BENEFIT-RISK ASSESSMENT OF COVID-19 VACCINE, MRNA (MRNA-1273) FOR MALES AGE 18-64 YEARS (preprint)

Since authorization of the Moderna mRNA COVID-19 Vaccine, real-world evidence has indicated its effectiveness in preventing COVID-19 cases. However, increased cases of mRNA vaccine-associated myocarditis/pericarditis have been reported, predominantly in young adults and adolescents. The Food and Drug Administration conducted benefit-risk assessment to inform review of the Biologics License Application for use of the Moderna vaccine among individuals ages 18 years and older. We modeled benefit-risk per million individuals who receive two complete doses of the vaccine. Benefit endpoints were vaccine-preventable COVID-19 cases, hospitalizations, intensive care unit (ICU) admissions, and deaths. The risk endpoints were vaccine-related myocarditis/pericarditis cases, hospitalizations, ICU admissions and deaths. The analysis was conducted on the age-stratified male population, due to data signals and previous work showing males to be the main risk group. We constructed six scenarios to evaluate the impact of uncertainty associated with pandemic dynamics, vaccine effectiveness (VE) against novel variants, and rates of vaccine-associated myocarditis/pericarditis cases on the model results. For our most likely scenario, we assumed the US COVID-19 incidence was for the week of December 25, 2021, and a VE of 30% against cases and 72% against hospitalization with the Omicron-dominant strain. Our source for estimating vaccine-attributable myocarditis/pericarditis rates was FDA's CBER Biologics Effectiveness and Safety (BEST) System databases. Overall, our results supported the conclusion that the benefits of the vaccine outweigh its risks. Remarkably, we predicted vaccinating one million 18-25 year-old males would prevent 82,484 cases, 4,766 hospitalizations, 1,144 ICU admissions, and 51 deaths due to COVID-19, comparing to 128 vaccine-attributable myocarditis/pericarditis cases, 110 hospitalizations, zero ICU admissions, and zero deaths. Uncertainties in the pandemic trajectory, effectiveness of vaccine against novel variants, and vaccine-attributable myocarditis/pericarditis rate are important limitations of our analysis. Also, the model does not evaluate potential long-term adverse effects due to either COVID-19 or vaccine-attributable myocarditis/pericarditis.

Individual bat viromes reveal the co-infection, spillover and emergence risk of potential zoonotic viruses (preprint)

Bats are reservoir hosts for many zoonotic viruses. Despite this, relatively little is known about the diversity and abundance of viruses within bats at the level of individual animals, and hence the frequency of virus co-infection and inter-species transmission. Using an unbiased meta-transcriptomics approach we characterised the mammalian associated viruses present in 149 individual bats sampled from Yunnan province, China. This revealed a high frequency of virus co-infection and species spillover among the animals studied, with 12 viruses shared among different bat species, which in turn facilitates virus recombination and reassortment. Of note, we identified five viral species that are likely to be pathogenic to humans or livestock, including a novel recombinant SARS-like coronavirus that is closely related to both SARS-CoV-2 and SARS-CoV, with only five amino acid differences between its receptor-binding domain sequence and that of the earliest sequences of SARS-CoV-2. Functional analysis predicts that this recombinant coronavirus can utilize the human ACE2 receptor such that it is likely to be of high zoonotic risk. Our study highlights the common occurrence of inter-species transmission and co-infection of bat viruses, as well as their implications for virus emergence.

Association between delayed surgery and survival in early-stage cervical cancer in mainland China: Implications during the coronavirus pandemic (preprint)

Objective: The COVID-19 pandemic has had a significant impact on oncogynecologic patients worldwide, particularly with respect to delayed diagnosis and treatment. During the COVID-19 pandemic, few studies have examined the impact of delayed surgery on survival in early-stage cervical cancer patients. The purpose of this study was to determine the effect of delayed surgical time on survival in patients with early cervical cancer. Design A retrospective cohort study. Setting A single general hospital in Shaanxi, Northwest China. Population A total of 1207women with early cervical cancer were recruited between April 2013 and December 2018 in Mainland China and followed up until 29 Feb 2022. Methods This retrospective cohort study was conducted in a comprehensive tertiary hospital in Shaanxi, Xi’an, China. We used a Cox proportional hazard model with delay time in weeks as a categorical variable to analyse the effect of surgical delay time on survival. Main Outcome Measures The 5-year overall and disease-free survival were used as the primary outcome measures. Results A total of 800 participants were included in the final cohort. In the multivariate Cox regression analysis (median follow-up, 58 months), patients in the long delay time group had DFS (5-year rates, 91.5% versus 90.9%, HR 0.99, 95% CI 0.62~1.59, P=0.98) and OS (5-year rates of 92.9% versus 90.8%, HR 0.68, 95% CI 0.42~1.10, P=0.11) similar to those in the short delay time group. Conclusions Our findings indicate that a 12-week delay in surgery is not associated with long-term survival in women with early-stage cervical cancer.

New insights into price drivers of crude oil futures markets: Evidence from quantile ARDL approach (preprint)

This paper investigates the cointegration between possible determinants of crude oil futures prices during the COVID-19 pandemic period. We perform comparative analysis of WTI and newly-launched Shanghai crude oil futures (SC) via the Autoregressive Distributed Lag (ARDL) model and Quantile Autoregressive Distributed Lag (QARDL) model. The empirical results confirm that economic policy uncertainty, stock markets, interest rates and coronavirus panic are important drivers of WTI futures prices. Our findings also suggest that the US and China's stock markets play vital roles in movements of SC futures prices. Meanwhile, CSI300 stock index has a significant positive short-run impact on SC futures prices while S\&P500 prices possess a positive nexus with SC futures prices both in long-run and short-run. Overall, these empirical evidences provide practical implications for investors and policymakers.

A Quantitative Evaluation of COVID-19 Epidemiological Models (preprint)

Quantifying how accurate epidemiological models of COVID-19 forecast the number of future cases and deaths can help frame how to incorporate mathematical models to inform public health decisions. Here we analyze and score the predictive ability of publicly available COVID-19 epidemiological models on the COVID-19 Forecast Hub. Our score uses the posted forecast cumulative distributions to compute the log-likelihood for held-out COVID-19 positive cases and deaths. Scores are updated continuously as new data become available, and model performance is tracked over time. We use model scores to construct ensemble models based on past performance. Our publicly available quantitative framework may aid in improving modeling frameworks, and assist policy makers in selecting modeling paradigms to balance the delicate trade-offs between the economy and public health.

Combined metabolic cofactor supplementation accelerates recovery in mild-to-moderate COVID-19 (preprint)

BACKGROUND The characteristics of COVID-19 outbreak and high fatality rate of COVID-19 infection have attracted the attention of scientists due to the strong interactions between components of metabolic syndrome, metabolic abnormalities, and viral pathobiology of COVID-19. Combined metabolic cofactors supplementation (CMCS) consisting of L-serine, N-acetyl-L-cysteine (NAC), nicotinamide riboside (NR), and L-carnitine tartrate is being studied for the treatment of patients with COVID-19. METHODS We conducted a placebo-controlled, phase-2 clinical trial involving ambulatory COVID-19 patients. A total of 100 patients were randomly assigned on a 3:1 basis to hydroxychloroquine plus CMCS or hydroxychloroquine plus placebo. The total treatment period for the hydroxychloroquine was 5 days, and for the CMCS/placebo was 14 days. Clinical status was evaluated daily by phone, using a binomial scale for subject reported presence or absence for multiple COVID-19 related symptoms. Plasma samples for clinical chemistry analyses were collected on day 0 and day 14. RESULTS A total of 93 patients completed the trial. The combination of CMCS and hydroxychloroquine significantly reduced the average complete recovery time compared with hydroxychloroquine and placebo (6.6 days vs 9.3 days, respectively). Moreover, there was a significant reduction in ALT, AST and LDH levels on day 14 compared to day 0 in the hydroxychloroquine plus CMCS group. The adverse effects were uncommon and self-limiting. CONCLUSIONS In patients with mild-to-moderate COVID-19, CMCS resulted in a significant reduction in recovery time and liver enzymes associated with hepatic function compared to placebo. We observed that CMSC is associated with a low incidence of adverse events.

Effect of Thymoquinone on Acute Kidney Injury Induced by Sepsis in BALB/c Mice.

Acute kidney injury (AKI) is a common complication of sepsis and has also been observed in some patients suffering from the new coronavirus pneumonia COVID-19, which is currently a major global concern. Thymoquinone (TQ) is one of the most active ingredients in Nigella sativa seeds. It has a variety of beneficial properties including anti-inflammatory and antioxidative activities. Here, we investigated the possible protective effects of TQ against kidney damage in septic BALB/c mice. Eight-week-old male BALB/c mice were divided into four groups: control, TQ, cecal ligation and puncture (CLP), and TQ+CLP. CLP was performed after 2 weeks of TQ gavage. After 48 h, we measured the histopathological alterations in the kidney tissue and the serum levels of creatinine (CRE) and blood urea nitrogen (BUN). We also evaluated pyroptosis (NLRP3, caspase-1), apoptosis (caspase-3, caspase-8), proinflammatory (TNF-α, IL-1ß, and IL-6)-related protein and gene expression levels. Our results demonstrated that TQ inhibited CLP-induced increased serum CRE and BUN levels. It also significantly inhibited the high levels of NLRP3, caspase-1, caspase-3, caspase-8, TNF-α, IL-1ß, and IL-6 induced by CLP. Furthermore, NF-κB protein level was significantly decreased in the TQ+CLP group than in the CLP group. Together, our results indicate that TQ may be a potential therapeutic agent for sepsis-induced AKI.

The treatment and follow-up of 'recurrence' with discharged COVID-19 patients: data from Guizhou, China.

We reported 20 cases of discharged COVID-19 patients whose RT-PCR test results showed 're-positive'. After finding 're-positive', these patients were admitted to hospital for the second time and were followed up until the end of May 2020. We recorded detailed treatment and follow-up process, and collected relevant data. The possible causes and potential clinical significance of this phenomenon are discussed.

Serum calcium as a biomarker of clinical severity and prognosis in patients with coronavirus disease 2019.

The aim of this study was to investigate the correlations between serum calcium and clinical outcomes in patients with coronavirus disease 2019 (COVID-19). In this retrospective study, serum calcium levels, hormone levels and clinical laboratory parameters on admission were recorded. The clinical outcome variables were also recorded. From February 10 to February 28, 2020, 241 patients were enrolled. Of these patients, 180 (74.7%) had hypocalcemia on admission. The median serum calcium levels were 2.12 (IQR, 2.04-2.20) mmol/L, median parathyroid hormone (PTH) levels were 55.27 (IQR, 42.73-73.15) pg/mL, and median 25-hydroxy-vitamin D (VD) levels were 10.20 (IQR, 8.20-12.65) ng/mL. The serum calcium levels were significantly positively correlated with VD levels (P =0.004) but negatively correlated with PTH levels (P =0.048). Patients with lower serum calcium levels (especially ≤2.0 mmol/L) had worse clinical parameters, higher incidences of organ injury and septic shock, and higher 28-day mortality. The areas under the receiver operating characteristic curves of multiple organ dysfunction syndrome, septic shock, and 28-day mortality were 0.923 (P <0.001), 0.905 (P =0.001), and 0.929 (P <0.001), respectively. In conclusion, serum calcium was associated with the clinical severity and prognosis of patients with COVID-19. Hypocalcemia may be associated with imbalanced VD and PTH levels.

An Interactive Data Visualization and Analytics Tool to Evaluate Mobility and Sociability Trends During COVID-19 (preprint)

The COVID-19 outbreak has dramatically changed travel behavior in affected cities. The C2SMART research team has been investigating the impact of COVID-19 on mobility and sociability. New York City (NYC) and Seattle, two of the cities most affected by COVID-19 in the U.S. were included in our initial study. An all-in-one dashboard with data mining and cloud computing capabilities was developed for interactive data analytics and visualization to facilitate the understanding of the impact of the outbreak and corresponding policies such as social distancing on transportation systems. This platform is updated regularly and continues to evolve with the addition of new data, impact metrics, and visualizations to assist public and decision-makers to make informed decisions. This paper presents the architecture of the COVID related mobility data dashboard and preliminary mobility and sociability metrics for NYC and Seattle.

The Impact of Isolation on the Transmission of COVID-19 and Estimation of Potential Second Epidemic in China (preprint)

The first case of Corona Virus Disease 2019 (COVID-19) was reported in Wuhan, China in December 2019. Since then, COVID-19 has quickly spread out to all provinces in China and over 150 countries or territories in the world. With the first level response to public health emergencies (FLRPHE) launched over the country, the outbreak of COVID-19 in China is achieving under control in China. We develop a mathematical model based on epidemiology of COVID-19, incorporating the isolation of healthy people, confirmed cases and close contacts. We calculate the basic reproduction numbers 2.5 in China (excluding Hubei province) and 2.9 in Hubei province with the initial time on January 30 which show the severe infectivity of COVID-19, and verify that the current isolation method effectively contains the transmission of COVID-19. Under the isolation of healthy people, confirmed cases and close contacts, we find a noteworthy phenomenon that is the potential second epidemic of COVID-19, and estimate the peak time and value and the cumulative number of cases. Simulations show that the isolation of close contacts tracked measure can efficiently contain the transmission of the potential second epidemic of COVID-19. With isolation of all susceptible people or all infected people or both, there is no potential second epidemic of COVID-19. Furthermore, resumption of work and study can increase the transmission risk of the potential second epidemic of COVID-19.

Serum calcium as a biomarker of clinical severity and prognosis in patients with coronavirus disease 2019: a retrospective cross-sectional study (preprint)

Background: To investigate the correlations between serum calcium and clinical severity and outcomes in patients with coronavirus disease 2019 (COVID-19).Methods: In this clinical retrospective study, the levels of serum calcium, hormone levels and clinical laboratory parameters of admission were recorded. The clinical severity and outcome variables were also recorded.Results: From February 10 to February 28 2020, 241 patients were enrolled in this study. Of these patients, 180 (74.7%) had hypocalcemia on admission. The median serum calcium levels were 2.12 (IQR, 2.04-2.20) mmol/L, median parathyroid hormone (PTH) levels were 55.27 (IQR, 42.73-73.15) pg/mL, median 25-hydroxy-vitamin D (VD) levels were 10.20 (IQR, 8.20-12.65) ng/mL. The serum calcium levels were significantly positive correlated with VD levels (P =0.004), whereas negative correlated with PTH levels (P = 0.048). Patients with lower serum calcium levels (especially ≤2.0 mmol/L) had worse clinical parameters, higher incidence of organ injury septic shock and higher 28-day mortality. The areas under the receiver operating characteristic curves of multiple organ dysfunction syndrome, septic shock, and 28-day mortality were 0.923 (P <0.001), 0.905 (P =0.001), and 0.929 (P <0.001), respectively. The overall mortality of COVID-19 was 4.1% (10/241), whereas the mortality of critical patients was up to 40.0% (10/25). Conclusions: Serum calcium was associated with clinical severity and prognosis of patients with COVID-19. Hypocalcemia may be associated with imbalanced VD and PTH.

A COVID-19 Case Report from Asymptomatic Contact: Implication for Contact Isolation and Incubation Management (preprint)

An outbreak caused by coronavirus disease 2019 (COVID-19) occurred in Wuhan City, Hubei Province, China, in December 2019. Up to March 2, 2020, at least 80180 cases have been reported. Most of the patients had a history of visiting Hubei Province or contacting with people who had ever stayed in or passed by Hubei Province, or exposed to symptoms. Some patients got infected only from asymptomatic contacts. This study aimed to report the epidemic features and lab identification of a patient confirmed with COVID-19 infection only from asymptomatic contact.