If you have a rare disease, you may be the only person in Australia with that condition.

You may not know, however, that being diagnosed with a rare disease means you are part of a community of up to two million Australians with one of these conditions. And more than 300 million people globally.

Read more: When you're sick, the support you'll get may depend on the 'worth' of your disease

Today, health minister Greg Hunt announced Australia will have its first National Strategic Action Plan for rare diseases.

This action plan will harness the power of rare disease advocates, patients and families, clinicians, researchers, peak bodies, industry and government to improve care for people with rare diseases.

A rare disease is one that is very uncommon. The most widely accepted definition stipulates a rare disease affects fewer than five in 10,000 people.

Rare diseases are serious, complex, usually chronic, often life-limiting and most have no cure.

We know of about 7,000 different rare diseases, most with a genetic origin. Many begin in childhood.

Rare diseases are often progressive they get worse over time and can be associated with physical or intellectual disability.

Examples of rare diseases are uncommon childhood cancers such as hepatoblastoma (a cancer of the liver), and other better-known conditions like cystic fibrosis and phenylketonuria (a birth defect that causes an amino acid called phenylalanine to build up in the body, and untreated can lead to intellectual disability, seizures and behavioural problems). Both are symptomatic from birth. Huntingtons disease is another, but only shows symptoms in adulthood, even though its inherited.

Read more: Explainer: what is cystic fibrosis and how is it treated?

For a person living with a rare disease, and the people around them, the journey to obtaining a diagnosis and receiving treatment can be difficult, complex, worrying, confusing and isolating.

Rare diseases are difficult to diagnose because individually they occur so infrequently, and symptoms can be very complex. My research and another Australian study show it can take years to get the final correct diagnosis. Most health professionals have never diagnosed or cared for a person with osteogenesis imperfecta, Fabry disease or any other of the 7,000 rare diseases.

Added to this, the onset of symptoms for a rare disease can occur anywhere between birth and adulthood, and diagnostic tests are lacking or difficult to access.

But diagnosis is only part of the puzzle. People with rare diseases typically need complex care from large teams of health professionals because with many rare diseases, several body systems are affected. Also, given the often-progressive nature of the condition, care needs can change sometimes dramatically over time.

Important questions also arise around life expectancy and what the risks would be if the person with a rare disease was to start a family. Would their children inherit the disease? Genetic counsellors can help with these sorts of questions.

Read more: No matter how you fund it, medical research is a good investment

Further, care is costly to families and to the health system. The cost of providing hospital care to just one child with a rare lung disorder who eventually needed a lung transplant amounted to almost A$1 million before the childs ninth birthday.

The market for drugs for rare diseases, often called orphan drugs, is small. Although governments incentivise the pharmaceutical industry to develop orphan drugs, there are no effective drug treatments for most rare diseases.

In recognition that rare cancers and rare diseases traditionally lose out to more common diseases in terms of research, additional targeted funding has recently been allocated to boost research in Australia. In 2019 the NHMRC and the Medical Research Future Fund pledged A$15 million over five years for rare cancers, rare diseases and unmet need.

While a positive step, we are still lagging behind other countries. The United States, for example, spent US$3.5 billion (A$5.3 billion) on rare disease research in 2011.

The action plan recognises people with a rare disease and their right to equitable access to health and support services, timely and accurate diagnosis and the best available treatments. It aims to increase rare disease awareness and education, enhance care and support, and drive research and data collection.

Its roll out should lead to better outcomes for people with rare diseases and less worry and frustration for families. For example, access to care coordinators or care navigators could help guide people and families through our often-fragmented health, disability and social care systems.

Read more: Personalised medicine has obvious benefits but has anyone thought about the issues?

Recent advances in personalised medicine, where a persons specific genomic make-up could be used to tailor specific medicines for that persons particular disease, holds much promise for people with rare diseases in the future.

Genetic testing for critically ill babies and children is already resulting in faster diagnosis and treatment of rare diseases.

The action plan aims to build on and support the sustainability of these important developments.

If you or a family member has a rare disease, and youd like more information, the Rare Voices Australia website is a good place to start.

Nicole Millis, CEO of Rare Voices Australia, co-authored this article.

The rest is here:
What is a rare disease? It's not as simple as it sounds - The Conversation AU

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JACKSONVILLE, Fla. A few years have passed since Deidra Radel was a young woman proudly wearing her Navy uniform. As a mom and wife, her life was going great.

Then-- in her early 40s -- she found herself stuck with the awful symptoms of menopause. Hot flashes. Night sweats. Draining fatigue. Radel went to a doctor in South Florida and was given a type of Hormone Replacement Therapy (HRT), which went under her skin.

"It was terrible! I looked like a teenage boy," she said. She actually took selfies of all the acne that hit her to document the bad results of the HRT.

"I wanted to cry," she says.

Turns out she got an incorrect mix of hormones in her HRT, but the experience was so bad Radel figured she would just deal with her symptoms and never try HRT again.

Radel

Then she heard about an internal medicine physician at Mayo Clinic Jacksonville, Dr. Jackie Thielen. She came to Jacksonville from Mayo Rochester as an expert on women's health issues. Radel had a long meeting with Thielen, and she wound up taking a customized treatment of HRT.

Does she have any symptoms at all now? Hot flashes? Fatigue? Horrible night sweats?

"No. No. No!" Radel said. She's back to full steam with her family. In fact, she agreed to share her story to encourage other women to talk with their doctors and not just suffer from menopause.

Radel

The message to all women? In Thielen's words: "Women do not have to suffer in silence."

Here are some facts about menopause from Thielen:

When a woman goes 12 consecutive months with no periods

"But really menopause can occur between ages 40 and 58," Thielen said. "A woman can experience symptoms leading up to the actual menopause for years."

Thielen points to current research that says some women need estrogen or some form of HRT early on after menopause to cut down their risk of medical troubles.

Thielen says a study, which hit the news in 2002, made women and some doctors frightened of HRT. She says the bad rap continues. "We're trying to change that," Thielen said.

Some women may need to avoid HRT. Those may include particular forms of breast cancer. Women with a certain history of blood clots may need to steer clear as well but even in those cases there could be safe ways to take HRT.

For example, Dr. Thielen says anti-depressants are showing solid results in stopping hot flashes. It doesn't mean you're depressed. "It's all about brain chemistry," Dr. Thielen says.

A Woman's Health Specialty Center will open this spring at Mayo Clinic in Florida. It will provide a team approach for the evaluation, diagnosis and treatment of women's unique needs. Those include:

For more information on menopause click hereand here.

Read more from the original source:
Hot flashes: How this veteran won the battle against menopause - FirstCoastNews.com WTLV-WJXX

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Arizona Republican lawmakers are pushing a bill to effectively ban transgender girls from interscholastic sports.

A coalition of over 150 businesses is opposing a bill currently being considered by the Arizona state House of Representatives that would impose invasive medical exams on transgender girls who want to play sports.

One Community, a coalition of LGBTQ-friendly Arizona businesses and individuals, announced on Wednesday that the Arizona Diamondbacks, the Arizona Lodging & Tourism Association, the Arizona School Boards Association, and TechNet had all signed on to a letter in opposition to the bill, along with law firms, restaurants, media companies, resorts, and a yoga studio.

They are all concerned that the bill, H.B. 2706, authored by Republican state Rep. Nancy Barto and co-sponsored by 22 of her GOP colleagues, would effectively prevent transgender girls from participating with interscholastic or intramural girls teams.

If a kid's gender were ever disputed, the bill would require a kid who's gender was disputed to provide a signed physician's statement that "indicates the student's sex based solely on all" of three factors: their "internal and external reproductive anatomy," a measurement of their "endogenously produced levels of testosterone," and an "analysis" of their genetic makeup.

The bill, which stipulates that "athletic teams or sports designated for females, women, or girls may not be open to students of the male sex," would block a student from participating who couldn't provide a physician's statement meeting the strict criteria.

Barto named the bill the "Save Women's Sports Act." A national anti-trans group has been pushing similar bills in other states.

"Science is what it is," Barto told a local newspaper earlier this month. "The difference between males and females is obvious."

But one parent disputed this during a legislative hearing earlier this month. She noted that many trans kids who transition before puberty, including her own daughter, do not produce the male hormones that could provide an athletic advantage and others take hormone-suppressing drugs.

"Gender is far more complex than our genitals," she told the lawmakers.

The ACLU of Arizona opposes the bill and warned on Monday: "AZ's #HB2706 would subject girl athletes to invasive examinations such as: -a physical exam of the childs genitals, -a blood test, -and genetic testing".

"Girls should not be subjected to ANY of these over-the-top invasive medical exams in order for them to play sports," the ACLU said.

Still, the House Rules Committee voted on Wednesday to send the bill to the full House.

Republicans hold a majority in both chambers of the Arizona Legislature, and because Gov. Doug Ducey (R) has a history of opposing LGBTQ rights, it could well become law.

But Arizona businesses have reason to worry about the bill's impact if it does beyond how much it would harm student athletes.

In 2014, the GOP-controlled legislature passed S.B. 1062, a bill which would have allowed businesses to discriminate against LGBTQ people as long as they cited religious beliefs. Amid threats of an economic boycott of Arizona, then-Gov. Jan Brewer, a Republican, vetoed the bill.

Since that time, boycotts of other states over their new anti-LGBTQ laws have caused significant economic impact. After North Carolina passed its infamous "bathroom bill" in 2016, the state lost tens of millions of dollars in business. One 2017 analysis before that law's partial repeal predicted more than $3.76 billion in lost business for North Carolina over a dozen years.

Published with permission of The American Independent Foundation.

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New GOP bill would require invasive medical exams of trans kids who want to play sports - The American Independent

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for The month of march is Endometriosis Awareness Month. The world is to draw attention to the relatively unknown, yet common disease areas. 200 million women around the world suffer it, and in the united kingdom, the disease is common. The disease is in the taboesfeer, " says physician and researcher Esther van Barneveld, and that is if they want to stop it. Six questions about endometriosis.

"Endometriosis is a chronic disease. Tissue on the lining of your womb, it is in areas outside the uterus (womb). It is usually found in the peritoneum or the organs in the abdomen. It is also found in the vagina, a scar from an emergency c-section. It is a tissue that grows, it creates chronic inflammation, and that gives you different problems."

"this can range from no symptoms to, in extreme abdominal pain, particularly during menstruation. If the endometriosis on the bowel wall, it may also have problems to give. Or, in the bladder, for example, blaasklachten. Some women have pain during intercourse. Women with endometriosis may be less fertile. This can be the result of growths, and adhesions of the fallopian tubes, and ovaries."

"Worldwide, approximately one in ten women suffers from endometriosis. In the Netherlands, it is estimated that around 400,000 are women. Endometriosis is as common as diabetes and rheumatoid arthritis. However, you can hear most of the time, something about it. As the impact is huge and can be. The quality of life for women with endometriosis is often significantly lower than in women who don't have it."

"Women have to think for yourself is the pain in the menstrual period should. Also, general practitioners and specialists to prescribe for the symptoms are often at a 'normal' menstrual pain. In some cases women are frightened, as aansteller to be seen, and they dare not complain to get out. The diagnosis is, on average, only every eight years. That is why it is important to keep the veil on for endometriosis, to stop it."

"to be The most effective treatment for endometriosis is hormone therapy, that is, the menstrual period is suppressed, such as the oral contraceptive pill, or have a hormoonspiraaltje. It does, however, mean that women have during this treatment can not become pregnant. In addition, the hormonal treatments that often have side-effects.

"Women who do not have the hormones capable of, or willing to use, and are most dependent on pain killers. An exploratory surgery in which endometriosis is removed, is sometimes a possibility, but the symptoms are often not clear. Up to 75% of the patients after surgery symptoms to keep. How can this be, it is still not clear. There is a research need."

"all Kinds of organizations, including the national Endometriosis Foundation, which is committed to the endometriosis is known to do. There is also research being done; for example, we are in the Centre of excellence for Endometriosis in Maastricht, responsible for the development of a patintenapp. That can help you with the research, and, at a later stage in the process of monitoring the disease and evaluating the treatment. The app measures the action in real time, taking into account the factors that may have an impact on pain, such as diet, sleep, and stress."

"with The knowledge we can apply it in the treatment. This leads to faster and improve the quality of care that the person is focused, and thus more. We can also test whether a new treatment is effective, or yoga or any other therapy, for example, can help."

now, Of Barneveld, is a physician-researcher at the Centre for Endometriosis of the Maastricht university medical centre (UMC+) and GROW School for Oncology and Developmental Biology.

Link:
Pain due to disease in endometriosis: Women think that they are hiring' - Celeb's Net

Recommendation and review posted by Bethany Smith

From Family Features

Michele Adams is quick to say, I dont want to throw anyone under the bus, but it took her being hit by a car for her thyroid disease to finally be diagnosed.

Adams has always been an active person, but for a few years, she had felt tired and had a constant tightness in her throat. She was diagnosed with post-nasal drip but did not feel relief after a year of treatment.

I thought this exhaustion, hoarse voice and lump in my throat were just my new normal, Adams said. Id accepted it, and I shouldnt have.

During this time, Adams went on a bike ride in northeastern New Jersey something she still does frequently. However, on this day, Adams was struck by a car as she was biking.

The incident resulted in an MRI scan. Adams was not seriously injured, but doctors noticed something unexpected. The scan revealed nodules in her lower neck, which suggested thyroid disease.

I now realize I had symptoms of a thyroid condition for years, Adams said. Id had it up to here with not feeling like myself. Once I had the MRI results, I knew to seek out a thyroid expert, and I found an endocrinologist.

Thyroid disease is more common than diabetes and heart disease, but more than half of Americans with thyroid disease are unaware, according to the American Association of Clinical Endocrinologists (AACE). This lack of awareness can endanger a persons health and well-being.

The thyroid is a butterfly-shaped gland located low in the front of the neck below the Adams apple. It produces thyroid hormones that influence almost every cell, tissue and organ in the human body.

Common signs of thyroid diseases include:

Cheryl Rosenfeld, D.O., is a thyroid expert and AACE member. Rosenfeld is also the physician who treated Adams thyroid disease.

If the thyroid does not function correctly, it can affect every possible aspect of a persons life, Rosenfeld said. Remember that thyroid conditions can cause changes in mental health, including depression. Ive also spoken to patients whove experienced an inability to concentrate, which seriously affected their performance at work.

Several disorders can arise if the thyroid produces too much hormone (hyperthyroidism) or not enough (hypothyroidism).

Other thyroid diseases include:

Undiagnosed thyroid issues can also place a person at increased risk for heart disease, osteoporosis, infertility and other serious conditions.

Once I was placed on treatment for Hashimotos and hypothyroidism, my life changed completely, Adams said. My throat is no longer sore, and Im able to go out with my family or spend time at the gym without feeling completely drained of energy.

The first step to ensure your thyroid gland functions properly is to speak with a health care provider about your symptoms and whether a thyroid test is needed.

Anendocrinologistis aspecially trained doctor who is qualified to diagnose and treat hormone-related diseases and conditions, including thyroid cancer and all other diseases related to the thyroidgland.

Visitthyroidawareness.comto learn more about thyroid health.

SOURCE:American Association of Clinical Endocrinologists

More here:
It Impacts Weight, Sleep and Mental Health... - The Apopka Voice

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A similar but much larger case series (also authored by the medical advisor to Abortion Pill Rescue and medical director of Culture of Life Family Health Care) reports that it was approved by an institutional review board. It still remains deeply flawed, according to experts. This series, published in Issues in Law & Medicine in 2018, looked at data from 754 pregnant people who called an unspecified hotline between June 24, 2012, to June 21, 2016, and explained that they had taken mifepristone but not misoprostol and were interested in continuing their pregnancies. Just over 200 potential participants were excluded for various reasons, like deciding to continue with the abortion or a lack of follow-up. Out of the 547 participants included in the analysis who received progesterone, 257 gave birth, but again, that doesnt translate into scientific proof that abortion reversal works. There was no consistency in terms of where or how the patients received progesterone, how far along they were in the pregnancy, or whether or not they had an ultrasound before the reversal to confirm if there even was still a viable embryo present.

Trying to base medical protocols and legislation on this kind of fundamentally flimsy research goes against both science and the moral responsibilities of health care providers.

Elizabeth Nash, senior state issues manager at the Guttmacher Institute, says that abortion reversal laws are such an example of overreach that reproductive advocates were surprised to see more states propose bills after Arizonas got shot down in 2016.

On top of creating a policy based on incomplete evidence, these laws get into a very important question on informed consent, Nash tells SELF, explaining that no ethical physician would move forward with an abortion unless they were absolutely sure of their patients choice.

I cant emphasize strongly enough that when people enter an abortion facility, the only thing on the providers mind is whether this decision and process is what a woman clearly wants, Lisa Harris, M.D., Ph.D., a professor of obstetrics-gynecology and medical ethics at Michigan Medical at the University of Michigan in Ann Arbor and coauthor on the abortion regret systematic review mentioned earlier, tells SELF. It was already an ethical breach to offer [abortion reversal] care, and now its even more so because there are legitimate safety concerns. If someone in my community offered this, I would say it is outside the bounds of whats considered efficacious and safe.

Bonnie Steinbock, Ph.D., a professor emerita of medical ethics at Albany/State University of New York, agrees, telling SELF, I dont think [theres] any justification for offering something, much less mandating that doctors [provide it], when they simply dont know what the safety of the thing theyre offering is.

Drs. Harris and Grossman have concerns regarding how these laws might influence patients decisions if they incorrectly believe abortion reversal is actually possible.

It could mislead some women into thinking they dont have to be 100% sure of their decision because they could just change their mind after taking the pill, Dr. Grossman says. He compared these laws to recent bills attempting to require physicians to re-implant ectopic pregnancies, which he and Dr. Creinin say is biologically impossible.

Both types of legislation mandate medical treatment that is completely unproven and potentially dangerous, Dr. Grossman says. Thats the new fact of the anti-abortion movement, and thats very concerning. I cannot think of another example where, essentially, legislators are making up a treatment or basing it on the poorest quality evidence. Its only related to abortion where we allow that to take place.

The question now is how lawmakers will react to new worries about the risks of trying to reverse an abortion.

I really hope that the well-being of people seeking abortion is first and foremost in the hearts and minds of legislators, and that with this new evidence, they might reconsider the requirement, Dr. Harris says. If legislators are unwilling to consider that, its going to be increasingly hard for me to imagine that laws like that come at all from compassion for people seeking abortion care.

Related:

Link:
No, Its Not Medically Possible to Reverse Abortions - Self

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Dr. John Haygarth knew that there was something suspicious about Perkinss Metallic Tractors. Hed heard all the theories about the newly patented medical deviceabout the way flesh reacted to metal, about noxious electrical fluids being expelled from the body. Hed heard that people plagued by rheumatism, pleurisy, and toothache swore the instrument offered them miraculous relief. Even George Washington was said to own a set. But Haygarth, a physician who had pioneered a method of preventing smallpox, sensed a sham. He set out to find the evidence.

The year was 1799, and the Perkins tractors were already an international phenomenon. The device consisted of a pair of metallic rodsrounded on one end and tapering, at the other, to a point. Its inventor, Elisha Perkins, insisted that gently stroking each tractor over the affected area in alternation would draw off the electricity and provide relief. Thousands of sets were sold, for twenty-five dollars each. People were even said to have auctioned off their horses just to get hold of a pair. And, in an era when your alternatives might be bloodletting, leeches, and purging, you could see the appeal.

Haygarth had a pair of dummy tractors created, carved carefully from wood and painted to resemble the originals. They were to be used on five unsuspecting patients at Bath General Hospital, in England, each suffering from chronic rheumatism. Using the lightest of touches, the fakes were drawn over the affected areas, with remarkable results. Four of the five patients declared that their pain was relieved. One reported a tingling sensation that lasted for two hours. Another regained the ability to walk.

The following day, Haygarth repeated his test using the true metallic tractors, with the same results. Other physicians soon followed his lead, using increasingly elaborate fakes of their own: nails, pencils, even old tobacco pipes in place of the tractors. Each brought the truth more clearly into focus: the tractors were no better than make-believe.

This humble experiment wasnt the only one of its kind. By the start of the nineteenth century, experimentation had already driven two centuries of significant changes in science. The Royal Society of London, the scientific academy of which Haygarth was an elected fellow, began insisting that all claims needed to be verified and reproduced before they could be accepted as scientific fact. A shakeup was under way. Astronomy had split off from astrology. Chemistry had become disentangled from alchemy. The motto of the society neatly encapsulated the new spirit of inquiry: Nullius in Verba. Translation: Take nobodys word for it.

Physics, chemistry, and medicine have had their revolution. But now, driven by experimentation, a further transformation is in the air. Thats the argument of The Power of Experiments (M.I.T.), by Michael Luca and MaxH. Bazerman, both professors at the Harvard Business School. When it comes to driving our decisions in a world of data, they say, the age of experiments is only beginning.

In fact, if youve recently used Facebook, browsed Netflix, or run a Google search, you have almost certainly participated in an experiment of some kind. Google alone ran fifteen thousand of them in 2018, involving countless unsuspecting Internet users. We dont want high-level executives discussing whether a blue background or a yellow background will lead to more ad clicks, Hal Varian, Googles chief economist, tells the authors. Why debate this point, since we can simply run an experiment to find out?

Luca and Bazerman focus on a new breed of large-scale social experiments, the power of which has already been demonstrated in the public sector. As they note, governments have used experiments to find better ways to get their citizens to pay taxes on time, say, or to donate organs after death. N.G.O.s have successfully deployed experiments in developing countries to test the effects of everything from tampons to textbooks. The impact of a simple experiment can be dramatic, particularly in monetary terms.

A few years ago, if you searched for eBay on Google, the top two results would take you directly to the auction sites home page. The second one was produced organically by the Google algorithm; the first was an advertisement, paid for by eBay and meant to pop up whenever its name appeared as a keyword in someones search.

Steve Tadelis, a professor of economics at the University of California, Berkeley, was spending a year at eBay at the time, and was suspicious about the value of placing such ads. Wouldnt people get to eBay anyway if they were searching for it, without the sponsored results? But, as Luca and Bazerman recount, eBays marketing group defended the millions of dollars spent on the ads each year, noting that many people who clicked on them ended up buying things on eBay.

An experiment was in order. By turning Google ads on and off, Tadelis and his research team tracked the traffic coming to their site and discovered thatas Tadelis had suspectedmuch of the money eBay had been shelling out was wasted. The marketing team had an exaggerated notion of how valuable those ads were: without the sponsored result, searchers would simply click on the free organic links instead. The company could (and did) save itself millions.

Theres an important point in all of this: instead of going by our possibly unreliable intuition, we can, in a range of cases, know for sure whether an intervention has an effect by running a trial and collecting the evidence. Its a step that Esther Duflo, who shared a Nobel Prize in Economics for her work using experiments to study how global poverty can be alleviated, makes a particularly strong case for. Without gathering and analyzing the evidence, she has said, we are not any better than the medieval doctors and their leeches.

The most reliable way to test an intervention is by using a type of experiment known as a randomized controlled trial (R.C.T.). You randomly assign subjects to groups and then treat each group differently. One group will receive the intervention, while another, the control group, will not. Control here is key. The aim is to make the groups as similar as possible, to constrain as many variables as you can manage, because if the only thing allowed to change freely is the intervention itself you can study its true effect. In the tech world, the intervention might simply be a different Web-page layout or a new pricing plan. Here, the usual term is A/B testing, but the objective is the same: to create some basis for comparison.

Such studies tell you whether something works, though not why. Haygarths experiment wasnt a randomized trial by modern standards, but he nonetheless proved the power of experimenting: by directly comparing the experiences of patients on the day they got treated with the tractors with their experiences on the day they were treated with the fakes, he could show that the tractors were duds. The second set of observations served as a kind of control group.

Without a properly randomized control group, there is no real way to measure whether something is working. Take the case of the Scared Straight program, developed in the United States to discourage at-risk kids from choosing a life of crime. The theory seemed sound. By taking young offenders on organized visits to prison and allowing them to meet murderers and armed robbers, theyd see the terrifying consequences of breaking the law, and be less likely to do so themselves in the future.

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Big Tech Is Testing You - The New Yorker

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Spring is around the corner, and with it comes the start of Daylight Saving Time.

DST is one of the oddest times of the year. It begins the second Sunday in March at 2 a.m., so this year on Sunday, March 8 the clocks will be turned ahead one hour. It ends Nov. 1 when we fall back an hour and return to Standard Time.

Some people find it difficult to adapt to DST because by moving the clocks back or ahead we gain or lose an hour of sleep. It also means work schedules and other events change their time.

It might seem inconsequential at first, but DST messes with your body clock and it can take about one week for the body to adjust to new schedules and times for sleeping, eating and other activities, according to the Centers for Disease Control and Prevention.

The reason for this is a disruption in the circadian rhythm. Also known as your sleep/wake cycle, the circadian rhythm is a 24-hour internal clock that cycles between sleepiness and alertness at regular intervals.

Basically the circadian rhythm communicates to the brain when we should sleep and when we should be awake, says Dr. Alison Lima, a board certified family medicine physician at WellSpan Family Medicine.

With daylight saving, suddenly the hourly schedule is different so it throws people off, Lima says.

Light is the main environmental cue. Light suppresses the secretion of the sleep-inducing hormone melatonin. So it is important to expose yourself to the light during the waking hours as much as possible and on the contrary, do not expose yourself to bright light when it is dark outside.

Until your body adjusts to the new times and brighter evenings, you might have trouble falling asleep, staying asleep, or waking up at the right times.

Does the time change affect everyone the same way?

No. People adjust differently. For children, however, it could be more challenging because bedtime is now different, Lima says.

Gradually adjust your childs nap and sleep times by 10 to 15 minutes each day before the time change so the shift is more gradual for them. Following a regular routine from dinnertime to bedtime will help your child slow things down and be ready to snuggle up.

People who sleep seven or less hours per day can have consequences that are more serious because sleep disruptions can affect cognitive performance. Studies link the lack of sleep at the start of DST to car accidents, workplace injuries, suicide, and depression among other things.

A group of U.S. researchers conducted a study and determined that the risk of a heart attack increased 24 percent the Monday after switching over to daylight saving time. However, the risk diminished over the remainder of the week. By contrast, it dropped 21 percent on the Tuesday after the fall time change.

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One way to help your body adjust is to gradually change the times for sleep, eating, and activity, Lima says. Start shifting your normal routine a little bit, maybe a week or two before DST starts, to ease the transition into the new schedule.

Lima doesnt recommend taking a nap in the middle of the day if you feel tired after the switch to DST because its going to decrease your ability to sleep at night.

Work through the new schedule. Stick through it and you will be able to fall asleep when you should, Lima says. And avoid doing things that close to bedtime.

The more you pay attention to your body and identify feelings of alertness or drowsiness, the better you ll feel.

Here are some tips to a smoother transition to DST:

Avoid naps. If you have to take a short nap during the day, take it early and for no longer than 20 minutes.

Don't stay up later than usual. Go to bed at your usual time to avoid messing with your internal clock. Set your bedside alarm or smartphone as you usually would and fight the urge to stay up late.

Practice good sleep hygiene. Take advantage of this moment to perform a sleep reset. Don't look at screens before bed and if you do, make sure to use blue light blocking glasses in order to avoid straining your eyes. Keep your bedroom at a temperature conducive for soothing you into a deep sleep.

Skip caffeine. As the week progresses, you may become sleepy at unusual times. Let sleep kick in naturally and avoid caffeinated beverages after lunchtime. Opt for decaf instead.

Stick to a routine with kids. You shouldn't expect the first week after the time change to go off without a hitch, but sticking to your usual schedule may be the best course of action. Some children who are more sensitive to schedule shifts may require a more extended adjustment period. However, things should be back to normal within two weeks.

Pay attention to your pets. An hour change may not seem like a lot to you, but it may confuse your pets. Keep the adjustment in mind when planning feeding times and outdoor bathroom visits. If you're on a schedule, know that it may take a few weeks before your pets get settled into a new routine.

Bring snacks to work. Your stomach isn't keeping track of the clock; it may grumble outside of your designated lunch break. Bring a few extra snacks along just in case.

Be especially vigilant while driving to protect yourself since others around you may be sleepier and at risk for making an error that can cause a vehicle crash.

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Does daylight-saving time mess with your internal clock? Here are tips to manage the time change - LancasterOnline

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When asked to picture someone having a heart attack, many people would imagine a man clutching his chest in sudden pain and dropping to the ground. However, this scenario isnt always accurate. In women, heart attack symptoms are often more subtle.

Women and men differ when it comes to heart health. Its important for women to understand our unique symptoms and cardiovascular concerns, so we can recognize when were at risk and take steps to protect our health.

In the United States, cardiovascular disease is the leading cause of death for women, causing one in three deaths each year more than all cancers combined. While chest pain is the most common symptom of a heart attack, its often not very severe in women.

In fact, sometimes it may not even be the most noticeable symptom. Women are more likely to experience pain in other areas, such as the neck, jaw, shoulder, arm, upper back or abdomen.

In addition, women frequently experience other symptoms, including shortness of breath, nausea or vomiting, sweating, lightheadedness, unusual fatigue, indigestion or palpitations. Women also tend to experience symptoms more often at rest, or when asleep, compared to men.

Also, certain heart conditions are exclusive to women. One of those conditions is peripartum cardiomyopathy, which is weakening of the heart muscle during pregnancy or shortly after delivery.

Women and men share many of the same risk factors for heart disease, including high cholesterol, high blood pressure, diabetes, smoking, family history of heart disease and obesity.

However, there are risk factors that affect women specifically. These include postmenopausal state, hormone replacement therapy as well as pregnancy complications like preeclampsia or gestational diabetes. Also, inflammatory disorders like lupus and rheumatoid arthritis can impact womens cardiovascular risk.

The good news is we have more treatment options now than a decade ago, from heart disease prevention and management to surgical cardiac procedures.

Two recent developments were working with at Tower Health Medical Group are the MitraClip, a percutaneous procedure to treat leaky mitral valve, and the Watchman procedure, which helps prevent stroke in patients with atrial fibrillation who cannot take blood thinning medications.

We can reduce the risk of heart disease by living a healthy lifestyle. Its important to quit smoking, exercise regularly, eat a healthy diet, manage your stress, limit alcohol intake and take medications as prescribed.

In addition, know your numbers: blood pressure, cholesterol level, blood glucose level and weight. Work with your doctor to understand whats too high or too low and how to keep them within normal range.

When it comes to heart health, time matters. Taking preventive steps now and catching problems early will help. Make sure you schedule an annual wellness visit with your physician. This is the most important step in cardiovascular screening.

During the visit, your physician can review your individual risk factors of heart disease, check weight and blood pressure and discuss screening blood tests. Women with increased cardiac risk may require additional testing or referral to cardiologist.

Be proactive and take control of your health. Not only will it help your heart, but itll boost your overall well-being.

Agnieszka Mochon, M.D., practices cardiology with Tower Health Medical Group.

More:
Boosting women's heart health takes more than wearing red - Reading Eagle

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From Bicycling

While there is no cure for Alzheimers disease, more evidence is surfacing that shows your lifestyle and diet may be able to help ward it off. A recent study published in Neurology found that what you eat is not only good for your body, but also beneficial for your brain. Eating leafy greens, veggies, and berries daily plus drinking tea can help reduce your risk of dementia by 48 percent.

The study looked at the eating habits of 921 people in the Rush Memory and Aging Project who complete annual neurologic evaluations and dietary assessments that include reporting the frequency they ate 144 foods over the previous year.

The results showed that those who had a high intake of flavanols, an antioxidant that helps reduce inflammation, were 48 percent less likely to later develop dementia than the people in the lowest intake group. Thats likely because the anti-inflammatory properties of flavanols can prevent over-activation of inflammatory cells, helping to reduce cellular damage.

When this cellular damage occurs in the brain, is thought to be one of the potential causes of Alzheimers and vascular-type dementia, Thomas Holland, M.D., a physician scientist at Rush University Medical Center in the Rush Institute for Healthy Aging, told Runners World. In total, researchers found that over 30 fruits, vegetables, and beverages contribute to the beneficial flavanols that can ward off dementia. Though not an exhaustive list, certain foods contributed to high intake of flavanols in the self-reported diets of the participants.

[Find 52 weeks of tips and motivation, with space to fill in your mileage and favorite routes, with the Bicycling Training Journal.]

These results show the types foods we are consuming do matter, Holland said. And, though important, it is not just the nutrients in the foods we eat that contribute to our health. Its also the bioactives (chemicals, such as antioxidants, in foods that affect our bodies) contained in them.

Eat your fruits and vegetables, particularly dark leafy greens, and drink some tea every now and again, Holland said. A healthy diet that contains various fruits and vegetables is critical for continued health, especially brain health and is a strong component of a healthy lifestyle.

The bottom line: Adding one serving of dark leafy greens a day, one cup of raw veggies, one serving of other veggies a day, a handful of berries at least five times a week, and a cup of tea (preferably without sugar) can help lower your risk of dementia. A healthy diet combined with exercisewhich has also been shown to help delay cognitive declineenough sleep, and other brain-stimulating activities, such as reading, will help boost your brain health.

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More Evidence That Antioxidant-Rich Foods Can Boost Your Brain Health - Yahoo Lifestyle

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Boulder Feb 26, 2020 (Thomson StreetEvents) -- Edited Transcript of Clovis Oncology Inc earnings conference call or presentation Monday, February 24, 2020 at 9:30:00pm GMT

Clovis Oncology, Inc. - VP of IR

* Daniel W. Muehl

Clovis Oncology, Inc. - Executive VP & CFO

* Patrick J. Mahaffy

Clovis Oncology, Inc. - Co-Founder, CEO, President & Executive Director

SVB Leerink LLC, Research Division - MD of Targeted Oncology & Senior Research Analyst

H.C. Wainwright & Co, LLC, Research Division - MD of Equity Research & Senior Healthcare Analyst

* Kennen B. MacKay

RBC Capital Markets, Research Division - MD & Co-Head of US Biotechnology Research

Ladies and gentlemen, thank you for standing by and welcome to the Clovis Oncology Fourth Quarter and Full Year 2019 Conference Call. (Operator Instructions)

I would now like to hand the conference over to your speaker today, Anna Sussman, VP of Investor Relations. Thank you. Please go ahead.

Anna Sussman, Clovis Oncology, Inc. - VP of IR [2]

Thank you, Mike. Good afternoon, everyone, and welcome to the Clovis Oncology fourth quarter and fiscal year 2019 conference call. Thank you for joining us. You have likely seen this afternoon's news release. If not, it's available on our website at clovisoncology.com. As a reminder, this conference call is being recorded and webcast. Remarks may be accessed live on our website during the call and will be available in our archive for the next several weeks.

Today's agenda includes the following: Patrick Mahaffy, our President and CEO, will discuss the key components and highlights of today's corporate update; and Dan Muehl, Clovis' Chief Financial Officer, will cover the quarter and year's financial results in greater detail. Pat will make a few closing remarks, and then we'll open the call for Q&A, during which time Lindsey Rolfe, our Chief Medical Officer, will also be available to answer questions.

Before we begin, please note that during today's conference call, we may make forward-looking statements within the meaning of the federal securities laws, including statements concerning our financial outlook and expected business plans. All these statements are subject to risks and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements. Please refer to our recent filings with the SEC for a full review of the risks and uncertainties associated with our business. Forward-looking statements speak only as of the date on which they are made, and Clovis undertakes no obligation to update or revise any forward-looking statements.

Now I'll turn the call over to Pat Mahaffy.

Patrick J. Mahaffy, Clovis Oncology, Inc. - Co-Founder, CEO, President & Executive Director [3]

Thanks, Anna. Welcome, everybody. We appreciate your time today. I'll begin with a commercial update for Rubraca. I'm pleased to report that our global net revenue for the fourth quarter of 2019 was $39.3 million, up 5% sequentially from Q3 2019 and up 30% over Q4 2018. This sequential quarter growth was driven primarily by increased revenue in Germany and launches in England and Italy during the fourth quarter.

For the full year 2019, global net revenue was $143 million, up 50% from 2018. The year-over-year growth for the quarter and the year was driven largely by growth in U.S. sales, including overall growth in total volume and better management of the patient assistance program, offset to some extent by higher gross to net adjustments.

We've seen stepwise growth over the last several quarters, including the 12% increase in U.S. sales from Q2 2019 to Q3 2019 and are pleased that we have maintained this higher level of sales in Q4 2019.

Our key near-term objectives remain the same. Grow U.S. ovarian cancer revenues by increasing market share in, and overall adoption of the maintenance treatment indication in the recurrent ovarian cancer setting; increase European revenues through Rubraca ovarian cancer launches in England, Italy, France and Spain, along with driving continued revenue growth in Germany. I should note that the adoption of maintenance treatment in ovarian cancer in Europe is similar to that of the U.S., and we and our competitors are making considerable efforts to overcome observation or watch and wait as the standard approach to treating recurrent ovarian cancer; and hopefully, on or before our PDUFA date of May 15, begin to grow revenue through with the addition of the potential new indication in the U.S. for the treatment of BRCA1/2 mutant recurrent, metastatic, castrate-resistant prostate cancer or mCRPC. And that brings us to our most near-term development and regulatory program in this setting.

In November 2019, we submitted our planned supplemental new drug application, or sNDA, for Rubraca as a monotherapy treatment of adult patients with BRCA1/2 mutant-recurrent, metastatic CRPC. The filing was based on data from the TRITON2 clinical program in advanced prostate cancer. In January 2020, we announced that the FDA accepted our sNDA for Rubraca and granted priority review status to the application with the PDUFA date of May 15, 2020. We're actively preparing for Rubraca launch in prostate cancer in the U.S., which we will commence upon receipt of FDA approval.

We think that Rubraca represents an important hormone-free and chemotherapy-free option for our targeted population of men in the U.S. who have metastatic CRPC, approximately 12% of whom have a mutation of BRCA. We've been encouraged by our interactions with both the medical community and to a lesser extent, the urology community about the potential of Rubraca to address the unmet medical need in recurrent CRPC. We are actively engaged in launch preparations, including sales force training, and we will be ready to launch on approval, which we expect to occur on or before May 15.

Now I'll briefly discuss the latest updates to our clinical pipeline for Rubraca. During the fourth quarter, we initiated the LODESTAR study, our Phase II pan-tumor study to evaluate Rubraca in homologous recombination repair genes across tumor types. The study will evaluate Rubraca in patients with recurrent solid tumors associated with the deleterious homologous recombination repair or HRR gene mutations. Based on our interactions with FDA, the study may be registration-enabling for a targeted gene and tumor-agnostic label, if data from the trial support an accelerated approval.

Next, I'd like to briefly highlight our combination studies with BMS for both Rubraca and lucitanib, and then I'll discuss our newest compound, FAP-2286. We remain enthusiastic about our ongoing clinical collaboration with Bristol-Myers Squibb. I'll take a moment to review certain of our combination studies for both Rubraca and lucitanib with nivolumab. I'll begin with the Rubraca combination. FRACTION-GC is a BMS-sponsored, multi-arm Phase II study evaluating the combinations of each of Opdivo and Yervoy with Rubraca as well as Opdivo, Yervoy and Rubraca in combination for the treatment of advanced gastric cancer. This is the first sponsored study to explore this triplet combination and it is now enrolling patients into the safety lead-in portion of the study.

The Clovis sponsored Phase III ATHENA trial in first-line maintenance for advanced ovarian cancer continues to enroll well, and we anticipate completing enrollment in this 1,000 patient study in the second quarter of 2020. With ATHENA, we believe we are uniquely positioned to evaluate Rubraca in terms of 2 outcomes: as monotherapy versus placebo in the first-line maintenance setting in the HRD population, inclusive of BRCA and in the all-comers or intent-to-treat population as well as any potential advantage of the combination of Rubraca and Opdivo in the same patient populations. ATHENA is the first frontline switch maintenance study designed to show both PARP monotherapy and PARP/PD-1 combination therapy in one study design.

I'll take a moment to review the analysis plan for ATHENA. First, expected in the second half of 2021, we will see the results of Rubraca monotherapy versus placebo in all study populations and then probably a year or more later, we will see the results of Rubraca plus Opdivo versus Rubraca in all study populations. In each of these analyses, we will first evaluate outcomes in the HRD population, including BRCA, and then step down to the entire intent-to-treat population.

To wrap up Rubraca and move to lucitanib, I'll note that SEASTAR, our Clovis-sponsored Phase Ib/II study that includes multiple single-arm Rubraca combination studies, including the combination of Rubraca with lucitanib in ovarian cancer, is currently enrolling the dose-finding Phase Ib portion of the study. Lucitanib, of course, is our investigational inhibitor tyrosine kinases including vascular endothelial growth factor receptors 1 through 3, platelet-derived growth factor receptors alpha and beta and fibroblast growth factor receptors 1 through 3.

As we have discussed on prior calls, there are very encouraging data in studies of a drug similar to lucitanib, which inhibits the same 3 pathways when combined with the PD-1 inhibitor. This provides us a compelling clinical rationale for the development of lucitanib in combination with the PD-1. We believe the combination of lucitanib with the PD-1 targeting monoclonal antibody represents a large potential opportunity in multiple solid tumor types.

Angiogenesis has been shown to be immunosuppressive within the tumor microenvironment, dampening antitumor immune responses. Preclinical data demonstrates that the anti-tumor activity of the PD-1 inhibitor is enhanced through the inhibition of angiogenesis by lucitanib, which targets 3 relevant proangiogenic pathways as well as simultaneously targeting tumor cell proliferation and anti-VEGFR therapy resistance driven by PDGF and FGF receptors.

In February 2019, we announced the expansion of our clinical collaboration with Bristol-Myers Squibb to include planned combinations of Opdivo with lucitanib. The Clovis-sponsored LIO-1 study is a Phase Ib/II study evaluating lucitanib in combination with Opdivo. LIO-1 is now enrolling patients with gynecological and other solid tumors. We hope to have preliminary data from this study as well as the Rubraca/lucitanib combination study at medical meetings in 2020.

In addition, the BMS-sponsored CHECKMATE 79X study is a Phase I/II study evaluating multiple combinations with Opdivo, including an arm in combination with lucitanib in patients with second-line non-small cell lung cancer. This study is expected to initiate in early 2020.

Now let me describe the newest addition to the Clovis pipeline, our peptide-targeted radiopharmaceutical therapy program and our lead compound FAP-2286. In September 2019, we announced a global licensing and collaboration agreement with 3B Pharmaceuticals, with initial focus on the peptide-targeted radionuclide therapy and imaging agent targeting fibroblast activation protein alpha, commonly referred to as FAP. FAP is highly expressed in cancer associated fibroblasts, which are found in the majority of cancer types, potentially making it a suitable target across a wide array of solid tumors. It is highly expressed in many epithelial cancers, including more than 90% of breast, lung, colorectal and pancreatic carcinomas. Clovis will conduct global clinical trials and has obtained U.S. and global rights, excluding Europe where 3BP retains rights. We are planning to submit the IND for FAP-2286 in the second half of this year.

In addition, we and 3BP are collaborating on a discovery program directed at 3 additional targets for radionuclide therapy, to which we have global rights. [We've regarded] this program for many reasons, including, of course, the opportunity to be a leader in the emerging field of targeted radiotherapy for treatment for solid tumors. In this case, we also have the opportunity to be the first to clinically develop an FAP-targeted radionuclide, and we are also enthusiastic about the targets that are the subject of our discovery collaboration.

In addition, while our initial development focus is on monotherapy, there is an evident biological rationale to combine targeted radionuclide therapy with cancer therapies, including anti-PD-1 agents as well as with Rubraca. And we intend to explore these combinations first preclinically and potentially clinically as well.

Now some of you may be familiar with the history of PSMA-targeted radionuclides, in particular, lutetium PSMA-617, which was used extensively under named patient use in Germany and certain other countries prior to the initiation of any formal clinical development programs. While we do not anticipate such extensive named patient use like that, which occurred for lutetium PSMA-617, we have had expressions of interest for named patient use from German physicians.

To this end in December 2019, Professor Dr. Richard Baum presented his initial independent clinical experience with FAP-2286 in the first named patient use of the compound in the imaging and treatment settings at the International Centers for Precision Oncology Foundation Symposium in Germany. Professor Dr. Baum's early results in patients with advanced solid tumors, including breast, pancreatic, colorectal and ovarian cancers, showed the following: images of 10 patients imaged with PET/CT with Gallium 68, FAP-2286 were completely consistent with standard of care FDG-PET/CT scans in the same patients. In patients treated with lutetium FAP-2286, there were encouraging tumor accumulation and retention and a reported lack of significant adverse effects was demonstrated within the first 2 months after the first dose.

As a reminder, named patient programs are not clinical trials and the treating physician independently makes all decisions including dose and assessment of efficacy and safety. We found this reported experience encouraging, and our focus remains on initiating a broad clinical development program for our FAP-targeted compound. We currently plan to submit an IND application for FAP-2286 in the second half of 2020, followed by a Phase I study to determine the dose and tolerability of the FAP-targeting therapeutic agent with expansion cohorts planned in multiple tumor types as part of the global development program.

Thus far, in radiotherapeutic development, physicians have used an imaging agent, mostly Gallium 68, to identify patients with the appropriate level of tumor target, which in our case would be FAP. We are exploring opportunities to generate imaging data for FAP-2286, potentially even before our IND is submitted. Not only would this information will be useful to gain additional experience with FAP-2286 and better understand the characteristics of FAP expression in multiple tumor types, but further it would allow us to collaborate with academic institutions eager to explore the potential of FAP as an imaging and treatment target.

And with that, I'll turn the call over to Dan to discuss fourth quarter and fiscal year 2019 financial results.

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Daniel W. Muehl, Clovis Oncology, Inc. - Executive VP & CFO [4]

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Thanks, Pat, and hello, everyone. We reported net product revenue for Rubraca of $39.3 million for Q4 2019, which included U.S. net product revenue of $36.1 million and ex U.S. net product revenue of $3.2 million compared to the net product revenue reported in Q4 2018 of $30.4 million all of which was in the U.S. This represents a 5% increase over Q3 2019 and a 30% increase year-over-year. U.S. net product revenues was $36.1 million for the fourth quarter, in line with the $36.5 million reported in Q3 and up 19% from the $30.4 million recorded in Q4 2018.

The supply of free drug distributed to eligible patients in the U.S. through the Rubraca patient assistance program for Q4 2019 was 18% of the overall commercial supply compared to 20% in Q3 2019. This represented $8 million in commercial value for Q4 2019 compared to $9 million in Q3 2019 and $10.4 million in Q4 2018. Ex U.S., net product revenue was $3.2 million for the fourth quarter, which represents a $2.1 million increase from the previous quarter, driven primarily by increased revenue in Germany and launches in England and Italy during the fourth quarter.

Net product revenue for 2019 was $143 million, which included $137.2 million and $5.8 million in U.S. and ex U.S. product revenues, respectively. This compares to $95.4 million in net product revenues in 2018, all from the U.S. This represents an increase of 50% year-over-year.

U.S. net product revenue was $137.2 million in 2019, up 44% from the $95.4 million reported in 2018. This was largely driven by growth in total volume and better management of the patient assistance program, offset to some extent by higher gross to net adjustments. The supply of free drug distributed to eligible patients in the U.S. through the Rubraca patient assistance program in 2019 was 20% of the overall commercial supply compared to 26% in 2018. This represented $34.8 million in commercial value for 2019 compared to $33.4 million in 2018.

Gross to net adjustments totaled 17.4% in Q4 2019 and 15% for the full year 2019 compared to 10.1% in Q4 2018 and 10.4% for the full year 2018. The increase in gross to net adjustments reflects an increase in the U.S. and the impact of growing European sales. We expect gross to net adjustments to be in the mid-teens in 2020, pending the revenue mix between U.S. and Europe.

Turning now to a discussion of cash. As of December 31, we had $296.7 million in cash, cash equivalents and available for sale securities. In August 2019, Clovis repurchased $190.3 million aggregate principal amount of its 2.5% convertible senior notes due 2021. Approximately $97.2 million aggregate principal amount of these notes remain outstanding.

In January 2020, Clovis repurchased $123.4 million aggregate principal amount of its 4.5% convertible senior notes due 2024 that were initially issued in August 2019. This transaction will save $28 million in cash on interest payments under the notes issued in 2019, and approximately $148 million aggregate principal amount of these notes remain outstanding. Additionally, the company has $300 million in aggregate principal amount outstanding of its 1.25% convertible senior notes due 2025.

And as of December 31, we had drawn approximately $35 million under the TPG ATHENA clinical trial financing and had up to $140 million available to draw under the agreement to fund expenses of the ATHENA trial through Q3 2022.

Based on the company's anticipated revenue, spending, available financing sources and existing cash, cash equivalents and available for sale securities, we believe we have sufficient cash, cash equivalents and available-for-sale securities to fund our operating plan into the second half of 2021. This does not include any cash repayment that may be required to pay off unless we refinance, the remaining $97.2 million aggregate principal amount of the 2.5% convertible notes due 2021 at their maturity in September of 2021.

Net cash used in operating activities was $70.1 million for Q4 2019 and $323.6 million for the fiscal year 2019 compared with $82.7 million for Q4 2018 and $366 million for the comparable periods in 2018. In addition, borrowings under the TPG ATHENA financing provided $13.8 million in cash in Q4 2019, reducing net cash utilized in operating activities to $56.3 million during the quarter. Net cash used in operating activities for Q4 2019 included an upfront payment of $9.4 million to 3B Pharmaceuticals related to the in-licensing of FAP-2286.

Net cash used in operating activities was $127.1 million for the second half of 2019 and $196.5 million for the first half of 2019, a reduction of $69.4 million or 35%. In addition, borrowings under the TPG ATHENA financing provided $8.6 million in the first half and $26 million in the second half of 2019, reducing net cash utilized in operating activities by $86.8 million or 46% from the first half to the second half of 2019.

We reported a net loss for Q4 of 2019 of $99.5 million or $1.81 per share and $400.4 million or a net loss of $7.43 per share for fiscal year 2019. In 2018, the net loss for the fourth quarter was $99.3 million or $1.88 per share and $368 million or a net loss of $7.07 per share for the full year. Net loss for Q4 and fiscal year 2019 included share-based compensation expense of $12.6 million and $54.3 million compared to $11.4 million and $49.1 million for the comparable periods in 2018.

Research and development expenses totaled $72.5 million for Q4 2019 and $283.1 million for the full year 2019 compared to $71.2 million and $231.3 million for the comparable periods in 2018. The increase for the full year is primarily due to higher research and development costs for Rubraca clinical trials.

Selling, general and administrative expenses totaled $45.2 million for Q4 2019 and $182.8 million for the full year 2019 compared to $49.1 million and $175.8 million for the comparable periods in 2018. Selling, general and administrative expenses increased for the full year due to commercialization activities for Rubraca including increased costs associated with building out the European commercial infrastructure.

Now I'll turn the call back to Pat.

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Patrick J. Mahaffy, Clovis Oncology, Inc. - Co-Founder, CEO, President & Executive Director [5]

--------------------------------------------------------------------------------

Thanks, Dan. Happy birthday. We are pleased with our progress in the fourth quarter and in 2019 in total. We demonstrated strong sales growth in 2019 with Rubraca in the second-line ovarian cancer maintenance setting. In the U.S., we remain focused on growing our share of the ovarian cancer PARP inhibitor market as well as expanding second-line maintenance PARP adoption overall. In Europe, Rubraca is now reimbursed in Germany, England, Italy, France and Spain, and during the course of 2019, we launched in Germany, England and Italy. Rubraca launched earlier this month in France and will launch shortly in Spain.

In addition to our sales progress, we also showed a significant reduction in our net cash utilized in operations, which was 60 -- or excuse me, $86.8 million or 46% lower in the second half of 2019 and in the first half of 2019, reflecting reductions in product supply costs, milestone payments, disciplined with head count additions, clinical trial management and the benefits of the TPG ATHENA financing. We submitted the supplemental NDA for Rubraca in BRCA1/2 mutant recurrent metastatic CRPC in mid-November. And we're pleased that the FDA granted priority review designation for the application and a PDUFA date of May 15, 2020. This provides the potential for a U.S. launch in a second tumor type in May of this year.

We remain enthusiastic about the potential for lucitanib with 2 Clovis-sponsored combination studies now open for enrollment: one with Rubraca in advanced ovarian cancer as part of SEASTAR as well as one in combination with Opdivo in advanced gynecological cancers and other solid tumors. We hope to have initial data from these trials at medical meetings in 2020.

And finally, we look forward to submitting the IND for FAP-2286 in the second half of 2020, and we're enthusiastic about the opportunity to develop this compound specifically and potentially up to 3 additional radionuclide therapies in this emerging field. We believe with this program, we have the opportunity to become a leader in the development of this important new treatment modality for multiple solid tumor types.

And with that, I'd be happy to answer any questions you may have.

================================================================================

Questions and Answers

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Operator [1]

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(Operator Instructions) Your first question comes from Kevin MacKay (sic) [Kennen MacKay] from RBC Capital.

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Kennen B. MacKay, RBC Capital Markets, Research Division - MD & Co-Head of US Biotechnology Research [2]

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Maybe if you could talk a little bit more about some of the Rubraca dynamics in the U.S. market? It seems like maybe there was a slight volume decline after backing up the gross to net and free drug impact, but would love if you could maybe help contextualize that market and again, the dynamics going on there a little bit more.

And then a follow-up on lucitanib. We saw some very impressive VEGF plus checkpoint data in prostate cancer from the COSMIC trial at ASCO GU. I was wondering if -- how you were thinking about targeting prostate center with lucitanib if there are any plans there with the thinking that maybe it would just be a far and less competitive field than the more validated RCC space?

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Patrick J. Mahaffy, Clovis Oncology, Inc. - Co-Founder, CEO, President & Executive Director [3]

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Yes. So first dynamic in the market, we actually did see a volume increase in Q4, it was modest, but we did see a volume increase. We were affected by the higher gross to net, which reflects some contracting, we, as other companies have done in the space. The thing I'll also point to is that while we don't have a good perfect data set from olaparib. It does appear that sales, for instance, for ZEJULA were also flat to down in Q4 compared to Q3. It could just be a dynamic of the quarter.

I also think it's important to note, as I said in my prepared remarks, we saw a 13% increase in Q3 compared to Q2, and we maintained that increase in Q4. And I think that it's important as you look back at our reported sales that our growth hasn't really occurred on a linear quarterly basis. What we've seen is $32 million and $32 million and then jumped to $36 million, and now we're $36 million, and hopefully, we'll see another jump beginning in some quarter in 2020.

So I think that we had held our own in this market. We still need with our competitors to do everything we can to grow adoption of second-line maintenance, so that we can really not only take more share, but benefit from kind of a rising tide lifting all boats, a better adoption, and so that will remain a focus of ours in 2020.

As to the data for a VEGF inhibitor plus a PD-L1 that were presented at ASCO GU, obviously, we've paid attention to that, too. We think it's worth further exploration for us potentially with the PD-1, potentially if that was of interest to Bristol, but we -- it's early days to figure out what the next step for us would be. But we, like you, were impressed with the data and see an evident opportunity for the combination of the VEGFs for a pan-angiogenesis compound like lucitanib with a PD-1.

One thing you said, Kennen, I just want to address, as you said, rather than go into the very crowded RCC space, that has not been our priority. Our priority have been these kind of [ecological] cancers and some other solid tumor indications where we have precedent data for Keytruda with pembro, but it is not a subject of our study activities now to pursue RCC.

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Operator [4]

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Your next question comes from Michael Schmidt from Guggenheim.

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Michael Werner Schmidt, Guggenheim Securities, LLC, Research Division - Senior Analyst & Senior MD [5]

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I had a couple around prostate cancer. First of all, congrats on the PDUFA date, the acceptance and then the PDUFA date, obviously. Just wondering how you think about the competitive dynamics in BRCA-positive prostate cancer longer term with other companies, obviously, having started additional trials in earlier lines of therapy in mCRPC. And just wondering how you think about maybe the initial market dynamics and longer term the potential for Rubraca in prostate cancer?

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Patrick J. Mahaffy, Clovis Oncology, Inc. - Co-Founder, CEO, President & Executive Director [6]

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Yes. So we think for now and for a reasonable future, the PARP inhibitor approvals will be limited to us and to olaparib. Each of the other competitors running a single-arm study are reasonably behind based on the enrollment rates that they showed mostly recently at ASCO GU, which was only a couple of weeks ago. So that's pretty up-to-date data. So we -- like anybody, we'd love to be alone, but we're confident that we have a good chance of being first or tied for first based on AZ's announcement of their timing, and obviously, ahead of any other competitors. So 2 is better than 3, which is what we base in ovarian right now.

With regard to earlier line opportunities in prostate, the exploration being done by some others has recently started studies combining their PARP inhibitors with, for instance, abiraterone or enzalutamide. We will start a combination study with enzalutamide before the end of this year in collaboration with a number of investigators, we're already effectively signed up for this. So I think that in the event there is an opportunity to combine a PARP inhibitor with an enzalutamide or an abiraterone or one of the next gen products, we will be competitive in that space in a reasonably similar time frame to the other trials that are seeking the same indication.

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Edited Transcript of CLVS earnings conference call or presentation 24-Feb-20 9:30pm GMT - Yahoo Finance

Recommendation and review posted by Bethany Smith

This article originally appeared on VICE US.

In plain white text atop a blue-to-pink gradient, Solace greets new users with a dictionary definition of its name: comfort or consolation in a time of distress or sadness. Its a fitting name for an app that aims to give trans people more information about various aspects of transitiona one-stop resource for people who know they are trans, but dont know how to be trans.

After entering some basic informationtheir name, their pronouns, and their location by statethe user is presented with some common transition goals, as Solace terms them. These include all of the major transition milestones like beginning hormone replacement therapy and updating the name and gender marker on ones passport, as well as seemingly mundane (but surprisingly difficult) tasks like buying the right bra.

The goal, according to Solace co-founder Robbi Katherine Anthony, is to help users make their transitions as easy as possiblesomething she wished she could be able to say about her own.

Transition is beautiful, but its also incredibly hard, Anthony told VICE.

Born in New Mexico, the 27-year-old software developer now lives in Spokane, Washington. She came up with the idea and designs Solace with fellow developer Patrick McHugh, and turned to Crowdbotics, a software company in Berkeley, to build out the app. As Solaces only full-time employees, Anthony and McHugh run an extraordinarily lean operation, bouncing between Anthonys home, her 1998 blue Honda CR-V, and whatever coworking space they might be working in on a given day. Its fly or die every single day here, said Anthony. But shes committed to making something that she hopes makes transition a little less confusing, a tool she would have appreciated if it had existed all those years ago.

My transition has been rough, she told VICE. But Ill be damned if I dont do everything in my power to help others avoid that.

Solace co-founders Patrick McHugh (L) and Robbi Katherine Anthony (R). Photo courtesy of Robbi Katherine Anthony.

Anthony said that one of the biggest hurdles she faced in the early stages of her transition was finding out how to transition in the first place. She blamed a lot of this inaccessibility on gatekeeping, a term that, in a trans context, often refers to the many ways in which a health care professional can refuse gender-affirming care to a trans patientsay, a doctor who wont prescribe hormones, or surgeon who wont operate on a woman he doesnt find attractive or cis-passing enough for his standards. Anthony told VICE that she experienced this kind of medical gatekeeping firsthand, but she also used the term to describe her experiences with other trans people.

Certain people in the community become gatekeepers of information, Anthony said. Transition is a model of oral tradition, but if you have to meet people in order to transition, that inherently limits transition to people who can access that network. Some people physically cannot do that or dont want to. That information is also highly anecdotal, which she said is a problem because it ignores how one persons circumstances are not analogous to another persons.

Solace disrupts that model, she continued. If the process could be reduced from finding the right gatekeepers to having a compendium that allows you to proceed on your own terms, I think it would be healthier.

I asked Anthony if creating Solace, an app designed to circumvent community gatekeepers, might turn her into the very trans community gatekeeper she set out to circumvent.

Thats a really fair question, Anthony said. Gatekeeping, in its most nefarious forms, requires folks to do some interaction in order to get information. Whether its being approved by a moderator to join a group, seeking out a time or space or venue based on terms dictated by someone else, or being forced to curry favor with someone for them to share informationthats gatekeeping in my book.

Solace, which launched in December 2019, is quite unlike any of the other trans-specific apps available through Apples App Store. Searching for trans or transgender on my iPhone turns up an endless scroll of dating apps for cis men trying to meet trans women and crossdressers with nearly illegibile, knockoff brand names like Tinded, Sinder, and Transdr. Theyre mostly godawful, Anthony said. Fetishizing trans people... transsexual dating dot this, and stuff. There are a few practical options that actually seem to have been designed with a trans user in mind, like audio recording apps to practice voice modification, crowdsourced safe restroom finders, and a selfie-driven transition tracker. But nothing is quite as comprehensive as Solace, which contains more than 180,000 words of text, according to Anthonys estimate.

The app gives users the ability to curate a custom checklist of transition tasks, which are divided into three categories: legal (updating your birth certificate, what you can do about workplace discrimination); lifestyle (coming out to your family, connecting with other trans people); and medical (facial feminization surgery, laser hair removal, family planning). Every item is comprehensive, containing lots of actionable information about the task at hand. The coming out to family entry, for example, includes both tips on what to do (write a coming out letter to each and every family member, ask to be called by your name and pronouns, be ready to explain what transgender means) along with general advice (make sure you are sober when you come out, be prepared to lose your housing or financial support).

Many of the resources are tailored to the users gender identity and location, as non-discrimination laws and the legal hoops one has to hop through in order to change the name and gender marker on their state-issued documents vary by state. For example, the page for updating your birth certificate in Arizona correctly notes that youll need an affidavit, a certified copy of a court order, a photo copy of a valid government-issued ID, a signed letter from your physician verifying that youve undergone a sex change operation, and a small fee. The page for Washington is significantly shorter, as the Evergreen State doesnt require surgery or a fee.

Solace is free to download and the creators have no intention of selling user data to third parties. We will never charge a penny, Anthony said. Were currently donor supported. We tap into foundation support, sometimes as grants. Were structured as a nonprofit. This community faces a disproportionate amount of poverty, so putting a paywall on this thing felt counterintuitive to what we were trying to do. And data-mining, she paused. Our stomachs turn at the thought of it.

Anthony declined to share how many people have downloaded Solace since launch, though she said she and McHugh are currently halfway to reaching their 2020 user goal. The app has had a number of updates since its December launch, like the addition of more detailed information regarding Medicaid coverage for trans care in different parts of the country. Anthony said that she also plans to integrate a news aggregator with articles about a variety of trans topics, implement dynamic pronouns within the apps copyto match the pronouns the user enters, and launch a mode for parents and guardians of trans kids.

Listening to Anthony talk, I couldnt help but think about how different my experience with transitioning has been. Its not that I havent had to seek out other trans people to find out who they see for laser hair removal or whether progesterones really worth the hype; Ive had to do all of those things. The difference is that I view them as positives rather than negatives. Ive found a lot of value in talking to other trans people about their experiences and sifting through their anecdotal experiences to figure out what might be right for me. Im deeply grateful for all the friendships Ive made and communities Ive joined after putting myself in uncomfortable, new social situations. I asked Anthony if she was concerned that an app like Solace might lead trans people away from their local communities. Its a byproduct were aware of, she said, but I wouldnt say that its a goal of ours.

Our entire ethos is about providing this community with agency, and part of agency is allowing people to access information on their own terms, she said.

Solace might not be of that much use to me, an extrovert in a major city whos already in community with other trans people (and my questions at this point of my transition are more existential than they are practicalless about how do I do this or how do I do that, and more about what do I do now). But it could be useful to people who dont know any trans people, or live in a part of the country with no visible local community, and might be particularly helpful for early transitioners or trans people who havent come out yet and are still trying to figure out where to begin.

Regardless of who makes use of Solaces many comprehensive resources, Anthony was clear about one thing: she doesnt want anyone to rely on the app forever. The ultimate sign of Solaces success is that the user deletes the app because they dont need it anymore, she said.

Follow Harron Walker on Twitter .

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Want to Transition? There's an App for That - VICE UK

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News Release, Smithsonian National Zoo

Scientists at the Smithsonian Conservation Biology Institute (SCBI) and the Columbus Zoo have successfully transferred cheetah embryos produced by in vitro fertilization (IVF) to a surrogate cheetah mom for the first time. Two cubs were born Feb. 19 to 3-year-old mom Izzy, though the cubs biological mom is 6 1/2-year-old Kibibi. Cheetahs naturally have low genetic diversity due to near extinction at the end of the last ice age. However, techniques scientists use to boost genetic diversity and health in other endangered and vulnerable species have not had much success in cheetahs. IVF embryo transfer will help scientists and zoos build the most robust and genetically healthy insurance population of cheetahs in human care possible, and potentially could even help the genetics of wild cheetahs.

For the embryo-transfer procedure, scientists collected semen from a male cheetah living at Fossil Rim Wildlife Center in Texas in February 2019 and froze it. They then harvested eggs from Kibibi at the Columbus Zoo Nov. 19, 2019, and performed IVF, fertilizing the eggs in a laboratory with the sperm collected in Texas earlier that year. The fertilized embryos were then transferred to Izzys oviduct Nov. 21, 2019. It was only the third time scientists had ever attempted the procedure. Kibibi had never given birth to a cub and is genetically valuable, but she is unlikely to ever reproduce on her own. Her valuable genes were at risk of never being passed on. Izzy, the surrogate, is less genetically valuable and is not currently recommended to breed, but she was hand-raised as a cub and very comfortable with keepers, which made her a good candidate as a surrogate cheetah mom.

The success of this groundbreaking procedure would not have been possible without the incredible dedication, collaboration and scientific expertise of the teams at the Smithsonian Conservation Biology Institute, Fossil Rim Wildlife Center and the ColumbusZoo and Aquarium, said Tom Stalf, president and CEO of the Columbus Zoo and Aquarium. The additional knowledge we gained throughout this process will serve as an importantresource in the future, and we are proud towork with our zoological colleagues on perfecting innovative methods that ultimately can have a direct impacton protecting rare species like cheetahs.

In December 2019, about a month after the procedure, veterinarians at the Columbus Zoo detected two fetuses on an ultrasound. Cheetah pregnancies typically last between 90 and 96 days. Izzy was monitored closely during her pregnancy and received regular ultrasounds and radiographs. Veterinarians and keepers at the Columbus Zoo noticed Izzy began showing signs she was in labor Wednesday, Feb. 19. The cubs were born later that evening at 9:50 p.m. and 10:20 p.m.They have been observed nursing, and the first-day birth weights were 480 grams for the male and 350 grams for the female.

SCBI scientists have been studying IVF and embryo transfer in cheetahs for 15 years. In 2005, they began working on collecting and inseminating oocytes, or eggs, in the lab. By 2011, they were able to harvest eggs and fertilize them and routinely produce embryos. Embryo transfer was the next step in their research.

We have been performing artificial inseminations in cheetahs for decades, and there hasnt been a cub born in almost 20 years, said Adrienne Crosier, cheetah biologist at the Smithsonian Conservation Biology Institute and one of the scientists who performed the embryo transfer. Just the fact that we were successful with embryo transfer after only the third attempt gives me hope for the future of this technique for improving cheetah management, potentially on a global scale. This is a huge scientific breakthrough and, in many ways, is much better because it gives us much more flexibility with limited genetic material. This is an amazing milestone for cheetahswe can extend a cheetahs biological clock.

Approximately one-third of the cheetah population living in zoos is removed from the breeding matrix due to age, health or behavior, and cheetahs ability to reproduce after 8 years of age declines significantly. The Association of Zoos and Aquariums Cheetah Species Survival Plan (SSP) has been working to increase the number of cubs born each year and maximize the effective breeding population, or the number of individuals contributing genetically to offspring.

For me, the birth of these IVF cubs is a significant breakthrough for cheetah reproduction, but the implications are enormous, said Pierre Comizzoli, a reproductive biologist at the Smithsonian Conservation Biology Institute and one of the scientists who performed the embryo transfer. We continue to improve our understanding of fertility and develop new tools for other species. This is how we make rapid progress with rare and endangered species. One species breakthrough opens the door for another.

Nearly all cheetahs recommended breeding by the SSP live at large off-exhibit facilities like SCBI, Fossil Rim Wildlife Center and The Wilds, which can care for more cats and collectively manage tens of thousands of acres, which has increased the number of cubs born each year. Embryo transfer will help ensure that more cheetahs breed contributing to the genetic diversity of the population and its sustainability. Male cheetahs can father cubs with the females who are their best genetic matches without having to move to the same zoos or facilities as the females. Scientists can collect sperm samples from males, freeze them and then use the sperm for embryo transfer at any point in the future.

Cheetahs are listed as vulnerable by the International Union for Conservation of Nature. During the past 50 years, cheetahs have become extinct in at least 13 countries in Africa, and there are about 7,500 cheetahs remaining in the wild. Habitat destruction, conflict with humans and hunting have caused their numbers to decline.

The Smithsonian Conservation Biology Institute plays a leading role in the Smithsonians global efforts to save wildlife species from extinction and train future generations of conservationists. SCBI spearheads research programs at its headquarters in Front Royal, Virginia, the Smithsonians National Zoo in Washington, D.C., and at field research stations and training sites worldwide. SCBI scientists tackle some of todays most complex conservation challenges by applying and sharing what they learn about animal behavior and reproduction, ecology, genetics, migration, and conservation sustainability.

The Southern Maryland Chronicle is a local, small business entrusted to provide factual, unbiased reporting to the Southern Maryland Community.While we look to local businesses for advertising, we hope to keep that cost as low as possible in order to attract even the smallest of local businesses and help them get out to the public. We must also be able to pay employees(part-time and full-time), along with equipment, and website related things. We never want to make the Chronicle a pay-wall style news site.

To that end, we are looking to the community to offer donations. Whether its a one-time donation or you set up a reoccurring monthly donation. It is all appreciated. All donations at this time will be going to furthering the Chronicle through hiring individuals that have the same goals of providing fair, and unbiased news to the community. For now, donations will be going to a business PayPal account I have set-up for the Southern Maryland Chronicle, KDC Designs. All business transactions currently occur within this PayPal account. If you have any questions regarding this you can email me at davidhiggins@southernmarylandchronicle.com

Thank you for all of your support and I hope to continue bringing Southern Maryland the best news possible for a very long time. David M. Higgins II

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First Cheetah Cubs Born as Result of Embryo Transfer - The Southern Maryland Chronicle

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Like many other respiratory conditions, COVID-19the disease caused by SARS-CoV-2can vary widely among patients. The vast majority of confirmed cases are considered mild, involving mostly cold-like symptoms to mild pneumonia, according to the latest and largest set of data on the new coronavirus outbreak released February 17 by the Chinese Center for Disease Control and Prevention.

Fourteen percent of confirmed cases have been severe, involving serious pneumonia and shortness of breath. Another 5 percent of patients confirmed to have the disease developed respiratory failure, septic shock, and/or multi-organ failurewhat the agency calls critical cases potentially resulting in death. Roughly 2.3 percent of confirmed cases did result in death.

Scientists are working to understand why some people suffer more from the virus than others. It is also unclear why the new coronaviruslike its cousins SARS and MERSappears to be more deadly than other coronaviruses that regularly circulate among people each winter and typically cause cold symptoms. I think its going to take a really, really long time to understand the mechanistic, biological basis of why some people get sicker than others, says Angela Rasmussen, a virologist at Columbia Universitys Mailman School of Public Health.

In the meantime, the latest data from China and research on other coronaviruses provide some hints.

The latest data from China stem from an analysis of nearly 45,000 confirmed cases, and on the whole suggest that the people most likely to develop severe forms of COVID-19 are those with pre-existing illnesses and the elderly.

While less than 1 percent of people who were otherwise healthy died from the disease, the fatality rate for people with cardiovascular disease was 10.5 percent. That figure was 7.3 percent for diabetes patients and around 6 percent for those with chronic respiratory disease, hypertension, or cancer.

While overall, 2.3 percent of known cases proved fatalwhich many experts say is likely an overestimate of the mortality rate, given that many mild cases might go undiagnosedpatients 80 years or older were most at risk, with 14.8 percent of them dying. Deaths occurred in every age group except in children under the age of nine, and, generally speaking, we see relatively few cases among children, World Health Organization Director General Tedros Adhanom Ghebreyesus said last week.

This pattern of increasing severity with age differs from that of some other viral outbreaks, notably the 1918 flu pandemic, for which mortality was high in young children and in people between 20 and 40 years of age. However, its broadly consistent with records of the SARS and MERS coronavirus outbreaks, notes Lisa Gralinski, a virologist at the University of North Carolina at Chapel Hill. If youre over fifty or sixty and you have some other health issues and if youre unlucky enough to be exposed to this virus, it could be very bad, she says.

I think its going to take a really, really long time to understand the mechanistic, biological basis of why some people get sicker than others.

Angela Rasmussen, Columbia University

Scientists dont know what exactly happens in older age groups. But based on research on other respiratory viruses, experts theorize that whether a coronavirus infection takes a turn for the worse depends on a persons immune response. The virus matters, but the host response matters at least as much, and probably more, says Stanley Perlman, a virologist and pediatric infectious disease specialist at the University of Iowa.

Once SARS-CoV-2 gets inside the human respiratory tract, its thought to infect and multiply in cells lining the airway, causing damage that kicks the immune system into action. In most people, it should trigger a wave of local inflammation, recruiting immune cells in the vicinity to eradicate the pathogen. The immune response then recedes, and patients recover.

For reasons that arent entirely clear, some peopleespecially the elderly and sickmay have dysfunctional immune systems that fail to keep the response to particular pathogens in check. This could cause an uncontrolled immune response, triggering an overproduction of immune cells and their signaling molecules and leading to a cytokine storm often associated with a flood of immune cells into the lung. Thats when you end up with a lot of these really severe inflammatory disease conditions like pneumonia, shortness of breath, inflammation of the airway, and so forth, says Rasmussen.

Local inflammation can turn into widespread inflammation of the lungs, which then has ripple effects across all organs of the body. This could also happen if the virus replicates faster than the immune system can respond, so that it then has to play catch-up to contain the pathogena situation that could also cause the immune defense to spiral out of control. With mice, we know that in some cases, particularly for SARS and MERS coronaviruses, virus replication is very rapid and in some cases overwhelming to the immune system, says Perlman.

Its harder to explain why young, healthy people also sometimes die from the diseasefor instance, Li Wenliang, a 34-year-old doctor who first sounded the alarm about the virus. He died a few weeks after contracting the pathogen.

Genetic and environmental risk factors might help explain the severity of infections. Though its clear that genetic factors can strongly determine the outcome of viral infections in miceas some of Rasmussens work has shown for Ebola, for instanceresearchers havent yet been able to tease out specific genes or variants in mice, let alone in people, that are responsible for varying degrees of illness. Environmental factors, such as smoking or air quality, may also play a role in disease severity, Rasmussen adds.

A lot of research has gone into understanding what causes respiratory failure that results from systemic inflammation of the lungsalso called acute respiratory distress syndrome (ARDS)that can occur from coronaviruses and other infections. Yet researchers still dont know how it occurs exactly, let alone how to treat it, Gralinksi notes. Its still a really poorly understood issue.

An intriguing finding in the new data released last week is that although similar numbers of men and women have contracted SARS-CoV-2, more men are dying from the disease. The death rate for males was 2.8 percent and 1.7 percent for women. Rasmussen is quick to caution that although the data encompass nearly 45,000 patients, thats still not that many people to determine if theres really a gender biasyoud have to look at this in a much larger population of patients in a number of different countries, she says.

That said, if there is a bias, it would be consistent with what epidemiologists have observed during the SARS and MERS outbreaks. In the 2003 SARS outbreak in Hong Kong, for instance, nearly 22 percent of infected men died, compared to around 13 percent of women. In an analysis of MERS infections between 2017 and 2018, around 32 percent of men died, and nearly 26 percent of women. The difference could have something to do with the fact that the gene for the ACE-2 receptor, which is used by both SARS-CoV-2 and the SARS virus to enter host cells, is found on the X chromosome, she speculates. If its a particular variant of the protein that makes people more susceptible to the virus, then females could compensate for that one bad variant because theyd have two copies of the X chromosome, whereas men would be stuck with only one copy. Or, it could be that men are more likely to be smokers and so their lungs are already a bit compromised. Theres definitely more to be teased out there, Gralinski says.

Some of Perlmans research, which demonstrated that the sex disparity also holds true in SARS-infected mice, points to the hormone estrogen as possibly having protective effects: Removing the ovaries of infected female mice or blocking the estrogen receptor made the animals more likely to die compared to infected control mice. The effects are probably more pronounced in mice than in people, Perlman tells The New York Times.

Whether patients develop antibodies after SARS-CoV-2 infection that will protect them against future infections is still a mystery. Surveys of SARS patients around five or 10 years after their recovery suggest that the coronavirus antibodies dont persist for very long, Gralinski says. They found either very low levels or no antibodies that were able to recognize SARS proteins.

However, for the new coronavirus, we would expect some immunity, at least in the short term, she says.

There are seven coronaviruses known to infect people. Four of them229E, NL63, OC43, and HKU1typically cause a cold and only rarely result in death. The other threeMERS-CoV, SARS-CoV, and the new SARS-CoV-2have varying degrees of lethality. In the 2003 SARS outbreak, 10 percent of infected people died. Between 2012 and 2019, MERS killed 23 percent of infected people. Although the case fatality rate of COVID-19 is lower, the virus has already killed more people than the other two outbreaks combined, which some have attributed to the pathogens fast transmission.

The cold-causing coronaviruses, as well as many other viruses that cause common colds, are typically restricted to the upper respiratory tract, that is, the nose and sinuses. Both SARS-CoV and SARS-CoV-2, however, are capable of invading deep into the lungs, something that is associated with more severe disease.

One possible reason for this is that the virus binds to the ACE-2 receptor on human cells in order to gain entry. This receptor is present in ciliated epithelial cells in the upper and lower airway, as well as in type II pneumocytes, which reside in the alveoli in the lower airway and produce lung-lubricating proteins. The type II pneumocytes are . . . important for lung function, so this is part of why the lower respiratory disease can be so severe, notes Gralinksi.

The new coronavirus also appears to use the ACE-2 receptor, which may help partially explain why, like SARS, it is more deadly than the other four coronaviruses. Those pathogens use different receptors, except for NL63, which also uses the ACE-2 receptor but binds to it with less affinity, says Gralinski. (MERS is thought to use an entirely different receptor, which is also present in the lower airways.)

To understand these questions fully will take time, research, and consistent funding for long-term studies. Coronavirus funding has been criticized for following a boom-and-bust cycle; viral spillovers from animals to people cause an initial surge of interest that tends to wane until the next outbreak occurs, Rasmussen warns.

Im hopeful that in this case it will be really apparent to everybody in the world that we need to be funding this type of basic science, fundamental science, to understand these mechanisms of disease, she says. Otherwise, were going to be in the same situation when the next outbreak happenswhether its a coronavirus or something else.

Katarina Zimmer is a New Yorkbased freelance journalist. Find her on Twitter@katarinazimmer.

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Why Some COVID-19 Cases Are Worse than Others - The Scientist

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Abstract

The red panda (Ailurus fulgens), an endangered Himalaya-endemic mammal, has been classified as two subspecies or even two species the Himalayan red panda (A. fulgens) and the Chinese red panda (Ailurus styani) based on differences in morphology and biogeography. However, this classification has remained controversial largely due to lack of genetic evidence, directly impairing scientific conservation management. Data from 65 whole genomes, 49 Y-chromosomes, and 49 mitochondrial genomes provide the first comprehensive genetic evidence for species divergence in red pandas, demonstrating substantial inter-species genetic divergence for all three markers and correcting species-distribution boundaries. Combined with morphological evidence, these data thus clearly define two phylogenetic species in red pandas. We also demonstrate different demographic trajectories in the two species: A. styani has experienced two population bottlenecks and one large population expansion over time, whereas A. fulgens has experienced three bottlenecks and one very small expansion, resulting in very low genetic diversity, high linkage disequilibrium, and high genetic load.

The delimitation of species, subspecies, and population is fundamental for insights into the biology and evolution of species and effective conservation management. Traditionally, species, subspecies, or population delimitation is based on reproductive isolation, geographic isolation, and/or morphological differences and does not consider the role of gene flow. The misclassification of basal taxa will result in erroneous or misleading conclusions about the species evolutionary history and adaptive mechanisms, and potentially inappropriate conservation management decisions for threatened species (1, 2).

The red panda (Ailurus fulgens), an endangered Himalaya-endemic mammal, was once widely distributed across Eurasia but is now restricted at the southeastern and southern edges of the Qinghai-Tibetan Plateau within an altitude range of 2200 to 4800 m (3). On the basis of differences in morphology (e.g., skull morphology, coat color, and tail ring) and geographic distribution (Fig. 1 and table S1), red pandas are classified into two subspecies, the Himalayan subspecies (A. f. fulgens Cuvier, 1825) and the Chinese subspecies (A. f. styani Thomas, 1902) (4, 5). Morphologically, the Chinese subspecies has much larger zygomatic breadth, the greatest skull length, stronger frontal convexity, more distinct tail rings, and redder face coat color with less white on it (Fig. 1) (5, 6). On the basis of these morphological differences, C. Groves even proposed that the two subspecies should be updated as two distinct species: the Himalayan red panda (A. fulgens) and the Chinese red panda (A. styani) (6). The Nujiang River is considered the geographic boundary between the two species (7). The Himalayan red panda is distributed in Nepal, Bhutan, northern India, northern Myanmar, and Tibet and western Yunnan Province of China, while the Chinese red panda inhabits Yunnan and Sichuan provinces of China. The subspecies or species classification has remained controversial largely due to the lack of genetic evidence, and their distribution boundary may also be inaccurate because of the morphological similarity of red pandas on both sides of the Nujiang River (6, 8, 9). For instance, the skull size and morphology of red pandas from southeastern Tibet were more similar to those of the Chinese red panda than the Himalayan red panda (6). Although previous studies attempted to use mitochondrial DNA or microsatellite markers to explore this problem, the very small sample size from the Himalayan red panda and the limited ability of the molecular markers resulted in failure to resolve the species delimitation (1012). Next-generation sequencing technology not only provides whole-genome data but also enables the identification of Y chromosome sequences in nonmodel animals, which were difficult to obtain previously (13, 14). Thus, it is now feasible to use whole genomes, Y chromosomes, and mitochondrial genomes to comprehensively delimit species, subspecies, and populations. Here, with sufficient sampling of the Himalayan red panda, we performed whole-genome resequencing, Y chromosome single-nucleotide polymorphism (SNP) genotyping, and mitochondrial genome assembly of wild red pandas covering most of the distribution ranges of the two species, aiming to clarify species differentiation, population divergence, demographic history, and the impacts of population bottlenecks on genetic evolutionary potential.

(A and C) The Chinese red panda. (B and D) The Himalayan red panda. (A and B) The face coat color of the Chinese red panda is redder with less white on it than that of the Himalayan red panda. (C and D) The tail rings of the Chinese red panda are more distinct than those of the Himalayan red panda, with the dark rings being more dark red and the pale rings being more whitish. Photo credit: (A) Yunfang Xiu, Straits (Fuzhou) Giant Panda Research and Exchange Center, China; does not require permission. (B) Arjun Thapa, Institute of Zoology, Chinese Academy of Sciences. (C) Yibo Hu, Institute of Zoology, Chinese Academy of Sciences. (D) Chiranjibi Prasad Pokheral, Central Zoo, Jawalkhel, Lalitpur, Nepal; does not require permission.

We performed whole-genome resequencing for 65 wild red pandas, with an average of 98.7% genome coverage and 13.9-fold sequencing depth for each individual based on the red panda reference genome (belonging to the Chinese red panda) of 2.34 Gb (15). Using the SNP-calling strategy of the Genome Analysis Toolkit (GATK), we identified a total of 4,932,036 SNPs for further analysis (table S4). On the basis of the whole-genome SNPs, the phylogenetic tree, principal components analysis (PCA), and ADMIXTURE results revealed substantial genetic divergence between the two species, providing the first genomic evidence of species differentiation (Fig. 2, B to D). The middle Himalaya population (MH) belonging to the Himalayan red panda was first divergent from the populations of the Chinese red panda (Fig. 2, B and D). Furthermore, four distinct genetic populations were identified: MH (n = 18), eastern Himalaya-Gaoligong (EH-GLG, n = 3 and 13, respectively), Xiaoxiangling-Liangshan (XXL-LS, n = 12 and 8, respectively), and Qionglai (QL, n = 10) (Fig. 2, B to D; fig. S1; and table S5). The individual SLL1 is the only sampled red panda from the Saluli Mountains (SLL), and its genetic assignment implied gene flow between the SLL population and its adjacent XXL and GLG populations (Fig. 2C). Because of the very small sample size, SLL1 was excluded in any population-level analyses. Traditionally, MH, EH, and the GLG individuals at the western side of the Nujiang River were classified as the Himalayan red panda, while the GLG individuals at the eastern side of Nujiang River, XXL, LS, and QL belonged to the Chinese red panda (7). Our results did not support the Nujiang River as the species distribution boundary because the EH and part of the GLG population at the western side of the Nujiang River clustered into a genetic population with other GLG individuals at the eastern side (Fig. 2, B to D). This EH-GLG genetic clustering was supported by morphological evidence that the morphology of red panda skulls from southeastern Tibet (namely, the EH population in this study) was more similar to that of the Chinese red panda than the Himalayan red panda (6). In addition, two individuals from Myanmar (GLG5 and GLG6) also clustered within the EH-GLG genetic cluster, suggesting that the Myanmar population belongs to the Chinese red panda. Thus, we infer that the Yalu Zangbu River, the largest geographic barrier to dispersal between the two species, may be the potential boundary for species distribution (Fig. 2A), although additional samples need to be collected from Bhutan and India to verify this inference.

(A) The geographic distribution of wild red panda samples under the background of habitat suitability. Red, QL population; purple, XXL-LS population; blue, SLL population; pink, EH-GLG; dark red, MH. (B) Maximum likelihood phylogenetic tree based on whole-genome SNPs, with the ferret as the outgroup. The values on the tree nodes indicate the bootstrap support of 50%. (C) ADMIXTURE result based on whole-genome SNPs with K = 2 to 7. (D) PCA result based on whole-genome SNPs. (E) Network map based on eight Y chromosome SNP haplotypes. (F) Network map based on 41 mitochondrial genome haplotypes.

Within the Chinese red panda, we further found population genetic differentiation. EH-GLG first diverged with XXL-LS-QL and then QL separated from XXL-LS (Fig. 2, B and C). Notably, we did not detect genetic substructure within EH-GLG spanning the famous Three Parallel Rivers (Nujiang River, Lancangjiang, and Jinshajiang), suggesting that the three large rivers did not hinder the gene flow of red pandas. This result is consistent with data from microsatellite markers (12).

Our Y chromosome SNP and mitochondrial genome results also supported the substantial divergence between the two species (Fig. 2, E and F; figs. S2 and S3; and tables S6 to S8). The haplotype networks and phylogenetic trees of both eight Y chromosome SNP (Y-SNP) haplotypes from 49 male individuals and 41 mitochondrial genome haplotypes from 49 individuals showed that the MH haplotypes (Himalayan red panda) clustered together and separated from the haplotypes of the Chinese red panda, highlighting the notable genetic divergence between the two species. In summary, regardless of the whole-genome SNPs, Y-SNPs, or mitochondrial genomes, notable genetic differentiation was found between the two species. Our comprehensive investigations reveal two evolutionarily significant units in red pandas. Under the phylogenetic species concept (16), it is reasonable to propose two species: the Himalayan red panda (A. fulgens) and the Chinese red panda (A. styani). This phylogenetic species classification was supported by their morphological differences (6).

The Y chromosome SNP and mitochondrial genome results revealed a female-biased gene flow pattern in red pandas (Fig. 2, E and F). Within the Chinese red panda, we observed different phylogeographic patterns between the mitochondrial genome and Y chromosome. The distribution of mitochondrial haplotypes was mixed and was not associated with the geographic sources of the individuals. By contrast, the distribution of Y-SNP haplotypes demonstrated an obvious phylogeographic structure: The haplotypes of EH-GLG were separated from those of XXL-LS-QL, and no shared Y-SNP haplotypes were found. These contrasting phylogeographic patterns reflected a female-mediated historical gene flow, implying female-biased dispersal and male-biased philopatry in red pandas. This dispersal pattern differs from the male-biased dispersal found in most mammals (17) but is similar to that of another bamboo-eating mammal, the giant panda (18, 19).

The pairwise sequentially Markovian coalescent (PSMC) analysis results showed that the demographic history of red panda could be traced back to approximately 3 million years (Ma) ago, and the two red panda species experienced obviously different demographic histories (Fig. 3A). The Chinese red panda from EH-GLG, XXL-LS, and QL experienced similar demographic trajectories: two population bottlenecks and one large population expansion. This species suffered from an obvious population decline approximately 0.8 Ma ago, which coincided with the occurrence of the Naynayxungla Glaciation (0.78 to 0.5 Ma ago). The population decline resulted in the first bottleneck approximately 0.3 Ma ago, mostly likely caused by the Penultimate Glaciation (0.3 to 0.13 Ma ago) (20). After the glaciations, the populations started to expand and reached a climax approximately 50 thousand years (ka) ago. Then, the arrival of the last glaciations again resulted in rapid population decline, and the second bottleneck occurred during the Last Glacial Maximum (~20 ka ago) (20).

(A) PSMC analysis revealed different demographic histories of the two species, with a generation time (g) of 6 years and a mutation rate () of 7.9 109 per site per generation. The time axis is logarithmic transformed. (B) Fastsimcoal2 simulation reconstructed the divergence, admixture, and demographic history of red panda species and populations. The time axis is logarithmic transformed, and the number of migrants per year between two adjacent populations is shown beside each arrow. (C) TreeMix analysis detected significant gene flow from the EH-GLG to XXL-LS populations. s.e., standard error.

The Himalayan red panda from MH underwent a demographic history differing from that of the Chinese red panda: three population bottlenecks and one small expansion (Fig. 3A). The difference began with the first population bottleneck approximately 0.25 Ma ago. In contrast to the subsequent population recovery of the Chinese red panda, the Himalayan red panda continued to decrease and then went through a second bottleneck approximately 90 ka ago. Afterward, the population started to increase very slowly, but soon the population again decreased due to the last glaciations. The PSMC results showed that even at the climax of population growth (~50 ka ago), the effective population size of the Himalayan red panda was only approximately 35% that of the Chinese red panda. In addition, the Bayesian skyline plot (BSP) analyses based on mitochondrial genomes indicated that both species experienced recent population declines most likely caused by the Last Glacial Maximum, supporting the PSMC results (fig. S4). The different demographic trajectories may result from geographic and climate differences. The Chinese red panda was mainly distributed in the Hengduan Mountains rather than the platform or adjacent edges of the Qinghai-Tibetan Plateau and thus might have suffered less impact of the Pleistocene glaciations. The interglacial warm climate and the vast region of the Hengduan Mountains might have facilitated the rapid population expansion of the Chinese red panda (3). By contrast, the Himalayan red panda lived in the adjacent southern edge of the Qinghai-Tibetan Plateau and might have suffered severe impact of the Pleistocene glaciations. Even during the interglacial period, the geographic proximity to glaciers and limited potential habitat might have restricted this species population recovery (21). In Holocene, the climate might have less impact on red panda populations (21), while increasing human activities became the main factor driving recent red panda population declines, which have been detected by microsatellite marker-based Bayesian population simulations (12).

We further uncovered the species/population divergence history using Fastsimcoal2 simulation. On the basis of the comparison of alternative population divergence models, we determined the best-support divergence/demography model (Fig. 3B, fig. S5, and table S9). The divergence between the Himalayan (MH) and Chinese red pandas (EH-GLG, XXL-LS, and QL) occurred 0.22 Ma ago, coincident with the first population bottleneck of the two species caused by the Penultimate Glaciation. Next, EH-GLG and XXL-LS-QL diverged 0.104 Ma ago. The divergence may have resulted from the widely unsuitable habitat located in the Daxueshan and SLL Mountains (21). Last, XXL-LS and QL diverged 26 ka ago, which was most likely caused by the Last Glacial Maximum. After the population divergence, MH, EH-GLG, and QL suffered from population decline, whereas XXL-LS experienced population growth. Asymmetrical gene flow was detected between adjacent divergent populations (Fig. 3B). After the early divergence between the two species, more gene flow occurred from the Chinese red panda to the Himalayan red panda. Regardless of historical or current gene flow, EH-GLG seemed to be the source population of gene flow with more gene flow into other adjacent populations, among the four genetic populations (Fig. 3B). This implies that EH-GLG might be the historical dispersal source of red pandas. TreeMix analysis also detected significant gene flow from EH-GLG to XXL-LS (Fig. 3C and fig. S6), consistent with the Fastsimcoal2 result.

Whole-genome variation analysis revealed that EH-GLG had the highest genetic diversity ( = 6.994 104, w = 5.271 104), whereas the Himalayan red panda (MH) had the lowest genetic diversity ( = 3.523 104, w = 2.428 104) (Fig. 4A and table S10). Y-SNP and mitochondrial genomic variations also showed that the Himalayan red panda (MH) had the lowest genetic variations (Fig. 4A and table S10). Genome-wide linkage disequilibrium (LD) analysis demonstrated that the Himalayan red panda (MH) had higher level of LD and slower LD decay with a reduced R2 correlation coefficient becoming stable at a distance of approximately 100 kb, whereas the populations of the Chinese red panda exhibited rapid LD decay with a reduced R2 becoming stable at a distance of approximately 40 kb (Fig. 4B). The genomic variations and LD patterns imply different demographic histories of the two species and, in particular, reflect the genetic impacts of long-term population bottlenecks in the Himalayan red panda.

(A) Genetic variations (nucleotide diversity) of different species and populations based on whole-genome SNPs, mitochondrial genomes, and Y chromosome SNPs. (B) LD of the four populations. (C) Ratios of homozygous derived deleterious or LoF variants to homozygous derived synonymous variants for different populations. The horizontal bars denote population means. (D) Distribution of ratios (non-MH/MH) and Z(FST) values. Data points located to the left of the left vertical dashed lines and the right of the right vertical dashed lines (corresponding to the 5% left and right tails of the empirical ratio distribution, respectively) and above the horizontal dashed line [the 5% right tail of the empirical Z(FST) distribution] were identified as selected regions for the MH (the Himalayan red panda, green points) and non-MH (the Chinese red panda, blue points) populations.

We further analyzed the relationship between demographic history and genetic loads carried by different red panda populations, as deleterious variations should be removed more efficiently in larger populations (22, 23). We investigated the distributions of four types of variations [loss of function (LoF), deleterious, tolerated, and synonymous mutations] in protein-coding genes. We found that the ratios of homozygous derived deleterious or LoF variants to homozygous derived synonymous variants were higher in the Himalayan red panda (MH) than in the Chinese red panda; by contrast, the ratios of nonhomozygous derived deleterious or LoF variants to nonhomozygous derived synonymous variants were comparable between the two species (Fig. 4C). This genetic load pattern showed that the Himalayan red panda experiencing long-term population bottlenecks carried more homozygous LoF and deleterious mutations and thus suffers a higher risk of continuing population decline.

Considering that the two red panda species live in different geographic ranges and climate environments and experienced long-term genetic divergence, we mainly focused on the identification of genomic signatures of selection and local adaptation between the two species. Using FST and methods, we identified 146 genes with top 5% maximum FST values and top 5% minimum 1/2 values in the Himalayan red panda (MH) (Fig. 4D and table S11). The functional enrichment found that some genes were enriched in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of vascular smooth muscle contraction (ko04270, P = 1.18 108) and melanogenesis (ko04916, P = 2.36 104) and the gene ontology (GO) term of positive regulation of endothelial cell proliferation (GO:0001938, P = 0.0197) (tables S12 and S13). The selection of these genes might be related with the distinct coat color of the Himalayan red panda and the adaptation to hypoxia and microclimate in high-elevation habitat (6).

In the Chinese red panda (EH-GLG, XXL-LS, and QL), we identified 178 genes under selection (Fig. 4D and table S14), which were partly enriched in the nonhomologous end-joining pathway (ko03450, P = 9.89 103) and the GO terms of regulation of response to DNA damage stimulus (GO:2001020, P = 3.35 103), cellular response to x-ray (GO:0071481, P = 3.69 103), double-strand break repair via nonhomologous end joining (GO:0006303, P = 0.0189), endothelial cell differentiation (GO:0045446, P = 0.0187), and regulation of response to oxidative stress (GO:1902882, P = 0.021) (tables S15 to S16). These selected genes were most likely involved in the adaptation to high ultraviolet radiation and hypoxia and microclimate in the Hengduan Mountains where the Chinese red panda mainly lives. Considering the recent divergence (0.22 Ma ago) between the Himalayan and Chinese red pandas, the ancestor of the two species should have adapted to a high-elevation environment before divergence because the latest and most significant uplift of the Qinghai-Tibetan Plateau have occurred 1.1 to 0.6 Ma ago and caused the altitude to increase up to 3000 m (24). Finding their common genetic mechanisms for high-elevation adaptation proved to be difficult based on our comparison of population genome data. The above functional enrichment results more likely reflected the adaptation of both red pandas to the local microclimate and habitat environment. Recent study showed that the two red panda species have separate climatic spaces dominated by precipitation-associated variables in the Himalayan red panda and by temperature-associated variables in the Chinese red panda (21).

Our analyses of whole genomes, Y chromosomes, and mitochondrial genomes revealed substantial genetic differentiation between the Himalayan and Chinese red pandas and provide the most comprehensive genetic evidence of species delimitation. When combined with previously identified morphological differences (6), the classification of two phylogenetic species is well defined. Our genomic evidence rejected the previous viewpoint of the Nujiang River as the species distribution boundary and revealed that the red pandas living in southeastern Tibet and northern Myanmar belong to the Chinese red panda, while the red pandas inhabiting southern Tibet belong to the Himalayan red panda together with the Nepalese individuals. We infer that the Yalu Zangbu River is most likely the geographic boundary for species distribution because this river is the largest geographic barrier between the two species. However, further verification with samples from Bhutan and India is needed. The delimitation of two red panda species has crucial implications for their conservation, and effective species-specific conservation plans could be formulated to protect the declining red panda populations (25). For a long time, the unclear status of species classification and distribution boundary hindered the scientific design of conservation measures. Because of the wrong distribution boundary, the EH-GLG population was split to belong to two species, which could result in inappropriate conservation measures for EH-GLG population and possibly detrimental interbreeding between the two species in captivity. Within the Chinese red panda, our results revealed three genetic populations: EH-GLG, XXL-LS, and QL, suggesting three management units for scientific conservation. In particular, the EH-GLG population spans southeastern Tibet and northwestern Yunnan of China, northern Myanmar, and northeastern India, which needs transboundary international cooperation for effective conservation. The QL population has the lowest genomic diversity and thus needs more attention to the conservation of its genetic evolutionary potential.

Our findings uncover the genetic impacts of long-term population bottlenecks in the Himalayan red panda, thus providing critical insights into the genetic status and evolutionary history of this poorly understood species. The long-term population bottleneck severely impaired its genetic evolutionary potential, resulting in the lowest genetic diversity but higher genetic load. The Himalayan red panda was estimated to have a small population size (26), and thus maintaining and increasing this species population size and genetic diversity are critical for their long-term persistence. In particular, the Himalayan red panda population spans southern Tibet of China, Nepal, India, and Bhutan, which needs urgent transboundary international cooperation to protect this decreasing species.

Our findings reveal that in addition to Pleistocene glaciations and recent human activity, female-biased gene flow has played an important role in shaping the demographic trajectories and genetic structure of red pandas. As a Himalaya-endemic species, our findings will also help understand the phylogeographic patterns of fauna distributed in the Himalaya-Hengduan Mountains biodiversity hotspot.

We collected blood, muscle, and skin samples of 65 wild red pandas from seven main geographic populations for whole-genome resequencing. Of the 65 individuals, 18 individuals were from the middle Himalayan Mountains (MH), 3 from the eastern Himalayan Mountains (EH), 13 from the Gaoligong Mountains (GLG), 1 from the Saluli Mountains (SLL), 12 from the Xiaoxiangling Mountains (XXL), 8 from the Liangshan Mountains (LS), and 10 from the Qionglai Mountains (QL) (Fig. 2A and table S2). For Y chromosome SNP genotyping, we first used red pandaspecific sex determination primers (27) to identify the sexes of the available wild samples. As a result, 49 wild male red pandas were used, including 13 from the MH population, 2 from EH, 10 from GLG, 8 from XXL, 5 from LS, and 11 from QL (table S2). For mitochondrial genome assembly, we successfully assembled 49 complete mitochondrial genomes from the whole-genome resequencing data for 49 of 65 wild red pandas, including 13 from MH, 2 from EH, 9 from GLG, 12 from XXL, 4 from LS, and 9 from QL (table S2).

We extracted genomic DNA from blood, muscle, and skin samples using the QIAGEN DNeasy Blood & Tissue Kit. Then, we constructed genomic libraries of insert size 200 to 500 base pairs and performed genome resequencing of the average 10 for each individual using the Illumina HiSeq 2000 and X Ten sequencing platforms (table S3). To identify population-level SNPs, the Illumina sequencing reads were aligned to the red panda reference genome (15) with Burrows-Wheeler Alignment (BWA) tool v0.7.8 (28), and polymerase chain reaction (PCR) duplicates were removed by SAMtools v0.1.19 (29). The UnifiedGenotyper method in GATK v3.1-1-g07a4bf8 software (30) was used for SNP calling with default parameters across the 65 individuals. To obtain reliable SNP, we performed a filtering step with the following set of parameters: depth 4, MQ 40, FS 60, QD 4, maf 0.05, and miss 0.2.

Previously, we de novo sequenced a wild male red panda genome (15), which enabled us to develop Y chromosome SNPs. Using a genome synteny searching strategy and the female dog genome (boxer breed) and the dog male-specific Y chromosome sequences (Doberman breed) as the reference, Fan et al. recently identified a set of nine male-specific Y chromosome scaffolds with a total length of 964 kb from the male red panda genome assembly (table S5) (31). Using the 964-kb male-specific Y chromosome scaffolds as the reference, we aligned the whole-genome resequencing reads of 18 male red pandas to the reference genome using BWA and then performed SNP calling using SAMtools and GATK. As a result, a total of 63 Y-SNPs were identified. Furthermore, we screened 22 Y-SNPs with confirmed polymorphism and good PCR/sequencing performance. Then, we genotyped these Y-SNPs for a total of 49 male red pandas. With the genotyping of more individuals, we found five additional Y-SNPs. As a whole, the dataset of 49 male red pandas with 27 Y-SNPs was used for subsequent paternal population genetics analysis (tables S2, S6, and S7).

We used the Assembly by Reduced Complexity method (32) to assemble mitochondrial genome with the published red panda mitochondrial genome as a reference (33) (GenBank accession: AM711897). First, the sequencing reads of each of the 65 red pandas were mapped onto the mitochondrial genome reference. Second, the mitochondrial genome reference was classified into multiple bins, and the alignment results were used to distribute reads into specific bins. Third, assembly was performed for each bin to produce contigs. Last, the initial reference was replaced with assembled contigs, and the above processes were iterated until stopping criteria have been met (32). The mitochondrial genome sequence used lastly excluded the highly repetitive sequences within the D-loop region.

We conducted PCA for whole-genome SNPs using the program GCTA v1.24.2 (34). A maximum likelihood phylogenetic tree was constructed by RAxML software (35) with the GTRGAMMA model and 100 bootstraps, and the ascertainment bias correction was performed to correct for the impact of invariable sites in the data. Ferret was used as the outgroup (36). Population genetic structure was inferred by ADMIXTURE v1.23 software (37) with default settings. We did not assume any prior information about the genetic structure and predefined the number of genetic clusters (K) from two to seven. We used POPART v1.7 (38) to construct a median-joining network for the Y-SNP haplotypes and mitochondrial genome haplotypes. We constructed the phylogenetic tree based on mitochondrial genomes of 15,238 bp (excluding the D-loop region) using BEAST v1.8.2 (39) with ferret as the outgroup. The best substitution model of GTR + I was selected on the basis of the Bayesian Information Criterion by ModelGenerator v0.85 (40). A strict clock rate was selected on the basis of the assessment of coefficient of variation. A total of 8 108 iterations were implemented with 10% burn-ins. The BEAST running results were assessed by Tracer v1.5 and were annotated by TreeAnnotator v1.10. We constructed the phylogenetic tree based on Y-SNPs data using the maximum likelihood method implemented in RAxML (35), with the ascertainment bias correction and ferret as the outgroup.

To reconstruct the detailed demographic history of each red panda population, we applied the simulation PSMC v0.6.4-r49 (41) to the whole diploid genome sequences, with the following set of parameters: -N 30 t 15 r 5 -p 4 + 25*2 + 4 + 6. We excluded sex-chromosome sequences of the red panda genome by aligning the red panda genome with the dog genome. We selected two to three high-depth sequenced individuals from each population for PSMC analysis (table S3). We estimated the nucleotide mutation rate of red panda using ferret as the comparison species and the following formula: = D g/2T, where D is the observed frequency of pairwise differences between two species, T is the estimated divergence time, and g is the estimated generation time for the two species (42). In this study, the generation time (g) was set to 6 years (26), the estimated divergence time was set to 39.9 Ma ago (15), and D was estimated to be 0.10558. On the basis of the above formula and the corresponding values, a mutation rate of 7.9 109 mutations per site per generation was estimated for the red panda. In addition, we performed BSP analyses based on mitochondrial genomes of 15,994 bp for two species separately, using BEAST v1.8.2. The best substitution model of HKY + I was selected by ModelGenerator v0.85. A strict clock rate was selected with a nucleotide substitution rate (43) of 1.9 108. A total of 8 108 iterations were implemented with 10% burn-ins. The BEAST running results were assessed, and the BSP plots were produced by Tracer v1.5.

We used the flexible and robust simulation-based composite-likelihood approach implemented in Fastsimcoal2 v2.5.2.21 (44) to infer species/population divergence and demographic history with the following parameters: -n 100000 -N 100000 -d -M 0.001 -l 10 -L 40 -q --multiSFS -C10 -c8. Because of the memory limit of Fastsimcoal2 running, we selected 55 individuals among 65 red pandas for simulation analysis (table S2). Four alternative population divergence and demographic models were explored. For each model, we ran the program 50 times with varying starting points to ensure convergence and retained the fitting with the highest likelihood. The best model was selected through the maximum value of the likelihoods. Parametric bootstrap estimates were obtained on the basis of 100 simulated data sets (table S9). In addition, we performed population-level admixture analysis for detecting gene flow among genetic populations using the TreeMix method (45) with the following running parameters: treemix bootstrap k 1000 se noss m 1~5.

For whole-genome data, the nucleotide diversity () (46) and Wattersons estimator (w) (47) of each genetic population were calculated using VariScan v2.0.3 (48). A sliding window approach was used with a 50-kb window sliding in 10-kb steps. We estimated the genetic diversity for the mitochondrial genome data of 15,994 bp and Y-SNPs data using DNASP v5.10.01 (49). To assess the LD pattern in red pandas, the correlation coefficient (R2) between any two loci in each genetic population was calculated using vcftools v0.1.14 (50). Parameters were set as follows: --ld window -bp 500000 geno -r2. Average R2 values were calculated for pairwise markers with the same distance.

We used ANNOVAR (51) to annotate and classify the effects of SNP variants on protein-coding gene sequences. Then, the coding sequence variants were classified as LoF, missense, and synonymous variants. LoF variant denoted variants with gain of a stop codon. The missense variants were further categorized as deleterious and tolerated missense mutations by SIFT 4G (52). We determined the ancestral allele at each SNP position through comparison with the ferret genome (36). To detect the genetic load of each red panda population, for each individual, we counted the relative proportions of homozygous ancestral, heterozygous, and homozygous derived alleles for LoF, deleterious, tolerated, and synonymous variants, respectively. Furthermore, we calculated the ratio of homozygous derived LoF variants (or deleterious variants) to homozygous derived synonymous variants and the ratio of nonhomozygous derived LoF variants (or deleterious variants) to nonhomozygous derived synonymous variants for each individual.

In general, positive selection gives rise to lower genetic diversity within populations and higher genetic differentiation between populations (53). The genetic differentiation index FST (54) and the average proportion of pairwise mismatches over all compared sequences (55) have been widely used to detect selection (53). To detect selection signals possibly associated with local adaptation, we used a sliding-window method (50-kb windows with 25-kb increments) to calculate the genome-wide distribution of FST values and ratios for the two species, implemented in vcftools v0.1.14. We applied z transformation for FST values and log2 transformation for ratios and considered the windows with the top 5% Z(FST) and log2( ratio) values simultaneously as the candidate outliers under strong selection. All outlier windows were assigned to corresponding SNPs and genes. We used the GeneTrail2 method (56) to perform KEGG pathway and GO term enrichment analyses for selected genes located in specific regions. Each significantly enriched category included at least two genes, and the hypergeometric test was used to estimate significance (P < 0.05).

Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/6/9/eaax5751/DC1

Fig. S1. PCA plot of red panda whole-genome SNPs data, with PC1, PC2, and PC3 explaining 28.5, 4.1, and 3.6% of the observed variations, respectively.

Fig. S2. Phylogenetic tree based on 41 mitochondrial genome haplotypes, showing two significant species lineages (A. fulgens and A. styani).

Fig. S3. Phylogenetic tree based on eight Y chromosome SNPs haplotypes, showing two significant species lineages (A. fulgens and A. styani).

Fig. S4. Bayesian skyline plot (BSP) analysis results based on mitochondrial genomes.

Fig. S5. Four alternative population divergence models for Fastsimcoal2 simulations, with the maximum estimated likelihood values shown.

Fig. S6. Residual fit from the maximum likelihood tree estimated by TreeMix.

Table S1. Summary of the morphological differences between the Himalayan and Chinese red pandas.

Table S2. Sample information for whole-genome resequencing, Y chromosome SNP genotyping, mitochondrial genome assembly, and Fastsimcoal2 analysis.

Table S3. Summary of whole-genome resequencing data for 65 red panda individuals that include the individuals for PSMC analysis.

Table S4. Summary of SNP calling based on 65 red panda individuals.

Table S5. Cross-validation error result for varying values of K in the ADMIXTURE analysis.

Table S6. PCR primer information for validating the six male-specific Y-scaffolds of red pandas.

Table S7. PCR primer information for amplifying the SNPs on the male-specific Y-scaffolds.

Table S8. Eight Y-SNP haplotypes identified from 27 Y-SNPs of 49 male red panda individuals.

Table S9. Confidence intervals of key parameters for the best population divergence and demographic model estimated by Fastsimcoal2.

Table S10. Genetic diversity of whole genome, Y chromosome, and mitochondrial genome for different species and populations of red pandas.

Table S11. The 146 genes under selection with top 5% maximum FST values and top 5% minimum 1/2 values in the Himalayan red panda (MH).

Table S12. Significantly enriched KEGG pathways for the 146 genes under selection in the Himalayan red panda (MH).

Table S13. Significantly enriched GO terms of biological processes for the 146 genes under selection in the Himalayan red panda (MH).

Table S14. The 178 genes under selection with top 5% maximum FST values and top 5% minimum 1/2 values in the Chinese red panda (EH-GLG, XXL-LS, and QL).

Table S15. Significantly enriched KEGG pathways for the 178 genes under selection in the Chinese red panda (EH-GLG, XXL-LS, and QL).

Table S16. Significantly enriched GO terms of biological processes for the 178 genes under selection in the Chinese red panda (EH-GLG, XXL-LS, and QL).

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

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A. Glatston, F. Wei, Than, Zaw, Sherpa, A. Ailurus fulgens. The IUCN Red List of Threatened Species 2015: e.T714A45195924 (2015).

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M. Nei, Molecular Evolutionary Genetics (Columbia Univ. Press, 1987).

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Genomic evidence for two phylogenetic species and long-term population bottlenecks in red pandas - Science Advances

Recommendation and review posted by Bethany Smith

For the last 46,000 years, a small bird that died during the last ice age has sat frozen, shielded from decay and scavengers, until two Russian men hunting for fossil mammoth tusks discovered its body in Siberian permafrost.

The bird was in such good shape, it looked "like it [had] died just a few days ago," said Love Daln, a professor of evolutionary genetics at the Centre for Palaeogenetics in Stockholm, who was with the ivory hunters, Boris Berezhnov and Spartak Khabrov, when they discovered the bird.

"[The bird] is in pristine condition," Daln told Live Science in an email. The find is extraordinary because "small animals like this would normally disintegrate very quickly after death, due to scavengers and microbial activity."

Related: Photos: Is ice age cat mummy a lion or a lynx?

The frozen flier is one-of-a-kind find, too: It's the only near-intact bird carcass documented from the last ice age, Daln added.

When the fossil hunters first uncovered the bird in September 2018, Daln and his colleagues had no idea of the mystery bird's age or species. So, Daln "collected a couple of feathers and a small piece of tissue for radiocarbon dating and DNA sequencing," he said.

He brought the ice age samples to his lab, where postdoctoral researcher Nicolas Dussex, the lead author of a new study on the bird, analyzed the remains.

Radiocarbon dating revealed that the bird lived during the same time as other ice age beasts, including mammoths, horses, woolly rhinos, bison and lynx.

To discover the bird's species, the researchers sequenced its mitochondrial DNA, genetic data that is passed down through the maternal line. Although the bird's mitochondrial DNA was fragmentary there were "many millions of short DNA sequences," Daln said, a common occurrence in ancient specimens the team was able to piece together these short sequences with the help of a computer program.

Then, the scientists took the finished mitochondrial DNA puzzle and searched for a match in an online database that has the genetic sequences of nearly every bird alive today. The results revealed that the ice age bird was a female horned lark (Eremophila alpestris).

This discovery sheds light on the transformation of the so-called mammoth steppe. When this bird was alive, the land was a mix of steppe (unforested grassland) and tundra (treeless, frozen ground), according to pollen records from 50,000 to 30,000 years ago.

When the last ice age ended about 11,700 years ago, the mammoth steppe transitioned into the three main Eurasian environments that exist today: the northern tundra, the taiga (a coniferous forest) in the middle, and the steppe in the south, said Daln, the senior researcher on the new study.

Nowadays, there are two subspecies of horned lark: "one living on the tundra in the far north of Eurasia and the other in the steppe in the south, in Mongolia and its neighboring countries," Daln said.

It appears that the newly discovered bird is an "ancestor of two different subspecies of horned lark," he said. As the environment changed, however, the horned lark diverged into the two evolutionary lineages that exist today, Daln said.

"So all in all, this study provides an example on how climate change at the end of the last ice age could have led to the formation of new subspecies," he said.

The study was published online Feb. 21 in the journal Communications Biology.

Originally published on Live Science.

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46,000-year-old bird, frozen in Siberian permafrost, looks like it 'died a few days ago' - Livescience.com

Recommendation and review posted by Bethany Smith

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When he was 13 years old, a mere boy was effectively the American ambassador to Russia, in Saint Petersburg. This was because the lad was fluent in French while his nominal superior, the ambassador himself, was not. The boy had already, at his fathers instruction, translated works of Plutarch from Greek and poems by Horace from Latin. His name was John Quincy Adams.

When Gian Carlo Menotti was 11 years old, he wrote his first opera, both the libretto and the music: The Death of Pierrot. You may know him for his popular opera Amahl and the Night Visitors. His first formal training in music came when he entered the Milan Conservatory, at age 12.

When he was 14 years old, Srinivasa Ramanujan discovered the general solution to quadratic equations (those of the form ax^4 + bx^3 + cx^2 + dx + e = 0), which had evaded mankind until 1540. Without formal instruction, the boy had already mastered college level mathematics. In this respect, as in his deeply religious sensibility, he was like Pascalwho, according to his sister, played with conic sections when he was a small child.

When he was 15 years old, a very bright Jewish boy living in New York City left school to work for his familys jewelry company. He worked hard and became a vice president, but his real love was poetry. Eventually he left the company and went to Europe to study for three years on his own. His name was Louis Untermeyer, and he was for several generations the single man most responsible for bringing poetry to American schoolchildren.

We have undertaken a great experiment unknown to any society until a hundred years ago. It is the education of boys en masse by women, always indoors and in the company of girls. I think we can say, with reservations, that the experiment has failed.

When he was 13 years old, Thomas Edison, who had hardly ever gone to school but was taught mainly by his mother and through his own reading, was earning fifty dollars a week selling newspapers and candy on the railroad trains in and out of Detroit. He used the profits to buy scientific equipment. He was well on his way to becoming the Wizard of Menlo Park.

When he was four years old, Liberace began to play the piano. At eight, he met the great Paderewski, whose techniques he had been studying assiduously. The two became friends ever after. The boy was his familys main financial support during the Great Depression.

We might multiply examples forever, of boys doing things that astonished their elders: Mozart, Michelangelo, Bach, Haydn, Capablanca, Morphy, and Newton. And shall we forget Our Lord at age 12, spending a couple of days all by Himself in the Temple, engaging the rabbis in debate and stunning them with His questions and answers?

Where are these boys now?

I draw a conclusion that never occurred to me when I was younger. We have undertaken a great experiment unknown to any society until a hundred years ago. It is the education of boys en masse by women, always indoors and in the company of girls. I think we can say, with reservations, that the experiment has failed.

Im not saying that no woman can teach boys, because that is obviously not true. Many a woman can do so very well. There are women who simply like boys and their ways, and who take no perverse delight in trying to force-feed them a feminine etiquette. Such women may prefer to teach Treasure Island to boys than to teach Anne of Green Gables to girls. They will know better than to expect boys to catch fire from stories of gossip and social climbing, however finely written. My observation is of a general truth, not a universal one.

I understand, too, that there is much blame to go around. If in other respects boys had a healthy world to grow up in, their often uninspiring experiences in the schoolroom would not harm them so muchif they all had a father in the home, for instancebut millions do not. If they spent most of their waking hours outdoors, exploring, hunting, fishing, and playingbut school, television, and computers have seen to that. If they were learning to plow the earth, cut down trees, dig wells, or lay pipes alongside older brothers and unclesbut wheres the opportunity, even supposing that the law would permit them to help? If they knew that excellence or competence were necessary for a good young lady to give them a second glancebut porn is a flick of the finger away.

For a long time, a still healthy world mitigated the effects of the experiment and masked the results. No longer. Nor will any demographic objections apply. We are comparing apples with apples. The boys come from the same homes as their sisters, the same schools, and the same social environment. Since the standard deviation for intelligence distribution among males is wider than among females, causing a flatter curve, with males dominating at both the high and the low end, we should expect somewhat more boys to enroll in college, not fewer. But we are not getting anything close to that. It is a terrible waste of mind and talent and energy, and it bodes ill for marriage. Feminists refute themselves performatively when they decline to marry men who are less competent than they are.

If we were talking about any other demographic group so obviously ill-served and so colossally underachieving, with neither poverty nor genetics nor social situation to plead even a specious excuse, there would be a national outcry. There is no such outcry, and this suggests a few things.

If we were talking about any other demographic group so obviously ill-served and so colossally underachieving, with neither poverty nor genetics nor social situation to plead even a specious excuse, there would be a national outcry. There is no such outcry, and this suggests a few things.

One is that nobody cares. If you hire a man to teach English in your school, and the girls languish because they cant stand his manners or the things he chooses to teach, you let that man go; its his fault. If you hire a woman for the same job in the same place, and the boys languish because they cant stand her manners or the things she chooses to teach, she keeps her job as long as she wants; its their fault. Again, I am speaking generally. If some individual boy or girl fails in your class, that may not be your fault. But if a whole group fails, you are not the person for that job.

Our carelessness implies, strangely enough, that we take patriarchy for granted. We speak and act as if boys must assume the entire responsibility for their failures. They are not granted the luxury of expressing anger or frustration. Crocodila feminista may shed big tears about how unfair it is to boys to tell them they must restrain or deny their hurt feelingsrestraint that is in the emotional realm analogous to the restraint they must exercise in the physical realm, restraint without which a lot of weaker people would be hobbling around with black eyes. The same women shed no tears when they imply that boys must like Beloved or lump it. Rather, they seem content to have the boys check out in sullen silence, so they do not have to deal with them and their needs. They are like female pastors of Protestant congregations who, far from being ambitious to lead men in spiritual warfare, are relieved when men do not show up; a few older fellows to tend the roof, the boiler, and the driveway are all they need.

But what if we want the boys to fail? Not, of course, that this boy should fail, a motive that would be outright wicked. I mean that theres something about how we live that fears the fearless man, the far-sighted man, the man for whom all the contemporary pieties are straw. To rob the house, you must bind the strong man first. Strong men and strong women make for strong familiesfor truly strong men and women honor strength in the other sexand strong families can resist and threaten our overlords in politics, education, entertainment, and industry. The conformists of our time are all revolutionary in the same stale, dispirited way, ruining good, old things and then turning to structures of the masses to make up for it. For those in the middle classes and above, the result has been a life of cushioned mediocrityone comfortable with the largely hidden hierarchies that keep man small and tidy, and fearful of the too near and personal hierarchies that can make man fit to participate in greatness.

However that may be, the facts speak for themselves. The experiment has failed. It is time for men to resume the responsibility to educate their sons.

This article first appeared HERE.

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Why Boys Are Failing - Catholic Citizens of Illinois

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The most emotional issue my patients have is hair loss, says New York dermatologist Cheryl Karcher, MD below a jaw-dropping before-and-after photo shared to her Instagram page. On the left half of the photo shared is a young womans exposed hairlinethe hair is so thin and sparse, the entire scalp is visible wherever your eye is drawn. On the right side of the photo, the same woman, but with an almost unbelievable amount of thicker hair, and, somehow, a sense of renewed confidence.

The secret? A little thing called nanofat.

In the past we only had PRP to offer that had to be done three times or more. Sometimes it would work, sometimes it didnt. Now we have nanofat hair restoration, which needs to be done just once, and is much more effective way to treat hair loss and grow hair, explains Dr. Karcher.

You May Also Like: How Low Level Laser Therapy Actually Works to Thicken Hair

So what is nanofat? According to Dr. Karcher, its derived from our own adipose tissue, whereas the ever popular PRP is derived from our blood. Nanofat includes adipose-derived stromal vascular fraction, which contains stem cells as well as growth factors. PRP contains the growth factors released from platelets in the blood, she adds. The procedure itself involves extracting anywhere from 20 to 40 millilitersof fat, usually from the abdomen, then processing it through mechanical filters, before injecting.

Like PRP, the possibilities of what nanofat can help with doesnt stop at the hairline. After the nanofat is processed to the point where there is no fat left, only stem cells and growth factors, it is injected into the scalp, the face, the neck, the decollete, or to improve sun damage, skin pigmentation, decrease wrinkles, and of course grow hair, says Dr. Karcher.

When nanofat is used for hair restoration, Dr. Karcher says she first injects the nanofat, then injects the patients PRP on top of it to act as a fertilizer for the nanofat. Perhaps the best part? Theres little to no painDr. Karcher says the most pain patients feel is during the PRP injections, so the scalp is numbed topicallyand no downtime. When nanofat is used on the face, chest or other areas, Dr. Karcher warns there may be some downtime of erythema and swelling or bruising. If injected for [skin] rejuvenation via microneedling the downtime is only about 48 hours.

While Dr. Karcher has seen unparalleled results from nanofat hair restoration, it is only ideal for patients who have some hair still present on the scalppatients who are completely bald may not be ideal candidates for the procedure. The only time I ever use PRP for hair restoration now is in a patient that doesnt have enough fat to harvest. The nanofat is just one treatment and the results seem to be superior. However, as La Jolla, CA plastic surgeon Robert Singer, MD notes, there is no safety or efficacy data surrounding nanofat treatment as of press time.

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Doctors Are Injecting This Naturally-Derived Substance to Restore Hair Thicknessand Its Not PRP - NewBeauty Magazine

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Treatment for sickle cell disease has come a long way since the 1970s when the life expectancy of people living with it was less than 20 years.

People with sickle cell disease are not only living longer life expectancy is now 42 to 47 years of age but are enjoying a better quality of life, too.

"In the Philadelphia area, there has been great pediatric care for sickle cells disease and because of that people who have it are living very well," said Dr. Farzana Sayani, a hematologist at Penn Medicine.

Sayani is the director of a comprehensive sickle cell program focusing on adults living with the disease. Penn also has an active transition program for youth transitioning from a pediatric institution to adult care.

Sickle cell disease is an inherited red blood cell disorder that affects about 100,000 Americans.It is most often found in people of African or Hispanic descent.About 1 in 365 African-American babies are born with sickle cell disease, according to Sayani.

People who have the disease inherit an abnormal type of hemoglobin in their red blood cells, called Hemoglobin S, from both their mother and father.When only one parent has the hemoglobin S gene, a child will have the sickle cell trait, but usually does not develop the disease. But they may pass it on to their children.

Hemoglobin is the protein in the blood responsible for carrying oxygen to the rest of the body. Hemoglobin S causes red blood cells to become stiff and sickle-shaped. Instead of being round in shape, they look like crescent moons.

Sickle cells are sticky and can bind together, blocking the flow of blood and preventing oxygen from getting where it needs to go in the body. This causes sudden attacks of pain referred to as a pain crisis.

There are severaldifferent types of sickle cell disease.Hemoglobin SS, also known as sickle cell anemia, is the most common and most severe type of sickle cell disease.

Anemia occurs when red blood cells die at a rate faster than the body can replace them. Normal red blood cells generally live for 90 to 120 days. Sickled cells only live for 10 to 20 days. This shorter life-to-death cycle is harder for the body to sustain.

Another form,Hemoglobin SC, is not as severe as sickle cell anemia, but it can still cause significant complications, Sayani said.Other forms include Hemoglobin S0 thalassemia, Hemoglobin S+ thalassemia, Hemoglobin SD and Hemoglobin SE.

Sickle cell disease screening is a mandatory part of newborn screenings in Pennsylvania.

If the screening is positive, the family is informed and plugged into the health care system in order to receive the proper care.

If the disease is not diagnosed at birth, a blood test can confirm it at any age in which symptoms start to surface.

The severity of sickle cell disease can vary.

Each individual is affected differently, making it difficult to predict who will get what complications, Sayani said. That is why a comprehensive sickle cell program is so important.

Early signs include a yellowish tint to the skin or jaundice, fatigue and a painful swelling of the hands and feet.

"Young children with sickle cell disease may be tired, not eat very well and have delayed growth," Sayani said. "They may also develop anemia, be at greater risk of infection and start to experience pain crises."

Acute pain crises, also known as vaso-occlusive crises, can lead to long stays in the hospital to manage the crippling pain. Children with sickle cell disease also tend to experience delayed growth and puberty.

As a person with sickle cell disease grows older, the sickled red blood cells start to affect various organs, bones and joints.

This can lead to acute chest syndrome, which occurs when damaged lung tissues makes it difficult to breathe. Brain complications, including stroke, are possible.People with sickle cell disease are also prone to heart damage, eye problems, and infections like chlamydia, salmonella and staphylococcus. Chronic and acute pain is common.

There are different types of medicine that can help manage sickle cell disease.

Last year, an oral medicine was approved that makes sickle cells less likely to sickle. So was an intravenous medicine that has been shown to reduce pain crises and hospitalizations by 50%. Some people living with sickle cell disease also may need regular blood transfusions.

Hydroxyurea has also been used successfully for many years to reduce pain crises and the need for blood transfusions and hospitalizations.

Currently, blood and bone marrow transplant is the only way to cure the disease. But it is not an option for everyone because of the difficulty of finding a well-matched stem cell donor.

A related donor is best but only about a third of sickle cell patients have a donor that is related and fully-matched, Sayani said.

While these transplants have a 85% or more success rate, they also are associated with significant risks, including organ dysfunction, infection and graft vs. host disease which can be quite debilitating.

Transplants completed in children have the best results, Sayani said. But because of the risks involved, doctors only suggest it for patients with severe forms of the disease.

Early clinical trials with gene therapy are also showing promise, she added.

More:
New sickle cell disease treatments are helping people live longer and giving them a higher quality of life - PhillyVoice.com

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Lance was diagnosed with cerebral palsy a year ago. His family hopes non-FDA approved stem cell treatment for the disease can help him walk and talk.

CAMP HILL, Pa. A family in Cumberland County has turned to stem cells to treat their two-year-old son diagnosed with cerebral palsy. The only problem: stem cell treatment for the disease hasn't been approved by the FDA.

The day he was born, when he wheeled him down the hall and he was only a pound, and I started to cry and said, will he live? And he said, of course Hes only small," said Danielle Maxwell, Lance's mom.

The words, "he's only small," are what Lance's mom and father Rob have lived by since the day he was born. The preemie, born three months early, has been through several surgeries and complications along the way. But, Lance has always been a fighter.

Lance fought so hard just to survive the beginning of life, and come home with us," said Danielle. "And he is just so happy and loving and amazing.

About a year ago, Lance was diagnosed with cerebral palsy. Doctors told his family, he will never walk, talk or take care of himself.

We just dont believe that," said Danielle. "We dont.

Lance receives a lot of different therapies but, his parents did not want to just stop there.

We both overwhelmingly feel, he never gave up, he never gave up on us, he never gave up on himself," said Rob. "So, we owe it to him to give him the opportunity. Its really that simple, he deserves the opportunity."

Danielle began researching stem cell therapies, even speaking to doctors in countries overseas where treatment with stem cells is more readily accessible than in the U.S. The FDA has approved stem cell treatments for some conditions but not cerebral palsy. However, trials to determine the effectiveness of stem cell treatment for the disease are underway.

What weve seen is a small but real appearing improvement in motor function," said Doctor Charles Cox with University of Texas Health in Houston, began a trial in 2013 on the safety and effectiveness of banked cord blood or bone marrow stem cells in children with cerebral palsy, and is now just wrapping up the results from the trial.

The overall results of this study depend if youre a glass half full or half empty kind of person," said Dr. Cox. "It is not a compelling miraculous result. Its not, Oh my God, this child was treated and look at this profound benefit.'"

Because stem cell treatment for cerebral palsy is still in trial phases, it's not approved treatment by the FDA. However, the Maxwells did find a doctor in Harrisburg willing to transfer stem cells from a full-term baby's umbilical cord to Lance. But, since it isn't FDA approved, we were not allowed to be there to show Lance receiving the stem cells. The Maxwells are hopeful following this procedure Lance may someday walk and more importantly be able to communicate with them.

He wants to be involved," said Rob. "You can tell hes trying to communicate he just cant get over that hump. We believe stem cells could be that bridge to help him move a little faster.

Danielle says, it will take about six months to see if the stem cells will have any definitive benefits for Lance. But, already says she's seeing progress. She says Lance is not able to stand on his own.

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Cumberland County family turns to non-FDA approved stem cell treatment to help two-year-old son with cerebral palsy - FOX43.com

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Feb 25, 2020 12:00 AM

Every ten minutes, someone passes away from a blood disorder. Thats 148 people a day. There is a way to prevent many of these deathsa bone marrow transplant. DNA matching has the power to help thousands of people waiting for a life-saving bone marrow donation, but this special donor list depends entirely upon the willingness of individuals to sign up. Could your unique DNA hold the match that helps one person live to see tomorrow? Heres how you can find out.

Be The Match is a global hub for bone marrow donor registry working with hundreds of partners to support the transplant community. Signing up is easy online. You provide registration information, receive a kit in the mail, use the DNA swab as directed, and send it back for DNA typing. Your potentially life-saving information is secure and becomes available to specialized doctors around the world.

Even if you arent a match right away, the fact that every three minutes a person is diagnosed with a blood disorder means you could be called at any time to be a hero in someones time of need. Paloma Cariello, MD, MPH, says, Its absolutely a life-saving procedure. Its a new life that people getwe call it a new birthday, and at many hospitals they give it as a new birthday date in their chart. We sing Happy Birthday. Its a big event.

To find a close enough match to help fortify a patients immune system, doctors have to be precise. They first reach out to family, but even then, only 30% of patients find a good match. The odds of finding a match in an unrelated donor can be as low as 18%, especially with minorities.

The need for more individuals of every background cannot be overstated, says University of Utah Health Hematologist Sagar Patel, MD. He emphasizes the need for ethnic minorities to register. Every ethnicity is represented in the pool of patients, so the donor pool likewise needs to be diversified to improve the availability of similar DNA typing.

If a doctor finds you to be a suitable match, they select the ideal method for their patient and prepare you for donation. There are two donation methods: peripheral blood stem cell (PBSC) donation and bone marrow donation. Because every donor is carefully screened and prepared, and because a small amount of fluid is ultimately needed, neither procedure method impacts the performance of your own immune system, says Cariello.

With PBSC retrieval, you receive a stimulant for five days to increase the presence of blood-forming cells in your blood stream. Then a refined process of extraction occurs: Your blood is drawn, a machine collects just the cells the patient needs, and your remaining fluids are safely returned to you. This process can usually be done in one eight-hour session. Most donors report a full recovery within a week to 10 days, but you will be followed-up with until your full recovery.

If the doctor determines that the patient needs bone marrow, your procedure is a bit different. Marrow needs to be drawn from your pelvic bones. It happens in a hospital and under anesthesia, and you will feel no pain as the donation is collected. You can go back to routine activity the same day, and your system fully replenishes within four to six weeks.

Even with thousands of people in need, only about one in 430 donors in the Be The Match system are called in as a match. And the simple processes and expert professional care you receive minimize potential risk. A common side effect is bruising at the procedure sites, and some donors occasionally experience mild pain, fatigue, or dizziness. Reactions related to the use of anesthesia might also occur.

With such little risk, it shouldnt be a question as to whether you sign up, but when. And today is a perfect day. The low odds of finding a cure that these patients face are as extreme as the high rewards that await themand youwhen you make the choice to become a donor. Visit BeTheMatch.org to learn more and to become the one who initiates the miraculous call: We found a match.

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Be a Bone Marrow Hero - University of Utah Health Care

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Its not just Wolverine that has the ability to rebuild and restore wounded tissue. In fact, we all have a quite remarkable capacity to heal when we suffer an injury, thanks to our ability to produce new stem cells. Obviously, there is a limit to how much damage our bodies can repair, although researchers may have just discovered a way to enhance our powers of restoration by increasing the rate at which these stem cells are generated.

A new study in the journal Regenerative Medicine describes how scientists were able to stimulate the self-repair response of rats in order to rebuild broken spines. Healing similar injuries in humans is currently not possible, and the study authors are hopeful that their technique could one day help people recover from a range of previously untreatable injuries.

Rats in the study were given a cocktail of two drugs, one of which is normally administered during bone marrow transplants while the other is used for bladder control. This caused the rats bone marrow to produce an elevated number of mesenchymal stem cells, which are stem cells that can develop into bone tissue.

As a consequence, enhanced calcium binding was seen at the site of the rats spinal injuries, speeding up the formation of new bone and healing the wounds.

The figure on the right shows the level of healing with no treatment, while the figure on the left shows the effect of the two drugs in combination. The red coloring indicates calcium incorporating into the bone, which is associated with enhanced healing. Image: Imperial College London

We know that when bones break they will heal, and this requires the activation of stem cells in the bone, explained study co-author Sara Rankin in a statement. However, when the damage is severe, there are limits to what the body can do of its own accord.

We hope that by using these existing medications to mobilize stem cells, as we were able to do in rats in our new study, we could potentially call up extra numbers of these stem cells, in order to boost our bodies own ability to mend itself and accelerate the repair process.

Because the drugs involved are already widely used, the researchers are hopeful that human trials can proceed without the need for extensive safety testing. If these trials produce the same results as those seen in rats, then this treatment could help to not only repair spinal injuries, but to speed up the rate at which broken bones heal and even mend damaged tissues in other organs.

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Scientists May Have Found A Way To Boost The Body's Ability To Heal Itself - IFLScience

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A mum has shared the emotional experience of meeting the stranger who saved her son's life.

Alfie Commons, now aged four, was just seven months old when he was diagnosed with leukaemia in 2016.

After three rounds of chemotherapy failed, Alfie received a life-saving bone marrow donation from a school teacher in Germany, who recently made the trip to the UK to meet him.

Alfie's mum, Lorna Commons, 40, of Toton has spoken about the experience in the hope it will encourage more people to sign up to become potential donors.

Looking back to the day of diagnosis, she said Alfie had been to his GP for a third time in February 2016 after suffering a cold since Christmas.

She said: "The GP told us to go to A&E for further tests as he was a little concerned.

"We got to Queen's Medical Centre in the morning and by early evening, we had the diagnosis; Alfie had infant acute lymphoblastic leukaemia (ALL)."

Ms Commons, who works in HR, added: "Even now, four years down the line, I still feel the emotions of that day. Nothing can prepare you."

The plan was to treat Alfie with chemotherapy, but after the first round failed, Ms Commons was told his only chance of survival was to get a bone marrow transplant.

The family was told Alfie was unlikely to leave hospital for the next six months.

She added: "Worse was to follow, his second course also failed and on the same day, we were told that Alfies nine-year-old brother, Billy, wasnt a bloodstemcellmatch for him either.

"The fear of losing Alfie was overwhelming, I felt helpless but I had to carry on for Alfies sake.

The transplant could not go ahead without the cancer being near enough eradicated and even when the good news came that a donor had been located, Alfie still had a mountain to climb.

After a third failed round of chemotherapy, Alfie was put on a trial immunotherapy drug as a '"last ditch attempt". Against all the odds, it worked.

"I think at that point all the doctors and nurses were preparing us for the worst. Your head has to go there," Ms Commons said.

"But then the cancer went, and it was enough to give us the bridge to getting the transplant done."

While the transplant was a success, Alfie suffered for months with Graft versus Host Disease (GvHD) on his skin and in his gut, which is the body's reaction to the new stem cells.

However, doctor's were encouraged the body was gradually accepting the cells and beginning to produce cells of their own.

On February 19, Alfie and his mum were able to meet the woman who saved his life after she made the 600-mile trip.

Christin Bouvier, 34, from Schwerin in Germany, was matched with Alfie after she registered in 2010 with DKMS, a charity dedicated to the fight against blood cancer.

The school teacher had been on the bloodstemcellregister for a number of years before she was contacted and tested as a match for Alfie.

Ms Bouvier said: When they told me that the recipient was a baby I just cried.

"Its a moment that is always with me and whenever I feel a bit down, I think back to it as it always brings me so much happiness!"

Ms Commons said she had been able to contact Ms Bouvier anonymously, as per UK law, but they were permitted to meet two years after the transplant.

Ms Bouvier added: It was always a dream to meet Lorna and Alfie and I never thought it would happen I was so delighted when Lorna invited me. I was very nervous but also very excited to meet them both in person.

"I knew the meeting would be one of those very special moments in my life."

Ms Commons feels the meeting has meant a new chapter has begun in both hers and Alfie's life and she is now focussed on the positives.

She added: "For something so small, there really is no greater gift than being a donor - I get to see my child grow up. To meet Christin, I was able to say 'this is what you've done'.

"We will be in each other's lives forever now - Alfie has her DNA in his blood. But Christin and I also share a special bond, we're just so similar and some people say we even look like sisters.

Alfie is such a special little boy and I truly believe that this story can make a real difference and save more lives.

"There is a match out there for everyone with blood cancer, people just need to come forward and register."

Anyone aged between 17-55 and in general good health can go on standby as a potential lifesaver.

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Mum meets the stem cell donor who saved her four-year-old son's life - Nottinghamshire Live

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Scientists believe that humans will soon be able to recover from injuries such as broken spines, as treatment looks to boost the body's ability to heal itself.

A new study in the journal Regenerative Medicine describes how scientists were able to stimulate the self-repair response in rats.

Rats in the study were given two drugs, one of which is usually given to bone marrow transplant patients, and another which is used for bladder control.

This cocktail caused the rats' bone marrow to produce a greater number of mesenchymal stem cells, the cells which can develop into bone tissue.

As a result, enhanced calcium binding was seen at the site of the rats' spinal injuries, speeding up the production of new bone as well as healing wounds.

The study's authors hope that one day, such treatments will work on humans.

"We know that when bones break they will heal, and this requires the activation of stem cells in the bone," study co-author Sara Rankin from the National Heart and Lung Institute at Imperial College London, said in a statement.

"However, when the damage is severe, there are limits to what the body can do of its own accord.

"We hope that by using these existing medications to mobilise stem cells, as we were able to do in rats in our new study, we could potentially call up extra numbers of these stem cells, in order to boost our bodies' own ability to mend itself and accelerate the repair process."

Both drugs tested on rats are already widely used, so researchers are hopeful human trails can begin soon.

If these trials produce the same results as those seen in rats, then it's hoped the treatment could help to not only repair spinal injuries but also speed up the rate at which broken bones heal and mend damaged tissues in other organs.

Dr Tariq Fellous, first author of the research, said: "We first need to see if these medications release the stem cells in healthy volunteers before we can test them in patients with fractures.

"We have the drugs and know they are safe to use in humans we just need the funding for the human trials."

Dr Andia Redpath, who also co-authored the paper, added that repurposing existing medicines - so-called Regenerative Pharmacology - could have major potential as an efficient and cheaper way of treating diseases.

"Rather than devising new stem cell treatments from scratch that involve lengthy and expensive trials, our approach harnesses the power of the body's own stem cells, using existing drugs.

"We already know the treatments in our study are safe, it's now just a matter of exploring further if they help our bodies heal."

Stem cells are providing incredible new medical breakthroughs all the time.

Earlier this month, scientists trialled 3D-printed skin containing stem cells to treat burns victims .

Continued here:
Humans soon able to regrow spines as body given 'new power to heal itself' - Daily Star

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Over the past few years, there has been a significant increase in the number of bone marrow registries. Increasing awareness, coupled with a rise in promotional campaigns run by healthcare practitioners, is majorly responsible for the rise in the number of bone marrow registries globally. The trend is especially quite prominent in developed regions.

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Major Players operating in market: This report focuses on top manufacturers in global market, with production, price, revenue and market share for each manufacturer, covering: Cellular Biomedicine Group, Cellular Dynamics International, Cesca Therapeutics, CHA Biotech, Chugai Pharmaceutical, CORESTEM, Gamida Cell, Global Stem Cells Group, Hemostemix, Histocell, Mesoblast, TiGenix, Translational Biosciences.

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Bone Marrow Transplant Market report gain strategically significant competitor information, analysis, and insights to formulate effective R&D strategies, identify emerging players with the potentially strong product portfolio and create effective counter-strategies to gain competitive advantage. Bone Marrow Transplant market report identifies potential new clients or partners in the target demographic, develop strategic initiatives by understanding the focus areas of leading companies, plan mergers and acquisitions effectively by identifying key players.

Thus the Bone Marrow Transplant report conclude overall growth of the industry with the product lifecycle over the coming years, market space, market opportunities, market risk, the market overview of the Bone Marrow Transplant. It explains the gap between supply and consumption, tables and figures, SWOT analysis of the leading enterprises in the Bone Marrow Transplant Report.

Market Segment by Regions, regional analysis coversEurope: Germany, France, UK, Russia, Italy and Benelux;Middle East: Saudi Arabia, Israel, UAE and Iran;Africa: South Africa, Nigeria, Egypt and Algeria.

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Reason to Access- Save and reduce time carrying out entry-level research by identifying the growth, size, leading players and segments in the global Bone Marrow Transplant Market- Highlights key business priorities in order to assist companies to realign their business strategies.- The key findings and recommendations highlight crucial progressive industry trends in the Bone Marrow Transplant Market, thereby allowing players to develop effective long term strategies.- Develop/modify business expansion plans by using substantial growth offering developed and emerging markets.- Scrutinise in-depth global market trends and outlook coupled with the factors driving the market, as well as those hindering it.- Enhance the decision-making process by understanding the strategies that underpin commercial interest with respect to products, segmentation and industry verticals.

For more information on this press release visit: http://www.sbwire.com/press-releases/bone-marrow-transplant-lower-risk-of-disease-recurrence-and-significant-rise-in-the-number-of-healthy-donors-drive-the-market-growth-1278593.htm

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Bone Marrow Transplant: Lower Risk of Disease Recurrence and Significant Rise in the Number of Healthy Donors Drive the Market Growth - Press Release...

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