ABSTRACT
Stimulator of interferon genes, namely STING, an adaptor protein located in the endoplasmic reticulum, has been recognized as a shining target for cancer and infection research. However, STING agonists cyclic dinucleotides (CDNs) have shown almost zero efficacy in phase I clinical trials as a monotherapy, likely due to poor cellular permeability and rapid diffusion despite intratumoral injection. These deficiencies further affect other applications of CDNs, such as pandemic SARS-CoV-2 prevention and therapy. Here, we rationally design a supramolecular cytosolic delivery system based on controllable recognition of calixarene, namely CASTING (CAlixarene-STING), to improve CDN druggability, including degradation stability, cellular permeability, and tissue retention. CASTING efficiently enhances the immunostimulatory potency of CDG(SF) [a chemically modified cyclic di-GMP (CDG)] to generate an immunogenic microenvironment for melanoma regression, anti-PD-1 response rate increase, and durable memory formation against tumor recurrence. More importantly, CASTING displays a superior adjuvant activity on SARS-CoV-2 recombinant spike/receptor binding domain vaccines, inducing robust and coordinated T-cell and antibody responses against SARS-CoV-2 infection in vivo. Collectively, the CASTING design represents an innovative advancement to facilitate the clinical translational capability of STING agonists. [GRAPHICS] .
ABSTRACT
Objective: To rapidly evaluate the level of healthcare resource demand for laboratory testing and prevention and control of corona virus disease 2019 (COVID-19) in different epidemic situation, and prepare for the capacity planning, stockpile distribution, and funding raising for infectious disease epidemic response. Methods: An susceptible, exposed, infectious, removed infectious disease dynamics model with confirmed asymptomatic infection cases and symptomatic hospitalized patients was introduced to simulate different COVID-19 epidemic situation and predict the numbers of hospitalized or isolated patients, and based on the current COVID-19 prevention and control measures in China, the demands of resources for laboratory testing and prevention and control of COVID-19 were evaluated. Results: When community or local transmission or outbreaks occur and total population nucleic acid testing is implemented, the need for human resources is 3.3-89.1 times higher than the reserved, and the current resources of medical personal protective equipment and instruments can meet the need. The surge in asymptomatic infections can also increase the human resource demand for laboratory testing and pose challenge to the prevention and control of the disease. When vaccine protection coverage reach ≥50%, appropriate adjustment of the prevention and control measures can reduce the need for laboratory and human resources. Conclusions: There is a great need in our country to reserve the human resources for laboratory testing and disease prevention and control for the response of the possible epidemic of COVID-19. Challenges to human resources resulted from total population nucleic acid testing and its necessity need to be considered. Conducting non-pharmaceutical interventions and encouraging more people to be vaccinated can mitigate the shock on healthcare resource demand in COVID-19 prevention and control.
Subject(s)
COVID-19 , Pandemics , Humans , Pandemics/prevention & control , Personal Protective Equipment , SARS-CoV-2ABSTRACT
Purpose To understand the long term effect of COVID-19 on 1) heart transplant waitlist trends and on 2) heart transplant case numbers in the United States. Methods The number of new adult heart transplant waitlist additions and transplant procedures were obtained from the UNOS database. Our time frame includes the 52 weeks between September 3, 2019 and September 4, 2020. Temporal changes in waitlist additions and heart transplants were analyzed using interrupted time series analyses with two transition periods. The first transition from the pre-COVID to the post-COVID era was determined as the week of March 11, 2020, when the first state imposed stay-at-home orders. The second transition period was determined as the first state re-opening during the week of April 22, 2020. Results Weekly waitlist additions were decreasing at -0.19 additions per week (95% CI: -0.35 to -0.03, p=0.018) prior to the COVID-19 era, defined as before the week of March 11, 2020, with a significant decrease in weekly waitlist additions of -2.09 (95% CI: -2.44 to -1.73, p< 0.001) during the post-COVID-19 era and prior to the first state re-opening the week of April 22, 2020 (Figure A). Weekly waitlist additions increased at 2.16 additions per week (95% CI: 1.81 to 2.51, p<0.001) following the first state announcing re-opening the week of April 22, 2020. Weekly transplants were relatively unstable, although decreasing at -0.003 transplants per week (95% CI: -0.279 to 0.273, p=0.984) in the pre-COVID era, and were trending downward at -0.18 transplants per week (95% CI: -0.3702 to 0.0036, p=0.054) thereafter (Figure B). The number of transplants rebounded and increased significantly at 0.49 transplants per week (95% CI: 0.26 to 0.72, p<0.001) after April 22, 2020. Conclusion The number of heart transplants and waitlist additions decreased significantly due to COVID-19 and rebounded following the first US state reopening the week of April 22, 2020. Waitlist additions continue to rise past levels observed during the pre-COVID era.
ABSTRACT
Editor office's response for Ahead of Print article withdrawn The article "Potential false-positive rate among the 'asymptomatic infected individuals' in close contacts of COVID-19 patients" was under strong discussion after pre-published. Questions from the readers mainly focused on the article's results and conclusions were depended on theoretical deduction, but not the field epidemiology data and further researches were needed to prove the current theory. Based on previous discussions, the article was decided to be offline by the editorial board from the pre-publish lists. Objective: As the prevention and control of COVID-19continues to advance, the active nucleic acid test screening in the close contacts of the patients has been carrying out in many parts of China. However, the false-positive rate of positive results in the screening has not been reported up to now. But to clearify the false-positive rate during screening is important in COVID-19 control and prevention. Methods: Point values and reasonable ranges of the indicators which impact the false-positive rate of positive results were estimated based on the information available to us at present. The false-positive rate of positive results in the active screening was deduced, and univariate and multivariate-probabilistic sensitivity analyses were performed to understand the robustness of the findings. Results: When the infection rate of the close contacts and the sensitivity and specificity of reported results were taken as the point estimates, the positive predictive value of the active screening was only 19.67%, in contrast, the false-positive rate of positive results was 80.33%. The multivariate-probabilistic sensitivity analysis results supported the base-case findings, with a 75% probability for the false-positive rate of positive results over 47%. Conclusions: In the close contacts of COVID-19 patients, nearly half or even more of the 'asymptomatic infected individuals' reported in the active nucleic acid test screening might be false positives.