Treatment and outcomes of 95 post-Covid patients with an antidepressant and neurobiological explanations (preprint)

After Covid-19 infection, 12.5% develop a post-Covid-syndrome. Symptoms affect numerous organ systems, but after one year they are mainly neurological and neuropsychiatric in nature. There is evidence that treatment with selective serotonin reuptake inhibitors (SSRIs) during Covid-19 infection decreases the likelihood of a post-Covid condition, but there is no known research on treating post-Covid syndrome itself with SSRIs. This study used an exploratory questionnaire and found that 63,4% of 95 post-Covid syndrome patients reported a reasonably good to strong response to an SSRI. Outcomes were measured with three different measures that correlated strongly with each other. Brainfog and sensory overload decreased the most. Patients experienced improved well-being. The response to SSRIs in post-Covid conditions was explained by seven possible neurobiological mechanisms as reported in the recent literature. The promising results of this study should be followed by a randomized controlled trial.

Analytical Insights Into the Spread of an Epidemic through Joint Modeling of Disease Dynamics and Attitudes towards Prophylactic Measures and Vaccines (preprint)

In this age of mass media and, in particular, social media-driven perception of reality, coupling disease and prophylactic opinion dynamics models can provide better insights into disease evolution than using a disease model alone. We develop in this work two disease-opinion dynamics models based on the epidemiology of the new coronavirus disease (COVID-19) and the availability or not of imperfect vaccines. We assume that susceptibility to infection decreases with the level of prophylactic attitude (personal hygiene, social distancing), and changes in prophylactic attitudes of susceptible individuals occur in response to perceived disease prevalence and vaccination coverage and efficacy in the population. We derive and discuss the disease-free equilibriums and reproduction numbers in the introduced models. We further assess the impacts of the distribution of opinions at disease introduction, the ability to detect presymptomatic, asymptomatic and symptomatic positive COVID-19 cases, the behavioural responses to the outbreak and the introduction of vaccination, and the effects of distortions of disease prevalence by public policy and mass media on disease dynamics. The insights highlighted from the proposed models are expected to make informative contributions to public policy in a context of opinion fluxes in response to perceived disease prevalence.

Development of a novel angiotensin converting enzyme 2 stimulator with broad implications in SARS-CoV2 and type 1 diabetes (preprint)

Angiotensin-converting enzyme 2 (ACE2) is protective in cardiovascular disease, lung injury and diabetes yet paradoxically underlies our susceptibility to SARs-CoV2 infection and the fatal heart and lung disease it can induce. Furthermore, diabetic patients have chronic, systemic inflammation and altered ACE2 expression resulting in increased risk of severe COVID-19 and the associated mortality. A drug that could increase ACE2 activity and inhibit cellular uptake of severe acute respiratory syndrome coronavirus 2 (SARs-CoV2), thus decrease infection, would be of high relevance to cardiovascular disease, diabetes and SARs-CoV2 infection. While the need for such a drug lead was highlighted over a decade ago receiving over 600 citations,1 to date, no such drugs are available.2 Here, we report the development of a novel ACE2 stimulator, designated ‘2A’(international PCT filed), which is a 10 amino acid peptide derived from a snake venom, and demonstrate its in vitro and in vivo efficacy against SARs-CoV2 infection and associated lung inflammation. Peptide 2A also provides remarkable protection against glycaemic dysregulation, weight loss and disease severity in a mouse model of type 1 diabetes. No untoward effects of 2A were observed in these pre-clinical models suggesting its strong clinical translation potential. 

Cross-sectional Ct distributions from qPCR tests can provide an early warning signal for the spread of COVID-19 in communities (preprint)

Background: SARS-CoV-2 PCR testing data has been widely used for COVID-19 surveillance. Existing COVID-19 forecasting models mainly rely on case counts, even though the binary PCR results provide a limited picture of the pandemic trajectory. Most forecasting models have failed to accurately predict the COVID-19 waves before they occur. Recently a model utilizing cross-sectional population cycle threshold (Ct) values obtained from PCR tests (Ct-based model) was developed to overcome the limitations of using only binary PCR results. In this study, we aimed to improve on COVID-19 forecasting models using features derived from the Ct-based model, to detect epidemic waves earlier than case-based trajectories. Methods: PCR data was collected weekly at Northeastern University (NU) between August 2020 and January 2022. The NU campus epidemic trajectories were generated from the campus incidence rates. In addition, epidemic trajectories were generated for Suffolk County, where NU is located, based on publicly available case-counts. A novel forecasting approach was developed by enhancing a recent deep learning model with Ct-based features, along with the default features of the model. For this, cross-sectional Ct values from PCR data were used to generate Ct-based epidemic trajectories, including effective reproductive rate (Rt) and incidence. The improvement in forecasting performance was compared using absolute errors and residual squared errors with respect to actual observed cases at the 7-day and 14-day forecasting horizons. The model was also tested prospectively over the period January 2022 to April 2022. Results: Rt estimates from the Ct-based model preceded NU campus and Suffolk County cases by 12 and 14 days respectively, with a three-way synched Spearman correlation of 0.57. Enhancing the forecasting models with Ct-based information significantly decreased absolute error and residual squared error compared to the original model without Ct features (p-value <0.001 for both 7 and 14-days forecasting horizons). Conclusion: Ct-based epidemic trajectories can herald an earlier signal for impending epidemic waves in the community and forecast transmission peaks. Moreover, COVID-19 forecasting models can be enhanced using these Ct features to improve their forecasting accuracy. Policy implications: We make the case that public health agencies should publish Ct values along with the binary positive/negative PCR results. Early and accurate forecasting

SARS-CoV-2 variants show a gradual declining pathogenicity and pro-inflammatory cytokine stimulation and an increasing antigenic and anti-inflammatory cytokine induction (preprint)

Hyper-transmissibility with decreased disease severity are typical characteristics of Omicron variant. To understand this phenomenon, we used various bioinformatics approaches to analyze randomly selected genome sequences (one each) of the Gamma, Delta, and Omicron variants submitted to NCBI from 15 to 31 December 2021. We show that: (i) Pathogenicity of SARS-CoV-2 variants decreases in the order: Wuhan > Gamma > Delta > Omicron; however, the antigenic property follows the order: Omicron > Gamma > Wuhan > Delta. (ii) Omicron Spike RBD has lower pathogenicity but higher antigenicity than that of other variants. (iii) Decreased disease severity by Omicron variant may be due to its decreased pro-inflammatory and IL-6 stimulation and increased IFN-{gamma} and IL-4 induction efficacy. (iv) Mutations in N protein are associated with decreased IL-6 induction and human DDX21-mediated increased IL-4 production in Omicron. (v) Due to mutations, the stability of S, M, N, and E proteins decrease in the order: Omicron > Gamma > Delta > Wuhan. (vi) Stronger Spike-hACE2 binding in Omicron is associated with its increased transmissibility. However, the lowest stability of the Omicron Spike protein makes Spike-hACE2 interaction unstable for systemic infection and for causing severe disease. Finally (vii), the highest instability of Omicron E protein may also be associated with decreased viral maturation and low viral load leading to less severe disease and faster recovery. Our method may be used for other similar viruses, and these findings will contribute to the understanding of the dynamics of SARS-CoV-2 variants and the management of emerging variants.

Immunomodulation by intravenous omega-3 fatty acid treatment in older subjects hospitalized for COVID-19: a single-blind randomized controlled trial (preprint)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) with respiratory distress and systemic hyperinflammation. The primary objective of this single-blind randomized controlled proof-of-concept clinical trial was to establish the effects of intravenous (i.v.) omega-3 (n-3) polyunstaurated fatty acid (PUFA) treatment compared to placebo on inflammatory markers in COVID-19, represented by leukocytes as well as inflammatory protein and lipid mediators. Here we also present an exploratory analysis of the mechanisms of action to elucidate the potential to resolve the COVID-19 hyperinflammation through interfering with lipid mediators. Inclusion criteria were COVID-19 diagnosis and clinical status requiring hospitalization. After randomized 1:1 to a once daily i.v. infusion (2 mL/kg) of either placebo (NaCl) or n-3 PUFA emulsion containing 10g of fish oil per 100 mL, results from 22 older subjects (mean age 81+/-6.1 years) were analyzed. The neutrophil to lymphocyte ratio was significantly decreased after n-3 PUFA administration. Changes in the PUFA metabolome assessed by LC-MS/MS-based lipid metabolite analysis established increased proresolving lipid mediator precursor levels and decreased formation of leukotoxin and isoleukotoxin diols by n-3 PUFA treatment. The mechanistic exploration revealed decreased immunothrombosis and preserved interferon-response. Finally, n-3 PUFA treatment may serve to limit cortisone-induced immunosuppression, including preserving leukocyte phagocytic capacity. In conclusion, i.v. n-3 PUFA administration was safe and feasible during hospitalization of multimorbid older subjects for COVID-19. The results identified a n-3 PUFA treatment mediated lipid signature of increased proresolving precursor levels and decreased leukotoxin diols in parallel to beneficial immune responses. EudraCT: 2020-002293-28; clinicaltrials.gov: NCT04647604.

Epidemiology study of SARS-CoV-2 pandemic in India, the first and second wave (preprint)

Background and objectives: SARS-CoV-2 has wrecked the world for the past 17 months. India has been hit by the second wave of the virus which has been characterized by new symptoms. This study focuses on the pattern of infection over the last 13 months utilizing epidemic model to predict course of the pandemic. Material and methods: The data was collected from covid19india.org to perform analysis based on age and gender distribution. Statistical analysis was performed to determine the relation between confirmed and recovered cases while SIR epidemic model was used to determine the course of the pandemic in the country and the changes that have occurred from the first to the second wave. Results and discussions: Results show infectivity rate to be higher in ages 20-50 while mortality is higher in 50-80 age group while 60-70% of the infected population are males. Each of the 9 states have their own salient feature curves of infection. It was seen that the confirmed and recovered cases are more correlated at present than previous wave. The curves for both waves show a polynomial distribution while the reproduction number data shows an almost U-shaped curve indicating decrease of infection spread in the middle phase when the first wave was on a decline before picking up again owing to the second wave. Interpretations and conclusion: The gender and age distribution shows that although lower age group is more infected, mortality is high for higher age groups, on the other hand males are more prone to the infection. The statistical analysis shows the nature of spread of the disease, the data of which is quantified by the SIR model based study.

A SARS-CoV-2 variant of concern triggers Fc effector function with increased cross-reactivity (preprint)

SARS-CoV-2 variants of concern (VOCs) exhibit escape from neutralizing antibodies, causing concern about vaccine effectiveness. However, while non-neutralizing cytotoxic functions of antibodies are associated with decreased disease severity and vaccine protection, Fc effector function escape from VOCs is poorly defined. Furthermore, whether VOCs trigger Fc functions with altered specificity, as has been reported for neutralization, is unknown. Here, we demonstrate that the Beta VOC partially evades Fc effector activity in individuals infected with the original (D614G) variant. However, not all functions are equivalently affected, suggesting differential targeting by antibodies mediating distinct Fc functions. Furthermore, Beta infection triggered responses with significantly improved Fc cross-reactivity against global VOCs compared to either D614G infected or Ad26.COV2.S vaccinated individuals. This suggests that, as for neutralization, the infecting spike sequence impacts Fc effector function. These data have important implications for vaccine strategies that incorporate VOCs, suggesting these may induce broader Fc effector responses.

The consequences of anthropomorphic and teleological beliefs in a global pandemic (preprint)

To describe something in terms of its purpose or function is to describe its teleology. Previous studies have found that teleological beliefs are positively related to anthropomorphism, and that anthropomorphism decreases the perceived unpredictability of non-human agents. In the current study, we explore these relationships using the highly salient example of beliefs about the coronavirus pandemic. Results showed that both anthropomorphism and teleology were negatively associated with perceived uncertainty and threat, and positively associated with self-reported behavioural change in response to the pandemic. These findings suggest that highly anthropomorphic and teleological individuals may view coronavirus as agentive and goal directed. While anthropomorphic and teleological beliefs may facilitate behavioural change in response to the pandemic, we found that the associated reduction in uncertainty and threat may be detrimental to behavioural change. We discuss the implications of these findings for messaging about global events more broadly.

Persistent intestinal dysbiosis after SARS-CoV-2 infection in Brazilian patients (preprint)

Background: The massive secretion of inflammatory cytokines is associated with the Coronavirus Disease 2019 (COVID-19) severity and poor prognosis, as well as, in long COVID, the pathophysiology seems to be related to immune deregulation. The patient's immune status can influence the response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus infection, and this immunity is affected by the intestinal microbiota condition (eubiotic or dysbiotic). This study aimed to evaluate the intestinal microbiota of patients infected with SARS-CoV-2 with different clinical manifestations and post-COVID-19 (post-COV) periods, and correlate with the use of antibiotics during the acute disease. Results: According to the beta diversity, we observed significant differences between microbial communities in stool samples from post-COV patients when compared with healthy controls. Additionally, we detected four different clusters when we grouped patients into asymptomatic, mild, moderate, and severe disease. Patients who took antibiotics during the COVID-19 course showed decreased richness of the gut microbiota, even months after the disease resolution. We detected some genera possibly associated with the persistent post-COV dysbiosis, including increased Prevotella, Dialister, Haemophillus, Barnesiella, Desulfovibrio, Bilophila, Alistipes, Parabacteroides and Bacteroides, suggesting the impact of the disease in the gut microbiota. Besides that, we found some genera associated with antibiotic-induced dysbiosis in post-COV patients, including decreased Akkermansia and Bifidobacterium species. Conclusions: Therefore, we hypothesized that persistent dysbiosis and indiscriminate use of antibiotics during the COVID-19 pandemic may be associated with long COVID syndromes, suggesting the involvement of the gut-lung axis. These data suggest that intestinal microbiota modulation may represent a therapeutic approach for long COVID.

Elastomeric Harnesses Decrease Aerosol Particles Leak and Improve the Fit of Surgical Masks (preprint)

ABSTRACT Importance The outbreak of Coronavirus diseases 2019 (COVID-19) disease has increased demand for N95 respirators, surgical masks, and other facial coverings to stop the spread of SARS-CoV-2. Research shows that N95 respirators perform the best at filtering viral droplets and aerosols, however these masks are much more difficult to manufacture and expensive to distribute on a large scale, which led to shortages during the pandemic. Surgical masks, on the other hand, were more widely available and have been previously used to mitigate the spread of tuberculosis and influenza. Objectives To evaluate the filter filtration efficiency (FFE) of three elastomeric harness designs in hospital and research settings in order to improve facemask seal. Design, setting and participants A multi-institutional collaboration between engineers and health professionals, conducted between November 2020 and March 2021, was set up to design an elastomeric harness to improve the face seal of a surgical mask. Three elastomeric harness designs were created with harness designs 1 and 2 tested in a research laboratory setting and harness design 2.1 tested in a hospital setting. The initial harness design 1 was laser cut for testing and design 2 was developed to improve the detected particle leakage around the nose bridge area by introducing more material in that region. Design 2.1 is developed for hospital settings with less material around the nose bridge to reduce vision disruption. The designs were tested on mannequins and human volunteers using IR imaging and standard fit testing equipment. Main Outcomes and Measures Our elastomeric harness can improve the seal of a surgical mask allowing it to pass the fit test used to evaluate N95 respirators. 24/39 participants achieved a passing score of 100 or more while wearing the second harness design. IR imaging determined that the nasal sidewalls region of the mask is most prone to leakage when using our first elastomeric harness. Conclusions and Relevance Overall, these results confirm that elastomeric harnesses combined with surgical masks improve their ability to filter aerosolized particles, which is especially important when in close proximity to individuals who are infectious or while performing aerosol-generating medical procedures.

유라시아경제연합(EAEU) 통합과정 평가와 한국의 협력전략(The Evaluation of the Integrating Process of the EAEU and the Economic Cooperation Strategy between Korea and EAEU) (preprint)

Korean Abstract: EAEU 통합과정에서 나타난 성과는 다음과 같다. 첫째, 경제통합체로서 제도적 기반이 조성되었다. 둘째, 새로운 관세법이 제정되고, 금융, 전력, 석유ㆍ석유제품, 가스, 교통 서비스 분야에서 공동시장 조성을 위한 기반이 마련되었다. 셋째, 2017년부터 GDP 및 무역액이 증가하면서 통합의 효과가 서서히 나타나기 시작했다. 넷째, 다수의 비회원국과 자유무역협정 또는 무역ㆍ경제 협정이 체결되었다. 이러한 성과에도 불구하고 EAEU가 가진 한계는 다음과 같다. 첫째, EAEU는 초국적 경제통합체로 기능하는 데 구조적 한계를 보인다. 둘째, 낮은 관세 조화 수준으로 인해 ‘제한된 관세동맹’에 머물러 있고, 완전한 공동시장도 아직 가시화되지 않았다. 셋째, 러시아의 리더십 한계로 인해 통합의 추진력이 약화하고 있다. 넷째, 보호주의적 특징이 경제통합의 성과를 제한하고 있다. 이러한 성과와 한계를 고려할 때, EAEU 통합과정 발전에 대한 전망을 다음과 같이 제시할 수 있다. 첫째, EAEU가 해체될 가능성은 희박하지만 더 높은 수준의 경제통합을 달성하기도 쉽지 않아 보인다. 둘째, 공동시장의 완전한 작동, 정부 조달 분야의 발전, 거시경제 안정성 유지 등이 이루어진다면 역내 무역이 더욱 촉진될 수 있을 것이다. 셋째, 신규 회원국 확보를 통한 거시경제적 잠재력 강화가 필요할 것으로 보인다. 따라서 탈소비에트 국가들과의 협력 확대를 목표로 하는 ‘신북방정책’을 추진하는 한국의 입장에서 EAEU는 무역 확대 및 무역 다변화와 한국의 새로운 성장동력 창출을 지원하는 파트너가 될 수 있다고 판단된다. 본 보고서는 한-EAEU 경제협력 전략으로 민간 및 시장 주도형 경제협력 전략을 제안하며, 그 추진전략과 협력방안으로 첫째, 현재 시장에서 산업협력 중점 분야의 식별과 지원, 둘째, 미래지향적 산업협력 중점 분야의 선정과 지원, 셋째, 한-EAEU FTA 추진을 제시한다. 첫째, 현재 시장에서 산업협력 중점 분야 협력방안은 다음과 같다. 한국의 대세계 주력 수출산업의 EAEU 수직분업 산업(광물, 코크ㆍ정유ㆍ핵연료, 금속 등)과 상대 권역에서 수입되어 양 권역에서 내수로 소비되는 산업(광물 및 수송기기 등)은 시장에서 이미 성과를 보이고 있으므로, 즉 시장 주도 및 민간 주도의 무역 협력 구조와 체계가 작동하고 있으므로, 제3장에서 산업협력 중점분야로 선정되었다. 이 산업군에서의 산업협력 강화방안은 다음과 같다. ① 정부는 정부간 협력 차원에서 양 권역의 교역 잠재력 제약요인을 해소하기 위한 협력 및 소통 체계를 제도화하는 노력을 지속해야 할 것이다. ② 한국의 대EAEU 수입품 및 EAEU의 대한국 수입품에 대한 관세인하 노력이 필요하다. ③ 기존의 ODA 프로그램을 활용하여 EAEU 국가를 대상으로 수출 능력 경험 전수사업, 세관 등 무역원활화 지원사업, 각종 시장경제 능력 강화사업 등을 실행할 것을 권고한다. 둘째, 미래지향적 산업협력 중점 분야와 협력방안은 다음과 같다. EAEU 국가들은 현재 산업화를 통한 자국경제의 성장과 4차산업 시대의 변화에 부합하는 디지털경제와 신산업 육성이라는 과제에 직면하고 있다. 한국은 이미 산업화를 달성한 국가로서, 국내시장에서 한계에 부딪힌 우리 중소기업의 성장을 위한 협력파트너로서 EAEU 국가들과의 산업협력 강화가 필요하다. 또한 EAEU 전체에서 디지털경제 육성은 중요한 과제로 추진되고 있으므로 러시아 등 EAEU 내에서 주도적인 국가와의 협력을 통해 디지털경제 기반구축과 자율주행차, 인공지능(AI), 클라우드 등 상호보완적인 다양한 분야에서 공동의 산업생태계 구축이 필요하다. 최근의 코로나19 사태와 관련하여 의료ㆍ보건 분야에서의 협력은 어느 때보다 중요한 과제가 되었다. EAEU 국가들의 의료체계나 의약품, 의료기기 시장의 발전 가능성이 높다는 점을 고려하면 한국 의료기관의 경영 컨설팅과 위탁경영, 의료기기와 의약품 수출과 같은 분야에서 전망이 밝다. 셋째, 한-EAEU FTA 추진전략과 협력방안은 다음과 같다. 양국의 산업 환경을 고려하면서 단계적인 논의를 통해 상호이익이 되는 방향에서 한-EAEU FTA를 추진할 필요가 있다. CGE 연구 결과에 따르면 FTA가 발효될 경우 한국의 GDP를 소폭 증가시키지만 영향의 정도는 산업별로 다르다. 한국 곡물산업의 피해가 가장 크고, 제조업 분야에서는 특히 금속, 전기ㆍ전자, 기계 산업에 부정적 효과가 발생할 것으로 예상된다. 반면 육류, 가공식품, 수송기기 산업에는 긍정적인 효과가 나타날 것으로 예측된다. 서비스업을 크게 도소매, 운송, 보건복지, 사업서비스 등으로 구분하여 FTA의 영향 정도를 분석한 결과 대체적으로 서비스업의 생산은 증가할 것으로 예상된다. 반면 EAEU 국가 중에서는 러시아와 키르기스스탄의 GDP는 증가하는 반면, 카자흐스탄, 벨라루스, 아르메니아의 GDP는 감소한다. EAEU 국가의 제조업 및 서비스업에서의 산업생산이 감소할 것으로 나타나므로 향후 FTA 혹은 경제협력에서 이 분야들에 대한 정밀한 협력방안을 강구할 필요가 있다. 종합하면 한국과 EAEU FTA가 어느 일국에게만 일방적으로 유리한 결과를 낳지 않으므로 양국이 FTA를 통해 서로가 윈-윈 할 수 있는 협력방안을 모색해야 할 것이다. 특히 한국이 높은 경쟁력을 가지고 있는 수송기기 산업에서의 기술지원, 신기술협력사업, ODA 등을 통해 우리나라가 피해를 볼 것으로 예상되는 산업의 피해를 최소화하고 상대국의 피해산업도 보완할 수 있는 양국간 협력관계를 형성해야 할 것이다.English Abstract: 1. Evaluation of the integration process of the EAEUThe results of the integration process of the EAEU are as follows: first, the EAEU has created an institutional foundation as an economic integrator. Second, the EAEU has enacted new tariff laws and laid the foundation for creating a common market in finance, electricity, petroleum and petroleum products, gas, and transportation services. Third, the effect of the integration of EAEU began to emerge as GDP and trade volume increased since 2017 gradually. Fourth, the EAEU has signed free trade agreements or trade and economic treaties with several non-member countries. Notwithstanding these achievements, the limitations of the EAEU are as follows: first, the EAEU has structural limitations in functioning as a trans-national economic integrator. Second, due to the EAEU’s low level of tariff harmonization, it remains in a “limited customs union,” and the complete single market of the EAEU has not yet been visible. Third, the limitations in Russia’s leadership have weakened the drive for the integration of the EAEU. Fourth, the protective features of the EAEU result in poor performance in economic integration.Considering these achievements and limitations of EAEU, the prospects for developing the integration process of the EAEU will be as follows: first, it is unlikely that the EAEU will be dissolved, but it is difficult for the EAEU to achieve a high level of economic integration. If the common market is fully operational, the government procurements could be activated, and macroeconomic stability could be maintained, and regional trade could be further promoted. Third, to strengthen the macroeconomic potential, it would be required of the enlargement of EU with securing new member states. South Korea is pushing for a “New Northern Policy” to expand economic cooperation with the former Soviet countries. Therefore, the EAEU is believed to become a partner in developing and diversifying trade, and creating new growth engines for Korea.2. Strategy and measures for Korea-EAEU economic cooperation1) Korea-EAEU Economic Cooperation StrategyThis report proposes a private and market-driven strategy as the economic cooperation strategy between Korea and EAEU. It suggests identifying and supporting the industrial cooperation-focused areas in the current market, selecting and supporting future-oriented industrial cooperation, and promoting Korea-EAEU FTA.2) Cooperation plan in areas focused on industrial cooperation in the current marketKorea’s major export industries are already showing results in the market, including the EAEU vertical division (minerals, coke, oil, nuclear fuel, metals, etc.) and industries imported from other regions and consumed as domestic demand in both regions. In other words, market-led and private-led trade cooperation structures and systems are working, so they were selected as the focus areas for industrial cooperation in Chapter 3. The measures to strengthen industrial cooperation in these industrial groups are as follows: first, from the perspective of intergovernmental cooperation, the government should continue to work together to address the constraints of trade potential in both regions and institutionalize communication systems. Second, it is suggested to make efforts to reduce tariffs on Korea’s imports of EAEU and EAEU’s imports of Korea. Third, it is recommended to implement projects to transfer export capabilities of EAEU countries, support projects to revitalize trade sources such as customs and strengthen market economy capabilities by utilizing existing ODA programs.3) Future-oriented industrial cooperation areas and cooperation measuresEAEU countries are currently facing the challenges of growing their economies through industrialization and fostering a digital economy and new industries in line with changes in the Fourth Industrial Revolution age. Korea, a country with already achieved industrialization, needs to strengthen industrial cooperation with EAEU countries for a cooperative partnership to grow small and medium-sized enterprises facing limitations in the domestic market. Besides, fostering the digital economy at the overall level of the EAEU is a critical task. By strengthening cooperation with leading countries within the EAEU, such as Russia, it is necessary to build a digital economy infrastructure and establish a collaborative industrial ecosystem in various fields in self-driving cars, artificial intelligence(AI), and the cloud. In the recent Covid 19 pandemic, cooperation in the medical and health sectors has become more critical than ever. Considering the high possibility of developing the medical system, medicine, and medical device markets in EAEU countries, the outlook for Korean medical institutions’ management consulting, consignment management, and medical device and drug exports is bright.4) Strategies and cooperation measures for the Korea-EAEU FTAConsidering the environment of the two countries’ industries, it is necessary to push for the Korea-EAEU FTA in a direction that benefits each other through phased discussions.According to a CGE study, the effect of the FTA will slightly increase Korea’s GDP, but the impact of each industry is different. If the Korea-EAEU FTA goes into effect, the damage to the Korean grain industry is the biggest, and it is expected to have a negative effect on the metal, electricity, electronics, and machinery industries, especially among the manufacturing sectors. On the other hand, it is expected to positively affect the meat, processed foods, and transportation equipment industries. As a result of analyzing the extent of the FTA’s impact by dividing the service industry into wholesale and retail, transportation, health and welfare, and business services, the service industry’s production is expected to increase in general. Among EAEU countries, Russia and Kyrgyzstan’s GDP increases, while Kazakhstan, Belarus, and Armenia’s GDP decrease. Industrial production in the manufacturing and service industries of EAEU countries is expected to decline, and precise cooperation measures in these areas need to be sought in future FTA or economic cooperation.Taken together, the two should seek ways to cooperate through the FTA, as the Korea-EAEU FTA has no unilaterally favorable results for only one country. In particular, cooperative relations between the two countries should be formed to boost technical support, new technology cooperation projects, and ODA in the highly competitive transportation equipment industry and minimize damage to particular industries in Korea.

DECREASED BREADTH OF THE ANTIBODY RESPONSE TO THE SPIKE PROTEIN OF SARS-CoV-2 AFTER REPEATED VACCINATION (preprint)

ABSTRACT The rapid development of vaccines to prevent infection by SARS-CoV-2 virus causing COVID-19 makes necessary to compare the capacity of the different vaccines in terms of development of a protective humoral response. Here, we have used a highly sensitive and reliable flow cytometry method to measure the titers of antibodies of the IgG1 isotype in blood of healthy volunteers after receiving one or two doses of the vaccines being administered in Spain. We took advantage of the multiplexed capacity of the method to measure simultaneously the reactivity of antibodies with the S protein of the original strain Wuhan and the variants B.1.1.7 (Alpha), B.1.617.2 (Delta) and B.1.617.1 (Kappa). We found significant differences in the titer of anti-S antibodies produced after a first dose of the vaccines ChAdOx1 nCov-19/AstraZeneca, mRNA-1273/Moderna, BNT162b2/Pfizer-BioNTech and Ad26.COV.S/Janssen. Most important, we found a relative reduction in the reactivity of the sera with the Alpha, Delta and Kappa variants, versus the Wuhan one, after the second boosting immunization. These data allow to make a comparison of different vaccines in terms of anti-S antibody generation and cast doubts about the convenience of repeatedly immunizing with the same S protein sequence.

Understanding Adverse Population Sentiment Towards the Spread of COVID-19 in the United States (preprint)

Background - During the ongoing COVID-19 pandemic, the immediate threat of illness and mortality is not the only concern. In the United States, COVID-19 is not only causing physical suffering to patients, but also great levels of adverse sentiment (e.g., fear, panic, anxiety) among the public. Such secondary threats can be anticipated and explained through sentiment analysis of social media, such as Twitter. Methods - We obtained a dataset of geotagged tweets on the topic of COVID-19 in the contiguous United States during the period of 11/1/2019 - 9/15/2020. We classified each tweet into "adverse" and "non-adverse" using the NRC Emotion Lexicon and tallied up the counts for each category per county per day. We utilized the space-time scan statistic to find clusters and a three-stage regression approach to identify socioeconomic and demographic correlates of adverse sentiment. Results - We identified substantial spatiotemporal variation in adverse sentiment in our study area/period. After an initial period of low-level adverse sentiment (11/1/2019 - 1/15/2020), we observed a steep increase and subsequent fluctuation at a higher level (1/16/2020 - 9/15/2020). The number of daily tweets was low initially (11/1/2019 - 1/22/2020), followed by spikes and subsequent decreases until the end of the study period. The space-time scan statistic identified 12 clusters of adverse sentiment of varying size, location, and strength. Clusters were generally active during the time period of late March to May/June 2020. Increased adverse sentiment was associated with decreased racial/ethnic heterogeneity, decreased rurality, higher vulnerability in terms of minority status and language, and housing type and transportation. Conclusions - We utilized a dataset of geotagged tweets to identify the spatiotemporal patterns and the spatial correlates of adverse population sentiment during the first two waves of the COVID-19 pandemic in the United States. The characteristics of areas with high adverse sentiment may be relevant for communication of containment measures. The combination of spatial clustering and regression can be beneficial for understanding of the ramifications of COVID-19, as well as disease outbreaks in general.

Indirect Effects of the COVID-19 Pandemic on Childhood Infection in England: A Population Based Observational Study (preprint)

Background: Children are largely unaffected following Sars-CoV-2 infection with low rates of significant disease and the inflammatory syndrome MIS-C. However, the lives of children have been substantially disrupted by the pandemic through physical distancing measures and the impact on health systems and economies. In this study, the impact of the COVID-19 pandemic on hospital admissions for childhood respiratory infections, severe invasive infections, and vaccine preventable disease in England was assessed along with associated mortality outcomes.Methods: In this population-based observational study, we examined hospital admission data from every National Health Service hospital from Mar 1 2017 to Feb 28 2021. We report monthly and annual numbers of individuals hospitalised with 19 common childhood respiratory, severe invasive, and vaccine preventable infections. We compare the frequency of admissions for these conditions before and after the onset of the pandemic in England and calculate percentage changes since Mar 1 2020 for each infection overall and by demographic characteristics including age, region, deprivation, and comorbidity, and quantify mortality outcomes.Findings: In the 12 months from Mar 1 2020, there were significant reductions compared with the preceding 36 months in the numbers of children admitted for every infection studied except pyelonephritis. These reductions were seen in all geographic regions, Index of Multiple Deprivation categories, ethnic groups and in those with underlying comorbidities. Among the respiratory infections, the greatest percentage reductions were for influenza where the number of individuals admitted decreased by 94% (95% CI 88, 97) from 5,061 (annual mean from Mar 1 2017 - Feb 29 2020) to 290 in the 12 months after Mar 1 2020, and for bronchiolitis where the number of individuals admitted decreased by over 80% (95% CI 78, 83) from 41,777 (annual mean 2017–2020) to 7,883 in 2020-21. Among the severe invasive infections, percentage decreases ranged from 20% (95% CI 13, 26) for osteomyelitis to 54% (95% CI 51, 56) for meningitis. Among the vaccine preventable infections, the greatest reduction was for measles, where the number of individuals admitted in the 12 months after Mar 1 2020 (n=12) was 92% lower (95% CI 84, 96) than the average number admitted in the previous three years (n=143). Admissions for Neisseria meningitidis decreased by 70% (95% CI 55, 80), and admissions for Streptococcus pneumoniae, Haemophilus influenzae and mumps more than halved. Alongside the decreases in admissions, there were also decreases in the absolute numbers of 60-day fatalities after admission for sepsis, meningitis, bronchiolitis, pneumonia, viral wheeze and upper respiratory tract infection (RTI). For pneumonia, although the absolute number of 60-day fatalities decreased (from a 3-year average of 159 to 115 after Mar 1 2020), the proportion of individuals admitted who died within 60 days increased (age-sex adjusted odds ratio 1.73, 95% CI 1.42, 2.11).Interpretation: During the COVID-19 pandemic, a range of behavioural changes (adoption of non-pharmacological interventions (NPIs)) and societal strategies (school closures, lockdowns and restricted travel) were used to reduce transmission of SARS CoV2 which have also significantly reduced transmission of common and severe childhood infections. NPIs could be used in the future to better protect healthcare systems and the most vulnerable children in society.Funding Information: Public Health England, Health Data Research UK, and the National Institute for Health Research Oxford Biomedical Research Centre.Declaration of Interests: None to declare. Ethics Approval Statement: Ethical approval to study the record-linked datasets was obtained from the Central and South Bristol Multi-Centre Research Ethics Committee (04/Q2006/176). All patient records were pseudonymized by the data providers through encryption of personal identifiers.

A Flexible Agent-Based Model to Study COVID-19 Outbreak -- A Generic Approach (preprint)

Understanding dynamics of an outbreak like that of COVID-19 is important in designing effective control measures. This study aims to develop an agent based model that compares changes in infection progression by manipulating different parameters in a synthetic population. Model input includes population characteristics like age, sex, working status etc. of each individual and other factors influencing disease dynamics. Depending on number of epicentres of infection, location of primary cases, sensitivity, proportion of asymptomatic and frequency or duration of lockdown, our simulator tracks every individual and hence infection progression through community over time. In a closed community of 10000 people, it is seen that without any lockdown, number of cases peak around 6th week and wanes off around 15th week. If primary case is located inside dense population cluster like slums, cases peak early and wane off slowly. With introduction of lockdown, cases peak at slower rate. If sensitivity of identifying infection decreases, cases and deaths increase. Number of cases declines with increase in proportion of asymptomatic cases. The model is robust and provides reproducible estimates with realistic parameter values. It also guides in identifying measures to control outbreak in a community. It is flexible in accommodating different parameters like infectivity period, yield of testing, socio-economic strata, daily travel, awareness level, population density, social distancing, lockdown etc. and can be tailored to study other infections with similar transmission pattern.

Janus Kinase Inhibition Ameliorates Cerebral Ischemic Injury and Neuroinflammation through Reducing NLRP3 Inflammasome Activation via JAK2/STAT3 Pathway Inhibition (preprint)

BackgroundEvidence shows that inflammatory responses play multiphasic roles in stroke pathogenesis. Ruxolitinib (Rux), a selective oral JAK 1/2 inhibitor, is efficacious in COVID-19 by reducing inflammation via the JAK2/STAT3 pathway. MethodsHere, we investigated whether JAK2 inhibition has neuroprotective effects against ischemic stroke (IS) in MCAO mice in vivo and in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) model, and explored the potential molecular mechanisms. Rux was applied to MCAO mice. Immunofluorescence staining, RT-qPCR, and western blots were used to measure the expression of NLRP3 inflammation components and proinflammatory cytokines as well as JAK2/STAT3 pathway. Local STAT3 deficiency in brain tissue was established to investigate the interplay between NLRP3 and STAT3 signaling.ResultsRux treatment obviously improved neurological scores, decreased the infarct size and ameliorated cerebral edema 3 days after stroke. In addition, immunofluorescence staining and western blots showed that Rux application inhibited the expression of NLRP3 inflammasome components, proteins related to the NLRP3 inflammasome and phosphorylated STAT3 (p-STAT3) in neurons. Furthermore, Rux administration inhibited the expression of proinflammatory cytokines, including TNF-α, IFN-γ, HMBG1, IL-1β, IL-2, and IL-6 in middle cerebral artery occlusion (MCAO) model mice, suggesting that Rux may alleviate IS injury by inhibiting proinflammatory reactions via JAK2/STAT3 signaling pathway regulation. Local STAT3 deficiency decreased histone H3 and H4 acetylation on the NLRP3 promoter and the NLRP3 inflammasome component expression, indicating that the NLRP3 inflammasome may be directly regulated by STAT3 signaling. Finally, the effect of Rux on the NLRP3 inflammasome was further assessed in a HT22 cell OGD/R model in vitro. Rux application markedly suppressed lipopolysaccharide (LPS)-induced NLRP3 inflammasome secretion and JAK2/STAT3 pathway activation in vitro the in OGD/R HT22 cell model.ConclusionJAK2 inhibition by Rux in MCAO mice decreased STAT3 phosphorylation, thus inhibiting downstream proinflammatory cytokines and H3 and H4 acetylation on the NLRP3 promoter, resulting in downregulation of NLRP3 inflammasome component expression.

Post-Anticoagulant D-Dimer Is a Highly Prognostic Biomarker of COVID-19 Mortality (preprint)

Background: Clinical biomarkers that accurately predict mortality are needed for the effective management of patients with severe COVID-19 illness. Here, we determine whether changes in D-dimer levels after anticoagulation are predictive of in-hospital mortality.Methods: Adult patients hospitalized for severe COVID-19 who received therapeutic anticoagulation for thromboprophylaxis were identified from a large COVID-19 database of the Mount Sinai Health System in New York City. We studied the ability post-anticoagulant D-dimer levels to predict in-hospital mortality, while taking into consideration 65 other clinically important covariates including patient demographics, comorbidities, vital signs and laboratory tests at baseline.Findings: 1835 adult patients with PCR-confirmed COVID-19 who received therapeutic anticoagulation during hospitalization were included. Overall, 26% of patients died in the hospital. Significantly different in-hospital mortality rates were observed in patient groups based on the mean D-dimer levels and its trend following anticoagulation initiation: 49% for the high mean-increase trend (HI) group; 27% for the high-decrease (HD) group; 21% for the low-increase (LI) group; and 9% for the low-decrease (LD) group (p<0·001). Using penalized logistic regression models to simultaneously analyze 67 clinical variables, the HI (adjusted odds ratios [ORadj]: 6·58, 95% CI 3·81-11·16), LI (ORadj: 4·06, 95% CI 2·23-7·38) and HD (ORadj: 2·37; 95% CI 1·37-4·09) post-anticoagulant D-dimer groups had the highest odds for in-hospital mortality when compared to the LD group.Interpretation: D-dimer levels and its trend following anticoagulation are highly predictive of in-hospital mortality and may help guide resource allocation and identify candidates for studies of emerging treatments for severe COVID-19.Funding: NoneDeclaration of Interests: Authors have no competing interests to declare.Ethics Approval Statement: The Icahn School of Medicine at Mount Sinai Institutional Review Boardconsidered the study exempt.