Antibiotics Use in Hospitalised COVID-19 Patients in a Tertiary Care Centre: A Descriptive Cross-sectional Study and Heart Mitochondria. JORMA JYRKKANEN 2023-03-23

Antibiotics Use in Hospitalised COVID-19 Patients in a Tertiary Care Centre: A Descriptive Cross-sectional Study and Heart Mitochondria. JORMA JYRKKANEN 2023-03-23

Thapa B, Pathak SB, Jha N, Sijapati MJ, Shankar PR. Antibiotics Use in Hospitalised COVID-19 Patients in a Tertiary Care Centre: A Descriptive Cross-sectional Study. JNMA J Nepal Med Assoc. 2022 Jul 1;60(251):625-630. doi: 10.31729/jnma.7394. PMID: 36705203; PMCID: PMC9297358. ABSTRACT Introduction: Antimicrobial resistance is a global health problem. The widespread and improper antibiotics use is the leading cause of antimicrobial resistance. Bacterial co-infection in COVID-19 patients is the basis for the use of antibiotics in the management of COVID-19. COVID-19 pandemic has seriously impacted antibiotic stewardship and increased the global usage of antibiotics, worsening the antimicrobial resistance problem. The use of antibiotics among COVID-19 patients is high but there are limited studies in the context of Nepal. This study aimed to find out the prevalence of antibiotic use among hospitalised COVID-19 patients in a tertiary care centre. Introduction: Antimicrobial resistance is a global health problem. The widespread and improper antibiotics use is the leading cause of antimicrobial resistance. Bacterial co-infection in COVID-19 patients is the basis for the use of antibiotics in the management of COVID-19. COVID-19 pandemic has seriously impacted antibiotic stewardship and increased the global usage of antibiotics, worsening the antimicrobial resistance problem. The use of antibiotics among COVID-19 patients is high but there are limited studies in the context of Nepal. This study aimed to find out the prevalence of antibiotic use among hospitalised COVID-19 patients in a tertiary care centre. Methods: A descriptive cross-sectional study was conducted on hospitalised COVID-19 patients from April 2021 to June 2021 in a tertiary care centre. Ethical approval was taken from the Institutional Review Committee (Reference number: 2078/79/05). The hospital data were collected in the proforma by reviewing the patient's medical records during the study period of 2 months. Convenience sampling was used. Point estimate and 95% Confidence Interval were calculated. Results: Among 106 hospitalised COVID-19 patients, the prevalence of antibiotics use was 104 (98.11%) (95.52-100, 95% Confidence Interval). About 74 (71.15%) of patients received multiple antibiotics. The most common classes of antibiotics used were cephalosporins, seen in 85 (81.73%) and macrolides, seen in 57 (54.81%) patients. Conclusions: The prevalence of antibiotics use among hospitalised COVID-19 patients was found to be higher when compared to other studies conducted in similar settings. Keywords: antibiotics, bacterial infection, co-infection, COVID-19 Go to: INTRODUCTION Antimicrobial resistance (AMR) is a major threat to global public health due to the increasing incidence of resistant human pathogens.1,2 The widespread and improper use of antibiotics is the leading cause of AMR.1 Coronavirus Disease 2019 (COVID-19) is a viral disease thus untreatable by antibiotics, but the viral respiratory infections may clinically progress to bacterial pneumonia requiring antibiotic administration.2 This co-pathogenesis is the basis for use of antibiotics in COVID-19. But appropriate use of antibiotics is utmost to prevent AMR. COVID-19 pandemic has seriously impacted antibiotic stewardship and single-handedly increased the global usage of antibiotics, causing a cascading effect on the AMR problem. The use of antibiotics among COVID-19 patients is high but there are limited studies in the context of Nepal.3-5 This study aimed to find out the prevalence of antibiotics use among COVID-19 patients of a tertiary care centre. Go to: METHODS A descriptive cross-sectional study was conducted at KIST Medical College and Teaching Hospital after taking ethical approval from the Institutional Review Committee (Reference number: 2078/79/05). The study was conducted during the study period from 6 August 2021 to 6 October 2021 during which hospitalised COVID-19 patients admitted from April 2021 to June 2021 were studied. All the COVID-19 cases confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) test who were admitted in the dedicated COVID-19 ward, high dependency unit (HDU) and intensive care units (ICU) were enrolled. Patients who had incomplete documentation were excluded from the study. Convenience sampling was used. The sample size was calculated using the following formula: n=Z2×p×qe2=1.962×0.50×0.500.102=97 Where, n = minimum required sample size Z = 1.96 at 95% Confidence Interval (CI) p = prevalence taken as 50% for maximum sample size calculation q = 1-p e = margin of error, 10% Minimum sample size calculated was 97. However, we enrolled 106 cases. The collected data from hospital records was entered in the proforma by reviewing the patient's medical records during the study period of two months. Demographic profile of patients like age and sex, clinical profile like co-morbidity and disease severity, management profile like level of care required for patients' treatment, number and type of antibiotics used, route of antibiotic administration, duration of antibiotics used, and estimated cost of antibiotics used for the treatment were assessed. The patients who were treated with at least one antibiotic were included. All the cases were classified as a mild disease, moderate disease, or severe disease.6 In our study, 17 different antibiotics were used belonging to seven different antibiotic classes. They are namely cephalosporin (ceftriaxone, cefixime, cefoperazone, and cefepime), macrolides (azithromycin, clindamycin, and erythromycin), penicillin group (piperacillin, amoxicillin), quinolones (moxifloxacin, levofloxacin, ciprofloxacin), imidazoles (metronidazole), carbapenem (meropenem) and beta-lactamase inhibitors (clavulanic acid, tazobactam, sulbactam). The data were entered and analysed using IBM SPSS Statistics 21.0. Point estimate and 95% CI were calculated. Go to: RESULTS Among 106 hospitalised COVID-19 patients, the prevalence of use of antibiotics was 104 (98.11%) (95.52-100, 95% CI). The mean number of antibiotics used per patient was 1.86 ±0.64. A total of 74 (71.15%) patients were under two or more antibiotic therapy. Around 60 (57.69%) patients were treated with intravenous as well as per oral route of administration of antibiotics. The mean number of days of admission was 6.44±4.81 days. The mean duration of antibiotics use was 6.33 ±2.72 days. About 30 (28.85%) received a 5 day course of antibiotics while 25 (24.04%) patients received a 7 days course of antibiotics. Only 23 (22.12%) received antibiotic therapy for more than 7 days. The mean estimated expenditure on antibiotics was NPR 4,645±8, 498 (USD 38.71±70.82) (Table 1). Table 1 Use of antibiotics in management of COVID-19 patients (n = 104). Characteristics n (%) Number of antibiotics used 1 30 (28.85) 2 59 (56.73) 3 15 (14.42) Route of antibiotics Intravenous route only 37 (35.58) Per oral route only 7 (6.73) Intravenous and per oral route 60 (57.69) Total number of days of antibiotics use ≤7 days 81 (77.88) >7 days 23 (22.12) Estimated expenditure on antibiotics therapy NPR (US dollar) ≤1,200 (USD 10) 43 (41.35) 1201 to 6,000 (USD 11 to 50) 42 (40.38) 6,001 to 12, 000 (USD 51 to 100) 8 (7.69) 12,001 to 24,000 (USD 101 to 200) 7 (6.73) >24,000 (USD 200) 4 (3.85) Open in a separate window The mean age of the patients was 55.84±18 years. A total of 54 (51.92%) patients were males. Around 59 (56.73%) had at least one comorbid condition with the most common conditions being hypertension seen in 39 (37.50%) and diabetes mellitus seen in 23 (22.16%) (Table 2). Table 2 Demographic characteristics of hospitalised COVID-19 patients who received antibiotic therapy (n= 104). Age group n (%) ≤20 years 5 (4.81) 21 to 40 years 18 (17.31) 41 to 60 years 37 (35.58) 61 to 80 years 37 (35.58) >80 years 7 (6.73) Sex Males 54 (51.92) Females 50 (48.08) Comorbidities Diabetes mellitus 23 (22.16) Hypertension 39 (37.50) Chronic Obstructive Pulmonary 10 (9.62) Disease (COPD) Hypothyroidism 12 (11.54) Psychiatric illness 2 (1.92) Heart failure 2 (1.92) Autoimmune disease 2 (1.92) Chronic kidney disease 1 (0.96) Open in a separate window Severe COVID-19 represented 37 (35.58%) of total patients, 16 (15.38%) of them were managed in ICU with ventilator support. Moderate COVID-19 cases also accounted for 37 (35.58%) of total patients. These patients were mostly managed in a dedicated COVID-19 ward with 2 (1.92%) cases managed in ICU and 2 (1.92%) in HDU. All 30 (28.84%) mild cases were managed in the ward (Table 3). Table 3 COVID-19 severity and level of care received by the patients who received antibiotic therapy (n = 104). Level of care Mild n (%) Moderate n (%) Severe n (%) Total n (%) ICU with ventilator support - - 16 (15.38) 16 (15.38) ICU without ventilator support - 2 (1.92) 4 (3.85) 6 (5.77) HDU - 2 (1.92) 15 (14.42) 17 (16.35) Ward 30 (28.84) 33 (31.73) 2 (1.92) 65 (62.50) Open in a separate window The most common class of antibiotics used was cephalosporins in 85 (81.73%) patients followed by macrolides in 57 (54.81 %). Cefixime used in all cases was a substitute for ceftriaxone in oral form in 18 (17.31%) patients who were previously prescribed ceftriaxone. Beta-lactamase inhibitors were used in 35 (33.65%) in conjunction with penicillin (amoxicillin) or cephalosporin group of drugs (cefoperazone, cefepime). The most common combination used was cephalosporin with macrolides at 38 (36.54%) (Table 4). Table 4 Types of antibiotics used in management of COVID-19 patients (n = 104). Antibiotics n (%) Cephalosporins prescribed parenterally 85 (81.73) Ceftriaxone 76 (73.08) Cefepime sulbactam 3 (2.88) Cefoperazone sulbactam 6 (5.77) Cephalosporins prescribed enterally 18 (17.31) Cefixime 18 (17.31) Macrolides 57 (54.81) Azithromycin 55 (52.88) Erythromycin 1 (0.96) Clindamycin 1 (0.96) Penicillins 26 (25.00) Piperacillin tazobactam 14 (13.46) Amoxicillin clavulanic acid 12 (11.54) Quinolones 11 (10.58) Moxifloxacin 9 (8.65) Levofloxacin 2 (1.92) Ciprofloxacin 1 (0.96) Imidazoles 10 (9.62) Metronidazole 10 (9.62) Carbapenems 4 (3.85) Meropenem 4 (3.85) THIS IS A COCKTAIL THAT IS VERY DANGEROUS TO HEART MITOCHONDRIA-JORMA JYRKKANEN COMMENT DISCUSSION The prevalence of use of antibiotics was 98.1%. About 71.15% patients were treated with two or more antibiotics. The mean number of antibiotics used per patient was 1.86. The mean duration of antibiotics use was 6.33 days. Seventeen different antibiotics were used belonging to 7 different antibiotic classes. The most common class of antibiotics used was cephalosporin at 85 (81.73%) and macrolides at 57 (54.81%). Even before the COVID-19 pandemic, AMR was projected to become responsible for approximately 10 million deaths worldwide in the coming three decades.7 COVID-19 has undoubtedly affected antibiotic stewardship and has increased antibiotic consumption patterns globally, adding to the already existing global AMR problem. Because of this, the mortality due to AMR is expected to be higher in post COVID era.2 This pandemic has disrupted health delivery systems worldwide. This has increased the overuse of antibiotics, eventually leading to resistant organisms requiring aggressive treatment.8 Thus AMR is a problem of greater concern than COVID-19 which has unfortunately been overshadowed amidst the pandemic.7,9 Increased use of antibiotics is more challenging, especially in the low and middle-income countries (LMIC) due to the inefficiency and inadequacy of health care services.2 The Infectious Diseases Society of America (IDSA) states that only 8% of the COVID-19 patients acquired bacterial/fungal superinfections requiring antibiotics.10 However, a study showed 72% of COVID-19 patients received empirical broad-spectrum antibiotics, even when bacterial coinfection was absent.11 Current World Health Organization guidelines indicate that antibiotics should not be prescribed in mild or moderate COVID-19 cases unless there are pre-existing symptoms of bacterial co-infection. Furthermore, when treating severe cases with an empirical antimicrobial agent, the overall condition of the patient, local bacterial epidemiology, and clinical judgement should be integrated, to ensure judicial antimicrobial usage.12 In COVID-19 patients, antibiotics are used for potential anti-inflammatory, immune-modulating, and potential antiviral properties. But the antiviral mechanism of these agents is doubtful. This widespread antibiotic use is likely to worsen preexisting AMR crisis.13 The influenza pandemic was largely a problem of viral infection complicated by bacterial co-pathogenesis.14 This has been our basis for use of a wide range antibiotics empirically though COVID-19 is primarily a viral pathology and is not conventionally treated with antibiotics. In a study, 71.00% of the hospitalised COVID-19 patients received antibiotics despite a confirmed bacterial co-infection rate of only 1%.3 Antibiotic was used in 95.00% COVID-19 patients when secondary bacterial infection was only found in 15.00%.4 A systematic review showed the mean rate of antibiotic use was 74.00 %.5 In our study, the prevalence of use of antibiotics was 98.10% which is very high when compared to above studies. In most cases antibiotics use often empirical. Empiric antibiotics were often used for the concern of community-acquired pneumonia (89.00%).15 This showed that antibiotic therapy has been used often empirically in the majority of patients even when very few were proven to have bacterial coinfection. In our study, 17 different antibiotics belonging to seven antibiotic classes were used. Similar to our study a wide range of antibiotics use was documented in other studies.1,5,10,13,15-18 Many other classes of antibiotics other than above were used in other studies for the management of COVID-19 patients. They are aminoglycosides,1 glycopeptide antibiotic like vancomycin and teicoplanin,10 oxazolidinones like linezolid, tetracycline and cyclic lipopeptides like daptomycin.17 Most of these are newer classes of antibiotics and increased use of these should raise a red flag among concerned clinicians, pharmacists, microbiologists, public health experts, hospitals, local authorities as well as regulatory bodies. Carbapenem, fluoroquinolones, and aminoglycoside were highly prevalent in ICU patients.1 Similar to this carbapenem was exclusively used for ICU patients in our study. Other commonly used antibiotics among ICU patients were fluoroquinolones, cephalosporin, piperacillin with tazobactam, and macrolides. In general, ICU addmission compromises of a very sick patient with superadded bacterial infection and in regard to COVID-19, it comprises of severe COVID-19 infection often requiring ventilatory support. In such conditions, it is common practice to use multiple higher and broad-spectrum antibiotics. The common antibiotics in use were ceftriaxone (54.00%), vancomycin (48.00%), azithromycin (47.00%), and cefepime (45.00%).10 In our study ceftriaxone (73.08%) and azithromycin (52.88%) were widely used but cefepime was used in 2.88% of patients and vancomycin was not used at all. Higher antibiotics like cefepime and vancomycin should only be used when there is a valid indication, otherwise, it may result in resistant infection which will be very hard to treat. Ceftriaxone and azithromycin are often the most common antibiotics used in the management of COVID-19 patients.10,13,15,16 Most of the local guidelines as well as some international guidelines advocate for use of these antibiotics based on the epidemiology of local pathogens and resistance patterns. The advantage of the use of these antibiotics is that it covers most of the opportunistic pathogens that could cause secondary infection in COVID-19. But on the other hand, wide and inappropriate use of these antibiotics can lead to with emergence resistance of these common, cheap, and very efficient antibiotics. Macrolide, specifically azithromycin, was the most common antibiotic used in the clinical management of COVID-19.13 Macrolides, particularly azithromycin, were used in the treatment of more than half of the patients in our study. These drugs are often used to cover atypical organism that have the potential to cause a secondary infection.10,11 Fluoroquinolones were most used, (56.80%), followed by ceftriaxone (39.50%), then azithromycin (29.10%), and carbapenems were only used in two patients.18 Unlike to above study, in our study fluoroquinolones were used less (10.58%) and ceftriaxone and azithromycin was basically used in most patients. But similarity was observed between ours and the above study regarding the use of carbapenems, which was used in 3.85% of patients. Wide use of carbapenem, used in up to 40.10% of patients was also reported.5 carbapenem is often used as a reserved antibiotic for severe infection thus minimal use of these in COVID-19 signifies the presence of good antibiotics stewardship and antibiotic management system among concerned institutions while wide use can signify the opposite. The most common antibiotic used was third-generation cephalosporin (ceftriaxone) (53.80%), moxifloxacin (29.50%), and doxycycline (25.40%).5 Similar to the above study the most common class of antibiotics used in our study was cephalosporin (81.74%), around 90.00% of which was third-generation cephalosporin namely ceftriaxone (76/85). But unlike the above, Moxifloxacin was used in only 8.65% and doxycycline or other tetracycline group of drugs was not used at all in our study. A study showed all patients were receiving at least one antibiotic with 31.08% receiving a single antibiotic and 68.91% receiving multiple antibiotics.5 Similar to this study, 98.10% of patients in our study received at least one antibiotic, 28.35% received single antibiotic agents and 71.15% received multiple antibiotics. But the mean number of antibiotics used in the study above was 2.02 which is more when compared to 1.85 in our study. In 34.6%, three antibiotics were given simultaneously while 9.6% received only one antibiotic.16 Unlike the above, in our study three antibiotics were used in only 14.42% and a single antibiotic was used in 28.85%. The use of multiple antibiotics is worrisome as this might represent unchecked use of antibiotics which will contribute to the worldwide problem of AMR. In our study, patients with comorbidity were found to have received multiple antibiotics (72.90%). Around 74.00% of patients with diabetes were on multiple antibiotics. Similar findings were documented in another study.5 This might be due to COVID-19 patients with comorbidities like diabetes, airway diseases, hypertension being at greater risk of developing secondary bacterial infection.19 After predicting the risk of secondary infection, multiple antibiotics were used empirically in those patients. Overall, patients presenting with severe disease received more antibiotics.5 This is also true for our study. COVID-19 patients with co-morbidities and severe COVID-19 are the two most vulnerable groups of patients, thus multiple antibiotics have been found to be used liberally in these patients. These situations can be dealt with systematically by establishing standard antibiotic prescribing guidelines considering local pathogens and sensitivity patterns to antibiotics. This could be further reinforced by appropriate clinical knowledge, laboratory facilities, and surveillance systems. In our study the mean duration of antibiotics treatment was 6.33 days which is nearly half when compared to 12.71 days with a range from 3 days to 23 days.16 Similar result was found in another study.18 Both of these, decreased and extended duration of antibiotic treatment might represent inappropriate and improper use of antibiotics regimen. Because both, underuse and overuse of antibiotics can result in the emergence of resistance. Our study is a single centred study and has a small sample size. Therefore, our findings may not be generalizable to other settings. Go to: CONCLUSIONS The prevalence of use of antibiotics among hospitalised COVID-19 patients was found to be higher when compared to other studies conducted in similar settings. Potential bacterial co-infection has been the basis for the use of antibiotics in the management of COVID-19 patients. The rate and number of antibiotics used for mild to moderate disease were also high. The common class of antibiotics used are cephalosporin and macrolides namely ceftriaxone and azithromycin. Higher class antibiotics were mostly used in the management of severe disease in ICU and with ventilator support. However, judicial use of antibiotics among COVID-19 patients with variable severity especially among those admitted in ICU and on ventilatory support could be promoted in order to reduce AMR during this COVID-19 pandemic. Robust antibiotic stewardship programs and surveillance systems should be implemented. Go to: ACKNOWLEDGMENTS The authors would like to acknowledge KIST Medical College and Teaching Hospital for their support. Go to: Conflict of Interest None. Go to: REFERENCES 1. Zeshan B, Karobari MI, Afzal N, Siddiq A, Basha S, Basheer SN, et al. The Usage of Antibiotics by COVID-19 Patients with Comorbidities: The Risk of Increased Antimicrobial Resistance. Antibiotics (Basel). 2021 Dec 29;11(1):35. doi: 10.3390/antibiotics11010035. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 2. Rizvi SG, Ahammad SZ. COVID-19 and antimicrobial resistance: A cross-study. Sci Total Environ. 2022 Feb 10;807(Pt 2):150873. doi: 10.1016/j.scitotenv.2021.150873. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 3. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020 Feb 15;395(10223):507–13. doi: 10.1016/S0140-6736(20)30211-7. 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Jyrkkanen, Jorma. (2020). Antibiotic induced changes to mitochondria result in potential contributions to carcinogenesis, heart pathologies, other medical conditions and ecosystem risks. Journal of Cardiology and Cardiovascular Medicine. 5. 163-171. 10.29328/journal.jccm.1001104. In addition to providing energy to support the synthesis of the macromolecules essential for immune cell proliferation, mitochondria also act as signaling organelles, driving activation of immune cells via metabolic intermediates, mitochondrial DNA (mtDNA), and reactive oxygen species (ROS).Mar 22, 2022 Introduction Immune dysregulation, characterized by an imbalance between a systemic inflammatory response syndrome and a compensatory anti-inflammatory response syndrome, is often observed in critically ill patients [1, 2]. This imbalance between the pro- and anti-inflammatory responses frequently leads to immunoparalysis in critically ill patients, rendering them more susceptible to further infections, and is associated with increased mortality [3]. Currently, no effective treatments are available to restore immune homeostasis and reduce mortality in these patients, largely due to the heterogeneity in patients’ immune status and more importantly the lack of understanding of the underlying cause of such immune dysfunction [2, 4]. Immune response is not a standalone process but is interconnected with other cellular activities, a very important one of which is cellular metabolism. Metabolic pathways and immune response are tightly intertwined both in health and in disease [5]. The link between immune cell function and mitochondrial function is now well recognized and a field known as “immunometabolism” is dedicated to understanding the relationship between immune and metabolic pathways [6,7,8]. Mitochondria play a crucial role in regulating not only the growth, but also the function, of immune cells. In addition to providing energy to support the synthesis of the macromolecules essential for immune cell proliferation, mitochondria also act as signaling organelles, driving activation of immune cells via metabolic intermediates, mitochondrial DNA (mtDNA), and reactive oxygen species (ROS). In addition, mitochondrial dynamics (fusion and fission), biogenesis (synthesis of new mitochondria), and mitophagy (degradation of damaged mitochondria) also play important roles in regulating immune cell functions. Knowledge in immunometabolism in critical illness, in particularly sepsis, opens up a new paradigm in patient care. Potential therapies targeting metabolic pathways, instead of solely immune-related pathways, might be the way to repair cellular function and restore immune homeostasis [4]. The other aspect of immunometabolism—looking at how immune responses influence metabolic pathways—is equally important, but beyond the scope of this review. Interaction between metabolism and immune response at the organ level has been reviewed elsewhere [6]. Mitochondrial Machinery That Mediates and Regulates Immune Responses in Critical Illness Apart from being the powerhouse of the cell, the mitochondrion has emerged as a signaling hub that shapes and modulates how the immune system responds to infection or trauma. Mitochondrial dysfunction is evident in leukocytes from critically ill patients, and is believed to be the underlying cause of immunoparalysis and may account for the development of organ dysfunction [7,8,9]. Early recovery of mitochondrial function correlates with improved recovery in critically ill patients [10]. Metabolic Reprogramming The immune-regulating mitochondrial machinery is a complex network involving many pathways and mechanisms that diverge and converge at various levels. Metabolic reprogramming is one mechanism that has been well studied in both innate and adaptive immune cells. Immune cells at different activation states (quiescent vs. activated), or with different functions (pro-inflammatory vs. anti-inflammatory), and different cell types (granulocytes, macrophages, dendritic cells, T- and B-lymphocytes), make use of different metabolic pathways (e.g., glycolysis, oxidative phosphorylation, fatty acid metabolism) to produce ATP [11]. The choice of different metabolic pathways, supports the energy demand of cells at different activation state. For example, upon infection or stimulation, immune cells become activated and produce cytokines and hence tend to favor glycolysis over oxidative phosphorylation for fast turnaround of ATP. Although the same amount of starting material, such as glucose, is used, oxidative phosphorylation generates 18 times more ATP than glycolysis, although is a lot slower. On the other hand, the choice of metabolic pathway determines the fate of the immune cells, i.e., naïve or memory, effector or regulatory, etc. However, the environment that the cells are in in the first place, triggers the changes in the metabolic pathways. The overall trend is that neutrophils, inflammatory macrophages (M1 macrophages), activated effector T cells, and dendritic cells rely more on aerobic glycolysis, whereas alternatively polarized macrophages (M2 macrophages), regulatory T cells (Tregs), and memory T cells prefer oxidative phosphorylation and fatty acid oxidation for energy production [8, 11, 12]. Metabolic reprogramming serves an important role in catering for the immune cells’ energy demand at different phases of their activation and proliferation. However, imbalance across the metabolic pathways could have serious pathological impact. One example may be the hyperlactatemia often seen in critically ill patients. Increased aerobic glycolysis in the activated immune cells during the initial hyper- inflammatory response is believed to contribute to the increase in blood lactate levels in sepsis [13, 14]. Mitochondrial ROS and mtDNA Metabolic reprogramming sets the scene for the immune response, which is then subjected to many more modifications and regulations by factors that are directly or indirectly related to mitochondrial metabolism. Two important mitochondria-related immune regulators that have been well studied are mitochondrial ROS and mtDNA. Mitochondrial ROS are produced in healthy mitochondria, as a by-product of oxidative phosphorylation. At low dose, mitochondrial ROS serve important signaling functions, especially in the innate immune response. They are known to mediate NLRP3 inflammasome activation, leading to production of the pro-inflammatory cytokines, interleukin (IL)-1β and IL-18 [8, 15]. Mitochondrial ROS also induce a type-I interferon (IFN) response via mitochondrial antiviral-signaling (MAVS) and the IFN regulatory factor 3 (IRF3) pathway [16]. However, the level of mitochondrial ROS needs to be tightly regulated by the antioxidant system. Excessive mitochondrial ROS can cause oxidative damage to proteins/enzymes involved in oxidative phosphorylation and create mutations in mtDNA, contributing to the immune dysregulations as seen in critical illness [17]. Like mitochon-drial ROS, mtDNA also plays an important role in innate immunity [12]. In healthy cells, mtDNA is located in the matrix of mitochondria, encoding 13 proteins, all of which are components of oxidative phosphorylation. mtDNA is released to the cytosol upon mitochondrial dysfunction which involves changes to the integrity or permeability of the mitochondrial membrane. mtDNA, released into the cytosol, can activate the NLRP3 inflammasome with release of IL-1β and IL-18. Due to its bacterial origin, cytosolic mtDNA also serves as a damage-associated molecular pattern (DAMP), which can be recognized by intracellular pattern recognition receptors (PRRs), such as Toll-like receptor 9 (TLR9), and initiate the nuclear factor-kappa B (NF-κB)-dependent pro-inflammatory signaling pathway. In addition, cytosolic mtDNA can also be sensed by cyclic GMP-AMP synthase (cGAS) and activate the cGAS/stimulator of IFN genes (cGAS/STING) pathway and its downstream IFN response [18]. mtDNA can also be released into the circulation and cause systemic inflammation. Circulating mtDNA has been associated with mortality in critically ill patients [19]. Succinate and Itaconate In addition to mitochondrial ROS and mtDNA, metabolites such as succinate and itaconate have also emerged as part of immune-regulating mitochondrial machinery [4, 20]. Both succinate and itaconate are intermediates from the tricarboxylic acid (TCA) cycle with opposite effects on the immune response. The TCA cycle generates nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2), providing electrons to fuel oxidative phosphorylation. Succinate accumulation occurs under conditions such as hypoxia or inflammation. It can be released from mitochondria into the cytosol and functions as a signal transducer promoting pro-inflammatory gene expression via hypoxia-inducible factor 1α (HIF-1α) activation. Accumulation and oxidation of succinate by succinate dehydrogenase (SDH) in the mitochondria also leads to increased production of mitochondrial ROS via a process called reverse electron transport. This further enhances the pro- inflammatory effect of succinate. Like ROS, the level of succinate needs to be carefully regulated due to its inflammation aggravating effect. Plasma succinate has been proposed as a predictor of mortality for critically ill patients who are severely injured [21]. Itaconate, which is derived from cis-aconitate of the TCA cycle, is a succinate-regulating factor. It is shown to counteract the pro-inflammatory effect of succinate by inhibiting SDH. Itaconate can also be released into the cytosol and activate transcription factor NF-E2 p45-related factor 2 (Nrf2), a master regulator of antioxidant and anti-inflammatory responses [22]. Recently, itaconate has also been shown to inhibit the inflammatory response in macrophages through activating transcription factor 3 (ATF3). Mitochondrial Dynamics The above mentioned immune-regulating mitochondrial factors are centered around the biochemical aspect of mitochondrial biology. Another important aspect of immune-regulating mitochondrial machinery is mitochondrial dynamics, which is to maintain and provide infrastructural support for the immune response. The size and shape of mitochondria undergo constant change through fusion and fission, which is important for maintaining the health and function of mitochondria. First, fusion incorporates newly synthesized mitochondria (from mitochondrial biogenesis) into the current mitochondrial network. Second, fusion also allows for mixing of proteins and/or mtDNA between the existing mitochondria, which on one hand enhances the metabolic capacity of the mitochondria, and on the other enables the damaged proteins and/or mutated mtDNA to be segregated from the healthy ones. Finally, segregation is achieved via fission and the damaged mitochondria can be destroyed through a process known as mitophagy. The proportion of mitochondria with damaged proteins or mutated mtDNA is kept below a critical threshold level through this process to maintain mitochondrial function [23, 24]. In addition to quality control, mitochondrial fusion and fission also participate in immune regulation. In activated T cells, there is an increase in fission, which creates round and fragmented mitochondria with loose cristae, favoring aerobic glycolysis. And in 146 memory T cells, increased fusion generates elongated mitochondria which favors oxidative phosphorylation and fatty acid oxidation [8, 25]. Immunometabolism: The Perfect World Scenario vs. the Critical Illness Scenario So far, we have presented a list of mitochondrial components that are thought to play important roles in regulating the immune response. Our list is far from complete, but does highlight a few mechanisms that could relate to the development of immune dysregulation in critical illness. Figure 1 illustrates what we think would happen to the immune response when metabolism was in perfect control (the perfect world scenario) and when it became inconsistent and changeable (the critical illness scenario). In the perfect world scenario, the presence of an insult (e.g., infection or a trauma-related stress signal), would trigger metabolic reprogramming, switching from oxidative phosphorylation to glycolysis. This would enable activation of immune cells and production of pro-inflammatory cytokines and other mediators. At the same time, mitochondrial fission would increase to keep up with the metabolic reprogramming. The slightly elevated mitochondrial ROS and succinate in response to initial insult or cytokines would promote the pro-inflammatory response. Once the insult was eliminated, mitochondrial fusion would increase to create fused elongated mitochondria that favor oxidative phosphorylation and fatty acid oxidation. This would allow activation of regulatory immune cells and production of anti-inflammatory cytokines and other mediators. And itaconate would counteract the effect of succinate, activate the Nrf2-mediated antioxidant pathway to dampen down mitochondrial ROS, and activate ATF3 to inhibit the inflammatory response in macrophages. Immune homeostasis would be achieved as a result. Fig. 1 figure 1 Immunometabolism in the ‘perfect world scenario’ vs. the ‘critical illness scenario’. OXPHOS oxidative phosphorylation, FAO fatty acid oxidation Full size image In the critical illness scenario, initial metabolic reprogramming from oxidative phosphorylation to glycolysis would go on for longer than necessary, generating excessive lactate (hyperlactatemia) and pro-inflammatory cytokines and mediators. A disrupted mitochondrial fusion/fission cycle could be to blame, one which could not support the timely switch to oxidative phosphorylation and fatty acid oxidation. The anti-inflammatory response would eventually kick in but by then damage would already have occurred to mitochondria and mtDNA because of excessive production of ROS in response to stress or cytokines. Excessive ROS and released mtDNA would aggravate the pro-inflammatory response, which in turn would trigger a more aggressive anti-inflammatory response to try and salvage the situation. The competition between pro- and anti-inflammatory responses would exhaust the nutrients and lead to shutdown of the whole metabolic system. Cells would either die or go into hibernation to preserve energy [26]. This scenario is an over-simplified version of what might happen in the actual disease setting, without considering the crosstalk between cells and organs and many other factors that are not included here. It is designed to shed light on the interaction between the immune response and metabolism. Potential of Mitochondria-Targeting Therapy in Critical Care Our understanding thus far leads us to think that targeting mitochondria could perhaps correct the underlying cause of immune dysfunction in critical illness and lead to better recovery of the patients. The central role of mitochondrial dynamics in supporting and initiating metabolic reprogramming would make it the perfect therapeutic target. To get the fusion/fission cycle going, the mitochondrial network needs to be replenished by newly synthesized mitochondria via biogenesis. Therapies that could potentially boost mitochondrial biogenesis are mitochondrial transplantation, metformin, nitric oxide (NO), and carbon monoxide. Mitochondrial transplantation has been used successfully in pediatric patients with myocardial ischemia–reperfusion injury [27]. Metformin can activate peroxisome proliferator-activated receptor (PPAR)-gamma coactivator-1α (PGC-1α), and Nrf2, the master regulator of mitochondrial biogenesis and antioxidant systems [28]. Premorbid use of metfor-min is associated with lower mortality in sepsis [29]. NO and carbon monoxide can also enhance mitochondrial biogenesis [30,31,32]. Dietary nitrite has been trialed in patients with coronary artery disease (ClinicalTrials.gov Identifier: NCT00069654). Other therapies, such as mitochondria-targeted antioxidant (MitoQ) [33], could also be beneficial in protecting mtDNA and oxidative phosphorylation from oxidative damage. MitoQ has been trialed in people with Parkinson’s disease (ClinicalTrials. gov Identifier: NCT00329056). Challenges of Applying Mitochondria-Targeting Therapy in Critical Care There are challenges to overcome before mitochondria-targeting therapy would be possible. First, how do we assess mitochondrial dysfunction in the clinic and identify patients who would benefit from such therapy? A few possible ways could be considered. Non-invasive assessment of mitochondrial oxygen metabolism using a novel device called the COMET monitor was tested on 40 patients during the acute phase of sepsis. This device is based on the protoporphyrin IX-triplet state lifetime technique (PpIX-TSLT) and has been shown to be feasible [33]. This technology is still in its early phase of clinical application but does offer some hope. Another possible biomarker that could potentially be used for assessing mitochondrial dysfunction is plasma mtDNA, but its sensitivity and specificity need further investigation [19, 34, 35]. Furthermore, we could consider using immune response markers as a surrogate markers, one such example could be IFNα inducible protein 27 (IFI27) [36]. If we could overcome the first challenge, the second would be how to deliver mitochondria-targeting therapies to the right organ at the right time. Conclusion In this chapter, we have demonstrated the important role of mitochondria in regulating the immune response and proposed a scenario that explains immune–metabolism crosstalk in the context of critical illness. We have highlighted the role of mitochon-drial dynamics in overseeing and supporting metabolic reprogramming during immune cell activation. Mitochondrial ROS can be friend or foe when it comes to immune regulation. Two TCA intermediates—succinate and itaconate—with opposite effects have emerged as important players of the immune-regulating mitochon-drial machinery. Our understanding in immunometabolism could take us to the next era of critical care: mitochondria-targeting therapy. Availability of data and material Not applicable. References Duggal NA, Snelson C, Shaheen U, Pearce V, Lord JM. Innate and adaptive immune dysregulation in critically ill ICU patients. Sci Rep. 2018;8:10186. Article Google Scholar Surbatovic M, Vojvodic D, Khan W. Immune response in critically ill patients. Mediat Inflamm. 2018;2018:9524315. Article Google Scholar Frazier WJ, Hall MW. Immunoparalysis and adverse outcomes from critical illness. Pediatr Clin N Am. 2008;55:647–68. Article Google Scholar Koutroulis I, Batabyal R, McNamara B, Ledda M, Hoptay C, Freishtat RJ. Sepsis immuno-metabolism: from defining sepsis to understanding how energy production affects immune response. Crit Care Explor. 2019;1:e0061. 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Covid-19 secret is with Baric, Daszak and Zhengli Who Did the Gain of Function and Baric Later the NoSeeUm Coverup 2023-03-20 Repost Jorma Jyrkkanen

Covid-19 secret is with Baric, Daszak and Zhengli Who Did the Gain of Function and Baric Later the NoSeeUm Coverup These folks woked together with a large team under the funding of Fauci, the Government and even President Biden to craft a deadly population whacking killer bioweapon and even created technology to hide the fact. The NoSeeUm Technology of Baric.

(Left to right): Ralph Baric, Peter Daszak, Shi Zhengli. A group of Chinese scientists lobbied to rename ‘SARS-CoV-2’ to ‘2019-nCoV’. In the correspondence, the scientists feared that the virus would become known as ‘Wuhan Coronavirus’ or ‘Wuhan Pneumonia’. The truth behind the science around the origin of the SARS-CoV-2 lies with Ralph Baric of the University of North Carolina, Peter Daszak of EcoHealth Alliance and Prof Shi Zhengli of the Wuhan Institute of Virology (WIV). According to the email obtained by the US Right To Know organization, on January 13, 2020, in an email to Peter Daszak at 6.50 pm, Ralph Baric, states: “Hi Peter, I have to participate in an NIH call tomorrow at 10. I believe it’s a strategic meeting designed to help craft a NIH response plan to the WU-CoV. Hope things are going well. Looks like we found our highly variable SARS-like CoV! Ralph” In reply to Ralph Baric’s email, Peter Daszak at 7.55 pm states: “It sounds like we’re on the same call! And my exact thoughts are of the highly variable SARS-like CoV. I’ve told journalists about it, but it’s a complicated story for them to get across.” On 13 January 2020, before China or the World Health Organisation (WHO) made any official statement on the nature of the coronavirus, both Ralph Baric and Peter Daszak in their emails appear to be confident that the coronavirus in China is a “highly variable SARS-like CoV”. Most importantly, Ralph Baric refers to the coronavirus as “Our highly variable SARS-like COV”, displaying a familiarity with the virus. Reportedly, in 2013, the American virologist Ralph Baric approached Zhengli Shi at a meeting. Shi had detected the genome of a new virus, called SHC014, that was one of the two closest relatives to the original SARS virus, but her team had not been able to culture it in the laboratory. Baric had developed a way around that problem—a technique termed as “reverse genetics” in coronaviruses. Not only did it allow him to bring an actual virus to life from its genetic code, but he could mix and match parts of multiple viruses. He wanted to take the “spike” gene from SHC014 and move it into a genetic copy of the SARS virus he already had in his laboratory. The spike molecule is what lets a coronavirus open a cell and get inside it. The resulting chimera would demonstrate whether the spike of SHC014 would attach to human cells. Baric asked Shi Zhengli if he could have the genetic data for SHC014. “She was gracious enough to send us those sequences almost immediately,” he told media. His team introduced the virus modified with that code into mice and into a petri dish of human airway cells. Sure enough, the chimera exhibited “robust replication” in the human cells—evidence that nature was full of coronaviruses ready to leap directly to people. It is no surprise that a group of Chinese scientists lobbied through US Professor of the University of North Carolina Ralph Baric to rename «SARS-CoV-2» given by the Coronavirus Study Group (CSG) of the International Committee on Virus Taxonomy (ICTV) to “2019-nCoV”. In the correspondence, the Chinese scientists feared that the virus would become known as “Wuhan Coronavirus” or “Wuhan Pneumonia”. In an email dated 13/2/2020, Professor Shi Zhengli wrote to Ralph Baric. The subject of the email was “Virus Name”. The email had an attached document titled, “A unique and unified name for the novel coronavirus from Wuhan SJ clean”. The email stated: “Dear Ralph, We heard that the 2019-nCoV was renamed as SARS-CoV-2. We had a fierce discussion among Chinese virologists. We have some comments on this name, I’m wondering if the CoV study group would consider a revision. I attached the comments from me and my Chinese colleague.” The document from Prof. Shi Zhengli to Prof. Ralph Baric states: “A unique and unified name is needed for the novel coronavirus identified from Wuhan. An outbreak of unusual pneumonia of unknown cause in Wuhan, China, was first reported in December 2019. By 5 January 2020, Chinese scientists had quickly identified the causative agent a new type of coronavirus (CoV) belonging to the Betacoronaviruses genus of the Coronavirdae family that also includes severe acute respiratory syndrome (SARS)-CoV and the Middle East respiratory syndrome (MERS)- CoV. On 12 January 2020, the World Health Organization (WHO) temporarily named the virus as 2019 novel coronavirus (2019-nCoV). On 30 January, WHO recommended naming the disease as “2019-nCoV acute respiratory disease”. On 8 February 2020, the China National Health Commission (CNHC) announced naming the disease as “Novel CoronavirusPneumonia” (NCP). On 11 February 2020, WHO renamed the disease “coronavirus disease2019” (COVID-19). On 7 February 2020, the Coronavirus Study Group (CSG) of the International Committee on Virus Taxonomy (ICTV) posted a manuscript at bioRxiv and suggested designating the novel coronavirus as “severe acute respiratory syndrome coronavirus 2(SA RS-CoV-2)” based on the phylogenetic analysis of related coronaviruses. Zhengli further in her document to Ralph Baric says, “By 11th February 2020, the new coronavirus had caused more than 40,000 confirmed infections and more than 1000 deaths, mostly in mainland China, despite efforts by the Chinese government and its people to contain the spread of the virus in past weeks. lt goes without saying that the effects of the epidemic on all the aspects of Chinese life are devastating and, possibly, irreversible. Consequently, appropriately naming the virus and disease becomes a matter of importance to the Chinese people, in general, and virologists, in specific, and the issue has been fervently discussed and debated among scientists with the outcome, so far, as noted above. We fully agree that the new virus and SARS-CoV belong to the same virus species by classification. However, the consensus opinion of Chinese virologists is that none of the currently proposed names reflects the uniqueness and characteristics of the novel virus and that more consideration is needed for naming the virus. Based on the following reasons, we propose giving a unique and unified name to the new virus.” Prof Shi Zhengli, also known as the “Batwoman”, continues to impress upon Ralph Baric on behalf of the group of Chinese scientists. She says, “All proposed names are either too generic, or too similar, to previously well-known viruses, or contain an Arabic number. This makes it hard to remember or recognize, leading to a tendency among the general population and scientists alike to use a shorthand term such as ‘Wuhan coronavirus’ or ‘Wuhan pneumonia’. This has, in fact. been the case since it was named as 2019-nCoV. This practice would, however, stigmatize and insult the people in Wuhan, who are still suffering from the outbreak.” The document sent by Prof Zhengli to Ralph Baric, further states, “The new virus is still evolving, and it is still too early to predict the outcome of the current outbreak. However, it is already clear that the infection of the new virus has diverse symptoms, from asymptomatic infection to severe pneumonia and even death. It has less case-fatality rate and higher transmissibility than SARS-CoV, indicating its clear difference from SARS-CoV. Again. therefore, it is not appropriate to designate the new virus as SARS-CoV-2 before we know more properties of the virus.” Baric, Daszak and Zhengli were working together on the gain-of-function research. Scientists have posited that SARS-CoV-2 may be a product of WIV’s experiments on an unpublished bat coronavirus that is more closely related to SARS-CoV-2 than RaTG13. “First, SARS-CoV-2 may have evolved in bats, which are known reservoirs of immense coronavirus diversity, and then spread directly, or indirectly via an intermediate host, to humans through natural mechanisms. The degree of anticipated but undiscovered natural diversity clearly lends support to this scenario, as well as support to other scenarios. Second, SARS-CoV-2 or a recent ancestor virus may have been collected by humans from a bat or other animal and then brought to a laboratory where it was stored knowingly or unknowingly, propagated and perhaps manipulated genetically to understand its biological properties and then released accidentally.“ Wuhan Institute of Virology authorities shut down outside access to its virus database in September 2019, thereby making it difficult to verify that “The Wuhan lab has many bat samples not yet worked out or results published. There are some concerns that some of their samples may not have been handled properly and leaked out of the lab.” Savio Rodrigues is the founder and editor-in-chief of Goa Chronicle. NATURE MEDICINE PUBLICATION FOLLOWS naturenews article Published: 12 November 2015 Engineered bat virus stirs debate over risky research Declan Butler Nature (2015)Cite this article Lab-made coronavirus related to SARS can infect human cells. An experiment that created a hybrid version of a bat coronavirus — one related to the virus that causes SARS (severe acute respiratory syndrome) — has triggered renewed debate over whether engineering lab variants of viruses with possible pandemic potential is worth the risks. In an article published in Nature Medicine1 on 9 November, scientists investigated a virus called SHC014, which is found in horseshoe bats in China. The researchers created a chimaeric virus, made up of a surface protein of SHC014 and the backbone of a SARS virus that had been adapted to grow in mice and to mimic human disease. The chimaera infected human airway cells — proving that the surface protein of SHC014 has the necessary structure to bind to a key receptor on the cells and to infect them. It also caused disease in mice, but did not kill them. Although almost all coronaviruses isolated from bats have not been able to bind to the key human receptor, SHC014 is not the first that can do so. In 2013, researchers reported this ability for the first time in a different coronavirus isolated from the same bat population2. The findings reinforce suspicions that bat coronaviruses capable of directly infecting humans (rather than first needing to evolve in an intermediate animal host) may be more common than previously thought, the researchers say. But other virologists question whether the information gleaned from the experiment justifies the potential risk. Although the extent of any risk is difficult to assess, Simon Wain-Hobson, a virologist at the Pasteur Institute in Paris, points out that the researchers have created a novel virus that “grows remarkably well” in human cells. “If the virus escaped, nobody could predict the trajectory,” he says. Creation of a chimaera The argument is essentially a rerun of the debate over whether to allow lab research that increases the virulence, ease of spread or host range of dangerous pathogens — what is known as ‘gain-of-function’ research. In October 2014, the US government imposed a moratorium on federal funding of such research on the viruses that cause SARS, influenza and MERS (Middle East respiratory syndrome, a deadly disease caused by a virus that sporadically jumps from camels to people). The latest study was already under way before the US moratorium began, and the US National Institutes of Health (NIH) allowed it to proceed while it was under review by the agency, says Ralph Baric, an infectious-disease researcher at the University of North Carolina at Chapel Hill, a co-author of the study. The NIH eventually concluded that the work was not so risky as to fall under the moratorium, he says. But Wain-Hobson disapproves of the study because, he says, it provides little benefit, and reveals little about the risk that the wild SHC014 virus in bats poses to humans. Other experiments in the study show that the virus in wild bats would need to evolve to pose any threat to humans — a change that may never happen, although it cannot be ruled out. Baric and his team reconstructed the wild virus from its genome sequence and found that it grew poorly in human cell cultures and caused no significant disease in mice. “The only impact of this work is the creation, in a lab, of a new, non-natural risk,” agrees Richard Ebright, a molecular biologist and biodefence expert at Rutgers University in Piscataway, New Jersey. Both Ebright and Wain-Hobson are long-standing critics of gain-of-function research. In their paper, the study authors also concede that funders may think twice about allowing such experiments in the future. “Scientific review panels may deem similar studies building chimeric viruses based on circulating strains too risky to pursue,” they write, adding that discussion is needed as to “whether these types of chimeric virus studies warrant further investigation versus the inherent risks involved”. Useful research But Baric and others say the research did have benefits. The study findings “move this virus from a candidate emerging pathogen to a clear and present danger”, says Peter Daszak, who co-authored the 2013 paper. Daszak is president of the EcoHealth Alliance, an international network of scientists, headquartered in New York City, that samples viruses from animals and people in emerging-diseases hotspots across the globe. Studies testing hybrid viruses in human cell culture and animal models are limited in what they can say about the threat posed by a wild virus, Daszak agrees. But he argues that they can help indicate which pathogens should be prioritized for further research attention. Without the experiments, says Baric, the SHC014 virus would still be seen as not a threat. Previously, scientists had believed, on the basis of molecular modelling and other studies, that it should not be able to infect human cells. The latest work shows that the virus has already overcome critical barriers, such as being able to latch onto human receptors and efficiently infect human airway cells, he says. “I don’t think you can ignore that.” He plans to do further studies with the virus in non-human primates, which may yield data more relevant to humans. References Menachery, V. D. et al. Nature Med. http://dx.doi.org/10.1038/nm.3985 (2015). Ge, X.-Y. et al. Nature 503, 535–538 (2013). Share this: TwitterFacebook Related Fauci Funded Seamless Ligation ‘noseeum’ technology Development by Ralf Baric an N. Carolina U to Hide Virus Tampering March 14, 2023 In "Bat Lady" Fauci Funded Bioweapon Development Since 2002 March 16, 2023 In "bioweapons" Bill Gates Crimes 2023-03-02 Jorma A Jyrkkanen, BSc,PDP March 2, 2023 In "crimes" Tags: SARS COV, VIRUS, WEAPONIZATION This entry was posted on March 20, 2023 at 3:21 pm and is filed under Uncategorized.

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TECHNICAL NOTE ON A POSSIBLE NANOWORM MWCNT IN PFIZER VACCINE. 2021-05-03. JORMA JYRKKANEN

Jorma Jyrkkanen, Bsc, PDP Environmental Carcinogens 2021-05-03 Jorma Jyrkkanen. I was asked to comment on the following release by Dr. Robert Young. Dr. Robert Young: ”Please identify the black nano worm in the Pfizer vaccine as seen under pHase contrast microscopy? In the phase contrast microscopy video above, you have asked me to review and comment. I would suggest the following: what you are viewing is a carbon multi-walled nanotube (MWCNTs) which I have shown to elicit asbestos-like toxicological effects on cell membranes and their genetics. To reduce needs for human risk I have suggested that the physicochemical characteristics or reactivity of nano materials should be used to predict a serious health hazard. Fibre-shape and the ability to generate reactive oxygen species (ROS) are important indicators of highly acidic hazardous materials. Asbestos is one of those known toxic acidic ROS generators, while MWCNTs may either produce or scavenge ROS. However, certain biomolecules, such as albumin – used as dispersants in nano material or particulate preparations for toxicological testing in vivo and in vitro – may reduce the surface reactivity of these nano materials. Testing MWCNT materials induced highly variable cytotoxic effects which generally are related to the abundance and characteristics of agglomerates/aggregates and to the rate of sedimentation. I have found that All carbon nano materials – MWCNTs, like the one you are asking about in the above video, will scavenge hydroxyl radicals which is a major alkaline buffer (OH-) released by lymphocytes to protect the alkaline design of the body fluids for the purpose of reducing proton/hydrogen concentrations in the body fluids, leading to the risk of decompensated acidosis in all of the fluids or solutions of the body which I have tested, including the vascular and interstitial fluids of the Interstitium, leading to pathological blood coagulation, hypoxia and death by suffocation. The effect of bovine serum albumin (BSA) in cell culture medium with and without BEAS 2B cells on radical formation/scavenging by five MWCNTs, Printex 90 carbon black, crocidolite asbestos, and glass wool, using electron spin resonance (ESR) spectroscopy, showed cytotoxic effects measured by trypan blue exclusion assay among the materials tested. Two types of long, needle-like MWCNTs (average diameter > 74 and 64.2 nm, average length 5.7 and 4.0 μm, respectively) induced, in addition to a scavenging effect, a dose-dependent formation of a unique, yet unidentified radical or antioxidant release in both absence and presence of cells, which also coincides with cytotoxicity of these nanotubes or in simple terms MWCNTs are a contributing factor in the cause of a cancerous condition. Based upon the microscopic evaluation presented in the above video it is my professional opinion that what is being viewed is a MWCNTs or a carbon nanotube which is highly cytotoxic or acidifying to blood, interstitial fluid compartments and intracellular fluids which may lead to cell membrane degeneration and genetic mutation of the body cells putting at risk the healthy state of all glands, organs and tissues.” Jorma: I am very concerned about his findings. There are ramifications down the road if what he says is true for long term health. Any messing with ROS stability can lead to aging of the subject and diseases associated with that. Jorma: Asbestos can induce mesothelioma. ROS instability can lead to a host of cancers by DNA mutations. Heart disease risk is also increased by ROS excess. Pete: What the heck can we do if these things are implanted into the most "common" forms of medicines, meant for all. I mean how can we fight the obviously pure evil carried out by the" scientific community" and big pharma? Jorma: We are unwitting subjects in an experiment that may turn out to include not only virus response but also population control. I got the Phizer shot but am 76 so if it kills me nobody will ever know because I am already in the death zone for men. The next five yrs will tell the result. Do not do the kids.

Testimony of Dr Meryl NASS before the Health and Human Services Committee. 2023-03-03, Repost Jorma Jyrkkanen

Testimony of Meryl Nass, MD before the Health and Human Services Committee January 11, 2022 Honorable Chairpersons, Members and Senators, I write in support of LD 867. There are many reasons why preventing COVID vaccine mandates until adequate, sufficient safety studies have been performed is the right decision for this committee and legislature. 1. COVID vaccines are experimental Let me say, first, that no matter what claims have been made regarding these vaccines, they are not "safe and effective." "Safe and effective" is an FDA 'term of art'1 that may only be applied to licensed drugs and vaccines. All currently available COVID vaccines in the United States are unlicensed and experimental, a.k.a. investigational. Medicines and vaccines are either licensed products or experimental products. There is no gray area between them in US law. Whether or not research is explicitly conducted, the use of experimental products (including those issued under an Emergency Use Authorization) falls under the Nuremberg Code and under US law regulating experimental drugs. As former FDA Commissioner Stephen Hahn himself noted, "EUA products are still considered investigational."2 According to 21CFR Subchapter D Part 312:3 "an experiment is any use of a drug except for the use of a marketed drug in the course of medical practice." Vaccines are considered a subset of drugs by FDA.4 And the use of unlicensed, Emergency Use Authorized vaccines is thus, by definition, experimental. US law requires that humans receiving experimental products must provide written informed consent.5 However, when the PREP Act creating Emergency Use Authorizations (EUAs) was written, this requirement was loosened slightly for emergencies in which EUA products would be used. The required disclosures when using EUAs were specified below. Please note the option to accept or refuse. 21 U.S. Code § 360bbb–3 - Authorization for medical products for use in emergencies6 (ii) Appropriate conditions designed to ensure that individuals to whom the product is administered are informed— 1 https://www.fda.gov/science-research/risk-communication/fdas-risk-communication-research-agenda 2 https://www.usatoday.com/story/news/2020/11/24/fda-commissioner-stephen-hahn-timing-safety-covid-19- vaccine/6393865002/ 3https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=312.3#:~:text=Clinical%20investigation %20means%20any%20experiment,the%20course%20of%20medical%20practice. 4 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7152379/ 5 https://www.ecfr.gov/on/2018-07-19/title-45/subtitle-A/subchapter-A/part-46#sp45.1.46.a 6 https://www.law.cornell.edu/uscode/text/21/360bbb-3 2 (I) that the Secretary has authorized the emergency use of the product; (II) of the significant known and potential benefits and risks of such use, and of the extent to which such benefits and risks are unknown; and (III) of the option to accept or refuse administration of the product, of the consequences, if any, of refusing administration of the product, and of the alternatives to the product that are available and of their benefits and risks. All Moderna, Janssen (Johnson and Johnson) and all childhood Pfizer-BioNTech vaccines are being used under EUAs. And while the adult Pfizer-BioNTech vaccine is supposed to be licensed with brand name Comirnaty, in fact the Pfizer vaccines being used in the US today are EUA products as well. 2. While FDA licensed Comirnaty, the only approved COVID vaccine, only Emergency Use Authorized (experimental) vaccines are being used Despite claims to the contrary, the only vaccine currently available in the US is the Pfizer- BioNTech, not the licensed and branded Comirnaty. The Pfizer-BioNTech vaccine is authorized under an Emergency Use Authorization, which provides a broad liability shield to the manufacturer, distributor, administrator, program planner, and virtually anyone else involved in the vaccination process. The branded product, on the other hand, is subject to ordinary liability claims at the present time. Exactly three weeks after FDA issued Comirnaty a license, the National Library of Medicine, part of the NIH, posted information that Pfizer was not planning to make Comirnaty available in the US while the EUA vaccine was still available:7 "SEPTEMBER 13, 2021 Pfizer received FDA BLA license for its COVID-19 vaccine Pfizer received FDA BLA license on 8/23/2021 for its COVID-19 vaccine for use in individuals 16 and older (COMIRNATY). At that time, the FDA published a BLA package insert that included the approved new COVID-19 vaccine tradename COMIRNATY and listed 2 new NDCs (0069-1000-03, 0069-1000-02) and images of labels with the new tradename. At present, Pfizer does not plan to produce any product with these new NDCs and labels over the next few months while EUA authorized product is still available and being made available for U.S. distribution. As such, the CDC, AMA, and drug compendia may not publish these new codes until Pfizer has determined when the product will be produced with the BLA labels." FDA extended the vaccine's EUA authorization on the same day it licensed the vaccine. 7 https://dailymed.nlm.nih.gov/dailymed/dailymed-announcements-details.cfm?date=2021-09-13 3 FDA appears to have been acceding to the White House demand that the vaccine be licensed, in order for it to be mandated for large sectors of the US population. Under an EUA, which specifies that potential recipients have the right to refuse,8 mandates cannot be imposed. So a license was issued, allowing the administration to inform the public that the vaccine was fully approved and licensed. But in fact, the public was unable to access the licensed vaccine. Why was this convoluted regulatory process performed? While under EUA, Pfizer has an almost bulletproof liability shield. According to the Congressional Research Service (CRS) on September 23, 2021,9 "courts have characterized PREP Act immunity as 'sweeping.'" The CRS explains, "the PREP Act immunizes a covered person from legal liability for all claims for loss relation to the administration or use of a covered countermeasure." 3. FDA instructed Pfizer-BioNTech that FDA's Congressionally-mandated databases are inadequate to assess the danger of myocarditis (and other potential COVID vaccine side effects) and therefore Pfizer-BioNTech must perform studies to evaluate these risks over the next six years On the day FDA issued a license for Comirnaty, August 23, 2021, FDA instructed Pfizer- BioNTech that it did NOT have sufficient information on serious potential risks of the product, and required Pfizer and BioNTech, the manufacturers, to conduct a series of studies to assess these potential risks.10 These studies were to be performed on both products: the licensed Comirnaty and the EUA Pfizer-BioNTech vaccine. Note that they include the requirement for a safety study in pregnancy, which will not be completed until December 31, 2025. I have reproduced part of what FDA wrote about these required safety studies below, directly from pages 6-11 of the FDA approval letter sent to BioNTech, linked below. FDA's admission that it cannot assess these safety risks, and that up to 6 years will be taken to study them, provides us with additional de facto evidence that the Pfizer vaccines cannot be termed safe, as many of the fundamental safety studies are only now getting started. https://www.fda.gov/media/151710/download "POSTMARKETING REQUIREMENTS UNDER SECTION 505(o) Section 505(o) of the Federal Food, Drug, and Cosmetic Act (FDCA) authorizes FDA to require holders of approved drug and biological product applications to conduct postmarketing studies and clinical trials for certain purposes, if FDA makes certain findings required by the statute (section 505(o)(3)(A), 21 U.S.C. 355(o)(3)(A)). We have determined that an analysis of spontaneous postmarketing adverse events reported under section 505(k)(1) of the FDCA will not be sufficient to assess known 8 https://www.law.cornell.edu/uscode/text/21/360bbb-3 9 https://crsreports.congress.gov/product/pdf/LSB/LSB10443 10 https://www.fda.gov/media/151710/download 4 serious risks of myocarditis and pericarditis and identify an unexpected serious risk of subclinical myocarditis. Furthermore, the pharmacovigilance system that FDA is required to maintain under section 505(k)(3) of the FDCA is not sufficient to assess these serious risks. Therefore, based on appropriate scientific data, we have determined that you are required to conduct the following studies: 4. Study C4591009, entitled “A Non-Interventional Post-Approval Safety Study of the Pfizer-BioNTech COVID-19 mRNA Vaccine in the United States,” to evaluate the occurrence of myocarditis and pericarditis following administration of COMIRNATY. We acknowledge the timetable you submitted on August 21, 2021, which states that you will conduct this study according to the following schedule: Final Protocol Submission: August 31, 2021 Monitoring Report Submission: October 31, 2022 Interim Report Submission: October 31, 2023 Study Completion: June 30, 2025 Final Report Submission: October 31, 2025 5. Study C4591021, entitled “Post Conditional Approval [EUA] Active Surveillance Study Among Individuals in Europe Receiving the Pfizer-BioNTech Coronavirus Page 7 – STN BL 125742/0 – Elisa Harkins Disease 2019 (COVID-19) Vaccine,” to evaluate the occurrence of myocarditis and pericarditis following administration of COMIRNATY. We acknowledge the timetable you submitted on August 21, 2021, which states that you will conduct this study according to the following schedule: Final Protocol Submission: August 11, 2021 Progress Report Submission: September 30, 2021 Interim Report 1 Submission: March 31, 2022 Interim Report 2 Submission: September 30, 2022 Interim Report 3 Submission: March 31, 2023 Interim Report 4 Submission: September 30, 2023 Interim Report 5 Submission: March 31, 2024 Study Completion: March 31, 2024 Final Report Submission: September 30, 2024 6. Study C4591021 sub-study to describe the natural history of myocarditis and pericarditis following administration of COMIRNATY. We acknowledge the timetable you submitted on August 21, 2021, which states that you will conduct this study according to the following schedule: Final Protocol Submission: January 31, 2022 Study Completion: March 31, 2024 Final Report Submission: September 30, 2024 7. Study C4591036, a prospective cohort study with at least 5 years of follow-up for potential long-term sequelae of myocarditis after vaccination (in collaboration with Pediatric Heart Network). We acknowledge the timetable you submitted on August 21, 2021, which states that you will conduct this study according to the following schedule: Final Protocol Submission: November 30, 2021 Study Completion: December 31, 2026 Page 8 – STN BL 125742/0 – Elisa Harkins Final Report Submission: May 31, 2027 8. Study C4591007 sub-study to prospectively assess the incidence of subclinical myocarditis following administration of the second dose of COMIRNATY in a subset of participants 5 through 15 years of age. We acknowledge the timetable you submitted on August 21, 2021, which states that you will conduct this assessment according to the 5 following schedule: Final Protocol Submission: September 30, 2021 Study Completion: November 30, 2023 Final Report Submission: May 31, 2024 9. Study C4591031 sub-study to prospectively assess the incidence of subclinical myocarditis following administration of a third dose of COMIRNATY in a subset of participants 16 to 30 years of age. We acknowledge the timetable you submitted on August 21, 2021, which states that you will conduct this study according to the following schedule: Final Protocol Submission: November 30, 2021 Study Completion: June 30, 2022. Final Report Submission: December 31, 2022 ... 10. Study C4591022, entitled “Pfizer-BioNTech COVID-19 Vaccine [the EUA vaccine] Exposure during Pregnancy: A Non-Interventional Post-Approval Safety Study of Pregnancy and Infant Outcomes in the Organization of Teratology Information Specialists (OTIS)/MotherToBaby Pregnancy Registry.” Final Protocol Submission: July 1, 2021 Study Completion: June 30, 2025 Final Report Submission: December 31, 2025 4. The World Health Organization does not recommend COVID vaccines for normal children The WHO website "WHO SHOULD GET VACCINATED"11 states the following: Children and adolescents tend to have milder disease compared to adults, so unless they are part of a group at higher risk of severe COVID-19, it is less urgent to vaccinate them than older people, those with chronic health conditions and health workers. More evidence is needed on the use of the different COVID-19 vaccines in children to be able to make general recommendations on vaccinating children against COVID-19. WHO's Strategic Advisory Group of Experts (SAGE) has concluded that the Pfizer/BionTech vaccine is suitable for use by people aged 12 years and above. Children aged between 12 and 15 who are at high risk may be offered this vaccine alongside other priority groups for vaccination. Vaccine trials for children are ongoing and WHO will update its recommendations when the evidence or epidemiological situation warrants a change in policy. If the World Health Organization believes there is insufficient evidence to support general vaccination of normal children, why would this committee and the Maine Legislature think otherwise? To sum up: 11 https://www.who.int/emergencies/diseases/novel-coronavirus-2019/covid-19-vaccines/advice

Bill Gates Crimes Short List. 2023-03-02. Jorma Jyrkkanen, BSc, PDP

Bill Gates Crimes Short List. 2023-03-02. Jorma Jyrkkanen, BSc, PDP Jorma Jyrkkanen

BILL GATES CRIMES: U.S. patents show CDC ownership of Coronavirus. Both China and the U.S. involved in the creation of Wuhan SARS-CoV-2. Gates and CCP controlled WHO appoints criminal Tedros. CDC, FDA, CIA, NIH, Gates, Fauci, Baric, Rockefeller are all involved in Federal Crimes.

Bill Gates and the Rockefeller foundation paid Google, Facebook, Politico, Wikipedia, Fact Checkers in order to censor and control all the information.

The CIA has been using Operation Mockingbird for years and has over 3,000 agents implanted in Mainstream Media to control the population. Event 201 was sponsored by Bill Gates, the Johns Hopkins Center for Health Security (CIA) and the World Economic Forum to enforce a worldwide Pandemic response 5 months before the WHO fraudulently declared a global pandemic. It was a planned coordinated criminal effort worldwide.

In January 2017 Anthony Fauci said there will be a surprise virus outbreak before the end of 2020. Bill Gates in 2015 talked of a future pandemic and lied in April 2020 when he said they did not simulate or practice for a pandemic. Klaus Schwab in his book Covid-19 The Great Reset shows Covid was the Trojan Horse to Reset the World according to the UN 2030 Agenda. Build Back Better slogan is a criminal coordinated effort to remove human rights and institute a one world government. Bill Gates and the Rockefeller foundation bribes the WHO, NIH, NIAID, CDC, FDA, Medical Schools and Journals to control the health industry and public health policy. WHO Chief Tedros involved in genocide killing and torture in Ethiopia. Tedros is a known member of the communist party. He is Beijing's and Bill Gates puppet. As a Health Minister he was accused of covering up three Cholera Epidemics and committing crimes against humanity. The CCP and Bill Gates helped put Tedros in charge of the WHO.

John D. Rockefeller over 100 years ago seized the U.S. Media and took control over public health using toxic petroleum based drugs for profit and controlled the American Medical Association blacklisting and expelling any doctors who practiced natural medicine. Rockefeller's poison injections and medicines started causing cancer in early years and to cover it up formed the American Cancer Society. Medical error is the 3rd leading cause of death in America. Bill Gates used India and Africa as guinea pigs for pharmaceutical companies to make a financial killing while killing a lot of people in the process including killing innocent children and babies with vaccines. Bill Gates controls GAVI The Vaccine Alliance to vaccinate the world with his poisons.

National Security Study Memorandum NSSM 200 Implications of Worldwide Population Growth For U.S. Security and Overseas Interests December 10, 1974 (THE KISSINGER REPORT) shows the intention of governments to reduce the population. Bill Gates is one of the key funders in the Stratosphere experiment to block out the sun for Climate Change by releasing poisons in the air. Environmental Scientist call it global genocide experiment. Gates has invested over one billion dollars in the Earth Now Global Surveillance project to launch hundreds of satellites to monitor people everywhere 24/7 a day. In partnership with MIT Bill Gates has developed a new technology that allows vaccines to be injected under your skin along with your medical records. Bill Gates Gates funded genetically modified mosquitoes released in the USA to allow human immunization by means of mosquito bites "Flying Syringes." Bill Gates had business dealings and a relationship with Jeffrey Epstein, a convicted child sex criminal. Why would he choose to partner with the world's most notorious pedophile? To Blackmail? BILL GATES NAME APPEARS ON THE EPSTEIN ISLAND VISITOR LIST

BILL GATES GOES TO VISIT CHINA TOP BRASS. WHATS HE SELLING?