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.

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.

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.

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.

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.

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.

The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a global public health crisis. The nucleocapsid (N) protein plays a pivotal role in a variety of biological processes in the life cycle of SARS-CoV-2, such as viral assembly. In this study, we investigated the liquid-liquid phase separation (LLPS) capacity of the N protein of seven SARS-CoV-2 strains, including the variants of concern (VOC) and interest (VOI), and its impact on viral replication. Using bioinformatic tools, we analyzed 11,433,558 complete genomes of SARS-CoV-2 and revealed a high degree of sequence conservation of N gene. While all the seven N proteins could undergo LLPS with RNA, the mutations in N impair its capacity of LLPS. With a SARS-CoV-2 trans-complementation system, we showed that SARS-CoV-2 variants carrying mutated N proteins exhibit impaired replication, highlighting the importance of LLPS of N in viral replication. We further demonstrated that (-)-gallocatechin gallate (GCG) efficiently inhibits the LLPS of N proteins and significantly suppresses the replication of different SARS-CoV-2 strains. Thus, our findings indicate that targeting the N-LLPS could be a viable strategy for the development of antiviral treatments against various SARS-CoV-2 strains, including those yet to emerge.

This review provides a broad overview of lessons learned in the five years since COVID-19 was identified. It is a bimodal disease, starting with an initially virus-driven phase, followed by resolution or ensuing inappropriate immune activation causing severe inflammation that is no longer strictly virus dependent. Humoral immunity is beneficial for preventing or attenuating the early stage, without benefit once the later stage begins. Neutralizing antibodies elicited by natural infection or vaccination are short-lived and highly vulnerable to viral sequence variation. By contrast, cellular immunity, particularly the CD8+ T cell arm, has a role in preventing or attenuating severe disease, is far less susceptible to viral variation, and is longer-lived than antibodies. Finally, an ill-defined phenomenon of prolonged symptoms after acute infection, termed "long COVID," is poorly understood but may involve various immunologic defects that are hyperactivating or immunosuppressive. Remaining issues include needing to better understand the immune dysregulation of severe disease to allow more tailored therapeutic interventions, developing antibody strategies that cope with the viral spike sequence variability, prolonging vaccine efficacy, and unraveling the mechanisms of long COVID to design therapeutic approaches.

The antibody-mediated immune response is crucial for the development of protective immunity against SARS-CoV-2, the virus responsible for the COVID-19 pandemic. Understanding the interaction between SARS-CoV-2 and the immune system is critical because new variants emerge as a result of the virus's ongoing evolution. Understanding the function of B cells in the SARS-CoV-2 infection process is critical for developing effective and long-lasting vaccines against this virus. Triggered by the innate immune response, B cells transform into memory B cells (MBCs). It is fascinating to observe how MBCs provide enduring immune defence, not only eradicating the infection but also safeguarding against future reinfection. If there is a lack of B cell activation or if the B cells are not functioning properly, it can lead to a serious manifestation of the disease and make immunisation less effective. Individuals with disruptions in the B cells have shown increased production of cytokines and chemokines, resulting in a poor prognosis for the disease. Therefore, we have developed an updated review article to gain insight into the involvement of B cells in SARS-CoV-2 infection. The discussion has covered the generation, functioning, and dynamics of neutralising antibodies (nAbs). Furthermore, we have emphasised immunotherapeutics that rely on nAbs.

The use of lung ultrasound (LUS) has recently become vital in the diagnosis and prognosis of various respiratory diseases. Its role in COVID-19 requires further investigation.

Twenty-five consecutive, non-ICU hospitalized COVID-19 patients were included. LUS was performed on admission and sequentially every 3 days at 8 points in the chest. Based on the LUS findings a score was designed. Logarithmic regression models and ROC curve analysis were applied.

A statistically significant positive correlation was found between LUS score at admission and the severity of SARS-COV-2 infection. Higher LUS score was significantly associated with lower PaO2/FiO2 ratio, use of HFNC, longer hospitalization and greater extent of chest CT infiltrates. A significant association between LUS score and risk of death or intubation or HFNC was found. For one point of increase in the score, risk of death or intubation or HFNC increased 1.93-fold (95% CI 1.02 to 3.65). The predictive role of the score was very satisfactory (area under the ROC curve = 0.87).

Lung ultrasound findings were significantly positively associated with clinical and radiological markers of severity of SARS-CoV-2 pneumonia. It therefore constitutes a promising and reliable technique for assessing pneumonia, comparable to chest CT.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to pose a significant global public health threat, particularly to older adults, pregnant women, and individuals with underlying chronic conditions. Dysregulated immune responses to SARS-CoV-2 infection are believed to contribute to the progression of COVID-19 in severe cases. Previous studies indicates that a deficiency in type I interferon (IFN-I) immunity accounts for approximately 15 %-20 % of patients with severe pneumonia caused by COVID-19, highlighting the potential therapeutic importance of modulating IFN-I signals. Natural products and their derivatives, due to their structural diversity and novel scaffolds, play a crucial role in drug discovery. Some of these natural products targeting IFN-I have demonstrated applications in infectious diseases and inflammatory conditions. However, the immunomodulatory potential of IFN-I in critical COVID-19 pneumonia and the natural compounds regulating the related signal pathway remain not fully understood. In this review, we offer a comprehensive assessment of the association between IFN-I and severe COVID-19, exploring its mechanisms and integrating information on natural compounds effective for IFN-I regulation. Focusing on the primary targets of IFN-I, we also summarize the regulatory mechanisms of natural products, their impact on IFNs, and their therapeutic roles in viral infections. Collectively, by synthesizing these findings, our goal is to provide a valuable reference for future research and to inspire innovative treatment strategies for COVID-19.

The COVID-19 pandemic was associated with a global decrease in antimicrobial consumption (AMC) in 2020. However, the persistence of this downwards trend is not known at a global level. This study examined the global and longer-term trends in AMC after the emergence of COVID-19.

The change rate of AMC was compared (a) 2020 over 2019, (b) 2021 over 2020, and (c) 2022 over 2021 using monthly sales volume data of antimicrobials in 69 countries obtained from the IQVIA MIDAS information service. Changepoints were detected using time-series data of global monthly antimicrobial sales from November 2016 to December 2023. We defined antimicrobials as oral and parenteral drugs classified as J1 by the Anatomical Therapeutic Chemical code. Antimicrobial sales were reported in standard units, as defined by IQVIA. We assessed the data using standard units per 1000 population per day, with populations based on World Population Prospects data issued by the United Nations. In addition, interrupted time-series analysis was used to examine the impact of movement restrictions in G7 countries.

In the IQVIA MIDAS data, 68 of the 69 countries had more than one changepoint between 2016 and 2023. Of these 68 countries, 61 experienced a decrease in AMC after the COVID-19 pandemic started. However, 53 of these 61 countries showed a reverse increasing trend in AMC in 2022. Interrupted time-series analysis revealed that movement restrictions had a negative impact on AMC in all G7 countries.

The global decrease in AMC in 2020 might not have been because of COVID-19 itself but to non-pharmaceutical interventions such as movement restrictions. Human mobility could possibly be one of the key determinants of antimicrobial use at the population level.

To study the prevalence and timing of neurological manifestations, including cognitive involvement, in patients hospitalized for Coronavirus disease 2019 (COVID-19). To analyze the pathogenic mechanisms and any association they have with disease severity.

Longitudinal cohort study with prospective follow-up of patients who required hospitalization. Patients under 65 who had no pre-existing cognitive impairment and did not require an ICU stay were evaluated 3 and 12 months after discharge using a battery of neuropsychological tests.

Of 205 patients hospitalized for COVID-19, 153 (74.6%) presented with neurological manifestations. The most frequent were myalgia (32.7%), headache (31.7%), dysgeusia (29.2%), and anosmia (24.9%). Patients with more severe illness at the time of hospitalization presented fewer neurological manifestations. Of the 62 patients who underwent neuropsychological examination 3 months after discharge, 22.6% had impaired attention, 19.4% impaired working memory, 16.1% impaired learning and retrieval, 9.7% impaired executive functions, and 8.2% impaired processing speed. Patients with anosmia also presented with more headache (OR 5.45; p < 0.001) and greater risk of working memory impairment (OR 5.87; p 0.03). At follow-up 12 months after hospital discharge, 14.3% of patients still showed impaired attention, 2.4% impaired working memory, 2.5% impaired executive functions, and 2.5% impaired processing speed.

Neurological manifestations are common in patients hospitalized for COVID-19 regardless of severity. The high prevalence of anosmia and its association with headache and working memory impairment at 3 months, suggest potential direct or indirect damage to the prefrontal cortex via invasion of the olfactory bulb by COVID-19.

Polymethacrylate and its derivatives are widely used in food industry and biomedical applications for their plasticity, biocompatibility and optical transparency. However, susceptibility to bacterial growth on their surfaces limits their applications. In this study, linear and branched polyethyleneimine (PEI) molecules were grafted onto poly(ethyl methacrylate) (PEMA) via aminolysis using a simple one-step method to enhance the antibacterial properties of PEMA films. PEI-modified PEMA films were characterized by ATR-FTIR, X-ray photoelectron spectroscopy (XPS), field emission scanning electron microscopy (FESEM) and thermal gravimetric analysis (TGA). The modified films exhibited optimal bactericidal efficiency of 98.0 % against Escherichia coli (E. coli) and over 99.9 % against Staphylococcus aureus (S. aureus). Furthermore, hydrolysis was found to contribute to anchoring PEI onto PEMA as well. Though branched PEI exhibited a higher grafting amount than the linear ones under same conditions, PEMA modified with linear PEI presented a similar or even higher antibacterial efficiency than those grafted with branched PEI. Overall, PEI-grafted PEMA films prepared with simple one-step method exhibit effective antibacterial properties and good biocompatibilities, making them promising candidates for biomedical devices and other applications.

For patients with rheumatoid arthritis (RA) unresponsive to first-line biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), the selection of second-line b/tsDMARDs is crucial to prevent progression to difficult-to-treat rheumatoid arthritis (D2TRA). However, indicators for selection are lacking. This study aimed to identify optimal second-line b/tsDMARDs among the phase III treatment strategies based on European League Against Rheumatism (EULAR) RA management recommendations.

A total of 687 RA patients treated with second-line b/tsDMARDs (tumor necrosis factor inhibitor (n = 246), interleukin-6 receptor inhibitor [n = 195], cytotoxic T-lymphocyte-associated protein 4 immunoglobulin [n = 119], and Janus kinase inhibitor [n = 127]) were enrolled between October 2013 and April 2023. Rates of patients achieving Clinical Disease Activity Index (CDAI) remission and CDAI low disease activity (LDA), changes in CDAI, persistence rates, and adverse events within 24 weeks after treatment initiation were compared among the four groups. Propensity score-based inverse probability of treatment weighting (PS-IPTW) was used to minimize selection bias.

After PS-IPTW adjustment, the Janus kinase inhibitor (JAKi) group had the highest persistence rate among the four groups. At 24 weeks, the JAKi group showed the greatest improvement in CDAI and the highest CDAI remission rate. Among patients treated with JAKi as second-line b/tsDMARDs, upadacitinib (UPA) was most likely to achieve CDAI remission at 24 weeks. The comparison between the UPA group (n = 32) and the non-UPA JAKi group (tofacitinib and baricitinib [n = 95]) showed comparable persistence rates but significantly lower CDAI scores and higher CDAI remission rate at 24 weeks in the UPA group. No significant difference was noted in the overall incidence of adverse events among the four groups treated with b/tsDMARDs or between the groups treated with JAKi.

Selecting JAKi, especially UPA, may effectively improve the disease activity for RA patients unresponsive to first-line b/tsDMARDs. Further large-scale studies are needed to clarify the efficacy and safety of UPA.

FIRST registry (approval number#04-23): October 2013, retrospectively registered.

It has been suggested that the use of statin pills beforehand could potentially influence the outcomes when individuals are hospitalized with COVID-19. In this study, we investigated how the prior use of statin medication could influence the COVID-19 severity parameters. In this retrospective cohort study, we categorized COVID-19 patients into 2 groups: statin users and non-users. Then, various data including age, gender, the patient's need for ventilation support, the lowest oxygen blood saturation level, the length of hospitalization, receiving remdesivir treatment, and their COVID-19 vaccination status were collected. Out of 168 patients, 62 had taken statin medication before being admitted. Using statins decreased the patient's need for ventilation support, length of hospitalization, ventilation duration, and oxygen saturation level (P < .001). Interaction effect analysis showed that receiving remdesivir statically affected the length of hospitalization, ventilation duration, and oxygen saturation level but did not significantly affect the association between statins and needing to ventilator. The use of statin pills before COVID-19 admission reduced the requirement for ventilator support.

Coronavirus disease 2019 (COVID-19) is a deadly human viral disease with a high rate of infection, morbidity, and mortality. Although vaccines and antiviral treatments are available, hospitalizations remain steady, and concerns about long-term consequences persist. Therefore, there is a great urgency to develop novel therapies. Here, we analyzed the role of miR-155, one of the most powerful drivers of host antiviral responses including immune and inflammatory responses, in the pathogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Endogenous microRNAs (miRNAs, miRs) are key molecules in preventing viral entry and replication while building an antiviral cellular defense. Our study reveals that miR-155 expression is elevated in patients with COVID-19. Using a mouse model transgenic for human angiotensin-converting enzyme receptor 2, we evaluated the potential of anti-miR-155 therapy. Treating SARS-CoV-2-infected mice with anti-miR-155 significantly reduced miR-155 expression, improved survival, and slightly increased body weight. Notably, these mice showed altered expression of cytokines in the lungs. These findings suggest anti-miR-155 could be a promising therapy to mitigate the cytokine storm and long-lasting symptoms induced by SARS-CoV-2 infection, improving public health outcomes and enhancing global pandemic preparedness.

Various pattern recognition receptors (PRRs), including toll-like receptors (TLRs), play a crucial role in recognizing invading pathogens as well as damage-associated molecular patterns (DAMPs) released in response to infection. The resulting signaling cascades initiate appropriate immune responses to eliminate these pathogens. Current evidence suggests that SARS-CoV-2-driven activation of TLR4, whether through direct recognition of the spike glycoprotein (alone or in combination with endotoxin) or by sensing various TLR4-activating DAMPs or alarmins released during viral infection, acts as a critical mediator of antiviral immunity. However, TLR4 exerts a dual role in COVID-19, demonstrating both beneficial and deleterious effects. Dysregulated TLR4 signaling is implicated in the proinflammatory consequences linked to the immunopathogenesis of COVID-19. Additionally, TLR4 polymorphisms contribute to severity of the disease. Given its significant immunoregulatory impact on COVID-19 immunopathology and host immunity, TLR4 has emerged as a key target for developing inhibitors and immunotherapeutic strategies to mitigate the adverse effects associated with SARS-CoV-2 and related infections. Furthermore, TLR4 agonists are also being explored as adjuvants to enhance immune responses to SARS-CoV-2 vaccines.

Atrial fibrillation (AF) is associated with a high burden of cardiovascular disease, which has been worsened during the coronavirus disease 2019 (COVID-19) pandemic. The purpose of this study was to assess the association between clinical markers, especially interleukin-6 (IL-6) and other inflammatory biomarkers, and the severity of COVID-19 in patients with AF.

This retrospective cohort study categorized patients based on clinical presentations and laboratory results to investigate the prognostic significance of inflammatory markers in COVID-19 outcomes among those with AF. The study included 100 hospitalized COVID-19 patients aged between 40 to 80 years and was conducted at the Chapidze Hospital in Tbilisi, Georgia. Patients were then grouped by disease severity according to computed tomography (CT) scores, clinical symptoms, respiratory rate and oxygen saturation. Levels of IL-6 were obtained at three time points during hospitalization. A broad range of laboratory tests, including C-reactive protein (CRP), ferritin, and D-dimer, were also conducted.

Patients with AF demonstrated significantly elevated levels of IL-6 (P = 0.024), CRP (P = 0.001), and ferritin (P < 0.001), suggesting a severe inflammatory response. D-dimer levels were also notably higher in the AF group (P < 0.005), indicating an increased risk of thrombotic complications. Oxygen saturation levels were significantly lower (P = 0.004) and CT scores higher in patients with AF. Furthermore, the length of hospitalization was longer among patients with AF (median duration significantly higher, P = 0.032), indicating a more severe disease course.

The proinflammatory markers such as IL-6 are independent predictive markers of COVID-19 severity in AF patients. Overall, it highlights urgent treatment approaches, such as available anti-inflammatory drugs, for COVID-19 patients with arrhythmias. Combining these biomarkers into clinical routines helps us better identify patients at risk and how to treat them.

A major challenge with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has been assessing the intensity, dynamics, and determinants of the antibody responses after infection and/or vaccination. Therefore, we aimed to characterize the longitudinal dynamics of the antibody responses among naturally infected individuals and individuals who achieved hybrid immunity in a large Canadian cohort. We demonstrate that anti-Spike IgGs and neutralizing antibody dynamics vary greatly among individuals with COVID-19, in peak antibody levels, rate of waning, and longevity of the antibody response. Additionally, we found an association between robust antibody responses and individuals with severe COVID-19 clinical symptoms during the first-month post-symptom onset. For individuals who achieved hybrid immunity, a robust increase in anti-S1 IgGs and neutralizing antibodies followed the first vaccination dose; however, there was a minimal increase in the anti-S1 IgGs and neutralizing antibody titers after administration of the second dose of the vaccine. Furthermore, neutralizing antibodies elicited by the wild-type virus alone were largely ineffective against emerging variants of concern in our natural infection-only cohort, in contrast to a much broader and more robust neutralization profile observed in individuals who achieved hybrid immunity. Our findings emphasize the need for global SARS-CoV-2 vaccination efforts to further sustain protective immune responses required to minimize viral spread and disease severity in the population. As SARS-CoV-2 variants continue to emerge, understanding the interplay between previous infections, vaccine durability, and virus evolution will be critical for guiding ongoing vaccination strategies.

A major challenge with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has been assessing the intensity, dynamics, and determinants of the antibody response after infection and/or vaccination. Our paper addresses this in a large Canadian cohort with antibody responses that were generated by natural infection as well as vaccine in some persons studied.

The aim of this study was to analyze whether patients with SARS-CoV-2 who received surgical tracheotomy had a lower incidence of postoperative bleeding if their LMWH was postponed or canceled on the day of surgery.

Patients with SARS-CoV-2 admitted to the intensive care units who underwent surgical tracheotomy were assessed retrospectively through their medical records. Data on comorbidity, LMWH dose, and timing were collected. Bleedings < 72 h post surgery were noted as stomal or airway bleedings.

All 101 patients included were on LMWH. Twenty-two patients had no change of dose of LMWH, 24 patients had their dose of LMWH postponed to post surgery, and 50 patients had their dose reduced to only the evening dose on the day of surgery. Twenty-six patients had a stomal bleeding, one patient had an airway bleeding, and four patients had both stomal and airway bleedings. No significant difference in the incidence of bleeding was identified between various groups of different LMWH doses or timing, reduced dose versus no change of dose, OR 1.29 (95% CI 0.42-3.92). Postponed dose versus no change of dose of LMWH, OR 1.03 (95% CI 0.28-3.75). Increasing age was correlated to a higher risk of bleeding post-surgery by an OR of 1.64 (95% CI 1.06-2.54, p = 0.026 for every 10 years added). No fatal bleeding related to surgical tracheotomy was observed.

Decreased doses of LMWH on the day of surgery were not associated with a risk reduction for post-surgical bleeding in patients with SARS-CoV-2 who received tracheotomy. Increasing age was a risk factor for post-surgical bleeding.

Retrospective, level 3.

The outbreak of COVID-19 pandemic has caused substantial health loss worldwide, and the long-term sequelae of COVID, resulting from repeated coronavirus infection, have emerged as a new public health concern. We report the widespread presence of abnormal metallomic profiles in the sera of patients who have recovered from SARS-CoV-2 coronavirus infection, even after 6 months post-discharge from hospital. We measured the concentrations of Fe, Cu, Zn, Se, Cr, Mn, Ba, Ni, Pb, Ag, As, Cd, Co, and V in the sera of 25 recovered participants and 38 healthy controls in the cross-sectional study. Higher concentrations of Cu, Ag, As, Ba, Cd, Ni, Pb, Cr and V were observed in the recovered participants, whereas lower concentrations of Fe and Se were obtained in these participants. Except for Zn, Mn, and Co, all other elements showed significant differences (p < 0.05) between the two groups, with variations dependent on age and gender. Further correlation analysis between metallome and metabolome indicated that SARS-CoV-2 infection continues to disrupt metallic homeostasis and affect metabolic processes, such as lipid metabolism and cell respiration, as well as the functions of certain organs (e.g., liver, kidney, and heart), even after 6 months recovery. Our findings provide novel insights into the potential long-term effect of COVID-19 on the human body from a new perspective of metallomics.

New strategies are needed to prevent and control upcoming outbreaks of SARS-CoV-2 infections, independent of vaccination. SARS-CoV-2 binds to the human ACE-2 receptor through the receptor binding domain (RBD) of the spike (S) protein, allowing the virus to enter human cells and begin replication. When peptides corresponding to four regions of RBD containing previously reported ACE-2 interaction sites were explored, the sequence 392 to 421, peptide p392wt, bound strongly to ACE-2 and inhibited wild-type RBD binding to ACE-2. Interestingly, p392 peptides corresponding to mutated sequences from different SARS-CoV-2 VOCs, including the current VOC BA.5 and KP.3, bound less strongly to ACE-2, but showed partially better inhibition of the ACE-2 interaction of all tested RBDs. When studied in a SARS-CoV-2 pseudovirus assay, the p392 peptides showed a good inhibition rate of 98.8±8.1 % at a peptide concentration of ~244 μmol/L, while none of the p392 peptides inhibited antibody binding to the RBD, suggesting that peptide treatment is sufficient in the presence of anti-RBD antibodies. Interestingly these peptides were active in the presence of diluted human serum and non-toxic to human cell lines.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has varied presentations from asymptomatic to death. Efforts to identify factors responsible for differential COVID-19 severity include but are not limited to genome wide association studies (GWAS) and transcriptomic analysis. More recently, variability in host epigenomic profiles have garnered attention, providing links to disease severity. However, whole epigenome analysis of the respiratory tract, the target tissue of SARS-CoV-2, remains ill-defined.

We interrogated the nasal methylome to identify pathophysiologic drivers in COVID-19 severity through whole genome bisulfite sequencing (WGBS) of nasal samples from COVID-19 positive individuals with severe and mild presentation of disease. We noted differential DNA methylation in intergenic regions and low methylated regions (LMRs), demonstrating the importance of distal regulatory elements in gene regulation in COVID-19 illness. Additionally, we demonstrated differential methylation of pathways implicated in immune cell recruitment and function, and the inflammatory response. We found significant hypermethylation of the FUT4 promoter implicating impaired neutrophil adhesion in severe disease. We also identified hypermethylation of ELF5 binding sites suggesting downregulation of ELF5 targets in the nasal cavity as a factor in COVID-19 phenotypic variability.

This study demonstrated DNA methylation as a marker of the immune response to SARS-CoV-2 infection, with enhancer-like elements playing significant roles. It is difficult to discern whether this differential methylation is a predisposing factor to severe COVID-19, or if methylation differences occur in response to disease severity. These differences in the nasal methylome may contribute to disease severity, or conversely, the nasal immune system may respond to severe infection through differential immune cell recruitment and immune function, and through differential regulation of the inflammatory response.

Carbon monoxide (CO) is a novel anti-inflammatory molecule, but the effects of CO on SARS-CoV-2 spike RBD (S-RBD)-induced human bronchial epithelial cytokines release remains unclear. CO was delivered using CO-releasing molecule 3 (CORM-3). The effects of S-RBD, ATPγS and CO on cytokines secretion were determined by enzyme-linked immunosorbent assay (ELISA) in 16HBE14o-human bronchial epithelial cell line. The inhibitory effect of CO on S-RBD-induced ERK phosphorylation was assessed by Western blot analysis. The regulatory effect of CO on extracellular nucleotide-induced ion transport was quantified by short-circuit current (ISC). S-RBD evoked CCL5 and IL-6 release and this effect could be suppressed by CO. However, CO failed to inhibit ATP release induced by S-RBD while decreased ATP-induced CCL5 and IL-6 secretion as well as ion transport. Furthermore, CO significantly inhibited ERK phosphorylation induced by S-RBD. These findings suggest an anti-inflammatory role of CO during inflammation induced by S-RBD and extracellular nucleotide in human bronchiol epithelial cells.

The objective of this study was to better understand immune failure mechanisms during severe acute respiratory syndrome coronavirus 2, SARS-CoV-2 infection, which are critical for developing targeted vaccines and effective treatments. We collected 34 cases representing different disease severities and performed high-quality single-cell TCR/BCR sequencing to analyze the peripheral immune cell profiles. Additionally, we assessed antibody-neutralizing activity through in vitro experiments. Our integrated multiomics analysis uncovers a profound immune paradox in severe COVID-19: hyperinflammation coexists with immunosuppression, driven by distinct yet interconnected dysregulatory mechanisms. Severe patients develop robust humoral immunity, evidenced by clonally expanded plasma cells producing neutralizing antibodies (e.g., IGHG1-dominated responses) and antigen-specific T cell activation. However, these protective responses are counteracted by myeloid-driven immunosuppression, particularly CD14+ HMGB2+ monocytes exhibiting metabolic reprogramming and HLA-DR downregulation, coupled with progressive T cell exhaustion characterized by IFN-γ/TNF-α hyperactivation and impaired antigen presentation. Importantly, prolonged viral persistence in severe cases arises from a failure to coordinate humoral and cellular immunity-antibody-mediated neutralization cannot compensate for defective cytotoxic T cell function and monocyte-mediated immune suppression. These findings highlight the necessity for therapeutic strategies that simultaneously enhance antibody effector functions (e.g., Fc optimization), restore exhausted T cells, and reverse myeloid suppression. They also highlight the importance of vaccines designed to elicit balanced B cell memory and durable T cell responses, which are critical to preventing severe disease progression. By addressing the dual challenges of hyperinflammation and immunosuppression, such approaches could restore immune coordination and improve outcomes in severe COVID-19.

The death rate of hematological malignancies is high, and the death rate of patients with COVID-19 infection is further increased. Although there have been expert consensus and relevant guidelines to introduce the recommendations of the guidelines for patients with hematological malignancies complicated with COVID-19 infection, there is limited understanding of the clinical characteristics of Chinese patients with acute leukemia complicated with COVID-19 infection.

This study aimed to analyze the clinical manifestations, mortality, and determinants of viral shedding duration in Chinese AL patients infected with COVID-19.

We conducted a retrospective study of 100 AL patients with COVID-19 infection in Henan Province, China, from December 1, 2022, to January 31, 2023. Data on demographics, leukemia subtype, symptoms, treatments (antibiotics/antivirals), and viral shedding duration were collected. Follow-up was conducted over three months to assess mortality. Univariate and multivariate analyses were performed to identify risk factors.

The median age was 49.5 years (58% male, 42% female), with 76% having acute myeloid leukemia (AML) and 24% acute lymphoblastic leukemia (ALL). Most patients (86%) were asymptomatic. Antibiotics and antivirals were administered to 35% and 25% of patients, respectively. Severe cases and fatalities exhibited prolonged viral shedding. Neutropenic patients on antibiotics had significantly extended shedding duration, whereas antiviral therapy or delayed primary disease management shortened it. The overall mortality rate was 6%. Univariate analysis identified neutropenia as a key mortality risk factor, though multivariate analysis showed no significant associations.

Early antiviral treatment may reduce viral shedding duration and potentially mitigate symptom severity and mortality in AL patients with COVID-19. Neutropenia emerged as a critical factor influencing outcomes. These findings underscore the importance of tailored therapeutic strategies for this high-risk population.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent involved in the coronavirus disease 2019 (COVID-19) pandemic. The development of infectious titration methods is crucial to provide data for a better understanding of transmission routes, as well as to validate the efficacy of inactivation treatments. Nevertheless, the low-throughput analytical capacity of traditional methods may be a limiting factor for a large screening of samples. The aim of the study was to develop a Real-Time Cell Analysis (RTCA) assay based on the measurement of cell impedance to quantify infectious SARS-CoV-2. The kinetics of cell impedance showed a virus-specific Cell Index (CI) drop. This enabled the correlation between viral concentrations and time at which a 50 % drop in CI values was observed (tCI50), with establishment of a standard curve. In parallel, the improved Spearman and Kärber method was used to quantify infectious titer since the virus-induced CI drop is correlated to the Cytopathic Effect. The estimated uncertainty was respectively 0.57, 0.36, and 0.26 log10 with 4, 8, and 16 wells per dilution. Thus, the RTCA assay is a powerful tool with a greatly simplified workflow for effective risk assessment in the field of food and environmental virology.