Targeting immunometabolism against acute lung injury.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening conditions triggered by multiple intra- and extra-pulmonary injury factors, characterized by complicated molecular mechanisms and high mortality. Great strides have been made in the field of immunometabolism to clarify the interplay between intracellular metabolism and immune function in the past few years. Emerging evidence unveils the crucial roles of immunometabolism in inflammatory response and ALI. During ALI, both macrophages and lymphocytes undergo robust metabolic reprogramming and discrete epigenetic changes after activated. Apart from providing ATP and biosynthetic precursors, these metabolic cellular reactions and processes in lung also regulate inflammation and immunity.In fact, metabolic reprogramming involving glucose metabolism and fatty acidoxidation (FAO) acts as a double-edged sword in inflammatory response, which not only drives inflammasome activation but also elicits anti-inflammatory response. Additionally, the features and roles of metabolic reprogramming in different immune cells are not exactly the same. Here, we outline the evidence implicating how adverse factors shape immunometabolism in differentiation types of immune cells during ALI and summarize key proteins associated with energy expenditure and metabolic reprogramming. Finally, novel therapeutic targets in metabolic intermediates and enzymes together with current challenges in immunometabolism against ALI were discussed.

Analysis of influenza epidemics in northern China during 2018-2021 and exploration of early diagnosis on influenza B (preprint)

Background: Research on the impacts of COVID-19 towards influenza and the early diagnosis of influenza B is limited. This study aimed to analyze the impacts of COVID-19 pandemic on influenza epidemics in northern China and explore the early-diagnosis indicators of influenza B. Methods: 1. Data of influenza-like illness (ILI) and influenza virological surveillance in northern China during 2018-2021 winter influenza season were collected to analyze the impacts of COVID-19 pandemic on influenza epidemics.  2. Clinical characteristics of 38 influenza B positive patients and 38 influenza B negative patients confirmed during 2021 winter influenza season were retrospectively observed. Clinical symptoms and blood routine indicators of both groups were compared and analyzed. Results: 1. During 2020 and 2021 winter influenza season, ILI% and influenza virus positive rate in northern China were both lower than those in 2018 and 2019, with the influenza B (Victoria) dominating.  2. Compared with influenza B negative group, the systemic symptoms in influenza B positive group were significantly increased. The value of white blood cell, neutrophils%, C-reactive protein and serum amyloid A in influenza B positive group were significantly lower than those in negative group, while the lymphocytes% and monocytes% were higher than those in negative group and both could be regarded as the diagnostic indicators of influenza B. Conclusions: Influenza epidemics were greatly reduced during COVID-19 pandemic, with influenza B rebounding from 2021, and continuous surveillance is still needed. Both clinical features and blood routine indicators can be helpful towards the early diagnosis on influenza B.

The efficacy and safety of remdesivir and its combination with other drug for the treatment of COVID-19: a systematic review and meta-analysis (preprint)

Background Remdesivir was considered to be a specific drug for Corona Virus Disease 2019. This systematic review aims to evaluate remdesivir monotherapy and combination therapy related clinical efficacy and risk. Research design and methods PubMed, Embase, SCIE, Cochrane Library, and American Clinical trial Center were searched up to 1 April 2022. We included randomized controlled trials (RCTs) comparing Remdesivir monotherapy with control drugs, or comparing different combination therapy. Results 11 RCTs and 32 observational studies were included in analysis. In the main outcome, remdesivir use reduced mortality in patients with severe COVID-19 and improve recovery in patients. In other clinical outcomes, remdesivir use was associated with improved clinical status. In safety outcomes, remdesivir use did not cause liver or kidney damage. Compared with remdesivir alone, remdesivir combined with other drugs-steroids, favipiravir, and convalescent plasma- had no effect on mortality. In addition, remdesivir combined with tocilizumab may increase mortality. Conclusion Results of the systematic review showed that remdesivir was positive in COVID-19, especially patients with severe COVID-19. The more effective treatment of COVID-19 with other drugs combined with remdesivir is urgent and challenging research. Trial registration number PROSPERO registration number: CRD42022322859.

Dust events affect the occurrence of influenza: A case-crossover study in an arid city of China (preprint)

Background Air aerosol is believed to be an important pathway for infectious disease transmission like COVID-19 as well as influenza. Therefore, we hypothesized that there might be a strong association between dust events and influenza, especially in semi-arid areas. This study aims to explore the effects of ambient particulate matter (PM) and dust events on laboratory-confirmed influenza cases in a semi-arid city.Methods A descriptive analysis of daily laboratory-confirmed influenza (influenza) cases, PM (PM10 and PM2.5), meteorological parameters and dust events were conducted from 2014 to 2019 in Lanzhou, China. The Case-crossover design combined with conditional Poisson regression models was used to estimate the lagging effects of PM and dust events on influenza. In addition, a hierarchical model was used to quantitatively evaluate the interactive effect of PM with ambient temperature and absolute humidity on influenza.Results We found that PM and dust events had a significant effect on influenza. The effects of PM10 and PM2.5 on influenza became stronger as the cumulative lag days increased, the greatest estimated relative risks (RRs) were 1.018 (1.011,1.024) and 1.06 1(1.034,1.087), respectively. Compared with the non-dust days, the effects of dust events with duration ≥ 1 day and with duration ≥ 2 days on influenza were the strongest at lag0 day, with the estimated RRs of 1.245 (95% CI: 1.061–1.463) and 1.483 (95% CI: 1.232–1.784), respectively. Subgroup analysis showed that pre-school children and school-aged children were more sensitive to PM and dust events exposure. Besides, we also found the low humidity and temperature had an interaction with PM, which could aggravate the risk of influenza.Conclusions Ambient PM and dust events exposure may increase the risk of laboratory-confirmed influenza, and the risk of laboratory-confirmed influenza increased with the dust events duration. These findings will provide additional epidemiological evidence for future influenza prevention and environmental protection.

Implementing a school-based HIV intervention program during public health emergencies: Lessons learned in The Bahamas (preprint)

Background Natural disasters and public health crises can disrupt communities’ capacities to implement important public health programs. A nationwide implementation of an evidence-based HIV prevention program, Focus on Youth in The Caribbean (FOYC) and Caribbean Informed Parents and Children Together (CImPACT), in The Bahamas suffered severe disruption from Hurricane Dorian and the COVID-19 pandemic, especially in its more remote islands. We explored the teacher- and school-level factors that affected implementation of the program in these islands during those disruptions.Methods Data were collected from 47 Grade 6 teachers and 984 students in 34 government elementary schools during the 2020–2021 school year. Teachers completed a pre-implementation questionnaire to record their characteristics and perceptions that might affect their implementation fidelity and an annual program training workshop. School coordinators and high-performing teachers acting as mentors received additional training to provide teachers with monitoring, feedback, and additional support. Teachers submitted data on their completion of the 9 sessions and 35 core activities of FOYC + CImPACT. The fidelity outcomes were the number of sessions and core activities taught by teachers each year.Results On average, teachers taught 60% of sessions and 53% of core activities. Teachers with “very good” school coordinators (34% of teachers) taught more activities than those with “satisfactory” (43%) or no (34%) school coordinator (27.5 vs. 16.8 vs. 14.8, F = 12.86, P < 0.001). Teachers who had attended online training or both online and in-person training taught more sessions (6.1 vs. 6.2 vs. 3.6, F = 4.76, P < 0.01) and more core activities (21.1 vs. 20.8 vs. 12.6, F = 3.35, P < 0.05) than those who received no training. Teachers’ implementation was associated with improved student outcomes (preventive reproductive health skills, self-efficacy, and intention).Conclusions Implementation fidelity in the Family Islands suffered from Hurricane Dorian and the COVID-19 pandemic that disrupted education in The Bahamas. However, we identified several strategies that supported teachers’ implementation in response to these events. Teacher training and implementation monitoring increased implementation fidelity despite external challenges, and students achieved the desired learning outcomes. These strategies can better support teachers’ implementation of school-based interventions during future crises.

Sustainable impact of COVID-19 on education projects: aspects of naturalism.

History records show that pandemics and threats have always given new directions to the thinking, working, and learning styles. This article attempts to thoroughly document the positive core of coronavirus 2019 (COVID-19) and its impact on global social psychology, ecological stability, and development. Structural equation modeling (SEM) is used to test the hypotheses and comprehend the objectives of the study. The findings of the study reveals that the path coefficients for the variables health consciousness, naturalism, financial impact and self-development, sustainability, compassion, gregariousness, sympathy, and cooperation demonstrate that the factors have a positive and significant effect on COVID-19 prevention. Moreover, the content analysis was conducted on recently published reports, blog content, newspapers, and social media. The pieces of evidence from history have been cited to justify the perspective. Furthermore, to appraise the opinions of professionals of different walks of life, an online survey was conducted, and results were discussed with expert medical professionals. Outcomes establish that the pandemics give birth to creativity, instigate innovations, prompt inventions, establish human ties, and foster altruistic elements of compassion and emotionalism.

Systematic comparison of ranking aggregation methods for gene lists in experimental results (preprint)

A common experimental output in biomedical science is a list of genes implicated in a given biological process or disease. The results of a group of studies answering the same, or similar, questions can be combined by meta-analysis to find a consensus or a more reliable answer. Ranking aggregation methods can be used to combine gene lists from various sources in meta-analyses. Evaluating a ranking aggregation method on a specific type of dataset before using it is required to support the reliability of the result since the property of a dataset can influence the performance of an algorithm. Evaluation of aggregation methods is usually based on a simulated database especially for the algorithms designed for gene lists because of the lack of a known truth for real data. However, simulated datasets tend to be too small compared to experimental data and neglect key features, including heterogeneity of quality, relevance and the inclusion of unranked lists. In this study, a group of existing methods and their variations which are suitable for meta-analysis of gene lists are compared using simulated and real data. Simulated data was used to explore the performance of the aggregation methods as a function of emulating the common scenarios of real genomics data, with various heterogeneity of quality, noise level, and a mix of unranked and ranked data using 20000 possible entities. In addition to the evaluation with simulated data, a comparison using real genomic data on the SARS-CoV-2 virus, cancer (NSCLC), and bacteria (macrophage apoptosis) was performed. We summarise our evaluation results in terms of a simple flowchart to select a ranking aggregation method for genomics data.

Characteristics and Prognosis of Antibody Non-Responders with COVID-19 (preprint)

Background：The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been spreading globally. The information regarding the characteristics and prognosis of antibody non-responders with COVID-19 is scarce.Method: In this retrospective, single-center study, we included all the patients with confirmed COVID-19 using real-time reverse transcriptase-polymerase chain reaction (RT-PCR) admitted to the Fire God Mountain hospital from February 3, 2020, to April 14, 2020. A total of 1921 patients were divided into the antibody-negative group (n=94) and antibody-positive group (n=1827), and the 1:1 propensity score matching (PSM) was used to match two groups.Results: In the antibody negative group, 40 patients (42.6%) were male, 54 patients (57.4%) were female, and 49 patients (52.1%) were older than 65 years old. Cough was the most common symptoms in the antibody negative group. White blood cell counts (WBC) 6.6×109/L [5.0, 9.1], Neutrophils 4.3×109/L [3.1, 6.6], C-reactive protein 7.3 mg/L [1.3, 49.0], Procalcitonin (PCT) 0.1 ng/mL [0.0, 0.2], Interleukin-6 (IL-6) 64.2 [1.5, 28.7], Lactate dehydrogenase (LDH) 193.8 U/L [154.9,260.6], Creatine kinase 60.5 U/L [40.5, 103.7], Creatine kinase isoenzyme 10.3 ng/mL [8.2, 14.5], Urea nitrogen 5.3 mmol/L [4.0, 8.7] and Creatinine 77.7 μmol/L [60.6, 98.7] were significantly higher in antibody negative patients than in antibody positive group (P<0.005). The days of nucleic acid negative conversion in the antibody negative group was shorter than that in the antibody positive group (P < 0.001). Meanwhile, the hospitalization time of antibody negative patients was shorter than that of antibody positive patients (8.0 [6.0, 10.0] VS 13.0 [8.2, 23.0], P < 0.001).Conclusion: Some COVID-19 patients without specific antibodies had mild symptoms, but the inflammatory reaction caused by innate clinical immunity was more intense than those with antibodies, and the virus was cleared faster. The production of specific antibodies was unnecessary for SARS-CoV-2 clearance, and non-specific immune responses played an essential role in virus clearance.

Whole genome sequencing identifies multiple loci for critical illness caused by COVID-19 (preprint)

Critical illness in COVID-19 is caused by inflammatory lung injury, mediated by the host immune system. We and others have shown that host genetic variation influences the development of illness requiring critical care1 or hospitalisation2;3;4 following SARS-Co-V2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study is designed to compare genetic variants in critically-ill cases with population controls in order to find underlying disease mechanisms. Here, we use whole genome sequencing and statistical fine mapping in 7,491 critically-ill cases compared with 48,400 population controls to discover and replicate 22 independent variants that significantly predispose to life-threatening COVID-19. We identify 15 new independent associations with critical COVID-19, including variants within genes involved in interferon signalling (IL10RB, PLSCR1), leucocyte differentiation (BCL11A), and blood type antigen secretor status (FUT2). Using transcriptome-wide association and colocalisation to infer the effect of gene expression on disease severity, we find evidence implicating expression of multiple genes, including reduced expression of a membrane flippase (ATP11A), and increased mucin expression (MUC1), in critical disease. We show that comparison between critically-ill cases and population controls is highly efficient for genetic association analysis and enables detection of therapeutically-relevant mechanisms of disease. Therapeutic predictions arising from these findings require testing in clinical trials.

Severe Adaptive Immune Suppression May be Why Patients with Severe COVID-19 Cannot be Discharged From the ICU Even After Negative Viral Tests (preprint)

Background: During the COVID-19 pandemic, a phenomenon emerged in which some patients with severe disease were critically ill and could not be discharged from the ICU even though they exhibited negative viral tests. In general, continuous negative viral tests are thought to indicate that the virus has been cleared from the body and that the patients can be considered "recovered". However, because these patients were still critically ill, they obviously had not truly recovered from the disease. We sought to investigate why these patients were still critically ill even though they exhibited negative viral tests by analyzing the gene expression profiles of their peripheral immune cells using transcriptome sequencing. Methods: Fourteen severe COVID-19 patients with at least 3 negative virus tests but were still in critical ill and could not be discharged from the ICU were enrolled. Blood samples from 14 patients and 5 healthy donors were collected. Total RNA was extracted from nucleated cells for RNA-Sequencing. FeatureCounts v1.5.0-p3 was used to count the reads numbers mapped to each gene. Results: All enrolled patients, regardless of changes in genes related to different symptoms and inflammatory responses, showed universally and severely decreased expression of adaptive immunity-related genes, especially those related to T/B cell arms and HLA molecules, and that these patients exhibited long-term secondary infections. This adaptive immune suppression is unlikely due to classic immune checkpoint molecules such as PD-1 or long-term use of glucocorticoids but may be caused by an unknown mechanism that has not yet been discovered. Conclusions: Our findings strongly suggest that an initial recovery of these severe COVID-19 patients, as indicated by negative viral tests, may not indicate actual recovery. They still suffer from secondary infections for a long period of time because of severe adaptive immunosuppression and need to receive a variety of antibiotics, antifungal drugs, or combination therapies. Appropriate methods should be used to detect their adaptive immune function, and appropriate immunotherapy that can activate the adaptive immune response should be developed. Trial registration: Not applicable (this study does not involve intervention on human participants).