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Sunday, November 21, 2021

'Deepfaking the mind' could improve brain-computer interfaces for people with disabilities

 Researchers at the USC Viterbi School of Engineering are using generative adversarial networks (GANs)—technology best known for creating deepfake videos and photorealistic human faces—to improve brain-computer interfaces for people with disabilities.

In a paper published in Nature Biomedical Engineering, the team successfully taught an AI to generate synthetic brain activity data. The data, specifically  called spike trains, can be fed into  to improve the usability of  (BCI).

BCI systems work by analyzing a person's brain signals and translating that  into commands, allowing the user to control  like computer cursors using only their thoughts. These devices can improve quality of life for people with motor dysfunction or paralysis, even those struggling with locked-in syndrome—when a person is fully conscious but unable to move or communicate.

Various forms of BCI are already available, from caps that measure brain signals to devices implanted in brain tissues. New use cases are being identified all the time, from neurorehabilitation to treating depression. But despite all of this promise, it has proved challenging to make these systems fast and robust enough for the real world.

Specifically, to make sense of their inputs, BCIs need huge amounts of neural data and long periods of training, calibration and learning.

"Getting enough data for the algorithms that power BCIs can be difficult, expensive, or even impossible if paralyzed individuals are not able to produce sufficiently robust brain signals," said Laurent Itti, a computer science professor and study co-author.

Another obstacle: the technology is user-specific and has to be trained from scratch for each person.

Generating synthetic neurological data

What if, instead, you could create synthetic neurological data—artificially computer-generated data—that could "stand in" for data obtained from the real world?

Enter generative adversarial networks. Known for creating "deep fakes," GANs can create a virtually unlimited number of new, similar images by running through a trial-and-error process.

Lead author Shixian Wen, a Ph.D. student advised by Itti, wondered if GANs could also create training data for BCIs by generating synthetic neurological data indistinguishable from the real thing.

In an experiment described in the paper, the researchers trained a deep-learning spike synthesizer with one session of data recorded from a monkey reaching for an object. Then, they used the synthesizer to generate large amounts of similar—albeit fake—neural data.

The team then combined the synthesized data with small amounts of new real data—either from the same monkey on a different day, or from a different monkey—to train a BCI. This approach got the system up and running much faster than current standard methods. In fact, the researchers found that GAN-synthesized neural data improved a BCI's overall training speed by up to 20 times.

"Less than a minute's worth of real data combined with the synthetic data works as well as 20 minutes of real data," said Wen.

"It is the first time we've seen AI generate the recipe for thought or movement via the creation of synthetic spike trains. This research is a critical step towards making BCIs more suitable for  use."

Additionally, after training on one experimental session, the system rapidly adapted to new sessions, or subjects, using limited additional neural data.

"That's the big innovation here—creating fake spike trains that look just like they come from this person as they imagine doing different motions, then also using this data to assist with learning on the next person," said Itti.

Beyond BCIs, GAN-generated synthetic data could lead to breakthroughs in other data-hungry areas of artificial intelligence by speeding up training and improving performance.

"When a company is ready to start commercializing a robotic skeleton, robotic arm or speech synthesis system, they should look at this method, because it might help them with accelerating the training and retraining," said Itti. "As for using GAN to improve brain-computer interfaces, I think this is only the beginning."


Explore further

Machine learning, meet human emotions: How to help a computer monitor your mental state

More information: Shixian Wen et al, Rapid adaptation of brain–computer interfaces to new neuronal ensembles or participants via generative modelling, Nature Biomedical Engineering (2021). DOI: 10.1038/s41551-021-00811-z
https://medicalxpress.com/news/2021-11-deepfaking-mind-brain-computer-interfaces-people.html

COVID-19 targets human adrenal glands

 


PDF: https://www.thelancet.com/action/showPdf?pii=S2213-8587%2821%2900291-6

COVID-19 develops due to infection with SARS-CoV-2, which particularly in elderly with certain comorbidities (eg, metabolic syndrome) can cause severe pneumonia and acute respiratory distress syndrome. Some patients with severe COVID-19 will develop a life-threatening sepsis with its typical manifestations including disseminated intravascular coagulation and multiorgan dysfunction. Latest evidence suggests that even early treatment with inhaled steroids such as budesonide might prevent clinical deterioration in patients with COVID-19. This evidence underlines the potentially important role for adrenal steroids in coping with COVID-19.
The adrenal gland is an effector organ of the hypothalamic–pituitary–adrenal axis and the main source of glucocorticoids, which are critical to manage and to survive sepsis. Therefore, patients with pre-existing adrenal insufficiency are advised to double their doses of glucocorticoid supplementation after developing moderate to more severe forms of COVID-19.
Adrenal glands are vulnerable to sepsis-induced organ damage and their high vascularisation and blood supply makes them particularly susceptible to endothelial dysfunction and haemorrhage. Accordingly, adrenal endothelial damage, bilateral haemorrhages, and infarctions have been already reported in patients with COVID-19. Adrenal glands contain the highest concentration of antioxidants to compensate enhanced generation of reactive oxygen species, side products of steroidogenesis, which together with elevated intra-adrenal inflammation can contribute to adrenocortical cell death. Furthermore, sepsis-associated critical illness-related corticosteroid insufficiency, which describes coexistence of the hypothalamic–pituitary–adrenal dysfunction, reduced cortisol metabolism, and tissue resistance to glucocorticoids, was reported in critically ill patients with COVID-19. Low cortisol and adrenocorticotropic hormone (ACTH) responses during acute phase of infections consistent with critical illness-related corticosteroid insufficiency diagnosis (random plasma cortisol level lower than 10 μg/dL) were reported in one study with patients suffering from mild to moderate COVID-19 manifestations. It is however possible those other factors triggered by COVID-19 such as hypothalamic or pituitary damage, adrenal infarcts, or previously undiagnosed conditions, such as antiphospholipid syndrome, might be responsible for reduced function of adrenal glands. However, contrary to this observation, a study with patients with moderate to severe COVID-19 revealed a very high cortisol response with values exceeding 744 nmol/L, which were positively correlated with severity of disease. In this clinical study, highly elevated cortisol concentrations showed an adequate adrenal cortisol production possibly reflecting the elevated stress level of those severely affected patients. However, since ACTH measurements were not done, it is impossible to verify whether high concentrations of cortisol in those patients resulted from an increment of cortisol, or were confounded by reduced glucocorticoid metabolism.
A critical and yet unsolved major question is whether SARS-CoV-2 infection can contribute either directly or indirectly to adrenal gland dysfunction observed in some patients with COVID-19 or contribute to the slow recovery of some patients with long COVID.
We performed a comprehensive histopathological examination of adrenal tissue sections from autopsies of patients that died due to COVID-19 (40 cases), collected from three different pathology centres in Regensburg, Dresden, and Zurich (appendix pp 1–3). We observed evidence of cellular damage and frequently small vessel vasculitis (endotheliitis) in the periadrenal fat tissue (six cases with low and 13 cases with high density; appendix p 10) and much milder occurrence in adrenal parenchyma (ten cases with low and one case with moderate score; appendix p 10), but no evidence of thrombi formation was found (appendix p 10). Endotheliitis has been scored according to a semi-quantitative immunohistochemistry analysis as described in the appendix (p 4). Additionally, in the majority of cases (38 cases), we noticed enhanced perivascular lymphoplasmacellular infiltration of different density and sporadically a mild extravasation of erythrocytes (appendix p 10). However, no evidence of widespread haemorrhages and degradation of adrenocortical cells were found, which is consistent with histological findings reported previously. In another autopsy study analysing adrenal glands of patients with COVID-19, additional signs of acute fibrinoid necrosis of small vessels in adrenal parenchyma, subendothelial vacuolisation and apoptotic debris were found.
Adrenal gland is frequently targeted by bacteria and viruses, including SARS-CoV, which was responsible for the 2002–04 outbreak of SARS in Asia. Considering that SARS-CoV-2 shares cellular receptors with SARS-CoV, including angiotensin-converting enzyme 2 and transmembrane protease serine subtype 2, its tropism to the adrenal gland is therefore conceivable.
To investigate whether adrenal vascular cells and possibly steroid-producing cells are direct targets of SARS-CoV-2, we examined SARS-CoV-2 presence in adrenal gland tissues obtained from the 40 patients with COVID-19 (appendix pp 1–3). Adrenal tissues from patients who died before the COVID-19 pandemic were used as negative controls to validate antibody specificity. Using a monoclonal antibody (clone 1A9; appendix p 11), we detected SARS-CoV-2 spike protein in adrenocortical cells in 18 (45%) of 40 adrenal gland tissues (figure Bappendix p 12). In the same number of adrenal tissues (18 [45%] of 40), we have detected SARS-CoV-2 mRNA using in situ hybridisation (ISH; figure Aappendix p 12). The concordance rate between immunohistochemistry and ISH methods was 90% (36/40). Scattered and rather focal expression pattern of SARS-CoV-2 spike protein was found in the adrenal cortex (figure A and Bappendix p 12). In addition, SARS-CoV-2 expression was confirmed in 15 out of 30 adrenal gland tissues of patients with COVID-19 by multiplex RT-qPCR (appendix pp 6–7). The concordance between ISH, immunohistochemistry, and RT-qPCR techniques for SARS-CoV-2 positivity was only 23%, which is a technical limitation of our study possibly reflecting the low number of virus-positive cells. However, when considering triple-negative samples, an overall 53% consensus was found (appendix pp 7–8).
Figure thumbnail gr1
FigureDetection of SARS-CoV-2 in human adrenal gland from a patient who died due to COVID-19
Finally, to confirm the identity of infected cells, we have performed an ultrastructural analysis of adrenal tissue from a triple-positive patient case (by immunohistochemistry, ISH, and RT-qPCR), and found numerous SARS-CoV-2 virus-like particles in cells enriched with liposomes, which are typical markers of adrenocortical cells (figure C). The cortical identity of SARS-CoV-2 spike positive cells was also shown using serial tissue sections, demarcating regions with double positivity for viral protein and StAR RNA (appendix p 12). Furthermore, susceptibility of adrenocortical cells to SARS-CoV-2 infection was confirmed by in-vitro experiments (appendix p 7) showing detection of viral spike protein in adrenocortical carcinoma cells (NCI-H295R) cultured in a medium containing SARS-CoV-2 (figure D), and its absence in mock-treated control cells (figure E). We showed an uptake of viral particles in the adrenocortical cells, by ISH, immunohistochemistry, RT-qPCR and electron microscopy (figure A–C). Mechanistically, an uptake of SARS-CoV-2 like particles might involve expression of ACE2 in vascular cells (appendix p 13) and perhaps of the shorter isoform of ACE2 together with TMPRSS2 and other known or currently unknown virus-entry facilitating factors in adrenocortical cells (appendix p 13). An example of such factor is scavenger receptor type 1, which is highly expressed in adrenocortical cells.
Several forms of regulated cell necrosis were implicated in sepsis-mediated adrenal gland damage. One of the prime examples of regulated necrosis triggered by sepsis-associated tissue inflammation is necroptosis. The necrotic process is characterised by loss of membrane integrity and release of danger-associated molecular patterns, which further promote tissue inflammation (necroinflammation) involving enhanced activation of the complement system and related activation of neutrophils. Whether necroptosis might be involved in COVID-19-associated adrenal damage is currently unknown. In our study, we showed prominent expression of phospho Mixed Lineage Kinase Domain Like Pseudokinase (pMLKL) indicating necroptosis activation in adrenomedullary cells (appendix p 14) in adrenal glands of COVID-19 patients. However, since we have also observed pMLKL expression in adrenal glands obtained from autopsies done before the COVID-19 pandemic (controls), necroptosis activation in medullary cells might be a rather frequent and SARS-CoV-2 independent event. However, contrary to the adrenal medulla, pMLKL positivity in the adrenal cortex was only found in virus-positive regions (appendix p 14). This finding suggests that SARS-CoV-2 infection might have directly triggered activation of necroptosis in infected cells in the adrenal cortex, whereas pMLKL expression in the adrenal medulla seems rather an indirect consequence of systemic inflammation.
In summary, in our study of 40 patients who died from COVID-19, we did not observe widespread degradation of human adrenals that might lead to manifestation of the adrenal crisis. However, our study shows that the adrenal gland is a prominent target for the viral infection and ensuing cellular damage, which could trigger a predisposition for adrenal dysfunction. Whether those changes directly contribute to adrenal insufficiency seen in some patients with COVID-19 or lead to its complications (such as long COVID) remains unclear. Large multicentre clinical studies should address this question.
WK, HC, and SRB declare funds from Deutsche Forschungsgemeinschaft (project number 314061271, TRR 205/1 [“The Adrenal: Central Relay in Health and Disease”] to WK and SRB; HA 8297/1-1 to HC), during the conduct of this Correspondence. All other authors declare no competing interests. We thank Maria Schuster, Linda Friedrich, and Uta Lehnert for performing some of the immunohistochemical staining and in-situ hybridisation.

Disney World pauses vaccine mandate after DeSantis signs new legislation

 A vaccine mandate for Walt Disney World employees was paused after Florida Gov. Ron DeSantis (R) signed legislation prohibiting businesses from requiring inoculations without exemptions.

Disney told The Washington Post on Saturday that the company “will address legal developments as appropriate,” but argued that their "approach to mandatory vaccines has been the right one.”

Over 90 percent of “active” employees based in Florida have provided proof of vaccination to Disney, the company said in a statement to the newspaper.

Earlier this year, Walt Disney World required non-union and salaried workers in addition to unionized employees to get a vaccine to stay employed.

Last week, DeSantis signed legislation that requires businesses to allow for exemptions to vaccine mandates, including prior COVID-19 recovery and religious or health reasons.

The legislation also allows employees to undergo regular COVID-19 testing or use personal protective equipment (PPE) in lieu of being required to get the vaccine. Additionally, governmental and educational institutions are not allowed to require vaccinations for their employees.

“There’s times you need to stand up and you need to make your voice heard, and we had the ability to do it,” DeSantis said during a press conference last Thursday. 

“At the end of the day, nobody in Florida should be losing their job over these jabs. We want people to be able to work, we want people to be able to provide for their families. We want people to be able to have livelihoods, and that’s just the way it’s going to be in this state,” he added.

Small businesses that employ 99 people or fewer that violate the law can be fined $10,000 per violation while larger businesses can receive $50,000 per violation.

https://thehill.com/homenews/state-watch/582522-walt-disney-world-pauses-vaccine-mandate-after-desantis-signs-new

Fauci hopes COVID-19 booster increases durability to not need it regularly

 President Biden’s chief medical adviser Anthony Fauci said on Sunday that he hopes COVID-19 boosters will increase vaccine durability so that “you will not necessarily need it” every six months or year.

“We would hope - and this is something that we're looking at very carefully - that that third shot with the mRNA not only boosts you way up but increases the durability so that you will not necessarily need it every six months or a year,” Fauci said during “This Week” on ABC.

“We're hoping it pushes it out more. If it doesn't, and the data show we do need it more often, then we'll do it,” he added.

Centers for Disease Control and Prevention (CDC) Director Rochelle Walensky signed off on a CDC advisory panel’s recommendation to increase eligibility for booster shots to all American adults. 

The decision means that all adults who are at least six months out since receiving their second shot of the Pfizer or Moderna vaccines are now able to get their third shot of the COVID-19 vaccine. 

"Booster shots have demonstrated the ability to safely increase people’s protection against infection and severe outcomes and are an important public health tool to strengthen our defenses against the virus as we enter the winter holidays. Based on the compelling evidence, all adults over 18 should now have equitable access to a COVID-19 booster dose," Walensky said in a statement regarding the news.

The decision comes only weeks after children as young as 5 years old became eligible to get COVID-19 vaccine, much to the relief of parents and health officials seeking to have their kids inoculated in time for holiday gatherings. 

Despite widespread vaccine availability, however, it has not stopped the U.S. from passing the grim milestone last week of recording more COVID-19 deaths in 2021 than last year.

https://thehill.com/homenews/sunday-talk-shows/582525-fauci-hopes-covid19-booster-increases-durability-to-not-need-it-regularly

Saturday, November 20, 2021

Biden's Medicare drug price negotiations will leave pharma mostly unscathed: CBO

 The pharma industry should emerge mostly unscathed if President Joseph Biden's Build Back Better bill makes its way into law. While the legislation would open the door to limited Medicare negotiations and cap price hikes at the rate of inflation, the cost to the industry and its pace of innovation would be minimal, a government analysis found.

The provisions in the bill aimed at lowering prescription drug costs would save the U.S. government—and cost the pharmaceutical industry—about $160 billion over 10 years, The Hill reported Friday, citing a Congressional Budget Office (CBO) cost estimate published Thursday. 

Letting Medicare negotiate certain drug prices would bring about $80 billion in savings, the analysis found. Meanwhile, capping price hikes at the rate of inflation would yield about $80 billion in additional savings, CBO predicts.

The $160 billion in estimated savings from Build Back Better pales in comparison to the $450 billion projected savings from Speaker Nancy Pelosi's 2019 drug pricing bill. That bill proposed universal Medicare negotiations and sought to apply those negotiated prices across the U.S. insurance landscape.

After the CBO published its Build Back Better assessment on Thursday, the House passed the bill on Friday.

In all, the Build Back Better drug pricing framework is "not a bad outcome" for the industry, Evercore ISI analysts wrote in a note to clients earlier this month. Not all drugs would be subject to negotiation, for one. Instead, the plan would kick off in 2025 with a focus on the 10 costliest Medicare medicines, followed by 15 medicines in 2026 and 2027 and 20 medicines in 2028 and beyond. 

Most drugs wouldn't be affected by negotiations, the analysts said. 

Meanwhile, price hike caps under the framework would roll out in 2023. The caps would be tied to the rate of inflation, and the rule would apply to commercial insurance coverage, too. That could ultimately entice drugmakers to boost their products' launch prices, the Evercore team said. 

Some lawmakers and members of the industry have warned that the measures could stifle innovation. Still, the provisions would take a minimal toll on new drugs coming to market, the CBO said. 

If the provisions become law, the pharma industry will bring just one fewer medicine to market over the next decade, The Hill reports.

The plan would only have a "modest" impact on new drug launches over the next 30 years, Juliette Cubanski, deputy director of the program on Medicare policy at KFF, tweeted on Thursday. Just ten fewer drugs would be developed over the next 30 years, versus an estimated 1,300 approvals over that time, Cubanksi said. 

Top lobbying group PhRMA sees things differently. The group's CEO said the "consequences of this heavy-handed drug pricing plan will make a broken insurance system worse and throw sand in the gears of medical progress" In addition, the legislation "doesn’t address perverse incentives in the system that are leading to higher costs for patients," Ubl said.

Pharma has turned on its lobbying engine in response to the drug pricing talks, spending a whopping $263 million on lobbying in 2021 as of early November, CBS News reported.

https://www.fiercepharma.com/pharma/biden-s-medicare-drug-price-negotiations-will-leave-pharma-mostly-unscathed-cbo

Worst COVID-19 variant yet may arrive this spring: Georgetown immunologist

 Experts have been worried about a potential vaccine-resistant COVID-19 variant, and now one expert has a timeline of when we might see one in the United States.

Dr. Mark Dybul, a professor at Georgetown University Medical Center’s Department of Medicine and immunologist, said there will be a COVID-19 vaccine-resistant variant by spring 2022, according to Fortune.

  • “The faster we get boosted, the better off we’ll be for the next couple of months,” he said. “Sadly, every prediction I’ve made has pretty much come true. I hope I’m wrong this time, but I think by March, April, May, we will have a fully vaccine-resistant variant. There’s simply no way you can have such low rates of vaccination around the world with the virus ping-ponging between vaccinated and unvaccinated people. I’m an immunologist. The probability of us seeing a vaccine-resistant strain is very high.”
However, Dybul said that there will be advancements in therapeutics and vaccines to help stop the massive spread of that variant. Nasal sprays could help stop variants, too.
  • “I think we’ll have products like that in the next year and a half or so,” said Dybul, who was trained by Dr. Anthony Fauci, per Fortune. “So the longer term will be okay, but the next year and a half could be pretty rough.”

In October, Wales’ first ministerMark Drakeford, said he was concerned that a new COVID-19 variant resistant to vaccines will arrive soon.

  • “There is at least a possibility that that variant will turn out to be more resistant to vaccination than the current one we have,” he said.

Scientists in Germany warned in October that an older COVID-19 variant — called the A.30 variant — can evade the Pfizer and AstraZeneca COVID-19 vaccines, too.

Fauci warned in September that a “monster variant” could arrive that would make the delta variant look weak in comparison.

“There’s always a risk of, as you get more circulation of the virus in the community, that you’ll get enough accumulation of new mutations to get a variant substantially different than the ones we’re seeing now,” Fauci said on the MSNBC’s “Morning Joe.”

https://www.deseret.com/coronavirus/2021/11/17/22787447/covid-vaccine-resistant-coronavirus-variant-spring-2023

Blinken says US working to generate finance for vaccine manufacturing in Senegal

 U.S. Secretary of State Antony Blinken said on Saturday on a visit to Dakar's Institute Pasteur bio-medical research center that the United States was working with partners to generate more financing for vaccine manufacturing in Senegal.

https://www.marketscreener.com/news/latest/Blinken-says-US-working-to-generate-finance-for-vaccine-manufacturing-in-Senegal--37087767/