I can do a lot of things: I can finish any quote from Brooklyn Nine-Nine, I can spend four hours in a TJ Maxx and be endlessly entertained, and I can recite all of Hasan Minhajs Homecoming King from memory.

What I cant do is sleep.

More specifically, I cant fall asleep.

Most of the sleep problems that college students have and by extension, me can be traced back to a delayed circadian rhythm.

A circadian rhythm is our body's internal clock. Its what causes us to feel sleepy and energized at roughly the same times every day, regulating our levels of alertness with the time of day. A delayed rhythm is when your internal clock shifts ahead a couple of hours.

Dr. Vishesh Kapur, UWs director of sleep medicine, says this shift results in increased alertness late at night and a subsequent inability to fall asleep.

According to the Mayo Clinic, adults require between seven and nine hours of sleep per night. Most college students fall short of this requirement and end up building a sleep debt.

Sleep debt is exactly what it sounds like: sleep deprivation compounds on a nightly basis, resulting in longer-term sleep problems.

A student who only gets five to six hours of sleep per night is already around 10 hours in debt by the end of the week. To make up for this, we tend to sleep in on weekends, but even those extra couple of hours arent enough to make up for the week.

While hitting this target sleep goal isnt always easy, there are things you can do to help yourself get close.

For one, a consistent sleep schedule is key.

A nightly routine is a good way to maintain consistency. Whether it's watching an episode (or eight) of whatever it is that youre binging or relaxing with a face mask, doing it every day before sleeping will help you build a positive association between your routine and sleep.

Next, disengage. Turn off your phone, turn off your brain. Stop checking those emails; theyll be there in the morning.

This process of disconnecting lets your brain relax and avoid things that cause anxiety, which can impede sleep.

There is another part of sleep hygiene that is using the bed just for sleep, Kapur said.

This comes down to your brains psychological association with your bed. Studying or reading in bed creates a link in your brain between wakefulness and the bed.

If you spend more time in bed than you need, you spend more time awake in bed, Kapur said. And so, the association gets worse.

Instead of being tired when you get into bed, your brain might use that as a cue to wake up.

Alcohol right before bed can suppress some stages of sleep like REM sleep, which is required for memory consolidation. Alcohol also causes you to wake up in the middle of the night as it metabolizes.

While alcohol does not directly cause sleep apnea, research has shown that habitual drinkers are at a higher risk for developing the disorder.

So, what actually causes you to fall asleep?

Melatonin is the hormone that regulates your circadian rhythm. It is produced in response to darkness and helps maintain your sleep cycle. Melatonin supplements are available over-the-counter and can help with sleep disorders or even recovering after jet lag.

As the worlds leading sleep struggler, Ive grappled with the idea of taking melatonin for quite some time.

A lot of people use melatonin as a sleep aid, independent of changing the timing of their sleep, Kapur said. The danger there is that people end up on [a] high dose.

Instead of relying on melatonin to fall asleep, Kapur recommends taking it in low doses a couple of hours before you intend on falling asleep to help shift a delayed circadian rhythm and move you to an earlier bedtime.

It should be noted that depression, anxiety, and other mood disorders can often cause insomnia. Those conditions should be primarily addressed before adding treatment for insomnia itself.

Overall, most healthy sleep habits involve cutting things out as opposed to actively adopting new habits. Even so, sleeping is hard.

In an insane world, trying to turn your brain off and relaxing isnt as simple as putting your phone away, but its a step.

Reach Science Editor Ash Shah at wellness@dailyuw.com. Twitter: @itsashshah

Like what youre reading? Support high-quality student journalism by donatinghere.

See the article here:
A crash course: The do's and don'ts of dozing - Dailyuw

Recommendation and review posted by Bethany Smith

Image: Pancreatic adenocarcinoma (left) vs. normal ductal epithelium (right). Credit:Ed Uthman,CC BY 2.0

By the time a pancreatic tumour begins to cause symptoms, it is usually pretty advanced, since many of the tumours are silent.

Dr Anguraj Sadanandam, a team leader in the Division of Molecular Pathologyat The Institute of Cancer Research, works on two types of pancreatic tumours: neuroendocrine tumours and adenocarcinomas.

Neuroendocrine tumours are exceptionally rare, making up just one to three per cent of all pancreatic cancers.

There are two types of pancreatic neuroendocrine tumour functional and non-functional. Functional tumours are tumours which produce hormones, which means theyre more likely to produce noticeable symptoms.

The majority of pancreatic neuroendocrine tumours, however, are non-functional, meaning they dont produce any hormones. These tumours grow silently, and without hormone production, they usually dont produce symptoms until they have advanced to a large size.

At this point, the tumours are usually inoperable, and treatment options are limited to palliative care.

In fact, pancreatic tumours are often diagnosed only when they have spread to other organs, and begin to cause symptoms there. Some 60% of patients diagnosed with non-functional pancreatic cancer have metastases at diagnosis half of these in the liver.

Diversity causes difficulty in clinical practice so says Dr Anguraj Sadanandam.

He recently published a reviewon the molecular biology of pancreatic neuroendocrine tumours.

There is a clear unmet need when it comes to pancreatic neuroendocrine cancer we know that patients diagnosed with pancreatic tumours are not seeing the same improvements in treatment that we see for other cancer types.

Our researchers are dedicated to tackling cancers that continue to have very poor survival rates such as pancreatic cancer.

Find out more

Pancreatic neuroendocrine tumours are divided into grades by the World Health Organisation based on features of the cells that are common when we look down the microscope.

When cells divide, they make a complete copy of all of their chromosomes.

Under ordinary circumstances, a cell keeps all of its genetic material wound up and compact inside of the nucleus the control centre of the cell. In order to divide, the cell unwinds all of its chromosomes and unzips them to make copies.

By using special staining, scientists are able to assess how many cells have visible chromosomes. Visible chromosomes give a good indication that the cell is in the middle of dividing.

If lots of cells show signs of being in the middle of dividing, scientists can get an indication of how fast the tumour is growing and how aggressive it is. More cells making copies means more growth and a highly aggressive tumour.

Combining this information about cell division with other visible changes to cells results in pancreatic tumours being divided into three grades.

Grade 1 tumours have the best prognosis patients have a median overall survival of 12 years with this type of tumour.

Median overall survival refers to the length of time from either the date of diagnosis or the start of treatment for a disease that half of patients in a group are still alive.

Grade 3 tumours have the worst prognosis, with a median overall survival of just 10 months.

Roy Bowdery was diagnosed with pancreatic cancer in April 2014 following a prolonged period of pain in his stomach and back.

His pancreatic cancer was an adenocarcinoma these cancers have different biology from neuroendocrine tumours, but survival compared to other more common cancers is also relatively poor.

Although one-year survival rates for pancreatic cancers have been improving in recent years, there hasnt been much of an improvement in five and 10-year survival rates since the 1970s.

Despite repeated trips to his local GP, it took several weeks before Roy was sent for a CT scan as part of a local bowel cancer screening programme, and it was only then that doctors discovered the tumour on his pancreas.

Fortunately, Roy qualified for the Whipple procedure a 10-hour surgery to remove thelower half of the stomach, duodenum, gall bladder, bile duct and the head of the pancreas.

This was followed up with six months of chemotherapy.

Roy now lives cancer-free, but goes for check ups every six months. He knows he's one of the lucky few. One in four people die within the first month of diagnosis and only 1 per cent of patients survive 10 years.

"Pancreatic cancer is a really brutal type of cancer," Roy explains. "It's the most fatal of all common cancers. I've just gone over the five year mark, and now my aim is to get into the one per cent."

Since his diagnosis, Roy has been actively campaigning to change the journey for others in the future.

"The figures haven't improved in my five years, and they haven't even improved in the last 40 years. There needs to be more research, and there needs to be a quick, easy diagnostic test to catch the cancer early, so more people get a chance at surgery and get a chance to survive.

We are now poised to outsmart cancer with the worlds first anti-evolution 'Darwinian' drug discovery programme, in which we will focus on understanding, anticipating and overcoming cancer evolution, and preventing drug resistance.

Find out more

Although the World Health Organisations grading of tumours is useful in that they give some indication of prognosis, there are substantial differences in tumours within the same grade, and this makes personalised treatment for these tumours hugely challenging.

Dr Sadanandam published a major paper five years ago which divided pancreatic neuroendocrine tumours into molecular subtypes.

The study recreated pancreatic cancer in mice, and together with data from human cancers the researchers were able to classify the tumours in three different ways.

Untangling the complexities of the cancer and categorising the tumours can help when it comes to making decisions about treatment - the aim is always to personalise treatment as much as possible for the specific tumour and the specific patient in front of you.

In other types of cancer, recent research has drastically improved our ability to give a precision diagnosis to each patient, which not only improves the accuracy of the information we can give to a patient about how their cancer is likely to progress, but also allows clinicians to pick the best possible treatments.

For example, recent research from the ICRshowed that testing men for faults in DNA repair genes in their tumours could identify those most likely to respond to a new type of search-and-destroy treatment.

The treatment seeks out a particular molecule called PSMA (prostate-specific membrane antigen) on the surface of prostate cancer cells and uses a radioactive particle to kill the cells.

This type of approach - finding something unique to a particular cancer type, identifying it and targeting treatments against it is the next big challenge when it comes to pancreatic cancer.

Dr Sadanandam explains:

There is a clear unmet clinical need for novel prognostic and predictive biomarkers to complement the World Health Organisations grading system.

We need more detailed information with which we can categorise tumours to guide us in determining overall survival rates and to support individualised treatment decisions for patients.

In order to bring pancreatic cancers to a level playing field with other cancers, research focusing on comparisons is key.

By examining the similarities pancreatic cancers have to other types of cancer, scientists can begin to unravel the specific cell changes that make the tumours so aggressive and difficult to pin down.

In order to bring pancreatic cancers to a level playing field other cancers, research focusing on comparisons is key. Thats an approach Dr Sadanandam is taking in an ongoing study which is comparing the similarities pancreatic and other cancers have to colon cancers.

By classifying and reclassifying cancers into different subtypes, the problem becomes easier to tackle like categorising your belongings before tackling a big spring clean.

Other ICR researchers are taking the same approach Professor Chris Lord, Deputy Head of the Division of Breast Cancer Researchat the ICR works with PrecisionPanc, a research platform which has collaborators from across the cancer research spectrum.

They are translating basic scientific discoveries into the clinic by looking at the genetics of pancreatic cancers, and developing biomarkers which help doctors understand the roadmap of a patients cancer. They are also working hard to develop new treatments to tackle the tumours.

There is a long way to go before the playing field is leveled, but further research will pave the way for smarter, kinder treatments.

Excerpt from:
Squaring up to silent tumours: the research burden of pancreatic cancer - The Institute of Cancer Research

Recommendation and review posted by Bethany Smith

Frank Lawlis possesses a deep Texas drawl, one that makes the now-iconic intonation of Dr. Phil McGraw his decades-long friend and business associate seem almost city-slicker by comparison. His down-home voice, along with the bolo ties, pale eyes and unkempt white hair, are a comfort to the clients who travel to his private practice from all over the country in the hope that he can help mend minds even those minds that other doctors cannot.

The Lawlis Peavey PsychoNeuroPlasticity Center, in suburban Lewisville north of Dallas, primarily caters, by his estimate, to troubled adolescents as well as people decades older "who've never been able to launch themselves," he says. A battery of tests, including brain mapping, is administered in an attempt to pinpoint the problem during a two-day visit. Only a diagnosis is provided in exchange for the $9,295 fee, not treatment.

The Lewisville center is where Lawlis screens select Dr. Phil guests as well as many clients who've found their way through the door because they watch the CBS-syndicated daytime show. It's also where, in between rooms devoted to a hyperbaric chamber and a sensory deprivation compartment, Lawlis takes his seat in a remote studio for his regular Dr. Phil segments.

Lawlis, 79, holds an influential position as chief content adviser to McGraw. Drawing more than 3 million viewers each weekday, Dr. Phil has been the No. 1 syndicated talk show by a healthy margin, ahead of competitors like Ellen and Live With Kelly and Ryan, since Oprah Winfrey left broadcast TV in 2011. McGraw, who has branded himself as an authoritative voice on the nation's public health issues, made an estimated $95 million in 2019, according to Forbes, and received a star on the Walk of Fame on Feb. 21.

Without the platform of Dr. Phil, Lawlis, who espouses ideas and treatments considered controversial and even dangerous by the mainstream medical community, might be a figure on the margins of public health. But his ability to directly impact the show's guests, and inform its massive audience, makes him a figure of consequence.

Dr. Phil viewers recognize Lawlis from his frequent appearances as a designated expert on the show, during which McGraw treats Lawlis with notable respect, often introducing him as one the foremost authors or experts on whatever subject he's conferring on. (Lawlis was McGraw's Ph.D. adviser decades ago.) Beamed in from Texas and donning a white coat, Lawlis weighs in on everything from opioid dependency to autism. In a 2017 segment focused on Chase, a 19-year-old man who claimed his life had spiraled out of control after a marijuana-induced panic attack, McGraw said he was sending him to the Lewisville clinic to get a "scan of your brain." Lawlis, who ventured that "we also might have a feature of PTSD" to explore, explained that techniques "that work very quickly" would be utilized that "will help resolve him back to where he was before." Hearing the news back in Los Angeles on the Paramount lot, Chase and his family dissolved into hugs and tears as the crowd applauded.

While the talking-head segments are Lawlis' most visible contribution to the show, more important is his behind-the-scenes input, acting as the guru's guru. In coordination with producers, Lawlis vets would-be guests with psychological problems, consults with McGraw on how to advise them during their segments (despite his famed honorific, McGraw holds no license to practice medicine), examines the thorniest cases at his Texas clinic and helps coordinate treatment at favored rehab facilities. "There's probably not a show that goes on the air that doesn't have Dr. Lawlis' feedback," explains Dr. Barbara Peavey, Lawlis' private practice partner. Lawlis also has weighed in on McGraw's congressional testimony the TV host has been invited to Capitol Hill to speak about mental health and advised on his best-selling books.

Lawlis derives multiple income streams from his work with Dr. Phil as an adviser to the show, as a proprietor of the clinic where additional services are performed on selected guests, and as a consultant to the rehab facility where many are later treated. (Guests themselves are not paid to appear on Dr. Phil.)

Even apart from his work with McGraw, Lawlis boasts an eclectic rsum. His sojourns have included heading a prayer healing foundation in Santa Fe for cancer patients, running a Silicon Valley institute dedicated to the study of transpersonal psychology mystical experiences, spiritual crises, altered states of consciousness and consulting on a mental wellness program pertaining to employee overwork in Japan for a division of Toyota. For the past two decades, he's worked part-time, designing exams as the testing director for the American branch of the international high-IQ society Mensa. (He's never applied to become a member: "I don't think it makes ethical sense that I take the test that I already know about.") There he sees the effect of Big Pharma a perceived nemesis through much of his work observing that the organization has been grappling with doping among applicants: "Adderall is a big one."

Lawlis sees himself as an anti-establishment maverick. He fondly recalls the Dallas Police raiding a pain group he once ran at an area hospital circa 1980, during which as an experiment in pain relief he passed around a peace pipe whose tobacco included willow bark and sage. The authorities wanted to arrest him on a marijuana charge. "But three of the participants were actually cops, so it was dropped," he says. "The [hospital] administration said never to do it again."

In another incident at a medical facility in Fort Worth, Texas, he constructed a saltwater floatation tank for patient use that soon leaked into the cardiac intensive care unit below. "It turned out to be one of the best things that ever happened," Lawlis remembers. "I walked in, expecting to be fired, and the chief of staff said, 'Frank, don't make anything! If you want something made, we'll do it for you!' He did and it was beautiful." Lawlis shrugs, amused. "I'm always looking over my shoulder, afraid of going to prison."

Lawlis, who's from a small West Texas town, contends his lifelong contrarianism was set in motion by a pair of character-establishing childhood experiences. By his account, he was "born dead," or at least his folks told him so growing up: Because of birthing complications involving pain medication, he'd been oxygen deprived and brain damaged. "This notion existed in my family from that point on even when I got my Ph.D.," he says. "I had tremendous problems in school. Now it could be explained in other ways, like ADHD."

The other defining feature shadowing his youth was his mother's chronic ill health, largely gastric and arthritic in scope, which required more than two dozen operations. "As a kid, I lost faith in Western medicine," Lawlis says. "I had the insight that many of my mother's problems were psychological. My father [a pharmacist turned pharmaceutical sales representative] wanted me to be a doctor. But seeing the failure for her in terms of pills and surgery, I wanted to be somebody who could help through behavior."

Lawlis, inspired in part by The Eleventh Hour, a 1960s NBC medical drama about psychiatry, compares his chosen vocation to a secular ministry and has taught at several schools, including the University of North Texas, where he met McGraw. His future boss stood out to Lawlis from his pupil's first day in his doctoral-level class in advanced personality. "There were about 12 people in there, and all of them were writing notes down like crazy except him," Lawlis says. "He was looking at me like he already knew it. We would have conversations, and he did know it. I made a decision that he was either the dumbest guy or the smartest guy I've ever dealt with."

The pair grew close, bonding over their mutual pasts as college football players and their hobbyists' joy in piloting small planes. In the decades that followed, before national prominence on Dr. Phil, they teamed on business ventures, including a never-launched set of seminars for physicians.

Later, when McGraw had set up his litigation services firm Courtroom Sciences, which inspired the CBS drama Bull, his mentor was regularly contracted out as an expert witness in personal injury cases. "I would testify as to what money [the plaintiff] would've made as opposed to how much money he's capable of now," Lawlis says.

Since Dr. Phil's 2002 debut, McGraw has faced criticism over his credibility. He's taken it all in stride. During a segment on the Late Show With David Letterman the following year, he pulled out a list of epithets (including "half-baked quack") the host had called him and good-naturedly read them on-air. In 2017, medical news outlet STAT and The Boston Globe published an investigation into the alleged exploitation of Dr. Phil guests with addiction problems, asserting some had been allowed easy access to alcohol and drugs in immediate advance of showtime. Martin Greenberg, a psychologist who serves as Dr. Phil's director of professional affairs, denied the claims. Previously, McGraw found himself fighting a yearslong class-action lawsuit involving the psychotherapist customers of a service called the LearnDrPhil Network. The litigation claimed the service had, in exchange for their participation in the program, dangled referrals from the large pool of Dr. Phil viewers. Lawlis was part of the endeavor and named as a defendant in the case, which was settled in 2009. Lawlis says now of the service, "That's gone away."

McGraw's engagement with celebrity mental health issues also has drawn criticism. Britney Spears' parents said he violated their trust after he publicly spoke about a private visit with the troubled pop singer in 2008. Eight years later, a heavily promoted November sweeps episode of Dr. Phil focused on a disoriented Shelley Duvall. Mia Farrow and Ron Perlman called it exploitative. Lawlis stands by the program. "You can't script what a person says, and sometimes the guests are their worst enemies. We don't exploit a person's problems," he says. "I always think we can do better, but I think we do a better job than anybody else has ever done with the types of things we deal with."

***

About 20 Dr. Phil guests cycle through the PsychoNeuroPlasticity Center each season. Its website notes it helps clients with ADHD, autism, mood disorders, OCD, PTSD and other challenges. "I can tell you that for the majority [of visitors]," Peavey explains, "it's 'I've heard about you through Dr. Phil.' "

Peavey, who was once Lawlis' student and now handles the administrative end of their partnership, says multiple show guests have confided that they initially contacted Dr. Phil with the specific intent to secure an expenses-covered visit to the Texas clinic. (Insurers may also cover a portion of the price tag.)

The customized screening includes a variety of diagnostic tests, among them the use of a medical instrument designed by Lawlis and his son, an electrical engineer, called the Bio-Acoustical Utilization Device, or BAUD. It emits calibrated sounds in each ear think of drumming rhythms with the intended benefit of influencing brain function. In 2006, the FDA granted Lawlis permission to use and sell the BAUD "for relaxation training and muscle reeducation and prescription use." Lawlis, meanwhile, characterizes the BAUD as a panacea for a variety of health problems. "A person comes in with PTSD and you give him the BAUD and after 30 minutes it goes away," he claims.

In 2014, the Texas State Board of Examiners of Psychologists disciplined Lawlis and Peavey for the same offense: Allowing one of their staffers, who was not licensed, to provide psychological services under their watch for more than a year. More recently, according to the agency's records, Peavey was reprimanded for having signed an employee application to practice psychology in the state "that contained inaccurate and false information." Peavey is prohibited until August from "providing any supervision of psychological services provided by another person."

Lawlis was unwilling to substantively address his history with the Texas State Board. Peavey didn't clarify either.

In addition to his partnership stake at the Texas clinic, Lawlis is a salaried consultant at Los Angeles-based Creative Care, an inpatient rehabilitation center that specializes in dual diagnosis cases (the overlap of substance abuse and mental illness) and is one of fewer than two dozen "Dr. Phil Preferred" facilities in the country, meaning it's received his on-air seal of approval and is listed on the show's website resource page. Show guests often receive treatment there, their cost covered by the program. In return, Dr. Phil publicizes Creative Care on-air, an arrangement that drives nearly a third of its admissions, according to the rehab. The facility treats 300 people each year. Between two and four Dr. Phil guests, who have often already visited Lawlis' Texas assessment center, are in treatment at Creative Care during the show's season at any given time.

Creative Care has operated for three decades in Malibu, pioneering the region's so-called Rehab Riviera alongside Promises. Its facility on a 40-acre property just up the road from Broad Beach was wiped out by the Woolsey Fire in November 2018, so the center has temporarily resettled to a series of adjacent houses in Woodland Hills, where it can treat up to 24 clients. Lawlis visits for several days each month and works daily by email and phone.

Around the time of the fire, Dr. Farrah Khaleghi, the 30-year-old, recently credentialed psychologist daughter of Creative Care's husband-and-wife co-founders, was appointed its clinical director. "Dr. Lawlis calls me 'the phoenix,' " she explains during a visit to the facility in October. "I wanted to fine-tune all of our program elements. We survived. Let's use this opportunity for a rebirth." Though her parents have had an affiliation with Lawlis and Dr. Phil for more than 15 years, Khaleghi has leaned into Lawlis' methods to put her own stamp on the program a majority of the facility's clients now utilize some component of Lawlis' "Neuroplasticity Transformation Program," which includes use of a sensory deprivation chamber designed to his specifications.

The chamber is a heated waterbed in which clients, cloaked in darkness, speak to their therapist or listen to music. Close to half of those in treatment at Creative Care also make use of the BAUD: "It's an extra layer of support," says Khaleghi. "For our population that's so acute, with really serious mental health and addiction issues, the more tools the better."

By Khaleghi's account, her staff's use of Lawlis' techniques as a complement to the overall treatment regimen has been helpful in convincing clients not to self-discharge during their first month in residence, a common challenge for inpatient rehabs. "Sometimes people that really struggle with nervous system agitation itchy people that are always kind of fidgety neuroplasticity is a way to regulate them, to settle them down so they're not acting out as much and leaving," she says. "The first three or four weeks are super-vulnerable and this is soothing."

Khaleghi notes that the clients often find Lawlis' methods appealing because they're a departure from prescription treatment. "It's not invasive, it's not 'artificial,' it's really present-focused and organic," she says.

Creative Care has its own troubles, past and present. In 2012, the California Senate Office of Oversight and Outcomes produced a report, "Rogue Rehabs," about how the state "failed to police drug and alcohol homes, with deadly results." Creative Care was a key case study. The report noted that the facility had "offered medical care, contrary to state law, for 10 years."

In December, after THR's visit, California's Department of Health Care Services suspended its license following two client deaths. According to the Los Angeles County coroner's office, on Feb. 16, 2019, a 54-year-old woman died by suicide on-site, and on July 4, a 26-year-old man died of a fentanyl overdose. (A representative for Dr. Phil says that neither was a show guest.) "We have no comment," Khaleghi wrote by email when asked about these developments.

Lawlis and McGraw have recently cut ties with Creative Care, and the rehab has scrubbed its website of Dr. Phil material at the TV host's request. "Phil doesn't want anybody to think that he sent anybody to a program that has had its license suspended," Lawlis explains.

McGraw who declined to participate in this story wouldn't say why the facility had long persisted as a preferred provider of care despite its public record. He also wouldn't elaborate on Dr. Phil's vetting process for the treatment facilities it directs its guests and viewers toward.

A CBS spokesperson for the program did, however, provide a statement. "The platform provides the opportunity for guests to connect with and avail themselves to a variety of health care providers, including individual therapy, outpatient and inpatient facilities," it reads. "In doing so, guests meet with the resource representatives and decide for themselves if they choose to participate or not. By forming working relationships with hundreds of quality professionals and facilities, it is expected that these independent resources comply with the laws and regulations of their governing licensing or regulatory agencies. Upon being notified of alleged activity that raises significant regulatory concerns regarding any of these resources, the working relationship is terminated until the matter has been resolved within the rules and guidelines governing state agency or board."

***

Lawlis is strikingly confidentabout the BAUD, comparing his breakthroughs to Charles Goodyear's discovery of vulcanized rubber. By his account, 86 patients were treated by 19 therapists in a study he conducted, and "all were significantly improved, with most having no more symptoms in three sessions or less," he wrote in his 2015 book Psychoneuroplasticity Protocols for Addictions. (He's published more than a dozen books on various subjects.)

Yet despite such an impressive suggested outcome, other researchers have since ignored the device. This is because, Lawlis acknowledges, his own study was never accepted for publication. "Credibility is an issue," he says.

Lawlis who has been published in peer-reviewed outlets like Spine and the Journal of Psychosomatic Research blames conflict-of-interest policies for his inability to gain scientific traction for the BAUD. "I can't get it through a review committee," he says. "They say, 'I'm sorry, you have a self-interest in this. That's a problem.' "

Dr. Stephen Barrett, a psychiatrist and peer-review panelist for several top medical journals, has been skeptical of the BAUD for years, listing it as a questionable medical instrument on his anti-fraud watchdog website, Device Watch. "Conflict of interest isn't a legitimate reason not to be published," he says. "If the study is appropriate, journals simply disclose the conflict. The more likely reason he hasn't been published is that his research hasn't been adequate."

Lawlis contends the BAUD is useful for addressing not just PTSD but drug addiction, ADHD, depression, anxiety, phobia and pain. Barrett believes this transgresses the FDA's allowance, observing in particular that use for depression could be dangerous. "If the device is not effective, and you represent that it treats depression, you may be dealing with people who have the potential for suicide," he says.

Lawlis and Peavey have other views that counter prevailing accepted science. They question childhood immunization scheduling standards that have been established by the federal Centers for Disease Control and Prevention. "My theory is that if the child is still dealing with the mother's immune system," ventures Lawlis, "maybe in some instances the vaccines confuse the whole immune system. But if you wait a little longer, where you have more of a balanced person that can incorporate it, that might be the solution." The pair also express unease about what they perceive as the pernicious effects of mercury in vaccines, principally the MMR inoculation (scientific consensus has determined it's safe), believing such shots may be responsible for some of the problems their clients face.

Lawlis' belief that mercury may, as he put it in his 2010 book, The Autism Answer, induce "a cascade of poor auto-immune reactions which produce autistic behaviors," has led him to advocate for an unproven application of chelation therapy, a detoxification process in which heavy metals and minerals are removed from the body. The FDA has approved chelation therapy for heavy metal toxicity, such as lead poisoning, but warns against unapproved use for autism disorders.

Dr. Kelly Johnson-Arbor, a toxicology expert and co-head of the National Capital Poison Center in Washington, D.C., is alarmed. "Putting aside that the idea that vaccines cause autism has been widely discredited, this treatment approach is both unreliable and may even have negative effects," she says, noting that chelation also can have the deleterious consequence of extracting nutrients, from electrolytes to potassium. "There is no medical basis for it."

While Peavey speaks of chelation as an active component of the Texas practice, Lawlis claims "we have not used it for the last three or four years at all."

Lawlis ventures other arguable contentions as well. In 2008's Retraining the Brain (which McGraw blurbed, touting "groundbreaking techniques that can dramatically improve our lives"), he connects exposure to TV and video games after the age of 7 to ADD diagnosis. "The dust that comes from the heat shields and sound-proofing in the back of color television sets has been shown to have very negative effects on hormone levels and disruption of cognitive abilities," he writes. When asked about the evidence, he responds: "Well, let me just say this. I'm not at liberty to reveal the sources. But it has to do with some people I know in Washington that have been studying these waveforms, especially that come from cellphones and other sources."

***

At a Tex-Mex restaurant north of Dallas, Lawlis sweepingly dismisses the legitimacy of double-blind studies, the placebo-controlled, randomized trials that are a cornerstone of medical research. He argues that humans are too complex to provide a true control group. Regardless, "I read through the journals and they're not making any headway," anyway. "If you read the [studies'] titles, it's amazing how stupid the findings are: 'Children From Conflictual Families Don't Do Well.' " He goes on, "We haven't learned a goddamn thing from that particular approach."

Lawlis' wife, Dr. Susan Franks, a neuropsychologist on the faculty at the Texas College of Osteopathic Medicine in Fort Worth, contextualizes his view. "Where he gets frustrated is, because the double-blind trial puts everything in a box, how do you start moving out of the box?" she says. "How does science advance? He's just so outside the box. He's bringing in concepts and integrating everything and coming up with creative approaches."

As a contrast, Franks points to herself and other academic subspecialists. They're "very focused on the science and the numbers, and we're not the most creative people." She adds, "the data can't show everything."

Dr. Nina Shapiro, an extensively published UCLA surgeon and author of Hype: A Doctor's Guide to Medical Myths, Exaggerated Claims and Bad Advice, takes issue with the couple's outlook. "It's predatory on people who are desperate, on people who are seeking some sort of 'alternative,' " she says. "If you're someone with charisma and a following, it's enticing to a captive audience. But it's sad."

Lawlis' latest book, Healing Rhythms to Reset Wellness, will be published in April. He wrote it last year following "an a-ha moment when I was studying string theory and, at the same time, I was reading about Egypt's ancient medicine." The treatise, which underscores his break from the strictures of hard science "double-blind research," he writes, "doesn't take into account how human healing happens" contends that treating illness is about balancing circadian rhythms. "The reason we get sick," Lawlis says, "is that we get out of tune with our rhythms."

McGraw penned the book's foreword. "He offers works of magnitude, not frivolity, not pop psychology, not trends," he writes of his mentor, going on to extol their half-century relationship. "In everything he does, Dr. Lawlis' impact has been profound."

Email Gary Baum at gary.baum@thr.com.

This story first appeared in the Feb. 26 issue of The Hollywood Reporter magazine. Click here to subscribe.

Excerpt from:
The Controversial Therapist Shaping Dr. Phil - Hollywood Reporter

Recommendation and review posted by Bethany Smith

Image source: The Motley Fool.

Viking Therapeutics Inc(NASDAQ:VKTX)Q42019 Earnings CallFeb 26, 2020, 4:30 p.m. ET

Operator

Good day, and welcome to the Viking Therapeutics Fourth Quarter 2019 and Year-End Conference Call. [Operator Instructions]

I would now like to turn the conference over to Stephanie Diaz, Investor Relations. Please go ahead.

Stephanie C. Diaz -- President and Chief Executive Officer

Hello, and thank you all for participating in today's call. Joining me today is Brian Lian, Viking's President and CEO; and Greg Zante, Senior Vice President of Finance.

Before we begin, I'd like to caution that comments made during this conference call today, February 26, 2020, will contain forward-looking statements within the meaning of the Securities Act of 1933 concerning the current beliefs of the Company, which involves a number of assumptions, risks and uncertainties. Actual results could differ from these statements, and the Company undertakes no obligation to revise or update any statement made today. I encourage you to review all of the Company's filings with the Securities and Exchange Commission concerning these and other matters.

I'll now turn the call over to Brian Lian for his initial comments. Brian?

Brian Lian -- President and Chief Executive Officer

Thanks, Stephanie, and thanks to everyone listening on the webcast or by phone. Today we'll provide an overview of our fourth quarter and year-end 2019 financial results as well as an update on recent progress and developments related to our pipeline programs and operations. 2019 was a year of tremendous progress at Viking, building on the momentum that follows the successful outcomes of our completed clinical studies.

With respect to our lead program VK2809, our novel thyroid receptor beta agonist, we completed the important work required to support a Phase 2b study in patients with biopsy-confirmed NASH. And we are pleased to announce in November, the initiation of this important study. With respect to VK0214, our second thyroid receptor beta agonist, our efforts during 2019 focused on continuing the IND enabling work required to commence clinical studies of this molecule and we expect to file an IND for this program in the first half of this year.

I will provide additional detail on our development activities in a few minutes. But first, we'd like to review our fourth quarter and year end financial results. For that, I'll turn the call over to Greg Zante, Viking's Senior Vice President of Finance. Greg?

Greg Zante -- Senior Vice President of Finance.

Thanks, Brian. In conjunction with my comments, I'd like to recommend that participants refer to Viking's Form 10-K filing with the Securities and Exchange Commission, which we filed after the market close today for additional detail.

I'll first go over our financial results for the fourth quarter ended December 31, 2019. Our research and development expenses for the three-months ended December 31, 2019 were $6.5 million compared to $5.1 million for the same period in 2018. The increase was primarily due to increased expenses related to clinical studies with the initiation of the Phase 2b VOYAGE study during the quarter and manufacturing for our drug candidates, partially offset by decreased expenses related to our pre-clinical studies and services provided by third-party consultants. Our general and administrative expenses for the three months ended December 31, 2019 were $2.4 million compared to $1.9 million for the same period in 2018. The increase was primarily due to increased expenses related to stock-based compensation and professional fees.

For the three months ended December 31, 2019, Viking reported a net loss of $7.5 million, or $0.10 per share, compared to a net loss of $5.2 million, or $0.07 per share, in the corresponding period in 2018. The increase in net loss and net loss per share for the three months ended December 31, 2019 was primarily due to increased research and development and general and administrative expenses noted previously, as well as decreased interest income due to the decline in interest rates throughout 2019 as compared to prevailing interest rates during the fourth quarter of 2018.

Research and development expenses for the 12-months ended December 31, 2019 were $23.6 million compared to $19 million for the same period in 2018. The increase was primarily due to increased expenses related to manufacturing for our drug candidates, clinical studies, services provided by third-party consultants and salaries and benefits, partially offset by decreased expenses related to pre-clinical studies.

General and administrative expenses for the 12-months ended December 31, 2019 were $9.1 million compared to $7.1 million for the same period in 2018. The increase was primarily due to increased expenses related to stock-based compensation, services provided by third-party consultants, corporate insurance, legal and patent expenses and professional fees.

For the 12-months ended December 31, 2019, Viking reported a net loss of $25.8 million, or $0.36 per share compared to a net loss of $22.1 million, or $0.38 per share in the corresponding period in 2018. The increase in net loss for the 12-months ended December 31, 2019 was primarily due to increased research and development and general and administrative expenses as noted previously, partially offset by increased interest income as well as the elimination of expenses related to the change in fair value of the debt conversion feature liability due to the repayment of the Ligand, noted May 2018. The decrease in net loss per share for the 12-months ended December 31, 2019 was primarily driven by the additional weighted average shares outstanding at December 31, 2019 versus those outstanding at December 31, 2018, given the public equity financings that occurred during 2018.

Turning to the balance sheet. At December 31, 2019, Viking held cash, cash equivalents and short-term investments totaling $275.6 million and had 72,413,602 shares of common stock outstanding.

This concludes my financial review and I'll now turn the call back over to Brian.

Brian Lian -- President and Chief Executive Officer

Thanks, Greg. I'll now provide an update on recent progress and activity with our lead program VK2809. As a reminder, VK2809 is an orally available small molecule agonist of the thyroid hormone receptor that possesses selectivity for liver tissue as well as the beta receptor subtype suggesting promising therapeutic potential in a range of metabolic disorders including NASH. In September, 2018, we announced positive results from a 12-week Phase 2 trial of VK2809 in patients with hypercholesterolemia and non-alcoholic fatty liver disease. As we previously discussed, this trial successfully achieved both its primary and secondary endpoints, demonstrating potent reductions in liver fat content as well as improvements in plasma lipid measures. As a brief reminder patients receiving VK2809 experienced median relative reduction in liver fat ranging from 54% to approximately 60%, compared with approximately 9% for placebo.

The proportion of patients experiencing at least a 30% relative reduction in liver fat range from 77% to 100% with the overall average of 88%, compared with 17% for placebo patients. In addition, 70% of patients receiving VK2809 experienced at least a 50% relative reduction in liver fat content compared to baseline. VK2809 also produced significant reductions in plasma lipids, including LDL-cholesterol, triglycerides and atherogenic proteins such as apolipoprotein B and lipoprotein (a). This lipid lowering profile is a novel feature of thyroid receptor beta activation, and is a particular interest in the setting of NASH as it may suggest long-term cardiovascular benefit.

In addition to the impressive efficacy observed, VK2809 has also demonstrated an encouraging safety and tolerability profile. In the Phase 2 study, no serious adverse events were reported among patients receiving VK2809 or placebo and the overall numbers of adverse events were relatively evenly distributed across treatment arms. We believe VK2809's potent liver specific effects combined with the safety, tolerability and potential cardiovascular benefits, that is a part from competitive programs targeting NASH. And we are very pleased to advance this compound into a Phase 2b study in patients with biopsy-confirmed NASH. In preparation for this study, in 2019, we completed several additional clinical and pre-clinical evaluations of VK2809 to enable us to file a new IND with the FDA's Division of Gastroenterology and Inborn Errors Products. As a reminder, a new IND required because the prior IND was directed toward hyperlipidemia and was active in the division of metabolic and endocrine products. However, the GI division is where most NASH IND applications are reviewed.

In preparation for the NASH IND, during 2019, we completed several new studies in addition to the 12-week Phase 2 study I described a moment ago. These included a Phase 1 study to evaluate the safety, tolerability and pharmacokinetics of VK2809 when co-administered with atorvastatin. The results of this study confirmed previously reported data, demonstrating no meaningful interaction between VK2809 and with atorvastatin. We also conducted the Phase 1 study to evaluate the safety, tolerability and pharmacokinetics of VK2809 dosed in an every other day regimen. These data confirmed previously reported results, demonstrating that VK2809 possesses a predictable and consistent PK profile.

We also conducted a Phase 1 study to evaluate the safety, tolerability pharmacokinetics and pharmacodynamics of VK2809 under various dosing regimens. These data demonstrated that alternative dosing regimens may also produced improvements in measures of plasma lipids. And finally, we completed toxicity studies of 26 and 52 weeks in duration to support chronic dosing in humans. The results of this and prior work formed the basis of the new IND that was filed with the GI division. Following the IND filing in November, we announced the initiation of a Phase 2b study of VK2809 in patients with NASH. We've named this study as the VOYAGE study and we're excited to have it under way.

The VOYAGE study is a randomized, double-blind, placebo-controlled, multicenter trial designed to efficacy, safety and tolerability of VK2809 in patients with biopsy-confirmed NASH and fibrosis. The study will target enrollment of approximately 340 patients across five treatment arms, including 1 milligram daily; 2.5 milligrams daily; 5 milligrams every other day; 10 milligram every other day; and placebo. The target population includes patients with F2 and F3 fibrosis as well as up to 25% with F1 fibrosis. F1 patients must also possess additional risk factors to be eligible for enrollment. The primary endpoint of the study will evaluate the relative change in liver fat content, as assessed by magnetic resonance imaging, proton density fat fraction from baseline to week 12 in subjects treated with VK2809, as compared to placebo. Secondary objectives include evaluation of histologic changes assessed by hepatic biopsy after 52 weeks of dosing. We are currently dosing patients at clinical sites in the U.S. and expect to open additional sites outside the U.S. later this year.

In addition to commencing the VOYAGE study, in the fourth quarter, we submitted an abstract describing additional data from the prior 12 -week Phase 2 study of VK2809 for presentation at the annual meeting of the European Association for the Study of the Liver, or EASL. We were recently informed that this abstract has been selected for an oral presentation on April 17. We look forward to sharing these additional data at that time. Given the positive results from the previous Phase 2 trial and the supplemental data generated in multiple studies during 2019, we continue to believe that VK2809 demonstrates a compelling efficacy and safety profile with the potential to provide benefit to the millions of patients worldwide suffering from NASH. We look forward to sharing additional updates on VK2809 and the voyage study as the trial progresses.

I'll now provide an update on our VK0214 program. VK0214 is being evaluated as a potential treatment for X-linked adrenoleukodystrophy, or X-ALD. X-ALD is a devastating disease for which there is no approved treatment. The disease is caused by a defect in a peroxisomal transporter called ABCD1. This defect can result in an accumulation of very long-chain fatty acids in plasma and tissue and it is these elevated very long-chain fatty acid levels that are believed to contribute to the severe cerebral and motor neuron toxicities that are characteristic of the disease. The thyroid beta receptor is an important potential target for therapeutic intervention in X-ALD because it is believed to play a role in very long-chain fatty acid metabolism.

Like VK2809, VK0214 is an orally available small molecule bioreceptor agonist that possesses selectivity for the beta receptor subtype. To-date, results from in vitro and in vivo studies have demonstrated that administration of VK0214 results in a significant increase in the expression of the compensatory transporter, which is believed to result in a reduction of very long-chain fatty acids in both plasma and tissue. Given these promising results we believe VK0214 may provide benefit to patients with X-ALD and we are eager to move this program into the clinic. We are currently conducting IND enabling work for VK0214 and we expect to file the IND in the first half of this year, followed by initiation of a proof-of-concept study in humans.

With our two lead programs advancing in clinical development, we continue to carefully manage our balance sheet. As Greg reported earlier, we ended 2019 with approximately $275 million in cash and equivalents. We believe these resources provide ample runway to reach multiple clinical inflection points with both VK2809 and VK0214.

In closing, I'd like to reiterate that the important work completed in 2019 was critical to pave the way for realizing the potential of both VK2809 and VK0214. For VK2809, the compelling data generated in both 2018 and 2019 validate our belief that it is one of the most promising candidates in development today for the treatment of NASH. And we are excited to be advancing it through the clinic. We look forward to continue the enrollment in our Phase 2b VOYAGE study. With respect to VK0214, we continue working toward completion of the IND enabling studies that will allow us to initiate a proof-of-concept study in humans. It is our goal to file this IND during the first half of the year. Finally, our balance sheet remains strong, providing the resources to execute through multiple value-creating events.

This concludes our prepared comments for today. Thanks again for joining us. And I'd now like to open the call for questions. Operator.

Operator

Thank you. We will now begin the question-and-answer session. [Operator Instructions] Our first question today will come from Joon Lee of SunTrust. Please go ahead.

Joon Lee -- SunTrust -- Analyst

Hi. Thanks for taking my questions, and congrats on getting the podium presentation for 2809 at EASL. In addition to the additional data from the Phase 2 novel study, will you also be sharing additional pre-clinical tox data as well? And can you tell us where you are in submitting the full tox data to cover the entire 12 months? Is that imminent or has it already been submitted? And I have one more follow-up. Thank you.

Brian Lian -- President and Chief Executive Officer

Hey, Joon. Yes, thanks for the questions. No, as part of the presentation at EASL, we won't be disclosing any of the the toxicity studies that were completed in animals. The submission of the full 12 month dataset is imminent and yes, it's very near term, I'd say, all the reports are completed there are just -- undergoing final QC proofing.

Joon Lee -- SunTrust -- Analyst

Great. And can you tell us a little bit about the design of the X-ALD proof-of-concept study? What that would look like and what you would hope to learn from that initial study? Thank you.

Brian Lian -- President and Chief Executive Officer

Yes, no, great question. So the -- it's sort of a two-tiered clinical study, the first portion will target healthy volunteers in this is called the stacked design where you begin single ascending dose study in healthy volunteers and during that you begin dosing multiple saying dose study also in healthy volunteers in during that, then you begin enrolling patients with X-ALD. We would target a 28-day treatment window and look at very long-chain fatty acid changes after 28 days. And with those data then, if they are encouraging, we would then speak with the FDA about what the next steps might look like. But that would be the proof-of-concept.

Joon Lee -- SunTrust -- Analyst

And when do we hope to get the top line? If at all, on the initial study?

Brian Lian -- President and Chief Executive Officer

Yes, I would say, the most likely window for that is probably going to be first half of '21. I mean it's not impossible that it would be available later this year, but I would say first half of '21 is a safe bet.

Joon Lee -- SunTrust -- Analyst

Great. Thank you very much.

Brian Lian -- President and Chief Executive Officer

Okay, thanks.

Operator

Our next question will come from Steve Seedhouse of Raymond James. Please go ahead.

Steve Seedhouse -- Raymond James -- Analyst

Hi, good afternoon. My question is on one theme that's come up in the NASH deals in a couple recent Phase 2 studies and also at some of the recent meetings. And that is, I was hoping you could clarify generally what the biopsy reading protocol is for the Phase 2b study for example, how are biopsy is blinded or scrambled to the reading pathologist? How many pathologist are there? And are you going to be rereading baseline biopsies at the end of the study? Or does the screening biopsy kind of serve as the time zero comparator? Thanks.

Brian Lian -- President and Chief Executive Officer

Yes. Thanks, Steve. It's a great and complex question. I don't have the answer for all of the parts of it. We are using one pathologist, that person will be reviewing the baseline and end of treatment biopsy. We will not be reshuffling and reassessing the baseline at a later date. And I think that's about all I know on the logistics of the biopsy read procedure, but we're not going to send it out multiple people or reshuffle and do that sort of thing.

Steve Seedhouse -- Raymond James -- Analyst

Okay. Those details are already helpful actually, given the variant service between studies. So thank you for that. The other thing I just wanted to ask in terms of the enrollment for the Phase 2b study. Are you willing to say, kind of what inning you're in there or roughly how long you think it will take you to fully enroll the study?

Brian Lian -- President and Chief Executive Officer

Yes, I think it's early to say, it's the early innings via one way to answer that. But that's -- we're still in the in the ramp-up process opening sites and we are -- I think moving along according to schedule there. We will be adding 12 to 15 sites outside the U.S. and those are expected to come online in the second quarter. And it's a little early to give guidance on completion of enrollment. I certainly expect it to be in 2020 but tightening from there, I don't -- it's hard to do right now.

Steve Seedhouse -- Raymond James -- Analyst

Okay. I appreciate it. Thanks for taking the questions. I look forward to see any additional data at EASL.

Brian Lian -- President and Chief Executive Officer

Thanks, Steve.

Operator

Our next question will come from Derek Archila of Stifel. Please go ahead.

Bill Grau -- Stifel -- Analyst

Hi. Bill, on for Derek. Congrats on the progress in 2019. So first from us, can you just speak to, sort of what other biomarkers you're evaluating in the study? And then what -- which of those biomarkers you'll read out at the same time as the MRI-PDFF?

Brian Lian -- President and Chief Executive Officer

Yes. So we're looking at the health panel, we're looking at Proceed 3, we're looking at TIMP 1 and several others, I don't have that full list in front of me. And I'm not sure yet, it will read out all of that with the 12-week data, sometimes those take a little longer to -- different labs are doing those evaluations that might take a little bit longer to receive, but we'll play it by a year there. But there is a whole panel of other biomarkers, we're looking at.

Bill Grau -- Stifel -- Analyst

Great. And then can you brief -- just really briefly describe the differences between 0214 and 2809?

Brian Lian -- President and Chief Executive Officer

Yes. Yes, different structures. So, 0214 has a slightly different substitution pattern on one of the aromatic rings and as a result, it has a slightly better beta selectivity and the PD profile was just a little bit different. We always look at those guys in parallel in all of our animal studies and on some metrics, it's superior on other metrics 2809 is superior. So I think they're both tremendously effective in the in vivo models for NASH. But when you look at the X-ALD profile, VK0214 seems to be effective in X-ALD and VK2809 is not very effective there. So that was a key difference in the actual in vivo data.

Bill Grau -- Stifel -- Analyst

Does that have to do with the liver sensitivity of 2809?

Brian Lian -- President and Chief Executive Officer

Maybe. I don't know, it was a surprise to us to see that the delta there since they are similar in virtually every other assay. But it could, it could have that, I mean that could play a role there.

Bill Grau -- Stifel -- Analyst

Great. Thanks a lot.

Brian Lian -- President and Chief Executive Officer

Thanks for the questions.

Operator

Our next question will come from Scott Henry of Roth Capital. Please go ahead.

Scott Henry -- Roth Capital -- Analyst

Thank you, and good afternoon. Just a couple of questions. First, on the modeling for 2020. How should we think about R&D spend throughout the year? Should we ramp it steadily? And then as far as magnitude, perhaps relative to 2019, are we thinking double of 2019 spending? Just trying to get a sense on R&D for the year.

Brian Lian -- President and Chief Executive Officer

Yes, it's a good question. Thanks, Scott. It's going to be certainly higher than in 2019. And I would say overall, the spend will be about 50% higher, skewed a little bit. Well, it's going to be a gradual ramp. So 4Q is going to be higher than 1Q and 1Q is going to be higher than 4Q ''19. But when you think about overall R&D and overall opex, it's about 50%. Right now, we think it's going to be about 50% higher. Greg, do you have anything?

Greg Zante -- Senior Vice President of Finance.

Yes. No, that's right on target, I think yes.

Scott Henry -- Roth Capital -- Analyst

Okay, great. Thank you for that color. And just one question on the trial. I realize it's not new, but we haven't had a chance to talk about it. When you look at the five doses, I was a little surprised not to see a 5 milligram daily since it was relatively robust dose in the earlier trial. Any thoughts on deciding which ones to go with? And why always 5 milligrams every other day versus daily?

Brian Lian -- President and Chief Executive Officer

Yes. We definitely -- it's a great question. So we definitely wanted to have some overlap with the Phase 2a study for comparative purposes. We thought that going with the higher sort of a pulsatile dose might be advantageous. I mean, I think you could argue, 5 mg [Phonetic] study would be advantageous based on the data. But we chose to go 10 mg just to have that -- be the overlap dose and then step down from there. We went to 5 mg every other day because we know that, when we look the last three doses in the Phase 2a, they all pretty much stacked on top of each other. As far as efficacy. So we were -- we felt right on the far right hand side of the dose response curve. So we think that coming down as we are. We should still see efficacy and we have that overlap with the very effective 10 mg every other day from the Phase 2a study.

Scott Henry -- Roth Capital -- Analyst

Okay, great. Thank you for the additional color. And thank you for taking the question.

Brian Lian -- President and Chief Executive Officer

Read more:
Viking Therapeutics Inc (VKTX) Q4 2019 Earnings Call Transcript - Motley Fool

Recommendation and review posted by Bethany Smith

SOUTH SAN FRANCISCO, Calif., Feb. 27, 2020 (GLOBE NEWSWIRE) -- CytomX Therapeutics, Inc. (Nasdaq: CTMX), a clinical-stage oncology-focused biopharmaceutical company pioneering a novel class of investigational antibody therapeutics based on its Probody therapeutic technology platform, today reported full-year 2019 financial results.

As ofDecember 31, 2019, CytomX had cash, cash equivalents and short-term investments of$296.1 million.

During 2019, CytomX made substantial progress in advancing our clinical stage pipeline of innovative Probody therapeutics from Phase 1 platform proof of concept into Phase 2 clinical studies. We took major steps forward with our proprietary programs and in our partnerships and set the stage for significant updates throughout 2020, said Sean McCarthy, D.Phil., president, chief executive officer and chairman ofCytomX Therapeutics. We also strengthened our product development capabilities with the recruitment of deeply experienced leadership, positioning ourselves to maximize the potential of our lead, wholly-owned assets, CX-072 and CX-2009, and of our entire portfolio. My colleagues and I look forward to continued pipeline momentum throughout the coming year as we maintain our focus on the discovery, development and ultimate commercialization of potentially transformative cancer treatments.

Business Highlights and Recent Developments

Initiation of Combination Phase 2 Study of CX-072, An Anti-PD-L1 Probody Therapeutic

Initiation of Phase 2 Study of CX-2009, An Anti-CD166 Probody Drug Conjugate

Initiation of Part 2a of Ongoing Study by Bristol-Myers Squibb of BMS-986249, An Anti-CTLA-4 Probody Therapeutic

Ongoing Dose Escalation Phase 1 Study of CX-2029, An Anti-CD71 Probody Drug Conjugate, within AbbVie Alliance

Phase 1 Study Initiation by Bristol Myers Squibb of BMS-986288, An Anti-CTLA-4 Probody Therapeutic

ImmunoGen Collaboration

Probody T-Cell Bispecific Program

Clinical Development Team Appointments

Anticipated 2020 Milestones

PROCLAIM-CX-072 (Anti-PD-L1)

PROCLAIM-CX-2009 (Anti-CD166)

PROCLAIM-CX-2029 (Anti-CD71)

Full Year 2019 Financial Results

Cash, cash equivalents and short-term investments totaled $296.1 million as of December 31, 2019, compared to $436.1 million as of December 31, 2018.

Revenue was $57.5 million for the year ended December 31, 2019, compared to $59.5 million for the year ended December 31, 2018. The net decrease in revenue of $2.0 million for 2019 compared to 2018 was primarily due to a decrease in revenue of $13.1 million from AbbVie under the CD71 Co-Development and Licensing Agreement with AbbVie Unlimited Company (AbbVie), as well as decreases in revenue under our agreements with Amgen, Pfizer and ImmunoGen, partially offset by an increase in revenue from Bristol-Myers Squibb due to the accelerated recognition of revenue related to the cessation of research on certain targets under our agreement with Bristol-Myers Squibb in the first quarter of 2019.

Research and development expenses increased by $27.8 million during the year ended December 31, 2019 compared to the corresponding period in 2018. The increase was largely attributed to an increase in personnel-related expenses; expenses relating to the acquisition of technical know-how during the first quarter of 2019; license fees paid to the University of California, Santa Barbara (UCSB) in connection with an amendment to our license agreement with UCSB in the second quarter of 2019; and an upfront license fee paid to ImmunoGen in the fourth quarter of 2019 for the EpCAM program.

General and administrative expenses increased by $3.3 million during the year ended December 31, 2019 compared to the corresponding period in 2018. The increase was primarily due to an increase in personnel-related expenses due to an increase in headcount.

Teleconference Scheduled Today at 5:00 p.m. ETConference Call/Webcast InformationCytomX management will host a conference call today at 5:00 p.m. ET. Interested parties may access the live audio webcast of the teleconference through the Investor & News section of CytomX's website at http://ir.cytomx.com or by dialing 1-877-809-6037 (U.S. and Canada) or 1-615-247-0221 (International) and using the passcode 1686972. An archive of the webcast will be available on the CytomX website from February 27, 2020, until March 6, 2020.

About CytomX Therapeutics

CytomX is a clinical-stage, oncology-focused biopharmaceutical company with a vision of transforming lives with safer, more effective therapies. We are developing a novel class of investigational antibody therapeutics, based on our Probody technology platform, for the treatment of cancer. As leaders in the field, our innovative technology is designed to turn previously undruggable targets into druggable targets and to enable more effective combination therapies. CytomX and its partners, comprised of leading biotechnology and pharmaceutical companies, have developed a robust pipeline of potential best-in-class immunotherapies against clinically validated targets and potential first-in-class therapeutics against novel, difficult to drug targets. Five novel drug-candidates utilizing our Probody technology are in the clinic, with three in Phase 2 studies and two in Phase 1 studies. These clinical programs include cancer immunotherapies against validated targets such as a PD-L1-targeting Probody therapeutic wholly owned by CytomX (CX-072) and the CTLA-4-targeting Probody therapeutics partnered with Bristol-Myers Squibb (BMS-986249 and BMS-986288). The CytomX clinical stage pipeline also includes first-in-class Probody drug conjugates against previously undruggable targets, including a CD166-targeting Probody drug conjugate wholly owned by CytomX (CX-2009) and a CD71-targeting Probody drug conjugate partnered with AbbVie (CX-2029). CD166 and CD71 are among cancer targets that are considered to be inaccessible to conventional antibody drug conjugates due to their presence on many healthy tissues. In addition to its wholly owned programs, CytomX has strategic collaborations with AbbVie, Amgen and BMS. For additional information about CytomX Therapeutics, visit http://www.cytomx.com and follow us on LinkedIn and Twitter.

CytomX Therapeutics Forward-Looking Statements

This press release includes forward-looking statements. Such forward-looking statements involve known and unknown risks, uncertainties and other important factors that are difficult to predict, may be beyond our control, and may cause the actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied in such statements. In particular, clinical progress is based on preliminary data from ongoing clinical trials and anticipated future disclosures of data are based on assumptions of clinical trial enrollment in our clinical trials and the clinical trials of our collaborative partners. Accordingly, you should not rely on any of these forward-looking statements, including those relating to the potential benefits, safety and efficacy of CytomXs or any of its collaborative partners product candidates, administered separately or in combination, the potential benefits or applications of CytomXs Probody platform technology, CytomXs ability to develop and advance product candidates into and successfully complete clinical trials, including the ongoing clinical trials of CX-072 and CX-2009, and the timing of any future clinical trials to be initiated by CytomX or its collaborative partners. Risks and uncertainties that contribute to the uncertain nature of the forward-looking statements include: the unproven nature of CytomXs novel Probody Platform technology; five product candidates under its Probody platform are in the initial stages of clinical development and its other product candidates are currently in preclinical development, and the process by which preclinical and clinical development could potentially lead to an approved product is long and subject to significant risks and uncertainties, including the risk that enrollment in clinical trials may take longer than expected; the possibility that the results of early clinical trials may not be predictive of future results; the possibility that CytomXs clinical trials will not be successful; the possibility that current pre-clinical research may not result in additional product candidates; CytomXs dependence on the success of CX-072, CX-2009, CX-2029 and BMS 986249; CytomXs reliance on third parties for the manufacture of the companys product candidates; and possible regulatory developments in the United States and foreign countries. Additional applicable risks and uncertainties include those relating to our preclinical research and development, clinical development, and other risks identified under the heading "Risk Factors" included in CytomXs Annual Report on Form 10-K filed with the SEC on February 27, 2020. The forward-looking statements contained in this press release are based on information currently available to CytomX and speak only as of the date on which they are made. CytomX does not undertake and specifically disclaims any obligation to update any forward-looking statements, whether as a result of any new information, future events, changed circumstances or otherwise.

PROBODY is a registered trademark of CytomX Therapeutics.Yervoy and Opdivo are registered trademarks of Bristol-Myers Squibb.

CYTOMX THERAPEUTICS, INC.STATEMENTS OF OPERATIONS AND COMPREHENSIVE LOSS(in thousands, except share and per share data)

CYTOMX THERAPEUTICS, INC.BALANCE SHEETS(in thousands, except share and per share data)

Investor and Media Contact: Christopher Keenan VP, Investor Relations and Corporate Communicationsckeenan@cytomx.com650-383-0823

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CytomX Therapeutics Announces Full-Year 2019 Financial Results and Provides Business Update - GlobeNewswire

Recommendation and review posted by Bethany Smith

February 28, 2020 (LifeSiteNews) These numbers are just staggering: According to Swedens Board of Health and Welfare, there has been a 1,500% spike in diagnoses of gender dysphoriagirls believing they are boysamong teen girls between the ages of 13 and 17. According to the Guardian, this rise in numbers is a reflection of a shift in public opinion on transgenderism that has made many people more open to permitting young people to pursue gender reassignment surgery.

Critics say this spike has been enormously exacerbated by the fact that in 2018, under pressure from LGBT activists, Swedens government put forward a law that would eliminate the necessity for parental consent, reduce the minimum age for sex change surgeries from age 18 to age 15, and in some instances permit children even younger to transition. In response, some medical professionalsincluding one prestigious psychiatristwarned that so-called gender reassignment surgery on children was, in essence, an experiment with unknown consequences.

Sweden is not the only country witnessing a sudden spike in children and teensmostly girlsidentifying as the opposite sex. The United Kingdom has seen a 4,000% rise in children wanting to change their sex in ten years, from 97 in 2008 to 2,510 in 2017-2018. The same phenomenon is occurring in Canada, the United States, and Australia. Some experts have already pointed out that transgenderism is functioning as a social contagion, but LGBT activists are insisting that there has always been thousands upon thousands of children born into the wrong bodies that must become lifelong medical patients and undergo endless hormone treatments and surgeries.

There has been at least some pushback in the Swedish media, with one TV documentary highlighting a man who regretting transitioning and focusing on Karolinska University hospital in Stockholm, which has been criticized for hastily transitioning minors, and has even performed double mastectomies on girls as young as 14. Additionally, the Guardian noted, tragic stories began to surface.

At the same time,Filtermagazine profiled the case of Jennifer Ring, a 32-year-old trans woman who hanged herself four years after her surgery. An expert on psychosis who was shown her medical journal by her father, Avi Ring, was quoted as saying that she had shown clear signs of psychosis at the time she first sought treatment for gender dysphoria. Indeed, the first clinic she approached refused to treat her, citing signs of schizotypal symptoms and lack of a history of gender dysphoria. But the team at Karolinska went ahead. "Karolinska don't stop anyone; virtually 100% get sex reassignment," says Ring.

In response to the backlash, the Swedish government has delayed legislation lowering the minimum age for sex change surgery and instead asked the Board of Health and Welfare to re-examine the data in light of recent criticisms. The Boards report is scheduled for release on March 21, and in the meantime, the Swedish Agency for Health Technology Assessment was directed by the government to examine why so many teenage girls were suffering from gender dysphoria. Of the teen girls who reported gender dysphoria, 15.2% reported autism, 28.9% reported depression, 19.4% had ADHD, and 32.4% had some form of anxiety disorder.

To the Guardians credit, they noted that critics are now louder and more numerous, citing the experience of several de-transitioners and the opinions of a number of experts urging caution. For several years now, countries have rushed headlong into this sweeping social experiment at the behest of the LGBT movement, ignoring calls for pause, demonizing as transphobic anyone who attempted to criticize sex changes or hormone therapy for minors, and declaring that feminists and gay activists who also had concerns were also bigots. There is some indication that the scale of this experiment and the increasing number of voices offering an alternativeand often tragicexperience with the transgender movement is now forcing people to pause and consider the implications of what we are doing.

For the sake of thousands of teenage girls and boys who have been swept up in this social phenomenon, I certainly hope so.

Jonathons new podcast,The Van Maren Show, isdedicated to telling the stories of the pro-life and pro-family movement. In his latest episode, he interviews Bjorn Korf, an activist trying to fight kidnapping by governmentsocial services in Norway.The nightmarish stories he shares are heartbreaking, but can't be ignored.

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Cases of teen girls who believe theyre boys skyrockets in Sweden - Lifesite

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Women considering hormone therapy for menopausal symptoms can find lots of advice on what they should do and a lot of it isn't so good. It's just something we have to figure out, says Barbara Younger, 61, a children's book author based in North Carolina. It's very confusing now to know what to do.

For decades, people thought hormone therapy (also sometimes called hormone replacement therapy) for menopause symptoms also protected women's hearts, maintained bone strength, and helped prevent cancer. But evidence from the Women's Health Initiative research study found otherwise. The large population study found that American women over the age of 60 who took estrogen and progestin were actually at greater risk of breast cancer, stroke, and dangerous blood clots.

With the publication of one article, hormone replacement therapy went from making women live longer to killing them, says Owen Montgomery, MD, chairman of the department of obstetrics and gynecology at Drexel University College of Medicine in Philadelphia.

In fact, Dr. Montgomery says, risks and benefits of hormone therapy depend on a woman's age and family history of heart disease and cancer, among other factors. I spend a lot of time educating my patients about appropriate use of hormones for their specific case, he adds. Individualization is really important.

Women who have used hormone therapy and leading physicians have a variety of perspectives on the risks and benefits. Here are 10 things your own doctor might not tell you about hormone replacement that you need to know to make the best decision for yourself.

1. I might not be the right doctor for you. Some doctors are better at treating menopausal symptoms than others. Many OB/GYNs know the latest evidence for the benefits and risks of hormone therapy, but others do not. Bedside manner also matters. If your medical professional is not helping you, find another one! says Ellen Dolgen, a speaker, author, and health and wellness advocate who blogs about menopause.

The first doctor I went to didn't help me. So, I decided to find a new one, she adds. I decided to interview three doctors, and then I selected the doctor I felt would be the best business partner for me.

Dolgen suggests finding a provider who specializes in perimenopause and menopause. Menopause is a journey, and you want to go on this journey with a specialist who is up on the latest information and [someone] you feel comfortable speaking openly and honestly with, she says.

2. Hormone therapy may help stabilize your mood swings. Women who've used hormone therapy say it has helped them cope with the irritability and dramatic mood shifts that can accompany perimenopause and menopause. Barbara Younger had already gone through menopause without too much trouble. But after she had her uterus and ovaries removed to treat endometrial cancer, her normally upbeat mood plummeted. She suspected her ovaries had been making just enough estrogen that losing them made her feel PMS and menopausal stuff times three.

Her gynecologist prescribed a low-dose hormone patch. Within 24 hours my mood lifted, and I've been basically fine ever since, she says.

Younger, who blogs about menopause and endometrial cancer at Friend For The Ride, says she's a bit worried about taking hormones given her cancer history. She is planning to begin tapering off hormone therapy soon. For now, she adds, she's staying in close touch with her gynecologist and oncologist.

3. Bioidentical hormones are not better for you, and could be worse. Hormone preparations specially tailored to patients by compounding pharmacies, known as bioidentical hormones, are widely touted as being safer and more natural than Food and Drug Administration (FDA) approved versions of hormones. But this simply isn't true, says Margery Gass, MD, the executive director of the North American Menopause Society (NAMS) and a NAMS-certified menopause practitioner at the Cleveland Clinic in Ohio.

There is no hormone out there that women can use that can be harvested from the field, or the trees, or anyplace else, Dr. Gass says. All go through laboratories and have to be processed with multiple chemical steps to be in the form that humans can use.

Still, many women who take bioidenticals swear by them. Bioidenticals work, and it's a great option, says Candice Storms, 45, of Puyallup, Washington, who suffered severe menopausal symptoms after surgery to treat uterine cancer in which her ovaries were also removed.

4. Compounded hormone drugs are not FDA-tested for safety. Custom-compounded formulations of hormones are not made with FDA oversight, Gass warns. They are also not regulated by the FDA, not tested for safety, nor for quality or effectiveness, notes NAMS. Custom-made compounded drugs could have less, or more, of the hormone than a woman needs, and can also have added ingredients that may affect your safety. Unlike a prescription drug, a compounded preparation is not necessarily the same each time you pick up a new supply, and can vary among pharmacists and pharmacies.

5. You don't need blood or saliva tests of your hormone levels before starting hormone therapy. No physician organization recommends testing hormone levels before prescribing hormone therapy. Since symptoms of thyroid problems can mimic menopausal symptoms, however, doctors will typically test your thyroid function before prescribing hormone therapy. Also, Montgomery says, testing for levels of follicle-stimulating hormone (FSH, a hormone that helps regulate your menstrual cycle) can determine whether a woman's ovaries are still functioning. But testing hormone levels in saliva is nonscientific and almost useless, he adds, and whats more, insurers don't cover it.

6. Hormone therapy means having a new conversation with your doctor every year. Timing matters, when it comes to hormone therapy risks. The biggest misconception among his patients considering hormone therapy, according to Montgomery, is that it causes cancer, stroke, and heart disease in anyone who takes it. In fact, a large research review of studies, published in March 2015, found a slightly decreased risk of heart disease with hormone therapy for women who were younger than 60. However, hormone therapy was associated with a greater risk of stroke in older women.

A study reported in 2015, called the ELITE trial, found that women who took hormone therapy within six years of the onset of menopause saw heart-related benefits. They had slower progression of plaque buildup in their arteries (known as atherosclerosis, this buildup increases the risk of stroke and heart attack) than women who took placebo. But taking hormones later, 10 years or more after menopause onset, did not affect atherosclerosis progression.

Risks and benefits for an individual woman change as she ages, Montgomery says, and women who choose to take hormone therapy should not continue indefinitely. It needs to be a conversation with your doctor every year.

7. Hormone therapy can be tailored to your symptoms and needs. These days, hormone treatment comes in many forms. Systemic estrogen, in which the hormone is delivered to the entire body, can be taken via pills, patches, creams, gels, even sprays. You can also use creams, tablets, or rings to deliver low-dose estrogen directly to the vagina.

For example, if a woman's only problem is vaginal dryness and painful experiences with sexual activity, we can use a very low dose vaginal product that just treats the vagina and has for the most part a local effect, says Gass.

8. Vaginal hormone therapy may help when you have overactive bladder symptoms. Many women begin to experience frequent urination and even incontinence as menopause nears. Hormone therapy delivered locally to the vagina may help ease these symptoms, according to a research review of 34 studies published in 2012.

On the other hand, the same review found evidence that so-called systemic hormone therapy pills and patches that deliver the hormone to your entire body could actually make urinary symptoms worse.

RELATED: 10 Things Your Doctor Wont Tell You About Hysterectomy

9. You can take hormone therapy while you are in perimenopause. You're considered to have gone through menopause if you haven't had your period for a full year. But women often experience symptoms for years before menopause actually happens. This time in a woman's life, when she's still menstruating but her body has begun to phase out of childbearing mode, is known as perimenopause.

And perimenopause may last a lot longer than previously thought. The Study of Women's Health Across the Nation, which is following 3,302 women as they transition to menopause, found more than half had hot flashes and night sweats for longer than seven years.

Women in perimenopause can take hormone therapy to address their symptoms, Montgomery says, although he may prescribe a lower dose for these women than for those who have already reached menopause.

10. If you are going through menopause you don't necessarily need to have your hormones replaced. Menopause isn't much fun, to say the least, but it's a normal part of life. In fact, while treating menopausal symptoms with hormones used to be called hormone replacement therapy, Montgomery says, experts now prefer the term hormone therapy. While hormone therapy is great for menopausal symptoms, it won't keep you young forever, no matter what bioidentical hormone advocate Suzanne Somers says.

We take the position that menopause is a normal and natural occurrence in a woman's life, no more pathological than puberty, says Gass. It's a little bit like puberty, in reverse.

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10 Things Your Doctor Won't Tell You About Hormone Therapy

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A new study upends the conventional belief that women who experience early menopause (45 years old or younger) have more cardiovascular health issues later on than women who develop menopause closer to the normal age. The study, published in February 2020 in the journal Heart, found that women who go through menopause at an earlier age dont later have more troublesome blood pressure levels, blood cholesterol, or other traditional heart disease risk factors compared with women who go through menopause later in life.

Doctors had previously assumed the premature cardiovascular deaths in these women were likely caused by the increase in traditional risk factors, such as weight gain, that often happen as women go through the menopausal transition and estrogen levels drop, says Tomas Ayala, MD, a board-certified cardiologist at the heart center at Mercy Medical Center in Baltimore, who was not involved in the study.

RELATED: 12 Women Over 60 Who Inspire Wellness and Living Your Best Life

The study, conducted by researchers at British medical centers, looked at females in Britains comprehensive UK Medical Research Council National Survey of Health and Development, which has followed participants over many years.

In roughly 1,000 women they were able to track the numbers for their blood pressure, unhealthy blood fats, body mass index (BMI), fasting blood glucose, and waist circumference (an indicator of the most dangerous fat around the abdominal organs) from midlife or even earlier, through age 69.

What they found was that by age 69, women who had gone through early menopause whether naturally or from surgery did not have unhealthier levels of these markers than women who entered the change later.

Our findings suggest that the impact of timing and type of period cessation on conventional cardiovascular disease intermediates from midlife is likely to be small, the authors conclude.

RELATED: 10 Ways to Beat Menopausal Belly Fat

Still, all women have a higher risk of heart disease once they reach menopause and lose the bulk of their estrogen. The clock starts ticking at menopause for increased cardiovascular disease risk, Dr. Ayala says. Thats why all women of menopausal age need to take heart disease seriously, he says.

A womans cardiovascular system is hugely impacted by the loss of ovarian hormones, agrees Felice Gersh, MD, a board-certified gynecologist and integrative medicine physician in Irvine, California, and a consultative faculty member at the University of Arizona College of Medicine. Dr. Gersh, who cowrote an editorial that accompanied the study, notes that disease and death from heart issues start happening as early as womens fifties and sixties, not only in older ages.

There are numerous theories about how estrogen in premenopausal women helps the heart, but none are proven. Most have to do with the way estrogen protects the lining of your blood vessels, known as the endothelium. According to the editorial, estrogen offers anti-inflammatory, antioxidant, and anti-proliferative pathways in the endothelium, and its steep reduction after menopause contributes to dysfunction in the vessels.

RELATED: Fitness After 40 and Beyond: What to Know About Midlife Exercise Needs

The study presents another example of how womens heart health is different from mens, Gersh says. For example, women have different symptoms when having a heart attack, are more likely than men to die from their first heart attack, and develop heart failure through a different pathway, she observes.

Rather than labeling female symptoms as atypical, they should be labeled as what they are: female-typical symptomatology, Gersh says.

The results of this study are likely to change the way cardiologists treat womens heart risks.

Before this study, if a patient had gone through menopause early, we would have been very aggressive in treating her high blood pressure, cholesterol, and other traditional risk factors, Ayala says. Doctors should still treat these, he says, but maybe we dont have to go overboard or be super-aggressive because these factors are not impacted by the earlier age of menopause the way doctors had thought.

Regardless of a womans age when she enters menopause, getting serious about heart disease prevention is paramount. How best to do that remains controversial, but Gersh and her coauthor wrote in the editorial that hormone therapy (HT, or HRT) likely offers the best hope.

The current state of research is enough to justify the use of human-identical HRT with most women as they go through menopause, they wrote in the editorial, although they call for additional studies to document the benefits more fully.

HT had previously been used after menopause in part to aid a womans heart. But many abandoned this treatment after the famed Womens Health Initiative (WHI) trial was prematurely stopped in 2002 due to concerns about detrimental health effects. Many doctors, including Ayala, now think the panic over the results was excessive. The risks for cardiovascular disease in the study were well overblown, Ayala observes.

Gersh says the WHI shouldnt have tarnished HT the way it did, because that study included women well past their menopause transition and it used conjugated estrogens made from horse urine.

RELATED: Some Hormone Therapies Are More Effective Than Others in Preventing Heart Disease

Ayala says that he generally recommends HT to his female cardiology patients in their forties and early fifties and will continue to do so in the face of the revelation that treating traditional heart risks is not enough.

Gersh advocates that most women at the start of menopause should be offered HT with human-identical transdermal estradiol also known as bioidentical estrogen delivered by a patch or gel into the skin, along with micronized progesterone for women who have not had a hysterectomy. The key exception: women with diagnosed cancers involving estrogen receptorpositive tumors.

Much of what is viewed as the consequence of aging is actually a consequence of hormonal deficiency, especially when it comes to the heart, Gersh says. With proper informed consent, each woman can then decide for herself what path she chooses to follow.

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Early Menopause Does Not Increase Your Risk of Heart Disease, Study Finds - Everyday Health

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Seasonal depression is real, and millions of Americans have a form of Seasonal Affective Disorder, or SAD. The darker, colder times of year is thought to be when SAD is the worst for many people.

Organic Authority has written about how you can add more healthy, natural light to your days with red light therapy. This article focused on the skin and anti-aging benefits of red light therapy (RLT), used by Hollywood stars like the Kardashians and Jessica Alba for all-natural beauty and collagen treatments.

Im the co-founder of Joovv, and we make some of the leading in-home RLT devices that many estheticians and Hollywood A-listers are using every day. But RLT is hardly just for skin and beauty. In fact, it has a huge base of clinical research behind it that shows a wide range of natural health benefits like improved sleep, pain relief, hormone regulation, and fitness & performance gains. Some leading mental health researchers and physicians are even using it to treat patients and reduce the symptoms of SAD.

During a red light therapy session, your body absorbs wavelengths of natural red and near infrared light. Its just like the wavelengths youd get from sunlight, but without the heat or damaging UV rays. This is why red light therapy is gaining popularity as a solution for SAD: its a safe, easy way to add natural light to your day without the need for sunny weather.

Natural light stimulates the mitochondria in your cells and helps your body increase your adenosine triphosphate (ATP) energy production. (To understand why this is so important, check out Organic Authority's guide to keeping your mitochondria healthy and strong.)

This increased cellular energy from natural light makes a big difference for skin health, sleep, and inflammation relief. And new science and research shows big potential for SAD and depression as well. In 2018, the Elated-2 Pilot Trial tested the effects of red light therapy treatments on people with major depression over the course of eight weeks. The research team wrote that RLT showed antidepressant properties and was safe, easy to use, and well-tolerated.

Most people already know about SAD lamps. These are the lamps that mimic the sun with super-bright artificial light. They definitely light up a dark room, but ultimately its still just artificial blue light, not natural light like the sun.

By contrast, a medical-grade red light therapy device like Joovv actually lets your body bask in a clinically-relevant dose of natural light in just 10-15 minutes. Its quick, easy, and there are almost no risks or side effects.

Dr. Marc Schoen of UCLA Medical School has over 25 years of experience treating mental health disorders.

In tandem with psychotherapy, using red light therapy appears to catapult patients out of an acute depressive state faster than any other modality.

Dr. Schoen has also spoken about how red and near infrared light therapy can improve anxiety and compulsive disorders. Hes one of a growing number of researchers and physicians using Joovv devices or other RLT products to improve mental health outcomes.

Many people who struggle with depression have sleep disorders too, and this is another area where red light therapy treatments are making a big impact on natural health.

Light is a major cue for your brain, telling you when your body should sleep and be awake. When people are surrounded by bright, artificial light from screens all the time, it can seriously throw your circadian rhythm out of whack. Every time we look at our phones or watch TV or use a laptop, were subjecting our eyes to intensely bright lightlight with a higher color temperature than the noonday sun.

Red light therapy is a much gentler color of light, and its been shown in studies to help your brain re-establish a consistent sleep cycle and produce more natural melatonin. Getting quality sleep can go a long way for your mental health, especially in the winter.

With the recent clinical successes around natural light, and given how easy it is to use a red light therapy device in your home, I expect RLT to become a bigger part of peoples mental health and self-care routines. More and more studies are coming out all the time showing a huge range of health benefits from natural light. The work on SAD and depression is especially promising for people with the Winter Blues.

Theres nothing we can do about how early it gets dark at this time of year. But with a quality red light therapy device like Joovv, you can make sure your body is getting all the natural light it needs.

If red light therapy interests you, check out Joovv. When you purchase a Joovv device through Organic Authority and use the code, OA, you'll receive a free gift with purchase!

Related on Organic AuthorityBlue Light Might Be Disrupting Your Sleep Cycles: Here's What to Do About ItDon't Do Early Mornings? You May Have a Sleep DisorderDo These 10 Daily Tasks at the Best Time of Day for Your Body Clock (Sex Included!)

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Note! The opinions and views expressed by the authors at Organic Authority in blogs and on social media and more, are theirs alone and do not necessarily reflect the views, opinions or position of Organic Authority, Inc and do not necessarily represent the views of Organic Authority sponsors and/or partners. Organic Authority content is for informational and entertainment purposes, and any views expressed should not be accepted as a substitute for qualified expertise. Any highlighted alternative studies are intended to spark conversation and are for information purposes only. We are not here to diagnose or treat any health or medical conditions, nor should this be relied upon as a substitute for professional medical advice, diagnosis or treatment, even if it features the advice of medical practitioners and physicians. When making any lifestyle or health changes, consult your primary care physician.

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Here's Why Red Light Therapy Might Be the Best Natural Solution for Seasonal Depression - Organic Authority

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At 8 PM on the evening of Friday, July 13, 1934, German Reich Chancellor Adolf Hitler stepped to the speakers lectern of the Reichstag in Berlins Kroll Opera House to explain his murderous conduct during the recent Nazi Blood Purge against the top leadership cadre of the brownshirted SA Stormtroopers during the weekend of June 30-July 2, 1934.

In front of him stood steel-helmeted, armed SS troopers, and there were more placed strategically throughout the chamber, the first and only time such an event occurred throughout the 12 years of the Third Reich. Indeed, Hitler feared assassination from his own followers as a result of the national murder weekend, and rightly so, for some of the victims had been his most intimate followers, such as his SA Chief of Staff, Captain Ernst Rohm.

During his address, the chancellor for the first time made public mention of the sex life of the man who had been reputedly closest to him, a man whose alleged homosexuality was reportedly well known throughout Nazi Germany and even abroad.

The life which the Chief of Staffand with him a certain circle of othersbegan to lead was intolerable from any National Socialist point of view, Hitler said. As if it were not terrible enough that he himself and his circle of devotees broke every single law of decency and modesty, still worse, this poison now began to spread in ever-increasing circles.

But worst of all was the fact that, out of a certain common predisposition, a sect gradually began to form in the SA which made up the nucleus of a conspiracy directed not only against the normal conceptions of a healthy people, but against the security of the state as well.

Thus, the Fhrer was officially acting as if he had not known about Rohms homosexuality since the first days of their association in 1920, when, in fact, he had turned a blind eye toward it from the start because he needed such men as the burly brawler and his thugs in the movement.

In his book The Hidden Hitler, German author Lothar Machtan claims that the Fhrer himself was gay and that the two men may have been lovers.

Ironically, just as the Nazis persecuted the Jews in part because some of their own top leaders were, in fact, at least partly Jewish, including SS General Reinhard Heydrich and Luftwaffe Field Marshal Erhard Milch, so, too, did they also do the same with homosexuals, as a means of covering their tracks in a sense.

States Andrew Hollinger, assistant director of media relations and communications for the United States Holocaust Memorial Museum, As part of the Nazis attempt to purify German society and propagate an Aryan master race, they condemned homosexuals as socially aberrant.

Soon after taking office on January 30, 1933, Hitler banned all homosexual and lesbian organizations. Brownshirted Stormtroopers raided the institutions and gathering places of homosexuals. Greatly weakened and driven underground, this subculture had flourished in the relative freedom of the 1920s, in the pubs and cafs of Berlin, Hamburg, Munich, Bremen and other cities.

Indeed, by 1928, there were an estimated 1.2 million homosexual men in the Weimar Republic. Legal prosecution of homosexuals did not begin under the Third Reich, however, but under the Second Reich of Kaiser Wilhelm I in 1871, the year the new German Empire was established by Reich Chancellor Prince Otto von Bismarck, the Iron Chancellor.

Paragraph 175 of the criminal code outlawed acts of unnatural indecency between men. Six years later, this was redefined by the German Supreme Court as an intercourse-like act alone, thus making arrests and convictions of homosexuals relatively difficult. On the other hand, since 1900 under the reign of Kaiser Wilhelm II, the German Regular Police or Kripo had been compiling lists of suspected homosexual men called pink lists from all across the Reichbut little or no use was ever made of them.

By 1932, however, on the eve of the Nazis assumption of governmental power, Berlins municipal leaders began enforcing public morality laws to close bars and social clubs catering to homosexual customers. On January 30, 1933, Adolf Hitler was named Chancellor of the German Reich by President and Field Marshal Paul von Hindenburg, and everything began to change as the Nazis espoused a platform of law and order, traditional values, an ideology of virulent anti-Semitism, and the persecution of unwanted social groups.

Dr. Magnus Hirshfeld, a homosexualphysician, was the victim of Nazi violence when his Institute for Sexual Science was vandalized bystudent groups in May 1933.

Recalled one homosexual, Then came the thunderbolt of January 30, 1933, and we knew that a change of political climate had taken place. What we had tried to prevent had taken place. Over the years, more and more of my political friends disappeared, of my Jewish and of my homosexual friends. Fear came over us with the increasingly coordinated pressure of the Nazis.

For Heavens sake not to attract attention, to exercise restraint, [and] 1933 was the starting point for the persecution of homosexuals. Already in this year we had heard of raids on homosexual pubs and meeting places. Maybe individual, politically uneducated homosexuals who were only interested in immediate gratification did not recognize the significance of the year 1933, but for us homosexuals who were also politically active, who had defended the Weimar Republic, and who had tried to forestall the Nazi threat, 1933 initially signified a reinforcing of our resistance.

In order not to mutually incriminate ourselves, we decided to no longer recognize each other. When we came across each other in the street, we passed by without looking at one another. There were certain possibilities for us to meet, but that never happened in public.

For a politicized homosexual, visiting places which were part of the homosexual subculture was too dangerous. Friends told me that raids on bars were becoming more frequent, and someone had written on the wall of the Hamburg S-Bahn between Dammtor Station and the main station, Street of the Lost.

That was some sort of film or book title. We found this graffiti very amusing, for most of us tried to cope with the thing by developing a sort of gallows humor.

On May 6, 1933, Nazi student groups and sympathizers ransacked the Institute for Sexual Science founded by Dr. Magnus Hirshfeld, a Jewish homosexual physician. According to Hollinger, Dr. Hirshfeld was one of Germanys leading advocates of civil rights for homosexuals. Four days later, much of his Institutes library was destroyed in a public book burning. The notorious event was sponsored by Nazi Germanys Minister of Propaganda and Public Enlightenment Dr. Josef Goebbels.

The institute had sponsored research and discussion on marital problems, sexually transmitted diseases, and laws relating to sexual offenses, abortion, and homosexuality. For 30 years, Dr. Hirshfeld spearheaded efforts to decriminalize homosexuality. In 1933, he happened to be in France, where he remained until his death.

On June 8, 1933, and in November 1934, the Scientific-Humanitarian Committee and the Human Rights League, both homosexual rights organizations, were dissolved. Captain Rohm was shot on July 2, 1934, without trial, and the previous April 20, the Gestapo, established by Luftwaffe chief and Prussian Prime Minister Hermann Gring, was taken over by Reichsfuhrer SS Heinrich Himmler. In October Himmler set up a division to deal with homosexuals within the department.

One of its first acts was to instruct the Kripo to gather all the pink lists from across the Third Reich. On June 28, 1935, the Nazis published their revised Paragraph 175 provisions, and subsequent judicial interpretations expanded the range of punishable indecencies between men. These now included simple looking and simple touching.

The harsher, amended version of Paragraph 175 went into effect on September 1, 1935, thus punishing a broader range of lewd and lascivious behavior between men. In 1936 Himmler became national chief of the German Police, and on October 10 created the Reich Central Office for Combatting Homosexuality and Abortion, or Special Office (II S), a subdepartment of Executive Department II of the Gestapo.

During 1936-1939, a total of 78,000 men were arrested under the new, broadened Paragraph 175. Prosecutions reached their peak between 1937 and 1939, asserts Hollinger. Half of all convictions for homosexual activity under the Nazi regime occurred during those years. The police stepped up raids on homosexual meeting places, seized address books of arrested men to find additional suspects, and created networks of informers to compile lists of names and make arrests.

On February 18, 1937, Reichsfuhrer Himmler addressed his higher SS and police leaders at Bad Tolz on the subject of homosexuality as he saw it. With a static number of women, we have two million men too few on account of those who fell in the war [of 1914-1918]. You can well imagine how this imbalance of two million homosexuals and two million war dead, or in other words a lack of about four million men capable of having sex, has upset the sexual balance sheet of Germany, and will result in a catastrophe.

Ernst Rohm, head of the notorious SA, was an early member of Hitlers inner circle until he was killed in the blood purge of 1934. Rohm was a homosexual.

There are those homosexuals who take the view that what I do is my business, a purely private matter; however, all things which take place in the sexual sphere are not the private affair of the individual, but signify the life and death of the nation, signify world power or Swissification. The people which has many children has the candidature for world power and world domination. A people of good race which has too few children has a one-way ticket to the grave, for insignificance in 50 or a hundred years, for burial in 250 years

Therefore, we must be absolutely clear that if we continue to have this burden in Germany, without being able to fight it, then that is the end of Germany, and the end of the Germanic world.

The Nazis also felt that homosexuals formed self-serving groups, the emergence of a state within a state that could disrupt the social harmony and fabric of the Reich. In addition, Nazi policy asserted that homosexual men carried a degeneracy that threatened the disciplined masculinity of Germany. In some cases, homosexuality was deemed a mental illness, and thus many men were institutionalized while others were forced to choose between voluntary castration and imprisonment.

This voluntary castration, encouraged openly after 1935, was so that homosexual men could free themselves from their degenerate sex drive, or so the euphemisms went. In the Nazi concentration camps, they were subjected to forced castration in medical experiments as well.

Indeed, at Buchenwald, SS Dr. Karl Vaernet performed operations designed to convert men to heterosexuals, including the surgical insertion of a capsule that released the male hormone testosterone. Such procedures reflected the desire by Himmler and others to find a medical solution to homosexuality, explains Hollinger.

During the 12 years of the Third Reich from 1933 to 1945, an estimated 100,000 of the approximately 1-2 million homosexual men in Germany were arrested, and of these 50,000 officially defined as gay were sentenced under Paragraph 175. Most of these were held in regular prisons, while from 5,000 to 15,000 more were incarcerated in concentration camps. How many of the latter died? No one knows for sure, but researcher Rudiger Lautmann believes that the death rate for the 175ers may have been as high as 60 percent.

States Hollinger, All prisoners of the camps wore marks of various colors and shapes, which allowed guards and camp functionaries to identify them by category. The uniforms of those sentenced as homosexuals included a large black dot and a 175 drawn on the back of the jacket. Later, a pink triangular patch appeared. Many survivors have testified that men with pink triangles were often treated particularly severely by guards and inmates alike because of widespread biases against homosexuals.

The vast majority of homosexual victims were males; lesbians were not subjected to systematic persecution. While lesbian bars were closed, few women are believed to have been arrested. Paragraph 175 did not mention female homosexuality, and lesbianism was seen by many Nazi officials as alien to the nature of the Aryan woman. In some cases, the police arrested lesbians as asocials or prostitutes.

One woman, Henny Schermann, was arrested in 1940 in Frankfurt and was labeled a licentious lesbian on her mug shot, but she was also a stateless Jew, a sufficient cause for deportation and gassing in a euthanasia killing center in Germany in 1942, a year after the program was to have been officially halted at Hitlers order.

On September 1, 1939, Nazi Germany invaded Poland and World War II began, vastly increasing Himmlers powers across the whole of German-occupied Europe, although the SS did not generally persecute and arrest homosexuals outside the Reich. In July 1940, Himmler issued orders to the officers of the Kripo that homosexuals convicted under Paragraph 175 who were known to have had more than one sexual partner were to be sent directly to a concentration camp after their formal release from prison. Beginning in 1943, the SS, in concert with the German Ministry of Justice, launched an explicit program of extermination through work to destroy Germanys habitual criminals, including homosexuals.

The vast majority of homosexuals persecuted by the Nazis included native Germans and acquired Austrians after the 1938 annexation of that nation. Asserts Hollinger, Unlike Jews, men arrested as homosexuals were not systematically deported to Nazi-established ghettos in Eastern Europe, nor were they transported in mass groups of homosexual prisoners to Nazi extermination camps in Poland.

The war ended on May 8, 1945, with the total defeat of the Third Reich and the collapse of the Nazi state, and yet Paragraph 175 remained in effect under the new Allied governments that partitioned the former Nazi Germany. Some homosexuals liberated from Nazi camps were even transferred to German prisons to serve out the remainder of their sentences under Paragraph 175.

Standing mutely at attention in bitterly cold weather, prisoners at the Sachsenhausen concentrationcamp are under the watchful eyes of Nazi guards. This photo was taken on December 19, 1938.

Eleven years after the war ended, in June 1956, the Federal Republic of Germany Reparation Law for Victims of National Socialism declared that internment in a concentration camp for homosexuality disqualified an individual from receiving state compensation. In 1969, Paragraph 175 was revised to decriminalize homosexual relations between men over the age of 21.

On May 8, 1985, the 40th anniversary of the end of the war, homosexuals murdered by the Nazis received their first public acknowledgment in a speech by West German President Richard von Weizacker, and in 1994 after the reunification of East and West Germany, Paragraph 175 was abolished altogether. Finally, in 2002, the German Parliament pardoned homosexuals convicted by the Nazis under Paragraph 175. Thus, the wheel had finally come full circle to where it was prior to 1871.

Towson, Maryland, freelance writer Blaine Taylor is the author of 12 books on World War II.

This article first appeared at the Warfare History Network.

Image: Wikimedia Commons.

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Nazi Germany's Forgotten Victims: Homosexuals and Jehova's Witnesses - The National Interest Online

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Women with multiple sclerosis (MS) who have never given birth and those who began menopause prematurely tend to develop progressive forms of the disease earlier, a study from theMayo Clinicsuggests.

These findings were presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2020, running through Saturday, Feb. 29, in Florida.

Burcu Zeydan, MD, a Mayo Clinic physician, shared the results in the oral presentation Nulliparity Or Early Menopause Are Associated With Earlier Evolution Of Progressive Multiple Sclerosis In Women.

Being a woman is the strongest risk factor for developing MS, Zeydan said.

The disease is more common in women, with recent studies suggesting that it affects three times more women than men.

Gender also has an influence on the different stages of the disease. In those with relapsing-remitting MS(RRMS), women tend to have disease onset at earlier ages, while disability worsening is faster in men. The opposite is seen in the diseases progressive phase, with men tending to have onset at earlier ages and women showing faster disability worsening.

Pregnancy is known to potentially slow disability worsening and reduce relapse rates in women, while menopause potentially speeds up disability worsening,Zeydan said.

However, the influence of pregnancy and menopause on progressive MS has not been thoroughly studied.

Mayo Clinic researchers set out to explore the potential association of progressive MS with female sex, pregnancy, and menopause.

Their study enrolled 134 women and 68 men with progressive MS, and they analyzed various patient characteristics, such as the number of completed pregnancies, the age at menopause considered premature, or early, if it started at or before age 45 as well as age at onset of progressive MS andRRMS.

A group of postmenopausal women without MS, serving as controls, were also assessed.

Results showed that women who had never given birth, referred to as nulliparous (32 patients), developed progressive MS at earlier ages, a mean of 41.4 years old, than did women who had given birth at least once (95 patients), a mean age of 47.1.

Interestingly, nulliparity was more common among MS patients (23%) than among controls (15%).

The higher the number of viable pregnancies (those that conclude with a birth), the older the age at onset of progressive MS, the researchers found. Onset ranged from a mean of 41.4 years old in women with no pregnancies, to 52.6 for women with four or more viable pregnancies.

Similar trends were observed insecondary progressive MS (SPMS) and RRMS patient subgroups. Women who never had a viable pregnancy developed SPMS at an earlier age a mean of 41.5 than did women who gave birth once or more (47.3 years old). Among those with RRMS, nulliparous women had disease onset at a mean age of 27.5, and women with one or more viable births at a mean age of 33.

Most patients with RRMSeventually develop SPMS, the researchers noted.

The number of pregnancies also had an effect on the age of SPMS onset ranging from 41.5 years old for no pregnancies, to 52.6 for four or more. A similar effect was seen for RRMS onset from 27.5 years old for women with no pregnancies, to 35.8 for those four or more.

Among patients with SPMS, women developed RRMS at an earlier age (mean of 31.4) than did men (mean age, 36).

The transition from RRMS to SPMS was faster in women with early menopause (12.9 years) than in patients who began menopause at whats considered a normal age (17.8 years). This transition, nevertheless, took longer in women than it did in men, who moved from RRMS to SPMS in a mean of 10.4 years.

Among woman who developed SPMS after going through menopause, progression from RRMS was faster in those with premature menopause (13.9 years) than in those who did not go into early menopause (25.4 years).

Overall, nulliparity or premature/early menopause seem to be associated with earlier onset of progressive MS, Zeydan said. But she emphasized that the study does not establish a direct causality between the two.

There is further need for a larger study to understand whether these factors lead to earlier development of progressive MS, or whether MS-associated factors lead to nulliparity or earlier menopause, the researchers wrote.

Based on these results, Zeydan suggested that women with MS, especially, should rethink how pregnancy and surgical menopause counseling is done, and consider the option of menopausal hormone therapies.

Our observations are intriguing as there is evolving knowledge of the impact ofestrogenon neuroprotection associated withastrocyteandmicroglianetworks, and their relevance to progressive MS,she said.

Estrogen levels rise above whats typical during pregnancy; they drop below typical levels when women go through menopause. Microglia and astrocytes are types of cells that provide support to nerve cells in the brain and spinal cord; both have been implicated in thedamaging immune reactionsand theformation of lesionsseen in MS.

Ana is a molecular biologist with a passion for communication and discovery. As a science writer, her goal is to provide readers, in particular patients and healthcare providers, with clear and quality information about the latest medical advances. Ana holds a Ph.D. in Biomedical Sciences from the University of Lisbon, Portugal, where she specialized in infectious diseases, epigenetics, and gene expression.

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Patrcia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.

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The weather is hot. I can hardly sleep at night because I sweat profusely leaving my bed and pillow so wet. I have to wake up about two times in the night to take my bath. It is no any better in the day, because I am always drenched in sweat.

These are some of the complaints of most Nigerians due to the current hot and humid weather nationwide, even in coastal areas, such as Lagos.

Indeed, the situation is causing concern across the country as meteorologists and medical experts warn of its dangers on human and natural resources.

From an average temperature of 33 degree Celsius and 70 per cent humidity in Lagos to 39 degree Celsius and 11 per cent in Maiduguri, the excessive sweating and heath rashes have become regular these days, making it difficult for many, especially children, to sleep comfortably at night.

Medical experts warn that the extreme weather could lead to more dire consequences, such as kidney failure, stroke, excessive bleeding and skin cancer in Albinos.

On their part, scientists blame the situation on increased Ultra Violet (UV) rays caused by the depletion of the ozone layer, warning that this could sterilise trees.

But to the meteorologists, the hot weather is a normal phenomenon around this period of the year due to transition from dry to rainy season.

According to a research review, an increase in heat waves worldwide linked to climate change might be behind the epidemics of kidney disease detected in workers, who are increasingly exposed to heat and dehydration.

A Consultant Public Health Physician at the Lagos University Teaching Hospital (LUTH), Idi-Araba, Prof Akin Osibogun, had told The Guardian: When the weather is persistently hot and humid, as being experienced now, what happens is that there will be heat exhaustion and dehydration.

When this loss of bodily fluid continues without adequate replacement, it will affect the body organs, especially the kidney that is involved with ultra-filtration. This can lead to kidney failure. Rapid water loss causes the kidneys functioning to slow down, resulting in temporary or permanent kidney failure.

Extreme heat causes rapid water loss, resulting in acute electrolyte imbalance. The kidney, unable to cope with the water loss, fails to flush out the requisite amount of creatinine and other toxins from the body. Coupled with a lack of consistent water intake, this brings about permanent or temporary kidney failure.

He continued: Another thing that can happen under this kind of hot and humid weather is that it will affect the brain and blood. It makes the blood less viscous and can easily escape from the vessels, causing excessive bleeding and haemorrhagic stroke.

It can also cause skin cancer, but only in Abinos. People with black (dark) skin are protected from the carcinogenic effect of direct ultra-violet rays from the sun, because their skins have melanin. In most cases, they develop rashes, which can be very discomforting.

Previous study published in Asian Journal of Pharmaceutical and Clinical Research found that burden of renal diseases might increase, as the period of hot weather becomes more frequent, and this is further aggravated in advanced age and people with chronic diseases, such as diabetes and hypertension.

Another study published in the Clinical Journal of the American Society of Nephrology noted that extreme heat exposure could have immediate health effects, causing dehydration, heat exhaustion and heat stroke, as well as worsening pre-existing chronic disease, which can be fatal.

The researchers said although chronic kidney disease is often caused by diabetes or high blood pressure, it could also be the result of recurrent heat exposure with physical activity and not enough hydration, which puts a heavy strain on the kidneys.

Meanwhile, new research has shown people really do get hot and bothered in warm weather. A study has found stress hormones rise in tandem with the thermometer.

The discovery sheds fresh light on a phenomenon that has puzzled scientists for years.

Dubbed the summertime blues there is a wealth of evidence from the past few decades linking heat exposure to aggression, suicide and violence.

Now a Polish team has found this all boils down to the fact that levels of the stress hormone cortisol are lower in winter than summer, and the heat-driven rise makes us tetchy.

It could have implications for public health because the chemical is vital to regulating sugar, salt and fluids throughout the body.

The report was first published in DailyMailUK Online.

Dr. Dominika Kanikowska, a pathophysiologist at Poznan University of Medical Sciences, said having more circulating when it is warm was a surprise.

She said: These non-intuitive findings contradict traditional concepts of the taxing physical toll of winter and the relaxed ease of summer.

The original data that first associated heat with hostility came from crime statistics. Analyses noted those involving violence increased in summer especially when it was warmer than average.

Numerous theories have been suggested including raised temperatures causing an increase in heart rate, testosterone and other metabolic reactions that trigger the sympathetic nervous system.

This is responsible for the fight-or-flight response so people are more inclined to fight.

Kanikowska and colleagues say the reason is simple: it all boils down to the effect of the weather on cortisol.

It is referred to as the stress hormone because it is released into the bloodstream during difficult or upsetting situations.

Kanikowska said: The hormone helps reduce inflammation and is essential for maintaining overall health.

Cortisol levels are typically highest in the morning and gradually drop throughout the day. Levels are lower in the evening to maintain healthy sleeping patterns.

Illness, lack of sleep and certain medications can affect cortisol levels more than normal daily fluctuations.

Her researchers studied a group of female medical students on two separate days in both winter and summer. They found cortisol levels to be higher on the latter dates. Inflammation levels did not change significantly between seasons.

Kanikowska said there have been studies into the seasonal variability of the hormone but these have shown inconsistent results.

This is possibly because participants were tested in their own homes and not in a uniform setting.

She said her study presented at an American Physiological Society meeting in San Diego was the most thorough of its kind.

They took saliva samples every two hours during each testing period a full 24-hour cycle to measure levels of cortisol and markers of inflammation.

The volunteers also completed a lifestyle questionnaire during each session about their sleep schedule, diet and physical activity levels.

Also, a new research suggests that drinking sugary, caffeinated soft drinks while exercising in hot weather may increase the risk of kidney disease. The study is published ahead of print in the American Journal of PhysiologyRegulatory, Integrative and Comparative Physiology.

A research team from the University at Buffalo in New York studied healthy adults in a laboratory environment that mimicked working at an agricultural site on a hot day (95 degrees Fahrenheit). The volunteers completed an hour-long exercise cycle consisting of a 30-minute treadmill workout followed by three different five-minute lifting, dexterity and sledgehammer swinging activities. After 45 minutes of exercise, the volunteers rested for 15 minutes in the same room while drinking 16 ounces of either a high-fructose, caffeinated soft drink or water. After the break, they repeated the cycle three more times for a total of four hours. Before leaving the laboratory, the volunteers were given more of their assigned beverage to drink before consuming any further fluids. The volume was either 1 liter or a volume equal to 115 percent of their body weight lost through sweating, if that amount was greater. The researchers measured the participants core body temperature, heart rate, blood pressure, body weight and markers of kidney injury before, immediately after and 24 hours after each trial. All volunteers participated in both soft drink and water trials separated by at least seven days.

The research team found higher levels of creatinine in the blood and a lower glomerular filtration ratemarkers for kidney injuryafter the soft drink trial. These temporary changes did not occur when the participants drank water. In addition, the participants blood levels of vasopressin, an anti-diuretic hormone that raises blood pressure, was higher and they were mildly dehydrated during and after the soft drink trial. The consumption of soft drinks during and following exercise in the heat does not rehydrate, the researchers explained. Thus, consuming soft drinks as a rehydration beverage during exercise in the heat may not be ideal. Further work will need to discern the long-term effects of soft drink consumption during exercise in the heat, and its relation to the risk of kidney disease.

Also, according to a study titled Investigating Effects of Climate Change on Health Risks in Nigeria and published in ONLINE FIRST by Ilevbare Femi, cerebra-spinal meningitis is one of the infectious diseases likely to be caused by climate change. Incidences of meningitis, for instance, have been on the rise in Nigeria due to excessive heat. According to Akingbade, cases of meningitis have been reported to increase in Nigeria as a result of excessive heat.

Meningitis is a disease caused by an infection due to bacteria, viruses and protozoa, of the meanings, which is the thin lining that surrounds the brain and the spinal cord.

The results of another study suggest future temperature increases due to climate change have the potential to significantly increase meningitis cases in both the early (20202035) and late (20602075) twenty-first century, and for the seasonal onset of meningitis to begin about a month earlier on average by late century, in October rather than November.

Also, climatic conditions have been shown to affect water-borne diseases in Nigeria. The changes in climatic conditions are germane to lengthen the transmission seasons of important vector-borne diseases and alter their geographic range. Malaria has been identified to be caused by climate conditions due to unicellular organism known as Plasmodium and transmitted by the bite of infected female Anopheles mosquitoes. Evidence shows that malaria accounted for over 45 per cent of all outpatients and about 50 per cent of the Nigerians suffer from at least one episode of malaria each year.

Scholars have argued that global warming, a consequence of climate change, could be linkeddirectly or indirectlyto the persistence as well as the re-emergence of malaria epidemics. The association between climate change and malaria spread is complex and remains a subject of controversy and debates. Therefore, Adewuyi and Adefemi posited that the spread and severity of malaria in several places and the increased incidences of the disease in some regions could indeed be associated with the effects and consequences of climate change. With this assertion, Adewuyi and Adefemi suggest that the biology of the Plasmodium spp, the ecology of mosquitoes and even the susceptibility of humans to malaria could all be affected directly/indirectly by extreme climatic events.

In Nigeria, evidence suggests an estimated 137,600 diarrhoeal deaths in children under-15 years of age in the baseline period of 2008. Furthermore, it was reported that under a high emissions event, diarrhoeal deaths which are linked to climate change in children under 15 years of age are projected to be 9.8 per cent of the over 76,000 diarrhoeal deaths predicted in 2030.

Evidence has proven that climate change has environmental and economic consequences on human health. The effects on human diseases such as skin cancer have been relatively under-emphasised. There is a direct link between ultraviolet (UV) exposure from the sun and the development of malignant skin disease.

One profound effect of climate change is among the aged persons in Nigeria. According to Aina and Adewoyin, the vulnerable age are particularly more at risk of climate-related diseases because of the effect of their age on their physiological and immunological compositions. Research has provided credence that the aged are more at risk of climate-related diseases because they have a lower physiological reserve, possess a slower rate of metabolism and a weakened immune system and have a higher morbidity rate.

SolutionsOn what Nigerians should do to protect themselves, Osibogun, who is the immediate past Chief Dedical director (CMD) of LUTH, said: We should reduce our exposure to the sun. It depends on the kind of work you do, but reduce the number of hours you stay under the sun, or rather outside, although some people, like bricklayers, cannot help but stay in the sun all day.

The negative effect could also be reduced by drinking enough water to replace the lost fluid from excessive sweating. Try and carry bottled water wherever you go and drink at least three litres of water daily.

A consultant meteorologist, Mr. Cyprian Okoloye, formerly with the Central Forecast Office of the Nigeria Meteorological Agency (NIMET), noted: The weather is not unusual. We are approaching the transition period between the dry season and rainy season. Usually, during the transition period, you experience very hot and humid weather. In a couple of days, you may see some showers.

The situation will return after the showers, even harsher conditions.

According to the United States Centers for Disease Control and Prevention (CDC), people at greatest risk for heat-related illness can take the following protective actions to prevent illness or death:*Stay in air-conditioned buildings as much as you can. Contact your local health department or locate an air-conditioned shelter in your area. Air-conditioning is the number one way to protect yourself against heat-related illness and death. If your home is not air-conditioned, reduce your risk for heat-related illness by spending time in public facilities that are air-conditioned and using air conditioning in vehicles.*Do not rely on a fan as your main cooling device during an extreme heat event.*Drink more water than usual and dont wait until youre thirsty to drink.*Check on a friend or neighbor and have someone do the same for you.*Dont use the stove or oven to cookit will make you and your house hotter.

Even young and healthy people can get sick from the heat if they participate in strenuous physical activities during hot weather:*Limit your outdoor activity, especially midday when the sun is hottest.*Wear and reapply sunscreen as indicated on the package.*Pace your activity. Start activities slow and pick up the pace gradually.*Drink more water than usual and dont wait until youre thirsty to drink more. *Muscle cramping may be an early sign of heat-related illness.*Wear loose, lightweight, light-colored clothing.

If you play a sport that practices during hot weather, protect yourself and look out for your teammates:*Schedule workouts and practices earlier or later in the day when the temperature is cooler.*Monitor a teammates condition, and have someone do the same for you.*Seek medical care right away if you or a teammate has symptoms of heat-related illness.

Everyone should take these steps to prevent heat-related illnesses, injuries, and death during hot weather:*Stay in an air-conditioned indoor location as much as you can.*Drink plenty of fluids even if you dont feel thirsty.*Schedule outdoor activities carefully.*Wear loose, lightweight, light-colored clothing and sunscreen.*Pace yourself.*Take cool showers or baths to cool down.*Check on a friend or neighbour and have someone do the same for you.*Never leave children or pets in cars.*Check the local news for health and safety updates.

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Coping with extremely hot, humid weather - Guardian

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Jamie Prock, RN-BSN, is an OB Nurse currently practicing within the Indian Health Service.

One of the biggest topics I encounter surrounding labor and delivery is induction of labor. I sit and listen to the process be explained, but I consistently admit patients for induction that remain confused or simply have unrealistic expectations of this process. I am going to break it down for you.

First things first, just like no child you have will be exactly likethe other; no pregnancy will go the same either. Induction and delivery are no exception to this rule. If you have had children previously, I do suspect that you have some knowledge of this process, but please understand that medicine and recommendations are constantly evolving. The process will likely not be the same twice. That being said, let us dive into what exactly induction of labor means.

Induction of labor is simply a process designed to push your body into labor. Labor is achieved in a variety of ways and using different mechanisms. During the natural process, the cervix begins to efface, or thin out, and start to dilate, or open. This process is preparing to allow the baby to travel through the birth canal and be delivered. With an induction, your physician or midwife, and your labor nurseprovide medications to assist in this process.

Depending on where your body is in the process will determine how your induction begins, continues, and progresses. If your body has done some of the work on its own, it is possible that you just need the body to begin having adequate contractions. If it has not, cervical ripening is the starting point. Cervical ripening is a term that refers to the process of effacing. As the cervix effaces, it will also begin to open. This is generally accomplished either mechanically or with medication.

Cervical ripening drugs include cervadil, or dinoprostone. This vaginal insert stays in place for 12 hours. Cytotec is a medication that can be taken orally or placed vaginally during this process. Of note, Cytotec is also given rectally in the case of post-partum hemorrhage. Mechanical means of ripening are a cooks catheter, also known as a Foley bulb. This is inserted into the cervix, designed to mechanically cause dilation and effacement. It will usually come out on its own when the cervix is dilated to four or more. These are the most common forms of cervical ripening.

After ripening has been achieved, Pitocin is usually started. Pitocin is a synthetic hormone designed to mimic the natural hormone, oxytocin, which is produced by the body. Pitocin is started at a low rate and gradually increased until adequate labor is achieved. The purpose of this drug is simply to cause contractions. The contractions will continue to push the baby down and open the cervix until dilation is complete and you are ready to push.

RELATED:10 Things To Know About Getting Induced For Labor

As you can see, induction of labor is a process. Natural labor is also a process. Both processes can take some time and do not happen quickly. This is one of the most common misconceptions of induction. For the record, there is no magic pill to make you instantly have a baby. This process could be quick, as in hours, or it could take a few days. A long induction does not mean it is not working, simply taking longer. Make sure you are ready, have realistic expectations, and ask questions when you are having an induction.

How To Cope With Pregnancy While Also Going Through A Divorce

Jamie Prock, RN-BSN, is an OB Nurse currently practicing within the Indian Health Service. During her career, she has worked at various locations throughout the Oklahoma and Arkansas region. She obtained her A.A.S. in Nursing from Bacone College in Muskogee, OK. Then went on to receive her B.S.N. from Oklahoma Wesleyan College in Bartlesville, OK. Prior to her education in the Nursing Profession, she attended the University of Arkansas with a Journalism major. After giving birth to her first son, she decided she wanted to be a labor and delivery nurse. Mrs. Prock also teaches nursing students part time at Rogers State University. She is a Fetal Monitoring Instructor for AWHONN. She continues to work on her Masters in Nursing while working full time. She is married to Russell, and together they have six children with a grandchild on the way. In her spare time, she enjoys spending time with her family, listening to music, journaling, and cooking.

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What Does Induction Of Labor Mean? | BabyGaga - BabyGaga

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Body stiffness is frequent when waking up within the morning. But taking it evenly could be overwhelming. There could be main causes behind the frequent ache within the joints, Swati Sharma is telling

If I bear in mind the time earlier this yr, I used to look at my grandmother's agility. In the morning, I and I needed to rise up as nicely. If the mom ever complained of backache, she used to get taunted, she has develop into older than us.

->When I used to be of mom's age, I too began complaining of backache or joint ache like her. The stiffness and joint ache of the physique is not seen by taking a look at age. In the morning it takes about fifteen minutes to maintain the toes down from the mattress after opening the eyes. Sometimes the shoulders are stiff, generally the heels are moaning in ache. The knee turns and the knee begins to reply. In the span of twenty years, the tempo of each life and illnesses has develop into very quick. These stiffness and ache occurring within the morning inform some story, you additionally hear:

These are the indicators of illnessesMorning stiffness in joints is a direct indication that youve began having bone issues. How critical the issue is is a matter of investigation. Anoop Agarwal, an orthopedic physician, says that if the stiffness happens in lots of joints, a person might develop systemic inflammatory illness. The poisonous substances current within the blood concurrently have an effect on many joints. These sorts of illnesses are often susceptible to a number of sorts of arthritis resembling rheumatoid arthritis, seronegative arthritis. This downside is discovered extra in ladies than males.

Males are usually extra prone to have ankylosing spondylitis. There is stiffness within the muscle mass of the waist, neck or again. Plantar fasciitis causes ache on account of swelling within the ankles, particularly within the morning. This sort of ache will get higher after waking up within the morning. Uric acid additionally has an necessary position in the issue of stiffness and joint ache that happens after waking up within the morning. Many sorts of issues happen even when uric acid will increase within the physique. Joint ache is one in all them. If uric acid doesnt come out of the physique, then it begins gathering within the type of crystals within the joints.

Catering and way of life is accountableOur meals and way of life are quickly altering like a gadget's specialty. Due to this, the issues occurring on the age of 60 have began to happen on the age of 40. Outside meals has develop into part of our way of life. Our behavior of solely giving significance to services has distracted our consideration from well being. Dr. Anoop says that the meals that involves the door, we have no idea. Apart from this, on account of haste and style, weve adopted junk meals a lot that the physique doesnt get sufficient diet. Regular consumption of such meals will increase the quantity of poisons within the blood. It is critical to grasp right here that the dietary supplements discovered within the drug shops can not compensate for the pure diet from the meals gadgets. Apart from this, the wasteful way of life can also be liable for this stiffness within the physique. Due to the ever growing busyness, our relationship with train and nature is sort of damaged. Staying indoors, not getting sufficient daylight and ineffective timetable for sleep are additionally liable for bone and muscle issues.

Some steps in the direction of therapy'The downside is handled by controlling its causes. Whether its hormone modifications or diet, its worthwhile to take note of your meals. You should determine that the physique will get all types of vitamins in enough amount. Many occasions weight-reduction plan to handle the determine additionally reduces diet. To drop some pounds, its higher to have a balanced food plan and train repeatedly.'Lack of calcium within the physique can also be liable for joint ache. To overcome this deficiency, you may take calcium and vitamin-D dietary supplements with the recommendation of a health care provider. Try to take vitamin-D naturally. Vitamin-D works to hold calcium within the physique to the bones. Due to deficiency of vitamin-D, calcium is wasted contained in the physique. For this, each morning spend 20 minutes in daylight in 50 % open physique. No matter how busy the life-style is, dont forget to take a 30-minute stroll. Blood circulation is sweet by taking a stroll and the toxins dont accumulate within the physique. 'Do not take the stiffness within the physique evenly within the morning. Seek medical recommendation earlier than it turns into a major problem. Use the information with fomentation and oil therapeutic massage as per the recommendation of the physician.

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These causes could also be behind the frequent joint ache - Sahiwal Tv

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A class action lawsuit says that Peter Thomas Roth makes false anti-aging claims about two of its product lines the Rose Stem Gel products and the Water Drench line of products. Plaintiffs Angela Clair, Bonnie McDonald, and Miley-Isabella Oien say they purchased products from the two lines in question, believing the claims made by Peter Thomas Roth about the capability of the products.The Peter Thomas Roth class action claims that the skincare company falsely advertises that the line of Rose Stem Cell products can improve and repair human skin because of the presence of rose stem cells in them. Ring of Fires Farron Cousins discusses this with Scott Hardy, the President of Top Class Actions.

Transcript:

*This transcript was generated by a third-party transcription software company, so please excuse any typos.

Farron Cousins:Most people think when they buy a product that contains some kind of stem cell, that theyre getting a top of the line product that is definitely going to work. After all, we all know the benefits of stem cells. They have been involved in countless medical breakthroughs even up to this day. So yeah, consumers across the planet would love to buy a product containing stem cells, but unfortunately theres different kinds of stem cells and that has now gotten one company, Peter Thomas Roth, in quite a bit of trouble with a new lawsuit.

Joining me now to explain this is Scott Hardy with Top Class Actions and Scott, yeah, everybody wants to get their hands on products with stem cells, especially in this case, anti-aging creams because you assume you put that on your face with these stem cells, its obviously gonna do some really great things because stem cells can do that. But as I mentioned, different kinds of stem cells here. You know, this isnt the human stem cells. This is something else, isnt it?

Scott Hardy:Thats right. You have Peter Thomas Roth and their anti-aging products, which are promising, according to this glass action, some amazing results. And with these stem cells, they, you know, like you said, you hear stem cells, you say, oh, I could rub this in. Stem cells are magical. They will make me look younger. Itll be great. Well, in this they had their Rose Stem Gel products, the Peter Thomas Roth Rose Stem Gel products, which have stem cells from roses. Now, Im not quite sure how that helps us as humans, but according to Peter Thomas Roth and their marketing agreements, these stem cells can have anti-aging and restorative benefits. But as like a lot of these class actions, the class actions saying that theres no science behind it that supports that. They also have their Water Drench line and the Water Drench line says that it draws moisture from the atmosphere into the users skin.

I mean, that is special and claims that the product will hold a thousand times its weight in water and provide hydration up to 72 hours. But again, unfortunately according to this class action, theres just no science to back it up. So you have these folks that are buying these products, hoping that it will help clear away their wrinkles, restore their face. You know, any age marks theyll, thats going to help, thats going to help them disappear with these Rose stem cells and this amazing Peter Thomas Roth Water Drench. But the science isnt backing it up is what the plaintiff attorneys are saying.

Farron Cousins:Well, and that, you know, makes total sense because human stem cells work because theyre cells that are not necessarily programmed for a specific function. So when you put them in the body, when you put them in a certain part of the body, they will kind of take on the role that the other cells in that area do. For example, you have a damaged liver and you get injected with stem cells in the liver, they will become or can become, excuse me, liver cells. So you would think if youre putting stem cells on your face, theyre going to become human skin cells. But you cant do that with a different, I mean, were not even talking about a different animal here. Were talking about a different organism all together. Roses, Im sorry, but human cells cannot bond with plant cells like that.

I mean, that, thats not a thing that is even scientifically possible. Maybe somewhere in the future were going to be able to merge with plants, I doubt it, but this company is saying, no, no, no. A stem cell is a stem cell, right? This is going to do well for you. And then I got to say with this Water Drench product, this would be a miracle product all around the world. You know, help your body draw in moisture from just the air. Oh my God, think of the problems we could solve. This, this, this truly is snake oil in my opinion, reading this, looking at these complaints, this stuff is pure snake oil, man.

Scott Hardy:Yeah, I mean thats what were seeing here. Were getting a bunch of comments on this. People that have bought these products and didnt see any results, and thats the big problem is that if youre going to promise these results, if youre going to say that we have this special benefit, we have these special ingredients that make our product amazing, then it needs to deliver. And you have to have studies that back that up. You have to be able to say, hey, these are folks that used the Peter Thomas Roth Rose Stem Gel and this is the benefits that they saw and, you know, all of these claims about the stem cells and the extra hydration. There has to be some science instead of just thinking, well maybe itll work and then putting on their box and selling it.

Farron Cousins:Well and, you know this, this should be a fairly easy one for the lawyers here to prove. I mean, they can look and see if there is in fact any science to back any of this up. Obviously theres past customers to see if theres anything here. So hopefully this is going to be a slam dunk for the lawyers thats going to result in a pretty decent settlement for the people whove been using these products regularly. Again, when its based on science, science is either there or its not. So again, hopefully this is fairly easy and, you know, if it is, this could be one of those ones that settles probably long before it actually makes it to a trial.

Scott Hardy:Exactly. Now, unless your face is actually part rosebud, then maybe that really would help have a, a real positive impact. But I dont know anybody, even if they smell nice, that it might help with.

Farron Cousins:Right. For more information on this issue, you can follow the link in the description of this video, head over to Top Class Actions, and while youre there, make sure you sign up for their weekly newsletter. Scott Hardy with Top Class Actions, thank you very much for talking with us.

Scott Hardy:Youre welcome. Thanks for your time, Farron.

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Lawsuit Claims Anti-Aging Skin Cream Is Totally Useless - The Ring of Fire Network - The Ring of Fire Network

Recommendation and review posted by Bethany Smith

There is new hope for patients with a rare autoimmune disorder. In mild cases, scleroderma causes areas of hardened skin. But in severe cases, it can also cause deadly hardening of internal organs like the lungs.

A transplant typically used to treat cancer is having remarkable results for patients who had little hope of surviving.

A year ago, Chuck Beschta couldn't walk more than a few minutes without stopping to rest.

"Just going out and doing normal activities outside raking the lawn, mowing the grass, shoveling the driveway, whatever, snow blowing those became impossible," he said.

After months of testing, he was diagnosed with severe scleroderma, which was hardening his skin. But even worse, it was hardening his lungs, making it hard to breathe.

"He was getting worse despite the best therapy we had to offer," University of Wisconsin rheumatologist Dr. Kevin McKown said.

McKown recommended a stem cell transplant newly approved for scleroderma to reboot Beschta's immune system.

"There's a process by which they try to remove the autoreactive immune cells, the cells that are caught in the immune process, and then they infuse that back in and hope that the body will basically take up and graft that immune system," McKown said.

Beschta saw almost immediate results. His skin was softer and his breathing improved. He hopes his scleroderma has been cured.

"I think we can be optimistic, and so far the people who have been followed out as far as 10 years out don't seem to be getting it back," McKown said.

Without a transplant, less than half the patients who have diffuse scleroderma and severe lung disease live 10 years past diagnosis.

Stem cell transplants are commonly used to treat leukemia and lymphoma, cancers that affect the blood and lymphatic system.

MEDICAL BREAKTHROUGHSRESEARCH SUMMARYTOPIC: NEW THERAPY FOR SCLERODERMAREPORT: MB #4698

BACKGROUND: Scleroderma is an autoimmune rheumatic disease where an overproduction of collagen produced in the body tissues causes the skin and internal organs to harden. The symptoms and effects range by person, but some common symptoms include hardened patches of skin (locations on the body vary,) painful and numb-feeling fingers and toes, and sharp internal pain in the esophagus, intestines, heart, lungs, or kidneys. Women are four times as likely to have scleroderma and the onset is between 30 and 50 years of age. However, anyone from infants to the elderly can have scleroderma. Possible risk factors include having certain gene variations as other family members, ethnic groups, exposure to certain medications or drugs, and already having another autoimmune disease, like rheumatoid arthritis, lupus or Sjogren's syndrome. (Source: https://www.scleroderma.org/site/SPageNavigator/patients_whatis.html;jsessionid=00000000.app30132b?NONCE_TOKEN=9B76519DF6B5819859319F0B63B805C9#.XheCGVVKhaQ , https://www.mayoclinic.org/diseases-conditions/scleroderma/symptoms-causes/syc-20351952 )

DIAGNOSING: A physical exam will be conducted as well as a blood test to check for elevated levels of antibodies the immune system produced. The doctor will also take a sample of skin to be tested in the lab. If there are complaints about internal pain, the doctor may run other tests, including imaging, organ function, and other blood tests. (Source: https://www.mayoclinic.org/diseases-conditions/scleroderma/diagnosis-treatment/drc-20351957 )

NEW TECHNOLOGY: A new stem cell transplant that's commonly known to treat cancer is improving the quality and quantity of life for those with scleroderma. Rheumatologists at University of Wisconsin Health tested the treatment since they have already been conducting bone marrow transplants for decades. Surgeons take out a sample of the patient's bone marrow, isolate the stem cells, and use radiation and chemotherapy to clean out their immune system. The same stem cells are later injected back into the patient's immune system with the hope that new cells will grow and the system is rid of the bad ones. The process is dangerous when the cells are taken out because the patient's immune system is more vulnerable, making infections more likely to occur. However, after four and a half years, 79% of patients that underwent the treatment were alive without serious complications compared to 50% that were treated with the original drugs. (Source: https://madison.com/wsj/news/local/health-med-fit/man-with-severe-autoimmune-disease-gets-stem-cell-transplant-at/article_7e8e17a5-21da-52f8-b728-fe584dab2b77.html)

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New technique developed to treat hardening of internal organs - WNDU-TV

Recommendation and review posted by Bethany Smith

INTRODUCTION

Severe combined immunodeficiency (SCID) is a heterogeneous group of genetic diseases characterized by severe T cell lymphopenia, causing increased susceptibility to viral, bacterial, and fungal infections since early in life (1). Most forms of SCID are due to genetic defects that are intrinsic to hematopoietic cells and can be successfully treated by allogeneic hematopoietic stem cell transplantation (HSCT). However, SCID may also be caused by genetic abnormalities that are intrinsic to thymic epithelium development and function; in such cases, thymus transplantation, but not hematopoietic cell transplantation, is required to cure the disease. Only a few genetic abnormalities, including complete DiGeorge syndrome, and pathogenic variants affecting FOXN1 or CHD7, are known to cause SCID as a result of abnormal thymic development in humans (1).

PAX1 is a member of the paired box (PAX) family of transcription factors and plays a critical role in pattern formation during embryogenesis. It is expressed in the pharyngeal pouches that give rise to the thymus, tonsils, parathyroid glands, thyroid, and middle ear development during human embryogenesis (2). Pax1 deficiency in mice is characterized by anomalies of the vertebral column and variable degrees of thymic hypoplasia and thymocyte number and maturation (35). In humans, a homozygous pathogenic PAX1 p.Gly166Val variant (6) and a homozygous frameshift insertion (c.1173_1174insGCCCG) (7) have been identified in patients with otofaciocervical syndrome type 2 (OTFCS2), a rare disorder characterized by facial dysmorphism, external ear anomalies with preauricular pits and hearing impairment, branchial cysts or fistulas, anomalies of the vertebrae and the shoulder girdle, and mild intellectual disability. Recently, another homozygous pathogenic PAX1 variant (p.Cys368*) has been reported in two affected children from a consanguineous family of North African descent, who presented with OTFCS2 associated with T B+ SCID (8). However, limited information was provided on the immunological phenotype of these patients, and the functional consequences of the PAX1 variant were not investigated. Here, we provide an in-depth clinical, biochemical, and immunological description of multiple patients with OTFCS2 associated with SCID who carried biallelic deleterious PAX1 variants. By performing transfection experiments, molecular modeling, molecular dynamics (MD) simulation, and in vitro differentiation of control- and patient-derived induced pluripotent stem cells (iPSCs) to thymic epithelial progenitor (TEP) cells, we sought to assess the effects of human PAX1 deficiency on thymus development and function.

Patient 1 (P1) is a male infant born to parents whose families were from the same rural region in Germany (Fig. 1A). Bilateral microtia, malar prominence, narrow alae nasi, cupid bow lip, and retrognathia were noticed at birth (fig. S1, A and B). Imaging studies demonstrated severely stenotic external auditory canal on the right side and narrow left auditory canal (fig. S1C), congenital kyphosis at C3-C4 and L3 levels, moderate spinal canal narrowing (fig. S1, D to F), and traction on the cauda equina (fig. S1G). Diffuse erythematous rash (fig. S1H), lymphadenopathy, elevated serum immunoglobulin E (IgE), and eosinophilia were present, consistent with Omenn syndrome. On chest x-ray, the thymus shadow was not visible, and split cervical vertebral bodies, hooked distal clavicles, and a shallow dysplastic glenoid fossa were seen (fig. S1I). This infection history during infancy included Staphylococcus aureus bacteremia, pneumonia, cellulitis, and diarrhea due to Clostridium difficile.

(A) Pedigrees and results of Sanger sequencing in patients with PAX1 variants and in healthy controls. For both family A and family B, results of Sanger sequencing in the heterozygous parents are also shown. (B) Schematic representation of the PAX1 protein and location of the variants identified in affected individuals.

P2 and P3 have been previously described (8) as patients V:1 and V:18, respectively, and are part of a large consanguineous family of Moroccan origin (Fig. 1A). At birth, P2 was noticed to have frontal and parietal bossing, hypertelorism, small nose with hypoplastic nasal root, low-set ears with agenesis of the left pinna and hypoplasia of the right pinna, scapular winging, and bilateral cryptorchidism. Imaging studies showed impaired development of internal auditory canals bilaterally and lack of a thymic shadow. P3 manifested similar facial dysmorphisms as P2, along with left facial nerve palsy, severe dorsal and lumbar scoliosis, and deafness. Imaging studies documented lack of thymic shadow, abnormal appearance of vertebrae, clavicles and shoulder blades, narrowing of both external auditory canals (fig. S1J), abnormalities of the middle ear, and presence of tubular structures with features of a dental element behind the mandibular condyle (fig. S1, K and L). Subject V:3 from the same family died early in life with a history of severe infections, but no formal medical records are available.

P4 and P7 are siblings born to consanguineous parents from Saudi Arabia. P7 was noticed to have severe bilateral microtia, postauricular sinuses, and micrognathia. He suffered from chronic diarrhea, recurrent respiratory infections, exfoliative dermatitis, regional dissemination of Bacille Calmette-Guerin (BCG-itis), and lymphadenopathy and died at 1 year of age.

P4 is a female with a history of chronic diarrhea, recurrent respiratory infections, and poor weight gain since the age of 1 month. Physical examination showed small malformed ears, a skin tag on the right ear, facial asymmetry, small nose with depressed nasal bridge, and small almond-shaped eyes. A skeletal survey showed wedge-shaped vertebral body at T11 and deficient posterior element of the sacrum at S4 and S5.

P5 and P6 were siblings born to consanguineous parents and belonged to the same extended family as P4 and P7. P5 had small, low-set malformed ears, triangular mouth, down-slanting palpebral fissures, a small nose with a depressed nasal bridge, and right facial palsy. She developed recurrent respiratory infections, chronic diarrhea, severe exfoliative dermatitis, and BCG-itis and was diagnosed with Omenn syndrome. She died at 8 months of age with progressive severe pneumonitis.

P6 was screened for immunodeficiency at birth because of the positive family history. She had malformed and low-set small ears, small chin, protruding forehead, and generalized eczema. A skeletal survey showed central depression of the vertebral bodies in the thoracic and lumbar spine. Her immunological workup was consistent with T B+ NK+ (natural killerpositive) SCID. She suffered from recurrent respiratory infections and chronic diarrhea and died at 9 months of age with respiratory syncytial virus (RSV) pneumonia.

The main immunological findings at presentation in P1 to P6 are shown in Table 1. In particular, P1 had significant T cell lymphopenia. His CD4+ lymphocytes were largely (98%) CD45R0+, no CD4+ CD45RA+ CD31+ cells were detected, and T cell proliferation to phytohemagglutinin (PHA) was impaired (fig. S2A). T cell receptor (TCR) excision circles (TRECs) were below the limit of detection, indicating lack of thymopoiesis. TCR V spectratyping revealed T cell oligoclonality (fig. S2B). Elevated serum IgE and eosinophilia were present, consistent with an Omenn syndrome presentation.

AEoC, absolute eosinophil count; ALC, absolute lymphocyte count; ANC, absolute neutrophil count; n.d.: not done; cpm, counts per minute.

Laboratory investigations in P2 at 2 weeks of age revealed profound T cell lymphopenia, markedly reduced proliferative response to mitogens, and increased serum IgE. An inguinal lymph node biopsy showed severe lymphoid depletion, with primary follicles without germinal centers, associated with nearly complete absence of CD3+ T cells, but presence of B and NK cells and sparse plasma cells, and increased number of CD68+ histiocytes and eosinophils (fig. S3). A diagnosis of T B+ NK+ SCID was established.

Severe T cell lymphopenia was observed in P3, P4, and P6, associated with virtually absent in vitro T cell proliferation to PHA in P4 and P6, consistent with a diagnosis of T B+ NK+ SCID (Table 1). Last, P5 was diagnosed as having Omenn syndrome based on generalized erythroderma, lymphocytosis, eosinophilia, hypogammaglobulinemia, increased IgE, and severely reduced in vitro T cell proliferation to PHA.

Because of severe immunological abnormalities, HSCT was attempted in P1 to P4 before the gene defect was known. Details of transplant, chimerism, and immune reconstitution are shown in Table 2. In all cases, a conditioning regimen was used. Two patients (P1 and P4) attained full donor chimerism. P2 failed to engraft, developed interstitial pneumonitis, and died 5.5 months after HSCT. In P3, initial engraftment was followed by secondary graft failure, and a second HSCT was performed, resulting in mixed chimerism. Although three of the patients attained either full or mixed donor chimerism, none of them achieved reconstitution of the T cell compartment. In P1, who exhibits full donor chimerism, all T cells have a CD45R0+ phenotype and therefore likely represent donor-derived T cells contained in the graft that have undergone peripheral expansion. P3 attained mixed chimerism but remained with persistent severe T cell lymphopenia. She developed Pneumocystis jiroveci pneumonia, recurrent gastrointestinal infections, and liver failure and died of septic shock at the age of 4 years and 7 months. P4, who attained full chimerism but failed to reconstitute T cells, developed severe autoimmune hemolytic anemia, requiring multiple courses of rituximab and immunosuppressive therapy. Together, these data indicate that HSCT was unable to correct the profound T cell immunodeficiency of this disease.

ATG, anti-thymocyte globulin; PBSC, peripheral blood stem cells; URD, unrelated donor.

Before HSCT, karyotype analysis revealed no cytogenetic abnormalities in P1, P2, and P3. No evidence for copy number variation (CNV) was found by chromosomal microarray analysis in P1, and search for 22q11 deletion in P2 by in situ fluorescence hybridization was negative. No pathogenic variants in any of the known SCID-causing genes were identified in P4 by a targeted next-generation sequencing primary immunodeficiency gene panel. In an attempt to define the molecular mechanisms of the disease, whole-exome sequencing (WES) was performed in P1, P2, and P4 independently (fig. S4 and table S1). In P1, a total of 153,376 variants were identified. Assuming autosomal recessive inheritance, and upon filtering for homozygous, rare, nonsynonymous changes in coding regions and splice sites, 38 variants were considered. Among these, functional annotation identified the PAX1 NM_006192.3 c.463_465del variant, predicted to cause an in-frame deletion of asparagine at position 155 (p.Asn155del) of the PAX1 protein, as the most likely cause of the disease. In P2, 87,423 variants were detected. Assuming an autosomal recessive inheritance, and upon filtering for homozygous, nonsynonymous, and rare (minor allele frequency < 0.01) variants falling in coding regions or splice sites, 18 such variants were considered. Functional filtering of these revealed the PAX1 c.1104C>A variant, predicted to cause a premature termination at codon 368 (p.Cys368*), as the most likely cause of the disease. In P4, 60,772 variants were detected. Upon filtering for homozygous, nonsynonymous, rare (in-house Saudi variant database <0.005) variants, which were restricted to exonic or splice sites, contained in an autozygome region identified on chromosome 20 by high-density genotyping, and shared with P5 and P6, only two variants were identified, including the PAX1 c.439G>C variant, predicted to cause a p.Val147Leu amino acid change.

Sanger sequencing confirmed homozygosity for the suspected pathogenic PAX1 variants in P1 to P6 (Fig. 1A). The Val147 and the Asn155 amino acid residues are in the DNA-binding paired box domain, and the Cys368 residue is in the transactivation domain of the PAX1 protein (Fig. 1B). All these positions are evolutionarily conserved (fig. S5). The scaled CADD (combined annotation dependent depletion) score (CADD-Phred) for the p.Val147Leu, p.Asn155del, and p.Cys368* variants is 28.1, 21.2, and 38, respectively, significantly higher than the mutation significance cutoff (MSC) score (9), which for the PAX1 gene is 12.06. Together, these data strongly support a pathogenic role of the PAX1 variants identified. Of note, while molecular and cellular studies to confirm the pathogenic role of the PAX1 variants were under way, another group independently attempted WES in P3 and in other family members (but not in P2) and reported the occurrence of the p.Cys368* variant in P3 (8).

To examine the effects of the PAX1 variants at the protein level, we transfected 293T cells with plasmids encoding for either wild-type (WT) or mutant PAX1 complementary DNA (cDNA) and analyzed protein expression by Western blot. In this assay, we also included the PAX1 p.Gly166Val variant, which had been previously reported in a patient with OTFCS2 (6). As shown in Fig. 2A, all mutant proteins were expressed at similar levels as WT PAX1, with the p.Cys368* mutant migrating as a lower molecular weight product, as predicted. To check whether the identified variants altered the subcellular localization of the PAX1 protein, 293T cells were transfected with PAX1 constructs with an N-terminal HA tag, and immunofluorescence was performed with tetramethyl rhodamine isothiocyanate (TRITC)conjugated anti-HA antibody. As shown in Fig. 2B, both WT and mutant PAX proteins were detected in the nucleus, indicating that these variants do not affect subcellular localization.

(A) Western blot showing expression of WT and mutant human PAX1 proteins upon transient transfection in 293T cells. (B) Left: Intracellular protein localization upon transfection of HA-tagged WT and mutant PAX1 constructs into 293T cells, followed by staining with TRITC anti-HA. Right: Counterstaining with DAPI, demonstrating that the mutant PAX1 protein retains nuclear translocation capacity. Scale bar, 10 m. (C) Results of a luciferase reporter assay demonstrating reduced transcriptional activity of mutant PAX1 proteins, corresponding to the PAX1 variants detected in patients. The promoter region of Nkx3-2 was used to drive luciferase expression. Results of six independent experiments (each run in triplicate) are shown (means SEM). P value was calculated with one-way ANOVA and adjusted by Dunnetts multiple comparisons test. **P < 0.01; ***P < 0.0001.

Next, we tested the transcriptional activity of the PAX1 mutant proteins. Little is known on transcriptional targets of human PAX1; however, the Nkx3-2 promoter has been identified as a PAX1 target in mice (10). Therefore, we generated a reporter system in which luciferase expression is driven by the mouse Nkx3-2 promoter. In parallel, we generated both WT (Pax1WT) and mutant (Pax1Val138Leu, Pax1Asn146del, Pax1Cys359*, and Pax1Gly157Val) N-terminal HA-tagged mouse Pax1 constructs, which encode for mouse mutant PAX1 proteins corresponding to the human p.Val147Leu, p.Asn155del, p.Cys368*, and p.Gly166Val variants, respectively. Western blot analysis confirmed that the mutant mouse PAX1 proteins were expressed at similar levels as WT PAX1 (fig. S6). Upon cotransfection of the Nkx3.2-luciferase reporter plasmid and of either WT or mutant PAX1 expression plasmids into 293T cells, analysis of luciferase activity showed that the p.Val138Leu, p.Asn146del, and p.Cys359* PAX1 mutant proteins had significantly reduced reporter expression when compared with WT PAX1 (Fig. 2C and data file S1). A similar defect was also observed for the p.Gly157Val mutant, confirming previous findings (6). These data suggest that the human p.Val147Leu, p.Asn155del, and p.Cys368* variants do not affect protein stability or subcellular localization but alter PAX1 transcriptional activity.

The structure of the human PAX1 protein has not been solved experimentally. However, a crystal structure is available for the paired box domain of the highly homologous PAX6 protein (11). Sequence alignment between the paired box domain of PAX6 and PAX1 proteins reveals a high level of conservation with a similarity of 71%, with a 100% coverage of the region to be modeled as calculated with the BLOSUM80 matrix from PSI-BLAST (E = 1.3691 1020). As reported by Kelm et al. (12), this degree of homology often yields a model for the target (PAX1) with an accuracy of less than 1 root mean square deviation (RMSD) of atomic mobility to the experimentally solved structure of the template (PAX6). Because the p.Val147Leu and p.Asn155del mutants fall within the paired box domain of the protein, we assessed whether the reduced functional activity of the mouse p.Val138Leu and p.Asn146del (and by inference, the human p.Val147Leu and p.Asn155del) variants results from an altered structure and/or abnormal DNA binding. To do this, we first developed a structural model of the paired box domain of WT and mutant PAX1 bound to DNA, based on its homology to the published crystal structure of PAX6 [Protein Data Bank (PDB): 6PAX] (11) by the satisfaction of spatial restraints method using Modeler (13). Structural alignment revealed that the paired box domains of the PAX1 and PAX6 proteins are almost identical with a template modeling (TM) score of 0.99963 and RMSD of 0.08 as measured by the TM align algorithm (14). In addition, the high quality of the model is reflected by the fact that 99% of the residues are in the allowed regions of the (phi) versus (psi) angles of the Ramachandran plot, as shown in fig. S7 (15). Therefore, we used this model to derive a corresponding model for the p.Val147Leu and p.Asn155del variants and for the previously described p.Gly166Val PAX1 variant (6), using in silico site-directed mutagenesis and energy minimization refinement as previously described (16). As shown in Fig. 3A, the paired box domain of all three mutant PAX1 proteins retains a structure composed of two globular domains separated by a linker. These structural models were then used in MD simulations for both their free and DNA-bound forms to define how they differ in both structure and time-dependent dynamic behavior from the canonical WT PAX1 protein.

(A) Molecular modeling of the paired box domain of WT and mutant PAX1 proteins, showing the presence of two globular domain separated by a linker. Note that the asparagine residue at position 155 is adjacent to linker domain, and its deletion results in shortening of the last turn of the third helix in the first globular domain of the paired box domain. (B) Molecular superimposition of WT (in light blue) and mutant PAX1 variants after MD simulation, showing that both the Val147Leu and Asn155del variants predominantly affect the conformation of the C-terminal globular domain, whereas both globular domains are affected by the Gly166Val variant. (C) RMSF values of WT PAX1 and of the Val147Leu, Asn155del, and Gly166Val variants during MD simulations. RMSF values are used here as a measure of the flexibility of different regions of the protein during the MD simulations. The Y axes indicate the magnitude of the fluctuation, whereas the X axes indicate the specific location of each amino acid within the paired box domain.

Because the p.Val147Leu variant is located in the first globular domain, the p.Asn155del is also located in this domain and adjacent to the highly flexible linker, and the p.Gly166Val variant is within the linker, we initially performed 200-ps MD simulations of PAX1 in the absence of DNA to capture potential alterations of the rapid movement of this region of the protein in relationship to the N- and C-terminal helix-loop-helix domains. To gain additional insights into the behavior of the protein, we extended these simulations to 10 ns, in the absence or presence of DNA. When a harmonic restraint is applied to reduce the conformational changes in both globular domains during the 200-ps simulation, the linker is observed to move freely. In this situation, the molecular movement of WT PAX1 paired box domain resembles a barbell-shaped harmonic oscillator, where the globular domains move relative to each other without forming bonds that lock them together in space.

At the end of the 200 ps, in the absence of DNA, the linker of PAX1 shortens and the protein populates a conformational landscape where the globular domains come in close proximity to each other, with the linker located between the N-terminal helix 3 (H3) and the C-terminal helix 1 (H1), respectively (fig. S8). In the most extended conformation of the linker, the interglobular domain distance measured from the Gly158 -C to the Pro175 -C shortens from an original 38.946 to 21.414 (SD = 2.421, P = 0.0001). This shortening contributes to the differences in the RMSD curve, where in the first part of the simulation we observed significant changes due to this shortening, whereas the difference in conformational sampling decreases toward the end of the run. Identical results were obtained in 10-ns simulations. Thus, this H3-Linker-H1 state is likely the one that the PAX1 binding domain adopts when in conformational equilibrium before binding to DNA. In this manner, the linker would be free to contact the minor groove of the DNA and extend in a manner that allows the positioning of both globular domains for full binding. These results led us to set up simulations that would enable gathering information on potential differences in DNA binding among the WT and mutant PAX1 variants.

To investigate whether alterations in the structure or the dynamics of the PAX1 variants have the potential to affect the protein function as a transcription factors, we modeled these proteins in complex with DNA. For this purpose, we again used the bound form of PAX6 as a template. Figure S9 shows the energy-minimized structure of these models before MD simulations. Because the variants identified in the patients either change the sequence of the linker (p.Gly166Val) or the N-terminal globular domain (p.Val147Leu and p.Asn155del), we compared the structures of these variants with WT PAX1 after MD simulation. Because the structure of the DNA interacting with WT or mutant PAX1 proteins was the same in all models shown in fig. S9, we removed it to facilitate the observation of changes that occur in the PAX1 polypeptide chain. When compared with WT PAX1, the p.Val147Leu and the p.Asn155del variants associated with OTFCS2 + SCID differ in particular at the C-terminal second globular domain, as shown by molecular superimposition (Fig. 3B). This result is consistent with the measured root mean square fluctuation (RMSF) values, which shows that the second globular domain is highly flexible in the p.Val147Leu and p.Asn155del mutant proteins (Fig. 3C). By contrast, RMSF values in the first globular domain were lower in all mutant proteins (and especially so in the p.Asn155del and p.Gly166Val mutants) as compared with WT PAX1. Considering these changes, we evaluated potential alterations in the ability of these proteins to recognize and bind to DNA in silico. For this purpose, we analyzed the PAX1-DNA interface. As shown in Fig. 4, as compared with WT PAX1, a lower number of amino acid residues contacting DNA were present within the paired box domain of the p.Val147Leu and p.Asn155del PAX1 mutants. These alterations are more pronounced for the C-terminal region of the domain, which contacts the 3 half of the oligonucleotide and is necessary to maintain appropriate binding to DNA. This altered pattern of interaction with DNA observed in silico may contribute to the altered transcriptional activity of the PAX1 mutant proteins.

Nucleotide residues, in which the paired box domain of either WT or PAX1 mutant proteins establishes interaction, are shown in black. The amino acids contacting nucleotides of target DNA are indicated on the Y axis for each PAX1 protein. The red and green colors indicate loss and gain of DNA binding, respectively.

To gain insights into how pathogenic PAX1 variants may perturb the developmental program of thymic epithelial cells (TECs), we reprogrammed fibroblasts from a healthy control, P1, and P4 to iPSCs and subsequently differentiated these to TEP cells using a previously published protocol (17) with some modifications (see Materials and Methods). Quantitative real-time polymerase chain reaction (qRT-PCR) showed a comparable stemness profile in both control and patient iPSCs (fig. S10), and cytogenetic analysis confirmed their karyotypic integrity. iPSCs were then exposed in vitro to a cocktail of growth factors and molecules that provide essential cues to allow differentiation into definitive endoderm (DE) and eventually into TEP cells (fig. S11A).

To assess changes in the gene expression profile of cells during differentiation, we performed RNA sequencing (RNA-seq) in control cells collected in triplicate at iPS [day 0 (d0)], DE (d5), and TEP (d14) stages of cell differentiation. For each condition, between 15 and 20 million reads were obtained per well. As shown in fig. S11B, during differentiation of control iPSCs to DE and TEPs, we observed progressive changes of gene expression profile, with increased expression of stemness (OCT4, MYC, SOX2, TERT, DNMT3B, and NANOG), endoderm (EOMES, CXCR4, and SOX17), and epithelial (KRT8, CLDN1, EPCAM, LAMA1, and KRT19) genes at iPS, DE, and TEP stages, respectively. In addition, expression of ASXL1, HES1, SHH, GATA3, HOXA3, PSEN1, ZBTB1, HAND2, and MAFB genes, which are all part of the gene set Thymus development, was up-regulated at TEP stage (fig. S11B). Gene set enrichment analysis (GSEA) confirmed differential expression of genes involved in somatic cell maintenance and endoderm development, as well as in other pathways related to differentiation of tissues derived from the third and fourth pharyngeal pouches (fig. S11C).

To assess the reproducibility of the differentiation protocol, we differentiated the same control iPS line twice to TEP cells (named C1 and C2, respectively) in parallel to differentiation of P1 and P4 iPSCs to TEP cells in two distinct differentiation experiments. As shown in Fig. 5A, a similar pattern of changes in the gene expression profile was observed when differentiating control (C1) and P1 iPSCs or control (C2) and P4 iPSCs to TEP cells. In both experiments, control and patient cells showed increased expression of stemness genes at the iPS stage, whereas enhanced expression of epithelial marker genes and of other genes included in the Thymus development gene set was detected at TEP stage. Furthermore, immunohistochemistry analysis confirmed that both control and P1 TEP cells expressed cytokeratin 8 (KRT8), a marker of TECs (fig. S12) (18).

(A) Heatmap of differentially expressed genes between iPS and TEP stage as determined by RNA-seq. Each heatmap shows the top 3000 genes, which were differentially expressed between iPS and TEP cells, with a significance (q < 0.01) by the two-group comparison (t test). Genes whose expression was found to be up-regulated at the TEP stage included epithelial cell markers (EPCAM, KRT8, and KRT19) as well as several genes (PSEN1, HES1, ASXL1, HOXA3, HAND2, EPHB3, and GATA3), which appeared at the leading edge of GSEA of thymus development in (B). (B and C) GSEA on thymus development gene set by preranked genes according to signed log10 adjusted P value. The adjusted P value was acquired by DEseq2 analysis using normalized read count of RNA seq data. FDR, false discovery rate. (D) qRT-PCR analysis of FOXN1 and DLL4 expression at TEP stage of differentiation. Results are from five independent experiments for control and P1, and four independent experiments for control and P4, with triplicates in each case (mean SEM). The P value was calculated with two-tailed paired t test. P < 0.05 was considered to be significant. (E) Thymus development genes with evidence of differential expression between patient and control cells (adjusted P < 0.1 and concordant pattern of expression in both RNA-seq experiments). For this comparison, we considered genes that were part of the Thymus development gene set in MSigDB v7.0, and in the top 30 FOXN1 target genes reported in (19). The values displayed are the signed log10 adjusted P value for differential expression.

GSEA confirmed that upon differentiation of control iPSCs to TEP cells, genes involved in thymus development were more abundantly expressed at the TEP stage both in control and in PAX1 mutant cells (Fig. 5B). Despite similar changes in gene expression profile during differentiation of control- and patient-derived iPSCs to TEP cells, GSEA demonstrated that genes involved in thymus development were more abundantly expressed in control than in patient TEP cells (Fig. 5C). To gain additional mechanistic insights into the severe T cell immunodeficiency of P1 and P4, we performed multiple rounds of differentiation of control and patient iPSCs to TEP cells (five times for control and P1 and four times for control and P4 cells, respectively) and used qRT-PCR to analyze the expression of FOXN1, a master regulator of TEC development (19, 20), and to its target DLL4, a Notch ligand that plays a critical role in T cell commitment (21). FOXN1 expression was significantly reduced in P1 and P4 TEPs as compared with control cells, and a similar trend was observed for DLL4, although the latter significance was reached only when comparing P1 with control TEPs (Fig. 5D and data file S1). Analysis of RNA-seq data revealed several other genes that showed concordantly reduced expression in P1 and P4 TEPs versus control TEPs, reaching statistical significance in at least one of the patients TEP lines (Fig. 5E and table S2). These included STC2, CD83, ZAR1, and ANKMY1, which are known FOXN1 target genes (19); TP63, a regulator of TEC proliferation and aging (22, 23); BMP4, which has been implied in thymus development (24, 25) and in maintenance of TEPs (26, 27); and EYA1 and PAX9, which are involved in patterning of pharyngeal endoderm (28, 29). Together, these data indicate that multiple mechanisms contribute to the thymic defects associated with PAX1 deficiency. Consistent with this, and with the syndromic features manifested by the patients, we observed that several genes included in the Neural crest cell differentiation, Ear development, Cartilage development, Pharyngeal system development, and Skeletal system development gene sets also manifested differential expression in P1 and P4 versus control TEPs (fig. S13).

We have studied six patients from three unrelated families in whom biallelic, loss-of-function PAX1 variants underlie a clinical phenotype characterized by OTFCS2 and severe T cell immunodeficiency. The first example of a biallelic, rare PAX1 variant (p.Gly166Val) in a patient with autosomal recessive OTFCS2 was provided by Pohl et al. (6), who also showed reduced transcriptional activity of the mutant PAX1 protein. However, no data on the patients immunological phenotype were provided. More recently, Patil et al. (7) have described two siblings with a homozygous frameshift PAX1 variant causing OTFCS2; one of them lacked a thymic shadow on chest x-ray. Last, the clinical features of OTFCS2 and SCID have been recently reported by Paganini et al. (8) in two of the patients studied here (P2 and P3), but no immunological or mechanistic characterization was provided.

Several mouse models of PAX1 deficiency, due to distinct variants in the Pax1 gene, have been described, including the undulated (un), undulated extensive (unex), undulated short-tail (unS), and undulated intermediate (un-i) models (30). All of these mutant strains display thymic abnormalities, which are more severe in the unS model (30); however, none of them results in complete athymia. A more profound phenotype, with lack of thymus and parathyroids, associated with craniofacial and skeletal abnormalities, has been observed in Pax9/ mice (31). No cases have been reported of humans with biallelic PAX9 pathogenic variants, and heterozygous PAX9 variants in humans are associated with hypodontia but not with thymic defects (32). Together, these data suggest that the impact of PAX1 and PAX9 on thymus development may be different in humans and mice.

To gain insights into the molecular mechanisms by which PAX1 deficiency may cause syndromic SCID in humans, we have first investigated the expression, subcellular localization, and transactivation activity of PAX1 mutant proteins using transient transfection and luciferase reporter studies. Although transient transfection may result in protein overexpression and therefore cannot be directly compared with protein expression in vivo, the PAX1 p.Val147Leu, p.Asn155del, and p.Cys368* mutant proteins retained the capacity to translocate to the nucleus, and the equivalent murine mutant proteins showed decreased transcription factor activity in vitro. Similar results were obtained for the PAX1 p.Gly166Val (and the mouse equivalent p.Gly157Val) variants, confirming previous observations (6). To further investigate the mechanisms underlying the impaired transcriptional activity of the mutant PAX1 proteins, we have performed structural modeling, using the crystal structure of the PAX6 paired box domain as a template. The results suggest that the structural behavior of the paired box domain (consisting of two globular domains interconnected by a linker) was retained in the p.Val147Leu, p.Asn155del, and p.Gly166Val mutants. MD simulation studies have demonstrated that these variants alter the flexibility of the paired box domain and are predicted to alter binding of PAX1 to its target DNA. Our in silico studies suggest that the mutants differ in their ability to gain or lose binding to distinct nucleotides, with possible impact on the severity of clinical and immunological phenotype. Fine characterization of the molecular mechanisms underlying such heterogeneity will require resolution of the crystal structure of the PAX1 paired box domain and precise identification of its human DNA target sequence(s).

By exposing control- and patient-derived iPSCs to defined differentiation cues, we have successfully differentiated iPSCs to TEPs. Comparison of gene expression profile in control- and patient-derived cells at the TEP stage of in vitro differentiation demonstrated altered expression of genes involved in thymus development in patient cells. In particular, qRT-PCR analysis revealed reduced expression of FOXN1, a master gene of thymus development, and of several FOXN1 target genes, including DLL4. Biallelic FOXN1 pathogenic variants in humans are responsible for a syndromic form of SCID that is the equivalent to what is observed in the nude mouse (33, 34). We have recently reported that FOXN1 haploinsufficiency in humans causes severe T cell lymphopenia at birth (35). The reduced levels of FOXN1 expression observed in patient TEPs (and, by inference, in the patients thymus) may therefore play a direct role in the severe T cell lymphopenia observed in these patients. However, analysis of gene expression profile in patient and control TEPs suggests that other mechanisms, besides reduced FOXN1 expression, may also contribute to impaired thymic development associated with PAX1 deficiency. In particular, reduced TP63 expression may cause impaired TEC proliferation and hence thymic hypoplasia. Moreover, we observed that both P1 and P4 TEPs displayed significantly reduced expression of BMP4 as compared with control TEPs. Conditional deletion of Bmp4 from the pharyngeal endoderm before Foxn1 expression disrupts thymus morphogenesis in mice (24). Furthermore, recent studies have indicated that BMP4 plays a critical role in maintenance of TEC progenitors (27), and reduced BMP4 expression might alter replenishment of the TEC compartment. Future studies based on precise enumeration of TEPs generated in vitro from patient- and control-derived iPSCs may help test this hypothesis. In any case, these data suggest that PAX1 deficiency causes early and more global effects on the development of tissues derived from the third and fourth pharyngeal pouches, including the thymus. Consistent with this hypothesis, patient TEPs were concordant in the abnormal expression of a number of genes involved in skeletal, cartilage, pharyngeal, neural crest, and ear development. Abnormalities in these pathways during differentiation of tissues derived from the third and fourth pharyngeal pouches are likely to contribute to the broad range of malformations observed in the patients reported here.

Last, we have reported that HSCT, which was attempted in four of the six patients, failed to correct the T cell immunodeficiency, despite engraftment in three of them. PAX1 deficiency should be added to the list of severe T cell immunodeficiencies characterized by a primary thymic defect, which also includes complete DiGeorge syndrome, CHARGE syndrome, and FOXN1 deficiency (1). Thymus transplantation represents the treatment of choice to correct the immunodeficiency in these disorders (3638). By contrast, use of unmanipulated HSCT may allow engraftment of donor-derived postthymic T cells that may expand in the recipient, as also observed in P1 in this study, but does not permit de novo generation of a polyclonal repertoire of nave T cells (39). In summary, we have provided mechanistic insights into the pathophysiology of OTFCS2 associated with severe T cell immunodeficiency, an autosomal recessive condition caused by PAX1 variants, and have demonstrated the thymic-intrinsic nature of the immunodeficiency of this condition.

The scope of the study was to identify the molecular basis of a syndromic form of SCID and to perform genomic, molecular, biochemical, structural modeling, and in vitro disease modeling studies to analyze deleterious effects of the PAX1 variants identified. All patients provided written informed consent, according to protocols approved by the local Institutional Review Boards (IRBs). Research studies were performed under National Institutes of Health (NIH) IRB-approved protocol 16-I-N139. For P4, public disclosure of secondary genomic findings was not permitted by the protocol and consent form approved by the local IRB.

WES was performed on P1 and his healthy parents and on P2 and P4 without parental samples. Detailed methods for capture, library preparation, and bioinformatic analysis are described in the Supplementary Materials. Candidate variants were confirmed by Sanger sequencing and described according to Human Genome Variation Society (HGVS) guidelines. For P1 and P2, WES data have been deposited to the National Center for Biotechnology Information (NCBI) Sequence Read Archive (SRA) Submission Portal, with the following ID: PRJNA601119.

Flow cytometry studies were performed on either a 10-color Gallios (Beckman Coulter, Brea, CA) or an 8-color Canto II (BD Biosciences, San Jose, CA) cytometer, and results were analyzed using Kaluza software v1.5 (Beckman Coulter, Brea, CA). T cell proliferation studies were performed using Edu-based (Thermo Fisher Scientific, Waltham, MA) flow cytometry method in P1, and tritiated thymidine (3HTdR) incorporation in P2, P4, P5, and P6. TCR V repertoire spectratyping was carried out using a fragment length method on a capillary electrophoresis system (ABI 3730xl DNA Sequencer, Applied Biosystems Inc., Thermo Fisher, Waltham, MA), and data were analyzed using the GeneMarker (v.2.4.0) software (SoftGenetics, State College, PA). All reference values for interpretation were established in the laboratory using healthy pediatric donors recruited via an IRB-approved protocol.

293T cells were plated as 4 105 cells per well in a 12-well plate. After 24 hours, cells were transfected with 1.2 g of pCMV-HA-N vector containing either WT or mutant PAX1 cDNAs, with the Lipofectamine 3000 transfection kit (Thermo Fisher Scientific) following the manufacturers instructions. After 24 hours, cells were collected, lysed, and transferred onto a nitrocellulose membrane. Immunoblotting was performed with rat anti-PAX1/Pax1 monoclonal antibody (mAb) (clone 5A2) (40), followed by staining with horseradish peroxidase (HRP)conjugated goat anti-rat IgG (ab97057; Abcam, Cambridge, MA). After stripping, the membrane was reblotted with rabbit anti-actin mAb (clone 13E5; Cell Signaling Technology, Danvers, MA), followed by Amersham enhanced chemiluminescence anti-rabbit IgG, HRP-linked whole antibody (NA934; GE Healthcare, Helsinki, Finland).

To analyze PAX1 subcellular localization, 293T cells were cultured in polylysine-coated -Slide 8 well (ibidi, Fitchburg, WI) and transfected with 100 ng of pCMV-HA-N vector containing either WT or mutant PAX1 cDNA, with the Lipofectamine 3000 transfection kit (Thermo Fisher Scientific) following the manufacturers instructions. After 24 hours, cells were fixed in 4% paraformaldehyde with phosphate-buffered saline (PBS) for 30 min at room temperature, washed twice in PBS, and then blocked for 1 hour with 10% donkey serum and 0.1% Triton X-100 with PBS at room temperature. Cells were incubated with mouse anti-HA-TRITC mAb (clone H9037; MilliporeSigma, St. Louis) diluted 1:200 in PBS and with 4,6-diamidino-2-phenylindole (DAPI) at room temperature for 1 hour in the dark. Images were obtained with a Leica SP8 (690/730) confocal microscope.

For immunofluorescence analysis of KRT8 expression by TEPs, cells were fixed in 4% paraformaldehyde with PBS for 30 min at room temperature, washed twice in PBS, blocked for 1 hour in 10% donkey serum and 0.1% Triton X-100 with PBS at room temperature, and incubated overnight at 4C with mouse anti-KRT8 antibody (ab2530, C-43) (Abcam, Cambridge, MA) diluted 1:200 in PBS, then for 1 hour at room temperature in the dark with donkey anti-mouse IgG (H+L) Alexa Fluor 488 (ab150105; Abcam) at 1:500 dilution in PBS, and with DAPI (Thermo Fisher Scientific) at 1:1000 dilution in PBS. Images were taken with a Leica SP8 (690/730) confocal microscope.

The promoter region of the mouse Nkx3-2 gene was amplified and cloned into the firefly reporter plasmid pGL4.10 luc2 vector (Promega, Madison, WI), as described (6, 10). To generate expression plasmids containing the mouse Pax1WT, Pax1V138L, Pax1N146del, Pax1G157V, and Pax1C359* coding sequences, the coding sequence of mouse Pax1 (NM_008780.2) was amplified by RT-PCR from isolated adult mouse thymus RNA and cloned into a pCMV-HA-N vector (Addgene, Cambridge, MA) with the In-Fusion HD EcoDry Cloning Kit (Clontech, Mountain View, CA). Pax1 mutant variants were generated by site-directed mutagenesis, and the PCR products were ligated with the Quick Ligation Kit (NEB, Ipswich, MA) and cloned by Turbo competent cells (NEB, Ipswich, MA). The correct sequence of the constructs was confirmed by Sanger sequencing.

The transcriptional activity of WT and mutant PAX1 mouse proteins was assessed in a luciferase reporter assay. 293T cells were cultured in Dulbeccos modified Eagles medium (DMEM) containing 10% fetal bovine serum with antibiotics and plated in 24-well plates 24 hours before transfection. Transient transfections were performed in triplicate with TransIT-293 Transfection Reagent (Mirus, Madison, WI) according to the manufacturers instructions. Cells were cotransfected with 30 ng of either WT or mutant Pax1 expression plasmids, 15 ng of firefly reporter plasmid Nkx3-2-pGL4.10 luc2, and 3 ng of pRL-TK vector (Promega, Madison, WI) for normalization. After 48 hours, cell extracts were collected and frozen in lysis buffer overnight at 20C. After thawing, firefly and renilla luciferase activities were measured using a Dual-Luciferase Reporter Assay Kit (Promega, Madison, WI) and Paradigm Detection platform (Beckman Coulter, Indianapolis, IN). To correct for variations in transfection efficiency, firefly luciferase activity was normalized to renilla luciferase activity. The luciferase activity of pCMV-HA-N vector, which had no Pax1 cDNA, was assumed to have 0% activity, whereas the Pax1WT vector was assumed to have 100% activity.

The three-dimensional complex structures of WT and mutant PAX1 models bound to DNA were generated by homology-based methods (16) using the previously solved structure of the highly homologous protein, PAX6 (PDB: 6PAX) (11). Intermolecular interactions of the PAX1 paired box domain of WT/mutant PAX1 to DNA complex were calculated in the Receptor-Ligand function of Discovery Studio Client 4.0 using the default parameters (BIOVIA, San Diego, CA). The MD simulations were performed as described (16).

Primary skin fibroblasts from P1, P4, and a healthy control (BJ fibroblast line, American Type Culture Collection) were reprogrammed to iPSCs by infection with the nonintegrating CytoTune Sendai viral vector kit (Thermo Fisher Scientific) as described (41).

For differentiation, iPSCs were transferred to plates coated with Corning Matrigel human embryonic stem cell (hESC)qualified Matrix. After four to five passages, the cells were plated on Matrigel-coated 24-well plates at a density of 2.5 105 cells/cm2. For differentiation to DE and TEPs, iPSCs were exposed to various factors and differentiation cues, according to the protocol by Parent et al. (17), with some modifications. In particular, between d1 and d5, iPSC differentiation was carried out in RPMI 1640 medium (Thermo Fisher Scientific, Waltham, MA) supplemented with 1% penicillin/streptomycin, 1% l-glutamine, and increasing concentrations of KSR (0% on d1, 0.2% on d2 and d3, and 2% on d4 and d5). In the period d6 to d14, cells were differentiated in DMEM/F12 with 1% penicillin/streptomycin, 1% l-glutamine, and 0.5% (v/v) B-27 supplement (Thermo Fisher Scientific, Waltham, MA). During this period of time, the following factors were added to the culture: activin A, 100 ng/ml (d1 to d5); Wnt3a, 25 ng/ml (d1) or 50 ng/ml (d8 to d14); all-trans retinoic acid (RA), 0.25 M (d6 to d8) or 0.1 M (d9 to d14); BMP4, 50 ng/ml (d6 to d14); LY364947, 5 mM (d6 to d9); FGF8b, 50 ng/ml (d8 to d14); and KAAD-cyclopamine, 0.5 mM (d8 to d14). Supplements and factors were from Thermo Fisher Scientific, Waltham, MA (B27, KSR); R&D Systems, Minneapolis, MN (activin A, Wnt3a, BMP4, and FGF8b); and MilliporeSigma, St. Louis, MO (RA, KAAD-cyclopamine, LY364947).

Microgram quantities of total RNA were isolated using the RNeasy Kit (QIAGEN, Hilden, Germany) from triplicate samples of control-, P1-, and P4-derived iPSCs, as well as from the corresponding iPSC-derived cells at DE and TEP stages. RNA integrity was tested by microfluidic electrophoresis on a TapeStation system (Agilent, Santa Clara, CA). RNA purity and concentration were assessed using the NanoDrop One UV-Vis Spectrophotometer (Thermo Fischer Scientific, Waltham, MA). Directional, mRNA-seq libraries for experiment 1 were produced using TruSeq Stranded mRNA Library Prep Kit for NeoPrep (catalog no. NP-202-1001) from Illumina (San Diego, CA). Directional, mRNA-seq libraries for experiment 2 were produced using New England Biolabs product NEBNext Poly(A) mRNA Magnetic Isolation Module (catalog no. E7490L), New England Biolabs product NEBNext Ultra II Directional RNA Library Prep Kit for Illumina (catalog no. E7760L), and NEBNext Multiplex Oligos for Illumina (Dual Index Primers Set 1) (catalog no. E7600S) (New England Biolabs, Ipswich MA), with an input of 100 ng of total RNA per sample.

Sequencing was performed on an Illumina NextSeq 500 system, running Illumina NextSeq Control Software System Suite version 2.1.2 and RTA version 2.4.11. The final library pool was sequenced via 1 75base pair (bp) run configuration using the product NextSeq 500/550 High Output v2 sequencing kit, 75 cycles (catalog no. FC-404-2005). Between 15 106 and 20 106 reads were obtained from each sample. RNA-seq FASTQ files were aligned to the reference human genome assembly (GRCh38) with STAR v2.6.0 (42). The transcript annotation (GTF) file was obtained from GENCODE (release 28) (43). The binary alignment files (.bam) were then used to generate a matrix of read counts with the featureCounts program of the package Subread v.1.6.2 (44). Exonic fragments were grouped at the level of genes, based on the GENCODE 28 annotation file. Normalization and differential expression analysis for RNA-seq data were performed with the DESeq2 (45) package in R (46).

Independent pairwise analyses were performed on triplicate samples of cells at each stage of differentiation (iPSC, DE, and TEP). To handle the lower power associated with small numbers of samples, DESeq2 uses an empirical Bayesian procedure to stabilize the log fold change estimates. The Wald test was then applied to the log fold change in each gene, followed by multiple-testing adjustment with the method of Benjamini and Hochberg (47).

For the heatmap of gene expression, t test and hierarchical clustering were computed by Qlucore Omics Explorer 3.3 (Qlucore, Lund, Sweden) for iPSC and TEP stage comparison (Fig. 5A), with cutoff q values of less than 0.01. Analysis of variance (ANOVA) and hierarchical clustering were used for the three-stage (iPSC, DE, and TEP) comparison (fig. S11B). Normalization and differential expression analysis of the RNA-seq data used for GSEA were performed with DESeq2 package in R v.3.5.1. RNA-seq data have been uploaded to the NCBI Gene Expression Omnibus (GEO), under accession no. GSE138784.

GSEA was performed with the GSEA software (48) (http://www.broadinstitute.org/gsea) using a preranked dataset of gene expression differences, 1000 permutations, and the softwares classic enrichment statistic option. Genes were ranked based on the DESeq2 output by taking the signed log10 adjusted P value for differential expression. Gene sets for enrichment analysis correspond to Gene Ontology (GO) Biological Processes and were obtained from the Molecular Signatures Database version 7.0 (GMT file: c5.bp.v7.0.symbols.gmt).

RNA was isolated from control, P1, and P4 cells at iPSC and TEP stages of differentiation, using RNeasy kit (QIAGEN, Hilden, Germany). cDNA was synthesized by a qScript cDNA Synthesis kit (Quantabio, Beverly, MA) according to the manufacturers protocol. qRT-PCR was performed on a 7500 RT-PCR system (Applied Biosystems, Waltham, MA) using PerfeCTa SYBR Green FastMix, Low ROX (Quantabio, Beverly, MA). Gene expression was quantified by normalization to the housekeeping gene TBP for each sample. Primers used for individual genes are reported in the Supplementary Materials.

Statistical analysis was undertaken in GraphPad Prism (v8.0). For luciferase reporter assay, P values were calculated with one-way ANOVA and adjusted by Dunnetts multiple comparisons test. The data are means SEM of six independent experiments (WT, n = 6; Val138Leu, n = 3; Asn146del, n = 5; Cys359*, n = 5; Gly157Val, n = 5; empty, n = 6). For qRT-PCR data, Students t test (paired, two-tailed) was performed. The data are means SEM in Fig. 5D, and means SD in fig. S10. P < 0.05 was considered to be significant. Statistical analysis of RNA-seq data is described above.

Acknowledgments: We thank E. Thorland for interpretive assistance with the CNV analysis and B. Bigio for uploading WES data. WES data have been deposited to the NCBI SRA Submission Portal, with the following ID: PRJNA601119. RNA-seq data have been uploaded to the NCBI GEO, under accession no. GSE138784. Funding: This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), NIH and by the Angelo Nocivelli Foundation. Y.Y. was supported by JSPS Research Fellowship for Japanese Biomedical and Behavioral Research at the NIH and had travel support from The ITO Foundation for the Promotion of Medical Science. R.U. was supported by NIH/NIDDK R01 DK52913, Advancing a Healthier Wisconsin (AHW) Endowment and the Linda T. and Johm A. Mellowes Endowed Innovation and Discovery Fund. L.M.F. is funded by the Division of Intramural Research of the National Institute of Arthritis, Musculoskeletal and Skin Diseases, at the National Institutes of Health. A.A. is supported by King Abdulaziz City for Science and Technology. Author contributions: Y.Y. performed experiments and wrote the manuscript. R.U. performed structural modeling and MD simulation studies. L.M.F. supervised analysis of RNA-seq and GSEA data. F.O.-C., T.G.M., and S. Ganesan assisted with RNA-seq studies. S. Giliani and S.M. performed Sanger sequencing and Western blot analysis and analyzed WES data. K.Z., A.M.A., H.A., F.Z., C.A.V., and B.B. performed and analyzed WES. A.K.D. generated iPSCs. A.J., R.W.M., A.H.F., C.A., B.K.A.-S., and H.A.-M. provided clinical care and description of the patients. F.F. performed lymph node pathology. M.P.B., M.L.H., and C.M. performed and interpreted imaging studies. J.L.C. and R.S.A. contributed to supervision of the project and to writing of the manuscript. L.D.N. was responsible for the entire research project and wrote the manuscript. Competing interests: The authors declare that they have no competing interests. Data and materials availability: Fibroblast and iPSC lines from P1 and P4 are available upon request but are contingent upon approval of material transfer agreement by the NIAID, NIH. WES data have been uploaded to the NCBI SRA Submission Portal, with the following ID: PRJNA601119. The RNA-seq dataset for this study has been uploaded to the NCBI GEO, under accession no. GSE138784. The GEO accession includes links to the NCBI SRA database, from which the raw data will be accessible in FASTQ format, under accession no. SRP225226.

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PAX1 is essential for development and function of the human thymus - Science

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If your skin is looking dull or is congested, consider using an exfoliating cleanser two to three times a week to decongest and reveal bright, glowy skin. This cleanser uses glycolic acid, a chemical exfoliant that helps turn over dead skin cells to treat concerns such as uneven skin tone, rough skin, and fine lines.

Best Expert-Recommended Cleanser: Differin Daily Refreshing Cleanser, $8.49, amazon.com

I am a big fan of Differin Gel .1% adapalene, [and] I love this new addition to the line, says Dendy Engelman, M.D., a board-certified dermatologist. When cleansing, you dont want to strip the skin of natural oils. This can cause your skin to go into oil production overdrive. This cleanser uses vitamin B and glycerin to gently cleanse; vitamin B to calm the skin and provide relief to inflammation and redness, and glycerin to prevent water loss so the skins natural oils can nourish and repair.

Best Drugstore Makeup Remover: Almay Micellar Biodegradable Makeup Wipes, $4.99 (orig. $5.99), amazon.com

By now we all know and love micellar water for how effectively it removes makeup and cleanses skin in just one step. For those who need a refresh, micelles work like tiny magnets to attract impurities off the skin. We love these makeup wipes because they allow us to easily remove our makeup (even the stubborn waterproof kind) at the end of the day without irritating even the most sensitive of skin. This product won five extra points during our testing period for its biodegradable material, which is made up of plant fibers and wood pulp, and it will completely compost in just three months.

Best Luxury Makeup Remover: First Aid Beauty Conditioning Eye Makeup Remover, $18, ulta.com

Eye makeup can be a fickle foe when it comes to taking it off at the end of the night. Too often leftover mascara clings to our lashes, eyeshadow lingers in the creases of our lids, and eyeliner finds its way to our inner eye areano thank you. This oil-free formula works to remove even waterproof makeup without leaving a trace or any greasy residue. To use, apply some liquid onto a cotton ball, place over the eye area for five seconds, then gently pull down and away. Bonus pointit uses soothing chamomile and is fragrance-free, so its suitable for sensitive skin, too.

Best Expert-Recommended Makeup Remover: Simple Water Boost Micellar Make-up Remover Eye Pads, $8.49, cvs.com

This budget-friendly product uses micellar technologies to remove even the most longwear makeup without irritating skin. Anyone who knows me can attest to the fact that I go all out with both eyeshadow and mascara every day, so when it comes to taking it off, I need something thats going to really workand requires the least amount of elbow grease on my part, says Lisa DeSantis, Deputy Beauty Director of Real Simple and Health magazines. These rounds are saturated with just enough of the hardworking micellar formula to remove even the most stubborn eye makeup.

Best Drugstore Toner: Burts Bees Micellar Toning Water With Rose Water, $8.99, target.com

If youre looking for a wallet-friendly toner that wont sting your skin (no skincare product ever should) or dry you out, this product is for you. This alcohol-free formula uses calming rose petal extract, hydrating glycerin, and tone-balancing lactic acid.

Best Luxury Toner: belif Aqua BombHydrating Toner, $28, sephora.com

Imagine a facial toner that feels like a cup of water for your skinthats this one. It combines hydrating ingredients like glycerin with soothing ones like oat extract and calendula for a pleasant experience thats both effective in removing makeup and debris and gentle on the skin.

Best Expert-Recommended Toner: Peter Thomas Roth Water Drench Hyaluronic Cloud Hydrating Toner Mist, $28, dermstore.com

This product uses hyaluronic acid to hydrate and instantly reduce the appearance of fine lines and wrinkles, says Deanne Robinson, M.D., a dermatologist based in Connecticut.

Best Drugstore Serum: Honest Beauty Vitamin C Radiance Serum, $27.99, amazon.com

Vitamin C is a powerful antioxidant that neutralizes free radicals, which come from the sun, pollution, stress, and smokingfactors that can ultimately damage the cells DNAand gives your skin a radiant boost. Regularly using a vitamin C skincare product can boost collagen production and reverse cell damage, which in turn helps skin look firmer and looking younger, and even helps fade and prevent brown spots or pigmentation.

Best Luxury Serum: La Mer Regenerating Serum, $365, sephora.com

Environmental factors such as pollution, free radicals, and harmful UV rays can take a real toll on your skin, making it show signs of aging sooner. This super-charged serum uses antioxidants, seaweed extract, and a new proprietary blend that helps boost the skins natural collagen to reduce the appearance of fine lines, pores, and redness. One HG tester says that after using it for a few weeks, shed never seen her skin look healthier: I feel like I can see a whole new layer of skin on my face.

Best Expert-Recommended Serum: La Roche-Posay Hyalu B5 Serum, $29.99, dermstore.com

Kavita Mariwalla, M.D., a board-certified dermatologist based in West Islip, NY, adores this budget-friendly pick: I love this product for a few reasons: 1) Price point. For the quality of ingredients in it, it is priced really well. 2) B5 is a great ingredient for all skin types and madecassoside is a hero ingredient that acts as an antioxidant but also skin soother. Combine that with its hyaluronic acid and youve got a serum that has great workhouse ingredients in it.

Best Drugstore Moisturizer: Olay Regenerist Whip Face Moisturizer SPF 40, $38.99, ulta.com

To protect your skin from the sun, opt for a face moisturizer with SPF to streamline your routine. Testers loved that this Olay pick looked smooth on skin and acted as the perfect primer for makeup.

Best Luxury Moisturizer: Drunk Elephant Lala RetroWhipped Cream Moisturizer, $60, sephora.com

Testers liked that this cream instantly melted into their skin and made it feel healthy, hydrated, and glowy. It uses a mix of oils, ceramides, and antioxidants, which together provide moisture and help skin retain that moisture. Its also formulated at an ideal pH level of 5.2, so it wont throw your skin off. Oh, and did we mention it has a fun pump? The pump dispenses the perfect-sized amount of moisturizer onto your skin without any of the mess.

Best Expert-Recommended Moisturizer: Cetaphil Ultra Healing Lotion with Ceramides, $19.97, amazon.com

Although this moisturizing lotion is technically formulated for the body, Tiffany Libby, M.D., a board-certified dermatologist in Rhode Island, recommends it for the face as well. I use this on my body and face when I need to double down on my moisture, especially in the winter months, and I love that it is formulated with ceramides to help enhance my skin barrier and keep my skin smooth and hydrated, she says.

Best Drugstore Face Oil: e.l.f. All The Feels Facial Oil, $11.99, target.com

Squalane, hemp seed oil, and rosehip seed oil make this lightweight facial oil the perfect last step in your skincare routine. Simply apply a few drops onto your skin after your moisturizer, then pat it in to encourage absorption and help lock in your skincare.

Best Luxury Face Oil: Snow Fox Herbal Youth Oil, $40, saksfifthavenue.com

This silky-feeling serum combines hydrating and anti-aging properties into one product. It uses blueberry seed oil, which studies show contains high levels of antioxidant properties that protect skin from free radicals, and an exotic herb called Brazilian Paracressextract, which is a muscle relaxant that helps relieve micro-tension. HG testers raved that it gave their skin a healthy glow, one of them even saying it made her skin look like there was a ring light shining on her face at all times. Natural-looking radiance with no filterwere here for it.

Best Expert-Recommended Face Oil: Mary Kay Naturally Nourishing Oil, $48, marykay.com

[This blend] uses a delicious combination of almond, olive, and sesame oils which leave your skin super hydrated, says Ursula Carranza, Beauty and Fashion Director of People en Espaol. You can even use it on your cuticles and on the ends of your hair!

Best Drugstore Eye Cream: Inkey List Caffeine, $9.99, sephora.com

Consider this concentrate a cup of coffee for your under-eye area. Studies show that when applied topically, caffeine can temporarily plump the skin, so a jolt of java-infused product to your weary eyes will make you look instantly more awake.

Best Luxury Eye Cream: Cl de Peau Enhancing Eye Contour Cream Supreme, $270, nordstrom.com

It takes six years to extract the iris extract in this luxe cream (three to cultivate and three to dry), the key result being plumper, firmer, revived skin. Using the cold steel applicator is kind of like jade rolling, and I visibly notice it de-puffing my eyes, mentioned one HG tester, adding that the difference between eyes after applying on just one side was very drastic.

Best Expert-Recommended Eye Cream: Care Skincare Eye + Lip Nourishing Cream, $30, careskincare.com

Formulated to treat and repair the delicate area around the eyes and around the lips, this dense cream with a light diffusing finish softens the look of fine lines and dark circles, says Dr. Robinson. It absorbs quickly and wont drift into eyes or interfere with makeup.

Best Drugstore Exfoliator: Yes To Grapefruit AHA + BHA Exfoliating Tonic, $14.99, amazon.com

AHAs and beta hydroxy acids (BHAs) are known chemical exfoliants that help remove dead skin cells and excess sebum inside the pores. This product is packed with 10% AHA and BHA, making it a powerful exfoliator that more sensitive skin types should probably avoid. However, if your skin can tolerate it, using it two to three times a week will help you achieve a more even skin texture and a newfound radiance.

Best Luxury Exfoliator: Pestle & Mortar Exfoliate Glycolic Acid Toner, $38, neimanmarcus.com

Brighten, tone, and reveal a more radiant face with the help of this glycolic-based exfoliator that will gently slough away dead skin cells. This non-irritating, vegan, and fragrance-free formula is suitable for all skin types.

Best Expert-Recommended Exfoliator: SkinBetter AlphaRet Peel Pads, $95, skinbetter.com

This new peel is an exfoliation powerhouse. Using lactic, glycolic, and salicylic acids, it exfoliates using AHAs and BHAs, targeting discoloration and age spots, boosting collagen and elastin production, and penetrating deep into the cell to dissolve dead skin buildup, explains Dr. Engelman. It contains a patented retinoid, AlphaRet and it also helps treat acne.

Best Drugstore Face Mask: AveenoOat Face Mask with Pomegranate Seed Extract, $8.38, amazon.com

This brightening face mask is a great option for people with dry skinit uses colloidal oatmeal to maintain the skins natural moisture barrier while treating and calming, dried skin. Studies show that pomegranate, the products key ingredient promotes skin cell turnover, which will help users achieve a more radiant appearance. The texture is rich and velvety, and youll get the best results if used two to three times a week.

Best Luxury Face Mask: Glow Recipe Avocado Melt Retinol Sleeping Mask, $49, sephora.com

Face masks dont have to be rinse-and-go. This Glow Recipe mask can be used overnight for added benefits or can work in as little as 20 minutes as a quick skin-boost if thats your preference. Its a good introduction to retinol, the gold-standard of anti-aging ingredients, since its gentle enough that even sensitive skin types can use it without irritation. One HG tester commented that her skin looked less congested the day after using it, and adding that she didnt notice any dryness sometimes associated with retinol products. Additionally, our testers were impressed by how cooling it felt on skin, how soft it felt after washing off, and how it didnt transfer onto their pillows when using overnight.

Best Expert-Recommended Face Mask: SkinBetter Refresh Detoxifying Scrub Mask, $55, skinbetter.com

The clay minerals [in this mask] absorb unwanted oil and remove toxins, while biodegradable spherical beads to lightly resurface the skin, explains Dr. Robinson of her top pick. It can even be used as a spot treatment on areas of focus!

Best Drugstore Sunscreen: La Roche-Posay Anthelios SPF 50 Mineral Sunscreen, $22.99, amazon.com

This mineral sunscreen is oil-free (so non-comedogenic), non-greasy, and easily blends into all skin shades without leaving a white cast. If youre a minimalist who prefers multi-purpose products, this SPF 50 made for face and body should be your go-to. Its TSA-approved too, so you can throw it into your carry-on next time you travel to the beach.

Best Luxury Sunscreen: Coola Mineral Sun Silk Crme SPF 30, $42, amazon.com

The silky feel this mineral sunscreen leaves on the skin will make you feel like a million bucks. And while yes, it makes you feel like you have a Chinchilla-soft face, what we love most about this sunscreen is its formulabecause science. It has UVA and UVB protection, which means that it will help protect your skin from both the suns harmful rays and also from the blue-light emitted from your smart-phone and laptop.

Best Expert-Recommended Sunscreen: Paulas Choice On-The-Go Shielding Powder SPF 30, $29, dermstore.com

Dermatologists recommend reapplying your sunscreen every two hours, but realistically, not too many of us are down for applying a lotion over our makeup throughout the day. Thats why this powder formula is so greatit comes in what looks like a makeup brush, and all you have to do is swipe it across your face to achieve your recommended SPF dose. Plus, it gets rid of excess shine, as Carranza points out.

Best Drugstore Lip Treatment: Awake BeautyMoisture Balm Daytime Lip Mask, $14, ulta.com

This hydrating lip mask smells a little like a watermelon Jelly Rancher and works like a charm thanks to its concentrated blend of vitamin E, olive, argan, rosehip, and raspberry seed oil. Testers unanimously gave it a high score for seeing noticeably healthier lips the day after using it. For best results, use overnight since it is on the thicker side.

Best Luxury Lip Treatment: Biossance Squalane + Rose Vegan Lip Balm, $18, sephora.com

A recent poll showed that 3 percent of the US population say they are vegan, which may not seem like a lot, but that amounts to nearly 10 million people (or nearly the entire population of the state of Michigan). For those 10 million, it may be important to pick a vegan lip treatment that aligns with their dietand this is the best one. It uses plant-derived squalane, rose oil, ceramides, and algae to nourish and plump skin. Apply at night and wake up to smoother and visibly healthier lips.

Best Expert-Recommended Lip Treatment: Hourglass No 28 Tinted Lip Treatment Oil, $49, sephora.com

Treat your mouth to a luxurious anti-aging treatment that rivals even the best high-shine lip glosses on the market. It uses top-notch ingredients that work to hydrate and plump the lips, comes in four colors, and has Carranzas stamp of approval: Its the perfect lip oilits deeply hydrating without being sticky, gives your lips an amazing shine, and the gold-plated applicator is to die for!

Best Self-Tanning Face Towelettes: Haute Bronze Face Towel, $35, haute-bronze.com

For those hoping to get a sun-kissed glow without having to spend time in the sun, these bronzing face towels are a holy grail, and theyre so easy to use! Just unfold the towel, and using circular motions apply it to dry, clean skinthats it! Plus, since it is a towel, its carry-on approved.

Best Self-Tanning Face Serum: Tan-Luxe Super Glow Hyaluronic Self-Tan Serum, $49, sephora.com

My goal: maintaining a year-round healthy glow without the harmful sun exposure. The answer: this magic fluid, shares DeSantis. Its an anti-aging serum and tanning formula rolled into one, so it helps me cut down on my skincare steps every morning and night, and Im left with a believable bronze that scores me tons of compliments.

Best Face Roller: MDNA Skincare The Beauty Roller, $150 (orig. $200), nordstrom.com

This tool is great for de-puffing and encouraging lymphatic drainage, since the grooves and rolling action stimulates circulation and relieves tension, says Dr. Engelman. It can also help drive your serum deep into the skin which allows your products to work better for younot to mention, it feels great! Regular lymphatic drainage can help reduce puffiness and can temporarily help sculpt the face for a more lifted look.

Best Gua Sha: Wildling Empress Stone, $65, wildling.com

If youre more of a Gua Sha person, clean beauty expert and HelloGiggles columnist Jessica Yarbrough recommends this product, saying its at the top of her list. I have an extensive collection of what I like to call non-skincare skincare products, things that support my skin without technically absorbing into my skin, she explains. With this in hand, [giving myself a] mindful facial massage has become a daily morning ritual, and my skin is healthier and glowier for it.

Best Device: Finishing Touch Flawless Dermaplane Glo, $19.88, amazon.com

Dermaplaning is a treatment primarily found at a dermatologist or estheticians office, wherein a sharp blade sloughs away the peach fuzz and dead skin cells from the uppermost layer of the skin, leaving your face radiant and baby-soft. This at-home device isnt as sharp as a professionals would be, for obvious safety reasons, but its effective in removing fuzz and excessive dead skin cell buildup. It also comes with a built-in light that improves visibility and in turn, helps you get better results.

Best Tweezers: Tweezerman Rose Gold Point Tweezer, $20.32, amazon.com

Designed for precision, this pointed-tip tweezer is the answer to effectively removing stubble, pesky ingrown hairs, and super-fine facial strands.

Skincare products arent, and shouldnt, be reserved for only the face. Advancements in skincare technology have allowed for the creation of body care products that blew our minds this year. From those that protect our skin from environmental aggressors and reverse signs of aging by altering our genetic code to innovative fuss-free packaging and bath products that are vagina-friendly, here are the body products were currently crushing on.

Best Drugstore Body Wash: Dove Body Wash Mousse with Rose Oil, $5.99, target.com

Body wash, but in a mousse. This gentle body wash has a subtle rose scent that you can actually scratch-and-sniff on the bottle to test out before purchasing. A little goes a long way for head-to-toe moisture.

Best Luxury Body Wash: LOccitane Almond Shower Shake, $25, amazon.com

Because we clearly love a fun body wash, its no wonder we loved this shower shake. Studies show that when applied topically, almond oil improves skin tone and prevents UV damage, and its the key ingredient in this product. To use, shake the bottle to mix the ingredients into a milky formula and apply onto wet skin. It will leave your body feeling hydrated and soft.. Now, Alexa, play OutKasts Hey Ya!.

Best Expert-Recommended Body Wash: Olay Moisture Ribbons Plus Shea Butter + Blue Lotus Body Wash, $6.99, walgreens.com

Dr. Mariwalla recommends this moisturizing body wash for its shea butterwhich studies show is anti-inflammatory, rich in antioxidants, and is a rich emollientperfect for sensitive skin types.

Best Drugstore Body Lotion: Curl Dry Skin Therapy Itch Defense, $10.94, amazon.com

Tackle dry, itchy skin with this fast-absorbing body lotion that almost instantly soothes and calms skin. This moisturizer, has approval from the National Psoriasis Foundation and holds a seal from the National Eczema Association, is packed with ceramides, vitamin E, and oatmeal extractand its moisturizing effects last all day.

Best Luxury Body Lotion: Augustinus Bader The Body Cream, $165, neimanmarcus.com

The advanced skincare technology in this cream makes this splurge worth the while. It uses epigenetic technology, which essentially tells the skin cells to be healthy overall and can over time alter your genetic code, and helping treat stretch marks, bumpy skin, and cellulite.

Best Expert-Recommended Body Lotion: CetaphilRestoring Lotion with Antioxidants, $19.97, amazon.com

Cetaphil took their classic lotion and supercharged it, says Dr. Engelman. This product is safe for sensitive skin and the added antioxidants and niacinamides will neutralize free radical damage and repair the skin barrier. Niacinamides have a similar effect to retinol, strengthening the skin barrier. However, unlike retinol, it fortifies from the get-go without sensitivity or irritation.

Best Drugstore Hand Cream: eos Shea Better Coconut Hand Cream, $2.98, amazon.com

Go here to read the rest:
The best beauty products from the 2020 Beauty Crush Awards - Yahoo Lifestyle

Recommendation and review posted by Bethany Smith

Numerous revelations about the world have been made in various forms throughout history. Researchers and scientists have continuously managed to discover new ways we can understand the world around us.

Major scientific breakthroughs have been made that helped improve our way of life and will make it easier for us to achieve even more amazing innovation eventually. The 21st century was especially fruitful for the advancements in technology and science. Many of the essential revelations in history were made during the last 100 years. This article will attempt to name the most important ones.

In 2015, the National Aeronautics and Space Administration managed to find evidence that proves that there is liquid water on Mars. Scientists were aided by the first spectrometer provided by NASA, called the Mars Reconnaissance Orbiter.

With its help, they were able to detect hydrated salts all over the distant planet. The hydrated salts are more prevalent during the warmer seasons, which means that water is a crucial ingredient in their development.

Many scientists believe this to be the most crucial discovery of the 21st century. Since Albert Einsteins theory of relativity was published, the thought of time travel has excited scientific minds all over the world.

The LIGO (Laser Interferometer Gravitational-Wave Observatory) project in the United States is responsible for the detection of gravitational waves, which would imply that with enough research time travel could be possible. Journey to the earliest parts of our universe does not seem as impossible as before since this discovery.

Proof of the existence of Dark Matter was found in 2006 by a team of researchers, led by Maxim Markevitch of the Harvard-Smithsonian Center for Astrophysics in Cambridge. They proved its existence by measuring the location of mass that gets created when galaxies collide. Specific clusters of mass get disconnected, and a large amount of visible matter is what makes up dark matter. While this sounds overly complex, the important thing to remember is that this proves that dark matter makes up for 68% of the universe.

Through stem cell research, we can provide better access to organs for patients, meaning that patients no longer need to wait for donors, making it easier to cure certain conditions. Stem cells make it possible to grow an indefinite number of cells of the same type, but other types of cells also arise from that process. This means that it is possible to regenerate organs using skin cells. In the future, the discovery could make it so that the organs needed for treatment are created in a laboratory.

The process of face transplantation uses tissues of a dead person to replace another persons face. It is a complicated process that was first successfully performed in France in 2005. This transplant was only partial, but the first full-face transplant happened only five years later in Spain.

Since then, people with significant congenital disabilities or facial disfigures caused by diseases or burns have had this procedure performed on them in multiple countries. What seemed like science fiction in the 1990s is a reality now.

HIV is considered to be one of the deadliest viruses in the history of humankind. While we still have not found a cure for AIDS, the disease that is a result of an HIV that has advanced too much, we did manage to improve the treatment of HIV.

With the new methods, some of which were developed in Germany, patients with HIV can live longer, almost being able to lead healthy lives. With these exciting advancements, millions of lives have been saved, and it is only a matter of time before we find a complete cure.

Scientists atthe Massachusetts Institute of Technology (MIT)managed to find a way to create false memories and plant them into the brains of mice. While this enormous scientific breakthrough can help us better understand the concept of mind and help us with dealing with mental health issues, it can still be problematic.

It does seem like a scene out of an old science fiction movie, but with this advancement, it could be possible to manipulate a persons memory, and who knows what consequences that could have.

Scientists at the University of Twente have developed robotic body parts using biomechanics. They managed to create robotic arms that can make life easier for people with severe muscular dystrophy. They also implemented previous research on prosthetics in creating these limbs. These robotic body parts could prove to be extremely helpful for wounded soldiers, people suffering from disabilities or older people.

A photon was teleported into space with the help of a laser beam by Canadian scientists. This process is called quantum teleportation, and it can be used to transport information about something, not its physical state. However, it is a step in the right direction of possibly making teleportation of physical matter possible someday.

The process itself was incredibly hard and required extreme precision. Photons are tiny, meaning that it will be a while until we can successfully teleport larger items.

Although the World Wide Web originated much earlier, it was not until the 21st century that we saw everything the internet is capable of. And it is a fitting way to end this list because it impacted more lives than anything else. Thanks to the internet, we can do things we could only imagine 20 years ago, basically from anywhere in the world. We can access any information, watch every movie in existence, or talk to people halfway around the world. It is the discovery of all the possibilities of the internet that made this century what it is, at least for now.

Where and when was the first face transplant procedure performed?

The first face transplant procedure was performed in France in 2005.

Visit link:
10 Of The Biggest World Revelations In The 21st Century - World Atlas

Recommendation and review posted by Bethany Smith

Stop laughing. I know, my initial reaction too was, really it took genetics to tell us that? But this is serious.really.

Males are 99.9% the same when compared to other males, and females are as well when compared to other females, but males and females are only 98.5% equal to each other outside of the X and Y chromosomes. The genetic difference between men and women is 15 times greater than between two men or two women. In fact, its equal to that of men and male chimpanzees. So men really are from.never mind. Its OK to laugh now

Weve been taught that other than X and Y,males and females are genetically exactly the same. They arent.

Does this matter? Dr. David Page, Director of the Whitehead Institute and MacArthur Genius Grant winner, says it absolutely does. He has discovered that both the X and Y chromosomes function throughout the entire body, not just within the reproductive tract.

In his words, Humane Genome, we have a problem. Medicine and research fails to take into account this most fundamental difference. We arent unisex, and our bodies know this every cell knows it at the molecular level, according to Dr. Page.

For example, some non-reproductive tract diseases appear in vastly different percentages in men and women. Autism is found in 5 times as many males as females, Lupus in 6 times as many women as men and Rheumatoid Arthritis in 5 times as many women as men. In other diseases, men and women either react differently to diseasetreatment, react differently to the disease itself, or both. Dr. Page explains more andsuggests a way forward inthis short but very informative video.

About Dr. David Page:

David Page, Director of the Whitehead Institute and professor of biology at MIT, has shaped modern genomics and mapped the Y chromosome. His renowned studies of the sex chromosomes have shaped modern understandings of reproductive health, fertility and sex disorders.

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Human Genetics Revolution Tells Us That Men and Women Are ...

Recommendation and review posted by Bethany Smith

TSLN Rep: Dennis Ginkens

Date of Sale: Feb. 8, 2020

Location: at the Farm, Clearbrook, MN

Auctioneer: Tracy Harl

Averages:

75 Bulls $3,870

30 Bred Females $2,523

12 Open heifers $1,263

Lot 61 at $10,000-Black, PB SM Bull, RFS Grizzly G65, s. by Ellingson Load Up, sold to Steve Fallgatter, ND

Lot 14 at $8,000Black, blood SM Bull, RFS Gage G15, s. by WS Proclamation, sold to Kellers Broken Heart Ranch, ND

Lot 13 at $6,000Black, PB SM Bull, RFS Gentry G8, s. by WS Proclamation, sold to Emmons Ranch, MT

High selling Bred Female & Heifer

Lot 82 at $4,000 Black, PB Bred, RFS Miss Francie F57s. by Ellingson Load up, bred to Direct Impact, sold to Mark Nesemeier, ND.

Lot 120 at $1,700 Red, PB Open, RFS Miss Georgia, G160 s. by KBHR Kingsman, sold to Brant Farms, MN

More here:
Rtdeen Farms 22nd Annual Genetics with a Vision Production Sale - Tri-State Livestock News

Recommendation and review posted by Bethany Smith

The lion commonly referred to as the king of the jungle, is one of the most popular animals in the wild and a member of the Big Five Game. It is a widely recognized animal symbol in most cultures and has been extensively depicted in paintings and sculptures, national flags, and literature. Lions are social species belonging to the family Felidae or cats. They mainly inhabit savanna and grasslands and are rarely found in forests. There are two subspecies of lions; Panthera leo leo consisting of Central African, West African, Barbary, and Asiatic lions and Panthera leo melanochaita consisting of Southern African lions. This article focuses on the Asiatic lion and its characteristics, habitat, classification, and related information.

A large population of the lion was found in the vast African savannah alongside herds of antelopes and zebras which serve as their food. Apart from Africa, lions were common in Eurasia. However, systematic hunting, especially by the British colonials brought the species in Eurasia to near extinction. The subsequent conservation efforts ensured that the Asiatic lion survived. Despite their restricted distribution, the story of the species remains one of the rare conservation successes. The Asiatic lion is restricted to Gir National Park and its environs in Gujarat and it is listed as Endangered on the IUCN Red List because of its small population which is about 650 individuals (as of 2017). It is sometimes referred to as Persian lion or Indian lion. The Asiatic lion is one of the five pantherine cats in India.

The Asiatic lion is a subspecies of lions that split from the African lions about 100,000 years ago and prowled across Asia and the Middle East. The subspecies was first described in 1826 by Johanna N Meyer (Austrian) and named it Felis leo persicus. Phylogeographic analysis of lions indicates that all the modern lions including the Asiatic lion may have originated from Sub-Saharan African lion. Lions migrated from East and Southern Africa to eastern North Africa, West Africa, and into Turkey, northern India, and Southern Europe via the Arabian Peninsula. The Asiatic lion is closely related to West and North African lions than the Southern and Eastern Lions. It is believed that the Indian lion maintained its connection with the Central and North African lions until the lions in the Middle East and Europe became extinct following the interruption of the gene flow. Because of the close molecular genetics and morphological similarities with the now extinct Barbary lion, the Asiatic lion has been subsumed to Panthera leo leo.

The Asiatic lion is smaller than the African lion. The male is slightly bigger than the female lion, with the male weighing approximately 160-190 kg while the female weighs 110-120 kg. The shoulder height for the male Asiatic lion is 3.51-3.94 feet and the female is 2.6-3.5 feet. The maximum recorded length of a male lion in Gir National Park is 115 inches (from head to tail). The fur of the Asiatic lion ranges ruddy-tawny to sandy or buffish gray. Like the African lions, the males also have mane at the top of their heads but the growth is shorter, making it possible to see the ears. The mane on the throat and cheeks are scanty. The skull of adult males is about 13 inches and of the female is 11.5-11.9 inches. The Asiatic lions tail tuft is larger than the African lion. The outstanding feature common in the species but absent in their African counterparts is the fold of skin on the belly.

Approximately 545 square miles in Saurashtras Gir forest has been set aside as a conservation sanctuary for the Asiatic lions. The sanctuary and its environments are the only places where the Asiatic lions can be found. However, the lions occurred in eastern Turkey, Saudi Arabia, Mesopotamia, Bengal, and Iran in the 19th century. Since the turn of the 20th century, the lions are restricted to the Gir Forest National Park and the surrounding environs. The national park is approximately 100 square miles and was established in 1965. Human activities are not allowed in the national park and the surrounding area.

The Asiatic lions inhabit the Girnar and Gir hill systems comprising large land of thorny forest, savannah, and tropical and subtropical dry broadleaf forest. The lions are protected in five protected areas; Gir National Park, Gir Sanctuary, Pania Sanctuary, Girnar Sanctuary, and Mitiyala Sanctuary. The national park, Gir, and Pania sanctuaries are the core habitats for the lions and form the Gir Conservation Area. There are plans to establish an additional sanctuary near the Barda Wildlife Sanctuary. In 2019, a lioness and a sub-adult were sighted in villages about 31 miles from Chotila (Surendranagar District), making the district the 5th in Gujarat to host the lions. The villages are about 43 miles from Ger Forest.

Although lions are social species, the male Asiatic lions are generally solitary and may form a loose pride of up to three males. The females are more social and often have a strong pride of up to 12 females and their cubs. The pride of female lions will always share carcasses among themselves. Males and females only associate for a short time during the mating season. The males have a large home range (56-89 square miles) compared to the female (26-33 square miles).

Asiatic lions prefer larger prey with weight ranging from 420 to 1,210 pounds. Domestic cattle have been the main source of food for the lion in Gir Forest. Inside the national park, they mainly prey on sambar, buffalo, chital, nilgai, and cattle. Buffalos and cattle are mainly hunted outside the protected areas where there is no wild prey. The dominant male lion consumes almost half of the kill while the rest is shared by the coalition partners.

The mating season for the Asiatic lions falls between September and January. The mating period is between 3 to six days, during which the lions do not hunt and only survive on water. The lions gestation period is 110 days after which 1-4 cubs are born. The female lions take care of cubs for an average of 24 months before they give birth to another set. However, the interval between births can be shorter if the cubs die.

Asiatic lion is the lone representative of P. l. leo species outside of Africa. It was almost driven to extinction by human actions in the 19th century. Thanks to human efforts, the lions have been brought back to the brink. The lions are counted every five years, with the census involving people from the surrounding villages. About 300 rangers recruited from the surrounding area track, count, and record each lion. In 2015, 523 individual lions were counted including 201 adult females, 109 adult males, and 203 cubs.

The Asiatic lions, like other wild animals in India, face the usual threat of poaching and habitat loss. Although the government has banned poaching of lions throughout the country, there have been reports of poaching in recent years involving organized gangs who prefer lions to tigers. Although wells have been dug within the protected areas to provide water for the wildlife, some lions have reportedly drowned in the wells.

Three major roads and a railway track pass through the protected area. Although these have been fenced off, the continued use has caused disturbance to the lions. The three big temples inside the protected area attract a large number of pilgrims, especially during certain times of the year.

Since the 1990s, the population of Asiatic lions has increased significantly. About 200 of these lions reside outside the protected area, leading to an increase in conflict between them and humans. Although the lions have helped to keep away animals such as wild pigs and nilgais ways, the locals have attacked and killed some lions for preying on their livestock. There have also been cases of lions attacking and killing humans. However, with the changing lifestyle and values, the lion-human conflict has greatly reduced.

The existence of the Asiatic lions as a single sub-populations makes them vulnerable to extinction in case of an event such as wildfire or epidemic. They also exposed to the threat of genetic inbreeding because of their existence in one place.

The Asiatic Lion Reintroduction Project is one of the most successful conservation stories in India. The project was an initiative of the government of India to safeguard the Asiatic lions from extinction. It involved the relocation of people living around Gir to create room for the lions. So far, over 500 square miles has been declared a protected area and a habitat for the Asiatic lions. To increase conservation awareness, the seal of the state of Gujarat depicts three Asiatic lions above its name. WWF-India is working with local partners such as the Gujarat Forest Department to barricade the wells. It is also working to undertake studies to assess the habitat change to address issues of poaching and manage conflict. There is also a dedicated team of game rangers who take the injured lions to the treatment center located in the park. The effort has seen several injured lions rescued and treated on time.

Continued here:
The Story Of The Asiatic Lion: Surviving Only In Gujarat, India - World Atlas

Recommendation and review posted by Bethany Smith

SELBYVILLE, Del., Feb. 27, 2020 /PRNewswire/ -- Global Market Insights, Inc. has recently added a new report on genetic testing market which estimates the global market valuationfor genetic testing will cross US$ 28.5 billion by 2026. A growing demand for DTC genetic testing will drivemarket expansion over the forecast period. Genetic testing can project the risk of diseases, identify carriers and establish diagnoses. DTC genetic testing can help individuals identify ancestral origins and predisposition to certain illnesses. This can enable individuals to prepare or prevent the onset of certain diseases. Increasing awareness among people regarding their health will drive industry growth.

Growing adoption of genetic testing in oncology and genetic diseases in North America will propel the market expansion. Genetic testing to determine the probability of cancer and rare diseases helps in planning the treatment. Genetic testing helps in the formulation of the most effective treatment for cancer and other diseases. Hence, the growing application of genetic testing in cancer and genomic disorders will fuel the genetic testing market growth.

Requesta sample of this research report @https://www.gminsights.com/request-sample/detail/2490

Nutrigenomic testing was valued at USD 408.9 million in 2019 and will witness significant growth over the forecast period. Nutrigenomic testing determines how genetic variations change the individual reaction to nutrients. Nutrigenomic can assist with optimum nutritional planning. Rising incidence of obesity due to increased consumption of junk food and sedentary lifestyle will fuel the segment growth over the forecast period. Furthermore, growing awareness regarding customized diets will fuel market growth.

The cancer testing market held nearly 52% market share in 2019 and will exhibit robust growth in the forecast period. The growth can be attributed to the advancements in genetic testing that can confirm the diagnosis. Furthermore, genetic testing can help with the formulation of the most effective drugs for the treatment of cancer, improving patient outcomes. These factors will boost the growth of the cancer testing segment.

The European genetic testing market held a substantial value in 2019 and is poised to exhibit nearly 13% CAGR over the forecast period. The growing geriatric population will boostdemand for genetic testing in the region. Furthermore, presence of key market players in the region will positively impact the technology adoption. Additionally, favorable government initiatives to harmonize genetic testing and ensure accurate and reliable results will boost market growth.

Browse key industry insights spread across 146 pages with 138 market data tables & 8 figures & charts from the report, "Genetic Testing Market Share & Forecast, 2020 2026" in detail along with the table of contents:

https://www.gminsights.com/industry-analysis/genetic-testing-market

Some major findings of the genetic testing market report include:

Few notable players in the genetic testing market share are 23andME, Abbott Molecular, Bayer Diagnostics, Cepheid, Counsyl, PacBio, Illumina Inc., Qiagen, Roche Diagnostics, BioCartis, and Siemens. The market players are adopting strategies such as innovative product launches and acquisitions to expand their customer base and market share.

Make an inquiry for purchasing this report @https://www.gminsights.com/inquiry-before-buying/2490

Partial chapters of report table of contents (TOC):

Chapter 2. Executive Summary

2.1. Genetic testing industry 360synopsis, 2015 - 2026

2.1.1. Business trends

2.1.2. Test-type trends

2.1.3. Application trends

2.1.4. Regional trends

Chapter 3. Genetic Testing Industry Insights

3.1. Industry segmentation

3.2. Industry landscape, 2015 - 2026

3.3. Industry impact forces

3.3.1. Growth drivers

3.3.1.1. Physician adoption of genetic tests into clinical care

3.3.1.2. Technological advancements and availability of new tests

3.3.1.3. Growing application of genetic testing in oncology and genetic diseases in North America

3.3.1.4. Consumer interest in personalized medicines in Europe

3.3.1.5. Growing demand for direct-to-consumer genetic testing

3.3.2. Industry pitfalls & challenges

3.3.2.1. High costs of genetic testing

3.3.2.2. Dearth of experienced professionals and advanced infrastructure in developing and underdeveloped economies

3.4. Growth potential analysis

3.4.1. By test type

3.4.2. By application

3.5. Regulatory landscape

3.5.1. U.S.

3.5.2. Europe

3.6. Market share analysis, 2018

3.6.1. Market share analysis, by North America, 2018

3.6.2. Market share analysis, by Europe, 2018

3.6.3. Market share analysis, by Asia Pacific, 2018

3.6.4. Market share analysis, by Latin America, 2018

3.6.5. Market share analysis, by Middle East & Africa, 2018

3.7. Porter's analysis

3.8. Competitive landscape, 2018

3.8.1. Strategy dashboard

3.9. PESTEL analysis

About Global Market Insights

Global Market Insights, Inc., headquartered inDelaware, U.S., is a global market research and consulting service provider, offering syndicated and custom research reports along with growth consulting services. Our business intelligence and industry research reports offer clients with penetrative insights and actionable market data specially designed and presented to aid strategic decision making. These exhaustive reports are designed via a proprietary research methodology and are available for key industries such as chemicals, advanced materials, technology, renewable energy and biotechnology.

GMIPulse,our business analytics platformoffers an online, interactive option of exploring our proprietary industry research data in an easy-to-use and dynamic manner. Clients get to explore market intelligence across 11 top-level categories and hundreds of industry segments within them, covering regional, company level and cross-sectional statistics that make our offering a stand-out for decision-makers.

Contact Us:

Arun HegdeCorporate Sales, USAGlobal Market Insights, Inc.Phone:1-302-846-7766Toll Free:1-888-689-0688Email:sales@gminsights.com

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genetic-testing-market-size-will.jpg Genetic Testing Market size will exceed $28.5 Bn by 2026 Genetic Testing Market size slated to surpass USD 28.5 billion by 2026, according to a new research report by Global Market Insights, Inc.

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Direct-to-Consumer Genetic Testing Market

Prenatal and New-born Genetic Testing Market

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Genetic Testing Market demand to hit USD 28.5 Bn by 2026: Global Market Insights, Inc. - P&T Community

Recommendation and review posted by Bethany Smith

Ohtawara, Japan; February 27, 2020 - Canon Medical Systems Corporation (Canon Medical) announces the start of development of a rapid genetic testing system for the novel coronavirus (COVID-19) reaffirming the companys commitment to the basic research and development of rapid diagnostic test kits. This project is part of a research program focusing on the development of diagnostic methods for COVID-19 led by the Japan Agency for Medical Research and Development (AMED).1)

Canon Medical was selected to participate in this research program in cooperation with Nagasaki University. This was in recognition of Canon Medicals strength in leveraging the companys technologies in delivering practical solutions to support medical emergencies, notably by supplying Ebola rapid test kits to the Republic of Guinea in 2015,2) donating Ebola rapid test kits to the Democratic Republic of the Congo in 2019, and through the manufacturing approval and sale of the Genelyzer KIT (a reagent kit for Zika virus RNA testing) in 2018.3)

The test and the reagents developed for COVID-19 RNA testing is based on the LAMP method4) developed by Eiken Chemical Co., Ltd., and are used with a compact isothermal amplified gene fluorescent detector manufactured by Canon Medical to detect the presence of virus. Compared to the conventional test method of real-time PCR, the LAMP method allows for detection of the virus to be performed more easily and quickly, which makes it suitable for testing in local areas where infection is prevalent.

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About Canon Medical Systems USA, Inc.Canon Medical Systems USA, Inc., headquartered in Tustin, Calif., markets, sells, distributes and services radiology and cardiovascular systems, including CT, MR, ultrasound, X-ray and interventional X-ray equipment. For more information, visit Canon Medical Systems website at https://us.medical.canon.

About Canon Medical Systems CorporationCanon Medical offers a full range of diagnostic medical imaging solutions including CT, X-Ray, Ultrasound, Vascular and MR, as well as a full suite of Healthcare IT solutions, across the globe. In line with our continued Made for Life philosophy, patients are at the heart of everything we do. Our mission is to provide medical professionals with solutions that support their efforts in contributing to the health and wellbeing of patients worldwide. Our goal is to deliver optimum health opportunities for patients through uncompromised performance, comfort and safety features.

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Canon Medical to commence development of a rapid genetic testing system for the novel coronavirus (COVID-19) - DOTmed HealthCare Business News

Recommendation and review posted by Bethany Smith