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

Glutted Economy – 3 (India)

A grave mistake in the imposition of a universal and global lockdown is the impact on the economy. Let us be open, the lockdown was boisterous, more with nationalistic fervor and less on science and an understanding of the principles of disease transmission. Sometimes back, I wrote about the concept of degree of separation and retrospectively, that explains the unsolved and enigmatic transmission in Europe and non-transmission of the virus in Shanghai despite Wuhan being badly impacted.

Learning from the ‘Kelly Criterion’

First unraveled in 1956, The Kelly Criterion helps with applying the IT principles to gambling and investment. In a simple sense, it is about risk management and seize and sizing the opportunities despite the challenging situation. Though the principle cannot be used as is, the underlying fundamentals remain the same.

A grave mistake in the imposition of a universal and global lockdown is the impact on the economy. Let us be open, the lockdown was boisterous, more with nationalistic fervor and less on science and an understanding of the principles of disease transmission. Sometimes back, I wrote about the concept of degree of separation and retrospectively, that explains the unsolved and enigmatic transmission in Europe and non-transmission of the virus in Shanghai despite Wuhan being badly impacted.

Credits: Brookings Institute

It is unwise to blame policymakers or the executioners; understanding the crus of the new problem through a different set of eyes is thus critical. As, Einstein famously said, “We cannot solve our problems with the same thinking we used when we created them.” SARS CoV2 posed a similar challenge. We used the old yardstick to measure the new problem. Relying too much on R nout, to define such a critical national and global policy was such a deficit in our thinking. We have seen, despite lockdowns, we haven’t seen a complete break in the transmission of the cycle. Something is definitely amiss. Not that the virus has learned some tricks better than the natural laws, but the fact that we haven’t understood the complete spectrum, of dodging the virus. The economy is the lifeblood. How can we survive without an ongoing economy?

Cognitive dissonance: Dichotomy or Anomalous Behavior

We see the severe and widening chasm between several key parameters, typically called dichotomous or anomalous behavior. I was talking with my uncle back in India. He stays in our ancestral village where we own agricultural land. I asked him how is Covid-19 in our native village? Is it disrupting the agricultural activities of the Rabi crop cycle? He said, there is no COVID-19 in the village or the surrounding villages, despite our village is just 9 miles from a moderately big city of 1.5 million. On further questioning, he said, those working in the town, keep themselves isolated if not quarantined. If this is a fair data point that I can trust, and if I can extrapolate, then it is a seminal observation that will provide deep insight from such lockdown of the villages? Does that mean, we have to let the village interact with the Town? What would be the right model to break the transmission cycle and keep the economy moving in the countryside? Understand, though integrated, the metropolitan and countryside economy are two different arms that offer support to the national economy. More so, the countryside economy is still at the center stage of the national economy and provides a foundation for the national economy and not vice versa. At least if one arm continues, we are still in good shape. This is a key observation for any agriculturally leaning economy.

Let us visit another example. Many amongst you might have seen the stock market index. I call it sentiment, not a true reflection or an indicator of the business activities. Look at the divergence between the stock market index and the ground realities. This is not just afflicting the US, most economies are in this state. India is no exception. China can be, because everything is well masked and we truly don’t know the true nature of the devastation, despite receiving contradictory cues about the health of the Chinese economy. The business has been almost stalled, businesses across have been hurt because of the tortuous and tumultuous perversion of the virus as it is wading its way through the different strata of society. Is there a connection between the indicators and the health of the economy?

Such divergences create cognitive dissonance on the collective consciousness of the common man and result in defiance, that ultimately takes a toll, on the health as well as the economy of the nation and the global economy. Especially, this comes after the world had just recovered from the massive recession of 2008-09. Since 2000, post dotcom bubble burst, the economy has pretty much been dragged, by demand and has truly not been sprouting spontaneously.

Below excerpts from New York Times, “India’s economy shrank 7.5 percent in the three months that ended in September compared with a year earlier, government figures showed on Friday. The data reflects the deepening of India’s severest recession since at least 1996 when the country first began publishing its gross domestic product numbers. The new figures firmly ensconced India’s position among the world’s worst-performing major economies, despite expansive government spending designed to rescue the thousands of small businesses severely battered by its long, hastily imposed lockdown”.

https://www.financialexpress.com/economy/covid-19-pandemic-may-be-good-news-for-indias-economy-or-may-be-bad-for-china/1954207/

https://economictimes.indiatimes.com/news/international/business/global-economy-could-shrink-by-almost-1-in-2020-due-to-covid-19-pandemic-united-nations/articleshow/74943235.cms

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

Future’s Heady Mix

We all know Joe was a Vice President under President Obama. Of course, that eight years tenure was remarkable in achievements and misses. However, it carries the risk of bringing the same mind set as earlier and the key concern with problem space, is that if you try to solve the problems with the same fervor and approach as earlier, it is bound for failure.

Unless President Elect consciously makes a choice to select his options, and unless enough time is spent in understanding the changed realities on the new world, he is unlikely to make significant dent to resolution of existing scenarios. In fact, there is a potential for situations going downhill and precipitating the Trump phenomenon. Understandable, four years are not enough for a significant change to happen, but four years are enough for laying a foundation for the future global and national engagement.

Good Morning Biden, the world is a new place now!

Now that the hand recount from Georgia is over, the winner is clearly Joe Biden, unless a sabotage or a coup is underway. With Georgia in Joe Biden’s plate, the validity of the count is much reinforced. That is the reason, why I feel this is a fresh morning for Joe, the President Elect.

What’s in store for the future?

We all know Joe was a Vice President under President Obama. Of course, that eight years tenure was remarkable in achievements and misses. However, it carries the risk of bringing the same mind set as earlier and the key concern with problem space, is that if you try to solve the problems with the same fervor and approach as earlier, it is bound for failure. Unless President Elect consciously makes a choice to select his options, and unless enough time is spent in understanding the changed realities on the new world, he is unlikely to make significant dent to resolution of existing scenarios. In fact, there is a potential for situations going downhill and precipitating the Trump phenomenon. Understandable, four years are not enough for a significant change to happen, but four years are enough for laying a foundation for the future global and national engagement.

The last decade saw major populists taking over several democracies. A quick revisit will help us understand, democracy has given way to demagogy, that’s barring Putins Russia and Xi’s China. The rise of Duterte in the Philippines, Bolsonaro in Brazil, Johnson in the UK, Modi in India, Erdogan in Turkey are just few handful examples. Of course, I am not counting Pakistan, which has a democratic face to the military dictatorship.

Added to these are more spicy stuff happening in the Middle East. Syria, and Iran are consolidating their grip, whereas, feudalist and autocrats are advancing their handshake to those espousing the values and torch bearer of democracies, such as France and Germany.

Even those countries who are deeply committed to democratic ideals are leaning on China for economic support. Spain and a few more western European nation are leading that trend.

Given this heady mix of toxic cocktail, the ideas of yesteryears, such as replacing democracy, world politically and militarily dominated by the US, unilateral wars etc are unlikely to be productive.

Biden is taking the mantle of leadership under such circumstances. A fresh and distinct mindset is required. Can this be achieved by adding yesteryears bureaucrats? It’s needs deep introspection and reflection of the events that have unfurled on the global stage. Just accepting the populist leaders and offering a collaborative handshake is not enough.

The world has to understand the phenomenon called Trumpism (not related with Donald Trump), and see why we left behind such a huge swath of population, that such populist and radical nationalists have evolved?

This is a rude reality that Biden will awaken to while taking charge of the US on Jan 20, 2021.

Shashank Heda,
Dallas, Texas

https://www.visualcapitalist.com/americas-debt-27-trillion-and-counting/

Scale back Xi! (In Picture)

Xi’s ultimate ambition of having China dominate the World, itself is disdain to the ultimate ‘Character and Values’ embedded in Chinese Culture. Xi has to take cognizance of the four traditional Chinese values of “courtesy, righteousness, honesty and shame” to influence his actions and behavior. Xi, it is time to scale back and stick to basics and ignore your self ambitions of becoming a generation leader. That may sound nemesis for a great country like China. (Word count 400; reading time 2-3 minutes). You will love the cartoon caricatures from various cited sources.

I talked about Glutted Economy in one of my blogs few weeks back.

Now we have clear signs of defaults with state run enterprises in China. To me, if China is not printing currency, it is bound to be a castle build from cards. The entire pack will cone down if it decouples with the global economy.

For generations now, we have learnt that businessman avoid confrontations and open war. China is a business economy, they cannot and should not entertain confrontation.

However, every leader has an ambition to grow beyond and Xi Jinping too wants to be the greatest leader that China ever produced, even beyond Mao.

In his stride to be the greatest, he is making mistake of opening multiple ambitious fronts, gleefully ignoring that it takes generations to transform a country.

If i were Xi, I would only focus on the technology vision and usher in that great vision. I would specifically avoid confrontations and that too with 26 neighbors or countries at the same time.

Understandable, these are rhetoric’s but that too consumes resources, efforts and time. Understandable those are distractions for internal citizenry but despite, at what cost?

Because, when you lose face in Mansarovar, and the four finger, China and especially Xi creates an awkward moment both internally and externally, that is not conducive to the image of a great leader.

To quote Xi Jinping, “ultimately, character and values, and not just talent, ability and popularity, are important determinants of actions and behavior”. Xi may once again have to take cognizance of the four traditional Chinese values of “courtesy, righteousness, honesty and shame”.  Xi, it is time to scale back and stick to basics.


China braces for multiple bond defaults at state-owned enterprises
https://asia.nikkei.com/Spotlight/Caixin/China-braces-for-multiple-bond-defaults-at-state-owned-enterprises

https://theaseanpost.com/article/xi-jinpings-grand-vision

https://www.legacyias.com/kailash-mansarovar-yatra-route-from-completed/

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