Rubber Meets the Road.

Let’s start where I want to end this topic, and I know you won’t like me saying this. The pandemic is likely to swagger around more than anticipated. If we anticipated it to end sooner, if not early 2021, it bores disappointment. It’s just not the delay in rolling out the vaccine. Let’s see the multitude of issues why the pandemic is likely to last longer.

Vaccine Nationalism is an integrated world is unlikely to protect a nationality unless the borders are strictly closed. Well, any isolationism and walls are unlikely to stop the Humboldt of global integration. If the rich or the have (those with technology), are planning to cover their nationals, the virus is likely to linger longer in those deprived.

What are the consequences?

Most of us are aware of the new mutations in the virus that imposed an immediate lockdown in the UK. This mutant variant is secondary to the virus gaining survival by mutating and escaping. Such mutants are like to hamper our interventions right from screening to vaccination.

Is it a global vaccine rollout?

Of course nor, the vaccine rollout has started in the EU, UK, US, Brazil, Mexico, Canada, Japan, China, and a select few countries. However, several countries are lagging behind either because they have no funds or no technology or logistics to deploy a complex vaccine delivery program. Add to that the regular protagonist of the ‘conspiracy theory’ school, and you compound the problem to a level of practical reality.

Surprise – Many doctors are evading vaccine

I was surprised to see practicing doctors avoiding vaccines. This is not an isolated but a pervasive phenomenon. There are still lingering doubts about the virus getting integrated into the human genome, which is unlikely to happen. Another misconception is heavy metal contamination of the vaccine. You and I are more exposed to the unknown quantity of heavy metals in our produce from Mexico or the disposable material we are exposed to. First, I may disagree if such contaminations are possible with the vaccines, and even if those were, it is unlikely that you get a significant dose to perturb your system. Another misconception that is going around – that the vaccine is made in cow or pig. I just piety these folks who work on churning the rumors mills devoid of research, reasoning, and rationale.

The cold chain and logistics

It is a formidable challenge to manage the cold chain in a diverse world like ours, even if we presume that vaccination will be adopted uniformly. Having worked as a molecular oncology fellow, I know that especially the RNA vaccines from Moderna and Pfizer need a distinct cold chain, and any disruption is likely to compromise the efficacy of the vaccine significantly. Now consider the vast and remote corners where the vaccines have to be carried out if we were to target complete eradication of the virus.

These are not easily surmountable challenges and devoid of a strategy and execution plan that is customized to individual locales (countries, regions, etc.), it is unlikely to achieve the desired goal of covering 60%-80% population. If the virus lingers, it will mutate and likely stay with humanity for longer than the expected period of time. It will evade our detection gold standard, such as RT PCR. It may create resistance to drugs such as Remdesevir, or worst, become more aggressive and, last, render our vaccines useless. That’s why we vaccinate ourselves annually for flu.

Let us hope for the best.

Hope is not the best strategy; instead, hope is the worst strategy. A thorough understanding of the global target population dynamics vis a vis the vaccination program is required. Strategies alone cannot help; execution of the plan will be the harbinger to success. Until then…

I wish you all a very safe 2021!

Shashank Heda,

Dallas, Texas

The Culpable Trend Continues

Of course, we saw during Covid how China suppressed the Covid investigation, manipulated the data and cleared the crime scene.

Recently, I saw news that China is targeting a GDP of 8 and above fir 2021. It is no news that China is under severe debt, industry is recuperating to gradual recovery, (and of course it will be, because its global customers are still reeling under recession), and it has quadrupled its expenses during a time depleted revenue flow and persistent pressure of aggressive spending on aggressive militarization.

Credits: John H Tuckers, The Riverfront Times

Now comes the real news

It has suspended the regulating agency which rates the progress. And why not? It has to, if it needs to pain all hunky dory, like the old style communist propaganda.

Eventually, we know, with one stroke of Perestroika, the entire communist castle came crumbling down. It’s just a matter of time, such artificial models have no sustenance, they glitter like a nighttime bugs, and lose the flare with the arrival of twilight.

Shashank Heda
Dallas, Texas

Chinese regulator suspends rating agency over Yongcheng default
https://asia.nikkei.com/Business/Markets/China-debt-crunch/Chinese-regulator-suspends-rating-agency-over-Yongcheng-default

Sleep Walking

Let’s scratch the surface

You all know how the bulls are raging on the stock markets globally. Most indices have skyrocketed while the economies of the world are reeling under covid.

Credits: Ben Carlson, https://fortune.com/2019/10/29/stock-market-rally-2019-christmas-eoy/

In a world full of non-ideal things, this one is no outlier, not because the markets display anomalous behavior but because the sentiments are so disconnected from the ground realities.

They say Covid is a disease of the affluent. Though I may disagree with that observation, however, stock market sentiments are the affluent’ sentiments. None of us want to see it lose, so we succumb to sentiments than the bottom line of individual companies comprising the index.

What’s so wrong if stocks are rising, especially in a sagging economy?

Absolutely a great question. Let’s understand the dichotomy and the disconnect. Presume my shares from a listed company shot up by 27% in the last nine months; obviously, I gained those. That offers a relative advantage over those struggling to survive and sustain.

However, let’s understand the stimulus bill. If only we have a great economy, ideally, we would not have the required stimulus. Interest rates would not have been low, millions would not have defaulted on their payments and mortgages, and unemployment would have been on the decline.

When the indicators are not connected with the ground reality, we are bound to land up in a ditch. Just imagine my leg is on the gas paddle, and I am pressing it hard; my car is cruising at astonishing speed, but the indicator says 22 mph.

When the indicators do not capture realities, we live in the castle, when the bourgeoisie falter, that revolutions are born. To douse the fire, we provide stimulus and subsidies. The vicious cycle keeps going endless while we churn a class of have-nots and increase the chasm with the have’s.

https://fortune.com/2019/10/29/stock-market-rally-2019-christmas-eoy/

Global stock markets form K-shape as investors search for growth
https://asia.nikkei.com/Spotlight/Datawatch/Global-stock-markets-form-K-shape-as-investors-search-for-growth

School Closure and Kids Infectivity?

Excerpts:

Are my kids susceptible?

Now that COVID has started raging once again across the US, it is very possible that the schools in your area may decide to close or remain open. Select states may choose to keep the schools open, whereas others may decide to close. Is there any data to support the spread of disease with the schools opting to remain open?

It is important to understand if the Kids are infectious? Are they likely to be an asymptomatic carrier? Are they more susceptible? Do they have enough antibody response? A map of the US with states mandated school closure is provided in this blog. (Word count 795, reading time 3-4 minutes).

Are kids “Briefly Infectious”?

Now that some states have mandated the schools to reopen, and though the kids have the option to physically attend or participate remotely, it is important to understand the implications for the family.

3% or 9% Threshold? What’s Right?

NY Mayor Bill D Blasio imposed a 3% moratorium on the case positivity rate to keep the school system open. You may see your state or local officials changing their decision to keep the schools closed if they see a rising number. The debate of 3% or 5% is seemingly not important. These numbers are related to the incidence of test positivity on a daily basis. Presume, you have 100 people visiting for testing, and 9 are positive (9%). Now presume, you have 500 people visiting for testing, and 3 per 100 are positive (3% but a total of 15 cases). Obviously, the absolute number matters most. However, New York Governor Andrew Cuomo or Iowa, Gov. Kim Reynolds has set the state’s closure threshold at 9 percent and 15 percent respectively. Why is the difference?

Hospital Beds influence the policy decision

The absolute numbers posted above make it clear that the more the number of the population infected, the more the number of beds required to treat the population. In fact, if the severity of the cases rises, another parameter that frequently influences the decision is the total number of ICU beds. If the system is inundated, these beds become significantly crunched and so lockdowns are enforced.  

These exact sentiments were communicated by Dr. Celine Gounder, Adviser to President Elect Joe Biden, when she said, “there may come a tipping point where you do need to go back to virtual schooling. But I think the priority is to try to keep schools open as much as possible, and to provide the resources for that to happen”.

Impact of Lockdown

Lockdowns have a significant impact on the daily lives and economic health of a nation or state. It has been observed that Lockdown has rendered a significant portion of working women to discontinue work and focus on the kids. This almost significantly reduces household income and increases stress and unhappiness due to an inability to meet family needs. Across the globe, educational planners are concerned about the pandemic inflicting an indelible harm to the academic development to the kids.

Are kids more susceptible? 

Recent research points to the Type 1 IFN that offers protection with the innate and adaptive immune response. As we age, the functioning is likely to get compromised and make us vulnerable. That is the reason, kids are less affected, whereas the elderly are more likely affected due to COVID. Second, children, have powerful innate immunity that mounts a severe and rapid response to the viruses, thus not allowing the viruses to gain a foothold, thus sparing them from severe disease. 

Do Children have a less protective response? 

Research from Karolinska Institute in Stockholm has demonstrated that the antibodies produced by kids are IgG type whereas, those produced by adults are of several types. The IgG antibodies bind to the S protein, whereas the diverse range of antibodies produced by adults bind to various proteins and help better neutralization of the virus.

The range of antibodies that children produced differed from those of adults. Children primarily made one type of antibody, called IgG, that binds to the spike protein on the surface of the virus. Adults, by contrast, made several types of antibodies that bind to the spike protein and other viral proteins, and these antibodies were more powerful than IgG at neutralizing the virus. Adult COVID-19 cohorts had anti-spike (S) IgG, IgM, and IgA antibodies, as well as anti-nucleocapsid (N) IgG antibodies, while children with and without MIS-C had reduced breadth of anti-SARS-CoV-2-specific antibodies, predominantly generating IgG antibodies specific for the S protein but not the N protein. 

Are Schools the Superspreaders? 

According to a report from Ney York Times, very little transmission happened in schools. The latest data shows that random testing since October has produced a positivity rate of just 0.17 percent.  Please visit an article cited below from the Journal of Pediatrics, an official journal of the American Academy of Pediatrics.

Take-Home Message:

  1. Kids may have better immunity burst to deal with SARS CoV2 but they may not have a complete armamentarium of antibodies to deal with every aspect of the virus.
  2. Kids may be less susceptible to the virus, but that does not rule out a possibility of MIS-C.
  3. Elderly parents at home are susceptible to infections from the kids, even if you presume, the kids are likely to have less probability of the disease. Grandparents and other senior elderly family members should be segregated from the kids to provide adequate protection. 

https://www.edweek.org/ew/section/multimedia/map-coronavirus-and-school-closures.html

https://www.nature.com/articles/s41590-020-00826-9

Compiled on behalf of COVIDRxExchange, a Nonprofit initiative 

Note: This is not a medical advice or recommendations. Please consult your doctor or local policy planner while making a decision. This is author’s personal Opinion and readers are strictly advised to consult medical professionals. Follow your local official advice and guidelines while trying to prevent the spread of coronavirus.

Visit Vaccine and Drones (https://mymilieu.org/2020/11/16/vaccines-and-drones/) to learn more about the effectiveness of the vaccines.

https://pediatrics.aappublications.org/content/pediatrics/early/2020/10/16/peds.2020-031971.full.pdf.

https://www.edweek.org/ew/articles/2020/03/20/when-americas-schools-shut-down-we-all.html

On The Line of Fire?

What went wrong with Padmashri, Padmabhushan Mr. S. P. Balasubramanyam, the legendary singer from India? He was recovering and suddenly he deteriorated and succumbed to the illness.

COVID can surprise you anytime, even in the recovery period. I got another note from social media, of a young doctor, a father of a six-month child – obviously a young family. He succumbed to complications of COVID. He was waiting to be discharged and go home.

Well, these unusual stories are gradually becoming common, and I thought of sharing it with you since doctors are seeing such scenarios very often. What is going wrong? Can we truly control it? Understanding these 10 points may possibly help prevent COVID-19. (Reading time 5 – 6 minutes; Scientific perspective).

(Note: We are planning to conduct a cross cutting expert global advisory session to clarify all relevant questions. We are planning to conduct this half day session before the start of the SECOND WAVE. Please share your questions to me in person or on this page as we are crowd sourcing questions from all).

Well, these unusual stories are gradually becoming common, and I thought of sharing it since doctors are seeing such scenarios very often (Please scroll to the bottom of the blog to see the detailed note). 

I had another gentleman who went to a Salon. He argued that he should support the local economy, a lame excuse. Well, even if he wants to support the local economy, he can donate bigger amounts and support the local economy, like many others who have supported their dependent workforce.  Time and again, I have been sharing rejoinders on awareness and precautions, and I am summarizing those below – 

1. A Constantly Mutating Virus:

The virus is constantly changing. It has a gene called RDRP (RNA-dependent RNA Polymerase) that encodes for an enzyme that makes a template for the RNA’s to produce in copies in billions. RDRP has a vulnerable to mutations and this results in the constantly changing nature of the virus. It is this enzyme that makes a (defective) template resulting in mutations. Every time, RDRP makes a template, it ends up producing an erroneous copy that results in mutant copies with every generation of the virus reproduction. 

2. Comorbidities and Unknown Risk:

Selective comorbidities and risk factors are known,however many are yet unknown. We all now know that diabetes, hypertension, smoking, cardiac problems, asthma, immune-compromised, and other respiratory illnesses predispose to COVID. However, we are seeing several youngsters without any of these comorbidities who are suffering and sometimes succumbing to COVID. 

3. Incomplete understanding of the Impact:

Also, we see that some have comorbidities and dies of COVID, whereas others with similar comorbidities survive despite having COVID. Knowing your comorbidities, science still cannot say if your disease will be asymptomatic, mild, moderate, or severe. 

4. Clean recovery or Long Haul Disease:

Despite the recovery, Science cannot predict if you will be ‘long hauler’, i.e. those have long term consequences. According to few reports, almost 10% to 1/3 recovered patients land up with Long Haul disease. The legendary singer, mentioned above, started showing signs of recovery, including light speech and physical activities. He deteriorated due to post COVID complication and eventually died of post recovery complications. 

5. Status of Vaccines:

Vaccines are in pipeline and serious efforts are being made to develop and durable vaccines but we don’t have one that we can rely upon. 

6. Repurposed drugs but No Specific Drugs:

We have supportive drugs but no specific drugs to remove the virus. We know it very well that HCQ was the mainstay at the beginning of the pandemic. Later, it fell into disrepute. Steroids were questioned and only after the ‘Recovery Trial’ substantiated the use of steroids with a randomized controlled trial, that changed the management of COVID. Tocilizumab similarly came in and had an ignominious walkout after the COVECTA trial. Just a few days back, the Japanese FDA approved Favipiravir. the later drug, with its RNA-dependent RNA polymerase activity, has anecdotal evidence of effectiveness since it’s a proofreading enzyme that renders the removal of nucleoside analog (drug molecule) and despite continue inducing mutations. Changes to the use of these guidelines may be anticipated as well. 

Different modalities of therapy for treating COVID-19.

7. Reinfections:

Several are indeed recovering but several reports of reinfections are emerging. It is a fact that several people are recovering from COVID, however, it is equally true that many lands up with severe disease, and those recovering are having long-term debility and need rehabilitation? 

8. Asymptomatic Spreader:

Are you sure, if you will just get the mild form of COVID or remain asymptomatic? Even if you remain asymptomatic, are you sure, you will not pass it on to your family members and if they get COVID, are you sure, like you, they too will be unscathed?   

9. Herd Immunity:

It is like playing with fire. Some insist that we should expose ourselves to build our innate resistance. Remember, this is not a natural virus, also, it evokes severe inflammatory and immune reactions within the body. It is structured or has been structured to keep changing. Our immune systems are built to remember, called immune memory. The changing nature of the virus renders the previously learned immune phenomenon useless. So even if we expose ourselves, our immunity will not last long. It is similar to Influenza. We see a different strain at least every year. With COVID, we see a different strain every few weeks. 

10. Convalescent Plasma and Antibodies:

Plasma from patients having recovered from COVID-19 has antibodies to SARS CoV2. Plasma, thus drawn from recovered patients helps treat and or contain COVID in infected patients. The earliest experiment was done by Edward Jenner in 1796 when he scratched the fluid from the blisters of a cow suffering from smallpox into the skin of a normal healthy man and induced protection. As we now know, Smal Pox is completely irradicated. Convalescent plasma (CP) uses the same principle, of tapping into existing antibodies for treating existing COVID-19 patients. 

However, there is a catch. CP is nonspecific, ie. it has other unrequired antibodies that may trigger untoward reactions. Also, if the virus itself is changing, those antibodies are ineffective. More so, the antibody levels drop after a certain period. Thus monoclonal antibodies become relevant. Placebo controlled randomized trials are being underway (as of this writing) that will offer solace to the treatment of COVID-19. Antibodies have to be targeting specific proteins called epitopes. In the presence of changing epitopes, it is fluid to understand the reliance on monoclonal antibodies. 

Myriad Complexity –

a) Cytokine and Bradykinin Storm: For the common men, the difference is nimble, it does, however, matter for the doctors though. Cytokine storms – processes in which the immune system overreacts to an infection. Ideally, cytokines disappear once the virus copies reach a threshold. COVID, however, puts the body into an overdrive mode and produces cytokines that ultimately result in damage to the organs. (drives the body to produce the immune system keeps producing them and the organs take the brunt from these excess cytokines). Cytokines are associated with myeloid differentiation and disease severity, concurrently the T cells are reduced as is evident from the reduced numbers of CD4+ and CD8+ T cells in patients with COVID-19. 

b) Kallikrein–kinin system: Irrespective of the pathognomic phenomenon (mechanism of the disease), COVID unleashes vast reaction from your own body to damage itself. Think, of this like a natural defense which is supposed to protect you, has turned up against you, causing a perfect storm to disrupt and incapacitate you.

Remember the fluid build up around the lungs, which is primarily caused by bradykinins. Bradykinins causes the blood vessels leaky and result in edema (swelling) around vital organs such as the lungs (short of breath), muscle (body aches), gastrointestinal tract (diarrhea), kidneys (congestion and rising serum creatinine), and a multitude other clinical features.    

c) Endothelial Nitric Oxide System: Endothelial nitric oxide synthase (eNOS) becomes a potential therapeutic target. Hypercholesterolemia, diabetes mellitus, arterial hypertension, and smoking are associated both to nitric oxide synthesis reduction or degradation increase. This nitric oxide bioavailability reduction is followed by endothelial dysfunction

A Picture is Worth 1000 Words:

A review of the work – A great deal of work has been done in the treatment and or containment of COVID-19 in the last 9 months. LitCOV provides an exclusive insight on the amount of scientific literature exclusively within the field of COVID-19. Based on the data from Milken Institute, select treatment modalities have been captured in the pie chart below (cumulative progress in the treatment of COVID).

Reflections On Human Urge to Move Freely

Our fundamental human urge to move and intermingle has been severely constrained, however, historical evidence shows that no calamities remain constant. If you recollect, no rains, volcanoes, earthquakes, or twisters (andhi) remains forever. One day it wanes and so will this virus, it is nature’s law and this virus too will follow those laws. 

Remember, humanity has a significant resilience built-in and as the history of human evolution shows, it has never been subdued nor will it ever let any event subdue its spirit and independence. However, events have always taken a huge toll and we never know if we are on the line of fire. 

Death of COVID Treating Doctor:

A 38 yrs old male doctor gen practitioner was admitted to our hosp with COVID on the 6th day of illness with 60% lung involvement, SpO2 borderline with mild dyspnoea. He became critical in the next 2 -3 days with a typical cytokine storm. We shifted him to ICU and on NIV. He was quite tachypneic, tocilizumab 2 doses were given and his NIV requirements decreased ..and eventually, after 5 days of ICU stay, he was weaned off from NIV and stable on nasal prongs 4-5 L o2. Later, he was shifted to the ward with oxygen. On the previous day of his discharge, he developed abdominal distension and severe abdominal pain, and constipation. A Ryles tube was passed and was kept NBM, X-ray abdomen showed dilated bowel loops but no air-fluid levels. GI doc advised enema, a CT abdomen was advised, radiologist suspected some bowel ischemia, so the patient was shifted to Ruby Hospital, Pune. After struggling with the consequences of ischemic bowel complications, the patient succumbed due to Sepsis and multi-organ failure.

It is now a routine, to see notes such as the one below, on social media. 

Do you want to be on the line of Fire?

COVID-19 cytokine storm: The anger of inflammation; Cytokine. 2020 Sep; 133: 155151. Published online 2020 May 30. doi: 10.1016/j.cyto.2020.155151 PMCID: PMC7260598; PMID: 32544563

https://www.bio.org/policy/human-health/vaccines-biodefense/coronavirus/pipeline-tracker

https://covid-19tracker.milkeninstitute.org/#vaccines_intro

Second Surge and COVID-19 prevention

The risk of infection is the same for everyone in that environment, but the consequences of infection are different depending on age, ethnicity, and comorbidities. Are there any formulae to calculate that? Possibly, emperical estimates can be made using known facts. However, remember, humanity is still in the discovery phase of COVID. We have identofied few risks factors, eg. Comobidities. However, a complete risk stratification is not yet available. Neither do we know who will have mild, moderate or severe disease. (On Behalf of COVIDRxExchange)

Now that aerosols are established as factors disseminating COVID, it is important to realize that COVID is persistent in the air. A few days back, I had a gentleman eating food in a restaurant or the patio of the restaurant. As usual, my relationship made me ask a few questions about his understanding of the disease. He said if we can eat outside food at home, why can’t we eat outside food in the restaurant.

Let us understand and analyze the situation. COVID is not foodborne, COVID is not water-borne, COVID is an airborne infection. The air around you will determine if you are likely to get COVID. In a setting such as a restaurant, this gentleman has a high probability of acquiring COVID. Factors that need to be considered while understanding your chances of getting COVID are the estimated prevalence of infection in that space, contact time and distance, and the degree of aerosolization.

The risk of infection is the same for everyone in that environment, but the consequences of infection are different depending on age, ethnicity, and comorbidities. I often cite an example – of inside and outside risk. Presume, it is snowing and the roads are all icy and slippery. Driving under such inclement conditions is fraught with severe risk. If during such times, you have an emergency at home, you still have to venture out and take care of that. However, if I say I just want to drive and see the fun, obviously it is stupidity.

Thus risk assessment becomes an important factor. Outside risk versus your own vulnerability. That also means that despite the outside risk is high, if you have a critical/essential function that needs immediate attention, you may want to consider doing that. However, if the vulnerability is high, ie. the impact is high, it also means that you want to seriously consider the probability of getting the disease. Thus likelihood and impact are important aspects that you want to consider.

Mitigation depends upon several aspects, face shields, masks (quality is important), and the time of exposure and the (presumably) pre & post-exposure mitigation you perform.

A simple approach to estimate your exposure can be shown in the below formula –

Exposure estimation = (Prevalence of the virus in the air) X (contact time) X (Distance of separation) X (inversely related to your protection mechanisms) X (your internal vulnerability).

The most significant aspect of COVID is that, as of now, SCIENCE DOES NOT HAVE A COMPLETE UNDERSTANDING OF AN INDIVIDUAL’S INTRINSIC RISK.

This is an opinion, not an advisory and you should consult your doctor to seek any advice. The author is not responsible or liable if you use this piece without consultation and advice from your doctor.

https://www.bmj.com/content/370/bmj.m3616

Let us not play God

It is not about China. It is about the human intrigue and opportunity to produce a new organism that unleashes vast implications for us as humanity. The day we start playing nature (God) that day, we should consider as doomsday, because we now know COVID very well and we are seeing how it erupted and further fractured our fault-lines and exposed us – logically, scientifically, politically, ideologically and just the very way we are organized and evolved as humanity.

Interesting repudiation. This is exactly what I was discussing in the first quarter of this year. The introduction is very intuitive and logically engaging. The policy makers across the world are turning a blind eye towards this synthetic source of the virus. However, it shows the power of how human can go wrong in trying to second guess the nature and remix and refactor its native form.

Again, it is not about China. It is about the human intrigue and opportunity to produce a new organism that unleashes vast implications for us as humanity. The day we start playing nature (God) that day, we should consider as doomsday, because we now know COVID very well and we are seeing how it erupted and further fractured our fault-lines and exposed us – logically, scientifically, politically, ideologically and just the very way we are organized and evolved as humanity.

  1. Has SARS-CoV-2 been subjected to in vitro manipulation?

1.1 Genomic sequence analysis reveals that ZC45, or a closely related bat coronavirus, should be the backbone used for the creation of SARS-CoV-2
1.2 The receptor-binding motif of SARS-CoV-2 Spike cannot be born from nature and should have been created through genetic engineering
1.3 An unusual furin-cleavage site is present in the Spike protein of SARS-CoV-2 and is associated with the augmented virulence of the virus

  1. Delineation of a synthetic route of SARS-CoV-2
    2.1 Possible scheme in designing the laboratory-creation of the novel coronavirus
    2.2 A postulated synthetic route for the creation of SARS-CoV-2

Step 1: Engineering the RBM of the Spike for hACE2-binding (1.5 months)
Step 2: Engineering a furin-cleavage site at the S1/S2 junction (0.5 month)
Step 3: Obtain an ORF1b gene that contains the sequence of the short RdRp segment from RaBtCoV/4991 (1 month, yet can be carried out concurrently with Steps 1 and 2)
Step 4: Produce the designed viral genome using reverse genetics and recover live viruses (0.5 month)
Step 5: Optimize the virus for fitness and improve its hACE2-binding affinity in vivo (2.5-3 months)

It is noteworthy that, based on the work done on SARS-CoV, the hACE2-mice, although suitable for SARS-CoV-2 adaptation, is not a good model to reflect the virus’ transmissibility and associated clinical symptoms in humans.

We also speculate that the extensive laboratory-adaptation, which is oriented toward enhanced transmissibility and lethality, may have driven the virus too far. As a result, SARS-CoV-2 might have lost the capacity to attenuate on both transmissibility and lethality during its current adaptation in the human population.

Serial passage is a quick and intensive process, where the adaptation of the virus is accelerated. Although intended to mimic natural evolution, serial passage is much more limited in both time and scale.

The following facts about SARS-CoV-2 are well-supported:

  1. If it was a laboratory product, the most critical element in its creation, the backbone/template virus (ZC45/ZXC21), is owned by military research laboratories in China.
  2. The genome sequence of SARS-CoV-2 has likely undergone genetic engineering, through which the virus has gained the ability to target humans with enhanced virulence and infectivity.
  3. The characteristics and pathogenic effects of SARS-CoV-2 are unprecedented. The virus is highly transmissible, onset-hidden, multi-organ targeting, sequelae-unclear, lethal, and associated with various symptoms and complications.
  4. SARS-CoV-2 caused a world-wide pandemic, taking hundreds of thousands of lives and shutting down the global economy. It has a destructive power like no other.

On point 2 above, I would like to add that, it is possible the military labs never realized the virulence of the new virus since most of the experiments were done on cell lines and animal models, such as laboratory rats and monkeys.

Bleach or Alcohol Based Disinfectant

With rapidly diminishing availability of commercial cleaning supplies, simply diluted bleach, which is readily available, can effectively disinfect homes, offices, and environment to prevent sustained transmission from inanimate objects. Bleach, when used in right dilution, can serve as an alternate option for Alcohol Based Disinfectant. However, the dilutions are important so are the adverse effects from exposure.

SARS-CoV-2 suggests that COVID-19 may remain viable for hours to days, on inanimate surfaces, such as metal, glass, or plastic, for up to 9 days. With exponentially rising COVID-19 cases in the United States, commercial disinfect supplies are in high demand and will unquestionably be limited in the near future. We will have to get creative with available resources, all the while taking safety precautions to ensure our efforts improve and not worsen the ongoing situation.

While the exact viral load on inanimate surfaces is unknown during an outbreak, it is critical to disinfect frequently touched surfaces. With rapidly diminishing availability of commercial cleaning supplies, simply diluted bleach, which is readily available, can effectively disinfect homes, offices, and environment to prevent sustained transmission from inanimate objects. As with many disinfectants, minimizing long-term skin contact and ensuring good ventilation can minimize clinical toxicity.

The virus can efficiently be inactivated by 62% to 71% ethanol, 0.5% hydrogen peroxide, or 0.1% sodium hypochlorite within 1 minute. Dilutions of ∼0.1% sodium hypochlorite are clinically effective with minimal irritation or sensitization.5 One should be mindful that corrosive injury on mucous membrane/skin contact is possible with excess volumes or mishandling, so appropriate caution and moderation are necessary. This solution should ideally be used within 1 month of preparation and stored in a closed, opaque container at room temperature.

∼0.1% sodium hypochlorite can be made by a roughly 1:50 dilution of household bleach (∼5.25% to 6% sodium hypochlorite) in tap water. The proposed formulation is shown to disinfect surfaces of the novel coronavirus. The Centers for Disease Control and Prevention (CDC) also recommends an approximately 1:50 dilution to disinfect COVID-19, explicitly noting 5 tablespoons (one-third cup) bleach per gallon of water or 4 teaspoons bleach per quart of water.

https://www.sciencedirect.com/science/article/pii/S0190962220306095

Am I Culpable for Spreading Virus?

This is a classic example of invincibility and complacency – that nothing will happen to me even while the entire world is suffering from COVID.

Passengers went on a cruise while COVID was raging, presuming that COVID won’t infect their isolation on the ship (in deep water!) never realizing that asymptomatics are the core carrier rather than those who are actively infected.

Exactly this is what happens around us. Yesterday, I was talking with a friend and I realized, he was not using a mask despite the incidence being very high in their state.

That’s pathetic, I understand coronavirus is not seen and leave behind a trail of fragrance but understand, every time an asymptomatic exhales or sneezes, they blow approximately 54 million copies of the virus in the air. It is now known that these copies stay for at least 3-6 hours in the air. That air may drift in your direction and not having a mask while exposed to the potentially infectious airborne virus is culpable negligence, especially knowing that it may make you another asymptomatic carrier.

This pandemic is replete with examples where the asymptomatic have infected the gullible and innocent unexposed. It is the later who has taken the brunt from SARS CoV2.

Shashank Heda, MD
Dallas, Texas, US

Coronavirus: Dozens test positive for Covid-19 on Norwegian cruise ship
https://www.bbc.co.uk/news/world-europe-53636854

The ‘Good and Not So Good’ of COVID-19

While COVID-19 is taking a huge toll across the globe, humanity is displaying a polar reaction – a not so invincible risk taking attitude and a scared, vulnerability. The answer lies in between these two polar extremes. A balanced approach will help to prevent COVID at the individual and family level, which will eventually also be reflected as a social index for measuring our progress while preventing SARS CoV2 and treating COVID-19 patients.

I discussed the ‘good and not so good’ aspects associated with the prevention of COVID-19 and our own vulnerabilities. The initial battle with COVID is in our mind, where we either think we are vulnerable or invincible.

Let us visit the “Not So Good” part early. 

The spike of COVID-19 is huge across the sunbelt of the US. Several southern states are massively infected due to the COVID-19. The virus is seeing a massive resurgence in the UK, EU, and Australia. It is still in its ascendancy in India, Pakistan, Sri Lanka, and several southeast Asian countries. The Middle East is just catching the fever. Brazil and Latin America (currently in their winter) are seeing a heavy toll. 

While COVID-19 is still raging across the globe, humanity is displaying a polar reaction. On one side, we feel strong and ready to take risk, on the other side we are scared and vulnerable. Can we balance our approach and fight this virus? The answer is a definite yes. How do we do that?
The Good and Not so Good of COVID-19

Intrinsic Vulnerabilities are in our mind

You may be thinking, our body is vulnerable and weak and so we catch the infection. While, most amongst us are following precautions., precautions are not enough. We see at least two major vulnerabilities despite following precautions – 

  1. Strictly following precautions and giving up occasionally
  2. Not understanding the innate immunity and how that helps

Let us talk about the occasional vulnerability that we create and expose. 

Restless Inside Home

Several amongst you are restless inside the confines of your home. You are frustrated, bored and some are just angry enough to throw those precautions to disdain. You want to step outside, you are thinking the risk is not what it sounds like, you may be thinking you are young and have a very low probability of acquiring the viral infection. You may be thinking some socialization is ok, more is not good, so let us go for a walk, maybe pub, may have a blast with a limited circle of friends, maybe shopping, etc. etc. 

Are you Alone? 

Think like this – 

1. If the risk is low, why do we see the resurgence or ascendancy of COVID across the globe? 

2. If you are young, have no risk factors, why are young people succumbing to illness?

3. If you say, your ethnicity provides protection? Can you check the mortality data for those exposed within your ethnicity? 

You may be thinking little social interactions are good (walks, pubs, dinners, outings, little shopping, little business, etc.). It is exactly these vulnerabilities that are perpetuating the spread of viruses. 

Do you know?

For every symptomatic patient, we have anywhere from 5 to 10 asymptomatic patients. Are you sure you are interacting with someone asymptomatic (carrier) and have no virus? I have seen several cases where the person stepping out got the asymptomatic carrier, infected those innocent parents/kids/spouse/family members and the later died. Consider these scenarios

  1. I don’t think you can live with the guilt of being responsible for the death of near or dear one. 
  2. Presuming you will survive, what is the guarantee that your organs will not be compromised for a long time? 
  3. Let us presume, you die from illness, have you thought of the implications of your loss on those surviving? Please read surviving with COVID stories and make your choice. 

How do you protect yourself?

CDC has given guidelines for protecting yourself. Every Government has made the best attempts in guiding their citizen from COVID-19. Following those is the utmost while undertaking any activities for your local area. 

Activate your Internal Resilience 

First and foremost, please decrease your exposure and risk. However, boosting your immune system with Yoga, Physical Activities, Sleep, Balanced Diet (and avoid refined diet), and meditation are great ways of doing so. I also saw some interesting read on Mayo Clinics. However, several educational institutions are providing a wealth of knowledge on those. However, reaching out to your doctor at the first instance of suspicion is best. 

The Good News

In its July 7, 2020 issue, Nature Immunology carried an interesting article on why the disease burden varies differently across regions. Simultaneously, the same paper has speculated that previous infection from Common Cold Coronaviruses (CCC) exposure also provides protection, against SARS CoV2. Excerpts from the article below

‘Pre-existing T cell immunity is related to CCC exposure, it will become important to better understand the patterns of CCC exposure in space and time. It is well established that the four main CCCs are cyclical in their prevalence, following multiyear cycles, which can differ across geographical locations. This leads to the speculative hypothesis that differences in CCC geo-distribution might correlate with the burden of COVID-19 disease severity. Furthermore, highly speculative hypotheses related to pre-existing memory T cells can be proposed regarding COVID-19 and age. Children are less susceptible to COVID-19 clinical symptoms. Older people are much more susceptible to fatal COVID-19. The reasons for both are unclear’. 

If these speculations are proven, it can rightly be said that T Cells have a lasting memory towards previous CCC that may be reactivated during a SARS CoV2 infection and offer protection. 

https://www.nature.com/articles/s41577-020-0389-z

Shashank Heda,

Dallas, Texas

(On behalf of CovidRxExchange) 

a nonprofit initiative to help global doctors fight Covid-19

Visit – https://www.covid-19rxexchange.org/)