Virological features and pathogenicity of SARS-CoV-2 Omicron BA.2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.2 was a dominant circulating SARS-CoV-2 variant worldwide. Recent reports hint that BA.2 is similarly potent regarding antibody evasion but may be more transmissible than BA.1. The pathogenicity of BA.2 remains unclear and is of critical public health significance. Here we investigated the virological features and pathogenicity of BA.2 with in vitro and in vivo models. We show that BA.2 is less dependent on transmembrane protease serine 2 (TMPRSS2) for virus entry in comparison with BA.1 in vitro. In K18-hACE2 mice, BA.2 replicates more efficiently than BA.1 in the nasal turbinates and replicates marginally less efficiently in the lungs, leading to decreased body weight loss and improved survival. Our study indicates that BA.2 is similarly attenuated in lungs compared with BA.1 but is potentially more transmissible because of its better replication at the nasal turbinates.

Small Area Forecasting of Opioid-Related Mortality: Bayesian Spatiotemporal Dynamic Modeling Approach.

BACKGROUND: Opioid-related overdose mortality has remained at crisis levels across the United States, increasing 5-fold and worsened during the COVID-19 pandemic. The ability to provide forecasts of opioid-related mortality at granular geographical and temporal scales may help guide preemptive public health responses. Current forecasting models focus on prediction on a large geographical scale, such as states or counties, lacking the spatial granularity that local public health officials desire to guide policy decisions and resource allocation. OBJECTIVE: The overarching objective of our study was to develop Bayesian spatiotemporal dynamic models to predict opioid-related mortality counts and rates at temporally and geographically granular scales (ie, ZIP Code Tabulation Areas [ZCTAs]) for Massachusetts. METHODS: We obtained decedent data from the Massachusetts Registry of Vital Records and Statistics for 2005 through 2019. We developed Bayesian spatiotemporal dynamic models to predict opioid-related mortality across Massachusetts' 537 ZCTAs. We evaluated the prediction performance of our models using the one-year ahead approach. We investigated the potential improvement of prediction accuracy by incorporating ZCTA-level demographic and socioeconomic determinants. We identified ZCTAs with the highest predicted opioid-related mortality in terms of rates and counts and stratified them by rural and urban areas. RESULTS: Bayesian dynamic models with the full spatial and temporal dependency performed best. Inclusion of the ZCTA-level demographic and socioeconomic variables as predictors improved the prediction accuracy, but only in the model that did not account for the neighborhood-level spatial dependency of the ZCTAs. Predictions were better for urban areas than for rural areas, which were more sparsely populated. Using the best performing model and the Massachusetts opioid-related mortality data from 2005 through 2019, our models suggested a stabilizing pattern in opioid-related overdose mortality in 2020 and 2021 if there were no disruptive changes to the trends observed for 2005-2019. CONCLUSIONS: Our Bayesian spatiotemporal models focused on opioid-related overdose mortality data facilitated prediction approaches that can inform preemptive public health decision-making and resource allocation. While sparse data from rural and less populated locales typically pose special challenges in small area predictions, our dynamic Bayesian models, which maximized information borrowing across geographic areas and time points, were used to provide more accurate predictions for small areas. Such approaches can be replicated in other jurisdictions and at varying temporal and geographical levels. We encourage the formation of a modeling consortium for fatal opioid-related overdose predictions, where different modeling techniques could be ensembled to inform public health policy.

Chapter 14 - Vitamins and SARS-CoV-2

Vitamins are very important to stay healthy. Taking macronutrients and micronutrients based on the body’s needs prevents us from diseases and can treat them. Vitamins have proven to help deal with severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) patients. Vitamin C intake seems to boost immunity. Several studies suggested that vitamin C intake can lower the extent of upper respiratory tract infections (URTIs) besides its other biological functions such as collagen formation and wound healing. Vitamin C works as an anti-oxidant, counteracting the free radicals during an infection. Whenever an infection or disease occurs, it causes the production of reactive oxygen species, or such oxidizing agents help in the inactivation of viruses. Vitamin D is another important micronutrient to treat and prevent URTIs. Commonly, it is recommended for bone and teeth health, but it has also been used for regulating and boosting the immune system. Nutraceutical applications of vitamins are inevitable. Different natural products and foods are good sources of vitamins that can be taken for improved functions of the human body and treatment of diseases. Besides the oral route, vitamins C and D can also be supplied via micro or nanoparticles through other routes. An adequate intake of vitamins positively affects the body in the fight against infections. So, it can also help reduce the severity of illness and morbidity of patients suffering from SARS-CoV-2 infection.

Ultrasound combined with glial cell line-derived neurotrophic factor-loaded microbubbles for the targeted treatment of drug addiction.

Drug addiction is a serious problem globally, recently exacerbated by the COVID-19 pandemic. Glial cell-derived neurotrophic factor (GDNF) is considered a potentially effective strategy for the treatment of addiction. Previous animal experiments have proven that GDNF has a good therapeutic effect on drug addiction, but its clinical application is limited due to its poor blood-brain barrier (BBB) permeability. Low-frequency focused ultrasound, combined with microbubbles, is a non-invasive and reversible technique for locally-targeted BBB opening. In the present study, magnetic resonance imaging-guided low-frequency focused ultrasound, combined with GDNF microbubbles, was used to target BBB opening in the ventral tegmental area (VTA) region. The effects of GDNF on morphine-induced conditioned place preference (CPP) and acute withdrawal symptoms in rats after a partially opened BBB were evaluated by behavioral observation. Western blot was used to detect changes in tyrosine hydroxylase (TH) expression levels in the VTA region after different treatments, and high performance liquid chromatography was used to detect the changes in monoamine neurotransmitter content. The results showed that ultrasound combined with GDNF microbubbles targeted and opened the BBB in the VTA region, and significantly increased GDNF content, destroyed morphine-induced CPP, and reduced the withdrawal symptoms of morphine addiction in rats. Furthermore, the up-regulation of TH expression and the increase of norepinephrine and dopamine content induced by morphine were significantly reversed, and the increase of 5-hydroxytryptamine content was partially reversed. Therefore, ultrasound combined with GDNF microbubbles to target and open the BBB can effectively increase the content of central GDNF, thus playing a therapeutic role in morphine addiction. Our study provides a new approach to locally open the BBB and target delivery of neurotrophic factors, such as GDNF, to treat brain diseases like addiction.

Spike mutations contributing to the altered entry preference of SARS-CoV-2 omicron BA.1 and BA.2.

SARS-CoV-2 B.1.1.529.1 (Omicron BA.1) emerged in November 2021 and quickly became the predominant circulating SARS-CoV-2 variant globally. Omicron BA.1 contains more than 30 mutations in the spike protein, which contribute to its altered virological features when compared to the ancestral SARS-CoV-2 or previous SARS-CoV-2 variants. Recent studies by us and others demonstrated that Omicron BA.1 is less dependent on transmembrane serine protease 2 (TMPRSS2), less efficient in spike cleavage, less fusogenic, and adopts an altered propensity to utilize the plasma membrane and endosomal pathways for virus entry. Ongoing studies suggest that these virological features of Omicron BA.1 are in part retained by the subsequent Omicron sublineages. However, the exact spike determinants that contribute to these altered features of Omicron remain incompletely understood. In this study, we investigated the spike determinants for the observed virological characteristics of Omicron. By screening for the individual changes on Omicron BA.1 and BA.2 spike, we identify that 69-70 deletion, E484A, and H655Y contribute to the reduced TMPRSS2 usage while 25-27 deletion, S375F, and T376A result in less efficient spike cleavage. Among the shared spike mutations of BA.1 and BA.2, S375F and H655Y reduce spike-mediated fusogenicity. Interestingly, the H655Y change consistently reduces serine protease usage while increases the use of endosomal proteases. In keeping with these findings, the H655Y substitution alone reduces plasma membrane entry and facilitates endosomal entry when compared to SARS-CoV-2 WT. Overall, our study identifies key changes in Omicron spike that contributes to our understanding on the virological determinant and pathogenicity of Omicron.

CD8 T cells contribute to vaccine protection against SARS-CoV-2 in macaques.

Spike-specific neutralizing antibodies (NAbs) are generally considered key correlates of vaccine protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Recently, robust vaccine prevention of severe disease with SARS-CoV-2 variants that largely escape NAb responses has been reported, suggesting a role for other immune parameters for virologic control. However, direct data demonstrating a role of CD8+ T cells in vaccine protection have not yet been reported. In this study, we show that vaccine-elicited CD8+ T cells contribute substantially to virologic control after SARS-CoV-2 challenge in rhesus macaques. We vaccinated 30 macaques with a single immunization of the adenovirus vector-based vaccine Ad26.COV2.S or sham and then challenged them with 5 × 105 median tissue culture infectious dose SARS-CoV-2 B.1.617.2 (Delta) by the intranasal and intratracheal routes. All vaccinated animals were infected by this high-dose challenge but showed rapid virologic control in nasal swabs and bronchoalveolar lavage by day 4 after challenge. However, administration of an anti-CD8α- or anti-CD8ß-depleting monoclonal antibody in vaccinated animals before SARS-CoV-2 challenge resulted in higher levels of peak and day 4 virus in both the upper and lower respiratory tracts. These data demonstrate that CD8+ T cells contribute substantially to vaccine protection against SARS-CoV-2 replication in macaques.

Bacillus Calmette-Guérin-induced trained immunity protects against SARS-CoV-2 challenge in K18-hACE2 mice.

SARS-CoV-2 has been confirmed in over 450 million confirmed cases since 2019. Although several vaccines have been certified by the WHO and people are being vaccinated on a global scale, it has been reported that multiple SARS-CoV-2 variants can escape neutralization by antibodies, resulting in vaccine breakthrough infections. Bacillus Calmette-Guérin (BCG) is known to induce heterologous protection based on trained immune responses. Here, we investigated whether BCG-induced trained immunity protected against SARS-CoV-2 in the K18-hACE2 mouse model. Our data demonstrate that i.v. BCG (BCG-i.v.) vaccination induces robust trained innate immune responses and provides protection against WT SARS-CoV-2, as well as the B.1.617.1 and B.1.617.2 variants. Further studies suggest that myeloid cell differentiation and activation of the glycolysis pathway are associated with BCG-induced training immunity in K18-hACE2 mice. Overall, our study provides the experimental evidence that establishes a causal relationship between BCG-i.v. vaccination and protection against SARS-CoV-2 challenge.

Changes In Mental Health, Social Engagement, and Physical Activities During the COVID-19 Pandemic

The current COVID-19 pandemic has profoundly changed our behaviors and health, especially vulnerable community-dwelling older adults. This symposium includes three presentations that evaluated the pandemic’s impacts on mental health, social engagement and physical activity in healthy community-living older adults and those with dementia. Dr. Wenjun Li and his team examined the pandemic impact on mental health and social engagement among relatively healthy older adults residing in suburban and rural neighborhoods in Central Massachusetts, USA. The study reported significant variations in pandemic impacts by sex, age, race, income, living arrangement, and neighborhood housing density, suggesting the pandemic has had disproportionally negative impacts on socially and economically disadvantaged vulnerable older adults. Dr. W. Quin Yow and her team evaluated the impacts of government mandated social distancing and lockdowns on older adults with dementia and their caregivers in Singapore. The study found significant increases in irritability, aggression and hallucinations among older adults with dementia, and possible deterioration of health conditions and heightened moderate level of stress. The results suggest that social distancing may have resulted in negative outcomes in this vulnerable population with dementia and their caregivers. Dr. Ladda Thiamwong reported her team’s efforts on forming an international aging research collaborative to mitigate heath consequences of COVID-19 crisis from the international perspective. The team consists of ten scholars from five countries, including Hong Kong, Nepal, Singapore, Thailand, and the United States. They collect data using combinations of online and face-to-face surveys. Their important findings will be discussed in detail in this symposium.

Changes In Social Isolation, Anxiety and Depression Among Older Adults During The COVID-19 Pandemic

Social distancing and business lockdowns may have severe negative impact on daily living, mental and physical health of community-living older adults. Our Healthy Aging and Neighborhood Study surveyed 370 older adults in Central Massachusetts in 2020 and 2021. Participants were queried about pre-post pandemic changes in social and physical activities, mental and physical health, and lifestyle factors including food purchasing, diet and physical exercise;and attitude towards and receiving of vaccination. The study is ongoing and data are being accumulated. Preliminary analysis suggested that social distancing and lockdowns have negative impacted social engagement, communications with close friends, relatives and family members, food purchasing, frequency of outdoor exercises, especially group activities. The impact appeared to differ by sex, advancing age, and living arrangement. In summary, social distancing and business lockdowns may have negative impacts on most older adults while the impacts were more severe in those older and socioeconomically disadvantaged.

A novel linker-immunodominant site (LIS) vaccine targeting the SARS-CoV-2 spike protein protects against severe COVID-19 in Syrian hamsters.

The Coronavirus Disease 2019 (COVID-19) pandemic is unlikely to abate until sufficient herd immunity is built up by either natural infection or vaccination. We previously identified ten linear immunodominant sites on the SARS-CoV-2 spike protein of which four are located within the RBD. Therefore, we designed two linkerimmunodominant site (LIS) vaccine candidates which are composed of four immunodominant sites within the RBD (RBD-ID) or all the 10 immunodominant sites within the whole spike (S-ID). They were administered by subcutaneous injection and were tested for immunogenicity and in vivo protective efficacy in a hamster model for COVID-19. We showed that the S-ID vaccine induced significantly better neutralizing antibody response than RBD-ID and alum control. As expected, hamsters vaccinated by S-ID had significantly less body weight loss, lung viral load, and histopathological changes of pneumonia. The S-ID has the potential to be an effective vaccine for protection against COVID-19.

[Differential diagnosis of high altitude pulmonary edema and COVID-19 with computed tomography feature].

To investigate the computed tomography (CT) characteristics and differential diagnosis of high altitude pulmonary edema (HAPE) and COVID-19, CT findings of 52 cases of HAPE confirmed in Medical Station of Sanshili Barracks, PLA 950 Hospital from May 1, 2020 to May 30, 2020 were collected retrospectively. The size, number, location, distribution, density and morphology of the pulmonary lesions of these CT data were analyzed and compared with some already existed COVID-19 CT images which come from two files, "Radiological diagnosis of COVID-19: expert recommendation from the Chinese Society of Radiology (First edition)" and "A rapid advice guideline for the diagnosis and treatment of 2019 novel corona-virus (2019-nCoV) infected pneumonia (standard version)". The simple or multiple ground-glass opacity (GGO) lesions are located both in the HAPE and COVID-19 at the early stage, but only the thickening of interlobular septa, called "crazy paving pattern" belongs to COVID-19. At the next period, some increased cloudy shadows are located in HAPE, while lesions of COVID-19 are more likely to develop parallel to the direction of the pleura, and some of the lesions show the bronchial inflation. At the most serious stage, both the shadows in HAPE and COVID-19 become white, but the lesions of HAPE in the right lung are more serious than that of left lung. In summary, some cloudy shadows are the feature of HAPE CT image, and "crazy paving pattern" and "pleural parallel sign" belong to the COVID-19 CT, which can be used for differential diagnosis.