Discovering and overcoming the bias in neoantigen identification by unified machine learning models (preprint)

Neoantigens, formed by genetic mutations in tumor cells, are abnormal peptides that can trigger immune responses. Precisely identifying neoantigens from vast mutations is the key to tumor immunotherapy design. There are three main steps in the neoantigen immune process, i.e., binding with MHCs, extracellular presentation, and induction of immunogenicity. Various machine learning methods have been developed to predict the probability of one of the three events, but the overall accuracy of neoantigen identification remains far from satisfactory. To gain a systematic understanding of the key factors of neoantigen identification, we developed a unified transformer-based machine learning framework ImmuBPI that comprised three tasks and achieved state-of-the-art performance. Through cross-task model interpretation, we have discovered an underestimation of data bias for immunogenicity prediction, which has led to skewed discriminatory boundaries of current machine learning models. We designed a mutual information-based debiasing strategy that performed well on mutation variants immunogenicity prediction, a task where current methods fell short. Clustering immunogenic peptides with debiased representations uncovers unique preferences for biophysical properties, such as hydrophobicity and polarity. These observations serve as an important complement to the past understanding that accurately predicting neoantigen is constrained by limited data, highlighting the necessity of bias control. We expect this study will provide novel and insightful perspectives for neoantigen prediction methods and benefit future neoantigen-mediated immunotherapy designs.

Effects of bamlanivimab alone or in combination with etesevimab on subsequent hospitalization and mortality in outpatients with COVID-19: a systematic review and meta-analysis.

Background: Coronavirus disease 2019 (COVID-19) has caused an enormous loss of life worldwide. The spike protein of the severe acute respiratory syndrome coronavirus 2 is the cause of its virulence. Bamlanivimab, a recombinant monoclonal antibody, has been used alone or in combination with etesevimab to provide passive immunity and improve clinical outcomes. A systematic review and meta-analysis was conducted to investigate the therapeutic effects of bamlanivimab with or without etesevimab (BAM/ETE) treatment. Methods: Our study was registered in PROSPERO (registry number CRD42021270206). We searched the following electronic databases, without language restrictions, until January 2023: PubMed, Embase, medRxiv, and the Cochrane database. A systematic review and meta-analysis was conducted based on the search results. Results: Eighteen publications with a total of 28,577 patients were identified. Non-hospitalized patients given bamlanivimab with or without etesevimab had a significantly lower risk of subsequent hospitalization (18 trials, odds ratio (OR): 0.37, 95% confidence interval (CI): [0.29-0.49], I2: 69%; p < 0.01) and mortality (15 trials, OR: 0.27, 95% CI [0.17-0.43], I2: 0%; p = 0.85). Bamlanivimab monotherapy also reduced the subsequent risk of hospitalization (16 trials, OR: 0.43, 95% CI [0.34-0.54], I2: 57%; p = 0.01) and mortality (14 trials, OR: 0.28, 95% CI [0.17-0.46], I2: 0%; p = 0.9). Adverse events from these medications were uncommon and tolerable. Conclusions: In this meta-analysis, we found the use of bamlanivimab with or without etesevimab contributed to a significantly-reduced risk of subsequent hospitalization and mortality in non-hospitalized COVID-19 patients. However, resistance to monoclonal antibodies was observed in COVID-19 variants, resulting in the halting of the clinical use of BAM/ETE. Clinicians' experiences with BAM/ETE indicate the importance of genomic surveillance. BAM/ETE may be repurposed as a potential component of a cocktail regimen in treating future COVID variants.

Genome-wide detection of human variants that disrupt intronic branchpoints.

Pre-messenger RNA splicing is initiated with the recognition of a single-nucleotide intronic branchpoint (BP) within a BP motif by spliceosome elements. Forty-eight rare variants in 43 human genes have been reported to alter splicing and cause disease by disrupting BP. However, until now, no computational approach was available to efficiently detect such variants in massively parallel sequencing data. We established a comprehensive human genome-wide BP database by integrating existing BP data and generating new BP data from RNA sequencing of lariat debranching enzyme DBR1-mutated patients and from machine-learning predictions. We characterized multiple features of BP in major and minor introns and found that BP and BP-2 (two nucleotides upstream of BP) positions exhibit a lower rate of variation in human populations and higher evolutionary conservation than the intronic background, while being comparable to the exonic background. We developed BPHunter as a genome-wide computational approach to systematically and efficiently detect intronic variants that may disrupt BP recognition. BPHunter retrospectively identified 40 of the 48 known pathogenic BP variants, in which we summarized a strategy for prioritizing BP variant candidates. The remaining eight variants all create AG-dinucleotides between the BP and acceptor site, which is the likely reason for missplicing. We demonstrated the practical utility of BPHunter prospectively by using it to identify a novel germline heterozygous BP variant of STAT2 in a patient with critical COVID-19 pneumonia and a novel somatic intronic 59-nucleotide deletion of ITPKB in a lymphoma patient, both of which were validated experimentally. BPHunter is publicly available from https://hgidsoft.rockefeller.edu/BPHunter and https://github.com/casanova-lab/BPHunter.

Anti-SARS-CoV-2 spike immunoglobulin G and immunoglobulin M titers decline as interval from the second inactivated vaccine dose to the onset of illness is prolonged in breakthrough infection patients.

BACKGROUND: Understanding of the early immune response in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infections is limited. METHODS: Ninety-eight patients with coronavirus disease 2019 (COVID-19) breakthrough infections were divided into two groups, with intervals from receiving the second dose of inactivated vaccine to the onset of illness <60 or ≥60 days. RESULTS: The median lymphocyte count and the median anti-SARS-CoV-2 spike immunoglobulin G (IgG) and immunoglobulin M (IgM) titers were higher in the <60-day interval group compared with the corresponding medians in the ≥60-day interval group (p = 0.005, p = 0.001, and p = 0.001, respectively). The median interleukin-6 (IL-6) level in the <60-day interval group was significantly lower than the median IL-6 level in the ≥60-day interval group (p < 0.001). CONCLUSIONS: Our results highlight the different anti-SARS-CoV-2 spike IgG and IgM antibody titers among patients with different intervals from receiving the second dose of inactivated vaccine to the onset of illness.

Oral Liushen pill for patients with COVID-19: A prospective randomized controlled trial.

We examined the efficacy and safety of Liushen pill combined with basic treatment for patients with COVID-19. In total, 181 patients hospitalized with COVID-19, classified as asymptomatic mild type, were randomly divided into the experimental (n = 91) and control (n = 90) groups and were administered placebo (Maizao decoction) and Maizao decoction and Liushen pill, in addition to standard care, respectively. The negative conversion rate of nucleic acid (Day 7), hospital discharge rate (Days 8, 10, and 14), symptom disappearance rate (Days 3, 5, and 7), inflammatory cytokine levels, and adverse events were compared between the groups. The negative viral conversion rate was significantly higher in the experimental than in the control group (48.35 vs. 31.11%, p < 0.05). Subgroup analysis showed a similar significant trend when the Ct value was ≤30 at baseline. After 10 days, the hospital discharge rate was significantly higher in the experimental than in the control group (69.23 vs. 53.33%, p < 0.05). After 3-day medication, the headache symptoms significantly disappeared in the experimental (88.57%) compared to the control group (63.33%) (p < 0.05). After 5 days, the symptom disappearance rates of headache and cough were significantly higher in the experimental (97.14%) than in the control group (97.14 vs. 80.00, p < 0.05; 82.65 vs. 58.93%, p < 0.01, respectively). Posttreatment, the procalcitonin level was significantly lower in the experimental than in the control group (0.09 ± 0.00 vs. 0.14 ± 0.05 ng/L; p < 0.05). There were no significant between-group differences in clinical safety test indices. Early intervention with Liushen pill improved cough and headache and increased negative viral conversion and discharge rate.

Comparison of the duration of viral RNA shedding and anti-SARS-CoV-2 spike IgG and IgM antibody titers in COVID-19 patients who were vaccinated with inactivated vaccines or not: a retrospective study.

BACKGROUND: At present, the role of inactivated vaccines in viral RNA shedding among Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) breakthrough infections is still unknown. METHODS: We collected data of 147 coronavirus disease 2019 (COVID-19) patients with mild-to-moderate illness who were hospitalized in the Third People's Hospital of Yangzhou from 7 to 20 August 2021 and analyzed the differences in symptoms and laboratory tests among fully vaccinated (FV), partially vaccinated (PV) and unvaccinated (UV) patients. RESULTS: The median duration of viral RNA shedding was shorter in the FV (12 [IQR, 9.5-14] days) and PV (13 [IQR, 9-16.75] days) groups than in the UV group (15 [IQR, 11.75-17.25] days) (adjusted P < 0.001 and adjusted P = 0.23, respectively). The median titers of SARS-CoV-2-specific IgG and IgM were significantly higher in the FV (12.29 S/co [IQR, 2.08-63.59] and 0.3 S/co [IQR, 0.05-2.29], respectively) and PV (0.68 S/co [IQR, 0.14-28.69] and 0.12 S/co [0.03-5.23], respectively) groups than in the UV group (0.06 S/co [IQR, 0.03-0.47] and 0.04 S/co [IQR, 0.02-0.07]) (adjusted P < 0.001 and adjusted P = 0.008, respectively). CONCLUSIONS: Inactivated vaccines may shorten viral RNA shedding in breakthrough infected patients who have mild-to-moderate illness and may improve the ability of the host to generate specific antibodies to infection.

Autoantibodies against type I IFNs in patients with critical influenza pneumonia.

Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies neutralizing IFN-α2 alone (five patients) or with IFN-ω (eight patients) from a cohort of 279 patients (4.7%) aged 6-73 yr with critical influenza pneumonia. Nine and four patients had antibodies neutralizing high and low concentrations, respectively, of IFN-α2, and six and two patients had antibodies neutralizing high and low concentrations, respectively, of IFN-ω. The patients' autoantibodies increased influenza A virus replication in both A549 cells and reconstituted human airway epithelia. The prevalence of these antibodies was significantly higher than that in the general population for patients <70 yr of age (5.7 vs. 1.1%, P = 2.2 × 10-5), but not >70 yr of age (3.1 vs. 4.4%, P = 0.68). The risk of critical influenza was highest in patients with antibodies neutralizing high concentrations of both IFN-α2 and IFN-ω (OR = 11.7, P = 1.3 × 10-5), especially those <70 yr old (OR = 139.9, P = 3.1 × 10-10). We also identified 10 patients in additional influenza patient cohorts. Autoantibodies neutralizing type I IFNs account for ∼5% of cases of life-threatening influenza pneumonia in patients <70 yr old.

Prone position reduces the risk of patients with mild or moderate COVID-19 progressing to severe or even critical cases: a retrospective study.

BACKGROUND: To investigate whether prone position can reduce the risk of patients with mild or moderate COVID-19 who progress to severe or critical illness. METHODS: The prone position group was treated in prone position on the day of admission in addition to conventional treatment. Indicators such as saturation of pulse oximetry (SpO2), heart rate, blood pressure, respiratory rate, and prone position-related adverse events were recorded before prone ventilation, 5 min after prone position and 30 min after prone position. Meanwhile, the cases of severe and critical patients, the percentage of transformation and the final clinical outcome of this group were analyzed. Conversion rates and mortality were calculated for patients with mild or moderate COVID-19 retrieved from the database who received only conventional care without combined prone positioning as control group. RESULTS: (1) A total of 34 patients were included in prone position group. There were significant differences in SpO2 between the first 4 days after admission and the day of discharge (F = 3.17, P < 0.001). (2) The main complications were back and neck muscle soreness (55.9%), followed by abdominal distension (8.9%). (3) In control group, a total of 4873 cases of mild and moderate patients were included from 19 literatures, with an average deterioration rate of 22.7% and mortality rate of 1.7%. (4) In prone position group, there were no severe or critical transformation cases and also no death cases. The prone position group had a significantly lower deterioration rate when compared with the control group (χ2 = 9.962, P < 0.01). CONCLUSION: Prone position improves SpO2 in patients with mild or moderate COVID-19. It can also reduce the percentage of mild or moderate patients progressing to severe or critical patients. The application of prone position is a simple, feasible, safe and effective treatment method in such patients.

Student Experience and Satisfaction in Academic Libraries: A Comparative Study among Three Universities in Wuhan

In recent years, the spatial renovation of university libraries in various countries has focused on readers’ needs and followed the trend to develop learning spaces as a primary spatial form. In this study, we reviewed six spatial dimensions affecting student users’ learning experience. Specifically, we built a theory- and practice-based conceptual analysis framework to measure users’ satisfaction with recent spatial renovations at three university libraries in Wuhan, China. We used SPSS statistical software to conduct multiple linear regression analyses of spatial satisfaction. The findings show that five spatial dimensions significantly affect students’ satisfaction with library space, namely, service facility availability, quality of interior design, physical environment elements, spatial diversity, and learning space controllability. Service facility availability is the most critical factor affecting spatial satisfaction. In this study, we present empirical, evidence-based space elements that enhance user satisfaction with library spaces, and provide targeted design suggestions for future library space renovation and the optimization of space allocation and expansion of space services at university libraries in China.

Comparison and Analysis on the Existing Single-Herbal Strategies against Viral Myocarditis.

Purpose: Herbal medicine is one of crucial symbols of Chinese national medicine. Investigation on molecular responses of different herbal strategies against viral myocarditis is immeasurably conducive to targeting drug development in the current international absence of miracle treatment. Methods: Literature retrieval platforms were applied in the collection of existing empirical evidences for viral myocarditis-related single-herbal strategies. SwissTargetPrediction, Metascape, and Discovery Studio coordinating with multidatabases investigated underlying target genes, interactive proteins, and docking molecules in turn. Results: Six single-herbal medicines consisting of Huangqi (Hedysarum Multijugum Maxim), Yuganzi (Phyllanthi Fructus), Kushen (Sophorae Flavescentis Radix), Jianghuang (Curcumaelongae Rhizoma), Chaihu (Radix Bupleuri), and Jixueteng (Spatholobus Suberectus Dunn) meet the requirement. There were 11 overlapped and 73 unique natural components detected in these herbs. SLC6A2, SLC6A4, NOS2, PPARA, PPARG, ACHE, CYP2C19, CYP51A1, and CHRM2 were equally targeted by six herbs and identified as viral myocarditis-associated symbols. MCODE algorithm exposed the hub role of SRC and EGFR in strategies without Jianghuang. Subsequently, we learned intermolecular interactions of herbal components and their targeting heart-tissue-specific CHRM2, FABP3, TNNC1, TNNI3, TNNT2, and SCN5A and cardiac-myocytes-specific IL6, MMP1, and PLAT coupled with viral myocarditis. Ten interactive characteristics such as π-alkyl and van der Waals were modeled in which ARG111, LYS253, ILE114, and VAL11 on cardiac troponin (TNNC1-TNNI3-TNNT2) and ARG208, ASN106, and ALA258 on MMP1 fulfilled potential communicating anchor with ellagic acid, 5α, 9α-dihydroxymatrine, and leachianone g via hydrogen bond and hydrophobic interaction, respectively. Conclusions: The comprehensive outcomes uncover differences and linkages between six herbs against viral myocarditis through component and target analysis, fostering development of drugs.

Hydrogen-oxygen therapy alleviates clinical symptoms in twelve patients hospitalized with COVID-19: A retrospective study of medical records.

ABSTRACT: A global public health crisis caused by the 2019 novel coronavirus disease (COVID-19) leads to considerable morbidity and mortality, which bring great challenge to respiratory medicine. Hydrogen-oxygen therapy contributes to treat severe respiratory diseases and improve lung functions, yet there is no information to support the clinical use of this therapy in the COVID-19 pneumonia.A retrospective study of medical records was carried out in Shishou Hospital of Traditional Chinese Medicine in Hubei, China. COVID-19 patients (aged ≥ 30 years) admitted to the hospital from January 29 to March 20, 2020 were subjected to control group (n = 12) who received routine therapy and case group (n = 12) who received additional hydrogen-oxygen therapy. The clinical characteristics of COVID-19 patients were analyzed. The physiological and biochemical indexes, including immune inflammation indicators, electrolytes, myocardial enzyme profile, and functions of liver and kidney, were examined and investigated before and after hydrogen-oxygen therapy.The results showed significant decreases in the neutrophil percentage and the concentration and abnormal proportion of C-reactive protein in COVID-19 patients received additional hydrogen-oxygen therapy.This novel therapeutic may alleviate clinical symptoms of COVID-19 patients by suppressing inflammation responses.

Combining economic recovery with climate change mitigation: A global evaluation of financial instruments

Although some countries are gradually returning to production and life, the COVID-19 pandemic continues to affect the world, further motivating recovery policies. Using a global computable general equilibrium (CGE) model, this study evaluates the environmental and economic impacts of COVID-19 on the world, both today and in the longer term. This study explores the post-pandemic impacts conditional on varied fiscal policies (including forgone revenue and additional spending) and their combination with a carbon tax. This study finds that the pandemic shocks in 2020 slowed regional economies worldwide, and a continued pandemic in 2021 will further stymie economic activity. Among the government’s recovery policies, indirect tax reduction has the best positive stimulus to regional economies;however, it is not conducive to low-carbon energy development and will also lead to an increase in CO2 and pollutant emissions. A post-pandemic green recovery plan could prioritize replacing indirect production taxes with taxes on GHG emissions, which would both improve economic turnover metrics and reduce environmental emissions in 2021. In the long run, this tax shift will not only minimize the economic damage to the global economy but also help governments around the world to get back on track in meeting the goals of the Paris Agreement.

Repurposing Colchicine in Treating Patients with COVID-19: A Systematic Review and Meta-Analysis.

Coronavirus disease 2019 (COVID-19) had caused huge health losses worldwide. Several drugs had been applied to treat patients with COVID-19, and repurposing colchicine had been proposed for its anti-inflammatory properties via several pathways. In this systematic review, we evaluated the effects of colchicine treatment. From inception to May 31, 2021, databases, including PubMed, EMbase, medRxiv, and Research Square were searched, and 11 studies were enrolled. A total of 17,205 COVID-19 patients with male predominance (62.9%) were analyzed. Patients with colchicine treatment had a significantly lower risk of mortality (odds ratio (OR): 0.57, 95% confidence interval (CI): 0.38-0.87, I2: 72%; p < 0.01) and a non-significantly lower rate of mechanical ventilation (OR: 0.67, 95%CI: 0.39-1.15). The side effects were mild and not significantly different (OR: 2.03, 95%CI: 0.51-8.09). Subgroup analysis with randomized controlled trials showed no statistically significant difference in the mortality (OR: 0.80, 95%CI: 0.44-1.46, I2: 33%; p = 0.22). In conclusion, our meta-analysis found that colchicine treatment was associated with a significantly lower risk of mortality in patients with COVID-19. However, this benefit was not observed in the subgroup analysis of randomized controlled trials. Further randomized controlled studies are required to confirm the potential benefits of colchicine treatment.

Therapeutic mechanisms of mesenchymal stem cells in acute respiratory distress syndrome reveal potentials for Covid-19 treatment.

The mortality rate of critically ill patients with acute respiratory distress syndrome (ARDS) is 30.9% to 46.1%. The emergence of the coronavirus disease 2019 (Covid-19) has become a global issue with raising dire concerns. Patients with severe Covid-19 may progress toward ARDS. Mesenchymal stem cells (MSCs) can be derived from bone marrow, umbilical cord, adipose tissue and so on. The easy accessibility and low immunogenicity enable MSCs for allogeneic administration, and thus they were widely used in animal and clinical studies. Accumulating evidence suggests that mesenchymal stem cell infusion can ameliorate ARDS. However, the underlying mechanisms of MSCs need to be discussed. Recent studies showed MSCs can modulate immune/inflammatory cells, attenuate endoplasmic reticulum stress, and inhibit pulmonary fibrosis. The paracrine cytokines and exosomes may account for these beneficial effects. In this review, we summarize the therapeutic mechanisms of MSCs in ARDS, analyzed the most recent animal experiments and Covid-19 clinical trial results, discussed the adverse effects and prospects in the recent studies, and highlight the potential roles of MSC therapy for Covid-19 patients with ARDS.

The Pattern of Liver Dysfunction in Patients with COVID-19: A Retrospective Study (preprint)

Background. Information about liver dysfunction in patients with COVID-19 is scarce. We aimed to explored the pattern and risk factors of liver dysfunction in patients with COVID-19.Methods. In this retrospective study, we included all consecutive confirmed patients with COVID-19 in Fuyang Second People’s Hospital between January 20 and February 25, 2020 and collected clinical characteristics until discharge. The pattern and risk factors of liver dysfunction, viral shedding and outcome were analyzed.Results. Totally, 146 patients were analyzed. The median age was 44.9 years and 54.1% were men, 43.8% patients presented liver dysfunction (22.6% on admission, 21.2% during hospitalization). The percentage of elevated ALT (15.1% on admission and 24.7% during hospitalization) were significantly higher than ALP (2.1% on admission and 3.4% during hospitalization) (P < 0.001). Four clinical types were identified, type 1 (persistent normal liver function, 56.2%), type 2 (normal liver function on admission developed to liver dysfunction during hospitalization, 21.2%), type 3 (liver dysfunction on admission restored to normal on discharge, 13.0%) and type 4 (persistent liver dysfunction, 9.6%). The median duration of viral shedding was 12.0 (type 1), 15.0 (type 2), 14.0 (type 3) and 18.0 (type 4) days (P < 0.001). Prolonged viral shedding and severity were potential risk factors associated with liver dysfunction. Conclusions. The incidence of liver dysfunction in patients with COVID-19 is common but not severe, which mainly due to SARS-CoV-2-mediated immune injury on hepatocyte rather than cholangiocyte, DILI and underlying chronic liver disease should not be neglect. 

Transmissibility of coronavirus disease 2019 (COVID-19) in Chinese cities with different transmission dynamics of imported cases (preprint)

BackgroundMonitoring the time-varying reproduction number (Rt) of the disease is useful in determining whether there is sustained transmission in a population. In this study, we examined Rt of COVID-19 and compared its transmissibility between different intervention periods in Hangzhou and Shenzhen. MethodsDaily aggregated counts of confirmed imported and local cases between January 1, 2020 and March 13, 2020 were analysed. A likelihood function was constructed to estimate Rt, accounting for imported cases. ResultsAlthough Hangzhou had fewer number of cases than Shenzhen, Shenzhen had higher proportion of imported cases than Hangzhou (83% vs 29%). Since the epidemic of COVID-19 in Shenzhen was dominated by imported cases, Rt was kept below unity through time. On the contrary, Rt was greater than unity in Hangzhou from 16 January to 7 February due to the surge in local cases. Credits to the Wuhan lockdown and outbreak response measures following the local lockdown, Rt decreased steadily and dropped below unity in mid-February. ConclusionThe lockdown measures and local outbreak responses helped reduce the potential of local transmission in Hangzhou and Shenzhen. Meanwhile, cities with similar epidemic trend could have different transmission dynamics given the variation in imported cases.