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Monday, September 11, 2023

Key failure in AMD that may lead to progression and vision loss

 Research led by Nicolas Bazan, MD, Ph.D., Boyd Professor, Ernest C. and Yvette C. Villere Chair for the Study of Retinal Degeneration, and Director of the Neuroscience Center of Excellence at LSU Health New Orleans School of Medicine, suggests that age-related macular degeneration (AMD) decreases an essential fatty acid, preventing the formation of a class of protective molecules and reducing repair potential. The discovery may also open new therapeutic avenues for AMD. The findings are published in Experimental Eye Research.

The study shows that AMD decreases peripheral retinal  (DHA) 22:6 in rod photoreceptor cells, limiting the elongation of fatty acids to form very-long-chain polyunsaturated fatty acids (VLC-PUFAs). VLC-PUFAs are precursors of elovanoids, bioactive chemical messengers made from omega-3 very- long-chain polyunsaturated fatty acids.

Elovanoids, discovered by the Bazan lab, have been shown to restore the structure and integrity of damaged photoreceptor cells by repairing, remodeling and regenerating healthy cells. The loss of the neuroprotective precursors of elovanoids in the retina periphery from AMD facilitates uncompensated stress and cell loss.

"Biosynthetic fatty acid pathway insufficiencies may be a fundamental factor in the onset and progression of macular degenerative diseases leading to blindness," notes Dr. Bazan. "These findings open important immediate avenues for therapeutic exploration for AMD."

The research team also found major differences between genders. According to the National Institutes of Health, 66% of AMD-affected persons are female. Females have higher DHA 22:6 than males because of estrogen effects. As they age and estrogen decreases, so does DHA 22:6, and as a result, women can become increasingly susceptible to .

"In AMD, the female retina loses peripheral rod VLC-PUFAs to about 33% less than in males, limiting elovanoid formation and its protective bioactivity," adds Bazan.

According to the Bright Focus Foundation, nearly 20 million US adults have some form of age-related macular degeneration. An estimated 18 million people aged 40 and older were living with early-stage macular degeneration in 2019, and 1.49 million had late-stage macular degeneration. Around 200 million people worldwide are thought to be living with AMD, a number expected to reach 288 million by 2040.

Age is a prominent risk factor for age-related macular degeneration. The risk of getting advanced age-related macular degeneration increases from 2% for those ages 50–59, to nearly 30% for those over the age of 75. The direct health care costs of visual impairment due to age-related  in the U.S., Canada, and Cuba are estimated at $98 billion.

Other authors of the study include Drs. William Gordon, Marie-Audrey Kautzmann, and Bok Kyoo Jun, along with Megan Cothern at LSU Health New Orleans' Neuroscience Center of Excellence and Dr. Zhide Fang at LSU Health New Orleans School of Public Health.

More information: William C. Gordon et al, Rod-specific downregulation of omega-3 very-long-chain polyunsaturated fatty acid pathway in age-related macular degeneration, Experimental Eye Research (2023). DOI: 10.1016/j.exer.2023.109639


https://medicalxpress.com/news/2023-09-key-failure-amd-vision-loss.html

'Inverse vaccine' shows potential to treat multiple sclerosis and other autoimmune diseases

 A new type of vaccine developed by researchers at the University of Chicago's Pritzker School of Molecular Engineering (PME) has shown in the lab setting that it can completely reverse autoimmune diseases like multiple sclerosis, type 1 diabetes, and Crohn's disease—all without shutting down the rest of the immune system.

A typical vaccine teaches the  to recognize a virus or bacteria as an enemy that should be attacked. The new "inverse vaccine" does just the opposite: it removes the immune system's memory of one molecule. While such immune memory erasure would be unwanted for , it can stop autoimmune reactions like those seen in multiple sclerosis, type I diabetes,  or Crohn's disease, in which the immune system attacks a person's healthy tissues.

The inverse vaccine, described this week in Nature Biomedical Engineering, takes advantage of how the liver naturally marks molecules from broken-down cells with "do not attack" flags to prevent autoimmune reactions to cells that die by natural processes.

PME researchers coupled an antigen—a molecule being attacked by the immune system—with a molecule resembling a fragment of an aged cell that the liver would recognize as friend, rather than foe. The team showed how the vaccine could successfully stop the autoimmune reaction associated with a multiple-sclerosis-like disease.

"In the past, we showed that we could use this approach to prevent autoimmunity," said Jeffrey Hubbell, the Eugene Bell Professor in Tissue Engineering and lead author of the new paper. "But what is so exciting about this work is that we have shown that we can treat diseases like multiple sclerosis after there is already ongoing inflammation, which is more useful in a real-world context."

Unwinding an immune response

The job of the immune system's T cells is to recognize unwanted cells and molecules—from viruses and bacteria to cancers—as foreign to the body and get rid of them. Once T cells launch an initial attack against an antigen, they retain a memory of the invader to eliminate it more quickly in the future.

T cells can make mistakes, however, and recognize healthy cells as foreign. In people with Crohn's disease, for instance, the immune system attacks cells of the small intestine; in those with multiple sclerosis, T cells mount an attack against myelin, the protective coating around nerves.

Hubbell and his colleagues knew that the body has a mechanism for ensuring that immune reactions don't occur in response to every damaged cell in the body— a phenomenon known as peripheral immune tolerance and carried out in the liver. They discovered in recent years that tagging molecules with a sugar known as N-acetylgalactosamine (pGal) could mimic this process, sending the molecules to the liver where tolerance to them develops.

"The idea is that we can attach any molecule we want to pGal and it will teach the immune system to tolerate it," explained Hubbell. "Rather than rev up immunity as with a vaccine, we can tamp it down in a very specific way with an inverse vaccine."

In the new study, the researchers focused on a multiple-sclerosis-like disease in which the immune system attacks myelin, leading to weakness and numbness, loss of vision and, eventually mobility problems and paralysis. The team linked myelin proteins to pGal and tested the effect of the new inverse vaccine. The immune system, they found, stopped attacking myelin, allowing nerves to function correctly again and reversing symptoms of disease in animals.

In a series of other experiments, the scientists showed that the same approach worked to minimize other ongoing immune reactions.

Toward clinical trials

Today,  are generally treated with drugs that broadly shut down the .

"These treatments can be very effective, but you're also blocking the immune responses necessary to fight off infections and so there are a lot of side effects," said Hubbell. "If we could treat patients with an inverse  instead, it could be much more specific and lead to fewer side effects."

More work is needed to study Hubbell's pGal compounds in humans, but initial phase I safety trials have already been carried out in people with celiac disease, an autoimmune disease that is associated with eating wheat, barley and rye, and phase I safety trials are under way in multiple sclerosis. Those trials are conducted by the pharmaceutical company Anokion SA, which helped fund the new work and which Hubbell cofounded and is a consultant, board member and equity holder. The Alper Family Foundation also helped fund the research.

"There are no clinically approved inverse vaccines yet, but we're incredibly excited about moving this technology forward," says Hubbell.

More information: Andrew C. Tremain et al, Synthetically glycosylated antigens for the antigen-specific suppression of established immune responses, Nature Biomedical Engineering (2023). DOI: 10.1038/s41551-023-01086-2


https://medicalxpress.com/news/2023-09-inverse-vaccine-potential-multiple-sclerosis.html

The Dirty Secret About How Masks Really "Work"

 by Clayton Baker, MD, via The Brownstone Institute,

It is difficult to believe that Public HealthTM is trying to force America to mask up again, but here we are.

The question is, why?

The dirty secret is this: Masks don’t work by controlling the virus. Masks work by controlling the people.

If we’re talking about stopping the spread of the virus, masks simply don’t work.

But if we’re talking about stoking fear, instilling blind obedience to state authorities, sowing discord between citizens, and publicly “outing” skeptics and dissidents – in other words, creating an authoritarian, even totalitarian system of public health – then masks work very well indeed.

MASKS DON’T WORK AT CONTROLLING THE VIRUS

By this late date, it has been established beyond honest scientific doubt that masking is ineffective at stopping the contraction and spread of COVID-19. This is true both at the microscopic level and at the population level.

The early mask mandates regarding COVID-19 were largely “justified” on the assertion that the SARS-CoV-2 virus was not prone to airborne spread. However, the SARS-CoV-2 virus has since been proven to be an airborne virus (like influenza), meaning it can remain circulating in room air for extended periods of time, and spreads in this manner. SARS-CoV-2 viruses have also been proven to be much smaller in size than the holes in cloth and surgical masks.

Therefore, at a microscopic level, Harvey Risch is correct: trying to block the SARS-CoV-2 virus with a surgical mask is quite literally like trying to keep mosquitos out of your yard by erecting a chain-link fence.

At a population level, the latest Cochrane meta-analysis of the available randomized, controlled trials surrounding masking and respiratory viruses concluded that “Wearing masks in the community probably makes little or no difference to the outcome of influenza‐like illness (ILI)/COVID‐19 like illness compared to not wearing masks. Wearing masks in the community probably makes little or no difference to the outcome of laboratory‐confirmed influenza/SARS‐CoV‐2 compared to not wearing masks.”

(It should be noted that as the mask debate has been resurrected, Cochrane has been under intense pressure by pro-mask entities to addend and modify their comments about this study, to which the organization has capitulated.)

Furthermore, this study is only one in addition to the hundreds of other studies that clearly outline the epidemiologic ineffectiveness and real harms of masks, many of which have been known since at least 2021.

To summarize: at the microscopic level, masks do not stop the exit or entry of the virus into human bodies, and at the population level, mask use has not been shown to provide any benefit, and has been shown to have numerous harms.

MASKS DO WORK AT CONTROLLING PEOPLE

The entire Public HealthTM enterprise in the West has a strong political and authoritarian impulse built into it from its very conception. While a detailed review of this is beyond the scope of this article, it harkens back at least to the figure of Rudolf Virchow, the preeminent 19th century German physician, opponent of Semmelweis and Darwin, and founder of so-called “social medicine,” who famously wrote that “Medicine is a social science, and politics nothing but medicine at a larger scale.”

The attitude that Public HealthTM should possess the power to dictate national and local political policy for the “public good” (as they, the “experts,” unilaterally determine it to be) has increased over the past century, especially in the United States. Around it there have grown vast, lucrative industries, from which (since at least the Bayh-Dole Act), Public HealthTM officials often profit handsomely. The vaccine industry is only the most obvious of these.

During the COVID era, the authoritarianism of Public HealthTM morphed into totalitarian mode, with the unprecedented lockdowns, school closures, travel restrictions, vaccine mandates, etc. that we all endured. The most visible and most easily enforceable symbol of this power grab were masks. 

Masks, even the comically useless ones made of old handkerchiefs, or the filthy, week-old paper surgical ones seen on countless chins, signaled compliance and submission. For the very real Public HealthTM purpose of unquestioning obedience, masks work very well indeed.

Masks are effective at instilling fear in people. Fearful people more readily submit to authority, particularly when that authority promises a solution to the cause of their fear.

Masks are effective as virtue signals of compliance, bolstering the submissive person’s ego. Masks also impose a very strong peer-pressure effect, which pushes uncertain persons toward following the crowd.

Masks are effective at humiliating people. They are uncomfortable, ugly, dirty, and unnatural. They truly are “face diapers.” In a word, masks are degrading. If the ways of the old Eastern bloc taught us anything, it is that the systematic degradation of individuals, especially for patently stupid reasons, is highly effective at promoting totalitarian ends.

Masks are also extremely effective in exposing dissidents. Who dares to stand up against the state? There’s one, right over there. Shame on them. Shun them. Arrest them.

That’s how masks really “work”, and that’s why the Public HealthTM types love them. 

That’s why they’re trying to bring them back.

https://www.zerohedge.com/medical/dirty-secret-about-how-masks-really-work

Arbutus cuts coronavirus and oral RNA destabilizer programs, extends cash runway

 Progressing development of hepatitis B virus (HBV) compounds imdusiran (AB-729) and AB-101, an oral PD-L1 inhibitor

Discontinuing all coronavirus and oral RNA destabilizer programs, including AB-343 and AB-161

Extending cash runway through Q3 2025

https://finance.yahoo.com/news/arbutus-announces-pipeline-updates-dosing-201500319.html

Acelyrin misses primary endpoint in Hidradenitis Suppurativa trial

 The primary endpoint of HiSCR75 at week 16 did not meet statistical significance in the Non-Responder Imputation (NRI) primary analysis.

HiSCR75 did meet statistical significance at week 16 in a Last Observation Carried Forward sensitivity analysis.

HiSCR response rates of izokibep 160mg weekly (QW) were consistent with Part A open label results, demonstrating early onset of HiSCR100 at week 4, increasing through week 12 to 38% of patients in the Independently Conducted Pre-Planned Interim Analysis.

Response was dose ordered, and safety was consistent with prior izokibep experience and not dose-limiting.

Izokibep appears to be demonstrating consistent early and high orders of response without safety or tolerability limitation.

Conference call and webcast to be held at 5:30 p.m. ET today.

ACELYRIN will host a conference call and webcast today, September 11, 2023, at 5:30 p.m. ET to review these trial results. A live webcast of the conference call can be accessed in the “Investors & Media” section of ACELYRIN’s website at www.acelyrin.com. A recording of the webcast will be available approximately two hours after the event, and will be archived on the Company’s website for approximately 30 days.

https://finance.yahoo.com/news/acelyrin-inc-announces-top-line-200500307.html

Level-Funded Health Insurance Plans, A Missed Opportunity

 Sixty-five percent of all workers with employer-sponsored health coverage are in self-insured plans, which generally means that the employer, not an independent insurance company, is responsible for the cost of paying out claims from the pool of funds collected in the forms of premiums. Among that population, however, a significant portion are in so-called level-funded plans, which have been described by the Kaiser Family Foundation as “a nominally self-insured option for small or mid-sized employers that incorporates stop loss insurance with relatively low attachment points.”

In 2022, 36 percent of covered workers at small firms reported enrollment in a level-funded plan. Despite their popularity, level-funded plans have historically received little attention from policymakers, analysts, and academics. Although that may be changing: On July 12th, the Department of Health and Human Services issued a request for information (RFI) on level-funded health insurance plans, and in June, the House of Representatives passed legislation clarifying the legal status of self-insured arrangements.

In this Forefront article, we describe the distinctive features of level-funded plans, clarify how they operate, explore their potential in creating value for employers and workers, and suggest directions for policymakers to consider. 

Features Of Level-Funded Plans

1. Stop Loss Coverage

Level-funded plans typically include stop loss coverage. In fact, almost all but the very largest self-insured plans include stop loss coverage to mitigate the employer’s risk exposure to excessive claims. Stop-loss insurance kicks in once claims reach a predetermined amount, thus limiting the employer's financial liability. Stop loss coverage, and the carrier offering it, is invisible to the plan’s beneficiaries, who never interact with the stop loss coverage because beneficiaries hit their maximum out-of-pocket limit long before a stop loss claim would be triggered. If a claim triggers the stop loss coverage, the plan usually pays the claims first and then files the claim to the stop loss carrier.

Stop loss coverage can be based on a per-person or plan aggregate basis, or both. The per-person stop loss deductible for a self-insured plan can be as low as $40,000, far exceeding any beneficiary’s maximum out-of-pocket limit. It is the plan, not the beneficiary, that is responsible for paying for the claims up to the per-person stop loss deductible. The other type of stop loss coverage is based on the plan’s aggregated claims. Stop loss coverage kicks in only if the aggregated claims exceed a limit (known as the attachment point) determined by actuaries who underwrite the group’s risk on behalf of the stop loss carrier.

2. Predictable Monthly Payments

Most self-insured plans, including level-funded plans, pay fixed plan administration fees to their plan administrator and stop loss premiums to their stop loss carrier on a monthly basis. Level-funded plans differ from non-level-funded plans only in how they pay medical and pharmacy claims. Non-level-funded plans pay claims (through the plan administrator) as they are incurred, usually approving them in batches once a week. In contrast, level-funded plans prepay claims on a monthly basis. The plan’s maximum annual liability (i.e., attachment point) is divided by twelve, and the plan pays that amount each month to the plan administrator, who uses it to pay claims as they are incurred. If actual claims exceed those prepayments, then the administrator files stop loss claims. If actual claims are lower than the pre-payments, then the employer receives the unspent funds back (or as a credit) at the end of the year.

Therefore, level-funded plans provide employers with certainty through predictable monthly payments. Unlike fully-insured plans where premiums are fixed, level-funded plans' monthly payments can be adjusted downward based on the actual claims experience—if claims are lower than expected, the employer may receive a refund or credit. Additionally, level-funded plans, similar to other self-insured plans, have the flexibility to unbundle, organize, and negotiate services separately, and thus are less likely to suffer the disadvantages of fully-insured plans, such as bloated costs.

3. Flexible Benefit Design

Like all self-insured plans, level-funded plans enjoy the flexibility in plan design, such as vendor selection (including using independent plan administrators), concierge navigation to preferred sites of care, and waiving cost-sharing for beneficiaries who seek care from high-quality clinicians and facilities. Level-funded plans can also use independent pharmacy solutions to reduce their members’ prescription drug costs and include direct primary care, a comprehensive, value-based delivery model that focuses on prevention and overall health. The flexibility in plan design allows level-funded plans to adopt ever-evolving, innovative features that can save money, improve quality of care, and align the interests among providers, patients, and employers.

These advantages make innovative benefit design and affordable coverage more accessible to smaller employers and employers with small profit margins when offered through a level-funded structure. In 2020, 47.2 percent of small businesses offered health coverage to their employees. Today, just 31 percent do so. Rising health costs are one reason, and the primary cause of the small group market decline. Level-funded plans are one solution to help reverse this trend by making coverage more affordable for small employers.

Urgent Clarifications

Some elements of the Biden Administration’s RFI suggested that it may have been drafted by officials who lack a precise understanding of level-funded plans. Such confusion is common among policy makers and the public.

With the intention of making the RFI as productive and useful as possible, we offer clarifications as follows.

1. Service Coverage And Consumer Protection

The RFI mentions concerns from “interested parties” about whether stop loss policies on level-funded plans have the same benefits and consumer protections as those described in the plan document given to workers to explain the benefit. They believe there is a risk of inconsistency between what the coverage is, and what is described to workers, and that this risk may be greater for smaller level-funded plans.

As a fundamental element of due diligence for all self-insured plans, the stop loss coverage should mirror the plan document. In fact, there is neither a legal difference in the required diligence nor an empirical difference in the likelihood of failure in diligence between level-funded plans and other self-insured plans. Beneficiaries in all self-insured plans have the same rights and can equally seek recourse under existing law if the plan trustees violate their fiduciary obligations in this regard. Furthermore, no evidence suggests that smaller groups are less competent in understanding the Employee Retirement Income Security Act of 1974 (ERISA) or less informed about their fiduciary obligation to ensure that the policies match.

2. Multiple-Employer Welfare Arrangements

The RFI also discusses whether level-funded plans are potentially un-declared multi-employer welfare arrangements (MEWAs) -- a grouping of similarly situated employers who buy coverage together. 

But level funded plans are not MEWAs. In fact, level funded arrangements segregate the funds and the risk of each group in their book of business to avoid becoming a MEWA. Specifically, each group is underwritten and rated on the basis of its own risk -- and receives its own stop loss policy on that basis. These clear safeguards protect level-funded plans from running afoul of MEWA rules, which the government has been robustly enforcing.

3. Self-Selection Of Low-Risk Groups

Another concern expressed in the RFI is whether level-funded plans are primarily attractive to low-risk small groups, thus pulling them away from the fully-insured small group market. It is important to note that, compared with the self-insured market, the fully-insured market is more profitable for insurance carriers. It also suffers from more severe misalignments of interest between carriers and employers, resulting in greater price growth. No one should expect employers to forgo more attractive insurance options – including self-insured plans, such as level-funded plans -- for the sake of improving fully-insured plans’ risk pool . In fact, employers owe a fiduciary duty to their workers and shareholders to seek the best possible insurance plan at the lowest price.

As more and more employers are priced out of the fully-insured market and look for more affordable options, level-funded plans are proliferating to meet this need, creating a dynamic insurance market that would save money for small employers while benefitting taxpayers and the economy. Even so, it should be noted that this direction conflicts with the interests of some stakeholders that might otherwise benefit from expanding one-size-fits-some models that limit choice.

Focus On Fostering Level-Funded Plans To Create Value For Employers And Workers

The self-insured market is the primary source of health insurance innovation, quality improvements, and savings creation for patients and employers and other plan sponsors. Level-funded plans reduce risk and streamline administration by offering a fixed monthly price that covers the cost of administration and stop-loss, and fully funds the claims risk for the year. Employers have flexibility to design their plans, and they can shop for the best deals based on attachment points that make sense to them. These features are especially important for small employers, who face tough market conditions, and often cannot compete with larger firms that provide a range of benefits to attract and retain talent. Many employers have deployed the flexible structure and attractive features of level-funded plans, thus creating value for themselves, their workers and families, and taxpayers.

However, some states have started limiting small employers’ ability to offer self-insured plans. While states lack jurisdiction over self-insured plans directly (which fall under ERISA and outside of state law in most circumstances), some states have effectively eliminated small employer access by banning the sale of level-funded plans to certain size groups or making the sale of low attachment point plans illegal. This has been done or attempted, for example, in New Jersey, Nevada, New York, and Texas among other states. A common refrain from some lawmakers and regulators is that, while consumers want choices, they are incapable of understanding different plans. However, there is no evidence to suggest smaller groups are less competent in understanding plan options. We believe there are other more well-established challenges that the federal government should focus on addressing.

In 2022, 103 million individuals received health coverage through a self-insured health plan. That is an enormous population that could benefit if policy makers make the most of level-funded plans, by allowing innovative options to compete freely with existing options.

To that end, Congress should protect access to level-funded plans and reinsurance (including low attachment point reinsurance) policies by ensuring they remain available for sale and purchase in all states. This would involve clarifying ERISA preemption with respect to self-insured arrangements for small businesses. The Self Insurance Protection Act would do exactly that, preempting state laws that prohibit group health plans from obtaining stop-loss policies. The legislation passed the House on June 22, 2023 as part of a broader small business health package (H.R. 3799). The Senate should act now to pass the legislation and send it to President Biden for his signature.

Most self-insured plans, including level-funded plans, are administered by large insurance conglomerates that are known to have undisclosed conflicts of interest and hidden compensation streams from stop-loss carriers, pharmacy benefit managers, and even navigation vendors that negatively impact employers and workers through higher premiums and out-of-pocket costs. Even when new regulations, such as the Transparency in Coverage Rule, introduce sunlight to a market, many incumbent players find ways to remain in the shadows: So far the quality of data disclosure and the absence of attestation from insurance companies have thwarted both the letter and spirit of the rule.

One antidote to such efforts aimed at stymieing change: Protect the power of new market entrants to bring the kind of competitive pressure that inspires both new and old entities to innovate, create value, and improve consumers’ experience. When it comes to level-funded plans, federal policy makers should be focused on transparency and education, not restricting choices, especially for more affordable options.

https://www.healthaffairs.org/content/forefront/its-misunderstanding-level-funded-health-insurance-plans-administration-missing

Novavax Dives As Pfizer, Moderna Snag First Nods For Covid Boosters

Novavax (NVAX) stock crumbled Monday after the Food and Drug Administration signed off on updated Covid boosters from rivals Pfizer (PFE) and Moderna (MRNA).

The news comes as Novavax plans to present its vaccine data before a panel of advisors to the Centers for Disease Control and Prevention on Tuesday. This gives Pfizer and Moderna a slight lead with their messenger RNA shots compared with the protein-based technology used by Novavax.

"Novavax is currently responding to the FDA's requests to facilitate final review, and timing is ultimately at the discretion of the FDA," the company said in a news release. Novavax is aiming to vaccinate people age 12 and older in the U.S.

https://www.investors.com/news/technology/novavax-stock-dives-as-pfizer-moderna-win-first-fda-ok-for-covid-boosters/