It Ain’t Over Till It’s Over…but It’s Never Over — Emerging and Reemerging Infectious Diseases

List of authors.

Anthony S. Fauci, M.D.

https://www.nejm.org/doi/full/10.1056/NEJMp2213814

As I prepare to step down from my dual positions at the National Institute of Allergy and Infectious Diseases (NIAID), where I have been a physician-scientist for 54 years and the director for 38 years, a bit of reflection is inevitable. As I think back over my career, what stands out most is the striking evolution of the field of infectious diseases and the changing perception of the importance and relevance of the field by both the academic community and the public.

I completed my residency training in internal medicine in 1968 and decided to undertake a 3-year combined fellowship in infectious diseases and clinical immunology at NIAID. Unbeknownst to me as a young physician, certain scholars and pundits in the 1960s were opining that with the advent of highly effective vaccines for many childhood diseases and a growing array of antibiotics, the threat of infectious diseases — and perhaps, with it, the need for infectious-disease specialists — was fast disappearing.1 Despite my passion for the field I was entering, I might have reconsidered my choice of a subspecialty had I known of this skepticism about the discipline’s future. Of course, at the time, malaria, tuberculosis, and other diseases of low- and middle-income countries were killing millions of people per year. Oblivious to this inherent contradiction, I happily pursued my clinical and research interests in host defenses and infectious diseases.

When I was several years out of my fellowship, I was somewhat taken aback when Dr. Robert Petersdorf, an icon in the field of infectious diseases, published a provocative article in the Journal suggesting that infectious diseases as a subspecialty of internal medicine was fading into oblivion.2 In an article entitled “The Doctors’ Dilemma,” he wrote regarding the number of young physicians entering training in the various internal medicine subspecialties, “Even with my great personal loyalties to infectious disease, I cannot conceive a need for 309 more infectious-disease experts unless they spend their time culturing each other.”

Of course, we all aspire to be part of a dynamic field. Was my chosen field now static? Dr. Petersdorf (who would become my friend and part-time mentor as we and others coedited Harrison’s Principles of Internal Medicine) gave voice to a common viewpoint that lacked a full appreciation of the truly dynamic nature of infectious diseases, especially regarding the potential for newly emerging and reemerging infections. In the 1960s and 1970s, most physicians were aware of the possibility of pandemics, in light of the familiar precedent of the historic influenza pandemic of 1918, as well as the more recent influenza pandemics of 1957 and 1968. However, the emergence of a truly new infectious disease that could dramatically affect society was still a purely hypothetical concept.

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>>17934685

That all changed in the summer of 1981 with the recognition of the first cases of what would become known as AIDS. The global impact of this disease is staggering: since the start of the pandemic, more than 84 million people have been infected with HIV, the virus that causes AIDS, of whom 40 million have died. In 2021 alone, 650,000 people died from AIDS-related conditions, and 1.5 million were newly infected. Today, more than 38 million people are living with HIV.

Although a safe and effective HIV vaccine has not yet been developed, scientific advances led to the development of highly effective antiretroviral drugs that have transformed HIV infection from an almost-always-fatal disease to a manageable chronic disease associated with a nearly normal life expectancy. Given the lack of global equity in the accessibility of these lifesaving drugs, HIV/AIDS continues, exacting a terrible toll in morbidity and mortality, 41 years after it was first recognized.

If there is any silver lining to the emergence of HIV/AIDS, it is that the disease sharply increased interest in infectious diseases among young people entering the field of medicine. Indeed, with the emergence of HIV/AIDS, we sorely needed those 309 infectious-disease trainees that Dr. Petersdorf was concerned about — and many more. To his credit, years after his article was published, Dr. Petersdorf readily admitted that he had not fully appreciated the potential impact of emerging infections and became something of a cheerleader for young physicians to pursue careers in infectious diseases and specifically in HIV/AIDS practice and research.

Selected Landmark Events in Infectious-Disease Emergence Leading up to and during the Author’s Four-Decade Tenure as NIAID Director.

DRC denotes Democratic Republic of Congo, MERS Middle East respiratory syndrome, SARS severe acute respiratory syndrome, and XDR extensively drug-resistant.

Of course, the threat and reality of emerging infections did not stop with HIV/AIDS. During my tenure as NIAID director, we were challenged with the emergence or reemergence of numerous infectious diseases with varying degrees of regional or global impact (see timeline). Included among these were the first known human cases of H5N1 and H7N9 influenza; the first pandemic of the 21st century (in 2009) caused by H1N1 influenza; multiple outbreaks of Ebola in Africa; Zika in the Americas; severe acute respiratory syndrome (SARS) caused by a novel coronavirus; Middle East respiratory syndrome (MERS) caused by another emergent coronavirus; and of course Covid-19, the loudest wake-up call in more than a century to our vulnerability to outbreaks of emerging infectious diseases.

The devastation that Covid-19 has inflicted globally is truly historic and highlights the world’s overall lack of public health preparedness for an outbreak of this magnitude. One highly successful element of the response to Covid-19, however, was the rapid development — enabled by years of investment in basic and applied research — of highly adaptable vaccine platforms such as mRNA (among others) and the use of structural biology tools to design vaccine immunogens. The unprecedented speed with which safe and highly effective Covid-19 vaccines were developed, proven effective, and distributed resulted in millions of lives saved.3 Over the years, many subspecialties of medicine have benefited greatly from breathtaking technological advances. The same can now be said of the field of infectious diseases, particularly with the tools we now have for responding to emerging infectious diseases, such as the rapid and high-throughput sequencing of viral genomes; the development of rapid, highly specific multiplex diagnostics; and the use of structure-based immunogen design combined with novel platforms for vaccines.4

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>>17934689

If anyone had any doubt about the dynamic nature of infectious diseases and, by extension, the discipline of infectious diseases, our experience over the four decades since the recognition of AIDS should have completely dispelled such skepticism. Today, there is no reason to believe that the threat of emerging infections will diminish, since their underlying causes are present and most likely increasing. The emergence of new infections and the reemergence of old ones are largely the result of human interactions with and encroachment on nature. As human societies expand in a progressively interconnected world and the human–animal interface is perturbed, opportunities are created, often aided by climate changes, for unstable infectious agents to emerge, jump species, and in some cases adapt to spread among humans.5

An inevitable conclusion of my reflections on the evolution of the field of infectious diseases is that the pundits of years ago were incorrect and that the discipline is certainly not static; it is truly dynamic. In addition to the obvious need to continue to improve on our capabilities for dealing with established infectious diseases such as malaria and tuberculosis, among others, it is now clear that emerging infectious diseases are truly a perpetual challenge. As one of my favorite pundits, Yogi Berra, once said, “It ain’t over till it’s over.” Clearly, we can now extend that axiom: when it comes to emerging infectious diseases, it’s never over. As infectious-disease specialists, we must be perpetually prepared and able to respond to the perpetual challenge.

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Amyloidogenesis of SARS-CoV-2 Spike Protein

https://pubs.acs.org/doi/10.1021/jacs.2c03925

Abstract

SARS-CoV-2 infection is associated with a surprising number of morbidities. Uncanny similarities with amyloid-disease associated blood coagulation and fibrinolytic disturbances together with neurologic and cardiac problems led us to investigate the amyloidogenicity of the SARS-CoV-2 spike protein (S-protein). Amyloid fibril assays of peptide library mixtures and theoretical predictions identified seven amyloidogenic sequences within the S-protein. All seven peptides in isolation formed aggregates during incubation at 37 °C. Three 20-amino acid long synthetic spike peptides (sequence 192–211, 601–620, 1166–1185) fulfilled three amyloid fibril criteria: nucleation dependent polymerization kinetics by ThT, Congo red positivity, and ultrastructural fibrillar morphology. Full-length folded S-protein did not form amyloid fibrils, but amyloid-like fibrils with evident branching were formed during 24 h of S-protein coincubation with the protease neutrophil elastase (NE) in vitro. NE efficiently cleaved S-protein, rendering exposure of amyloidogenic segments and accumulation of the amyloidogenic peptide 194–203, part of the most amyloidogenic synthetic spike peptide. NE is overexpressed at inflamed sites of viral infection. Our data propose a molecular mechanism for potential amyloidogenesis of SARS-CoV-2 S-protein in humans facilitated by endoproteolysis. The prospective of S-protein amyloidogenesis in COVID-19 disease associated pathogenesis can be important in understanding the disease and long COVID-19.

>>17934713

Coronaviruses use the homotrimeric surface spike protein (S-protein) to attach to human cells. Each SARS-CoV-2 S-protein subunit comprises 1273 amino acids. (1) Four common coronaviruses (OC43, 229E, NL63, and HKU1) infect humans and colonize the respiratory tract. Recently emerged SARS, MERS, and since 2019 also SARS-CoV-2 result in severe disease. Although coronavirus infections are common, not before COVID-19 has such a wide distribution of complex symptoms involving organs other than the respiratory tract been reported. COVID-19 pathogenesis is multifactorial and complex. (2) Severe COVID-19 includes acute respiratory distress syndrome (ARDS) from innate immune system inflammatory reactions resulting in lung damage; (3) cytokine storm; (4) heart damage, including heart muscle inflammation; kidney damage; neurological damage; damage to the circulatory system resulting in poor blood flow. Long-COVID-19 symptoms include persistent emotional illness and mental health conditions resembling neurodegenerative diseases. (2) What could be the basis for this pathogenesis?

Amyloidosis from several culprit proteins manifests as systemic and localized disorders with many phenotypes overlapping with reported COVID-19 symptoms. It has been proposed that severe inflammatory disease including ARDS in combination with SARS-CoV-2 protein aggregation might induce systemic AA amyloidosis. (5) Neurotropic colonization and cross-seeding of S-protein amyloid fibrils to induce aggregation of endogenous proteins has been discussed in the context of neurodegeneration. (6) Notably, blood clotting associated with extracellular amyloidotic fibrillar aggregates in the bloodstream has been reported in COVID-19 patients. (7) Hypercoagulation/impaired fibrinolysis was demonstrated in blood plasma from healthy donors experimentally spiked with S-protein. (7)

Amyloidosis is associated with cerebral amyloid angiopathy, blood coagulation disruption, fibrinolytic disturbance, (8,9) FXII Kallikrein/Kinin activation, and thromboinflammation, (10) suggesting potential links between S-protein amyloidogenesis and COVID-19 phenotypes. We therefore hypothesized a potential molecular link between S-protein and amyloid formation. Inspired by previous hypotheses about human and viral protein amyloids and interactions between them, (11−13) in particular SARS-CoV spike proteins, (6,14,15) we asked the question: Is SARS-CoV-2 S-protein amyloidogenic?

We obtained a 316 peptide pool library (divided into two subpools) from a peptide scan through the entire SARS-CoV-2 S-protein (ProteinID: P0DTC2) (Supporting Information). In vitro amyloid fibrils were formed in both peptide subpools (Supporting Information, Figure S1). Encouraged by the results, we generated 20-AA peptides from the full-length SARS-CoV-2 S-protein. We aimed to address the most amyloidogenic sequences and used the WALTZ (https://waltz.switchlab.org) prediction algorithm (16) to identify such segments (Table 1, Supporting Information).

https://www.theblock.co/amp/post/194274/ceo-paxful-tells-customers-get-bitcoin-off-platform

Bitcoin trading platform Paxful CEO tells customers to get their crypto off its platform

Paxful’s CEO Ray Youssef urged users to self-custody their bitcoin.

Youssef said that trusting platforms to safeguard your crypto kept users at “mercy of these custodians and their morals.”

The CEO of the peer-to-peer bitcoin trading platform Paxful Ray Youssef told customers to get their bitcoin off the platform and move it into self-custody.

Youssef cited the collapse of Sam Bankman-Fried's crypto exchange FTX as reasons for urging Paxful's 11 million customers to self-custody their cryptocurrency.

"I take great pride in protecting our community’s funds and, unlike others in our industry, I have never touched our customers’ money," Youssef said in an email to users. "My sole responsibility is to help and serve you. That’s why today I’m messaging all of our users to move your Bitcoin to self-custody. You should not keep your savings on Paxful, or any exchange, and only keep what you trade here."

Last month, cryptocurrency exchange volumes jumped compared to October as the collapse of FTX roiled markets, with decentralized platforms seeing an increase of 93% as doubled to $65 billion from $34 billion. Centralized exchange volumes rose by 24% to $673 billion, up from $543 billion in October, according to The Block data.

Youssef adds that when customers trust platforms to safeguard their crypto, "you're at the mercy of these custodians and their morals."

"Bitcoin has given us the chance to finally be in control and we must take it," Youssef said.

https://twitter.com/NEWSMAX/status/1602604247941779456

NEWSMAX

@NEWSMAX

For the first time, scientists have produced a fusion reaction that creates a net energy gain, a key milestone in the quest for abundant zero-carbon power, the Department of Energy plans to announce.

https://twitter.com/disclosetv/status/1602629866423304192

Disclose.tv

@disclosetv

NEW - Pope warns at the Vatican that he has seen "omens of even greater destruction and desolation" for mankind.

Mayor Lori Lightfoot has revealed the City of Chicago's plan to block live transmissions of Chicago Police and Fire Department scanners - restricting access to transmissions that have always been available to the public and to the news media.

Chicago News Media Concerned Over Plan to Encrypt Police Scanners. Read Their Open Letter

https://www.nbcchicago.com/news/local/chicago-news-media-concerned-over-plan-to-encrypt-police-fire-scanners/3020141/

To our Readers, Viewers, and Listeners,

Mayor Lori Lightfoot has revealed the City of Chicago’s plan to block live transmissions of Chicago Police scanners – restricting access to transmissions that have always been available to the public and to the news media. We are a coalition of Chicago-area news organizations concerned with this planned encryption and are sharing our concerns to raise awareness about how the City’s plan will impact our ability to provide timely, accurate and potentially life-saving news to you.

Our newsrooms monitor emergency scanner traffic to report everything from traffic congestion to developing threats to public safety.

As news unfolded about the July 4th shooting in Highland Park, the media and the public turned to police scanners and reporting informed by police scanners to take cover, to stay safe, to locate the missing. A coalition member was able to report on a shooting last month in Chicago’s River North neighborhood as the perpetrators remained at large, alerting the public of this imminent danger.

But now, things have changed.

A shooting took place at a courthouse and police district in Chicago last week in broad daylight. The perpetrators fired more than 40 shots and escaped on an expressway. You did not see, hear, or read about that incident as it was happening. The City of Chicago prevented you from knowing about this dangerous incident by blocking all live scanner transmissions. This jeopardized the lives of everyone at that police department, everyone at that courthouse, everyone on that expressway.

Also last week, we learned that a man armed with a rifle was walking down the street in the city’s West Pullman neighborhood. He was later shot by Chicago Police. We were not able to alert the public as it was happening. All of this took place around dinnertime, as people returned home from work and children returned home from school.

Real-time access to police scanners promotes transparency and accountability by law enforcement. An analysis of the scanner transmissions in the Uvalde, Texas school shooting revealed that law enforcement’s response was not as local authorities had first portrayed it. The availability of scanner communications also directly led to the videorecording of the killing of Alton Sterling by two Baton Rouge police officers. To put it simply, the media’s informative reporting on these events would never have been possible without real-time access to scanners.

Earlier this year, we learned that Chicago officials intended to prevent Chicago media from hearing these essential real-time scanner transmissions. The City claimed several reasons for the switch, including minimizing disruptions by unauthorized users who transmit fake calls, preventing criminals from monitoring police, and maintaining the safety of first responders. The City has never identified members of the press as the disruptors. And members of the press are regularly in touch with officials to ensure that our reporting does not jeopardize police investigations or public safety.

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We reached out to officials to ask that accredited members of the press be granted access to the newly encrypted channels, but the City responded that both the press and the public would only be provided access on a 30-minute delay. We strongly believe that any scanner transmission delay will negatively impact public safety and could put lives in jeopardy when mere seconds matter, for example, during an active shooter event, a tornado, a fire, a bomb scare, a plane crash; virtually any emergency event where the public might need to seek safety or shelter.

Further, in our view, encryption and delays run counter to resounding calls for greater transparency in law enforcement. The City has also already taken the liberty of completely removing some of these recorded transmissions from its delayed broadcast, effectively causing certain police or fire incidents to vanish - as though they never happened. This is censorship in its purest form.

We asked to meet in person with the City to further address these issues, but despite multiple attempts, Mayor Lori Lightfoot flatly refuses to even discuss the matter. In short, the Mayor’s decision to restrict our access to scanner channels will harm our ability to keep you, our readers, viewers, and listeners, safe and informed, and render it more difficult to hold our government and its personnel accountable. To borrow language from the highest federal appellate court sitting in Chicago, “The newsworthiness of a particular story is often fleeting. To delay or postpone disclosure undermines the benefit of public scrutiny and may have the same result as complete suppression.” We couldn’t agree more.

CBS 2 Chicago

NBC 5 Chicago

ABC 7 Chicago

WGN-TV

Fox 32 Chicago

Chicago Sun Times

Chicago Tribune

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>>17934799

> Nobody else can see it.

all observer anons see it

he is not 'wise' so much as a 'watcher'. grigori. A 'manager' of the gregorian calendar would know when #timesup, as that is their purpose

>>17934861

>Sounds Like Witchcraft

who else openly dresses as a wizard, holds thousands of grimoires and leads worldwide workings every week and twice annually from a basilisk/basilika? exactly.

James Woods has not responded…

https://twitter.com/hwinkler4real/status/1601978136555446274

Henry Winkler

@hwinkler4real

IS IT at all possible that Dr. Fauci is an incredible Doctor and American at the SAME time ????

>>17934929

>>17934929

>Henry Winkler

>James Woods