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Background: Limited data are available describing the effects of SARS-CoV-2 breakthrough infections on the plasma proteome., Methods: PCR-positive SARS-CoV-2 patients, enrolled in a natural history study, underwent analysis of the plasma proteome. A prospective cohort of 66 unvaccinated and 24 vaccinated persons with different degrees of infection severity were evaluated acutely (within 40 days of symptom onset), and at three and ten months. Comparisons based on vaccination status alone and unsupervised hierarchical clustering were performed. A second cohort of vaccinated Omicron patients were evaluated acutely and at ten months., Results: Acutely, unvaccinated patients manifested overexpression of proteins involved in immune and inflammatory responses, while vaccinated patients exhibited adaptive immune responses without significant inflammation. At three and ten months, only unvaccinated patients had diminished but sustained inflammatory (C3b, CCL15, IL17RE) and immune responses (DEFA5,TREM1). Both groups had underexpression of pathways essential for cellular function, signaling, and angiogenesis (AKT1, MAPK14, HSPB1) across phases. Unsupervised clustering, based on protein expression, identified four groups of patients with variable vaccination rates demonstrating that additional clinical factors influence the plasma proteome. The proteome of vaccinated Omicron patients did not differ from vaccinated pre-Omicron patients., Conclusions: Vaccination attenuates the inflammatory response to SARS-CoV-2 infection across phases. However, at ten months after symptom onset, changes in the plasma proteome persist in both vaccinated and unvaccinated individuals, which may be relevant to post-acute sequelae of SARS-CoV-2 and other viral infections associated with post-acute infection syndromes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Huapaya, Gairhe, Kanth, Tian, Demirkale, Regenold, Sun, Lynch, Luo, Forsberg, Dewar, Rehman, Li, Krack, Kuruppu, Aboye, Barnett, Strich, Davey, Childs, Chertow, Kovacs, Torabi-Parizi and Suffredini.)

Protein-based subunit vaccines like RBD-Fc are promising tools to fight COVID-19. RBD-Fc fuses the receptor-binding domain (RBD) of the SARS-CoV-2 virus spike protein with the Fc region of human IgG1, making it more immunogenic than RBD alone. Earlier work showed that combining RBD-Fc with iNKT cell agonists as adjuvants improved neutralizing antibodies but did not sufficiently enhance T cell responses, a limitation RBD-Fc vaccines share with common adjuvants. Here we demonstrate that aluminum hydroxide combined with α-C-GC, a C-glycoside iNKT cell agonist, significantly improved the RBD-Fc vaccine's induction of RBD-specific T-cell responses. Additionally, aluminum hydroxide with α-GC-CPOEt, a phosphonate diester derivative, synergistically elicited more robust neutralizing antibodies. Remarkably, modifying αGC with phosphate (OPO 3 H 2 ) or phosphonate (CPO 3 H 2 ) to potentially enhance aluminum hydroxide interaction did not improve efficacy over unmodified αGC with aluminum hydroxide. These findings underscore the straightforward yet potent potential of this approach in advancing COVID-19 vaccine development and provide insights for iNKT cell-based immunotherapy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Rui Luo, Zheng Liu, Ya-Qian Li, and Cheng Yan are listed as inventors on a pending patent application about αGC-CPOEt. All other authors declare no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Dynamical mathematical models defined by a system of differential equations are typically not easily accessible to non-experts. However, forecasts based on these types of models can help gain insights into the mechanisms driving the process and may outcompete simpler phenomenological growth models. Here we introduce a friendly toolbox, SpatialWavePredict, to characterize and forecast the spatial wave sub-epidemic model, which captures diverse wave dynamics by aggregating multiple asynchronous growth processes and has outperformed simpler phenomenological growth models in short-term forecasts of various infectious diseases outbreaks including SARS, Ebola, and the early waves of the COVID-19 pandemic in the US., Results: This tutorial-based primer introduces and illustrates a user-friendly MATLAB toolbox for fitting and forecasting time-series trajectories using an ensemble spatial wave sub-epidemic model based on ordinary differential equations. Scientists, policymakers, and students can use the toolbox to conduct real-time short-term forecasts. The five-parameter epidemic wave model in the toolbox aggregates linked overlapping sub-epidemics and captures a rich spectrum of epidemic wave dynamics, including oscillatory wave behavior and plateaus. An ensemble strategy aims to improve forecasting performance by combining the resulting top-ranked models. The toolbox provides a tutorial for forecasting time-series trajectories, including the full uncertainty distribution derived through parametric bootstrapping, which is needed to construct prediction intervals and evaluate their accuracy. Functions are available to assess forecasting performance, estimation methods, error structures in the data, and forecasting horizons. The toolbox also includes functions to quantify forecasting performance using metrics that evaluate point and distributional forecasts, including the weighted interval score., Conclusions: We have developed the first comprehensive toolbox to characterize and forecast time-series data using an ensemble spatial wave sub-epidemic wave model. As an epidemic situation or contagion occurs, the tools presented in this tutorial can facilitate policymakers to guide the implementation of containment strategies and assess the impact of control interventions. We demonstrate the functionality of the toolbox with examples, including a tutorial video, and is illustrated using daily data on the COVID-19 pandemic in the USA., (© 2024. The Author(s).)

Aims: To examine the effectiveness of Self-Help Plus (SH+) as an intervention for alleviating stress levels and mental health problems among healthcare workers., Methods: This was a prospective, two-arm, unblinded, parallel-designed randomised controlled trial. Participants were recruited at all levels of medical facilities within all municipal districts of Guangzhou. Eligible participants were adult healthcare workers experiencing psychological stress (10-item Perceived Stress Scale scores of ≥15) but without serious mental health problems or active suicidal ideation. A self-help psychological intervention developed by the World Health Organization in alleviating psychological stress and preventing the development of mental health problems. The primary outcome was psychological stress, assessed at the 3-month follow-up. Secondary outcomes were depression symptoms, anxiety symptoms, insomnia, positive affect (PA) and self-kindness assessed at the 3-month follow-up., Results: Between November 2021 and April 2022, 270 participants were enrolled and randomly assigned to either SH+ ( n = 135) or the control group ( n = 135). The SH+ group had significantly lower stress at the 3-month follow-up ( b = -1.23, 95% CI = -2.36, -0.10, p = 0.033) compared to the control group. The interaction effect indicated that the intervention effect in reducing stress differed over time ( b = -0.89, 95% CI = -1.50, -0.27, p = 0.005). Analysis of the secondary outcomes suggested that SH+ led to statistically significant improvements in most of the secondary outcomes, including depression, insomnia, PA and self-kindness., Conclusions: This is the first known randomised controlled trial ever conducted to improve stress and mental health problems among healthcare workers experiencing psychological stress in a low-resource setting. SH+ was found to be an effective strategy for alleviating psychological stress and reducing symptoms of common mental problems. SH+ has the potential to be scaled-up as a public health strategy to reduce the burden of mental health problems in healthcare workers exposed to high levels of stress.

Background: The long-term sequelae of Coronavirus disease 2019 (COVID-19) in children are unclear. We investigated COVID-19 symptoms in school-aged children to determine their impact on patients and their families., Methods: This cross-sectional study, conducted on February 25-28, 2023, selected a representative kindergarten and 9-year school from Shenzhen, China. There were randomly two classes each for the 12 grades from kindergarten to junior high school. The school-aged children were aged 3-16 years. Literate parents completed an online questionnaire related to their children's COVID-19 symptoms since December 1, 2022. Descriptive statistics were computed as necessary. Univariate and multivariable linear regression analyses were performed, and variables with a p-value < 0.05 were considered to have a significant association with the subjective feeling scores for COVID-19 infection., Results: We included 936 school-aged children, with a COVID-19 infection rate of 68.5%. The prevalence of LC 28 (illness with symptoms lasting for 28 days) was 3.4%. During acute infection, the median number of the 641 children's symptoms was 3.0 (IQR: 1.0-5.0) and the median score of subjective feelings was 15.0 (IQR: 11.0-24.5). The top three symptoms were fever, cough/expectoration, and rhinobyon. Age of 13-16 years (adjusted beta: 3.60, 95% CI: 0.32-6.88) and comorbidities (adjusted beta: 3.47, 95% CI: 1.20-5.73) were independently associated with higher subjective feelings (p < 0.05). The top three characteristics associated with LC 28 were alopecia (33.3%, 5/15), cognitive dysfunction (29.2%, 7/24), and emotional problem (28.6%, 6/21)., Conclusions: Children with COVID-19 have a short duration of symptoms and milder symptoms, so they can self-medicate to minimize hospital crowding. Children with basic diseases require prompt attention. Although LC 28 is uncommon in children, mental and psychological problems after COVID-19 recovery should not be ignored., (© 2024. The Author(s).)

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection has many neurological manifestations, and its effects on the nervous system are increasingly recognized. There has been no systematic analysis of electroencephalography (EEG) characteristics in children exhibiting neurological symptoms of Coronavirus disease 2019 (COVID-19). The primary aim of this study was to describe the EEG characteristics caused by COVID-19 infection in children who were showing neurological symptoms and to assess the relationship between COVID-19-related EEG changes and clinical features in these children., Method: This study included 125 pediatric patients infected with SARS-CoV2 and showing neurological symptoms, and their continuous EEG was recorded. In addition, the demographic and clinical characteristics of these patients were analyzed and the correlation between the two was investigated., Results: Abnormal EEG findings were detected in 31.20% (N = 39) of the patients. Abnormal discharges (43.59%) were the most common EEG abnormalities, followed by background abnormalities (41.03%). The proportion of patients diagnosed with febrile seizure was higher in the normal EEG group than in the abnormal EEG group (P = 0.002), while the opposite was true for epilepsy and encephalitis/encephalopathy (P = 0.016 and P = 0.003, respectively). The independent associated factors of abnormal EEG were age and total length of stay (P < 0.001 and P = 0.003, respectively). Non-specific EEG abnormalities were found in COVID-19-related encephalitis/encephalopathy., Conclusion: Our study corroborated that a small group of pediatric patients infected by COVID-19 and showing neurological symptoms may exhibit abnormal EEG. This study could help improve the understanding of clinical and EEG characteristics in children with COVID-19 and inform triage policies in other hospitals during the COVID-19 pandemic., (© 2024. The Author(s).)

Background: The ability of generating effective humoral immune responses to SARS-CoV-2 infection has not been clarified in lymphoma patients. The study aimed to investigate the antibody (Ab) production after SARS-Cov-2 infection and clarify the factors affecting the Ab generation in these patients., Patients & Methods: 80 lymphoma patients and 51 healthy controls were included in this prospective observational study. Clinical factors and treatment regimens affecting Ab positive rate (APR) and Ab levels were analyzed by univariate and multivariate methods., Results: The anti-SARS-CoV-2 IgG APR and Ab levels in lymphoma patients were significantly lower than those in healthy controls. Lymphoma patients with COVID-19 vaccination had significantly higher APR and Ab levels compared with those without vaccination. Additionally, the use of dexamethasone for COVID-19 treatment had a negative impact on Ab levels. For the impact of treatment regimens on the APR and Ab levels, the results showed that patients treated with ≥ 6 times CD20 monoclonal Ab (mAb) and patients treated with autologous hematopoietic stem cell transplantation (ASCT) prior to infection produced a statistically lower APR and Ab levels compared with those treated with 1-5 times CD20 mAb and those treated without ASCT, respectively. Furthermore, multiple regression analysis indicated that the number of anti-CD20 treatment was an independent predictor for both APR and Ab levels., Conclusions: Humoral immune response to SARS-CoV-2 infection was impaired in lymphoma patients partly due to anti-CD20 and ASCT treatment. COVID-19 vaccination may be more needed for these patients., (© 2024. The Author(s).)

The SARS-CoV-2 main protease (M pro , also named 3CL pro ) is a promising antiviral target against COVID-19 due to its functional importance in viral replication and transcription. Herein, we report the discovery of a series of α-ketoamide derivatives as a new class of SARS-CoV-2 M pro inhibitors. Structure-activity relationship (SAR) of these compounds was analyzed, which led to the identification of a potent M pro inhibitor (27h) with an IC 50 value of 10.9 nM. The crystal structure of M pro in complex with 27h revealed that α-ketoamide warhead covalently bound to Cys145s of the protease. In an in vitro antiviral assay, 27h showed excellent activity with an EC 50 value of 43.6 nM, comparable to the positive control, Nirmatrelvir. This compound displayed high target specificity for M pro against human proteases and low toxicity. It also possesses favorable pharmacokinetic properties. Overall, compound 27h could be a promising lead compound for drug discovery targeting SARS-CoV-2 M pro and deserves further in-depth studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Patients with ALI (acute lung injury)/ARDS (acute respiratory distress syndrome) are often septic and with poor prognosis, which leads to a high mortality rate of 25-40%. Despite the advances in medicine, there are no effective pharmacological therapies for ALI/ARDS due to the short systemic circulation and poor specificity in the lungs. To address this problem, we prepared TP-loaded nanoparticles (TP-NPs) through the emulsification-and-evaporation method, and then the platelet membrane vesicles were extracted and coated onto the surface of the NPs to constitute the biomimetic PM@TP-NPs. In a LPS-induced ALI mouse model, PM@TP-NPs showed good biocompatibility and biosafety, which was evidenced by no significant toxic effect on cell viability and no hemolysis of red blood cells. In ALI mice, the PM@TP-NPs showed favorable anti-inflammation and enhanced therapeutic activity of TPs compared to the free drug. Administration of PM@TP-NPs effectively inhibited lung vascular injury, evidenced by the decreased lung vascular permeability, reduced pro-inflammatory cytokine burden, evidenced by decreased inflammatory cell (macrophages, neutrophils, etc .) infiltration in the bronchoalveolar lavage fluid (BALF) and lung tissues, and inhibited the secretion of pro-inflammatory cytokines and NLRP3 inflammasome activation. ALI/ARDS is defined by damage to the alveolar epithelium and endothelium; thus, effective intervention targeting pulmonary vascular endothelial cells (VECs) is crucial for the treatment of respiratory diseases. For further determination of the targeting of PM cloaked NPs, healthy mice were also administered with the same NPs. Interestingly, the PM cloaked NPs only showed highly efficient targeting to the inflamed lungs and VECs, but no accumulation in healthy lungs and VECs. The data demonstrated that this biomimetic nanoplatform could be used as a potential strategy for personalized therapies in the treatment of inflammatory diseases, such as ALI/ARDS, and even COVID-19-associated pneumonia.

Ophiocordyceps sinensis is a precious Chinese traditional herb with a long medicinal history. This study used UPLC-MS metabolomics to explore and compare the metabolic profiles of the stroma (OSBSz), sclerotium (OSBSh), and mycelium (OSBS) of O sinensis to analyze their differential metabolites and identified potential active components. Then combined with network pharmacology and molecular docking to explore the mechanism of differential metabolites with anti-influenza properties. The results indicate that the stroma, sclerotium, and mycelium showed significant differences in metabolites. The key pathways for differential metabolites were butanoate metabolism, thiamin metabolism, alanine, aspartate and glutamate metabolism, citrate cycle, and arginine biosynthesis. Protein-protein interaction analysis identified potential targets, including SRC, RHOA, HSP90AA1, VEGFA, ITGB1, PRKCA, and ITGA1, and the key protective pathways in-volved PI3K-Akt, HIF-1, influenza A, and Coronavirus disease 2019. The molecular docking results showed that the core metabolite D-(-)-glutamine has high binding affinity with SRC, RHOA, and EGFR, re-flecting the multi-component and multi-target network system of O sinensis. In short, the combination of metabonomics, network pharmacology and macromolecular docking technology provides a new way to explore the anti-influenza research of O sinensis. This is undoubtedly an important theoretical support for the clinical application of O sinensis in the future., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: An increasing amount of evidence suggests that psoriasis and nonalcoholic steatohepatitis (NASH) may occur simultaneously, whereas the underlying mechanisms remain unclear. Our research aims to explore the potential comorbidity mechanism in psoriasis and nonalcoholic steatohepatitis., Materials and Methods: The expression profiles of psoriasis (GSE30999, GSE13355) and NASH (GSE24807, GSE17470) were downloaded from GEO datasets. Next, common differently expressed genes (DEGs) of psoriasis and NASH were investigated. Then, GO and KEGG enrichment, protein interaction network (PPI) construction, and hub gene identification for DEGs were performed. Finally, immune cells expression, target genes predicted by common miRNAs, and transcription factors interaction analysis for hub genes were carried out., Results: Twenty DEGs were identified in totally. GO analysis revealed response to the virus was the most enriched term, and hepatitis C and coronavirus disease-COVID-19 infection-associated pathways were mainly enriched in KEGG. A total of eight hub genes were collected, including IFIT1, IFIT3, OAS1, HPGDS, IFI27, IFI44, CXCL10, IRF9, and 11 TFs were predicted. Then, neutrophils and monocytes were identified as immune cells that express the most hub genes. Moreover, five common miRNAs for psoriasis and NASH and one common miRNAs (hsa-miR-1305)-mRNAs (CHL1, MBNL2) network were presented., Conclusion: CHL1 and MBNL2 may participate in the process of psoriasis and NASH via regulating hsa-miR-1305, and together with eight hub genes may be potential therapeutic targets for future treatment for the co-occurrence of these two diseases. This comprehensive bioinformatic analysis provides new insights on molecular pathogenesis and identification of potential therapeutic targets for the co-occurrence of them., (© 2023 The Authors. Skin Research and Technology published by John Wiley & Sons Ltd.)

Background: The COVID-19 pandemic continues to impact global health and China requires a 14-day quarantine for individuals on flights with positive COVID-19 cases. This quarantine can impact mental well-being, including sleep. This study aims to examine the impact of psychosocial and behavioral factors on insomnia among individuals undergoing quarantine in hotels., Methods: This study was a cross-sectional survey carried out in Guangzhou, China. The data was gathered through online questionnaires distributed to international passengers who arrived in Guangzhou on flights and were required to undergo a 14-day quarantine in hotels arranged by the local government. The questionnaires were sent to the participants through the government health hotline "12,320.", Results: Of the 1003 passengers who were quarantined, 6.7% reported significant anxiety and 25.0% had varying degrees of insomnia. Anxiety was positively associated with insomnia (β = 0.92, P < 0.001), while collectivism (β = -0.07, P = 0.036), indoor exercise (β = -0.50, P < 0.001), and the perceived people orientation of the public health service (β = -0.20, P = 0.001) were negatively associated with insomnia. The study also identified moderating effects, such that a higher sense of collectivism, a greater frequency of indoor exercise, and a higher perception of the people-oriented of the public health service were associated with a lower impact of anxiety on insomnia. These moderating effects were also observed in participants with varying degrees of insomnia., Conclusions: This study reveals that a proportion of people undergoing entry quarantine experience insomnia and confirms how psychosocial and behavioral factors can alleviate insomnia in this population., (© 2023. The Author(s).)

Objectives: As coronavirus disease 2019 (COVID-19) spread, many states implemented nonpharmaceutical interventions in the absence of effective therapies with varying degrees of success. Our aim was to evaluate restrictions comparing two regions of Georgia and their impact on outcomes as measured by confirmed illness and deaths., Methods: Using The New York Times COVID-19 incidence data and mandate information from various web sites, we examined trends in cases and deaths using joinpoint analysis at the region and county level before and after the implementation of a mandate., Results: We found that rates of cases and deaths showed the greatest decrease in acceleration after the simultaneous implementation of a statewide shelter-in-place for vulnerable populations combined with social distancing for businesses and limiting gatherings to <10 people. County-level shelters-in-place, business closures, limits on gatherings to <10, and mask mandates showed significant case rate decreases after a county implemented them. School closures had no consistent effect on either outcome., Conclusions: Our findings indicate that protecting vulnerable populations, implementing social distancing, and mandating masks may be effective countermeasures to containment while mitigating the economic and psychosocial effects of strict shelters-in-place and business closures. In addition, states should consider allowing local municipalities the flexibility to enact nonpharmaceutical interventions that are more or less restrictive than the state-level mandates under some conditions in which the data indicate it is necessary to protect communities from disease or undue economic burden.

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes non-symptomatic infection, mild influenza-like symptoms to pneumonia, severe acute respiratory distress syndrome, and even death, reflecting different clinical symptoms of viral infection. However, the mechanism of its pathogenicity remains unclear. Host-specific traits have a breakthrough significance for studying the pathogenicity of SARS-CoV-2. We previously reported SARS-CoV-2/BMA8, a mouse-adapted strain, was lethal to aged BALB/c mice but not to aged C57BL/6N mice. Here, we further investigate the differences in pathogenicity of BMA8 strain against wild-type aged C57BL/6N and BALB/c mice., Methods: Whole blood and tissues were collected from mice before and after BMA8 strain infection. Viral replication and infectivity were assessed by detection of viral RNA copies and viral titers; the degree of inflammation in mice was tested by whole blood cell count, ELISA and RT-qPCR assays; the pathogenicity of SARS-CoV-2/BMA8 in mice was measured by Histopathology and Immunohistochemistry; and the immune level of mice was evaluated by flow cytometry to detect the number of CD8 + T cells., Results: Our results suggest that SARS-CoV-2/BMA8 strain caused lower pathogenicity and inflammation level in C57BL/6N mice than in BALB/c mice. Interestingly, BALB/c mice whose MHC class I haplotype is H-2K d showed more severe pathogenicity after infection with BMA8 strain, while blockade of H-2K b in C57BL/6N mice was also able to cause this phenomenon. Furthermore, H-2K b inhibition increased the expression of cytokines/chemokines and accelerated the decrease of CD8 + T cells caused by SARS-CoV-2/BMA8 infection., Conclusions: Taken together, our work shows that host MHC molecules play a crucial role in the pathogenicity differences of SARS-CoV-2/BMA8 infection. This provides a more profound insight into the pathogenesis of SARS-CoV-2, and contributes enlightenment and guidance for controlling the virus spread., (© 2023. The Author(s).)

Objective: To assess safety data of the inactivated COVID-19 vaccines in a real-world sample of people with autoimmune encephalitis (pwAE)., Methods: A cross-sectional study was performed between 1 March and 30 April 2022. We invited pwAE from our previous ONE-WC (Outcome of Autoimmune Encephalitis Study in Western China) registration study database, to attend neurological clinics, at West China Hospital to participate in a face-to-face survey using a custom-designed questionnaire for this study. The ONE-WC study began in October 2011 and prospectively enrolled pwAE from four large comprehensive neurological centers in Sichuan province, China., Results: Of the 387 pwAE, 240 (62.0%) completed the questionnaire. Half the 240 participants (121, 50.4%) reported receiving at least one dose of COVID-19 vaccine, which in all but two patients received inactivated COVID-19 vaccine. Among vaccinated pwAE, the median age was 35 years (range 15-69) and 57.8% of them were women. The most frequent reasons that unvaccinated individuals reported for not receiving the COVID-19 vaccine were concern about vaccine-induced relapse of AE (50.4%) and advice from a physician to delay vaccination (21.0%). Small proportions of vaccinated individuals reported adverse events after the first dose (11.5%) or the second dose (10.2%), and none of the adverse events was serious. Across the entire sample, one individual reported relapsing within 30 days after the first dose and three individuals reported relapsing more than 120 days after the first dose., Conclusions: This real-world survey indicates an overall favorable safety profile of the inactivated COVID-19 vaccine for pwAE., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

The coronavirus disease of 2019 pandemic has catalyzed the rapid development of mRNA vaccines, whereas, how to optimize the mRNA sequence of exogenous gene such as severe acute respiratory syndrome coronavirus 2 spike to fit human cells remains a critical challenge. A new algorithm, iDRO (integrated deep-learning-based mRNA optimization), is developed to optimize multiple components of mRNA sequences based on given amino acid sequences of target protein. Considering the biological constraints, we divided iDRO into two steps: open reading frame (ORF) optimization and 5' untranslated region (UTR) and 3'UTR generation. In ORF optimization, BiLSTM-CRF (bidirectional long-short-term memory with conditional random field) is employed to determine the codon for each amino acid. In UTR generation, RNA-Bart (bidirectional auto-regressive transformer) is proposed to output the corresponding UTR. The results show that the optimized sequences of exogenous genes acquired the pattern of human endogenous gene sequence. In experimental validation, the mRNA sequence optimized by our method, compared with conventional method, shows higher protein expression. To the best of our knowledge, this is the first study by introducing deep-learning methods to integrated mRNA sequence optimization, and these results may contribute to the development of mRNA therapeutics., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Importance: Noninvasive stool-based screening tests (SBTs) are effective alternatives to colonoscopy. However, a positive SBT result requires timely follow-up colonoscopy (FU-CY) to complete the colorectal cancer screening paradigm., Objectives: To evaluate FU-CY rates after a positive SBT result and to assess the association of the early COVID-19 pandemic with FU-CY rates., Design, Setting, and Participants: This mixed-methods cohort study included retrospective analysis of deidentified administrative claims and electronic health records data between June 1, 2015, and June 30, 2021, from the Optum Labs Data Warehouse and qualitative, semistructured interviews with clinicians from 5 health care organizations (HCOs). The study population included data from average-risk primary care patients aged 50 to 75 years with a positive SBT result between January 1, 2017, and June 30, 2020, at 39 HCOs., Main Outcomes and Measures: The primary outcome was the FU-CY rate within 1 year of a positive SBT result according to patient age, sex, race, ethnicity, insurance type, Charlson Comorbidity Index (CCI), and prior SBT use., Results: This cohort study included 32 769 individuals (16 929 [51.7%] female; mean [SD] age, 63.1 [7.1] years; 2092 [6.4%] of Black and 28 832 [88.0%] of White race; and 825 [2.5%] of Hispanic ethnicity). The FU-CY rates were 43.3% within 90 days of the positive SBT result, 51.4% within 180 days, and 56.1% within 360 days (n = 32 769). In interviews, clinicians were uniformly surprised by the low FU-CY rates. Rates varied by race, ethnicity, insurance type, presence of comorbidities, and SBT used. In the Cox proportional hazards regression model, the strongest positive association was with multitarget stool DNA use (hazard ratio, 1.63 [95% CI, 1.57-1.68] relative to fecal immunochemical tests; P < .001), and the strongest negative association was with the presence of comorbidities (hazard ratio, 0.64 [95% CI, 0.59-0.71] for a CCI of >4 relative to 0; P < .001). The early COVID-19 pandemic was associated with lower FU-CY rates., Conclusions and Relevance: This study found that FU-CY rates after a positive SBT result for colorectal cancer screening were low among an average-risk population, with the median HCO achieving a 53.4% FU-CY rate within 1 year. Socioeconomic factors and the COVID-19 pandemic were associated with lower FU-CY rates, presenting opportunities for targeted intervention by clinicians and health care systems.

The coronavirus disease 2019 (COVID-19) pandemic caused extensive loss of life worldwide. Further, the COVID-19 and influenza mix-infection had caused great distress to the diagnosis of the disease. To control illness progression and limit viral spread within the population, a real-time reverse-transcription PCR (RT-PCR) assay for early diagnosis of COVID-19 was developed, but detection was time-consuming (4-6 h). To improve the diagnosis of COVID-19 and influenza, we herein developed a recombinase polymerase amplification (RPA) method for simple and rapid amplification of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19 and Influenza A (H1N1, H3N2) and B (influenza B). Genes encoding the matrix protein (M) for H1N1, and the hemagglutinin (HA) for H3N2, and the polymerase A (PA) for Influenza B, and the nucleocapsid protein (N), the RNA-dependent-RNA polymerase (RdRP) in the open reading frame 1ab (ORF1ab) region, and the envelope protein (E) for SARS-CoV-2 were selected, and specific primers were designed. We validated our method using SARS-CoV-2, H1N1, H3N2 and influenza B plasmid standards and RNA samples extracted from COVID-19 and Influenza A/B (RT-PCR-verified) positive patients. The method could detect SARS-CoV-2 plasmid standard DNA quantitatively between 10 2 and 10 5 copies/ml with a log linearity of 0.99 in 22 min. And this method also be very effective in simultaneous detection of H1N1, H3N2 and influenza B. Clinical validation of 100 cases revealed a sensitivity of 100% for differentiating COVID-19 patients from healthy controls when the specificity was set at 90%. These results demonstrate that this nucleic acid testing method is advantageous compared with traditional PCR and other isothermal nucleic acid amplification methods in terms of time and portability. This method could potentially be used for detection of SARS-CoV-2, H1N1, H3N2 and influenza B, and adapted for point-of-care (POC) detection of a broad range of infectious pathogens in resource-limited settings., (© 2022 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

The coronavirus disease 2019 (COVID-19) pandemic has posed a profound psychological impact on healthcare workers. However, the role of positive affect in moderating the effect of perceived stress on the psychological states of healthcare workers remains unknown. This study aimed to analyze the moderating effect of positive affect on the association between stress and the mental health of healthcare workers during the COVID-19 pandemic. This cross-sectional study evaluated the relationships between perceived stress (the Perceived Stress Scale), positive affect (the Positive and Negative Affect Schedule), depression (the Patient Health Questionnaire-9), and anxiety (the Generalized Anxiety Disorder 7-item Scale) during the COVID-19 pandemic in 644 Chinese healthcare workers who completed online self-reports. The results revealed a significant negative association between positive affect and psychological problems, including stress, depression, and anxiety. At the total group level, multiple regression analysis showed that positive affect alleviated the influence of perceived stress on depression, but no significant moderating effect was found for anxiety. In the subgroups divided by perceived stress, the moderating effect of positive affect on depression was only significant in healthcare workers with a high level of perceived stress. These results suggested that positive affect played a moderative role in alleviating the effect of stress on depression among healthcare workers, particularly those with a high level of stress, thus emphasizing the importance of positive affect as an intervention strategy for promoting the mental health of healthcare workers in the context of the ongoing COVID-19 pandemic.

Adjuvants are essential components of vaccines. Invariant natural killer T (iNKT) cells are a distinct subset of T cells that function to bridge the innate and adaptive immunities and are capable of mediating strong and rapid responses to a range of diseases, including cancer and infectious disease. An increasing amount of evidence suggests that iNKT cells can help fight viral infection. In particular, iNKT-secreting IL-4 is a key mediator of humoral immunity and has a positive correlation with the levels of neutralizing antibodies. As iNKT cell agonists, αGC glycolipid (α-galactosylceramide, or KRN7000) and its analogues as vaccine adjuvants have begun to provide vaccinologists with a new toolset. Herein we found that a new iNKT-cell agonist αGC-CPOEt elicited a strong cytokine response with increased IL-4 production. Remarkably, after three immunizations, SARS-CoV-2 RBD-Fc adjuvanted by αGC-CPOEt evoked robust neutralizing antibody responses that were about 5.5-fold more than those induced by αGC/RBD-Fc and 25-fold greater than those induced by unadjuvanted RBD-Fc. These findings imply that αGC-CPOEt could be investigated further as a new COVID-19 vaccine adjuvant to prevent current and future infectious disease outbreaks.

We analyze an ensemble of n-sub-epidemic modeling for forecasting the trajectory of epidemics and pandemics. These ensemble modeling approaches, and models that integrate sub-epidemics to capture complex temporal dynamics, have demonstrated powerful forecasting capability. This modeling framework can characterize complex epidemic patterns, including plateaus, epidemic resurgences, and epidemic waves characterized by multiple peaks of different sizes. We systematically assess their calibration and short-term forecasting performance in short-term forecasts for the COVID-19 pandemic in the USA from late April 2020 to late February 2022. We compare their performance with two commonly used statistical ARIMA models. The best fit sub-epidemic model and three ensemble models constructed using the top-ranking sub-epidemic models consistently outperformed the ARIMA models in terms of the weighted interval score (WIS) and the coverage of the 95% prediction interval across the 10-, 20-, and 30-day short-term forecasts. In our 30-day forecasts, the average WIS ranged from 377.6 to 421.3 for the sub-epidemic models, whereas it ranged from 439.29 to 767.05 for the ARIMA models. Across 98 short-term forecasts, the ensemble model incorporating the top four ranking sub-epidemic models (Ensemble(4)) outperformed the (log) ARIMA model 66.3% of the time, and the ARIMA model, 69.4% of the time in 30-day ahead forecasts in terms of the WIS. Ensemble(4) consistently yielded the best performance in terms of the metrics that account for the uncertainty of the predictions. This framework can be readily applied to investigate the spread of epidemics and pandemics beyond COVID-19, as well as other dynamic growth processes found in nature and society that would benefit from short-term predictions., Competing Interests: The authors have declared that no competing interests exist.

Background: From the end of 2019 to now, coronavirus disease 2019 (COVID-19) has put enormous strain on the world's health systems. As a characteristic sign of COVID-19 patient, olfactory dysfunction (OD) poses considerable problems for patients. In China, acupuncture has been widely used to treat OD caused by COVID-19, but there is still a lack of evidence-based medical evaluation. This study was designed to evaluate the effectiveness and safety of acupuncture for the treatment of COVID-19 OD., Methods: According to the retrieval strategies, randomized controlled trials on the acupuncture for COVID-19 OD were obtained from Cochrane Central Register of Controlled Trials, Embase, PubMed, Web of Science, the Chinese National Knowledge Infrastructure, the Chinese Biomedical Literature Database, the Chinese Scientific Journal Database and the Wanfang Database, regardless of publication date, or language. Studies were screened based on inclusion and exclusion criteria, and the Cochrane risk bias assessment tool was used to evaluate the quality of the studies. The meta-analysis was performed using Review Manager (RevMan 5.3) and STATA 14.2 software. Ultimately, the evidentiary grade for the results will be evaluated., Results: The results of this meta-analysis will be submitted to a peer-reviewed journal for publication., Conclusion: This study will provide up-to-date summary proof for evaluating the effectiveness and safety of acupuncture for COVID-19 OD., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: Indigenous populations have been disproportionately affected during pandemics. We investigated COVID-19 mortality estimates among indigenous and non-indigenous populations at national and sub-national levels in Mexico., Methods: We obtained data from the Ministry of Health, Mexico, on 2,173,036 laboratory-confirmed RT-PCR positive COVID-19 cases and 238,803 deaths. We estimated mortality per 1000 person-weeks, mortality rate ratio (RR) among indigenous vs. non-indigenous groups, and hazard ratio (HR) for COVID-19 deaths across four waves of the pandemic, from February 2020 to March 2022. We also assessed differences in the reproduction number (R t )., Results: The mortality rate among indigenous populations of Mexico was 68% higher than that of non-indigenous groups. Out of 32 federal entities, 23 exhibited higher mortality rates among indigenous groups (P < 0.05 in 13 entities). The fourth wave showed the highest RR (2.40). The crude HR was 1.67 (95% CI: 1.62, 1.72), which decreased to 1.08 (95% CI: 1.04, 1.11) after controlling for other covariates. During the intense fourth wave, the R t among the two groups was comparable., Conclusion: Indigenous status is a significant risk factor for COVID-19 mortality in Mexico. Our findings may reflect disparities in non-pharmaceutical (e.g., handwashing and using facemasks), and COVID-19 vaccination interventions among indigenous and non-indigenous populations in Mexico., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: When facing major emergency public accidents, men and women may react differently. Our research aimed to assess the influence of gender difference on social support, information preference, biological rhythm, psychological distress, and the possible interaction among these factors during the COVID-19 pandemic., Methods: In this cross-sectional study, 3,237 respondents aged 12 years and older finished the online survey. Levels of social support, information preference, biological rhythm, and psychological distress were assessed using validated scales. A path analysis was conducted to explore possible associations among these variables., Results: The path analysis indicated that women with high levels of social support had a lower possibility of biological rhythm disorders and lower levels of somatization symptoms of psychological distress during the COVID-19 pandemic. The influence of social support on somatization symptoms was exerted via biological rhythm. Women tended to believe both negative and positive information, while men preferred more extreme information., Conclusion: Our results highlighted gender difference in study variables during the COVID-19 pandemic and the importance of social support in alleviating psychological distress and biological rhythm disorders. Moreover, we confirmed that information preference differed significantly by somatization symptoms of psychological distress, suggesting extra efforts to provide more individualized epidemic information. Longitudinal research is required to further explore casual inferences., Competing Interests: The authors have declared that no competing interests exist.

Repeated outbreaks of coronavirus disease 2019 (COVID-19) have forced people to shift most of their work and life activities from offline to online, leading to a growing problem of Internet dependence and even Internet addiction. However, the mechanism of the association between COVID-19-related intolerance of uncertainty (COVID-19 IU) and Internet addiction during the second wave of COVID-19 is still unclear. The current study explored the association between COVID-19 IU and Internet addiction as mediated by depression and risk perception based on the Uncertainty-Depression-Perception-Addiction model (UDPA). A total of 1,137 adult participants were recruited, and COVID-19 IU, depression, risk perception, Internet addiction, and demographic variables were analyzed. The results showed that COVID-19 IU was significantly and positively associated with Internet addiction and that this relationship was mediated in parallel by depression and risk perception. Our findings further extend the Interaction of Person-Affect-Cognition-Execution (I-PACE) model from the perspective of applicability in the unique context of COVID-19. Furthermore, the study suggests that individuals could decrease their dependence on the Internet to prevent Internet addiction during the second wave of the pandemic through effective interventions that include lowering COVID-19 IU, improving emotion regulation, and developing reasonable perceptions of risk., (© 2022 Institute of Psychology, Chinese Academy of Sciences and John Wiley & Sons Australia, Ltd.)

Colombia announced the first case of severe acute respiratory syndrome coronavirus 2 on March 6, 2020. Since then, the country has reported a total of 5,002,387 cases and 127,258 deaths as of October 31, 2021. The aggressive transmission dynamics of SARS-CoV-2 motivate an investigation of COVID-19 at the national and regional levels in Colombia. We utilize the case incidence and mortality data to estimate the transmission potential and generate short-term forecasts of the COVID-19 pandemic to inform the public health policies using previously validated mathematical models. The analysis is augmented by the examination of geographic heterogeneity of COVID-19 at the departmental level along with the investigation of mobility and social media trends. Overall, the national and regional reproduction numbers show sustained disease transmission during the early phase of the pandemic, exhibiting sub-exponential growth dynamics. Whereas the most recent estimates of reproduction number indicate disease containment, with Rt<1.0 as of October 31, 2021. On the forecasting front, the sub-epidemic model performs best at capturing the 30-day ahead COVID-19 trajectory compared to the Richards and generalized logistic growth model. Nevertheless, the spatial variability in the incidence rate patterns across different departments can be grouped into four distinct clusters. As the case incidence surged in July 2020, an increase in mobility patterns was also observed. On the contrary, a spike in the number of tweets indicating the stay-at-home orders was observed in November 2020 when the case incidence had already plateaued, indicating the pandemic fatigue in the country., Competing Interests: The authors have declared that no competing interests exist.

Infection with SARS-CoV-2, the causative agent of COVID-19, causes mild to moderate disease in most patients but carries a risk of morbidity and mortality. Seriously affected individuals manifest disorders of hemostasis and a cytokine storm, but it is not understood how these manifestations of severe COVID-19 are linked. Here, we showed that the SARS-CoV-2 spike protein engaged the CD42b receptor to activate platelets via 2 distinct signaling pathways and promoted platelet-monocyte communication through the engagement of P selectin/PGSL-1 and CD40L/CD40, which led to proinflammatory cytokine production by monocytes. These results explain why hypercoagulation, monocyte activation, and a cytokine storm are correlated in patients severely affected by COVID-19 and suggest a potential target for therapeutic intervention.

Background: Children and older adults with coronavirus disease 2019 (COVID-19) display a distinct spectrum of disease severity yet the risk factors aren't well understood. We sought to examine the expression pattern of angiotensin-converting enzyme 2 (ACE2), the cell-entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the role of lung progenitor cells in children and older patients., Methods: We retrospectively analyzed clinical features in a cohort of 299 patients with COVID-19. The expression and distribution of ACE2 and lung progenitor cells were systematically examined using a combination of public single-cell RNA-seq data sets, lung biopsies, and ex vivo infection of lung tissues with SARS-CoV-2 pseudovirus in children and older adults. We also followed up patients who had recovered from COVID-19., Results: Compared with children, older patients (>50 years.) were more likely to develop into serious pneumonia with reduced lymphocytes and aberrant inflammatory response (P = .001). The expression level of ACE2 and lung progenitor cell markers were generally decreased in older patients. Notably, ACE2 positive cells were mainly distributed in the alveolar region, including SFTPC positive cells, but rarely in airway regions in the older adults (P < .01). The follow-up of discharged patients revealed a prolonged recovery from pneumonia in the older (P < .025)., Conclusions: Compared to children, ACE2 positive cells are generally decreased in older adults and mainly presented in the lower pulmonary tract. The lung progenitor cells are also decreased. These risk factors may impact disease severity and recovery from pneumonia caused by SARS-Cov-2 infection in older patients., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objectives: This study examined how socio-demographic, climate and population health characteristics shaped the geospatial variability in excess mortality patterns during the COVID-19 pandemic in Mexico., Methods: We used Serfling regression models to estimate all-cause excess mortality rates for all 32 Mexican states. The association between socio-demographic, climate, health indicators and excess mortality rates were determined using multiple linear regression analyses. Functional data analysis characterized clusters of states with distinct excess mortality growth rate curves., Results: The overall all-cause excess deaths rate during the COVID-19 pandemic in Mexico until April 10, 2021 was estimated at 39.66 per 10 000 population. The lowest excess death rates were observed in southeastern states including Chiapas (12.72) and Oaxaca (13.42), whereas Mexico City had the highest rate (106.17), followed by Tlaxcala (51.99). We found a positive association of excess mortality rates with aging index, marginalization index, and average household size (P < 0.001) in the final adjusted model (Model R 2 =77%). We identified four distinct clusters with qualitatively similar excess mortality curves., Conclusion: Central states exhibited the highest excess mortality rates, whereas the distribution of aging index, marginalization index, and average household size explained the variability in excess mortality rates across Mexico., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Coronavirus disease 2019 (COVID-19) broke out and then became a global epidemic at the end of 2019. With the increasing number of deaths, early identification of disease severity and interpretation of pathogenesis are very important. Aiming to identify biomarkers for disease severity and progression of COVID-19, 75 COVID-19 patients, 34 healthy controls and 23 patients with pandemic influenza A(H1N1) were recruited in this study. Using liquid chip technology, 48 cytokines and chemokines were examined, among which 33 were significantly elevated in COVID-19 patients compared with healthy controls. HGF and IL-1β were strongly associated with APACHE II score in the first week after disease onset. IP-10, HGF and IL-10 were correlated positively with virus titers. Cytokines were significantly correlated with creatinine, troponin I, international normalized ratio and procalcitonin within two weeks after disease onset. Univariate analyses were carried out, and 6 cytokines including G-CSF, HGF, IL-10, IL-18, M-CSF and SCGF-β were found to be associated with the severity of COVID-19. 11 kinds of cytokines could predict the severity of COVID-19, among which IP-10 and M-CSF were excellent predictors for disease severity. In conclusion, the levels of cytokines in COVID-19 were significantly correlated with the severity of the disease in the early stage, and serum cytokines could be used as warning indicators of the severity and progression of COVID-19. Early stratification of disease and intervention to reduce hypercytokinaemia may improve the prognosis of COVID-19 patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Guo, Wang, Xia, Shi, Chen, Zheng, Chen, Gao, Guo, Ji, Huang, Luo, Zhang, Zuo, Chen, Xu, Xia, Zhu, Xu, Qiu, Sheng, Xu and Li.)

Mexico has experienced one of the highest COVID-19 mortality rates in the world. A delayed implementation of social distancing interventions in late March 2020 and a phased reopening of the country in June 2020 has facilitated sustained disease transmission in the region. In this study we systematically generate and compare 30-day ahead forecasts using previously validated growth models based on mortality trends from the Institute for Health Metrics and Evaluation for Mexico and Mexico City in near real-time. Moreover, we estimate reproduction numbers for SARS-CoV-2 based on the methods that rely on genomic data as well as case incidence data. Subsequently, functional data analysis techniques are utilized to analyze the shapes of COVID-19 growth rate curves at the state level to characterize the spatiotemporal transmission patterns of SARS-CoV-2. The early estimates of the reproduction number for Mexico were estimated between Rt ~1.1-1.3 from the genomic and case incidence data. Moreover, the mean estimate of Rt has fluctuated around ~1.0 from late July till end of September 2020. The spatial analysis characterizes the state-level dynamics of COVID-19 into four groups with distinct epidemic trajectories based on epidemic growth rates. Our results show that the sequential mortality forecasts from the GLM and Richards model predict a downward trend in the number of deaths for all thirteen forecast periods for Mexico and Mexico City. However, the sub-epidemic and IHME models perform better predicting a more realistic stable trajectory of COVID-19 mortality trends for the last three forecast periods (09/21-10/21, 09/28-10/27, 09/28-10/27) for Mexico and Mexico City. Our findings indicate that phenomenological models are useful tools for short-term epidemic forecasting albeit forecasts need to be interpreted with caution given the dynamic implementation and lifting of social distancing measures., Competing Interests: The authors declare no conflict of interest.

There is a worldwide pandemic of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; yet our understanding remains limited on the characteristic of antibodies, especially for dynamic long-term tracking. Sequential serum samples were collected up to 416 days post onset of symptoms (POS) from 102 patients who were hospitalized with coronavirus disease 2019 (COVID-19). Immunoglobulin (Ig)G, IgM, and IgA levels targeting SARS-CoV-2 spike 1 receptor-binding domain (S1-RBD), spike 2 extracellular domain (S2-ECD), and nucleocapsid protein (N) were quantified as well as neutralizing activity. We were pleasantly surprised to find that the antibody remained detective and effective for more than a year POS. We also found the varied reactions of different antibodies as time passed: N-IgA rose most rapidly in the early stage of infection, while S2-IgG was present at a high level in the long time of observation. This study described the long traceable antibody response of the COVID-19 and offered hints about targets to screen for postinfectious immunity and for vaccination development of SARS-CoV-2., Competing Interests: One author has declared that the following interests are relevant to the submitted work. QC is an employee of Hangzhou Chemi Health Technology Co., Ltd. He prepared the strip of QD-labeled LFIA and had nothing to do with the detection and data analysis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Shi, Weng, Wu, Dai, Luo, Chen, Zhu, Lu, Cheng, Chen, Liu, Wu, Wu, Jin, Guo, Chen, Wu, Yao and Zheng.)

The COVID-19 pandemic has become a worldwide health crisis. So far, most studies have focused on the epidemiology and pathogenesis of this infectious disease. Little attention has been given to the disease sequelae in patients recovering from COVID-19, and nothing is known about the mechanisms underlying these sequelae. Herein, we profiled the serum proteome of a cohort of COVID-19 patients in the disease onset and recovery stages. Based on the close integration of our proteomic analysis with clinical data, we propose that COVID-19 is associated with prolonged disorders in cholesterol metabolism and myocardium, even in the recovery stage. We identify potential biomarkers for these disorders. Moreover, severely affected patients presented more serious disturbances in these pathways. Our findings potentially support clinical decision-making to improve the prognosis and treatment of patients.

Background and Objectives: To evaluate the nutritional status of critically ill patients with COVID-19 and to determine which route of nutrition support is advantageous., Methods and Study Design: This retrospective study was conducted in the ICU of a designated COVID-19 hospital. Patients were divided into an enteral nutrition (EN) group and parenteral nutrition (PN) group according to the initial route of nutrition support. NRS-2002 and NUTRIC were used to assess nutritional status. Blood nutritional markers such as albumin, total protein and hemoglobin were compared at baseline and seven days later. The primary endpoint was 28-day mortality., Results: A total of 27 patients were enrolled in the study - 14 in the EN group and 13 in the PN group - and there were no significant demographic differences between groups. Most patients (96.3% NRS2002 score ≥5, 85.2% NUTRIC score ≥5) were at high nutritional risk. There was no significant difference in baseline albumin, total protein and hemoglobin levels between groups. After 7 days, albumin levels were significantly higher in the EN group than in the PN group (p=0.030). There was no significant difference in the other two indicators. The 28-day mortality was 50% in the EN group and 76.9% in the PN group. Kaplan-Meier survival analysis revealed significant differences between the groups (p=0.030). Cox proportional risk regression indicated that route of nutrition support was also an independent prognostic risk factor., Conclusions: The incidence of nutritional risk in critically ill patients with COVID-19 is very high. Early EN may be beneficial to patient outcomes.

Background: Coronavirus disease 2019 (COVID-19) has emerged as a major global health threat with a great number of deaths worldwide. Despite abundant data on that many COVID-19 patients also displayed kidney disease, there is limited information available about the recovery of kidney disease after discharge., Methods: Retrospective and prospective cohort study to patients with new-onset kidney disease during the COVID-19 hospitalization, admitted between January 28 to February 26, 2020. The median follow-up was 4 months after discharge. The follow-up patients were divided into the recovery group and non-recovery group. Descriptive statistics and between-groups comparison were used., Results: In total, 143 discharged patients with new-onset kidney disease during the COVID-19 hospitalization were included. Patients had a median age was 64 (IQR, 51-70) years, and 59.4% of patients were men. During 4-months median follow-up, 91% (130 of 143) patients recovered from kidney disease, and 9% (13 of 143) patients haven't recovered. The median age of patients in the non-recovery group was 72 years, which was significantly higher than the median age of 62 years in the recovery group. Discharge serum creatinine was significantly higher in the non-recovery group than in the recovery group., Conclusions: Most of the new-onset kidney diseases during hospitalization of COVID-19 patients recovered 4 months after discharge. We recommend that COVID-19 patients with new-onset kidney disease be followed after discharge to assess kidney recovery, especially elderly patients or patients with high discharge creatinine.

The relationship between gut microbes and COVID-19 or H1N1 infections is not fully understood. Here, we compared the gut mycobiota of 67 COVID-19 patients, 35 H1N1-infected patients and 48 healthy controls (HCs) using internal transcribed spacer (ITS) 3-ITS4 sequencing and analysed their associations with clinical features and the bacterial microbiota. Compared to HCs, the fungal burden was higher. Fungal mycobiota dysbiosis in both COVID-19 and H1N1-infected patients was mainly characterized by the depletion of fungi such as Aspergillus and Penicillium, but several fungi, including Candida glabrata, were enriched in H1N1-infected patients. The gut mycobiota profiles in COVID-19 patients with mild and severe symptoms were similar. Hospitalization had no apparent additional effects. In COVID-19 patients, Mucoromycota was positively correlated with Fusicatenibacter, Aspergillus niger was positively correlated with diarrhoea, and Penicillium citrinum was negatively correlated with C-reactive protein (CRP). In H1N1-infected patients, Aspergillus penicilloides was positively correlated with Lachnospiraceae members, Aspergillus was positively correlated with CRP, and Mucoromycota was negatively correlated with procalcitonin. Therefore, gut mycobiota dysbiosis occurs in both COVID-19 patients and H1N1-infected patients and does not improve until the patients are discharged and no longer require medical attention.

The uncertainty caused by the COVID-19 pandemic has exacerbated negative emotions, especially among adolescents, who feel unable to tolerate the uncertainty of the epidemic. However, the mechanism by which the intolerance of COVID-19-related uncertainty (COVID-19 IU) affects negative emotions in adolescents remains unclear. This study explored the underlying mechanism from COVID-19 IU to negative emotions using a moderated mediation model in adolescents. In total, 3037 teenagers completed a cross-sectional survey including measures of COVID-19 IU, risk perception, social exclusion, perceived efficacy, and negative emotions. The results showed that COVID-19 IU positively predicted negative emotions and that risk perception and social exclusion mediated this relationship. In addition, both the direct effect of COVID-19 IU on negative emotions and the mediating effect of risk perception on this relationship were moderated by perceived efficacy; in particular, COVID-19 IU had a greater impact on negative emotions among adolescents with lower levels of perceived efficacy. These findings suggest that COVID-19 IU is closely associated with negative emotions among adolescents and that effective measures should be taken to enable adolescents to improve their perceived efficacy and develop a reasonable perception of risk, help them eliminate the stigma of the disease, and strengthen their connections with society.

Background: Effective antiviral drugs for COVID-19 are still lacking. This study aims to evaluate the clinical outcomes and plasma concentrations of baloxavir acid and favipiravir in COVID-19 patients., Methods: Favipiravir and baloxavir acid were evaluated for their antiviral activity against SARS-CoV-2 in vitro before the trial initiation. We conducted an exploratory trial with 3 arms involving hospitalized adult patients with COVID-19. Patients were randomized assigned in a 1:1:1 ratio into baloxavir marboxil group, favipiravir group, and control group. The primary outcome was the percentage of subjects with viral negative by Day 14 and the time from randomization to clinical improvement. Virus load reduction, blood drug concentration and clinical presentation were also observed. The trial was registered with Chinese Clinical Trial Registry (ChiCTR 2000029544)., Results: Baloxavir acid showed antiviral activity in vitro with the half-maximal effective concentration (EC 50 ) of 5.48 μM comparable to arbidol and lopinavir, but favipiravir didn't demonstrate significant antiviral activity up to 100 μM. Thirty patients were enrolled. The percentage of patients who turned viral negative after 14-day treatment was 70%, 77%, and 100% in the baloxavir marboxil, favipiravir, and control group respectively, with the medians of time from randomization to clinical improvement was 14, 14 and 15 days, respectively. One reason for the lack of virological effect and clinical benefits may be due to insufficient concentrations of these drugs relative to their antiviral activities. One of the limitations of this study is the time from symptom onset to randomization, especially in the baloxavir marboxil and control groups, which is higher than the favipiravir group., Conclusions: Our findings could not prove a benefit of addition of either baloxavir marboxil or favipiravir under the trial dosages to the existing standard treatment., (Copyright © 2020. Published by Elsevier B.V.)

Since the detection of the first case of COVID-19 in Chile on March 3rd, 2020, a total of 513,188 cases, including ~14,302 deaths have been reported in Chile as of November 2nd, 2020. Here, we estimate the reproduction number throughout the epidemic in Chile and study the effectiveness of control interventions especially the effectiveness of lockdowns by conducting short-term forecasts based on the early transmission dynamics of COVID-19. Chile's incidence curve displays early sub-exponential growth dynamics with the deceleration of growth parameter, p, estimated at 0.8 (95% CI: 0.7, 0.8) and the reproduction number, R, estimated at 1.8 (95% CI: 1.6, 1.9). Our findings indicate that the control measures at the start of the epidemic significantly slowed down the spread of the virus. However, the relaxation of restrictions and spread of the virus in low-income neighborhoods in May led to a new surge of infections, followed by the reimposition of lockdowns in Greater Santiago and other municipalities. These measures have decelerated the virus spread with R estimated at ~0.96 (95% CI: 0.95, 0.98) as of November 2nd, 2020. The early sub-exponential growth trend (p ~0.8) of the COVID-19 epidemic transformed into a linear growth trend (p ~0.5) as of July 7th, 2020, after the reimposition of lockdowns. While the broad scale social distancing interventions have slowed the virus spread, the number of new COVID-19 cases continue to accrue, underscoring the need for persistent social distancing and active case detection and isolation efforts to maintain the epidemic under control., Competing Interests: The authors have declared that no competing interests exist.

Introduction: An increasing number of children with severe coronavirus disease 2019 (COVID-19) is being reported, yet the spectrum of disease severity and expression patterns of angiotensin-converting enzyme 2 (ACE2) in children at different developmental stages are largely unknow. Methods: We analysed clinical features in a cohort of 173 children with COVID-19 (0-15 yrs.-old) between January 22, 2020 and March 15, 2020. We systematically examined the expression and distribution of ACE2 in different developmental stages of children by using a combination of children's lung biopsies, pluripotent stem cell-derived lung cells, RNA-sequencing profiles, and ex vivo SARS-CoV-2 pseudoviral infections. Results: It revealed that infants (< 1yrs.-old), with a weaker potency of immune response, are more vulnerable to develop pneumonia whereas older children (> 1 yrs.-old) are more resistant to lung injury. The expression levels of ACE2 however do not vary by age in children's lung. ACE2 is notably expressed not only in Alveolar Type II (AT II) cells, but also in SOX9 positive lung progenitor cells detected in both pluripotent stem cell derivatives and infants' lungs. The ACE2 + SOX9 + cells are readily infected by SARS-CoV-2 pseudovirus and the numbers of the double positive cells are significantly decreased in older children. Conclusions: Infants (< 1 yrs.-old) with SARS-CoV-2 infection are more vulnerable to lung injuries. ACE2 expression in multiple types of lung cells including SOX9 positive progenitor cells, in cooperation with an unestablished immune system, could be risk factors contributing to vulnerability of infants with COVID-19. There is a need to continue monitoring lung development in young children who have recovered from SARS-CoV-2 infection., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Sublingual immunotherapy (SLIT) had good effectiveness for children with allergic rhinitis (AR). However, no studies explored the effect of persistent allergen exposure on SLIT treatment. Coronavirus disease 2019 (COVID-19) restricts outdoor activities of children significantly. We aimed to evaluate the effectiveness of SLIT during this special period., Methods: A total of 335 AR children who sensitize to house dust mite (HDM) undergoing SLIT were recruited in this study. The clinical effectiveness and safety were evaluated at different time points using symptom and medication scores. The serum total IgE and specific IgE (sIgE) at different time points were detected by using the Unicap system., Results: The total nasal symptoms score (TNSS) and total medication score (TMS) during the epidemic of COVID-19 increased significantly compared with the same period last year (p < 0.05), despite that they were still significantly lower than baseline levels (p < 0.05). The occurrence of adverse reactions at different time points had no significant differences. We also found that the family of the good response group had more frequent bedding cleaning. Both the tIgE and sIgE levels had no significant changes during SLIT treatment., Conclusion: Our results suggest that continuous HDM exposure reduced the effectiveness of SLIT, whereas effective reduction of HDM levels by frequent bed cleaning will be helpful during the SLIT treatment., (© 2021 S. Karger AG, Basel.)

Background: Coronavirus disease 2019 (COVID-19) is an emerging serious global health problem. Gastrointestinal symptoms are common in COVID-19 patients, and severe acute respiratory syndrome coronavirus 2 RNA has been detected in stool specimens. However, the relationship between the gut microbiome and disease remains to be established., Methods: We conducted a cross-sectional study of 30 patients with COVID-19, 24 patients with influenza A(H1N1), and 30 matched healthy controls (HCs) to identify differences in the gut microbiota by 16S ribosomal RNA gene V3-V4 region sequencing., Results: Compared with HCs, COVID-19 patients had significantly reduced bacterial diversity; a significantly higher relative abundance of opportunistic pathogens, such as Streptococcus, Rothia, Veillonella, and Actinomyces; and a lower relative abundance of beneficial symbionts. Five biomarkers showed high accuracy for distinguishing COVID-19 patients from HCs with an area under the curve (AUC) up to 0.89. Patients with H1N1 displayed lower diversity and different overall microbial composition compared with COVID-19 patients. Seven biomarkers were selected to distinguish the 2 cohorts (AUC = 0.94)., Conclusions: The gut microbial signature of patients with COVID-19 was different from that of H1N1 patients and HCs. Our study suggests the potential value of the gut microbiota as a diagnostic biomarker and therapeutic target for COVID-19, but further validation is needed., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

COVID-19, caused by SARS-CoV-2, is an acute and rapidly developing pandemic, which leads to a global health crisis. SARS-CoV-2 primarily attacks human alveoli and causes severe lung infection and damage. To better understand the molecular basis of this disease, we sought to characterize the responses of alveolar epithelium and its adjacent microvascular endothelium to viral infection under a co-culture system. SARS-CoV-2 infection caused massive virus replication and dramatic organelles remodeling in alveolar epithelial cells, alone. While, viral infection affected endothelial cells in an indirect manner, which was mediated by infected alveolar epithelium. Proteomics analysis and TEM examinations showed viral infection caused global proteomic modulations and marked ultrastructural changes in both epithelial cells and endothelial cells under the co-culture system. In particular, viral infection elicited global protein changes and structural reorganizations across many sub-cellular compartments in epithelial cells. Among the affected organelles, mitochondrion seems to be a primary target organelle. Besides, according to EM and proteomic results, we identified Daurisoline, a potent autophagy inhibitor, could inhibit virus replication effectively in host cells. Collectively, our study revealed an unrecognized cross-talk between epithelium and endothelium, which contributed to alveolar-capillary injury during SARS-CoV-2 infection. These new findings will expand our understanding of COVID-19 and may also be helpful for targeted drug development.

Ximiao Yu,1,&ast; Ruiqi Luo,2,&ast; Guijuan Xie,2 Jiali Ji,3,4 Jiehong Wang,1 Xiyue Li,3 Xiaojun Qian,2 Xun Wang1,2,5 1Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu Province, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, Jiangnan University Medical Center, Jiangnan University (Wuxi No.2 People’s Hospital), Wuxi, Jiangsu Province, People’s Republic of China; 3Department of Pulmonary and Critical Care Medicine, The Affiliated Wuxi No. 2 People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu Province, People’s Republic of China; 4Department of Pulmonary and Critical Care Medicine, The First People’s Hospital of Changzhou, Changzhou, Jiangsu Province, People’s Republic of China; 5Department of Medicine, Nantong University, Nantong, Jiangsu Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xun Wang, Department of Pulmonary and Critical Care Medicine, Jiangnan University Medical Center, Jiangnan University (Wuxi No.2 People’s Hospital), Wuxi, Jiangsu Province, 214126, People’s Republic of China, Email 081104125@fudan.edu.cnPurpose: This retrospective study aims to compare the effectiveness and safety of four oral antiviral drugs including Simnotrelvir/Ritonavir, Nirmatrelvir/Ritonavir, Azvudine and Molnupiravir in hospitalized patients with Coronavirus Disease 2019 (COVID-19) in a real-world setting, providing evidence to guide clinical practice against COVID-19.Patients and Methods: Patients with mild or moderate COVID-19 hospitalized at Wuxi City’s Second People’s Hospital during December 2022 to June 2023 were included in this study. Patients were grouped by the antiviral drug received. The primary endpoint was the length of hospital stay. Patients were further divided into subgroups for stratified analysis, considering age, timing of medication, and drug mechanisms, to explore whether these factors could influence the treatment efficacy.Results: Of the enrolled 195 patients receiving any treatment, 42 received Nirmatrelvir/Ritonavir, 33 received Molnupiravir, 81 received Simnotrelvir/Ritonavir, and 39 received Azvudine. Patients in Nirmatrelvir/Ritonavir and Simnotrelvir/Ritonavir groups had significantly shorter hospital stays compared to those in Azvudine group (P < 0.05). No significant difference was observed in hospital stays between those initiating antiviral therapy within or more than five days after symptom onset (P = 0.1109). Among patients with comorbidities, the Nirmatrelvir/Ritonavir and Simnotrelvir/Ritonavir group showed shorter hospital stays than the Azvudine group (P < 0.05). No serious treatment-related adverse events were observed across the groups.Conclusion: In this retrospective study, Nirmatrelvir/Ritonavir and Simnotrelvir/Ritonavir exerts stronger potency on reducing duration of hospital stays in hospitalized patient with COVID-19, suggestive of a better choice for antiviral therapy. Patients who fail to take antiviral drugs in time after symptom onset would still benefit from these antiviral regimens. Additional well-designed clinical trials with large sample size are still needed to further confirm the effectiveness of these antivirals.Keywords: antivirals, COVID-19, molnupiravir, simnotrelvir/ritonavir, azvudine, nirmatrelvir/ritonavir

Corticosteroids are commonly used as adjuvant therapy for acute respiratory distress syndrome by many clinicians because of their perceived anti-inflammatory effects. However, for patients with severe viral pneumonia, the corticosteroid treatment is highly controversial. The purpose of this review is to systematically evaluate the effect and potential mechanism of corticosteroid administration in pandemic viral pneumonia. We comprehensively searched all manuscripts on corticosteroid therapy for influenza, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and SARS coronavirus 2 (SARS-CoV-2) viral pneumonia from the PubMed, EMBASE, Web of Science and Cochrane Library databases. We systematically summarized the effects of corticosteroid therapy for pandemic viral pneumonia and the potential mechanism of action for corticosteroids in coronavirus disease 2019 (COVID-19). Observational studies showed that corticosteroid treatment was associated with increased mortality and nosocomial infections for influenza and delayed virus clearance for SARS-CoV and MERS-CoV. Limited data on corticosteroid therapy for COVID-19 were reported. Corticosteroids were used in about a fifth of patients (670/2995, 22.4%). Although clinical observational studies reported the improvement in symptoms and oxygenation for individuals with severe COVID-19 who received corticosteroid therapy, case fatality rate in the corticosteroid group was significantly higher than that in the non-corticosteroid group (69/443, 15.6% versus 56/1310, 4.3%). Compared individuals with non-severe disease, those with severe disease were more likely to receive corticosteroid therapy (201/382, 52.6% versus 201/1310, 15.3%). Although there is no evidence that corticosteroid therapy reduces mortality in people with COVID-19, some improvements in clinical symptoms and oxygenation were reported in some clinical observational studies. Excessive inflammatory response and lymphopenia might be critical factors associated with severity of and mortality from COVID-19. Sufficiently powered randomized controlled trials with rigorous inclusion/exclusion criteria and standardized dose and duration of corticosteroids are needed to verify the effectiveness and safety of corticosteroid therapy. [ABSTRACT FROM AUTHOR]