StemCell Therapy

May 25, 2021

By Nate Smelle

On the edge of summer in North Hastings, we usually expect a series of returns to arrive with the season and change our routines. Right on schedule, the annual influx of blood-suckers showed up over the long weekend to make their presence known.

With the sun shining and a long list of work outdoors to be done, there was no avoiding the seasonal bloodletting that was due. Before stepping outside Sunday morning to begin the day of chores ahead, it appeared by the swarm of mosquitoes literally knocking on the door that my donation of plasma was highly anticipated.

As every resident of North Hastings knows, it doesnt take long to form a collection of homegrown remedies to help ease the the pain and suffering caused by these tiny, yet ferocious creatures. From spraying vinegar on bites to numb the itch, to planting beebalm or marigolds to keep the thirsty insects at bay; there are more than enough recipes for homemade repellents and medicines to fill a newspaper. In my experience, however, the most effective way to limit the necessary suffering caused by these winged-armies of mosquitoes and blackflies invading our airspace is the same remedy used to repel vampires garlic.

Since my time spent at the family cottage near Fenelon Falls as a child, I can recall my grandparents selling me on the value of this potent and precious plant. While there are a multitude of ways to prepare and use garlic as an eco-friendly bug spray, I have always found it most powerful when it is ingested.

For this reason, during the past month and a half I have been eating as much garlic as humanly possible. A big fan of its flavour, an extra clove or two of garlic can redefine the taste of any dish on the menu. A highly nutritious plant, garlic is known to: boost the functioning of the immune system; help fight a variety of illnesses, including the common cold; reduce blood pressure; improve cholesterol levels; contain antioxidants that are said to help prevent Alzheimers disease and dementia; improve bone health; and, detoxify the body. Complimenting its medicinal abilities, is the fact it can be grown relatively easily here in North Hastings.

Walking out my front door and into the shape-shifting clouds of insects on Sunday, I watched as the overwhelming majority of these creatures of the night caught a whiff of my exposed limbs, and decided to keep searching for another donor. Of course not everyone of the insects was deterred by my preemptive dosing of preventative medicine.

Despite my long-term strategy when it comes to biting insect control, I have made it part of my routine over the years to allow the first brave mosquito of the season to have its fill. Watching as this lucky diner began to feed, I laughed as I thought of how much energy and resources we humans invest in the avoidance of this timeless interaction. I guess His Holiness the Dalai Lama was correct when he said, If you think you are too small to make a difference, try sleeping with a mosquito.

Go here to read the rest:
Sleeping with a mosquito | Bancroft this Week - Bancroft This Week

Often, messages that pose as health promoting are actually the opposite. There are obvious examples, like the doctor pushingan all-meat diet, or the celebrity wellness influencer telling the world that voluntarily getting stung by bees will reduce inflammation. But the more dangerous messaging is subtler, more insidious, and widespread: that fat bodies are inherently unhealthy.

In a recent New York Times article, healthcolumnist Jane Brody points out that Americans have been hit harder by COVID than most other countries, then blames this on our personal health habits, namely diet and exercise. She spends most of the column raising alarm bells about quarantine weight gain,high-calorie foods, and fatness in general.

In doing so, shes not promoting healthier habits. The truth is, health and weight are not nearly as entwined as we think they are. (Not to mentiontheres far more to Americas COVID crisis than personal health; limited access to health care, systemic discrimination and inequality, and thepoliticizationof the virus have all played huge roles.) Overemphasizing weight loss is stigmatizing and can actually be detrimental to individual health. Heres why we need to rethink this kind of messaging.

Brody talks of the many people in her life who have packed on quite a few pounds of health-robbing body fat this past year. This isan undeniably stigmatizing statement, andit also makes a major assumption that happens to be false: that gaining weight, or being naturallybigger-bodied, is inherently unhealthy. (As a journalist, Im constantly irritated that other journalists can writethings like this without citing a shred of evidence, whereas I have to add an entire paragraph with several citations every time I suggest that weight loss isnt always a helpful or realistic goal.)

Its possible to be healthy at a higher weight, just as its possible to be unhealthy at a lower one. One 2016 study in theJournal of the American Medical Associationeven found that Danish adults in the overweight BMI category actually lived the longest. Being at a higher weight is associated with a higher risk of certain diseases, yes, but that doesnt mean someone at a higher weight is necessarily unhealthy. You absolutely cannot infer health information or information about ones health behaviors based solely on their weight, says Mary Himmelstein, a researcher at the University of Connecticuts Rudd Center for Food Policy andObesity. Someone in a thin body may be completely sedentary and eat a diet of mostly processed foods and very few fruits and vegetables, while someone in a larger body might be extremely active and eat loads of nutrient-rich foods.

All of this to say:the relationship between weight and health is far too complicated to make blanket statements like health-robbing body fat. Both weight gain and weight loss can be healthful or harmful.It all depends on context.

For years, Brody has presented herself as a living example of sustainable weight lossabout 50 years ago, she lost 40 pounds in twoyears and has kept that weight off since.In this particular column, she offers up her personal eating regimen as the solution to pandemic weight gain (and fatness in general): eat a diet based primarily on vegetables, with fish, beans, and nonfat milk [as ones]main sources of protein, along with a bit of portion-controlled ice cream, the occasional burger, and daily exercise. But while that approach may seem realistic compared to all the fad diets out there, experts warn that its not as accessible as Brody makes it sound.

This I can do it, so can youattitude is out of touch with many peoples reality, says Jennifer Jackson, a dietitian based inAlbuquerque, New Mexico. The nonprofit Feeding Americaestimates that 15 percent of Americans cant afford enough nutritious food to meet their needs, and Bloomberg reported earlier this year that 12 percent of Americans live in poverty. Stressors like working multiple jobs, raising children (especially as a single parent), lacking health insurance, and living in unsafe neighborhoods alsomake prioritizing good nutrition more complicated. Health behaviors often have more to do with someones privilege than their motivation, Jackson says.

Even if everyone did eat according to Brodys recommendations, it doesnt mean we would all magically be at what Brody and the BMIscale (theheight-to-weight ratio used to group people into weight categories)deema healthy weight.Weight is not simply calories in, calories out, Himmelstein says. In fact, the bodyactively resists weight loss: a2015 literature review published in the International Journal of Obesity explains that the body generally adapts to calorie deficits by burning fewer calories, using less stored fat for energy, decreasing the fullness-signaling hormone leptin, and increasing the hunger-signaling hormone ghrelin. Its also widely accepted that theres a genetic component to obesity, and a 2018 review in Current Obesity Report outlines the significant amount of evidence suggesting that stress plays a big role in body weight as well.

Weight and weight gain are the result of our genetics, our physiology, our environment, our personal stress levels, and our behaviors,the authors write. Assuming that weight is impacted only, or primarily, by our behaviors, is wildly inaccurate. Andmaintaining weight loss long-term is even harder than acheiving it in the first place. A 2020 review in The BMJ found that while diets lead to weight loss and health improvements in the first six months, these benefits typically disappear by the one-year mark.

Relentlessly encouraging weight loss does more harm than good. Fat-shaming messaging increases weight stigma, which increases stress and inflammationwhich are negative health outcomes, says Amee Severson, a dietitian and the owner of Prosper Nutrition in Bellingham,Washington.A 2015 study in Obesity, ofwhich Himmelstein was the lead author, found that individuals who reported experiencing weight stigma had higher levels of cortisol, a stress hormone, than those who did not. Chronically elevated levels of cortisol have repeatedly been linked to an increased risk of many diseases, as outlined in this 2017 review published in the EXCLI Journal.And a 2018 study in Health Psychology, also authored by Himmelstein, found that coping with weight stigma can negatively impact both physical and mental health.

While articles like Brodys are presumably meant to promote health and healthy behaviors, they actually do the opposite. A small 2014 study of 93 college-agewomenin the Journal of Experimental Social Psychology found that thosewho saw themselves as overweight felt less capable of controlling their eating and consumed more calories after reading a weight-stigmatizing news articlethan those who read a non-stigmatizing article. A larger 2017 study in Preventative Medicine found that experiencing weight stigma as an adolescent significantly increased a persons risk for binge eating and unhealthy weight-control behaviors as an adult. And, as Severson points out, it makes bigger-bodied people less likely to seek out health care, too.

No one owes it to the world to be healthy. I think that every single person has the right to choose how important health is to them, Severson says. People are allowed to have different values, and healthy behaviors like eating nutritious foods and getting regular movement are not a moral obligation.

Health is personal, and what is considered healthy when it comes to eating and other behaviors varies between individuals. Its incredibly difficult to give effective health advice to a large audience, but theres still room for health-promoting messages in the media. We need to thinkcritically about the harmcertain messages may cause. Mandating fruits and vegetables for people who cant afford them is offensive and misguided. Demonizing fat and weight gain is demoralizing and harmful to people who live in larger bodies. We know that shame doesnt motivate healthy behaviorsand itabsolutely harms health.

View post:
Fat-Shaming People Won't Improve Their Health | Outside Online - Outside

Americas Health Rankings reports that almost 50% of pregnant women in the U.S.did not originally intend to conceive. Furthermore, it states that over half of the nations female population will experience an unexpected pregnancy by the time they are 45 years old. The unintended conception rate (and birthrate in the U.S. in general) has actually declined in the past few years and may continue to drop, but it remains high at the moment. This is largely due to failure to utilize proper contraception or incorrect usage of it. Many younger individuals are not fully educated on the matter but continue to participate in sexual activities regardless, often acting on incorrect information gleaned from less than credible sources such as peers. Others lack access to preventative measures. There are three main options for women in this situation, keeping the baby, giving it up for adoption and getting it aborted. The latter is one many choose for a variety of reasons, including health concerns, personal trauma and life circumstances. However, some regret making this decision. There is an option for those who had a medical abortion and fall into this category calledabortion pill reversal.

A medical abortion consists of two phases in which two kinds of pills are taken, one type in each phase. The first is called mifepristone; it keeps the hormone progesterone, which helps the womb get ready for and nurture the baby, from being absorbed by taking up bonding spots on receptors so the chemical cannot attach to them. The reversal process works by essentially overriding this effect. The body is flooded with progesterone in the hope that there will be so much of it that mifepristone cant prevent all of it from being taken into the womb.

The process only works if the woman has only taken the first medicine; after the second dose of pills, it is ineffective. It is also best done as soon as possible after beginning the abortion, preferably within 24 hours. There have been a few cases where it worked when done within 72 hours, but in general the faster the reversal starts, the higher the likelihood is of it taking effect.

The reversal of the abortion pill is a relatively new concept, thought up within the past two decades. There has been a great deal of controversy over it as many people claim that it does not work. These individuals argue that there is not enough scientific evidence to support it as a viable method and cite incidents where it didnt produce the desired effects as proof that progesterone does not reverse the effects of mifepristone. Since there have been situations where women successfully remained pregnant after the progesterone process, the answer to the conflict has yet to be fully settled. There have also been ones where those who only took the first pill and not the second but did not choose reversal carried their babies to term, adding another factor to the complex issue. The American Association of Pro-Life Obstetricians and Gynecologists does support the validity of the procedure, though.

The process of reversing the abortion pill with progesterone is a controversial one. It has, however, appeared to be successful in many real-life cases.

Image byArek SochafromPixabay

Follow this link:
Abortion Pill Reversal: Answering Your Questions About the Controversial Treatment - Medical News Bulletin

More than half of all American adults have now received at least one dose of the three available COVID-19 vaccines, according to the the Centers for Disease Control and Prevention (CDC). Cases of the novel coronavirus have been plummeting since February, and theyll likely keep falling if people continue lining up for their shots, according to Anthony Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases.

One thing that is quite certain is that when you have a vaccine, or a group of vaccines, that are as highly effective in the real world ... as these vaccines are, and you get a substantial proportion of the population vaccinated, the chances of there being a surge are extraordinarily low, Dr. Fauci told The Washington Post this week.

The COVID-19 vaccines, which have been proven to prevent serious and symptomatic SARS-CoV-2 infections, are like a positive wild card on our side. The most recent and serious COVID-19 peak occurred at the end of 2020 and the beginning of 2021, a point when virtually no one in the country was vaccinated, Dr. Fauci said.

Now, the vaccines have the power to keep it from happening again. I really dont foresee there being the risk of a surge, provided we continue to get people vaccinated at the rate we have now, Dr. Fauci said.

For the latest health news, join Prevention Premium to gain exclusive access to expert-backed wellness content you can trust.

Experts agree. Just look at the numbers, which have been dropping steadily as vaccinations have ramped up, says Stephen Gluckman, M.D., an infectious disease expert and medical director of Penn Global Medicine. That really can only be attributed to the vaccine, because the other preventative measureswhich are very effective, by the waywere already in place and were not effective enough.

Masking, social distancing, and hand-washing have still been invaluable in the fight against COVID-19 and other seasonal illnesses; for example, flu activity has been much lower than in previous seasons, likely due to these practices, experts say.

The available vaccines are remarkable, even if theyre not 100% effective, because they decrease the number of serious, symptomatic infections. By keeping people less sick, the vaccines also reduce the risk of mutations, Dr. Gluckman explains, meaning that deadlier or more infectious variants (like the ones that were first identified in the U.K. and California) are less likely to develop and spread.

Earlier this month, President Joe Biden announced he aims to administer at least one dose of the COVID-19 vaccines to 70% of American adults by July 4. Nine states, including New Jersey, Hawaii, and New Mexico, have already met this goal at the time of publication. About 62% of American adults have received one dose of the COVID-19 vaccine, and about 50% of adults are considered to be fully vaccinated, per the CDC. (Note that these figures only reflect vaccination rates in adults, not the full U.S. population.)

Although the exact percentage of vaccinated people necessary to achieve herd immunity remains unclear, Dr. Fauci has previously estimated that 70% to 85% of the population must be fully vaccinated to significantly prevent community spread. Bidens plan focuses only on adults, but children are crucial to herd immunity as well; vaccine approval for kids under 12 could hopefully come in the next few months.

Although we dont know exactly how long individual immunity will last post vaccine, Dr. Fauci isnt worried about the effects wearing off soon: I think [the vaccines] will be effective long enough that we will get to the point where we are not going to be necessarily worrying about a surge, he said in the interview. (Plus, Pfizer, Moderna, and Johnson & Johnson are already in the process of testing booster doses to maintain protection.)

In some areas, face coverings are becoming less common due to the CDCs updated masking guidancebut thats dangerous for unvaccinated people, for those who are immunocompromised, and for anyone in a crowded area. Its still crucial to become fully vaccinated before you go without a mask in high-risk spaces, like hospitals or public transportation.

Somehow, that might have gotten lost in the announcement about masks, Dr. Gluckman says. If you choose to wear a mask because you want to, theres no harm in doing so. It helps keep you and those around you safe.

But ultimately, doing your part for your community means lining up for your dose. Theres still enough [COVID-19] around for yet another surge, says Dr. Gluckman. The way to prevent that is by getting vaccinated.

This article is accurate as of press time. However, as the COVID-19 pandemic rapidly evolves and the scientific communitys understanding of the novel coronavirus develops, some of the information may have changed since it was last updated. While we aim to keep all of our stories up to date, please visit online resources provided by the CDC, WHO, and your local public health department to stay informed on the latest news. Always talk to your doctor for professional medical advice.

This content is created and maintained by a third party, and imported onto this page to help users provide their email addresses. You may be able to find more information about this and similar content at piano.io

See the original post here:
Dr. Fauci Explains How We Can Avoid Another COVID-19 Surge This Winter - Prevention.com

AUSTIN, TX / ACCESSWIRE / May 20, 2021 / SmallCapVoice.com Inc. ("SCV") announces the availability of a new interview with Troy Grogan, CEO of USA Equities Corp. (OTCQB:USAQ), to discuss the Company's digital medicine and virtual care platform designed to make healthcare encounters more efficient, cost-effective and comfortable for both the physician and patient.

Speaking with SCV's Stuart Smith, Grogan outlined the five focal points that drive USAQ's business model and growth trajectory. This structure generates recurring revenue for both USAQ and its physician clients, while the Company's remote-patient monitoring technology meets greater demand for virtual care in post-pandemic healthcare.

The full interview can be heard at: https://www.smallcapvoice.com/interview-usa-equities-corp-usaq/.

"Only 15 or so months ago, we wouldn't have thought virtual care technologies and digital medicine would come to the forefront but they are here and they're here to stay," Grogan explained. "A lot of patients have really felt the benefit of not having to go into a doctor's office and sit in a waiting room to get good, quality care. We're a part of that new ecosystem."

Healthcare providers also benefit from efficient digital care. USAQ's target market is a growing field of solo, independent practices looking for ways to generate revenue and become more efficient with their services. The Company's reimbursable Software-as-a-Service (Saas) technology enables these small businesses to achieve recurring revenue at high gross margins while addressing the preventative care of multiple chronic conditions, said Grogan.

As a public company, USAQ has the obvious advantage of access to capital markets, but it's the individual healthcare professional and retail investor that the Company seeks to obtain as key stakeholders.

"Instead of going to [venture capitalists] and institutional investors, we've gone to our clients and let them have an opportunity to invest in the future of medicine and join us alongside in the future upside that we have," Grogan stated. "We're a publicly traded company as opposed to being privately held to give retail investors to have a piece of the future of medicine."

Grogan's diverse experience in healthcare in the U.S. and abroad has given him a well-rounded perspective of the healthcare industry. This insight is the foundation of the tactical manner used to assemble the Company's management and advisory board.

"Along this journey of 10 years, I've built a very solid team around me of medical educators, doctors, business development experts in network development for physicians and growing physician networks," he said. "As an early-stage company, you can't just gain authority and credibility overnight. Often, you have to bring a team around you that brings credibility to the forefront."

In 2020, USAQ leveraged this expertise to launch two apps and present at the University of Miami Allergy Diagnostics and Allergen Immunotherapy Virtual CME Event, a continuing education course for over 100 doctors to demonstrate that the future of medicine is headed toward physician-directed digital medicine and preventative health technologies that streamline the care process.

Next month, USAQ will participate in a second workshop at the University of Miami's Miller School of Medicine to further educate medical practitioners on the Company's solutions and to continue to build its client base.

"This is a key point," said Grogan. "This is the type of doctor that we're getting as a client. Their behavior is that they want to be educated in these new areas, they want to do things that are slightly out of the scope of their practice but want to make sure they have the right credentials to do it, and they're looking to make more revenue."

Moving into the second half of 2021, Grogan said the Company will add more products to its customer base, more efficiently amortizing its sales and marketing. He concluded the interview with a recap in USAQ's recent financial performance and its ability to double revenues sequentially from one quarter to the next.

The full interview can be heard at: https://www.smallcapvoice.com/interview-usa-equities-corp-usaq/.

About USA Equities Corp.

USA Equities Corp. (OTCQB:USAQ) is focused on providing value-based healthcare solutions, clinical informatics and algorithmic personalized medicine including digital therapeutics, behavior-based remote patient monitoring, chronic care and preventive medicine. The Company's products are intended to allow general practice physicians to increase their revenues by cost effectively diagnosing and treating chronic diseases that are generally referred to specialists. The Company's products and information service portfolio are directed toward prevention, early detection, management and reversal of cardio-metabolic and other chronic diseases. Our principal objectives are to develop proprietary software tools, devices and approaches, providing more granular, timely and specific clinical decision-making information for practicing physicians and other health care providers to address today's obese, diabetic and cardiovascular disease population.

For additional information, visit the Company's website at http://www.USAQCorp.com

Forward-Looking Statements

Certain matters discussed in this press release are forward-looking statements' intended to qualify for the safe harbor from liability established by the Private Securities Litigation Reform Act of 1995. In particular, the Company's statements regarding trends in the marketplace, future revenues, future products and potential future results and acquisitions, are examples of such forward-looking statements. Forward-looking statements are generally identified by words such as may', could', believes', estimates', targets', expects', or intends' and other similar words that express risks and uncertainties. These statements are subject to numerous risks and uncertainties, including, but not limited to, the timing of the introduction of new products, the inherent discrepancy in actual results from estimates, projections and forecasts made by management, regulatory delays, changes in government funding and budgets, and other factors, including general economic conditions, not within the Company's control. The factors discussed herein and expressed from time to time in the Company's filings with the Securities and Exchange Commission could cause actual results and developments to be materially different from those expressed in or implied by such statements. The forward-looking statements are made only as of the date of this press release and the Company undertakes no obligation to publicly update such forward-looking statements to reflect subsequent events or circumstances.

About SmallCapVoice.com

SmallCapVoice.com, Inc. is a recognized corporate investor relations firm, with clients nationwide, known for its ability to help emerging growth companies, small cap and micro-cap stocks build a following among retail and institutional investors. SmallCapVoice.com utilizes its stock newsletter to feature its daily stock picks, podcasts, as well as its clients' financial news releases. SmallCapVoice.com also offers individual investors all the tools they need to make informed decisions about the stocks in which they are interested. Tools like stock charts, stock alerts, and Company Information Sheets can assist with investing in stocks that are traded on the OTCMarkets. To learn more about SmallCapVoice.com and its services, please visit https://www.smallcapvoice.com/small-cap-stock-otc-investor-relations-financial-public-relations/.

Socialize with SmallCapVoice and their clients at

Facebook: https://www.facebook.com/SmallCapVoice/Twitter: https://twitter.com/smallcapvoiceInstagram: https://www.instagram.com/smallcapvoice/

CONTACT:

Investor & Media Contact

Olivia GiamancoUSA Equities Corp.(929) 379-6503[emailprotected]

SmallCapVoice.com

Stuart T. Smith512-267-2430[emailprotected]

SOURCE: SmallCapVoice.com

View source version on accesswire.com: https://www.accesswire.com/648246/USA-Equities-Corp-OTCQBUSAQ-Discusses-its-Digital-Medicine-as-the-Future-of-Healthcare-in-Audio-Interview-with-SmallCapVoicecom

The rest is here:
USA Equities Corp. (OTCQB:USAQ) Discusses its Digital Medicine as the Future of Healthcare in Audio Interview with SmallCapVoice.com - GuruFocus.com

Editor's Note: We at POPSUGAR recognize that people of many genders and identities, including but not limited to women, may or may not have female sex organs, such as a cervix or vagina. This particular story includes language from experts, government agencies, and studies that generally refer to people with female sex organs as women.

It's been roughly two decades since the US launched a nationwide vaccination effort against the human papillomavirus (HPV), a sexually transmitted virus that increases the likelihood of developing certain cancers. While the campaign is widely viewed as a success, it has led only to a stagnant reduction in infection rates in the Black and Latinx communities and not just because, historically, these communities have been more likely to express vaccine hesitancy. The first two vaccines created to slow HPV transmission did not address the strains of the virus that are most common in women who researchers identify as Black or Hispanic, the demographic that is also most likely to be diagnosed with HPV-associated diseases, including cervical cancer.

Young millennials like myself and older members of Gen Z may recall getting Gardasil-4 or Cervarix-2, the first vaccines that were developed to curb the spread of HPV. Gardasil-4 and Cervarix-2 were administered to young people and children as young as 9 years old, and required a two- or three-dose regimen, depending on the person's age at the time of their first dose. However, despite the success of these vaccines following their rollout in 2006, the Black and Latinx communities have continued to experience disproportionate levels of HPV-associated cancers. Thus, the creation of the Gardasil-9 vaccine the latest HPV vaccine that expands protection against multiple strains of high-risk HPV is essential in addressing this disparity.

Gardasil-9 is now the primary HPV vaccine in the US and has proven to be nearly 100 percent effective at preventing HPV-associated diseases, especially when administered early in life. But what does this mean for those who were already vaccinated, or are perhaps considering it for the first time? Here's what you need to know to protect yourself and those you care about most.

First, let's talk about the basics. Though most HPV infections resolve on their own within two years of transmission, nearly 80 million Americans are currently living with the virus, with 14 million HPV infections occurring annually. The 37 known strains of HPV are divided into "high-risk" and "low-risk" categories. Low-risk strains are known to carry a lower risk of a person who contracts HPV later being diagnosed with HPV-associated cancers, and their symptoms are typically milder in nature. In contrast, high-risk strains present the highest risk of causing cervical, oropharyngeal, anal, and other types of cancers. Overall, 14 of the 37 strains of HPV are considered high-risk strains, with strains 16 and 18 causing 70 percent of cervical cancers and precancerous lesions.

Despite the Gardasil-4 and Cervarix-2 vaccines being responsible for massive decreases in HPV and HPV-associated cancers, more recent studies have shown that not all Americans benefited equally. A 2013 study conducted by researchers at Duke University School of Medicine found that white people tend to primarily contract HPV strains 16, 18, 33, 39, and 59, while Black participants in the study carried strains 31, 35, 45, 56, 58, 66, and 68. Moreover, a study published in 2015 by the American Association For Cancer Research found that some of the same strains that affected Black women at higher rates were even more common in Hispanic women living along the Texas-Mexico border.

The original Gardasil, a quadrivalent vaccine, was designed to prevent HPV strains 6, 11, 16, and 18; Cervarix, a bivalent vaccine, only targeted strains 16 and 18. By contrast, Gardasil-9 protects against HPV strains 6, 11, 16, 18, 31, 33, 45, 52, and 58 widening the net for the communities that are most at risk for HPV-associated cancers.

"I think the original vaccines not covering more high-grade strains is not necessarily a failure of medicine or research. I think it's just a function of how science and discovery go," Ukachi Emeruwa, MD, MPH, an ob-gyn and clinical fellow in maternal-fetal medicine at Columbia University Irving Medical Center in New York, told POPSUGAR. "Medications and vaccinations should change not because they were unsafe when they came out, but because we make them available as soon as we find something helpful and then change them to make them even better every time we can."

Gardasil-9 is recommended for young people ages 11 to 26, as well as adults up to age 45 who, after discussing their risk factors with their doctor, decide that they could benefit from being vaccinated. However, Chinedu Nwabuobi, MD, an ob-gyn at a large health system in Columbus, OH, explained that people who have already received the required doses of the Gardasil-4 or Cervarix-2 vaccines are not advised to undergo an additional course with Gardasil-9. I, personally, chose to get the Gardasil-9 vaccine recently at 28 years old, because I never completed my third dose of the HPV vaccine after receiving my first at age 11. I was informed by my own doctor that there's no specific amount of time that needs to pass before you begin your course of Gardasil-9 should you choose to do so.

If you're unvaccinated and still skeptical or hesitant to add the vaccine to your to-do list, know that there are benefits beyond cancer prevention (which is a massive one). "HPV is also associated with genital warts," Dr. Nwabuobi told POPSUGAR. "In addition, management of abnormal pap smears which may be attributed to high-risk HPV may include a procedure called a cone biopsy. During this procedure, a portion of your cervix that contains abnormal cells is removed surgically," which may increase your risk for premature delivery if you decide to have a baby later on. "As a maternal-fetal medicine doctor, I deal with preterm birth issues frequently, and prevention of this condition is very paramount whenever possible," Dr. Nwabuobi explained.

Experts generally agree that more work needs to be done to ensure equitable healthcare and public health education for those who are most affected by HPV. The fact that such disparities exist suggests that preventive strategies including identification of and treatment for precancerous lesions aren't reaching the Black and Latinx communities the way they should, Dr. Emeruwa explained. "Until we can get to a point in which the way we share knowledge, build trust, and distribute interventions is equitable, I don't see us making a dent in that disparity."

As we've seen during the COVID-19 pandemic, vaccination efforts are futile when a population isn't properly informed about the vaccine and granted equitable access to it. "Ultimately, I think the first step in closing the gaps is for healthcare providers to engage women of color through education and unbiased counseling," Dr. Nwabuobi said, adding that the government can also address these disparities by engaging communities of color with awareness campaigns focused on cervical cancer and by expanding healthcare coverage. It's well-documented within public health research that Black and Latina women are least likely to have health insurance coverage and access to healthcare and by extension, preventative treatments due to issues like poverty and systemic and medical racism.

"I think the future of women's health is understanding and respecting that medicine and health do not operate in a vacuum," Dr. Emeruwa explained. "Access to care and infrastructure that promotes healthy behavior, policy, financial resources, discrimination, racism, cultural competency, historical context all of these and more directly impact any intervention or treatment that we develop. It's not all genetics and biology the way we used to or would want to believe." She continued: "If we want to mend and close the gaps in healthcare, our research and care have to start to investigate women's health through this more holistic lens."

Though a major overhaul is needed within the medical and public health communities, the development of the Gardasil-9 vaccine to specifically address the HPV strains that are most prevalent in Black and Latina women is indicative of an era of healthcare dedicated to addressing both bodily and societal ills.

While that work continues, you should do everything you can to reduce your risk. "Other than getting the HPV vaccine, the best way to lower your chance of getting HPV is to use latex condoms and dental dams the right way every time you have sex," Dr. Nwabuobi said, noting that you should also get routine cervical cancer screenings, starting at age 21. In the battle against HPV, it's important to arm yourself with every resource available.

Read more:
The HPV Vaccine Now Targets the Strains That Are Most Common in Black and Latina Women - POPSUGAR

When Uddhab Gautam got his first vaccine dose back in February, Covid-19 cases in Nepal were low.

Now, three months later, coronavirus infections in the Himalayan nation have spiraled out of control, leading to a shortage of hospital beds and oxygen, and sending most of the country into lockdown.

But despite needing it more than ever, the 67-year-old retired banker has no idea when he'll get his second dose of Covishield, the AstraZeneca vaccine manufactured by the Serum Institute of India (SII).

Gautam's predicament is similar to one shared by millions worldwide: asIndia's own coronavirus crisis has spiraled, SII --the world's largest vaccine maker-- can no longer export its goods.

Last week, the SII said it wouldn't restart deliveries to COVAX, a worldwide initiative aimed at distributing vaccines to countries regardless of wealth, until the end of thisyear.

While SII's decision will be a lifeline for India, which is still reporting about 200,000 new cases a day, the delay poses a huge problem for developing countries that depend on COVAX to control large outbreaks of their own.

The world is already 140 million doses short -- and by the end of June, that gap will have reached190 million shots, the United Nations children's agency, one of the partners in COVAX, said last week. There is currently no timeframe for resolving the shortage, UNICEF said.

That creates a very real problem, not just for countries with limited access to vaccines where cases are exploding, but also for the whole world.

Read the full story:

Continued here:
(1) Current approach to preventing Covid-19 at the Olympics is "dangerous," US expert says - CNN

Ryan Stewart| Special to The Oklahoman

The coronavirus has never been a problem limited to people. Since the pandemic's start, the virus's potential to impact pets, livestock and wildlife has been a global concern.

But will the four-legged friends we share our homes with need vaccines? It's unlikely in the short term, said Oklahoma Medical Research Foundation attending veterinarian Jennie Criley, D.V.M.

"Although there are a few reports of dogs and cats testing positive for SARS-CoV-2, the virus that causes COVID-19, they typically show no or very mild symptoms," said Criley, who is also the director of comparative medicine at OMRF. "Currently, there is no evidence that dogs and cats play a significant role in transmitting the virus to humans or other animals."

According to the American Veterinary Medical Association, livestock like horses, pigs and poultry don't appear to be naturally susceptible to SARS-CoV-2, the virus that causes COVID-19. While results of studies of the virus in cattle are conflicting, the AVMA notes it doesn't appear they can be easily infected either.

More: What to know about the COVID-19 variant identified in Oklahoma

But there is one notable exception, Criley said: Mink. Millions of the small, weasel-like mammals are bred on farms worldwide, and they can be infected by and potentially transmit the coronavirus to humans.

"The concern is that the virus could thrive in animals, mutate, and then pass back to humans," said OMRF physician-scientist Hal Scofield, M.D. "Given that the probable origin of COVID-19 was an animal likely a bat it's important that this be monitored."

In response, numerous vaccines for mink are in development. If the U.S. Department of Agriculture and health experts determine a companion animal SARS-CoV-2 vaccine is necessary, a vaccine developed for mink could eventually be adapted and approved for household pets.

More: Oklahoma's slowing COVID-19 vaccination rate could leave state vulnerable

Criley added that if research shows a COVID-19 vaccine for our pets is needed to protect animal and human health, it wouldn't be the first time.

"Rabies is a classic example of a vaccination given to our pets that keeps them safe and that saves human lives," Criley said. But, she added, it's best not to worry. Current work is all preliminary when it comes to man's best friends.

"Keep your pet up to date with all preventative health care recommended by your veterinarian," Criley said. "And remember, pets have become used to people being home more while we have been working remotely. Be sure to give them some extra TLC if you are transitioning back to working outside of the home office."

Ryan Stewart is media relations coordinator for Oklahoma Medical Research Foundation.

See more here:
Will the four-legged friends we share our homes with need vaccines? - Oklahoman.com

ROCKAWAY, N.J.--(BUSINESS WIRE)--electroCore, a commercial stage bioelectronic medicine company, has developed a non-drug and non-invasive alternative to pharmaceuticals that safely and effectively stimulates the vagus nerve to communicate with the brain and help optimize the bodys own ability to control problems impacting its health. While vagus nerve stimulation (VNS) has been available for decades, electroCore has transformed the industry with non-invasive vagus nerve stimulation (nVNS) therapy which taps into the power and potential of the vagus nerve via a portable device.

For quite awhile the scientific and medical research community has been captivated by the vagus nerve, the bodys longest nerve which connects information between the brain and important parts of the body including, the heart, lungs, voice box, stomach, ears, and other organs. By activating the vagus nerve with a safe and comfortable electrical stimulation through the skin, we believe we can neuromodulate, or adjust the brain signals to safely treat a variety of conditions, says JP Errico, founder at electroCore.

Implanted Vagus Nerve Stimulation (iVNS), which involves the surgical implantation of a device, was one of the first major breakthroughs highlighting how electrical stimulation could be used to treat conditions such as depression, epilepsy, infectious disease, and heart disease. In 2008, electroCore joined this medical exploration and two years later created a non-invasive way of delivering VNS therapy. Between 2011 and 2017, nVNS received CE Marks, which means it fulfilled the requirements of relevant European product directives in addition to performance and safety standards, for the treatment of multiple conditions in neurology, psychiatry, and gastroenterology. In 2017, electroCores nVNS received its first FDA clearance for the acute treatment of episodic cluster headache. Since then, electroCores game changing nVNS therapy received four additional FDA clearances as well as growing acknowledgement from health care providers and patients as a front-line, non-drug option for the treatment and prevention of migraine and cluster headache.

nVNS has not only transformed the way healthcare providers treat migraine and cluster headache but has also advanced how doctors treat veterans, adolescents, athletes, and long haul COVID-19 patients with migraine. nVNS is a safe, convenient, effective treatment for people who wish to avoid both the short and long term side effects and inconveniences that can be associated with injectable, inhaled, or pill-based medicine, states Dr. Peter Staats, chief medical officer of electroCore.

The creation of a safe, patient-controlled way of activating the vagus nerve has opened the door for the research and clinical community to study the vagus nerves potential to treat several conditions more easily and safely.

At the forefront of medicine, electroCore and other organizations are expanding research on the vagus nerve with clinical studies of nVNSs effectiveness on conditions including COVID-19, post-traumatic headache, traumatic brain injury, post-traumatic stress disorder, Parkinsons disease, epilepsy, stroke, sub-arachnoid hemorrhage and addiction as well as a number of gastrointestinal and inflammatory conditions.

At electroCore, we are looking into treating some of the most challenging diseases in the world with nVNS. What makes non-invasive nerve stimulation so exciting is the ability for the patient to self-administer the treatment, says Dr. Staats. Because the device is portable, it is empowering patients to literally take control of their condition into their own hands.

About electroCore, Inc.

electroCore, Inc. is a commercial stage bioelectronic medicine company dedicated to improving patient outcomes through its platform non-invasive vagus nerve stimulation therapy initially focused on the treatment of multiple conditions in neurology. The companys current indications are the preventative treatment of cluster headache and migraine and acute treatment of migraine and episodic cluster headache.

For more information, visit http://www.electrocore.com.

About gammaCoreTM

gammaCoreTM (nVNS) is the first non-invasive, hand-held medical therapy applied at the neck as an adjunctive therapy to treat migraine and cluster headache through the utilization of a mild electrical stimulation to the vagus nerve that passes through the skin. Designed as a portable, easy-to-use technology, gammaCore can be self-administered by patients, as needed, without the potential side effects associated with commonly prescribed drugs. When placed on a patients neck over the vagus nerve, gammaCore stimulates the nerves afferent fibers, which may lead to a reduction of pain in patients.

gammaCore is FDA cleared in the United States for adjunctive use for the preventive treatment of cluster headache in adult patients, the acute treatment of pain associated with episodic cluster headache in adult patients, and the acute and preventive treatment of migraine in adolescent (ages 12 and older) and adult patients. gammaCore is CE-marked in the European Union for the acute and/or prophylactic treatment of primary headache (Migraine, Cluster Headache, Trigeminal Autonomic Cephalalgias and Hemicrania Continua) and Medication Overuse Headache in adults.

Forward-Looking Statements

This press release may contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements include, but are not limited to, statements about electroCore's business prospects and clinical and product development plans, its pipeline or potential markets for its technologies, the timing, outcome and impact of regulatory, clinical and commercial developments including commercialization of, and potential reimbursement for, its nVNS technology and products, the business, operating or financial impact of any clinical trials or studies, and other statements that are not historical in nature, particularly those that utilize terminology such as "anticipates," "will," "expects," "believes," "intends," other words of similar meaning, derivations of such words and the use of future dates. Actual results could differ from those projected in any forward-looking statements due to numerous factors. Such factors include, among others, the ability to raise the additional funding needed to continue to pursue electroCores business and product development plans, the inherent uncertainties associated with developing new products or technologies, the ability to commercialize gammaCore, the potential impact and effects of COVID-19 on the business of electroCore, electroCores results of operations and financial performance, and any measures electroCore has and may take in response to COVID-19 and any expectations electroCore may have with respect thereto, competition in the industry in which electroCore operates and overall market conditions. Any forward-looking statements are made as of the date of this press release, and electroCore assumes no obligation to update the forward-looking statements or to update the reasons why actual results could differ from those projected in the forward-looking statements, except as required by law. Investors should consult all of the information set forth herein and should also refer to the risk factor disclosure set forth in the reports and other documents electroCore files with the SEC available at http://www.sec.gov.

Here is the original post:
The Ins & Outs of nVNS: Non-Invasive Vagus Nerve Stimulation Device Prevents and Relieves Pain From Migraines, Cluster Headaches & Other...

//= do_shortcode('[in-content-square]')?> Picture by TheShiv76 on Pixabay.

Jez Hemming, local democracy reporter

A new medical school for the north could be ready by 2025 and well know what it costs by the summer, a health board chief executive has revealed.

Jo Whitehead, CEO of Betsi Cadwaladr University Health Board, revealed the news in her report to the boards monthly meeting on Thursdsay.

The new Medical and Health Sciences School will be a collaboration between the health board and Bangor University, if it gets approval from Welsh Government.

A study of what the capacity of the school should be is in the final stages and proposals should be lodged with Minister for Health and Social Care Eluned Morgan by the end of July, said Whitehead.

In her report, she said: BCUHB and Bangor University are working in partnership and have established programme arrangements in order achieve the shared ambition of developing a transformational Medical and Health Sciences School in North Wales by 2025.

Work to develop capital investment plans is progressing with an ambition initial estimates expected to be completed in June 2021 and final estimates to be available in July 2021.

An economic impact assessment will also be completed at the same time to help the business case for the new venture.

The proposed curriculum for the school will haveinter-professional, preventative and community led health and medicine at its core, she said.

Students

Students at the school will be given placements around North Wales as part of their practical experience which will hopefully lead to more doctors and future consultants settling in the health board area.

Betsi Cadwaladr has struggled to recruit to clinical positions over the past few years.

Eighteen medical students have already been undertaking a significant part of their training at Bangor University during the current academic year, as part of the C21 collaboration with Cardiff University with 19 attending the previous year.

Welsh Government said it had invested 7m into facilitatingthe course but students still have to take part of it in Cardiff.

When the idea of a North Wales MedicalSchool was first announced in September last year, former Welsh Health Minister Vaughan Gething said he wanted a task and finish group to assess if the proposal was practical and achievable.

A task and finish group chaired by Professor Elizabeth Treasure, has been looking at the idea since last autumn.

Go here to read the rest:
New medical school in the north could be ready by 2025, says health board chief - Nation.Cymru

Retired firefighter Glen Midbo was enjoying a Budweiser on a recent afternoon while doing renovations on his house. His quiet suburban block on the southern tip of Staten Island is a stones throw from the beach. Standing under a flag of former President Donald Trump holding a machine gun, Midbo explained why he would be one of the last holdouts for the COVID-19 vaccine.

They came out with it too quick, said Midbo, 62, a resident of the mostly conservative, white and well-off neighborhood of Tottenville. I just want to make sure theres no side effects. I dont even feel threatened by this disease at all. I didnt even obey all the rules of this thingsocial distancing and masking and all thisand I didnt get sick.

On the opposite end of the island in Port Richmond, a neighborhood thats more than a third Latino, Selvin Vazquez Castillo expressed his own doubts about the vaccine. Ive read things on the internet that its caused people a lot of different reactions and has left people in the hospital, the 28-year-old construction worker said in Spanish. So, I said, Oh no, I dont want to be in the hospital.

Most barriers to accessing COVID-19 vaccines in New York City have come down, even on Staten Island, where theres no public hospital, and it took months of advocacy to open a city-run hub on the South Shore. But ongoing reluctance to get the shots has emerged as a key hurdle that New York, and the country as a whole, must overcome to control the pandemic. Pockets of unvaccinated people can continue to serve as a haven for the coronavirus, as evidenced by ongoing surges upstate in Lewis County and Cortland County. What is broadly deemed vaccine hesitancy encompasses a range of attitudes among people with myriad backgrounds, varying comprehension of health information and different levels of resistance.

No zip code on Staten Island is reporting more than 50% of residents with their first shot.

Reservations about the vaccineswhich are often, but not always, grounded in questions about their safety, according to Kaiser Family Foundation (KFF) surveyscut across political and cultural divides. And that research shows different strategies will change peoples minds depending on why theyve delayed their shots so far.

To explore the ways in which hesitancy can manifest, WNYC/Gothamist headed to Staten Island, the borough thats home to the most Republicans in the city as well as the solidly blue, ethnically diverse North Shore with its enclaves of Latino and African immigrants.

Retired firefighter Glen Midbo stands under a Trump flag outside his house in Tottenville, Staten Island. Midbo says he will only get the vaccine if remaining unvaccinated limits what he can do. Caroline Lewis

Staten Islands vaccination rate39% fully inoculated, 45% with at least one dosefalls just below the citywide tallies of 40% and 49%, respectively. While other boroughs have neighborhoods with very high and very low levels of vaccine saturation, much of Staten Island hovers somewhere in the middle. No zip code is reporting more than 50% of residents with their first shot, as of May 21st.

Organizers on Staten Island who have been working on getting residents vaccinated over recent months shared some of the rationales they hear from the reluctant.

Among African immigrants in Stapleton, Park Hill, and Mariners Harbor, misinformation about the virus and vaccines is spreading via Facebook and WhatsApp, said Abou Sy Diakhate, co-chair of the Staten Island Immigrant Council and a board member of the Staten Island Long-Term Recovery Organization.

Videos went viral promoting the conspiracy theory that the vaccine is part of the plot to reduce the black race, said Diakhate. This is how they look at it. And they ask me this.

This is part of the institutional racism that we're talking about.

He added that people in the communities he serves dont tend to rely on American media for information, and some dont speak English. Like others who spoke to WNYC/Gothamist, Diakhate said he thought initial barriers to finding appointments or clinics exacerbated this hesitancy. Sometimes, when they lack access, they say, OK, you know what? It's fine. We are used to this. This is part of the institutional racism that we're talking about.

Although there is no longer a vaccine shortage and everyone older than 12 is eligible, Diakhate says he has yet to get a shot himself because he wants to let those who are more vulnerable go first.

An April survey of 1,007 people in the New York metro area90% unvaccinatedfound that most were not hardline anti-vaxxers. Only 4% said they would not get a COVID-19 jab for any reason. About two-thirds of those without shots65%said they were waiting for reassurance that no serious complications would result from the vaccines. So far, hundreds of millions of Americans have taken doses of Pfizer, Moderna and Johnson & Johnson vaccines, and close monitoring has shown that they are overwhelmingly safe and effective. Long-term negative consequences are extremely unlikely.

Another 22.3% said they wanted to see how the vaccines affected other people. Nearly 10% said they preferred to let high-risk people have first dibs. The survey, conducted by the CUNY Graduate School of Public Health and Health Policy, is yet to be published.

The only reason I'll take the vaccination is if it will let me go to my house in Norway.

Asked what would make them feel more ready, 15% of the unvaccinated respondents said they would value a recommendation from their doctor. The doctors office was also by far the preferred setting for a shot, favored by 39% of respondents. KFF surveys note similar findings on trusted messengers.

A lot of the people that we contacted from our Stapleton senior center said they're waiting until [the vaccine is] available in their doctor's office, and they're waiting for their doctor to administer it, said Allison Cohen, the communications director for the JCC of Staten Island, who also headed up the organizations massive vaccination effort at its locations across the borough.

So far, primary care doctors have not been selected as major providers of the COVID-19 vaccinesa policy that needs to change as the city moves toward reaching children and potentially offering booster shots, according to Dr. Scott Ratzan, a lecturer at the CUNY School of Public Health and executive director of CONVINCE USA, an organization promoting vaccine literacy. But Ratzan also acknowledged that the clinical setting people feel most comfortable in can also vary by demographic.

Michelle Molina, executive director of El Centro del Inmigrante in Port Richmond, says Latinos from other boroughs often come to her community center for COVID vaccinations because its a trusted organization among immigrants, particularly those who are undocumented. She has been encouraged so far by all the people who started out hesitant but are now taking the vaccines. The center provides a wide range of services, including a dispatch center for day laborers, allowing Molina to offer regular reminders about the shots.

Day laborers wait to be dispatched outside El Centro Del Inmigrante in Port Richmond, Staten Island. The center has gotten many immigrants vaccinated and helped some overcome their initial hesitancy. Caroline Lewis

We still have a lot of work to do as far as the parents, Molina said. A lot of parents will say, Yes, I wanted to get vaccinated, and I did. But my kids are a different story. I'm not willing to take that chance with my kids.

Vazquez Castillo, the construction worker, says he finally booked an appointment. But it took the recent deaths of three friends from COVID-19 and a referral from an acquaintance to El Centro for him to do it.

Before his friends passed away, Vazquez Castillo admits, I didnt believe in COVID. Even now, he has questions about how the vaccines work. One questionI have read online, but I'm not that sure because the internet is not 100% trustworthydo they put the COVID inside your body? Vazquez Castillo asked. (They dont.)

Community organizers talked about the need for more forums where people could pose clinicians all their questions, especially now that parents are deciding whether to give consent for their kids. Ratzan said he is working with employers to provide accurate, actionable COVID-19 information to their employees.

Nationally, the share of people who want to wait and see on the vaccines safety or how others react to it shrank during the first couple of months of the rollout, before plateauing between March and April, according to the Kaiser Family Foundation. Those putting off their shots for these reasons include about one in five Republicans, and roughly the same share applies to Black adults, Hispanic adults, and those without a college degree. A quarter of young adults between 18 and 29 also say theyre holding off.

Notably, while Republicans have been slower to seek vaccinations than Democrats, the share that is willing continues to increase. Each person who spoke to WNYC/Gothamist had different answers for what, if anything, would ultimately motivate them toward the preventative medicine.

A woman yells as New York City Sheriffs stand guard outside of the restaurant Mac's Public House at the start of a rally against state and city mandates to stop indoor dining to control the spread of the coronavirus in Staten Island, December 2nd, 2020. JUSTIN LANE/EPA-EFE/Shutterstock

Despite vowing to wait as long as possible, Midbo, the retired firefighter in Tottenville, said hed get inoculated if it was the only way to circumvent travel restrictions or other limitations on what he could do. The only reason I'll take the vaccination is if it will let me go to my house in Norway, Midbo said. If they won't let me in a restaurant or bar or something like that because I don't have the vaccine, OK, I'll do it.

Others said incentives based on mandates wouldnt help. I'm a Libertarian, said a Tottenville retiree named Bruce, who would only give his first name. I don't believe in government overreach, and I don't want to live in a nanny state. Still, he emphasized, hes not an anti-vaxxer; he merely wants to see more data on the vaccines. I hope we do reach herd immunity, he said.

Some sitting outside the Staten Island Mall Monday said the people they knew were mostly coming around to the idea regardless of their politics. But one woman, Marie Linea, 67, said she would not take a COVID shot under any circumstances, even if it meant she had to keep wearing her mask while others shed theirs. Linea rattled off several popular myths, including that the virus was man-made and that young people shouldnt get the vaccines because they can cause infertility. They're injecting stuff that is going to change your DNA, she said, which is also untrue. You're going to have problems down the line, you know, mentally.

Not everyone who didnt rush to get a shot right away has such clear-cut reasons. On Monday, Kurt Perkert, 62, a Port Richmond resident who maintains properties in the area, said he had recently booked his first appointment.

I've been procrastinating, he said. Im busy.

From his porch, Perkert hailed a friend passing by, Stanley Federowski, 67, who said he lives alone in West Brighton and doesnt plan to get vaccinated. Asked if he worried about COVID-19, Federowski said, No, I dont worry about nothing. I just do whatever I do and that's it. I don't even think about it. He said maybe if they were offering money, hed consider it. Governor Andrew Cuomo launched an initiative this week whereby state-run vaccine sites will give out free lottery tickets for a chance to win $5 million, following in the footsteps of Ohio.

The mayor and governor continue to plead with residents to capitalize on the free COVID-19 vaccines if they havent already, insisting its the way to restore normalcy and ensure everyones safety as businesses, schools, and entertainment venues reopen. But Olivia Drabczyk, a teacher who has done vaccine outreach during her run for City Council on Staten Islands South Shore, says some people are hearing mixed messages.

Seeing that, whether or not they've gotten [vaccinated], the city is still reopening, she said, has taken away some urgency for people who are already hesitant.

Link:
Vaccine Hesitancy Greatest Hits: How Some Staten Islanders Are Overcoming The Reluctance - Gothamist

A man receives his Covid-19 vaccination at the John Scott Vaccination Centre in Green Lanes, north ... [+] London, where Hatzola, in partnership with the NHS and Hackney Council are delivering a coronavirus vaccine clinic for the local Orthodox Jewish community. Picture date: Sunday March 21, 2021. (Photo by Stefan Rousseau/PA Images via Getty Images)

The Orthodox Jewish community was hit hard by the Covid-19 pandemic. Swift community action ensued; Jewish schools were closed and synagogues were shuttered. While anticipation for the Covid-19 vaccine grew, physicians and leaders within the community wondered: will Orthodox Jews get the Covid-19 vaccine?

A new study published by Dr Ellie Carmody, Assistant Professor, Division of Infectious Diseases and Immunology at NYU Grossman School of Medicine and co-authors, surveyed 102 Orthodox Jews in Brooklyn, NY between December 2020 and January 2021. At that time, 41% were undecided about the vaccine and 47% were strongly hesitant.

While many U.S. citizens fought for access to the vaccine, others were understandably hesitant to take a new vaccine. The vaccine has had its fair share of doubt including concerns about fertility and safety monitoring (neither concern has been proven).

In the past, Shoshana Bernstein, an Orthodox community activist in NY, worked to educate community members about the measles vaccine. Her experience taught her that the majority of Orthodox Jews do indeed vaccinate.There are outliers who are openly anti-vax and the movable middle who are unsure. Unfortunately, it has become more and more the norm for the media to focus on Orthodox Jews which can and does create the erroneous assumptions.

At the same time, Ms. Bernstein explained that the insular lifestyle of many demographics in the Orthodox Jewish community limits their access to credible medical information. Many individuals in these communities dont use the internet, social media, and smartphones. There, Ms. Bernstein recommends it is imperative that culturally sensitive, written and spoken education be written and made available.Unlike the secular world, written publications are very much alive and well in the Orthodox Community.Dial-in hotlines and Yiddish language radio stations reach a large swath of the population and should be utilized.Doctors, nurses, physician assistants and urgent care centers are generally widely trusted and should be provided written material.

Dr Miriam Andrusier, MD, MPH a member of the Hasidic community in Crown Heights, Brooklyn, echoes Ms. Bernsteins concerns about targeted misinformation. Both in terms of how the virus spreads and what information people have available to them are very unique and could be quite insular. The Orthodox Jewish community is very tight knit. The ways in which information is dispensed and shared is very unique: people tend to get a lot of their information from social media and groups like Whats App where it is incredibly easy to pass along misinformation that can be forwarded thousands of times within minutes.

When the pandemic eased in the summer of 2020, anti-vax and anti-medical establishment groups made efforts to spread misinformation specifically in the Orthodox Jewish community. At an event in Crown Heights on February 16th, 2021, Dr. Simone Gold urged attendees not to get the Covid-19 vaccine because dying from Covid-19 itself is exceedingly uncommon. The second speaker, Rabbi Michoel Green told (unverified) stories of individuals who lost relatives and suffered side effects from the vaccine.

The anti-vaccine movement is finding fertile ground in people today in general because they succeed by sowing fear, uncertainty and doubt, and this pandemic is already rampant in all three, says Dr. Alissa Minkin, a pediatrician and Chair of the Jewish Orthodox Womens Medical Association (JOWMA) Preventative Health Committee. Dr Minkin also hosts the JOWMA Podcast, which covers health topics geared towards the Orthodox community. Full disclosure- I serve as president of JOWMA and have been actively involved in JOWMAs educational efforts for the Covid-19 vaccine.

Dr. Minkin believes the politicization and polarization of this pandemic is contributing to anti-vaccine sentiment across the board, not just in the Orthodox community. Because religion is not one of the metrics for vaccine uptake, we do not have exact statistics for percent vaccinated in each of these communities.

While the exacts numbers of those vaccinated in the Orthodox community isnt quite clear, informal surveys by synagogues, physicians, and schools indicate that vaccine uptake is high. Suri Kasirer, President of Kasirer LLC, the #1 lobbying firm in New York, has been working with government and community organizations like JOWMA to educate NY residents about the Covid-19 vaccine. I come from this community, which was among the most impacted by the pandemic. In reaching out to the Orthodox community with timely information about the vaccine, there are unique challenges, such as language barriers, or limited access to TV and the Internet.Were so proud to have helped effectively counter disinformation and build confidence in the vaccine as we see this vibrant community back to good health post-pandemic.

"Most of my elderly patients wanted to get the vaccine as soon as it was available. As part of my work as the medical director of Chevra Hatzalah Volunteer Ambulance Corps, we facilitated hundreds of vaccines to home-bound Holocuast survivors, said Dr Jason Zimmerman, medical director at Boro Park Center for Rehabilitation and Nursing in Brooklyn, NY.

Dr. Zimmerman cares for patients from the Orthodox community in Brooklyn, NY. He shared Many younger patients were initially hesitant to take the vaccine, but over the past few months, they've watched their healthcare providers, family and friends get vaccinated and this visibility has really helped alleviate people's initial hesitation."

Dr. Minkin believes that while we havent yet reached herd immunity, the percent of people who had Covid-19 already are contributing to the percent who are immune along with the vaccinated. There are good reasons to get vaccinated even if you had Covid-19, but public health officials should acknowledge that people who had Covid-19 are making a risk benefit decision from a different position than those who never had it.

Dr. Ellie Carmody MD, MPH, agrees that some hesitancy around the vaccine may be understood from a scientific and health perspective. Within some Orthodoxcommunities that have been very highlyimpacted by Covid-19, reasons for not vaccinating are complex.Some are wary of new technologies and are subject to similar misinformation that circulates within wider anti-vaccination discourse.But for many people who have had Covid-19, there is simplynot a sense of urgency to be vaccinated, given that they observe that symptomatic re-infections in their communities are low and they feel protected.

Dr. Carmody believes that vaccine strategies should be re-evaluated for those who have recovered from Covid-19, as more studies demonstrate that there is a robust immune memory response to one dose of either an mRNA vaccine or adenoviral vector vaccine in people who have recovered from Covid-19.

A one-dose immunity booster may be more well received than a two-dose mRNA vaccineseries, as it validates the contribution of natural immunity toward protection from disease.One-dose mRNA vaccine strategies could also help stretch the world's supply of these vaccines, said Dr Carmody.

In the meantime, educating patients about Covid-19 vaccination remains a priority.

See original here:
Hit Hard By The Pandemic, Orthodox Jews Are Choosing The Covid-19 Vaccine - Forbes

The International Society for Stem Cell Research (ISSCR) today released updated guidelines for stem cell research and its translation to medicine.

Developed in response to recent scientific and clinical advances, the revised guidelines provide a series of detailed and practical recommendations that set out global standards for how these emerging technologies should be harnessed.

Stem cell research has huge potential it could help pave the way for new therapies for ailments ranging from Parkinsons disease to childhood kidney failure. But scientific advances in this field can present unique ethical and policy issues beyond that seen in other areas of medical research.

The science is advancing at breakneck pace. Just in the past couple of months, we have seen model human embryos grown from skin cells, and the creation of human-monkey embryos for use in research.

The ISSCR has long recognised the need to set clear ethical boundaries for stem cell research. Previous guidelines have provided advice on techniques such as the use of human embryos to create stem cells, and set the required standards when using these technologies to create new medicines.

They have also explicitly banned certain practices, such as reproductive cloning and the sale of unproven therapies that claim to be made of stem cells.

The 2021 guidelines an update on the previous version, released in 2016 aim to set standards for the many recent advances in stem cell and human embryo research. These include chimeric embryos containing cells from humans and other animals, organoids grown from stem cells to create tissue that resembles particular human organs, and models of human embryos arrangements of human cells that mimic the early stages of embryo development.

The guidelines contain a clear requirement for certain new stem cell research approaches only to be conducted after a specialised review process. This review should be independent of the researchers, and include community members as well as people with expertise in the relevant science, ethics and law.

This is beyond what is typically required by a university or research institute where medical research is conducted. Besides evaluating the merit of the proposed research, the new reviews should also consider whether there are alternative ways to do the research, the source of stem cells and how they were obtained, and the minimum time required to reach the research goals, particularly in relation to human embryo and related research.

Specialised review is not a new concept. The previous guidelines required it when researchers made stem cells from human embryos or sought to culture human embryos in the lab. But now researchers will now also be required to seek higher review when they create model embryos such as blastoids, or study the development of animal-human embryos in animal wombs.

Researchers developing new therapies for mitochondrial disease will also be required to seek higher-level review before attempting to transfer to the uterus of a woman human embryos in which affected mitochondria (a part of the cells energy-production apparatus) have been replaced.

Importantly, the revised guidelines also clearly rule out certain activities. These continue to include reproductive cloning and attempts to form a pregnancy in a woman from genetically edited human embryos or from model embryos made from stem cells. Prohibited activities also now include using eggs and sperm made from human stem cells for reproduction, or transferring a human-animal chimeric embryo into the uterus of a woman or an ape.

Read more: China's failed gene-edited baby experiment proves we're not ready for human embryo modification

The guidelines also call for a public conversation about whether we should allow limited lab research on human embryos beyond the existing limit of 14 days development. Historically, it has not been possible to support human embryonic development outside the body beyond this stage. However, recent advances in human embryo culture raise the possibility that this may now be technically feasible.

Extending the amount of time in culture - in terms of days - could potentially yield new treatments for developmental conditions or infertility, but will also raise concerns about whether possible benefits justify this research. Any decisions to overturn this long-held signpost would need to be carefully deliberated and take into consideration existing law, community values and discussion around what the new limit should be.

The revised guidelines also reinforce the need for informed consent for the collection of human material and participation in stem cell clinical trials, and reiterate that no new stem cell treatment should be made available before it is tested for safety and effectiveness in well-designed and publicly visible clinical trials. The ISSCR continues to condemn the commercial use of unproven stem cell treatments.

While stem cell science holds much promise, it is paramount that research is scientifically and ethically rigorous, with appropriate oversight, transparency and public accountability.

The fact these guidelines are driven by experts including stem cell scientists, doctors, ethicists, lawyers and industry representatives from across 14 countries indicates a deep sense of responsibility and integrity within the research community, and a desire to ensure science remains in step with community values.

However, these guidelines are recommendations, not laws.

Researchers will need to abide by their respective national or state regulations and ethical standards. Some countries already have regulatory frameworks that are consistent with the new recommendations. In other places there is no national guidance around laboratory and clinical stem cell research at all, or existing law touches on some but not all of the emerging applications of stem cell research.

Read more: As scientists move closer to making part human, part animal organisms, what are the concerns?

For example, in Australia there is already an established pathway for higher-level review of embryo models created from stem cells. However, the same legislation currently bans any attempt to use mitochondrial transfer techniques to create embryos for research or to achieve a pregnancy both of which are permissible under the new ISSCR guidelines.

Rather than attempting to impose a set of hard-and-fast rules on an ever-evolving research field, the new guidelines attempt to address emerging issues and drive important discussions at domestic level. Ultimately, it is the public and the regulators who will need to set the standards.

See the rest here:
New global guidelines for stem cell research aim to drive discussions, not lay down the law - The Conversation AU

News and research before you hear about it on CNBC and others. Claim your 1-week free trial to StreetInsider Premium here.

Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending approval of KEYTRUDA, Mercks anti-PD-1 therapy, in combination with platinum- and fluoropyrimidine-based chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic carcinoma of the esophagus or human epidermal growth factor receptor 2 (HER2)-negative gastroesophageal junction (GEJ) adenocarcinoma in adults whose tumors express PD-L1 (Combined Positive Score [CPS] 10). The CHMPs recommendation will now be reviewed by the European Commission for marketing authorization in the European Union, and a final decision is expected in the second quarter of 2021.

Patients with metastatic esophageal cancer currently face five-year survival rates of just 5%, said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. There is a critical need for new treatment options in the first-line setting that can potentially extend their lives. Todays positive opinion for KEYTRUDA is an important step forward for patients in Europe with certain types of gastrointestinal cancers.

The positive CHMP opinion is based on results from the pivotal Phase 3 KEYNOTE-590 trial, in which KEYTRUDA plus 5-fluorouracil (5-FU) and cisplatin demonstrated significant improvements in overall survival and progression-free survival compared with 5-FU and cisplatin alone in patients regardless of histology or PD-L1 expression status. KEYTRUDA plus 5-FU and cisplatin reduced the risk of death by 27% (HR=0.73 [95% CI, 0.62-0.86]; p

Merck is studying KEYTRUDA across multiple settings and stages of gastrointestinal cancer including esophageal, gastric, hepatobiliary, pancreatic, colorectal and anal cancers through its broad clinical program.

About Esophageal Cancer

Esophageal cancer begins in the inner layer (mucosa) of the esophagus and grows outward. Esophageal cancer is the eighth most commonly diagnosed cancer and the sixth leading cause of death from cancer worldwide. Globally, it is estimated there were more than 604,000 new cases of esophageal cancer diagnosed and approximately 544,000 deaths resulting from the disease in 2020. In Europe, it is estimated there were more than 52,000 new cases of esophageal cancer diagnosed and approximately 45,000 deaths resulting from the disease in 2020.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,400 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS 10), as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Carcinoma

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after 2 or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

Cervical Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Tumor Mutational Burden-High

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% of these patients interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (

KEYTRUDA with Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen, which was at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after antiPD-1/PD-L1 treatment. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between antiPD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using antiPD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an antiPD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-054, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (20%) with KEYTRUDA was diarrhea (28%).

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

More:
Merck (MRK) Granted Positive EU CHMP Opinion for KEYTRUDA (pembrolizumab) in Combination with Chemotherapy - StreetInsider.com

Opinion Supports Use of KEYTRUDA in Combination With Platinum- and Fluoropyrimidine-Based Chemotherapy in Patients Whose Tumors Express PD-L1 (CPS 10)

Recommendation Based on Significant Survival Benefit Demonstrated With KEYTRUDA Plus Chemotherapy Versus Chemotherapy in Phase 3 KEYNOTE-590 Trial

Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending approval of KEYTRUDA, Mercks anti-PD-1 therapy, in combination with platinum- and fluoropyrimidine-based chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic carcinoma of the esophagus or human epidermal growth factor receptor 2 (HER2)-negative gastroesophageal junction (GEJ) adenocarcinoma in adults whose tumors express PD-L1 (Combined Positive Score [CPS] 10). The CHMPs recommendation will now be reviewed by the European Commission for marketing authorization in the European Union, and a final decision is expected in the second quarter of 2021.

Patients with metastatic esophageal cancer currently face five-year survival rates of just 5%, said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. There is a critical need for new treatment options in the first-line setting that can potentially extend their lives. Todays positive opinion for KEYTRUDA is an important step forward for patients in Europe with certain types of gastrointestinal cancers.

The positive CHMP opinion is based on results from the pivotal Phase 3 KEYNOTE-590 trial, in which KEYTRUDA plus 5-fluorouracil (5-FU) and cisplatin demonstrated significant improvements in overall survival and progression-free survival compared with 5-FU and cisplatin alone in patients regardless of histology or PD-L1 expression status. KEYTRUDA plus 5-FU and cisplatin reduced the risk of death by 27% (HR=0.73 [95% CI, 0.62-0.86]; p

Merck is studying KEYTRUDA across multiple settings and stages of gastrointestinal cancer including esophageal, gastric, hepatobiliary, pancreatic, colorectal and anal cancers through its broad clinical program.

About Esophageal Cancer

Esophageal cancer begins in the inner layer (mucosa) of the esophagus and grows outward. Esophageal cancer is the eighth most commonly diagnosed cancer and the sixth leading cause of death from cancer worldwide. Globally, it is estimated there were more than 604,000 new cases of esophageal cancer diagnosed and approximately 544,000 deaths resulting from the disease in 2020. In Europe, it is estimated there were more than 52,000 new cases of esophageal cancer diagnosed and approximately 45,000 deaths resulting from the disease in 2020.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,400 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patients likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS 10), as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Carcinoma

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after 2 or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

Cervical Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Tumor Mutational Burden-High

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% of these patients interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (

KEYTRUDA with Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen, which was at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after antiPD-1/PD-L1 treatment. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between antiPD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using antiPD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an antiPD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-054, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (20%) with KEYTRUDA was diarrhea (28%).

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

Read more here:
Merck Receives Positive EU CHMP Opinion for KEYTRUDA in Combination With Chemotherapy as First-Line Treatment for Certain Patients With Esophageal...

Introduction

Although novel drugs have successfully entered the clinical arena of heart failure with reduced ejection fraction (HFrEF), such as the PARADIGM-HF-derived angiotensin receptor neprilysin inhibitor (ARNI), disease-modifying therapies with a prognostic impact for patients affected by heart failure with preserved ejection fraction (HFpEF) are still lacking.15 HF is a complex and highly prevalent syndrome for which the heart undergoes a substantial structural remodeling in patients at risk for major cardiovascular diseases (CVDs) (Figure 1).16 Geneenvironment interactions can be mediated by specific patterns of epigenetic-sensitive changes (mainly DNA methylation and histone modifications) which may modulate the individual responsiveness to HF development.614 This complex molecular circuit seems to trigger early cardiomyocyte loss, cardiac-remodeling, and micro- and macrovascular damage contributing to the development of major CVDs which may lead to differential HF clinical phenotypes.614 Of note, the reversible nature of epigenetic-sensitive changes has been translated in the clinical management of specific hematological malignancies with the approval by the Food and Drug Administration (FDA) of some epidrugs, such as decitabine (Dacogen) and azacitidine (Vidaza), as DNA methylation inhibitors, as well as vorinostat (Zolinza), belinostat (Beleodaq), romidepsin (Istodax), and panobinostat (Farydak), as histone deacetylase inhibitors (HDACi).15 Epidrugs are now providing a novel vision for personalized therapy of HF and heart transplantation, opening up novel options for management of the affected patients.1518 At molecular level, we can classify the epidrugs in: direct epidrugs [eg, the bromodomain and extra-terminal (BET) protein inhibitor apabetalone]; and repurposed drugs with potential, indirect (non-classical) epigenetic-oriented interference by which they may exert cardioprotective functions [eg, hydralazine, metformin, statins, and sodium-glucose co-transporter-2 inhibitors (SGLT2i)] or nutraceutical compounds [eg, omega-3 polyunsaturated fatty acids (PUFAs)]. Encouraging results are coming from large randomized trials evaluating the putative beneficial effects of combining epidrugs with the conventional therapy in patients with HF.1422 Our goal is to update on the emerging epigenetic-based strategies which may be useful in the prevention and treatment of HFrEF and HFpEF (Figure 1).

Figure 1 The possible role of epitherapy in the current framework of HFrEF and HFpEF management. The unstable transition state from the ACC/AHA Stage A/B to Stage C/D-Acute/Hospitalized HF is the key point in the treatment of HFrEF and HFpEF. The epitherapy, mainly apabetalone, statins, metformin, SGLT2i, and PUFAs in addition to the standard of the care may improve personalized therapy of affected patients.

Abbreviations: HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; SGLT2i, sodium glucose co-transporter 2 inhibitors; PUFAs, polyunsaturated fatty acids.

The bromodomain and extra terminal domain (BET) proteins, including the ubiquitous BRD2, BRD3, BRD4, and the testis-restricted BRDT, are epigenetic readers (via bromodomains) existing in the form of nuclear multidomain docking platforms which control the cell-specific activation of gene expression profiles.23 Experimental data demonstrated that BETs regulate vascular cells, cardiac myocytes, and inflammatory cells,24 and their activity may be extended to the regulation of calcification, thrombosis, as well as lipid and lipoprotein metabolism, all of which participate in atherogenesis.2527 In particular, BRD4 facilitated the expression of multiple proinflammatory and proatherosclerotic targets involved in thrombosis, leukocyte adhesion, and endothelial barrier function, thus identifying BRD4 as a possible therapeutic target in CVD setting.24 The quinazolone (RVX-208), known as apabetalone, is a derivative of the plant polyphenol resveratrol. Apabetalone acts as a direct epidrug by selectively targeting the BET family member BRD4 to block its interaction with acetylated lysines located in histones.28 Apabetalone-BRD4 binding can impact cholesterol levels and inflammation; in fact, apabetalone stimulates ApoA-I gene expression and increases high-density lipoprotein (HDL).29,30 Besides, apabetalone may attenuate the development of cardiac hypertrophy31 and cardiac fibrosis,32 suggesting novel options for the management of HF.

Resverlogix developed apabetalone (RVX-208), a first-in-class, orally available, small molecule for the treatment of atherosclerosis and associated CVDs.20 BETonMACE (NCT02586155) is the first Phase 3 clinical trial evaluating the cardiovascular efficacy and safety of apabetalone.22 Recent results from the BETonMACE study have demonstrated that apabetalone is associated with a reduction in first HF hospitalization and cardiovascular death in patients with type 2 diabetes and recent acute coronary syndrome as compared to controls (placebo-treated patients).22 Additionally, a significant increase in HDL and a decrease in alkaline phosphatase levels have been observed following 24 weeks of apabetalone treatment as compared to the placebo group.22 However, investigators were unable to make a distinction between HF in the setting of preserved or reduced ejection fraction. Thus, further clinical trials should be designed to evaluate the putative beneficial effects of apabetalone in HFrEF and HFpEF, separately.

Preclinical studies demonstrated that pharmacological HDACi,3336 BET inhibitors,31,37 and DNA methylation inhibitors38 can attenuate cardiac remodeling (cardiomyocyte hypertrophy and fibrosis). Although not originally developed as epidrugs, hydralazine (anti-hypertensive drug), metformin, and SGLT2i (anti-diabetic drugs), statins (anti-dyslipidemic drugs), and PUFAs (nutraceuticals) might have downstream epigenetic-oriented effects in cardiac cells. Hydralazine, for example, lowers blood pressure by a direct relaxation of vascular smooth muscle; additionally, it may reduce DNA methylation and improve cardiac function through increasing sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) and modulating calcium homeostasis in cardiomyocytes.39 Statins are used as a first-line treatment to decrease serum cholesterol levels in dyslipidemic patients and as primary and secondary prophylaxis against atherosclerosis and associated CVDs.6 Many of their non-classical pleiotropic properties relevant for endothelial health are mediated by epigenetic mechanisms which improve blood flow, decrease LDL oxidation, enhance atherosclerotic plaque stability and decrease proliferation of vascular smooth muscle cells and platelet aggregation.6 Metformin is a first-line drug in the treatment of overweight and obese type 2 diabetic patients.10 Mechanistically, metformin may also have epigenetic-oriented effects through activating the AMP-activated protein kinase (AMPK) which, in turn, can phosphorylate and inhibit epigenetic enzymes such as histone acetyltransferases (HATs), class II HDAC, and DNA methyltransferases (DNMTs).40 Both metformin41,42 and statins43,44 may reduce cardiac fibrosis; however, whether their beneficial effects are mediated by epigenetic-oriented responses has yet to be demonstrated. Furthermore, SGLT2i are a new group of oral drugs used for treating type 2 diabetes and its cardiovascular/renal complications.45 Animal models have demonstrated that empagliflozin46,47 and dapagliflozin48 may improve hemodynamics in HF by increasing renal protection and cardiac fibrosis. Interestingly, inflammation and glucotoxicity (AGE/RAGE signaling) were epigenetically prevented by empagliflozin;49 this observation has provided insights about mechanisms by which SGLT2i can reduce cardiovascular mortality in man (EMPA-REG trial).50

An effective therapy for HFpEF has yet to be established. Hydralazine is frequently used in HFrEF, and represents a potential DNA methylation inhibitor.39 DNA methylation is the most studied direct epigenetic change with potential clinical implications in major CVDs and the development of HF.7,14 This epigenetic signature mainly involves methylation of CpG islands in the gene promoters leading to a specific long-term silencing of gene expression.7,14 A completed Phase 2 clinical trial (NCT01516346) evaluated the effect of prolonged therapy (24 weeks) with isosorbide dinitrate (ISDN) hydralazine on arterial wave reflections (primary endpoint) as well as left ventricular (LV) mass, fibrosis and diastolic function, and exercise capacity (6-minute walk test) in patients with HFpEF, New York Heart Association (NYHA) Class IIIV symptoms, and standard therapy as defined by ACEi, ARB, beta-blockers, or calcium channel blockers (CCBs).51 Results from this trial reported that ISDN, with or without hydralazine, had deleterious effects on reflection magnitude, LV remodeling, or submaximal exercise thus not supporting their routine use in patients with HFpEF.51

Metformin has been associated with a reduced mortality in patients with HFpEF, even if female gender was associated with worse outcomes.52 Recently, it has been observed that a long-term treatment with metformin can improve LV diastolic function and hypertrophy, decrease the incidence of new-onset HFpEF, and delay disease progression in patients with type 2 diabetes and hypertension.53 Besides, a prospective phase 2 clinical trial (NCT03629340) is testing the therapeutic efficacy of metformin in patients with pulmonary hypertension and HFpEF by evaluating exercise hemodynamics, functional capacity, skeletal muscle signaling, and insulin sensitivity. However, results have not been published. A recent study based on the JASPER registry, a multicenter, observational, prospective cohort of Japanese patients aged 20 years requiring hospitalization for acute HFpEF has reported that the use of statins could reduce mortality in affected patients without coronary heart disease.54 Furthermore, the use of statins was associated with improved clinical outcomes in patients with HFpEF but not in patients with HFrEF (or mid-range ejection fraction).55 A reduced rate of major adverse cardiac events, cardiovascular death and all-cause mortality was associated with SGLT2i treatment in both HFpEF and HFrEF patients as compared to placebo.56,57 However, the observed cardiovascular and renal benefits cannot be fully explained by improvement in risk factors (such as glycemia, blood pressure or dyslipidemias) suggesting that other molecular mechanisms may explain the cardiovascular benefits.56 Interestingly, the SGLT2i-related epigenetic interference may arise from their ability to increase the circulating and tissue levels of -hydroxybutyrate, a specific molecule able to generate a pattern of histone modifications (known as -hydroxybutyrylation) which are associated with the beneficial effects of fasting.58 Besides, the DELIVER (NCT03619213) multicenter, randomized, double-blind, placebo-controlled study of 6263 HFpEF patients will evaluate the effect of dapagliflozin 10 mg (1 per day) as compared to placebo in addition to the standard of care in order to reduce the composite of cardiovascular death or HF events. However, results have not yet been published.

The use of metformin has been generally considered a contraindication in HFrEF patients owing the potential risk of lactic acidosis; however, recent evidence has reported that metformin can provide beneficial effects in reducing the risk of incident HF and mortality in diabetic patients.5961 A completed, observational clinical trial (NCT03546062) has recently performed the evaluation of seriated cardiac biopsies from healthy implanted hearts in type 2 diabetes recipients during 12-month follow-up upon heart transplantation.21 Even if the intra-cardiomyocyte lipid accumulation in type 2 diabetes recipients may start in the early stages after heart transplantation, metformin therapy could reduce lipid accumulation independently of immunosuppressive therapy.21 The DANHEART trial (NCT03514108), a multicenter, randomized, double-blind, placebo-controlled study in 1500 patients with HFrEF will evaluate: 1) whether hydralazine-isosorbide dinitrate as compared to placebo may reduce the incidence of death and HF hospitalization, and 2) if metformin as compared to placebo may reduce the incidence of death, worsening of HF, acute myocardial infarction, and stroke in patients with diabetes or prediabetes. Two large randomized trials demonstrated that statins did not have beneficial effects in management of patients with HFrEF.62,63 Specifically, the CORONA phase 3 trial randomized more than 5000 patients with ischemic HFrEF to rosuvastatin as compared to placebo resulting in no benefits on the primary endpoints, as death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke.62 According to CORONA trial, the GISSI-HF study randomized almost 5000 patients with clinically apparent HF of any cause to rosuvastatin as compared to placebo and observed no benefits on the primary endpoints, as all-cause death or cardiovascular hospitalization.63 However, it is needed to highlight that both trials demonstrated that statins are safe in HF patients. In contrast with the previous evidence, the trial based on the Swedish Heart Failure Registry (21,864 patients with HFrEF, of whom 10,345 were treated with statins) reported an association between the use of statins and improved outcomes, as all-cause mortality, cardiovascular mortality, HF hospitalization, and combined all-cause mortality or cardiovascular hospitalization, especially in patients with ischemic HF.64 Thus, further randomized controlled trials focused on ischemic HF may be warranted. Omega-3 polyunsaturated fatty acids (PUFAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are key players in modulating inflammatory process by limiting leucocyte chemotaxis, adhesion molecule expression, leucocyte-endothelium interaction as well as T cell reactivity.65 EPA and DHA are mainly gained from marine food consumption and large population-based studies have shown that Mediterranean diet with PUFA supplementation may aid to prevent CVDs owing to their ability in promoting the release of nitric oxide from endothelial cells and decreasing serum levels of triglycerides.66 Recent evidence has indicated that PUFAs can significantly affect the cellular epigenome mainly thought DNA methylation-sensitive mechanisms.67,68 The GISSI multicenter, double-blind trial enrolled 6975 HF patients (New York Heart Association class IIIV, irrespective of cause and LV ejection fraction) and randomized them to low dose (0.84 g per day) of PUFAs as compared to placebo. PUFAs supplementation reduced risk for total mortality and HF hospitalization when added to standard therapy.19 Furthermore, in the OMEGA-REMODEL trial, high-dose of PUFAs (3.4 g per day) for 6 months post-myocardial infarction reduced infarct size and non-infarct myocardial fibrosis as well as improved ventricular systolic function.69 Taken together, these results suggest that PUFAs may aid to prevent HFrEF. More recently, the MESA longitudinal trial including 6562 participants 45 to 84 years has demonstrated that higher plasma levels of EPA were significantly associated with reduced risk both in HFpEF and HFrEF.70

Although the possibility of improving the HF standard of care with epidrugs is still in its infancy, the BETonMACE study has provided promising results about the use of apabetalone in reducing hospitalization and cardiovascular death. Preclinical models of cardiac remodeling demonstrated that metformin, statins, SGLT2i, and PUFAs4148 can improve vascular health and cardiac fibrosis by modulating specific molecular pathways, and, in part, through downstream epigenetic interference, especially for hydralazine39 and empagliflozin (Figure 2).49 Of note, metformin and SGLT2i can impact on the epigenetic memory phenomenon. This latter suggests that an early glycemia normalization can arrest hyperglycemia-induced epigenetic processes associated with enhanced oxidative stress and glycation of cellular proteins and lipids.71,72 In parallel, an increasing number of clinical trials is evaluating the putative beneficial repurposing of metformin, statins, SGLT2i, and PUFAs in patients with HFpEF and/or HFrEF;19,6264,69,7375 however, despite experimental evidence, none of these trials evaluated their potential epigenetic effects involved in improving the cardiac function. This gap should be overcome to improve personalized therapy of patients with HF. Thus, further randomized trials are needed to clarify whether apabetalone, as well as non-canonical repurposed epidrugs, will really be able to save failing hearts in different HF clinical phenotypes or prevent irreversible damages in high-risk patients. In this context, Network Medicine approaches may help to evaluate a possible repurposing of epidrugs in patients with major CVDs.15,76,77

Figure 2 Direct and indirect epigenetic drugs in preclinical models of HF. Cardiac remodeling includes different pathological phenotypes and each type of drug can selectively improve inflammation, cardiac fibrosis and hypertrophy, calcium homeostasis, and lipid metabolism.

Abbreviations: HF, heart failure; SGLT2i, sodium glucose co-transporter 2 inhibitors.

This work was supported by PRIN2017F8ZB89 from Italian Ministry of University and Research (MIUR) (PI Prof Napoli) and Ricerca Corrente (RC) 2019 from Italian Ministry of Health (PI Prof. Napoli).

The authors report no conflicts of interest in this work.

1. Gronda E, Sacchi S, Benincasa G, et al. Unresolved issues in left ventricular postischemic remodeling and progression to heart failure. J Cardiovasc Med (Hagerstown). 2019;20:640649. doi:10.2459/JCM.0000000000000834.

2. Gronda E, Vanoli E, Sacchi S, et al. Risk of heart failure progression in patients with reduced ejection fraction: mechanisms and therapeutic options. Heart Fail Rev. 2020;25(2):295303. doi:10.1007/s10741-019-09823-z

3. Sokos GG, Raina A. Understanding the early mortality benefit observed in the PARADIGM-HF trial: considerations for the management of heart failure with sacubitril/valsartan. Vasc Health Risk Manag. 2020;16:4151. doi:10.2147/VHRM.S197291

4. Cacciatore F, Amarelli C, Maiello C, et al. Sacubitril/valsartan in patients listed for heart transplantation: effect on physical frailty. ESC Heart Fail. 2020;7:757762. doi:10.1002/ehf2.12610.

5. Clark KAA, Velazquez EJ. Heart failure with preserved ejection fraction: time for a reset. JAMA. 2020;324:15061508. doi:10.1001/jama.2020.15566.

6. Schiano C, Benincasa G, Franzese M, et al. Epigenetic-sensitive pathways in personalized therapy of major cardiovascular diseases. Pharmacol Ther. 2020;210:107514. doi:10.1016/j.pharmthera.2020.107514.

7. Schiano C, Benincasa G, Infante T, et al. Integrated analysis of DNA methylation profile of HLA-G gene and imaging in coronary heart disease: pilot study. PLoS One. 2020;15:e0236951. doi:10.1371/journal.pone.0236951.

8. Benincasa G, Cuomo O, Vasco M, et al. Epigenetic-sensitive challenges of cardiohepatic interactions: clinical and therapeutic implications in heart failure patients. Eur J Gastroenterol Hepatol. 2020. doi:10.1097/MEG.0000000000001867.

9. Benincasa G, Franzese M, Schiano C, et al. DNA methylation profiling of CD04+/CD08+ T cells reveals pathogenic mechanisms in increasing hyperglycemia: PIRAMIDE pilot study. Ann Med Surg (Lond). 2020;60:218226. doi:10.1016/j.amsu.2020.10.016.

10. Napoli C, Benincasa G, Schiano C, et al. Differential epigenetic factors in the prediction of cardiovascular risk in diabetic patients. Eur Heart J Cardiovasc Pharmacother. 2020;6:239247. doi:10.1093/ehjcvp/pvz062.

11. Napoli C, Coscioni E, de Nigris F, et al. Emergent expansion of clinical epigenetics in patients with cardiovascular diseases. Curr Opin Cardiol. 2021;36(3):295300. doi:10.1097/HCO.0000000000000843.

12. Infante T, Forte E, Schiano C, et al. Evidence of association of circulating epigenetic-sensitive biomarkers with suspected coronary heart disease evaluated by Cardiac Computed Tomography. PLoS One. 2019;14:e0210909. doi:10.1371/journal.pone.0210909.

13. de Nigris F, Cacciatore F, Mancini FP, et al. Epigenetic hallmarks of fetal early atherosclerotic lesions in humans. JAMA Cardiol. 2018;3:11841191. doi:10.1001/jamacardio.2018.3546.

14. Napoli C, Benincasa G, Donatelli F, et al. Precision medicine in distinct heart failure phenotypes: focus on clinical epigenetics. Am Heart J. 2020;224:113128. doi:10.1016/j.ahj.2020.03.007.

15. Sarno F, Benincasa G, List M, et al. Clinical epigenetics settings for cancer and cardiovascular diseases: real-life applications of network medicine at the bedside. Clin Epigenetics. 2021;13:66. doi:10.1186/s13148-021-01047-z.

16. Grimaldi V, Vietri MT, Schiano C, et al. Epigenetic reprogramming in atherosclerosis. Curr Atheroscler Rep. 2014;17:476. doi:10.1007/s11883-014-0476-3.

17. Sabia C, Picascia A, Grimaldi V, et al. The epigenetic promise to improve prognosis of heart failure and heart transplantation. Transplant Rev (Orlando). 2017;31:249256. doi:10.1016/j.trre.2017.08.004.

18. Vasco M, Benincasa G, Fiorito C, et al. Clinical epigenetics and acute/chronic rejection in solid organ transplantation: an update. Transplant Rev (Orlando). 2021;35:100609. doi:10.1016/j.trre.2021.100609.

19. Tavazzi L, Maggioni AP, Marchioli R, et al. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:12231230. doi:10.1016/S0140-6736(08)61239-8.

20. Ray KK, Nicholls SJ, Buhr KA, et al. Effect of apabetalone added to standard therapy on major adverse cardiovascular events in patients with recent acute coronary syndrome and type 2 diabetes: a randomized clinical trial. JAMA. 2020;323:15651573. doi:10.1001/jama.2020.3308.

21. Marfella R, Amarelli C, Cacciatore F, et al. Lipid accumulation in hearts transplanted from nondiabetic donors to diabetic recipients. J Am Coll Cardiol. 2020;75:12491262. doi:10.1016/j.jacc.2020.01.018.

22. Nicholls SJ, Schwartz GG, Buhr KA, et al. Apabetalone and hospitalization for heart failure in patients following an acute coronary syndrome: a prespecified analysis of the BETonMACE study. Cardiovasc Diabetol. 2021;20:13. doi:10.1186/s12933-020-01199-x.

23. Gaucher J, Boussouar F, Montellier E, et al. Bromodomain-dependent stage-specific male genome programming by Brdt. EMBO J. 2012;31:38093820. doi:10.1038/emboj.2012.233.

24. Borck PC, Guo LW, Plutzky J. BET epigenetic reader proteins in cardiovascular transcriptional programs. Circ Res. 2020;126:11901208. doi:10.1161/CIRCRESAHA.120.315929.

25. Tonini C, Colardo M, Colella B, et al. Inhibition of bromodomain and extraterminal domain (BET) proteins by JQ1 unravels a novel epigenetic modulation to control lipid homeostasis. Int J Mol Sci. 2020;21:1297. doi:10.3390/ijms21041297.

26. Nicodeme E, Jeffrey KL, Schaefer U, et al. Suppression of inflammation by a synthetic histone mimic. Nature. 2010;468:11191123. doi:10.1038/nature09589.

27. Dey A, Yang W, Gegonne A, et al. BRD4 directs hematopoietic stem cell development and modulates macrophage inflammatory responses. EMBO J. 2019;38:e100293. doi:10.15252/embj.2018100293.

28. Picaud S, Wells C, Felletar I, et al. RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain. Proc Natl Acad Sci U S A. 2013;110:1975419759. doi:10.1073/pnas.1310658110.

29. McLure KG, Gesner EM, Tsujikawa L, et al. RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist. PLoS One. 2013;8:e83190. doi:10.1371/journal.pone.0083190.

30. Bailey D, Jahagirdar R, Gordon A, et al. RVX-208: a small molecule that increases apolipoprotein A-I and high-density lipoprotein cholesterol in vitro and in vivo. J Am Coll Cardiol. 2010;55:25802589. doi:10.1016/j.jacc.2010.02.035.

31. Anand P, Brown JD, Lin CY, et al. BET bromodomains mediate transcriptional pause release in heart failure. Cell. 2013;154:569582. doi:10.1016/j.cell.2013.07.013.

32. Song S, Liu L, Yu Y, et al. Inhibition of BRD4 attenuates transverse aortic constriction- and TGF--induced endothelial-mesenchymal transition and cardiac fibrosis. J Mol Cell Cardiol. 2019;127:8396. doi:10.1016/j.yjmcc.2018.12.002.

33. Ooi JY, Tuano NK, Rafehi H, et al. HDAC inhibition attenuates cardiac hypertrophy by acetylation and deacetylation of target genes. Epigenetics. 2015;10:418430. doi:10.1080/15592294.2015.1024406.

34. Ferguson BS, McKinsey TA. Non-sirtuin histone deacetylases in the control of cardiac aging. J Mol Cell Cardiol. 2015;83:1420. doi:10.1016/j.yjmcc.2015.03.010.

35. Chen Y, Du J, Zhao YT, et al. Histone deacetylase (HDAC) inhibition improves myocardial function and prevents cardiac remodeling in diabetic mice. Cardiovasc Diabetol. 2015;14:99. doi:10.1186/s12933-015-0262-8.

36. Zhang CL, McKinsey TA, Chang S, et al. Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell. 2002;110(4):479488. doi:10.1016/s0092-8674(02)00861-9

37. Spiltoir JI, Stratton MS, Cavasin MA, et al. BET acetyl-lysine binding proteins control pathological cardiac hypertrophy. J Mol Cell Cardiol. 2013;63:175179. doi:10.1016/j.yjmcc.2013.07.017.

38. Russell-Hallinan A, Neary R, Watson CJ, et al. Repurposing from oncology to cardiology: low-dose 5-azacytidine attenuates pathological cardiac remodeling in response to pressure overload injury. J Cardiovasc Pharmacol Ther. 2020:107424842097923. doi:10.1177/1074248420979235

39. Kao YH, Cheng CC, Chen YC, et al. Hydralazine-induced promoter demethylation enhances sarcoplasmic reticulum Ca2+ -ATPase and calcium homeostasis in cardiac myocytes. Lab Invest. 2011;91:12911297. doi:10.1038/labinvest.2011.92.

40. Bridgeman SC, Ellison GC, Melton PE, et al. Epigenetic effects of metformin: from molecular mechanisms to clinical implications. Diabetes Obes Metab. 2018;20(7):15531562. doi:10.1111/dom.13262.

41. Xiao H, Ma X, Feng W, et al. Metformin attenuates cardiac fibrosis by inhibiting the TGFbeta1-Smad3 signalling pathway. Cardiovasc Res. 2010;87:504513. doi:10.1093/cvr/cvq066.

42. Zhao Q, Song W, Huang J, et al. Metformin decreased myocardial fibrosis and apoptosis in hyperhomocysteinemia -induced cardiac hypertrophy. Curr Res Transl Med. 2021;69:103270. doi:10.1016/j.retram.2020.103270.

43. Oesterle A, Laufs U, Liao JK. Pleiotropic effects of statins on the cardiovascular system. Circ Res. 2017;120:229243. doi:10.1161/CIRCRESAHA.116.308537.

44. Sun F, Duan W, Zhang Y, et al. Simvastatin alleviates cardiac fibrosis induced by infarction via up-regulation of TGF- receptor III expression. Br J Pharmacol. 2015;172:37793792. doi:10.1111/bph.13166.

45. Gronda E, Jessup M, Iacoviello M, et al. Glucose metabolism in the kidney: neurohormonal activation and heart failure development. J Am Heart Assoc. 2020;9(23):e018889. doi:10.1161/JAHA.120.018889.

46. Lee HC, Shiou YL, Jhuo SJ, et al. The sodium-glucose co-transporter 2 inhibitor empagliflozin attenuates cardiac fibrosis and improves ventricular hemodynamics in hypertensive heart failure rats. Cardiovasc Diabetol. 2019;18:45. doi:10.1186/s12933-019-0849-6.

47. Li C, Zhang J, Xue M, et al. SGLT2 inhibition with empagliflozin attenuates myocardial oxidative stress and fibrosis in diabetic mice heart. Cardiovasc Diabetol. 2019;18:15. doi:10.1186/s12933-019-0816-2.

48. Arow M, Waldman M, Yadin D, et al. Sodium-glucose cotransporter 2 inhibitor Dapagliflozin attenuates diabetic cardiomyopathy. Cardiovasc Diabetol. 2020;19:7. doi:10.1186/s12933-019-0980-4.

49. Steven S, Oelze M, Hanf A, et al. The SGLT2 inhibitor empagliflozin improves the primary diabetic complications in ZDF rats. Redox Biol. 2017;13:370385. doi:10.1016/j.redox.2017.06.009.

50. Zinman B, Lachin JM, Inzucchi SE. Empagliflozin, cardiovascular outcomes, and mortality in type 2 Diabetes. N Engl J Med. 2016;374:1094. doi:10.1056/NEJMc1600827

51. Zamani P, Akers S, Soto-Calderon H, et al. Isosorbide Dinitrate, with or without hydralazine, does not reduce wave reflections, left ventricular hypertrophy, or myocardial fibrosis in patients with heart failure with preserved ejection fraction. J Am Heart Assoc. 2017;6:e004262. doi:10.1161/JAHA.116.004262.

52. Halabi A, Sen J, Huynh Q, et al. Metformin treatment in heart failure with preserved ejection fraction: a systematic review and meta-regression analysis. Cardiovasc Diabetol. 2020;19(1):124. doi:10.1186/s12933-020-01100-w.

53. Gu J, Yin ZF, Zhang JF, et al. Association between long-term prescription of metformin and the progression of heart failure with preserved ejection fraction in patients with type 2 diabetes mellitus and hypertension. Int J Cardiol. 2020;306:140145. doi:10.1016/j.ijcard.2019.11.087.

54. Marume K, Takashio S, Nagai T, et al. Effect of statins on mortality in heart failure with preserved ejection fraction without coronary artery disease. Report from the JASPER Study. Circ J. 2019;83:357367. doi:10.1253/circj.CJ-18-0639.

55. Lee MS, Duan L, Clare R, et al. Comparison of effects of statin use on mortality in patients with heart failure and preserved versus reduced left ventricular ejection fraction. Am J Cardiol. 2018;122:405412. doi:10.1016/j.amjcard.2018.04.027.

56. Lam CSP, Chandramouli C, Ahooja V, Verma S. SGLT-2 inhibitors in heart failure: current management, unmet needs, and therapeutic prospects. J Am Heart Assoc. 2019;8:e013389. doi:10.1161/JAHA.119.013389.

57. Zannad F, Ferreira JP, Pocock SJ, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet. 2020;396:819829. doi:10.1016/S0140-6736(20)31824-9.

58. Nishitani S, Fukuhara A, Shin J, et al. Metabolomic and microarray analyses of adipose tissue of dapagliflozin-treated mice, and effects of 3-hydroxybutyrate on induction of adiponectin in adipocytes. Sci Rep. 2018;8:8805. doi:10.1038/s41598-018-27181-y.

59. Wong AK, AlZadjali MA, Choy AM, et al. Insulin resistance: a potential new target for therapy in patients with heart failure. Cardiovasc Ther. 2008;26:203213. doi:10.1111/j.1755-5922.2008.00053.x.

60. Pantalone KM, Kattan MW, Yu C, et al. The risk of developing coronary artery disease or congestive heart failure, and overall mortality, in type 2 diabetic patients receiving rosiglitazone, pioglitazone, metformin, or sulfonylureas: a retrospective analysis. Acta Diabetol. 2009;46:145154. doi:10.1007/s00592-008-0090-3.

61. Papanas N, Maltezos E, Mikhailidis DP. Metformin and heart failure: never say never again. Expert Opin Pharmacother. 2012;13:18. doi:10.1517/14656566.2012.638283.

62. Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med. 2007;357:22482261. doi:10.1056/NEJMoa0706201.

63. Tavazzi L, Maggioni AP, Marchioli R, et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:12311239. doi:10.1016/S0140-6736(08)61240-4.

64. Alehagen U, Benson L, Edner M, et al. Association between use of statins and outcomes in heart failure with reduced ejection fraction: prospective propensity score matched cohort study of 21 864 patients in the Swedish Heart Failure Registry. Circ Heart Fail. 2015;8:252260. doi:10.1161/CIRCHEARTFAILURE.114.001730.

65. Calder PC. Omega-3 polyunsaturated fatty acids and inflammatory processes: nutrition or pharmacology? Br J Clin Pharmacol. 2013;75:645662. doi:10.1111/j.1365-2125.2012.04374.x.

66. Mohebi-Nejad A, Bikdeli B. Omega-3 supplements and cardiovascular diseases. Tanaffos. 2014;13:614.

67. Burdge GC, Lillycrop KA. Fatty acids and epigenetics. Curr Opin Clin Nutr Metab Care. 2014;17:156161. doi:10.1097/MCO.0000000000000023.

68. de la Rocha C, Prez-Mojica JE, Len SZ, et al. Associations between whole peripheral blood fatty acids and DNA methylation in humans. Sci Rep. 2016;6:25867. doi:10.1038/srep25867.

69. Heydari B, Abdullah S, Pottala JV, et al. Effect of omega-3 acid ethyl esters on left ventricular remodeling after acute myocardial infarction: the OMEGA-REMODEL randomized clinical trial. Circulation. 2016;134:378391. doi:10.1161/CIRCULATIONAHA.115.019949.

70. Block RC, Liu L, Herrington DM, et al. Predicting risk for incident heart failure with omega-3 fatty acids: from MESA. JACC Heart Fail. 2019;7:651661. doi:10.1016/j.jchf.2019.03.008.

71. Berezin A. Metabolic memory phenomenon in diabetes mellitus: achieving and perspectives. Diabetes Metab Syndr. 2016;10:S17683. doi:10.1016/j.dsx.2016.03.016.

72. Sommese L, Benincasa G, Lanza M, et al. Novel epigenetic-sensitive clinical challenges both in type 1 and type 2 diabetes. J Diabetes Complications. 2018;32:10761084. doi:10.1016/j.jdiacomp.2018.08.012.

73. Trum M, Wagner S, Maier LS, et al. CaMKII and GLUT1 in heart failure and the role of gliflozins. Biochim Biophys Acta Mol Basis Dis. 2020;1866:165729. doi:10.1016/j.bbadis.2020.165729.

74. Nikolic M, Zivkovic V, Jovic JJ, et al. SGLT2 inhibitors: a focus on cardiac benefits and potential mechanisms. Heart Fail Rev. 2021. doi:10.1007/s10741-021-10079-9.

75. Mohammadzadeh N, Montecucco F, Carbone F, et al. Statins: epidrugs with effects on endothelial health? Eur J Clin Invest. 2020;50:e13388. doi:10.1111/eci.13388.

76. Benincasa G, DeMeo DL, Glass K, Silverman EK, Napoli C. Epigenetics and pulmonary diseases in the horizon of precision medicine: a review. Eur Respir J. 2020 Nov 19:2003406. doi:10.1183/13993003.03406-2020.77.

77. Benincasa G, Marfella R, Della Mura N, et al. Strengths and opportunities of network medicine in cardiovascular diseases. Circ J. 2020 Jan 24;84(2):144152. doi:10.1253/circj.CJ-19-0879.

See original here:
Epigenetic therapies for heart failure | VHRM - Dove Medical Press

Newswise Irvine, CA May 13, 2021 A new University of California, Irvine-led study finds low serum levels of the sugar N-acetylglucosamine (GlcNAc), is associated with progressive disability and neurodegeneration in multiple sclerosis (MS).

The study, done in collaboration with researchers from Charit Universittsmedizin Berlin, Germany, and the University of Toronto, Canada, is titled, Association of a Marker of N-Acetylglucosamine With Progressive Multiple Sclerosis and Neurodegeneration, The study was published this week in JAMA Neurology.

The study suggests that GlcNAc, which has been previously shown to promote re-myelination and suppress neurodegeneration in animal models of MS, is reduced in serum of progressive MS patients and those with worse clinical disability and neurodegeneration.

We found the serum levels of a marker of GlcNAc was markedly reduced in progressive MS patients compared to healthy controls and patients with relapsing-remitting multiple sclerosis explained Michael Demetriou, MD, PhD, FRCP(C), professor of neurology, microbiology and molecular genetics at UCI School of Medicine, and senior author on the paper.

First author of the study, Alexander Brandt, MD, adjunct associate professor of neurology at the UCI School of Medicine and previously associated with the Experimental and Clinical Research Center, Charit Universittsmedizin Berlin and Max Delbrueck Center for Molecular Medicine, Germany, added, Lower GlcNAc serum marker levels correlated with multiple measures of neurodegeneration in MS, namely worse expanded disability status scale scores, lower thalamic volume, and thinner retinal nerve fiber layer. Also, low baseline serum levels correlated with a greater percentage of brain volume loss at 18 months, he said.

GlcNAc regulates protein glycosylation, a fundamental process that decorates the surface of all cells with complex sugars. Previous preclinical, human genetic and ex vivo human mechanistic studies revealed that GlcNAc reduces proinflammatory immune responses, promotes myelin repair, and decreases neurodegeneration. Combined with the new findings, the data suggest that GlcNAc deficiency may promote progressive disease and neurodegeneration in patients with MS. However, additional human clinical studies are required to confirm this hypothesis.

Our findings open new potential avenues to identify patients at risk of disease progression and neurodegeneration, so clinicians can develop and adjust therapies accordingly, said Michael Sy, MD, PhD, assistant professor in residence in the Department of Neurology at UCI and a co-author of the study.

MS is characterized by recurrent episodes of neurologic dysfunction resulting from acute inflammatory demyelination. Progressive MS is distinguished by continuous inflammation, failure to remyelinate, and progressive neurodegeneration, causing accrual of irreversible neurologic disability. Neurodegeneration is the major contributor to progressive neurological disability in MS patients, yet mechanisms are poorly understood and there are no current treatments for neurodegeneration.

This study was funded in part by a grant from the National Institute of Allergy and Infectious Disease and the National Center for Complimentary and Integrative Health as well as the Excellence Initiative and the Excellence Strategy of the German Federal and State Governments.

About the UCI School of Medicine

Each year, the UCI School of Medicine educates more than 400 medical students, and nearly 150 doctoral and masters students. More than 700 residents and fellows are trained at UCI Medical Center and affiliated institutions. The School of Medicine offers an MD; a dual MD/PhD medical scientist training program; and PhDs and masters degrees in anatomy and neurobiology, biomedical sciences, genetic counseling, epidemiology, environmental health sciences, pathology, pharmacology, physiology and biophysics, and translational sciences. Medical students also may pursue an MD/MBA, an MD/masters in public health, or an MD/masters degree through one of three mission-based programs: the Health Education to Advance Leaders in Integrative Medicine (HEAL-IM), the Leadership Education to Advance Diversity-African, Black and Caribbean (LEAD-ABC), and the Program in Medical Education for the Latino Community (PRIME-LC). The UCI School of Medicine is accredited by the Liaison Committee on Medical Accreditation and ranks among the top 50 nationwide for research. For more information, visit som.uci.edu.

Read the original:
New study finds low levels of a sugar metabolite associates with disability and neurodegeneration in multiple sclerosis - Newswise

Sara Cernadas-Martn with the research vessel Seawolf behind her. Photo by John Griffin

Sara Cernadas-Martn is a self-described interdisciplinary scientist with knowledge spanning the fields of marine biology, molecular genetics, and conservation ecology, with an M.S. and a PhD from Stony Brook University.

Beyond her passion for studying and preserving the diversity of marine life in our local waters, Cernadas-Martn is equally as dedicated to fostering diversity within the human race, making her the ideal person to serve as co-chair for the School of Marine and Atmospheric Science (SoMAS) Diversity, Equity and Inclusivity Committee.

As an Hispanic scientist, I am committed to increasing diversity on campus and making an extra effort to promote higher education within the Hispanic community and other underrepresented racial, ethnic and social groups, Cernadas-Martn said.Hispanics are highly underrepresented in undergraduate and graduate schools in America, which is especially discouraging when considering that the Hispanic population is the largest ethnic minority group in the country. I strongly believe that having a diverse student body benefits everyone involved.

For her masters project, Sara studied the distribution of ammonia oxidizing bacteria in the Cariaco Basin near Venezuela, an oxygen minimum zone with a permanently anoxic (oxygen-depleted) deep layer, under the supervision of Professor Gordon Taylor. Her PhD thesis focused on the multidisciplinary ecological characterization of summer flounder (Paralichthys dentatus) in Shinnecock Bay using acoustic telemetry, diet analysis and otolith (earstones in bony fishes) microchemistry under the supervision of Professor Ellen Pikitch.

Cernadas-Martn is currently working with the Institute for Ocean Conservation Science (IOCS) as a senior postdoctoral associate at Stony Brook, where her work focuses on managing the research component of ShiRP fisheries (Shinnecock Bay Restoration Program) and establishing a new environmental DNA program for tracking fish species richness in the South Shore Long Island estuaries.

In 2019, Cernadas-Martn was also selected as the recipient of the distinguished Nuria Protopopescu Memorial Teaching Award, presented annually to a graduate student based on demonstrated excellence in teaching, innovation and creativity in instructional plans and materials, and engagement with and dedication to their students.

Although I enjoy working with students of all backgrounds, I have always taken special interest in Latinx students, making sure they felt motivated, included and most importantly, had fun while doing science, she said. At first, many of these students were hesitant to be assertive while in the field or in the classroom. I came to realize, in sharing the same language, I could help students to overcome their natural timidity and become more engaged in their research and learning experience.

Of particular interest to Cernadas-Martn is extending educational opportunities to students from diverse backgrounds, including first-generation college students, international students, and students with a wide range of educational experiences and goals.

Her academic achievements and community involvement, along with her focused effort on student diversity and integration, have been recognized by Stony Brook University with the prestigious W. Burghardt Turner Fellowship, a highly competitive fellowship which acknowledges the academic and research achievements of underrepresented doctoral students and requires a strong commitment to inclusivity and community development.

Another of Cernadas-Martns personal goals is to help improve the integration of international students into the wider academic community.

I remember when I first got to Stony Brook University from Spain. I was in shock, she recalled. I was happy for having made it into graduate school, but at the same time had to deal with a language barrier and being away from my family and friends. The first few months are critical times in the life of an international student and can potentially handicap academic performance.

Cernadas-Martn believes efficient integration is key to helping international students realize that there are opportunities in this new chapter of their lives. During my first years of graduate school, I did my best to help improve social interactions among students in my department, she said. One example were the flamenco nights I hosted once a month at a Spanish restaurant open to everyone in my department, where I was able to share the culinary, musical and folkloric traditions of my culture.

To that end, Cernadas-Martn has volunteered with the Graduate Student Club of her department as the activities coordinator, creating and running a departmental photo competition since 2012, among other undertakings.

Perhaps some of her compassion originated from her own medical struggles.As a college freshman, she overcame bone cancer, which impeded her from attending school. She recovered, but suffered a relapse in the middle of her sophomore year.

During my graduate career I have been, once again, plagued with health issues, which included three major spinal surgeries, she said, adding that the surgeries set back her graduation timeline and consequently constrained the ability of her research grants to cover laboratory costs and living expenses.

However, I was lucky enough to have a few professors, family and friends who supported me and encouraged me to finish my degree, she said. It did take me longer than most people, but I did it. Looking back, I cant thank those people in my life enough. I aim to be a support system for as many students as possible, motivating them to move forward despite setbacks and encouraging them to pursue their passion.

Glenn Jochum

Continued here:
Cernadas-Martn Is a Champion for Marine and Human Diversity | | SBU News - Stony Brook News

Four Penn Faculty: Election to the National Academy of Sciences

Four members of the University of Pennsylvania faculty have been elected to the United States National Academy of Sciences (NAS). They join 120 members, 59 of whom are women, the most elected in a single year, and 30 international members, elected by their peers this year to NAS. Recognized for distinguished and continuing achievements in original research, this new class brings the total number of active members to 2,461 and of international members to 511.

Marisa Bartolomei is the Perelman Professor of Cell and Developmental Biology in the department of cell and developmental biology in the Perelman School of Medicine. She is also the co-director of the Penn Epigenetics Institute. Crossing into the disciplines of cell and molecular biology, pharmacology, and neuroscience, Dr. Bartolomei and her lab investigate genomic imprinting in mice. Specifically, they focus on the H19 gene, which is only expressed in maternal alleles, in order to better uncover the mechanisms behind imprinting and the effects of the environment, assisted reproductive technologies, and endocrine disruptors. Her lab also looks into the molecular and genetic systems behind X inactivation in mice. Her research has been published widely in journals including Nature, Nature Biotechnology, Development, and PLoS Genetics.

Michael Kearns is the National Center Professor of Management & Technology in the department of computer and information science in the School of Engineering and Applied Science. He also holds secondary appointments in the School of Arts & Sciences department of economics and the departments of statistics and operations, information and decisions at the Wharton School. He is an expert in machine learning, algorithmic game theory, and microeconomics, and applies both theoretical research and experimental techniques to better understand the social dimensions of new information technology, such as its impact on privacy and fairness. Dr. Kearns is also the founding director of Penns Warren Center for Network and Data Sciences, which draws on researchers from around the University to study some of the most pressing problems of the digital age. Dr. Kearns is also the co-author of The Ethical Algorithm, which shows how seemingly objective data science techniques can produce biased outcomes.

Diana Mutz is the Samuel A. Stouffer Professor of Political Science and Communication in the Annenberg School for Communication. She also serves as director of the Institute for the Study of Citizens and Politics; she is also an affiliate of the Warren Center. She studies political communication, political psychology, and public opinion, and her research focuses on how the American mass public relates to the political world and how people form opinions on issues and candidates. She received a 2017 Carnegie Fellowship and a 2016 Guggenheim Fellowship to pursue research on globalization and public opinion, and in 2011 received the Lifetime Career Achievement Award in Political Communication from the American Political Science Association. In addition to many journal articles, Dr. Mutz is the author of Impersonal Influence: How Perceptions of Mass Collectives Affect Political Attitudes, Hearing the Other Side: Deliberative Versus Participatory Democracy, and In-Your-Face Politics: The Consequences of Uncivil Media.

M. Celeste Simon is the Arthur H. Rubenstein, MB BCh, Professor in the department of cell and developmental biology in the Perelman School of Medicine and the scientific director of The Abramson Family Cancer Research Institute. She and her lab research the metabolism of cancer cells, tumor immunology, metastasis, and how healthy cells and cancer cells respond to a lack of oxygen and nutrients. Her work uses both animal models and cancer patient samples, and her goal is to create techniques to treat various tumors like kidney cancer, soft tissue sarcoma, liver cancer, and pancreatic cancer. Dr. Simon was the recipient of a National Cancer Institute Outstanding Investigator Award in 2017, and she has authored more than 275 articles in journals including Cell, Science, Nature, Cancer Discovery, Nature Genetics, and Cancer Cell.

More:
Four Penn Faculty: Election to the National Academy of Sciences - UPENN Almanac

The controversy over genetically engineered organisms (sometimes called genetically modified organisms, or GMOs) is genuine, not faux but only because of uninformed, exaggerated concerns about the most recent techniques newness. What is faux and disingenuous are the arguments put forth by genetic engineerings opponents.

Humans have been modifying the DNA of our food for thousands of years (even though we didnt know that DNA was mediating the changes until the 20th century).We call it agriculture.Early farmers (>10,000 years ago) used selective breeding to guide DNA changes in crops and animals to better suit our needs.Approximately a hundred years ago plant breeders began using harsh chemicals and/or radiation to randomly change, or mutate, the DNA of crop plants.These mutagens caused innumerable changes to the DNA, none of which was characterized or examined for safety.The plant breeders looked and selected for desired traits of various kinds.Problems were rare.

Today more than half of all food crops have mutagenesis breeding as part of their pedigree. Ancestral varieties bear little resemblance to the domesticated crops we eat today. There are many striking pictorial examples here.

Approximately 40 years ago agricultural scientists and plant breeders began to use recombinant DNA technology (gene splicing) to make far more precise and predictable changes to the DNA in our crop plants.This molecular genetic engineering (GE) typically takes a gene with a known function, e.g., one that expresses a protein toxic to certain insect predators, and transfers it into a crop, enabling the GE crop to protect itself from insect pests. This one trait, resulting from the introduction of a gene from the bacterium Bacillus thuringiensis (abbreviated Bt) into plants, has allowed farmers around the world to reduce broad spectrum insecticide spraying by billions of pounds.

Since the advent in the 1970s of this recombinant DNA technology, which enables segments of DNA to be moved readily and more precisely from one organism to another, molecular genetic engineering techniques have become increasingly more sophisticated, precise, and predictable. This evolution has culminated in the most recent discoveries, the CRISPR-Cas9 system and base editing.

CRISPR (short for Clustered Regularly Interspaced Short Palindromic Repeats) is a natural defense system that bacteria use against invading viruses. CRISPR can recognize specific DNA sequences, while the enzyme Cas9 cuts the DNA at the recognized sequence. As often happens in scienceand reminiscent of mutagenesis a century ago and recombinant DNA technology in the 1970smolecular biologists quickly copied, adapted, and improved the naturally occurring system. Using CRISPR-Cas9, scientists can target and edit DNA at precise locations, deleting, inserting, or modifying genes in microorganisms, plants and animals, and even humans.

CRISPR-Cas9 presages a revolution in agriculture and human medicine because it is so much more precise and predictable than earlier techniques. Precision and predictability are important to ensure that results are safe and achieve their desired ends. There are notable historical examples of older, pre-molecular techniques of genetic modification in agriculture that misfired.Examples include:

Despite their success for farmers of all types, from subsistence to huge-scale commercial, GE crops have been discriminated against by regulators and demonized by activists. In the early 1970s, at a conclave now referred to as the Asilomar Conference, a group of scientists none involved in agriculture or food science raised concerns about hypothetical hazards that might arise from the use of the newly discovered molecular genetic modification technique recombinant DNA technology, or gene-splicing. However, they failed to appreciate the history of genetic modification by means of cruder, less predictable technologies, described below.

The Asilomar Conference led to guidelines published by the U.S. National Institutes of Health (NIH) for the application of these techniques for any purpose.These process-based guidelines, which were applicable exclusively to recombinant DNA technology, were in addition to the preexisting product-focused regulatory requirements of other federal agencies that had statutory oversight of food, drugs, certain plants, pesticides, and so on.

The NIH guidelines, which were in effect the original sin of precautionary, unscientific regulation, were quite stringent. For example, without regulatory approval, the intentional release of recombinant DNA-modified organisms into the environment, or fermentation (in contained fermenters) at volumes greater than ten liters, required explicit prior approval by the NIH and local Institutional Biosafety Committees.

Given the seamless continuum of techniques for genetic modification described above, such requirements were unwarranted.No analogous blanket restrictions existed for similar or even virtually identical plants, microorganisms, or other organisms modified by traditional techniques, such as chemical or irradiation mutagenesis or wide-cross hybridizations.

Thus, uninformed, ill-founded, and exaggerated concerns about the risks of recombinant DNA-modified organisms in medical, agricultural, and environmental applications precipitated the regulation of recombinant organismsregulation triggered simply by the process, or technique, of genetic modification, rather than the product, i.e., the characteristics of the modified organism itself. This was an unfortunate precedentas was entrusting technology regulation to a research agency, the NIH, whose legacy plagues regulation worldwide today. Most industrial countries, including the US, have specific regulatory agencies like the US Food and Drug Administration and European Medicines Agency that regulate product safety. Research agencies rarely are involved in regulating products or processes.

The regulatory burden on the use of recombinant DNA technologywhich some people (mostly activists and regulators) consider gives rise to a mythical category of organisms called Genetically Modified Organisms, or GMOs, was, and remains, disproportionate to its risk, and the opportunity costs of regulatory delays and expenses are formidable. According to Wendelyn Jones at DuPont Crop Protection, a survey found that the cost of discovery, development and authorization of a new plant biotechnology trait introduced between 2008 and 2012 was $136 million. On average, about 26 percent of those costs ($35.1 million) were incurred as part of the regulatory testing and registration process.

A salient question currently for regulators, scientists, and consumers is whether gene editing will fall down the same rabbit hole. Unfortunately, much of the discussion focuses on irrelevant issues such as whether organisms that could arise naturally or that are not transgenic (containing DNA from different sources) should be subject to more lenient regulation than GMOs. As should be evident from the discussion above, such issues have no implications for riskand, therefore, for regulation. In fact, modern plant breeding techniques, including genome editing, are more precise, circumscribed, and predictable than other methods in other words, if anything, likely to be safer. This assessment is neither new nor novel. A landmark report from the U.S. National Research Council concluded in 1989:

These critical points, clearly articulated more than 30 years ago and about which there is virtual unanimity in the scientific community, have not sunk in.

There is an ongoing need for genetic modification in agriculture. Gene editing could play a key role in Englands sugar beet sector, for example, and Britains farming and in February, environment minister George Eustice told the annual conference of the National Farmers Union that the sugar beet sector could use the assistance of gene editing technologies to overcome yield reduction due to virus infection. He added: Gene editing is really just a more targeted, faster approach to move traits from one plant to another but within the same species so in that respect it is no different from conventional breeding.

The first part of Eustaces statement is accurate, but the second part gives the misimpression that although gene edited crops are analogous to conventional breedingand, therefore, presumably harmlessthey are sufficiently far removed from dreaded GMOs that they should be exempt from the onerous regulation appropriate for the latter. Until now, in the European Union, gene editing has been strictly regulated in the same way as GMOs. Their oversight might diverge in the future, however, inasmuch as serious attention is being paid to this new technology and its enormous potential.

But preferential regulatory treatment of gene editing over recombinant DNA-mediated modifications would represent expediency over logic: The NRC report (as well as other, innumerable, similar analyses) makes it clear that an approach that deregulates gene editing but not recombinant DNA modifications would ignore the seamless continuum that exists among methods of genetic modification, and that it would be unscientific.There is no reason to throw transgenic recombinant DNA constructions under the regulatory bus.

The relationships among genome editing, plant breeding, and GMO crops are more interconnected, complex and nuanced than it may appear at first glance.Plant breeding itself has long been a murky science in terms of genetics and heredity.While Britains Eustice lauds genome editing because it involves only intra-species modification, the history of plant breeding has long included distant or wide crosses to move beneficial traits such as disease resistance from one plant species or one genus to another.Almost a century of wide cross hybridizations, which involve the movement of genes from one species or genus to another, has given rise to plantsincluding everyday varieties of corn, oats, pumpkin, wheat, black currants, tomatoes, and potatoes, among othersthat do not and could not exist in nature. Indeed, with the exception of wild berries, wild game, wild mushrooms, and fish and shellfish, virtually everything in North American and European diets has been genetically improved in some way.Compared to the new molecular modification technologies, these wide crosses are crude and less predictable.

Another wrinkle is that plant scientists have discovered what have been termed natural GMOs, which further confounds the terminology.These include whiteflies harboring plant genes that protect them from pesticides, horizontal gene transfer between different species of grasses, sweet potato harboring sequences from the bacterium Agrobacterium, and aphids which express a red fungal pigment to protect them from would-be predators.This is more evidence that the term GMO itself has become meaningless.

This brings us back to the regulatory conundrum surrounding the way forward with the various products of genetic engineering using different technologies. Eager to avoid the delays, impasses and rejections and inflated opportunity costs that have confounded GMOs, many in the scientific and commercial communities are willing to play down the novelty of genome editing, while, in effect, conceding that recombinant DNA constructions should continue to be stringently regulated.

However, as we have discussed, the comparison of genome editing and recombinant DNA is a distinction without a difference, especially when viewed against the backdrop of the crude constructions of (largely unregulated) traditional plant breeding.Trying to draw meaningful distinctions between molecular genetic engineering and other techniques for the purpose of regulation is rather like debating how many angels can dance on the head of a pin.Its way past time that for purposes of regulatory policy, we began to think in terms of the risk posed by organisms and their products, rather than which technology(ies) was employed.

Kathleen Hefferon, Ph.D., teaches microbiology at Cornell University. Find Kathleen on Twitter@KHefferon

Henry Miller, a physician and molecular biologist, is a senior fellow at the Pacific Research Institute. He was a Research Associate at the NIH and the founding director of the U.S. FDAs Office of Biotechnology. Find Henry on Twitter@henryimiller

Go here to see the original:
Is there a difference between a gene-edited organism and a 'GMO'? The question has important implications for regulation - Genetic Literacy Project