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Why are the epidemic patterns of COVID-19 so different among different cities or countries which are similar in their populations, medical infrastructures, and people's behavior? Why are forecasts or predictions made by so-called experts often grossly wrong, concerning the numbers of people who get infected or die? The purpose of this study is to better understand the stochastic nature of an epidemic disease, and answer the above questions. Much of the work on infectious diseases has been based on "SIR deterministic models," (Kermack and McKendrick:1927.) We will explore stochastic models that can capture the essence of the seemingly erratic behavior of an infectious disease. A stochastic model, in its formulation, takes into account the random nature of an infectious disease. The stochastic model we study here is based on the "birth-and-death process with immigration" (BDI for short), which was proposed in the study of population growth or extinction of some biological species. The BDI process model ,however, has not been investigated by the epidemiology community. The BDI process is one of a few birth-and-death processes, which we can solve analytically. Its time-dependent probability distribution function is a "negative binomial distribution" with its parameter $r$ less than $1$. The "coefficient of variation" of the process is larger than $\sqrt{1/r} > 1$. Furthermore, it has a long tail like the zeta distribution. These properties explain why infection patterns exhibit enormously large variations. The number of infected predicted by a deterministic model is much greater than the median of the distribution. This explains why any forecast based on a deterministic model will fail more often than not. 28 pages, 14 figures

AbstractBackgroundSince the start of the new Coronavirus (COVID-19) outbreak in December 2019, pharmacists worldwide are playing a key role adopting innovative strategies to minimize the adverse impact of the pandemic.ObjectivesTo identify and describe core services provided by the pharmacist during the COVID-19 pandemic.MethodsA literature search was performed in MEDLINE, Embase, Scopus, and LILACS for studies published between December 1st, 2019 and May 20th, 2020 without language restriction. Studies that reported services provided by pharmacists during the COVID-19 pandemic were included. Two independent authors performed study selection and data extraction with a consensus process. The pharmacist’s intervention identified in the included studies were described based on key domains in the DEPICT v.2.ResultsA total of 1,189 records were identified, of which 11 studies fully met the eligibility criteria. Most of them were conducted in the United States of America (n=4) and China (n=4). The most common type of publication were letters (n=4) describing the workplace of the pharmacist in hospitals (n=8). These findings showed the different roles of pharmacists during the COVID-19 pandemic, such as disease prevention and infection control, adequate storage and drug supply, patient care and support for healthcare professionals. Pharmacists’ interventions were mostly conducted for healthcare professionals and patients (n=7), through one-to-one contact (n=11), telephone (n=6) or video conference (n=5). The pharmacists’ main responsibility was to provide drug information for healthcare professionals (n=7) as well as patient counseling (n=8).ConclusionsA reasonable number of studies that described the role of the pharmacists during the COVID-19 pandemic were found. All studies reported actions taken by pharmacists, although without providing a satisfactory description. Thus, future research with more detailed description as well as an evaluation of the impact of pharmacist intervention is needed in order to guide future actions in this and-or other pandemic.

Abstract Background Coronaviruses pose a serious threat to global health as evidenced by Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and COVID-19. SARS Coronavirus (SARS-CoV), MERS Coronavirus (MERS-CoV), and the novel coronavirus, previously dubbed 2019-nCoV, and now officially named SARS-CoV-2, are the causative agents of the SARS, MERS, and COVID-19 disease outbreaks, respectively. Safe vaccines that rapidly induce potent and long-lasting virus-specific immune responses against these infectious agents are urgently needed. The coronavirus spike (S) protein, a characteristic structural component of the viral envelope, is considered a key target for vaccines for the prevention of coronavirus infection. Methods We first generated codon optimized MERS-S1 subunit vaccines fused with a foldon trimerization domain to mimic the native viral structure. In variant constructs, we engineered immune stimulants (RS09 or flagellin, as TLR4 or TLR5 agonists, respectively) into this trimeric design. We comprehensively tested the pre-clinical immunogenicity of MERS-CoV vaccines in mice when delivered subcutaneously by traditional needle injection, or intracutaneously by dissolving microneedle arrays (MNAs) by evaluating virus specific IgG antibodies in the serum of vaccinated mice by ELISA and using virus neutralization assays. Driven by the urgent need for COVID-19 vaccines, we utilized this strategy to rapidly develop MNA SARS-CoV-2 subunit vaccines and tested their pre-clinical immunogenicity in vivo by exploiting our substantial experience with MNA MERS-CoV vaccines. Findings Here we describe the development of MNA delivered MERS-CoV vaccines and their pre-clinical immunogenicity. Specifically, MNA delivered MERS-S1 subunit vaccines elicited strong and long-lasting antigen-specific antibody responses. Building on our ongoing efforts to develop MERS-CoV vaccines, promising immunogenicity of MNA-delivered MERS-CoV vaccines, and our experience with MNA fabrication and delivery, including clinical trials, we rapidly designed and produced clinically-translatable MNA SARS-CoV-2 subunit vaccines within 4 weeks of the identification of the SARS-CoV-2 S1 sequence. Most importantly, these MNA delivered SARS-CoV-2 S1 subunit vaccines elicited potent antigen-specific antibody responses that were evident beginning 2 weeks after immunization. Interpretation MNA delivery of coronaviruses-S1 subunit vaccines is a promising immunization strategy against coronavirus infection. Progressive scientific and technological efforts enable quicker responses to emerging pandemics. Our ongoing efforts to develop MNA-MERS-S1 subunit vaccines enabled us to rapidly design and produce MNA SARS-CoV-2 subunit vaccines capable of inducing potent virus-specific antibody responses. Collectively, our results support the clinical development of MNA delivered recombinant protein subunit vaccines against SARS, MERS, COVID-19, and other emerging infectious diseases.

AbstractBats are known to be reservoirs of several highly pathogenic viruses. Hence, the interest in bat virus discovery has been increasing rapidly over the last decade. So far, most studies have focused on a single type of virus detection method, either PCR, virus isolation or virome sequencing. Here we present a comprehensive approach in virus discovery, using all three discovery methods on samples from the same bats. By family-specific PCR screening we found sequences of paramyxoviruses, adenoviruses, herpesviruses and one coronavirus. By cell culture we isolated a novel bat adenovirus and bat orthoreovirus. Virome sequencing revealed viral sequences of ten different virus families and orders: three bat nairoviruses, three phenuiviruses, one orbivirus, one rotavirus, one orthoreovirus, one mononegavirus, five parvoviruses, seven picornaviruses, three retroviruses, one totivirus and two thymoviruses were discovered. Of all viruses identified by family-specific PCR in the original samples, none was found by metagenomic sequencing. Vice versa, none of the viruses found by the metagenomic virome approach was detected by family-specific PCRs targeting the same family. The discrepancy of detected viruses by different detection approaches suggests that a combined approach using different detection methods is necessary for virus discovery studies.

ABSTRACT During the COVID-19 pandemic, a case of a long-term persistence of SARS-CoV-2 infection (from March 26 to May 20, 2020) was identified at a private hospital in São Paulo, SP, Brazil. The long-term positivity for SARS-CoV-2 in reverse transcriptase polymerase chain reaction tests of a patient diagnosed with COVID-19 suggests, at least part of patients who recovered, may still carry and transmit the SARS-CoV-2 virus. This fact emphasizes the importance of having at least two negative reverse transcriptase polymerase chain reaction test results for SARS-CoV-2. Serological assays were not particularly helpful in the case described, since the patient had very low antibodies titers at the end of the follow-up period. Low viral loads may not be detected by current molecular methods, leading to wrong conclusions regarding viral clearance.

As the world continues to battle the SARS-CoV-2 pandemic, it is a stark reminder of the devastation biological threats can cause. In an unprecedented way the global community saw a massive surge in the demand for diagnostic capacities, which had a substantial impact on biosafety and biosecurity. Laboratories had to cope with a surge in laboratory testing capacity, while resources and training possibilities were limited. In addition, the pandemic highlighted the impact biological threats can have, thereby giving rise to new dialogue about biosecurity and new biological threats. This paper aims to highlight some of the most pressing issues regarding biosafety and biosecurity observed during the COVID-19 pandemic with special focus on low and lower middle-income countries. The authors provide lessons learned, tools and recommendations to improve future biosafety and biosecurity and increase preparedness for the next global health crisis.

Importance: Since January 2020, Singapore has implemented comprehensive measures to suppress SARS-CoV-2. Despite this, the country has experienced contrasting epidemics, with limited transmission in the community and explosive outbreaks in migrant worker dormitories. Objective: To estimate SARS-CoV-2 infection incidence among migrant workers and the general population in Singapore. Design: Prospective serological cohort studies. Setting: Two cohort studies — in a migrant worker dormitory and in the general population in Singapore. Participants: 478 residents of a SARS-CoV-2-affected migrant worker dormitory were followed up between May and July 2020, with blood samples collected on recruitment and after 2 and 6 weeks. In addition, 937 community-dwelling adult Singapore residents, for whom pre-pandemic sera were available, were recruited. These individuals also provided a serum sample on recruitment in November/December 2020. Exposure: Exposure to SARS-CoV-2 in a densely populated migrant worker dormitory and in the general population. Main outcomes and measures: The main outcome measures were the incidences of SARS-CoV-2 infection in migrant workers and in the general population, as determined by the detection of neutralizing antibodies against SARS-CoV-2, and adjusting for assay sensitivity and specificity using a Bayesian modeling framework. Results: No evidence of community SARS-CoV-2 exposure was found in Singapore prior to September 2019. It was estimated that < 2 per 1000 adult residents in the community were infected with SARS-CoV-2 in 2020 (cumulative seroprevalence: 0.16%; 95% CrI: 0.008–0.72%). Comparison with comprehensive national case notification data suggested that around 1 in 4 infections in the general population were associated with symptoms. In contrast, in the migrant worker cohort, almost two-thirds had been infected by July 2020 (cumulative seroprevalence: 63.8%; 95% CrI: 57.9–70.3%); no symptoms were reported in almost all of these infections. Conclusions and relevance: Our findings demonstrate that SARS-CoV-2 suppression is possible with strict and rapid implementation of border restrictions, case isolation, contact tracing, quarantining, and social-distancing measures. However, the risk of large-scale epidemics in densely populated environments requires specific consideration in preparedness planning. Prioritization of these settings in vaccination strategies should minimize the risk of future resurgences and potential spillover of transmission to the wider community.

Abstract Background To mitigate the psychological burdens of COVID-19 for frontline clinicians (FCs), we adapted an existing evidence-based resiliency program, Stress Management and Resilience Training Relaxation Response Program (SMART-3RP), for FCs. This analysis explores moderators of stress coping to determine which subgroups of FCs benefited most from SMART-3RP. Methods 102 FCs from Mass General Brigham hospitals engaged in the adapted SMART-3RP. Assessments were completed at group entry (Week 0) and completion (Week 4). The primary outcome was stress coping, and we examined 15 possible baseline moderators. We fit linear mixed effects regression models and assessed potential baseline moderators using a likelihood ratio test. We report model-based estimates and confidence intervals for each moderator-by-time interaction (i.e., differential effect), where positive/negative values indicate more/less improvement in average perceived stress coping. Results Stress coping improved from Week 0 to Week 4 (mean improvement [95% CI] = 0.9 [0.6 to 1.2]). FCs with higher anxiety (differential effect [95% CI] = 0.3 [0.1 to 0.4]), depression (0.4 [0.2 to 0.6]), and loneliness (0.4 [0.1 to 0.6]), but lower levels of mindfulness (CAMS-Rfocus: 1.0 [0.4 to 1.6]; CAMS-Raccept: 1.3 [0.7 to 2.0]) and self-compassion (0.4, [0.1 to 0.8]) at baseline experienced greater benefits in perceived stress coping from the SMART-3RP. Baseline health uncertainty along with sociodemographic and work characteristics did not moderate stress coping. Discussion Results highlight particular sub-populations of FCs that may benefit more from a stress management intervention, especially during emergency responses (e.g., COVID-19 pandemic).

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2, a new member of the genus Betacoronavirus, is a pandemic virus, which has caused numerous fatalities, particularly in the elderly and persons with underlying morbidities. At present, there are no approved vaccines nor antiviral therapies available. The detection and quantification of SARS-CoV-2-neutralizing antibodies plays a crucial role in the assessment of the immune status of convalescent COVID-19 patients, evaluation of recombinant therapeutic antibodies, and the evaluation of novel vaccines. To detect SARS-CoV-2-neutralizing antibodies, classically, a virus-neutralization test has to be performed at biosafety level 3, considerably limiting the general use of this test. In the present work, a biosafety level 1 pseudotype virus assay based on a propagation-incompetent vesicular stomatitis virus (VSV) has been used to determine the neutralizing antibody titers in convalescent COVID-19 patients. The neutralization titers in serum of two independently analyzed patient cohorts were available within 18 h and correlated well with those obtained with a classical SARS-CoV-2 neutralization test (Pearson correlation coefficients of r = 0.929 and r = 0.939, respectively). Most convalescent COVID-19 patients had only low titers of neutralizing antibodies (ND50 < 320). The sera of convalescent COVID-19 patients also neutralized pseudotype virus displaying the SARS-CoV-1 spike protein on their surface, which is homologous to the SARS-CoV-2 spike protein. In summary, we report a robust virus-neutralization assay, which can be used at low biosafety level 1 to rapidly quantify SARS-CoV-2-neutralizing antibodies in convalescent COVID-19 patients and vaccinated individuals.