In Search of a Haplotype

The new variant of the virus has already spread out to over 45 countries. While scientists are understanding the impact of the mutant variants, what should we do as individuals and societies to counter the potential threat from the virus?

In this article, I have provided an insight on personal and administrative/social preparation that needs attention.

(Word Count 942, reading time 4 -5 minutes).

By now, we all know the virus is mutating, and mutating every few weeks. For those who are not aware of what a mutation is, it is a change in the genetic program embedded within the virus. However, only a few mutations have possible implications on the infectivity, ability to induce severity, response to the drug, and the response to vaccines. All of these are critical for individuals, families, and society in general. Of course, everything is intertwined and ultimately has an impact on the socioeconomic structure. We have seen the devastation of several families. When the virus went on the rampage, we saw how the economies faltered and GDP’s collapse.

Variants and their implications

We all know that the UK, EU, and the US are badly reeling under the virus. Hospital beds and ICU bed availability in many regions are critically stretched, and so are the human resources like HCW. London Mayor Sadik has already implemented a lockdown with punitive citations for overriding the lockdown. Rightly so, despite our freedom mongering and yearning for personal freedom, we ultimately land up with the hospitals.

At least three variants are known with possible implications on the infectivity, severity of the disease, resistance to drugs, and efficacy of the vaccines. N501, B1.1.1.7, D614G and A222 are mainly prevalent in the UK, South Africa, and the EU. All these variants are known to be more contagious than the wild type, that is universally prevalent. Also, a collaborative study between Duke University, Los Alamos National Laboratory and Sheffield University has revealed that D614G variant is associated with higher viral loads in the upper respiratory tract. As of now, we are not yet sure if there is a variant that exists in LA and other parts of the US that are reeling under the virus. At least 45 countries have so far reported the presence of these new variants as of Jan 10, 2021. The National Laboratories from individual countries are searching for the virus’s existence within their societies and implications if any.

Japanese National Institute of Infectious Disease has similarly identified a new strain after the Japanese Government realized passengers’ arrival with the variant viruses. Naturally, the imposition of a ban on incoming flights from infected countries is the first knee jerk response. Many countries have reimposed the ban on travel from those countries with the presence of this virus. While the respective Governments are working to identify the new virus variants, individuals and the administration should gear up to deal with the increased threat level.

Credits: News Medical Lifesciences, Dr. Liji Thomas, MD. D614G mutation now the dominant variant in the global COVID-19 pandemic
  1. Individually, we all should follow the precautions stringently. Masks, social distancing, and containment strategies such as quarantine are basic. However, never presume that asymptomatic individuals are non-infectious. Research has proven without a doubt that asymptomatics are the ones who are spreading the virus. It goes beyond saying that kids harbor more viruses and remain asymptomatic. Kindergarten and schools can be the potential source of spread. While many schools have opted to go into virtual schooling, it is challenging for the daycare centers to do so. It is best to huddle into your bubble and only interact when it is essential or critical, understanding that those interactions should follow the strictest precautions mentioned above.

Vaccines
Vaccines are derived based on a certain genotype of the virus. If the virus changes its structure, the vaccines may have a potential dent in its efficacy. Second, vaccines, even if they are efficacious, may protect only the ones who are vaccinated. Vaccinated individuals may still harbor the virus. Thus, protection has to continue despite vaccines.

  1. City and Corporation Planning – Many cities, especially in South East Asia, are basking and boasting their success with COVID-19. COVID-19, as well all know, can strike back anytime. Complacency is not alone a defunct but also a counterproductive strategy. Europe and other countries undergoing a severe COVID-19 pandemic spike have realized how the spike overstretches the HCW. Doctors are overburdened, and so are the supporting staff.

Realistic modeling of the unfolding second spike is critical. R Naught, which was widely used at the pandemic initiation, has been revealed to have several flaws. It only threw our economy into shambles and society into unrequired chaos. Newer modeling that is closer to realism is the need of the time.

Second, the infrastructure that was propped up during the pandemic’s initial phase helped but was not necessarily sufficient. We need to identify a more long term viable solution to our healthcare services to deal with the virus. Using the same knee jerk response is unlikely to provide an adequate safeguard. Mere lockdowns are too insufficient and, at best knee jerk; we need more than a rational response, now that we know the pandemic better from our recent experience.

  1. Society – Herd Immunity
    Sweden, the UK, and the US are great examples that serve as potent examples that herd immunity is not enough. It does not offer protection without collateral. The collateral is the death and devastation of an individual with a permanent compromise with residual sequelae on health. Those who survived COVID-19 are physically either compromised in functioning or occasionally rendered dependent on supplemental oxygen.

The only and ultimate panacea would be a natural selection of a haplotype (a genotype) that would be less infective, cause inconsequential disease, and still respond to drugs and vaccines. The emergence of such strains is a natural selection process. The virus will possibly realize that if it has to cohabitate like several other bugs, in a symbiotic relationship with human beings.

Shashank Heda, MD.
Dallas, Texas
(For COVIDRxExchange, a global nonprofit initiative for disseminating insight and expertise in the care of COVID)

https://www.lanl.gov/discover/news-release-archive/2020/July/0702-newer-variant-covid-dominates-infections.php

https://www.news-medical.net/news/20200925/D614G-mutation-now-the-dominant-variant-in-the-global-COVID-19-pandemic.aspx

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

Humanity Needs a Hand

Religion and technology represent two different yearnings of mankind, each representing a stride. While we are marooned in the past with our utter conviction to our faith, we take a stride forward with technology and fall. For a real progress, we truly need evolution and progress on our ideologies and faith, rather than technological advances. Only when we sync up the steps that we, as humanity, will be able to walk into the future.

When I review radicals and ultra-right-wing or conservatives’ history, i feel humanity’s one leg is shackled and marooned in the long past. One leg taking a massive stride towards logic and technology. This stride has created an unstable gait for humanity for us to falter and fall.

By no means is religion written dictums or rules that we have to follow ardently. Those are the principles and guidelines provided to society and human beings for peaceful coexistence during those times. Rituals and artifacts are all the more superficial. Those are meant for cementing the abstract for the commoner to embody himself/herself. They also offer a sense of identity and a vivid recollection and subscription to faith and ideology.

Over a period of time, however, we have fossilized the rituals and artifacts and petrified the system by willful ignorance and erosion of the principles.

At each epoch, we had divine enlightenment from people such as Lord Krishna, Lord Ram Gautam Buddha, Lord Mahavir, Jesus, Md. Paigamber, who taught us the way of living. They knew the daily hustle and bustle of living are not conducive to reflecting on the finer and cognitive and supra cognitive aspects of living.

I sometimes wonder and pity humanity that we have not adopted the right way of life as enshrined in those religious tenets’ principles despite such supreme deliverances. Instead, we recede into the ideological conflict of imposing “my rightful ideology over your rightful ideology,” a moral fraud. We act not as simple animals but as rascals, if not demons, and destroy humanity with those divine injunctions.

No religion is barred from this radical regression, not to name any, we all have consigned to just the superficial, the tangible as it appears and lost the substance. Some religions are more intolerant than others, but all have genuinely lost the path of religion and faith, have failed to evolve, adapt, and adopt. Such is moral perfidy and erosion that it takes us a thousand years and a messiah to enlighten the next generation. Until then, we will be locked in this disturbing chasm of stride and fall.

Shashank Heda
Dallas, Texas

Iran’s Supreme Leader: Who might succeed Ali Khamenei?
https://www.bbc.co.uk/news/world-middle-east-55257059

Ahh, I so much love China!

Ahh I love China. A totalitarian state never has to deal with the dilemma of a democracy. Life if simple, just lease your intellect to the state and work like a hen in the poultry. You have the best of the living conditions, nutrients, also a few micronutrients and absolutely controlled temperature. I love life in Chicken Farms! They have everything to serve the state (owner) and can live their stipulated life until the state desires. Let me admit, more than the blog, I liked the links shared, especially from Freedom House, Philosophy forum and the Economist.

Ahh, I so much love China and Russia

Well, liberal democracy has to walk along with all the stakeholders, unlike a totalitarian state. However, when it comes to imposing critical and essential restrictions, as was done by New York that Gov. Andrew M. Cuomo, to contain and control Coronavirus spread in New York, it was struck down by the conservative supreme court bench in favor of the Orthodox Jewish Organization and the Roman Catholic, the former having a high incidence of COVID.

As I read from the New York Times (link cited below), “The restrictions are strict. In shifting “red zones,” where the coronavirus risk is highest, no more than 10 people may attend religious services. In slightly less dangerous “orange zones,” which are also fluid, attendance is capped at 25. This applies even to churches that can seat more than 1,000 people”. “The Constitution does not forbid states from responding to public health crises through regulations that treat religious institutions equally or more favorably than comparable secular institutions, particularly when those regulations save lives,” Justice Sotomayor wrote. “Because New York’s Covid-19 restrictions do just that, I respectfully dissent.”

I am not sure how these numbers arise? 10, 25, 50, 100 etc. I have seen such flaunt numbers from different administrations, only to create fault lines and not fix the solution. At least my simple logic dictates that these numbers are irrelevant, and should directly be correlated with the index case or the sentinel case.

Is a numeric threshold right?

I was talking with my uncle back in India and I realized, the small village where our farms are, have no COVID in their vicinity. Obviously, I was concerned for the second crop and other agricultural activities. The best practice is to quarantine the cities and not the countryside, which as free of disease. Let the commerce flow and let the business flourish if the impact is minimal.

When I talk with my network in China, I see that the lockdown has strictly adhered to. Well, who is right? Liberal democracy with one foot backward and one foot forward, or a totalitarian state with both feet aligned?

There can never be a cookie-cutter approach or a standardized way to resolve this conundrum. Our only recourse is to evaluate each situation separately? A lot of human intelligence (Can AI help?). Irrespective, it is an individual choice versus the state responsibility towards all. Science cannot be ignored despite knowing its incompleteness. However, we can only see on the basis of current visibility.

It is obvious, that a bench is favoring a decision despite its lack of requisite (medical) background, competence and expertise to assess public health and its accountable for the people. At least for now, the public concern is thrown out of the window.

It is hard to customize and still retain the luster of the fundamental amendments (the first, second, etc.). However, it is a rope walk and if you ask a lazy person like me, I love China!

Shashank Heda

https://thephilosophyforum.com/discussion/6368/centrist-and-small-government-debate

https://freedomhouse.org/report/special-report/2017/breaking-down-democracy

https://www.economist.com/essay/2014/02/27/whats-gone-wrong-with-democracy

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

Can I Get Severe COVID?

Are you vulnerable to develop a severe COVID-19? How to predict if you are likely to get a mild disease or a severe disease? Since the onset of COVID-19, we know that 80% of those affected are likely to have mild disease, 15% a moderate disease and 5% have severe disease. We never knew why only 5% had a severe disease. Also, we knew that elderly patients had more mortality and male gender was more affected because of the disease.

This fact kept the medical community guessing the cause, until we found out that certain genes have mutations or certain antibodies develop in this high risk patients that counter the protection offered by our innate immune mechanism. At least for now, a piece of puzzle is solved.

This article talks in detail revealed by latest research that help us understand those changes that makes these vulnerable population for a severe disease. You may want to know if you have those intrinsic vulnerability?

Silence of the Genes or their products

Why Some Patients Have Severe COVID? Why More Males dies of COVID and Why the disease is more mortal in elderlies? The genetics underlying severe COVID-19There is a crucial role of type I IFNs that offers protective immunity against SARS-CoV-2. After the initial infection, small amounts of IFNs are induced by the virus that become crucial in offering a protection against severe disease. However, few patients have developed neutralizing auto-Abs against type I IFNs, like inborn errors of type I IFN production. This sways the balance in favor of the virus and results in devastating disease due to absence of innate and adaptive immune responses.

Two pathways in which these genes can be perturbed are –

1) Genetic mutations resulting in deletion or functional compromise of the type I IFNs.
2) Development of antibobodies to type I IFNs. The immune system is complex and involves many genes, including those that encode cytokines known as interferons (IFNs).

Individuals who lack specific IFNs can be more susceptible to infectious diseases. Furthermore, the autoantibody system dampens IFN response to prevent damage from pathogen-induced inflammation. Adaptive autoimmunity impairs innate and intrinsic antiviral immunity.

A crucial role of type I IFNs in protective immunity against SARS-CoV-2. These auto-Abs against type I IFNs were clinically silent until the patients were infected with SARS-CoV-2—a poor inducer of type I IFNs which suggests that the small amounts of IFNs induced by the virus are important for protection against severe disease. At least 10% of patients with life-threatening COVID-19 pneumonia have neutralizing auto-Abs against type I IFNs. Two studies now examine the likelihood that genetics affects the risk of severe coronavirus disease 2019 (COVID-19) through components of this system. Genetics may determine the clinical course of the infection. High titers of neutralizing autoantibodies against type I IFN-α2 and IFN-ω in about 10% of patients with severe COVID-19 pneumonia. These autoantibodies were not found either in infected people who were asymptomatic or had milder phenotype or in healthy individuals. Together, these studies identify a means by which individuals at highest risk of life-threatening COVID-19 can be identified.

A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least

a) 2.6% of women and
b) 12.5% of men.

Provide an explanation for the excess of men among patients with life-threatening COVID-19 and the increase in risk with age. They also provide a means of identifying individuals at risk of developing life-threatening COVID-19 and ensuring their enrolment in vaccine trials. Finally, they pave the way for prevention and treatment, including plasmapheresis, plasmablast depletion, and recombinant type I IFNs not targeted by the auto-Abs (e.g., IFN-β).2) At least 10% of patients with life-threatening COVID-19 pneumonia have neutralizing auto-Abs against type I IFNs. With our accompanying description of patients with inborn errors of type I IFNs and life-threatening COVID-19, this study highlights the crucial role of type I IFNs in protective immunity against SARS-CoV-2.These auto-Abs against type I IFNs were clinically silent until the patients were infected with SARS-CoV-2—a poor inducer of type I IFNs which suggests that the small amounts of IFNs induced by the virus are important for protection against severe disease. The neutralizing auto-Abs against type I IFNs, like inborn errors of type I IFN production, tip the balance in favor of the virus, which results in devastating disease with insufficient, and even perhaps deleterious, innate and adaptive immune responses.

At least for now, a piece of puzzle is solved. We now know that if Type 1 IFN develop auto-antibodies, or have mutations in the genes, or any (gene) silencing ensues, then it is possible, you may have individual vulnerability. The last aspect, silencing of the genes through methylation, though not yet proven may be potentially possible. Let us wait for science to unravel more.

Translational Medicine

What is typically called as translational medicine, it takes time to transfer the technological advances from laboratories to bed side. However, with COVID-19, we have seen a significantly reduced latency from lab to bed side (bed side here means for common use in practice).

Science  23 Oct 2020: Vol. 370, Issue 6515, eabd4585; DOI: 10.1126/science.abd4585

https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.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