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A health-care worker prepares to administer a free monkeypox vaccine in Wilton Manors, Florida. The question: Can vaccination slow the outbreak? Joe Raedle/Getty Images hide caption

A health-care worker prepares to administer a free monkeypox vaccine in Wilton Manors, Florida. The question: Can vaccination slow the outbreak?

Finally, we have a glimmer of good news about monkeypox: The outbreaks in some countries, including the U.K., Germany and parts of Canada, are starting to slow down.

On top of that, the outbreak in New York City may also be peaking and on the decline, according to new data from the city's health department.

All these outbreaks are "far from extinguished," says infectious disease specialist Dr. Donald Vinh at McGill University in Montreal. But there are signs that, in some places, "they're a bit more under control than they had been."

For example, in the U.K., the number of new cases reported each day has steadily declined since late July, dropping from 50 daily cases to only about 25. (By contrast, here in the U.S., daily cases are still increasing. Since late July, the U.S. daily count has risen from 350 new cases to 450 cases.)

Some health officials credit the monkeypox vaccine and its quick rollout as the key factor that's slowing the spread of the virus in the U.K..

"Over 25,000 have been vaccinated with the smallpox vaccine, as part of the strategy to contain the monkeypox outbreak in the UK.," the U.K. Health Security Agency wrote on Twitter on Tuesday. "These 1000s of vaccines, given by the NHS to those at highest risk of exposure, should have a significant impact on the transmission of the virus."

Indeed, the U.K. and parts of Canada rolled out the vaccine in late May, weeks before doses became available in most U.S. cities.

But does the monkeypox vaccine have the ability to stop or curb the spread of the virus? To answer that question, we need to first understand a few basics about this vaccine.

What actually is the monkeypox vaccine? How does it work?

So the monkeypox vaccine is actually the smallpox vaccine. Maybe that sounds a bit strange, but in fact the two pox viruses are related. They're a bit like cousins.

Health-care workers used an earlier version of this vaccine to eradicate smallpox in the 1970s. So versions of this vaccine have been given to hundreds of millions of people over the past century. It has a long track record.

Back in the late 1980s, researchers started to notice something remarkable about this vaccine. During a monkeypox outbreak in the Democratic Republic of the Congo (then called Zaire), people who were immunized against smallpox were less likely to get monkeypox. They were protected. And not by just a little but by quite a bit. In a small study, published in 1988, researchers estimated the smallpox vaccine offered about 85% protection against monkeypox.

Now, the virus in this study was a different variant of monkeypox than the one circulating in the current international outbreak and that variant wasn't spreading primarily through sexual contact, as monkeypox is doing today. So we don't know how well these findings will translate to protection during the current outbreak. Which brings us to the next question.

How well does the vaccine protect against a monkeypox infection?

The short answer is: "We don't know," says infectious disease specialist Dr. Boghuma Titanji at Emory University.

There's no doubt the vaccine will offer some protection, Titanji says. "But right now, we still need studies in people to understand what level that protection actually is."

In North America and Europe, countries are primarily rolling out a vaccine called JYNNEOS, which was developed in the early 21st century. The goal with this vaccine is to increase its safety compared to the older vaccine, whose life-threatening complications, including encephalitis and skin necrosis, occurred in about 4 out of every million people vaccinated. That vaccine also could cause damaging skin lesions in people with eczema or weakened immune systems. (Note: There is a shortage of the JYNNEOS vaccine, and no doses have been shared with or sold to countries in Africa, which have experienced monkeypox outbreaks since the 1970s.)

Although older versions of the vaccine have been tested thoroughly in people, there has never been a large, clinical study to measure JYNNEOS's ability to protect against a monkeypox infection in people or to stop transmission of the virus.

What is known about the vaccine, in terms of its efficacy against monkeypox, comes from studies in macaques, and immunological studies in people, which demonstrated the vaccine triggers the production of monkeypox antibodies in people's blood.

"So we know that the vaccine does stimulate the immune system and people produce antibodies when they receive the vaccine," Titanji says, "but we don't have a clinical data in humans to actually tell us, 'Okay, that immune response translates to this level of protection against getting infected with monkeypox or reducing the severity of monkeypox disease if you do get infected.' "

And it's not a guarantee of protection. In this current outbreak, scientists have already begun to document breakthrough infection with this vaccine, the World Health Organization reported Thursday. "[This] is also really important information because it tells us that the vaccine is not 100% effective in any given circumstance," said Dr. Rosamund Lewis of WHO. "We cannot expect 100% effectiveness at the moment based on this emerging information."

And so when Titanji gives a person the JYNNEOS vaccine at her clinic, she is very clear about what the vaccine can and can't do. "I tell them, 'We do know that you're going to get some protection from this vaccine. Some protection is better than no protection. We also do know that the vaccine can reduce the severity of the disease if you do get infected. But we don't know for a fact that you would be completely protected from getting monkeypox.' "

Can this vaccine if given to the people who need it the most slow down the outbreak?

So the new data from the U.K. and Germany suggest that indeed this vaccine can curb the spread of monkeypox.

But Dr. Vinh at McGill University says it's way too soon to say the vaccine, alone, is the only factor contributing to the slow down in these countries. "No single measure is going to really be the solution here," says Vinh.

In addition to vaccination, people at high risk need to learn how they can protect themselves. And doctors have to learn how to spot monkeypox cases, he says.

Right now the percentage of monkeypox tests coming back positive is still incredibly high, Titanji says. "The positivity rate is close to 40%." And that means doctors are missing many cases. Specifically, they are still mistaking monkeypox for other sexually transmitted diseases such as syphyllis.

"I can tell you, from the lens of a clinician, that monkeypox is very, very easy to mistake for another infectious disease," she says.

Some people have had to visit clinics two or three times and even have been treated for another STD before the clinician suspects monkeypox.

"You really have to maintain a very high index of suspicion because some of the lesions are so subtle and the clinical presentation is so variable," she says. "At this phase of the outbreak, we should be over testing rather than under testing. If a doctor even remotely suspects monkeypox, they should be sending a test for it."

Otherwise people can't receive treatment for monkeypox and they can unknowingly spread it to others. And the outbreak will continue to grow while people wait to receive a vaccine and for that vaccine to begin working.

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Can the monkeypox vaccine stop the current outbreak? : Goats and Soda - NPR

Taiwan researchers sort through eggs used for the cultivation of swine flu vaccine, in a plant in ... [+] Taichung, on June 18, 2009. Taiwan is set to mass produce swine flu vaccine in October, as the island's confirmed cases rose to 58 as of June 17. AFP PHOTO/PATRICK LIN (Photo credit should read PATRICK LIN/AFP via Getty Images)

This is a short series about a recent breakthrough on the road to developing a much sought-after broadly neutralizing vaccine against all influenza A viruses. If successful, it may act as a precursor to a truly universal flu vaccine, one that protects against all types, subtypes, and lineages of the virus. The breakthrough may also provide a blueprint for developing a Covid-19 vaccine that retains its efficacy in the face of new variants.

In the first part of this series, I gave a brief overview of the history and nature of influenza viruses, including why it has been so difficult to develop successful vaccines. The next few articles discuss some of the attempts that have been made to overcome these challenges, including their shortcomings. And in the last installments, I will offer a detailed analysis of the latest and most promising advances in the field.

The Seasonal Approach

Picking up where we left off in the previous article, any successful influenza vaccine has to account for the ability of influenza viruses to mutate. Genetic mutations to vital proteins can lead to antigenic variation changes to parts of the virus that our immune system relies on to stimulate its memory. Although various different parts of the virus serve as antigens, the surface proteins that help it enter and exit host cells are some of the most important. Changes to these proteins can prevent our antibodies from recognizing the virus, rendering them unable to block its spread. Antigenic variation is responsible for influenza reinfections, leading to seasonal flu outbreaks.

In an attempt to circumvent the issue of antigenic variation, vaccine manufacturers update the flu shot each year based on the latest circulating influenza strains. The idea is to expose our immune system to the antigens it is most likely to encounter during flu season, helping it to build up its antigen-specific defenses in advance once our immune system has built up its memory, it can jump into action straight away should we become infected.

Which influenza strains ultimately get used to make the yearly flu shot is decided on the basis of data collected throughout the year by the World Health Organizations (WHO) Global Influenza Surveillance and Response System (GISRS). This surveillance and response system is made up of roughly 150 different laboratories spread across the globe, each of which gathers thousands of influenza samples from sick patients. The most prevalent viral strains are then shared with five WHO Collaborating Centers for Influenza, which perform further analysis. Two times a year once in preparation for flu season in the Northern Hemisphere, and another in preparation for flu season in the Southern Hemisphere Directors of the WHO Collaborating Centers, Essential Regulatory Laboratories, and representatives of a few of the smaller national laboratories come together to: review the results of surveillance, laboratory, and clinical studies, and the availability of flu vaccine viruses and make recommendations on the composition of flu vaccines. Once the WHO vaccine composition committee has made its recommendations, each country makes a final decision on which viruses they will choose to use in their flu vaccines.

In the United States, all influenza vaccines are quadrivalent, meaning they contain four different influenza viruses. This is done to broaden protection against the various influenza subtypes and lineages known to drive seasonal outbreaks: influenza A (H1N1), influenza A (H3N2), influenza B/Victoria, and influenza B/Yamagata. Quadrivalent vaccines will also protect against any other influenza viruses that are antigenically similar.

Although this may seem like a relatively reliable process, there is one glaring drawback to the seasonal vaccination approach: vaccines produced in this way are nowhere near as effective as we might hope. At best, they protect 60% of people from illness, but this number can, and often does, drop much lower. For the influenza A (H3N2) subtype, vaccine effectiveness hovers around 33%. Of course, any protection is better than no protection, but it is still suboptimal remember, these numbers represent best case scenarios, years where the viruses selected for use in vaccines are well matched to those that actually end up circulating during the flu season. So, where are things going wrong?

Missing the Target: Egg-based Vaccines

Selection of candidate vaccine viruses (CVVs) is only one part of the equation, growing them is another. This is no simple feat considering they need to be available in bulk, enough to make millions of vaccines. For the past 70 years, the majority of manufacturers have turned to chicken eggs in order to achieve the necessary growth (Figure 1). The candidate vaccine viruses are injected into fertilized hens eggs and left to incubate for a few days. During this period, the viruses are able to replicate. The fluid in the eggs is then extracted and the viruses are killed (inactivated). Finally, the antigen of choice usually the hemagglutinin surface protein is isolated from the killed viruses and purified, making it ready for use in vaccines. Even now, most flu vaccines continue to be egg-based.

FIGURE 1. An overview of the steps involved in producing egg-based vaccines.

But there are two issues with this approach. First, growing the viruses in eggs is a fairly slow process. This means the selection of candidate vaccine viruses has to happen far in advance of flu season, to make sure manufacturers have enough time to produce the amounts needed. In the six to nine months it takes to grow and purify enough virus, the wild type influenza strains continue to mutate and change. If these changes impact the antigen, the wild type viruses may escape the immunity that the vaccines provide us, reducing their effectiveness. When this happens, the viruses are referred to as escape mutants.

A growing body of research suggests that a second factor may be even more important: egg-adapted changes. Because the candidate vaccine viruses are human influenza viruses, growing them in chicken eggs carries the risk that they adapt to the new immune niche while replicating. The immune niche of chickens is different to that of humans, so adaptations that improve viral fitness in chickens may result in genetic and antigenic changes to the viruses. As before, these changes can lead to a drop in vaccine effectiveness, since the vaccine strains no longer resemble the circulating wild type strains; the egg-adapted vaccines end up training our immune system to recognize the wrong viruses, thus hampering its ability to respond efficiently come flu season.

Egg Substitutes: New Ways of Growing Candidate Viruses

In response to these issues, manufacturers have tried to develop new production methods that avoid using chicken eggs to culture candidate viruses. This search has led to a cell-based approach and a recombinant approach (Figure 2).

FIGURE 2. Timeline of current influenza vaccine production methods. Schematic overview of egg-based, ... [+] cell-based and protein-based (recombinant) influenza vaccine production.

Cell-based vaccines are produced using candidate viruses grown in mammalian cells rather than chicken eggs. Aside from this, the manufacturing process between the two is virtually identical: candidate vaccine viruses are grown in mammalian cell cultures by the CDC, these are then handed over to private manufacturers who inoculate the viruses into mammalian cells, the viruses are left to replicate for a few days before being harvested, and finally, purified. Although approved in 2012, it wasnt until this past 2021-2022 flu season that fully egg-free, cell-based vaccines were produced previously, the initial production of candidate vaccine viruses by the CDC was still done using fertilized hens eggs, and only after being handed over to the private sector were the viruses mass-produced in mammalian cells.

Using the cell-based approach eliminates egg-adapted changes in candidate viruses, keeping the viruses as close as possible to the wild type influenza strains predicted to circulate during flu season. An added benefit of cell-based vaccines is that the production process can be scaled up more quickly; mammalian cells can be frozen in advance to ensure steady supply, which could prove especially useful during pandemic outbreaks.

In theory, the lack of egg-adapted changes should improve vaccine effectiveness. But what about in practice? Although there still hasnt been enough research for a clear consensus to develop, initial findings suggest the difference in effectiveness is modest at best, and statistically insignificant at worst. This hints that egg-adapted changes might not play as important of a role as initially suspected; low vaccine efficacy can occur even when eggs are not used in the manufacturing process. That said, the 2021-2022 flu season marks the first time truly egg-free cell-based vaccines in which all four viruses are derived entirely through cell-based methods were used, so perhaps future research will yield different results. For now, things dont look too promising.

Recombinant vaccines provide a third option, and manage to overcome a crucial issue faced by the other two options: the lengthy, tedious virus production process. Whereas egg- and cell-based vaccines depend on candidate virus samples, recombinant manufacturing skips this step. Instead, recombinant vaccines are made by isolating the gene that makes the hemagglutinin surface protein from a wild type influenza virus. Once isolated, this gene is combined with a different kind of virus, called baculovirus. The new virus is known as a recombinant baculovirus and it is used to ferry the gene that makes the hemagglutinin antigen into a host cell line. As soon as the gene enters the cells, they begin to mass produce the hemagglutinin antigen. The antigen can then be extracted and purified before being assembled into a vaccine.

Given that they are entirely egg-free and dont require candidate virus samples, recombinant vaccines bypass the issue of egg-dependent changes. Due to the speed of production, there is also a decreased risk of escape mutants developing. As before, there is a paucity of comparative research, making it difficult to draw any firm conclusions, but early findings suggest recombinant vaccines may be more effective than traditional egg-based and cell-based vaccines, including improved antibody production.

Takeaway

Developing consistently protective influenza vaccines has proven difficult, with effectiveness frequently hovering somewhere between 40 and 60%. Too low, considering the threat posed by influenza.

A big part of the challenge is the mutability of the virus; it is constantly changing, making it hard for our immune system to keep up and retain useful memories of previous encounters. In response, public health agencies and scientists around the world develop new vaccines every year that prime our immune systems for the latest circulating strains. Sometimes scientists miss the mark with their predictions, in which case the circulating influenza strains do not match up with those in the vaccine, undermining vaccine effectiveness. At other times predictions are right on the money, but the vaccine production process impairs effectiveness either by being too slow and giving the wild type viruses time to mutate again, or because of mutations to the candidate vaccine strains during mass-production in chicken eggs.

Cell-based and recombinant vaccines aim to resolve the issues on the production side of things. The former by skipping the need for eggs, and by extension, the threat of egg-adapted changes. The latter by skipping the need for eggs as well as cutting down the time it takes to produce the vaccines, reducing the risk of escape mutants. Despite these advances, vaccine effectiveness has not yet seen the boost it needs.

The below table gives a summary of the advantages and disadvantages associated with these three production processes.

FIGURE 3. Advantages and disadvantages of strategies for influenza virus vaccine production.

The next article in this series will look at two additional technologies: intranasal vaccines and mRNA vaccines. Might they succeed where the more traditional strategies have wavered?

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Getting A Grip On Influenza: The Pursuit Of A Universal Vaccine (Part 2) - Forbes

Your immune system is on a mission, constantly assessing threats, identifying invaders, and neutralizing or killing them off. It is a finely tuned network of organs, cells, proteins, and chemicals engaged in an existential battle. It asks the question: is this me or is this not me? And if its not me, what is it? Friend or foe?

Without the immune system, which has been honed and refined throughout the millennia of our existence as a species, we could not survive.

Samir N. Khleif, M.D., is also on a mission: to outsmart and disable cancer by overcoming its ability to evade or tolerate immunotherapeutic approaches.

Dr. Khleif, a practicing medical oncologist, a Biomedical Scholar, and professor, is the director of the Center for Immunology and Immunotherapy and the Loop Immuno-Oncology Research Laboratory at the Lombardi Comprehensive Cancer Center at Medstar Georgetown University Hospital. He and his team of assistant professors, post docs, research assistants, graduate students, and trainees focus on understanding how the immune system works, delineating the mechanisms of immune response and resistance to immunotherapy and re-engineering the immune cells with the goal of developing novel immune therapeutics.

Khleif is a long-time pioneer in cancer immunotherapy. Before joining Georgetown, he served as Director of Georgia Cancer Center, Augusta University, where he oversaw the development of a large integrated program focused on immunology, inflammation, tolerance basic science, and immune therapy. He also led the Cancer Vaccine Section, a nationally active Immune Therapy Program at the National Institutes of Health-National Cancer Institute, where he was one of the early pioneers of cancer vaccines and led some of the clinical trials. (Fun fact: Moderna and BioNTech, the names behind the mRNA technology now used to protect us against COVID, started out as cancer vaccine companies.)

He currently holds numerous patents and has published several important studies unraveling the understanding of the interaction of immune cells and cancer and on the mechanisms of tumor-induced suppression and the strategies used to overcome them. His research team has also developed models to understand how different kinds of immune therapies can be combined to work synergistically and he translated these findings into clinical trials with the intention of more widespread use.

We recently met with him in his lab to learn more about immunology a subject weve all come to know since the pandemic and to discuss his research. For all his stellar achievements and fierce intellect, he was a gracious host and a passionate teacher. He is also, we later learned, a painter and a musician who plays keyboard, saxophone, piano, and the violin, amateurly, he insists. His top scientist of all time is Albert Einstein and his favorite D.C. restaurant is Komi.

Commenting on the upcoming BellRinger Ride benefit for Lombardi, Khleif sees similarities between his life mission and bicycling: both activities have an anticipation to reach the end goal along with hard work and a sense of exploration or adventure. To find out what BellRingers all about, see our sidebar in our print edition here.

Born in Syria to Palestinian refugee parents, Khleif attended college and medical school in Jordan after spending seven weeks in Vermont to learn English. Although he originally wanted to be a physicist, his father swayed him into medicine where a love of research led him to the study of virology, molecular biology, vaccines and, now, his work in harnessing the power of immune system to disable cancer cell growth and proliferation.

For Khleif, the joy of discovery is the catalyst for his work. The more discoveries you find, he says, the more addicted you get. I tell my team: when you discover something, ask yourself, why did nature create like this? Why does it exist? Can we recreate it when its missing? How can we use this as a tool for therapy?

Khleif and his team concentrate on four main areas of research: tumor immunology and immunotherapeutics (unraveling the mechanism through which the immune system and cancer cells interact ); T-cell plasticity (how T-cells, a type of immune cell, can be re-reengineered to amp up their immune response); immunotherapeutic resistance (how and why tumors learn to override the patients natural defenses and therefore become unresponsive to immuno- and other therapies); and combination immunotherapy design (identifying the best combination of immunotherapeutics to enhance the best clinical response).

Interestingly, the lab is also studying how some natural products, such as vitamin C and selenium, can be used to boost immunity, reprogram and repair immune cells, and reverse the damage that cancer causes on the immune system. So, stock up on your fruits, vegetables and seafood.

In his other life as an advocate for global health and impact-driven healthcare, he led the development and served as the founding CEO of the King Hussein Cancer Center in Amman, Jordan, the regional cancer center in the Middle East. He also led the planning and development of cancer care projects in low-income countries dedicated to bringing cancer education, research, and treatment to underserved areas around the world.

Every day, as your immune system conducts its intricate surveillance, it is working to dispatch dangers before they become serious health risks. Dangers like an errant cell that may grow into cancer. With immunotherapy in their arsenal, Khleif and his team are unlocking new strategies to dethrone the emperor of all maladies and save, he estimates, millions of lives.

To learn more about Dr. Khleif, his research, patents, and publications go to: https://gufaculty360.georgetown.edu/s/contact/00336000019h06bAAA/samir-khleif. You can also view his patient-oriented video on immunotherapy here: https://youtu.be/afdq8Op-jQM

For a highly accessible and entertaining resource on the immune system, check out Philipp Dettmers Immune, https://youtu.be/afdq8Op-jQM. If you or a family member have been diagnosed with cancer and would like to better understand immunotherapy, visit the Cancer Support Community here: https://www.cancersupportcommunity.org/immunotherapy-cancer-it-right-you .

And to support innovative cancer research at the Georgetown Lombardi Comprehensive Cancer Center, join the inaugural BellRinger Bike Ride on Oct. 22. Donate or learn more at bellringer.org.

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Bells Are Ringing! How Immunotherapy is Unlocking Doors to a Cancer Cure - Georgetowner

Berkeley Immune Support Formula provides supplements to the diet that can help in the boosting of the immune system and thus be and remain physically stronger.

Los Angeles, CA (August 13, 2022) The immune system is an essential part of the human body as it works as the shield that protects it from different kinds of diseases. Berkeley Immune Support Formula highly recommends one to be immunoreactive and suggests some of the daily care that one can take as a measure to keep a check on it, such as checking the vitamin D, keeping control of weight, and having an immune support booster, and others.

The product of the organization is mainly derived from many vegetables such as broccoli and cabbage due to which the organization also recommends that one can intake those in other forms as well. As their product is composed of more such elements rich in the DIM, it promises to give a better immune system result and prove itself the best immune support booster.

The product has been designed to aid the cause of raising funds for nature-based biomedical research. The product is said to be rich in Selenium, Zinc, Sulforaphane, Lycopene, Zeaxanthin, Lutein, Citrus Bioflavonoids, and Vitamin D3. The manufacturers of the product have many experiences with the DIM substance. The sulforaphane that is delivered by the immune support booster product is said to be specially manufactured by the scientists for the product.

Through the Berkeley Formula product, the organization makes a promise to the customers to provide the nutrients, which will be equal to a bowl of salad. The product is said to be the first of its kind that is composed of a mixture of bioflavonoids and phytonutrients. The product supplied by the organization is said to be manufactured for the most bioavailability, and it is also said to be giving bioactive quantities of the DIM to the consumers.

The Berkeley Formula product is regarded as a very effective bioavailable supplement of the DIM and immune system booster by many doctors and scientists. In fact, they have been found to do more research on the products along with the addition of other nutrients. The product is also said to be very effective for sportspeople, relieving stress from work or school, pollution of the environment, the process of aging, and sleep deprivation as an immune system booster.

About Berkeley Immune Support Formula

The organization was founded by Dr. Leonard Bjeldanes, Dr. Gary Firestone, Dr. Christopher Benz, Dr. Giuseppe Del Priore, and Dr. Bob Eghbalieh. These doctors have a specialty in the product supplied by the organization which is the DIM supplements, and in clinical research. The main purpose of this research is to contribute to the medical field with the help of their products. The main goal of the organization is to help people lead a healthy life, via the development of top-class nutrition goods. The two divisions of the organization function, that are the nutritional sciences and the biopharmaceuticals functions in the marketing of their product and in the development of the different types of cures for deadly diseases by boosting the immune system of the body.

For more information about the services of the company and knowing the offers, please visit https://www.berkeleyformula.com/

Media Contact:

Berkeley Immune Support Formula

1434 Westwood Blvd. Suite #5, LA, CA 90024

Phone: 877-777-0719

Email: [emailprotected]

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Have The Immune System Booster Through the Dietary Supplements Only from Berkeley Immune Support Formula - Digital Journal

The1918 influenza pandemicresulted in the loss of over 3% of the worlds population at least 50 million people. But it wasnt the flu virus that caused the majority of these deaths.

Ananalysis of lung samplescollected during that flu pandemic indicated that most of the deaths were likely due to bacterial pneumonia, which ran rampant in the absence of antibiotics. Even in more recent history, like the1957 H2N2and2009 H1N1flu pandemics, nearly 18% of patients with viral pneumonia had additional bacterial infections that increased their risk of death. And theCOVID-19 pandemicis no different.

With yet another flu season fast approaching in the midst of the ongoing COVID-19 pandemic, lessening the harm caused by these viruses is important to prevent deaths and reduce infections. However, many deaths associated with the flu and COVID-19 dont occur at the hand of the virus alone. Instead, its asecondary bacterial infectionthat is often at the root of the devastating consequences attributed to an initial viral infection.

I am animmunologistwho studies why and how cells die during bacterial and viral infections. Understanding the synergy between these microbes is critical not only for effective diagnosis and treatment, but also for managing current pandemics and preventing future ones. My colleagues and Ipublished a studyshowing how an immune system protein crucial to fighting against viruses also plays an indispensable role in fighting bacteria.

Multiple pathogens can cause multiple infections in different ways. Scientists distinguish each typebased on the timingof when each infection occurs.Coinfectionrefers to two or more different pathogens causing infections at the same time.Secondary or superinfections, on the other hand, refer to sequential infections that occur after an initial infection. Theyre often caused by pathogens resistant to antibiotics used to treat the primary infection.

How viral and bacterial infections interact with each other increases the potential harm they can cause. Viral respiratory infections can increase the likelihood of bacterial infections and lead to worse disease. The reason why this happens is often multifaceted.

Within your respiratory tract, the epithelial cells lining your airways and lungs serve as the first line of defense against inhaled pathogens and debris. However,viruses can kill these cellsand disrupt this protective barrier, allowing inhaled bacteria to invade. They can alsochange the surface of epithelial cellsto make them easier for bacteria to attach to.

Viruses can also alter the surface ofepithelial and immune cellsbyreducing the number of receptorsthat help these cells recognize and mount a response against pathogens. This reduction means fewer immune cells report to the viral infection site, giving bacteria an opening to launch another infection.

Patients who have a bacterial infection at the same time theyre battling the seasonal flu are more likely to wind up in a hospital.Nearly a quarterof patients admitted to the ICU with severe influenza also have a bacterial infection. One study on the 2010 to 2018 flu seasons found thatnearly 20% of patientsadmitted to the hospital with flu-associated pneumonia had acquired bacterial infections.

Another studyof patients hospitalized with viral or bacterial infections found that nearly half had a coinfection with another pathogen. These patients also had nearly double the risk of dying within 30 days compared to those with only a single infection.

Interestingly, thetwo bacteria speciesmost commonly involved in coinfections with the influenza virus areStreptococcus pneumoniaeandStaphylococcus aureus, which normally exist in the respiratory tract without causing disease. However, the influenza virus can damage the cell barrier of the lungs and disrupt immune function enough to make patients susceptible to infection by these otherwise benign bacteria.

Secondary bacterial infections are also exacerbating the COVID-19 pandemic. A 2021 review estimated that16% to 28% of adultshospitalized for COVID-19 also had a bacterial infection. These patients stayed in the hospital for twice as long, were four times more likely to need mechanical ventilation and had three times greater odds of dying compared to patients with only COVID-19.

The immune systemresponds differentlyto viruses and bacteria.Antiviralsdont work on bacteria, and antibiotics dont work on viruses. A better understanding of what pathways the body uses to regulate both antiviral and antibacterial infections is critical to addressing secondary and coinfections.

Recent workby my colleagues and me may provide a clue. Wesequenced the RNAof one type of immune cell, macrophages, in mice to identify what molecules were present in cells that were either protected from or died due to bacterial infection.

We identifiedZ-DNA binding protein (ZBP1), a molecule already known to play a regulatory role in how the immune system responds to influenza. Specifically, ZBP1detects influenza viruseswithin the lungs and signals infected epithelial and immune cells to self-destruct. This induced cell death eliminates the virus and promotes recruitment of additional immune cells to the infection site.

Building off this finding that ZBP1 is important for fighting viral infection, we found that macrophages infected withYersinia pseudotuberculosis, a type of bacteria that causes foodborne illness, also use this protein to initiatecell death. This limits bacterial replication while also sendinginflammatory signalsthat help clear bacteria.

These findings raise the possibility that ZBP1 may play a dual role in how the body responds to viral and bacterial infections. Its possible that treatments that increase ZBP1 in certain types of cells may be useful in managing bacterial and viral coinfections.

Hayley Muendleinis an assistant research professor of immunology in the Tufts University Graduate School of Biomedical Sciences.

This article was originally published onThe Conversation. Read theoriginal story.

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COVID-19 and Flu Viruses Often Have a Deadly Accomplice: Bacterial Infections - Tufts Now

Eating grapes is potentially the cheapest, easiest way to improve your immune system, your metabolism, and your brain health. Foraround $2.09 per pound, grapes contain a bounty of essential nutrients including Vitamin C, antioxidants, calcium, and more. Now, three new studies suggest that just adding two cups of grapes to a high-fat diet can provideremarkable health benefits, surpassingour understanding of the benefits of grapes.

Dr. John Pezzuto examined the health benefits of grapes with a team of researchers from Western New England University. The three studies focus on lifespan, metabolism, fatty liver disease, and brain health, revealing that grape consumption yielded reductions in fatty liver and extended lifespans. To conduct the studies, the researchers analyzed how grape consumption altered gene expression in mice. Despite not conducting human tests, the researchers emphasize that these resultscan reliablytranslate to human health issues.

We have all heard the saying you are what you eat,' which is obviously true since we all start out as a fetus and end up being an adult by eating food, Western New England University Researcher and senior author of three new studies Dr. John Pezzuto said. But these studies add an entirely new dimension to that old saying. Not only is food converted to our body parts, but as shown by our work with dietary grapes, it actually changes our genetic expression. That is truly remarkable.

Pezzutos first study concluded that grape consumption triggered unique gene expressions in the mice. This study found that grape consumption led to a reduced risk of fatty liver disease and expanded the overall lifespan of the animal consuming the grapes. To properly conduct the study, the animals followed a high-fat western style diet. Published in Foods, this study claims that grape consumption can modulate the adverse effects of a traditional Western diet, preventing oxidative damage.

What is the effect of this alteration of gene expression? Fatty liver, which affects around 25% of the worlds population and can eventually lead to untoward effects, including liver cancer, is prevented or delayed, the researchers stated. The genes responsible for the development of fatty liver were altered in a beneficial way by feeding grapes.

The second study, published in Food & Function, found that the consumption of grapes changes metabolism. When Pezzuto and his research team introduced grapes to mice following high-fat diets,researchers found increased levels of antioxidant genes in the mice. The study concluded that grapes help reprogram the metabolism of the gut microbiota, increasing the efficiency of the liver and energy production.

Many people think about taking dietary supplements that boast high antioxidant activity, Pezzuto said. In actual fact, though, you cannot consume enough of an antioxidant to make a big difference. But if you change the level of antioxidant gene expression, as we observed with grapes added to the diet, the result is a catalytic response that can make a real difference.

Published in the journal Antioxidants, the final study observed how grape consumptionbenefits brain function. Theresearch highlights that a high-fat diet presents negative behavioral and cognitive pressures on the brain. In contrast, grape consumptionhelps alleviate these pressures, havinga positive effect on the brain and brain metabolism. The researchers noted that this initial conclusion will require more research to determine the extent of the positive impacts.

Although it is not an exact science to translate years of lifespan from a mouse to a human, our best estimate is the change observed in the study would correspond to an additional 4-5 years in the life of a human, Pezzuto said. Precisely how all of this relates to humans remains to be seen, but it is clear that the addition of grapes to the diet changes gene expression in more than the liver.

This February, a study found that a mostly plant-based diet can prolong life expectancy by over 10 years. The team of Norweigan researchers found that introducing more plant-based foods earlier in life helps cut down the risk of life-threatening disease and improves your overall health. Following an "optimal" diet defined as primarily plant-based a little fish showed long-term health benefits, whereas diets high in red or processed meat showed an inverse relationship.

Another study from last March found that eating more plant-based is key tomaintaining a healthy gut. This study concluded that by improving gut health, you can improve longevity and prolong your lifespan. The researchers claim that building a healthy microbiome at an earlier age is essential to better health in old age.

For more plant-based happenings, visit The Beet's News articles.

Here are the best foods to eat on repeat, to boost immunity and fight inflammation. And stay off the red meat.

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Eat This Fruit Daily to Stay Sharp and Live Longer, Research Find - The Beet

With the countrys third COVID fall approaching, the United States is expected to soon start ramping up its autumn COVID-19 booster campaign.

This years rollout will include something new. Moderna and Pfizer-BioNtech are working on bivalent boosters that include both the original vaccine formula and a component that targets the Omicron BA.4 and BA.5 subvariants of the coronavirus.

While the Biden administration has yet to reveal details of the rollout plan (expect more on that later), heres what we know so far.

The Omicron variant has overcome much of the protection against infection offered by two doses of the mRNA vaccines (such as Moderna and Pfizer-BioNTech).

A first booster restores some of that protection, but this wanes considerably within about three months after vaccination.

In spite of that, Dr. David Cutler, a family medicine physician at Providence Saint Johns Health Center in Santa Monica, Calif., told Healthline that the current vaccines continue to offer strong protection against severe illness and death.

This is especially true of the boosters.

In May 2022, unvaccinated people were six times more likely to die of COVID-19, compared to people vaccinated with at least a primary series (for most, two doses of the mRNA vaccines), according to the Centers for Disease Control and Prevention (CDC).

Among people 50 years and older, unvaccinated people were 29 times more likely to die of COVID-19 than those who had received the primary series and at least two booster doses, agency data showed.

The current COVID-19 vaccines and boosters are based on the original strain of the virus. As CDC data shows, these still offer strong protection against severe disease caused by Omicron.

However, in order to better target the variants likely to be circulating in the fall, the Food and Drug Administration (FDA) asked vaccine makers in June 2022 to update their boosters to include a component that targets the currently circulating Omicron BA.4 and BA.5 subvariants.

We think the Omicron-specific boosters will improve immunity against the existing Omicron variants. This may be particularly helpful during the anticipated winter surge, Dr. Jimmy Johannes, a pulmonologist and critical care medicine specialist at MemorialCare Long Beach Medical Center in California, told Healthline.

However, not all scientists agree that Omicron-specific boosters will provide greater protection than the current ones.

Cutler thinks the strongest benefit of Omicron-specific boosters will be for people who are unvaccinated or have not received the full primary series and any booster(s) for which they are eligible.

One problem with choosing which booster to use in the fall is its impossible to know for certain which variants will be circulating by then, although some experts expect it to be a descendant of one of the currently circulating Omicron variants.

Data presented at an FDA vaccine advisory committee meeting in June 2022, though, suggests that vaccination with a variant-specific booster such as one targeting Omicron might lead to a broadened antibody response against the coronavirus.

Data from Moderna shows the potential for this kind of broader immune response. The companys bivalent Omicron BA.1 booster also produced a higher level of neutralizing antibodies against BA.4 and BA.5 than the original booster, according to preliminary data.

On August 15, the United Kingdoms Medicines and Healthcare Products Regulatory Agency approved Modernas bivalent Omicron BA.1 booster for use in adults.

The Moderna and Pfizer-BioNTech boosters based on the original strain of the coronavirus are currently available for anyone who is eligible for a first or second booster.

The bivalent boosters from those companies are expected to be available in early to mid-September, Dr. Ashish Jha, White House COVID-19 response team coordinator, said in a virtual discussion with the U.S. Chamber of Commerce Foundation on August 16.

Before these boosters can be rolled out, though, the FDA will need to authorize them and the CDC will need to sign off on their use.

The fourth vaccine in the country, Novavaxs protein-based vaccine, was authorized by the FDA on July 13, 2022 for use as a two-dose primary series. This vaccine is based on the original strain of the coronavirus.

The company announced the next month that it had applied for FDA authorization of this vaccine as a booster. It is also testing an Omicron-specific vaccine and a bivalent vaccine that targets Omicron and the original strain, the company said in a release.

Everyone currently eligible for a COVID-19 booster will still be eligible in the fall, including:

Johannes said anyone at risk of severe COVID-19, or complications of a coronavirus infection, should consider getting boosted when the bivalent vaccine is available.

This includes older adults, as well as those with chronic medical conditions such as heart disease, liver or kidney disease, a chronic respiratory condition, cancer, an immune compromising condition, high blood pressure or diabetes.

The Biden administration is also expected to open up second boosters this fall to adults under age 50 when the bivalent vaccines are available. This expansion of eligibility was put on hold when vaccine makers said they could deliver the bivalent vaccines in early fall.

When the bivalent boosters are available in the fall, these will be used for all booster shots in the United States, including first and second boosters.

Pregnant women are also eligible for boosters.

The [COVID-19 mRNA] vaccines have now been given to tens of millions of pregnant women. They are extremely safe, said Jha during the online Chamber of Commerce call. We have seen little to no side effects [in pregnant women], the same side effects that most of us get the sore arm, sometimes 24 hours of feeling fatigued or a little bit run down.

Bolstering the safety profile of these vaccines, a large study from Canada published August 17, 2022, in The BMJ found that women who received a COVID-19 vaccine during pregnancy did not have a higher risk of having a preterm birth, a baby who was small for their gestational age at birth, or a stillbirth.

No details are available yet on the fall booster rollout, but it will likely be similar to the initial booster release last year, with vaccines mainly available at doctors offices and pharmacies. Some mass vaccinations may also happen in certain locations.

To find a vaccination site near you, check out the federal Vaccines.gov or your states COVID-19 vaccine website.

Its difficult to know what the coronavirus will do in the fall will there be a large spike early in September or will a new variant emerge? In addition, theres no guarantee that the bivalent vaccines will definitely be available in September.

As a result, the CDC recommends getting boosted as soon as you are eligible, with whichever booster is available. This is especially important for adults 50 years and older or those with compromised immune systems.

It can take one to two weeks after receiving a booster for your immune system to be fully primed. So if you are eligible now and get boosted, you will be better protected should cases surge as we head into the fall and winter.

You can always get the bivalent vaccine when it is available. Jha said you will want to space out those two boosters at least a little bit, probably 4 to 8 weeks.

The CDC may also weigh in on the timing between boosters when it reviews the data on the Omicron-specific boosters.

Jha said if you are planning on getting the seasonal flu shot this fall, you can definitely get this alongside a COVID-19 booster.

The CDC recommends that people get vaccinated against the flu by the end of October to ensure they have strong immune protection at the peak of the flu season, which generally happens in February.

Scientists dont know yet if the coronavirus that causes COVID-19 will follow a similar seasonal pattern, but cases have tended to increase in colder parts of the country as people head indoors for the fall and winter.

Although the FDA asked vaccine makers to update their boosters to include an Omicron-specific component, it did not advise them yet to update the vaccine for the primary series.

This suggests that unvaccinated people will receive the original vaccine, which the agency said provides a base of protection against serious outcomes of COVID-19.

Read more here:
The Next COVID-19 Booster Shots Will Target Omicron: What to Know - Healthline

Eating a nutrient-dense diet can help someone recover from COVID-19 by supporting their immune system and managing inflammation. This may be particularly important if they lose their sense of taste or smell and have the temptation to eat stronger tasting, less nutritious foods.

People can support their bodies in recovery at home by eating a nutritious diet. This article looks at what experts advise to eat when individuals have COVID-19.

This article also details the symptoms of COVID-19, how the loss of taste and smell affects diet, what to do if vomiting occurs, and some frequently asked questions.

Eating a nutritious diet is an essential consideration in recovering from COVID-19. Research suggests that insufficient nutrition is a risk factor for severe COVID-19, and key nutrients can help support the immune system and manage inflammation.

The following foods and nutrients may help a person recover from the disease.

According to a 2022 review, experts associate a diet involving healthy, plant-based foods with a lower risk and severity of COVID-19. In addition, the study found that a healthy, plant-based diet may particularly benefit people with higher socioeconomic deprivation.

A diet high in saturated fat increases angiotensin-converting enzyme, the main entry point for coronavirus into cells. Research suggests that diets, such as the Mediterranean diet, which are low in saturated fat and high in nutrients from plant foods, can provide more antioxidants for the body. Antioxidants may help fight viruses and support the immune system.

Therefore, eating the following foods can provide fiber, essential vitamins and minerals, and phytochemicals, which are helpful compounds that plants produce.

Learn more about the Mediterranean diet.

According to a 2020 review, high quality proteins, such as fish, eggs, and lean meat, are an essential part of an anti-inflammatory diet that helps produce antibodies and fight off infection.

Learn more about tips and tricks to eat more protein.

The review also notes that dietary fiber consumption correlates with lower mortality from infectious and respiratory diseases. Consuming fiber can also lead to more favorable gut bacteria, which lowers inflammation. People can consume beneficial fiber in:

Learn more about high fiber foods.

Omega-3 fatty acids, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may have beneficial effects on COVID-19. These include:

Oily fish is a high source of omega-3 fatty acids. Additionally, plant-based foods, such as flaxseed, walnuts, and hemp, contain alpha-linolenic acid, which the body can convert to EPA and DHA. People can also take an omega-3 supplement from fish or algae.

Learn more about omega-3-rich foods.

Some studies have found that vitamin C can shorten the duration of colds and may improve respiratory symptoms. Vitamin C acts as an antioxidant and regulates the immune system and gene expression.

Other research suggests that vitamin C may help improve inflammation markers in people with coronavirus, but people should not consider it as a treatment in supplement form.

However, people can include vitamin C-rich foods in their diet when they have COVID-19 to help support their immune system. These include:

Learn more about foods high in vitamin C.

Vitamin D plays an important role in the bodys immune system. Scientists previously suggested that dietary sources of vitamin D were particularly important during the pandemic because many people had less exposure to the sun during the lockdown.

People get vitamin D from exposure to the sun and foods such as beef liver, egg yolks, cheese, and fortified breakfast cereals.

Learn more about foods high in vitamin D and other sources.

Some research suggests zinc may reduce viral replication and gastrointestinal and respiratory symptoms of COVID-19. However, most research has focused on zinc supplements, so it is difficult to say whether eating zinc foods can help.

However, zinc is an essential mineral for immune function, and eating foods that contain the substance may support recovery from illness.

Foods containing zinc include:

Learn more about foods high in zinc.

A 2020 meta-analysis of research estimates that 48% of patients with COVID-19 globally experienced a loss of smell and around 41% experienced a loss of taste. In some people, these symptoms may persist as part of long COVID.

Learn more about how COVID causes loss of taste and smell.

People who experience a loss of smell or taste may go off foods they usually eat or prefer foods with more salt, sugar, or fat, as they may be able to taste these more. However, individuals need to ensure they eat plenty of fruit and vegetables for their vitamin and antioxidant benefits. Avoiding too many high sugar or high fat foods is also advisable, as these can be inflammatory.

Taste disorder experts advise eating fruits and vegetables individually rather than as combination dishes such as casseroles and one-pots. This is because combination dishes hide individual flavors and dilute the taste.

Additionally, people can try adding more robust flavors such as citrus, herbs, and spices.

Some people experience nausea or vomiting as symptoms of COVID-19. They may not feel like eating but should ensure they hydrate with fluids.

Individuals should consult a doctor if they have excessive vomiting or go off food for longer than expected.

Learn more about food poisoning versus COVID-19.

Here are some frequently asked questions about COVID-19 and food.

According to the CDC, most people with mild to moderate COVID-19 can spread SARS-CoV-2, the virus that causes the disease, no more than 10 days after symptom onset.

However, most individuals with more severe to critical illnesses are likely to be able to spread the virus no more than 20 days after their symptoms began.

The Food and Drug Administration (FDA) advises that there is no evidence of food packaging having associations with the transmission of SARS-CoV-2.

However, people can wipe down food packaging with an antibacterial wipe as an extra precaution.

Research suggests optimal nutrition and dietary nutrient intake can affect the immune system. So eating a nutritious, balanced diet can help people fight the virus.

When someone has COVID-19, they should aim to eat a nutritious, balanced diet that supports their immune system.

Nutrients, such as vitamin C, zinc, and omega-3 fatty acids, can help the process of recovery. Similarly, a person should ensure adequate fiber and protein from nutritious sources.

If someone has lost their sense of taste or smell, they should avoid eating too many inflammatory foods such as sugar and fat. Instead, they may want to try eating individual fruits and vegetables rather than one-pot meals that disguise their flavor.

Read more here:
What to eat when you have COVID - Medical News Today

These days, the word inflammation is enough to make anyone nervous. A growing body of research associates it with diabetes, heart disease, rheumatoid arthritis, asthma, and more leading us to buy anti-inflammatory supplements and eat antioxidant-rich foods. Many of these supplements and eating habits are healthy, but theres an important point that were missing: Good inflammation also exists, and its very important for our bodies. Heres why.

As explained in a 2018 Oncotarget research paper, inflammation is a biological response of the immune system. And it gets useful when an infection enters the body.

Certain signaling molecules in the immune system will recognize foreign molecules in the body as pathogens. When this happens, the molecules issue an alarm to innate immune cells (which recognize certain molecules on many different pathogens think of them as general fighters), which begin attacking the infection. This response results in inflammation, which takes the form of fever, chills and sweats, sinus congestion, and other symptoms.

While innate immune cells do a good job of attacking infections, they arent the best equipped for targeting specific pathogens. Thats where T and B cells come in. (Think of these as specialized fighters). T cells either target specific pathogens and infected cells or help control the immune response. B cells create customized antibodies (proteins) that attach to pathogens in order to help destroy them. T and B cells take longer to respond to an infection, but are crucial to clearing it out of the body.

In addition, the immune system can recognize toxic compounds that enter the body or sit on top of the skin. This recognition process causes an inflammatory response (such as swelling or redness). With time, specific cells help clear the toxic molecules to prevent them from causing further damage to the body.

If youve ever scratched your leg or twisted your ankle, youre familiar with the inflammation that follows. The body sends blood, fluid, and white blood cells to the injured area to start mitigating the damage and begin repairs.

While pain, redness, and swelling arent pleasant, theyre an important step in the healing process. Without an inflammatory response, our cuts and bruises would never heal.

The key difference between good and bad inflammation appears when an inflammatory response becomes chronic. Acute inflammation is generally good, because its a useful response to immediate injuries or infections. Chronic inflammation, however, occurs when the inflammatory response goes on for too long, or the response is too great.

Examples of this include allergic reactions, rheumatoid arthritis, and heart disease. During an allergic reaction, the immune system inaccurately detects an allergen (like peanut butter) as a foreign invader and mounts a response so huge that it harms the body. In heart disease, sustained, low levels of inflammation can irritate blood vessels and promote the formation of plaque. And in rheumatoid arthritis, the immune system attacks the lining of the joints.

The takeaway? Finding ways to reduce chronic inflammation is a good thing. Just remember that good inflammation happens for a reason.

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3 Ways Good Inflammation Helps Your Body - First For Women

ACLF is a systemic inflammatory disease accompanied by immune dysfunction and disturbances in energy metabolism. ACLF has a high short-term mortality, which increases with the incidence of failing organs. Although many studies regarding ACLF have been performed, its underlying mechanisms remain to be fully explored. Meanwhile, it has been demonstrated that a strong immune response is a key mechanism of ACLF18,19. Therefore, we explored the intrinsic mechanisms of immune cell infiltration in ACLF using an effective informational biology approach.

Herein, we identified macrophage-associated co-expressed gene modules in ACLF for the first time using a combination of WGCNA and CIBERSORT. We identified immune-related key genes and provided new pathways for future studies on effective targets for ACLF treatments. After bioinformatics and qRT-PCR experiments, 10 immune-related hub genes were identified and mir-16-5p and mir-26a-5p were validated. Altogether, these results might provide new strategies for understanding the pathogenesis of ACLF and developing targeted therapeutic molecules.

In the present study, we evaluated potential pathways and biological processes of ACLF using enrichment analyses. GSEA is characterized by the analysis of collections of genes rather than individual genes, which helps to avoid the inability to reproduce individual high-scoring genes due to poor annotation. In the GSE142255 dataset, the GSEA indicated that immune response, inflammatory pathways, and metabolic pathways were mainly involved in ACLF. Then, we found that the downregulated DEGs were mainly engaged in immune response and inflammatory reaction, while upregulated ones regulated biosynthetic and substance metabolism pathways. These results reflected two major biological processes that co-occurred during the progression of ACLF regulated by different genes: imbalance of immune-inflammatory response and energy metabolism. According to the BP analysis, immune cell activation, differentiation, proliferation, and migration were the major biological processes in ACLF, leading to an expanding inflammatory response. Recently, it was reported that excessive activation of the immune response not only causes a systemic inflammatory response, which subsequently mediates immune-related tissue damage, but also leads to high energy demand. Consequently, the immune system competes with peripheral organs for energy, triggering an immune-related energy crisis in the organism and increasing the risk of organ failure18,20,21. Overall, it was suggested that the hyperimmune response and dysfunctional energy metabolism in ACLF are biologically coupled processes, largely influencing ACLF progress.

CIBERSORT is a widely used deconvolution machine algorithm for estimating the composition of immune cells. It shows superior performance in the identification and fine delineation of immune cells when processing highly noisy mixture data8,22. Here, the CIBERSORT results showed that the population of M0 and M1 macrophages was significantly increased in ACLF patients compared to healthy subjects. We also labeled markers on the surface of macrophages by immunofluorescence and validated their increase in M1 macrophages in the liver of ACLF rats. Macrophages can be polarized into M1 or M2 phenotypes. M1 macrophages can release significant influxes of inflammatory factors and induce cytokine storms with pro-inflammatory effects. On the other hand, M2 macrophages secrete tissue repair factors and exhibit anti-inflammatory and reparative properties23,24. Kupffer cells, a type of macrophage that resides in the hepatic sinusoids, mainly perform innate immune and inflammatory responses25. To search for highly related gene modules, WGCNA identifies similar gene clusters and gene modules by hierarchical clustering. WGCNA also supports the analysis of correlations between gene modules and phenotypic traits26,27. To identify gene clusters associated with macrophages, we performed WGCNA and identified gene modules closely related to M1 macrophage polarization, including the coral1 (containing 3631 genes) and darkseagreen4 (containing 307 genes) modules. Based on the WGCNAs gene modules, we screened immune-related DEGs and constructed a PPI network to find ACLF immune-related hub genes.

Ten hub genes were screened using CytoHubba: RSL1D1, RPS5, CCL5, HSPA8, PRKCQ, MMP9, ITGAM, LCK, IL7R, and HP (Table 3). The differential expression of hub genes was further confirmed by qRT-PCR in ACLF rats. Overall, MMP9, ITGAM, and IL7R were highly expressed during ACLF. Furthermore, ACLF has high 28-day mortality that is closely related to the degree of organ failure in patients. Hence, we used the GSE168048 microarray containing gene expression data of ACLF patients who survived or died at 28days for further investigation. We verified that the expression of RPS5, PRKCQ, MMP9, LCK, ITGAM, IL7R, and CCL5 differed between surviving and deceased patients, suggesting that these genes might be closely related to ACLF progression and could be used to predict ACLF survival status at 28days. Notably, downregulated genes were mostly involved in the promotion of immune response, while the upregulated gene, MMP9, was associated with hepatocyte necrosis. These results suggested that the coexistence of immune paralysis and cell necrosis is a potential ACLF mechanism leading to poor prognosis.

Moreover, miRNAs are potential targets in numerous diseases and control various biological processes. As short-chain RNAs with a coding length of only about 22 nucleotides, miRNAs cannot directly be translated into proteins, but rather regulate protein synthesis by disrupting the stability of target mRNAs and inhibiting their translation through complementary pairing28. Studies have explored the relationship between miRNAs and diseases and proposed the use of miRNAs as a biomarker for disease diagnosis and prognosis as well as a small molecule drug target29. Considering the time and cost of experimental studies, we adopted a database approach combined with experimental validation to study miRNAs that were significantly altered in ACLF. The miRNet 2.0 integrates data from 15 prediction databases and provides visual analytics to enable a more comprehensive and convenient evaluation of the interactions between miRNAs, mRNAs, lncRNAs, and transcription factors15. Herein, we used miRNet 2.0 to construct a miRNA-hub genes network to explore potential miRNAs related to ACLF. During the validation, two miRNAs were significantly altered in ACLF rats: mir-16-5p presented increased expression and mir-26a-5p showed decreased expression. M1 macrophages can transfer mir-16-5p to gastric cancer (GC) cells by secreting exosomes and triggering a T-cell immune response to suppress tumor formation by decreasing the expression of PD-L130. It has been demonstrated that mir-26a-5p decreases with ACLF progression and is associated with worsening liver function and increasing liver disease severity31. However, further studies are needed to validate the potential association between miRNA regulatory networks and ACLF.

Predicting potential disease-associated miRNAs is very meaningful and challenging. Thus, researchers have developed several computational methods and models to perform those predictions. These models can be classified into four categories: score functions, complex network algorithms, machine learning, and multiple biological information29. For example, Chen et al.32 proposed an inductive matrix filling model (IMCMDA) for miRNA-disease association prediction. By integrating miRNA and disease similarity information into the matrix-populated objective function, a low-dimensional representation matrix of miRNAs and diseases was obtained, which was finally combined into a miRNA-disease association score matrix. Chen et al.33 improved the HGIMDA model and further provided the MDHGI model. This model first decomposes the miRNA-disease association matrix to remove data noise, then uses the topological information implied to make predictions through heterogeneous graph inference. It combines machine learning with network analysis methods to make effective predictions for new disease-miRNA associations. Further, Chen et al. proposed an Ensemble of Decision Tree-based MiRNA-Disease Association prediction (EDTMDA) model34 based on the construction of multiple decision trees by randomly selecting negative samples, miRNA features, and disease features, and by dimensionality reduction of the features. The mean of the predicted values from these decision trees is used as the miRNA-disease association score. This model incorporates feature dimensionality reduction into integrated learning to remove noise and redundant information in the learning process and reduce the computational complexity of the model with higher prediction accuracy. Moreover, Liu et al.35 proposed a DFELMDA-based deep forest integrated learning approach to infer miRNA-disease correlations. This model trains a random forest by constructing two auto-encoders based on miRNAs and diseases, extracting low-dimensional feature representation, and finally predicting potential miRNA-disease associations through the random forest. This model combines feature and deep forest-integrated learning models to enhance the prediction accuracy. Bioinformatics-based prediction methods are constantly evolving. Nevertheless, different models have almost different predictive performance for the same datasets. Hence, it is not only necessary to collect large-scale experimental data but also consider other algorithms to improve predictive performance for specific diseases.

Besides the methods covered in this study, the multi-field predictive research of bioinformatics offers a unique perspective on the exploration of diagnostic and therapeutic tools for diseases, not only for ACLF. Currently, with the development of genome-wide technologies, there is an increasing need to explore models that detail the exact mechanisms in which genes and proteins interact to form complex living systems. A gene regulatory network (GRN) is a network of interactions between gene molecules. An improved Markov blanket discovery algorithm based on IMBDANET has been proposed and can effectively distinguish between direct and indirect regulatory genes from GN and reduce the false-positive rate in the network inference process36. Additionally, RWRNET is an algorithm of Random Walk with Restart (RWR) modified by restart probability, initial probability vector, and roaming network applied to GRN that continuously maps the global topology of the network and estimates the affinity between nodes in the network through circular iterations until all nodes are traversed37. In contrast, IMBDANET uses a Markov blanket discovery algorithm for network topology analysis and processing, identifying direct and indirect regulatory genes while solving the problem of isolated nodes. On the other hand, RWRNET focuses on global network topology information but it cannot handle isolated nodes. Finally, the integration of different methods can be more beneficial for the prediction of gene regulatory relationships.

Here, we combined WGCNA and CIBERSORT algorithms and employed GSEA, KEGG, and GO enrichment analyses to explore immune-related hub genes and potential biological mechanisms in ACLF. The hub genes and miRNAs involved in ACLF regulation were also further validated. Since there are few studies regarding ACLF mechanisms, adopting bioinformatics analyses provided valid information and guidance for our research. However, our current study also has some limitations. First, we used an animal model rather than samples from humans to validate the ACLF immune-related hub genes, and the results from animal studies should be treated with caution. Furthermore, although these hub genes and miRNAs were altered and might be involved in the development of ACLF, whether these genes can be new therapeutic targets for ACLF still needs to be explored. Therefore, further experiments are required to validate our findings and explore potential ACLF mechanisms.

Original post:
Bioinformatics analyses of potential ACLF biological mechanisms and identification of immune-related hub genes and vital miRNAs | Scientific Reports -...

The largest army of immune cells in the body work together to filter out all the pathogens we inhale every day, defeating viruses and other invaders without us ever knowing.

But viruses have evolved tricks of their own, allowing them to infect the cells and use its molecular machinery to copy itself over and over before spreading down into the lungs and the rest of the body.

Current generation COVID-19 vaccines offer fantastic protection against serious illness and death by recruiting antibodies in the blood that can block the virus spreading to the organs. But these vaccines struggle to generate antibodies in the nose.

The big issue is infection. The current gen of vaccines dont stop infection, said Associate Professor Nathan Bartlett, head of viral immunology at Hunter Medical Research Institute and the University of Newcastle. The virus can continue to circulate, attacking the vulnerable and finding new ways to mutate around our defences.

At least eight nasal vaccines for COVID-19 are in development, according to the World Health Organisation.

They include a phase 1 trial of Tetherexs nasal COVID-19 vaccine SC-Ad6-1 led by the University of Queenslands Associate Professor Paul Griffin. The spray contains a harmless virus modified to look like SARS-CoV-2. The virus infects nose cells and replicates theoretically prompting the immune system into a strong response.

People wear face masks in Melbourne in July.Credit:Getty

Bartlett is working with ENA Respiratory to develop INNA-051, a nose spray full of molecules that bind to cell receptors that trigger the bodys powerful innate immune system, which is capable of fighting off viruses without needing antibodies or T cells. It gives the immune system a head start, Bartlett said.

However, that head start lasts only a week. Bartlett expects the spray would need to be used every week to maintain protection.

In animal trials, the treatment dramatically reduced COVID-19s ability to replicate in the nose. The treatment Bartlett is careful not to call it a vaccine is now in phase 2 clinical trials in humans.

Nasal vaccines face a key challenge: getting a strong and long-lasting immune response in the nose.

The nose is constantly exposed to viruses, bacteria and pollution, so every time we breathe in, immune cells there are much less aggressive than in other parts of the body.

All the stuff were breathing in, if we responded aggressively, wed have a lot more allergies, Griffin said. And antibodies generated in the nose are typically short-lived.

Another problem is getting the dose right. This is easy with a syringe into a vein, but very difficult when spraying fluid into the nose. What if the users nose is blocked? What if they sneeze? The vaccines also need to be carefully designed to not cause an allergic reaction.

And then there is the mucus itself. Vaccines need to penetrate it to get an immune response and then must stay around long enough to really fire up the system a tough task when mucus is constantly being cleaned out of the nose.

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Griffin said he was confident well get at least one intranasal protection soon. Bartlett is less so. He points out that regulators are unlikely to offer quick emergency approval to new vaccines now and any vaccine that gets approved would likely be out of date immediately, as the virus continues to mutate.

Whether it will have a huge impact on this pandemic, Im not sure, he said. But its critical for protecting us against the next one.

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Nasal vaccines could snuff out COVID, but the hurdles are not to be sneezed at - Sydney Morning Herald

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Paxlovid is one of a handful of drugs authorized to treat COVID-19 in the United States. As recently experienced by President Biden, its use is not without challenges and sometimes leads to relapse. The President, like many others, tested negative for COVID-19 after five days of Paxlovid treatment, then tested positive again a few days later.

Although such treatment rebound rates are assumed to be low, there is little data to support or dispute that assumption. Researchers at Case Western University looked at the real-world experiences of 13,644 patients who were treated with Paxlovid or Lagevrio (molnupiravir) during the first half of 2022. The study was intended to determine the prevalence of three types of rebound outcomes with these two therapies, each of which has emergency use authorizations as treatments for COVID-19.

Comparing Paxlovid and Lagevrio

In that study (currently in preprinton medRxiv, co-author Pamela Davis, M.D. and colleagues found that the 7-day and 30-day rebound rates associated with Paxlovid treatments, respectively, were 3.53% and 5.4% for COVID-19 reinfection; 2.31% and 5.87% for COVID-19 symptoms; and 0.44% and 0.77% for hospitalizations.

The rebound rates for patients treated with Lagevrio were somewhat higher. The 7-day and 30-day rebound rates for this therapy were 5.86% and 8.59% for COVID-19 infection; 3.75% and 8.21% for COVID-19 symptoms; and 0.84% and 1.39% for hospitalizations. Propensity-score matching rendered these differences negligible, however.

Patients who rebounded from either therapy had a significantly higher prevalence of underlying medical conditions than those without, the authors noted in the paper. However, There is no underlying condition that stands out, Davis told BioSpace. We had thought (the rebound group would be composed of) immunocompromised people, but heart disease, hypertension, mood disorders and so on, all are increased in the rebound group.

The implications upon dosage or duration of treatment have not been determined, she said, but changes should be considered. If I had a patient with risk factors, for whom the disease might be more than a nuisance, I might be tempted to treat for a longer period of time.Also, I would try to start the drug earlier in the course of the disease, when the virus has had less time to replicate, but I have no data to show that would work, she acknowledged.

Davis and her colleagues called for continued surveillance of patients after treatment with either Paxlovid or Lagevrio, and for additional studies to determine the mechanism of action of the rebound as well as the most effective dosing and duration regimen.

Paxlovid is the combination of two drugs: nirmatrelvir, which blocks viral replication, and ritonavir, which slows the degradation of nirmatrelvir. Ian Chan, co-founder and CEO of Abpro, told BioSpace the therapy is like a carpet-bombing approach. It can kill COVID, and healthy cells as well. Because its a small molecule it also can have multiple drug-to-drug interactions, so its high efficacy comes with high toxicity, he noted. There also a risk for COVID to mutate around it, developing resistance as the virus changes.

No one yet knows why Paxlovid rebound occurs but, Our theory is that because this drug is prescribed very early on, there is less chance for the immune system to develop a response (to the virus), Chan said.

One solution to therapeutic rebound, he said, is to develop more types of therapies. COVID-19, unfortunately, is going to be around for a while. We need a battery of different treatments just to be ready for the different possible scenarios.

Abpro is developing monoclonal antibody (mAb) therapies for COVID-19, as well as for immuno-oncology and ophthalmology. The benefit, Chan explained, is that the safety of mAbs has been proven. These are natural molecules your immune system already is producing on a day-to-day basis. Their toxicity generally is very low and efficacy is very high, and they are very targeted therapies, he said. So far, there have been no therapeutic relapses.

Potential Therapies for the Immunocompromised

To treat COVID-19, Abpro is focusing on treatments for the approximately 15 million immunocompromised individuals in the U.S. who, because of their weakened immune systems, dont respond to vaccines.

The companys lead compound, ABP-300, is in Phase II clinical trials. It basically prevents the virus from binding in the body, thus neutralizing it. Other antibodies are undergoing investigational new drug application (IND)-enabling studies.

One of those, ABP-C19-01, is a cocktail of antibodies that lowers patients risk of contracting COVID-19 if they are exposed to the SARS-CoV-2 virus. This therapy isnt a vaccine, Chan stressed. Vaccines are meant to stimulate an immune response, which generates an antibody. This delivers the antibody directly. It is complementary to vaccines.

Another company, 3CL Pharma, a subsidiary of Todos Medical, is developing possible mitigations for Paxlovid rebound that work by supporting the immune system and inhibiting 3CL protease activity. Its solutions include Tollovir and Tollovid.

A Phase II trial of Tollovir, which is being developed to treat hospitalized COVID-19 patients, was completed in May in Israel.

Were developing Tollovir as an alternative for Paxlovid, Gerald Commissiong, CEO of Todos Medical, told BioSpace. It is similar to the nirmatrelvir portion of Paxlovid, but is a botanical, so it works slower. Also, rather than affecting the virus directly, Tollovir works on the 3CL protease, which is responsible for helping a virus that already has replicated to infect other cells.

The other compound, Tollovid, is being developed as an over-the-counter dietary supplement. According to Todos literature, it has very strong 3CL inhibition. It may be taken as a 5-day regimen, or in a daily formulation for immune system support. It may become a rescue agent for Paxlovid rebound.

Continue reading here:
Paxlovid Rebound: RWE Analysis and Alternative Therapies in Development - BioSpace

Clinico-pathological features of the GC patients

Eighty patients were enrolled in this study between July 2014 and December 2019 (Table1). The median age of the patients was 60 years (range, 5466 years), and most patients were men (76.3%). Among the 60 patients subjected to immunotherapy, 21 were treated with standard-of-care anti-PD-1/PD-L1 antibodies and 39 were treated as part of clinical trials (NCT03472365, NCT03713905). Archived pre-treatment samples were available from all patients. Ten (12.5%) patients were EBV(+) and 11 (13.75%) had confirmed deficient DNA mismatch repair (dMMR) GC.

To investigate the landscape of TIICs within the GC specimens, we quantified the density and spatial location of immune cells in 80 full-face formalin-fixed paraffin-embedded (FFPE) samples via m-IHC staining; the multiplex determination of the sub-cellular expression of 16 proteins was performed (Fig.1a). First, haematoxylin and eosin (H&E)-stained tissue sections were reviewed by two pathologists (S.Y. and H.Y.J.) to identify tumour core (TC), invasion margin (IM), and peri-tumoural normal (N) areas, which we refer to as regions of interest (ROIs) (Fig.1b). The m-IHC panels analysed are depicted in Fig.1cf. A total of 6488 high-power fields (TC: 4477, IM: 993, N: 1018) were imaged for all patients. A supervised image analysis system (inForm) was used to classify each image into tumour nests and stromal areas based on machine learning (Fig.1g). Cell segmentation showed nuclear, cytoplasmic and membranous outlines. Cell phenotyping data were obtained based on the positivity and relative intensity of all markers in one panel. The cell density, calculated for all regions (tumour + stroma), was measured separately in the tumour and stroma. Thereafter, TIICs were analysed at the single-cell level and 26 major populations were characterised (Supplementary Fig.1a).

a Schematic representation of the experimental design and analytical methods used in this study. b Selection of the regions of interest (ROIs) in representative images of haematoxylin and eosin (H&E)-stained formalin-fixed paraffin-embedded tissues. TC, tumour core; IM, invasion margin; N, normal tissue. Scale bar: 3mm. cf Representative composite and single-stained images of the multiplex immunohistochemistry panels used. Scale bar: 200m. g Overview of the automated image analysis pipeline.

To examine the distribution of TIICs within the tumour microenvironment, we analysed their spatial density in the TC, IM, and N areas. The enriched co-occurrence of immune populations defines a structured immune environment (Supplementary Fig.1a). A significant increase in the overall density of CD68+ cells was observed within the TC compared with that in the adjacent normal tissues; an opposite trend was observed for CD8+ and CD20+ cells (Fig.2a). Next, for a higher degree of detail, the distribution of each TIIC was explored. CD8+, CD8+PD-1LAG-3, CD20+ and CD68+CD163+HLA-DR cells accumulated at the IM and decreased toward the TC. In contrast, CD8+PD-1+TIM-3+, CD8+PD-1TIM3+, CD8+PD-1+LAG-3+TIM-3+, CD8+PD-1+LAG-3TIM-3+, CD4+FoxP3+CTLA-4+, CD4+FoxP3CTLA-4+, CD68+, CD68+HLA-DR+CD163 cells accumulated at the TC and decreased toward the IM. Interestingly, a higher density of CD4+FoxP3+ and CD4+FoxP3+PD-L1+ cells was found within the TC than in normal tissues (Fig.2b, Supplementary Fig.1b), highlighting the heterogeneous distribution of TIICs in GC.

a Constitution of the main tumour-infiltrating immune cell (TIIC) populations. KruskalWallis test with the Dunns multiple comparison test. b Density of TIICs across the regions of interest (n=80). TC, tumour core; IM, invasion margin; N, normal tissue. Immunofluorescence staining images refer to the co-expression of the corresponding markers and DAPI (nuclei). Scale bar: 20m. Box and whiskers represent mean1090 percentile. KruskalWallis test with Dunns multiple comparison test. c TIIC density grouped by subtypes. d Overall survival of 80 patients based on the density of TIICs. The individual TIICs were divided into high (>two-thirds of the patients; blue line) or low density (two-thirds of patients; red line). Log-rank (MantelCox) test was used. A two-sided P<0.05 was considered statistically significant.

Additionally, the localisation of TIICs with respect to the tumour nest and stroma areas (defined in Fig.1g) was further examined. CD8+, CD4+ and CD20+ cells were located primarily in the stroma and were less prevalent in the tumour nest. In contrast, CD66b+ cells were more prevalent in the tumour nest than in the stroma (Supplementary Fig.2a).

To evaluate the tumour immune microenvironment in GC, we compared the density of TIICs in the context of distinct clinico-pathological factors (Fig.2c, Supplementary Fig.3ae). Generally, there were few significant differences between Lauren classification, tumour differentiation and tumour location (oesophagogastric junction or not) with respect to densities of TIICs (Supplementary Tables15, Supplementary Fig.4a). Additionally, there were few differences in the density of TIICs between HER2-positive and -negative GC (Fig.2c). Overall, the density of total CD8+, CD4+ and CD68+ cells was associated with the disease stage. Additionally, advanced-stage GC (III-IV) samples showed a higher density of exhausted CD8+ T cells, CD4+FoxP3 cells and so on.

Furthermore, we analysed the density of TIICs in GC of different molecular subtypes (Supplementary Tables68). Interestingly, EBV-positive tumours showed higher densities of CD8+PD-1LAG-3 T cells than EBV-negative ones. EBV (+) GCs were characterised by abundant immune cell infiltration; however, not all EBV (+) patients responded to immunotherapy, indicating that specific immune cell infiltration is needed. Proficient MMR (pMMR) tumours showed a significantly higher abundance of total CD4+, CD68+, CD20+ and CD66b+ cells than dMMR tumours. Higher CD68+ and CD66b+ cells (neutrophils) are known to contribute to resistance to PD-1/PD-L1 treatment in several cancers13,19. We classified patients into four combined positive score (CPS) groups: CPS<1, 1 CPS<5, 5 CPS<10 and CPS10. Remarkably, the abundance of TIICs, including CD8+, CD4+, CD68+, CD20+ and CD66b+ cells, significantly increased with the increase in CPS, indicating a hotter tumour immune environment. However, the comparison between CPS 5-10 and CPS10 did not show a significant difference, providing evidence for the cut-off selection in clinical trials of anti-PD-1/PD-L1-based therapies. Altogether, as shown in Fig.2c, our results suggest that the infiltration pattern of immune cells depends on, but is not restricted to, GC molecular subtypes.

Next, we sought to understand whether the number of TIICs is correlated with patient survival. We found that higher levels of tumour-infiltrating T cell subsets, including CD8+PD-1+LAG-3+TIM-3+, CD4+FoxP3+CTLA-4+ T and CD68+STING+ cells, were associated with inferior overall survival (OS) in 80 patients (Fig.2d, Supplementary Fig.4b). CD8+PD-1+LAG-3+TIM-3+ cells [high vs. low, hazard ratio (HR) 1.98, 95% confidence interval (CI; 1.123.50)] and CD68+STING+ cells [high vs. low, HR 1.83, 95%CI (1.013.33)] were significantly associated with OS, as revealed by multivariate Cox analysis (Supplementary Table9). Collectively, these data highlight the clinical relevance of tumour-infiltrating T cells in the survival of GC patients.

Additionally, we analysed the prognostic value of the density of TIICs in the context of tumour and stromal cells. The data showed a similar trend for CD4+FoxP3CTLA-4+ T and CD4+FoxP3+CTLA-4+ T cells in both contexts. However, higher infiltration of CD8+PD-1+LAG-3+TIM-3+ T cells and CD68+ macrophages was associated with poorer OS with respect to tumour nests. In addition, higher infiltration of CD8+PD-1+TIM-3+ T cells, CD66b+ neutrophils and CD68+STING+ macrophages was related to a shorter OS with respect to the stroma (Supplementary Fig.2b). Therefore, these results highlight the value of studying immune cell density in defined tissue regions.

Given our ability to precisely define the positions of individual tumour cells and TIICs, we next sought to evaluate the clinical significance of the proximity between them. The observation that certain TIICs, including CD68+ cells, were enriched in the tumour region suggested that the proximity of TIICs to tumour cells might influence their phenotype. To further study these localisation patterns, a bioinformatics tool (pdist; see Methods) that determines the nucleus-to-nucleus distances between any two cell types was used. To incorporate both cell proximity and quantity, an effective score parameter was established: the proportion of TIICs near tumour cells (within the defined distance criteria introduced; Fig.3a). In other words, this score was calculated by the number of paired immune cells and tumour cells divided by the total number of immune cells across the whole slides to maintain the spatial variation to a large extent. Therefore, using this formula, a higher effective score indicates that within a certain distance, there is a higher density of tumour cells around the immune cells. Importantly, across the three distances considered (010/020/030m), CD8+PD-1+LAG-3+ T cells and CD66b+ neutrophils were the ones with higher effective scores (Fig.3b).

a Illustration of the distance analysis involving immune and tumour cells. Red dots: tumour cells; green dots: immune cells. The white translucent circle represents the radius. Effective score=number of paired immune cells and tumour cells/number of immune cells. Scale bar: 100m. b The distribution of the effective score of tumour-infiltrating immune cell (TIIC) populations in the tumour core in 10-, 20- and 30m increments (n=80). Error bars represent meanSEM. c Effective score of TIICs in patients grouped by gastric cancer subtypes. EBV, EpsteinBarr virus status; MMR, DNA mismatch repair; CPS, combined positive score. d Overall survival of the 80 patients based on the effective densities (010m and 020m) of TIICs. The individual immune infiltrate values were divided into high (> two-thirds of the patients in the cohort; blue line) or low density ( two-thirds of patients in the cohort; red line). Statistical relevance was defined using the log-rank (MantelCox) test. A two-sided P<0.05 was considered statistically significant.

We also calculated the distance between each TIIC and the closest tumour cell. Neutrophils, B cells and macrophages were located closer to tumour cells. We then analysed the distances between TIICs and tumour cells according to the PD-L1 CPS. In general, TIICs were located closer to tumour cells in patients with CPS10 (compared with the picture with respect to all other groups; Supplementary Fig.6a).

Interestingly, the effective scores also differed between different GC molecular subtypes, including those depending on the EBV, PD-L1 CPS, MMR and HER2 status (Supplementary Figs.5ae, 6b; Supplementary Tables1017). For instance, a significantly higher effective score of exhausted T cells (CD8+PD-1+LAG-3+TIM-3, CD8+PD-1TIM-3+), M1 (CD68+CD163+HLA-DR) and M2 (CD68+HLA-DR+CD163) macrophages within a 20m radius was observed in HER2-negative GC compared with that in HER2-positive GC (Fig.3c, Supplementary Fig.5b).

The combination of multiplexed imaging and machine learning implied that the density of TIICs within GC is linked to patient survival. For further detail, the effective density (the absolute number of TIICs near tumour cells within a 20m radius) was used as an additional measurement. This radius was pre-selected to identify immune cell populations most likely capable of effective, direct, cell-to-cell interactions with tumour cells, consistent with prior studies in multiple gastrointestinal tumour types11,20,21. Curiously, we found that patients with higher effective densities (radius of 020m) of CD68+STING+ macrophages, CD68+HLA-DR+CD163 STING+ macrophages and neutrophils showed significantly shorter OS than those with lower effective densities (Fig.3d). Importantly, the prognostic value was still significant after adjustment using the multivariate Cox model (Supplementary Table18). Other immune cell phenotypes were not associated with OS (Supplementary Figs.6c and 7c). These results indicate that the influence of TIICs on patient survival is dependent not only on the number of TIICs but also on their proximity to tumour cells. Overall, our data highlight that both the location and density of TIICs should be taken into consideration for prognosis predictions.

Human tumours contain exhausted T cells expressing multiple immune checkpoints; it has been proposed that these cells mediate resistance to PD-1 blockade. Thus, next, we investigated whether the density of TIICs and respective effective scores were associated with the clinical outcomes of anti-PD-1/PD-L1 immunotherapy. All 60 patients who received immunotherapy were assigned to the training (n=44, generated retrospectively from 15/11/2016 to 17/7/2019) and validation (n=16, generated prospectively from 29/7/2019 to 19/12/2019) cohorts. Importantly, we ensured that the clinical characteristics of the training and validation cohorts were balanced (Table2). We used logistic regression analysis to assess the association between TIICs and the objective response rate (ORR) in the training cohort. Importantly, we found that the density of CD4+FoxP3PD-L1+ T cells and the effective score of CD8+PD-1+LAG-3 T cells were closely associated with a positive response to anti-PD-1/PD-L1 therapy; conversely, CD8+PD-1LAG-3 T cells and CD68+STING+ macrophages were closely associated with a negative response to anti-PD-1/PD-L1 therapy (Supplementary Table19).

The density of CD4+FoxP3PD-L1+ T cells, CD8+PD-1LAG3 T cells and CD68+STING+ macrophages, and the effective score of CD8+PD-1+LAG3 T cells were used to define a TIIC signature (Fig.4a), with the potential to improve the ability of identifying responders to anti-PD-1/PD-L1 immunotherapy. We used four types of machine learning models and calculated the area under the curve (AUC) of the training and validation cohorts, including extra tree classifier (ETC), AdaBoost classifier (ABC), gradient boosting classifier (GBC) and multi-layer perceptron (MLP) models. In the validation cohort, the average AUCs of the four algorithms were 0.80, 0.85, 0.77 and 0.75, respectively (Fig.4b, c, Supplementary Table20). The corresponding 95% CIs were narrow, suggesting that the TIIC signature can indeed be used to predict the response to immunotherapy (Supplementary Table20). Importantly, the four algorithms showed a similar performance before and after adjusting for the hyper-parameters, indicating the strength of the predictive value of the TIIC signature itself (Supplementary Fig.7a). Furthermore, we explored the predictive power of the TIIC score combined with CPS, EBV status and MMR status. The combined TIIC signature had a better AUC in the ETC, GBC and ABC models, but not in the MLP model (Supplementary Table21).

a Definition of the tumour-infiltrating immune cell (TIIC) signature. Red arrows highlight specific immune cells. b Average area under the curve (AUC) of TIIC signature and combined TIIC signature (TIIC+ EpsteinBarr virus status+mismatch repair status+PD-L1 combined positive score) in the four machine learning models in the validation cohort. c Representative receiver operating characteristic (ROC) curves for the performance of the identified TIIC signature and combined TIIC signature in gastric cancer patients subjected to immunotherapy in the validation cohort. ETC extra tree classifier, GBC gradient boosting classifier, ABC AdaBoost classifier, MLP multi-layer perceptron.

We quantified the contribution of each marker in the prediction models through feature importance using the scikit-learn package (Supplementary Tables22, 23). We outputted the feature importance and the average value of each parameter to present its contribution. As shown in Fig.5a, the effective score of CD8+PD-1+LAG-3 cells had higher feature importance than the density of CD68+STING+, CD4+FoxP3PD-L1+, or CD8+PD-1LAG-3 cells in ETC, GBC and ABC machine learning models. As presented in Fig.5b, the effective score of CD8+PD-1+LAG-3 cells had higher feature importance than that of the other three immune cell types, EBV, MMR and PD-L1 CPS. Thus, the dominant predictive marker is the spatial organisation for response to immunotherapy.

a, b The feature importance of each marker in the prediction model. c, d KaplanMeier curves of the (c) immune-related progression-free survival (irPFS) and (d) immune-related overall survival (irOS) of anti-PD-1/PD-L1-treated patients stratified by the tumour-infiltrating immune cell (TIIC) signature in the validation cohort. Log-rank (MantelCox) test was used for analysis.

We also evaluated the predictive values of other candidate biomarkers. AUCs of 0.58 and 0.76 in the training and validation cohorts, respectively, were defined for PD-L1 CPS (Supplementary Fig.7b). We analysed the treatment response based on EBV status, MMR status and HER2 expression in univariate and multivariable logistic regression models (Supplementary Table24). EBV-positive status and dMMR tended to be associated with a better response. The association of HER2 expression with treatment response was not consistent between univariate and multivariable models. Therefore, taken together, our data suggest that the TIIC signature has a greater power for patient stratification (Supplementary Fig.7b).

Next, we investigated the prognostic use of the TIIC signature; the univariate Cox proportional hazard regression model was used to calculate the HR of each indicator. Then, we used the HR of each indicator as the weight to multiply the value of the indicator itself and then calculated the weighted sum of the four indicators. In this analysis, we categorised patients into high- and low-score groups based on the TIIC signature. The difference in the survival probability over time between the groups was calculated using the KaplanMeier method. As expected, we observed a significant difference in both immune-related progression-free survival (irPFS) and immune-related overall survival (irOS) in the validation cohort (Fig.5c, d, Supplementary Table25). Therefore, the TIIC signature might be useful to identify patients that will show active anti-tumour immune responses a priori.

See the article here:
Predicting response to immunotherapy in gastric cancer via multi-dimensional analyses of the tumour immune microenvironment - Nature.com

Wilmington, Delaware, United States, Transparency Market Research Inc. The conventional low-priced mainstay drugs for the treatment of malaria, sulphadoxine-pyrimethamine (SP) and chloroquine (CQ), are witnessing a decline in sales, as they are becoming comparatively ineffective. During the last two decades in Asia, the issue has become a major concern. This has resulted in the adoption of artemisinin (derived from the Chinese herb Artemisia annua) in Africa as a standard treatment.

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It helped in setting a milestone for the artemisinin combination therapy market. The herb has been used to treat fevers and malaria for more than 2000 years. The World Health Organization (WHO) has adopted artemisinin-based combination therapy (ACTs) as the first-line treatment for plasmodium falciparum malaria.

As a combination therapy, it has demonstrated superiority to other drugs because of its ability to wipe out parasites and its life cycle stages faster. Its use with cancer transferrin to cure cancer is also adding value to the artemisinin combination therapy market.

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Triple ACTs (TACTs) combine with artemisinin and two other existing partner drugs to work effectively as stop-gap therapy for the treatment of multidrug-resistant malaria. It will be used till the arrival of new antimalarial drugs. TACTs are secure, competent, well-accepted, and economical. This artemisinin combination therapy is likely to gain wider acceptance among the target consumers. The barriers in the deployment should be identified and stakeholders should make efforts to overcome them, which will new growth avenues in artemisinin combination therapy market.

Artemisinin Combination Therapy Market Introduction

Artemisinin is a plant derivative isolated from Artemisia annua, or sweet wormwood, which is known to effectively and swiftly reduce the number of plasmodium parasites in the blood of malaria patients. The WHO recommends artemisinin combination therapies (ACTs) as the first line of treatment for uncomplicated plasmodium falciparum malaria and as the second line of treatment for chloroquine-resistant P. vivax malaria.

This therapy combines an artemisinin derivative along with a partner drug, wherein artemisinin aids in reducing the number of parasites and the partner drug eliminates the remaining parasites. Efficacy of the treatment is determined by the drug combined with artemisinin, such as artesunate-mefloquine, dihydroartemisininpiperaquine, and artemether-lumefantrine.

Falciparum malaria was one of the most common lethal infections which was treated with chloroquine and sulfadoxine-pyrimethamine. However, these drugs are not effective as treatment primarily in the tropical regions owing to the resistance developed against these drugs. According to the Medicines Malaria Venture (MMV), over 445,000 deaths were reported in 2016 due to malaria. The globally rising malaria endemic and the changing climatic conditions would contribute to the trend aiding in the artemisinin combination therapy market growth.

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Artemisinin Combination Therapy Market- Competitive Landscape

The strategies adopted by the market players to enhance their market position include indication extension, focus on geographic expansion, and research & development. The national funding allocations, as announced by the Global Fund for 2018-2020, report that the funding available for the promotion of malaria programs is around US$1 billion.

Novartis AG

Novartis AG, established in 1895, is engaged in research, development, manufacturing and marketing of healthcare products across a range of areas, including neuroscience, ophthalmology, immunology, hepatology, respiratory, cardiology, dermatology, and cardio metabolic.

Sanofi

Sanofi, a leading pharmaceutical company is engaged in the manufacturing of prescription pharmaceuticals and vaccines. It is engaged in the development of cardiovascular, metabolic disorder, central nervous system (CNS), oncology, and thrombosis drugs and medicines.

Ipca Laboratories Ltd.

Ipca Laboratories is an Indian pharmaceutical company engaged in the manufacturing of over 350 formulations and 80 APIs for a range of therapeutic indications. According to the company, it is the market leader in India for anti-malarials with a market share of over 34% in 2018.

Artemisinin Combination Therapy Market - Dynamics

Growing malaria endemic

Malaria is a major health concern in endemic countries such as Sudan, wherein over 75% of the population is at the risk of acquiring the disease. Moreover, the widespread presence of chloroquine-resistant strains of P. falciparum in the malaria endemic countries makes artemisinin combination therapy the preferred choice of treatment. This is projected to fuel the growth of the artemisinin combination therapy market.

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Increase in the procurement of ACT treatment courses

Increase in access to ACTs in the malaria-endemic countries contributes to the rising success in reducing the global malaria burden. According to the WHO, over 2.7 billion ACT treatment courses were procured by global countries between 2010 and 2017. Moreover, over 62% of these procurements were made by the public sector. Strong pipeline for the development of new anti-malarial drugs and launch of newer artemisinin combinations for the treatment of malaria boost to the growth of the global artemisinin combination therapy market.

Challenges related to the availability of raw materials

Challenges pertaining to the availability of intermediate products and raw materials in the production of artemisinin-based combination therapies from agricultural sources are expected to restrain the global artemisinin combination therapy market. Furthermore, volatility in the artemisinin market leading to concerns over supply tightening could create significant risks to patients and market participants.

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Artemisinin Combination Therapy Market Insights and Emerging Trends by 2027 - BioSpace

The National Academies of Sciences, Engineering, and Medicine (NASEM) released on August 9, 2022, a report entitled Review of Fate, Exposure, and Effects of Sunscreens in Aquatic Environments and Implications for Sunscreen Usage and Human Health. NASEM was tasked by Congress and funded by the U.S. Environmental Protection Agency (EPA) to undertake a consensus study of the potential risk of ultraviolet (UV) filters on already threatened aquatic environments and the potential consequence to human health should sunscreen usage or composition be modified. NASEMs report reviews the state of science on the sources and inputs, fate, exposure, and effects of UV filters in aquatic environments, and the availability and applicability of data for conducting ecological risk assessments (ERA). It also reviews the epidemiological and clinical literature on the efficacy of sunscreen in preventing UV damage to human skin, the state of knowledge on potential human behavior changes, and the resulting health impacts related to skin cancer prevention from changes in sunscreen usage (e.g., reducing sunscreen use or switching to sunscreens with different active ingredients).

NASEM notes that the scope of the study is limited to the United States. According to the report, there are currently 16 UV filters allowed by the U.S. Food and Drug Administration (FDA) for use in any sunscreen sold in the United States, plus an additional proprietary UV filter, ecamsule, approved for use in limited products. While UV filters are used in a broad range of products, NASEMs scope was to focus on their use in sunscreens. The 16 UV filters include two inorganic UV filters, titanium dioxide and zinc oxide. The summary of the attributes of UV filters relevant for assessment of environmental risk includes the following information for titanium oxide and zinc oxide:

[View source.]

Original post:
NASEM Recommends That EPA Conduct Ecological Risk Assessment of UV Filters Found in Sunscreen, Including Titanium Oxide and Zinc Oxide - JD Supra

For the GeNose C19 sensor array, the sensitivity of each sensor during exposure to varying VOC concentrations depends on the used active material. Moreover, the sensor behaviors might be slightly altered when they were tested to the breath samples from different patients, although they were from the same group (either positive or negative COVID-19). This occurrence could be understood because the content and complexity of the exhaled VOCs are diverse, as discovered in another breath analysis study using GCIMS24. Several VOC biomarkers could be identified as the discriminants for distinguishing between positive and negative COVID-19 patients (e.g., ethanal, acetone, acetone/2-butanone cluster, 2-butanone, methanol monomer and dimer, octanal, feature 144, isoprene, heptanal, propanol, and propanal)24. Nonetheless, the compounds observed from two different hospitals (i.e., Edinburgh, the United Kingdom (UK), and Dortmund, Germany) in their study were dissimilar for the same case of COVID-19 patients, which then added more complexity in analyzing the obtained breath data. These limitations were due to uncertainties in the instrument setup, operating conditions, and background contamination levels.

Thus far, a detailed study in those matters has not been performed. Meanwhile, another clinical GCIMS study conducted by researchers in Beijing, China, suggested several other potential breath-borne VOC biomarkers for COVID-19 (i.e., acetone (C3H6O), ethyl butanoate, butyraldehyde, and isopropanol)72. They found that the decrease and increase in acetone (C3H6O) and ethyl butanoate levels, respectively, due to the changes in metabolites resulting from SARS-CoV-2 infections, are distinctive for COVID-19 patients72,73. Moreover, the average measured isopropanol and butyraldehyde for the COVID-19 patients were lower than those for the healthy control and lung cancer and non-COVID-19 respiratory infection patients. The metabolomics of exhaled breaths in critically ill COVID-19 patients were also investigated from a research consortium in France using a proton transfer reaction quadrupole time-of-flight mass spectrometer74. They observed four prominent VOCs (i.e., methylpent-2-enal, 2,4-octadiene, 1-chloroheptane, and nonanal) that could discriminate between COVID-19 and non-COVID-19 acute respiratory distress syndrome patients74. Overall, the reported MS studies in several different countries (i.e., UK, Germany, France, and China) indicate that the distinctive VOC biomarkers for COVID-19 may vary across the world and should be further investigated based on the community, race, and cases with large cohorts75.

In contrast to the MS method that attempts to quantitatively find and identify the exact VOC biomarkers from exhaled breaths, our technique used in GeNose C19 focuses more on the AI-based pattern analysis of integrated sensor responses to complex VOCs, qualitatively resulting from the combined extra-pulmonary metabolic and gastrointestinal manifestations of COVID-1976. Thus, the breath data analysis and decision-making procedure can be performed in a simple way and short time, respectively, with a high detection accuracy. To enable this, besides having a high sensitivity, chemoresistive sensors should ideally be designed to possess a high selectivity to a specific analyte in a gas mixture and zero cross-sensitivity to other compounds in the operating background. Such sensors were normally constructed in hybrid organic/inorganic structures with 3D nano-architectures (e.g., nanofibers, nanowires, and nanofins), enhancing the active surface-area-to-volume ratios77,78. Here, the surfaces of semiconductor nanostructures were often functionalized with certain self-assembled monolayers or polymers to specifically detect the target gas molecules32,34,79. Nevertheless, these organic materials suffer from low robustness. They are all well-known to degrade within a short duration of use (i.e., their chemical compositions will alter downgrading the sensor performance). As a result, pure inorganic materials (metal oxide semiconductors) are still preferably manufactured by sensor companies and widely used in gas sensing applications, including in the GeNose 19 system. Here, a single sensor alone is not sufficient for performing a specific breath pattern recognition because exhaled VOCs might have similar characteristics. This selectivity drawback could be alleviated by employing an array of 10 sensors with different sensitivities and integrating the machine learning-based breath pattern recognition algorithms.

Furthermore, to demonstrate the proof of concept ability of GeNose C19 for detecting VOCs in human breaths, we performed additional sensing assessments for acetone vapors in a modified test setup (see Supplementary Fig. 2). However, COVID-19 itself cannot be detected by simply sensing or measuring the acetone alone. This testing was mainly dedicated to demonstrate that the GeNose C19 sensor array can detect one of the VOCs normally contained in human breaths and exhibits different sensitivity levels when exposed to various gas concentration levels, which also mimics the real case of exhaled breaths from different persons or patients. The gas sensing configuration for the acetone testing, which utilizes a microsyringe for vapor injection, has already been used in our former experiments for other VOC sensor types (e.g., nanofiber-functionalized QCMs for sensing trimethylamine and butanol gases)35,80,81. Acetone was chosen as a VOC model in this additional study because it is not only produced in the rebreathed breath (0.8 to 2.0 ppm)82, along with other VOCs (alcohol) and CO, but is also one of the significant breath-borne COVID-19 biomarkers based on the study by Chen et al.72. Moreover, in clinical practices, breath-containing acetone has been extensively examined to diagnose other diseases (i.e., lung cancer, diabetes mellitus, starvation, and ketogenic diet)83.

As shown in Supplementary Fig. 2b, c, the S3 and S7 sensors (or their extracted features of F3 and F7) demonstrated the poorest responses toward acetone vapors. Conversely, the S2, S8, and S9 sensors exhibited higher sensitivities than the others. The sensor output signals given by the GeNose C19 data acquisition system agree well with those measured by a calibrated digital voltmeter. Increasing the acetone vapor concentrations from 0.04 to 0.1L with 0.02 intervals resulted in higher responses of the three sensors (S2, S8, and S9), whereas the S3 and S7 sensors were irresponsive (see Supplementary Fig. 2d). In particular, each vapor concentration was measured 10 times to acquire quantitative results. Lastly, as depicted in Supplementary Fig. 2e, LDA discriminated the output voltages produced by the sensors during their exposures to four different acetone concentrations (i.e., 0.040.1L).

In terms of ambient conditions, temperature and humidity might influence the performances of metal oxide semiconductor sensors84. Thus, to investigate their effect, we also performed cross-sensitivity assessments in respect to the two parameters for all the employed GeNose C19 sensors (see Supplementary Figs. 3 and 4). This testing is important because depending on the sensitivities of the sensors toward temperature and humidity, the obtained sensor results during the breath analysis can be disturbed, leading to a difficult interpretation of the data. Moreover, if the sensors are too reactive to the two ambient parameters, the measured data can then be unreliable to analyze the effect of VOCs in the human breath because changes in the signals were mainly affected by the temperature and humidity, not the target gases. Such a cross-sensitivity is a common reliability test for gas sensors. For GeNose C19, the environmental effect can be minimalized and controlled by performing two main procedures. First, environmental checking needs to be conducted while placing GeNose C19 in the measurement room/area. Here, the selection of the machine placement (analysis on air circulation, humidity, and temperature) plays a key role in maintaining good-quality results. GeNose C19 could sense the environmental humidity and temperature levels by utilizing humidity and temperature sensors integrated inside the system. The measurement was displayed in the program interface. Hence, the user or operator could notice the condition. In a real situation during breath sampling, the machine could only be operated if the humidity and temperature inside the chamber were in the ranges of 3050% and 2642C, as defined by the AI-based program in the system. Such a setting is adjustable to meet future demand and placement environments. Second, after checking the environmental condition, the baseline normalization protocol during the sample analysis can be done (see Methods on the GeNose preconditioning). During the AI interpretation of the VOC patterns, several protocols were employed, including signal baseline normalization. By performing baseline normalization, all the sensors that behaved and started from different baselines in different environments can always be calibrated to the standard normalization. Hence, the adaptability of the machine can be improved in new foreign environments.

In the case of acetone testing, the sensors yielded similar responses from three repeated measurements, indicating their reliable sensing results. The sensor resistance decreased (i.e., a higher output voltage was obtained) when the temperature was ramped up from 40C to 46C, and the humidity was kept stable at (30%1%) RH (see Supplementary Fig. 3). Different from silicon micromechanical resonant sensors that have frequency shift interferences caused by the temperature-induced Youngs modulus change (material softening)37,85, the resistance decrease in the employed metal oxide semiconductor sensors (e.g., n-type SnO2 with a bandgap of 3.6eV) at high temperatures was caused by the increasing number of electrons that have sufficient energy crossing to the conduction band and thus contributing to the conductivity86. Because this is a natural characteristic of semiconductor materials, we could overcome this effect in GeNose C19 by controlling the temperature inside the test chamber at relatively stable values (i.e., (42C2C)) during the sensing phase of the exhaled breath.

Similar to the trend shown in the cross-temperature test, the sensor resistance also dropped to a lower value, resulting in a higher output voltage when the relative humidity was raised from 30% to 35% and the temperature was set constant at (40C1C) (see Supplementary Fig. 4). The electrical characteristics of metal oxide semiconductors changed due to the water adsorption on their surface while being exposed to humid air. Two different mechanisms of chemisorption and physisorption processes took place to create the first layer (i.e., chemisorbed layer) and its subsequent films of water molecules (i.e., physisorbed water layers), respectively87. If the first chemisorbed layer has been formed, then the successive layers of water molecules will be physically adsorbed on the first hydroxyl layer. Because of the high electrostatic fields in the chemisorbed layer, the dissociation of physisorbed water can easily occur, producing hydronium ion (H3O+) groups. Here, the conduction mechanism relies on the coverage of adsorbed water on the metal oxide semiconductor. First, in the event only hydroxyl ions exist on the metal oxide surface, the charge carriers of protons (H+) resulting from hydroxyl dissociation will hop between adjacent hydroxyl groups. Second, after the water molecules have been adsorbed but not fully covered the oxide surfaces, the charge transfer will be dominated by H3O+ diffusion on hydroxyl groups, despite the occurring proton transfer between adjacent water molecules in clusters. Finally, once the continuous film of the first physisorbed water has been formed (i.e., full coverage of metal oxide by the physisorbed water layer), proton hopping between neighboring water molecules in the continuous film will be responsible for the charge transport88. More detailed explanations of the sensing mechanism and adsorption of water molecules on metal oxide semiconductor surfaces are described elsewhere84,87,88. Again, in the conducted cross-sensitivity measurements (Supplementary Fig. 4), the signal changes of the GeNose C19 sensors affected by humidity are relatively lower (i.e., <100mV) compared to those exposed to exhaled breaths (i.e., ~1V, as shown in Fig. 3a, b). Thus, temperature and humidity will insignificantly influence the system performance during breath measurements, when GeNose C19 has been well preconditioned.

To confirm the performance of our GeNose C19, RT-qPCR was used as the reference standard on the basis of the health service standard protocol underlined by the Indonesian Ministry of Health. Based on the analysis of the RT-qPCR protocol using Bayes theorem, RT-PCR tests cannot be solely relied upon as the gold standard for SARS-CoV-2 diagnosis at scale. Instead, a clinical assessment supported by a range of expert diagnostic tests should be used. Here, although our study mentioned that RT-qPCR was used as the reference standard, clinical data from each patient were also collected and analyzed.

According to a recently published systematic review study, the need for repeated testing in patients with suspicion of SARS-Cov-2 infection was reinforced because up to 54% of COVID-19 patients might have an initial false-negative RT-qPCR89. Meanwhile, in the case of false-positive rates of RT-qPCR, much lower values (i.e., 016.7% with an interquartile range of 0.84.0%)90,91 were exhibited in several studies, which were affected by the quality assurance testing in laboratories. Public Health England also reported that RT-qPCR assays showed a specificity of over 95%, so up to 5% of cases were false positives91. Moreover, the overall false-positive rate of high throughput, automated, sample-to-answer nucleic acid amplification testing on different commercial assays was only 0.04% (3/7,242, 95% CI, 0.01% to 0.12%)92. False-positive SARS-CoV-2 RT-qPCR results could originate from different sources (e.g., contamination during sampling, extraction, PCR amplification, production of lab reagents, cross-reaction with other viruses, sample mix-ups, software problems, data entry errors, and result miscommunication)93. In our case, all the bought and used reagents were checked and calibrated daily to avoid false positives (i.e., no false positive of RT-qPCR result was found in this study). Meanwhile, the false-negative of the RT-qPCR result was found in three patients in their first examination, but positive results were revealed on the second examination the next day. Again, the detailed test procedure can be found in the Methods.

Currently, diagnostic methods used to screen COVID-19 are antigen test, rapid molecular test, and chest CT scan. Antigen tests have an average sensitivity of 56.2% (95% CI: 29.579.8%) and average specificity of 99.5% (95% CI: 98.199.9%)94. The average sensitivity and specificity for the rapid molecular tests are 95.2% (95% CI: 86.798.3%) and 98.9% (95% CI: 97.399.5%), respectively94. Meanwhile, chest CT scan possesses an average sensitivity and specificity of 87.9% (95% CI: 84.690.6%) and 80.0% (95% CI: 74.984.3%), respectively95. Nonetheless, these diagnostic methods have their drawbacks. The average sensitivity of antigen tests is not high, as shown by the study above, and it declines when the viral load decreases, which often happens to COVID-19 patients. Moreover, the sample collection is invasive (by a nasopharyngeal or oropharyngeal swab). Rapid molecular testing also employs an invasive sample collection method (by a nasopharyngeal or oropharyngeal swab), and the turnaround time of point-of-care rapid molecular tests still takes at least 20 min96. Moreover, chest CT scan exposes patients to radiation and is not specific.

Compared to these diagnostic methods, GeNose C19 has the potential to be a screening test. A breath test with the portable GeNose C19 is noninvasive and easy to use because it only requires patients to breathe into a sampling bag with minimal preparation, has a fast analysis time, and does not have radiation concerns. Similar to other biological samplings in several laboratory examinations (e.g., blood glucose sampling and chemical blood analysis), GeNose C19 also requires preparation of subjects before breath sampling, such as fasting (i.e., refraining from eating, smoking, or drinking anything other than water at minimum 1h before sampling). However, the duration of the analysis starting from the breath sampling to the test result decision only takes ~3min. The sensitivity and specificity results of GeNose C19 from the profiling tests show that combining GeNose C19 with an optimum machine learning algorithm can accurately distinguish between positive and negative COVID-19 patients. Hence, it opens an opportunity for using this developed breathalyzer as a rapid, noninvasive COVID-19 screening device based on exhaled breath-print identification.

Several factors may influence breath-prints, i.e., pathological and disease-related conditions (smoking, comorbidities, and medication), physiological factors (age, sex, food, and beverages), and sampling-related issues (bias with VOCs in the environment)97. A previous study revealed that older age altered breath-prints in patients with lung cancer98. There were concerns that several other respiratory diseases may present similar VOC patterns to those from the COVID-19. Several studies reported that several comorbid and confounding factors (e.g., chronic obstructive pulmonary disease, asthma, tuberculosis, and lung cancer) might affect the composition of VOCs99,100. Thus, patients with other respiratory diseases can have different patterns of VOCs that result in different sensor signals, suggesting that the electronic nose may still determine the COVID-19 infection to a certain degree by continuing to train its AI database in reading VOCs from confirmed positive COVID-19 patients. Our studies showed no significant difference in the detected sensor signal patterns of patients with comorbidities compared to those without comorbidities. Nonetheless, due to the few comorbid cases obtained in our subjects, which could be considered the limitation in our current study, the influence of existing comorbidities on the VOC pattern cannot be concluded and will be further evaluated in the next research.

Food and beverages (e.g., poultry meat and plant oil) can influence breath-prints, whereas smoking may increase the levels of benzene, 2-butanone, and pentane and simultaneously decrease the level of butyl acetate in exhaled breaths101,102,103. In our study, none of the patients was smoker. The comorbidities were also comparable between the case and control groups. There was no significant difference in the consumption of food and beverages between the two groups. The measurements were conducted in the same environment for all the participants. Thus, there was no bias with other interfering VOCs.

However, the possible presence of physiological variations resulting from physiological and biochemical changes in the body due to alterations in the respiratory rhythm affected by the manipulated breathing technique should also be considered61. Therefore, in our work, breath sampling was performed in such a defined protocol to collect only the third exhaled end-tidal breath. Accordingly, the natural breathing pattern and rhythm can be preserved, resulting in minimal changes in VOCs. We avoided excessive effort or repeated sampling in each breath collection as previous studies reported that it might alter the quality of collected VOCs104. The disturbance from other factors to breath test results is minimal. However, such confounding factors are most likely present in the real implementation and can affect at least breath-prints to a certain degree. Further study is now being conducted to reveal the effects of various confounders.

Our study using GeNose C19 did not evaluate the distinctive concentration of each VOC found in breath samples of patients with positive or negative COVID-19. However, to investigate the types of VOCs produced in exhaled breaths of the positive and negative COVID-19 patients, we conducted another characterization based on GCMS for several exhaled breaths of patients (see Supplementary Table 3). In the extracted results, there was no significant difference in the composition of VOCs between patients with positive and negative COVID-19, suggesting that the difference in the breath-print pattern may be contributed by the variation in the concentration or proportion of several VOCs rather than the presence of one or two signature VOCs. For example, acetone was reported to be one of the VOCs with the highest concentration emitted by healthy humans104. However, in COVID-19-positive patients, acetone was reported to be in a lower proportion, compared to the healthcare worker or healthy control group72. Meanwhile, another VOC (i.e., ethyl butanoate) has been reported as one of the signature VOCs in COVID-19 patients, whose concentration is slightly higher compared to the healthy control72.

Anosmia (i.e., the olfactory system cannot accurately detect or correctly identify odors) is one of the most frequently identified COVID-19 symptoms45,105. CO has been linked with this issue because it is an olfactory transduction byproduct related to the reduction of cyclic nucleotide-gated channel activity that causes a loss of olfactory receptor neurons45,106. In our GCMS results (Supplementary Table 3), six sensors in GeNose C19 (i.e., S1, S3, S4, S5, S6, and S8) could detect CO. Aside from CO, the GCIMS studies in Dortmund, Germany, and Edinburgh, UK indicated that aldehydes (ethanol and octanal), ketones (acetone and butanone), and methanol are biomarkers for COVID-19 discrimination24. This result is however different from the finding from another research group in Garches, France, using the proton transfer reaction quadrupole time-of-flight MS, where four types of VOCs (i.e., 2,4-octadiene, methylpent-2-enal, 1-chloroheptane, and nonanal) could discriminate between COVID-19 and non-COVID-19 acute respiratory distress syndrome74. Studies conducted in two cities in the USA (Detroit, Michigan and Janesville, Wisconsin) by Liangou et al. reported another set of eight compounds (i.e., nitrogen oxide, acetaldehyde, butene, methanethiol, heptanal, ethanol, methanol-water cluster, and propionic acid) as key biomarkers for the COVID-19 identification in human breath. Moreover, in Leicester, UK, seven exhaled breath features (i.e., benzaldehyde, 1-propanol, 3,6-methylundecane, camphene, beta-cubebene, iodobenzene, and an unidentified compound) measured by the desorption coupled GCMS were employed to separate RT-qPCR-positive COVID-19 patients from healthy ones107. In our measurement, camphene was detected only in the negative COVID-19 breath sample by S10.

Furthermore, Chen et al. reported two sequential GCMS studies in Beijing, China, that resulted in totally different breath-borne biomarkers for COVID-19 screening, despite using the same measurement approach72,108. Their first measurement reported in 2020 indicated that COVID-19 and non-COVID-19 patients could be differentiated by solely monitoring three types of VOCs (i.e., ethyl butanoate, butyraldehyde, and isopropanol)72. Nonetheless, in their second report in 2021, acetone was detected as the biomarker among many VOC species because its levels were substantially lower for COVID-19-positive patients than those of other conditions73. In our GeNose C19 sensor array, acetone can be detected in S8109. Recently, ammonia has also been proposed as another biomarker for COVID-19, whose relation to complications stemming from the liver and kidneys was affected by the SARS-CoV-2 infection110.

In all the already described examples of MS studies worldwide, the identification and determination of specific COVID-19 biomarkers in breath clearly remain challenging. Here, different discriminant compounds can be yielded depending on several parameters (e.g., measurement technique, filtering approach, location, and breath sample type). Nonetheless, we can still extract some information from our GCMS results (Supplementary Table 3). A hydrocarbon of ethylene was sensed by S10 in the positive COVID-19 breath sample. Meanwhile, for the negative COVID-19 breath samples, other hydrocarbons (i.e., butyl aldoxime, decane, and benzene) were detected by S10. Furthermore, S2 and S9 could measure a few specific esters (i.e., benzoic acid, 3-hydroxymandelic acid, and acetic acid) in the negative COVID-19 samples. Generally, the appearances of the three sensors (S2, S9, and S10) were dominant as compared to those of the others. For instance, S2 and S9 were highly sensitive toward aldehydes and esters, whereas S10 was likely to be reactive toward hydrocarbons.

Regardless of the successful compound extraction and its association with GeNose C19 sensor array, our GCMS characterization was only performed in a low number of samples. Therefore, a further investigation with a larger number of breath samples still requires to be carried out in the near future to correlate the measurement results of GeNose C19 and GCMS methods in a more thorough way, especially in Indonesia. This method also includes more investigations on the possible influence from other respiratory-related viruses (e.g., influenza, respiratory syncytial virus, and rhinovirus). The presence of viruses other than SARS-CoV2 will affect the VOC profile in breaths to a certain degree. However, in our current setup, it will be mostly recognized by the AI algorithm in GeNose C19 as non-reactive, which means that it contains VOC-based breath-prints not typical to a SARS-CoV2 infection. Influenza and rhinovirus infections manifest a high amount of heptane, nitric oxide, and isoprene111. Consistently, our preliminary study on breath samples from a few patients confirmed to have rhinovirus based on RT-qPCR and showed a high response on S8, suggesting a high amount of isoprene or isopropanol. However, further comparison analysis with more numbers of validated breath samples data will be definitely necessary to obtain a solid conclusion on this matter.

In terms of the enhanced sensing technology, once the VOC biomarkers can be clearly determined, a molecular imprinting method could be applied to generate highly selective sensors that target these specific VOC markers. Hence, the sensitivity and specificity of GeNose C19 and its overall accuracy can be further improved. Another critical step for the system development is to conduct a diagnostic test with a large cohort to strongly elucidate its potential as a diagnostic tool in the near future.

Other limitations of our study are that a direct correlation between the level of the virus gained from the swab and the amount of VOC concentration could not be drawn. These conditions are partly caused by the fact that VOCs were not directly produced by the virus, but rather by host cells infected by the virus as a part of their metabolic response to the infection. GeNose C19 could only predict the presence of the virus based on the resulting VOCs in the breath produced by respiratory tract epithelial cells and immune cells that were infected by the SARS-CoV2 virus. Nevertheless, a study on the correlation between the positivity rate of breath results and level of the cycle threshold value (Ct value) gained from RT-qPCR examination has been of interest for the next research. Here, more insights into the performance of GeNose C19 will be gained in terms of sensitivity, specificity, and accuracy levels correlated with the level of Ct value of RT-qPCR. The Ct value itself is currently accepted as an alternative parameter to determine the level of the viral load in each individual on the basis of the minimum cycle threshold necessary to duplicate the viral component to be read. Nonetheless, GeNose C19 combined with RT-qPCR using the Ct value has a limitation for estimating the exact number of the viral load. It was also a question of whether a person with a positive PCR test result for SARS-CoV-2 is automatically infectious or infectious only if the Ct value is below a certain limit (e.g., Ct value of <35)112,113. In another study, knowing the typical viral load of SARS-CoV-2 in bodily fluids and host tissues, the total number and mass of SARS-CoV-2 virions in an infected person could be estimated114. Each infected person carries the total number and mass of SARS-CoV-2 virions of 1091011 virions and 1100g, respectively, during the peak infection114.

Again, this study was meant to demonstrate a proof of concept that breath sampling and detection can be used to predict COVID-19 infection. Essentially, the calculated performance values in our study show the reliability of the DNN algorithm in predicting the training and testing data of breath samples, suggesting the great potential of the GeNose technology, fortified by the DNN algorithm to be used as a COVID-19 screening tool. Here, we performed the study using a so-called open-label design, where we already knew the COVID-19 status of the subjects before conducting sampling and classifying the sampled data into case and control groups. Using this method, we read, found, and compared the breath sample pattern profiles in each respected group and employed them as training data to build our first AI database, in which all data were validated by the test results of RT-qPCR supported with clinical data. A combined measurement of GeNose C19 with GCMS will be conducted in the near future to answer questions related to distinctive VOCs for COVID-19.

Lastly, another critical step for the system development is to confirm the usability and performance in the clinical setting, where a study on the clinical diagnosis of COVID-19 with a larger number of exhaled breath samples is currently performed to prove the potential of GeNose C19 as a rapid COVID-19 screening tool using a cross-sectional design and double-blind randomized sampling. Here, breath samples and nasopharyngeal swab specimens are taken in the situation where the operator or sampler does not know the true condition of patients. A double-blind fashion means that neither the sampler nor subjects know their true condition during the sampling process. The breath samples were analyzed by GeNose C19 without knowing the result of RT-qPCR, and swab samples were examined by RT-qPCR without prior knowledge of the GeNose C19 result. Both results were then compared to each other to draw a conclusion. In this approach, RT-qPCR will still be used as the reference standard.

Read more from the original source:
Fast and noninvasive electronic nose for sniffing out COVID-19 based on exhaled breath-print recognition | npj Digital Medicine - Nature.com

Have insurers and defendants been overpaying for asbestos liability claims? Are there other ongoing toxic torts where that might be true today?

The questions arise as a result of a revolution thats now underway in genomic analysis and its application in civil litigation.

Genomic analyses of molecular data can allow medical scientists to identify an individuals genetic propensity to develop cancers like mesothelioma and other conditions. Beyond that, the frequency with which genomic analyses have been used in personal injury casesby both plaintiffs and defendantsis increasing rapidly.

How It Started

An early, impressive use of genomic analysis was in Bowen v. E.I. DuPont de Nemours & Co., 906 A.2d 787 (2006). There, children were born with heart-rending deformities, including malformed eyes. The claim was that fungicide exposure caused the deformities.

Shortly before trial, newly published, peer reviewed research showed that a pathogenic mutation to a particular gene (CHD7) could be the cause of the deformities, independent of any exposure to the fungicide. Genetic testing revealed the children at issue in fact carried pathogenic mutations to the CHD7 gene.

Ultimately, the genetic testing results caused plaintiffs experts to withdraw their prior opinions on causation, and so summary judgment was entered for the defendant fungicide maker.

Since then, there have been numerous orders around the country requiring some amount of genetic testing in a wide range of cases; the orders usually are in cases involving claims of medical malpractice, product liability and negligence. There have been some state-to-state variations and some denials of genetic testing, mainly when counsel did not make a detailed record. And some plaintiff lawyers undertake their own genetic testing before investing heavily in a case or make arguments based on the results of genetic tests.

The Asbestos Question

Many insurance claims professionals have been conditioned to think that virtually anyone who encountered asbestos in their career or life, and subsequently developed mesothelioma, probably had their disease caused by that exposure. Advances in genomics now reveal, however, that this is not necessarily true.

In fact, genomic analyses have scientifically established that a meaningful percentage of mesotheliomas are caused solely by genetic mutations, a fact that holds true for virtually all cancers. Those scientific findings are now reshaping expert testimony in mesothelioma litigation. In very recent deposition testimony (May and June of 2022) a genetic expert often called by plaintiffs (Dr. Joseph Testa) finally acknowledged that, in fact, some mesotheliomas are caused solely by genetic abnormalities.

That overdue acknowledgement arose from multiple factors:

But have insurers been overpaying on asbestos liability claims?

The answer is complicated by group settlements and the fact that there are so many repeat players in mesothelioma cases, thereby inducing trade-offs between cases. In short, yes, settlement payments have been made in some cases where asbestos causation was highly dubious or implausible. And importantly, there soon may well be bad faith claims against insurers who fail to fund genomic defenses in appropriate cases.

Genomic analyses can be highly effective in both mass tort and individual cases. Genomic analysis reports are unique to each person, and so costs are higher than costs for generic reports that have been used hundreds of times over many years and that include only a few paragraphs specific to the person. The costs for genomic analyses, however, are relatively small when compared to the potential jury verdicts in cases involving a person under 60 who has a terminal, painful cancer, especially in view of todays so-called nuclear verdicts. Logically, this potential for outsized verdicts compared to the cost of genomic defenses could fuel bad faith claims against insurers going forward.

The Economics: When to Use Genomic Analyses

Still, the question of precisely when it becomes economical to pursue genomic analysis as part of a defense doesnt have a clear-cut answer.

Genomic defenses are credible and appropriate only in some cases. An initial step is to look for the presence or absence of red flags (a term of art in the genetics literature) that suggest the likely or possible presence of pathogenic hereditary mutationsfor example, personal and family histories of cancer. For defendants, the presence of red flags can suggest investing in genomic analyses for high-value cases or to send a message to plaintiffs counsel to discourage suits against a defendant that does not belong in the case. Consider the math when the plaintiff has targeted only one or two defendants, the plaintiff is relatively young and successful, and counsel is seriously demanding eight-figures to settle the case.

Tsunamis Ahead

Hundreds of thousands of whole genome sequences, linked to anonymized medical data, are on the cusp of arriving at researchers doorsteps with the prospect of transforming both the scientific and legal systems.

Insurers need to understand the speed and scale of advances in this genomic knowledge. The next 10 years will bring multiple tsunami waves of genomic information. The first tsunami arrived last year with a UK groups release of 200,000 whole genome analyses, accompanied by anonymized medical records. Another tsunami will arrive in 2023 with the same groups release of an additional 300,000 whole genomes and anonymized medical records.

Assured Research LLC, a research and advisory firm focused exclusively on the P/C insurance industry, has been working with Law Science Policy law firm since 2015, when the two firms joined forces to describe the scientific, medical, and legal developments shaping a possible third wave of asbestos liabilities. (Related 2015 article, Genetic Markers May Fuel Next Wave of P/C Insurer Asbestos Reserve Hikes)

Since then, William Wilt, president of Assured Research, and Kirk Hartley, founder and principal of LSP, have spoken about these developments to actuarial and insurance audiences, hoping to impress upon insurance professionals the imperative of understanding the revolution now underway in genomic/medical analysis and its application in civil litigation. Hartley also teamed up with a multidisciplinary group of scientists and lawyers to create ToxicoGenomica, which provides fully integrated services for using genomic and systems biology data in civil litigation. ToxicoGenomica scientists have recently published articles showing that mesotheliomas and other cancers can be caused solely by genetic abnormalities, rather than by exposure to asbestos and other substances.

As a result of that research, and forthcoming waves of genomic data that will fuel more research in the next few years, Wilt and Hartley believe that insurers can no longer delay decisions to invest time, effort and money in understanding the application of genomic analysis to civil litigation. They delivered their urgent message is an Aug. 16, 2022, research note, Liability Insurance: Invest in Genomics Now, the Future is Arriving, published by Assured Research. The research note is presented in the form of a Q&A style discussion, with Wilt asking the questions and Hartley supplying the answers.

The accompanying article has been adapted from that research note with permission from the authors.

The tsunamis will continue as more whole genomes and medical records are released from government programs or other databases (see the chart for examples).

The medical records and genomes are now being mined, and disease-specific papers are now being released that far more reliably link specific genes to specific diseases, while other papers show gene/environment interaction. These genomic epidemiology papers in some instances will exonerate defendants and other times will support plaintiffs. Both outcomes create risks of major surprises for stakeholders who are not tracking genomic science as it advances. Stakeholders and lawyers need to start thinking about how they are going to cope with so much risk of a rapid change, and the fact that new knowledge will 1) effect pending claims, 2) may stimulate new claims, and 3) will influence underwriting considerations.

Even though the use of genomics could work for, or against, the defense (e.g., maybe it shows that a toxin was highly likely to have caused the plaintiffs disease), the best move for insurers is to engage early and intelligently in order to avoid extreme surprises. Simply put, the availability of massive amounts of anonymized medical records and matched genomic data is a never before event, and so existing actuarial models simply cannot be as reliable as they are for many other risks. The arrival of genomic epidemiology will not impose surprises and changes as fast or as broadly as did the arrival of COVID. But it seems realistic to suggest the need to manage change and the new data, perhaps by analogizing to the recent development of new forms of extreme weather models based on data and analytic methods that were not available 10 or even five years ago.

The volume of data truly will arrive in tsunamis, and the impact will be highly material for some toxicants. Actuaries simply will not find workable prior models; new methods and models are needed to better manage the changes that will arrive with hundreds of thousands and then millions of anonymized medical records and associated genomic data.

We cant predict the path or exact ramifications of the tsunami of genomic/medical data to be released over the upcoming decade. But, with great confidence, we can predict that insurers sticking their head in the sand take the risk of surprises and outcomes that could have been avoided.

The time has arrived to invest resources and, yes, money in understanding this scientific revolution and its ramifications for the liability landscape.

The accompanying article has been adapted from a Aug. 16, 2022 research note titled Liability Insurance: Invest in Genomics Now, the Future is Arriving, published by Assured Research. Wells Media is publishing with permission from the authors.

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During a pregnancy, women are offered prenatal genetic screening and diagnostic testing to determine whether a fetus is healthy or has certain genetic disorders or anomalies.

This information can help patients and their doctors prepare for the pregnancy. But some opt out of such testing, believing that babies should be born regardless of potential abnormalities.

For those who do choose to undergo such testing, maternal-fetal medicine specialists and genetic counselors usually work closely with the pregnant person or couple to explain in detail what the results mean for a birth, for mother and child, if a genetic disorder or fetal anomaly is detected. These health care providers can also provide the pregnant person or couple with guidance on what options are available to them after a diagnosis, which can include aborting apregnancy. That option, however, is limited or no longer available to women in many U.S. states.

Prenatal tests cant diagnose a genetic condition before 6 weeks

Without the protection of Roe v. Wade, the 1973 Supreme Court decision that legalized abortion nationwideand was overturnedin June, the procedure has become illegal or heavily restricted in at least 14 states. Six states Mississippi, Missouri, Tennessee, North Dakota, South Dakota and Ohio prohibit abortions when the fetus may have a genetic anomaly, and infive of those states, its now nearly impossible, because it is banned at about six weeks. This is so early in a pregnancy that many women at that point dont even know they are carrying a child.

A person's first [doctors] appointment in pregnancy doesn't usually happen until eight or 10 weeks, so never mind the rest of the story. That's when obstetric care begins, said Philip D. Connors, lead genetic counselor at Boston Medical Center.

Three [percent] to 4% of all pregnancies are going to be affected by some sort of complication related to a difference in fetal or embryonic development, a genetic condition. And essentially none of those can be screened for or diagnosed until after the gestational age limits that are being placed by some of these really discriminatory laws, Connors added.

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Dr. Tani Malhotra, a maternal-fetal medicine specialist in Cleveland,Ohio, a state where abortions are now illegal after six weeks and where there are no exceptions for cases of rape, incest or fatal fetal anomalies, said it is impossible to assess whether there are any issues with the fetus at such an early point in pregnancy.

The size of the embryo at six weeks is somewhere between 6 to 7 millimeters. It's less than 1 centimeter, and that centimeter is like the size of my finger, right? So it's just impossible for us to be able to detect abnormal findings on an ultrasound at that point, Malhotra said.

KatieSagaser, director of genetic counseling at Juno Diagnostics, a women's health company, told Yahoo News: Theres no genetic testing or screening that can be done prior to six weeks.

One method of testing which she said has revolutionized the landscape of prenatal chromosome screening and is mostly used today is a noninvasive prenatal screening technology known as NIPT or NIPS. This can detect genetic variations as early as nine weeks into pregnancy, using a blood sample from the mother. But the test, Sagaser said, can only indicate if there is a potential problem, and does not replace diagnostic testing, such as chorionic villus sampling (CVS) or amniocentesis, which study the cells from the fetus or placenta and can confirm a diagnosis.

The earliest a CVS diagnostic test can be performed is at the 10th week of pregnancy. Amniocentesisis usually conducted at between 15 and 20 weeks of pregnancy, but can technically be done up until a person gives birth, according to the American College of Obstetricians and Gynecologists.

WASHINGTON, DC - JUNE 24: Abortion-rights activists gather in front of the Supreme Court building following the announcement to the Dobbs v Jackson Women's Health Organization ruling on June 24, 2022 in Washington, DC. (Photo by Nathan Howard/Getty Images)

Aborting a pregnancy because of genetic anomalies

As prenatal screening testing like NIPS has become more common, selective terminations involving genetic conditions have too. Some studies have shown that parents often decide to terminate a pregnancy, even after finding a mild form of a genetic condition, including Turner and Klinefelter syndromes.

Down syndrome is the most common chromosomal disorder in the U.S., and about 6,000 babies are born with it in the U.S. each year, according to the Centers for Disease Control and Prevention.

A published review of studies, which included 24 publications studying pregnancy terminations after a prenatal diagnosis of Down syndrome in the U.S., found that 67% ofthose pregnancies end in abortion.

Terminating a pregnancy after the 2nd trimester because of medical complications

Its notable, however, that the majority of abortions in the U.S.(91%) occur at or before 13 weeks of gestation. Abortions late in pregnancy are rare,butMalhotra said some of the main reasons why they do happen include delays and other barriers in obtaining abortion care, or after discovering medical complications. Those complications often include the discovery of lethal fetal anomalies, which can be detected during a fetal anatomy scan that is usually performed at around 20 weeks of pregnancy. Terminations at this stage, Malhotra said, are difficult and traumatic, because these pregnancies are often desired.

It's really tragic, as you're telling these patients who have been continuing their pregnancy. They're at 20 weeks. They're excited about the pregnancy. They're planning their baby showers. They come to that ultrasound hoping to be able to find out the sex of the baby and you tell them this devastating news, that there is an abnormality that is either not compatible with life, or is going to have significant impact on the quality of life after birth, the Ohio doctor said.

Malhotra told Yahoo News that Ohios new abortion law has made her job even tougher, because she also has to tell patients in these situations who wish to terminate the pregnancy that they cannot receive such care in their state.

It is just horrible, because not only are you giving them this tragic, heartbreaking news, but you're stigmatizing their care, because you're saying, Oh, this thing is illegal here, but you could go to another state. So they have to travel to another state to do something that's illegal, which is a part of medical care, Malhotra said. If they're not able to go out of the state, then we're asking them to take on risks associated with a pregnancy, which we know inherently, pregnancy is not risk-free.

In addition, she explained, she needs to inform these patients that they must act rapidly. Abortions later in a pregnancy are more complex and also more expensive. Medication abortion, which can be taken at home, can only be safely used in the first 70 days, or 10 weeks of pregnancy. After that, women need a surgical abortion, which typically takes about two days and requires inpatient care. A patient who needs to go out of state to receive care must therefore also take into account additional costs related to travel and lodging.

Because of the abortion bans that have gone into effect in the Midwest, surrounding states where the procedure is protected have seen an increase in patients, Malhotra said. They are really backed up, currently complicating the scheduling of an abortion, she said.

Another important reason to act quickly in these situations, according to Malhotra, is because most states do not permit abortions after 24 weeks when a fetus has reached viability and can survive outside the uterus. According to the Guttmacher Institute, a research group focused on reproductive health, 17 states impose a ban at viability.

Little research has been conducted on what happens to women who are unable to terminate a pregnancy because of a fetal genetic condition or anomaly. However, one study conducted by the University of California, San Francisco, that tracked 1,000 women unable to get an abortion because they had passed the gestational limits, found they were more likely to fall into poverty, as well as have worse financial, health and family outcomes, than those who had terminated their pregnancies.

Opponents of abortions conducted as a result of screening for disabilities believe that such procedures are unjust, because all human beings have inherent value from the moment of conception. Malhotra, on the other hand, told Yahoo News that she finds it absolutely horrible to put patients in a position where they dont have a choice anymore.

There are multiple reasons women may choose to terminate a pregnancy because of a genetic condition or anomaly, ranging from the emotional and financial cost of raising a disabled child to the effect that this may have on the existing children in a family, as well as the feeling that it is cruel to give birth to a child who may need a lifetime of constant medical intervention.

Connors said that terminations due to genetic or fetal anomalies are comparatively rare, but are often emphasized unduly in conversations on abortion and abortion care. It inadvertently leads to a narrative about what makes a good or a bad abortion, he said.

Sagaser agreed, saying:There's no benefit to us as a society to say, Oh, there's this one population that really needs access to abortion care more so than other people.'

Everyone deserves to be able to make the choices that are right for them and their family in that unique situation, she added.

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Restrictive abortion laws are limiting the options parents have after receiving genetic test results, experts say - Yahoo Singapore News

Article In Brief

Neurologists who see patients with neurologic conditions who are pregnant, or who are considering pregnancy, said the Supreme Court decision to reverse Roe v. Wade, the right to an abortion, interferes with their ability to provide informed decisions about health care for their patients.

Neurologists who care for patients who are pregnant, or who are planning pregnancies, are facing new discussions about clinical care in the wake of the Supreme Court's June 24 Dobbs v. Jackson Women's Health Organization decision to reverse the historic Roe V. Wade 50-year precedent to legalize abortion.

Neurologists have a critical window into how the reversal of Roe will impact patients with neurologic disease. Neurologic health is inextricably linked with reproductive health, said Sara LaHue, MD, a neurohospitalist and assistant professor of clinical neurology at the University of California, San Francisco.

...Bans on abortion will immediately affect the delivery of current standard neurologic care for many patients, specifically standards that depend on planning or preventing pregnancies using individual choice, Dr. LaHue and colleagues wrote in a viewpoint on the impact of the Dobbs decision on neurology in the July 13 issue of JAMA Neurology article.

I dare say that there are very few specialties within neurology that don't have some connection to how reproductive health influences the health of our patients, said Diana Cejas, MD, MPH, a child neurologist who specializes in autism spectrum disorders, intellectual disabilities, and neurodevelopmental disabilities.

As a pediatric neurologist, I talk about these issues with my patients all the time: the risks of certain medications to a developing fetus, the need to be on birth control, what it would mean for them if they got pregnant. There are all kinds of implications for reproductive health that we are involved with as neurologists. We have patients with significant illnesses and chronic disability within neurology, for whom pregnancy could be devastating if not life-threatening. This decision is absolutely going to affect our patients' health and the way we practice.

Many neurologic conditions that commonly affect women in their reproductive years, including epilepsy, migraine, multiple sclerosis, myasthenia gravis, and brain tumors, are often managed with medications that are known to be teratogenic, with many more lacking clear evidence about their teratogenicity.

As an epileptologist, I see many patients who are on antiseizure medications known to be teratogenic, such as valproic acid, said Ima Ebong, MD, an assistant professor of neurology at the University of Kentucky.

We have conversations about reproductive health and what the consequences of these medications can be, weighing the pros and cons of treating your epilepsy and the protections you need to put in place for yourself and potentially a pregnancy, including barrier contraception, hormonal contraception, and having the ability to abort a pregnancy if necessary. Not every patient wants to use contraception, even though we recommend it; none of the methods are 100 percent effective, and many antiseizure medications lower the efficacy of contraceptives, so it is unavoidable that some people will become pregnant while on these medications. With the reversal of Roe, in some states women no longer have the ability to make these decisions for themselves, and I think it's inevitable that we will see increases in serious birth defects as a result.

Similarly, both the National Multiple Sclerosis Society and the Food and Drug Administration recommend discontinuing the use of most disease-modifying therapies (DMTs) for multiple sclerosis while trying to conceive, during pregnancy, or breastfeeding.

Glatiramer acetate and interferon beta are thought to be the safest of the DMTs, so if a woman wants to get pregnant with active disease, in rare situations a neurologist might leave a woman on one of those therapies, but they are modestly effective compared to the highly effective newer agents, said Amy Hessler, DO, FAAN, who recently left her position as director of women's neurology at the University of Kentucky to establish a women's neurology clinic in Jacksonville, FL.

Teriflunomide is the worst oneif accidental pregnancy occurs while on this agent, the medication is immediately stopped and a rapid elimination procedure is required urgently, as well as counseling [for] the mother about the increased risk of teratogenicity. Dimethyl fumarate should be stopped at the same time the woman stops contraception, due to uncertain but potential risks. Fingolimod is also associated with increased risk of adverse fetal outcomes. There are pregnancy registries associated with all these medications to make the best treatment decisions. Also, there is risk to the woman of rebound relapse if she is rapidly taken off her MS medication, particularly with fingolimod and natalizumab. It can be hard to get it back under control and it can even be life-threatening.

If one of our patients were to become pregnant while on any of these medications that can cause severe teratogenic effects, there are currently no options for them in Texas, said Audrey Nath, MD, PhD, a pediatric epileptologist and clinical assistant professor of neurology at the University of Texas Medical Branch in Galveston.

Concerns about legal restrictions or even prosecution for the use of these medications in a patient's reproductive years could potentially lead neurologists to be restrictive in their prescribing of appropriate therapies, Dr. LaHue and coauthors suggested in the JAMA Neurology article.

In a climate of increased limitations on reproductive rights, whereby pregnancies cannot be reliably timed or prevented, neurologists might possibly restrict use of the effective medications that are standard care for other patient groups because of potential concerns about causing fetal harm, they wrote. This could increase risk of morbidity, mortality, and irreversible disability accumulation for women with neurologic diseases.

Attempts to restrict the use of such medications even when prescribed by a physician have already been reported in states that have banned abortion. Methotrexate, a folate antagonist that can cause miscarriage at high doses and is the preferred treatment for ectopic pregnancy, is also one of the most used drugs for the treatment of inflammatory conditions such as rheumatoid arthritis, lupus, psoriasis and psoriatic arthritis, and Crohn's disease. It is sometimes used off label for the treatment of multiple sclerosis and as a less expensive, steroid-sparing agent for the treatment of myasthenia gravis.

But the cases that keep Dr. Nath up at night are those pertaining to children and teenage girls she has cared for with intellectual disabilities caused by neurodevelopmental conditions. These conditions may be due to a genetic disorder that affects brain development, brain injury earlier in life, or childhood seizure disorders that can affect cognition, she said.

It's well known that young women with intellectual disabilities are at higher risk for unplanned and unwanted pregnancy, Dr. Nath said. They are more likely to be targeted for sexual assault, they may be easier to manipulate because of their intellectual disability and find themselves in situations that they can't handle, and they are at high risk for becoming pregnant because they may not take birth control reliably or even be aware of their menstrual cycles.

They may not even realize they are pregnant, she added. The entire pregnancy and delivery process can be very traumatic for someone with an intellectual disability who may be functioning at a level much below their actual age, and young girls like this are a very high-risk population for pregnancy and delivery.

Women with a family history of neurogenetic disorders, ranging from neurofibromatosis to Fabry disease, Canavan disease, and Tay-Sachs disease are likely to be denied the option to make decisions about their pregnancy depending on the state they live in, said Janet F. Waters, MD, FAAN, clinical associate professor of neurology and division chief for women's neurology at the University of Pittsburgh Medical Center. Previously, these women could undergo testing during pregnancy and make a choice as to whether to continue if the child would be born with these significant and sometimes fatal neurologic diseases, but now they will not have the option.

Sonika Agarwal, MBBS, MD, previously practiced maternal fetal medicine in India and now specializes in fetal and neonatal neurology at the Children's Hospital of Philadelphia of the University of Pennsylvania.

Our role as pediatric neurologists should extend to women's health care before, during, and between pregnancies to maximize both the woman's health and the neonatal outcome which impacts pediatric health, Dr. Agarwal said. This ruling takes away both the patient's autonomy and the primacy of the physician-patient relationship. The only way we can render safe, effective, and evidence-based care in what are often profoundly challenging situations is to come together as a team of medical experts, critically evaluate all testinggenetics, imaging scans for the fetal brain and other systemsand any complications in the pregnant woman's health and go through the complex process of counseling a pregnant woman/couple about the likely prognosis and outcomes.

For example, she continued, in cases of anencephaly, we know the baby is not going to survive. There are other neurologic conditions where the baby may survive but would face significant challenges around birth and need lifelong support due to a severe and complex brain malformation or extensive brain destruction by stroke or brain bleed; we can reasonably say they will have a profoundly impaired neurological function or quality of life, or a reduced lifespan where they will live only for a few years sustaining on life support with feeding and breathing tubes. In these challenging fetal neurologic consultations, the clinicians and the parents together weigh all the information about the quality of life and possible outcomes for the unborn baby and the medical team supports them in the decision-making process. This critical relationship between patient and medical professionals is not something that should be intruded on by legislators.

Abortion bans also limit clinicians' options for managing women who develop life-threatening problems during pregnancy, said Mary Angela O'Neal, MD, FAAN, division chief of general neurology at Brigham and Women's Hospital in Boston and an expert in the neurology of pregnancy.

I've had patients diagnosed with brain cancer in pregnancy, and the treatment for mom is not something that's going to be good for the babysurgery, radiation, chemotherapy or all three. This is a very difficult choice for families to make, but it should be theirs. Or when a woman develops pre-eclampsia, that can cause stroke, hemorrhage, and death, and the only treatment is delivery. Will induction of labor in circumstances like these, such as in the late second trimester when the baby is unlikely to survive, be allowed under some of these state laws?

No one seems to know for sure, as many of these laws are vague and choices about enforcement are left up to local and state officials. In Ohio, for example, state law says that abortion is permitted only in a medical emergency requiring the immediate performance or inducement of an abortion to prevent death or irreversible bodily harm that delay in the performance or inducement of the abortion would create.

With such vague, open-to-interpretation language, how do clinicians decide just how immediate the medical emergency is? If states write laws that are completely vague about what the requirements are, they can still have abortion on the books, but have an environment in which no physician is willing to provide it, Melissa Murray, a law professor at New York University, told opinion writer Michelle Goldberg in a July 14 article in the New York Times.

Dr. Waters is haunted by the case of a woman who was brought to Magee-Womens Hospital at about 21 weeks of pregnancy in flagrant eclampsia like no case I have seen before. She had hidden her pregnancy from a strict family and sought no prenatal care; her pregnancy was diagnosed only after she came to the hospital with seizures and was given a routine pregnancy test prior to undergoing a head CT.

By the time she reached us, this woman was blind, she had so much brain edema that she was essentially comatose. We had to save the mom and save her fast, said Dr. Waters. We had to go through basically a delivery at 21 weeks, which would be considered an abortion under many of these laws. The baby was already gone, but what if it had still been alive? In a state with an abortion ban, what choice do you make? In any decision about delivery, the woman has to come first.

Although abortion remains legal and likely to be protected in 19 states, women in large swaths of the country will have to travel long distances to access an abortion, which poses a significant problem of equity.

Here in Kentucky, our trigger ban was enjoined by a court, but if it goes into place, leaving the state is not realistic for the average person, said Dr. Ebong. Kentucky is a very poor state, and the nearest states are West Virginia, Tennessee, and Ohio, which are in the same boat as Kentucky when it comes to their laws. Women can't just get a plane ticket to go further for an abortion, that's not a realistic option and it shouldn't have to be. You should have access close to where you are.

Individuals who have more resources are going to have more choices, agreed Dr. O'Neal. This will affect lower-income people more devastatingly because they're not going to have the financial and other resources to be able to make those choices. We know that people from marginalized communities have less opportunity to have neurologic care to plan and optimize their medications, so they are at even more risk. Their choices are being taken away from them as we speak, and I can't see this as doing anything but magnifying the already existing inequities.

These laws are directly in conflict with our code of ethics as neurologists and as physicians, which is to put our patient's best interest first, said Dr. Cejas. We won't be able to provide appropriate care. Regardless of what a person thinks about abortion from an ideological perspective, abortion is health care, and it is a medical procedure, and we have to offer our patients multiple options with respect to their care. But as more of these restrictions come into place, we'll see more and more neurologists put into positions where taking the best care of our patients from a medical and ethical perspective is in conflict with what we are allowed to do from a legal perspective. When I talk to colleagues in states with these bans already in place, they don't know what to do and what to tell their patients. And what will our hospitals do to protect us and our right to provide optimal care?

The AAN, Association of American Medical Colleges, the American Medical Association, the American Academy of Pediatrics, the American Psychiatric Association, the American Epilepsy Society, as well as the Child Neurology Foundation and Child Neurology Society, have all published statements in response to the Supreme Court decision, focusing on the primacy of the relationship between physicians and their patients in making health care decisions.

Dr. Nath urges neurologists to make their voices heard by becoming more involved in advocacy. When we have our voices heard in the rooms where they are writing legislation, that can have a very big impact, particularly within state legislatures, she said. This is one among many issues that shows us that we need to have a seat at the table. It's a wakeup call for us. It matters who's in these legislatures, and your professional and life experience matters.

In this issue, we cover the impact of the recent Supreme Court decision overturning Roe vs. Wade on the field of neurology. The editors of Neurology Today believe that abortion is health care, and health care decisions should be made between patients and their physicians. We fear for the impact on the health of women with neurologic disorders, who may find themselves in life-threatening situations due to this decision. We will continue to cover the impact of the Supreme Court decision on our patients and our practice.

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Neurologists Discuss the Impact of Roe v. Wade Reversal on... : Neurology Today - LWW Journals

The U.S. Supreme Court on June 24 overturned Roe v. Wade, the 1973 decision that had provided a constitutional right to abortion. The ruling was expected to lead to abortion bans in roughly half the states, although the timing of those laws taking effect varies.

Some Republican-led states banned or severely limited abortion immediately after the Dobbs v. Jackson decision, while other restrictions will take effect later.

In anticipation of the decision, several states led by Democrats took steps to protect abortion access. The decision also set up the potential for legal fights between the states over whether providers and those who help women obtain abortions can be sued or prosecuted.

Here is an overview of the impact the ruling has had so far in every state and the status of their laws.

ALABAMA

Political control: Alabamas Republican-controlled Legislature and Republican governor want to ban or restrict access to abortions.

Whats happened since Dobbs: Hours after the Dobbs ruling, a judge lifted an order that had blocked a 2019 law with one of the nations most stringent abortion bans from being enforced.

Whats in effect: The ban is now in effect. It makes it a felony to perform an abortion at any stage of pregnancy with no exceptions for rape or incest. There is an exception in cases where the womans health is at serious risk. The penalty is up to 99 years in prison.

Clinics offering abortions? No.

Whats next: Some Republican lawmakers have said they would like to see the state replace the 2019 ban with a slightly less stringent bill that would allow exceptions in cases of rape or incest. Proponents said the 2019 ban was deliberately strict in the hopes of sparking a court challenge to Roe.

ALASKA

Political control: Republicans hold a majority of seats in the Legislature, but the House has a bipartisan coalition majority composed largely of Democrats. Republican Gov. Mike Dunleavy, who believes life begins at conception, is seeking reelection. His main challengers independent former Gov. Bill Walker, and Democrat Les Gara have said they would protect abortion rights if elected.

Whats happened since Dobbs: The Legislature ended its regular session before the decision came out, and there has been no push for a special session.

Whats in effect: The state Supreme Court has interpreted the right to privacy in the state constitution as encompassing abortion rights.

Clinics offering abortions? Yes.

Whats next: Voters in the fall will be asked if they want to hold a constitutional convention, a question that comes up every 10 years. Many conservatives who want to overhaul how judges are selected and do away with the interpretation that the constitutions right to privacy clause allows for abortion rights see an opportunity in pushing for a convention.

ARIZONA

Political control: The GOP controls both chambers of the state Legislature. Republican Gov. Doug Ducey must leave office in January because of term limits.

Whats happened since Dobbs: Legal uncertainty about two different abortion laws prompted clinics to stop providing the procedure. Republican Attorney General Mark Brnovich has asked a judge to lift a decades-old order that blocks enforcement of an abortion ban passed before Arizona was a state. But a new law scheduled to take effect Sept. 24 would be less stringent, banning abortions after 15 weeks of pregnancy. Also after the Dobbs ruling, the U.S. Supreme Court began allowing the state to enforce a 2021 ban on abortions done solely because the fetus has a genetic abnormality such as Down syndrome. But a federal judge in Phoenix in July blocked enforcement of another part of that so-called personhood law that grants legal rights to fertilized eggs or fetuses. Abortion rights supporters said that could have been used to charge providers with assault, child abuse or other crimes for otherwise-legal abortions.

Whats in effect: The law before Dobbs barred abortions after about 22 weeks.

Clinics offering abortions? No.

Whats next: More court battles are expected over whether the earlier, more complete ban is in effect and whether Arizonas less stringent law can take effect in September.

ARKANSAS

Political control: The Legislature and governors office are controlled by Republicans. Gov. Asa Hutchinson is term-limited and will leave office in January. Republican nominee Sarah Sanders, press secretary to former President Donald Trump, is widely favored to succeed him in the November election.

Whats happened since Dobbs: A trigger ban on most abortions adopted in 2019 went into effect.

Whats in effect: Abortions are banned with the exception of when the procedure is needed to protect the life of the mother in a medical emergency.

Clinics offering abortions? No.

Whats next: Hutchinson favors exceptions in the case of pregnancies caused by rape or incest, but he does not expect to ask lawmakers to consider it at a special legislative session.

CALIFORNIA

Political control: Democrats who support access to abortion control all statewide elected offices and have large majorities in the Legislature.

Whats happened since Dobbs: The day of the Dobbs ruling, Gov. Gavin Newsome signed a bill intended to protect patients or providers from being sued in states that have abortion bans. He has also launched a commitment with Oregon and Washington to defend access to abortion.

Whats in effect: Abortion is legal in California until viability, generally considered to be around 24 weeks.

Clinics offering abortion? Yes.

Whats next: Lawmakers plan to put a constitutional amendment on the ballot in November that would explicitly guarantee the right to an abortion and contraceptives.

COLORADO

Political Control: Colorados Democratic-controlled Legislature adopted and its Democratic governor signed into law a fundamental right to abortions in April.

Whats happened since Dobbs: After the legislature introduced the bill codifying abortion rights, Colorado Governor Jared Polis signed an executive order saying Coloradans will not participate in out-of-state abortion-related investigations.

Whats in effect: Colorados Reproductive Health Equity Act declares fundamental rights to abortions at any stage of pregnancy. The law also prohibits local governments from denying, restricting, or depriving individuals of an abortion. State law still prohibits public funding for abortions and requires that minors inform their parents.

Clinics offering abortions? Yes.

Whats next: Republican lawmakers in Colorado have spoken about legislative challenges to the new state law. Colorado clinics are gearing up for an expected wave of out-of-state abortion seekers as surrounding states pass abortion bans.

CONNECTICUT

Political control: Democrats who control the Connecticut General Assembly support access to abortion, as does the states Democratic governor.

Whats happened since Dobbs: A law protecting abortion providers from other states bans took effect July 1. It created a legal cause of action for providers and others sued in another state, enabling them to recover certain legal costs. It also limits the governors discretion to extradite someone accused of performing an abortion, as well as participation by Connecticut courts and agencies in those lawsuits.

Whats in effect: Abortion is legal in Connecticut until viability, generally considered to be around 24 weeks. A law adopted in 2022 allows advanced practice registered nurses, nurse-midwives or physician assistants to perform aspiration abortions in the first 12 weeks of pregnancy.

Clinics offering abortions? Yes.

Whats next: Theres been discussion of amending the state constitution to enshrine the right to abortion, which could take many years.

DELAWARE

Political control: Democrats control the governors office and the General Assembly and have taken several steps to ensure access to abortion.

Whats happened since Dobbs: The state already had a 2017 law to codify the right to abortion and a 2022 law allowing physician assistants and advanced practiced registered nurses to prescribe abortion-inducing medications. After the ruling, the state adopted another law allowing physician assistants, certified nurse practitioners and nurse midwives to perform abortions before viability that includes legal protections for providers and patients.

Whats in effect: Abortion is legal until viability.

Clinics offering abortions? Yes.

Whats next: With protections in place, no major abortion policy changes are expected.

DISTRICT OF COLUMBIA

Political control: The local government in the nations capital is controlled by Democrats, with a Democratic mayor and the D.C. Council split between Democrats and nominal independent politicians, who are all, invariably, Democrats.

Whats happened since Dobbs: No policy changes have come about since the ruling.

Whats in effect: Abortion is legal at all stages of pregnancy.

Clinics offering abortions? Yes.

Whats next: The D.C. Council is considering legislation that would declare Washington, D.C., a sanctuary city for those coming from states where abortion is banned. But because Congress has oversight power over D.C. laws, a future ban or restrictions remain possible depending on control of Congress.

FLORIDA

Political control: Republicans control the House and Senate and governors office, with GOP Gov. Ron DeSantis pledging to expand pro-life protections after the Dobbs decision.

Whats happened since Dobbs: Floridas new 15-week abortion ban law went into effect July 1. The law is the subject of an ongoing lawsuit from abortion providers in Florida but remains in effect.

Whats in effect: The Florida law prohibits abortions after 15 weeks, with exceptions if the procedure is necessary to save the pregnant womans life, prevent serious injury or if the fetus has a fatal abnormality. It does not allow exceptions in cases where pregnancies were caused by rape, incest or human trafficking. Violators could face up to five years in prison. Physicians and other medical professionals could lose their licenses and face administrative fines of $10,000 for each violation.

Clinics offering abortions? Yes.

Whats next: The lawsuit against Floridas 15 week ban is ongoing and is expected to eventually reach the state Supreme Court. Republicans believe the conservative-controlled court will uphold the law.

GEORGIA

Political control: Georgia has a GOP-controlled General Assembly and a Republican governor who support abortion restrictions, but all are up for election this November.

Whats happened since Dobbs: A federal appeals court allowed the states 2019 abortion law to be enforced in a July 20 ruling after three years of being on hold.

Whats in effect: The law bans abortion when fetal cardiac activity can be detected and also declares a fetus a person for purposes including income tax deductions and child support. There are exceptions in cases of rape if a police report is filed and incest. There are exceptions if a womans life or health would be threatened.

Clinics offering abortions? No.

Whats next: Some Republican lawmakers and candidates want Georgia to go further and ban abortion entirely, but Gov. Brian Kemp is unlikely to call a special session before Novembers general election. Lawmakers are likely to consider further action when they return for their annual session in January. A major factor is whether Kemp is reelected or unseated by Democrat Stacey Abrams in Novembers election.

HAWAII

Political control: Hawaiis governor is a Democrat and Democrats control more than 90% of the seats in the state House and Senate.

Whats happened since Dobbs: The law hasnt changed.

Whats in effect: Hawaii legalized abortion in 1970, three years before Roe v. Wade. The state allows abortion until a fetus would be viable outside the womb. After that, its legal if a patients life or health is in danger.

Clinics offering abortions? Yes.

Whats next: Democratic lawmakers are considering how they might protect Hawaii medical workers from prosecution or civil litigation from other states for treating residents who arent full-time Hawaii residents such as military dependents or college students. Policymakers are paying attention to how the state may increase access to abortion on more rural islands where there is a doctor shortage, for example by boosting training for some nurses who under a new law passed last year are allowed to perform first-trimester abortions.

IDAHO

Political control: Republicans hold supermajorities in the House and Senate and oppose access to abortion, as does the states Republican governor.

Whats happened since Dobbs: The ruling triggered a ban on all abortions except in cases of reported rape or incest or to protect the mothers life. It is to take effect Aug. 25. President Joe Biden's administration has sued over the measure, arguing that it conflicts with a federal law requiring doctors to provide pregnant women with medically necessary treatment.

Whats in effect: Current law allows abortions up to viability, around 24 weeks, with exceptions to protect the womans life or in case of nonviable fetuses.

Clinics offering abortions? Yes.

Whats next: The Idaho Supreme Court is expected to rule in August on whether to lift an injunction that blocked enforcement of a law that could subject medical providers who perform abortions to lawsuits and criminal charges.

ILLINOIS

Political control: Illinois is overwhelmingly Democratic with laws providing greater access to abortion than most states. Democrats hold veto-proof supermajorities in the House and Senate, and the Democratic first-term governor seeking reelection this year, J.B. Pritzker, has promoted peaceful protests to protect the right to an abortion.

Whats happened since Dobbs: No major policy changes. Pritzker has called for a special legislative session to expand abortion rights.

Whats in effect: Abortion is legal in Illinois to the point of viability, and later to protect the patients life or health.

Clinics offering abortions? Yes.

More:
Abortion ruling prompts variety of reactions from states - ABC News