence and clinical investigations evaluating GM-CSF-based treatments (administration or inhibition) as a therapeutic strategy for treating respiratory infections, highlighting both supporting and contradictory findings.

The objective of this study was to identify the relationship between hospitalization treatment strategies leading to change in symptoms during 12-week follow-up among hospitalized patients during the COVID-19 outbreak. In this article, data from a prospective cohort study on COVID-19 patients admitted to Khorshid Hospital, Isfahan, Iran, from February 2020 to February 2021, were analyzed and reported. Patient characteristics, including socio-demographics, comorbidities, signs and symptoms, and treatments during hospitalization, were investigated. Also, to investigate the treatment effects adjusted by other confounding factors that lead to symptom change during follow-up, the binary classification trees, generalized linear mixed model, machine learning, and joint generalized estimating equation methods were applied. This research scrutinized the effects of various medications on COVID-19 patients in a prospective hospital-based cohort study, and found that heparin, methylprednisolone, ceftriaxone, and hydroxychloroquine were the most frequently prescribed medications. The results indicate that of patients under 65 years of age, 76% had a cough at the time of admission, while of patients with Cr levels of 1.1 or more, 80% had not lost weight at the time of admission. The results of fitted models showed that, during the follow-up, women are more likely to have shortness of breath (OR = 1.25; P-value: 0.039), fatigue (OR = 1.31; P-value: 0.013) and cough (OR = 1.29; P-value: 0.019) compared to men. Additionally, patients with symptoms of chest pain, fatigue and decreased appetite during admission are at a higher risk of experiencing fatigue during follow-up. Each day increase in the duration of ceftriaxone multiplies the odds of shortness of breath by 1.15 (P-value: 0.012). With each passing week, the odds of losing weight increase by 1.41 (P-value: 0.038), while the odds of shortness of breath and cough decrease by 0.84 (P-value: 0.005) and 0.56 (P-value: 0.000), respectively. In addition, each day increase in the duration of meropenem or methylprednisolone decreased the odds of weight loss at follow-up by 0.88 (P-value: 0.026) and 0.91 (P-value: 0.023), respectively (among those who took these medications). Identified prognostic factors can help clinicians and policymakers adapt management strategies for patients in any pandemic like COVID-19, which ultimately leads to better hospital decision-making and improved patient quality of life outcomes.

COronaVIrus Disease-2019 (COVID-19) is associated with a hypercoagulable state. Intracardiac thrombosis is a potentially serious complication but has seldom been evaluated in COVID-19 patients. We assessed the incidence, associated factors, and outcomes of COVID-19 patients with intracardiac thrombosis. In 2020, COVID-19 inpatients were identified from the National Inpatient Sample (NIS) database. Data on clinical characteristics, intracardiac thrombosis, and adverse outcomes were collected. Multivariable logistic regression was used to identify factors associated with intracardiac thrombosis, in-hospital mortality, and morbidities. In 2020, 1,683,785 COVID-19 inpatients (mean age 63.8 years, 32.2% females) were studied. Intracardiac thrombosis occurred in 0.10% (1830) of cases. In-hospital outcomes included 13.2% all-cause mortality, 3.5% cardiovascular mortality, 2.6% cardiac arrest, 4.4% acute coronary syndrome (ACS), 16.1% heart failure, 1.3% stroke, and 28.3% acute kidney injury (AKI). Key factors for intracardiac thrombosis were congestive heart failure history and coagulopathy. Intracardiac thrombosis independently linked to higher risks of all-cause mortality (odds ratio [OR]: 3.32 (2.42-4.54)), cardiovascular mortality (OR: 2.95 (1.96-4.44)), cardiac arrest (OR: 2.04 (1.22-3.43)), ACS (OR: 1.62 (1.17-2.22)), stroke (OR: 3.10 (2.11-4.56)), and AKI (OR: 2.13 (1.68-2.69)), but not heart failure. While rare, intracardiac thrombosis in COVID-19 patients independently raised in-hospital mortality and morbidity risks.

Coronavirus disease 2019 (COVID-19) survivors are concerned about the likelihood of developing further diseases. This study examines the global trends in scientific research on diabetes associated with COVID-19 from several perspectives. Bibliometric analyses are used to undertake a scientific review of the literature. The Web of Science Core Collection (WoSCC) database was used to acquire bibliographic information on diabetes related to COVID-19 from Jan 2020 to Dec. 2023. The visual map was built via advanced CiteSpace 6.2.R6. 7,348 papers were found. Khunti Kamlesh and Rizzo-Manfredi are the most well-known high-yield authors in this area, and the top ten authors collaborate extensively. Most of these papers came from universities. Harvard Medical School has the most publications, followed by Wuhan University and Huazhong University of Science and Technology. China and the United States are the countries with the most publications. Angiotensin-converting enzymes, chronic disease, intensive care unit, viral infection, and gestational diabetes mellitus were scored 0-11, 2, 3, and 4, respectively. Zhou et al.'s work on this topic, which appeared in the prominent medical journal The Lancet, was cited 1,366 times, highlighting its importance. "clinical characteristics," "diabetes mellitus," "metabolic syndrome," and "angiotensin-converting enzyme" were used as keywords for reference co-citation and clustering data identify. Over the last four years, related investigations have focused primarily on observing clinical aspects. This report is important for developing treatment strategies, directing future research, and guiding clinical practice.

Given their unique phagocytic function, inflammatory site tropism, and ability to penetrate deep into the lesion sites, macrophages are considered to have promising application potential in the field of living-cell drug delivery. The methods of drug delivery using macrophages primarily include intracellular phagocytic and extracellular drug loading. Comparatively, extracellular drug loading is potential less cytotoxicity and has minimal effects on the motility and orientation of cells. In this review, we provide an overview of the methods of extracellular drug loading, and examine the effects of the different properties of nanoformulations on extracellular drug-loaded delivery systems. In addition, we assess the prospects and challenges of a self-propelled macrophage-based drug delivery system. We hope this research contributes to optimizing the design of these drug delivery systems.

The outcome of the immune response depends on the content and magnitude of inflammatory mediators, the right time to start, and the duration of inflammatory responses. Patients with coronavirus disease 2019 (COVID-19) represent diverse disease severity. Understanding differences in immune responses in individuals with different disease severity levels can help elucidate disease mechanisms. Here, we serially analyzed the cytokine profiles of 809 patients with mild to critical COVID-19. The cytokine profile revealed an overall increase in IL-1β, IL-1Ra, TNF-α, IL-6, IL-2, IL-8, and IL-18 and impaired production of IFN-α and -β. Only an early rise in IL-1Ra, IL-6, and IL-2 levels was linked to worse disease outcomes. On the other hand, long-term rises in IL-1β, IL-1Ra, TNF-α, IL-6, IL-2, IL-8, and IL-18 levels were linked to worse disease outcomes. Principal component analysis identified a component, including IL-1β, TNF-α, IFN-α, and IL-12, that was associated with disease severity. Spearman analysis revealed that the correlation of IL-1β and IFN-α was entirely different between mild and critical patients. Therefore, the ratio of IL-1β to IFN-α seemed to be a suitable criterion for distinguishing critical patients from mild ones. The higher levels of the IL-1β to IFN-α ratio correlated with improved outcomes. These data point to an imbalance of IL-1β/IFNα, contributing to hyperinflammation in COVID-19.

Previous studies showed that agomelatine ameliorates doxorubicin-induced brain injury in rats. Furthermore, it protects neurons against oxidative stress triggered by acute ischemia reperfusion injury. So, this study aimed to investigate the possible neuroprotective effects of agomelatine on dexamethasone-induced neurotoxicity in rats and the underlying mechanisms. Subcutaneous injections of dexamethasone (10 mg/kg, 4 days) were used to induce neurotoxicity in rats. Agomelatine (10 mg/kg), luzindole (2.5 mg/kg, a melatonin receptor blocker), and luzindole plus agomelatine treatment commenced 3 days before dexamethasone injections and concurrent with dexamethasone injections. Elevated plus maze test, Y-maze test and open field test were carried out after 1 hour of the last dose of dexamethasone on day 7. On 8th day of the experiment, brain tissues were collected. Brain oxidative stress markers, immunohistochemical expression of β-amyloid and glial fibrillary acidic protein (GFAP) were measured. Moreover, histopathological changes in the cerebral cortex and hippocampus were recorded and the number of damaged cells was counted. Dexamethasone increased anxiety and memory impairment but decreased locomotor exploration activity. Furthermore, it increased brain oxidative stress, expression of β-amyloid and GFAP, increased the number of damaged neurons, and caused structural changes in cerebral cortex and hippocampus. All these deleterious changes were mitigated by agomelatine. Luzindole prior administration to agomelatine reversed the protective effects of agomelatine except its effect on lipid peroxidation. Collectively, these findings suggest that agomelatine can protect against dexamethasone-induced neurotoxicity partially by activating melatonin receptors in addition to exerting antioxidant effects.

Aging-associated vulnerability to coronavirus disease 2019 (COVID-19) remains poorly understood. Here, we show that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected aged mice lacking SIRT2, a cytosolic NAD+-dependent deacetylase, develop more severe disease and show increased mortality, while treatment with an NAD+ booster, 78c, protects aged mice from lethal infection. Mechanistically, we demonstrate that SIRT2 modulates the acetylation of cyclic GMP-AMP synthase (cGAS), an immune sensor for cytosolic DNA, and suppresses aging-associated cGAS activation and inflammation. Furthermore, we show that SARS-CoV-2 infection-induced inflammation is mediated at least in part by ORF3a, which triggers mtDNA release and cGAS activation. Collectively, our study reveals a molecular basis for aging-associated susceptibility to COVID-19 and suggests therapeutic approaches to protect aged populations from severe SARS-CoV-2 infection.

Obesity is a critical risk factor for ischemic heart disease (IHD), affecting 42% of the U.S. population. This study examines trends in obesity-related IHD mortality among U.S. adults aged 25 and older from 1999 to 2020, using the CDC WONDER database.

We analyzed IHD as the primary cause and obesity as a contributing factor, calculating age-adjusted (AAMRs) and crude mortality rates (CMRs) per 100,000 individuals. Joinpoint regression assessed annual percent changes (APC), stratifying by race, sex, age, and region.

From 1999 to 2020, 139,644 obesity-related IHD deaths were recorded. AAMR rose from 1.92 to 4.69 per 100,000. Rates were higher in men (3.79) than women (2.10), with Black Americans showing the highest AAMR (4.07). Older adults (65+) had the highest CMR (5.73). Nonmetropolitan areas exhibited higher AAMRs (3.47) than metropolitan regions (2.78). States with the highest mortality included Vermont, Oklahoma, Wyoming, Wisconsin and Iowa while Alabama, Virginia, Massachusetts, Connecticut and Georgia had the lowest.

The findings indicate a 2.5-fold increase in obesity-related IHD mortality, highlighting the need for targeted public health interventions and further research to address this growing public health concern.

The COVID-19 pandemic has affected all sectors of life. This study helps us better understand the perceptions and practices related to the COVID-19 pandemic in the oncology patient population of New Mexico. It also explores patient knowledge regarding safe practices and perceptions regarding vaccination.

The data for this cross-sectional survey study was collected from July 20, 2021 to September 6, 2021.

There were no significant differences noted in the incidence of COVID-19 infection based on race, comorbidities, or modality of treatment regardless of vaccination status. During the first peak of COVID-19 (Nov 2020 - Jan 2021), most participants followed strict safety precautions (54.2 %), fewer maintained these practices in the months prior to data collection (32.5 %) (Jul 2021 - Aug 2021). Among the participants who had declined vaccination against COVID-19, there were no significant differences based on race, comorbidities or treatment. Those oncology patients receiving treatments at the infusion center were much less vaccine hesitant (8.3 %) compared to those who were not (18.3 %). The odds of COVID-19 infection among patients that were vaccinated was 0.27 times lower than that of unvaccinated patients (95 % CI, 0.12 to 0.63; p 0.001). Vaccine-hesitant respondents reported long-term safety data (n = 11, 24.4 %) and physician recommendations (n = 10, 22.2 %) were likely to change their minds, but the most common response was that "nothing" would change their mind (n = 16, 35.6 %).

The pandemic is a dynamic landscape and physicians need to keep up to date with current guidelines and continue to have conversations with patients regarding strict safety precautions. Having an open discussion with patients regarding vaccine recommendations may help with decreasing vaccine hesitancy.

Individuals living with long COVID experience a range of symptoms that affect their ability to carry out daily activities or participate in social and community life. This study aimed to analyze association between functional disability and the occurrence of long COVID symptoms, as well as to analyze the effect of symptom persistence time on functional disability.

This is a cross-sectional study using data from the SulCovid-19 study, which interviewed individuals who had COVID-19 between December 2020 and March 2021. The functional disability outcome was assessed using the Basic Activities of Daily Living (BADL) and Instrumental Activities of Daily Living (IADL) scales, while the exposures were the symptoms of long COVID. Adjusted analyses between outcomes and exposures, stratified by time after the acute phase of infection, were performed using Poisson regression with robust variance adjustment.

The prevalence of BADL disability was 4.8% (95%CI 4.0;5.6), and for IADL disability, it was 8.4% (95%CI 7.4;9.4). The main symptoms associated with BADL disability were dyspnea, dry cough and sore throat, while for IADL, they were joint pain, muscle pain, loss of sensation, nasal congestion, sore throat and runny nose. When stratified by tertiles of time after the acute phase of infection, a relationship was found between BADL disability and dyspnea, ageusia and, nasal congestion in the 3rd tertile, while only ageusia was found to be related to IADL disability in the 3rd tertile.

Long COVID symptoms were associated wiht limitations in the functional capacity of adults and the seniors. The findings can be used to guide the care and rehabilitation of individuals with disabilities who have had COVID-19, particularly for referral to appropriate health professionals.

Innate lymphoid cells (ILCs) have emerged as pivotal players in the field of immunology, expanding our understanding of innate immunity beyond conventional paradigms. This comprehensive review delves into the multifaceted world of ILCs, beginning with their serendipitous discovery and traversing their ontogeny and heterogeneity. We explore the distinct subsets of ILCs unraveling their intriguing plasticity, which adds a layer of complexity to their functional repertoire. As we journey through the functional activities of ILCs, we address their role in immune responses against various infections, categorizing their interactions with helminthic parasites, bacterial pathogens, fungal infections, and viral invaders. Notably, this review offers a detailed examination of ILCs in the context of specific infections, such as Mycobacterium tuberculosis, Citrobacter rodentium, Clostridium difficile, Salmonella typhimurium, Helicobacter pylori, Listeria monocytogenes, Staphylococcus aureus, Pseudomonas aeruginosa, Influenza virus, Cytomegalovirus, Herpes simplex virus, and severe acute respiratory syndrome coronavirus 2. This selection aimed for a comprehensive exploration of ILCs in various infectious contexts, opting for microorganisms based on extensive research findings rather than considerations of virulence or emergence. Furthermore, we raise intriguing questions about the potential immune functional resemblances between ILCs and epithelial cells, shedding light on their interconnectedness within the mucosal microenvironment. The review culminates in a critical assessment of the therapeutic prospects of targeting ILCs during infection, emphasizing their promise as novel immunotherapeutic targets. Nevertheless, due to their recent discovery and evolving understanding, effectively manipulating ILCs is challenging. Ensuring specificity and safety while evaluating long-term effects in clinical settings will be crucial.

Tocilizumab, an IL-6 receptor antagonist, may prevent functional impairments in critically ill patients by attenuating the cytokine storm. This study investigated a potential effect of tocilizumab on preventing functional impairments in patients with severe coronavirus infection 2019 (COVID-19).

In a multicenter prospective observational study, patients with COVID-19 ≥ 20 years requiring mechanical ventilation admitted to the intensive care unit between April 2021 and September 2021 and discharged alive were followed for one year. A self-administered questionnaire on sequelae and functional impairments was mailed in August 2022, and data were collected. A multivariate logistic regression was used to assess the impact of tocilizumab on physical function, mental health, and Long COVID.

Of 157 analyzed patients, 41 received tocilizumab. The tocilizumab group had more severe illness, but a lower prevalence of physical impairment (17.1 % vs. 23.3 %, p = 0.41) and mental disorders (19.5 % vs. 39.7 %, p = 0.009) than the non-tocilizumab group. The prevalence of Long COVID was higher in the tocilizumab group (92.7 % vs. 80.2 %, p = 0.06), whereas fatigue/malaise was significantly lower (19.5 % vs. 37.1 %, p = 0.039). Adjusted odds ratios (95 % confidence interval) for physical impairment, mental disorders, and Long COVID with tocilizumab were 0.70 (0.2-2.1), 0.40 (0.16-1.01), and 2.94 (0.7-12.3), respectively, with no significant difference.

Tocilizumab was associated with a lower prevalence of physical impairment and mental disorders at 1 year in patients with severe COVID-19. Furthermore, Long COVID had a weaker impact on physical and cognitive functions.

Since the first officially reported case of COVID-19, the scientific community has spent much of its time understanding the dynamics of the virus. Several studies have indicated that some population segments are especially susceptible to COVID-19 complications, including pregnant and postpartum women. Although recommendations such as social distancing, proper sanitation, and the use of protection masks were crucial in slowing down the virus dissemination, the protection provided by vaccination is undeniable, especially for this particular group. Concerning deaths by COVID-19, it is natural to assume that daily deaths are related to reported hospitalized cases and to expect that, as vaccination increases, this effect gradually decreases. As far as we know, no other studies have addressed this issue. Therefore, this study introduces a novel generalized linear model with segmented interaction to fill this gap. The model was used to estimate the vaccination thresholds required to change the overall level and the daily hospitalized cases effect on daily deaths from COVID-19 in pregnant and postpartum women reported between January 3rd, 2021, and January 1st, 2022. Inference methods for the proposed model were developed. The results obtained indicate that, in the first period from May 25th to July 1st, 2021 (between 14,420 and 271,570 first doses, respectively), vaccination caused a significant gradual decrease in the effect of reported hospitalized cases on fatalities and, in a second period from July 25th to October 13th, 2021 (between 653,150 and 968,880 first doses, respectively), it induced a gradual reduction of the overall level of deaths. Using the average number of cases as a reference, during the period of observations, the expected number of deaths reduced from 6.16 to 0.36, a decrease of 94.16%. The importance of learning from COVID-19 data must be highlighted, as it provides us with critical insights to better prepare for future health crises.