The science around the use of masks by the general public to impede COVID-19 transmission is advancing rapidly. Policymakers need guidance on how masks should be used by the general population to combat the COVID-19 pandemic. In this narrative review, we develop an analytical framework to examine mask usage, considering and synthesizing the relevant literature to inform multiple areas: population impact; transmission characteristics; source control; PPE; sociological considerations; and implementation considerations. A primary route of transmission of COVID-19 is via respiratory droplets, and is known to be transmissible from presymptomatic and asymptomatic individuals. Reducing disease spread requires two things: first, limit contacts of infected individuals via physical distancing and other measures, and second, reduce the transmission probability per contact. The preponderance of evidence indicates that mask wearing reduces the transmissibility per contact by reducing transmission of infected droplets in both laboratory and clinical contexts. Public mask wearing is most effective at reducing spread of the virus when compliance is high. The decreased transmissibility could substantially reduce the death toll and economic impact while the cost of the intervention is low. Given the current shortages of medical masks we recommend the adoption of public cloth mask wearing, as an effective form of source control, in conjunction with existing hygiene, distancing, and contact tracing strategies. Because many respiratory droplets become smaller due to evaporation, we recommend increasing focus on a previously overlooked aspect of mask usage: mask-wearing by infectious people ("source control") with benefits at the population-level, rather than mask-wearing by susceptible people, such as health-care workers, with focus on individual outcomes. We recommend that public officials and governments strongly encourage the use of widespread face masks in public, including the use of appropriate regulation.

Objective: To describe outcomes of patients with coronavirus disease 2019 (COVID-19) in the outpatient setting after early treatment with zinc, low dose hydroxychloroquine, and azithromycin (the triple therapy) dependent on risk stratification. Design: Retrospective case series study. Setting: General practice. Participants: 141 COVID-19 patients with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in the year 2020. Main Outcome Measures: Risk-stratified treatment decision, rate of hospitalization and all-cause death. Results: Of 335 positively PCR-tested COVID-19 patients, 127 were treated with the triple therapy. 104 of 127 met the defined risk stratification criteria and were included in the analysis. In addition, 37 treated and eligible patients who were confirmed by IgG tests were included in the treatment group (total N=141). 208 of the 335 patients did not meet the risk stratification criteria and were not treated. After 4 days (median, IQR 3-6, available for N=66/141) of onset of symptoms, 141 patients (median age 58 years, IQR 40-67; 73% male) got a prescription for the triple therapy for 5 days. Independent public reference data from 377 confirmed COVID-19 patients of the same community were used as untreated control. 4 of 141 treated patients (2.8%) were hospitalized, which was significantly less (p<0.001) compared with 58 of 377 untreated patients (15.4%) (odds ratio 0.16, 95% CI 0.06-0.5). Therefore, the odds of hospitalization of treated patients were 84% less than in the untreated group. One patient (0.7%) died in the treatment group versus 13 patients (3.5%) in the untreated group (odds ratio 0.2, 95% CI 0.03-1.5; p=0.16). There were no cardiac side effects. Conclusions: Risk stratification-based treatment of COVID-19 outpatients as early as possible after symptom onset with the used triple therapy, including the combination of zinc with low dose hydroxychloroquine, was associated with significantly less hospitalizations and 5 times less all-cause deaths.

This study focuses on cardiovascular effects, particularly myocarditis and pericarditis events, after BNT162b2 mRNA COVID-19 vaccine injection in Thai adolescents. This prospective cohort study enrolled students from two schools aged 13–18 years who received the second dose of the BNT162b2 mRNA COVID-19 vaccine. Data including demographics, symptoms, vital signs, ECG, echocardiography and cardiac enzymes were collected at baseline, Day 3, Day 7, and Day 14 (optional) using case record forms.We enrolled 314 participants; of these, 13 participants were lost to follow up, leaving 301 participants for analysis. The most common cardiovascular effects were tachycardia (7.64%), shortness of breath (6.64%), palpitation (4.32%), chest pain (4.32%), and hypertension (3.99%). Seven participants (2.33%) exhibited at least one elevated cardiac biomarker or positive lab assessments. Cardiovascular effects were found in 29.24% of patients, ranging from tachycardia, palpitation, and myopericarditis. Myopericarditis was confirmed in one patient after vaccination. Two patients had suspected pericarditis and four patients had suspected subclinical myocarditis. Conclusion: Cardiovascular effects in adolescents after BNT162b2 mRNA COVID-19 vaccination included tachycardia, palpitation, and myocarditis. The clinical presentation of myopericarditis after vaccination was usually mild, with all cases fully recovering within 14 days. Hence, adolescents receiving mRNA vaccines should be monitored for side effects. Clinical Trial Registration: NCT05288231

The world is in the grips of the COVID-19 pandemic. Public health measures that can reduce the risk of infection and death in addition to quarantines are desperately needed. This article reviews the roles of vitamin D in reducing risk of respiratory tract infections, knowledge about the epidemiology of influenza and COVID-19, and how vitamin D supplementation might be a useful measure to reduce risk. Through several mechanisms, vitamin D can reduce risk of infections. Those mechanisms include inducing cathelicidins and defensins that can lower viral replication rates and reducing concentrations of pro-inflammatory cytokines that produce the inflammation that injures the lining of the lungs, leading to pneumonia, as well as increase concentrations of anti-inflammatory cytokines. Several observational studies and clinical trials reported that vitamin D supplementation reduced risk of influenza, whereas others did not. Evidence supporting the role of vitamin D in reducing risk of COVID-19 includes that the outbreak occurred in winter, a time when 25-hydroxyvitamin D [25(OH)D] concentrations are lowest; that the number of cases in the Southern Hemisphere near the end of summer are low; that vitamin D deficiency has been found to contribute to acute respiratory distress syndrome, and that case-fatality rates increase with age and with chronic disease comorbidity, both of which are associated with lower 25(OH)D concentration. To reduce risk of infection, it is recommended that people at risk of influenza and/or COVID-19 consider taking 10,000 IU/d of vitamin D₃ for a few weeks to rapidly raise 25(OH)D concentrations, followed by 5000 IU/d. The goal should be to raise 25(OH)D concentrations above 40–60 ng/ml (100–150 nmol/l). For treatment of people who become infected with COVID-19, higher vitamin D₃ doses might be useful. Randomized controlled trials and large population studies should be conducted to evaluate these recommendations.

Most striking observations in COVID-19 patients are the hints on pulmonary edema (also seen on CT scans as ground glass opacities), dry cough, fluid restrictions to prevent more severe hypoxia, the huge PEEP that is needed while lungs are compliant, and the fact that anti-inflammatory therapies are not powerful enough to counter the severity of the disease. We propose that the severity of the disease and many deaths are due to a local vascular problem due to activation of B1 receptors on endothelial cells in the lungs. SARS-CoV-2 enters the cell via ACE2, a cell membrane bound molecule with enzymatic activity that next to its role in RAS is needed to inactivate des-Arg⁹ bradykinin, the potent ligand of the bradykinin receptor type 1 (B1). In contrast to bradykinin receptor 2 (B2), the B1 receptor on endothelial cells is upregulated by proinflammatory cytokines. Without ACE2 acting as a guardian to inactivate the ligands of B1, the lung environment is prone for local vascular leakage leading to angioedema. Angioedema is likely a feature already early in disease, and might explain the typical CT scans and the feeling of people that they drown. In some patients, this is followed by a clinical worsening of disease around day 9 due to the formation antibodies directed against the spike (S)-antigen of the corona-virus that binds to ACE2 that could contribute to disease by enhancement of local immune cell influx and proinflammatory cytokines leading to damage. In parallel, inflammation induces more B1 expression, and possibly via antibody-dependent enhancement of viral infection leading to continued ACE2 dysfunction in the lung because of persistence of the virus. In this viewpoint we propose that a bradykinin-dependent local lung angioedema via B1 and B2 receptors is an important feature of COVID-19, resulting in a very high number of ICU admissions. We propose that blocking the B1 and B2 receptors might have an ameliorating effect on disease caused by COVID-19. This kinin-dependent pulmonary edema is resistant to corticosteroids or adrenaline and should be targeted as long as the virus is present. In addition, this pathway might indirectly be responsive to anti-inflammatory agents or neutralizing strategies for the anti-S-antibody induced effects, but by itself is likely to be insufficient to reverse all the pulmonary edema. Moreover, we provide a suggestion of how to ventilate in the ICU in the context of this hypothesis.

Background: Although no specific treatment for COVID 19 has been proven effective yet, some drugs with in vitro potential against SARS-CoV-2 virus have been proposed for clinical use. Hydroxychloroquine has in vitro anti-viral and immunomodulatory activity, but there is no current clinical evidence of its effectiveness on the outcome of the disease. Methods: We enrolled all 18-85 years old inpatients from Central Defense Hospital, Madrid, Spain, who were hospitalised due to COVID-19 and had a definitive outcome (either dead or discharged). We used a statistical survival analysis. Results: We analysed 220 medical records. 166 patients met the inclusion criteria. 48,8 % of patients not treated with HCQ died, versus 22% in the group of hydroxychloroquine (p=0,002). According to clinical picture at admission, hydroxychloroquine increased the mean cumulative survival in all groups from 1,4 to 1,8 times. This difference was statistically significant in the mild group. Conclusions: in a cohort of 166 patients between 18 to 85 years hospitalised with COVID-19, hydroxychloroquine treatment with an initial loading dose of 800mg improved patient survival when admitted in early stages of the disease. There was a non-statistically significant trend towards survival in all groups, which will need to be clarified in subsequent studies.

The coronavirus pandemic was declared by the World Health Organization (WHO) in 2020, and a global genetic vaccination program has been rapidly implemented as a fundamental solution. However, many countries around the world have reported that so-called genetic vaccines, such as those using modified mRNA encoding the spike protein and lipid nanoparticles as the drug delivery system, have resulted in post-vaccination thrombosis and subsequent cardiovascular damage, as well as a wide variety of diseases involving all organs and systems, including the nervous system. In this article, based on these circumstances and the volume of evidence that has recently come to light, we call the attention of medical professionals to the various risks associated with blood transfusions using blood products derived from people who have suffered from long COVID and from genetic vaccine recipients, including those who have received mRNA vaccines, and we make proposals regarding specific tests, testing methods, and regulations to deal with these risks. We expect that this proposal will serve as a basis for discussion on how to address post-vaccination syndrome and its consequences following these genetic vaccination programs.

We primarily study a possible link between 2021 COVID-19 vaccination uptake in Europe and monthly 2022 excess all-cause mortality, i.e., mortality higher than before the pandemic. Analyses of 31 countries weighted by population size show that all-cause mortality during the first nine months of 2022 increased more the higher the 2021 vaccination uptake; a one percentage point increase in 2021 vaccination uptake was associated with a monthly mortality increase in 2022 by 0.105 percent (95% CI, 0.075-0.134). When controlling for alternative explanations, the association remained robust, and we discuss the result emphasizing causality as well as potential ecological fallacy. Also, the study shows that 2021 all-cause mortality was lower the higher the vaccination uptake, but this association became non-significant when controlling for alternative explanations.

COVID-19, a new strain of coronavirus (CoV), was identified in Wuhan, China, in 2019. No specific therapies are available and investigations regarding COVID-19 treatment are lacking. Liu et al. (2020) successfully crystallised the COVID-19 main protease (M^pro), which is a potential drug target. The present study aimed to assess bioactive compounds found in medicinal plants as potential COVID-19 M^pro inhibitors, using a molecular docking study. Molecular docking was performed using Autodock 4.2, with the Lamarckian Genetic Algorithm, to analyse the probability of docking. COVID-19 M^pro was docked with several compounds, and docking was analysed by Autodock 4.2, Pymol version 1.7.4.5 Edu, and Biovia Discovery Studio 4.5. Nelfinavir and lopinavir were used as standards for comparison. The binding energies obtained from the docking of 6LU7 with native ligand, nelfinavir, lopinavir, kaempferol, quercetin, luteolin-7-glucoside, demethoxycurcumin, naringenin, apigenin-7-glucoside, oleuropein, curcumin, catechin, epicatechin-gallate, zingerol, gingerol, and allicin were -8.37, -10.72, -9.41, -8.58, -8.47, -8.17, -7.99, -7.89, -7.83, -7.31, -7.05, -7.24, -6.67, -5.40, -5.38, and -4.03 kcal/mol, respectively. Therefore, nelfinavir and lopinavir may represent potential treatment options, and kaempferol, quercetin, luteolin-7-glucoside, demethoxycurcumin, naringenin, apigenin-7-glucoside, oleuropein, curcumin, catechin, and epicatechin-gallate appeared to have the best potential to act as COVID-19 M^pro inhibitors. However, further research is necessary to investigate their potential medicinal use.

Background: COVID-19 vaccines have been linked to myocarditis which in some circumstances can be fatal. This systematic review aims to investigate potential causal links between COVID-19 vaccines and death from myocarditis using post-mortem analysis. Methods: We performed a systematic review of all published autopsy reports involving COVID-19 vaccination-related myocarditis through July 3^rd, 2023. All autopsy studies that include COVID-19 vaccine-induced myocarditis as a possible cause of death were included, without imposing any additional restrictions. Causality in each case was determined by three independent reviewers with cardiac pathology experience and expertise. Results: We initially identified 1,691 studies and, after screening for our inclusion criteria, included 14 papers that contained 28 autopsy cases. The cardiovascular system was the only organ system affected in 26 cases. In 2 cases, myocarditis was characterized as a consequence from multisystem inflammatory syndrome (MIS). The mean and median number of days from last COVID-19 vaccination until death was 6.2 and 3 days, respectively. Most of the deaths occurred within a week from the last injection. We established that all 28 deaths were causally linked to COVID-19 vaccination by independent adjudication. Conclusions: The temporal relationship, internal and external consistency seen among cases in this review with known COVID-19 vaccine-induced myocarditis, its pathobiological mechanisms and related excess death, complemented with autopsy confirmation, independent adjudication, and application of the Bradford Hill criteria to the overall epidemiology of vaccine myocarditis, suggests there is a high likelihood of a causal link between COVID-19 vaccines and death from suspected myocarditis in cases where sudden, unexpected death has occurred in a vaccinated person. Urgent investigation is required for the purpose of risk stratification and mitigation in order to reduce the population occurrence of fatal COVID-19 vaccine-induced myocarditis.

Currently, the world is struggling with the coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Prion-like domains are critical for virulence and the development of therapeutic targets; however, the prion-like domains in the SARS-CoV-2 proteome have not been analyzed. In this in silico study, using the PLAAC algorithm, we identified the presence of prion-like domains in the SARS-CoV-2 spike protein. Compared with other viruses, a striking difference was observed in the distribution of prion-like domains in the spike protein, since SARS-CoV-2 was the only coronavirus with a prion-like domain found in the receptor-binding domain of the S1 region of the spike protein. The presence and unique distribution of prion-like domains in the SARS-CoV-2 receptor-binding domains of the spike protein is particularly interesting, since although the SARS-CoV-2 and SARS-CoV S proteins share the same host cell receptor, angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 demonstrates a 10- to 20-fold higher affinity for ACE2. Finally, we identified prion-like domains in the α1 helix of the ACE2 receptor that interact with the viral receptor-binding domain of SARS-CoV-2. Taken together, the present findings indicate that the identified PrDs in the SARS-CoV-2 receptor-binding domain (RBD) and ACE2 region that interact with RBD have important functional roles in viral adhesion and entry.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused the Coronavirus Disease 2019 (COVID-19) worldwide pandemic in 2020. In response, most countries in the world implemented lockdowns, restricting their population’s movements, work, education, gatherings, and general activities in attempt to ‘flatten the curve’ of COVID-19 cases. The public health goal of lockdowns was to save the population from COVID-19 cases and deaths, and to prevent overwhelming health care systems with COVID-19 patients. In this narrative review I explain why I changed my mind about supporting lockdowns. First, I explain how the initial modeling predictions induced fear and crowd-effects [i.e., groupthink]. Second, I summarize important information that has emerged relevant to the modeling, including about infection fatality rate, high-risk groups, herd immunity thresholds, and exit strategies. Third, I describe how reality started sinking in, with information on significant collateral damage due to the response to the pandemic, and information placing the number of deaths in context and perspective. Fourth, I present a cost-benefit analysis of the response to COVID-19 that finds lockdowns are far more harmful to public health than COVID-19 can be. Controversies and objections about the main points made are considered and addressed. I close with some suggestions for moving forward.

Objectives Assess rates of adverse events (AE) after COVID-19 vaccines experienced by women of reproductive age, focusing on pregnancy and menstruation, using data collected by the US Centers for Disease Control and Prevention (CDC) Vaccine Adverse Events Reporting System (VAERS) database. Design Population-based retrospective cohort study. Setting US and global entries in US Centers for Disease Control and Prevention (CDC) Vaccine Adverse Events Reporting System (VAERS). Participants CDC VAERS entries from January 1, 1998 to June 30, 2022. Interventions None. Main Outcome Measures A proportional reporting ratio analysis is performed using data in the VAERS system comparing adverse events (AE) reported post-COVID-19 vaccines with that of post-Influenza vaccines. Results COVID-19 vaccines, when compared to the Influenza vaccines, are associated with a significant increase in AE with all proportional reporting ratios of > 2.0: menstrual abnormalities, miscarriage, fetal chromosomal abnormalities, fetal malformation, fetal cystic hygroma, fetal cardiac disorders, fetal arrhythmias, fetal cardiac arrest, fetal vascular malperfusion, fetal growth abnormalities, fetal abnormal surveillance, fetal placental thrombosis, low amniotic fluid, preeclampsia, premature delivery, preterm premature rupture of membrane, fetal death/stillbirth, and premature baby death (all p values were much smaller than 0.05). When normalized by time-available, doses-given, or persons-received, all COVID-19 vaccine AE far exceed the safety signal on all recognized thresholds. Conclusions Pregnancy complications and menstrual abnormalities are significantly more frequent following COVID-19 vaccinations than Influenza vaccinations. A worldwide moratorium on the use of COVID-19 vaccines in pregnancy is advised until randomized prospective trials document safety in pregnancy and long-term follow-up in offspring.

Novel coronavirus disease (COVID-19) has affected nearly 7 million individuals and claimed more than 0.4 million lives to date. There are several reports of gender differences related to infection and death due to COVID-19. This raises important questions such as “Whether there are differences based on gender in risk and severity of infection or mortality rate?” and “What are the biological explanation and mechanisms underlying these differences?” Emerging evidence has proposed sex-based immunological, genetic, and hormonal differences to explain this ambiguity. Besides biological differences, women have also faced social inequities and economic hardships due to this pandemic. Several recent studies have shown that independent of age males are at higher risk for severity and mortality in COVID-19 patients. Although susceptibility to SARS-CoV-2 was found to be similar across both genders in several disease cohorts, a disproportionate death ratio in men can be partly explained by the higher burden of pre-existing diseases and occupational exposures among men. From an immunological point of view, females can engage a more active immune response, which may protect them and counter infectious diseases as compared to men. This attribute of better immune responses towards pathogens is thought to be due to high estrogen levels in females. Here we review the current knowledge about sex differences in susceptibility, the severity of infection and mortality, host immune responses, and the role of sex hormones in COVID-19 disease.

The analysis reported here is unique in that it is the first study of the original data from the Pfizer/BioNTech BNT162b2 mRNA vaccine clinical trial (CA4591001) to be carried out by a group unaffiliated with the trial sponsor. Our study is a forensic analysis of the 38 trial subjects who died between July 27, 2020, the start of Phase 2/3 of the clinical trial, and March 13, 2021, the data end date of their 6-Month Interim Report. Phase 2/3 of the trial involved 44,060 subjects who were equally distributed into two groups and received Dose 1 of either the BNT162b2 mRNA vaccinated or the Placebo control (0.9% normal saline). At Week 20, when the BNT162b2 mRNA vaccine received Emergency Use Authorization from the U.S. FDA, subjects in the placebo arm were given the option to be BNT162b2 vaccinated. All but a few accepted. Surprisingly, a comparison of the number of subject deaths per week during the 33 Weeks of this study found no significant difference between the number of deaths in the vaccinated versus placebo arms for the first 20 weeks of the trial, the placebo-controlled portion of the trial. After Week 20, as subjects in the Placebo were unblinded and vaccinated, deaths among this still unvaccinated cohort of this group slowed and eventually plateaued. Deaths in the BNT162b2 vaccinated subjects continued at the same rate. Our analysis revealed inconsistencies between the subject data listed in the 6-Month Interim Report and publications authored by Pfizer/BioNTech trial site administrators. Most importantly, we found evidence of an over 3.7-fold increase in number of deaths due to cardiovascular events in BNT162b2 vaccinated subjects compared to Placebo controls. This significant adverse event signal was not reported by Pfizer/BioNTech. Potential sources of these data inconsistencies are identified.

Ongoing outbreak of pneumonia caused by novel coronavirus (2019-nCoV) began in December 2019 in Wuhan, China, and the number of new patients continues to increase. On the contrary to ongoing outbreak in China, however, there are limited secondary outbreaks caused by exported case outside the country. We here conducted simulations to estimate the impact of potential secondary outbreaks at a community outside China. Simulations using stochastic SEIR model was conducted, assuming one patient was imported to a community. Among 45 possible scenarios we prepared, the worst scenario resulted in total number of persons recovered or removed to be 997 (95% CrI 990-1,000) at day 100 and maximum number of symptomatic infectious patients per day of 335 (95% CrI 232-478). Calculated mean basic reproductive number (R0) was 6.5 (Interquartile range, IQR 5.6-7.2). However, with good case scenarios with different parameter led to no secondary case. Altering parameters, especially time to hospital visit could change the impact of secondary outbreak. With this multiple scenarios with different parameters, healthcare professionals might be able to prepare for this viral infection better.

The natural history of COVID-19 caused by SARS-CoV-2 is extremely variable, ranging from asymptomatic infection, to pneumonia, and to complications eventually fatal. We propose here the first model, explaining how the outcome of first, crucial 10-15 days after infection, hangs on the balance between the cumulative dose of viral exposure and the efficacy of the local innate immune response (natural IgA and IgM antibodies, MBL). If SARS-CoV-2 runs the blockade of this innate immunity and spreads from the upper airways to the alveoli in the early phases of the infections, it can replicate with no local resistance, causing pneumonia and releasing high amounts of antigens. The delayed and strong adaptive immune response (high affinity IgM and IgG antibodies) that follows, causes severe inflammation and triggers mediator cascades (complement, coagulation, and cytokine storm) leading to complications often requiring intensive therapy and being, in some patients, fatal. Strenuous exercise and high flow air in the incubation days and early stages of COVID-19, facilitates direct penetration of the virus to the lower airways and the alveoli, without impacting on the airway’s mucosae covered by neutralizing antibodies. This allows the virus to bypass the efficient immune barrier of the upper airways mucosa in young and healthy athletes. In conclusion, whether the virus or the adaptative immune response reach the lungs first, is a crucial factor deciding the fate of the patient. This “quantitative and time-sequence dependent” model has several implications for prevention, diagnosis, and therapy of COVID-19.

The COVID19 coronavirus SARS-CoV2 spreading in Wuhan and now worldwide has been shown to use angiotensin-converting enzyme 2 ACE2 as its host cell receptor, like the severe acute respiratory syndrome coronavirus (SARS-CoV). Epidemiology studies found different sex and age groups have different susceptibility to infection, and very skewed severity and mortality of the virus infection, with male, old age, and comorbidity being the most inflicted. Here by analyzing GTEx and other public data in 30 tissues across thousands of individuals, we found significantly higher expression in Asian females compared to males and other ethnic groups, an age dependent ACE2 expression decrease and a highly significant decrease in type II diabetic patients. Consistently, the most significant expression quantitative loci (eQTLs) contributing to high ACE2 expression are close to 100% in East Asians, >30% higher than other ethnic groups. Together with the shockingly common enrichment of viral infection pathways among ACE2 anti-expressed genes, binding of virus infection-related transcription factors at ACE2 regulatory regions, the repression of ACE2 expression by inflammatory cytokines and by type 2 diabetes, and the induction by estrogen and androgen (both decrease with age) established a negative correlation between ACE2 expression and CovID19 fatality at both population and molecular levels. Our results will be instrumental when designing potential prevention and treatment strategies for ACE2 binding coronaviruses in general.

The challenge regarding COVID-19 is to prevent complications and fatal evolution. Azithromycin (AZM) and hydroxychloroquine (HCQ) have proven their antiviral effect in vitro. We aimed to assess the efficacy and safety of AZM alone or combined to HCQ, prescribed, at an early stage, in patients with Covid-19, in a primary care setting. Eighty-eight patients received either no or a symptomatic treatment (NST) (n=34) or AZM alone (n=34) or AZM+HCQ (n=20). The efficacy end point was the time to clinical recovery and the safety end point was the occurrence of cardiovascular events. The mean (SD) times to achieve clinical recovery were respectively 25.8 days (11.1), 12.9 days (13.4) and 9.2 days (9.3), showing a statistically significant difference between NST and AZM alone (p<0.0001) or AZM+HCQ (p<0.0001). To improve the evidence level, a case-control analysis was performed on a sample of 57 patients (19/group) matched for age, sex and BMI. The statistical difference between NST and AZM was confirmed (p=0.0149) as well as the difference with AZM+HCQ (p=0.0002). No cardiac toxicity was recorded in any patient. No statistical difference was shown between AZM and AZM+HCQ groups, although the dual therapy tended to be more effective in patients over 50 years, based on an analysis using the cox model. In conclusion, AZM and AZM+HCQ favourably impacted the course of the disease. We need trials, ideally prospective/double blind, to show if a statistical difference can be evidenced with a broader group, and clarify the indications of each treatment depending on initial clinical presentation.

Background: A significant proportion of SARS-CoV-2-infected patients develops respiratory failure. Thromboembolism is also prevalent in coronavirus disease 2019 (Covid-19). Vitamin K plays a role in coagulation and possibly also in lung diseases. We therefore hypothesized that vitamin K is implicated in Covid-19 pathogenesis. Methods: 134 Covid-19 patients and 184 controls were included. Inactive vitamin K-dependent matrix Gla protein (i.e.dp-ucMGP) and prothrombin (i.e. PIVKA-II) were measured, which are inversely related to respectively extrahepatic and hepatic vitamin K status. Desmosine was measured to quantify elastic fiber degradation. Lung involvement and arterial calcifications severity were assessed by computed tomography. Results Dp-ucMGP was elevated in Covid-19 patients compared to controls (P=0.001). Higher dp-ucMGP was found in Covid-19 patients with poor compared to better outcomes (P=0.002). PIVKA-II was normal in 81.8%, mildly elevated in 14.0% and moderately elevated in 4.1% of Covid-19 patients not using vitamin K antagonists. Dp-ucMGP in Covid-19 patients was correlated with desmosine (P<0.001), thoracic aortic calcification (P<0.001) but not with pneumonia severity. Conclusions: Extrahepatic vitamin K status was severely reduced in Covid-19 patients, as reflected by elevated inactive MGP, and related to poor outcome. Procoagulant prothrombin activity remained preserved in the majority of Covid-19 patients, which is compatible with the increased thrombogenicity that is frequently observed in severe Covid-19. Impaired MGP activation was linked to accelerated elastic fiber degradation and premorbid vascular calcifications. A trial should assess whether increasing MGP and protein S activity by vitamin K administration improves Covid-19 outcomes.

Due to the health crisis caused by SARS-CoV-2, the creation of a new vaccine platform based on mRNA was implemented. Globally, around 13.32 billion COVID-19 vaccine doses of diverse platforms have been given, and up to this date, 69.7% of the total population received at least one injection of a COVID-19 vaccine. Although these vaccines prevent hospitalization and severe forms of the disease, increasing evidence has shown they do not produce sterilizing immunity, allowing people to suffer frequent re-infections. Recent research has also raised concerns that mRNA vaccines could induce immune tolerance, which, added to that caused by the virus itself, could complicate the clinical course of a COVID-19 infection. Furthermore, recent investigations have found high IgG4 levels in people who were administered two or more injections of mRNA vaccines. It has been suggested that an increase in IgG4 levels could have a protecting role by preventing immune over-activation, similar to that occurring during successful allergen-specific immunotherapy by inhibiting IgE-induced effects. Altogether, evidence suggests that the reported increase in the IgG4 levels detected after repeated vaccination with the mRNA vaccines is not a protective mechanism; rather, it may be a part of the immune tolerance mechanism to the spike protein that could promote unopposed SARS-CoV2 infection and replication by suppressing natural antiviral responses. IgG4-induced suppression of the immune system due to repeated vaccination can also cause autoimmune diseases, promotes cancer growth, and autoimmune myocarditis in susceptible individuals.

Currently, drug repurposing is an alternative to novel drug development for the treatment of COVID-19 patients. The antimalarial drug chloroquine (CQ) and its metabolite hydroxychloroquine (HCQ) are currently being tested in several clinical studies as potential candidates to limit SARS-CoV-2-mediated morbidity and mortality. CQ and HCQ (CQ/HCQ) inhibit pH-dependent steps of SARS-CoV-2 replication by increasing pH in intracellular vesicles and interfere with virus particle delivery into host cells. Besides direct antiviral effects, CQ/HCQ specifically target extracellular zinc to intracellular lysosomes where it interferes with RNA-dependent RNA polymerase activity and coronavirus replication. As zinc deficiency frequently occurs in elderly patients and in those with cardiovascular disease, chronic pulmonary disease, or diabetes, we hypothesize that CQ/HCQ plus zinc supplementation may be more effective in reducing COVID-19 morbidity and mortality than CQ or HCQ in monotherapy. Therefore, CQ/HCQ in combination with zinc should be considered as additional study arm for COVID-19 clinical trials.

Background. The main impetus behind the worldwide Covid-19 vaccination campaign in 2021 was to reduce the mortality attributed to SARS-CoV-2 infection in the preceding year. Nevertheless, rigorous analyses of the mortality benefits conferred by this massive vaccination effort have been lacking. Methods Statistics offers us an essential methodological approach for measuring the impacts of Covid-19 vaccination on public health. The mathematical relation between vaccinated-alive groups can be repeated between vaccinated-dead groups with relatively high statistical reliability because of the large population numbers involved. This method also confers greater statistical usefulness because it eliminates the Simpson effect. Results Calculations were performed for each of the following five(5) four-week intervals: weeks 35-38 (2021), weeks 39-42 (2021), weeks 43-46 (2021), weeks 47-50 (2021), and weeks 50(2021)-1(2022). The results obtained confirm that the mortality of the vaccinated coronavirus-infected groups was 14.5% higher on average than the mortality of non-vaccinated coronavirus-infected groups. Conclusions Vaccinated infected groups appear to have higher average mortality than their non-vaccinated infected counterparts. The findings suggest the legitimacy of extending the statistics between vaccinated living and vaccinated dead individuals for different age groups. Calculating the impact of Covid-19 vaccination on the mortality rate is a necessary step towards satisfying the first principle of medicine: “Primum non nocere”, “Do no harm”.

Background The World Health Organization has recently recognized Long COVID, calling the international medical community to strengthen research and comprehensive care of patients with this condition. However, if Long COVID pertains to children as well is not yet clear. Methods An anonymous, online survey was developed by an organization of parents of children suffering from persisting symptoms since initial infection. Parents were asked to report signs and symptoms, physical activity and mental health issues. Only children with symptoms persisting for more than four weeks were included. Results 510 children were included (56.3% females) infected between January 2020 and January 2021. At their initial COVID-19 infection, 22 (4.3%) children were hospitalized. Overall, children had persisting COVID-19 for a mean of 8.2 months (SD 3.9). Most frequent symptoms were: Tiredness and weakness (444 patients, 87.1% of sample), Fatigue (410, 80.4%), Headache (401, 78.6%), Abdominal pain (387, 75.9%), Muscle and joint pain (309, 60.6%), Post-exertional malaise (274, 53.7%), rash (267, 52.4%). 484 (94.9%) children had had at least four symptoms. 129 (25.3%) children have suffered constant COVID-19 infection symptoms, 252 (49.4%) have had periods of apparent recovery and then symptoms returning, and 97 (19.0%) had a prolonged period of wellness followed by symptoms. Only 51 (10.0%) children have returned to previous levels of physical activity. Parents reported a significant prevalence of Neuropsychiatric symptoms. Conclusions Our study provides further evidence on Long COVID in children. Symptoms like fatigue, headache, muscle and joint pain, rashes and heart palpitations, and mental health issues like lack of concentration and short memory problems, were particularly frequent and confirm previous observations, suggesting that they may characterize this condition. A better comprehension of Long COVID is urgently needed..

COVID-19, a rapidly spreading new strain of coronavirus, has affected more than 150 countries and received worldwide attention. The lack of efficacious drugs or vaccines against SARS-CoV-2 has further worsened the situation. Thus, there is an urgent need to boost up research for the development of effective therapeutics and affordable diagnostic against COVID-19. The crystallized form of SARS-CoV-2 main protease (Mpro) was demonstrated by a Chinese researcher Liu et al. (2020) which is a novel therapeutic drug target. This study was conducted to evaluate the efficacy of medicinal plant-based bioactive compounds against COVID-19 Mpro by molecular docking study. Molecular docking investigations were performed by using Molegro Virtual Docker 7 to analyze the inhibition probability of these compounds against COVID-19. COVID-19 Mpro was docked with 80 flavonoid compounds and the binding energies were obtained from the docking of (PDB ID: 6LU7: Resolution 2.16 Å) with the native ligand. According to obtained results, hesperidin, rutin, diosmin, apiin, diacetylcurcumin, (E)-1-(2-Hydroxy-4-methoxyphenyl)-3-[3-[(E)-3-(2-hydroxy-4- methoxyphenyl)-3-oxoprop-1-enyl]phenyl]prop-2-en-1-one, and beta,beta'-(4-Methoxy-1,3- phenylene)bis(2'-hydroxy-4',6'-dimethoxyacrylophenone have been found as more effective on COVID-19 than nelfinavir. So, this study will pave a way for doing advanced experimental research to evaluate the real medicinal potential of these compounds to cure COVID-19.

COVID-19 pandemic is a serious problem in the world today. The SARS-CoV-2 virus that causes COVID-19 has important proteins used for its infection and development, namely the protease and spike glycoprotein. The RBD (Receptor Binding Domain) of spike glycoprotein (RBD-S) can bind to the ACE2 (Angiotensin Converting Enzyme-2) receptor at the protease domain (PD) (PD-ACE2) of the host cell, thereby leading to a viral infection. This study aims to reveal the potential of compounds contained in Curcuma sp., Citrus sp., Alpinia galanga, and Caesalpinia sappan as anti SARS-CoV-2 through its binding to 3 protein receptors. The study was conducted by molecular docking using the MOE 2010 program (licensed from Faculty of Pharmacy UGM, Indonesia). The selected protein targets are RBD-S (PDB ID:6LXT), PD-ACE2 (PDB ID: 6VW1), and SARS-CoV-2 protease (PDB ID:6LU7). The affinities of bonds formed is represented as a docking score. The results show that hesperidin, one of the compounds in Citrus sp., has the lowest docking score for all three protein receptors representing the highest affinity to bind the receptors. Moreover, all of the citrus flavonoids possess good affinity to the respected receptors as well as curcumin, brazilin, and galangin, indicating that those compounds perform inhibitory potential for the viral infection and replication. In general, the results of this study indicate that Citrus sp. exhibit the best potential as an inhibitor to the development of the SARS-CoV-2, followed by galangal, sappan wood, and Curcuma sp. that can be consumed in daily life as prophylaxis of COVID-19.

Background: Coronavirus disease 2019 (COVID-19) pandemic are causing significant damages to many nations. For mitigating its risk, Japan’s Prime Minister called on all elementary, junior high and high schools nationwide to close beginning March 1, 2020. However, its effectiveness in decreasing disease burden has not been investigated. Methods: We used daily data on the report of COVID-19 and coronavirus infection incidence in Japan until March 31, 2020. Time series analysis were conducted using Bayesian method. Local linear trend models with interventional effect were constructed for number of newly reported cases of COVID-19, including asymptomatic infections. We considered that the effects of intervention start to appear 9 days after the school closure; i.e., on March 9. Results: The intervention of school closure did not appear to decrease the incidence of coronavirus infection. If the effectiveness of school closure began on March 9, mean coefficient α for effectiveness of the measure was calculated to be 0.08 (95% credible interval -0.36 to 0.65), and the actual reported cases were more than predicted, yet with rather wide credible interval. Sensitivity analyses using different dates also showed similar results. Conclusions: School closure carried out in Japan did not show the effectiveness to mitigate the transmission of novel coronavirus infection.

Background: Coronavirus disease 2019 (COVID-19) is a new viral respiratory disease and whether pregnant women are at increased risk of infection is unknown. Viral pneumonia is an important indirect cause of maternal death. Little is known about the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy. Objective: To describe the clinical characteristics of COVID-19 in pregnancy and their newborn infant, and we sought to explored whether the SARS-CoV-2 can be intrauterine vertically transmitted. Study Design: The study was a case series study conducted in the obstetric ward of Tongji Hospital affiliated to Huazhong University of science and technology, Wuhan, China. Demographic, clinical, laboratory and radiological profiles of the SARS-CoV-2 infection case series. A systematic testing procedure for SARS-CoV-2 infection using oropharyngeal swab, placenta tissue, vaginal mucus, and breast milk of mothers. and oropharyngeal swab, umbilical cord blood, and serum of newborns was conducted. Results: We have conducted the most thorough virological assessment to date, and we include a longer clinical observation in mother-infant dyads during hospitalization. The clinical course and outcomes of three pregnant women who acquired SARS-CoV-2 infection late pregnancy are described in mother-infant dyads. Two had caesarean delivery in their third trimester. All patients showed an uneventful perinatal course, and a successful outcome. No infants became infected by vertical transmission or during delivery. Conclusion: No evidence to suggest the potential risk of intrauterine vertical transmission in the case series and further in-depth study is needed. Both the pregnancy woman and infant showed fewer adverse maternal and neonatal outcomes.

The spread of 2019 novel coronavirus disease (COVID-19) throughout the world has been a severe challenge for public health. The human angiotensin-converting enzyme 2 (ACE2) has a remarkably high affinity binding to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). By the search for network database and re-analysis of pubic data, we found the level of ACE2 expression in adipose tissue was higher than that in lung tissue, which indicated the adipose tissue might be vulnerable to SARS-CoV-2 as well; the levels of ACE2 expressed by adipocytes and adipose progenitor cells were similar between non-obese individuals and obese individuals, but obese individuals have more adiposes so as to increase the number of ACE2-expressing cells; the expression of ACE2 in tumor tissues posed by five different types of cancers increased significantly compared with that in adjacent tissues. Thus, we suggest that more attentions might be given to obese individuals and the five types of cancer patients during the outbreak of COVID-19.

The novel coronavirus 2019 (COVID-19) pandemic is rapidly advancing despite public health measures. Pharmaceutical prophylaxis is an established approach to potentially control infectious diseases and is one solution to the urgent public health challenge posed by COVID-19. Screening and development of new vaccines and antivirals is expensive and time consuming while the repositioning of available drugs should receive priority attention as well as international government and agency support. Here we propose an old drug chloroquine (CQ) to be urgently repositioned as an ideal antiviral prophylactic against COVID-19. CQ has ability to block viral attachment and entry to host cells. Its proven clinical efficacy against a variety of viruses including COVID-19 and its current deployment in COVID-19 therapeutic trials strengthens its potential candidacy as a prophylactic. Furthermore, CQ has a long safety record, is inexpensive and widely available. Here we reviewed CQ's antiviral mechanisms, its laboratory efficacy activity against COVID-19, as well as CQ's pharmacokinetics in its established use against malaria and autoimmune diseases to recommend safe and potentially efficacious dose regimens for protection against COVID-19: a pre-exposure prophylaxis of 250-500mg daily and post-exposure prophylaxis at 8mg/kg/day for 3 days. We recommend further urgent research on CQ for COVID-19 prevention and urge that the above regimens be investigated in parallel with mass deployment by relevant agencies in attempts to contain the pandemic without unnecessary regulatory delays as benefits far outweigh risks or costs.

Evidence for the potential for airborne transmission of SARS-CoV-19 continues to accumulate, with important implications for healthcare workers, as well as the general public. Three lines of evidence support this conclusion.

The severity and outcome of coronavirus disease 2019 (COVID-19) largely depends on a patient’s age. Over 80% of hospitalizations are of those over 65 years of age with a 23-fold greater risk of death. In the clinic, COVID-19 patients most commonly present with fever, cough and dyspnea. Particularly in those over 65, it can progress to pneumonia, lung consolidation, cytokine release syndrome, endotheliitis, coagulopathy, multiple organ failure and death. Comorbidities such as cardiovascular disease, diabetes, obesity and hypertension increase the chances of fatal disease, but they alone do not explain the variability in COVID-19 symptoms. Here, we present the molecular differences between the young, middle-aged and elderly that may determine whether COVID-19 is a mild or life-threatening illness. We also discuss several biological age clocks that could be used in conjunction with genetic tests to identify both the mechanisms of the disease and individuals most at risk. Finally, based on these mechanisms, we discuss treatments that could increase survival in the elderly, not simply by inhibiting the virus, but by restoring patients’ ability to clear the infection.

The novel coronavirus pneumonia (COVID-19) is a contagious acute respiratory infectious disease whose causative agent has been demonstrated to be a novel virus of the coronavirus family, SARSCoV-2. A recent pre-print study has showed a heme attack on the 1-beta chain of hemoglobin by COVID19. Beta-thalassemia results of a default in the hemoglobin beta- chain synthesis. 1,5% global population are heterozygotes for this disease. In this study, by a multiple linear regression, we have analyzed the evolution of COVID-19 infection in three Italian regions (Puglia, Sardinia, Sicilia) with different beta-thalassemic prevalences, in order to search a link. The results have showed that betathalassemic heterozygote population prevalence is correlated to immunity against COVID-19, by a regression. This paper is only for academic discussion, the hypotheses and conclusions needs to be confirmed by further research .

The outbreak of novel coronavirus (COVID-19) infections in 2019 is in dire need of finding potential therapeutic agents. In this study, we used molecular docking to repurpose HIV protease inhibitors and nucleoside analogues for COVID-19, with evaluations based on docking scores calculated by AutoDock Vina and RosettaCommons. Our results suggest that Indinavir and Remdesivir possess the best docking scores, and comparison of the docking sites of the two drugs reveal a near perfect dock in the overlapping region of the protein pockets. After further investigation of the functional regions inferred from the proteins of SARS coronavirus, we discovered that Indinavir does not dock on any active sites of the protease, which may give rise to concern in regards to the efficacy of Indinavir. On the other hand, the docking site of Remdesivir is not compatible with any known functional regions, including template binding motifs, polymerization motifs and nucleoside triphosphate (NTP) binding motifs. However, when we tested the active form (CHEMBL2016761) of Remdesivir, the docking site revealed a perfect dock in the overlapping region of the NTP binding motif. This result suggests that Remdesivir could be a potential therapeutic agent. Clinical trials still must be done in order to confirm the curative effect of these drugs.

RLF-100 (Aviptadil), a synthetic form of Vasoactive Intestinal Peptide (VIP) is shown to block replication of the SARS-CoV-2 virus and has been granted Fast Track Designation by the US FDA for the treatment of Critical COVID-19 with Respiratory Failure. We describe the clinical course of the first patient treated with this investigational medication in an open label manner -- a 54 year old patient suffering antibody-mediated rejection of his double lung transplant who contracted COVID-19 with respiratory failure refractory to all currently available therapies. He received three infusions of RLF-100 under an FDA-approved emergency use IND. Within 24 hours of the third infusion, substantial improvement in oxygen saturation and radiographic improvement in characteristic COVID-19 pneumonitis was noted. He was discharged from intensive care at that point and scheduled for discharge to home at 1 week on room air. Despite an intervening hospitalization for trauma, he remains alive and free of respiratory failure at 28 days post treatment.

The symptoms most commonly reported by patients affected by coronavirus disease 2019 (COVID-19) include cough, fever, and shortness of breath. However, other major events usually observed in COVID-19 patients (e.g. high blood pressure, thrombosis, pulmonary embolism) seem to suggest that the virus is targeting the endothelium, one of the largest organs in the human body. Herein, we report both clinical and preclinical evidence supporting the hypothesis that the endothelium is a key target organ of COVID-19.

Covid-19 is a new coronavirus disease first described in December 2019. This respiratory illness is severe and potentially fatal. Severe cases make up to 15%, lethality ranges between 1.5 and more than 10 %. What is urgently needed is an efficient pharmacological treatment for the treatment of severe cases. During the infection of alveolar epithelial cells of the lung, the ACE2 receptor has a central function. The antimalarial drugs chloroquine phosphate (CQ) and hydroxychloroquine (HCQ) impair in vitro the terminal glycosylation of ACE2 without significant change of cell-surface ACE2 and, therefore, might be potent inhibitors of SARS-CoV-2 infections. Starting inhibition at 0.1 µM, CQ completely prevented in vitro infections at 10 µM, suggesting a prophylactic effect and preventing the virus spread 5 hours after infection. In a first clinical trial, CQ was effective in inhibiting exacerbation of pneumonia, improving lung imaging findings, promotion of virus-negative conversion, and shortening the disease. In addition, HCQ, which is three times more potent than CQ in SARS-CoV-2 infected cells (EC50 0.72 µM), was significantly associated with viral load reduction/disappearance in COVID-19 patients compared to controls. Theoretically, CQ and HCQ could thus be effectively used in the treatment of SARS-CoV pneumonia. From a pharmacological standpoint, however, the major problems of oral treatment with these drugs are possible severe side effects and toxicity. Concretely, this relates to (a) the inconsistent individual bioavailability of these drugs at the alveolar target cells, depending on intestinal resorption, hepatic first-pass metabolism and accumulation in liver, spleen and lung, and (b) the need for a relatively high concentration of 1-5 µM at the alveolar surface. Therefore, we propose in a first dose estimation the use of HCQ as an aerosol in a dosage of 2-4 mg per inhalation in order to reach sufficient therapeutic levels at the alveolar epithelial cells. By using a low-dose non-systemic aerosol, adverse drug reactions will markedly be reduced compared with oral application. This increase in tolerability enables a broader use for prevention and after contact with an infected person, which would be an advantage especially for the high-risk, often multi-morbid and elderly patients. Empirical data on self-medication with a one-week aerosol application by two of the authors is presented. Inhalation was well tolerated without relevant side effects.

SARS-CoV-2 (2019-nCoV), a novel coronavirus, caused the pneumonia outbreak in China and continue to expand. The host receptor for 2019-nCoV Angiotensin-converting enzyme 2 (ACE2), is the same as the host receptor for SARS-CoV. Targeting ACE2 holds the promise for preventing and inhibiting 2019-nCoV infection. Chinese Medicine herbs could be a valuable pool for identifying active compounds for treating infection of 2019-nCoV. In this study, we summarize several active compounds, including baicalin, Scutellarin, Hesperetin, Nicotianamine and glycyrrhizin that could have potential anti-2019-nCoV effects. We conduct molecular docking to predict their capacity for binding ACE2, which may prevent the 2019-nCoV infection. We propose that these selected compounds worth further investigation for preventing 2019-nCoV.

The current report represents a case of a 77-year-old man with Parkinson’s disease who died three weeks after receiving his third COVID-19 vaccination in January 2022. The patient was first vaccinated in May 2021 with the ChAdOx1 nCov- 19 vector vaccine, followed by two more doses with the BNT162b2 mRNA vaccine in July and December 2021. The family of the deceased requested an autopsy due to the ambivalent clinical features noted before death. The underlying illness (Parkinson’s disease) was confirmed by autopsy. However, no sign of a florid COVID-19 was discovered. Meanwhile, the immunohistochemical staining of the brain and heart revealed previously undiagnosed conditions. The brain, in distinctive, revealed multifocal necrotizing encephalitis with massive inflammatory lymphocyte infiltrates. In addition, the heart showed signs of serious myocarditis. Finally, immunohistochemical staining revealed that the SARS-CoV-2 spike protein was evident in the tissues investigated. Based on these immunohistochemical findings, it appears that the inflammatory changes in the patient's brain tissues are most likely the result of immunological processes. Concurrently, the absence of SARS-CoV-2 nucleocapsid-protein was evidenced, indicating that the detected spike-protein is unrelated to a SARS-CoV-2 infection. If such an infection was the cause of the spike protein, the SARS-CoV-2 nucleocapsid protein would also be detectable. As a consequence, the confirmed presence of the spike protein had to be attributed to the previous vaccination with the BNT162b2 mRNA vaccine that the deceased patient had received.

Background Critical patients with novel coronavirus pneumonia ( COVID-19) have worse outcome and high mortality. However, the histopathology of critical patient with COVID-19 remains undisclosed. Methods We performed the whole lung biopsy, and described the pathological changes of critical COVID-19 patient done with transplant by HE staining, immunohistochemistry and special staining observed under the microscopy. Findings The whole lungs displayed diffuse congestive appearance and partly haemorrhagic necrosis on gross examination. The haemorrhagic necrosis was prominently present in outer edge of the right lower lung. The cut surfaces of the lung displayed severe congestive and haemorrhagic changes. The main pathological changes showed massive pulmonary interstitial fibrosis, and partly hyaline degeneration, variable degrees of hemorrhagic pulmonary infarction. Small vessels hyperplasia, vessel wall thickening, lumen stenosis, occlusion and microthrombosis formation. Focal monocytes, lymphocytes and plasma cells infiltrating into pulmonary interstitium. Bronchiolitis and alveolitis with proliferation, atrophy, desquamation and squamous metaplasia of epithelial cells. Atrophy, vacuolar degeneration, proliferation, desquamation and squamous metaplasia in alveolar epithelial cells. Alveolar cavity congestion was prominent, and contained mucus, edema fluid, desquamated epithelial cells, and inflammatory cells. We also found several multinucleate giant cells and intracytoplasmic viral inclusion bodies. Special stains including Masson stain, sirius red staining, reticular fibers staining indicated massive pulmonary interstitial fibrosis. Immunohistochemistry showed positive for immunity cells including CD3, CD4, CD8, CD20, CD79a, CD5, CD38 and CD68. Interpretation We demonstrate the pathological findings of critical patient with COVID-19, which might provide a deep insight of the pathogenesis and severity of this disease.

There is a long trail of research studies testing the in vitro and in vivo efficacy of chloroquine and its derivatives in treating and preventing infection by various coronavirus species. More recent findings have highlighted the possibility of treating patients infected with the 2019 novel coronavirus, SARS-CoV-2. This review describes the mechanism of coronavirus infection, the mechanism of action of chloroquine, and summarizes the available literature highlighting the efficacy of chloroquine as an anti-coronavirus agent. These findings should encourage the wider scientific community to conduct thorough research on the possible efficacy of chloroquine and its derivatives in treating and preventing SARS-CoV-2 infection.

There is an urgent need to advance safe and affordable COVID-19 vaccines for low- and middle-income countries of Asia, Africa and Latin America. Such vaccines rely on proven technologies such as recombinant protein-based vaccines to facilitate its transfer for emerging market vaccine manufacturers. Our group is developing a two-pronged approach to advance recombinant protein-based vaccines to prevent COVID-19 caused by SARS CoV2 and other coronavirus infections. One vaccine is based on a yeast-derived (Pichia pastoris) recombinant protein comprised of the receptor binding domain (RBD) of the SARS-CoV formulated on alum and referred to as the CoV RBD219-N1 Vaccine. Potentially this vaccine could be used as a heterologous vaccine against COVID-19. A second vaccine specific for COVID-19 is also being advanced using the corresponding RBD of SARS-CoV-2. The first antigen has already undergone cGMP manufacture and is therefore “shovel ready” for advancing into clinical trials, following vialing and required GLP toxicology testing. Evidence for its potential efficacy to cross-protect against SARS-CoV-2 includes cross-neutralization and binding studies using polyclonal and monoclonal antibodies. Evidence in support of its safety profile include our internal assessments in a mouse challenge model using a lethal mouse adapted SARS strain, which show that SARS-CoV RBD 291N1 (when adsorbed to Alhydrogel®) does not elicit eosinophilic lung pathology. Together these findings suggest that recombinant protein-based vaccines based on the RBD warrant further development to prevent SARS, COVID-19 or other coronaviruses of pandemic potential.

We present a case of a 47-year-old male who died unexpectedly from acute pulmonary hemorrhage 555 days after completing the BNT162b2 (Pfizer) COVID-19 vaccination primary series. Before death, he exhibited symptoms of a mild respiratory infection. Despite a healthy medical history and no medication use, the patient’s condition rapidly deteriorated and he experienced severe respiratory distress, followed by cardiopulmonary arrest with evidence of profuse pulmonary bleeding. Autopsy findings revealed massive lung congestion without embolism, normal heart size, moderate coronary atherosclerosis without myocardial infarction, and no evidence of other hemorrhagic events. The patient tested negative for COVID-19 and other respiratory pathogens at autopsy. Despite these findings, the medical examiner determined the cause of death was attributed to atherosclerotic and hypertensive cardiovascular disease, without considering the recent pulmonary hemorrhage and unremarkable medical history. Investigation into the vaccine batch indicated a higher-than-average number of serious adverse events, including fatalities. The patient's BNT162b2 batch was among the top 2.8% for reported deaths. Moreover, the autopsy failed to investigate potential contributions from the vaccine, such as the presence of the Spike protein or related antibodies. The evidence suggests that the pulmonary hemorrhage, exacerbated by a viral infection, was the immediate cause of death, with the COVID-19 vaccine potentially playing a role in the development of cardiopulmonary pathology and hemorrhage. We propose autopsy protocols for COVID-19 vaccine recipients to better investigate vaccine-related pathologies among those with one or more prior injections.

Azithromycin has been shown to have a clinical efficacy against severe acute respiratory syndrome coronavirus 2 (SARS CoV-2); ivermectin has also demonstrated a remarkable experimental efficacy with a potential to be used for Coronavirus disease 2019 (COVID-19). Further, BCG vaccination is being considered for clinical trials aiming to test its potential for lowering COVID-19 morbidity and mortality. This article illustrates some structural and functional relationships that may gather these drugs and the author, basing on a combined pathophysiological and pharmacological approach, recommends the FDA-approved antidiarrhea drug; nitazoxanide, which has been previously suggested but unfortunately ignored, to be tested in combination with azithromycin for their potential activity against SARS CoV-2 soonest. The author recommends testing their combined administration as early during the clinical course of COVID-19 as possible. Further, basing on the same represented concept, the author recommends more trials for interferons to be tested against SARS CoV-2 especially in severe and critical cases.

More than 179,000 individuals have fallen ill of the Coronavirus disease (COVID-19) caused by the SARS-CoV-2 virus, which first emerged in China less than four months ago in December 2019. As of today, there exist no approved treatments against COVID-19. Vaccines are being developed, but they will take time, at least one year, to reach the population. Drug repositioning represents a fast track because already approved medicines have been broadly tested through multiple trials. We developed a repositioning strategy that mostly leads to candidates that are commonly used. The advantages are that they will facilitate proof of concept in humans through a “real-world evidence” approach and should be rapidly available to the population. We focus on the established research results that the unfolded protein response (UPR) and autophagy pathways of the host cells are essential to the life cycle of previously known coronaviruses. We performed the relevant bioinformatics analysis to understand and confirm if SARS-CoV-2 may interact with these druggable pathways. Based on these considerations, we prioritized two additional druggable pathways, which are important to the viral life cycle and tightly connected to UPR/autophagy signaling: the mitochondrial permeability transition pores (MPTP) and NLRP-3 inflammasome pathways. These four important pathways are perturbed in most major common diseases and have therefore been targeted by numerous broadly prescribed drugs. We have identified 97 approved drugs that are known to modulate these four identified pathways, and which represent, therefore, interesting repositioning candidates. Although it is indisputable that these drugs should never be used for immediate self-medication against COVID-19, we notice that some of them could also be prescribed to individuals who have COVID-19 comorbidities (e.g., hypertension). It is debated if these comorbidities are linked to the pathology itself (e.g., hypertension) or the drugs used to treat the pathology (e.g., sartans). Therefore, relevant preclinical tests and massive electronic health records (i.e., real-world evidence) must be used to pre-screen them and check the COVID-19 prognosis of individuals taking these drugs.

A novel coronavirus strain (severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first appeared in December 2019 and can cause acute respiratory distress syndrome and death. However, there are only limited therapy choices and no vaccine for SARS-CoV-2 is currently available. Here we report about a case of a SARS-CoV-2 caused pneumonia successfully treated with thalidomide. Thalidomide is an immunomodulatory and anti-inflammatory agent and was combined with a low-dose glucocorticoid. We suggest, that the effects of thalidomide might be related to regulating immunity, inhibiting the inflammatory cytokine surge, alleviating anxiety to reduce oxygen consumption, relieving vomit and lung exudation.

Studies in animal models have suggested that the ketogenic diet may be effective in the treatment of cancer. However, human cohort studies on the ketogenic diet have, thus far, failed to show benefits in cancer survival or in any other hard clinical endpoints of the disease. This paper presents a case report of a patient with glioblastoma multiforme. The patient had initially been treated with standard oncotherapy including surgery, radiotherapy and chemotherapy. Despite standard treatment, the patient experienced a recurrence of the glioblastoma seven months later. Subsequently, the patient refused radiotherapy and chemotherapy and opted to use the paleolithic ketogenic diet (PKD) as a stand-alone therapy. Following the adoption of the PKD, progression of the disease has been completely halted. At the time of writing, the patient has remained in remission for 48 months, is without side-effects and experiences an excellent quality of life without the use of any drugs.

Data on pathologic changes of the 2019 novel coronavirus disease (COVID-19) are scarce. To gain knowledge about the pathology that may contribute to disease progression and fatality, we performed post-mortem needle core biopsies of lung, liver, and heart in four patients who died of COVID-19 pneumonia. The patients’ ages ranged from 59 to 81, including 3 males and 1 female. Each patient had at least one underlying disease, including immunocompromised status (chronic lymphocytic leukemia and renal transplantation) or other conditions (cirrhosis, hypertension, and diabetes). Time from disease onset to death ranged from 15 to 52 days. All patients had elevated white blood cell counts, with significant rise toward the end, and all had lymphocytopenia except for the patient with leukemia. Histologically, the main findings are in the lungs, including injury to the alveolar epithelial cells, hyaline membrane formation, and hyperplasia of type II pneumocytes, all components of diffuse alveolar damage. Consolidation by fibroblastic proliferation with extracellular matrix and fibrin forming clusters in airspaces is evident. In one patient, the consolidation consists of abundant intra-alveolar neutrophilic infiltration, consistent with superimposed bacterial bronchopneumonia. The liver exhibits mild lobular infiltration by small lymphocytes, and centrilobular sinusoidal dilation. Patchy necrosis is also seen. The heart shows only focal mild fibrosis and mild myocardial hypertrophy, changes likely related to the underlying conditions. In conclusion, the post-mortem examinations show advanced diffuse alveolar damage, as well as superimposed bacterial pneumonia in some patients. Changes in the liver and heart are likely secondary or related to the underlying diseases.

An outbreak caused by coronavirus disease 2019 (COVID-19) occurred in Wuhan City, Hubei Province, China, in December 2019. Up to March 2, 2020, at least 80180 cases have been reported. Most of the patients had a history of visiting Hubei Province or contacting with people who had ever stayed in or passed by Hubei Province, or exposed to symptoms. Some patients got infected only from asymptomatic contacts. This study aimed to report the epidemic features and lab identification of a patient confirmed with COVID-19 infection only from asymptomatic contact.

SARS-CoV-2 is the causative agent for the ongoing COVID19 pandemic, and this virus belongs to the Coronaviridae family. Like other members of this family, the virus possesses a positive-sense single-stranded RNA genome. The genome encodes for the nsp12 protein, which houses the RNA-dependent-RNA polymerase (RdRP) activity responsible for the replication of the viral genome. A homology model of nsp12 was prepared using the structure of the SARS nsp12 (6NUR) as a model. The model was used to carry out in silico screening to identify molecules among natural products, or FDA approved drugs that can potentially inhibit the activity of nsp12. This exercise showed that vitamin B12 (methylcobalamin) may bind to the active site of the nsp12 protein. A model of the nsp12 in complex with substrate RNA and incoming NTP showed that Vitamin B12 binding site overlaps with that of the incoming nucleotide. A comparison of the calculated energies of binding for RNA plus NTP and methylcobalamin suggested that the vitamin may bind to the active site of nsp12 with significant affinity. It is, therefore, possible that methylcobalamin binding may prevent association with RNA and NTP and thus inhibit the RdRP activity of nsp12. Overall, our computational studies suggest that methylcobalamin form of vitamin B12 may serve as an effective inhibitor of the nsp12 protein.

Coronavirus disease 2019 (COVID-19) can lead to systemic coagulation activation and thrombotic complications. We investigated the incidence of objectively confirmed venous thromboembolism (VTE) in 198 hospitalized patients with COVID-19 in a single-center cohort study. Seventy-four patients (37%) were admitted to the intensive care unit (ICU). At time of data collection, 58 (29%) were still hospitalized and 14% had died. During a median follow-up of 5 days (IQR, 3-9), 33 patients (17%) were diagnosed with VTE of whom 22 (11%) had symptomatic VTE, despite routine thrombosis prophylaxis. The cumulative incidences of VTE at 7 and 14 days were 15% (95% CI, 9.3-22) and 34% (95% CI, 23-46), respectively. For symptomatic VTE, these were 11% (95% CI, 5.8-17) and 23% (95% CI, 14-33). VTE appeared to be associated with death (adjusted HR, 2.9; 95% CI, 1.02-8.0). The cumulative incidence of VTE was higher in the ICU (25% at 7 days 95% CI, 15-36, and 48% at 14 days, 95% CI, 33-61) than on the wards (any VTE and symptomatic VTE 6.5 % at 7 days (95% CI, 1.5-17) and 10% at 14 days (95% CI, 2.9-24)).The observed risk for VTE in COVID-19 is high, particularly in ICU patients, which should lead to a high level of clinical suspicion and low threshold for diagnostic imaging for DVT or PE. Future research should focus on optimal diagnostic and prophylactic strategies to prevent VTE and potentially improve survival.

Global differences in changes in the numbers of population-adjusted daily test-positive cases (NPDP) and deaths (NPDD) by COVID-19 were analyzed for 49 countries, including developed and developing countries. The changes as a proportion of national population were compared, adjusting by the beginning of test-positive cases increase (BPI) or deaths increase (BDI). Remarkable regional differences of more than 100 fold in NPDP and NPDD were observed. The trajectories of NPDD after BDI increased exponentially within 20 days in most countries. Machine learning analysis suggested that NPDD on 30 days after BDI was the highest in developed Western countries (1180 persons per hundred million), followed by countries in the Middle East (128), Latin America (97), and Asia (7). Furthermore, in Western countries with positive rates of the PCR test of less than 7.0%, the increase in NPDP was slowing-down two weeks after BPI, and subsequent NPDD was only 15% compared with those with higher positive rates, which suggested that the situation of testing might have affected the velocity of COVID-19 spread. The causes behind remarkable differences between regions possibly include genetic factors of inhabitants because distributions of the race and of the observed infection increasing rates were in good agreement globally.

Introduction: Lyme disease is a tickborne illness that generates controversy among medical providers and researchers. One of the key topics of debate is the existence of persistent infection with the Lyme spirochete, Borrelia burgdorferi, in patients who have been treated with recommended doses of antibiotics yet remain symptomatic. Persistent spirochetal infection despite antibiotic therapy has recently been demonstrated in non-human primates. We present evidence of persistent Borrelia infection despite antibiotic therapy in patients with ongoing Lyme disease symptoms. Materials & Methods: In this pilot study, culture of body fluids and tissues was performed in a randomly selected group of 12 patients with persistent Lyme disease symptoms who had been treated or who were being treated with antibiotics. Cultures were also performed on a group of 10 control subjects without Lyme disease. The cultures were subjected to corroborative microscopic, histopathological and molecular testing for Borrelia organisms in four independent laboratories in a blinded manner. Results: Motile spirochetes identified histopathologically as Borrelia were detected in culture specimens, and these spirochetes were genetically identified as Borrelia burgdorferi by three distinct polymerase chain reaction (PCR) methods. Spirochetes identified as Borrelia burgdorferi were cultured from the blood of seven subjects, from the genital secretions of ten subjects, and from a skin lesion of one subject. Cultures from control subjects without Lyme disease were negative for Borrelia using these methods. Conclusions: Using multiple corroborative detection methods, we showed that patients with persistent Lyme disease symptoms may have ongoing spirochetal infection despite antibiotic treatment, similar to findings in non-human primates. The optimal treatment for persistent Borrelia infection remains to be determined.

Since mid-December of 2019, coronavirus disease 2019 (COVID-19) has been spreading from Wuhan, China. As of February 21, total 75,773 confirmed cases worldwide have spread to more than two dozen countries. Transmission of COVID-19 can occur early in the course of infection since SARS-CoV-2 viral loads in asymptomatic patients are similar to that in the symptomatic patients. Therefore, more sensitive diagnostic methods are needed to detect early phase of the infection to prevent secondary or tertiary spreads. Here, we compare the RT-PCR confirmatory test results using two different SARS-CoV-2 viral RNAs from two Korean COVID-19 confirmed cases.RT-PCR method targeting the RdRP gene, which was recommended by WHO guideline, was less sensitive than targeting N genes (as per CDC guideline). Because many countries follow the WHO guideline, our findings may contribute to the early diagnosis of COVID-19.

The COVID-19 pandemics has had an unprecedented global impact, and the COVID-19 mass vaccination campaign has been commonly regarded as crucial to overcome the pandemics. Since all-cause mortality is the best way to measure the consequences of a health intervention, the present study was devised to analyze the all-cause mortality data of the United Kingdom (UK), which are made publicly available broken down by vaccination status. Data from January to May 2022 were retrospectively collected and analyzed according to age groups and vaccination status and the relative risk (RR) for all-cause mortality was calculated in comparison to the corresponding unvaccinated groups. All-cause mortality RR was also calculated from January to May 2021 for vaccinated people. Results show that the all-cause mortality RR was higher in people who received one or two doses of COVID-19 vaccines throughout the whole period and in any of the age groups considered. People vaccinated with three doses more than 21 days earlier had RRs lower than unvaccinated people, which however linearly increased over time. RR in vaccinated people of all ages in comparison to unvaccinated people were lower in January-May 2021, however they steadily grew over time. The finding that all-cause mortality RR in vaccinated in comparison to unvaccinated people increases over time requires careful examination to understand the underlying factors. Meanwhile, all the other major countries should undertake a systematic collection of all-causes mortality broken down by vaccination status, and mass vaccination campaigns should be suspended.

Abstract: A primary action of vitamin D is regulation of gene transcription. Many cell types possess genes that make antimicrobial peptides (AMPS) (endogenous antibiotics), recently discovered to be regulated by vitamin D. Two examples are cathelicidin and beta defensins, both bioactive against many different bacteria, fungi, mycobacteria, parasites and viruses. The signal transduction pathway is triggered by sensing microorganisms via cell surface receptors, causing intracellular production of calcitriol (1,25(OH)2D) and vitamin D receptors, leading to upregulation of AMP production. Serum 25(OH)D concentrations required to sustain adequate AMP production to eradicate infections are unknown. Vitamin D3 is photosynthesized in skin in amounts ranging from 10,000 (250 mcg) to 25,000 (625 mcg) International Units (IU) from 7-dehydrocholesterol after whole-body exposure to one minimal erythemal dose (MED) of ultraviolet B (UVB) radiation, and is impacted by many factors including geographic localities, seasonal changes and skin pigmentation. We and others have reported extended daily oral dosing with these amounts of vitamin D3 safe. We routinely observe serum 25(OH)D concentrations below 20ng/ml on new admissions, which have been reported insufficient to sustain AMP production. In contrast serum 25(OH)D concentrations above 100ng/ml have been reported after serial UVB treatments for psoriasis. Little vitamin D naturally occurs in food, and insufficient sun exposure may be causing worldwide deficiency. We review evidence suggesting that higher daily intakes of vitamin D3 than the currently recommended 600 (15 mcg) IU/day may be necessary to sustain AMP production in the face of an overwhelming infection, particularly in non-Hispanic blacks, a high risk population suffering the worst outcomes from COVID-19. We propose that increased vitamin D supplementation could provide a safe and cost-effective way to protect all populations from infections, in particular those from pandemic COVID-19.

The pharmacology of azithromycin, and the actions of certain bee products, suggest the possibility of overlap with the pathophysiology of COVID-19 at several points in the disease process. First, intercellular epithelial tight junctions of the respiratory tract serve as a critical barrier to invaders. Pathophysiological factors capable of disrupting this epithelial barrier include viral virulence factors such as those observed for other coronaviruses; virulence factors derived from potentially synergistic pathogens such as Candida albicans and Porphyramonas gingivalis; and imbalances in the host inflammatory response. Azithromycin, and to a lesser extent, certain bee products, appear to have actions that oppose such processes. Second, the matrikine PGP or its derivatives may contribute to risk in individuals at high risk for serious COVID-19 infection, especially during reactivation; but azithromycin is capable of modulating PGP in some contexts. Third, the most serious COVID-19 infections are associated with massive upregulation of inflammatory cytokines such as IL-6, TNF alpha, and other inflammatory cytokines. The anti inflammatory actions of azithromycin and bee derived products such as melittin are potentially capable of modulating these processes, as well. Azithromycin is already in current use as a treatment for COVID-19; however, it's utility as a protector of epithelial barrier function would be most likely to be realized in prophylactic context rather than in a treatment context. Similarly, since the anti inflammatory effects of bee products take time, their effectiveness of melittin and other bee products would be expected to be maximized in a prophylactic context. In the context of the current pandemic, prophylaxis with azithromycin, bee products, or both, might be warranted for individuals at high risk for serious COVID-19 infection.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has provoked major stresses on the health care systems of several countries, and caused the death of more than a quarter of a million people globally, mainly in the elderly population with pre-existing pathologies. Previous studies with coronavirus (SARS-CoV) point to gender differences in infection and disease progression with increased susceptibility in male patients, indicating that estrogens may be associated with physiological protection against the coronavirus. Therefore, the objectives of this work are threefold. First, we aim to summarize the SARS-CoV-2 infection pathway and the roles both the virus and patient play in COVID-19 (Coronavirus disease 2019) progression, clinical symptomology, and mortality. Second, we detail the effect estrogen has on viral infection and host infection response, including its role in both the regulation of key viral receptor expression and the mediation of inflammatory activity. Finally, we describe how ERs (estrogen receptors) and RAGE (receptor for advanced glycation end-products) play a critical role in metabolic pathways, which we envisage could maintain a close interplay with SARS-CoV and COVID-19 mortality rates, despite a current lack of research directly determining how. Taken together, we present the current state of the field regarding SARS-CoV-2 research and illuminate where research is needed to better define the role both estrogen and metabolic comorbidities have in the COVID-19 disease state, which can be key in screening potential therapeutic options as the search for effective treatments continue.

As the outbreak of COVID-19 has accelerated, an urgent need for finding strategies to combat the virus is growing. Thus, gaining more knowledge on the pathogenicity mechanisms of SARS-CoV-2, the causing agent of COVID-19, and its interaction with the immune system is of utmost importance. Although this novel virus is not well known yet, its structural and genetic similarity with SARS-CoV as well as the comparable pattern of age-mortality relations suggest that the previous findings on SARS can be applicable for COVID-19. Therefore, a systems biology study was conducted to investigate the most important signaling pathways activated by the virus. The results were then validated through a literature review on COVID-19 and the other closely related viruses, SARS and MERS. Interferons have shown to play a crucial role in the defense against coronavirus diseases. CoV can impede the interferon induction in humans. Moreover, STAT1, a key protein in the interferon-mediated immune response, is antagonized by the virus. This could explain the increased response threshold of immune cells to IFNs during CoV infections. A vivid correlation between the innate immune response threshold and the fatality rates in COVID-19 can be found. Differences in the dynamics of the interferon-related innate immune responses in children, adults, and elderly may explain the reported fatality rates. The increased mortality rates in the elderly can be explained by the higher threshold of interferon-mediated immune responses. Earlier induction of interferons in children and their less developed immune system could contribute to their near to zero fatality rate. Administration of interferon-inducing agents, such as poly (ICLC), could reduce the mortality of SARS at the very early stages of the disease. Interferon-γ combination with an interferon-I might induce synergistic effects and maximize the benefits. However, in-depth research is needed to validate it and determine the optimum dosage and timing to prevent unwanted results. Such interventions can act as a double-edged sword and aid the imbalance of the immune reactions, which may occur at the later stages of the disease. With the advancement of the disease and the virus overload, the responses would shift toward immnopathogenic over-reactions and probably cytokine storm. Moderating the activity of the immune system and supportive care in such conditions might be the optimum approach.

In the past decades, several new diseases have emerged in new geographical areas, with pathogens including Ebola, Zika, Nipah, and coronaviruses (CoVs). Recently, a new type of viral infection has emerged in Wuhan City, China, and initial genomic sequencing data of this virus does not match with previously sequenced CoVs, suggesting a novel CoV strain (2019-nCoV), which has now been termed as severe acute respiratory syndrome CoV-2 (SARS-CoV-2). Although Coronavirus disease 2019 (COVID-19) is suspected to originate from an animal host (zoonotic origin) followed by human-to-human transmission, the possibility of other routes such as food-borne transmission should not be ruled out. Compared to diseases caused by previously known human CoVs, COVID-19 shows less severe pathogenesis but higher transmission competence, as is evident from the continuously increasing number of confirmed cases globally. Compared to other emerging viruses such as Ebola virus, avian H7N9, SARS-CoV, or MERS-CoV, SARS-CoV-2 has shown relatively low pathogenicity and moderate transmissibility. Codon usage studies suggest that this novel virus may have been transferred from an animal source such as bats. Early diagnosis by real-time PCR and next-generation sequencing has facilitated the identification of the pathogen at an early stage. Since, no antiviral drug or vaccine exists to treat or prevent SARS-CoV-2, potential therapeutic strategies that are currently being evaluated predominantly stem from previous experience with treating SARS-CoV, MERS-CoV, and other emerging viral diseases. In this review, we address epidemiological, diagnostic, clinical, and therapeutic aspects, including perspectives of vaccines and preventive measures that have already been globally recommended.

Objective: To recommend how physicians can best respond to families whose hopes for a miracle via divine intervention influence their medical decisions, like, for example, making them not want to withdraw ventilatory support in cases of poor neurologic prognosis because they are still hoping for God to intervene. Methods: Auto-ethnographic analysis of chaplaincy experience in this clinical context yields a nuanced 90-second, point-of-care spiritual intervention physicians can use to address the religious aspect of families who base medical decisions on their hopes for a miracle via divine intervention. Explanation of how spiritual intervention dovetails with existing physician communication protocol for responding to families hoping for a miracle. Results: Spiritual intervention for religious aspect of miracle-hoping families is integrated into existing physician communication protocol for responding to families hoping for a miracle with recommendations for utilization of existing communication technology when necessary. Conclusion: Properly addressing the religious dimension of families hoping for a miracle may be helpful for physicians interested in decreasing their own stress levels, improving outcomes for this clinical context, and ensuring that unintentional discrimination does not perpetuate racial disparities in end-of-life care.

According to current literature and preliminary data, hydroxychloroquine (HCQ) seems potentially effective in the treatment of patients with Covid-19 pneumonia. The concentrations of HCQ in lungs might be well above that of plasma. Most likely, this property of HCQ provides effective drug concentrations in lungs. HCQ has a gradual onset of action in the treatment of rheumatic diseases. This could be valid for the treatment of Covid-19 pneumonia. It was suggested that regular HCQ administration in animals for a certain time might result in gradual accumulation of HCQ in tissues. Reduced perfusion, somewhat distorted architecture of lung tissue, edema and, suggested gradual accumulation of HCQ in lung tissue might cause reduced HCQ concentrations in pneumonic areas of the lungs in Covid-19 pneumonia. Patients with Covid-19 pneumonia and extensive lung involvement might have less HCQ concentrations in their lungs than patients having limited lung involvement. Furthermore, patients with Covid-19 pneumonia and extensive lung involvement might have more viral load than patients having limited lung involvement. That’s why treatment of patients with advanced Covid-19 pneumonia using HCQ might result in treatment failure, however HCQ might be effective in the treatment of patients with mild and moderate Covid-19 pneumonia. Using HCQ in Covid-19 pneumonia prophylaxis seems logical since providing enough accumulation of HCQ in the healthy lungs, before the arrival of the SARS-CoV-2 virus, might prevent Covid-19 pneumonia. However, the purpose of this paper is not to recommend using or not using HCQ for the treatment or for the prophylaxis of Covid-19 pneumonia. The purpose of this paper is only to try to bring a new perspective on the role of HCQ in the treatment or in the prophylaxis of Covid-19 pneumonia. This paper proposes only hypotheses, which need further researches to be confirmed.

In deaths and diseases attributed to tobacco smoke cardiovascular events exceed cancer and respiratory diseases. Second hand smoke (SHS) promotes the development of arteriosclerosis and can also trigger acute changes of endothelial function and of blood coagulability. Indoor smoking bans reduced coronary syndrome and myocardial infarction 10-20% within one year and were followed by sustainable decreases of stroke and diabetes. With a smoke-free hospitality industry people recognized tobacco smoke as an air pollutant, smoking in public was denormalized and social acceptance of smoking in front of children and pregnant women decreased also in homes and in cars. Combined effects with ambient air pollution are proven for active smoking and suspected for SHS. Contamination with third hand smoke (THS, “cold smoke”) persists for months in homes and cars, creating secondary pollutants that in some cases are more toxic (e.g., tobacco-specific nitrosamines). Remnants found in air, dust, and on surfaces (carpets, wallpapers, upholstery, soft toys) were associated with their metabolites in saliva and urine of children and with elevated levels of nicotine on hands and cotinine in urine of nonsmokers residing in homes previously occupied by smokers. In animal experiments effects of THS were found on thrombogenesis, insulin resistance through oxidative stress, on the developing immune system, lipid metabolism and alterations in liver, lung, skin and behavior. Much less is known about health effects for bystanders from the aerosols exhaled during “vaping” of e-cigarettes, but nicotine and other toxins from e-cigarettes are certainly a hazard, which should be prevented by the use of dermal and oral nicotine products, which are safer for nicotine replacement and without risk for bystanders.

A novel coronavirus called 2019-nCoV was recently found in Wuhan, Hubei Province of China, and now is spreading across China and other parts of the world. 2019-nCoV spreads more rapidly than SARS-CoV. Unfortunately, there is no drug to combat the virus. It is of high significance to develop a drug that can combat the virus effectively before the situation gets worse. It usually takes a much longer time to develop a drug using traditional methods. For 2019-nCoV, it is now better to rely on some alternative methods to develop drugs that can combat such a disease effectively since 2019-nCoV is highly homologous to SARS-CoV. In this paper, we first collected virus RNA sequences from the GISAID database, translated the RNA sequences into protein sequences, and built a protein 3D model using homology modeling. Coronavirus main protease is considered to be a major therapeutic target, thus this paper focused on drug screening based on the modeled 2019-nCov_main_protease structure. The deep learning based method DFCNN, developed by our group, can identify/rank the protein-ligand interactions with relatively high accuracy. DFCNN is capable of performing virtual screening quickly since no docking or molecular dynamic simulation is needed. DFCNN identifies potential drugs for 2019-nCoV protease by performing drug screening against 4 chemical compound databases. Also, we performed drug screening for all tripeptides against the binding site of 2019-nCov_main_protease since peptides often show better stability, more bio-availability and negligible immune responses. In the end, we provided the list of possible chemical ligands and peptide drugs for experimental validation.

Most recently, an outbreak of severe pneumonia caused by the infection of 2019-nCoV, a novel coronavirus first identified in Wuhan, China, imposes serious threats to public health. Many important aspects about 2019-nCoV remain largely unknown, among which, the limitation of antiviral therapies represents one of the most critical problems. More recently, it was confirmed that human ACE2 is the receptor for the entry of 2019-nCoV into lower respiratory tract epithelial cells. Give this observation, it is thus expected that the virus could be inhibited if we decrease the expression of ACE2. Here by screening two databases, Connectivity Map (CMap) and our JeaMoon Map (JMap), we identified a number of candidate agents that decrease ACE2 expression. CMap analysis identified 5 compounds, among which, Azathioprine is a possible therapeutic strategy for anti-2019-nCoV. Moreover, JMap analysis revealed a number of comounds, biologics, and traditional Chinese medicine, among which, Andrographis, Urtica, Sambucus, Astragalus, valproic acid, butyrate, and epoxomicin represent the most significant and possible strategies for anti-2019-nCoV therapies. This study provides a number of clues and possible therapeutic strategies for 2019-nCoV prevention and treatment.

Smoking is a risk factor for respiratory infections and there is reasonable concern that it may affect COVID-19 susceptibility and severity. Recent studies have focused on the interaction between smoking (and nicotine) and ACE2 expression, suggesting that ACE2 up-regulation could contribute to enhanced viral cell entry. However, case series have shown that there is an unexpectedly low prevalence of smoking among hospitalized COVID-19 cases. Since early April, we were the first to hypothesize that dysfunction of the nicotinic cholinergic system (NCS) may be implicated in the pathophysiology of severe COVID-19. We recently reported that many of the clinical manifestations of severe COVID-19 could be explained by dysregulation of the NCS. In this study, we present an amino acid sequence in the receptor binding domain of the SARS-CoV-2 Spike glycoprotein which is homologous to a sequence of a snake venom toxin. We present the 3D structural location of this “toxin-like” sequence on the Spike Glycoprotein. These findings suggest that SARS-CoV-2 could potentially interact with acetylcholine receptors causing dysregulation of the NCS and the cholinergic anti-inflammatory pathway.

COVID-19 is frequently associated with a coagulopathy with severe consequences. The mechanisms leading to a pro-coagulant state in these patients is multifactorial, including tissue destruction and inflammatory mechanisms. Based on the analysis of publicly available interactomes, we propose that SARS-CoV-2 infection causes a deficiency in C1 esterase inhibitor (C1-INH), a pathogen-specific mechanism that may help explain the pro-coagulant state in COVID-19 patients.

The very first infected novel coronavirus case (COVID-19) was found in Hubei, China in Dec. 2019. The COVID-19 pandemic has spread over 215 countries and areas in the world, and has significantly affected every aspect of our daily lives. At the time of writing this article, the numbers of infected cases and deaths still increase significantly and have no sign of a well-controlled situation, e.g., as of 14 April 2020, a cumulative total of 1,853,265 (118,854) infected (dead) COVID-19 cases were reported in the world. Motivated by recent advances and applications of artificial intelligence (AI) and big data in various areas, this paper aims at emphasizing their importance in responding to the COVID-19 outbreak and preventing the severe effects of the COVID-19 pandemic. We firstly present an overview of AI and big data, then identify their applications in fighting against COVID-19, next highlight challenges and issues associated with state-of-the-art solutions, and finally come up with recommendations for the communications to effectively control the COVID-19 situation. It is expected that this paper provides researchers and communities with new insights into the ways AI and big data improve the COVID-19 situation, and drives further studies in stopping the COVID-19 outbreak.

COVID-19 breakout in Italy has caused a huge number of severely ill patients with a serious increase in mortality. Although lungs seem to be the main target of the infection very few information are available about liver involvement in COVID-19 infection, that could possibly evocate a systemic disease targeting a lot of organs. Since now there are no reports of large series of histological evaluation of liver morphology in this setting. Knowledge of histological liver findings connected to clinical data is crucial in management of this disease.Post-mortem wedge liver biopsies from 48 patients died for COVID-19 infection were available from two main hospitals located in northern Italy, Lombardy; all sample were obtained during autopsies. No patient has a significant clinical complain of liver disease or signs of liver failure before and during hospitalization; for each of them laboratory data focused on liver were available. All liver samples showed minimal inflammation features; on the other side, many histological pictures compatible with vascular alterations were observed, characterized by portal vein braches number increase associated with lumen massive dilatation, partial or complete recent luminal thrombosis of portal and sinusoidal vessels, fibrosis of portal tract, focally severely enlarged and fibrotic. Our preliminary results concerning histological liver involvement in COVID-19 infection confirm the clinical impression that liver failure is not a main concern and this organ is not the target of significant inflammatory damage; histopatological findings are highly suggestive for marked alteration of intrahepatic blood vessel network secondary to systemic alterations induced by virus that could target, besides lung parenchyma, cardiovascular system, coagulation cascade or endothelial layer of blood vessels.

Coronaviruse disease (COVID-19) outbreak has created an emergency globally, and social distancing and isolation is the only solution to prevent its spread. Several countries have announced fully locked on to tackle this pandemic. The recent COVID-2019 has shaken the globe with incidence cases of more than half-million cases, and a mortality toll of more than twenty thousand to date. The coronavirus family is inclusive of pathogen of both – animal species and humans, encapsulating the isolated severe acute respiratory syndrome coronavirus (SARS-CoV). Researchers round the globe have been dexterously working to decode this lethal virus. Many mathematical frameworks have also been depicted which have helped to understand the dynamics of the COVID-19. Research on coronaviruses continues to explore various aspects of viral replication and pathogenesis to understanding the predilection of these viruses to switch between species, to develop an infection in a new host, and to identify significant reservoirs of coronaviruses will dramatically aid in our potential to prophesize when and where potential epidemics may occur. Many of the non-structural and accessory proteins encoded by the viruses remain unclear and unknown. This systematic review highlights the current situation of the pandemic, virus genomic composition, pathogenesis, symptomatology, diagnosis, and prognosis along with mathematical models of disease transmission and dynamics.

Exposure to vaccine lipid nanoparticles, mRNA, adenoviral DNA, and or Spike protein from one of the approved Covid-19 vaccines, or through secondary exposure, as through blood transfusion, is a potential source of harm. Blood reactions are an acknowledged side-effect of Covid-19 vaccination, not limited to hemolysis, paroxysmal nocturnal hemoglobinuria, chronic cold agglutinin disease, immune thrombocytopenia, haemophagocytosis, hemophagocytic lymphohistiocytosis, and many other blood related conditions. The observation of adverse events has motivated investigation into the cardiovascular mechanisms of harm by Covid-19 vaccines, and the biodistribution of vaccine contents. Biodistribution may not be limited to the body of the vaccine recipient, as a growing body of evidence demonstrates the possibility of secondary exposure to vaccine particles. These can be via bodily fluids and include the following routes of exposure: blood transfusion, organ transplantation, breastfeeding, and possibly other means. As covid-19 vaccines are associated with an increased risk of stroke, the persistence of vaccine artifacts in the blood presents a possible threat to a recipient of a blood donation from a vaccinated donor who suffered from vaccine induced thrombosis or thrombocytopenia. (VITT) We assess the feasibility and significance of these risks through an overview of the case report literature of blood disorders in vaccinated individuals, pharmacovigilance reports from the US Vaccine Adverse Events Reporting System (VAERS) and a meta-analysis of the available literature on organ transplants from vaccinated organ donors. Our analysis establishes biological mechanistic plausibility, a coherent safety signal in pharmacovigilance databases for secondary vaccine contents exposure (for the cases of blood transfusion and breastfeeding) and also an elevated level of adverse events in organ transplants from VITT-deceased donors, echoing increases in organ transplantation related complications seen in national statistics for some countries. Secondary exposure to vaccine artifacts is a potential explanation for some of the cases put forth, and requires a deeper investigation.

Epidemiological data indicate that 5.8% of cancer deaths world-wide are attributable to alcohol consumption. The risk of cancer is higher in tissues in closest contact on ingestion of alcohol, such as the oral cavity, pharynx and esophagus. The risk of these cancers is increased even in people who have only one alcoholic drink per day. However, since ethanol is not mutagenic and the carcinogenic metabolite of ethanol (acetaldehyde) is mostly produced in the liver, it is not clear why alcohol use preferentially exerts a local carcinogenic effect. It is well known that ethanol causes cell death at the concentrations present in alcoholic beverages; however, this effect has been overlooked probably because dead cells cannot give rise to cancer. Here I discuss that the cytotoxic effect of ethanol on the cells lining the oral cavity, pharynx and esophagus activates the division of the stem cells located in deeper layers of the mucosa to replace the dead cells. Every time stem cells divide, they become exposed to unavoidable errors associated with cell division (e.g., mutations arising during DNA replication and chromosomal alterations occurring during mitosis) and also become highly vulnerable to the genotoxic activity of endogenous and exogenous DNA-damaging agents (e.g., reactive oxygen species, acetaldehyde and tobacco carcinogens). Alcohol consumption probably increases the risk of developing cancer of the oral cavity, pharynx and esophagus by promoting the accumulation of cell divisions in the stem cells that maintain these tissues in homeostasis. Because the cytotoxic activity of ethanol is concentration-dependent, the risk of these cancers will not only increase with increasing amounts of ethanol, but also with increasing concentrations; an ounce of whisky is probably more carcinogenic when taken undiluted than when taken mixed with non-alcoholic beverages. The local cytotoxic effect of ethanol can also explain the known synergistic effect of alcohol and tobacco use on the risk of these cancers. Understanding the mechanisms of carcinogenicity of alcohol is important to reinforce the epidemiological evidence and to raise public awareness of the strong link between alcohol consumption and cancer.

Aims and Background: People living with mental disorders experience a disproportionately higher burden of tobacco-related disease than the general population. Long-term substitution with less harmful nicotine products could reduce the tobacco-related harm among this population. This study investigated the views and preferences of people with mental health disorders about different nicotine products and their use as long-term substitutes for cigarettes. Methods: Semi-structured focus group discussion followed by a brief questionnaire. The discussion transcripts were analysed for content and themes and quantitative data summarised with descriptive statistics. Results: Twenty-nine participants took part in four focus groups. Vaping devices were the most acceptable nicotine products discussed, however preferences for nicotine products were idiosyncratic and varied along aesthetic, pragmatic, sensory and symbolic dimensions. The concept of tobacco harm reduction was unfamiliar to participants, however they generally agreed with the logic of replacing cigarettes with less harmful nicotine products. Barriers to activating tobacco harm reduction included the symbolism of smoking and quitting; the importance placed on health; the consumer appeal of alternatives; and cost implications. Discussion and Conclusion: Engaging this population in tobacco harm reduction options will require communication that challenges black and white thinking (a conceptual framework in which smoking cigarettes or quitting all nicotine are the only legitimate options) as in practice this serves to support the continuance of smoking. Consumers should be encouraged to trial a range of nicotine products to find the most acceptable alternative to smoking that reduces health harms. Providing incentives to switch to nicotine products could help overcome barriers to using less harmful nicotine products among mental health consumers.

There is currently a lack of pathologic data on the novel coronavirus (SARS-CoV-2) pneumonia, or COVID-19, from autopsy or biopsy. Two patients who recently underwent lung lobectomies for adenocarcinoma were retrospectively found to have had COVID-19 at the time of surgery. These two cases thus provide important first opportunities to study the pathology of COVID-19. Pathologic examinations revealed that, apart from the tumors, the lungs of both patients exhibited edema, proteinaceous exudate, focal reactive hyperplasia of pneumocytes with patchy inflammatory cellular infiltration, and multinucleated giant cells. Hyaline membranes were not prominent. Since both patients did not exhibit symptoms of pneumonia at the time of surgery, these changes likely represent an early phase of the lung pathology of COVID-19 pneumonia.

Coronavirus disease 2019 (COVID-19) has been declared a global pandemic by the World Health Organization on March 11, 2020. COVID-19 is caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-Cov-2). Although primarily a respiratory disease, cardiovascular complications of COVID-19 have been increasingly recognized. In addition, higher fatality has been reported in COVID-19 patients with underlying cardiovascular diseases. Cancer survivors have a considerably increased risk for premature cardiovascular diseases, mainly due to cardiotoxic cancer treatments. Therefore, it is foreseeable that cancer survivors will be more vulnerable to cardiovascular complications caused by COVID-19. In this review, three scenarios for increased cardiovascular complications of COVID-19 in cancer patients are proposed. In the first scenario, cardiotoxic cancer treatment and COVID-19 synergize to exacerbate direct myocardial damage. In the second scenario, cardiotoxic cancer treatment leads to a reduced cardiac reserve in cancer survivors, making them more vulnerable to COVID-19 in a “two-hit” model. The third scenario suggests that several shared risk factors may aggravate cardiovascular complications caused by both cancer treatment and COVID-19. Taken together, cancer survivors may be more vulnerable to cardiovascular complications when challenged by the COVID-19, and special cardiovascular care should be given to these patients.

Smokeless tobacco (ST) products vary significantly in their oral carcinogenicity. Much is known about the differences in chemical, but not bacterial, constituents of these products. In this study, we explore the composition and function of the bacteriome in ST products from 4 countries using q-PCR and 16S rRNA-based next generation sequencing. The bacterial load (16S rRNA copies/gram) was lowest in Swedish snus (3.4E+6) and highest in Yemeni shammah (6.6E+11). A total of 491 species-level taxa, many of which are potentially novel, belonging to 178 genera and 11 phyla were identified. Species richness and diversity were highest for Swedish snus and lowest for Yemeni shammah. Bacillus, Paenibacillus, and Oceanobacillus spp. were the most abundant in American snuff; species of Pseudomonas, Massilia, Propionibacterium, Puniceispirillum and Gloeothece predominated in Swedish snus. In Sudanese toombak, Facklamia, Desemzia, Atopostipes and Lysinibacillus spp. accounted for the majority of the bacteriome. Yemeni shammah exclusively contained Bacillus spp. PICRUSt functional prediction showed that genes encoding cadmium/zinc and nickel transport systems were enriched in the presumptively “high carcinogenicity” products. The bacteriome of ST products thus differed qualitatively, quantitatively and functionally. The relevance of these differences, particularly with respect to nickel and cadmium, to oral carcinogenesis warrants further investigation.

The spillover of a virus from one host species to another requires both molecular and ecological risk factors to align. While extensive research both before and after the emergence of SARS-CoV-2 in 2019 implicates horseshoe bat as the significant reservoir genus for the new coronavirus, it remains unclear why it emerged at this time. One massive disruption to human-animal contact in 2019 is linked to the on-going African swine fever virus (ASFV) pandemic. This began in Georgia in 2007 and was introduced to China in 2018. Pork is the major meat source in the Chinese diet. Severe fluctuations in the pork market prior to December 2019, may have increased the transmission of zoonotic pathogens, including severe acute respiratory syndrome–related coronaviruses, from wildlife to humans, wildlife to livestock and non-local animals to local animals. The major production and consumption regions for pork are geographically separated in China. The dramatic shortage of pork following restrictions of pig movement and culling resulted in price increases, leading to alternative sources of meat and unusual animal and meat movements nationwide often involving wildlife and thus greatly increased opportunities for human-Sarbecovirus contacts. Pork prices were particularly high in southern provinces (Guangdong, Guangxi, Fujian, Jiangxi, Hunan, and Hubei), where wildlife is farmed on different scales and more frequently consumed. Shandong experienced the biggest losses in pork production (~1.7 million metric tons), which is also the largest mink farming province. Hence, human exposure to SARS-CoV-2 from wildlife or infected animals are more likely to have taken place in 2019, when China was experiencing the worst effects of the ASFV pandemic.

Rationale: Examining trends in patient characteristics, processes of care and outcomes, across an epidemic, provides important opportunities for learning. Objectives: To report and explore changes in admission rates, patient characteristics, processes of care and outcomes for all patients with COVID-19 admitted to intensive care units (ICUs) in England, Wales and Northern Ireland. Methods: Population cohort of 10,287 patients with COVID-19 in the Case Mix Programme national clinical audit from 1 February to 2 July, 2020. Analyses were stratified by time period (pre-peak, peak, post-peak) and geographical region. Multivariable logistic regression was used to estimate differences in 28-day mortality, adjusting for patient characteristics over time. Main results: Admissions to ICU peaked simultaneously across regions on 1 April, with ongoing admissions peaking ten days later. Compared with pre- and post-peak periods, patients admitted during the peak were slightly younger but had greater respiratory and renal dysfunction. Use of invasive ventilation and renal replacement reduced over time. Twenty-eight-day mortality reduced from 43.5% (95% CI 41.6% to 45.5%) pre-peak to 34.3% (95% CI 32.3% to 36.2%) post-peak; a difference of −8.8% (95% CI: −5.2%, −12.3%) after adjusting for patient characteristics. London experienced the highest admission rate and had higher mortality during the peak period but a greater reduction in post-peak mortality. Conclusion: This study highlights changes in patient characteristics, processes of care and outcomes, during the UK COVID-19 epidemic. After adjusting for the changes in patient characteristics and first 24-hour physiology, there was substantial improvement in 28-day mortality over the course of the epidemic.

Background: Vasoactive Intestinal Peptide (VIP) is known to bind to and protect the Alveolar Type II cell by blocking replication of the SARS-CoV-2 virus, upregulating surfactant production, blocking apoptosis, and blocking cytokine effects. RLF-100 (Aviptadil), a synthetic form of Vasoactive Intestinal Peptide (VIP) has been granted Fast Track Designation and is currently in phase 2/3 placebo-controlled trials. FDA has granted Emergency Use IND and Expanded Access Protocol approval for the use of RLF-100 in patients whose comorbidities render them ineligible for inclusion in the ongoing pivotal trial. Methods: This report describes the first 6 patients with Acute Respiratory Failure in Critical COVID-19, enrolled under Emergency Use IND were treated with three successive 12-hour infusions of intravenous Aviptadil at 50/100/150 pmol/kg/hr, while continuing to receive maximal ICU care. Results: Median patient follow-up time is 14 days. So far, all treated patients have survived. Improved radiographic appearance of typical “ground glass” COVID-19 features to varying degrees is seen in all patients within 72 hours. Improvement in blood oxygenation is seen in all patients, with complete remission from respiratory failure in 4 of 6 patients. An average 56% reduction in inflammatory markers was seen, together with a median 4 point reduction in the NIAID Ordinal Scale. 2/6 patients were discharged from the hospital and 1 patient was downgraded to the general medicine floor. Comment: The short term survival of 6/6 patients with respiratory failure in the setting of COVID-19 and major comorbidity is the most dramatic response ever seen with an antiviral agent. Improvement in radiographic appearance, oxygenation requirement, and inflammatory markers is consistent with in vitro evidence of direct anti-viral effect.

Systematic reviews of 591 primary studies of the modes of transmission for SARS-CoV-2 show significant methodological shortcomings and heterogeneity in the design, conduct, testing and reporting of SARS-CoV-2 transmission. While this is partly understandable at the outset of a pandemic, evidence rules of proof for assessing the transmission of this virus are needed for pre-sent and future pandemics of viral respiratory pathogens. We review the history of causality as-sessment related to microbial etiologies with a focus on respiratory viruses and suggest a hierar-chy of evidence to integrate clinical, epidemiologic, molecular and laboratory perspectives on transmission. The hierarchy, if applied to future studies, should narrow the uncertainty over the twin concepts of causality and transmission of human respiratory viruses. We attempt to address the translational gap between the current research evidence and the assessment of causality in the transmission of respiratory viruses with a focus on SARS-CoV-2. Experimentation, consistency and independent replication of research alongside our proposed framework provide a chain of evidence that can reduce the uncertainty over the transmission of respiratory viruses and increase the level of confidence in specific modes of transmission, informing the measures that should be undertaken to prevent transmission.

Severe outbreaks of infectious disease occur throughout the world with some reaching the level of an international pandemic: Coronavirus (COVID-19) is the most recent to do so. As such pandemics cause extensive loss of lives, hamper industrial operations, and cause economic losses in both developing and developed countries, it is critical to establish common standards of accuracy in the determination and reporting of cases. In particular, there are current concerns that countries are hiding or incorrectly reporting cases of COVID-19. In this paper, we set out a mechanism for using Zipf's law to establish the accuracy of international reporting of COVID-19 cases via a determination of whether an individual country's COVID-19 reporting follows a power-law for confirmed, recovered, and death cases. We observe that the probability of Zipf's law (P-values) for COVID-19 confirmed cases show that Uzbekistan has the highest P-value of 0.940, followed by Belize (0.929), and Qatar (0.897). For COVID-19 recovered cases, Iraq had the highest P-value of 0.901, followed by New Zealand (0.888), and Austria (0.884). Furthermore, for COVID-19 death cases, Bosnia and Herzegovina had the highest P-value of 0.874, followed by Lithuania (0.843), and Morocco (0.825). China, where the COVID-19 pandemic began, is a significant outlier in recording P-values lower than 0.1 for the confirmed, recovered, and death cases. This raises important questions, not only for China but also any country whose data exhibits P-values below this threshold. The main application of this work is to serve as an early warning for the World Health Organization (WHO) and other health regulatory bodies to perform more investigations in countries where COVID-19 datasets deviate significantly from Zipf's law. To this end, we also provide a tool for illustrating Zipf's law P-values on a global map in order to report anomalies.

Background: Smoking, including environmental tobacco smoke (ETS) exposure is a well-known risk factor for diabetes. Low socioeconomic status, especially lack of education, also is a risk factor for diabetes. Therefore, we assessed the association of education and smoking status, including ETS exposure, with the prevalence of diabetes. Methods: Data were from the 2007–2013 Korea National Health and Nutritional Evaluation Survey (KNHANES). Multivariable logistic regression examined associations between various lifestyle and health factors and prevalence of diabetes while controlling for potential confounding variables. Subgroup analysis was performed according to smoking status to determine factors associated with diabetes. Results: Of 19,303 individuals analyzed, 1,325 (11.4%) had diabetes. Greater average age, male sex, lower educational level, unemployment, and coexisting health problems were significantly associated with diabetes. Individuals with only elementary, middle, or high school level education had significantly greater odds ratios (p<0.05) compared to college graduates; smokers and nonsmokers exposed to ETS had significantly greater OR (p<0.05) than nonsmokers unexposed to ETS. Subgroup analysis of diabetics according to smoking status revealed significant associations (p<0.05) for diabetic nonsmokers exposed to ETS with female sex, single status, elementary level education, urban residence, National Health Insurance (NHI), hypertension, no alcohol intake, and no moderate physical activity. For diabetic smokers, there were significant associations (p<0.05) with elementary education, urban residence, lack of moderate physical activity, no alcohol intake, and NHI. Conclusions: The results suggested that smoking status, including ETS exposure, was associated with a higher prevalence of diabetes especially in populations with less education. Thus, we should direct efforts for controlling diabetes toward individuals with lower levels of education, and those who are smokers and nonsmokers exposed to ETS.

In response to the COVID-19 pandemic, the Philippines placed the majority of the country under enhanced community quarantine, restricting the movement of most of its 100 million plus population. These aggressive measures were initiated on March 15, 2020 and intensified on March 17. According to official data, the number of confirmed COVID-19 cases has exponentially increased during this period, but it is important to note that the number of patients tested also substantially increased during the same period. It is not conclusive that widespread transmission of COVID-19 only started in March and our analysis suggests that community transmission was happening earlier. In discussing extended quarantine measures, it is important to properly understand the trends and recognize the limitations of the data. The unintended consequences on the population, especially in lower-middle income countries with fragile health systems like the Philippines, must be carefully considered.

Almost 6% of cancers worldwide are attributable to alcohol consumption. Approximately half of them occur in tissues highly exposed to ethanol, such as the oral cavity, pharynx, upper larynx and esophagus. However, since ethanol is not mutagenic and the carcinogenic metabolite of ethanol (acetaldehyde) is mainly produced in the liver, it is unclear why alcohol consumption preferentially causes a local carcinogenic effect. We recently hypothesized that the cytotoxic activity of ethanol could explain the high risk of these cancers in alcohol users. Here we report that short-term exposures (2-3 seconds) to ethanol concentrations between 10% and 15% start to cause a marked cytotoxic effect on human epithelial keratinocytes in a concentration-dependent manner. After discussing new evidence that cancer is the end-result of the accumulation of cell divisions in stem cells, we explain why regular alcohol consumption imposes a high risk of cancer on these tissues. Briefly, the cytotoxicity of ethanol reduces the lifespan of the cells lining these tissues. The stem cells located in deeper layers need to divide more often than usual to renew the damaged epithelia. The accumulation of cell divisions in stem cells leads to the accumulation of cancer-promoting errors (e.g., mutations arising during DNA replication) that increase their risk of malignant transformation. Cell division also exposes the DNA of the stem cells to the genotoxic activity of acetaldehyde and tobacco carcinogens. We propose that choosing alcoholic beverages containing non-cytotoxic concentrations of ethanol, or diluting ethanol to non-cytotoxic concentrations, is a simple way to reduce the risk of cancer of the oral cavity, pharynx, larynx and esophagus in alcohol users. This preventive strategy may also abolish the known synergistic effect of alcohol drinking and tobacco smoking on the risk of these cancers.

The infected and fatal cases of Coronavirus Disease 2019 (COVID-19) keep increasing around the world, to explore the infection routes and pathogenesis of 2019-nCoV could be meaningful for prevention and treatment of COVID-19. Previous studies showed that the oral cavity is at potentially high risk of 2019-nCoV infection. The ACE2 receptor of 2019-nCoV was reported could express on oral epithelium and salivary glands, and 2019-nCoV could be detected in patients’ saliva. Recently, the amblygeustia were found to widely exist in the COVID-19 patients. To explore the potential mechanism of amblygeustia, we performed further analysis via independent in-house single-cell profiles. Our results showed that ACE2 was inclined to express in taste cells, which indicated that 2019-nCoV may invade into taste cells at the early stage of COVID-19, and lead to the amblygeustia of patients. Above findings about the 2019-nCoV and COVID-19 in oral cavity are valuable and enlightening for future epidemic prevention strategy.

Culture, gender and religion are closely linked each other’s, profoundly affect the role of each person within the Society, and also affect the ability to access to the health resources. We are now living a worldwide crisis due to the SARS-CoV-2 pandemic. In order to appropriately tackle it, an alliance between science, politics and citizens is needed. In this article, we summarize current evidences of how religions can represent, on one hand, a risk moment for spreading the virus (in relation with overcrowded events), on the other, a precious opportunity to engage people, and in particular minorities, in fighting the pandemic. To win this fight, we need a multicultural approach that takes into account every aspect of human life, and among these religion, which influences so much culture, everyday life and well-being.

Misinformation during the COVID-19 outbreak has shaped our perception of the disease. Some people thinkthe disease is a bioweapon while others are convinced that it is a hoax. Heightened anxiety often producesfearful rumors, some of which are absurd while others seem plausible and are laced with some truths. But, how does misinformation affect disease spread? In this paper, we construct a mathematical model parameterized by Ugandan data, to study the effect of misinformation on community COVID-19 spread. The analysis shows that misinformation leads to high number of COVID-19 cases in a community, and the effect is highest in the rumour initiators and spreaders. This analysis underscores the importance of addressing misinformation in COVID risk communication.

The novel COVID-19 disease is a contagious acute respiratory infectious disease whose causative agent has been demonstrated to be a new virus of the coronavirus family, SARS- CoV-2. Multiple studies have already reported that risk factors for severe disease include older age and the presence of at least one of several underlying health conditions. However, a recent physiopathological report and the French COVID-19 scientific council have postulated a protective effect of tobacco smoking. Thanks to a meta-analysis, we have been able to demonstrate the statistical significance in this regard of twelve series from China, France and in the US, reporting three different smoking status (current smoker,former smoker, with a smoking history) as well as disease severity (with respectively odds-ratio of 1.78 [1.08-3.10], 4.60 [3.13-7.17], 2.74 [0.63-5.89]). Subsequently and using a Bayesian approach we have established that past, and present smoking is associated with more severe COVID-19 outcomes. Finally, we refute claims linking general population smoking status (N=O(10^8) or O(10^9)) to much smaller disease course series (N=O(10^4)). The latter point in particular is presented to stimulate academic discussion, and must be further investigated by well-designed studies.

Background: Early-stage interventions in a potential pandemic are important tounderstand as they can make the difference between runaway exponential growththat is hard to turn back and stopping the spread before it gets that far. COVID-19 is an interesting case study because there have been very different outcomesin different localities. These variations are best studied after the fact if precisionis the goal; while a pandemic is still unfolding less precise analysis is of value inattempting to guide localities in the early stages to learn lessons of those that pre-ceded them. Methods: I examine three factors that could differentiate strategy: asymptomaticspread, differences in use of the Bacillus Calmette-Guerin (BCG) tuberculosis vac-cine and cloth face masks.Results:Differences in disease progression as well as the possibility of alternativestrategies to prevent COVID-19 from entering the runaway phase or damping itdown later can be elucidated by a study of asymptomatic infection. A study todemonstrate not only what fraction are asymptomatic but how contagious they arewill also inform policy on universal mask wearing. Conclusions: While a COVID-19 outbreak is at a level that makes accurate trace-and test possible, investigation of asymptomatic transmission is viable and shouldbe attempted to enhance understanding of spread and variability in the disease aswell as policy options for slowing the spread.

CoVID-19 is a multi-symptomatic disease which has made a global impact due to its ability to spread rapidly, and its relatively high mortality rate. Beyond the heroic efforts to develop vaccines, which we will not discuss, the response of scientists and clinicians to this complex problem has reflected the need to detect CoVID-19 rapidly, to diagnose patients likely to show adverse symptoms, and to treat severe and critical CoVID-19. Here we aim to encapsulate these varied and sometimes conflicting approaches and the resulting data in terms of chemistry and biology. In the process we highlight emerging concepts, and potential future applications that may arise out of this immense effort.

Since its inception in December 2019, Covid-19 has challenged the global scientific community. Some treatments were used in this infection, but doubts still persist regarding the use of medications ¹. More severe cases complicate with endothelial dysfunction, excess thrombin synthesis and decreased fibrinolysis which, associated with hypoxemia, lead to a hypercoagulability state ² and some authors indicate the use of anticoagulants for these ³. For mild cases, doubts remain regarding this indication. We will report the case of a patient with mild symptoms of covid-19, complicated by inferior mesenteric vein thrombosis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is characterized by a high mortality of elderly men with age-related comorbidities. In most of these patients, uncontrolled local and systemic hyperinflammation induces severe and often lethal outcomes. The aging process is characterized by the gradual development of a chronic subclinical systemic inflammation (inflamm-aging) and by acquired immune system impairment (immune senescence). Here, we advance the hypothesis that some key features of aging contribute to the disproportionate SARS-CoV-2 mortality suffered by elderly men. At least four well-recognized aging-related characteristics that are strongly expressed in older men go some way towards explaining why these patients account for the vast majority of fatalities: i. the presence of subclinical systemic inflammation without overt disease, ii. a blunted acquired immune system and type I interferon response due to the chronic inflammation; iii. the downregulation of ACE2 (SARS-CoV-2 receptor), which triggers inflammation, particularly in patients with age-related comorbid diseases such as type II diabetes; and iv. accelerated biological aging, as measured by epigenetic and senescence markers (e.g. telomere shortening) associated to the chronic inflammatory state. Though typical of the aged, especially of elderly men, it is conceivable that these features are also shared by some subsets of the younger population. The high mortality rate of SARS-CoV-2 infection suggests that clarification of the mechanisms of inflamm-aging and immune senescence can help combat not only age-related disorders but also SARS-CoV-2 infection.

Background. The Weekly Mortality Cycle among CoViD-19 patients has been studied.Methods. Mortality data obtained from the 'Worldometer' website were analyzed with a comparison of absolute values, percentages, and p-value. Results. For patients suffering from CoViD-19, the most favorable or the safest days of the week were Sundays and Mondays. Conclusion. The weekly cycle with decreased mortality on Sundays and Mondays is a unique phenomenon observed among victims of CoViD-19. Presumably the decreased mortality on certain days of the week related to the optimized therapeutic protocols used on the "safest days".

Despite needs for new therapies and improvements in existing approaches in cardiovascular, pulmonary, endocrine, and renal disease, investment in these areas is lagging relative to other specialties. This article summarizes a meeting of key stakeholders of U.S. Food and Drug Administration (FDA) officials, representatives from academia, national organizations, and patients and caregivers. The purpose was to identify and discuss high-priority issues, establish areas of common interest, and explore opportunities for collaboration. During the meeting (September 2016), the construct of a “multimorbidity continuum” emerged, in which chronic diseases are understood as their effects on the whole rather than individual organ systems. Cross-disciplinary priorities included: 1) the need to generate greater high-quality evidence at lower cost; 2) the imperative to develop and implement patient-centered approaches to clinical investigations; 3) the importance of trial participation in under-represented populations, particularly with comorbid conditions, and 4) the need for progress in tobacco regulation. Representatives from each therapeutic area reported on their consensus priorities, and FDA representatives discussed the agency’s role in facilitating broader approaches to therapeutic development and evaluation of disease as linked across organ systems rather than in isolation, and emphasized the importance of patient engagement, collaboration and communication across stakeholders.

Philip Morris International (PMI) has developed the Population Health Impact Model (PHIM) to quantify, in the absence of epidemiological data, the effects of marketing a candidate modified risk tobacco product (cMRTP) on the public health of a whole population. Various simulations were performed to understand the harm reduction impact on the U.S. population over a 20-year period under various scenarios. The overall reduction in smoking attributable deaths (SAD) over the 20-year period was estimated as 934,947 if smoking completely went away and between 516,944 and 780,433 if cMRTP use completely replaces smoking. The reduction in SADs was estimated as 172,458 for the World Health Organization (WHO) 2025 Target and between 70,274 and 90,155 for the gradual cMRTP uptake. Combining the scenarios (WHO 2025 Target and cMRTP uptake), the reductions were between 256,453 and 268,796, depending on the cMRTP effective dose. These results show how a cMRTP can reduce overall population harm additionally to existing tobacco control efforts.

On the 9th March 2020, the first patient with COVID-19 was admitted to ICU in the Royal Gwent Hospital, Newport, Wales. We prospectively recorded the rate of ICU admissions of 52 patients with COVID-19 over 60 days, focusing on the epidemiology of ethnicity and deprivation. Patients were 65% (34 of 52) male and had a median (IQR) age of 55 (48-62) years. Prevalent comorbidities included obesity (52%); diabetes (33%), and asthma (23%). COVID-19 hospital and ICU inpatient numbers peaked on days 23 and 39, respectively – a lag of 16 days. The ICU mortality rate was 33% (17 of 52). Black, Asian and Minority Ethnics (BAME) population represented 35% of ICU COVID-19 admissions (18 of 52) and 35% of deaths (6 of 17). Within the BAME group, 72% (13 of 18) were found to reside in geographical areas representing the 20% most deprived in Wales, versus 27% of Caucasians (9 of 33). Less than 5% of the population within the hospital catchment area are of BAME descent, yet they represent a disproportionately high proportion of patients with ICU admission and mortality suffering from COVID-19. The interplay between ethnicity and deprivation, which is complex, may be a factor in our findings. This in turn could be related to an increased prevalence of co-morbidities; higher community exposure; or genetic polymorphisms.

Objective: To investigate social, economic, and environmental contributors to quit or continue smoking and vaping during the COVID-19 pandemic. Methods: A qualitative study design was adopted to identify smokers’ beliefs in a LMIC, using a small community sample. Results: 276 participants were primarily surveyed. Motivation to continue smoking included temporary pleasurable effects, working remotely, stress or anxiety, whereas a motivator to quit smoking was the overlap with COVID-19 symptomatology. There was a rise in social awareness regarding the potential harm of smoking and vaping during the pandemic yet those participants who were younger felt they were immune from its morbid complications. Conclusions: With paradoxical associations of COVID-19 with cigarette and vape usage, it is important to pay attention to biases in data in favor of educating its users of the increased risk of severe disease.

In December 2019 a novel human-infecting coronavirus, named SARS-CoV-2 has been recognized to cause a pneumonia epidemic outbreak with different degree of severity in Wuhan, Hubei Province in China. Since then this epidemic spread worldwide an in the last week Europe and Italy also have been involved. Effective preventive and therapeutic strategies are absolutely required to block this serious public health concern. Unfortunately, SARS-CoV-2 has been isolated only recently, therefore a few studies concerning its immunopathogenesis and tretament are available. Therefore, on the basis of the assumption that the SARS-CoV-2 is genetically related to SARS-CoV (about 82% of genome homology) and that its characteristics, like the modality of transmission, the route of infection, the organ localization, the type of the immune response it may stimulate, the morbidity and the mortality rates are still poor-known, a literature search was performed to identify the reports assessing these elements in patients with SARS-CoV-induced infection. Therefore, we have analysed: 1) the structure of SARS CoV-2 and SARS CoV; 2) the clinical signs and symptoms and pathogenic mechanisms observed during the development of acute respiratory syndrome and the Cytokine Release Syndrome; 3) the modification of the cell microRNome and of the immune response in patients with SARS infection; 4) the possible role of some liposoluble compounds (such as vitamin A, D and E) in modulating directly or indirectly the replication ability of SARS-CoV-2 and host immune response.

Objective: SARS-Cov-2 infection or COVID-19 is a global pandemic. From the time of identification to till, multiple clinical symptoms and parameters have been identified by the researchers of various countries and regions regarding the diagnosis and presentations of COVID-19 disease. In this manuscript, we investigated the primary symptoms and basic hematological presentations of SARS-CoV-2 infection among the Bangladeshi patients. Methodology: We have collected the disease history of mild to moderate degree of COVID-19 patients; hematological and biochemical on admission reports of moderate degree COVID-19 patients. All of them were tested positive for SARS-CoV-2 by RT-PCR in different institutes in Bangladesh. Results: According to this study though COVID-19 patients in Bangladesh commonly presented with fever, cough, fatigue, shortness of breath, and sore throat, but symptoms like myalgia, diarrhea, skin rash, headache, Abdominal pain/cramp, nausea, vomiting, restlessness, and a higher temperature of >100⁰F have a greater presentation rate and more frequent than other published studies. CRP and Prothrombin time was found to increase in all the patients. Serum ferritin, ESR, SGPT, and D-Dimer were found increased among 53.85%, 80.43, 44%, and 25% patients respectively. 17.39% of the patients had leukocytosis and neutrophilia. 28.26% of patients presented with lymphocytopenia. 62.52% of patients had mild erythrocytopenia. Conclusion: Despite some similarities, our study has evaluated a different expression in presenting symptoms in the case of COVID-19 patients in Bangladesh. CRP, Prothrombin time, serum ferritin, ESR, SGPT, D-Dimer, erythrocytopenia, and lymphocytopenia can be initial diagnostic hematological findings and assessment for prognosis COVID-19 disease. Also, gender variations have a different scenario of clinical and laboratory appearance in this region.

COVID-19 Pandemic management has become the top priority of Government Institutions globally, which is justifiable seeing the high mortality of the disease. In India, Lockdowns by National, State and Local level administrations have greatly reduced the spread of the SARS COV-2 Virus. Some areas with a greater proportion of COVID-19 patients have been declared hotspots with increased restrictions on public activities through law enforcement. But quite often delay in identification of these hotspots leads to community transmission of the Virus thus aggravating the problem. A method to identify the areas which are at risk of becoming the next hotspot for the disease is the need of the hour[1]. In this Research document we will find the probable risk factors and make an appropriate scale to measure the vulnerability of an area, identified by its Postal code. To help with this a Pan India survey by the title of “Survey on General Indian population on the level of preparedness for COVID-19 pandemic” was launched and received around 1250 submissions, with the acquired data we will evaluate the risk factors and make appropriate scale to identify ‘pre-hotspots’.