Improving mRNA vaccine safety and efficiency with cationized lipid nanoparticle formula (preprint)

The widespread use of Covid-19 mRNA vaccines has highlighted the need to address rare but concerning side effects. Systemic off-target gene expression has been identified as a primary cause of acute adverse reactions and side effects associated with nucleoside-modified mRNA vaccines. In this study, we incorporated the permanent cationic lipid Dotap component into the mRNA-LNP formula associated with the FDA-approved mRNA vaccine Comirnaty to create a novel positively charged LNP carrier for mRNA vaccine delivery. Using the optimized LNP formula to prepare SARS-Cov-2 Spike mRNA vaccines for immunogenicity testing, Balb/c mice exhibited improved immunogenicity kinetics with initial antibody titers being lower but showing a continuous upward trend, ultimately reaching levels comparable to those of control mRNA vaccines 8 weeks after boost immunization. The mRNA vaccines encapsulated in the modified LNPs have demonstrated a superior safety profile in respect to systemic delivery of LNP constituents, off-target gene expression, and the systemic pro-inflammatory stimulation. Consequently, it may represent a safer alternative of conventional mRNA-LNP vaccines.

LC-MS/MS-PRM Quantification of IgG Glycoforms Using Stable Isotope Labeled IgG1 Fc Glycopeptide Standard.

Targeted quantification of proteins is a standard methodology with broad utility, but targeted quantification of glycoproteins has not reached its full potential. The lack of optimized workflows and isotopically labeled standards limits the acceptance of glycoproteomics quantification. In this work, we introduce an efficient and streamlined chemoenzymatic synthesis of a library of isotopically labeled glycopeptides of IgG1 which we use for quantification in an energy optimized LC-MS/MS-PRM workflow. Incorporation of the stable isotope labeled N-acetylglucosamine enables an efficient monitoring of all major fragment ions of the glycopeptides generated under the soft higher-energy C-trap dissociation (HCD) conditions, which reduces the coefficients of variability (CVs) of the quantification to 0.7-2.8%. Our results document, for the first time, that the workflow using a combination of stable isotope labeled standards with intrascan normalization enables quantification of the glycopeptides by an electron transfer dissociation (ETD) workflow, as well as the HCD workflow, with the highest sensitivity compared to traditional workflows. This was exemplified by a rapid quantification (13 min) of IgG1 Fc glycoforms from COVID-19 patients.

Adverse reactions to inactivated COVID-19 vaccination in patients with chronic liver disease: The effect of anxiety.

Studies have shown that patients with chronic liver disease are at a higher risk of contracting novel coronavirus pneumonia than healthy individuals, and many guidelines state that patients with chronic liver disease should be prioritized for COVID-19 vaccination, but there are a few studies on its safety in CLD patients. We aimed to evaluate the safety of the inactivated COVID-19 vaccine in patients with chronic liver disease, and the effect of anxiety on adverse reactions. A questionnaire survey for self-administered post-vaccination adverse reaction monitoring was conducted from June 17, 2021, to August 11, 2021, in patients with chronic liver disease attending a tertiary care hospital in Taizhou, China. We analyzed the data from of a total of 160 participants who scanned the QR code on social media to respond to the questionnaire. The overall incidence of adverse reactions after COVID-19 vaccination in patients with chronic liver disease was 44.4% (71/160), and the most common adverse reaction was local injection site reaction, accounting for 80.3% of adverse reactions (57/71). No serious adverse reactions were reported. Approximately 53.1% of the patients had anxiety about vaccination, and 51.8% of those who felt anxious reported adverse reactions. The safety of COVID-19 vaccination in patients with chronic liver disease is good, and there is a strong association between adverse reactions and vaccine anxiety. Pre-vaccination education for patients with vaccine anxiety and psychological counseling may reduce reports of adverse reactions and improve patients' confidence in the vaccine.

Willingness of Older Adults with Chronic Diseases to Receive a Booster Dose of Inactivated Coronavirus Disease 2019 Vaccine: A Cross-Sectional Study in Taizhou, China.

Vaccination is an important measure to control the spread of COVID-19 among elderly high-risk groups; however, the propensity to receive COVID-19 vaccine boosters has not been evaluated in these populations. Here, we aimed to investigate the willingness to receive a COVID-19 vaccine booster among the elderly chronic disease population in Taizhou, China. A cross-sectional, hospital-based survey was conducted in the outpatient department of a tertiary care hospital between 6 July and 11 August 2021 in Taizhou, China, and the data were uploaded to Wen-Juan-Xing, one of the largest online platforms used to collect survey data in China. The targeted population was non-oncology chronic disease patients aged 60 years and above. The minimum sample size was 229, determined by the G*Power software (v3.1.9.2, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany). A total of 254 patients with valid data were enrolled in this study, with a response rate of 82.5% (254/308). Chi-square tests and one-way binary regression were used to compare the proportions and the degree of influence of categorical factors. The magnitude of the effect for the comparisons was measured by Gramer's V. A multivariate binary logistic regression model was used to correct for confounders and to identify factors. All data were analyzed using SPSS v24.0 (IBM Corporation, Armonk, NY, USA). A total of 198 respondents (77.9%) were willing to receive a COVID-19 vaccine booster dose, and 77.6% of respondents were willing to receive the primary dose. Age < 70 years (OR 2.82), stable disease control (OR 2.79), confidence in the effectiveness of the COVID-19 vaccine (OR 3.11), and vaccine recipient (OR 5.02) were significantly associated with the willingness to receive a COVID-19 vaccine booster dose. Promoting primary dose vaccination is essential for advancing booster vaccination, and it is important to focus on elderly patients' confidence in the vaccine, in addition to strengthening health management and promoting disease stability. Follow-up studies should focus on elderly patients who belong to specific disease groups.

Relationship between knowledge, attitudes, and practices and COVID-19 vaccine hesitancy: A cross-sectional study in Taizhou, China.

Objective: This study aimed to explore COVID-19 vaccine hesitancy in Chinese adults and analyzed the relationship between knowledge, attitudes, practices (KAP), and COVID-19 vaccine hesitancy. Methods: A population-based self-administered online survey was conducted in Taizhou, China to evaluate the population's hesitancy to receive COVID-19 vaccination. A total of 2.463 adults received the invitation for the survey through WeChat (A Chinese app that is used for chat, social media, and mobile payment), and 1.788 interviewees answered the structured questionnaire. The overall response rate was 72.6%. Results: Total 45.2% of people were hesitant about the COVID-19 vaccination. Using binary logistic regression analysis, we found low perception of safety (Model 3: Odds ratio = 2.977, Confidence interval: 2.237-3.963) and efficacy (Model 3: OR = 1.904, 95%CI: 1.462-2.479) of the COVID-19 vaccine in adults is the most important risk factor for COVID-19 vaccine hesitation. People who know more about COVID-19 vaccination are less hesitant (Model 2: OR = 0.967, 95% CI: 0.951-0.983). People who did not seek information independently about the COVID-19 vaccine are more likely to be skeptical (Model 4: OR = 1.300, 95% CI: 1.058-1.598, P = 0.013). Conclusion: In China, the population had higher levels of COVID-19 vaccine hesitation, and their knowledge of the COVID-19 vaccine, perceptions of safety and efficacy, and physical health status were significantly associated with vaccine hesitation. These results provide ideas for promoting COVID-19 vaccination and intervention and have far-reaching implications for further strengthening research on vaccine hesitancy in COVID-19 and exploring strategies for COVID-19 vaccine promotion.

An ASIP for Neural Network Inference on Embedded Devices with 99% PE Utilization and 100% Memory Hidden under Low Silicon Cost.

The computation efficiency and flexibility of the accelerator hinder deep neural network (DNN) implementation in embedded applications. Although there are many publications on deep neural network (DNN) processors, there is still much room for deep optimization to further improve results. Multiple dimensions must be simultaneously considered when designing a DNN processor to reach the performance limit of the architecture, including architecture decision, flexibility, energy efficiency, and silicon cost minimization. Flexibility is defined as the ability to support as many multiple networks as possible and to easily adjust the scale. For energy efficiency, there are huge opportunities for power efficiency optimization, which involves access minimization and memory latency minimization based on on-chip memory minimization. Therefore, this work focused on low-power and low-latency data access with minimized silicon cost. This research was implemented based on an ASIP (application specific instruction set processor) in which an ISA was based on the caffe2 inference operator and the hardware design was based on a single instruction multiple data (SIMD) architecture. The scalability and system performance of our SoC extension scheme were demonstrated. The VLIW was used to execute multiple instructions in parallel. All costs for data access time were thus eliminated for the convolution layer. Finally, the processor was synthesized based on TSMC 65 nm technology with a 200 MHz clock, and the Soc extension scheme was analyzed in an experimental model. Our design was tested on several typical neural networks, achieving 196 GOPS at 200 MHz and 241 GOPS/W on the VGG16Net and AlexNet.

The impact of the Omicron epidemic on the health behavior in Cape Town, South Africa.

Background: South Africa was the first country with a case of Omicron variant infection diagnosed; therefore, this study aimed to elucidate the impact of the Omicron mutant strain outbreak on the health behavior of the South African population and encourage the population to adopt timely protective behaviors against Omicron mutant strain infection. Study design and methods: This was a population-based, cross-sectional study conducted in Cape Town, South Africa, in December 2021. We distributed 300 questionnaires to adults aged >18 years, and they were all returned. Results: Of the South African population, 60.3% expressed a high level of concern regarding Omicron; 89.3% improved on at least one of the following three health behaviors: mask-wearing, washing hands, and reducing socialization; and only 10.7% exhibited no improvement in health behaviors. Of these, 71.3% and 57.0% increased the length of time they wore a mask and washed their hands, respectively, and 47% decreased the number of times they socialized. Age, residence, education level, chronic disease, and whether they had received the COVID-19 vaccine were significantly different (p < 0.05) between the presence and absence of enhanced health behaviors. The levels of concern and knowledge regarding the Omicron virus significantly influenced health-behavior change (all P < 0.05). Conclusion: There has been a positive change in the South African population toward adopting mask-wearing, hand washing, and reducing socialization in response to the Omicron virus strain epidemic. Based on one health approach, it is important to focus on populations with chronic diseases, those who have not yet received the COVID-19 vaccine, and other populations with low rates of health behavior change.

Genetic Predisposition to Coronavirus Disease 2019 in Relation to Ten Cardiovascular Conditions: A Two-Sample Mendelian Randomization Study.

BACKGROUND: The long-term health consequences of coronavirus disease 2019 (COVID-19) remain largely unclear. This study aimed to apply the Mendelian randomization (MR) design to estimate the causal associations between COVID-19 and ten cardiovascular conditions. METHODS: Single-nucleotide polymorphisms (SNPs) associated with COVID-19 were used as instrumental variables to estimate the causal effect of COVID-19 on ten cardiovascular conditions. The random-effects inverse-variance weighted (IVW) method was conducted for the main analyses with a complementary analysis of the weighted median and MR-Egger approaches. RESULTS: In the IVW analysis, genetically predicted COVID-19 was suggestively associated with major coronary heart disease events (OR 1.081; 95% CI 1.007-1.16; P = 0.045) and heart failure (OR 1.049; 95% CI 1.001-1.1; P = 0.045) with similar estimates in weighted median regressions. No directional pleiotropic effects were observed in both funnel plots and MR-Egger intercepts. CONCLUSIONS: Our findings provide direct evidence that patients infected with COVID-19 are causally associated with increased risk of cardiovascular disease, especially for major coronary heart disease events and heart failure.

Comparison of Mental Health Symptom Changes from pre-COVID-19 to COVID-19 by Sex or Gender: A Systematic Review and Meta-analysis (preprint)

Background: Women and gender-diverse individuals face disproportionate socioeconomic burden during COVID-19. We compared mental health symptom changes since pre-COVID-19 by sex or gender. Methods: We searched MEDLINE, PsycINFO, CINAHL, EMBASE, Web of Science, China National Knowledge Infrastructure, Wanfang, medRxiv, and Open Science Framework December 31, 2019 to March 22, 2021 for studies that reported mental health outcomes prior to and during COVID-19 by sex or gender. We conducted restricted maximum-likelihood random-effects meta-analyses. Results: All 11 included studies (9 unique cohorts) compared females or women to males or men; none included gender-diverse individuals. Continuous symptom change differences were not statistically significant for depression (standardized mean difference [SMD]= 0.15, 95% CI -0.09 to 0.39; 3 studies, 4,159 participants; I2=77%) and stress (SMD= -0.09, 95% CI -0.21 to 0.02; 3 studies, 1,217 participants; I2=0%), but anxiety (SMD= 0.14, 95% CI 0.01 to 0.26; 3 studies, 4,028 participants; I2=34%) and general mental health (SMD= 0.15, 95% CI 0.12 to 0.18; 2 studies, 15,590 participants; I2=0%) worsened more among females or women than males or men. There were no significant differences in changes in proportion above a cut-off: anxiety (difference= 0.00, 95% CI -0.01 to 0.02; 2 studies, 6,684 participants; I2=0%), depression (difference= 0.12, 95% CI -0.04 to 0.28; 1 study, 217 participants), general mental health (difference= -0.03, 95% CI -0.09 to 0.04; 3 studies, 18,985 participants; I2=94%), stress (difference= 0.04, 95% CI -0.11 to 0.18; 1 study, 217 participants). Interpretation: Mental health outcomes did not differ or were somewhat worse among women than men.

Comparison of Mental Health Symptoms prior to and during COVID-19: Evidence from a Living Systematic Review and Meta-analysis (preprint)

ABSTRACT Objectives The rapid pace, high volume, and limited quality of mental health evidence being generated during COVID-19 poses a barrier to effective decision-making. The objective of the present report is to compare mental health outcomes assessed during COVID-19 to outcomes prior to COVID-19 in the general population and other population groups. Design Living systematic review. Data Sources MEDLINE (Ovid), PsycINFO (Ovid), CINAHL (EBSCO), EMBASE (Ovid), Web of Science Core Collection: Citation Indexes, China National Knowledge Infrastructure, Wanfang, medRxiv (preprints), and Open Science Framework Preprints (preprint server aggregator). The initial search was conducted on April 13, 2020 with ongoing weekly updates. Eligibility criteria for selecting studies For this report, we included studies that compared general mental health, anxiety symptoms, or depression symptoms, assessed January 1, 2020 or later, to the same outcomes collected between January 1, 2018 and December 31, 2019. We required ≥ 90% of participants pre-COVID-19 and during COVID-19 to be the same or the use of statistical methods to address missing data. For population groups with continuous outcomes for at least three studies in an outcome domain, we conducted restricted maximum-likelihood random-effects meta-analyses. Results As of March 22, 2021, we had identified 36 unique eligible studies with data from 33 cohorts. All reported COVID-19 outcomes between March and June 2020, and 3 studies also reported outcomes between September and November 2020. Estimates of changes in general mental health were close to zero in the general population (standardized mean difference [SMD] = 0.02, 95% CI -0.11 to 0.16, I 2 = 94.6%; 4 studies, N = 19,707) and among older adults (SMD = 0.02, 95% CI -0.11 to 0.16, I 2 = 90.4%; 4 studies, N = 5,520) and university students (SMD = -0.01, 95% CI -0.33 to 0.30, I 2 = 92.0%; 3 studies, N = 3,372). Changes in anxiety symptoms were close to zero and not statistically significant in university students (SMD = 0.00, 95% CI - 0.35 to 0.36, I 2 = 95.4%; 5 studies, N = 1,537); women or females (SMD = 0.02, 95% CI -0.35 to 0.39, I 2 = 92.3%; 3 studies, N = 2,778); and men or males (SMD = 0.07, 95% CI -0.01 to 0.15; I 2 = 0.01%; 3 studies, N = 1,250); anxiety symptoms increased, however, among people with pre-existing medical conditions (SMD = 0.27, 95% CI 0.01 to 0.54, I 2 = 91.0%; 3 studies, N = 2,053). Changes in depression symptoms were close to zero or small and not statistically significant among university students (SMD = 0.19, 95% CI -0.08 to 0.45, I 2 = 91.8%; 5 studies, N = 1,537); people with pre-existing medical conditions (SMD = 0.01, 95% CI -0.15 to 0.17, I 2 = 14.9%; 3 studies, N = 2,006); women or females (SMD = 0.21, 95% CI -0.14 to 0.55, I 2 = 91.2%; 3 studies, N = 2,843); and men or males (SMD = 0.00, 95% CI -0.21 to 0.22; I 2 = 92.3%; 4 studies, N = 3,661). In 3 studies with data from both March to June 2020 and September to November 2020, symptoms were unchanged from pre-COVID-19 at both time points or there were increases at the first assessment that had largely dissipated by the second assessment. Conclusions Evidence does not suggest a widespread negative effect on mental health symptoms in COVID-19, although it is possible that gaps in data have not allowed identification of changes in some vulnerable groups. Continued updating is needed as evidence accrues. Funding Canadian Institutes of Health Research (CMS-171703; MS1-173070); McGill Interdisciplinary Initiative in Infection and Immunity Emergency COVID-19 Research Fund (R2-42). Registration PROSPERO (CRD42020179703); registered on April 17, 2020.

Effects of COVID-19 Mental Health Interventions among Community-based Children, Adolescents, and Adults: A Living Systematic Review of Randomised Controlled Trials (preprint)

Background: Scalable interventions to address COVID-19 mental health are needed. Our objective was to assess effects of mental health interventions for community-based children, adolescents, and adults. Methods: We searched 9 databases (2 Chinese-language) from December 31, 2019 to March 22, 2021. We included randomised controlled trials with non-hospitalised, non-quarantined participants of interventions to address COVID-19 mental health challenges. We synthesized results descriptively but did not pool quantitatively due to substantial heterogeneity of populations and interventions and concerns about risk of bias. Findings: We identified 9 eligible trials, including 3 well-conducted, well-reported trials that tested interventions designed specifically for COVID-19 mental health challenges, plus 6 trials of standard interventions (e.g., individual or group therapy, expressive writing, mindfulness recordings) minimally adapted for COVID-19, all with risk of bias concerns. Among the 3 COVID-19-specific intervention trials, one (N = 670) found that a self-guided, internet-based cognitive-behavioural intervention targeting dysfunctional COVID-19 worry significantly reduced COVID-19 anxiety (standardized mean difference [SMD] 0.74, 95% CI 0.58 to 0.90) and depression symptoms (SMD 0.38, 95% CI 0.22 to 0.55) in Swedish general population participants. A lay-delivered telephone intervention for homebound older adults in the United States (N = 240) and a peer-moderated education and support intervention for people with a rare autoimmune condition from 12 countries (N = 172) significantly improved anxiety (SMD 0.35, 95% CI 0.09 to 0.60; SMD 0.31, 95% CI 0.03 to 0.58) and depressive symptoms (SMD 0.31, 95% CI 0.05 to 0.56; SMD 0.31, 95% CI 0.07 to 0.55) 6-weeks post-intervention, but these were not significant immediately post-intervention. No trials in children or adolescents were identified. Interpretation: Internet-based programs for the general population and lay- or peer-delivered interventions for vulnerable groups may be effective, scalable options for public mental health in COVID-19. More well-conducted trials, including for children and adolescents, are needed.