What predisposes individuals to Alzheimer's disease

 Mount Sinai researchers have achieved an unprecedented understanding of the genetic and molecular machinery in human microglia—immune cells that reside in the brain—that could provide valuable insights into how they contribute to the development and progression of Alzheimer's disease (AD). The team's findings were published in Nature Genetics.

Working with fresh human brain tissue harvested via biopsy or autopsy from 150 donors, researchers identified 21 candidate risk genes and highlighted one, SPI1, as a potential key regulator of microglia and AD risk.

"Our study is the largest human fresh-tissue microglia analysis to date of genetic risk factors that might predispose someone to Alzheimer's disease," says senior author Panos Roussos, MD, Ph.D., Professor of Psychiatry, and Genetic and Genomic Sciences, at the Icahn School of Medicine at Mount Sinai and Director of the Center for Disease Neurogenomics. "By better understanding the molecular and genetic mechanisms involved in microglia function, we're in a much better position to unravel the regulatory landscape that controls that function and contributes to AD. That knowledge could, in turn, pave the way for novel therapeutic interventions for a disease that currently has no effective treatments."

Microglia are primarily responsible for the immune response in the brain, and are also critical to the development and maintenance of neurons. While previous studies, including some at Mount Sinai, have identified microglia as playing a key role in the genetic risk and development of Alzheimer's disease, little is known about the epigenetic mechanics of how that occurs. Because microglia are challenging to isolate within the human brain, most previous studies have used either animal- or cell-line-based models which do not reflect the true complexity of microglia function in the brain. Another challenge has been relating AD genetic risk variation to specific molecular function because these risk factors are frequently found in the non-coding part of the genome (what used to be called "junk DNA"), which is more difficult to study.

The Mount Sinai team's solution was to access fresh brain tissue from biopsies or autopsies made possible by a collaboration between four brain bio-depositories, three at Mount Sinai and the other from Rush University Medical Center/Rush Alzheimer's Disease Center. "Using a total of 150 samples from these sources, we were able to isolate high-quality microglia, which provided unprecedented insights into genetic regulation by reflecting the entire set of regulatory components of microglia in both healthy and neurodegenerative patients," explains Dr. Roussos.

That process—comparing epigenetic, gene expression, and genetic information from the samples of both AD and healthy aged patients—allowed researchers to comprehensively describe how microglia functions are genetically regulated in humans. As part of their statistical analysis, they expanded the findings of prior genome-wide association studies to link identified AD-predisposing genetic variants to specific DNA regulatory sequences and genes whose dysregulation is known to directly contribute to the development of the disease. They further described the cell-wide regulatory mechanisms as a way of identifying genetic regions involved in specific aspects of the microglial activity.

From their investigation emerged new knowledge about the SPI1 gene, already known to scientists, as the main microglial transcription factor regulating a network of other transcription factors and genes that are genetically linked to AD. Data the team is generating could also be important to deciphering the molecular and genetic mysteries behind other neurodegenerative diseases in which microglia play a role, including Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis.

Dr. Roussos concedes that much work remains for his team to fully understand how the identified genes contribute to the development and progression of Alzheimer's disease, and how they could be targeted with new therapeutics. He is greatly encouraged, though, by the results of single-cell analysis by his lab of microglia using highly sophisticated instruments that are uncovering the unique interactions between different types of immune cells in the brain and its periphery that are related to neurodegenerative disease. "We're seeing very exciting results through our single-cell data," Dr. Roussos reports, "and that's bringing us ever closer to understanding the genetically driven variations and cell-specific interactions of inheritable diseases like Alzheimer's."

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Explore further

Can a human microglial atlas guide brain disorder research?

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More information: Roman Kosoy et al, Genetics of the human microglia regulome refines Alzheimer's disease risk loci, Nature Genetics (2022). DOI: 10.1038/s41588-022-01149-1

https://medicalxpress.com/news/2022-08-team-gains-insights-genetic-molecular.html

Extending the shelf life of vaccines

 Nearly half of all vaccines go to waste. This is due to the logistical obstacles involved in transporting them to diverse regions of the world. Most vaccines require strict temperature regulation from the manufacturing line to injection into a human arm. Maintaining a constant temperature along the cold (supply) chain is a challenging feat in the best of circumstances. In sub-Saharan Africa and other developing regions, for example, limited transport infrastructure and unreliable electricity compounds the already immense challenges of delivering viable vaccines.

Rising to the challenge, scientists from ETH Zurich's Macromolecular Engineering and Organic Chemistry Labs and entrepreneurs from Colorado-based Nanoly Bioscience worked together to develop a safe, versatile platform to increase the thermal stability of vaccines. Their aim? To vastly improve the distribution of viable vaccines and reduce the economic costs of the cold chain.

Like Tupperware for proteins

"Think of it like an egg," explains Bruno Marco-Dufort, a doctoral researcher in Professor Mark Tibbitt's Macromolecular Engineering lab. "At room temperature or in the refrigerator the egg maintains its viscous-like protein structure, but once it hits boiling water or the frying pan its structure changes permanently." It is similar for the proteins in a vaccine—once exposed to certain temperatures they clump together. Cooling them down again will not reverse their denaturation—you cannot "un-cook" the egg.

So rather than altering mother nature, Marco-Dufort and the research team developed a new type of hydrogel, the details of which were just published in the journal Science Advances. The gel is based on a biocompatible, synthetic polymer known as PEG that serves as a protective cloaking device for very large—yet invisible to the naked eye—complex molecules such as the proteins found in vaccines, antibodies, or gene therapies. The packaging works kind of like a molecular Tupperware, encapsulating the proteins and keeping them separated. It enables the proteins to withstand a higher range of temperature fluctuations. Instead of the traditional +2 to +8 degrees Celsius (35 to 45 degrees Fahrenheit) range for the cold chain, encapsulation allows for a range of 25 to 65 degrees Celsius (75 to 150 degrees Fahrenheit). Most importantly, the encapsulated cargo is simply released by adding a sugar solution, enabling easy on-demand recovery of the vaccines at their point of use.

Usage in cancer research

In addition to a higher rate of vaccine viability, the real game changer of this new biomedical hydrogel technology is the potential economic effect it could have on reducing costs and health risks associated with the cold chain. "In 2020, the overall market for cold chain services (from manufacturing to distribution) was $17.2 billion and forecasted to rise," the researchers reported. Rising costs pose potentially dire consequences for public health and public trust if vaccines arrive via a compromised cold chain.

"Most vaccines are sensitive to hot and cold. This creates a large barrier for global immunization campaigns, because vaccine distribution and administrative costs often exceed the costs of production," explains Marco-Dufort. While more investment will be needed to shore up the cold chain, encapsulation offers a cost saving solution that could be put towards production of more vaccines and thus, save more lives.

Yet, there is still a long way to go in terms of further research, safety studies, and clinical trials before the hydrogels can be implemented for vaccine distribution. Their more immediate use is for transporting heat sensitive enzymes used in cancer research, for example, or protein molecules for research in lab settings.

One step towards solving a global issue

While new biotechnologies and cost savings are a step in the right direction, there are still tremendous logistical, political, and socio-economic challenges in resolving the global issues surrounding equitable vaccine distribution and vaccine hesitancy. Marco-Dufort's motivation is undeterred. His childhood experience living in the Democratic Republic of the Congo instilled a deep appreciation for the need for vaccines against infectious diseases, not just for COVID-19, but also for Polio, Meningitis, and Ebola. He, more than most, is aware of the tremendous challenges people living in sub-Saharan Africa face in terms of access to vaccines where infectious diseases are still prevalent.

Mark Tibbitt, Bruno Marco-Dufort, and the team's work represent a substantive advancement in vaccine excipient development. Their work also offers a glimmer of hope for a positive societal impact. Even a small relief of the economic factors associated with the distribution of vaccines, medicines, and biomedical research could result in larger impacts down the road.

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Explore further

High temperatures, remote islands pose challenges for Asian jab distributor

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More information: Bruno Marco-Dufort et al, Thermal stabilization of diverse biologics using reversible hydrogels, Science Advances (2022). DOI: 10.1126/sciadv.abo0502. www.science.org/doi/10.1126/sciadv.abo0502

https://medicalxpress.com/news/2022-08-shelf-life-vaccines.html

New at-home, saliva-based COVID test as effective as PCR in preliminary analysis

 PCR tests, also called molecular tests or nucleic acid tests, are considered the gold standard in detecting the presence of SARS-CoV-2, the virus that gives rise to COVID-19. However, they can take a few days to process, resulting in unnecessary quarantine for negative individuals or delays for those who require proof of negative testing for travel or other commitments. Rapid antigen-detecting tests, on the other hand, are convenient, but less reliable than PCR tests. 

To bridge the gap between accuracy and convenience, Penn State researchers have developed an at-home, saliva-based testing platform that can provide results in 45 minutes. In preliminary tests, the platform detected the COVID-causing virus with the same level of sensitivity as PCR tests. Their results published this week (Aug. 3) in ACS Sensors. 

“PCR test results take about an hour to develop in a lab, but you have to factor in the time it takes to send the sample to a lab and for the lab to process it,” said principal investigator Weihua Guan, associate professor of electrical engineering and of biomedical engineering in Penn State’s College of Engineering. “We wanted to create a viable alternative to the PCR for people to use at home, without having to endure the invasive nasal test.”

Guan and his team developed a palm-sized testing kit, where an individual spits into a cartridge and inserts it into processing platform. Within 45 minutes, test results are sent to a custom android app developed by the researchers.

The platform uses reverse transcription loop-mediated isothermal amplification, or RT-LAMP, to detect the virus. The testing device first heats the saliva to 203 degrees Fahrenheit, the temperature at which viral particle shells break apart and release their genetic material. The genetic material is then mixed with pre-packaged reagents in a microfluidic cartridge. Finally, the sample is cooled to 149 degrees Fahrenheit, triggering another chemical reaction in which a few viral molecules are multiplied into billions of copies, making the virus easier to identify. If the virus is present in the saliva sample, the user will receive a positive result on their connected smartphone app.

To test the setup, Guan and his team infused human saliva samples purchased commercially with inactivated SARS-CoV-2 virus particles and ran the samples through the prototype. They also tested a couple of clinical specimens. The platform accurately determined whether every sample was positive or negative for the virus.

“We tested hundreds of mock samples and controlled the quantity of COVID particles in each one,” Guan said. “Our platform proved to be highly sensitive to the presence of the virus in both the mock and clinical samples, with the standards set by the PCR test as our benchmark.”

The researchers said they plan to continue testing their platform with more clinical COVID samples through a collaboration with Yusheng Zhu, medical director of the Clinical Chemistry and Automated Testing Laboratory at the Penn State Milton S. Hershey Medical Center. 

In addition to more clinical testing, the researchers also are working to improve the test’s short shelf life, as the enzymes in the prototype degrade at room temperature within three days of production. The team is experimenting with reagent lyophilization, a method of freeze-drying biological material that can extend enzyme shelf life. According to Guan, preliminary results indicate the method will allow the RT-LAMP test to last at least six months at room temperature in stores or in the medicine cabinet at home.

The researchers filed a provisional patent application on their device and said they plan to commercialize it, pending scaled-up clinical testing and review by the U.S. Food and Drug Administration.

Suresh V. Kuchipudi, interim director of Penn State’s Animal Diagnostic Laboratory (ADL) and Dorothy Foehr Huck and J. Lloyd Huck Chair in Emerging Infectious Diseases, and Michele Yon, research technologist with ADL, acquired the clinical samples tested in this work. Other contributors include Zifan Tang, Aneesh Kshirsagar and Tianyi Liu, all Penn State doctoral students in electrical engineering, and Jiarui Cui, a Penn State undergraduate student in electrical engineering.  

The National Institutes of Health, the National Science Foundation and the Penn State Coronavirus Research Seed Fund supported this work. 

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JOURNAL

ACS Sensors

DOI

10.1021/acssensors.2c01023 

https://www.eurekalert.org/news-releases/961103

New low-calorie sweetener could also improve gut health

 From the wide variety of sodas, candies and baked goods that are sold worldwide, it's clear that people love their sweet treats. But consuming too much white table sugar or artificial sweetener can lead to health issues. In the search for a better sweetener, researchers in ACS' Journal of Agricultural and Food Chemistry now report a low-calorie mixture that is as sweet as table sugar and, in lab experiments, feeds "good" gut microbes.

Artificial sweeteners have exploded in popularity because they let people consume sweets without the calories. However, while they're considered safe for human consumption, studies in animals and humans suggest that some of them can stimulate appetite, leading to increased food consumption and weight gain, as well as other negative health outcomes. So, researchers have been turning to the study of low-calorie or extremely sweet substances from natural sources as possible replacements. For example, galactooligosaccharides -- found in mammalian milk -- are low-calorie sugars with prebiotic activity that can be a source of energy for beneficial gut microbes, but they're not quite sweet enough to replace table sugar. Alternatively, extracts from the luo han guo fruit contain mogrosides -- compounds 200 to 300 times sweeter than table sugar. But these extracts sometimes have off-flavors, which can be removed with enzymes. So, F. Javier Moreno and colleagues wanted to take advantage of the best aspects of both natural substances, using enzymes to modify mogrosides while simultaneously producing galactooligosaccharides for a brand-new low-calorie sweetener.

The researchers started with lactose and mogroside V (the primary mogrosidein luo han guo fruit). When they added β-galactosidase enzymes, the researchers obtained a mixture that contained mostly galactooligosaccharides and a small amount of modified mogrosides. A trained sensory panel reported that the new combination had a sweetness similar to that of sucrose (table sugar), suggesting it could be acceptable to consumers. In test tube experiments, the new sweetener increased the levels of multiple human gut microbes that are beneficial, including Bifidobacterium and Lactobacillus bacterial species. In addition, increases in bacteria-produced metabolites, such as acetate, propionate and butyrate, indicated that the mixture could potentially have a prebiotic effect on the gut microbiome. The researchers say that the new sweetener holds promise in these initial analyses, and their next step is to more closely study the substance's impact on human gut health.

The authors acknowledge funding from Optibiotix Health Plc (York, U.K.), the Spanish Ministry of Science, Innovation and Universities, and the European Union's Horizon 2020 research and innovation program. One of the study's authors is employed by Optibiotix Health Plc.

Story Source:

Materials provided by American Chemical Society. Note: Content may be edited for style and length.

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Journal Reference:

1. Ana Muñoz-Labrador, Rosa Lebrón-Aguilar, Jesús E. Quintanilla-López, Plácido Galindo-Iranzo, Silvana M. Azcarate, Sofia Kolida, Vasiliki Kachrimanidou, Virginia Garcia-Cañas, Lisa Methven, Robert A. Rastall, F. Javier Moreno, Oswaldo Hernandez-Hernandez. Prebiotic Potential of a New Sweetener Based on Galactooligosaccharides and Modified Mogrosides. Journal of Agricultural and Food Chemistry, 2022; 70 (29): 9048 DOI: 10.1021/acs.jafc.2c01363

https://www.sciencedaily.com/releases/2022/08/220804130631.htm

Mitochondrial DNA mutations linked to heart disease risk

 Mitochondria are organelles found within most cells, best known for generating the chemical energy required to power cellular functions. Increasingly, however, researchers are discovering how mitochondrial function -- and dysfunction -- play critical roles in numerous diseases, and even aging.

In a new study published in the August 4, 2022 online issue of Immunity, scientists at University of California San Diego School of Medicine and Salk Institute for Biological Studies report a surprising link between mitochondria, inflammation and DNMT3A and TET2, a pair of genes that normally help regulate blood cell growth, but when mutated, are associated with an increased risk of atherosclerosis.

"We found that the genes DNMT3A and TET2, in addition to their normal job of altering chemical tags to regulate DNA, directly activate expression of a gene involved in mitochondrial inflammatory pathways, which hints as a new molecular target for atherosclerosis therapeutics," said Gerald Shadel, PhD, co-senior study author and director of the San Diego Nathan Shock Center of Excellence in the Basic Biology of Aging at Salk Institute. "They also interact with mitochondrial inflammatory pathways, which hints at a new molecular target for atherosclerosis therapeutics."

While studying the roles of DNMT3A and TET2 mutations in clonal hematopoiesis, which happens when stem cells begin making new blood cells with the same genetic mutation, co-senior study author Christopher Glass, MD, PhD, professor in the departments of Medicine and Cellular and Molecular Medicine at UC San Diego School of Medicine, and colleagues noted that abnormal inflammatory signaling related to DNMT3A and TET2 deficiency in blood cells played a major role in the inflammation response that promotes development of atherosclerosis.

But the question remained how DNMT3A and TET2 genes were involved in inflammation and atherosclerosis -- the buildup of fatty plaques in arteries and the primary underlying cause of cardiovascular disease. It is estimated approximately half of Americans between the ages of 45 and 84 have atherosclerosis, which is the single leading cause of death in the United States and westernized nations.

"The problem was we couldn't work out how DNMT3A and TET2 were involved because the proteins they code seemingly do opposite things regarding DNA regulation," said Glass. "Their antagonistic activity led us to believe there may be other mechanisms at play, which prompted us to take a different approach and contact Shadel, who had uncovered the same inflammatory pathway years earlier while examining responses to mitochondrial DNA stress."

What they found

Inside mitochondria resides a unique subset of the cell's DNA that must be organized and condensed correctly to sustain normal function. Shadel's team had previously investigated the effects of mitochondrial DNA stress by removing TFAM, a gene that helps ensure mitochondrial DNA is packaged correctly.

Shadel and colleagues determined that when TFAM levels are reduced, mitochondrial DNA is expelled from mitochondria into the cell's interior, setting off the same molecular alarms that alert cells to a bacterial or viral invader and trigger a defensive molecular pathway that prompts an inflammatory response.

Glass' and Shadel's labs worked together to better understand why DNMT3A and TET2 mutations led to inflammatory responses similar to those observed during mitochondrial DNA stress. The teams applied genetic engineering tools and cell imaging to examine cells from people with normal cells, those with loss of function mutations in DNMT3A or TET2 expression and those with atherosclerosis.

They discovered that experimentally reducing the expression of DNMT3A or TET2 in normal blood cells produced similar results to blood cells that had loss of function mutations and to blood cells from atherosclerosis patients. In all three cases, there was an increased inflammatory response.

They also observed that low levels of DNMT3A and TET2 expression in blood cells led to reduced TFAM expression, which in turn led to abnormal mitochondria DNA packaging, instigating inflammation due to released mitochondrial DNA.

"We discovered that DNMT3A and TET2 mutations prevent their ability to bind and activate the TFAM gene," said first author Isidoro Cobo, PhD, a postdoctoral scholar in Glass' lab. "Missing or reducing this binding activity leads to mitochondrial DNA release and an overactive mitochondrial inflammation response. We believe this may exacerbate plaque buildup in atherosclerosis."

Shadel said the findings broaden and deepen understanding of mitochondrial function and their role in disease.

"It's very exciting to see our discovery on TFAM depletion causing mitochondrial DNA stress and inflammation now have direct relevance for a disease like atherosclerosis," said Shadel. "Ever since we revealed this pathway, there has been an explosion of interest in mitochondria being involved in inflammation and many reports linking mitochondrial DNA release to other clinical contexts."

Therapeutics that target inflammation signaling pathways already exist for many other diseases. Glass and Shadel believe that blocking pathways that exacerbate atherosclerosis in patients with TET2A and DNMT3A mutations could form the basis for new treatments.

Co-authors include: Tiffany N. Tanaka, Addison Lana, Calvin Yeang, Claudia Han, Johannes Schlachetki, Jean Challcombe, Bthany R. Fixen, Rick Z. Li, Hannah Fields, Randy G. Tsai and Rafael Behar, all at UC San Diego; Kailash Chandra Mangalhara, Salk; Mashito Sakai, UC San Diego and Nippon Medical School, Japan; Michael Mokry, Wilhelmina Children's Hospital, the Netherlands; and Koen Prange and Menno Winther, University of Amsterdam, the Netherlands.

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Story Source:

Materials provided by University of California - San Diego. Original written by Scott LaFee. Note: Content may be edited for style and length.

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Journal Reference:

1. Isidoro Cobo, Tiffany N. Tanaka, Kailash Chandra Mangalhara, Addison Lana, Calvin Yeang, Claudia Han, Johannes Schlachetzki, Jean Challcombe, Bethany R. Fixsen, Mashito Sakai, Rick Z. Li, Hannah Fields, Michal Mokry, Randy G. Tsai, Rafael Bejar, Koen Prange, Menno de Winther, Gerald S. Shadel, Christopher K. Glass. DNA methyltransferase 3 alpha and TET methylcytosine dioxygenase 2 restrain mitochondrial DNA-mediated interferon signaling in macrophages. Immunity, 2022; DOI: 10.1016/j.immuni.2022.06.022

https://www.sciencedaily.com/releases/2022/08/220804161241.htm

B vitamins can potentially be used to treat advanced non-alcoholic fatty liver disease

 Scientists at Duke-NUS Medical School in Singapore have uncovered a mechanism that leads to an advanced form of fatty liver disease -- and it turns out that vitamin B12 and folic acid supplements could reverse this process.

These findings could help people with non-alcoholic fatty liver disease, an umbrella term for a range of liver conditions affecting people who drink little to no alcohol, which affects 25 per cent of all adults globally, and four in 10 adults in Singapore.

Non-alcoholic fatty liver disease involves fat build-up in the liver and is a leading cause of liver transplants worldwide. Its high prevalence is due to its association with diabetes and obesity -- two major public health problems in Singapore and other industrialised countries. When the condition progresses to inflammation and scar tissue formation, it is known as non-alcoholic steatohepatitis (NASH).

"While fat deposition in the liver is reversible in its early stages, its progression to NASH causes liver dysfunction, cirrhosis and increases the risk for liver cancer," said Dr Madhulika Tripathi, first author of the study, who is a senior research fellow with the Laboratory of Hormonal Regulation at Duke-NUS' Cardiovascular & Metabolic Programme.

Currently, there are no pharmacological treatments for NASH because scientists don't understand the mechanics of the disease. Although scientists know that NASH is associated with elevated blood levels of an amino acid called homocysteine, they didn't know what role, if any, it plays in the development of the disorder.

Dr Tripathi, study co-author Dr Brijesh Singh and their colleagues in Singapore, India, China and the US confirmed the association of homocysteine with NASH progression in preclinical models and humans. They also found that, as homocysteine levels increased in the liver, the amino acid attached to various liver proteins, changing their structure and impeding their functioning. In particular, when homocysteine attached to a protein called syntaxin 17, it blocked the protein from performing its role of transporting and digesting fat (known as autophagy, an essential cellular process by which cells remove malformed proteins or damaged organelles) in fatty acid metabolism, mitochondrial turnover, and inflammation prevention. This induced the development and progression of fatty liver disease to NASH.

Importantly, the researchers found that supplementing the diet in the preclinical models with vitamin B12 and folic acid increased the levels of syntaxin 17 in the liver and restored its role in autophagy. It also slowed NASH progression and reversed liver inflammation and fibrosis.

"Our findings are both exciting and important because they suggest that a relatively inexpensive therapy, vitamin B12 and folic acid, could be used to prevent and/or delay the progression of NASH," said Dr Singh. "Additionally, serum and hepatic homocysteine levels could serve as a biomarker for NASH severity."

Homocysteine may similarly affect other liver proteins, and finding out what they are is a future research direction for the team. They hope that further research will lead to the development of anti-NASH therapies.

Professor Paul M. Yen, Head of the Laboratory of Hormonal Regulation at Duke-NUS' Cardiovascular & Metabolic Disorders Programme, and senior author of the study, said, "The potential for using vitamin B12 and folate, which have high safety profiles and are designated as dietary supplements by the US Food and Drug Administration, as first-line therapies for the prevention and treatment of NASH could result in tremendous cost savings and reduce the health burden from NASH in both developed and developing countries."

Professor Patrick Casey, Senior Vice-Dean for Research at Duke-NUS, said, "Currently, the only treatment for patients with end-stage liver disease is to receive a transplant. The findings by Dr Tripathi and her colleagues demonstrate that a simple, affordable and accessible intervention could potentially halt or reverse the damage to the liver, bringing new hope to those suffering from fatty liver diseases. The team's findings underscore the value of basic scientific research, through which the scientific community continues to have a major positive impact on the lives of patients."

The research was published in the Journal of Hepatology.

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Story Source:

Materials provided by Duke-NUS Medical School. Note: Content may be edited for style and length.

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Journal Reference:

1. Madhulika Tripathi, Brijesh Kumar Singh, Jin Zhou, Keziah Tikno, Anissa Widjaja, Reddemma Sandireddy, Kabilesh Arul, Siti Aishah Binte Abdul Ghani, George Goh Boon Bee, Kiraely Adam Wong, Ho Jia Pei, Shamini Guna Shekeran, Rohit Anthony Sinha, Manvendra K. Singh, Stuart Alexander Cook, Ayako Suzuki, Teegan Reina Lim, Chang-Chuen Cheah, Jue Wang, Rui-Ping Xiao, Xiuqing Zhang, Pierce Kah Hoe Chow, Paul Michael Yen. Vitamin B12 and folate decrease inflammation and fibrosis in NASH by preventing Syntaxin 17 homocysteinylation. Journal of Hepatology, 2022; DOI: 10.1016/j.jhep.2022.06.033

https://www.sciencedaily.com/releases/2022/08/220805091251.htm

To Really Build Back Better, Put Patients First

 Lawmakers just unveiled their latest plan to bring down drug costs – they're calling it the Inflation Reduction Act.

The proposal is stitched together from the remains of Build Back Better, the stalled cornerstone of President Biden's domestic policy agenda, which Senate Democrats are fighting to get back on track.

It's good that lawmakers are continuing to push for drug pricing reform. After all, one in four prescription-drug takers in the United States say it's difficult to afford their medications. Among those with serious or chronic health conditions – which impact over half of U.S. adults and a disproportionate number of Medicare beneficiaries – affordability is an even greater concern. 

The proposed legislation does not address some of the fundamental problems of how drug prices are currently set. The focus on drug prices provides an opportunity for a broader policy debate over the role of middlemen in the system and where rebates go. Unfortunately, this legislation ignores the broader policy challenges facing the price setting process and relies on “negotiations” between HHS and drug manufacturers. This approach leaves intact a system that needs broader structural reforms. 

It may come as a surprise to some, but drug companies don't have the power to set prices for their products unilaterally. In order to get their drugs covered by insurance plans, pharmaceutical firms must work with insurers to negotiate prices both parties deem fair. Insurers frequently employ intermediaries known as pharmacy benefit managers, or PBMs, to manage these negotiations.

The current drug pricing system is complicated and includes incentives to increase list drug prices each year. Higher list prices yield more rebate dollars for PBMs.

The resulting discounts and rebates provided by drug companies are substantial – last year, their total value was $204 billion. PBMs pass most of these discounts to insurance companies, which in turn are able to set lower monthly premiums.

These lower premiums are great, but Medicare patients would benefit significantly more if they could simply receive those rebates themselves, in the form of lower copay and coinsurance fees for their medicines. According to data from the Department of Health and Human Services, if the law required patients to receive these discounts directly, Medicare drug-coverage enrollees would save more than $83 billion on their prescriptions over the next decade.

In fact, the so-called rebate rule, which was scheduled to take effect in 2027, would do just that, requiring PBMs and insurers to pass along discounts to patients through lower copays and coinsurance.

But unfortunately, the new legislation would further delay the implementation of the rebate rule. 

That would hurt America's most vulnerable patients: those living with chronic illness. Patients with a chronic health condition already spend five times more on health care than others. Passing rebates directly to them would significantly lessen their burden. For example, sharing rebates with people with diabetes would save the average patient close to $800 per year. 

Regrettably, there are other problems with the Inflation Reduction Act.

It would scrap the proposed $35 monthly cap on the out-of-pocket cost of insulin – a broadly popular and bipartisan idea that, like the rebate rule, would help the more than 35 million Americans living with diabetes and is a better approach for patients than what is proposed in the reconciliation bill. It would also allow premiums for Medicare drug-coverage enrollees to increase by 6% annually, rather than the 4% proposed in earlier versions of the legislation.

Meanwhile, the bill would do nothing to reduce coinsurance costs – the percentage of drug costs patients have to pay out of pocket after they meet their deductible. In most cases, coinsurance rates under Medicare are 25% of a prescription's list price.

Together, these omissions mean that millions of American patients – especially seniors and people with chronic diseases – will continue to contend with unnecessarily high drug costs. That could spur many to forgo needed treatments altogether, a phenomenon known as medication nonadherence, which results in around 125,000 deaths each year. 

There are some bright spots in the proposal, like the three-year extension of the expanded subsidies in the ACA. Failure to extend these subsidies would increase the number of uninsured making health care more expensive for patients. But on balance, the plan fails to meet the needs of the very patients it's supposed to help. 

Americans deserve better. As lawmakers revise the bill into its final form, they still have time to deliver.

Kenneth Thorpe is a professor of health policy at Emory University in Atlanta and chairman of the Partnership to Fight Chronic Disease.

https://www.realclearhealth.com/articles/2022/08/05/to_really_build_back_better_put_patients_first_111386.html