StemCell Therapy

A recent market study on the global CRISPR And CRISPR-Associated (Cas) Genes market reveals that the global CRISPR And CRISPR-Associated (Cas) Genes market is expected to reach a value of ~US$ XX by the end of 2029 growing at a CAGR of ~XX% during the forecast period (2019-2029).

The CRISPR And CRISPR-Associated (Cas) Genes market study includes a thorough analysis of the overall competitive landscape and the company profiles of leading market players involved in the global CRISPR And CRISPR-Associated (Cas) Genes market. Further, the presented study offers accurate insights pertaining to the different segments of the global CRISPR And CRISPR-Associated (Cas) Genes market such as the market share, value, revenue, and how each segment is expected to fair post the COVID-19 pandemic.

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The following doubts are addressed in the market report:

Key Highlights of the CRISPR And CRISPR-Associated (Cas) Genes Market Report

The presented report segregates the CRISPR And CRISPR-Associated (Cas) Genes market into different segments to ensure the readers gain a complete understanding of the different aspects of the CRISPR And CRISPR-Associated (Cas) Genes market.

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Segmentation of the CRISPR And CRISPR-Associated (Cas) Genes market

Competitive Outlook

This section of the report throws light on the recent mergers, collaborations, partnerships, and research and development activities within the CRISPR And CRISPR-Associated (Cas) Genes market on a global scale. Further, a detailed assessment of the pricing, marketing, and product development strategies adopted by leading market players is included in the CRISPR And CRISPR-Associated (Cas) Genes market report.

Sales and Pricing AnalysesReaders are provided with deeper sales analysis and pricing analysis for the global CRISPR And CRISPR-Associated (Cas) Genes market. As part of sales analysis, the report offers accurate statistics and figures for sales and revenue by region, by each type segment for the period 2015-2026.In the pricing analysis section of the report, readers are provided with validated statistics and figures for the price by players and price by region for the period 2015-2020 and price by each type segment for the period 2015-2020.Regional and Country-level AnalysisThe report offers an exhaustive geographical analysis of the global CRISPR And CRISPR-Associated (Cas) Genes market, covering important regions, viz, North America, Europe, China and Japan. It also covers key countries (regions), viz, U.S., Canada, Germany, France, U.K., Italy, Russia, China, Japan, South Korea, India, Australia, Taiwan, Indonesia, Thailand, Malaysia, Philippines, Vietnam, Mexico, Brazil, Turkey, Saudi Arabia, UAE, etc.The report includes country-wise and region-wise market size for the period 2015-2026. It also includes market size and forecast by each application segment in terms of sales for the period 2015-2026.Competition AnalysisIn the competitive analysis section of the report, leading as well as prominent players of the global CRISPR And CRISPR-Associated (Cas) Genes market are broadly studied on the basis of key factors. The report offers comprehensive analysis and accurate statistics on sales by the player for the period 2015-2020. It also offers detailed analysis supported by reliable statistics on price and revenue (global level) by player for the period 2015-2020.On the whole, the report proves to be an effective tool that players can use to gain a competitive edge over their competitors and ensure lasting success in the global CRISPR And CRISPR-Associated (Cas) Genes market. All of the findings, data, and information provided in the report are validated and revalidated with the help of trustworthy sources. The analysts who have authored the report took a unique and industry-best research and analysis approach for an in-depth study of the global CRISPR And CRISPR-Associated (Cas) Genes market.The following manufacturers are covered in this report:Caribou BiosciencesAddgeneCRISPR THERAPEUTICSMerck KGaAMirus Bio LLCEditas MedicineTakara Bio USAThermo Fisher ScientificHorizon Discovery GroupIntellia TherapeuticsGE Healthcare DharmaconCRISPR And CRISPR-Associated (Cas) Genes Breakdown Data by TypeGenome EditingGenetic engineeringgRNA Database/Gene LibrarCRISPR PlasmidHuman Stem CellsGenetically Modified Organisms/CropsCell Line EngineeringCRISPR And CRISPR-Associated (Cas) Genes Breakdown Data by ApplicationBiotechnology CompaniesPharmaceutical CompaniesAcademic InstitutesResearch and Development Institutes

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COVID-19: Responding to the business impacts of CRISPR And CRISPR-Associated (Cas) Genes Market 2019 Trends, Size, Segments, Emerging Technologies and...

FRIDAY, May 29, 2020 (HealthDay News) -- Marijuana has long been linked to a host of mental health risks, but the potent strains sold today may amplify those dangers, new research suggests.

"We know that people who use cannabis are more likely to report mental health problems than those who don't use cannabis, but we don't fully understand how recent increases in the strength and potency of cannabis affects this," explained study author Lindsey Hines, a senior research associate from the University of Bristol Medical School in England.

For the study, researchers examined data from a large, ongoing British study and focused on more than 1,000 people who were born in the early 1990s and reported recent pot use when they were 24. The scientists were also able to track which participants had suffered mental health problems as adolescents.

Among those who said they had used pot in the previous year, 13% said they had used high-potency cannabis.

Those who used high-potency pot were four times more likely to have problems with marijuana and two times more likely to suffer from anxiety than those who consumed lower-potency weed, the researchers found.

"People who use cannabis are more likely to report mental health problems than those who don't use cannabis, but reducing the potency and regularity of their cannabis use may be effective for lessening likelihood of harms from use," Hines said in a university news release.

"In countries where cannabis is sold legally, limiting the availability of high-potency cannabis may reduce the number of individuals who develop cannabis use disorders, prevent cannabis use escalating to a regular behavior, and reduce impacts on mental health," she added.

The report was published online May 28 in the journal JAMA Psychiatry.

This is not the first time marijuana has been tied to mental health problems: Research published in April in the journal Advances in Preventative Medicine found nearly half of people who have been or are now dependent on pot have some form of mental illness or dependence on another drug. That compares with 8% of people with no history of pot dependence.

Study author Esme Fuller-Thomson told HealthDay at the time that the study doesn't answer which came first, nor does it prove heavy pot use causes mental problems, but it does show a strong link.

"Not everyone that uses pot is going to develop mental health problems," said Fuller-Thomson, director of the Institute for Life Course and Aging at the University of Toronto.

Fuller-Thomson said she was concerned that legalization of pot will worsen mental health problems, especially among teens and young adults. Most users start as teens, and marijuana can harm the developing brain.

"My kids have to walk by three shops selling marijuana on their way to high school," she said. "We're now doing this very dangerous experiment on adolescents and young adults."

One psychiatrist agreed the trend is troubling.

As legalization of recreational marijuana spreads across the United States, more people are showing up in ERs with psychotic symptoms after consuming too much pot, said Dr. Itai Danovitch, chairman of psychiatry and behavioral neurosciences at Cedars-Sinai in Los Angeles.

"If somebody gets too high, they use more than intended, they can have psychotic symptoms. That typically resolves as the drug wears off," Danovitch said.

But some unlucky souls with a family history of mental illness might wind up with a full-fledged psychotic disorder that requires extended treatment, he noted.

"That risk is concentrated among a minority of people who have an existing vulnerability to develop a psychotic disorder, a family history of psychosis," Danovitch explained. "There are environmental factors that influence whether somebody develops schizophrenia who has a risk. It appears cannabis probably is one of those factors."

More information

For more on cannabis, head to the U.S. National Center for Complementary and Integrative Medicine.

SOURCES: University of Bristol, news release, May 28, 2020; Advances in Preventative Medicine, April 15, 2020

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High-Potency Pot Tied to Big Rise in Psychiatric Issues - HealthDay News

You know her when you see her. What many may not know is that a common figure in the Langdon community was nominated by Langdon Post #98 to be the North Dakota American Legion Legionnaire of the Year. Anna Spivey was announced as the 2019 recipient of the Legionnaire of the Year Award in the March issue of the ND American Legion News publication.

I knew they had nominated me, but I was surprised I had won. I feel that people must appreciate what I do, but I just try to do for the Legion and the community what I can with no expectation of reward, Spivey said.

Anna has 23 continuous years of membership with Post #98 following a long involvement in military life as both an active duty member and spouse of an active member. She hasnt been as active as she has been in the past with involvement in the county museum, Frost Fire, and, of course, veteran-related activities such as American Legion and veteran services.

I do these things, and Im always trying to promote and make people aware of what is available in the community. The Legion has all these youth programs. I try to make sure that information is put out. I just try to benefit the community, Spivey shared.

Anna was raised in the Wales area and graduated from Langdon High School. Upon graduation, she entered the US Army and attended basic training at Ft. McClennan, Ala.. Upon completion she was trained in the medical field at Ft. Sam Houston, Texas, then on to Ft. Benning, Ga., where she worked as a health nurse and in preventative medicine.

My duty assignment was army health nurse. We taught prenatal classes for parents and did all the immunizations for military dependents of our service members. The army health nurse would do basically what a public health nurse does, Spivey explained.

During her time in the military, she met Linwood Spivey, a career soldier who was also in the medical field as a combat medic. They were married and became proud parents of two sons. Linwood served two tours in Vietnam, one in Korea and was stationed in Germany twice. Over the course of her husbands career, Spivey was active and involved in their military lifestyle wherever they were stationed.

I have always tried to be helpful to people. On the last tour to Germany, I was part of like the advisory board for our commissary which would be like our grocery store. I was asked to be on that board. I was active with the Red Cross, teaching first aide classes and CPR classes, Spivey said.

Post #98 Commander Harvey Metzger shared that the decision to nominate Spivey for the Legionnaire of the Year was easy. Her commitment to service, not only to the Legion but to the community, is shown when, on her own initiative, she promotes the activities of the American Legion. Spivey does this not only for the local Post events but those of the Department and National as well. Anna is a member of the Posts Color Guard and Honor Guard. She is always a volunteer in helping with Legion baseball, selling anniversary coins, and placing 'Helmets for Heroes' throughout the county. She is active in getting the word out for Boys and Girls State and the oratorical contest. She supports any of Post 98 activities and fundraisers, often providing suggestions for events that she feels strongly about holding.

You can always count on her at the local Post #98 to help out whenever needed. I believe women can make a difference in the American Legion. We appreciate her and her service, Metzger said.

Spivey would have been recognized during the American Legions Department Convention usually held in late June, but due the current health crisis, the convention has been canceled. Recognition for her achievement has left the humble Spivey at a loss for words and surprised as she always tried to operate under the radar.

I try to stay in the background. I just try to make sure the information is put out in the community - what is available to people. I also try to help as I can. Of course, now Im reaching an age where its more difficult, Spivey said.

Spivey tries to promote the Legion and other service organizations as much as she can. She wants to take the opportunity to encourage younger generations to participate and begin helping to serve their community. Spivey is ready to mentor anyone who is interested to learn how to become the next Legionnaire of the Year.

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Anna Spivey named ND American Legionnaire of the Year - Cavalier County Extra

Mike Ellis, Anderson Independent Mail Published 7:43 a.m. ET May 28, 2020 | Updated 7:46 a.m. ET May 28, 2020

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This story is part of a series begun by USA TODAY capturing what America looks like as state economies slowly reopen. The Rebuilding America project examines what consumers can expect in key drivers of SC commerce.

Healthcare in Anderson County is likely to see fundamental changes in the wake of coronavirus.

Much of the fallout is not yet clear, but it will certainly accelerate telehealth, which isessentially meeting with doctors over video calls instead of in person, and will also accelerate changes in how billing works, said twoexperts from AnMed Health, Anderson County's main health care provider.

An independent physician, Dr. Shane Purcell, agreed those are the major two changes that can be predicted from the coronavirus pandemic at this time.

Purcell said that he would add a third change. His practice has been stable with no layoffsthroughout the coronavirus pandemic as other health systems, including AnMed Health, have had layoffs. Thatcould drive more health care providers and patients into practices like his.

Purcell is one of several doctors atDirect Access MD, an Anderson area family practice that operates outside of traditional insurance and government healthcare models and uses a membership model.

AnMed Health staff and bystanders take photos and video of F-16 planes from The South Carolina Air National Guard 169th Fighter Wing flying over the hospital in Anderson, S.C. Monday, April 27, 2020.(Photo: Ken Ruinard / staff)

Recent: AnMed Health to furlough employees, reduce salary of leadership because of coronavirus

Telehealth may be the most visible change to patients as medical offices go further and faster on long-existing trends in response to coronavirus concerns, said Michael Seemuller, a physician in family practice at Wren Medicine and chair of AnMed Health'sQuality and Safety Committee.

There are a lot of medical appointments that had been done in the past in person that can be done over a video chat, and it will likely become more widely used as people work to avoid potential infections and get comfortable with the format, he said.

The challenge with telehealth is that there is a lot that can be done remotely, such as routine visits, but there will always be people who need to see a doctor physically, for certain tests or checkups, Seemuller said.

Perhaps the biggest challenge, however, is access to telehealth, saidJuana Slade, chief diversity officer for AnMed Health.

She said she recently did a routine medical visit online, it took her 20 minutes.

But that is 20 minutes for someone who is familiar with computers, has the time and space to take 20 minutes and has Internet access that can often require money and locations that not everyone has, she said.

Fixing access in telehealth leads into the other major change, Sladesaid.

Virtual appointments: Coronavirus pandemic drives exponential growth of telehealth in the Upstate

The billing changes may not be as visible as telehealth to most people but may be more meaningful, the experts said.

AnMed Health, and other health systems,had already been working on value-based health care, which shiftsbilling from a per-procedure to an outcome-based billing process, Slade said.

The change will be driven by contractual incentives both from outside vendors and providers and from AnMed Health employees, she said.

Employees look at two wood pallets left on a wall on South Fant Street at AnMed Health, painted with words of encouragement and thanks in Anderson Thursday.(Photo: Ken Ruinard / staff)

If a hospital had been doing 100 of a given procedure with 85 good outcomes, it would have been paid more than if it did 90 of the same procedure with 85good outcomes. The new system aims to give contractual incentives on the outcome, rather than procedure side, and could result in fewer procedures being done because fewer are necessary, Slade said.

Doing fewer procedures would mean less income, illustrated by the furloughs at AnMed Health and in the broader health care economy. But changing the measurable to outcomes could lead to better health overall by nipping problems early, when they are cheaper, which also is better for people, Sladesaid. It also could help improve bottom-line revenue by reducing costs.

The change in emphasis to value-based billingcould help communities by focusing on underlying problems, shesaid.

Instead of treating heart attacks at the emergency room, typically the most expensive way to get health care, it would give AnMed Health incentives to treat a particular few blocks, for example, with preventative medicine like regular doctor's appointments that can be done virtually, Sladesaid.

The change won't be easy, and there are a lot of hurdles.

Slade estimates that 10 percent of health outcomes are up to the work of doctors and medical staff, the rest is the patient's responsibility, and a lot of the patient's outcome will be closely tied to factors like availability of healthy foods and good jobs, of education access and opportunities for health activities.

That means AnMed Health will be working a lot more with police and business communities to get those outcomes, Sladesaid.

Sarah Crowder of St. John's United Methodist Church decorate a cross with a white ribbon for health care workers to go with blue ribbons, before Maundy Thursday in the fellowship hall in Anderson Monday.(Photo: Ken Ruinard / staff)

And because much of this will tie back to regular, and increasingly virtual, doctor's visits, Internet access will be a big factor in any success.

The fallout from coronavirus has so far included furloughs for health care workers and others, it will likely have many other consequences for people's health and the financial structure of health care models in the country.

Many of those are unknown or subject to change, but an increase in telehealth and changes to billing structures are two fairly reliable predictions about the future of health care in Anderson County.

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Major changes coming to Anderson health care in wake of virus - Independent Mail

Updated at 10:15 p.m. May 27 with Mayor Lyda Krewson's announcement that Dr. Fred Echols will be acting health director

Members of the St. Louis Board of Alderman are questioning Dr. Fred Echols qualifications to be the city's health director.

After learning that Echols no longer has a license to practice medicine, the boards Rules Committee scheduled a meeting this week to investigate his credentials.

As a result, Echols has had to defend his expertise, and city officials and medical professionals have defended his record. But late Wednesday, Mayor Lyda Krewson announced that she and Echols agree that it's in the city's best interests to amend his appointment to acting director.

Under the city charter, the health director must have one of the following qualifications: be a licensed physician, have a master's in public health, or be certified by the American Board of Preventative Medicine and Public Health.

Echols graduated from the Boston University School of Medicine and served as a Navy doctor. He completed a public health training program at the Centers for Disease Control and Prevention and worked at the Illinois Department of Public Health and the St. Louis County Department of Public Health as an infectious disease specialist.

While Echols held a license to practice medicine in the Navy, he let it lapse after he completed his military service and started working in public and community health.

Krewson hired Echols as the citys health director early last year. Echols lack of a license surfaced earlier this spring when he testified in a lawsuit Arch City Defenders filed against the city that sought to block city officials from removing a homeless tent encampment downtown.

Echols and city attorney Julian Bush submitted a correction to Echols testimony in which he originally stated he was licensed to practice medicine. He had misheard the question and worked to correct the record as soon as he could, Echols said.

Alderwoman Sharon Tyus, D-1st Ward, called a joint meeting of the Health and Human Services and Rules committees on Wednesday to investigate Echols qualifications.

One of things thats important about civil service is that we vet people and make sure they meet the qualifications and make sure theyre not being unfairly advantaged or disadvantaged, said Tyus, who chairs the Rules Committee.

Tyus has been critical of the Health Departments response to the coronavirus pandemic, saying she is disappointed by a lack of testing in areas of north St. Louis where many have become ill from the virus.

When Alderwoman Megan Green, D-15th Ward, asked Bush if Echols meets the requirements outlined in the city charter, Bush said regretfully that Echols did not.

I think hes done a splendid job as director of health and hospitals; I think he almost satisfies those requirements, but hes not quite there. And I say that with great regret, Bush said.

Echols told members of the committees Wednesday that he has the educational qualifications to serve as director. He also defended his record, saying the department has worked tirelessly to promote better health for the citys poorest residents and black people in particular.

As long as Im in this role, my heart is in this community, he said. My integrity is really important to me as I move forward. Whether Im in the city or somewhere else, I always want to be truthful and forthcoming with information, particularly as it relates to me and my role and the impact that may have.

Dr. Will Ross, chairman of the Joint Board of Health and Hospitals, told the committee that the training Echols received at the CDC is equal to a public health degree.

I can say, based on my extensive knowledge of public health training programs, this program is robust enough to qualify anyone to serve in a public health leadership position, Ross said.

Krewson said that Echols experience and training are sterling and that he is fully qualified for the position.

Some seek to discredit this highly qualified physician; it is unclear what their motive is, Krewson wrote in a letter to the Board of Aldermen.

Dr. Echols credentials as an MD with extensive public health training are far superior to the minimum qualifications allowed by the city charter, she wrote.

In announcing the decision to amend Echols' appointment to acting director, Krewson wrote in a Facebook post that Echols has the training and experience necessary for the job.

Krewson wrote that in light of that distraction, and the opinion of Bush, she, Echols and Ross had decided it was best for Echols to serve as acting health director.

The committee is expected to resume the hearing Thursday.

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Members Of The Board Of Aldermen Question St. Louis Health Director's Qualifications - St. Louis Public Radio

For the foreseeable future, the preventative measures installed throughout the healthcare community to prevent the spread of coronavirus spread arent expected to go anywhere.

That, at least, is the prediction by those in local medical and senior care industries for the coming weeks and months as Tuscaloosa begins its slow crawl back to pre-COVID-19 conditions.

"I just think theres a lot of unknowns," said Dr. Phillip K. Bobo, "and the next month to month-and-a-half will be critical."

Bobo, a founding partner of Emergi-Care Clinic who has worked in the fields of emergency and family medicine for more than four decades, said he expects society to slowly return to normal as long as people believe it to be safe.

And that, he said, will take a while as many wait to see whether reopening restaurants and non-essential businesses will lead to a sharp increase of coronavirus cases.

"Theyre going tend to stay away from places that they think there will be a high likelihood of contact restaurants, obviously; all medical: hospitals doctors office, clinics, surgery centers all of those are going to have a slow comeback, I think," Bobo said. "If theres a second surge, then we dont know. If theres not a second surge and we survive it and we get into the fall (and) if theres no surge and people are doing better and were out functioning more and we have events ... I think itll come back more rapidly."

Until then, those needing medical procedures can expect to undergo scrutiny and safety measures. And those wanting to visit will still have to wait.

At DCH Health Systems Northport Medical Center and Regional Medical Center in Tuscaloosa, visitation either has been limited or not allowed at all.

Andy North, the hospital systems vice president of marketing and communications, said a number of preventative measures have been put in place since the coronavirus awareness took hold in early- to mid-March. These include universal masking of staff, physicians and visitors, temperature checks of everyone prior to entry, Plexiglas sneeze guards installed at most points of consumer interaction and, on most days, remote site screening services.

And while the Alabama Department of Public Health allowed elective surgeries to resume on May 1, there are currently no plans to relax these measures and, if necessary, the additional services may be halted.

"As a safeguard, the results of a COVID-19 test will be obtained on each patient prior to proceeding with the surgery," North said. "In addition, the current no visitation policy and processes will remain in place for now.

And in places where people are at risk, professionals are getting creative.

While no positive coronavirus cases have been reported at the Crimson Village assisted living facility off 18th Avenue East, Executive Director Rebecca Dennis said she intends to keep it that way.

"The biggest thing were up against right now is these residents are lacking the socialization," she said.

To provide some level of interactivity, Dennis said Crimson Village officials have taken to providing FaceTime conversations with residents and their relatives or bringing residents to windows to see their families through the safety of glass.

But, for now, there are no plans to allow face-to-face interactions like those that took place before the coronavirus arrived.

And, Dennis said, shes not sure when -- or if life will return to normal for Crimson Village seniors.

"Right now, Im not letting them come any closer than the front door," Dennis said. "And as far as physical contact, I dont think the health department or CDC is going to permit families to come in and do huggings and touchings any time soon.

"I know its going to continue for the next few weeks and probably several months. Whats the old saying? Well just have to play it by ear."

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Healthcare precautions likely to persist for near future - Tuscaloosa News

Friday, May 22, 2020 9:18 a.m. EDT by Thomson Reuters

By Michael Erman and Ankur Banerjee

(Reuters) - The anti-malarial drug hydroxychloroquine, which U.S. President Donald Trump says he has been taking and has urged others to use, was tied to an increased risk of death in hospitalized COVID-19 patients, a large study published on Friday showed.

In the study https://www.thelancet.com/lancet/article/s0140673620311806 that looked at more than 96,000 people hospitalized with COVID-19, the respiratory disease caused by the novel coronavirus, those treated with hydroxychloroquine or the related chloroquine had higher risk of death and heart rhythm problems than patients who were not given the medicines.

The study, published in the Lancet medical journal, showed no benefit for coronavirus patients taking the drugs.

Demand for the decades-old hydroxychloroquine has surged as Trump repeatedly promoted its use against the coronavirus, urging people to try it. "What have you got to lose?" he asked.

Trump said this week he has been taking hydroxychloroquine as a preventative medicine despite a lack of scientific evidence.

The Lancet study authors suggested that hydroxychloroquine and chloroquine should not be used to treat COVID-19 outside of clinical trials until studies confirm their safety and efficacy in such patients.

There is a frantic search for drugs to treat COVID-19 at the same time that multiple research teams pursue a safe and effective vaccine to combat a pathogen that has killed more than 335,000 people worldwide and sickened millions more.

The U.S. Food and Drug Administration has allowed healthcare providers to use the drugs for COVID-19 through an emergency-use authorization, but has not approved them to treat it.

Dr. Mandeep Mehra, one of the study's authors, said the research shows that the FDA should withdraw that authorization.

"That will help move this towards more, stronger evidence because it will then force the use of these drugs only in the setting of control trials," Mehra said in an interview. "That would be an extremely wise decision."

The FDA has said that, for safety reasons, hydroxychloroquine should be used only for hospitalized COVID-19 patients or those in clinical trials. The drug has been tied to dangerous heart rhythm problems.

The Lancet study looked at data from 671 hospitals where 14,888 patients were given either hydroxychloroquine or chloroquine, with or without an antibiotic, and 81,144 patients were not given such treatments.

Both drugs have shown evidence of effectiveness against the coronavirus in a laboratory setting, but studies in patients had proven inconclusive. Several small studies in Europe and China spurred interest in using hydroxychloroquine against COVID-19, but were criticized for lacking scientific rigor.

Several more recent studies have not shown the drug to be an effective COVID-19 treatment. Last week, two studies published in the medical journal BMJ showed that patients given hydroxychloroquine did not improve significantly over those who were not.

Hydroxychloroquine is used to treat lupus and rheumatoid arthritis as well as malaria.

Hospitalized patients tend to have a more severe version of COVID-19. Some proponents of the drugs for COVID-19 argue that they may need to be administered at an earlier stage to be effective.

There are ongoing randomized, controlled clinical trials to study the drug's effectiveness in preventing infection by the coronavirus as well as treating mild to moderate COVID-19. Some of those may yield results within weeks.

(Reporting by Ankur Banerjee and Manas Mishra in Bengaluru and Michael Erman in New York; Editing by Saumyadeb Chakrabarty, Bill Berkrot, Jonathan Oatis and Will Dunham)

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Drug touted by Trump to treat COVID-19 linked to higher death risk: study - WHTC News

BACAVI, Ariz.

Standing in his cornfield, Ahkima Honyumptewa said everything about the traditional Hopi lifestyle is meant to strengthen the body, mind and spirit.

Ive always had a connection to this land and a culture to lean on, said the 39-year-old Honyumptewa, who is of the Snake Clan. He suggests the best thing to do during this time of pandemic is to stay engaged in productive activities.

Thats how you can get out of all this craziness mentally, he said. What Im doing to get through is a lot of arts and crafts and farming. Directing energy toward anything constructive, including learning new skills, is a perfect way to make use of this time, and grow as a person, says Honyumptewa. If you keep busy and focused on something productive, youre mind is developing, he said.

As a Hopi farmer, Honyumptewa stresses the importance of going back to some of the basic traditional staples and modeling that for the young people. An award-winning artist, his schedule is that of discipline and structure, including getting up early every morning to work on his craft.

His artwork depicts the seasonal Katsina dances that occur in Hopi. I show the people what we see, he said. I portray it in paintings.

Honyumptewa says he enjoys sharing his culture through his work, which draws a lot of positive feedback, especially from young people. They are just in awe, he said. They take it to heart.

He also makes Hopi textiles and has won numerous awards, including Best of Show for weaving at the 2019 Museum of Northern Arizona Hopi show for a traditional manta, a shawl used for protection.

A dedicated runner, Honyumptewa puts in his miles across the mesas every week in the midday sun.

Be careful in life, but dont be afraid to live life, advises Honyumptewa. Be humble and truthful and we will get through this.

We catch sicknesses because our bodies are out balance, whether its a virus or a cold, said Honyumptewa. All of that is caused by an imbalance.

He said people who behave in a negative way or are mean to other people make themselves more vulnerable, because the energy builds and builds until explodes.

You start getting health problems and youre more vulnerable to sickness when your attitude and your whole being is devoted to to negativity, he said. Not only does it affect the person, he says, but everybody around them. Thats not how were supposed be acting, he said. Were supposed to be the other way. Were supposed to be honest, respectful, and kind.

Honyumptewa believes that people can best help others by first helping themselves through self-knowledge and healing. The number one way to fight any sickness or disease is through happiness, not only loving yourself but loving others, he said. The more you feel that positive energy, the more you protect yourself from harm.

Exercising, eating healthy, and studying new things are key to that, he said. He recommends learning about history, other cultures, sages, and practices such as martial arts and yoga. Study the truth to better the mind, he said.

Honyumptewa believes the best way to serve is through virtue. When you help people you start to gain trust and build connections, he said. As you generate more and more positive energy, you have enough to give it away, he said.

The more positive things you do, the more people want to be around you, said Honyumptewa. Even the animals want to be around you. This relates to the laws of karma, he says, which keep everything in balance. Treat people the way you want to be treated, he said. We all want to be treated with respect.

That also applies to leadership, he said, which keeps a people balanced. Without that, a nation is in chaos, he said. Theres corruption, mistrust, bribery. He believes that is the case with the United States government today. There are all kinds of side deals that the government does that we dont even know about as people, he said. Thats why I dont like this way of life because its like one big crime syndicate. This government robs and steals from the people our energies, our spirits, our selves.

Thats why the world is falling apart, he says, because we are all distracted. The real anti-Christ is someone pretending to be God, said Honyumptewa. Theyre covering it all up behind closed doors.

He says real, true people dont go around claiming they can do things, they just do it out of the goodness of their heart. Most importantly, we never ask anything in return, he said. Everything is supposed to be given freely. He says that is how you know the real medicine men. They dont go out advertising, he said.

Honyumptewa believes people should learn to depend on their own goodness and energy. The only way it works is through good, through compassion, and unconditional love, he said.

As a steward for the land, Honyumptewa feels a strong responsibility to take care of it. We were put here for a reason, he said. This is the center for all spiritual development. He said that was the whole purpose of Hopi migration, which led to Oraibi, from where he descends. The whole Southwest is the spiritual center and what we do here magnifies by ten, he said. If were not strong enough mentally, physically and spiritually, we can hurt ourselves if were unaware of that power that is here.

He says the power can be used for bad or good. For example, if you exercise and train on this land, you can develop ten times faster than anywhere else, he says. Thats why this land is so important, said Honyumtewa. Its a sacred, sacred spot.

Even the Bible talks about the area, he says. Everyone around the world knows this spot as the Garden of Eden, said Honyumptewa. Thats what the Hopi Mesas are, the actual spot of creation.

In the old days, there were springs flowing out of the mesas and water was abundant, he said. He believes all of North and South America belongs to the Natives. That was our responsibility as Native cultures of this land, to migrate and send spiritual roots into the ground, said Honyumptewa. That way the land knows who we are; it feels us.

Long ago, everyone knew that all things were connected, he said. Everything was intertwined, the planting, the ceremonies, the races, everyday life, he said. Thats why we were told not to go away from our culture because of our connection with the earth.

Honyumptewa says today it is a minority who are living by the old ways that served as a natural form of preventative medicine. His advice is to work toward giving up cravings and bad habits, born of this modern world.

It takes patience and time, he said. You just cant give up on yourself. Honyumptewa urges people not be afraid of death, which is a natural part of life, he said.

Life and death is a continuous cycle that repeats itself over and over again, he said. We evolve from stage to stage. Humanity is our teacher, said Honyumptewa. Its a teaching tool spiritually, he said. It teaches us how to connect universally.

He says politics and technology should be avoided, as they are meaningless to spiritual development and are a waste of time. We want to learn things now that will develop our spirit lifetimes from now, he said. The only way to progress through the cycle of life and death is enlightenment.

Related

More here:
Surviving the coronavirus crisis: A Hopi perspective - Navajo Times

Photo: Contributed

Is the wealth of information about your individual health risks worth the anxiety of knowing?

DNA testing kits have made it possible to access previously unmined information about your health. As a huge advocate of preventative medicine, Ive explored the pros and cons of accessing this wealth of information to see whether your spit is worth the price tag and the consequences.

Firstly, what is it? Companies like 23andMe offer a home-based saliva collection kit you spit in the tube and send it to the lab. From there, your DNA is extracted from the spit and a process called genotyping analyses the DNA.

You then receive a report with your health predispositions (diseases you are more likely to get due to your genes) and your carrier status of certain diseases, such as cystic fibrosis.

The most obvious benefit of getting your DNA tested is identifying your personal health predispositions. For instance, the report might indicate youre at risk of getting type 2 diabetes, or heart disease. With this information, you can make changes to your lifestyle to help prevent these diseases from occurring, such as quitting smoking, drinking less caffeine or eating less sugar.

Despite these benefits, it is important to consider the emotional stress of receiving unfortunate results. Finding out you are at high risk of Alzheimers has a huge emotional impact on an individual and their family, especially as there is little you can do to prevent it.

Personally, I wouldnt want to know Im at high risk for a disease I cant do anything about I think the anxiety the knowledge would cause wouldnt be worth the information.

Its also important to note that genealogy results arent definitive. For instance, they may identify the gene that can cause high cholesterol, which in turn can increase the risk of heart disease. However, the test doesnt take into account any other personal or environmental factors, such as your diet, exercise and lifestyle. Without input from your own family doctor or a genetic counsellor, the results cannot be taken as gospel.

The uses of genealogy DNA databases extend beyond personal use for health and ancestry information, and this is the part where I begin to question the safety of using these kits. Although companies have rigorous privacy policies, they do still keep your DNA and information in a database in order to identify future clients that may be within your family tree.

This data is vulnerable to hackers, but also to police and immigration officials. The CBSA uses genealogy DNA testing in an immigration setting to ascertain a persons identity, such as the country they originate from.

From the uses we know about, to those yet to be found Im not sure I want my DNA in a database with unknown potential.

There are also important financial implications that accompany genetic testing, such as the fact that some insurance companies now say you must disclose any genetic risk information you are aware of, which can mean higher premiums for health, life and travel insurance.

Having mused over the idea for several weeks, with my mouse hovering over the Add to Cart button more than once, Ive decided genetic testing is not for me, for now. I personally dont think you should need a genetic test to tell you to live a healthier lifestyle to exercise more, eat more greens and get better sleep.

If its something youre thinking about, or have done, I would love to hear your thoughts on it. If not, take it from me get out for a cycle or a run, spend more time with your family and eat some broccoli with a smile on your face.

See more here:
The benefits and the costs of home DNA tests - Health and Happiness - Castanet.net

Mike Haynes is a professor of economics at the University of Wolverhampton in the United Kingdom. His article, Capitalism, class, health and medicine, was published in 2009 by International Socialism and is republished with permission.

I ask myself how, as a physician, I find myself up to my ears with the problems of society, writes Michael Marmot. It is a question that committed doctors have been asking for several generations as they try to explain and cope with the way that illness is moulded by society. Evidence for the social gradient is astonishingly widespread. It affects us all. It is not just about the contrast between the rich and poor but is so fine grained that if we graph illness against some indicator of relative position we see that as relative position improves so does health. Wilkinson calculated that 50 to 75% of the differences in average life expectancy in rich countries are now determined by differences bound up in the distribution of income and related factors. Table 3 shows how this is reflected in the pattern of key illnesses in the UK.

Why should this be? Material need cannot be ignored. Income poverty is not the basis for a good life, and societies with the greatest levels of inequality will also have the largest numbers of poor people. But it is relative poverty and position that matter most. So what is going on? The biomedical answer seems to be that vulnerability and susceptibility to illness and death are related to the degree of adversity in our lives. Some exercise is good for you but relentless physical demands in circumstances over which you have no control drain the body. Similarly, some stress is good for you but relentless worrying about job, home, family, etc not only drains you emotionally but feeds back into physical and mental ill health:

The relationship among the nervous system, the endocrine system, and the immune system is emerging as the pathway that can help our understanding of the changes in health which are associated with changing social and economic conditions.

In other words, although illness arises from bodily processes it is really a product of social organisation. And this is crucial because health follows the social gradient it is not just about improving the conditions of the poorest. In health terms it is in our collective and individual interest to tackle the problem more systematically. As Marmot puts it:

Much of the discussion about social inequities in health has focused on the health disadvantage of the lower class. This is analogous to seeing social problems as particular to a disadvantaged minority, rather than a problem for society as a whole.

Table 3: The UK disease pattern by social group 1991-3, standardised rates per 100,000 for men aged 20-64.

Source: Acheson, 1997.

Marmots argument here is partly a reformulation of RH Tawneys famous comment that what thoughtful rich people call the problem of poverty, thoughtful poor people call with equal justice the problem of riches but it is more. The steeper the social gradient, not only the bigger the health gap between those at the top and those at the bottom, but also the lower the average position of all. The countries with the longest life expectancy are not the wealthiest but those with the smallest spread of income and the smallest proportion of the population in relative poverty. There is therefore a problem with thinking that because I am near the top in UK terms (and the level of inequality in the UK is one of the highest) I will live longer than someone at the bottom or in the middle. This is true. But it is also true that you would live longer still if society were more equal. It was realised in the 1990s that the mortality rate for the lowest social class in Sweden [with less inequality] is less than that for the top social class in the United Kingdom.

The narrow biomedical mechanism that produces this has three elements. The first is the psycho-social impact of pressure on bodily processes. This is socially determined. The second is our health behaviour and how we respond in terms of what we eat, whether we smoke and drink, take exercise, etc. This too is socially determined. The third is how supportive our family, friends and social networks are. This is also socially determined. Only then does the fourth issue, healthcare, become a central issue and, when it does, it too is socially determined.

If we look at our lifestyles as a whole, their patterns reflect either the accumulation of advantage or disadvantage. The story starts in the womb with fetal development, it is manifest in the early years, at primary and secondary school. It is then compounded by what type of job we get and how precarious our employment is, and so on. But why can this not be explained by people at the top choosing wisely and those at the bottom choosing badly?

The really interesting aspect of the social approach to health is how careful the analysis is of what conditions our behaviour. The cleverness of the Whitehall Studies of UK civil servants is a good example. The researchers took a large group in which the members appeared to be similar and apparently had some more positive elements in their work conditions. They then designed a study of how work, position, life, social situation, etc interacted and combined. This analysis allowed them to nail the myth that top managers are prone to more heart attacks because of pressure. They are not and we now know why. With responsibility comes status, power, control, means to relieve stress (membership of the gym, a night at the opera, a holiday villa) often arranged by your secretary and so on. As you move lower down, peoples lives become more bound up with lower status, less control and the need to battle and juggle a host of other commitments. It is the harassed worker on the shopfloor or in the office who is more at risk of a heart attack and, beneath them, the cleaner doing two jobs on the minimum wage. This also explains negative health behaviours and why these should give rise to different incidences of disease when the same immediate causal factors, eg smoking, appear to be present.

But some readers may be puzzling about a theoretical problem in the link between social class and the health gradient. Those who insist that we live in a class society have to defend themselves not only against those who deny the reality of class but also those who want to define it simply in terms of hierarchy. It is here that we run up against the fundamental weakness of the argument about social gradients in health. It is clear that they exist, but what causes them? What is the cause of the cause? To solve this problem we have to look behind the gradients and explore what determines the different incomes, jobs and degree of control that people have over their lives. This means that the central thing has to be class analysis and showing how any gradient is structured by ownership and control and not least, in capitalism, by ownership and control of the means of production.

Here several related concepts are absolutely central alienation, exploitation, class and class conflict. Inequalities are a consequence of how these interact and it is from this that social gradients and gradients of ill health flow. Marmot makes occasional gestures towards this but they are weak and inconsistent. The same is true of Wilkinson even though he has a more systematic grasp of the social side. To insist on the importance of this is not just about adding an additional layer of possibly superfluous explanation. It makes the argument stronger in terms of its logic and explanatory power, and it gives it a clearer political thrust because it also forces us to consistently address the political economy of both health causation and the limits of reform within the system.

Alienation, for example, is fundamental to explaining both our loss of control of social processes and the way that they are turned against us, and our resulting inability to relate to one another as proper human beings. Exploitation gives us the possibility of understanding how and why the rewards go to the few who make so little contribution to our real wealth. And class and class conflict help us to understand the resulting texture of social relationships and their antagonisms.

We can make these arguments work in a more precise fashion too. As organisations have become more powerful the argument arises about who has effective disposition of capital and labour within them. The key social argument here is that the more your position gives you control over capital and labour, control over yourself, your work, the work and lives of others, the lower the levels of ill health. The more your life is controlled by others the less the level of health. The social gradient is not simply about who has what but the capacity to command people and resources the very issue that is at the centre of class analysis.

But to take this analysis further we need people whose expertise is the analysis of capitalisms social structures to link up with the people whose expertise is in health and illness. One of the most creative ways of making the connection was set out nearly three decades ago by Eric Olin Wright. Wright took on the argument that class was disappearing in modern society because of the alleged explosion of groups in the middle. These groups appeared to stand between capital and labour; they had what he called contradictory class locations. He then devised a way of mapping these contradictions, focusing crucially on how much control of capital and labour they had. It becomes obvious in his analysis that these intermediate groups often have little and are therefore closer to labour than capital. This reflects what many of us understand intuitively: the badge may say manager but we all know that in reality it means some low-grade supervisory responsibilities that do not preclude trade union membership and even militancy.

Using these ideas to map how capitalism really operates and divides us has an obvious attraction for those seeking to more systematically underpin the analysis of health gradients, and some researchers have already looked in this direction. But heres the problem. Almost immediately Wright had set out this argument, he retreated under the pressure of the anti-class theorists. This has meant that it has fallen to others to defend this extension of class analysis as a way to understand capitalism. But it has also acted as a disincentive to use the argument to tighten the theoretical and empirical links between class and health.

But this argument raises other political issues and not least for the medical establishment. Prevention, as everyone knows, is better than cure. The most sophisticated and effective healthcare in the world cannot produce results as good as simply remaining healthy in the first place. But creating healthy societies and individuals largely results from action outside the health sector. Healthcare can never remove the gradients in causation, only deal with some of the consequences.

This type of argument is difficult to make. We are rightly appalled by inadequacies in healthcare but we tend to take for granted the inequalities in health causation. It is awful that when Julie had her heart attack in her 50s she had to wait 30 minutes for an ambulance; then there was the four-hour wait in accident & emergency and the dirty wards on which she eventually died. But the prior question is why she had a heart attack in her 50s and why Jane, who worked as a cleaner in the same office, had one a couple of years later and died before help could get there?

We need to take any argument about the role of medicine in health in two stages. The first is to stress the absolute importance of what is called primary prevention and not to fall into the trap of thinking that we can leave the causes of illness alone and focus on better treatment. Primary prevention saves lives but primary prevention may not involve medical measures in the narrow sense at all. Only three out of the 39 proposals made by the 1997 Acheson Report of the Inquiry into Inequalities in Health related directly to health service provision. If the problem is a choice between a worse treatment and a better one, we should obviously demand the better one. But the issue should not be about whether we can afford treatments but whether we can afford people to be ill. It is often said that medical costs will always rise. This is an absurd argument in itself because it ignores the way in which the drive for profit is behind the cost rises that exist. But even if it were true, reducing the numbers of ill people in the first place would reduce the cost problems. The less people that you have to treat, the more you can afford to spend on making those who have the genuine misfortune (and not the socially determined one) to fall ill. The real problem then is to alter the fundamentals of the generation of illness caused by class society.

Primary prevention is therefore politically challenging. There has always been a minority tendency in the medical establishment that links health improvement to real social reform, and within this group a smaller one still who continue to insist that so long as capitalism and class society exist we will remain trapped in unequal lives and unequal deaths. But many health professionals also see the immediate attraction of the medical fix. And so do we as patients once we get trapped in ill health. Even the members of the team that produced the original Black Report were split on this issue. According to Sir Douglas Black:

We were all agreed that education and preventative measures, specifically directed towards the socially deprived, were necessary. But the sociological members of the group considered that the consequent expenditure should be obtained by diversion from acute services. On the other hand the medical members felt that the acute services played a vital role in the prevention of chronic disability and could not be further cut back without serious effects on emergency care, on the training of doctors for both hospital work and for family practice and on the length of waiting lists. We spent a long time, without real success trying to resolve this matter.

This fudge is not enough. Consider the problem of mental ill health. Its burden continues to rise in the advanced world. There is a big question over whether the medical fix actually works. But suppose the evidence was clearer that it did. It would still not be enough for three reasons. First, it is inconceivable that enough professionals could be trained and employed to treat the many millions of casualties of our psychologically toxic social environment one at a time. Second, if the problem is the toxic environment then once people are returned to it their symptoms are likely to recur. Third, this approach does nothing to stop new cases appearing. But the same logic applies to other areas. Britain, for example, is acknowledged to have one of the poorest records in the advanced world for longer-term survival after major incidents like cancer and heart attacks. You can now guess that there may be two explanations for this. One is medical the weaknesses of early identification, treatment and follow up. The other is inequality. If inequality increases your chances of getting a life threatening disease, then however good the medical fix the pressure will be on again once you return to the environment that helped to cause the illness in the first place.

At this point, however, many take fright. It seems easier to imagine that the way forward is to work on medical solutions to ill health and demand more resources for these. But this takes us to the second issue of whether a health system run for profit can ever rationally answer human need. The answer is an unequivocal no. The first simple rule of healthcare is Tudor Harts inverse care law, which says that the availability of good medical care tends to vary inversely with the need for the population served [and this] operates more completely where medical care is most exposed to market forces. A national health system has to be based on principles of comprehensiveness, universality and equitability. Supply and demand, internal and external markets, subvert these principles and undermine the capacity of rational health planning. They even undermine the very sources of information which would make such planning possible. The result is variation in the coverage of basic services. With this comes a huge loss in real efficiency.

A second simple rule of healthcare then emerges: the more the logic of capitalism determines the supply of healthcare, the higher the costs, the larger the management layer, and the greater the diversion of resources away from treatment and care and into private hands. With this level of irrationality in the system we can then move to a third simple rule of healthcare: the more the logic of capitalism determines the supply of healthcare, the more the healthcare system itself may become a threat to social health.

Here is the original post:
From the Archive | Part two: Class, health and medicine - newframe.com

Heads up, ACT readers: According to a recent survey, your lifestyle is one of the healthiest in the country! In the inaugural AIA Vitality Wellbeing Index report, you score big on physical activity, you're non-smoking and you've ditched those sugary drinks. Take a flexible and well-hydrated bow.

For the rest of us, well it could be time for a friendly wake-up call, because the lifestyle choices we make now will contribute to our wellbeing long-term.

Lifestyle is often the driver of non-communicable diseases (think cardiovascular disease, diabetes, respiratory disease and cancer) which are responsible for 90 per cent of premature deaths in Australia and New Zealand and, according to the World Health Organization, may make you more susceptible to COVID-19.

The good news is that a bit of preventative healthcare can help. "Proactive preventative healthcare means taking small steps now to improve and maintain all aspects of your life," explains preventative health expert Dr Zac Turner.

"By having a lifestyle focus which considers the impact of exercise, diet, smoking and alcohol, it can enable great health outcomes."

While the ACT is ahead of the rest of the country with 18 per cent of the population meeting the physical activity guidelines, the recommended 150 minutes of moderate exercise per week is something we can all aim for.

Trainer and co-founder of Sydney's Flow Athletic, Ben Lucas, agrees. "A moderate intensity is an intensity that makes you work hard enough to burn off three to six times more energy per minute than when you are sitting," he says.

"Take a very brisk walk, ride a bike at a medium effort, do some light toning/strength training that doesn't involve the heaviest weights or some high intensity interval training."

Victoria tops the country on nutrition, the survey revealed, while NSW is all over the recommended daily fruit guidelines, and Tasmania has the most veggie eaters.

But it's not hard for every Australian to get on track. Integrative medicine practitioner Madeline Calfas says the biggest no-no is sugar, which can lead to health issues like diabetes, heart disease and high blood pressure.

"The best way to ensure you truly have a healthy diet is to follow the J.E.R.F. protocol: Just Eat Real Food," she advises. "By minimisingfoods that don't come from a packet, you can not only avoid hidden sugars, but you are also avoiding preservatives and additives that can wreak havoc in our bodies."

Smoking? Stop, or at least start cutting down, says Dr Turner. "If you go from 20 a day to 13, then nine, to six and then three, for example, over a three-month period there will be a significant improvement in your health," he says. "If you stop all together, in five to seven years you will get your lungs back to a pre-smoking state."

As for how much is OK when it comes to your favourite tipple, lifetime alcohol guidelines say we shouldn't consume more than two standard drinks a day.

"Drinking every day, or binge drinking more than four standard drinks on one day, means that you are putting your body at risk of alcohol-related illness such as fatty liver disease, diabetes, heart disease and depression," explains Calfas.

"Also, try to reduce the number of sugary drinks and cocktails you consume it's not just the alcohol that's the issue here."

Got all that? Turns out this preventative health lark is actually quite straightforward.

"Yes," agrees Dr Turner. "It's really all about keeping healthy people healthy."

And that's important no matter where you live.

AIA, with AIA Vitality, is on a mission to get all Australians making the small changes they need to become the healthier version of themselves. Head to aia.com.au/onelife for more healthy-living inspiration.

Original post:
How healthy are you, really? - 9Coach

The coronavirus pandemic may seem to be on a scale the Middle East has not seen before and in many ways, it is.

But the world and the region is no stranger to outbreaks of disease.

In fact, the UAE's first brush with a potential large-scale epidemic may have been in 1947, the year cholera tore through Egypt, Iraq and Syria, and arrived in Dubai, then part of the Trucial States, which was under British rule at the time.

The disease caused panic among the British, who put people into quarantine, grounded flights, sent for huge stocks of vaccines from London and went door-to-door to ensure people were inoculated against infection.

Because of the 1947 scare, the country was well equipped to address the outbreak

Sara Farhan, historian

It was this outbreak that caused some of the first examples of large-scale border closures, travel restrictions, quarantine, contact tracing and flight groundings.

And while the two diseases are very different (cholera is a bacterial infection that is transmitted via excrement in water, and Covid-19 is a respiratory illness transmitted by infected people or surfaces), the method in which outbreaks were dealt with 73 years ago provide a fascinating insight into how our healthcare has both developed, and remained the same.

The National has studied the 228-page report, A Outbreak of Cholera in the Trucial Coast, held by the British Library, and worked with a historian to determine how this could have informed the response to the 2020 pandemic.

"This is a lesson of how early state mitigation can prevent an outbreak," Sara Farhan, assistant professor of history and medicine historian at the American University of Sharjah, says.

"The scare prompted local officials to embark on an inoculation campaign, invest in advancing the health apparatus of their sheikhdoms, and ensure that should an outbreak occur, they would be adequately prepared to address it promptly and swiftly."

In September 1947, Egypt was experiencing a cholera outbreak that had yielded 20,804 cases and 10,277 deaths a staggering 50 per cent mortality rate. The epidemic went on to reach Syria, and neighbouring countries such as Iraq and Palestine. August 1947 was also when India was partitioned; during which, a devastating cholera outbreak killed millions across India and Pakistan.

This was all of great concern to the British, who wielded great influence over Egypt through its proprietorship of the Suez Canal, and were wary of the country's proximity to the Arabian Gulf and its trade routes. They feared that an outbreak in the Trucial States was only a matter of time.

"In the aftermath of the Second World War, British troops were in India, Iraq, Egypt, and the Trucial States to name a few. The connection between these areas facilitated a marvellous exchange of vibrant culture, people and ideas. These interactions also facilitated the communication of diseases," Farhan says.

"Cholera outbreaks emerged in the 19th century and quickly reached pandemic status through increased communication and improved transportation."

Much the same as Covid-19, cholera spread quickly through trade and ports, and caused economic and agricultural devastation.

The first case of cholera arrived in Dubai on November 4, 1947. In a letter, the residency agent of Sharjah informed the political agent in Bahrain of a case of cholera and two suspected deaths from the disease.

Immediately, demands were made to find out the patient's movements for the past 10 days, as well as their contacts. It was then requested that anyone the cholera patients had come into contact with, as well as the patient themselves, be isolated.

So, could this have been a very early form of contact tracing?

Perhaps, says Farhan. But it was also an instant and aggressive measure by the Brits to stymie the disease, as they "anticipated an outbreak similar to that reported in Egypt".

In Dubai, the report of the infected case outlined a servant dying after vomiting and purging. "He looked dried up," it says.

People who had come into contact with the deceased were moved to another house on the outskirts of the city.

"Under the circumstances, Dubai and Sharjah must be considered as infected localities and necessary quarantine restrictions imposed," the report says. "Till the contrary is proved by the non occurrence of further cases for a period of at least three weeks."

The next day, a letter to Bahrain outlined the fact the Trucial States had "limited resources to counter the outbreak" and a request was made for quarantine medical officer, Captain MLA Steele, to be permitted to fly to Sharjah by RAF plane "immediately".

In the following days, 20,000 cases of the cholera vaccine were sent for from Sharjah to London and a request was made that "inoculation is energetically carried out".

Quarantine efforts and border closures across the Arabian Gulf came quickly afterwards.

On November 6, Iraq closed its borders to travellers from India, Pakistan and the Arabian Gulf.

In Kuwait, travellers arriving from Egypt were quarantined for six days.

"The main reason for the isolation of Kuwait and Bahrain from Iraq is fear that travellers may leak through from Egypt without undergoing quarantine," a letter dated November 14, says.

"A case of America Oil Company employees who went to Kuwait from Egypt by air, stayed there, 'passed a day or two' and then flew on to Baghdad where they did not reveal they had recently been in Egypt and stayed at a hotel in quarantine."

Later, as guidelines were updated, the residency agent in Sharjah was instructed to stop all passenger traffic by dhows or steamer heading to Bahrain. Boats from Karachi and Bombay were ordered to have cholera inoculation certificates.

The scare led to the inoculation of a quarter of the populations of Sharjah and Dubai a cost-effective measure to dealing with the alternative a devastating cholera outbreak

Other travellers were warned they may suffer four days' delay "due to steamers being placed in quarantine at the entrance of the [Iraqi] port".

Cholera inoculation certificates were later introduced as mandatory for other countries.

"The policies were indicative that local officials were specifically isolating areas where there was a cholera outbreak Syria, Pakistan, India and Iraq," Farhan says.

And even 1947 wasn't immune from misinformation. As we are experiencing on social media amid the coronavirus outbreak, it isn't always easy to tell fact from fiction.

On November 8, Bahrain's political agent sent a seemingly contradictory report to all agents in the area, saying there was no cholera outbreak in Dubai as there was "bacteriological proof lacking".

"As a precaution Dubai is being treated as cholera infected and preventative measures are being taken," the same report says.

"The only means at our disposal of suppressing the epidemic is preventative inoculation and to try his best to inoculate every resident in Dubai."

Doctors then went door-to-door vaccinating the city's residents.

But to confuse matters further, at the same time, authorities in Dubai and in Bahrain were alerted to a report by the BBC that had "specifically mentioned Dubai as the port at which cholera had broken out". Questions abounded as to where the erroneous information had come from.

A report at the time from Sharjah to Bahrain reads: "The news about cholera was not sent by anyone from the Trucial Coast to BBC. On the 4th of November, the Officer Commanding, Royal Air Force, Sharjah, wired to Royal Air Force Headquarters informing them of the outbreak of cholera in Dubai as reported to him by the Medical Officer and it is very likely that the Royal Air Force or others passed on the information to BBC."

Farhan says this announcement "puzzled local health officials as only three cases were recorded and a handful of suspected cases."

"Nonetheless, local officials quickly adopted the policies of neighbouring countries. Sharjah grounded the Royal Air Force, and limited entry into the country."

Daily case counts were also enforced, much the same as they are today.

This came after a dressing down for the Bahrain resident from his counterpart in Kuwait on November 14 for his tardiness: "A report three days old is useless. I require an up-to-date daily telegraph report until Trucial Coast is officially declared free from infection."

Case counts were then sent each day.

Farhan says "it really forced local authorities to adopt preventive measures".

"The scare led to the inoculation of a quarter of the populations of Sharjah and Dubai a cost-effective measure to dealing with the alternative a devastating cholera outbreak."

Subsequent daily reports from Sharjah to Bahrain outlined zero new cases until November 21, two weeks after the first case.

That was the day Iraq relaxed its quarantine restrictions and resumed some flights, except its Cairo to Baghdad route.

Dhows from Bahrain, Kuwait and the Arabian Gulf were once more allowed to enter Iraq's Shatt Al Arab port after a traveller underwent one stool (faecal) examination. This was also on the understanding crew and passengers had been twice inoculated against cholera.

After another week of zero cases, as promised, Dubai relaxed its quarantine restrictions and Iraq relaxed all border restrictions.

However, people coming from Egypt were still required to undergo a stool examination and quarantine for six days.

In the end, the 1947 cholera outbreak in the Trucial States amounted to 12 suspected and three confirmed cases.

So how was a more sinister outbreak avoided? After all, this occurred a year before the World Health Organisation was formally founded, which put in place a more streamlined way of combatting and tracking infectious diseases.

Shortly after the inauguration of the WHO, all participating countries were required to report disease outbreaks, which were later published in the Weekly Epidemiological Record.

And it wasn't for another year, on January 1, 1949, that streamlined instructions for travellers arriving into the Trucial Coast were laid out.

"The scare in the Trucial States led to the delivery of a surplus of anti-cholera remedies as well as the inoculation of a quarter of the local population. It also led to the expansion of the public health apparatus," Farhan says.

"By 1949, the Trucial States began to take serious measures to advance its health apparatus. Hospitals, clinics, as well as vaccination policies and health protocols were implemented."

And the healthcare system in the region continued to be tested. Also in January 1949, Bahrain experienced a smallpox outbreak, which resulted in another contact tracing and quarantine drive.

So, could the 1947 cholera outbreak have informed our response to 2020's Covid-19 pandemic? It certainly laid the foundations for our healthcare system and large-scale disease outbreak response.

And lessons learnt in 1947 certainly stymied a pandemic situation 23 years later.

Farhan points to August 1970, when another cholera outbreak reached the Trucial States.

"Because of the 1947 scare, the country was well equipped to address the outbreak," she says.

Much has changed in the past 73 years. The UAE's healthcare system has rapidly developed and modernised. But our basic response remains the same. Perhaps, 70 years from now, we will be looking back to the Covid-19 response as the event that shaped our response to the next pandemic. Because there will be another one.

Updated: May 29, 2020 04:19 PM

See the original post:
What quarantine was like in 1947: the fascinating story of the Middle East's cholera outbreak - The National

KENILWORTH, N.J. & WOODCLIFF LAKE, N.J.--(BUSINESS WIRE)--May 28, 2020--

Merck (NYSE: MRK), known as MSD outside the United States and Canada, and Eisai today announced new data from analyses of two trials evaluating KEYTRUDA, Mercks anti-PD-1 therapy, plus LENVIMA, an orally available multiple receptor tyrosine kinase inhibitor discovered by Eisai. In the KEYNOTE-524/Study 116 and KEYNOTE-146/Study 111 trials, the KEYTRUDA plus LENVIMA combination demonstrated clinically meaningful objective response rates (ORR) in patients with unresectable hepatocellular carcinoma (HCC) with no prior systemic therapy and in patients with metastatic clear cell renal cell carcinoma (ccRCC) who progressed following immune checkpoint inhibitor therapy, respectively.

The tumor response rates demonstrated with KEYTRUDA plus LENVIMA in these studies underscore the potential of this combination regimen in certain types of hepatocellular and renal cell carcinoma, said Dr. Jonathan Cheng, Vice President, Oncology Clinical Research, Merck Research Laboratories. KEYTRUDA plus LENVIMA is an important pillar of our broad oncology research program, and we continue to advance the study of the combination across multiple types of cancers and stages of disease.

As data from our combination trials continue to read out, our enthusiasm for and belief in the potential of KEYTRUDA plus LENVIMA are strengthened by the growing body of evidence observed in multiple advanced cancers, said Dr. Takashi Owa, Chief Medicine Creation and Chief Discovery Officer, Oncology Business Group at Eisai. Our ongoing clinical study efforts on this combination exemplify our commitment to following the science and exploring possible solutions for patients affected by difficult-to-treat cancers.

Results from KEYNOTE-524/Study 116 (Abstract #4519) are being presented in a poster discussion session, and results from KEYNOTE-146/Study 111 (Abstract #5008) are being presented in an oral abstract session of the Virtual Scientific Program of the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting.

KEYNOTE-524/Study 116 Trial Design and Data (Abstract #4519)

KEYNOTE-524/Study 116 (ClinicalTrials.gov, NCT03006926 ) is a Phase 1b, open-label, single-arm trial evaluating the KEYTRUDA plus LENVIMA combination in 100 patients with unresectable HCC with no prior systemic therapy. Patients were treated with KEYTRUDA 200 mg intravenously every three weeks in combination with LENVIMA 8 or 12 mg (based on baseline body weight 60 kilograms or 60 kilograms, respectively) orally once daily. The primary endpoints are ORR and duration of response (DOR) by modified Response Evaluation Criteria in Solid Tumors (mRECIST) and RECIST v1.1 per independent imaging review (IIR). Secondary endpoints include progression-free survival (PFS), time to progression (TTP) and overall survival (OS). At data cutoff (Oct. 31, 2019) and a median duration of follow-up of 10.6 months (95% CI: 9.2-11.5), 37 patients were still on study treatment (KEYTRUDA plus LENVIMA: n=34; LENVIMA only: n=3), and median duration of treatment exposure to the KEYTRUDA plus LENVIMA combination was 7.9 months (range: 0.2-31.1).

The final analysis of the studys primary endpoints showed the KEYTRUDA plus LENVIMA combination demonstrated an ORR of 36% (n=36) (95% CI: 26.6-46.2), with a complete response rate of 1% (n=1) and a partial response rate of 35% (n=35), and a median DOR of 12.6 months (95% CI: 6.9-not estimable [NE]), using RECIST v1.1 criteria per IIR. As assessed using mRECIST criteria per IIR, the KEYTRUDA plus LENVIMA combination demonstrated an ORR of 46% (n=46) (95% CI: 36.0-56.3), with a complete response rate of 11% (n=11) and a partial response rate of 35% (n=35), and a median DOR of 8.6 months (95% CI: 6.9-NE).

Treatment-related adverse events (TRAEs) led to discontinuation of KEYTRUDA and LENVIMA in 6% of patients, discontinuation of KEYTRUDA in 10% of patients, and discontinuation of LENVIMA in 14% of patients. Grade 3 TRAEs occurred in 67% of patients (Grade 3: 63%; Grade 4: 1%; Grade 5: 3%). There was one Grade 4 TRAE (leukopenia/neutropenia), and there were three Grade 5 treatment-related deaths (acute respiratory failure/acute respiratory distress syndrome, intestinal perforation and abnormal hepatic function; n=1 for each). The most common TRAEs of any grade (20%) were hypertension (36%), diarrhea (35%), fatigue (30%), decreased appetite (28%), hypothyroidism (25%), palmar-plantar erythrodysesthesia syndrome (23%), decreased weight (22%), dysphonia (21%), increased aspartate aminotransferase (20%) and proteinuria (20%).

KEYNOTE-146/Study 111 Trial Design and Data from the RCC Cohort (Abstract #5008)

KEYNOTE-146/Study 111 (ClinicalTrials.gov, NCT02501096 ) is a Phase 1b/2, open-label, single-arm trial evaluating the KEYTRUDA plus LENVIMA combination in patients with selected solid tumors. Results from the RCC cohort of the Phase 2 part of the study are based on 104 patients with metastatic ccRCC with disease progression following PD-1/PD-L1 immune checkpoint inhibitor therapy using RECIST v1.1 criteria. Patients were treated with KEYTRUDA 200 mg intravenously every three weeks in combination with LENVIMA 20 mg orally once daily until unacceptable toxicity or disease progression. The primary endpoint is ORR at week 24 by immune-related RECIST (irRECIST) per investigator review. Secondary endpoints include ORR, PFS, OS, safety and tolerability for a maximum of 35 cycles/treatments (approximately two years).

At data cutoff (Apr. 9, 2020), results from the Phase 2 part of the study showed the KEYTRUDA plus LENVIMA combination demonstrated an ORR at week 24 of 51% (95% CI: 41-61) by irRECIST per investigator review. As assessed by irRECIST per investigator review, ORR was 55% (95% CI: 45-65), with a partial response rate of 55%, a stable disease rate of 36% and a progressive disease rate of 5% (5% were not evaluable). Median DOR was 12 months (95% CI: 9-18). Median PFS was 11.7 months (95% CI: 9.4-17.7), and the 12-month PFS rate was 45% (95% CI: 32-57). Median OS was not reached (NR) (95% CI:16.7-NR), and the 12-month OS rate was 77% (95% CI: 67-85).

As assessed by RECIST v1.1 per investigator review, ORR was 52% (95% CI: 42-62), with a partial response rate of 52%, a stable disease rate of 38% and a progressive disease rate of 6% (5% were not evaluable). Median DOR was 12 months (95% CI: 9-18). Median PFS was 11.3 months (95% CI: 7.6-17.7), and the 12-month PFS rate was 44% (95% CI: 31-55).

TRAEs led to discontinuation of KEYTRUDA and LENVIMA in 15% of patients, discontinuation of KEYTRUDA in 12% of patients, and discontinuation of LENVIMA in 12% of patients (2% due to proteinuria). The most common TRAEs that led to dose reduction of LENVIMA were fatigue (14%), diarrhea (10%) and proteinuria (9%). Grade 4 TRAEs included lipase increased, diverticulitis, large intestine perforation and myocardial infarction, and there were two Grade 5 treatment-related deaths of upper gastrointestinal hemorrhage and sudden death. The most common TRAEs of any grade (20%) were fatigue (53%), diarrhea (46%), proteinuria (39%), dysphonia (35%), hypertension (34%), nausea (32%), stomatitis (32%), arthralgia (29%), decreased appetite (28%), palmar-plantar erythrodysesthesia syndrome (25%), hypothyroidism (23%) and headache (22%).

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 1,200 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

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.

Small Cell Lung Cancer

KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of 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 confirmatory trials.

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 head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of 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.

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. 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 confirmatory trials. 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 [combined positive score (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 (MSI-H) 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.

Gastric Cancer

KEYTRUDA 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 two 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 Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Cervical Cancer

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).

Endometrial Carcinoma

KEYTRUDA, in combination with LENVIMA, is indicated for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation. 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 trial.

Selected Important Safety Information for KEYTRUDA

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients with various cancers receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%). Pneumonitis occurred in 8.2% (65/790) of NSCLC patients receiving KEYTRUDA as a single agent, including Grades 3-4 in 3.2% of patients, and occurred more frequently in patients with a history of prior thoracic radiation (17%) compared to those without (7.7%). Pneumonitis occurred in 6% (18/300) of HNSCC patients receiving KEYTRUDA as a single agent, including Grades 3-5 in 1.6% of patients, and occurred in 5.4% (15/276) of patients receiving KEYTRUDA in combination with platinum and FU as first-line therapy for advanced disease, including Grades 3-5 in 1.5% of patients.

Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-Mediated Hepatitis (KEYTRUDA) and Hepatotoxicity (KEYTRUDA in Combination With Axitinib)

Immune-Mediated Hepatitis

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hepatotoxicity in Combination With Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA alone. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes 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.

Immune-Mediated Endocrinopathies

KEYTRUDA can cause adrenal insufficiency (primary and secondary), hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Adrenal insufficiency occurred in 0.8% (22/2799) of patients, including Grade 2 (0.3%), 3 (0.3%), and 4 (<0.1%). Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC (16%) receiving KEYTRUDA, as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.

Monitor patients for signs and symptoms of adrenal insufficiency, hypophysitis (including hypopituitarism), thyroid function (prior to and periodically during treatment), and hyperglycemia. For adrenal insufficiency or hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 adrenal insufficiency or hypophysitis and withhold or discontinue KEYTRUDA for Grade 3 or Grade 4 adrenal insufficiency or hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

Immune-Mediated Nephritis and Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.

Immune-Mediated Skin Reactions

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Other Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barr syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use.

Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 (26%) developed graft-versus-host disease (GVHD) (1 fatal case) and 2 (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (1 fatal case). Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptorblocking antibody before transplantation. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions.

In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.

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 a PD-1 or PD-L1 blocking antibody 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-002, KEYTRUDA was permanently discontinued due to adverse reactions in 12% of 357 patients with advanced melanoma; the most common (1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). The most common adverse reactions were fatigue (43%), pruritus (28%), rash (24%), constipation (22%), nausea (22%), diarrhea (20%), and decreased appetite (20%).

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.

In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients with advanced NSCLC; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (20%) was fatigue (25%).

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).

Adverse reactions occurring in patients with SCLC were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.

In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (20%) were fatigue (33%), constipation (20%), and rash (20%).

In KEYNOTE-048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%).

In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism.

More:
KEYTRUDA (pembrolizumab) plus LENVIMA (lenvatinib) Combination Demonstrated Clinically Meaningful Tumor Response Rates in Unresectable Hepatocellular...

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In order to figure out a maintenance schedule that works for you, identifying which category your hair falls under straight, wavy, curly, or extra curly (coily) is a good place to start. However, according to Hannah Reid, a stylist at Nine Zero One Salon and a certified trichologist technician, there are many factors that determine someone's hair type. These include hair texture, structure, porosity, and density.

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It's easy to determine what your natural hair texture is. All you have to do is shower and let your hair dry without any product in it.

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Straight hair tends to require more frequent washing and lighter-weight formulas, while curlier hair can usually handle denser, more moisturizing shampoos and longer times between washes.

Your hair structure refers to the diameter or thickness of one individual strand and is categorized as either fine, medium, or thick (coarse). In order to determine your hair structure, Reid suggests plucking a single strand of hair from your head and laying it next to a piece of sewing thread.

"If your hair strand appears to be thinner than the thread, you have fine hair," Reid tells INSIDER. "If it appears thicker than the thread it is considered thick (coarse). Anything in between is medium."

Fine hair generally requires more frequent washing than coarse hair.

People often confuse hair structure for hair density, but they are not one and the same. While hair structure is determined by one single strand, your hair density refers to how much hair is on your head, per square inch.

The average person has roughly 2,200 strands of hair per square inch, but to count out that many pieces per square inch would be tedious. Instead, in order to determine your hair's density, Reid suggests putting your hair to the ponytail test.

"Put your hair in a ponytail then measure the circumference of your ponytail," instructs Reid. "If it measures less than 2 inches then it has low density. If it measures 2 to 3 inches then it's medium, 3 to 4 inches it's high density."

Low-density hair generally requires more frequent washings.

Like a sponge, your hair is porous in that it absorbs and retains moisture and oils. The question is, how well does it do this?

If your hair is highly porous, meaning the cuticle layer has gaps and tears in it, it absorbs moisture too quickly and releases moisture at a very high rate, says Reid. "This makes the hair dry, brittle and easily prone to breakage." But if your hair has low porosity, the cuticle layer doesn't open enough and barely absorbs any moisture at all. This can lead to product buildup, "because it is not actually penetrating into the hair shaft."

Generally, low-porosity hair will need to be washed more often due to product buildup, while high-porosity hair can go longer between washes.

Hair with medium porosity in which case the cuticle doesn't open too much or too little is the easiest to manage, Reid says. It allows in and retains just the right amount of moisture to make styling and coloring a breeze, and generally looks the healthiest, too.

So, how can you determine your hair's porosity? The easiest way is to fill a bowl of water and place one strand of hair in it, Reid says. "If it sinks to the bottom that means you have high porosity. If it floats below the surface, but doesn't touch the bottom, you have normal porosity. If it floats at the top of the water, you have low porosity."

Link:
How often should you wash your hair? We asked a trichologist to answer - Insider - INSIDER

Dominic Cummings has enlightened the nation with a brand new way to test your eyesight.

Indeed, if you're unsure whether your eyes are going a little "weird", he recommends you pack your wife and 4 year-old child into a car and take a 30 minute drive to your local castle.

Perhaps an early proponent of this exciting new science was Boris Johnson, who revealed during yesterday's press briefing that he has begun wearing glasses for the "first time in years" since recovering from the virus, which has indeed been linked to a temporary loss of the senses.

It seems that Johnson did already need glasses and has previously said he tries not to wear them as a "point of machismo", but who's to say he hasn't been guided by the brilliant scientific mind of his senior advisor?

Michael Gove has also come out in favour of the driving method. Although he admits that he's not an "authority on driving", he claimed on LBC that he has driven to test his eyesight "on occasion".

But if driving to a local beauty spot in the middle of a pandemic seems a little risky to you, don't worry, because there are other ways to test your eyesight.

Here's our top tips on how to look out for your eyes, even while we're in partial lockdown.

Go and visit an optician

This one seems so obvious now that Dominic Cummings is probably kicking himself!

If you are experiencing serious problems with your eyes, whether they're painful and bloodshot or your vision is impaired, you can phone up your local NHS opticians and ask them whether they're open for appointments.

Many opticians have remained open throughout the pandemic, although they are more likely to see patients with specific problems than for general check-ups. But it's definitely not unreasonable to suggest that Cummings could have booked himself an appointment after he'd isolated for 14 days rather than driving to a castle.

Try reading different-sized lettering

A Snellen chart, as they're officially known, can help you work our your vision's clarity.

If you don't happen to have one of those handy, you could try reading passages out of books with different sized fonts at different distances from your face. This isn't an exact science but it might help you ascertain whether you have a problem with the sharpness of your vision and whether you're near or far-sighted.

Take an online eye test

If you decide to take an online eye test, shop around first for one that looks trustworthy and ideally isn't accompanied by the word "Ad". Also, take the results as a loose guideline, not a conclusive result, until you can get yourself to an NHS eye appointment.

That being said, if you need to test your eyes at a moment's notice for instance, you suddenly realise you're faced with a 260 mile drive whilst experiencing coronavirus symptoms - an online eye test is an accessible tool to see if your eyes are playing tricks on you.

Get crafty with home eye testing

With a torch, tape measure and printed out test, you can actually give yourself or your child a home eye test as if you were sitting in an optician's.

Just have your patient sit in a chair opposite the test and get them to write down what they see when you flash a torch on each letter. It'll save you a whole lot of money in petrol!

Test your colour vision

If the problems you're noticing with your eyes has more to do with colour than clarity, what you need is an Ishihara colour test.

Try reading the numbers at the centre of these circles and if you can't, you may have daltonism or colour-blindness.

There are lots of ways to test your eyesight cheaply and safely that don't involve Barnard Castle and don't have to take place on your wife's birthday.

If you are having trouble with your eyes you can try to put on an optician's appointment, and if you suspect you are experiencing eye problems as a symptom of Covid-19 you should seek medical attention.

Despite all the options on this list, really a professional is the only one who can tell you how good or bad your eyesight is.

And you shouldn't get in the car and drive as a way of testing your eyesight.

Because what if you fail the test? That's putting you, and others, at risk.

See the original post here:
5 ways to test your eyesight that don't involve driving 30 miles to a castle on your wife's birthday - indy100

Ex-Greater Manchester Police chief constable Sir Peter Fahy told Radio 4's Today programme: Clearly, number one, that's ill-advised as a means of testing your eyesight as to whether you're fit to drive, but again it's hard to see - unless there's some justification that that was to take daily exercise - how that was justified.

Asked if it was a criminal offence, Sir Peter said: It certainly appears to be against the Highway Code.

It's not the way to test your eyesight, and put potentially other people in danger.

Rule 92 of the Highway Code dictates a number of requirements a drivers eyesight must meet to be considered safe to drive.

The rule also states police have the power to make a driver undertake an eyesight test.

Driving without meeting the required standards of vision is incredibly dangerous, and you can be prosecuted for doing so.

READ MORE:Dominic Cummings did NOT make mistake with lockdown trips

At the start of a driving test, you will be asked to read a number plate on a parked vehicle.

This is to test your eyesight, and if you cannot correctly read the plate you will fail your driving test.

To meet the standards of vision required for driving, you must be able to read (with glasses or contact lenses if you need them) a car number plate made after September 1, 2001, from a distance of 20 metres away.

You must also have a visual acuity of at least decimal 0.5 (6/12) on the Snellen scale, with contact lenses or glasses if required, in both eyes together or in one eye if you only have one.

Your field of vision must also meet the standards set.

There are different requirements for bus and lorry drivers.

Further information is available on the Government website HERE.

Visit link:
Highway Code eyesight requirements: What are the rules? - Express

MOTORISTShave been urged to test their eyesight amid concerns many behind the wheel do not realise they are too shortsighted to drive.

An awareness campaign by the DVLA in 2018 has resurfaced calling on drivers to test whether they can see a number plate from 20 metres away.

The number plate test reflects the legal distance from which all motorists should be able to read a sign.

It follows claims by the Prime Ministers chief aide Dominic Cummings, who said he drove to Barnard Castle in County Durham with his wife and son during the lockdown to test his eyesight.

What is the legal limitfor sight?

A DVLA survey indicated less than half of drivers knew that 20 metres was the legal limit for sight.

Five car lengths is said to roughly match the distance and road users are being encouraged to use the measure to test their vision on passing signs.

Anyone concerned about their vision should visit an optician or optometrist for an eye test, the DVLA said.

Motoristsshould carry out the 'number plate test' before driving

Wyn Parry, the DVLAs senior doctor, said:The number plate test is a simple and effective way for people to check their eyesight meets the required standards for driving.

The easiest and quickest way to do this is to work out what 20 metres looks like at the road side this is typically about the length of fivecars parked next to each other and then test yourself on whether you can clearly read the number plate.

Its an easy check to perform any time of day at the road side and takes just a couple of seconds.

Having good eyesight is essential for safe driving, so its really important for drivers to have regular eye tests.

Eyesight can naturally deteriorate over time, he added, meaning those who have never needed glasses before could eventually require a pair.

Top tips to check before driving for the first time in a while

For those whose cars have been parked up for a few weeks, MoneySavingExpert has published several key points that drivers should check before setting off on essential journeys:

See the article here:
How to properly test if your eyesight is good enough to drive - East Lothian Courier

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Connective Tissue Growth Factor Market 2020 Growing with Major Key Player BLR Bio LLC, FibroGen Inc, ProMetic Life Sciences Inc, RXi Pharmaceuticals...

Tissue Ablation Market

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Tissue Ablation Market Detailed Analysis Of Current Industry Figures With Forecasts Growth By 2026 - Cole of Duty

INTRODUCTION

Embryonic development is characterized by the temporal and spatial regulation of cell proliferation, migration, differentiation, and tissue formation. Although these processes are genetically determined, several signaling mechanisms including Wnt have been recognized as essential in regulating cell lineage specification and organogenesis (13).

The Na/Kadenosine triphosphatase (ATPase) (NKA), discovered in crab nerve fibers by Skou (4), belongs to the P-type ATPase superfamily. It has an enzymatic function that couples adenosine 5-triphosphate (ATP) hydrolysis to the transmembrane movement of Na+ and K+ in a cell lineagedependent manner. For example, while the NKA is involved in the formation of action potentials in excitable cells, its polarized distribution is key to the functionality of the epithelium.

In addition to its canonical enzymatic function, we and others have shown that the NKA has an enzymatic activityindependent signaling function through its interactions with membrane cholesterol and proteins such as Src, epidermal growth factor (EGF) receptor, and caveolin-1 (58). We use the term signaling with liberty here, referring to the ability of NKA to work as a receptor, a scaffold, and a signal integrator by regulating the functions of its interacting proteins. This newly appreciated signaling function of the NKA has been implicated in several cellular processes (912). However, direct genetic evidence supporting a role for NKA signaling in animal physiology and disease progression is still lacking. This is due, in part, to the technical difficulties in studying its signaling separately from its ATPase-mediated pumping function because the latter is required for the survival of animal cells (13). Fundamentally, it is unknown whether the signaling function is an intrinsic property of the protein NKA, as its Na+- and K+-driven enzymatic activity has been recognized as. Therefore, we were prompted to address two important questions: (i) Were the signaling and Na+/K+ transport functions of the NKA coevolved? (ii) If so, does the signaling function of NKA represent a primordial yet common mechanism for the regulation of a fundamental process in animal biology?

Structurally, the NKA is composed of both and subunits. The subunit contains the binding sites for Na+/K+ as well as ouabain, which are distinct from that of other P-type ATPases (14). It also has an N-terminal caveolin binding motif (CBM) proximal to the first transmembrane helix (fig. S1A). To assess the functionality of this motif, we made F97A and F100A mutations that map to the rat 1 NKA sequence. This strategy has been used by others to study the function of CBM in proteins other than the NKA (15). We used a knockdown and rescue protocol to generate a stable cell line (LW-mCBM) that essentially expresses just the CBM mutant 1, which was confirmed using [3H]ouabain binding assays (fig. S1B). Western blot and confocal imaging analyses showed that the expression of mutant 1 NKA in LW-mCBM was comparable to that in the control cell line, named AAC-19 cells (fig. S1, B and C). The expression of CBM mutant 1 was sufficient to restore the expression of the 1 subunit of the NKA, allowing normal plasma membrane targeting of the CBM mutant NKA in LW-mCBM cells (fig. S1, C and D). The successful generation of a stable CBM mutant 1 cell line suggests that the CBM is not essential for the enzymatic activity of the NKA because the ion-transporting function is necessary for animal cell survival (13). In further support, we conducted kinetic studies of the CBM mutant NKA. As shown in Fig. 1A, the overall enzymatic activity per unit of 1 NKA expression was identical between the control AAC-19 and LW-mCBM cells. The Km values of Na+, K+, and ouabain were comparable between the CBM mutant NKA and control (Fig. 1, B to D) (16). Together, these data indicate that the N-terminal CBM is not directly involved in the regulation of the enzymatic properties of the NKA.

(A) Crude membrane preparations were made from AAC-19 and LW-mCBM cells and measured for ouabain-sensitive ATPase activity as described in Material and Methods. (B) Ouabain concentration curve. Crude membrane from LW-mCBM cells was prepared and measured for ATPase activity in the presence of different concentrations of ouabain. Data are shown as percentage of control, and each point represents three independent experiments. Curve fit analysis and IC50 (median inhibitory concentration) were calculated by GraphPad. (C and D) Measurements of Na+ and K+ Km. Assays were done as in (B). The combined data were collected from at least three repeats, and Km value (means SEM) was calculated using GraphPad.

On the basis of the above, we next turned our attention to determining the effects of the CBM mutation on signaling capabilities of the 1 NKA. Specifically, we first conducted immunoprecipitation experiments. As we reported previously in many types of cells (8), immunoprecipitation of caveolin-1 coprecipitated 1 in AAC-19 cells. In contrast, mutation of the CBM resulted in an over 80% decrease in coprecipitated 1 in LW-mCBM cells (Fig. 2A).

(A) Cell lysates from AAC-19 and LW-mCBM were immunoprecipitated (IP) with polyclonal anticaveolin-1 antibody. Immunoprecipitated complex was analyzed by Western blot for 1 and caveolin-1 (n = 4). **P < 0.01 compared to AAC-19. (B) Cell lysates from AAC-19 and LW-mCBM cells were subjected to sucrose gradient fractionation as described in Materials and Methods. A representative Western blot of three independent experiments was shown. **P < 0.01 in comparison to AAC-19. (C) AAC-19 and LW-mCBM cells were treated with different concentrations of ouabain for 10 min and analyzed by Western blot. A representative Western blot was shown (n = 4). *P < 0.05 versus 0 mM ouabain. (D) Cell growth curves of AAC-19 and LW-mCBM. *P < 0.05 versus AAC-19 cells. (E) BrdU assay of AAC-19 and LW-mCBM. The values are means SEM from at least three independent experiments. Photo credit: Xiaoliang Wang, Marshall Institute for Interdisciplinary Research at Marshall University.

To substantiate these observations, we next conducted a detergent-free and carbonate-based density gradient fractionation procedure and found that 1 NKA and its main signaling partners (Src and caveolin-1) were co-enriched in the low-density caveolar fractions, as previously reported in epithelial cells (8, 17). In sharp contrast, the expression of the CBM mutant 1 caused the redistribution of these proteins from low-density to high-density fractions (Fig. 2B). Quantitatively, when the ratios of fraction 4/5 of each protein versus total were calculated, we found that the low-density fraction 4/5 prepared from the control AAC-19 cells contained ~60, ~70, and 80% of caveolin-1, Src, and 1 NKA, respectively. However, in LW-mCBM cells, only ~20% of caveolin-1, Src, and 1 NKA were detected in fraction 4/5 (Fig. 2B).

To address the functional consequences of the dissociation of the 1 NKA from its signaling partners in LW-mCBM cells, we exposed these cells to ouabain, a specific agonist of the receptor NKA/Src complex. As shown in Fig. 2C, while ouabain stimulated phosphorylation of extracellular signalregulated kinase (ERK), a downstream effector of the NKA/Src signaling pathway in AAC-19 cells (5, 8), it failed to do so in LW-mCBM cells.

We have previously shown that 1 NKA signaling is key to the dynamic regulation of cell growth (16, 18). As shown in Fig. 2D, LW-mCBM cells grew much slower than AAC-19 cells. 5-Bromo-2-deoxyuridine (BrdU) incorporation assays further verified that the expression of CBM mutant 1 resulted in an inhibition of cellular proliferation (Fig. 2E). In short, the above in vitro experiments indicate that the gain of CBM enables the NKA to perform the enzymatic activityindependent signaling functions.

With the preceding in vitro data suggesting that the CBM is critically important to the signaling function of the NKA, we next set forth to test the physiological significance of this finding. Thus, we generated a knock-in mouse line expressing the aforementioned CBM mutant 1. The CBM mutant (mCBM) mouse was generated using the Cre/LoxP gene targeting strategy (19), as depicted in fig. S2A. The chimeric offspring were crossed to C57BL6 females to yield mCBM heterozygous mice, and the desired F97A and F100A substitutions were verified (fig. S2B). mCBM heterozygous mice were born fertile and survived to adulthood. Our attempts to generate mCBM homozygous mice yielded no viable homozygous pups (Fig. 3A) in nearly 400 young mice genotyped by polymerase chain reaction (PCR). These results document for the first time that the CBM in the 1 subunit of the NKA represents a fundamental signaling mechanism essential for mouse embryonic development and survival.

(A) Early embryonic lethality of mCBM homozygous embryos. (B) Morphological comparison and body size of wild-type (WT) (top), heterozygous (middle), and homozygous (bottom) mCBM embryos at E9.5. Black bars, 0.3 mm. The arrows show the abnormal head morphology. Body size was measured from at least 12 embryos in different genotypes by ImageJ. Data are presented as means SEM. ***P < 0.01 versus the average of WT. (C) Sagittal sections of WT and homozygous (Homo) and heterozygous (Het) embryos at E9.5 with hematoxylin and eosin (H&E) staining. Homozygous embryos that had defective brain development indicated by open arrows. (D) Brain cross section of WT, homozygous, and heterozygous embryos at E9.5 with H&E staining. Homozygous embryos that had unclosed neural tube in forebrain, midbrain, and hindbrain were indicated by arrows; WT and heterozygous E9.5 embryos with closed neural tube were indicated by arrowhead. (E) Morphological comparison of WT and Na/K-ATPase 1 (+/) embryos at E9.5. White bars, 0.3 mm (n = 5 to 7). Photo credit: Xiaoliang Wang, Marshall Institute for Interdisciplinary Research at Marshall University.

There is evidence that endogenous ouabain is important in animal physiology because of its role in stimulating the signaling function of the NKA (10, 19, 20). Because the loss of the CBM abolishes ouabain-induced signal transduction in vitro, we tested whether administration of pNaKtide, a specific inhibitor of the receptor NKA/Src complex (21), would cause the same embryonic lethality as we observed in mCBM mice. As depicted in fig. S3, we observed no change in fetal survival after administration of pNaKtide to female mice before mating and continued until the end of pregnancy. It is important to mention that pNaKtide has been proven to be specific and effective in blocking the NKA/Src receptor signaling in vivo (2226), and our control experiments showed that pNaKtide could cross the placental barrier. Moreover, this lack of pNaKtide effect on mouse embryogenesis appears to be consistent with a previous report demonstrating that neutralization of endogenous ouabain by injection of an anti-ouabain antibody did affect the kidney development of neonatal mice but did not affect their overall survival (20). On the basis of these, we concluded that the NKA/Src receptor function in the CBM mutant embryo was not the direct cause of lethality and set out to identify a hitherto unrecognized NKA CBM-dependent yet NKA-Srcindependent underlying mechanism.

Embryo implantation within mice occurs around embryonic day 4.5 (E4.5) (27), followed by gastrulation around E5.5 to E7.5 (28), when the simple embryo develops into an organized and patterned structure with three germ layers (29). Subsequently, organogenesis takes place at E8.0 and onward; the patterned embryo starts to develop its organ systems including the brain, heart, limbs, and spinal cord.

To further analyze and explore the molecular mechanisms of the CBM mutation in the embryonic development of mice, we harvested the fertilized eggs at E1.5, and cultured them in vitro. It has previously been demonstrated that 1 knockout results in the failure of blastocyst formation (13). In contrast, we found that eggs from mCBM heterozygous parents developed into morphologically normal blastocysts. These findings indicate that loss of the CBM does not affect the molecular mechanisms necessary for blastocyst formation. Thus, a loss of functional 1 CBM and complete knockout of 1 NKA both result in embryonic lethality but differ by their specific mechanisms. Knockout of 1 NKA inevitably causes the loss of NKA enzymatic function, which is incompatible with life (13), and results in the failure of blastocyst formation in mice. In contrast, our in vitro data indicate that a loss of the CBM does not cause any notable alteration in NKA enzymatic activity, which is supported by the observation that mCBM mice are still capable of producing morphologically normal blastocysts. Consequently, CBM role in development appears to be critical at a developmental stage beyond blastocyst stage, and we further set out to identify this stage.

To this end, we collected and genotyped embryos or yolk sacs from mCBM heterozygous mice at different days of gestation. We first dissected 31 embryos at E12.5 from three different mice (Fig. 3A). Reabsorption and empty deciduae were observed in six implantation sites with only the mothers genotype detectable. At E9.5, we were able to dissect a total of 303 embryos. Sixty-four of them were mCBM homozygous (21%), 71 were wild-type (23%), and 168 were mCBM heterozygous (55%) (Fig. 3A).

To further analyze the embryonic developmental defects, we examined mCBM embryos at E7.5, E8.5, and E9.5. The embryos looked similar between wild-type and mCBM homozygous mice at E7.5 and E8.5 under dissection microscopy. However, we found several severe morphological defects in homozygous embryos at E9.5 (Fig. 3, C and D). First, the overall size of embryos was considerably reduced in mCBM homozygous embryos (about 35% the size of the wild-type embryos). In addition, the observed effect of the CBM mutant on embryonic size was gene dose dependent, as the mCBM heterozygous embryos were significantly smaller than those of wild-type embryos but much bigger than the homozygous embryos. Second, most homozygous embryos did not turn, a process normally initiated at E8.5, suggesting that the loss of a functional CBM was responsible for a developmental arrest at an early stage of organogenesis. Last, the most severe morphological defects were observed in the heads of the mCBM homozygous embryos. In addition to the reduced size (about 25% of the size of wild-type embryos), we observed that mCBM homozygous embryos failed to close their cephalic neural folds (anterior neuropore) as indicated by the arrow in Fig. 3B. This phenotype more closely resembled wild-type embryos at E8.0 to E8.5, suggesting again that the loss of CBM arrested organogenesis in its early stages. On the other hand, all heterozygous embryos, although smaller than wild-type embryos, showed normal head morphology (Fig. 3B).

To follow up on the above observations, we collected and made histological sections of wild-type, heterozygous, and homozygous embryos at E9.5 (Fig. 3, C and D). Normally, formation and closure of the anterior neuropore occurs at E9.5 (Fig. 3D). In sharp contrast, mCBM homozygous embryos developed defects in neural closure. Specifically, failure of neural tube closure at the level of forebrain, midbrain, and hindbrain was prominent in homozygous embryos (Fig. 3D).

To further explore the molecular mechanism by which the loss of the CBM led to defects in organogenesis, we next conducted RNA sequencing analyses (RNAseq) in wild-type and mCBM homozygous embryos. More than 17,000 genes were read out in either mCBM homozygous or wild-type samples. Data analyses indicated that 214 and 208 genes from mCBM homozygous embryos were significantly down- and up-regulated, respectively (fig. S4). Among them, the expression of a cluster of transcriptional factors important for neurogenesis was significantly reduced. As depicted in Fig. 4A, the expression of neurogenin 1 and 2 (Ngn1/2), two basic helix-loop-helix (bHLH) transcriptional factors (30), was significantly down-regulated in homozygous embryos. Ngn1/2 are considered to be determination factors for neurogenesis, while members of the NeuroD family of bHLH work downstream to promote neuronal differentiation (31). We found that the expression of NeuroD1/4 was further reduced in mCBM homozygous embryos. As expected from these findings, the marker of neural stem cells nestin (Nes) and other genes related to neurogenesis including huntington-associated protein 1 (Hap1), nuclear receptor subfamily 2 group E members 1 (Nr2e1), and adhesion G protein (heterotrimeric guanine nucleotidebinding protein)coupled receptor (Adgrb1) were all down-regulated in mCBM homozygous embryos (Fig. 4A). To verify these data, we performed reverse transcription quantitative PCR (RT-qPCR) analyses of both wild-type and mCBM homozygous embryos collected at E9.5. As depicted in Fig. 4 (B to D), the aforementioned transcriptional factors were all down-regulated in a cascade fashion. While a modest reduction was found with Ngn1/2, the expression of NeuroD1/4 was almost completely inhibited. To test whether the effects of the CBM mutation on the expression levels of these transcriptional factors were gene dose dependent, we also examined mRNA levels of Ngn1/2 and NeuroD1/4 in mCBM heterozygous embryos. As depicted in Fig. 4 (B and C), the expression of these genes followed the pattern found in homozygous embryos. The expression level in heterozygous embryos was significantly reduced compared to wild-type embryos but was much higher than that of mCBM homozygous embryos. These gene dosingdependent cascade effects suggest that the 1 NKA is an important upstream regulator but not a determinant of neurogenesis like Ngn1/2 (32) or a key receptor mechanism like Wnt is.

(A) RNAseq results of several neurogenesis and neural stem cell markers. Log2 ratio = 1 means twofold of change. *P < 0.05 compared to WT. (B and C) RT-qPCR analysis of selected gene expression in WT, heterozygous, and homozygous mCBM embryos at E9.5. (D) RT-qPCR analysis of neural stem cell marker gene expression in WT and homozygous mCBM E9.5 embryos. (E) RT-qPCR analysis of neurogenesis marker genes in WT and NKA 1+/ mouse E9.5 embryos. Quantitative data are presented as means SEM from at least six independent experiments. *P < 0.05, **P < 0.01 versus WT control.

As a control, we also assessed the expression of different isoforms of NKA and caveolin-1. As depicted in fig. S5, no changes were detected in the expression of the 1 isoform of the NKA. This is expected, as the mutations were only expressed on exon 4. Previous reports have demonstrated that, in addition to the 1 isoform, neurons also express the 3 isoform, while muscle and glial cells express the 2 isoform of the NKA (9). No difference was observed in the expression of 3, while the expression of 2 was too low to be measured. We were also unable to detect any change in the expression of caveolin-1.

The total amount of protein recognized by the anti-NKA 1 antibody is unchanged in mCBM heterozygous mouse tissues compared to that of the wild type, albeit with changes in distribution in caveolar versus noncaveolar fractions. This indicates that the CBM mutant protein is fully expressed, as observed in cells (fig. S1), and further demonstrates that a reduction of enzymatic activity is not responsible for the observed phenotype in mCBM homozygous embryos. However, because the expression of wild-type 1 in mCBM heterozygous animals is most likely reduced, the phenotypic changes we observed in these mice could be due to the reduction of wild-type 1 expression rather than the expression of CBM mutant 1. To address this important issue, we collected embryos from 1 NKA heterozygous (1+/) mice and their littermate controls (33). In contrast to mCBM heterozygotes, reduction of 1 expression alone did not change the size of embryos (Fig. 3D), head morphology, or the expression of neuronal transcriptional factors (Fig. 4E). Because NKA 1 haploinsufficiency did not phenocopy mCBM heterozygosity, it was concluded that the mCBM allele was responsible for the observed changes.

The CBM in NKA has a consensus sequence of FCxxxFGGF (fig. S6). To assess the generality of CBM-mediated regulation, we first turned to the conserveness of the CBM in animal NKA. A database search reveals that, like Wnt, the mature form of NKA (i.e., containing CBM, Na+/K+ binding sites, and subunit) is absent in unicellular organisms but present in all multicellular organisms within animal kingdom (fig. S6). Further analysis of published data confirms the coevolutionary nature of the CBM and the binding sites for Na+ and K+ in the NKA. The first indication is from the analysis of single-cell organisms. No mature form of NKA is found in these organisms (fig. S6A). However, Salpingoeca rosetta, a marine eukaryote belonging to the Choanoflagellates class, undergoes a very primitive level of cell differentiation and specialization in their life cycle and expresses a putative NKA with several conserved motifs involved in the binding of Na+/K+. On the other hand, it contains no CBM (fig. S6) and there is also no evidence that it expresses a subunit.

Second, as depicted in figs. S6 and S7, Caenorhabditis elegans, an example of a metazoan organism, expresses a mature form of NKA (eat-6) that contains binding sites for Na+ and K+ as well as the N-terminal CBM. It also expresses a couple of putative NKA such as catp-2 (34). However, they contain neither the CBM nor Na+ and K+ binding sites.

Third, although the X amino acids in the NKA CBM in invertebrates vary, only conserved substitutions occurred in this motif. This is in sharp contrast to many other membrane receptors/transducers such as Patched and G that also contain a consensus CBM (figs. S6 and S7). Within vertebrates, the CBM sequence FCRQLFGGF in NKA remains completely conserved across all species. Moreover, this sequence remains conserved in all isoforms of the subunit except for the 4 isoform, which is exclusively expressed in sperm. The 4 isoform in some species still adapts the CBM sequence found in invertebrates (fig. S6). Moreover, of a total of nine subunits found in zebrafish (35), five appear to be 1 homologs that, like the 4 isoform, contain both vertebrate and invertebrate CBM sequences.

Last, turning to the evolutionary aspect of the receptor NKA/Src complex, we found that the Src-binding NaKtide and Y260 sequences, in sharp contrast to the CBM, are only conserved in mammalian ATP1A1 (fig. S7). Therefore, the NKA/Src receptor may have evolved after the acquisition of the CBM, and hence is not a part of the fundamental regulation of animal organogenesis (fig. S3).

In short, the N-terminal CBM, like the binding sites for Na+ and K+, is conserved in all subunits of NKA in animals, even after taking into consideration gene duplications and the generation of different isoforms or homologs. Thus, we postulate that this CBM must be evolutionally conserved to enable the NKA, in parallel with its enzymatic function, to serve an important role in the origination of multicellular organisms within the animal kingdom.

Organogenesis represents a unique feature of multicellular organisms. In considering the preceding findings, we reasoned that the loss of NKA CBM would also affect embryonic development in invertebrates such as C. elegans. To test our hypothesis, we used CRISPR-Cas9 to knock in the equivalent CBM double mutations of F75A and F78A in C. elegans NKA gene eat-6 (named as syb575) (fig. S8). Similar to the impact of the expression of CBM mutant 1 NKA in mice, no homozygous worms were produced, whereas the heterozygous worms hatched normally. Moreover, by using the gene balancer nT1, we confirmed that the F75A and F78A double mutations induced embryonic lethality in syb575 homozygotes secondary to L1 arrest (Fig. 5A). Furthermore, the observed larval arrest due to the loss of the eat-6 CBM was rescued by a transgene expressing a wild-type eat-6 complementary DNA (cDNA) through an extrachromosomal array (Fig. 5B). The lethality phenotype in syb575 mutants was different from those of the eat-6 mutants defective in enzymatic (transport) activity, because while the eat-6 mutants had growth defects, they were able to grow past the L1 stage (36). An exception to this was a cold-sensitive eat-6 (ad792) mutant with severely reduced transport activity, which exhibited L1 arrest at lower temperatures similarly to the syb575 mutant worms (36). Overall, those data suggest that both CBM-mediated signaling and ion transport activity by the NKA are essential to full-scale organogenesis in C. elegans.

(A) Heterozygous CBM mutant (mCBM) worms syb575/nT1 have GFP signals in pharynx (pointed with the arrowhead), while mCBM homozygous worms are GFP negative and arrested at larval stage (pointed with an arrow). (B) Rescue with a WT eat-6 gene showing a mCBM homozygous worm with a transgenic marker sur-5::GFP. Arrow points the somatic GFP signals. (C) Mutation of CBM1 NKA (F97A; F100A) results in reduced colony formation in human iPSC (mCBM iPSC). (D) RT-qPCR analysis of stem cell markers and primary germ layer markers in WT and mCBM iPSC. *P < 0.05 compared to WT. n = 7. Photo credit: Liquan Cai, Marshall Institute for Interdisciplinary Research at Marshall University.

In short, our data indicate that loss of the NKA CBM results in defective organogenesis in both mice and C. elegans. This, together with our finding that the NKA CBM is conserved in all NKA regardless of isoform or homolog, indicates that the NKA was originally evolved as a dual functional protein in multicellular organisms, and that it represents a primordial and common mechanism for regulating stem cell differentiation and early stage of organogenesis in animals.

Turning now to even more general features of the CBM in organogenesis, we searched for the plant plasma membrane H-ATPase that functions equivalently to the animal NKA. Like the NKA, the plant plasma membrane H-ATPase also contains a sequence motif at the first transmembrane segment that is in accordance with the consensus CBM. This motif is completely conserved from blue algae to land plants but does not exist within yeast and bacteria (fig. S6).

To assess the human relevance of our findings, we used CRISPR-Cas9 gene editing to generate the same mutations in human induced pluripotent stem cells (iPSCs) (fig. S9). As depicted in Fig. 5C, the expression of mutant CBM 1 reduced the colony formation ability of human iPSCs. Concomitantly, this was accompanied by a significant reduction in the expression of stemness markers (both Nanog and Oct4), and transcriptional factors controlling germ layer differentiation (gene MIXL and T for mesoderm, OTX2 and SOX1 for ectoderm, and GATA4 and SOX17 for endoderm) (Fig. 5D). These findings confirm an essential role of the NKA CBM in the regulation of stem cell differentiation and suggest the potential utility of targeting the NKA for improving tissue regeneration.

The canonical Wnt pathway is made of multiple components localized in the plasma membrane and cytosol (2, 3). Functionally, this pathway is critically important in animal organogenesis (2, 37). For example, it plays an essential role in the establishment of neurogenic niches and regulates the differentiation of neural stem cells into neuroblasts during organogenesis by regulating the expression of transcriptional factors Ngn and NeuroD (37, 38). Thus, we were prompted by the observed neural defects in mice to test whether the expression of the CBM mutant 1 NKA affects Wnt/-catenin signaling.

In the first set of studies, we examined the cellular distribution of -catenin in LW-mCBM cells. As depicted in Fig. 6A, confocal imaging analysis showed that -catenin was distributed away from the plasma membrane in a vesicle-like form in LW-mCBM cells. To verify this finding, we fractionated the cell lysates as performed in Fig. 3B and observed that -catenin, like Src and caveolin-1, moved from the low-density fractions to high-density fractions when compared to control cells (Fig. 6B). Control experiments showed no changes in the expression of E-cadherin, glycogen synthase kinase3 (GSK-3), LRP5/6 (Low-density lipoprotein receptor-related protein 5 and 6), and -catenin in LW-mCBM cells (Fig. 6C).

(A) -Catenin staining of AAC-19 and LW-mCBM at basal level (n = 5). Blue arrow indicated -catenin signal in the cytoplasm of cells. (B) Sucrose gradient fractionation of -catenin in AAC-19 and LW-mCBM cells (n = 3). **P < 0.01. (C) Western blot analysis of Wnt/-catenin signaling proteins in AAC-19, LX-2, and LW-mCBM cells from at least six independent experiments. Two samples from each cell lines are presented. (D) Wnt3a induced TOPFlash luciferase report assay in AAC-19 and LW-mCBM (n = 8). ***P < 0.01. (E) Wnt3a induced expression of Wnt/-catenin targeting genes (n = 8). **P < 0.01. (F) Wnt3a induced TOPFlash luciferase report assay in AAC-19, LX-2, and LW-mCBM cells (n = 4). ***P < 0.01.

To test whether these changes in -catenin distribution alter the function of canonical Wnt signaling, we conducted a TOPFlash luciferase activity assay (39). Cells were transiently transfected with the reporter plasmid, exposed to Wnt3a conditional medium, and then subjected to TOPFlash luciferase assays. As shown in Fig. 6D, while Wnt3a induced a greater than 35-fold increase in luciferase activity in AAC-19 cells, it only produced a fourfold increase in LW-mCBM cells, which equates to an approximate 90% reduction in the dynamics of Wnt activation. To further test the impact of the CBM mutation on Wnt signaling, we examined the effects of Wnt3a on the expression of Wnt target genes. Cells were exposed to Wnt3a for 6 hours and subjected to RT-qPCR analysis. As depicted in Fig. 6E, while Wnt3a increased the expression of c-Myc, Lef, and NKD1 expression in AAC-19 cells, it failed to do so in LW-mCBM cells.

On the basis of the above observations, we reasoned that the NKA CBM might play an essential role in the dynamic regulation of Wnt signaling. We therefore analyzed Wnt signaling in our LX-2 cell line. This cell line was made by the same strategy used for the generation of LW-mCBM cells, and it expresses essentially just the 2 isoform (40). We have observed that 2 NKA, like CBM mutant 1, maintains cellular pumping capacity but is unable to signal via Src like a wild-type 1 NKA (40). However, unlike CBM mutant 1, 2 does contain the same CBM at the N terminus (fig. S6). As depicted in Fig. 6F, expression of the 2 isoform produced a rescue of Wnt signaling dynamics when compared to that in LW-mCBM cells, which reinforces the idea that the NKA CBM is key to the dynamics of Wnt signaling. Like in LW-mCBM cells, no change in -catenin expression was noted in LX-2 cells. However, compared to LW-mCBM cells, caveolin-1 expression was decreased in LX-2 cells, while ERK activity was increased (Fig. 6C). Together, these findings suggest that the conserved NKA CBM is essential for regulating Wnt signaling, which is independent of the pumping or CTS (ardiotonic steroid)activated Src-dependent signaling transduction.

To see whether there is evidence of Wnt signaling defects in mCBM homozygous embryos, we examined the RNAseq data using a tool kit of pathway analysis. As depicted in fig. S10, Wnt signaling appears to be defective at the transcriptional level. First, the expression of one of the Wnt receptors [Frizzled homolog 5 (Fzd5)] and one of the Wnt ligands (Wnt7b) was down-regulated (fig. S10A). Second, the Wnt/-catenin signaling inhibitor, secreted frizzled-related protein 5 (Sfrp5), was up-regulated in mCBM homozygous embryos. Third, the -catenin destruction complex component adenomatosis polyposis coli (APC) was down-regulated in mCBM homozygous embryos. All these defects in Wnt signaling were confirmed by RT-qPCR analysis of both wild-type and mCBM homozygous embryos at E9.5 (fig. S10B). In addition, APC down-regulation was also observed at the protein level in mCBM iPSCs (fig. S10C). Last, the defect in Wnt signaling was further substantiated by the altered expression of Wnt downstream target genes. As shown in fig. S10B, the expression of Lef and NKD1 was significantly reduced in mCBM homozygous embryos. The expression of c-Myc was too low to be detected.

Together, these data provide strong support to the notion that the CBM is a key to the regulation of Wnt by the NKA. We hypothesize that this critical function of the NKA CBM may explain why the CBM is conserved in all four subunit isoforms of the NKA. It is important to mention that the specific molecular defects in Wnt signaling that we have identified were tested in epithelial cells, a model we have previously used to characterize 1-specific signaling functions (16, 41). In view of the cell/tissue specificity of both NKA expression and subunit assemble (42) and Wnt signaling (13, 37), it is likely that this mechanism does not fully explain the Wnt signalingrelated defects in embryogenesis.

The enzymatic function of NKA coordinates the transmembrane movement of Na+/K+, which is essential for the survival of individual animal cells. At the tissue/organ level, the ATP-powered transport of Na+/K+ by the NKA is required for neuronal firing, muscle contraction, and the formation and functionality of epithelia and endothelia. The NKA was found to be essential for forming septate junction in Drosophila melanogaster (43, 44) via a regulatory mechanism independent of its ion-pumping activity. Here, we reveal an additional fundamentally important role of NKA in the regulation of signal transduction through a separate functional domain (CBM) unrelated to its enzymatic activity.

Our findings raise the question of why NKA acquired the CBM in addition to its binding sites for Na+ and K+. One possible explanation for this is that the additional functionality in NKA (fulfilled by the CBM) evolved for the purpose of regulating stem cell differentiation and organogenesis in multicellular organisms. Two observations support this hypothesis. First, both Wnt and NKA are present in the first multicellular organisms within the animal kingdom and are evolutionally conserved ever since. Thus, it is likely that the NKA and Wnt work in concert to enable stem cell differentiation and organogenesis in animals. Second, while Wnt is key to the cellular programs of stemness and cell lineage specification (2), it does not directly participate in cell lineagespecific activities of newly differentiated cells. Instead, this particular function might be fulfilled by the NKA. Conceivably, the NKA could have been evolved, as exemplified by the mitochondrial cytochrome c in ATP generation, to bring together two seemingly unrelated processes (i.e., Wnt signaling regulation via the CBM and ion transport through Na+ and K+ binding) into one signaling circuitry, which is critical to the dynamic regulation of transcriptional factors that are required for organogenesis in a temporally and spatially organized manner. Needless to say, this hypothesis remains to be tested. In addition, other important signaling pathways such as Notch and Sonic Hedgehog may also be regulated by NKA.

It is also of interest to note the evolutionary conserveness of the CBM in the plant plasma membrane H-ATPase. Like its counterpart within the animal kingdom, the plasma membrane H-ATPase is essential for plant organogenesis (45). Unlike the NKA, the plasma membrane H-ATPase exists in single-celled organisms such as yeast, and their ion-pumping function is regulated by similar mechanisms (46). However, yeast, with no use for cellular machinery needed for organogenesis, does not contain the H-ATPase with conserved CBM. Moreover, we also observed that no CBM exists in the plasma membrane Ca-ATPase (fig. S6), both of which belong to the same type II P-type ATPase family as the NKA. While the Ca-ATPase is a more ancient protein than the NKA, as its expression can be found in unicellular organisms, the H/K-ATPase appeared later than the NKA, at some point during the development of vertebrates. Thus, we suggest that the NKA may have evolved from a P-ATPase of unicellular organisms via the gain of both the CBM and Na+/K+ binding sites. In contrast, the H/K-ATPase may have evolved from the NKA, losing not only the Na+ binding site but also the CBM.

We have shown a direct interaction between the NKA and caveolin-1 (8, 17), which has been independently confirmed (47). The loss of the CBM significantly reduced the interaction between NKA and caveolin-1 as revealed by multiple assays. In addition to caveolin-1, we and others have reported several signal transductionrelated interactions (48). Of these, the potential interaction between 1 NKA and Src has attracted the most attention, especially in the past 10 years (7). While most studies indicated an important role of Src in CTS-activated signal transduction via 1 NKA, several publications have questioned whether 1 NKA interacts with Src directly to regulate Src functionality (49, 50). While this important difference remains to be experimentally addressed, we would like to point out the following facts. First, while we recognize the merit of using purified protein preparation to study protein interaction, it is important to recognize the limitation of using purified Src from bacterial expression system because they are heterogeneously phosphorylated. Second, we have reported multiple lines of evidence that support a direct interaction between 1 NKA and Src, including the identification of isoform-specific Src interaction, the mapping of potential Src-interacting sites in the 1 isoform, and the development of pNaKtide as Src inhibitor and receptor antagonist. These findings have substantially increased our understanding of 1 NKA/Src interaction in cell biology and animal physiology. It is important to mention that several groups not associated with us have successfully used pNaKtide to block ouabain and NKA signaling in vitro and in vivo (2326, 51). While our group and others continue to characterize the molecular basis and biological function of the NKA/Src receptor complex, we propound that the question of NKA/caveolin-1 interaction is a more pressing one in the context of this study. The role of CBM in caveolin-protein interaction and caveolae-related signaling is still debated (41, 52, 53).

Last, we conclude from these interesting findings that the NKA is not just an ion pump or a CBM-directed regulator but a critical multifunctional protein. This whole functionality underlies a hitherto unrecognized common mechanism essential for stem cell differentiation and organogenesis in multicellular organisms within the animal kingdom. Moreover, many recent studies also support the concept that the 1 NKA has acquired more functional motifs (e.g., Src-binding sites for the formation of NKA/Src receptor complex) during evolution. In addition, we have demonstrated that either knockdown of 1 NKA or the expression of an N-terminal fragment containing the CBM of the 1 subunit was sufficient to attenuate purinergic calcium signaling in renal epithelial cells (54). The 1 NKA is also found to be essential for CD36 and CD40 signaling in macrophages and renal epithelial cells (55, 56). Aside from the profound biological and fundamental implications, the previously unidentified NKA-mediated regulation of Wnt signaling through its N-terminal CBM may have substantial implications in our understanding of disease progression. The rapidly increasing appreciation of Wnt signaling in the pathogenesis of cancer and cardiovascular diseases (2, 3, 38) underlies the potential utility of NKA as a multidrug target (12, 22, 57, 58).

Acknowledgments: Funding: This work was supported by grants from: National Institutes of Health (NIH) Research Enhancement Award (R15) (R15 HL 145666); American Heart Association (AHA) Scientist Development Grant (#17SDG33661117); Brickstreet Foundation and the Huntington Foundation, which provide discretionary funds to the Joan C. Edwards School of Medicine. (These funds are both in the form of endowments that are held by Marshall University). Author contributions: Conceptualization: Z.X., X.W., J.X.X., L.C., G.-Z.Z., S.V.P., and J.I.S.; methodology: X.W., L.C., I.L., D.W., and G.-Z.Z.; investigation: X.W., L.C., X.C., J.W., Y.C., and J.Z.; writing (original draft): X.W., J.X.X., and Z.X.; writing (review and editing): Z.X., J.X.X., L.C., J.I.S., S.V.P., D.W., G.-Z.Z., and X.W.; funding acquisition: Z.X.; visualization: X.W. and Z.X. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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