Chronic airway epithelial hypoxia exacerbates injury in muco-obstructive lung disease through mucus hyperconcentration.

Unlike solid organs, human airway epithelia derive their oxygen from inspired air rather than the vasculature. Many pulmonary diseases are associated with intraluminal airway obstruction caused by aspirated foreign bodies, virus infection, tumors, or mucus plugs intrinsic to airway disease, including cystic fibrosis (CF). Consistent with requirements for luminal O2, airway epithelia surrounding mucus plugs in chronic obstructive pulmonary disease (COPD) lungs are hypoxic. Despite these observations, the effects of chronic hypoxia (CH) on airway epithelial host defense functions relevant to pulmonary disease have not been investigated. Molecular characterization of resected human lungs from individuals with a spectrum of muco-obstructive lung diseases (MOLDs) or COVID-19 identified molecular features of chronic hypoxia, including increased EGLN3 expression, in epithelia lining mucus-obstructed airways. In vitro experiments using cultured chronically hypoxic airway epithelia revealed conversion to a glycolytic metabolic state with maintenance of cellular architecture. Chronically hypoxic airway epithelia unexpectedly exhibited increased MUC5B mucin production and increased transepithelial Na+ and fluid absorption mediated by HIF1α/HIF2α-dependent up-regulation of ß and γENaC (epithelial Na+ channel) subunit expression. The combination of increased Na+ absorption and MUC5B production generated hyperconcentrated mucus predicted to perpetuate obstruction. Single-cell and bulk RNA sequencing analyses of chronically hypoxic cultured airway epithelia revealed transcriptional changes involved in airway wall remodeling, destruction, and angiogenesis. These results were confirmed by RNA-in situ hybridization studies of lungs from individuals with MOLD. Our data suggest that chronic airway epithelial hypoxia may be central to the pathogenesis of persistent mucus accumulation in MOLDs and associated airway wall damage.

Association of Glucose-Lowering Drugs With Outcomes in Patients With Diabetes Before Hospitalization for COVID-19: A Systematic Review and Network Meta-analysis.

Importance: Patients with COVID-19 have a high prevalence of diabetes, and diabetes and blood glucose control are determinants of intensive care unit admission and mortality. Objective: To evaluate the association between COVID-19-related adverse outcomes and 8 antihyperglycemic drugs in patients with diabetes who were subsequently diagnosed and hospitalized with COVID-19. Data Sources: Data were retrieved and collected in PubMed, Embase, Cochrane Central Register, Web of Science, and ClinicalTrials.gov from database inception to September 5, 2022. Study Selection: For this systematic review and network meta-analysis, randomized clinical trials and observational studies conducted among patients with diabetes while receiving glucose-lowering therapies for at least 14 days before the confirmation of COVID-19 infection were included after blinded review by 2 independent reviewers and consultations of disagreement by a third independent reviewer. Of 1802 studies initially identified, 31 observational studies met the criteria for further analysis. Data Extraction and Synthesis: This study follows the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline. Bayesian network meta-analyses were performed with random effects. Main Outcomes and Measures: A composite adverse outcome, including the need for intensive care unit admission, invasive and noninvasive mechanical ventilation, or in-hospital death. Results: Thirty-one distinct observational studies (3 689 010 patients with diabetes hospitalized for COVID-19) were included. The sodium-glucose cotransporter-2 inhibitors (SGLT-2is) were associated with relatively lower risks of adverse outcomes compared with insulin (log of odds ratio [logOR], 0.91; 95% credible interval [CrI], 0.57-1.26), dipeptidyl peptidase-4 inhibitors (logOR, 0.61; 95% CrI, 0.28-0.93), secretagogues (logOR, 0.37; 95% CrI, 0.02-0.72), and glucosidase inhibitors (logOR, 0.50; 95% CrI, 0.00-1.01). Based on the surface under the cumulative ranking curves value, SGLT-2is were associated with the lowest probability for adverse outcomes (6%), followed by glucagon-like peptide-1 receptor agonists (25%) and metformin (28%). A sensitivity analysis revealed that the study was reliable. Conclusions and Relevance: These findings suggest that the use of an SGLT-2i before COVID-19 infection is associated with lower COVID-19-related adverse outcomes. In addition to SGLT-2is, glucagon-like peptide-1 receptor agonists and metformin were also associated with relatively low risk of adverse outcomes.

Intelligent operation, maintenance, and control system for public building: towards infection risk mitigation and energy efficiency

During the post-COVID-19 era, it is important but challenging to synchronously mitigate the infection risk and optimize the energy savings in public buildings. While, ineffective control of ventilation and purification systems can result in increased energy consumption and cross-contamination. This paper is to develop intelligent operation, maintenance, and control system by coupling intelligent ventilation and air purification systems (negative ion generators). Optimal deployment of sensors is determined by Fuzzy C-mean (FCM), based on which CO2 concentration fields are rapidly predicted by combing the artificial neural network (ANN) and self-adaptive low-dimensional linear model (LLM). Negative oxygen ion and particle concentrations are simulated with different number of negative ion generators. Optimal ventilation rates and number of negative ion generators are decided. A visualization platform is established to display the effects of ventilation control, epidemic prevention, and pollutant removal. The rapid prediction error of LLM-based ANN for CO2 concentration was below 10% compared with the simulation. Fast decision reduced CO2 concentration below 1000 ppm, infection risk below 1.5%, and energy consumption by 27.4%. The largest removal efficiency was 81% with number of negative ion generators was 10. This work can promote intelligent operation, maintenance, and control systems considering infection prevention and energy sustainability.

[Preliminary Recommendations on the Timing of Lung Surgery after 
Novel Coronavirus Infection in Patients with Pulmonary Nodules and Lung Cancer].

In recent years, the corona virus disease 2019 (COVID-19) pandemic has had a huge impact on the global medical, political and economic fields. Since the beginning of the COVID-19 epidemic, our understanding of the impact of COVID-19 has grown exponentially. Recently, the COVID-19 epidemic has changed rapidly in China, and there has been controversy over how to carry out surgical operations for patients with lung neoplastic lesions. Some studies have shown that lung cancer patients undergoing surgery are more likely to experience respiratory failure and perioperative death after contracting COVID-19 than the general population, however, delays in cancer treatment are also associated with increased mortality among these patients. In particular, the novel coronavirus Omikron variant has a higher transmissibility and may escape the immunity obtained through the previous novel coronavirus infection and vaccination. In order to minimize the risk of novel coronavirus infection in surgical patients, it is necessary to develop new treatment guidelines, expert consensus and preventive measures. However, the current rapid change of the epidemic situation has led to insufficient time and evidence to develop guidelines and consensus. Therefore, thoracic surgeons need to evaluate specific patient populations at higher risk of severe complications before surgery and weigh the benefit of surgical treatment against the risk of novel coronavirus infection. We try to give some recommendations on lung surgery during the current domestic epidemic situation based on the guidelines and consensus of oncology and thoracic surgery organizations in different regions on lung surgery.
.

Intelligent operation, maintenance, and control system for public building: Towards infection risk mitigation and energy efficiency.

During the post-COVID-19 era, it is important but challenging to synchronously mitigate the infection risk and optimize the energy savings in public buildings. While, ineffective control of ventilation and purification systems can result in increased energy consumption and cross-contamination. This paper is to develop intelligent operation, maintenance, and control systems by coupling intelligent ventilation and air purification systems (negative ion generators). Optimal deployment of sensors is determined by Fuzzy C-mean (FCM), based on which CO2 concentration fields are rapidly predicted by combing the artificial neural network (ANN) and self-adaptive low-dimensional linear model (LLM). Negative oxygen ion and particle concentrations are simulated with different numbers of negative ion generators. Optimal ventilation rates and number of negative ion generators are decided. A visualization platform is established to display the effects of ventilation control, epidemic prevention, and pollutant removal. The rapid prediction error of LLM-based ANN for CO2 concentration was below 10% compared with the simulation. Fast decision reduced CO2 concentration below 1000 ppm, infection risk below 1.5%, and energy consumption by 27.4%. The largest removal efficiency was 81% when number of negative ion generators was 10. This work can promote intelligent operation, maintenance, and control systems considering infection prevention and energy sustainability.

Antibody responses to COVID-19 vaccination in people with obesity: A systematic review and meta-analysis.

COVID-19 vaccine is critical in preventing SARS-CoV-2 infection and transmission. However, obesity's effect on immune responses to COVID-19 vaccines is still unknown. We performed a meta-analysis of the literature and compared antibody responses with COVID-19 vaccines among persons with and without obesity. We used Pubmed, Embase, Web of Science, and Cochrane Library to identify all related studies up to April 2022. The Stata.14 software was used to analyze the selected data. Eleven studies were included in the present meta-analysis. Five of them provided absolute values of antibody titers in the obese group and non-obese group. Overall, we found that the obese population was significantly associated with lower antibody titers (standardized mean difference [SMD] = -0.228, 95% CI [-0.437, -0.019], P < 0.001) after COVID-19 vaccination. Significant heterogeneity was present in most pooled analyses but was reduced after subgroup analyses. No publication bias was observed in the present analysis. The Trim and Fill method did not change the results in the primary analysis. The present meta-analysis suggested that obesity was significantly associated with decreased antibody responses to SARS-CoV-2 vaccines. Future studies should be performed to unravel the mechanism of response to the COVID-19 vaccine in obese individuals.

Prevalence and Mechanisms of Mucus Accumulation in COVID-19 Lung Disease.

Rationale: The incidence and sites of mucus accumulation and molecular regulation of mucin gene expression in coronavirus (COVID-19) lung disease have not been reported. Objectives: To characterize the incidence of mucus accumulation and the mechanisms mediating mucin hypersecretion in COVID-19 lung disease. Methods: Airway mucus and mucins were evaluated in COVID-19 autopsy lungs by Alcian blue and periodic acid-Schiff staining, immunohistochemical staining, RNA in situ hybridization, and spatial transcriptional profiling. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected human bronchial epithelial (HBE) cultures were used to investigate mechanisms of SARS-CoV-2-induced mucin expression and synthesis and test candidate countermeasures. Measurements and Main Results: MUC5B and variably MUC5AC RNA concentrations were increased throughout all airway regions of COVID-19 autopsy lungs, notably in the subacute/chronic disease phase after SARS-CoV-2 clearance. In the distal lung, MUC5B-dominated mucus plugging was observed in 90% of subjects with COVID-19 in both morphologically identified bronchioles and microcysts, and MUC5B accumulated in damaged alveolar spaces. SARS-CoV-2-infected HBE cultures exhibited peak titers 3 days after inoculation, whereas induction of MUC5B/MUC5AC peaked 7-14 days after inoculation. SARS-CoV-2 infection of HBE cultures induced expression of epidermal growth factor receptor (EGFR) ligands and inflammatory cytokines (e.g., IL-1α/ß) associated with mucin gene regulation. Inhibiting EGFR/IL-1R pathways or administration of dexamethasone reduced SARS-CoV-2-induced mucin expression. Conclusions: SARS-CoV-2 infection is associated with a high prevalence of distal airspace mucus accumulation and increased MUC5B expression in COVID-19 autopsy lungs. HBE culture studies identified roles for EGFR and IL-1R signaling in mucin gene regulation after SARS-CoV-2 infection. These data suggest that time-sensitive mucolytic agents, specific pathway inhibitors, or corticosteroid administration may be therapeutic for COVID-19 lung disease.

Surface antimicrobial functionalization with polymers: fabrication, mechanisms and applications.

Undesirable adhesion of microbes such as bacteria, fungi and viruses onto surfaces affects many industries such as marine, food, textile, and healthcare. In particular in healthcare and food packaging, the effects of unwanted microbial contamination can be life-threatening. With the current global COVID-19 pandemic, interest in the development of surfaces with superior anti-viral and anti-bacterial activities has multiplied. Polymers carrying anti-microbial properties are extensively used to functionalize material surfaces to inactivate infection-causing and biocide-resistant microbes including COVID-19. This review aims to introduce the fabrication of polymer-based antimicrobial surfaces through physical and chemical modifications, followed by the discussion of the inactivation mechanisms of conventional biocidal agents and new-generation antimicrobial macromolecules in polymer-modified antimicrobial surfaces. The advanced applications of polymer-based antimicrobial surfaces on personal protective equipment against COVID-19, food packaging materials, biomedical devices, marine vessels and textiles are also summarized to express the research trend in academia and industry.

Travel intention during the COVID-19 epidemic: The influence of institutional and interpersonal trust.

The global pandemic, COVID-19, has dealt a heavy blow to the tourism industry. Therefore, exploring the mechanisms influencing travel intention in the post-epidemic era can help provide management insights for the recovery of the travel market. Relying on the logic of social cognition theory, we conducted an empirical analysis from the perspective of trust and found that institutional trust and interpersonal trust can positively predict travel intention in the context of the epidemic, while travelers' health risk perception and safety self-efficacy mediate the relationship between trust and travel intention. Moreover, we verified the moderating role of tourists' psychological resilience. Further, the study confirms that China's active prevention policy not only reduces the physical health harm caused by the epidemic, but also effectively increases individuals' institutional trust in a proactive government. Through China's active anti-epidemic policy, individuals were able to counteract the negative impact of the COVID 19 epidemic on their travel intention. Further, theoretical and practical implications are discussed.

Travel intention during the COVID-19 epidemic: The influence of institutional and interpersonal trust

The global pandemic, COVID-19, has dealt a heavy blow to the tourism industry. Therefore, exploring the mechanisms influencing travel intention in the post-epidemic era can help provide management insights for the recovery of the travel market. Relying on the logic of social cognition theory, we conducted an empirical analysis from the perspective of trust and found that institutional trust and interpersonal trust can positively predict travel intention in the context of the epidemic, while travelers’ health risk perception and safety self-efficacy mediate the relationship between trust and travel intention. Moreover, we verified the moderating role of tourists’ psychological resilience. Further, the study confirms that China’s active prevention policy not only reduces the physical health harm caused by the epidemic, but also effectively increases individuals’ institutional trust in a proactive government. Through China’s active anti-epidemic policy, individuals were able to counteract the negative impact of the COVID 19 epidemic on their travel intention. Further, theoretical and practical implications are discussed.

Efficacy and safety of recanalization therapy for acute ischemic stroke with COVID-19: A systematic review and meta-analysis.

Background: The novel coronavirus disease 2019 (COVID-19) has rapidly spread worldwide and created a tremendous threat to global health. Growing evidence suggests that patients with COVID-19 have more severe acute ischemic stroke (AIS). However, the overall efficacy and safety of recanalization therapy for AIS patients infected by the SARS-CoV-2 virus is unknown. Methods: The PRISMA guideline 2020 was followed. Two independent investigators systematically searched databases and ClinicalTrials.gov to identify relevant studies published up to 31 March 2022. AIS patients who received any recanalization treatments were categorized into those with COVID-19 and those without COVID-19. The main efficacy outcomes were patients' functional independence on discharge and successful recanalization, and the safety outcomes were in-hospital mortality and symptomatic intracranial hemorrhage. Subgroup analyses were implemented to assess the influence of admission National Institutes of Health Stroke Scale and different recanalization treatments on the outcomes. STATA software 12.0 was used for the statistical analysis. Results: This systematic review and meta-analysis identified 10 studies with 7,042 patients, including 596 COVID-19 positive patients and 6,446 COVID-19 negative patients. Of the total patients, 2,414 received intravenous thrombolysis while 4,628 underwent endovascular thrombectomy. COVID-19 positive patients had significantly lower rates of functional independence at discharge [odds ratio (OR) 0.30, 95% confidence interval (CI) 0.15 to 0.59, P = 0.001], lower rates of successful recanalization (OR 0.40, 95% CI 0.24 to 0.68, P = 0.001), longer length of hospital stay (weighted mean difference 5.09, 95% CI 1.25 to 8.94, P = 0.009) and higher mortality rates (OR 3.38, 95% CI 2.43 to 4.70, P < 0.0001). Patients with COVID-19 had a higher risk of symptomatic intracranial hemorrhage than the control group, although the difference did not reach statistical significance (OR 2.34, 95% CI 0.99 to 5.54, P = 0.053). Conclusions: Compared with COVID-19 negative AIS patients who received recanalization treatments, COVID-19 positive patients turned out to have poorer outcomes. Particular attention needs to be paid to the treatments for these COVID-19 patients to decrease mortality and morbidity. Long-term follow-up is necessary to evaluate the recanalization treatments for AIS patients with COVID-19. Systematic review registration: https://inplasy.com/inplasy-2022-4-0022/, identifier: INPLASY202240022.

The uneven reaction to combat the COVID-19 pandemic: Geovisualizing of fever clinics in mainland China

The COVID-19 pandemic has exerted unprecedented impacts on the world. Since its onset, China has established a network of fever clinics as an effective strategy to aggressively isolate and screen possible patients with COVID-19 symptoms. This study presents two fever clinic maps that visualize the uneven responses to the COVID-19 pandemic at the city level in mainland China. The maps highlight more resources in the southwest, northwest, east, and south China, and paucity in the far west parts of southwest and northwest China and in the north and northeast China.

Advances in the polymeric delivery of nucleic acid vaccines.

Nucleic acid vaccines, especially messenger RNA (mRNA) vaccines, display unique benefits in the current COVID-19 pandemic. The application of polymeric materials as delivery carriers has greatly promoted nucleic acid vaccine as a promising prophylactic and therapeutic strategy. The inherent properties of polymeric materials render nucleic acid vaccines with excellent in vivo stability, enhanced biosafety, specific cellular uptake, endolysosomal escape, and promoted antigen expression. Although polymeric delivery of nucleic acid vaccines has progressed significantly in the past decades, clinical translation of polymer-gene vaccine systems still faces insurmountable challenges. This review summarizes the diverse polymers and their characterizations and representative formulations for nucleic acid vaccine delivery. We also discussed existing problems, coping strategies, and prospect relevant to applications of nucleic acid vaccines and polymeric carriers. This review highlights the rational design and development of polymeric vaccine delivery systems towards meeting the goals of defending serious or emerging diseases.

Peptide-Antibody Fusions Engineered by Phage Display Exhibit an Ultrapotent and Broad Neutralization of SARS-CoV-2 Variants.

The spread of COVID-19 has been exacerbated by the emergence of variants of concern (VoC). Many VoC contain mutations in the spike protein (S-protein) and are implicated in infection and response to therapeutics. Bivalent neutralizing antibodies (nAbs) targeting the S-protein receptor-binding domain (RBD) are promising therapeutics for COVID-19, but they are limited by low potency and vulnerability to RBD mutations in VoC. To address these issues, we used naïve phage-displayed peptide libraries to isolate and optimize 16-residue peptides that bind to the RBD or the N-terminal domain (NTD) of the S-protein. We fused these peptides to the N-terminus of a moderate-affinity nAb to generate tetravalent peptide-IgG fusions, and we showed that both classes of peptides were able to improve affinities for the S-protein trimer by >100-fold (apparent KD < 1 pM). Critically, cell-based infection assays with a panel of six SARS-CoV-2 variants demonstrated that an RBD-binding peptide was able to enhance the neutralization potency of a high-affinity nAb >100-fold. Moreover, this peptide-IgG was able to neutralize variants that were resistant to the same nAb in the bivalent IgG format, including the dominant B.1.1.529 (Omicron) variant that is resistant to most clinically approved therapeutic nAbs. To show that this approach is general, we fused the same peptide to a clinically approved nAb drug and showed that it enabled the neutralization of a resistant variant. Taken together, these results establish minimal peptide fusions as a modular means to greatly enhance affinities, potencies, and breadth of coverage of nAbs as therapeutics for SARS-CoV-2.

Acute kidney injury after COVID-19 vaccines: a real-world study.

BACKGROUND: Acute kidney injury (AKI), a rare adverse event, cannot be ignored as millions of doses of coronavirus disease 2019 (COVID-19) vaccinations. We aimed to investigate the occurrence of post-vaccine AKI reported to the Vaccine Adverse Event Reporting System (VAERS). METHODS: After data mapping from December 2020 to June 2021, we summarized demographic and clinical features and outcomes of reported cases from three vaccines (Pfizer-BNT, MODERNA, and JANSSEN). The Bayesian and nonproportional analyses explored the correlations between COVID-19 vaccines and AKI. RESULTS: We identified 1133 AKI cases. Pfizer-BNT appeared to have a stronger AKI correlation than MODERNA and JANSSEN, based on the highest reporting odds ratio (ROR = 2.15, 95% confidence interval = 1.97, 2.36). We observed the differences in ages, comorbidities, current illnesses, post-vaccine AKI causes, and time to AKI onset (all p＜.05) among three vaccines. Most patients are elderly, with the highest age in MODERNA (68.41 years) and lowest in JANSSEN (59.75 years). Comorbidities were noticed in 58.83% of the cases and active infections in over 20% of cases. The leading cause of post-vaccine AKI was volume depletion (40.78%), followed by sepsis (11.74%). Patients in Pfizer-BNT had the worst outcome with 19.78% deaths, following 17.78% in MODERNA and 12.36% in JANSSEN (p = .217). The proportion of patients on dialysis was higher in JANSSEN than in Pfizer-BNT and MODERNA (14.61% vs. 6.54%, 10.62%, p = .008). CONCLUSION: AKI could occur after the COVID-19 vaccines, predominantly in elderly patients. However, the causality needs further identification.

ACE2 overexpressing mesenchymal stem cells alleviates COVID-19 lung injury by inhibiting pyroptosis.

Mesenchymal stem cells (MSCs) have shown some efficacy in the COVID-19 treatment. We proposed that exogenous supplementation of ACE2 via MSCs (ACE2-MSCs) might have better therapeutic effects. We constructed SARS-CoV-2 spike glycoprotein stably transfected AT-II and Beas-2B cells and used SARS-CoV-2 spike pseudovirus to infect hACE2 transgenic mice. The results showed that spike glycoprotein transfection triggers the release of apoptotic bodies and formation of membrane pores in pyroptosis. Inflammatory factors and pyroptosis factors were highly upregulated by spike glycoprotein transfection. SARS-CoV-2 spike pseudovirus worsened lung injury and increased the main factors of cytokine storm and pyroptosis. Compared to using MSCs or rh-ACE2 alone, the administration of ACE2-MSCs could significantly reduce these factors better and alleviate lung injury in vivo and in vitro, which might be because of the increased activities of secretory ACE2. Our proposal is a promising therapeutic solution for preclinical or clinical research.

Association of Current Active Illnesses and Severe Acute Kidney Injury after COVID-19 Vaccines: A Real-World Study.

The administration of COVID-19 vaccines has become increasingly essential to curb the pandemic. However, adverse events of acute kidney injury (AKI) emerge rapidly as the COVID-19 vaccination promotes. To investigate the intervenable risk factors of AKI, we searched the Vaccine Adverse Event Reporting System database and recorded adverse effects after COVID-19 vaccines from Dec 2020 to Jun 2021. We included 1149 AKI cases, of which 627 (54.6%) cases were reported following the Pfizer-BNT COVID-19 vaccine, and 433 (37.7%) were reported after the Moderna vaccine. A univariate analysis revealed that coexisting active illnesses (infections, uncontrolled hypertension, heart failure, etc.) have an unfavorable prognosis, with an increased risk of death (OR 2.35, 95% CI 1.70-3.25, p < 0.001). The other risk factors included older age and past disease histories. An adjusted regression analysis proved that coexisting active illnesses worsen AKI prognosis after COVID-19 vaccination, with a higher mortality risk (OR 2.19, 95% CI 1.48-3.25, p < 0.001). In subgroup analysis, we stratified different variables, and none revealed a significant effect modification on the association between coexisting active illnesses and AKI-associated death after vaccination (p-interaction >0.05). We found that coexisting active illnesses could complicate AKI after vaccines, but the potential causal relationship needed further investigation.