Potential influence of COVID-19 and dexamethasone on the reproductive system: what we know and can expect.

Dexamethasone is the first and an important therapy that significantly reduces the risk of death in patients with severe COVID-19 disease. Nevertheless, a lot of studies have revealed that it has adverse impacts on multiple systems of the body especially the reproductive system, and dexamethasone exposure during the human foetal period may be associated with various diseases. In this paper, we reviewed the literature regarding the adverse effects of COVID-19 and dexamethasone administration on the reproductive system as well as related disease pathogenesis, in an attempt to clarify the potential harms of dexamethasone treatment in COVID-19 patients. Overall, we strongly support the application of dexamethasone as a pharmaceutical therapy in critical COVID-19 patients before a better therapy is developed, but the adverse side effects that may arise cannot be ignored. Our review will help medical professionals in the prognosis and follow-up of patients treated with dexamethasone. In addition, given that a considerable amount of uncertainty, confusion and even controversy that still remains, further studies and more clinical trials are urgently needed to improve the understanding of the parameters and the effects of dexamethasone on reproductive function of patients with severe acute respiratory syndrome coronavirus 2 infection.

Serine-arginine protein kinases and their targets in viral infection and their inhibition.

Accumulating evidence has consolidated the interaction between viral infection and host alternative splicing. Serine-arginine (SR) proteins are a class of highly conserved splicing factors critical for the spliceosome maturation, alternative splicing and RNA metabolism. Serine-arginine protein kinases (SRPKs) are important kinases that specifically phosphorylate SR proteins to regulate their distribution and activities in the central pre-mRNA splicing and other cellular processes. In addition to the predominant SR proteins, other cytoplasmic proteins containing a serine-arginine repeat domain, including viral proteins, have been identified as substrates of SRPKs. Viral infection triggers a myriad of cellular events in the host and it is therefore not surprising that viruses explore SRPKs-mediated phosphorylation as an important regulatory node in virus-host interactions. In this review, we briefly summarize the regulation and biological function of SRPKs, highlighting their involvement in the infection process of several viruses, such as viral replication, transcription and capsid assembly. In addition, we review the structure-function relationships of currently available inhibitors of SRPKs and discuss their putative use as antivirals against well-characterized viruses or newly emerging viruses. We also highlight the viral proteins and cellular substrates targeted by SRPKs as potential antiviral therapeutic candidates.

Public Opinions toward COVID-19 Vaccine Mandates: A Machine Learning-based Analysis of U.S. Tweets

While it has been scientifically proven that COVID-19 vaccine is a safe and effective measure to reduce the severity of infection and curbing the spread of the SARS-CoV-2 virus, skepticism remains widespread, and in many countries vaccine mandates have been met with strong opposition. In this study, we applied machine learning-based analyses of the U.S.-based tweets covering the periods leading toward and after the Biden Administration's announcement of federal vaccine mandates, supplemented by a qualitative content analysis of a random sample of relevant tweets. The objective was to examine the beliefs held among twitter users toward vaccine mandates, as well as the evidence that they used to support their positions. The results show that while approximately 30% of the twitter users included in the dataset supported the measure, more users expressed differing opinions. Concerns raised included questioning on the political motive, infringement of personal liberties, and ineffectiveness in preventing infection.

Risk Perception, Perceived Government Coping Validity, and Individual Sleep Problems in the Early Stage of the COVID-19 Pandemic in China: Mediation Analysis Based on Negative Emotions.

This study aimed to investigate the relationship among risk perception, negative emotions, perceived government coping validity, and the sleep problem of the public, through regression analysis and mediation analysis of data from the early stages of the COVID-19 outbreak in China (three months after the outbreak). It found that people's perception of the risk of the pandemic, negative emotions, and perceived government coping validity significantly affected people's sleep quality and nightmares. Further analysis found that individuals' perception of risk not only affected their sleep but also intensified their negative emotions, ultimately impairing the quality of their sleep and leading to nightmares. However, having a high level of coping validity can mitigate negative emotions and consequently decrease the occurrence of nightmares, thereby enhancing the quality of sleep. Specifically, perceived government coping validity could not only directly reduce nightmares, but also indirectly reduce nightmares by lowering negative emotions. However, it could only indirectly improve sleep by reducing negative emotions. It implicated that improving and resolving sleep problems required not only medical intervention but also psychological intervention. Simultaneously, improving the government's response effectiveness could strengthen people's trust in the government, stabilize their mental states, and significantly improve their quality of life by reducing negative emotions and improving sleep.

Risk Perception, Perceived Government Coping Validity, and Individual Response in the Early Stage of the COVID-19 Pandemic in China.

As a major crisis event, the COVID-19 pandemic has affected the global economy, threatened the lives of the public, and caused varying degrees of impact on the public. Previous studies have shown that risk perception and government response had different impacts on the public, but they revealed more about the independent impact of risk perception and government response on the public. This study will comprehensively consider the impacts of these two factors on the behavior of the public in the early stage of the epidemic. We analyzed data from an online survey in the early days of the COVID-19 pandemic in China and categorized individual behaviors into three dimensions: entertainment and travel, work, and the stockpile of supplies. In addition, we defined the risk perception variables by two dimensions: knowledge of the epidemic itself and knowledge of the consequences of the epidemic. At the same time, we used an exploratory factor analysis to construct the variable of perceived government coping validity and then adopted the ordinal logit model for analysis. The results showed that in terms of entertainment and travel, people would not be affected even if they fully understood the epidemic itself; once they were aware of the negative social consequences of the epidemic, people would suspend entertainment and travel to prevent the spread of the virus. As for work or employment, people would not stop working or employment even if they realized the infectivity and harmfulness of the disease and its social consequences. Furthermore, fear of COVID-19 and the perception of uncontrolled COVID-19 significantly positively affected people's material stockpiling behavior. These results indicate that different risk perceptions had different effects on individual responses, and individual behaviors reflected different coping logics. In addition, the government's effective response to the epidemic would significantly reduce the negative impacts of the epidemic on the three dimensions of people's responses. These conclusions have certain policy implications for preventing and responding to outbreaks in other countries.

Drug Repositioning for Hand, Foot, and Mouth Disease.

Hand, foot, and mouth disease (HFMD) is a highly contagious disease in children caused by a group of enteroviruses. HFMD currently presents a major threat to infants and young children because of a lack of antiviral drugs in clinical practice. Drug repositioning is an attractive drug discovery strategy aimed at identifying and developing new drugs for diseases. Notably, repositioning of well-characterized therapeutics, including either approved or investigational drugs, is becoming a potential strategy to identify new treatments for virus infections. Various types of drugs, including antibacterial, cardiovascular, and anticancer agents, have been studied in relation to their therapeutic potential to treat HFMD. In this review, we summarize the major outbreaks of HFMD and the progress in drug repositioning to treat this disease. We also discuss the structural features and mode of action of these repositioned drugs and highlight the opportunities and challenges of drug repositioning for HFMD.

Nicotinamide n-Oxide Attenuates HSV-1-Induced Microglial Inflammation through Sirtuin-1/NF-κB Signaling.

HSV-1 is a typical neurotropic virus that infects the brain and causes keratitis, cold sores, and occasionally, acute herpes simplex encephalitis (HSE). The large amount of proinflammatory cytokines induced by HSV-1 infection is an important cause of neurotoxicity in the central nervous system (CNS). Microglia, as resident macrophages in CNS, are the first line of defense against neurotropic virus infection. Inhibiting the excessive production of inflammatory cytokines in overactivated microglia is a crucial strategy for the treatment of HSE. In the present study, we investigated the effect of nicotinamide n-oxide (NAMO), a metabolite mainly produced by gut microbe, on HSV-1-induced microglial inflammation and HSE. We found that NAMO significantly inhibits the production of cytokines induced by HSV-1 infection of microglia, such as IL-1ß, IL-6, and TNF-α. In addition, NAMO promotes the transition of microglia from the pro-inflammatory M1 type to the anti-inflammatory M2 type. More detailed studies revealed that NAMO enhances the expression of Sirtuin-1 and its deacetylase enzymatic activity, which in turn deacetylates the p65 subunit to inhibit NF-κB signaling, resulting in reduced inflammatory response and ameliorated HSE pathology. Therefore, Sirtuin-1/NF-κB axis may be promising therapeutic targets against HSV-1 infection-related diseases including HSE.

Sensitivity Enhanced Plasmonic Biosensor Using Bi2Se3-Graphene Heterostructures: A Theoretical Analysis.

This study provided a theoretical insight for designing novel plasmonic biosensors using bismuth selenide (Bi2Se3)-Graphene heterostructures. It was a van der Waals (vdWs) stacked configuration composed of gold (Au) film, few quintuple layer (QL) Bi2Se3 and few-layered graphene. In particular, the proposed biosensor was created by Goos-Hänchen (GH) shift rather than phase, resulting in a more sensitive biosensing response. Under the excitation of 632.8 nm, significant sensitivity enhancement performance was obtained via varying the thickness of Bi2Se3-Graphene heterostructures. The best configuration was 32 nm Au film-2-QL Bi2Se3-3-layer graphene, generating the largest GH shift, as high as -1.0202 × 104 µm. Moreover, the highest detection sensitivity was determined to be 8.5017 × 106 µm/RIU, responding to a tiny refractive index (RI) change of 0.0012 RIU (RIU, refractive index unit). More importantly, our proposed biosensor has shown a theoretical feasibility of monitoring virus samples. For example, there was an efficient linear detection range for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, 0~13.44 nanomole (nM)) and its Spike (S) glycoprotein (0~59.74 nM), respectively. It is expected that our proposed plasmonic biosensor has a potential application in performing sensitive detection of SARS-CoV-2.

Relative Risks of COVID-19-Associated Hospitalizations and Clinical Outcomes by Age and Race/Ethnicity-March 2020-March 2021.

Background: Limited data exist on population-based risks and risk ratios (RRs) of coronavirus disease 2019 (COVID-19)-associated hospitalizations and clinical outcomes stratified by age and race/ethnicity. Methods: Using data from electronic health records and claims from 4 US health systems for the period March 2020-March 2021, we calculated risk and RR by age and race/ethnicity for COVID-19-associated hospitalizations and clinical outcomes among adults (≥18 years). COVID-19-associated hospitalizations were defined based on COVID-19 discharge codes or a positive severe acute respiratory syndrome coronavirus 2 result. Proportions of acute exacerbations of underlying conditions were estimated among hospitalized patients with select underlying conditions, stratified by age and race/ethnicity. Results: Among 2.6 million adults included in the patient cohort, 6879 had COVID-19-associated hospitalizations during March 2020-March 2021 (risk: 264 per 100 000 population). Compared with younger, non-Hispanic White adults, non-Hispanic Black and Hispanic adults aged ≥65 years had the highest hospitalization risk ratios (RR, 8.6; 95% CI, 7.6-9.9; and RR, 9.3; 95% CI, 8.5-10.3, respectively). Among hospitalized adults with COVID-19 and renal disease or cardiovascular disease, the highest proportion of acute renal failure (55.5%) or congestive heart failure (43.9%) occurred in older, non-Hispanic Black patients. Among hospitalized adults with chronic lung disease or asthma, the highest proportion of respiratory failure (62.9%) or asthma exacerbation (66.7%) occurred in older, Hispanic patients. Conclusions: During the first year of the US COVID-19 pandemic in this cohort, older non-Hispanic Black and Hispanic adults had the highest relative risks of COVID-19-associated hospitalization and adverse outcomes and, among those with select underlying conditions, the highest occurrences of acute exacerbations of underlying conditions.

A Dramatic Response to Toripalimab With Chemotherapy and Antiangiogenic Agent Followed by Surgery in a Stage IIIB Lung Adenocarcinoma Patient With an Uncommon EGFR Mutation: A Case Report.

Lung cancer patients with high programmed cell death-ligand 1 (PD-L1) expression in tumor cells and epidermal growth factor receptor (EGFR) mutations are rare, but there is no clinical standard for which treatment such patients should receive. Here, we report a 52-year-old male smoker who was diagnosed with stage IIIB lung adenocarcinoma. A rare EGFR G719A mutation was detected in the lymph node samples by next-generation sequencing (NGS), and a high PD-L1 expression was found by immunohistochemistry (IHC). After 10 cycles of induction therapy (toripalimab plus pemetrexed plus nedaplatin plus apatinib), surgery was successfully performed, followed by 2 cycles of consolidation therapy (toripalimab plus pemetrexed) and 4 cycles of maintenance therapy (toripalimab). A progression-free survival (PFS) of 7 months was achieved. In this case, we showed that the programmed cell death protein 1 (PD-1) inhibitor toripalimab plus chemotherapy and apatinib was effective and tolerable in a locally advanced EGFR-mutant non-small cell lung cancer (NSCLC) patient with a positive PD-L1 expression.

They May Not Work! An evaluation of eleven sentiment analysis tools on seven social media datasets.

OBJECTIVE: Sentiment analysis is an important method for understanding emotions and opinions expressed through social media exchanges. Little work has been done to evaluate the performance of existing sentiment analysis tools on social media datasets, particularly those related to health, healthcare, or public health. This study aims to address the gap. MATERIAL AND METHODS: We evaluated 11 commonly used sentiment analysis tools on five health-related social media datasets curated in previously published studies. These datasets include Human Papillomavirus Vaccine, Health Care Reform, COVID-19 Masking, Vitals.com Physician Reviews, and the Breast Cancer Forum from MedHelp.org. For comparison, we also analyzed two non-health datasets based on movie reviews and generic tweets. We conducted a qualitative error analysis on the social media posts that were incorrectly classified by all tools. RESULTS: The existing sentiment analysis tools performed poorly with an average weighted F1 score below 0.6. The inter-tool agreement was also low; the average Fleiss Kappa score is 0.066. The qualitative error analysis identified two major causes for misclassification: (1) correct sentiment but on wrong subject(s) and (2) failure to properly interpret inexplicit/indirect sentiment expressions. DISCUSSION AND CONCLUSION: The performance of the existing sentiment analysis tools is insufficient to generate accurate sentiment classification results. The low inter-tool agreement suggests that the conclusion of a study could be entirely driven by the idiosyncrasies of the tool selected, rather than by the data. This is very concerning especially if the results may be used to inform important policy decisions such as mask or vaccination mandates.

Clinical and Gene Features of SARS-CoV-2-Positive Recurrence in Patients Recovered From COVID-19

There are still frequent reports that a number of recovered coronavirus disease 2019 (COVID-19) patients following discharge have re-detectable positive (RP) results by RT-PCR. Understanding the clinical and molecular characteristics of RP patients may have implications for curbing the COVID-19 pandemic. In this study, 318 COVID-19 convalescent patients, including 59 RP patients and 259 non-RP (NRP) patients, were enrolled. Among RP patients, women accounted for a significantly high proportion (67.8%), and the titers of IgG and IgM antibodies in this group were also significantly high. Differentially expressed genes (DEGs), including 692 upregulated and 383 downregulated genes, overlapped in two public GEO datasets containing RP and NRP blood cell samples. Enrichment analysis indicated that these DEGs were related to several key signaling pathways, such as viral infection, immune activation, and inflammatory responses. Importantly, 59 indicator genes constituting the core network exhibited high diagnostic values and were correlated with markers of different immune cells. Among these, 12 drug-related genes were associated with the RP results. Our work suggests that, in addition to clinically available features, blood cell transcriptome sequencing can be performed to obtain gene signatures for diagnosis of RP patients.

Serious Cardiovascular Adverse Events Associated with Hydroxychloroquine/Chloroquine Alone or with Azithromycin in Patients with COVID-19: A Pharmacovigilance Analysis of the FDA Adverse Event Reporting System (FAERS).

BACKGROUND: The use of hydroxychloroquine or chloroquine (HCQ/CQ) as monotherapy or combined with azithromycin for the treatment of coronavirus disease 2019 (COVID-19) may increase the risk of serious cardiovascular adverse events (SCAEs). OBJECTIVE: Our objective was to describe and evaluate the risk of SCAEs with HCQ/CQ as monotherapy or combined with azithromycin compared with that for therapeutic alternatives. METHODS: We performed a disproportionality analysis and descriptive case series using the US FDA Adverse Event Reporting System. RESULTS: Compared with remdesivir, HCQ/CQ was associated with increased reporting of SCAEs (reporting odds ratio [ROR] 2.1; 95% confidence interval [CI] 1.8-2.5), torsade de pointes (TdP)/QTc prolongation (ROR 35.4; 95% CI 19.4-64.5), and ventricular arrhythmia (ROR 2.5; 95% CI 1.6-3.9); similar results were found in comparison with other therapeutic alternatives. Compared with lopinavir/ritonavir, HCQ/CQ was associated with increased reporting of ventricular arrhythmia (ROR 10.5; 95% CI 3.3-33.4); RORs were larger when HCQ/CQ was used in combination with azithromycin. In 2020, 312 of the 575 reports of SCAEs listed concomitant use of HCQ/CQ and azithromycin, including QTc prolongation (61.4%), ventricular arrhythmia (12.0%), atrial fibrillation (8.2%), TdP (4.9%), and cardiac arrest (4.4%); 88 (15.3%) cases resulted in hospitalization and 79 (13.7%) resulted in death. In total, 122 fatal QTc prolongation-related cardiovascular reports were associated with 1.4 times higher odds of reported death than those induced by SCAEs; 87 patients received more than one QTc-prolonging agent. CONCLUSIONS: Patients treated with HCQ/CQ monotherapy or HCQ/CQ + azithromycin may be at increased risk of SCAEs, TdP/QTc prolongation, and ventricular arrhythmia. Cardiovascular risks need to be considered when evaluating the benefit/harm balance of treatment with HCQ/CQ, especially with the concurrent use of QTc-prolonging agents and cytochrome P450 3A4 inhibitors when treating COVID-19.

Oxidative stress transforms 3CLpro into an insoluble and more active form to promote SARS-CoV-2 replication.

3CLpro is a key proteinase for SARS-CoV-2 replication and serves as an important target for antiviral drug development. However, how its activity is regulated intracellularly is still obscure. In this study, we developed a 3CLpro protease activity reporter system to examine the impact of various factors, including nutrient supplements, ions, pHs, or oxidative stress inducers, on 3CLpro protease activity. We found that oxidative stress could increase the overall activity of 3CLpro. Not altering the expression, oxidative stress decreased the solubility of 3CLpro in the lysis buffer containing 1% Triton-X-100. The Triton-X-100-insoluble 3CLpro was correlated with aggregates' formation and responsible for the increased enzymatic activity. The disulfide bonds formed between Cys85 sites of 3CLpro protomers account for the insolubility and the aggregation of 3CLpro. Besides being regulated by oxidative stress, 3CLpro impaired the cellular antioxidant capacity by regulating the cleavage of GPx1 at its N-terminus. This cleavage could further elevate the 3CLpro-proximate oxidative activity, favor aggregation and activation of 3CLpro, and thus lead to a positive feedback loop. In summary, we reported that oxidative stress transforms 3CLpro into a detergent-insoluble form that is more enzymatically active, leading to increased viral replication/transcription. Our study provided mechanistic evidence that suggests the therapeutic potential of antioxidants in the clinical treatment of COVID-19 patients.

Associations of stay-at-home order and face-masking recommendation with trends in daily new cases and deaths of laboratory-confirmed COVID-19 in the United States

BACKGROUND AND OBJECTIVES: Public health interventions were associated with reduction in coronavirus disease 2019 (COVID-19) transmission in China, but their impacts on COVID-19 epidemiology in other countries are unclear. We examined the associations of stay-at-home order (SAHO) and face-masking recommendation with epidemiology of laboratory-confirmed COVID-19 in the United States. METHODS: In this quasi-experimental study, we modeled the temporal trends in daily new cases and deaths of COVID-19, and COVID-19 time-varying reproduction numbers (Rt) in the United States between March 1 and April 20, 2020, and conducted simulation studies. RESULTS: The number and proportion of U.S. residents under SAHO increased between March 19 and April 7, and plateaued at 29,0829,980 and 88.6%, respectively. Trends in COVID-19 daily cases and Rt reduced after March 23 (P<0.001) and further reduced on April 3 (P<0.001), which was associated with implementation of SAHO by 10 states on March 23, and face-masking recommendation on April 3, respectively. The estimates of Rt eventually fell below/around 1.0 on April 13. Similar turning points were identified in the trends of daily deaths with a lag time. Early implementation and early-removal of SAHO would be associated with significantly reduced and increased daily new cases and deaths, respectively.

Ventilation in worker dormitories and its impact on the spread of respiratory droplets.

Most of the COVID-19 cases in Singapore have primarily come from foreign worker dormitories. This people group is especially vulnerable partly because of behavioural habits, but the built environment they live in also plays a significant role. These dormitories are typically densely populated, so the living conditions are cramped. The short lease given to most dormitories also means the design does not typically focus on environmental performance, like good natural ventilation. This paper seeks to understand how these dormitories' design affects natural ventilation and, subsequently, the spread of the COVID-19 particles by looking at two existing worker dorms in Singapore. Findings show that some rooms are poorly orientated against the prevailing wind directions, so there is dominant stagnant air in these rooms, leading to respiratory droplets' long residence times. These particles can hover in the air for 10 min and more. Interventions like increased bed distance and removing upper deck beds only showed limited ventilation improvements in some rooms. Comparatively, internal wind scoops' strategic placement was more effective at directing wind towards more stagnant zones. Large canyon aspect ratios were also effective at removing particles from higher elevations.

Potential Adverse Effects of Dexamethasone Therapy on COVID-19 Patients: Review and Recommendations.

In the context of the coronavirus disease 2019 (COVID-19) pandemic, the global healthcare community has raced to find effective therapeutic agents against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To date, dexamethasone is the first and an important therapeutic to significantly reduce the risk of death in COVID-19 patients with severe disease. Due to powerful anti-inflammatory and immunosuppressive effects, dexamethasone could attenuate SARS-CoV-2-induced uncontrolled cytokine storm, severe acute respiratory distress syndrome and lung injury. Nevertheless, dexamethasone treatment is a double-edged sword, as numerous studies have revealed that it has significant adverse impacts later in life. In this article, we reviewed the literature regarding the adverse effects of dexamethasone administration on different organ systems as well as related disease pathogenesis in an attempt to clarify the potential harms that may arise in COVID-19 patients receiving dexamethasone treatment. Overall, taking the threat of COVID-19 pandemic into account, we think it is necessary to apply dexamethasone as a pharmaceutical therapy in critical patients. However, its adverse side effects cannot be ignored. Our review will help medical professionals in the prognosis and follow-up of patients treated with dexamethasone. In addition, given that a considerable amount of uncertainty, confusion and even controversy still exist, further studies and more clinical trials are urgently needed to improve our understanding of the parameters and the effects of dexamethasone on patients with SARS-CoV-2 infection.