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Saturday, October 1, 2022

Malone: Human Cyborgs Are Just The Beginning

 by Robert W. Malone via Who is Robert Malone,

Ever since I wrote the substack article on human augmentation and the UK Ministry of Defence and the German Military Complex , discussing that these two organizations advocate for human augmentation in a report entitled “Human Augmentation – The Dawn of a New Paradigm“, I have been wondering if the US government, that is to say the US Department of Defense (DoD) and the Administrative State which controls it, has developed similar plans.

This week I did a little research starting with the key words – “human augmentation” and “DoD” and there “it” is. The “it” being the strategy playbook and battlefield field plan for creating human cyborgs…

For those who lust for more stimulation and shaping after reading the following, this substack also relates to our June 16 substack entitled “ARPA-H, Intelligence Community within NIH”.

To begin – there are various “hints” from various governmental agencies that human augmentation research is underway and has been ongoing for a number of years. For instance, this article:

Inside the Military’s New Office for Cyborgs 2014

DARPA’s Arati Prabhakar Tells Defense One That Cutting-Edge Biology Research Is the Future of National Security

Defense One, April 1, 2014

The ability to link human brains to machines, create new life forms and build Star Trek-style disease detectors will be the focus of a new Defense Department office soon.

The new office, named the Biological Technology Office, or BTO, will serve as a clearinghouse for Defense Advanced Research Projects Agency, or DARPA, programs into brain research, synthetic biology and epidemiology. The office will cover everything from brewing up tomorrow’s bioweapon detectors and connecting humans to computers to designing entirely new types of super-strong living materials that could form the basis of future devices. Here are the key areas in more detail.

This author does let “the cat out of the bag”, so to speak, by his use of the word “cyborg” in the article’s title. That is the “military’s new office for cyborgs.” But the actual content of the article does little to enlighten us as to what the DoD actually has planned.

It is getting hard to tell who is driving the bus here, the Pentagon or Paramount pictures’ script writers. Do DARPA locker rooms have pinups of Jeri RyanDo Androids Dream of Electric Sheep? Is Bruce Sterling actually a deep state operative and CIA consultant?

(tolokonov/iStock)

Moving on to more recent news.


Another fascinating title and article – this search was a little like following the bread crumbs to grannies house…

Researchers Help DoD Consider Challenges of Human Enhancement

DEVCOM CBC Public Affairs
November 18th, 2019

Peter Emanuel, Ph.D., the Army’s Senior Research Scientist for Bioengineering, sees a future 30 years from now where a U.S. Soldier can direct a swarm of drones in battle through a direct brain-to-machine connection using a neural implant. The implant also allows him to see exactly what each of those drones is seeing, then digitally integrate this information in his brain and send it as data to other machines, fellow Soldiers or his command and control element.

This is a little more helpful.

Note that the person being interviewed for this article is Dr. Peter Emanuel. This is important later on in this Substack. Trust me, it is a “Where’s Waldo” kind of thing.

Also, interesting that now the DoD is using the language “human enhancement” – so much softer and gentler than “human cyborg,” don’t you think?


This article is even a little more current. Of note – The COVIDcrisis most definitely took the spotlight off the whole “human cyborg” research agenda. Something tells me that the DoD didn’t mind that too much.

US Space Force Chief Scientist Says Human Augmentation ‘Imperative’

The Defense Post, May 05, 2021

Today we’re on the brink of a new age: the age of human augmentation
 

Human augmentation should be embraced by the West to keep up with the competition, US Space Force chief scientist Dr. Joel Mozer said during an event last week at the Airforce Research Laboratory.

“In our business of national defense, it’s imperative that we embrace this new age, lest we fall behind our strategic competitors,” Mozer said.

Mozer added that unprecedented developments are forthcoming in areas such as artificial intelligence, which will allow the military to craft tactics and strategies that “no human could.” Autonomous programs will eventually provide real-time advice to commanders, and multiple autonomous agents will be able to assist commanders and decision-makers in reconnaissance and fire control.

The chief scientist further explained that human augmentation will eventually develop into technologies such as augmented reality and virtual reality — including “nerve stimulation” to enhance the simulation of physical sensations.

“You could put [an] individual into a state of flow, where learning is optimized and retention is maximized,” Mozer said. “This individual could be shaped into somebody with very high-performing potential.”

(I mean, who isn’t up for a little “nerve stimulation” among friends?)

The language used is really helpful in tracking the origins of the ideas. Bruce Sterling’s classic cyberpunk novel Schismatrix is all about the conflict between Shapers and Mechanists, Shapers being the group that alters the body through genetic modification and specialized mental training. Mechanists are the group that modifies bodies through computer software and external alterations.

Yeah, we’ve seen that movie too.


Then we have the Big Kahuna, the report that begins to lay out the true intent of the military in all of this.

This large, year-long assessment – commissioned by the Office of the Under Secretary of Defense for Research and Engineering and conducted by the DoD Biotechnologies for Health and Human Performance Council was published at the end of 2019. It is entitled:

Cyborg Soldier 2050: Human/Machine Fusion and the Implications for the Future of the DoD

Subject terms: “Cyborg” and “Human/Machine Enhancement”

That abstract of that assessment reads:

Abstract: The Office of the Under Secretary of Defense for Research and Engineering (Alexandria, VA) established the DOD Biotechnologies for Health and Human Performance Council (BHPC) study group to continually assess research and development in biotechnology. The BHPC group assesses scientific advances for improved health and performance with potential military application; identifies corresponding risks and opportunities and ethical, legal, and social implications; and provides senior leadership with recommendations for mitigating adversarial threats and maximizing opportunities for future U.S. forces. At the direction of the BHPC Executive Committee, the BHPC study group conducted a year-long assessment entitled “Cyborg Soldier 2050: Human/Machine Fusion and the Impact for the Future of the DOD”. The primary objective of this effort was to forecast and evaluate the military implications of machines that are physically integrated with the human body to augment and enhance human performance over the next 30 years. This report summarizes this assessment and findings; identifies four potential military-use cases for new technologies in this area; and assesses their impact upon the DOD organizational structure, warfighter doctrine and tactics, and interoperability with U.S. allies and civil society.

This analysis was made public when published, but then COVIDcrisis soon overwhelmed us all and it quickly faded from public memory.

If you didn’t read this report back in the beginning of 2020 or if you have forgotten about it, below is the executive summary of this 50 page report (or click on the linked title above to read the whole report):

EXECUTIVE SUMMARY

A DoD Biotechnologies for Health and Human Performance Council (BHPC; Alexandria, VA) study group surveyed a wide range of current and emerging technologies relevant to assisting and augmenting human performance in many domains. The team used this information to develop a series of vignettes as case studies for discussion and analysis including feasibility; military application; and ethical, legal, and social implication (ELSI) considerations. Ultimately, the team selected four vignettes as being technically feasible by 2050 or earlier. The following vignettes are relevant to military needs and offer capabilities beyond current military systems:

  • ocular enhancements to imaging, sight, and situational awareness;
  • restoration and programmed muscular control through an optogenetic bodysuit
  • sensor web;
  • auditory enhancement for communication and protection; and
  • direct neural enhancement of the human brain for two-way data transfer.

Although each of these technologies will offer the potential to incrementally enhance performance beyond the normal human baseline, the BHPC study group analysis suggested that the development of direct neural enhancements of the human brain for two-way data transfer would create a revolutionary advancement in future military capabilities. This technology is predicted to facilitate read/write capability between humans and machines and between humans through brain-to-brain interactions. These interactions would allow warfighters direct communication with unmanned and autonomous systems, as well as with other humans, to optimize command and control systems and operations. The potential for direct data exchange between human neural networks and microelectronic systems could revolutionize tactical warfighter communications, speed the transfer of knowledge throughout the chain of command, and ultimately dispel the “fog” of war. Direct neural enhancement of the human brain through neuro-silica interfaces could improve target acquisition and engagement and accelerate defensive and offensive systems.

Although the control of military hardware, enhanced situational awareness, and faster data assimilation afforded by direct neural control would fundamentally alter the battlefield by the year 2050, the other three cyborg technologies are also likely to be adopted in some form by warfighters and civil society. The BHPC study group predicted that human/machine enhancement technologies will become widely available before the year 2050 and will steadily mature, largely driven by civilian demand and a robust bio-economy that is at its earliest stages of development in today’s global market. The global healthcare market will fuel human/machine enhancement technologies primarily to augment the loss of functionality from injury or disease, and defense applications will likely not drive the market in its later stages. The BHPC study group anticipated that the gradual introduction of beneficial restorative cyborg technologies will, to an extent, acclimatize the population to their use.

The BHPC study group projected that introduction of augmented human beings into the general population, DOD active duty personnel, and near-peer competitors will accelerate in the years following 2050 and will lead to imbalances, inequalities, and inequities in established legal, security, and ethical frameworks. Each of these technologies will afford some level of performance improvement to end users, which will widen the performance gap between enhanced and unenhanced individuals and teams. The BHPC study group analyzed case studies and posed a series of questions to drive its assessment of the impact to DOD programs, policies, and operations. The following are the resulting recommendations (not listed in order of priority): (RM- I have only posted the top summaries for these recommendations, please go to the report for more detail).

1. DOD personnel must conduct global assessments of societal awareness and perceptions of human/machine enhancement technologies.

2. U.S. leadership should use existing and newly developed forums (e.g., NATO) to discuss impacts to interoperability with allied partners as we approach the year 2050. This will help develop policies and practices that will maximize interoperability of forces.

3. DOD should invest in the development of dynamic legal, security, and ethical frameworks under its control that anticipate emerging technologies.

4. Efforts should be undertaken to reverse negative cultural narratives of enhancement technologies.

5. DOD personnel should conduct tabletop wargames and targeted threat assessments to determine the doctrine and tactics of allied and adversarial forces.

6. The U.S. Government should support efforts to establish a whole-of-nation approach to human/machine enhancement technologies versus a whole-of-government approach.

7. The DOD should support foundational research to validate human/machine fusion technologies before fielding them and to track the long-term safety and impact on individuals and groups.


This rabbit hole then led me to the DARPA website – and wow! This research -to create human cyborgs, it is actually happening.

A quick glance at the Biological Technology Office and DARPA reveals that programatic goals of building cyborg capabilities are being conducted at an astounding rate. The webpage search engine allows a search of the non-classified programs already being developed. So, one can go to this site and envision many, if not most of these technologies listed as being used for warfare. The military is developing human augmentation for military uses, not civilian. This is important to keep in mind.

So, I spent a little time searching and webmining the more “interesting” DARPA projects. Below are just a few of the abstracts of research projects being funded by DARPA and the DoD:


The Measuring Biological Aptitude (MBA) program aims to address the need for a more capable fighting force by helping individual warfighters identify, measure, and track personalized biomarkers related to training and peak performance for specialized roles. If the program succeeds, MBA technologies will give warfighters the ability to understand the underlying biological processes that govern their performance. Specifically, these technologies would elucidate the internal expression circuits (e.g., genetic, epigenetic, metabolomic) that shape militarily relevant cognitive, behavioral, and physical traits. New devices for continuously tracking these expression circuits could be integrated into the body to provide instantaneous user feedback, helping the warfighter to improve performance throughout training, assessment, selection, and mission execution for a given military specialty.


DARPA’s multi-year AI Next portfolio of programs and investments seeks to develop contextual reasoning in artificial intelligence systems to improve human/machine teaming.

The Agile Teams (A-Teams) program aims to discover, test, and demonstrate generalizable mathematical abstractions for the design of agile human-machine teams and to provide predictive insight into team performance. While human-machine teams have been the subject of considerable past work in artificial intelligence and autonomy, designing agile team architectures remains largely a trial-and-error enterprise. The A-Teams program seeks to create a systematic methodology to design teams that best use the capabilities of both humans and machines and that can achieve enhanced performance in uncertain, dynamic, and co-evolving environments. These new abstractions will be validated using experimental testbeds aimed to support reproducible evaluation of human-machine team architectures in a diverse range of problem contexts.


The Hand Proprioception and Touch Interfaces (HAPTIX) program is pursuing key technologies to enable precision control of and sensory feedback from sensor-equipped upper-limb prosthetic devices. If successful, the resulting system would provide users near-natural control of prosthetic hands and arms via bi-directional peripheral nerve implants.

The Safe Genes program supports force protection and military health and readiness by protecting Service members from accidental or intentional misuse of genome editing technologies. Additional work will leverage advances in gene editing technology to expedite development of advanced prophylactic and therapeutic treatments against gene editors. Advances within the program will ensure the United States remains at the vanguard of the broadly accessible and rapidly progressing field of genome editing.

Safe Genes performer teams work across three primary technical focus areas to develop tools and methodologies to control, counter, and even reverse the effects of genome editing—including gene drives—in biological systems across scales. First, researchers are developing the genetic circuitry and genome editing machinery for robust, spatial, temporal, and reversible control of genome editing activity in living systems. Second, researchers are developing small molecules and molecular strategies to provide prophylactic and treatment solutions that prevent or limit genome editing activity and protect the genome integrity of organisms and populations. Third, researchers are developing “genetic remediation” strategies that eliminate unwanted engineered genes from a broad range of complex population and environmental contexts to restore systems to functional and genetic baseline states.

Overall, the Safe Genes program is creating a layered, modular, and adaptable solution set to: protect warfighters and the homeland against intentional or accidental misuse of genome editing technologies; prevent and/or reverse unwanted genetic changes in a given biological system; and facilitate the development of safe, precise, and effective medical treatments that use gene editors.


The Next-Generation Nonsurgical Neurotechnology (N3) program aims to develop high-performance, bi-directional brain-machine interfaces for able-bodied service members. Such interfaces would be enabling technology for diverse national security applications such as control of unmanned aerial vehicles and active cyber defense systems or teaming with computer systems to successfully multitask during complex military missions.

Whereas the most effective, state-of-the-art neural interfaces require surgery to implant electrodes into the brain, N3 technology would not require surgery and would be man-portable, thus making the technology accessible to a far wider population of potential users. Noninvasive neurotechnologies such as the electroencephalogram and transcranial direct current stimulation already exist, but do not offer the precision, signal resolution, and portability required for advanced applications by people working in real-world settings.

The envisioned N3 technology breaks through the limitations of existing technology by delivering an integrated device that does not require surgical implantation, but has the precision to read from and write to 16 independent channels within a 16mm3 volume of neural tissue within 50ms. Each channel is capable of specifically interacting with sub-millimeter regions of the brain with a spatial and temporal specificity that rivals existing invasive approaches. Individual devices can be combined to provide the ability to interface to multiple points in the brain at once.

To enable future non-invasive brain-machine interfaces, N3 researchers are working to develop solutions that address challenges such as the physics of scattering and weakening of signals as they pass through skin, skull, and brain tissue, as well as designing algorithms for decoding and encoding neural signals that are represented by other modalities such as light, acoustic, or electro-magnetic energy.


The Neural Evidence Aggregation Tool (NEAT) program aims to overcome current limitations by developing a new cognitive science tool that identifies people at risk of suicide by using preconscious brain signals rather than asking questions and waiting for consciously filtered responses. By aggregating preconscious brain signals to stimuli, NEAT would determine what a person believes to be true, false, or indeterminate about specific types of knowledge that could be used to detect signs of depression, anxiety, or suicidal ideation earlier and more reliably than ever before. If successful, NEAT will not only significantly augment behavioral health screening, but it could also serve as a new way to assess ultimate treatment efficacy, since patients will often tell their clinicians what they think the clinician wants to hear rather than how they are truly feeling. Ultimately, NEAT intends to augment current behavioral health screening programs by providing clinicians with previously unavailable information to enable earlier interventions and more reliable measures of successful treatment.


The research activities that are being conducted by DARPA and the DoD are considerable. Even the small sampling of abstracts published above only begins to document just how large this endeavor is.

These technologies are further along than we might think, and we deserve to know more about them. This is the future that our government is planning for us, whether we like it or not, and it is a future that is opaque. From genetic engineering to new synthetics development for neural implants, to replacing and enhancing limbs for warfare – our military is “going there.” But the truth is, some places “we” shouldn’t go. Just because they “can,” doesn’t mean they “should”.

If you have learned anything since January 2020, I hope that you have learned to question the wisdom and insight of the insider cliques within the US Government and “Administrative State” who believe that it is acceptable to march ahead with genetic and mechanical engineering of human beings without meaningful oversight, let alone self awareness and any sense of bioethical boundaries.

If we truly wish to have a say in these new technologies, society (which is to say “we”) must be informed. “We” have a right to be informed. That means you and me. As these technologies develop, transhumanism will become all the rage. Think about that. These new technologies will be what future generations will have to look forward to. Human cyborgs are their futures. They, that is human cyborgs, will be our children and our grandchildren.

We are Borg. Resistance is futile. You will be assimilated. Your life as it has been is over. From this time forward, you will service us.

Thanks, Paramount. We need more “normalizing their vision of the future” in our lives please.

The military is already working on propaganda to “reverse negative cultural narratives of enhancement technologies.” So, once again – we are being played before we even know what the playing field looks like.

Like I said before, we have all seen that movie too.

The full scope of this program needs to be revealed to the American people. Although the executive report barely mentions gene editing technologies, the military is investing heavily in them and clearly with the intention of using them for the war fighter. The executive report barely skims the surface of the research that is currently being carried out by DARPA, and that is only one office within the Department of Defense. The public’s right to know about this research and what the final goals are is crucial. Congress must demand answers and must demand open and transparent responses. As the report rightly points out, what happens in the military will make its way into the public sphere. We have a right to know what is being planned for our future “evolution.” I don’t use that word lightly. But that is how the UK Ministry of Defence has labeled human augmentation research.

Turns out that Silicon Valley darling and Klaus Schwab’s evil mini me Yuval Noah Harari (author of Homo Deus, which literally means “Man God”) is not so far out there in his thinking as we had thought.

The bioethics of human augmentation are complex. The regulatory processes must be developed before the technologies come into being, not the other way around. People must envision how these technologies will be used in civilian life, in military life and as life-saving treatments. People need to decide if and which of these technologies really are for the good of society. People need to become involved now.

That starts with education. Which begins with transparency by our government. In future Substacks, I hope that you and I will begin exploring the bioethics, the impact of these technologies, privacy issues, the targets, future visions of society and just what this all means.

After all, what could possibly go wrong?

https://www.zerohedge.com/technology/malone-human-cyborgs-are-just-beginning

Growing Global Reliance On Antidepressants

 According to the latest OECD data, Iceland continues to have one of the highest levels of antidepressant use in the world - with an average consumption of 16 daily doses per 100 inhabitants in 2021.

In general, the northern countries are among the biggest consumers, with Canada and Sweden also showing a ratio of over 10 doses per 100 inhabitants per day.

Worth noting however is the absence of the United States from the data.

As Statista's Martin Armstrong shows in the infographic below, antidepressant use has become more widespread all around the world, with major increases from 2015 to 2020 or 2021 observed in Iceland, Portugal and Sweden, as well as Belgium and Greece.

Infographic: The Growing Global Reliance on Antidepressants | Statista

You will find more infographics at Statista

The places with the lowest consumption levels of those analyzed are South Korea and Lithuania (not displayed), with a ratio of 2 to 3 daily doses per 100 people.

https://www.zerohedge.com/medical/growing-global-reliance-antidepressants

Senate passes bill to rework animal testing requirements for drug developers

 The US Senate passed via unanimous consent on Thursday afternoon a bipartisan bill that would alter a federal mandate for animal testing on new drugs, but stops short of removing animal testing entirely.


Touted as a much-needed modernization of FDA’s rules, co-sponsor Sens. Rand Paul (R-KY) and Cory Booker (D-NJ) have said the bill will stop lots of needless suffering of animals.



But the FDA has made clear that although drug companies seek to use as few animals as possible and to ensure their humane and proper care, animal testing is still crucial for drug development and for determining the toxicity of experimental compounds.


“Two or more species are typically tested because a drug may affect one differently from another. Such tests show whether a potential drug has toxic side effects and what its safety is at different doses. The results point the way for human testing and, much later, product labeling,” the FDA explains.


NIH also notes that researchers try to perform toxicology tests using biochemical or cell-based (in vitro) systems instead of with animals such as mice. But “the development of in vitro tests that can reliably identify chemical hazards resulting in cancer or birth defects is more difficult because of the complexity of the biological processes involved.”



The text of this bill shows it would replace the term “animal” in several key sections of the FDCA, and add the term “nonclinical test,” defined as in vitro, in silico, in chemico, and other nonhuman in vivo testing that may include animal tests.


The Senate-passed bill, which comes amid monkey shortages for researchers, also includes language from another bill sponsored by Sen. Ben Ray Luján (D-NM) to amend the Public Health Service Act to remove the animal testing requirement for biosimilars too.


On the House side, the chamber previously passed its user fee reauthorization as part of a package that also included these animal-related reforms.

https://endpts.com/senate-passes-bill-to-rework-animal-testing-requirements-for-drug-developers/

New inflation-linked drug rebates go into effect on Saturday

 Beginning October 1, biopharma companies can be charged rebates for any new drug price increases rising faster than the rate of inflation.


The new rebates are part of the newly signed Inflation Reduction Act, which introduces this new requirement that manufacturers pay rebates to Medicare for Part D drugs whose price increases exceed inflation, and in January 2023, the same will occur with Part B drugs.


The rebate system “was designed to reduce the frequency and size of drug price increases,” HHS says. The IRA also includes a provision that allows CMS to negotiate and/or cap the prices of 10 of the most expensive drugs.


While those negotiations will be limited, the rebates paid by the industry may be significant. HHS released a new report on Friday outlining what the IRA could do as more than 1,200 drug price increases from July 2021 to July 2022 exceeded the inflation rate of 8.5% for that time period. The report notes:


Most price increases occur at the beginning of January, with more than 3000 drugs experiencing a price increase in 2022, up from 2650 in 2016. The number of July price increases trended downward from 613 NDCs in 2016 to 203 in 2021, but in July of 2022, the number of increases rose to a level similar to that observed in 2016, with 601 increases.





HHS on Friday also released another report that “found a steady increase in prescription drug spending from $520 billion in 2016 to $603 billion in 2021. This increase was driven by increases in spending per prescription, and less so by increases in the number of prescriptions.”


And while the inflation-linked rebates will hit all pharma companies, HHS notes that drug spending “is heavily driven by a relatively small number of high-cost products. The cost of specialty drugs has continued to grow, totaling $301 billion in 2021, an increase of 43% since 2016.”

https://endpts.com/new-inflation-linked-drug-rebates-go-into-effect-on-saturday/

Main target of SARS-CoV-2 in brain and effects of virus on nervous system IDd

 A Brazilian study published in the journal PNAS describes some of the effects infection by SARS-CoV-2 can have on the central nervous system. A preliminary version (not yet peer-reviewed) posted in 2020 was one of the first to show that the virus that causes COVID-19 can infect brain cells, especially astrocytes. It also broke new ground by describing alterations in the structure of the cortex, the most neuron-rich brain region, even in cases of mild COVID-19.

The cerebral cortex is the outer layer of gray matter over the hemispheres. It is the largest site of neural integration in the  and plays a key role in complex functions such as memory, attention, consciousness, and language.

The investigation was conducted by several groups at the State University of Campinas (UNICAMP) and the University of São Paulo (USP). Researchers at the Brazilian Biosciences National Laboratory (LNBio), D'Or Institute (IDOR) and the Federal University of Rio de Janeiro (UFRJ) also contributed to the study.

"Two previous studies detected the presence of the novel coronavirus in the brain, but no one knew for sure if it was in the bloodstream,  [lining the blood vessels] or nerve cells. We showed for the first time that it does indeed infect and replicate in astrocytes, and that this can reduce neuron viability," Daniel Martins-de-Souza, one of the leaders of the study, told Agência FAPESP. Martins-de-Souza is a professor at UNICAMP's Biology Institute and a researcher affiliated with IDOR.

Astrocytes are the most abundant central nervous system cells. Their functions include providing biochemical support and nutrients for neurons; regulating levels of neurotransmitters and other substances that may interfere with neuronal functioning, such as potassium; maintaining the blood-brain barrier that protects the brain from pathogens and toxins; and helping to maintain brain homeostasis.

Infection of astrocytes was confirmed by experiments using brain tissue from 26 patients who died of COVID-19. The tissue samples were collected during autopsies conducted using minimally invasive procedures by Alexandre Fabro, a pathologist and professor at the University of São Paulo's Ribeirão Preto Medical School (FMRP-USP). The analysis was coordinated by Thiago Cunha, also a professor in FMRP-USP and a member of the Center for Research on Inflammatory Diseases (CRID).

The researchers used a technique known as immunohistochemistry, a staining process in which antibodies act as markers of viral antigens or other components of the tissue analyzed. "For example, we can insert one antibody into the sample to turn the astrocytes red on binding to them, another to mark the SARS-CoV-2 spike protein by making it green, and a third to highlight the virus's double-stranded RNA, which only appears during replication, by turning it magenta," Martins-de-Souza explained. "When the images produced during the experiment were overlaid, all three colors appeared simultaneously only in astrocytes."

According to Cunha, the presence of the virus was confirmed in five of the 26 samples analyzed. Alterations suggesting possible damage to the central nervous system were also found in these five samples.

"We observed signs of necrosis and inflammation, such as edema [swelling caused by a buildup of fluid], neuronal lesions and inflammatory cell infiltrates," he said.

The capacity of SARS-CoV-2 to infect brain tissue and its preference for astrocytes were confirmed by Adriano Sebolella and his group at FMRP-USP using the method of brain-derived slice cultures, an experimental model in which human brain tissue obtained during surgery to treat neurological diseases such as drug-refractory epilepsy, for example, is cultured in vitro and infected with the virus.

Persistent symptoms

In another part of the research, conducted in UNICAMP's School of Medical Sciences (FCM), 81 volunteers who had recovered from mild COVID-19 were submitted to magnetic resonance imaging (MRI) scans of their brains. These scans were performed 60 days after diagnostic testing on average. A third of the participants still had neurological or neuropsychiatric symptoms at the time. They complained mostly of headache (40%), fatigue (40%), memory alterations (30%), anxiety (28%), loss of smell (28%), depression (20%), daytime drowsiness (25%), loss of taste (16%) and low libido (14%).

"We posted a link for people interested in participating in the trial to register, and were surprised to get more than 200 volunteers in only a few days. Many were polysymptomatic, with widely varying complaints. In addition to the neuroimaging exam, they're being evaluated neurologically and taking standardized tests to measure performance in cognitive functions such as memory, attention and mental flexibility. In the article we present the initial results," said Clarissa Yasuda, a professor and member of the Brazilian Research Institute for Neuroscience and Neurotechnology (BRAINN).

Only volunteers diagnosed with COVID-19 by RT-PCR and not hospitalized were included in the study. The assessments were carried out after the end of the acute phase, and the results were compared with data for 145 healthy uninfected subjects.

The MRI scans showed that some volunteers had decreased cortical thickness in some brain regions compared with the average for controls.

"We observed atrophy in areas associated, for example with anxiety, one of the most frequent symptoms in the study group," Yasuda said. "Considering that the prevalence of anxiety disorders in the Brazilian population is 9%, the 28% we found is an alarmingly high number. We didn't expect these results in patients who had had the mild form of the disease."

In neuropsychological tests designed to evaluate cognitive functioning, the volunteers also underperformed in some tasks compared with the national average. The results were adjusted for age, sex and educational attainment, as well as the degree of fatigue reported by each participant.

"The question we're left with is this: Are these symptoms temporary or permanent? So far, we've found that some subjects improve, but unfortunately many continue to experience alterations," Yasuda said. "What's surprising is that many people have been reinfected by novel variants, and some report worse symptoms than they had since the first infection. In view of the novel virus, we see longitudinal follow-up as crucial to understand the evolution of the neuropsychiatric alterations over time and for this understanding to serve as a basis for the development of targeted therapies."

Energy metabolism affected

In IB-UNICAMP's Neuroproteomics Laboratory, which is headed by Martins-de-Souza, experiments were performed on brain tissue cells from people who died of COVID-19 and astrocytes cultured in vitro to find out how infection by SARS-CoV-2 affects nervous system cells from the biochemical standpoint.

The autopsy samples were obtained via collaboration with the group led by Paulo Saldiva, a professor at the University of São Paulo's Medical School (FM-USP). The proteome (all proteins present in the tissue) was mapped using mass spectrometry, a technique employed to identify different substances in biological samples according to their molecular mass.

"When the results were compared with those of uninfected subjects, several proteins with altered expression were found to be abundant in astrocytes, which validated the findings obtained by immunohistochemistry," Martins-de-Souza said. "We observed alterations in various biochemical pathways in the astrocytes, especially pathways associated with ."

The next step was to repeat the  in cultured astrocytes infected in the laboratory. The astrocytes were obtained from induced pluripotent stem cells (iPSCs). The method consists of reprogramming adult cells (derived from skin or other easily accessible tissues) to assume a stage of pluripotency similar to that of embryo stem cells. This first part was conducted in the IDOR laboratory of Stevens Rehen, a professor at UFRJ. Martins-de-Souza's team then used chemical stimuli to make the iPSCs differentiate into neural stem cells and eventually into astrocytes.

"The results were similar to those of the analysis of tissue samples obtained by autopsy in that they showed energy metabolism dysfunction," Martins-de-Souza said. "We then performed a metabolomic analysis [focusing on the metabolites produced by the cultured astrocytes], which evidenced glucose metabolism alterations. For some reason, infected astrocytes consume more glucose than usual, and yet cellular levels of pyruvate and lactate, the main energy substrates, decreased significantly."

Lactate is one of the products of glucose metabolism, and astrocytes export this metabolite to neurons, which use it as an energy source. The researchers' in vitro analysis showed that lactate levels in the cell culture medium were normal but decreased inside the cells. "Astrocytes appear to strive to maintain the energy supply to neurons even if this effort weakens their own functioning," Martins-de-Souza said.

As an outcome of this process, the functioning of the astrocytes' mitochondria (energy-producing organelles) was indeed altered, potentially influencing cerebral levels of such neurotransmitters as glutamate, which excites neurons and is associated with memory and learning, or gamma-aminobutyric acid (GABA), which inhibits excessive firing of neurons and can promote feelings of calm and relaxation.

"In another experiment, we attempted to culture neurons in the medium where the infected astrocytes had grown previously and measured a higher-than-expected cell death rate. In other words, this culture medium 'conditioned by infected astrocytes' weakened neuron viability," Martins-de-Souza said.

The findings described in the article confirm those of several previously published studies pointing to possible neurological and neuropsychiatric manifestations of COVID-19.

Results of experiments on hamsters conducted at the Institute of Biosciences (IB-USP), for example, reinforce the hypothesis that infection by SARS-CoV-2 accelerates astrocyte metabolism and increases the consumption of molecules used to generate energy, such as glucose and the amino acid glutamine. The results obtained by the group led by Jean Pierre Peron indicate that this metabolic alteration impairs the synthesis of a neurotransmitter that plays a key role in communication among neurons.

Unanswered questions

According to Martins-de-Souza, there is no consensus in the scientific literature on how SARS-CoV-2 reaches the brain. "Some animal experiments suggest the virus can cross the blood-brain barrier. There's also a suspicion that it infects the olfactory nerve and from there invades the central nervous system. But these are hypotheses for now," he said.

One of the discoveries revealed by the PNAS article is that the virus does not use the protein ACE-2 to invade central nervous system cells, as it does in the lungs. "Astrocytes don't have the protein in their membranes. Research by Flávio Veras [FMRP-USP] and his group shows that SARS-CoV-2 binds to the protein neuropilin in this case, illustrating its versatility in infecting different tissues," Martins-de-Souza said.

At UNICAMP's Neuroproteomics Laboratory, Martins-de-Souza analyzed nerve cells and others affected by COVID-19, such as adipocytes, immune system cells and gastrointestinal cells, to see how the infection altered the proteome.

"We're now compiling the data to look for peculiarities and differences in the alterations caused by the virus in these different tissues. Thousands of proteins and hundreds of biochemical pathways can be altered, with variations in each case. This knowledge will help guide the search for specific therapies for each system impaired by COVID-19," he said.

"We're also comparing the proteomic differences observed in  from patients who died of COVID-19 with proteomic differences we've found over the years in patients with schizophrenia. The symptoms of both conditions are quite similar. Psychosis, the most classic sign of schizophrenia, also occurs in people with COVID-19."

The aim of the study is to find out whether infection by SARS-CoV-2 can lead to degeneration of the white matter in the brain, made up mainly of glial cells ( and microglia) and axons (extensions of neurons). "We've observed a significant correspondence [in the pattern of proteomic alterations] associated with the energy metabolism and glial proteins that appear important in both COVID-19 and schizophrenia. These findings may perhaps provide a shortcut to treatments for the psychiatric symptoms of COVID-19," Martins-de-Souza pondered.

Marcelo Mori, a professor at IB-UNICAMP and a member of the Obesity and Comorbidities Research Center (OCRC), the study was only possible thanks to the collaboration of researchers with varied and complementary backgrounds and expertise. "It demonstrates that first-class competitive science is always interdisciplinary," he said. "It's hard to compete internationally if you stay inside your own lab, confining yourself to the techniques with which you're familiar and the equipment to which you have access."

More information: Fernanda Crunfli et al, Morphological, cellular, and molecular basis of brain infection in COVID-19 patients, Proceedings of the National Academy of Sciences (2022). DOI: 10.1073/pnas.2200960119

https://medicalxpress.com/news/2022-09-reveals-main-sars-cov-brain-effects.html

Some officials now say monkeypox elimination unlikely in US

 Some U.S. health officials are conceding that monkeypox is probably not going away anytime soon.

The disease’s spread is slowing but the virus is so widespread that elimination is unlikely, the Centers for Disease Control and Prevention said. That conclusion was in a recent CDC report, and echoed Friday by Marc Lipsitch, director of science in the agency’s disease-forecasting center.

Lipsitch hesitated to say monkeypox is permanently here to stay, but he said it stands to be a continuing threat for the next few years.

“It’s in many geographic locations within the country” as well as in other countries, Lipsitch told The Associated Press. “There’s no clear path in our mind to complete elimination domestically.”

The virus has mainly spread among gay and bisexual men, though health officials continue to stress that anyone can be infected. It’s important that people at risk take steps to prevent spread and that vaccination efforts continue, Lipsitch said.

The CDC report contained some good news: The U.S. outbreak seems to have peaked in early August. The average number of daily cases being reported — fewer than 150 — is about a third what it was reported in the middle of the summer, and officials expect the decline will continue for at least the next several weeks.

Lipsitch attributed the good news to increasing vaccinations, cautious behavior by people at risk and infection-derived immunity in the highest risk populations.

Dr. Tom Inglesby, director of the Johns Hopkins Center for Health Security, agreed that it’s unlikely that spread of monkeypox will stop in the U.S. anytime soon, but he said it’s still possible in the long term.

If domestic transmission were stopped, infections may still continue if people catch the virus while traveling internationally, he said. But the declining cases makes it seem like “we’ve turned a real corner.”

“The efforts underway are succeeding, and should be continued, if not intensified,” he said.

With case numbers going down, this is a good time for local health departments to take a new stab at doing intensive contact tracing to try to stop chains of transmission, he said.

Monkeypox is endemic in parts of Africa, where people have been infected through bites from rodents or small animals, but it wasn’t considered a disease that spreads easily among people until May, when infections emerged in Europe and the U.S.

There have been more than 67,000 cases reported in countries that have not historically seen monkeypox. The U.S. has the most infections of any country — more than 25,600. One U.S. death has been attributed to monkeypox.

More than 97% of U.S. cases are men. The vast majority have been men who reported recent sexual contact with other men.

Though cases have been declining, the proportion of new cases that have information about recent sexual contact is also down, officials said. That’s causing a growing blind spot about how the virus may be spreading, Lipsitch noted.

https://apnews.com/article/monkeypox-science-health-centers-for-disease-control-and-prevention-9f23d14764f886288138fe607157150e

Opthalmology Space Gains Clarity with Partnerships & Acquisitions by Outlook & Visus

 A cloudy ophthalmic space got a little clearer Wednesday with the announcements of two collaborations by Visus Therapeutics and Outlook Therapeutics, now preparing for FDA approval.

Outlook Therapeutics also tapped AmerisourceBergen to distribute ONS-5010. ONS-5010 is the monoclonal antibody bevacizumab to treat wet age-related macular degeneration, commonly referred to as wet AMD and other eye diseases.

Bevacizumab is one of the oldest monoclonal antibodies on the market, developed by Roche’s Genentech and previously approved to treat several cancers. Its best known under the brand name Avastin.

Outlook submitted a biologics license application to treat eye disease in March, but the FDA required the company to submit more data over the summer.

Analysts expect approval of the eye drug candidate, brand named Lytenava, sometime in 2023.

Outlook previously partnered with FUJIFILM Diosynth Biotechnologies and Ajinomoto Bio-pharma Services for material sourcing and manufacturing assistance in anticipation of a commercial launch.

“Following our recent Biologics License Application submission, entering a relationship with AmerisourceBergen for ONS-5010 is a critical step in the next phase of our pre-commercial strategy execution,” said Outlook Pres. and CEO C. Russell Trenary, III in a statement.

If ONS-5010 is approved, AmerisourceBergen’s Besse Medical will handle distribution. AmerisourceBergen’s Innomar Strategies will handle medical information and pharmacovigilance, or the monitoring, detection and prevention of adverse events.

Outlook and AmerisourceBergen are also discussing a distribution agreement for outside the U.S.

Meanwhile, Visus Therapeutics on Wednesday announced it's expanding its ophthalmic pipeline by acquiring the patents and assets of ViewPoint Therapeutics.

ViewPoint is developing an alpha-crystallin aggregation inhibitor as a non-surgical treatment for protein misfolding in the eye.

Misfolding causes cataracts and presbyopia, age-related near-sightedness. Presbyopia and cataracts are the leading causes of vision disability.

Alpha-crystallin aggregation inhibitors aim to restore lens clarity and have the potential to reverse near-sightedness and cataracts without surgery. Some 128 million U.S. adults have presbyopia. Most people treat age-related near-sightedness with reading glasses. More than half of U.S. adults older than 80 have cataracts.

Visus is currently conducting Phase III trials of its eye drops, Brimochol, for the treatment of presbyopia. Brimochol is a combination of carbachol and brimonidine tartrate. Carbachol is a miotic agent that constricts pupils.

“More than a third of the world’s population have presbyopia or cataracts, and this will only increase as the population ages,” said Dr. Eric Donnenfeld of Ophthalmic Consultants of New York and NYU. “A non-surgical approach to treating and possibly preventing cataracts and presbyopia could improve the quality of life of millions of people, globally, and would be a disruptive addition to the management of our patients.”

https://www.biospace.com/article/opthamology-space-gains-clarity/