People from across the South East are joining calls from the NHS urging more men to donate blood.

There's a worry not enough male donors are coming forward which could create problems because their cells can be more effective in helping sick people.

Danielle Jinadu knows how important blood donations are.

The 23-year-old law student has the life-threatening genetic disorder sickle cell disease, and needs eight units of blood every six weeks.

Like all patients who receive multiple transfusions, Danielle relies on a safe and secure supply of blood, and male donors help ensure blood is always there.

Danielle, who is studying law at the University of Warwick, said:"For me, blood transfusions are literally the difference between life and death. Without blood transfusions I know I would not be here alive at 23 years old.

"The people that give blood are often the hidden heroes. I will never get to know their names but they are extraordinary."

The NHS is worried though because there's an imbalance in donations.

Last year, only 40% of new blood donors in our region were men.Until the end of November, almost 12,500 women started donating blood in the South East - compared to just over 8,500 men.

Ellie Hudson knows how important male donors are.

Her son Finley needed three specialist blood transfusion when he was born...

He is one of around 120 people in the UK with the condition Diamond-Blackfan anemia which means he cannot produce red blood cells.

The two-year old now has monthly transfusions at Maidstone hospital.

Ellie said: He would go in once a year or so but since Finley was born he goes as regularly as he can. We are so thankful to everyone who donates, they really are lifesavers.

The NHS wants 48% of its donations this year in the South East to be from men.

Mike Stredder, the head of donor recruitment for NHS Blood and Transplant, said:

"All our donors are amazing. But we need more men to start donating blood in the South East during the New Year. Men's blood can be used in extraordinary, lifesaving ways, but we don't have enough new male donors coming forward. This is not about recruiting as many donors as possible - it's about getting the right gender mix.

"If you can't find an appointment right away don't worry - your blood will do extraordinary things if you donate in a few weeks instead."

You can find more information about becoming a blood donor here.

More:
Urgent need for male blood donors in the South East - ITV News

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Jesse Bloom, left, and Lea Starita are genetic scientists pursuing advances with the technique known as Deep Mutational Scanning, which will be the subject of a symposium and workshop at the University of Washington in Seattle on Jan. 13 and 14. (GeekWire Photo / Todd Bishop)

It has been nearly two decades since scientists accomplished the first complete sequencing of the human genome. This historic moment gave us an unprecedented view of human DNA, the genetic code that determines everything from our eye color to our chance of disease, unlocking some of the biggest mysteries of human life.

Twenty years later, despite the prevalence of genetic sequencing, considerable work remains to fulfill the promise of these advances to alleviate and cure human illness and disease.

Scientists and researchers are actually extremely good at reading genomes, but were very, very bad at understanding what were reading, said Lea Starita, co-director of Brotman Baty Institute for Precision Medicines Advanced Technology Lab, and research assistant professor in the Department of Genome Sciences at the University of Washington.

But that is changing thanks to new tools and approaches, including one called Deep Mutational Scanning. This powerful technique for determining genetic variants is generating widespread interest in the field of genetics and personalized medicine, and its the subject of a symposium and workshop on Jan. 13 and 14 at the University of Washington.

I think approaches like Deep Mutational Scanning will eventually allow us to make better countermeasures, both vaccines and drugs that will help us combat even these viruses that are changing very rapidly said Jesse Bloom, an evolutionary and computational biologist at the Fred Hutchinson Cancer Research Center, the Howard Hughes Medical Institute and the University of Washington Department of Genome Sciences.

Bloom, who researches the evolution of viruses, will deliver the keynote at the symposium, held by the Brotman Baty Institute and the Center for the Multiplex Assessment of Phenotype.

On this episode of the GeekWire Health Tech Podcast, we get a preview and a deeper understanding of Deep Mutational Scanning from Bloom and Starita.

Listen to the episode above, or subscribe in your favorite podcast app, and continue reading for an edited transcript.

Todd Bishop: Lets start with the landscape for precision medicine and personalized medicine. Can you give us a laypersons understanding of how personalized medicine differs from the medicine that most of us have encountered in our lives?

Lea Starita: One of the goals of precision medicine is to use the genomic sequence, the DNA sequence of the human in front of the doctor, to inform the best course of action that would be tailored to that person given their set of genes and the mutations within them.

TB: Some people in general might respond to certain treatments in certain ways and others might not. Today we dont know necessarily why thats the case, but personalized medicine is a quest to tailor the treatment or

Starita: To the individual. Exactly. Thats kind of personalized medicine, but you could also extend that to infectious disease to make sure that youre actually treating the pathogen that the person has, not the general pathogen, if you would. How would you say that, Jesse?

Jesse Bloom: I would elaborate on what Lea said when it comes to infectious diseases and other diseases. Not everybody gets equally sick when they are afflicted with the same underlying thing, and people tend to respond very differently to treatments. That obviously goes for genetic diseases caused by changes in our own genes like cancer, and it also happens with infectious diseases. For instance, the flu virus. Different people will get flu in the same year and some of them will get sicker than others, and thats personalized variation. Obviously wed like to be able to understand what the basis of that variation is and why some people get more sick in some years than others.

TB: Where are we today as a society, as a world, in the evolution of personalized medicine?

Starita: Pretty close to the starting line still. Theres been revolutions in DNA sequencing, for example. Weve got a thousand dollar genome, right? So were actually extremely good at reading genomes, but were very, very bad at understanding what were reading. So you could imagine youve got a human genome, its three billion base pairs times two, because youve got two copies of your genome, one from your mother, one from your father, and within that theres going to be millions of changes, little spelling mistakes all over the genome. We are right now very, very, very I cant even use enough verys bad at predicting which ones of those spelling mistakes are going to either be associated with disease or predictive of disease, even for genes where we know a lot about it. Even if that spelling mistake is in a spot in the genome we know a lot about, say breast cancer genes or something like that, we are still extraordinarily bad at understanding or predicting what effects those changes might have on health.

Bloom: In our research, were obviously also interested in how the genetics of a person influences how sick they get with an infectious disease, but we especially focus on the fact that the viruses themselves are changing a lot, as well. So theres changes in the virus as well as the fact that were all genetically different and those will interact with each other. In both cases, it really comes back to what Lea is saying is that I think weve reached the point in a lot of these fields where we can now determine the sequences of a humans genome or we can determine the sequence of a virus genome relatively easily. But its still very hard to understand what those changes mean. And so, thats really the goal of what were trying to do.

TB: What is deep mutational scanning in this context?

Lea Starita: A mutation is a change in the DNA sequence. DNA is just As, Cs, Ts and Gs. Some mutations which are called variants are harmless. You can think of a spelling mistake or a difference in spelling that wouldnt change the word, right? So the American gray, which is G-R-A-Y versus the British grey, G-R-E-Y. If you saw that in a sentence, its gray. Its the color.

But then it could be a spelling mistake that completely blows up the function of a protein, and then in that case, somebody could have a terrible genetic disease or could have an extremely high risk of cancer, or a flu virus could now be resistant to a drug or something like that, or resistant to your immune response. Or, mutations could also be beneficial, right? This is what allows evolution. This is how flu viruses of all the bacteria evolve to become drug resistant or gain some new enzymatic function that it needs to survive.

Bloom: For instance, in the case of mutations in the human genome, we know that everybody has mutations relative to the average human. Some of those mutations will have really major effects, some of them wont. The very traditional way or the way that people have first tried to understand what those mutations do is to sequence the genomes of a group of people and then compare them. Maybe here are people who got cancer and here are people who didnt get cancer and now you look to see which mutations are in the group that got cancer versus the group that didnt, and youll try to hypothesize that the mutations that are enriched in the group that did get cancer are associated with causing cancer.

This is a really powerful approach, but it comes with a shortcoming which is that theres a lot of mutations, and it gets very expensive to look across very, very large groups of people. And so the idea of a technique like deep mutational scanning is that we could simply do an experiment where we test all of the mutations on their own and we wouldnt have to do these sort of complicated population level comparisons to get at the answer. Because when youre comparing two people in the population, they tend to be different in a lot of ways, and its not a very well-controlled comparison. Whereas you can set up something in the lab where you have a gene that does have this mutation and does not have this mutation, and you can really directly see what the effect of that mutation is. Really, people have been doing that sort of experiment for many decades now. Whats new about deep mutational scanning is the idea that you can do that experiment on a lot of mutations all at once.

Starita: And its called deep because we try to make every possible spelling mistake. So every possible change in the amino acid sequence or the nucleotide sequence, which is the A, C, Ts and Gs, across the entire gene or the sequence were looking at.

Bloom: Lets say we were to compare me and Lea to figure out why one of us had some disease and other ones didnt. We could compare our genomes and theres going to be a lot of differences between them, and were not really going to know what difference is responsible. We dont even really know if it would be a change in their genomes thats responsible. It could be a change in something about our environment. So the idea behind deep mutational scanning is we would just take one gene. So in the case of Lea, she studies a particular gene thats related to breast cancer, and we would just make all of the individual changes in that gene and test what they do one by one. And then subsequently if we were to see that a mutation has some effect, if we were to then observe that mutation when we sequenced someones genome, we would have some idea of what it does.

Starita: The deep mutational scanning, the deep part is making all possible changes. We have all of that information at hand in an Excel file somewhere in the lab that says that this mutation is likely to cause damage to the function of the protein or the activity of the protein that it encodes. Making all of the possible mutations. Thats where the deep comes from.

TB: How exactly are you doing this? Is it because of advances in computer processing or is it because of a change in approach that has enabled this increase in volume of the different mutations you can look at?

Bloom: I would say that theres a number of technologies that have improved, but the really key one is the idea that the whole experiment can be done all at once. The traditional, if you were to go back a few decades way of doing an experiment like this, would be take one tube and put, lets say the normal or un-mutated gene variant in that, and then have another tube which has the mutant that you care about, and have somehow do an experiment on each of those two tubes and that works well.

But you can imagine if you had 10,000 tubes, it might start to become a little bit more difficult. And so the idea is that really the same way that people have gotten very good at sequencing all of these genomes, you can also use to make all of these measurements at once. The idea is you would now put all of different mutants together in the same tube and you would somehow set up the experiment, and this is really the crucial part of the whole thing, set up the experiment such that the cell or the virus or whatever youre looking at, how well it can grow in that tube depends on the effect of that mutation. And then you can just use the sequencing to read out how the frequencies of all of these mutations have changed. You would see that a good mutation that lets say helped the cell grow better would be more representative in the tube at the end, and a bad mutation would be less representative in the tube. And by doing this you could in principle group together tens of thousands or even hundreds of thousands or millions of mutations all at once and read it all out in one experiment.

Starita: This has been enabled by that same revolution that has given us the thousand dollar genome. These DNA sequencers that were now using, not really to sequence human genomes, but were using them as very expensive counting machines. So, were identifying the mutation and were counting it. Thats basically what were using the sequencers for. Instead of sequencing human genomes, were using them as a tool to count all of these different pieces of DNA that are in these cells.

TB: At what stage of development is deep mutational scanning?

Starita: It started about 10 years ago. The first couple of papers came out in 2009 and 2010 actually from the Genome Sciences department at University of Washington. Those started with short sequences and very simplified experiments, and we have been working over the years to build mutational scanning into better and more accurate model systems, but that are increasing the complexity of these experiments. And so weve gone from almost, Hey, thats a cute experiment you guys did, to doing impactful work that people are using in clinical genetics and things like that.

TB: When youre at a holiday party and somebody asks you what you do and then they get really into it and they ask you, Wait, what are the implications of not only personalized medicine but this deep mutational scanning? Whats this going to mean for my life?

Starita: Right now it hasnt been systematically used in the clinic, but well get phone calls from UW pathology that says, Hey, I have a patient that has this variant. We found the sequence variant and this patient has this phenotype. What does this mutation look like in your assay? And were like, Well, it looks like its damaging. And then they put all of that information together and they can actually go back to that patient and say, You are at high risk of cancer. Were going to take medical action. That has happened multiple times. Were working right now to try to figure out how to use the information that we are creating. So these maps of the effect of mutations on these very important proteins and how to systematically use them as evidence for or against their pathogenicity. Right now for a decent percentage of these people who are telling them, Well, youve got changes but we dont know what they do. We want those tests to be more informative. So you go, you get the test, they say, That is a bad one. That ones fine. That mutation is good. That ones OK. That one, though. That ones going to cause you problems. We want more people to have more informative genetic testing because right now in a decent proportion of tests come back with an I have no idea, answer.

Bloom: You can also think about mutations that affect resistance to some sort of drug. For many, many types of drugs, these include drugs against viruses, drugs against cancers and so on, the viruses and the cancers can become resistant by giving mutations that allow them to escape from that drug. In many cases there are even multiple drugs out there and you might have options of which drug to administer, but you might not really know which one. Clinicians have sort of built up lore that this drug tends to work more often or you try this one and then you try this other one, but because how well the drug works is probably in general determined by either the genetic mutations in lets say the cancer or the person or the genetic mutations in the virus or pathogen, if you knew what the effects of those mutations were ahead of time, you could make much more intelligent decisions about which drugs to administer. And there really shouldnt be a drug that works only 50 percent of the time; youre probably just not giving it in the right condition 50 perfect of the time. Wed like to be able to pick the right drug for the right condition all the time.

TB: And thats what precision medicine is about.

Starita: Yes.

TB: Deep mutational scanning as a tool.

Starita: To inform precision medicine.

Bloom: These deep mutational scanning techniques were really developed by people like Jay Shendure and Stan Fields, and Lea and Doug Fowler to look at these questions of precision medicine from the perspective of changes in our human genomes affecting our susceptibility to diseases. I actually work on mutations in a different context, which has mutations in the viruses that infect us and make us sick. These viruses evolve quite rapidly. In the case of flu virus, youre supposed to get the flu vaccine every year. The reason why you have to get it every year is the virus is always changing and we have to make the vaccine keep up with the virus. The same thing is true with drugs against viruses like flu or HIV. Sometimes the viruses will be resistant, sometimes the drugs will work. These again have to do with the very rapid genetic changes that are happening in the virus. So, were trying to use deep mutational scanning to understand how these mutations to these viruses will affect their ability to, lets say, escape someones immunity or escape a drug that might be used to treat that person.

TB: How far along are you on that path?

Bloom: Were making progress. One of the key things weve found is that the same mutation of the virus might have a different impact for different people. So we found using these approaches that the ways that you mutate a virus will allow the virus sometimes to escape from one persons immunity much better than from another persons immunity. And so were really right now trying to map out the heterogeneity across different people. And hopefully that could be used to understand what makes some people susceptible to a very specific viral strain versus other people.

TB: And so then would your research extend into the mutations in human genes in addition to the changes in the virus?

Bloom: You could imagine eventually wanting to look at all of those combinations together, and we are very interested in this, but the immediate research were focusing on right now actually probably is not so much driven by the genetics of the humans. In the case of influenza virus, like I was saying, we found that if theres a virus that has some particular mutation, it might, lets say, allow it to escape from your immunity but not allow it to escape from the immunity of me or Lea. That doesnt seem to be driven as much we think by our genetics, but rather our exposure histories. So in the case of influenza, were not born with any immunity to influenza virus. We build up that immunity over the course of our lifetime because we either get infected with flu or we get vaccinated with flu and then our body makes an immune response, which includes antibodies which block the virus. Each of us have our own personal history, not genetic history, but life history of which vaccinations and which infections weve gotten. And so, that will shape how our immune response sees the virus. As a result, we think that that doesnt really have so much of a genetic component as a historical component.

TB: Just going with the flu example, could this result in a future big picture where I go in to get my flu vaccine and its different than the one the next person might go in to get?

Bloom: What we would most like to do is use this knowledge to just design a vaccine that works for everybody. So that would just be the same vaccine that everyone could get. But its a very interesting I think at this point I would say its almost in the thought experiment stage to think about this. When you think of something like cancer, like Lea was saying, you can use these tools to understand when people have mutations that might make them at risk for a cancer, but thats actually often a very hard thing to intervene for, right? Its not so easy to prevent someone from getting cancer even if you know theyre at risk. But obviously if people are able to do that, theyre interested in spending a lot of money to do it, because cancer is a very severe thing and you often have a very long window to treat it.

Something like a flu virus is very much at the other end. If I had the omniscient capability to tell you that three days from now youre going to get infected with flu and youre going to get really sick, we could prevent that. We have the technology basically right now to prevent that, if its nothing else than just telling you to put on a bunch of Purell and dont leave your bedroom. But theres also actually some pretty good interventions including prophylactics to flu that work quite well. But the key thing is, right now we think of everyone in the world as being at risk all the time and you cant be treating everybody in the world all the time against flu. Theres just too many people and the risk that any person

Starita: Not that much Tamiflu on the market.

Bloom: Not that much, and the risk of it So I think to the extent that we could really identify whos at the most risk in any given year, that might allow us to use these interventions in a more targeted way. Thats the idea.

TB: And how does deep mutational scanning lead to that potentially?

Bloom: Yeah. So the idea, and at this point, this is really in the research phase, but the idea is if we could identify that say certain people or certain segments of the population, that because of the way their immunity, lets say, is working makes them very susceptible to the viral mutant that happens to have arisen in this particular year, we could then somehow either suggest that theyre more at risk or, as you suggested, design a vaccine thats specifically tailored to work for them. So thats the idea. I should make clear that that is not anywhere close to anybody even thinking of putting it into economic practice at this point because even the concepts behind it are really quite new. But I do think that theres a lot of potential if we think of these infectious diseases not so much as an act of God, where you just happened to someone sneezed on you as youre walking down the street, but actually a complex interaction between the mutations in the virus and your own either genetics or immune system, we can start to identify who might be more at risk for certain things in certain years, and that would at least open the door to using a lot of interventions we already have.

Starita: The first year was three years ago, and some very enthusiastic graduate students started it. Basically, it was almost like a giant lab meeting where everybody who is interested in this field came. Somebody tweeted it out and then all of a sudden people from UCSF were there and were like, What the heck? It was great and we all talked about the technology and how we were using it. The next year, the Brotman Baty Institute came in and were like, OK, well, maybe if we use some of this gift to support this, we can have a bigger meeting. And then it was 200 people in a big auditorium and that was great. And now this year, its a two-day symposium and workshop, and its also co-sponsored by a grant from the National Human Genome Research Institute. But now weve got hundreds of people, so about 200 people again, but now flying in from all over the world. Weve got invited speakers, and the workshop, which is Tuesday, is a more practical, If youre interested in this, how do you actually do these experiments?

TB: Whats driving the interest in deep mutational scanning?

Bloom: We are starting to have so much genetic information about really everything. It used to be, going back a couple of decades, a big deal to determine even the sequence of a single flu virus. It was totally unthinkable to determine the sequence of a human genome, right? If you dont know what mutations are there, you dont really care that much what they do. Now we can determine the sequence of tens of thousands of flu viruses. I mean, this is happening all the time, and we can determine the sequence of thousands, even tens of thousands of human genomes. So now it becomes, as Lea said, really important to go from just getting these sequences to understanding what the mutations that you observe in these sequences actually will mean for human health.

See this site for more on the Brotman Baty Institute for Precision Medicine and the Deep Mutational Scanning Symposium and Workshop, Jan. 13 and 14 in Seattle. The symposium is free to attend if youre in the Seattle area, and it will also be livestreamed, with archived video available afterward.

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Scientists pursue new genetic insights for health: Inside the world of deep mutational scanning - GeekWire

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Ultragenyx Pharmaceutical saw its shares jump around 27% in trading Friday after announcing positive top-line data out of its gene therapy trial.

Its a small number, just three patients that form part of a third cohort for the phase 1/2 study, as well as another small test but a longer-term look from the second cohort.

In cohort three testing the biotechs drug DTX301, an adeno-associated virus gene therapy for the treatment of ornithine transcarbamylase (OTC) deficiency, there were two confirmed female responders as well a third potential male responder who requires longer-term follow-up to confirm response status.

The Art of Recognizing Clinical Supply Risk Factors and Applying Proactive Measures to Avoid Study Delays and Disruptions

No two studies are the same and each clinical supply project carries unique risks. But what characteristics are most likely to raise a flag that issues are ahead? Are there certain types of clinical sponsors and studies that are at greater risk of experiencing supply challenges? And how do clinical sponsors know what is important to focus on and what is not? Join us for this webinar as we attempt to answer these questions.

Meanwhile, in cohort two, one female patient saw a new response after a year. The biotech added that the two previously disclosed responders in cohort one and two also remain clinically and metabolically stable at 104 and 78 weeks, respectively. Across all nine patients dosed in the study, up to six patients have demonstrated a response, it said in a statement.

RELATED: BIO: In conversation with Emil Kakkis, Ultragenyx CEO

OTC deficiency is a rare X-linked genetic disorder characterized by complete or partial lack of the enzyme OTC. Excess ammonia, which is a neurotoxin, travels to the central nervous system through the blood,

According to the National Organization for Rare Disorders, the severity and age of onset of OTC deficiency vary from person to person, even within the same family. A severe form of the disorder affects some infants, typically males, shortly after birth (neonatal period). A milder form of the disorder affects some children later in infancy. Both males and females may develop symptoms of OTC deficiency during childhood. Most carrier females are healthy, but may be prone to severe headaches following protein intake.

Analysts at Jefferies said the data looked better than expected and could be a positive spark to help turn the stock heading into 2020 events. It certainly did in the immediate term, with the biotechs shares up by 27% in mid-morning trading Friday.

We are encouraged to see a more uniform response at the higher doses including three female responders. To date, three patients in the study have discontinued alternate pathway medication and liberalized their diets while remaining clinically and metabolically stable, said Eric Crombez, M.D., chief medical officer of the Ultragenyx Gene Therapy development unit.

We are moving to prophylactic steroid use in the next cohort as we believe this could further enhance the level and consistency of expression that we have demonstrated so far.

See more here:
Ultragenyx shares jump on 'better than expected' gene therapy data - FierceBiotech

Recommendation and review posted by Bethany Smith

A B.C. transgender teens bid to obtain hormone therapy was legal, B.C.s Court of Appeal ruled unanimously Jan. 10 in supporting a lower court decision.

The child A.B. is able to assert his rights, and has done so in accordance with the law, Chief Justice Robert Bauman and Justice Barbara Fisher wrote in the decision.

The 15-year-old A.B. was born female but wanted to pursue therapy, a move approved by his mother, E.F., but not by his father, C.D. The parents are separated but share parenting duties.

Doctors found A.B. sufficiently mature to make the treatment decision on his own, and C.D. began legal action.

The appeal court had to examine three Supreme Court of BC orders before arriving at its conclusion that ABs consent to that treatment is valid, and no further consent from his parents, in particular CD, is required in that regard.

A February 2019 order declared A.B. validly able to consent to treatment, and that referring to A.B. as a girl or attempting to convince him to halt treatment would be considered family violence under the Family Law Act.

An April 2019 protection order restricted the fathers ability to speak with others, including media outlets and A.B., about his decision to receive therapy.

And, a July 2019 order dismissed C.D.s action initiated by C.D. as vexatious and an abuse of process.

The father appealed.

He claimed the orders violated his Charter-protected freedoms of belief and expression and what he terms parental rights, were procedurally unfair, and not in his childs best interests.

A.B., however, said the decisions were Charter-compliant and in his best interests as well as the statutory right of mature minors to make their own medical decisions.

His mother supported that claim.

The decision said A.B. has identified as male since he was 11 years old and began socially transitioning at 12, enrolling in school under a chosen male name and using male pronouns with his teachers and peers.

Around 13 years of age, after two years of consistently identifying as male, ABs persistent discomfort with his body led him to want to take steps to appear more masculine, the court said.

He was soon diagnosed with gender dysphoria, a recognized medical condition where a person experiences significant distress because the gender identity they experience differs from their genetic or biological gender, and how others perceive them, the court said.

A doctor said he could be a good candidate for treatment and another found such treatment was reasonable and in his best interests.

The process stopped once doctors found out about C.Ds opposition.

Doctors explained to C.D. that minors are permitted to consent to their own medical treatment under a section of the Infants Act.

One doctor asked for an opinion from the Provincial Health Services Authority Ethics Service, which agreed that A.B. demonstrated capacity to understand the treatment.

The teen was further referred to the B.C. Mental Health Centre, which found that he demonstrated detailed understanding of the risks and benefits of the treatment, and that he displayed reasonable judgment and insight.

C.D. filed suit to stop treatment in late 2018. Treatment was ordered stopped until the case could be heard.

The court said where a child has consented to health care under the Infants Act, the Family Law Act doesnt provide authority to start consideration of the childs best interests over medical treatment.

The court said the father continually disrespected his childs choices and in seemed oblivious to the effect of his behaviour on A.B. But, the court added, such effects did not rise to the level of family violence.

The court said C.D.s claims he parental rights under the Charter had been violated had no merit.

jhainsworth@glaciermedia.ca

@Jhainswo

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Trans teen can decide on hormone therapy, court rules - The Tri-City News

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INTRODUCTION

Congenital defects are a leading cause of morbidity worldwide, accounting for the deaths of 330,000 newborns every year. Brain malformations, including microcephaly and holoprosencephaly (HPE), are the most common congenital anomalies and place a heavy burden on the affected individuals and the health care system (13). HPE is a structural anomaly of the developing forebrain affecting 1:250 embryos and 1:16,000 live-born infants. Clinically, HPE encompasses a continuum of brain malformations and is accompanied with a spectrum of craniofacial defects in 80% of the cases; microcephaly and eye defects are among the most common features in affected individuals (4). In the majority of cases, the underlying cause remains uncertain due to the high complexity and the multigenic origin of these anomalies (5, 6). Lately, it has become clear that HPE is caused by a malfunction in key signaling pathways in the early embryo, leading to developmental defects in the organizing centers and midline structures (7). The defects involve a sequence of developmental steps that begin with Nodal signaling to establish the midline progenitors in the developing primitive streak (PS). It then continues with the proper positioning of the forming prechordal plate beneath the neuroectoderm and activation of midline Hedgehog signals to maintain the anterior identity of the forebrain. However, the restriction of HPE genetic determinants to a handful of NODAL and Sonic hedgehog (SHH) pathway regulators stems from our limited understanding of the molecular events governing specification of early and late midline structures. Expansion of this genetic repertoire has become a necessity to develop therapeutic options and improve molecular diagnosis of HPE.

Genes encoding transcription factors (TFs) and epigenetic regulators are relevant etiological candidates given their central role in integrating signaling cascades and orchestrating multiple biological processes. Deficiency in their function can disturb entire transcriptional programs, involving numerous genes and molecular pathways, leading to a complex pathological outcome. Consistent with this hypothesis, we have recently identified a loss-of-function (LOF) mutation in the transcriptional regulator PRDM15 in patients with a syndromic form of HPE. Here, we combine mouse genetics and epigenomic approaches to uncover the role of this TF in congenital brain malformations. Our findings establish PRDM15 as a key regulator of NOTCH and WNT/PCP pathways in the developing embryo, implicating them in regulation of anterior/posterior (A/P) patterning and forebrain development. In addition, we uncover new genetic variants in key components of these signaling pathways in patients with HPE. Collectively, our findings refine the molecular mechanisms governing forebrain development and set the stage for the identification of new HPE candidate genes.

Homozygosity mapping and whole-exome sequencing on patients with steroid resistant nephrotic syndrome (SRNS) identified three recessive mutations in PRDM15 (NM_001040424.2). These mutations are located in the sequences coding for the PR domain (c.461T>A; p.Met154Lys-M154K and c.568G>A; p.Glu190Lys-E190K) and the 15th zinc finger (c.2531G>A; p.Cys844Tyr-C844Y), respectively (Fig. 1A). Of particular interest, in four consanguineous families that have the variant encoding PRDM15 C844Y, the affected probands exhibited a syndromic form of SRNS consistent with the Galloway-Mowat syndrome (8). Besides renal defects, the patients displayed facial (narrow forehead, microcephaly, abnormal cerebral gyration, and ophthalmic abnormalities) and extracranial defects (heart malformations and postaxial polydactyly) (9).

(A) Schematic representation of the PRDM15 mutation positions and the affected domains. (B) Alkaline phosphatase (AP) staining of ESCs; the respective genotypes are indicated in the lower panel. Data are average of four independent cell cultures (n = 4) SD. Statistical tests were applied on differences observed in the percentage of completely undifferentiated colonies. Students t test (two sided) was used to determine significance. (C) Heat map of differentially expressed genes in ESCs upon the indicated genetic manipulations. (D) mRNA levels of Rspo1 in ESCs; the respective genotypes are indicated by color code. Expression levels were normalized to Ubiquitin (Ubb), and Prdm15fl/fl (empty vector) was used as reference. Data shown are from three independent experiments (n = 3). (E) Enrichment of PRDM15 binding on promoter regions of the target gene (Rspo1) in ESCsrespective genotypes are indicated by color codeas measured by ChIP-qPCR. Depicted is the average enrichment [data from three independent cell cultures (n = 3)] over percent of input. In (B) to (E), the endogenous mouse Prdm15 has been deleted by the addition of OHT (50 nM) after ectopic expression of WT or mutant human PRDM15 (hPR15). In (D) and (E), center values, mean; error bars, SD. Students t test (two sided) was used to determine significance.

We have recently demonstrated that PRDM15 regulates the transcription of Rpso1 and Spry1, two key components of the MAPK (mitogen-activated protein kinase)/ERK (extracellular signalregulated kinase) and WNT pathways, to maintain nave pluripotency of mouse embryonic stem cells (mESCs) (10). To evaluate the effects of these mutations on PRDM15 function, we ectopically expressed the three identified human variants in Prdm15-deficient embryonic stem cells (ESCs) (Prdm15/). Only hPR15-C844Y, which is associated with brain defects in humans, failed to restore ESC self-renewal (Fig. 1B), and most importantly, the global changes in gene expression, induced by loss of endogenous PRDM15 (Fig. 1C and table S1 (A to E)]. These data strongly suggest that hPR15-C844Y is a LOF mutation. While hPR15-M154K and hPR15-E190K rescued Rspo1 expression at levels comparable to the wild-type (WT) human PRDM15 (hPR15-WT), hPR15-C844Y failed to restore its transcript levels [quantitative polymerase chain reaction (qPCR)] and to activate its transcription in a luciferase reporter assay (Fig. 1D and fig. S1A).

To gain further insights into the impact of these mutations on PRDM15 function, we tested the stability of the encoded proteins and their cellular localization. Immunofluorescence staining, in a Prdm15/ background, showed that none of the mutations affected the nuclear localization of PRDM15 (fig. S1B). On the other hand, all three mutants encoded less stable proteins (fig. S1C). We have previously shown that the zinc finger domains are required for DNA binding and transcriptional activity of PRDM15 (10). Thus, we sought to test the ability of the various mutants to bind to chromatin. Consistent with an LOF of the zinc finger mutant, chromatin immunoprecipitation (ChIP)qPCR analysis revealed reduced enrichment of hPR15-C844Y at the promoter region of Rspo1 (Fig. 1E), a result compatible with its inability to promote its transcription (Fig. 1D and fig. S1A).

To gain molecular insights on the effects of PRDM15 LOF during mammalian development, we intercrossed Prdm15lacZ/+ heterozygous mice, which are healthy and fertile. A description of all the Prdm15 alleles and deleter strains used in this study is summarized in fig. S2A. Consistent with a fundamental role of PRDM15 during embryonic development, we obtained no homozygous mutant [Prdm15lazZ/lacZ knockout (KO)] pups (Fig. 2A), while of the hundreds Prdm15lacZ/+ embryos that were dissected at various stages of development, none showed any defects. Timed matings revealed the embryonic lethality of Prdm15lazZ/lacZ (KO) embryos occurs between embryonic days 12.5 (E12.5) and E14.5 (Fig. 2A). Notably, at E12.5, KO embryos were smaller and showed a spectrum of brain malformations affecting predominantly the anteriormost structures of the head, including the eyes (Fig. 2B), consistent with the brain and facial features observed in patients with the C844Y mutation. Coronal sections of the brain at this stage confirmed that the lateral and medial ganglionic eminences were underdeveloped. Furthermore, we noted an abnormal separation of the cerebral hemispheres, reminiscent of HPE (Fig. 2C). Classic HPE encompasses a continuum of brain anomalies caused by neural tube patterning defects that affect the anteriormost structures and is often accompanied by craniofacial defects involving the eyes (4, 11, 12).

(A) Genetic distribution of embryos from Prdm15+/LacZ intercrosses, indicating lethality between E12.5 and E14.5. (B) Phenotypic continuum of brain defects in E12.5 Prdm15lacZ/lacZ KO embryos. (C) Hematoxylin and eosin (H&E) staining of serial coronal sections of E12.5 brains from Prdm15+/+ WT (upper panel) and Prdm15lacZ/lacZ KO (lower panel) embryos. The mutants lack the complex organization of the anterior forebrain, including the lateral (LGE) and medial ganglionic eminences (MGE), the epithalamic and dorsal thalamic neuropeithelium (NE), and eyes. (D) Nestin-Cremeditated deletion of Prdm15 in neuronal precursors does not affect brain development. Representative images are shown in (B) to (D). LGE/MGE, lateral and medial ganglionic eminences; NE, neuropeithelium; NCX, neocortex; E, eye; LV, lateral ventricle; V, ventricle; TOT, total. (B and D) Photo credit: Messerschmidt and Mzoughi.

These results prompted us to delete Prdm15 specifically in the developing brain by crossing Prdm15fl/fl mice to the Nestin-Cre deleter strain. This Cre recombinase is active at ~E11 in neural stem cells/progenitors and would reveal whether PRDM15 is essential for the process of neurogenesis. The resulting Prdm15/::Nestin-CRE embryos did not show any apparent defects at E12.5 (Fig. 2D), were born at the expected Mendelian ratios, and developed into healthy adults (fig. S2B). This suggests that PRDM15 is required at earlier time points of forebrain specification.

Defects in Prdm15 KO embryos are apparent before the onset of neurulation, as mutants were markedly smaller and had an abnormal morphogenesis by E7.5 (fig. S3A). Between E6.5 and E7.5, two signaling centers act sequentially to pattern the forebrain in the mouse embryo (Fig. 3A) [reviewed in (1315)]. The first resides within the extraembryonic lineages and is called the anterior visceral endoderm (AVE). The AVE imparts anterior identity to the underlying epiblast, thereby restricting the site of gastrulationthe PSto the posterior epiblast. During gastrulation, a second specialized population of cells, known as the AME, emerges from the anterior PS (APS). These cells migrate anteriorly, giving rise to the anterior definitive endoderm and prechordal plate mesoderm. Their role is to produce secondary inductive cues that reinforce anterior identity in the overlying neural plate (Fig. 3A).

(A) Schematic of the signaling centers governing A/P patterning in the mouse embryo. (B) At E6.5, Foxa2 is expressed in the AVE (red line) and APS (red asterisk). At E7.5, Lhx1 transcripts label the visceral endoderm (VE) overlying the epiblast including the AVE as well nascent mesoderm and midline axial mesendoderm. In Prdm15 mutants (mut), Foxa2 expression is confined to the distal VE, with little enrichment in the prospective AVE. Lhx1 is detected in the VE and mesoderm of the middle Prdm15 mutant, but only in the VE of the one on the right. (C) Expression of T, Lefty2, Foxa2, Chordin, and Shh in WT and Prdm15lacZ/lacZ embryos at E7.5. In Prdm15 mutants, T is expressed normally in the PS; Lefty2 transcripts are down-regulated in nascent mesoderm; Foxa2 and Chordin expression remains high distally in the region of the APS (angled black-dashed line) but does not extend anteriorly in the midline axial mesendoderm (am); and Shh expression is similarly weak in the anterior midline (asterisk). n, node. (D) Expression of Six3/Shh or Otx2/Shh in WT (upper) and Prdm15lacZ/lacZ KO (lower) embryos at E8.5. Six3 and Otx2 expression highlights the reduction in anterior forebrain (fb) development (angled black dashed lines) in Prdm15lacZ/lacZ KO mutants. no, notochord; mb, midbrain; DVE, Distal Visceral Endoderm. Representative images are shown in (B) to (D). (C and D) Photo credit: Dun and Ong.

We reasoned that loss of PRDM15 might impair forebrain specification during the earliest events of anterior patterning and therefore examined the expression of a panel of marker genes diagnostic for defects in either the AVE or AME in Prdm15 KO embryos. Foxa2 is a marker of both, AVE and APS, in early PS stage embryos at E6.5. In Prdm15 KO embryos, in situ labeling shows expression in the distal visceral endoderm overlying the epiblast in a pattern typically observed 1 day earlier in WT embryos (Fig. 3B) (16). We conclude that Prdm15 KO embryos are developmentally delayed even before gastrulation. At E7.5, Lhx1 is expressed in the nascent mesoderm and anterior midline mesendoderm. In the smaller, delayed Prdm15 KO littermate embryos, Lhx1 is expressed normally throughout the visceral endoderm, including the AVE, as well as in the nascent mesoderm (Fig. 3B) (17, 18). Both FOXA2 and LHX1 are required for the formation and function of the AVE, and their activation provides evidence that the initial specification of the primary anterior-posterior axis by the AVE is normal in Prdm15 KO embryos.

We next examined the expression of PS (T and Lefty2) and AME (Foxa2, Chordin, and Shh) marker genes. By E7.5, Prdm15 KO embryos are easily recognizable due to a characteristic ruffling in the extraembryonic visceral endoderm, with a fully extended PS that expresses both T and Lefty2 (Fig. 3C). At this stage, Foxa2 is expressed in the node, which marks the anterior end of the PS, and the AME that extends rostrally in WT embryos. In contrast, in Prdm15 KO embryos, Foxa2 transcripts are present distally but do not extend anteriorly (Fig. 3C). A similar pattern is observed with Chordin, which also labels the node and AME in WT embryos but is confined to the APS in Prdm15 KOs (Fig. 3C). Shh expression is also diagnostic for the node and AME, but in KO embryos, only a few Shh-positive cells are observed along the anterior midline (Fig. 3C). Together, these results show that loss of PRDM15 specifically affects the production of the anterior AME. Consequently, the crucial refining signals produced by these cells that orchestrate the continued patterning and morphogenesis of the anterior neuroectoderm are lost, resulting in anterior truncations that are evident by diminished forebrain expression of Six3 and Otx2 in Prdm15 KO mutant embryos at E8.5 (Fig. 3D). To further corroborate these findings, we deleted Prdm15 specifically in the epiblast, using the Sox2-Cre transgene (fig. S3B) (19), while maintaining WT extraembryonic tissues. Consistent with an essential role for PRDM15 in the PS-derived AME and not AVE specification, Prdm15/::Sox2-CRE embryos died in utero starting at E12.5 (fig. S3C) and exhibited a spectrum of brain defects similar to those observed in Prdm15 KO embryos (fig. S3D).

To examine the impact of PRDM15 depletion on early embryonic processes, namely, A/P patterning, we sequenced the transcriptome of WT versus Prdm15 KO E6.5 embryos. We reasoned this could be the most critical stage for AME specification as AME cells emerge less than 24 hours later. Unbiased clustering of global gene expression separated WT versus Prdm15 KO embryos into distinct groups, indicating marked transcriptional differences (Fig. 4A and table S1F). Gene ontology (GO) analysis of the significantly down-regulated genes identified Pattern specification process, Head development, and Neural tube development among the enriched terms. Among these genes, several are important regulators of forebrain development and A/P patterning (Fig. 4B and fig. S4A, and table S1, G to H). We noted a striking reduction in the expression of key components of three signaling pathways: WNT, NOTCH, and SHH (Fig. 4C, fig. S4B, and table S1, I and J).

(A) Unbiased clustering heat map of the entire transcriptome in WT (n = 8) versus Prdm15lacz/lacz KO (n = 10) E6.5 embryos, analyzed by RNA sequencing. Heat maps of differentially expressed genes from the indicated GO categories (B) and KEGG pathway (C) identified as top hits in the RNA sequencing. Light and dark blue rectangles on the right side indicate genes whose promoter region is directly bound by PRDM15 in ESCs only or both in ESCs and E6.5 embryos, respectively. (D) Snapshots of representative PRDM15 ChIP tracks (UCSC genome browser). Examples of conserved target genes (binding sites) between E6.5 embryos (blue) and ESCs (orange) are shown.

We have recently shown that PRDM15 recognizes a defined DNA motif present at promoters or enhancers of target genes (10). To define the set of direct PRDM15 transcriptional targets, we performed ChIP sequencing (ChIP-seq) on mESCs and WT E6.5 embryos (table S1, K and L). Despite the limited biological material available from the pre-gastrula embryos, we identified 58 high-confidence promoter-bound targets, the majority of which (~84%) were also bound by PRDM15 in ESCs (Fig. 4D, fig. S4C, and table S1M). In addition, identification of the same PRDM15 consensus binding motif in both systems implies a conservation of its targets. We therefore chose to consider PRDM15-bound promoters identified in ESCs as relevant for our follow-up analyses. Among these, a handful of PRDM15 targets, including Rbpj, Notch3, Maml3 (NOTCH), Vangl2, Wnt5b, Gpc6, Nphp4 (noncanonical WNT), and Gas1 (SHH), were of particular interest as they are significantly down-regulated in the mutant embryos (fig. S4D). Collectively, these data indicate that lack of PRDM15 leads to transcriptional down-regulation of key regulators of developmentally important signaling pathways (NOTCH, noncanonical WNT, and SHH).

These results prompted us to perform a targeted analysis of the down-regulated PRDM15 target genes in a large cohort of patients with HPE (132 trios and 188 singletons). We found heterozygous variants in 99 genes, ~17% of them were likely to be damaging (table S2A). To gain insights on potential functional interactions between these genes, we generated functional protein association networks using STRING. Although the majority of the proteins did not seem to be functionally related, two main networks representing NOTCH and WNT/PCP signaling formed (Fig. 5A and table S2B), supporting their potential involvement in HPE pathobiology.

(A) Functional groups identified by protein association network analysis of PRDM15 target genes mutated in patients with HPE using STRING. (B) mRNA levels of the indicated genes in ESCs; the respective genotypes are indicated in the lower panel. Expression levels were normalized to Ubiquitin (Ubb), and Prdm15fl/fl (empty vector) was used as reference. Rspo1 expression levels were used as positive control in Fig. 1D. Data shown are from three independent experiments (n = 3). (C) Enrichment of PRDM15 binding on promoter regions of the indicated target genes in ESCsrespective genotypes are indicated in the lower panelas measured by ChIP-qPCR. ChIP on the Rspo1 promoter was used as a positive control for PRDM15 binding. Depicted is the average enrichment [data from three independent cell cultures (n = 3)] over percent of input. In (B) and (C), the endogenous mouse Prdm15 has been deleted by the addition of OHT (50 nM) after ectopic expression of WT or mutant human PRDM15. In (B) and (C), center values, mean; error bars, SD. Students t test (two sided) was used to determine significance.

To assess the ability of the PRDM15 mutants to regulate the expression of critical components of both pathways, we took two approaches. First, we performed rescue experiments in Prdm15/ ESCs by reintroducing WT or mutant PRDM15 expression constructs. While hPR15-M154K and hPR15-E190K restored the expression of target genes at levels comparable to the WT human PRDM15 (hPR15-WT), none were significantly rescued by hPR15-C844Y (Fig. 5B and fig. S5A). In addition, ChIP-qPCR analysis confirmed a reduced enrichment of hPR15-C844Y at the promoter regions of these target genes (Fig. 5C and fig. S5B), which is consistent with the failure to promote their transcription (Fig. 5B). Second, to confirm that the C844Y mutation in humans is indeed an LOF mutation, we introduced the corresponding homozygous mutation (C842Y) in mESCs using CRISPR-Cas9 technology (fig. S5, C to E). Although the C842Y knock-in allele did not affect Prdm15 transcript levels, the resulting protein was unstable and less abundant (fig. S6, A and B). qPCR confirmed that Prdm15C842Y cells express PRDM15 target genes (i.e., Rbpj, Notch3, Vangl2, etc.) at lower levels compared with WT (fig. S6C) and that endogenous PRDM15C842Y protein is unable to bind (ChIP-qPCR) to its target promoters (fig. S6D).

Our findings call for a future functional characterization of the NOTCH and PCP gene variants and should motivate targeted genetic mapping for new HPE candidates in regulators of both pathways.

We have identified new mutations in the PRDM15 gene in patients with SNRS. Although the mutations affecting the PR domain of the protein (M154K and E190K) are associated with isolated SRNS cases only, the zinc finger mutation (C844Y) causes a syndromic form of HPE. In our in vitro ESC system, these PR domain mutations reduced the stability of the encoded protein but rescued considerably the phenotypic and molecular changes induced by loss of the endogenous protein. This is consistent with the fact that these mutations in humans cause isolated SRNS only and could imply a context-dependent requirement for the PR domain. Alternatively, the differential impact of the PR versus ZNF mutations on protein stability may support a threshold model, where different levels of PRDM15 expression are required for the development of specific organ systems. On the other hand, the ZNF mutation (C844Y) had marked effects on PRDM15 function in both settings, which we attribute here to impaired binding of the mutant protein to regulatory regions of its transcriptional targets.

Similar to the LOF mutation in humans, genetic deletion of Prdm15 in mice leads to a broad spectrum of brain defects, affecting predominantly the anteriormost structures including the eyes. Such phenotypic continua are commonly assigned to allelism, polygenic origin, and the action of modifier genes. Yet, here we report that perturbation of a single transcriptional regulator can indeed affect an entire transcriptional network, relevant to both normal development and pathological manifestations.

Our findings show that PRDM15 promotes transcription of several regulators of the NOTCH and WNT/PCP pathways to orchestrate formation of midline structures. Perturbation of these transcriptional programs, upon PRDM15 depletion, disrupts forebrain development due to impaired AME specification and lack of SHH signaling, consistent with the sequence of developmental defects associated with HPE pathobiology (7).

Of note are the prominent phenotypic similarities between Prdm15 null embryos and genetic (or microsurgical) modulation of the Nodal signaling pathway in mouse. That is, Nodal hypomorphic alleles, assorted combinations of mutations in Smad2 and Smad3, as well as the mutations in the downstream effectors Foxh1 and Foxa2, all result in embryos with defective AME production and compromised anterior forebrain development (2023).

On the other hand, the characteristic ruffling of the visceral endoderm observed in Prdm15 KO embryos at E7.5 has been observed in other mutants where extraembryonic mesoderm (ExMeso) production during gastrulation is impaired, such as in loss of Smad1 (24), combined loss of Smad2 and Smad3 in the epiblast (21), or Otx2 (chimeric analysis) (25). It is, however, important to emphasize that epiblast-specific deletion of Prdm15 (Prdm15/::Sox2-CRE embryos) equally results in smaller embryos with defects in the formation of anterior structures (fig. S3). It is additionally possible that the developmental delay we observed in Prdm15 KO embryos disproportionally affects some parts of the gastrulating embryo, rather than an overall delay in epiblast proliferation before gastrulation.

On the basis of our molecular analysis, we conclude that like modulation of the Nodal signaling pathway, loss of Prdm15 specifically affects AME specification. Given the requirement of this critical signaling center in providing reinforcing anterior patterning signals, we favor a model in which its lack or dysfunction underlies the Prdm15 phenotype, rather than a paucity of mes(endo)derm produced during gastrulation by a mutant embryo experiencing developmental delay.

The restriction of HPE genetic determinants to a handful of NODAL and SHH pathway regulators stems from our limited understanding of the molecular events governing specification of early and late midline structures. Recent studies have implicated components of the WNT/PCP pathway in regulating polarity of the node along the A/P axis and linked their deregulation to structural anomalies of this critical organizing center (2629). Thus, it is not unexpected that perturbation of the WNT/PCP pathway affects the specification of APS derivatives, namely, the AME and node (29). In addition, while the links between mutations in PCP signaling and neural tube defects are well established (6, 3032), their involvement in HPE remains uncharted. NOTCH signaling, on the other hand, has been implicated in HPE only recently (33). Besides its established neurogenic role in the developing mouse telencephalon, growing evidence supports the involvement of key NOTCH regulators (for example Dll1 and Rbpj) in node morphogenesis and midline truncations (34, 35).

Our findings prompted us to perform a targeted search for mutations in a large cohort of patients with HPE. Our analysis of exome sequencing data from 132 trios and 188 singletons revealed multiple rare heterozygous variants in PRDM15 transcriptional targets involved in forebrain development. In silico protein association network analysis of these variants identified two major functional groups regulating the NOTCH and WNT/PCP pathways. We expect that our findings will encourage validation of the reported variants/mutations as well as further mining for additional HPE candidates in both pathways.

PRDM15 KO-first mice that harbor the Prdm15lacZ allele were obtained from the European Conditional Mouse Mutagenesis Program. Hemizygous (Prdm15lacZ/+) animal intercrossings were performed to obtain homozygous (Prdm15lacZ/lacZ) embryos. Further details on these animals and the conditional Prdm15fl/fl strain can be found in (10). To generate epiblast-specific Prdm15/ embryos, Prdm15fl/fl mice were first crossed to heterozygous Sox2-CRE transgenic animals [B6.Cg-Edil3Tg(Sox2-cre)1Amc/J; JAX Laboratory] (36). The resulting males (Prdm15/+::Sox2-CRE) were then crossed again to Prdm15fl/fl females. In this generation, a quarter of the progeny is expected to be Prdm15/::Sox2-CRE. The Sox2-CRE transgene was always propagated through male animals. A similar breeding strategy, using Nestin-CRE [B6.Cg-Tg(Nes-cre)1Kln/J; JAX Laboratory] transgenics, was followed to generate Prdm15/:: Nestin-CRE mice. All mice-related procedures were approved by the local Institutional Animal Care and Use Committee (IACUC) and performed in compliance with the respective guidelines (IACUC nos. 151042 and 18/10EGDM/90).

E12.5 embryos were fixed in 4% PFA (paraformaldehyde) for 48 hours before being mounted in OCT (Optimal Cutting Temperature) embedding compounds. Then, serial coronal sections of the brains (anterior-posterior) were made using a cryostat and immediately thaw mounted on poly-l-lysinecoated histological slides for hematoxylin and eosin staining.

Prdm15fl/fl; ROSA26-CreERT2 ESCs have been described in (10). For all experiments, ESCs were cultured in the conventional [serum + Lif (Leukemia Inhibitory Factor) (SL)] medium unless otherwise stated. OHT (4-Hydroxytamoxifen) (50 nM; SIGMA-H7904) was added to the culture medium overnight (O/N) to generate Prdm15/ cells.

Embryos were isolated between E6.5 and 8.5, genotyped, then processed for whole-mount in situ hybridization as described in (37) with the following probes: Foxa2, Lhx1, T, Lefty2, Chordin, Shh, Otx2, and Six3.

Full-length human PRDM15 cDNA (NM_001040424.2) was subcloned into the PiggyBac vector (DNA2.0, PJ549). Clones encoding the various PRDM15 mutations were generated using the QuickChange II XL Site-directed Mutagenesis Kit (Agilent Technologies). The sequence of primers used can be found in table S3.

To introduce the hC844Y/mC842Y point mutation, mESCs were transfected with PX458 [pSpCas9 (BB)-2A-GFP] vector expressing a guide RNA targeting the site to be mutated, along with a single-stranded oligonucleotide containing the target point mutation, to serve as a DNA repair template. Additional eight silent mutations have been introduced to avoid editing of the template by the CAS9 protein. Single clones were sorted and expanded in 2i medium. Genomic DNA was used for screening by digestion with XMN I restriction enzyme. DNA from potential mutants was cloned into the pCR 4-TOPO TA vector following the manufacturers instructions, and 5 to 10 colonies were sequenced. Details of the strategy and the sequence of the oligonucleotides used are described in fig. S5 and table S3.

To assess protein stability, Prdm15/ ESCs expressing either wild or mutant PRDM15 were treated with cycloheximide (CHX; 150 g/ml) (Sigma, no. C-7698), and then collected at different time points (2, 4, and 6 hours) for protein extraction and analysis by Western blotting. Samples collected immediately before treatment with CHX (t = 0) served as reference. Antibodies and dilutions used were PRDM15 (in house, 1:3500) and TUBA (Alpha-TUBULIN) (Sigma T5168, 1:10,000).

To assess ESC self-renewal/differentiation, cells were stained with alkaline phosphatase staining solution (AP detection kit, Millipore, SCR 004). In brief, 500 cells per well (12-well plates) were seeded in triplicates and cultured for 5 days with daily change of medium before being stained as per the suppliers recommendations.

ESCs were seeded on gelatin-coated eight-well glass slides (Millipore, PEZGS0816), at 3 103 per well, and cultured in 2i medium. Three days later, cells were fixed in 4% PFA at room temperature, permeabilized with 0.5% Triton X-100, and then blocked using 2% bovine serum albumin (BSA) for 1 hour at room temperature before O/N staining with anti- PRDM15 (in house, 1:100) at 4C. The next day, slides were washed with phosphate-buffered saline (PBS) (three times) and stained with Alexa Fluorconjugated secondary rabbit antibody at 37C (30 min). Last, slides were washed with PBS (three times) before they were mounted with a DAPI (4,6-diamidino-2-phenylindole)containing mounting medium (VECTASHIELD, Vector Laboratory H1200).

Total RNA from cells was isolated using PureLink RNA Mini Kit (Ambion, 1283-018A) according to the manufacturers instructions. RNA was retrotranscribed into cDNA using Maxima First Strand cDNA Synthesis Kit (Thermo Scientific, K1642) and subjected to quantitative real-time PCR (qRT-PCR) on an ABI PRISM 7500 machine. qPCRs (20 l) contained 10 l of SYBR Green PCR supermix (2), 4 l of a forward and reverse primer mix (final concentration, 200 nM), and 6 l of cDNA (20 ng). Primers sequences are listed in table S4.

The detailed procedure for ChIP experiments has been described previously (38); all steps were performed at 4C and protease inhibitor was added, unless stated otherwise. In brief, 20 to 40 million ESCs were fixed in 1% formaldehyde for 10 min at room temperature before quenching with 0.125 M glycine (5 min at room temperature). Cells were then washed in PBS and harvested in lysis buffer before freezing at 20C O/N. The following day, cells were pelleted by centrifugation, resuspended in ice-cold ChIP buffer, and sonicated for six cycles (30-s ON/30-s OFF) using a BRANSON Digital Sonifier (no. S540D). Lysates were then precleared for 2 hours in Sepharose A beads (blocked in 5 mg/ml BSA) before O/N incubation with PRDM15 antibody (4C). The next day, Protein A beads were added for 4 hours before washing then de-cross-linking in 1% SDS and 0.1 M NaHCO3 (65C, O/N). Last, DNA was eluted in T-buffer (pH 8) using QIAquick PCR Purification Kit, QIAGEN. Sequences of primers used in ChIP-qPCR are listed in table S4. For the E6.5 ChIP, approximately 40 to 50 embryos per experiment were pooled together and fixed immediately after isolation.

TruSeq ChIP Sample Prep Kit (IP-202-1012) was used for DNA library preparation. Sequencing was performed in the Illumina HiSeq 2000 and NextSeq 500 at the Genome Institute Singapore. Details of the bioinformatics analysis can be found in (10). In brief, the sequenced reads were aligned to the mm9 genome assembly using bowtie version 2. Peak calling was done using MACS 2.1.1 (https://github.com/taoliu/MACS). Peaks were then annotated using the ChIPpeakAnno package in Rpromoters were defined to be 5 kb upstream and 1 kb downstream of the transcription start site. Motif discovery was done using MEME-ChIP in the MEME Suite (http://meme-suite.org).

For E6.5 embryo transcriptome analysis, RNA was extracted from 8 WT and 10 Prdm15lacZ/lacZ littermates. RNA from ESCs was collected 3 days after ethanol/OHT treatment. Library preparation was performed following the TruSeq RNA Sample preparation v2 guide (Illumina). The sequenced reads were mapped to mm9 build of the mouse genome using STAR version 2.4.2a. Differential expression analysis was performed using the DESeq2 package in R. Only genes with an average FPKM (Fragment Per Kilobase Million) >1 are considered expressed. Enriched GO terms and KEGG pathway were identified using Metascape. Genes used for GO analysis were filtered based on statistical significance (P < 0.05) and fold change (log2 fold change of 0.322) in E6.5 embryo RNA sequencing. Heatmaps of gene expressions (FPKM) were generated with in-house scripts with R.

To identify potential new candidate genes associated with HPE, we searched for genetic variants in genes/proteins acting downstream of PRDM15. Exome sequencing data from a cohort of 320 patients with HPE (132 trios and 188 singletons) were evaluated. Filter criteria are as follows: allele frequency <0.0001 in ExAC database (39) de novo (if trio available); synonymous changes were omitted; and benign changes by ACMG 2015 (40) criteria were removed. To identify protein networks and functional groups, genes with potential HPE variants were subjected to protein association network analysis using STRING database (https://string-db.org).

All experiments were repeated at least three times with similar results. Each biological repeat was done in at least two to four technical replicates/independent cell cultures, where applicable. Normal distribution was assumed for all statistical analyses. Unpaired Students t test (two sided) was applied using GraphPad Prism (version 7.0) to determine the statistical significance of the observed differences. Changes were considered statistically significant when P < 0.05.

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PRDM15 loss of function links NOTCH and WNT/PCP signaling to patterning defects in holoprosencephaly - Science Advances

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How do I get stronger on the bike? you ask. Its that time of year: your races are done and you know where you stand performance-wise. You might find yourself wondering how some girls are so strong on the bike. How some guys ride by you as if youre standing still. Theres at least one explanation: strength. They have more of it than you (at present).

By Adam Johnston

If youre wondering what you can do this winter to improve your cycling (and your running and swimming, by the way), consider adding a regular strength training program to your routine (if youre not already doing so).

The majority of adult age group athletes are not limited by their muscular endurance. Theyre fond of their long training rides. They bump up to their competitive distances (whether it be standard, half or full) as quickly as they can. The ability to perform repeated muscular contractions at low levels of force is not what limits most athletes. Rather it is their muscular strength the ability to contract their muscles forcefully and/or against heavy resistance.

When most people start they typically improve almost regardless of what training they perform. Beginner and intermediate athletes get better quite simply by accumulating miles on the bike, running and in the pool. But once the initial break-in period has come and gone the next step is to focus on muscular strength.

Reams of information are available for the endurance athlete on strength training. This article isnt intended to regurgitate the research and advice thats readily available elsewhere. Rather, its meant to get you thinking of a few strength-related concerns and to consider a few things that you might not have anticipated when it comes to strength training for the endurance athlete.

Consider the following 10 strength training tips:

Be smart, be consistent, and get stronger for 2020.

Adam Johnston is the owner of WattsUp Cycling in Toronto. WattsUp Cycling offers an endurance athlete-specific strength training program on site. Visit http://www.wattsupcycling.ca to find out more.

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10 Ways to Get Stronger on the Bike - Triathlon Magazine Canada

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One of the nerve-racking parts of living with severe allergies is having to make the call about if and when an allergic reaction is anaphylaxis. A shot of epinephrine can save a life, but having to inject ourselves or our child with a needle is something we did not sign up for.

However, mistakes in the critical areas of recognizing and responding to anaphylaxis can mean the difference between life and death. Plus, studies are showing that prompt administration of epinephrine can simply reduce the chance that a food allergy reaction moves from relatively mild to severe anaphylaxis.

Over the years, Allergic Living readers have raised many questions related to epinephrine: from when to give it, to when a person needs a second dose, to issues such as how much heat or cold an epinephrine auto-injector can take, whether antihistamines mask anaphylaxis symptoms and more.

We asked Gina Clowes, the nationally known food allergy educator and parenting coach and consultant at AllergyMoms.com, to help us create a go-to epinephrine resource with answers to these vital questions.

Ginareached out to Dr. Julie Brown, anemergency medicine physician at Seattle Childrens Hospital, for her expertiseon the topic. Dr. Brown works closely with the food allergy community and has acontinuing research interest in epinephrine, auto-injectors and anaphylaxis. AsGina says, Were so grateful to Dr. Brown for agreeing to answer commonepinephrine questions. I find her insights and answers fascinating, and knowtheyll be helpful to a lot of people.

Following you will find written answers about epinephrine in a handy Q&A format. Plus, we include a podcast featuring Gina and Dr. Brown that offers further elaboration on some of the key answers.

Allergic Livings Epinephrine Q&A

Dr. Brown explained that epinephrine is adrenaline, the same hormone that is formed in the body in the fight or flight response. But it also has a very important role, probably by design, in turning off allergic reactions.

In the allergy context, she says epinephrine acts on a number of different receptors on cells in the body, and seems to reverse fairly pointedly all of the things that are happening in allergic reactions.

The reason is, the earlier you give epinephrine, the better outcomes are, says Dr. Brown. The longer one waits, the more likely the reaction is to progress and require multiple doses of epinephrine.

If we wait, were more likely to get sicker and have much more significant symptoms, she says. We are more likely to need multiple doses of epinephrine or need to stay in the hospital.

She reminds us that patients can start off having very mild symptoms, and then turn very quickly to getting very sick. What we want to do is to treat before things get serious. Sadly, most patients who have died from anaphylaxis had delayed treatment with epinephrine.

Dr. Brown generally recommends between 5 and 15 minutes as a reasonable timeframe between doses to determine if the epinephrine has taken effect. She says that if you have someone who looks like they are not breathing, they are turning blue, they are passed out, you would shorten the time window.

In such a case she says it may be reasonable to give a second dose, just to make sure that youve got a good amount of epinephrine circulating while awaiting an ambulance.

All About Epinephrine Podcast with Dr. Julie Brown and Gina Clowes

After the death of a U.K. teenager, whosecase involved getting two injections of epinephrine in the same thigh, therewas some suggestion that a second dose should have been given in the oppositethigh.

Thesuggestion was that this might increase the circulation of epinephrine in thebody. However, Dr. Brown does not seea concern with injecting a second dose in the same thigh. As this is such a largemuscle, she says you are highly unlikely to inject in the exact same location.

However, she agrees that there is no problem with injecting a second dose in the opposite thigh (to the first dose) if there is no barrier to doing so.

Ina severe anaphylactic reaction, Dr. Brown says there is a lot of fluid leakage fromthe blood vessels internally, which makes it hard for your body to pump enoughblood through your heart. Its often helpful for a person to lie down with feetelevated when suffering from a serious reaction.

Youare helping them to circulate their blood the best if theyre lying down,she says. And after youve given epinephrine, youre helping to circulatethat epinephrine the best if theyre lying down.

Shediscussed U.K. research into cases of patients who had died from anaphylaticshock. Some patients worsened after they stood up quickly or were propped up duringtheir extreme reactions. The lack of blood flow to the heart may have led to aheart attack, which contributed to the fatal outcome.

Dr.Brown recommends that patients experiencing active anaphylactic symptoms shouldlie down, if possible. However, I certainly see lots of kids who aresitting comfortably for hours in our emergency department, and they dont allneed to be lying down. She says this recommendation is probably mostimportant when a patient feels faint or light-headed or early in a reactionthat is progressing rapidly.

Importantly, she says, not everybody is going to be best off lying down. Dr. Brown gives the example of someone whos having respiratory distress as a symptom. If its upper airway difficulty, with what we call stridor the kind of noise where youre having trouble breathing in that person often needs to be sitting up and leaning forward. This is a position that allows your airways to be the most open.

In addition, she says that individuals who are vomiting should be lying on their side to reduce the chances of choking.

This is an issue of concern particularly in schools. The teacher should never send a kid in school on their own to the nurses office, says Dr. Brown. You dont know how the disease is going to progress between the classroom and the nurses office.

She recommends sending someone with the student, at a minimum, so they can monitor and advocate for the child or teen if needed. If the child is feeling faint, then help should be brought to the child, rather than sending the child to get help.

According to Dr. Brown, studies have shown there is epinephrine in your system for at least 6 hours. Its at a higher level for about an hour, and it peaks around 5 minutes. Theres a pretty decent amount [circulating] for 40 minutes.

Shesays people often think epinephrine only lasts 15 minutes because thats whenyoure suggested to take a second dose if needed. But it doesnt mean that thereisnt medication still on-board from the first dose.

Evidenceshows most people only need one dose of epinephrine, says Dr. Brown. One reasonis that it lasts for the duration of most reactions. A second reason is thatepinephrine stabilitizes mast cells, making them less twitchy, aneffect that may last even after the epinephrine is gone.

She says a third factor is that, even for patients who dont get epinephrine, a lot of these reactions will burn out on their own. Thank goodness for that, because everybody [with food allergies] has a first reaction where they arent carrying epinephrine! she says. Of course, you never want to count on it burning out on its own, so you should always treat anaphylaxis early with epinephrine.

Thegood news is: There are a number of studies that have looked at what happenedto epinephrine when you freeze it. Theyve shown that both refrigerating andfreezing epinephrine does not degrade epinephrine. So it maintains high levelsof epinephrine.

Dr. Brown and colleagues have further investigated what happens to auto-injector devices when frozen. Dr. Brown was senior author of a study [by Alex Cooper et al] in which 104 EpiPens were frozen for 24 hours, then thawed while their mates [from EpiPen 2-Pak cartons] were left at room temperature. The frozen-then-thawed devices fired a similar amount of epinephrine to their never-frozen paired device. When another 104 frozen-thawed devices were opened unfired, there was no damage to the syringes or other device parts.

This research didnt find any evidence of adverse effects to the device of having been frozen for 24 hours. It looks like freezing has pretty minimal effects on EpiPens, said Dr. Brown. She cautions that this research looked only at EpiPens, not other auto-injectors, and the impact on other devices could be different.

Dr. Brown explains that heat is much more problematic than cold. Previous research has shown that you can definitely see the degradation of epinephrine itself with high heat. She says temperatures in a car on a hot, sunny day can exceed 194 degrees F, and a device exposed to this sort of heat could have degradation of the epinephrine.

The device itself can also be negatively impacted by heat. Her teams ongoing research [lead investigator Samuel Agosti] is examining the impact of high heat, and exposing EpiPens and EpiPen Jrs to 183 degrees F for 8 hours. In this study, Dr. Brown reports, were seeing differences in the amount of epinephrine fired from heated-then-cooled devices compared with their unheated pairs [from EpiPen 2-Paks]. We are also having trouble getting some devices out of the cases.

Sherecommends replacing a device that has had significant heat exposure. Shecautions if it feels hot to the touch, I would say thats pretty suspect that thedevice is not reliable anymore. Theres a risk there.

Dr. Brown doesnt think so. She says that in the United States, we have safe devices that have really maximized needle lengths for serving a wide range of population and different-sized people. Longer needles might be more suitable for some extremely large patients, but those longer needles might be long enough to reach bone in many normal-weight patients.

She notes that the goal is to get the medicine into the thigh muscle, and the device mechanism that pushes the drug out also plays a role. So needle length isnt the only factor. Although there will always be challenges to meet every patients needs, Dr. Brown believes the options available the devices in the U.S. are probably doing a reasonable job, all things considered. She notes there is even a third dose option now, the Auvi-Q device for infants.

Dr. Brown had no concerns about airport scanners. Shes not aware of any specific research in this area, but doubts an airport scanner would have any ability to impact your dose of epinephrine or the functioning of the device.

Her team [led by investigator Andrew McCray] has researched this easy mistake to make and the news is not good for an EpiPen that has gone through the laundry. While prescribing information does not address what to do if the device is submerged in water, the EpiPen website says the carrier tube is not waterproof and that a submerged device should be replaced. However, Dr. Brown said: I still thought that they would do pretty well because it looks like a robust device that was based on a design developed for the military. But our results are not encouraging.

She reports that water gets lodged in the outer layer of the device, and more importantly the amount of drug that fires appears to be impacted. She recommends following the advice to replace an auto-injector that has gone through the washing machine.

Epinephrinedevices do continue to maintain a high level of the labeled dose of epinephrineas they age. While Dr. Brown recommends keeping current, unexpired deviceswhenever possible, she has little concern about the four-month expiration dateextension that the FDA issued on certain lot numbers during periods of shortage.

However, as Dr. Brown explains, the amount of epinephrine is only part of the story. There are epinephrine metabolites that occur as the medication ages. The safety or toxicity of these metabolites in the body in expired medication is unknown. While the theoretical risk of these metabolites shouldnt prevent use of a potentially life-saving medication in an emergency, it is a good reason to keep a current device on hand.

Shes aware that many allergy families keep older auto-injectors in case of emergency, but cautions that the level of epinephrine is getting pretty low after two years, and the level of metabolites is probably getting fairly high. Two years is probably a reasonable limit for keeping back-up devices. After that, its really time to just toss them in your med recycling bin.

With heat, light exposure or over time after expiration, epinephrine is degraded and metabolites begin to increase. Epinephrine metabolites can exceed FDA recommended levels well before the medication shows any discoloration, says Dr. Brown. However, some pharmacists still perpetuate the notion that as long as the medication is clear, its OK to use.

If the epinephrine has been exposed to heat, it can have a fairly significant increase in epinephrine metabolites and not be discolored. You cant rely on color tell you whether or not your device is safe to use, she cautions.

If it is discolored, it is unsafe. But if it was exposed to heat and is clear, it could still have significant degradation.

Although Dr. Brown acknowledges the concern of Benadryl masking anaphylaxis, she says that is giving antihistamines way more power than they have in allergic reaction. Her view is that if a reaction is going to be an anaphylactic one, an antihistamine wont stop it. There is no argument that epinephrine is the drug of choice to treat anaphylaxis, a life-threatening allergic reaction. But for a mild symptom, such as a mild runny nose or slight rash, she says its fine to give an antihistamine. Youre not going to mask anything. As long as youre still keeping a watchful eye for symptom progression.

She shares two caveats, though. Dr. Brown is among a growing number of experts who prefer a non-sedating antihistamine, such as Zyrtec, rather than Benadryl, as the latter is more sedating. She recommends this to avoid confusion between drowsiness from the medication and drowsiness related to anaphylaxis.

The second caveat is that if an antihistamine has been given for a single symptom, such as hives, you would still count that symptom as one system affected, even if the symptom resolves. She explains that if youve treated hives with an antihistamine and theyve improved, but half an hour later you go on to start vomiting, now youve hit two systems. According to most care plans, you would meet criteria for using epinephrine.

Interestingly, research shows conflicting benefits of corticosteroid medication in anaphylaxis. First, Brown explains there is a misconception that steroids take a long time to work, but theres some evidence that steroids actually can work within 30 minutes.

However, research from Canada suggests that steroids given prior to admission into the hospital increased intensive care admissions. She notes that its unclear if that truly was an effect of the steroids, or if perhaps steroids were being used instead of epinephrine.

There is also a notion that steroids decrease the risk of a biphasic or secondary reaction. But a review of cohort studies suggests that steroids are not having an impact on biphasic reactions. Brown concludes that theres really not a lot of great evidence to support that steroids are doing anything in anaphylaxis.

There are many other drugs and supports that can help a patient recover from an anaphylactic reaction such as fluids, oxygen, antihistamines, albuterol and other asthma medications. The additional drugs and monitoring available are why it is so important to seek medical care during an anaphylactic reaction.

Thefirst thing to remember is that [patient emergency anaphylaxis] care plans havea very low threshold for giving epinephrine. Often you are giving epinephrinebecause you meet this two-system criteria for giving epinephrine, Dr. Brownexplained.

Thatthreshold for using epinephrine by a lay person, who is not in a medicalsetting, is lower than it would be in a hospital. In the emergency departmentBrown notes:

The physician has the advantage of having you on monitors, of knowing your vital signs, what your exam is like, what kind of a timeframe were talking about. Time is very important in anaphylaxis, and thats not something that is incorporated into emergency care plans. The doctors will incorporate all that information into the decision-making about whether or not its appropriate to give more epinephrine at that time, whether or not they want to do something else, or whether they just want to watch further.

All of those may be safe and appropriate options in the emergency department setting, while you might make very different decisions if youre in the community and following your care plan.

Dr. Brown cautions that its important to understand that there is no rhyme or reason to food allergy reactions and that any reaction can become the bad reaction. You can have had very mild reactions all of your life, and then your next one can be really severe.

At the same time, it is wise to be aware that if youve had very life-threatening reactions in the past, then that may increase your chance of having one again, she says.

While our individual histories are things we cant necessarily change or impact, co-factors are things that we can be aware of. Dr. Brown explains that co-factors are things like exercise, heat, alcohol consumption, illness and menstruation. All of those can exacerbate your allergic reaction.

So if youre having a mild allergic reaction and you go out for a jog, that may really flare up that reaction. Or if youre having a bit of a reaction and you go take a hot shower, that may really activate all your masts cells and you may come out of the shower just covered in hives. Some people are exacerbated by cold, so they might go out on a very cold day and find that that sets them off. Illness certainly decreases peoples threshold for reaction. So they may find that they can tolerate a food pretty well most of the time, and then when they are ill have a decreased threshold for reacting to that food. Some women find around their menstruation theyre much more likely to react to certain foods, she says.

Dont be afraid of epinephrine. It is unfortunately so hard for so many people to get past the mental idea of giving themselves [or a child] a shot, but it invariably makes you feel so much better when youre having an allergic reaction, says Dr. Brown. It only does good things, it only keeps you safe. It really is a wonder drug in anaphylaxis.

She puts it succinctly: Dont be afraid to use it yourself. Dont be afraid to use it for your child. Youre only going to make things better.

Allergic Living and Gina Clowes extend our appreciation to Dr. Julie Brown for her generous time in helping to create this go-to resource for the food allergy community. Dr. Brown is an emergency medicine physician and co-director of emergency medical research at Seattle Childrens Hospital, with study interests in epinephrine, auto-injectors and anaphylaxis. Gina is the founder of AllergyMoms.com.

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All About Epinephrine: What It Does in a Reaction, How Long It Lasts, When It Gets Hot or Cold - Allergic Living

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Does Wanting A Lot of Sex Mean Youre Addicted? Experts Explain

You might be familiar with the statistic that claims men think about sex every seven seconds.

That statement has garnered plenty of skepticism from gentlemen thatve heard it, and not just because theres no research to back it up. After all, its difficult to see how someone could get anything accomplished if they thought about getting it on 500 times an hour (thats 8,000 times a day).

RELATED: Dealing With Porn Addiction

So lets ask the question on everyones mind: Is it normal to think about sex all the time?

According to a 1995 survey conducted by the Kinsey Institute, 54 percent of men said they think about sex several times a day, and 43 percent said its on their mind a few times per week or just a few times per month. Only 4 percent reported thinking about it less than once a month. Its worth noting that the Kinsey Institute survey included men of all ages, meaning their sex drives varied.

But when it comes to thinking about sex, at what point do all of those racy thoughts become problematic, going as far to interrupt your regular day-to-day routine?

The line between a typical horny guy and sex addict can get pretty blurry. To figure this out, AskMen spoke with three experts to clarify the difference.

Dr. Joshua Klapow, clinical psychologist and host of The Kurre and Klapow Show, asserts that sex drive can vary greatly among men, with age being one of the key factors that impact it. Still, even within the same age range, its very difficult to define whats normal.

Younger men (17-30), with more testosterone production on average will have stronger sex drive than older men, he explains. However, environmental and biological factors can impact that significantly. We see men in their 20s with moderate drive and men in their 50s with a strong drive. Sexual experience, social norms, learning history and expectations (i.e. how much sex theyve had in the past) all affect the degree of sexual drive.

Klapow also notes that life circumstances can have an effect on sex drive. For example, stress, grief, anxiety, and sleep deprivation can all come into play in terms of your sexual interest and activity.

Dr. Dawn Michael, clinical sexologist founder of TheHappySpouse.com, states that every man has his own unique sex drive.

Sex drive can be dependent on a mans pattern of masturbation and sexual release (orgasm), she says. If a man orgasms every day, his body gets used to that pattern.

Given that the Kinsey Institute study included participants within such a wide age range, its difficult to discern any norms for particular groups from the findings. However, Dr. Leslie Beth Wish, licensed clinical psychotherapist, relationship expert and author of Training Your Love Intuition, points at a 2016 study from Ohio State University as a more reliable source due to its focus on men between the ages of 18 to 25.

Researchers gave participants a counting machine, which they used to track their thoughts about sex. On average, participants had explicit thoughts about 19 times per day (or once every 1.26 hours). This may come as no surprise, but the men thought about food almost just as often (18 times per day).

In other words, even if youre thinking about sex about once every hour or two, youre right in line with the average for young men. How do you know if its becoming a problem? According to Klapow, if youre preoccupied with thoughts of sex to the point that they interfere with your ability to work, study, maintain relationships or have a social life, thats a red flag.

Experts agree that the definition of sex addiction is nuanced and delicate in fact, theres no official medical diagnosis for it.

We have to be careful to label someone as having a sex addiction, says Michael. The label sex addiction is very complicated and misused often. Some men are labeled sex addicts by their partners who may simply not have the same sex drive.

That said, there are some tell-tale signs that can suggest youre experiencing compulsive sexual behavior. Below, youll see some of the most common indicators of addiction via Klapow and Wish:

Wish states that sex addiction is often marked by a constant need to expand your sexual activities. Its not unlike a drug addiction, where you need to continually increase your dosage of the substance to experience the same pleasurable effects. For example, you might feel compelled to incorporate more elements of danger into your sex life for more of a thrill, or need to seek out increasingly hard-core pornography in order to reach an orgasm.

Our brain and body like variety, she adds. Imagine if you had to eat your favorite meal three times a day, every day. This loss of pleasure creates a compulsion for something new. Regardless of the next choice, that choice, too, most likely will stop being as satisfying, and, as a result, men get trapped in an endless cycle.

Even if some of the aforementioned signs sound familiar, all experts agree that sex addiction isnt something that should be self-diagnosed.

Wish points out that you could be overlooking a medical issue, such as a mental health disorder or hormone imbalance, at the root of your addiction. Additionally, Michael notes that past traumatic experiences may be contributing to this behavior, and those are best worked through with a professional such as a licensed counselor or therapist.

Ideally, consult a mental health professional who specializes in sexual addictions, advises Klapow. The key is to recognize that if you see yourself as having a sexual addiction, you are not likely to be able to modify your behavior on your own. Its important to contact a mental health professional as sexual addiction is not by itself a diagnosis and often is a problem that presents with other psychiatric problems (i.e. bipolar disorder, OCD, mania, etc.)

If you cant find a licensed professional who specializes in sexual addictions in your area, contact a licensed mental health professional, or talk to your primary care physician.

The bottom line? If your sexual thoughts and activities are negatively impacting your life in any way, then it may be time to figure out what you can do to address those compulsions. If they arent, take a deep breath and know that those frequent naughty thoughts are totally normal in fact, its just points at a healthy, active sex drive.

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Is It Normal to Want Sex All the Time? How to Tell If You're an Addict - AskMen

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Its well known that most industries are still overwhelmingly dominated by men. For instance, Wall Street, tech, construction, and engineering are only a few of the industries in which women are underrepresented, holding only 9 percent and 6 percent of the senior roles in venture capital and private equity. However, no one needs those statistics to confirm what we already know: There are specific fields in which women havent yet broken the infamous glass ceiling.

The most significant mistake analysts tend to make when discussing male-dominated industries is that they focus on the inequality itself. However, it can be far more fruitful to consider the advantages women bring to the table, both for themselves and for the industries involved.

The outcome of equal female representation in the workforce was summarized quite succinctly by management consulting giant McKinsey in 2018. They found that even though women make up around half of the worlds working-age population, they tend to be underrepresented, especially in the top roles of the workforce. Yet McKinsey estimates that women working at their full potential can add up to $28 trillion in additional global GDP by 2025. On a more micro level, an MIT study on workplace diversity has shown that splitting offices along gender lines drastically boosts productivity.

That gender diversity offers a workplace many benefits has been well covered, but what about the inclusion of women in a companys ranks boosts productivity and propels the business forward?

While there is abundant evidence showing women to be excellent communicators, multitaskers, and critical thinkers, psychological evidence also shows that men and women think slightly differently. Sometimes referred to as the battle of the hormones, there exists a phenomenon in which women and men bring different perspectives to the table due to their different genetic makeup and inherently opposing strengths and weaknesses. In other words, they complement each other in the workplace, joining forces to tackle obstacles neither gender would be able to face alone.

As the CEO of a tech company in the logistics industry, one of the most masculine industries imaginable, I have personally witnessed the wonders women can offer a world traditionally shaped by the minds of men. For example, I have observed how womens creativity improves specific processes inside companies thanks to their innovation, and how women who come from very little strive to achieve greatness, not just for themselves but for their companies, taking nothing for granted. And thats precisely it -- because women are aware that, despite the tremendous progress made in the fight against inequality, they are still afforded less professional opportunities than men, they know they have to work just a little harder. Armed with the mentality of fighting for every inch of progress, its hard to fail.

I also noticed this schism during my time in the Israeli Defense Forces, where I was rewarded for my hard work by perhaps the least likely of fans. Between 1999 and 2001, I served as an instructor of an infantry artillery unit, and afterward as an officer. Yes, the Israeli army has a reputation for gender diversity (as of 2011, 88-92 percent of all roles in the IDF were open to women), but military culture has been shaped by masculinity for thousands of years before any position was open to women, in any military. Also, some units are less used to having a woman around than others.

Units that absorb religious soldiers, for example, are bastions of gender bias because both religion and army culture have historically been patriarchal. And yet, even in these environments, there isnt a gap that cant be closed with a demonstration of knowledge and leadership.

During my time as an artillery training instructor, I trained a group of Yeshiva students -- deeply religious Jewish men who study Torah part-time while serving in the army. In other words, my trainees were accustomed to strict religious rules regulating the interactions between men and women. Every time I entered the infantry fighting vehicle (IFV) to train them, the soldiers backed up out of shock. It wasnt out of malice; its just that the religious rules they live by dont allow them even to touch a woman that is not their wife. Suddenly, they were expected to be trained by a woman soldier within the confined space of an IFV (for those not as familiar, they are quite small).

However, the initial feeling of confusion quickly transformed into mutual respect between the religious soldiers and me. By the end of the month-and-a-half training program, we had grown so close that they gave me a customized helmet and dog tag, with my name engraved on each. They so appreciated my professional contribution to our training sessions together that it changed their view on serving alongside a woman. It probably opened their minds in general.

Psychology is a useful tool and one that shouldnt be limited to individuals in need of guidance. The different perspectives diversity can offer industries such as cryptocurrency, blockchain, finance, and logistics, should be embraced as tried and true tools for propelling those industries forward. Since psychology teaches us about the secrets behind the ways men and women think, one of its central themes is that positivity is more effective than negativity. If were going to break bulletproof glass ceilings in boys-club industries, were going to have to explain why they would benefit from a womans touch once the shattered glass settles on those polished corporate tiles.

Hagar Valiano Rips is the CEO of Ladingo, and an entrepreneur and dynamic professional with more than 14 years of executive experience in business and product development across various industries. She started her first company at the age of 23 and sold it at 25. Valiano Rips also served as a commanding officer of an infantry unit in the Israeli Defense Forces.

Link:
Why Male-Dominated Industries Could Use a Woman's Touch: A Perspective from a Current CEO and Former Soldier - TechDay News

Recommendation and review posted by Bethany Smith

Every holiday, and on Black Friday and Cyber Monday and Random Discount Wednesday and Oh God Buy Stuff The High Street Is Dying Thursday, a load of miserable Opinions-For-Hire types churn out diatribes about why you absolutely should not buy anyone, including yourself, a DNA test in the sales or otherwise. And I'm here to tell you why they're wrong.

Before we get to why DNA tests are officially a good thing, let's run through some of the downsides those op-eds always bring up.

Yes, some people have found unexpected skeletons in their cupboards and sparked giant, multigenerational family arguments. But that's very rare most of us, for better or worse, don't have family histories that'd make a good daytime soap. And even if it does happen, wouldn't you rather know the truth? Where you really come from, and why you were lied to about it? It could have enormous impacts on your life choices.

Another concern is data security. Doom-mongers envisage a future where your genetic information is sold to health insurance companies, who jack up your premium as a result but that's much more of a concern for countries like the US than the UK, which still (at the time of writing, at least!) has a National Health Service. The NHS itself is on board with genetic testing, getting ready to offer a service of its own in return for contributing your anonymised data to lifesaving research.

Image: Nosha via Flickr CC

It's worth noting, too, that not all DNA testing is created equal. Some services are more geared towards looking at your ancestry and ethnicity information, while others only give surface-level results like "may be slightly more likely to have [X]", in which X can be anything from Alzheimer's to asparagus-scented wee. So depending on which service you've gone for, the information might be all but useless unless someone's trying to prove you ticked the wrong box on the ethnicity form when you applied for your job.

OK, so maybe not insurance companies, but what about your test results getting into other bad actors' hands? Well, yes, every damn company holding sensitive data has security issues, it seems the NHS very much included. However, I'm not overly worried that someone's going to download my info, insert it into some kind of biological 3D printer and start creating counterfeit versions of me. Even if that were possible, they'd needwaymore information than they'd get from a home DNA test.

The idea that your DNA test results constitute the source code for everything you are is a misconception. For starters, the tests only look at a tiny fraction of the human genome, but even if they didn't that's not how genes work. Yes, some problems and tendencies are genetic, but many are only influenced by your genes (often more than one), and some have absolutely sod-all to do with DNA whatsoever, being entirely caused by environmental factors. When you get the flu, does your DNA suddenly say "this person has the flu"? No. Is there a gay gene? No. Nobody's going to post your base pairs on Pastebin and recompile you.

As someone who's done many of these tests, I don't feel that my DNA is some kind of proprietary code I need to defend; in fact I'd open-source it if it meant we could work together on debugging some of the shit bits. Heck, maybe we can even fork me into a better person.

DNA data getting into evildoers' hands is one of those possibilities that sounds awful in theory, and it might well be awful in a few years when the whole system is more refined, but right now it would amount to "the terrorists have found out that you... HAVE A MODERATE CHANCE OF BEING BLUE EYED!" Not such a great Bond movie, is it?

You might also have seen some outcry when a popular DNA site was acquired for the purposes of solving crime, but assuming you and yours aren't massive criminals, that's probably not a huge worry either. In fact, DNA testing of relatives and descendants of suspects has solved a surprising number of cold cases in the US alone in the last few years, as well as identifying quite a few nameless bodies. Surely we can all agree that's a good thing.

While most of the worries about DNA testing are premature or arguable at this point, there are benefits that are real and tangible.

In my case, since my father is dead and I have no contact with my mother, a lot of the information I've found through DNA testing just wasn't available to me in other ways. There are plenty of people in similar situations folks who don't know who their birth parents were, have no contact with them, or aren't able to talk to them about matters of health and ancestry for one reason or another, for instance. DNA testing gives us a way to make family connections, in both the data and the relationship sense.

Last month, someone I share DNA with added me on Facebook. For some people, that might be strange and unnerving (in which case I'd say don't make your name public on your DNA profile I did because I wanted to find relatives), but for me it was wonderful. Being estranged from part of my immediate family means these connections mean more to me, and it's fascinating to look at the surnames, traits and lives of people all over the world who share my DNA segments.

For instance, until I had my DNA tested and analysed, I had zero idea about my considerable Jewish heritage. That led to a lot of genealogical research, ultimately helping me trace my family tree back to the 1700s. Now, when a new DNA relative contacts me (and they do, often it's like having email penpals), we can frequently figure out where our family trees connect, and fill each other in on cool details about our ancestors.

The health information can be life-changing too. In my case, I carry two genetic diseases that would make having a biological child pretty unwise. I already knew this from trying to donate my eggs a few years prior to the first test, and I don't want kids anyway, so it wasn't a nasty surprise but if I'd been planning babies, it would have been invaluable information. From this viewpoint, it seems almost crazy that most people go ahead and mix their genes with no idea what they might contain.

Of course, someone else with my results might have been devastated, but I would still argue it's better to know what you're facing. The same goes for the more serious heritable conditions that DNA tests can show. Yes, it's scary to think you might have a higher chance of getting a particular type of cancer, but it's not a certainty, and it might help you make those lifestyle changes you swear to every January. Or at least start living like you're not immortal, because newsflash: you're not.

In any case, the limited information you can get from home testing services can only give you clues, not the full picture, and some services are more accurate than others. As I mentioned, there's a lot besides raw DNA that makes a difference to how you turn out (see the whole field of epigenetics, for instance). Over time, we'll likely get more sophisticated information, which might one day mean we can start patching ourselves or at least developing medicines and treatments that interact with our unique makeup. But that's a long way off yet.

For now, there's a lot of valuable and fascinating data to be gleaned from testing your DNA, and a relatively low chance you'll ruin the next family reunion. Only you can decide what makes the most sense for you, and no test or article can tell you that.

Main image: Andy Leppard via Flickr CC

See the original post here:
Home DNA Tests Are Not the Devil - Gizmodo UK

Recommendation and review posted by Bethany Smith

More uniform response in Cohort 3 with two confirmed responders and one potential responder

New female responder in Cohort 2 for a total of three confirmed female responders across all cohorts

Up to six responders across all nine patients dosed in study

Prophylactic steroid cohort to begin in first half 2020; data expected in second half 2020

Ultragenyx to host conference call today at4:30 p.m. Eastern Time

NOVATO, Calif., Jan. 09, 2020 (GLOBE NEWSWIRE) -- Ultragenyx Pharmaceutical Inc. (RARE), a biopharmaceutical company focused on the development of novel products for rare and ultra-rare diseases, today announced topline positive safety and efficacy data from Cohort 3 and longer-term data from Cohort 2 of the ongoing Phase 1/2 study of DTX301, an investigational adeno-associated virus (AAV) gene therapy for the treatment of ornithine transcarbamylase (OTC) deficiency. In Cohort 3 (n=3), there were two confirmed female responders as well a third potential male responder who requires longer-term follow-up to confirm response status. In Cohort 2, one female patient has newly demonstrated a response starting at Week 52 which was confirmed at Week 78. The two previously disclosed responders in Cohort 1 and Cohort 2 also remain clinically and metabolically stable at 104 and 78 weeks, respectively. Across all nine patients dosed in the study, up to six patients have demonstrated a response.

We are encouraged to see a more uniform response at the higher doses including three female responders. To date, three patients in the study have discontinued alternate pathway medication and liberalized their diets while remaining clinically and metabolically stable, saidEric Crombez, M.D., Chief Medical Officer of the Ultragenyx Gene Therapy development unit. We are moving to prophylactic steroid use in the next cohort as we believe this could further enhance the level and consistency of expression that we have demonstrated so far.

Cohort 3 Efficacy Summary (as of December 9, 2019 cutoff date): One complete responder, one responder, and one potential responder

Patient 7 (complete responder, female): Patient 7 demonstrated a clinically meaningful 79 percent change in rate of ureagenesis, from a low of 24 percent of normal at baseline to the 51 to 64 percent range, and staying at 44 percent of normal at Week 52. During this period, she reported feeling significantly better and discontinued her alternate pathway medications and liberalized her protein-restricted diet. She has remained clinically and metabolically stable without a rise in ammonia.

Patient 8 (responder, female): Patient 8 demonstrated a significant and consistent 90 percent reduction in ammonia levels, time-normalized over a 24 hour period, from a high of 184 umol/L at baseline to 19 umol/L at Week 24, which is within the normal range. Potentially aberrant high baseline ureagenesis values inconsistent with her known more severe clinical status make her ureagenesis results uninterpretable. This patient was on a tapering course of steroids at the time of last assessment and has not yet discontinued alternate pathway medications or liberalized her diet. The investigator reported that her family says her health is the best it has ever been.

Patient 9 (potential responder, male):Patient 9 showed a 123 percent increase in rate of ureagenesis, from 25 percent of normal at baseline to 56 percent of normal at Week 12 while still on a steroid taper. Steroids have been shown to suppress rate of ureagenesis in other study patients. This patient has not yet discontinued alternate pathway medications or liberalized his diet. His ammonia levels have remained in the normal range and response status will be confirmed after additional follow-up.

Cohort 2 Efficacy Summary: Two responders including new responder and previously-disclosed male complete responder

Patient 6 (new responder, female):Patient 6 has now shown a 218 percent improvement in rate of ureagenesis, from 20 percent of normal at baseline to 61 percent at Week 52 and maintained at 64 percent at Week 78. In addition, she has shown a significant 74 percent reduction in ammonia levels from 156 umol/L at baseline to 40 umol/L at Week 78. She has started to taper her alternate pathway medications and liberalize her diet. With this new responder, there are two confirmed responders in cohort 2 out of three total patients.

Story continues

Safety SummaryAs of the data cutoff date, there have been no infusion-related adverse events and no treatment-related serious adverse events reported in the study. All adverse events have been Grade 1 or 2. All three patients in Cohort 3 had mild, clinically asymptomatic elevations in ALT levels, similar to what has been observed in other programs using AAV-based gene therapy. All three patients have been responding to reactive tapering courses of steroids, and all patients remain clinically stable.

Initiating Prophylactic Steroid Cohort As previously disclosed, a fourth cohort will enroll three patients at the 1.0 10^13 GC/kg dose, using prophylactic steroids. Patients will receive an 8-week tapering regimen of prophylactic steroids, starting at least 5 days prior to dosing with DTX301 at a starting steroid dose of 60 mg/day. The first patient is expected to be enrolled in the first half of 2020, and data from the prophylactic steroid cohort are expected in the second half of 2020.

Potential Phase 3 Study DesignUltragenyx is continuing discussions with the U.S. Food and Drug Administration (FDA) regarding the potential Phase 3 study design. Ammonia is expected to be a primary endpoint based on direct FDA feedback to date, with ureagenesis as a measure of biologic activity that supports the decision for patients to discontinue alternate pathway medications.

Conference Call and Webcast InformationUltragenyx will host a conference call today, Thursday, January 9, 2020, at 4:30 p.m. ET/ 1:30 p.m. PT during which Emil D. Kakkis, M.D., Ph.D., the company's Chief Executive Officer and President, will discuss the new data from the ongoing DTX301 Phase 1/2 Study. The live and replayed webcast of the call and slides will be available through the companys website at http://ir.ultragenyx.com/events.cfm. To participate in the live call by phone, dial (855) 797-6910 (USA) or (262) 912-6260 (international) and enter the passcode 5583103. The replay of the call will be available for one year.

About the OTC Phase 1/2 Study (DTX301)The Phase 1/2 study evaluates the change in the rate of ureagenesis, ammonia levels, neurocognitive assessment, biomarkers, and safety of DTX301 in patients with OTC deficiency. Three patients have been dosed in each of three dose cohorts of 2.0 10^12 GC/kg (Cohort 1), 6.0 10^12 GC/kg (Cohort 2), and 1.0 10^13 GC/kg (Cohort 3). Patients in the first three cohorts received steroids to reactively manage ALT elevations. In the fourth cohort, three patients will receive a 1.0 10^13 GC/kg dose and will all receive a prophylactic tapering course of steroids.

About OTC DeficiencyOTC deficiency, the most common urea cycle disorder, is caused by a genetic defect in a liver enzyme responsible for detoxification of ammonia. Individuals with OTC deficiency can build up excessive levels of ammonia in their blood, potentially resulting in acute and chronic neurological deficits and other toxicities. It is estimated that more than 10,000 patients are affected by OTC deficiency worldwide, of which approximately 80 percent are classified as late-onset and represent a clinical spectrum of disease severity. In the late-onset form of the disease, elevated ammonia can lead to significant medical issues for patients. Neonatal onset disease occurs only in males, presents as severe disease, and can be fatal at an early age. Approved therapies, which must be taken multiple times a day for the patient's entire life, do not eliminate the risk of future metabolic crises. Currently, the only curative approach is liver transplantation.

About DTX301DTX301 is an investigational AAV type 8 gene therapy designed to deliver stable expression and activity of OTC following a single intravenous infusion. It has been shown in preclinical studies to normalize levels of urinary orotic acid, a marker of ammonia metabolism. DTX301 was granted Orphan Drug Designation in both the United States and Europe.

About Ultragenyx Pharmaceutical Inc.Ultragenyx is a biopharmaceutical company committed to bringing to patients novel products for the treatment of serious rare and ultra-rare genetic diseases. The company has built a diverse portfolio of approved therapies and product candidates aimed at addressing diseases with high unmet medical need and clear biology for treatment, for which there are typically no approved therapies treating the underlying disease.

The company is led by a management team experienced in the development and commercialization of rare disease therapeutics. Ultragenyxs strategy is predicated upon time- and cost-efficient drug development, with the goal of delivering safe and effective therapies to patients with the utmost urgency.

For more information on Ultragenyx, please visit the Company's website atwww.ultragenyx.com.

Ultragenyx Forward-Looking Statements Except for the historical information contained herein, the matters set forth in this press release, including statements related to Ultragenyx's expectations regarding the timing, progress and plans for its clinical programs and clinical studies, future regulatory interactions, and the components and timing of regulatory submissions are forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements involve substantial risks and uncertainties that could cause our clinical development programs, collaboration with third parties, future results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, the uncertainties inherent in the clinical drug development process, including the potential for substantial delays and the risk that earlier study results may not be predictive of future study results, the lack of predictability in the regulatory approval process, the timing of regulatory filings and approvals (including whether such approvals can be obtained), and other matters that could affect sufficiency of existing cash, cash equivalents and short-term investments to fund operations and the availability or commercial potential of our products and drug candidates. Ultragenyx undertakes no obligation to update or revise any forward-looking statements. For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to the business of Ultragenyx in general, see Ultragenyx's Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission on November 6, 2019, and its subsequent periodic reports filed with the Securities and Exchange Commission.

Contact Ultragenyx Pharmaceutical Inc.Investors & MediaDanielle Keatley415-475-6876

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Ultragenyx Announces Positive Topline Cohort 3 Results and Improved Longer-Term Cohort 2 Results from Phase 1/2 Study of DTX301 Gene Therapy in...

Recommendation and review posted by Bethany Smith

What happened

Shares of CRISPR Therapeutics (NASDAQ:CRSP) rose over 113% last year, according to data provided by S&P Global Market Intelligence. The pharma stock built momentum throughout much of the year, but surged in October ahead of an important data presentation that ultimately lived up to the hype. That allowed the gene-editing stock to easily outperform the 28.8% gain of the S&P 500 in 2019.

The end-of-year rally was driven by promising clinical results for its lead drug candidate. The first two individuals, one with sickle cell disease (SCD) and one with transfusion-dependent beta thalassemia (TDT), dosed with CTX001 achieved functional cures after receiving an initial dose of the gene-editing product. The results need to be proven durable and replicated in a larger number of patients, but the update was about as good as investors could have hoped for at the current stage of development.

Image source: Getty Images.

Both SCD and TDT are caused by structural abnormalities in red blood cells. But these are one of the few cells in the human body that don't contain DNA. That means CRISPR Therapeutics has to harvest stem cells from the bone marrow of patients, apply gene editing to those extracted cells, and then inject the engineered stem cells back into patients (the ex vivo method). If the therapy works, then the engineered stem cells should produce functional red blood cells and potentially result in a cure.

In the early study, the ex vivo approach of CTX001 appeared to do just that. The TDT patient required an average of 16.5 blood transfusions per year in the two years before the clinical trial. Nine months after receiving the gene-editing treatment, the individual was transfusion independent (compared with an expected 12 transfusions) and expressed working copies of hemoglobin on 99.8% of red blood cells.

The SCD patient experienced an average of seven vaso-occlusive crises (painful blockages of blood vessels caused by abnormally shaped red blood cells) per year in the two years before the clinical trial. Four months after receiving the gene-editing treatment, the individual reported no vaso-occlusive crises (compared with an expectation for two such episodes) and expressed working copies of hemoglobin on 94.7% of red blood cells.

The early success of CTX001 bodes well for the ex vivo approach of CRISPR Therapeutics and its partner Vertex Pharmaceuticals(NASDAQ:VRTX), but investors should be careful not to extrapolate the results too broadly. Gene-editing tools that are applied inside the body (in vivo) face significantly steeper obstacles, such as the difficulty of delivering gene-editing payloads to specific tissue types inside the body. There's also the elephant in the room: Scientists are beginning to realize that current-generation CRISPR gene-editing tools don't work all that well.

Nonetheless, CRISPR Therapeutics is the top CRISPR-based gene-editing stock on the market. It has the cash, the partnerships, and the early results to back up its claim to that label.

Read the rest here:
Here's Why CRISPR Therapeutics Stock Jumped 113.2% in 2019 - Motley Fool

Recommendation and review posted by Bethany Smith

The bright wing patterns in butterflies in the genus Heliconius make for a highly visible palette to use CRISPR gene-editing techniques to investigate the evolution of wing patterns and the genes that influence them, say researchers at the Smithsonian Institute of Tropical Research. (Photo credit: Sebastian Menas/Instagram @mena_sebas)

To help shed light on some of these largest questions remaining in evolutionary biology, the authors of a paper published recently in Current Biology paper narrowed in on one evolutionary storyMllerian mimicry in Heliconius butterflies.

Laura Kraft

Heliconius butterflies synthesize compounds from the family of the cyanides and also feed on plants that have these compounds. So, they are very distasteful for predators, especially birds, says Carolina Concha, Ph.D., Biodiversity Genomics Fellow at the Smithsonian Institute of Tropical Research. In order to advertise their toxicity, these butterflies have evolved bright red, orange, yellow and blue warning colors with strong black banding. Unfortunately for the butterflies, birds typically have to bite and kill a few butterflies before learning that bright colors mean bad tastes. So over time, distantly related yet equally distasteful species of these butterflies have converged to have the exact same wing color and pattern so that both convergent species can benefit from an increased warning signal. This causes birds to learn faster by feeding on fewer individuals from either species.

These bright color patterns in Heliconius butterflies have evolved and diverged into a number of species found in Central and South America over the last 12 to 14 million years, but it was only within very recent evolutionary historythe last 2.5-4.5 million yearsthat some distantly related distasteful butterflies converged to have the same patterns. Says Concha, The wing patterns have diversified so much in such a short time, so you have these really diverse forms within a single species and at the same time, you have very distantly related species that converge in a single phenotype.

Carolina Concha, Ph.D., shows off the stack of display boxes of CRISPR-mutation butterflies that she and her collaborators have created in the Smithsonian Institute of Tropical Research in Gamboa, Panama. (Photo credit: Laura Kraft)

CRISPR allows us to make the same butterflies, with one gene missing. Its a way to interrogate nature and just ask What is the function of this gene? and Did it change during evolution?' says Arnaud Martin, author on the Current Biology paper and Assistant Professor at George Washington University. One of the earliest genes to be expressed during butterfly wing development is called WntA (pronounced WIN- tah), and it is thought to be a major gene controlling the paint by number system used by butterflies to color and pattern their wings. WntA was once expressed during embryonic development of many different types of organisms, including vertebrates, but has been lost in most. Perhaps after its role in embryonic development had become downplayed in butterflies, WntA developed a new role in wing patterning, defining the boundaries of black and color banding patterns on adult Heliconius butterfly wings.

The researchers proposed to use CRISPR as scissors to precisely cut out the section of DNA that codes for the WntA gene in a few Mllerian co-mimic pairs. They had two complimentary hypotheses: If mimetic wing patterns developed in different butterflies from using a highly similar gene regulatory mechanism involving WntA, then knocking out the gene should result in the same wing pattern changes in mutant butterflies of the different species. If, on the other hand, identical wing patterns were caused by highly different pathways involving WntA, then the wings of two species of mutant butterflies may exhibit different patterns.

Carolina Concha, Ph.D., carefully injects CRISPR into Heliconius butterfly eggs. If she can inject the eggs within two hours after they are laid, she gets less mosaicism in the CRISPR mutation than with three- or four-hour-old eggs. (Photo credit: Luca Livraghi)

After injecting thousands of eggs, Concha finally got full CRISPR knockout of three co-mimetic pairs of Heliconius butterflies. I honestly thought that co-mimetic Heliconius species were generated by similar tweaks of the same developmental pathways. I was wrong, says Owen McMillan, Ph.D., Dean of Academic Programs at STRI. In all three co-mimetic pairs, the resulting mutant butterflies had dramatically different wing color patterning after removing the WntA gene, supporting the second hypothesis that even highly different pathways can lead to the same wing pattern.

CRISPR allowed us to push our basic understanding of the pathways underlying wing pattern formation in entirely new directions. We have made great progress in identifying the key genes underlying pattern formation, but CRISPR allows us, for the first time, to understand how they work. It is a remarkably cool tool for discovery, says McMillan.

While major changes have been made to the regulatory pathway of WntA, resulting in these wing patterning differences, they do all focus on the same gene. But the really surprising part of this paper is that despite these butterflies developing under different conditions and experiencing different evolutionary histories over millions of years, they still converged upon the same phenotype with a completely different network of gene regulation. This really highlights that the genome has a few favorite genetic tools that drive the evolution of specific parts of the anatomy, but the way these tools can be used is flexible, says Martin

If youd like to learn more, here is a video showing the method of using CRISPR to change butterfly wing patterning:

Laura Kraftis a Ph.D. student at North Carolina State University and a National Science Foundation Graduate Research Fellow. When she isnttraveling the world, she spends her time making science more accessible through science writing and outreach. Email:ljkraft@ncsu.edu.

Related

Read the rest here:
CRISPR Cuts Through Layers of Butterfly Wing-Pattern Evolution - Entomology Today

Recommendation and review posted by Bethany Smith

Dublin, Jan. 09, 2020 (GLOBE NEWSWIRE) -- The "Global CRISPR Technology Market 2019-2025" report has been added to ResearchAndMarkets.com's offering.

The global CRISPR technology market is expected to witness a significant growth rate during the forecast period.

Industry giants are working in CRISPR technology development and are investing in the R&D of the technology. Such investments are expected to create an opportunity for the growth of the market in the near future.

The global CRISPR technology market is segmented on the basis of application and end-user. Based on the application, the market is segmented into biomedical applications, agricultural applications, and industrial applications. In fruit crops, CRISPR technology has numerous applications as it improves the important agronomic traits such as biotic and abiotic stress tolerance and fruit quality.

Further, on the basis of end-user, the market is segmented into pharmaceutical & biopharmaceutical companies, and academic & research institutes. CRISPR being a really new technology seeks the interest of everyone from doctors to academic & research institutes. CRISPR holds a lot of hidden potentials to cure many rare and incurable diseases that are still to be discovered and is driving the academic & research institutes as an end-user segment to grow with a significant rate in the market.

Geographically, the market is segmented into four major regions; North America, Europe, Asia-Pacific and Rest of the world (RoW). Among these, North America is expected to hold a prominent position in the global CRISPR technology market. The presence of major pharma companies in the region tends to enhance the growth of the global CRISPR market.

Further, the report covers the analysis of several players operating in the market. Some of the players include Thermo Fisher Scientific Inc., Merck KGaA, GenScript Biotech Corp., Horizon Discovery Group PLC, CRISPR Therapeutics AG, and others.

The report covers:

Key Topics Covered

1. Report Summary 1.1. Research Methods and Tools1.2. Market Breakdown 1.2.1. By Segments1.2.2. By Geography

2. Market Overview and Insights2.1. Scope of the Report 2.2. Analyst Insight & Current Market Trends2.2.1. Key Findings2.2.2. Recommendations2.2.3. Conclusion2.3. Rules & Regulations

3. Competitive Landscape3.1. Company Share Analysis3.2. Key Strategy Analysis3.3. Key Company Analysis 3.3.1. Thermo Fisher Scientific, Inc. 3.3.1.1. Overview3.3.1.2. Financial Analysis3.3.1.3. SWOT Analysis3.3.1.4. Recent Developments3.3.2. Merck KGaA3.3.2.1. Overview3.3.2.2. Financial Analysis3.3.2.3. SWOT Analysis3.3.2.4. Recent Developments3.3.3. GenScript Biotech Corp.3.3.3.1. Overview3.3.3.2. Financial Analysis3.3.3.3. SWOT Analysis3.3.3.4. Recent Developments3.3.4. Horizon Discovery Group PLC3.3.4.1. Overview3.3.4.2. Financial Analysis3.3.4.3. SWOT Analysis3.3.4.4. Recent Developments3.3.5. CRISPR Therapeutics AG3.3.5.1. Overview3.3.5.2. Financial Analysis3.3.5.3. SWOT Analysis3.3.5.4. Recent Developments

4. Market Determinants4.1. Motivators4.2. Restraints4.3. Opportunities

5. Market Segmentation5.1. CRISPR Technology Market by Application5.1.1. Biomedical Applications5.1.2. Agricultural Applications5.1.3. Industrial Applications5.2. Global CRISPR Technology Market by End-User5.2.1. Pharmaceutical and Biopharmaceutical Companies5.2.2. Academic & Research Institutes

6. Regional Analysis6.1. North America6.1.1. United States6.1.2. Canada6.2. Europe6.2.1. UK6.2.2. Germany6.2.3. Italy6.2.4. Spain6.2.5. France6.2.6. Rest of Europe6.3. Asia-Pacific6.3.1. China6.3.2. India6.3.3. Japan6.3.4. Rest of Asia-Pacific6.4. Rest of the World

7. Company Profiles7.1. AstraZeneca PLC7.2. BASF SE7.3. Beam Therapeutics Inc.7.4. Bio-Rad Laboratories, Inc.7.5. Caribou Bioscience Inc.7.6. Cellectics SA7.7. Cibus, Ltd.7.8. CRISPR Therapeutics AG7.9. Danaher Corp.7.10. Editas Medicine7.11. GeneCopoeia inc.7.12. GenScript Biotech Corp.7.13. Horizon Discovery Group PLC7.14. Intellia Therapeutics Inc.7.15. Lonza Group Ltd.7.16. Merck KGaA7.17. New England Biolabs, Inc.7.18. Origene Technologies, Inc.7.19. Pairwise Plants7.20. Precision Bioscience, Inc.7.21. Sangamo Therapeutics Inc.7.22. Thermo Fisher Scientific, Inc.7.23. Transposagen Biopharmaceuticals, Inc.7.24. Tropic Biosciences UK LTD.7.25. Yield10 Bioscience, Inc.

For more information about this report visit https://www.researchandmarkets.com/r/11g9aw

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Research and Markets also offers Custom Research services providing focused, comprehensive and tailored research.

CONTACT: ResearchAndMarkets.comLaura Wood, Senior Press Managerpress@researchandmarkets.comFor E.S.T Office Hours Call 1-917-300-0470For U.S./CAN Toll Free Call 1-800-526-8630For GMT Office Hours Call +353-1-416-8900

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CRISPR Technology Market Insights and Forecast, 2019-2025 - Analysis of Biomedical, Agricultural and Industrial Applications - Yahoo Finance

Recommendation and review posted by Bethany Smith

Scientists from China National Rice Research Institute reported that FLN2, a gene that encodes fructokinase-like protein2, influences sugar metabolism as well as rice plants response to salinity stress. The results of their study are published in Biomolecules.

Several mutagenized rice lines were grown under high salinity conditions to pinpoint the genes needed for the expression of salinity tolerance. Some rice lines with mutation in FLN2 showed susceptibility to salinity stress. Wild-type rice lines exposed to salinity stress showed up-regulated FLN2, while CRISPR-Cas9-generated lines with dysfunctional FLN2 exhibited hypersensitivity to salinity stress. Furthermore, sugar metabolism was reduced in the knockout line than in wild-type plants. This may imply that the compromised salinity tolerance in FLN2 knockout plants was caused by the shortage in assimilate needed for growth.

The researchers concluded that FLN2 is vital in seedling growth as well as in tolerance to salinity stress.

Read full, original article: Crop Biotech Update January 8, 2020

More here:
CRISPR-edited crops reveal gene responsible for salt tolerance in rice - Genetic Literacy Project

Recommendation and review posted by Bethany Smith

CRISPR Therapeutics AG (NASDAQ:CRSP) shareholders might be concerned after seeing the share price drop 11% in the last month. But that doesnt undermine the rather lovely longer-term return, if you measure over the last three years. In three years the stock price has launched 170% higher: a great result. To some, the recent share price pullback wouldnt be surprising after such a good run. The fundamental business performance will ultimately dictate whether the top is in, or if this is a stellar buying opportunity.

View our latest analysis for CRISPR Therapeutics

Because CRISPR Therapeutics made a loss in the last twelve months, we think the market is probably more focussed on revenue and revenue growth, at least for now. Generally speaking, companies without profits are expected to grow revenue every year, and at a good clip. Thats because its hard to be confident a company will be sustainable if revenue growth is negligible, and it never makes a profit.

In the last 3 years CRISPR Therapeutics saw its revenue grow at 87% per year. Thats much better than most loss-making companies. Along the way, the share price gained 39% per year, a solid pop by our standards. But it does seem like the market is paying attention to strong revenue growth. Thats not to say we think the share price is too high. In fact, it might be worth keeping an eye on this one.

You can see below how earnings and revenue have changed over time (discover the exact values by clicking on the image).

While the share price may move with revenue, other factors can also play a role. For example, weve discovered 4 warning signs for CRISPR Therapeutics (of which 1 is major) which any shareholder or potential investor should be aware of.

Were pleased to report that CRISPR Therapeutics rewarded shareholders with a total shareholder return of 64% over the last year. That gain actually surpasses the 39% TSR it generated (per year) over three years. The improving returns to shareholders suggests the stock is becoming more popular with time. Shareholders might want to examine this detailed historical graph of past earnings, revenue and cash flow.

If you like to buy stocks alongside management, then you might just love this free list of companies. (Hint: insiders have been buying them).

Please note, the market returns quoted in this article reflect the market weighted average returns of stocks that currently trade on US exchanges.

If you spot an error that warrants correction, please contact the editor at editorial-team@simplywallst.com. This article by Simply Wall St is general in nature. It does not constitute a recommendation to buy or sell any stock, and does not take account of your objectives, or your financial situation. Simply Wall St has no position in the stocks mentioned.

We aim to bring you long-term focused research analysis driven by fundamental data. Note that our analysis may not factor in the latest price-sensitive company announcements or qualitative material. Thank you for reading.

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Shareholders Are Thrilled That The CRISPR Therapeutics (NASDAQ:CRSP) Share Price Increased 170% - Simply Wall St

Recommendation and review posted by Bethany Smith

The roaring 20s are upon us, and the investment opportunities set in front of us are exhilarating. This new decade has a lot in store for us with tech as the driving force behind it.

FAANG was the acronym that drove the stock market to continuously new highs over the past decade: Facebook (FB), Amazon (AMZN), Apple (AAPL), Netflix (NFLX), and Google aka Alphabet (GOOGL). This is an acronym that I am sure you are familiar with. These stocks exponential returns may be exhausted, and a new set of equities are ready to take their place. It is time to look for the new FAANG.

When assessing market-shifting companies, you need to look for firms with an exciting product offering characterized by longevity and a substantial total addressable market (TAM). Firms with savvy management teams that are able to navigate through both the best and worst times nimbly.

I have chosen a new acronym of stocks that I believe could change the world in the roaring 20s. The companies include Crispr (CRSP), Sea Limited (SE), Alibaba (BABA), Nvidia (NVDA), and Splunk (SPLK) or SCANS, as I like to call it.

Here I will give a brief introduction of each stock and explain why I believe these shares will drive the market in this new decade.

Sea Limited (SE)

Sea is the leading internet company in Southeast Asia and Taiwan. These economies are digitalizing at an exponential rate, and Sea is well-positioned to take on the quickly expanding addressable market. The company operates three market leader segments, including an ecommerce platform, a digital entertainment division, and a digital payment company (Shopee, Garena, and AirPay, respectively).

The internet economy in Southeast Asia has tripled in the past 5 years to $100 billion and is expected to triple again by 2025 to $300 billion. Sea is growing at an even faster rate, with year-over-year topline appreciation in the high triple-digit percentages as the company continues to take an increasing amount of market share.

Sea Limited is going to be the tech powerhouse that helps turn the third world economies of Southeast Asia and Taiwan into digitalized world markets.

CRISPR (CRSP)

CRISPR is a biomedical firm that is on the verge of changing the world. This company can edit an individuals DNA, an achievement that is going to change modern medicine. This technology could be used to cure almost any disease if it is successfully implemented. What CRISPRs gene therapy does is splice out the bad or disease driving DNA and add healthy strands. The company is also a leader in regenerative stem-cell medicine, which could save the lives of 100s of thousands.

CRISPR has an established portfolio of life-changing therapies in its pipeline at various stages of development. Hemoglobinopathy is the closest to commercially viable and is currently in clinical trials. If it passes clinical trials, I see this stock jumping substantially.

These shares are still a risky asset considering the possibility that none of its gene-therapies make it past the clinical stage. Based on early trials, it appears that the therapy does indeed work, and this potential has begun to be priced into CRSP. The stock has appreciated 350% since it went public in late 2016, and I believe that this is just the beginning of its growth. The ability to change an individuals DNA is going to change the world of medicine.

Alibaba (BABA)

The Amazonof the East has been driving substantial growth, but I dont believe that investors are correctly valuing Alibabas fundamentals. BABA is trading at roughly 1/3rd of Amazons forward P/E valuation (seen below), despite achieving wider margins, stronger profitable, and a greater growth outlook. Alibaba is operating in one of the worlds largest and fastest-growing consumer markets (China).

Story continues

Alibaba controls not only Chinas ecommerce market but also its cloud computing space with a 47% market share. Its cloud computing space has the most room to run as Chinas cloud infrastructure continues to expand at an exponential rate high double-digit to triple-digit percentages.

Alibaba still has some geopolitical risk due to the US-China trade war, but as far as this next decades biggest equity drivers, I would replace AZMN with BABA in my portfolio.

Nvidia (NVDA)

This is the most exciting chip maker in the world today. Nvidia is known for the invention of the GPU, which is a chip original purposed for image rendering, but Nvidia has taken its capabilities far beyond this. Nvidias chips are hyper-fast and slowly becoming smarter as the technology develops. Its chips are becoming a necessity in data centers and are an essential element of AI development. I believe that one of Nvidias integrated circuits will be apart of the first true AI, which is going to change the world.

Nvidia is also leveraging 5G with its anticipated cloud gaming platform. Like cloud computing is the future of business data and analytics, cloud gaming is the future of gaming. Nvidia is making a big bet in this field with its cloud platform, GeForce NOW. This platform allows gamers to use their Macs or PCs for gaming anywhere with the high-speed, low-latency technology of Nvidias GPUs without needing Nvidias hardware locally.

Nvidia is undoubtedly a company of the future, and despite its 4-digit gains over the past decade, I believe that this stock still has legs to run. I dont think that the company has scratched the surface of what its chips could do.

Splunk (SPLK)

Splunk is a platform that helps companies utilize real-time machine data for collection, indexing, and alerts, allowing companies to uncover actionable insight from this data no matter the source or format. The company is leveraging AI and machining learning for forecasting and anticipative decision making.

Real-time data management is becoming increasingly necessary in business across industries as this digital age makes speed a competitive advantage. Splunk is well-positioned to take on the massive addressable market that is yet to recruit Splunks services. This firm is well-suited to transform the way our economy utilizes real-time data.

Take Away

The market driving stocks will undoubtedly make excellent long-term investments for the roaring 20s. SCANS will be a force to be reckoned with in this next decade. Short term volatility in these stocks shouldnt cause you to shy away from their long-term potential. I believe we may be on the edge of a market correction, so if you are worried about short-term earnings, I may wait for a pullback. If you are a long-term investor that is willing to ride this decades waves, I wouldnt hesitate to pull the trigger on these stocks.

Breakout Biotech Stocks with Triple-Digit Profit Potential

The biotech sector is projected to surge beyond $775 billion by 2024 as scientists develop treatments for thousands of diseases. Theyre also finding ways to edit the human genome to literally erase our vulnerability to these diseases.

Zacks has just released Century of Biology: 7 Biotech Stocks to Buy Right Now to help investors profit from 7 stocks poised for outperformance. Our recent biotech recommendations have produced gains of +98%, +119% and +164% in as little as 1 month. The stocks in this report could perform even better.

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Click to get this free report Splunk Inc. (SPLK) : Free Stock Analysis Report Sea Limited Sponsored ADR (SE) : Free Stock Analysis Report NVIDIA Corporation (NVDA) : Free Stock Analysis Report Netflix, Inc. (NFLX) : Free Stock Analysis Report Alphabet Inc. (GOOGL) : Free Stock Analysis Report Facebook, Inc. (FB) : Free Stock Analysis Report CRISPR Therapeutics AG (CRSP) : Free Stock Analysis Report Alibaba Group Holding Limited (BABA) : Free Stock Analysis Report Amazon.com, Inc. (AMZN) : Free Stock Analysis Report Apple Inc. (AAPL) : Free Stock Analysis Report To read this article on Zacks.com click here. Zacks Investment Research

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SNACS: The FAANG Of The Roaring 20s - Yahoo Finance

Recommendation and review posted by Bethany Smith

Due in large part to the J.P. Morgan Health Care conference in San Francisco, the biotechnology industrys marquee yearly confab, January is often a strong month for related equities and ETFs.

That conference can serve as a springboard for mergers and acquisitions activity and with the genomic space currently in the spotlight, an uptick in consolidation in that arena could benefit the Global X Genomics & Biotechnology ETF (Nasdaq: GNOM).

GNOM tracks the Solactive Genomics Index and seeks to invest in companies that potentially stand to benefit from further advances in the field of genomic science, such as companies involved in gene editing, genomic sequencing, genetic medicine/therapy, computational genomics, and biotechnology, according to Global X.

Companies are only eligible for inclusion if they generate at least 50% of their revenues from genomics related business operations. The index is market cap-weighted with a single security cap of 4.0% and a floor of 0.3%. The ETF provides exposure to CRISPR, gene editing and therapeutics companies. CRISPR, in particular, is an area to watch.

January is disproportionately represented both by a number of deals and dollar value over the past 5 years, Evercore ISI analyst Josh Schimmer wrote in a note out Wednesday morning, reports Josh Nathan-Kazis for Barrons. January has seen as high as 33% of a years total deals (5/15 in Jan 2018) and as high as 48% of a years total dollar value ($36bn/$76bn in Jan 2017).

GNOM tries to help investors take on a thematic multi-capitalization exposure to innovative elements that cover advancements in gene therapy bio-informatics, bio-inspired computing, molecular medicine, and pharmaceutical innovations. These advancements can also translate over to growth potential, potentially providing investors with long-term alpha with low correlation relative to traditional growth strategies.

Entering 2020, will companies look to keep their heads down with modest guidance? Schimmer wrote, according to Barrons. If so, we might see another choppy month, although the macro setup is quite different this time around with expectations around conservative price hikes already in sentiment.

For more thematic investing ideas, visit our Thematic Investing Channel.

The opinions and forecasts expressed herein are solely those of Tom Lydon, and may not actually come to pass. Information on this site should not be used or construed as an offer to sell, a solicitation of an offer to buy, or a recommendation for any product.

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Why This Thematic Healthcare Could be a January Winner - ETF Trends

Recommendation and review posted by Bethany Smith

CAMBRIDGE, Mass., Jan. 09, 2020 (GLOBE NEWSWIRE) -- Intellia Therapeutics, Inc. (NASDAQ: NTLA), a leading genome editing company focused on the development of curative therapeutics using CRISPR/Cas9 technology both in vivo and ex vivo, today provided an update on recent progress and the Companys 2020 priorities and expected milestones.

2020 will be a significant year for Intellia, as we execute on our full-spectrum strategy. With milestones anticipated across our pipeline, we are making important progress towards the development of curative treatments for severe diseases. In particular, we expect to dose ATTR patients with the first-ever systemically delivered CRISPR/Cas9-based therapy this year, and we are beginning IND-enabling activities for our newly announced development candidate, NTLA-5001, a WT1-TCR-directed engineered cell therapy, for treatment of AML, said Intellia President and Chief Executive Officer, John Leonard, M.D. We are focused on developing a robust platform with modular genome editing capabilities that enable a fast and reproducible path to development. Todays update reflects this strategy, and it also features the announcement of our third development program, an in vivo knockout approach for HAE. Importantly, this program leverages the infrastructure and insights from NTLA-2001 and underscores our ability to produce a rapid succession of new clinical candidates. We are excited by the strong momentum across our diverse pipeline and look forward to providing updates on our development programs in the upcoming year.

Program Updates and Anticipated 2020 Milestones:

Cash Position and Financial Guidance:

About Intellia Therapeutics

Intellia Therapeutics is a leading genome editing company focused on developing proprietary, curative therapeutics using the CRISPR/Cas9 system. Intellia believes the CRISPR/Cas9 technology has the potential to transform medicine by permanently editing disease-associated genes in the human body with a single treatment course, and through improved cell therapies that can treat cancer and immunological diseases, or can replace patients diseased cells. The combination of deep scientific, technical and clinical development experience, along with its leading intellectual property portfolio, puts Intellia in a unique position to unlock broad therapeutic applications of the CRISPR/Cas9 technology and create a new class of therapeutic products. Learn more about Intellia Therapeutics and CRISPR/Cas9 atintelliatx.comand follow us on Twitter @intelliatweets.

Forward-Looking Statements

This press release contains forward-looking statements of Intellia Therapeutics, Inc. (Intellia or the Company) within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements include, but are not limited to, express or implied statements regarding Intellias beliefs and expectations regarding its planned submission of an investigational new drug (IND) application for NTLA-2001 for the treatment of transthyretin amyloidosis (ATTR) in mid-2020; its plans to submit an IND application for NTLA-5001, its first T cell receptor (TCR)-directed engineered cell therapy development candidate for its acute myeloid leukemia (AML) program in the first half of 2021; its plans to nominate a development candidate for its hereditary angioedema (HAE) program in the first half of 2020; its plans to advance and complete preclinical studies, including non-human primate studies for its ATTR program, AML program, HAE program and other in vivo and ex vivo programs; its presentation of additional data at upcoming scientific conferences, and other preclinical data in 2020; the advancement and expansion of its CRISPR/Cas9 technology to develop human therapeutic products, as well as maintain and expand its related intellectual property portfolio; the ability to demonstrate its platforms modularity and replicate or apply results achieved in preclinical studies, including those in its ATTR, AML and HAE programs, in any future studies, including human clinical trials; its ability to develop other in vivo or ex vivo cell therapeutics of all types, and those targeting WT1 in AML in particular, using CRISPR/Cas9 technology; its business plans and objectives for its preclinical studies and clinical trials, including the therapeutic potential and clinical benefits thereof, as well as the potential patient populations that may be addressed by its ATTR program, AML program, HAE program and other in vivo and ex vivo programs; the impact of its collaborations on its development programs, including but not limited to its collaboration with Regeneron Pharmaceuticals, Inc. (Regeneron) and Regenerons ability to enter into a Co/Co agreement for the HAE program; statements regarding the timing of regulatory filings for its development programs; its use of capital, including expenses, future accumulated deficit and other financial results during 2019 or in the future; and the ability to fund operations through the end of 2021.

Any forward-looking statements in this press release are based on managements current expectations and beliefs of future events, and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to: risks related to Intellias ability to protect and maintain our intellectual property position; risks related to Intellias relationship with third parties, including our licensors; risks related to the ability of our licensors to protect and maintain their intellectual property position; uncertainties related to the initiation and conduct of studies and other development requirements for our product candidates; the risk that any one or more of Intellias product candidates will not be successfully developed and commercialized; and the risk that the results of preclinical studies or clinical studies will not be predictive of future results in connection with future studies. For a discussion of these and other risks and uncertainties, and other important factors, any of which could cause Intellias actual results to differ from those contained in the forward-looking statements, see the section entitled Risk Factors in Intellias most recent annual report on Form 10-K as well as discussions of potential risks, uncertainties, and other important factors in Intellias other filings with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and Intellia undertakes no duty to update this information unless required by law.

Intellia Contacts:

Investors:Lina LiAssociate DirectorInvestor Relations+1 857-706-1612lina.li@intelliatx.com

Media:Jennifer Mound SmoterSenior Vice PresidentExternal Affairs & Communications+1 857-706-1071jenn.smoter@intelliatx.com

Excerpt from:
Intellia Therapeutics Highlights Recent Progress and Anticipated 2020 Milestones - GlobeNewswire

Recommendation and review posted by Bethany Smith

Im not sure how the task fell to me, but over the years I have become my familys de facto genealogist. To my amateur sleuthing credit, I have uncovered more secrets and put to bed more family rumors than one could imagine. During my quest to learn more about my family heritage, I purchased a 23andMe genetic test, which can tell you not only the geographical roots of your human existence but also your migration routeand even genetic traits like the fear of public speaking. What I didnt realize at the time was the treasure trove of information that existed on the back end of a 23andMe test, information that may be even more important to my well-being and that of my descendants than knowing the likelihood that I move more than average during sleep.

This rich data is already collected as a part of these tests but is not directly reported to the user. It contains information on vulnerabilities in nutrition, inflammation, and detoxification capacity; susceptibility to heart or neurological disease, cognitive or mood dysfunction, and cancer; and deficiencies in cellular metabolism, including which nutrients are in higher demand. This is the kind of imperative knowledge I wanted to have, so I set out to find a professional to analyze it.

The journey took me to the Strata Integrated Wellness Spa at Garden of the Gods Resort & Club in Colorado Springs, Colorado, where I checked into one of its new casitas for a long weekend. There, Karly Powell, a registered naturopathic doctor with expertise in therapeutic nutrition and functional biochemistry, has developed a program called Decode Your DNA. In it, she conducts a specialized analysis of the raw data of a clients DNA to provide an understanding of an individuals genetic health background and deficiencies and then creates a personalized wellness plan.

According to Dr. Michael Barber, Stratas medical director, the most common issues are found are in the so-called methylation pathways, which control how our bodies handle nutrients, supplements, and medications. Abnormalities in these pathways can influence the risks for neurological, cardiac, cardiovascular, gastrointestinal, and other systemic illnesses. With my newly analyzed DNA information, Powell crafted a custom-made, gene-based prescription for me that included a long-term dietary program, targeted nutritional supplementation, and lifestyle modifications.

That weekend, I began to make her suggested modifications and utilized the doctors, physicians, clinicians, and therapists at Strata. Strata is one of the few spas in the country that offer this kind of personalized medicine paired with bespoke nutrition and fitness, as well as the opportunity to address cardiology, kinesiology, and energy needs in the same facility.

Many people say that your genesgeneticsare not your future but your potential, Barber says. Knowing in advance where one might be susceptible to issues such as heart disease, cognitive or mood dysfunction, cancer, or nutritional issues may allow a person to alter critical components of diet, exercise, [and] lifestyle to maximize their potential for optimal health.

See the article here:
Conducting Gene Therapy in Colorado - dujour.com

Recommendation and review posted by Bethany Smith

Vision 2020

Few industries change as rapidly and as dramatically as the broad, multifaceted realm of healthcare. From oncologists use of cancer fingerprinting and gene therapy to facial transplants for accident victims; from cutting-edge protocols to save the lives of stroke and heart-surgery patients to a dizzying array of new treatments to improve vision the list is seemingly endless, making it impossible to paint a full picture of where healthcare has come in the past decade.

But we at BusinessWest wanted to try anyway and, at the same time, look ahead at what the next decade might bring. So, appropriately, here at the dawn of 2020, we invited a wide range of healthcare professionals to tell us what has been the most notable evolution in their field of practice in the past 10 years, and what they expect or hope will be the most significant development to come in the next decade.

The answers were candid, thoughtful, sometimes surprising, but mostly hopeful. Despite the many challenges healthcare faces in these times of advancing technology, growing cost concerns, and demographic shifts, the main thread is still innovation smart people working on solutions that help more people access better care. After all, healthcare is, at its core, about improving peoples lives, even when they seek it out during their direst moments.

Innovation and promise. Thats what we believe a new decade will bring to all corners of the healthcare world that is, if these leaders, and countless others like them, have anything to say about it.

Joanne Marqusee

President and CEO, Cooley Dickinson Health Care

Joanne Marqusee

The most significant recent development in healthcare administration has been a recognition of the role patients play in their own healthcare. Crossing the Quality Chasm: A New Health System for the 21st Century, published in 2001 by the Institute for Healthcare Improvement, called for a massive redesign of the American healthcare system. Specifically, it provided Six Aims for Improvement, five of which focused on safety, effectiveness, timeliness, efficiency, and equity. Not talked about as much, the sixth aim was to make healthcare patient-centered.

While we still have a ways to go to truly be patient-centered, we have witnessed a sea change in the past decade in this regard. Patients are increasingly active participants in their care, questioning their doctors and other providers to ensure that they understand their options, using electronic medical records to engage in their care, and speaking out about what they want from treatment or forgoing treatment at the end of life. The best healthcare providers both organizations and individuals embrace these changes, welcoming patients as more than recipients of care, but rather active partners in their own care and decision making.

My hope for the most significant development over the next decade has to do with providing universal healthcare coverage while controlling healthcare costs. While we almost have universal coverage in Massachusetts, too much of the nation does not. A hotly debated topic, universal healthcare has many benefits, including increasing access to preventive and routine medical care, improving health outcomes, and decreasing health inequalities.

Dr. Nicholas Jabbour

Chairman, Department of Surgery, Baystate Medical Center

Dr. Nicholas Jabbour

The most significant development in surgery over the past decade has been the move toward less invasive surgical approaches made possible through advanced technology. These approaches include robotic and minimally invasive surgery, including intraluminal surgery in areas such as gastroenterology, cardiology, and neurosurgery for exemple, the passage of an inflatable catheter along the channel inside of a blood vessel to enable the insertion of a heart valve instead of making a large opening in the chest. As a result, we have seen a big shift from inpatient to outpatient surgery with shorter hospital stays and improved post-op recovery.

In the next decade, we foresee these innovations in less invasive surgery will be enhanced by better computing and software integration. This interaction will include the merging of radiological and potentially pathological information which is currently available in a digital format with real-time visualization of anatomical structure during surgery. This will offer surgeons the opportunity to improve the accuracy and speed of a surgical procedure while minimizing the risks.

The next decade will also see major innovation in the area of transplantation with the development of tissues or whole organs through bio-engineering manipulation of animal or a patients own cells. The integration of this bio-engineering manipulation with currently available technology, such as 3D printing and 3D imaging, will provide patients with the needed tissue or organ including valves, bone grafts, hernia mesh, skin, livers, and kidneys in a timely manner. This development will revolutionize the field of transplantation and surgery in general.

Karin Jeffers

President & CEO, Clinical & Support Options Inc.

Karin Jeffers

Over the past 10 years, weve seen a growing adoption within the behavioral-health and medical fields of holistic treatment models. While the two disciplines were once treated as different animals, the entire health field is now moving to treat both the body and the mind together. The next 10 years are likely to bring these two fields even closer.

Today, youre seeing behavioral-health clinicians being hired into physical health practices. Likewise, physical health providers are cross-training to better understand behavioral issues. Whereas, a decade ago, a behavioral-health client might be assigned a therapist or a psychiatrist, they are now gaining access to more robust set of supports, including nursing, case management, recovery coaching, and peer support from those with lived experience. Government mandates and payment model changes are forcing outcomes-based integration, too. Pediatricians, for example, must now do behavioral-health screenings of all youth under 21. In the mental-health space, youre seeing clinicians ask about weight, exercise, and other physical factors.

Were seeing significant movement on both the state and federal levels to value outcomes over volume. Its reflected in the criteria set by the Excellence in Mental Health Act for certified community behavioral-health clinics, a designation CSO has earned, and in the work we have done with the Substance Abuse and Mental Health Services Administration. Our ability to tailor programs, like our grant-funded work at the Friends of the Homeless shelter in Springfield, has literally saved lives among those experiencing homelessness and co-occurring conditions, like substance-use disorders.

In the coming years, we hope to see integrated care models become even more mainstream. Things appear headed in the right direction, but government action establishing payment reform within the behavioral-health field needs to be taken and the integrated models need to be appropriately funded. Such changes would affirm overall health and wellness to include both physical and behavioral health.

Dr. Yannis Raftopoulos

Director, Holyoke Medical Center Weight Management Program

Dr. Yannis Raftopoulos

Weight management is a rapidly evolving field, and I am fortunate to be part of it. One of the most significant innovations this field has experienced in the last 10 years was the development of a new gastric balloon. Packaged in a small capsule and swallowed with water, the Elipse balloon provides satiety while requiring no procedure or anesthesia for its placement and removal. Together with its excellent safety profile, the Elipse balloon is the least invasive and yet effective weight-loss modality available today. Elipse is manufactured in Massachusetts by Allurion Technologies.

I had the opportunity to be an investigator in the European trial which led to the Elipse market approval in the European Union in 2016. Recently, Holyoke Medical Center was among 10 U.S. sites in which an FDA-regulated trial was conducted. The trial was completed successfully, and Allurion has submitted data requesting FDA approval to market Elipse in the U.S. The balloons use in Europe shows that patients can lose more than one-fifth of their initial weight.

A New England Journal of Medicine study reported that 107.7 million children and 603.7 million adults, among 195 countries, were obese in 2015. High body-mass index accounted for 4 million deaths and contributed to 120 million disability-adjusted life-years. Obesity is a chronic disease, and its management requires long-term guidance and close patient-physician communication. Successful collaborations between existing best practices with technology innovations that will allow delivery of effective weight-management care on a massive and global scale could be the most significant evolution in the field in the next 10 years.

Dr. Hong-Yiou Lin

Radiation Oncologist, Mercy Medical Center

Dr. Hong-Yiou Lin

The advent of new medical oncology drugs has improved control of microscopic and, to a lesser extent, macroscopic disease, allowing local treatments, such as surgery or radiotherapy, to increase survival. To cure cancer, we need to eliminate cancer cells where they started, as well as any microscopic cells traveling through the body. The idea of using immunotherapy to fight cancer has been around for decades, but bringing this idea to the clinic has been hampered by the cleverness of cancer cells knowing how to evade detection by our immune system. Recently FDA-approved immunotherapy either takes away that invisibility cloak or wakes up our dormant immune cells to start fighting cancer.

The biggest development in oncology in the next 10 years will be personalized precision medicine, which allows the oncology team to tailor treatment to each patients unique cancer biology and life circumstances. Meanwhile, improvements in cancer diagnosis will come from novel PET radiotracers and new MRI sequences that allow for more accurate staging and identification of the best site to biopsy. Pathologists will use novel tools such as genome sequencing to supplement traditional microscopy to subclassify the specific type of cancer within a certain diagnosis instead of grouping into broad categories.

Surgical, medical, and radiation oncologists can then use the above information to decide on the best sequencing between surgery, systemic therapy, and radiotherapy to minimize side effects and maximize cure. Medical oncologists will be able to offer more drugs that target new mutations, overcome drug resistance, increase specificity to a mutation, or better fine-tune immunotherapy, targeting only cancer cells by enlisting gene modification as well as natural killer cells. Radiation oncologists will have new radiomic and genomic tools to personalize the radiation dose and volume, and when to offer radiotherapy.

In short, over the next 10 years, cancer care will continue to move away from the traditional one-size-fits-all model toward a more personalized approach.

Dr. Jonathan Bayuk

Medical Director, Allergy & Immunology Associates of New England

Dr. Jonathan Bayuk

There have been incredible and exciting advances in allergy and immunology in the last two years. However, the unmet needs of allergic and autoimmune-disease-afflicted patients has grown dramatically in the last 20 years. In response to the increasing prevalence and acuity of allergic diseases and autoimmune diseases, the world has launched products to help address these very severe patients. These medications are indicated for many conditions and work very well. They are generally safe, but are very expensive. These medicines are different than traditional pharmaceutical drugs as they are not chemicals, but biologically derived medicines designed to augment or modify the immune response. As such, they are call biologic medications.

In the field of allergy and immunology, we can now dramatically treat and potentially cure many diseases that in the past were very challenging to manage. The biologic medicines that we have now treat asthma, eczema, allergic disease, and hives. The patient selection is based on severity of their condition, and these medicines are only for moderately to severely affected people. If, as a medical profession, we were to place as many people as possible on these therapies, the cost would be astronomical and not sustainable.

However, is it fair to deny any of these patients access to these treatments who truly need them? I would argue that choice is a very difficult one to make, and as physicians, our primary goal is healing at whatever cost. As a nation, we have a dilemma. Can we afford the medicines we have or not? It is unclear that any serious legislative body is willing to tackle that question. For now, the use of these medicines is changing lives dramatically, and it is an exciting time to be able to use these newer tools to help our patients live better lives.

Dr. David Momnie

Owner, Chicopee Eye Care

Dr. David Momnie

What are the most significant advancements in eye care in the last decade? It depends on whom you ask. Retinal ophthalmologists would probably say its the treatment of wet macular degeneration, a leading cause of blindness, with anti-VEGF injections. Cataract surgeons would most likely cite small-incision surgery and new lens implants that often leave patients with 20/20 vision. Glaucoma specialists might tell you its the development of MIGS, or minimally invasive glaucoma surgery. These operations to lower the pressure in the eye use miniature devices and significantly reduce the complication rate.

Primary-care optometrists and ophthalmologists would no doubt talk about the advances in optical coherence tomography, a remarkable instrument using light waves that gives cross-sectional pictures of the retina. The technique is painless and non-invasive and is becoming the gold standard in eye care because it has revolutionized the diagnosis and treatment of glaucoma and macular degeneration. For optometrists specializing in contact lenses, using newly designed scleral lenses to restore vision in people with a corneal disease called keratoconus has been a major development. There are many other specialists in eye care, including LASIK surgeons, that have seen remarkable changes in technology.

What will the next decade bring? Artificial intelligence (AI) is becoming more accurate for screening, diagnosing, and treating eye conditions. AI systems can increasingly distinguish normal from abnormal pictures of the retina. Where there is a shortage of ophthalmologists and optometrists, AI screenings combined with telemedicine, providing remote care using communications technology, may be able to find and treat more people who are falling between the cracks of our healthcare system. The term 20/20 is the most common designation in eye care, and the year 2020 will probably usher in another decade of remarkable developments in our field.

Teresa Grogan

Chief Information Officer, VertitechIT

Teresa Grogan

From the perspective of technology that enables healthcare, the biggest game changer of the last decade has been the iPhone and now, essentially any smartphone.

Steve Jobs introduced the first iPhone in 2007 (a little over a decade ago), and physicians embraced it quickly. It started as a simple tool for doctors (applications like the PDR, or Physicians Desk Reference) for looking up drug interactions. Today, its a portable EMR, a virtual visit facilitator, and a remote-monitoring device for many healthcare providers, as many patients have embraced and insisted on this technology to improve access to care. As the cost decreases and cellular bandwidth improves, the rapid growth of the IoMT (Internet of Medical Things) will place smartphones at the center of the next wave of healthcare technology breakthroughs.

Looking forward, Id like to see complete elimination of passwords to access electronic information. While there has been some movement toward this with tap and go badges and fingerprint readers, a single standard is needed that would work regardless of the software program used. I hope there are greater strides in the creation, deployment, and adoption of other biometric technologies, like iris, face, or voice recognition, so that a healthcare professional could walk into a patient room or into a hospital and the computer systems would know his or her identity in immediate and secure fashion. If access to the data needed by a healthcare provider were as easy as turning on a light switch, the improvements in quality of life and efficiency in work for that provider would translate to improved patient outcomes.

Dr. Aaron Kugelmass

Vice President and Medical Director, Heart and Vascular Program, Baystate Health

Dr. Aaron Kugelmass

We have seen many improvements in cardiovascular care over the last 10 years, but the development, approval for clinical use, and dissemination of transcutaneous aortic valve replacement (TAVR) stands out as the most dramatic. This new technique allows cardiologists and cardiac surgeons, working together, to replace the aortic valve without opening a patients chest or utilizing heart-lung bypass, which has been the standard for decades. This less invasive approach is typically performed under X-ray guidance and involves accessing a blood vessel in the leg and guiding a catheter to the heart.

The TAVR procedure was first approved for clinical use in November 2011. It was initially limited to very sick patients, who were not candidates for traditional surgery because of the risk it posed to them. TAVR allowed patients who otherwise could not receive life-saving valve surgery to have their valves replaced with improvement in longevity. With time and experience, the procedure was approved for lower-risk patients as well, and more recently has been approved for the majority of patients, including those with low operative risk. TAVR has been shown to be equivalent or safer than traditional aortic valve-replacement surgery, and is quickly becoming the procedure of choice for most patients who require an aortic valve replacement. Since the procedure typically does not require open-heart surgery, recovery time is much shorter, with some patients going home within a day or two.

In the next 10 years, we expect that similar less-invasive procedures with shorter recovery time will be developed for other heart-valve conditions in patients who otherwise could not receive therapy.

Beth Cardillo

Certified Dementia Practitioner and Executive Director, Armbrook Village

Beth Cardillo

During the last 10 years, neuroscientists have been researching the causes of Alzheimers disease. There has been much discussion about which comes first the amyloid plaque or the fibrillary tangles that develop in the brain, which are roadblocks to cognition, thus causing the difficulties with Alzheimers and other related dementia. That question has not been answered yet. Researchers were able to isolate the APOE gene, which is a mutant gene that is found in familial Alzheimers disease, helping us to better diagnose it. We have also better understood how diet, exercising both body and brain, and lifestyle contribute to the disease. Currently there are 101 types of dementia, with Alzheimers accounting for 75% of cases.

The next 10 years will result in more preventive actions. One major action will be to help people avoid developing type 2 diabetes, which may be labeled the next cause of Alzheimers (this type of Alzheimers is already being called type 3 diabetes). There has been a major link between sugar in the hippocampus and Alzheimers disease. Though there is no cure yet for Alzheimers, we are finding more information based on genetics, diet, and PET scans, which can show shrinkage in the brain.

Every year, researchers are more hopeful that a new drug will be developed to eradicate the disease. The last new drug from Biogen was looking hopeful in clinical trials, but that turned out to be not the case. Prevention continues to be at the forefront, as well as participating in clinical trials. More people who do not have dementia or mild cognitive impairment are desperately needed for clinical trials so comparisons of the brain can be made.

Ellen Furman

Director of Nursing, American International College

Ellen Furman

As in all healthcare, the one thing that can be ascertained is constant change. The same can be said in nursing education today. No longer is the instructor-led lecture method of teaching considered best practice in education, but rather the shift to using class time to apply learned concepts. One way this is done is through the flipped classroom. Using this educational modality, students study the concepts being taught preceding the class, followed by class time where students apply these concepts in an interactive activity, thereby developing students abilities to think critically, reason, and make healthcare judgements based upon the application of knowledge.

Another change in nursing education is an expanded focus away from pure inpatient (hospital-based) clinical education to outpatient (community-based) clinical education. While hospital-based education remains essential, the realization that most healthcare provided is in outpatient settings has broadened the clinical experiences required to prepare the graduate registered nurse for care provision.

Additionally, with healthcare as complex as it is, nursing students are being taught to be prepared for entry into practice. Education regarding the use of evidence-based practice, how to apply for the licensure examination, preparation to be successful on the National Certification Licensure Exam, nurse residency opportunities, interviewing techniques, transitioning from student nurse to registered nurse, etc. are all taught using a variety of educational modalities based upon the current best available evidence in nursing education.

As we forge ahead in healthcare, nurse educators will continue to evolve to meet healthcare needs through the education of nursing students so as to prepare them to provide care to meet the needs of those we serve well into the future.

James Haas

Co-owner, Orthotics & Prosthetics Labs Inc.

James Haas

Advances in prosthetic technology have clearly been the most significant development in my field over the past decade. From knees and feet that adapt to different walking speeds and terrains to hands that send sensations of touch to the brain, every aspect of patient care has changed and continues to change at a rapid pace.

Prosthetic feet, knees, and sockets have been greatly impacted. Once made from multi-durometer foams and wood, the prosthetic feet of today are made from carbon, fiberglass, and kevlar laminated with modified epoxy resins. They store energy and adjust to uneven terrain and hills. Microprocessor knees have on-board sensors that detect movement and timing and then adjust a fluid/air control cylinder accordingly. These knees not only make it safer for a person to walk, they also lower the amount of effort amputees must use, resulting in a more natural gait. Sockets once made from stiff materials are now incorporated with soothing gels and flexible adjustable systems that allow a patient to make their own adjustments to improve their comfort.

As for the next decade, I hope to see national insurance fairness. Devices typically last about three to five years. Some people make them last longer, but others, especially growing children, need replacements more often. Many private insurance plans have annual caps and lifetime limits on coverage for orthotics and prosthetics. The Amputee Coalition of America authored insurance-fairness legislation and has lobbied for its implementation for over a decade. This legislation has been ratified in 20 states, including Massachusetts. The Fairness Act requires all insurance policies within the state to provide coverage for prosthetics and orthotics equal to or better than the federal Medicare program and have no coverage caps and lifetime restrictions.

Dr. Lisa Emirzian

Co-owner, EMA Dental

Dr. Lisa Emirzian

The most significant development in the field of dentistry over the past decade has been the integration of digital technology into our daily practices. There are three components of digital dentistry: data acquisition, digital planning, and, finally, the manufacturing of the restoration to be created. Data acquisition today is accomplished with digital radiographs, paperless charting, intra-oral scanners, cone-beam 3D scanners, and video imaging. For the planning process, we now have the ability to merge the data with software that enables computer-aided design and digital smile design, allowing dentists to perform complex procedures, including guided surgical treatments and smile designs, with optimum results. Fabrication and execution of the final restorations can be done in the office or, more often, in laboratories with highly sophisticated digital milling machines, stereolithography, and 3D printing.

In the next decade, we will see data fusion to ultimately create the virtual patient. The next-generation digital workflow will merge intra-oral 3D data with 3D dynamic facial scans, allowing dentists to create 3D smile designs and engineer the dentofacial rehabilitation. The integration of scanners and software will expedite the delivery of teeth in a day. In addition, multi-functional intra-oral scanners will allow for early detection of carious lesions and determine risk levels for different patients.

Above and beyond this foreseeable future, artificial intelligence (AI) will be the next paradigm shift. Companies are already looking for big-data collection and deep machine learning to help the practitioner in their everyday chores of diagnosis and treatment. AI cloud-based design platforms will input data, and AI engines in the background will aid in all parts of dental treatment, including diagnosis, design, and fabrication of final restoration.

Let us not forget one thing: the future is all about us people utilizing technology to enhance the human connection between doctor and patient.

John Hunt

CEO, Encompass Health Rehabilitation Hospital of Western Massachusetts

John Hunt

A significant rehabilitation development from the past includes one that may surprise you. Time. A luxury we once knew, time meant patients could recover in a hospital longer after a surgery, an accident, or an illness. Nurses had more time to assess patients to know exactly what they needed. Insurance companies approved longer patient stays through lengthy consideration. Ten years ago, a stroke survivor could recover for two weeks in a hospital and then join us for a rehabilitation stay that would last several weeks.

Today, a three- to five-day stay in the referring hospital, followed by a two-week stay in rehabilitation, is the norm. We are seeing significant decreases in the age of stroke survivors as well as an increase in the number patients who survive with cognitive and physical disabilities. Yet, we also see medical breakthroughs, including the discovery of tissue plasminogen activator (TPA) nothing short of a miracle. TPA actually reverses the effects of an evolving stroke in patients when used early on, making recoveries easier.

With new advanced technologies being introduced every year, rehabilitation continues to progress at a rapid speed. Looking into the future, evidence-based research will continue to grow to help us make knowledgeable decisions that ultimately impact patient outcomes. Increased clinical expertise will lead to higher functional gains in shorter amounts of time. As a result, acute inpatient rehabilitation will impact the lives of patients like weve never seen before.

Dr. Susan Bankoski Chunyk

Doctor of Audiology, Hampden Hearing Center

Dr. Susan Bankoski Chunyk

The most common treatment for hearing loss is hearing aids. Although digital processing has been available in hearing aids since 1996, the past 10 years have offered great leaps in technology for people with hearing loss. Each generation of computer chip provides faster and smarter processing of sound. Artificial intelligence allows the hearing-aid chip to adjust automatically as the listening environment changes, control acoustic feedback, and provide the best speech signal possible. People enjoy the convenience of current hearing aids Bluetooth streaming, smartphone apps, and rechargeable batteries.

These features are the icing on the cake, but the real cake is preservation of the speech signal, even in challenging listening situations. Since the primary complaint of people with hearing loss is understanding in noise, new hearing-aid technology works toward improving speech understanding while reducing listening effort in all environments. This significantly improves the individuals quality of life.

The negative effects of untreated hearing loss on quality of life are well-documented. Recent research has also confirmed a connection between many chronic health conditions including diabetes, cardiovascular disease, kidney disease, balance disorders, depression, and early-onset dementia and hearing loss. This research shows that hearing loss is not just an inevitable consequence of aging, but a health concern that should be treated as early as possible. My hope for the future is that all healthcare providers will recognize the value of optimal hearing in their patients overall health and well-being and, just as they monitor and treat other chronic health conditions, they will recommend early diagnosis and treatment of hearing loss.

Continued here:
The Region's Health Leaders on What's New and What the Next Decade Will Bring - Business West

Recommendation and review posted by Bethany Smith

LOS ANGELES, Jan. 7, 2020 /PRNewswire/ --Seeing the world through the eyes of a child is often filled with wonder and imagination. It should not include things like hospital beds, needles and chemotherapy. Sadly, these things are a reality for kids with cancer. To raise awareness about childhood cancers and the need to fund research to find cures and better treatments, the St. Baldrick's Foundation, a non-profit on a mission to defy childhood cancers, introduces its 2020 Ambassadors. The five Ambassador families, each touched by childhood cancer, will share their journeys of struggle and triumph, hope and despair, and give people a glimpse into their lives and what comes after hearing those life-changing words, "Your child has cancer."

Coming from all areas of the country, ages, disease types and stages of their cancer journey, the Ambassadors represent the more than 300,000 kids diagnosed with cancer each year worldwide and serve as a reminder that cancer doesn't discriminate.

This year's Ambassadors are:

Seth and Joel Deckerare identical twins with a very special bond not even cancer could separate. The twins did everything together. Along with their older brother, Nathaniel, they filled the Decker home with the sound of laughter and play. Seeing the boys push vehicles around and make loud noises or roar and stomp around pretending to be dinosaurs were familiar sights. But in an ironic twist of fate, the twins were both diagnosed with cancer: Seth was diagnosed with a rare form of acute myeloid leukemia (AML) in December 2016 and three months later, a biopsy revealed Joel also had AML. With the overlapping diagnoses and treatments, the family endured months of separation and treasured the few weeks they could be together at home. Despite both boys receiving bone marrow transplants and enduring complications from the procedures, they relapsed. Surrounded by their loving family, Joel died November 2017 at the age of 3, followed by Seth in May 2019 when he was 4 years old. The Decker family firmly believes much more research is needed for AML, especially when the disease has relapsed. They have created a St. Baldrick's Hero Fund in memory of Joel and Seth to support research that will help find new treatments and cures so other families won't have to say goodbye too soon.

Hudson Walker, 1, from Englewood, Colo., was diagnosed with Ewing sarcoma in February 2019, a rare disease that makes up only 2 percent of all childhood cancers and is very uncommon in babies. Chemotherapy began right away and surgery to remove her scapula resulted in the good news of clean margins. Hudson had a positive attitude through it all, even looking forward to going to the hospital to see the doctors, nurses and therapists who had become her friends. While happy she is cancer free after treatment, her parents know that her cancer journey is not over. As she grows, they will need to remain vigilant with monitoring potential late effects from chemotherapy. But for now, Hudson is enjoying each day, loving her family and her favorite things: queso, french fries, the color pink, unicorns, the movie Aladdin, and all kinds of music especially Lizzo and Kacey Musgraves. Armed with her sparkling personality and the bravery many of us only dream of, Hudson's family is confident she can take on any challenge life puts in her path.

Micah Bernstein, 9, from Carlsbad, Calif., has spent the bulk of his life fighting cancer. Micah was diagnosed with neuroblastoma in March 2012 at just 15 months old. He's had three surgeries, 21 cycles of chemotherapy and 36 sessions of radiation. Two separate phases of his treatment were centered around Unituxin, an immunotherapy drug developed with support from St. Baldrick's that received FDA approval while Micah was in treatment. Since then, Micah's blood work and scans have been clear for more than five years and he's been completely off treatment for nearly a year, which means an important milestone for Micah his first survivorship clinic visit in 2020. Micah is very interested in science and wants to become a doctor. He even has a message for researchers involved with St. Baldrick's: "Thank you for creating new medicines for kids with cancer. Those medicines save kids' lives, and one of them saved mine." Micah's parents, Jeff and Kate, are very passionate about helping to fund the most promising childhood cancer research and have established a St. Baldrick's Hero Fund, the Mighty Micah's Mission Fund, aiming to raise at least $100,000 to fund neuroblastoma research.

Austin Schuetz, 11, from Fall River, Wis., was diagnosed with a high-risk form of acute lymphoblastic leukemia just before his third birthday. Austin faced 3 years of treatment including intense chemotherapy, bone marrow biopsies, and six days of daily cranial radiation. Before Austin could finish treatment, he relapsed. At that point, a bone marrow transplant was his only option for a cure. When that didn't work to eradicate the leukemia, Austin needed a miracle. That miracle came in the form of a gene therapy that uses a child's own immune system to fight the cancer. Austin was accepted in a clinical trial, supported by the St. Baldrick's Foundation, that would collect his T-cells in a lab and train them to seek out and kill the cancer cells. The treatment worked, and Austin is now six years out from the clinical trial that saved his life. Because of research, Austin can enjoy the things he loves, like video games, basketball and Nerf guns.

Shamari Brazile, 14, from Cleveland Heights, Ohio, was diagnosed with osteosarcoma when she was 13 years old. In November 2017, during the middle of basketball season, she complained of pain in her right hip. When the pain didn't improve, tests revealed a mass on her pelvis. Shamari was diagnosed with osteosarcoma in March 2018 and started treatment right away. She endured 10 weeks of inpatient chemotherapy and surgery to remove the tumor, followed by 18 more weeks of chemotherapy before finishing treatment in December 2018. Less than three months after her last treatment, Shamari was already back on the lacrosse field, playing her favorite sport. In her free time, she also enjoys hanging out with friends, listening to music, drawing, teaching herself how to play the ukulele and writing short stories.

St. Baldrick's Ambassadors and their families will act as spokespeople for the St. Baldrick's Foundation, attend events and fundraisers and share their stories to educate the public about the realities of childhood cancers.

Continue following these six courageous storieson the St. Baldrick's blogand social media channels: Facebook,Twitter,YouTubeandVimeo. To learn how you canget involvedvisitwww.StBaldricks.org.

About St. Baldrick's FoundationAs the largest private funder of childhood cancer research grants, the St. Baldrick's Foundation is leading the charge to take childhood back from cancer. St. Baldrick's funds some of the most brilliant childhood cancer research experts who are working to find cures and better treatments for all childhood cancers. Kids need treatments as unique as they are and that starts with funding research just for them. Join us at StBaldricks.org to help support the best childhood cancer research, no matter where it takes place.

SOURCE St. Baldrick's Foundation

http://www.stbaldricks.org

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Meet the St. Baldrick's Foundation 2020 Ambassadors - PRNewswire

Recommendation and review posted by Bethany Smith

LEUKOTAC (inolimomab) is available again in France, following the granting of cohort ATU for the treatment of graft-versus-host disease, corticosteroid-resistant or corticosteroid-dependent, with grade II-IV

Lyon, FRANCE, January 9, 2020, ElsaLys Biotech announced today that the cATU has been granted by the ANSM and its clinical experts, after evaluation of a dossier containing data on the quality, safety and efficacy of the drug based on its administration in several hundred patients included in clinical trials or treatedvia named patient Temporary Authorization for Use (ATU nominative) until November 2015. This authorization includes the implementation of a reinforced monitoring (defined in the Protocol for Therapeutic Use) of the efficacy and safety data obtained in patients treated within the framework of this cATU. Inolimomab treatment can only be considered if the patient cannot be included in an ongoing clinical trial.

"We have data that support the benefit of inolimomab treatment in patients with acute corticosteroid-resistant or corticosteroid-dependent graft-versus-host disease (Grades II-IV in Glucksberg classification)," said Dr. David LIENS, Chief Medical Officer, ElsaLys Biotech. "We are delighted with this decision by the ANSM, which allows us to, once again, make inolimomab (1 mg/mL, solution for infusion) available to hematologists in the therapeutic emergency which is this pathology".

"While we continue to work on the filing of marketing authorization applications (MAA) in Europe and in the US, this ATU demonstrates the therapeutic value of inolimomab in the management of acute graft-versus-host disease (aGvHD). The ATU program in France allows patients, whose survival is at stake, to have access to a therapeutic solution before marketing in Europe, in close collaboration with the competent authority, the ANSM. The implementation of this cATU is effective immediately" said Dr. Christine GUILLEN, CEO and co-founder of ElsaLys Biotech.

Considering the potential emergency situation of the indication, it is recommended that hematology specialists anticipate the administrative procedures by contacting the ATU Cell (by Tel: 0800 08 90 81 - Fax: 01 56 59 05 60 or by e-mail: atu-leukotac@pharma-blue.com) which is at their disposal for any further information or request for a Protocol for Therapeutic Use and collection of information.

About inolimomab (LEUKOTAC)

Inolimomab (LEUKOTAC) is an immunotherapy monoclonal antibody that targets the interleukin-2 receptor (IL-2), a chemical molecule named cytokine that contributes to the development and proliferation of some white blood cells including T-cells responsible for aGvHD. By linking specifically to the a chain of the receptor (CD25), inolimomab prevents IL-2 from binding on the surface of the donors over-active T-cells which blocks their multiplication.

The efficacy of inolimomab in aGvHD lies mainly in its specificity and its preferential affinity to the CD25 receptor found on the surface of T-lymphocytes.

About steroid-resistant aGvHD

Formerly called bone marrow transplant, Hematopoietic Stem Cell Transplantation (HSCT) is the last therapeutic option for patients with certain blood cancers or severe immunodeficiency. In practice, the treatment is designed to replace the diseased blood cells of the patient with the hematopoietic stem cells of a matching donor (allograft).

Once grafted, these stem cells will produce new healthy and functional blood cells, including white blood cells that will allow patients to bridge their immune deficiency or to eliminate surviving cancer cells.

If this technique has made considerable progress in 60 years, half of transplant recipients are still victims of complications: side effects of conditioning pretreatment (that aims to prevent transplant rejection), long-term susceptibility to infections and GvHD. In the latter case, the donors over-active T-cells turn against the patients tissues: mucous membranes, skin, gastro-intestinal tract, liver and lungs. The acute form appears just after the transplant, the chronic form occurring several months later (preceded or not by an aGvHD).

Affecting between 30 to 55% of patients, GvHD is the main complication of transplantation. To halt this autoimmune disease, physicians combine corticosteroids with other immunosuppressive agents. The fact remains that some 30 to 50% of aGvHD gradually become resistant or dependant to these first-line treatments. To date clinicians do not have any standard of treatment approved in Europe for these patients for whom there is a strong unmet medical need. Thus, in Europe, 4,000 children and adults die each year from their aGvHD.

About ELSALYS BIOTECH

ELSALYS BIOTECH is a clinical stage immuno-oncology company which designs and develops a new generation of therapeutic antibodies targeting tumors and their immune and/or vascular microenvironment.

To convert these novel targets into drug candidates, the Company is currently conducting 5 proprietary development programs including inolimomab (LEUKOTAC), an immunotherapy antibody that has recently demonstrated its clinical superiority in Phase 3 and that is closed to market approval in an orphan post-cancer disease with very poor prognosis: steroid-resistant acute Graft-versus-Host Disease.

Founded in 2013, ELSALYS BIOTECH is located in the heart of the European cluster LYON BIOPOLE. Its shareholders are TRANSGENE, SOFIMAC INNOVATION, joined in 2015 by IM EUROPE, a subsidiary of INSTITUT MERIEUX, and CREDIT AGRICOLE CREATION, and in 2018 by LABORATOIRES THEA.

Stay in touch with ElsaLys Biotech and receive directly our press releases by filling our contact form on http://www.elsalysbiotech.com

And follow us on Twitter: @ElsalysBiotech

Contacts

ELSALYS BIOTECHDr. Christine GUILLENCEO and Co-founder+33 (0)4 37 28 73 00guillen@elsalysbiotech.com

PRESSEATCG PARTNERS Marie PUVIEUX (France) +33 (0)6 10 54 36 72Cline VOISIN (UK/US) +33 (0)6 62 12 53 39presse@atcg-partners.com

Originally posted here:
LEUKOTAC (inolimomab) is available again in France, following the granting of cohort ATU for the treatment of graft-versus-host disease,...

Recommendation and review posted by Bethany Smith

Last year left us with this piece of bombshell news: He Jiankui, the mastermind behind the CRISPR babies scandal, has been sentenced to three years in prison for violating Chinese laws on scientific research and medical management. Two of his colleagues also face prison for genetically engineering human embryos that eventually became the worlds first CRISPRd babies.

The story isnt over: at least one other scientist is eagerly following Hes footsteps in creating gene-edited humans, although he stresses that he wont implant any engineered embryos until receiving regulatory approval.

Biotech stories are rarely this dramatic. But as gene editing tools and assisted reproductive technologies increase in safety and precision, were bound to see ever more mind-bending headlines. Add in a dose of deep learning for drug discovery and synthetic biology, and its fair to say were getting closer to reshaping biology from the ground upboth ourselves and other living creatures around us.

Here are two stories in biotech were keeping our eyes on. Although successes likely wont come to fruition this year (sorry), these futuristic projects may be closer to reality than you think.

The idea of human-animal chimeras immediately triggers ethical aversion, but the dream of engineering replacement human organs in other animals is gaining momentum.

There are two main ways to do this. The slightly less ethically-fraught idea is to grow a fleet of pigs with heavily CRISPRd organs to make them more human-like. It sounds crazy, but scientists have already successfully transplanted pig hearts into baboonsa stand-in for people with heart failurewith some recipients living up to 180 days before they were euthanized. Despite having foreign hearts, the baboons were healthy and acted like their normal buoyant selves post-op.

But for cross-species transplantation, or xenotransplants to work in humans, we need to deal with PERVsa group of nasty pig genes scattered across the porcine genome, remnants of ancient viral infections that can tag along and potentially infect unsuspecting human recipients.

Theres plenty of progress here too: back in 2017 scientists at eGenesis, a startup spun off from Dr. George Churchs lab, used CRISPR to make PERV-free pig cells that eventually became PERV-free piglets after cloning. Then last month, eGenesis reported the birth of Pig3.0, the worlds most CRISPRd animal to further increase organ compatibility. These PERV-free genetic wonders had three pig genes that stimulate immunorejection removed, and nine brand new human genes to make themin theorymore compatible with human physiology. When raised to adulthood, pig3.0 could reproduce and pass on their genetic edits.

Although only a first clinical propotype that needs further validation and refinement, eGenesis is hopeful. According to one (perhaps overzealous) estimate, the first pig-to-human xenotranplant clinical trial could come in just two years.

The more ethically-challenged idea is to grow human organs directly inside other animalsin other words, engineer human-animal hybrid embryos and bring them to term. This approach marries two ethically uncomfortable technologies, germline editing and hybrids, into one solution that has many wondering if these engineered animals may somehow receive a dose of humanness by accident during development. What if, for example, human donor cells end up migrating to the hybrid animals brain?

Nevertheless, this year scientists at the University of Tokyo are planning to grow human tissue in rodent and pig embryos and transplant those hybrids into surrogates for further development. For now, bringing the embryos to term is completely out of the question. But the line between humans and other animals will only be further blurred in 2020, and scientists have begun debating a new label, substantially human, for living organisms that are mainly human in characteristicsbut not completely so.

With over 800 gene therapy trials in the running and several in mature stages, well likely see a leap in new gene medicine approvals and growth in CAR-T spheres. For now, although transformative, the three approved gene therapies have had lackluster market results, spurring some to ponder whether companies may cut down on investment.

The research community, however, is going strong, with a curious bifurcating trend emerging. Let me explain.

Genetic medicine, a grab-bag term for treatments that directly change genes or their expression, is usually an off-the-shelf solution. Cell therapies, such as the blood cancer breakthrough CAR-T, are extremely personalized in that a patients own immune cells are genetically enhanced. But the true power of genetic medicine lies in its potential for hyper-personalization, especially when it comes to rare genetic disorders. In contrast, CAR-Ts broader success may eventually rely on its ability to become one-size-fits-all.

One example of hyper-tailored gene medicine success is the harrowing story of Mila, a six-year-old with Batten disease, a neurodegenerative genetic disorder that is always fatal and was previously untreatable. Thanks to remarkable efforts from multiple teams, however, in just over a year scientists developed a new experimental therapy tailored to her unique genetic mutation. Since receiving the drug, Milas condition improved significantly.

Milas case is a proof-of-concept of the power of N=1 genetic medicine. Its unclear whether other children also carry her particular mutationBatten has more than a dozen different variants, each stemming from different genetic miscodingor if anyone else would ever benefit from the treatment.

For now, monumental costs and other necessary resources make it impossible to pull off similar feats for a broader population. This is a shame, because inherited diseases rarely have a single genetic cause. But costs for genome mapping and DNA synthesis are rapidly declining. Were starting to better understand how mutations lead to varied disorders. And with multiple gene medicines, such as antisense oligonucleotides (ASOs) finally making a comeback after 40 years, its not hard to envision a new era of hyper-personalized genetic treatments, especially for rare diseases.

In contrast, the path forward for CAR-T is to strip its personalization. Both FDA-approved CAR-T therapies require doctors to collect a patients own immune T cells, preserved and shipped to a manufacturer, genetically engineered to boost their cancer-hunting abilities, and infused back into patients. Each cycle is a race against the cancer clock, requiring about three to four weeks to manufacture. Shipping and labor costs further drive up the treatments price tag to hundreds of thousands of dollars per treatment.

These considerable problems have pushed scientists to actively research off-the-shelf CAR-T therapies, which can be made from healthy donor cells in giant batches and cryopreserved. The main stumbling block is immunorejection: engineered cells from donors can cause life-threatening immune problems, or be completely eliminated by the cancer patients immune system and lose efficacy.

The good news? Promising results are coming soon. One idea is to use T cells from umbilical cord blood, which are less likely to generate an immune response. Another is to engineer T cells from induced pluripotent stem cells (iPSC)mature cells returned back to a young, stem-like state. A patients skin cells, for example, could be made into iPSCs that constantly renew themselves, and only pushed to develop into cancer-fighting T cells when needed.

Yet another idea is to use gene editing to delete proteins on T cells that can trigger an immune responsethe first clinical trials with this approach are already underway. With at least nine different off-the-shelf CAR-T in early human trials, well likely see movement in industrialized CAR-T this year.

Theres lots of other stories in biotech we here at Singularity Hub are watching. For example, the use of AI in drug discovery, after years of hype, may finally meet its reckoning. That is, can the technology actually speed up the arduous process of finding new drug targets or the design of new drugs?

Another potentially game-changing story is that of Biogens Alzheimers drug candidate, which reported contradicting results last year but was still submitted to the FDA. If approved, itll be the first drug to slow cognitive decline in a decade. And of course, theres always the potential for another mind-breaking technological leap (or stumble?) thats hard to predict.

In other words: we cant wait to bring you new stories from biotechs cutting edge in 2020.

Image Credit: Image by Konstantin Kolosov from Pixabay

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The Top Biotech Trends We'll Be Watching in 2020 - Singularity Hub

Recommendation and review posted by Bethany Smith

PLC () dipped 3% to 286.52p in mid-afternoon after announcing the acquisition of multi-let office space in Staines, Surrey, as well as the sale of a London building to a private developer.

TWENTY was bought for 19mln, is currently let to four tenants and has a vacancy of 23%, while Quayside Lodge in Fulham, London, was sold for the same amount.

TWENTY Kingston Road offers strong reversionary potential with a yield of 7% once fully let and the acquisition is in line with our opportunistic approach, chief executive Fredrik Widlund said in a release.

s () lost 2% to 227.01p after posting like-for-like sales including fuel fell 1.1% in the 15 weeks to 4 January, while total retail sales slipped 0.9%.

The LFL sales slip was slightly worse than analyst expectations which had predicted that sales in the period would be mostly flat.

The FTSE 100 grocer is another major name in the sector suffering sales declines over the so-called golden Christmas quarter.

PLC () gained 6% to 86.63p in early afternoon trades on the back of an acquisition from Cemex SAB de CV ADR ().

The AIM-listed construction materials company will snap up the UK arm and some operation of the Mexican company for 178mln in cash, debt-free.

It will add 170mln tonnes of mineral reserves and resources while adding to the development of Breedons national asphalt strategy and increasing footprint in areas where it is underrepresented.

() rose 7% to 0.41p after updating investors on the Bonya tungsten and copper deposit in Australia resource potential.

Thor is drilling to establish Bonya as a source of ore to extend the life of its nearby Molyhil project.

Latest holes to be drilled showed best results of a 23m intersection at a grade of 0.58% WO3 (tungsten) from the surface at White Violet and a 9m copper band at Samarkand.

Pharos Energy PLC (LON:PHAR) slipped 5% to 55p at lunchtime after informing investors that the 2020 dividend will be halved compared to the 2019 payment.

The oiler will issue 2.75p per share, a yield of 5% on yesterday's close of 58p, to focus on capital investment in the expanded portfolio.

Production in Egypt came as a disappointment as well, with 6mln barrels of oil per day (boe/d) as opposed to the 6.5mln boe/d guidance.

() lost 4% to 156.5p as the footwear retailer posted lower profits but managed to keep the final divi at 8p per share.

The AIM-listed firm attributed the decline to government imposed increases in its operating costs.

For the year ended 5 October, the company reported an underlying pre-tax profit of 9.8mln, down from 11.4mln in the prior year, while revenues edged up 0.9% to 1.62bn.

MPAC Group PLC () shares were trading 16% higher at 240p in late morning after upgrading full-year profit expectations for the second time in four months.

The company, which provides high speed packaging and automation services, attributed the continuing momentum to a strong Q4 order intake and accelerated project execution.

I am confident that we will be able to report an excellent financial performance for 2019 and improved outlook for 2020 which gives us confidence for the future progress of the business, chief executive Tony Steels said in a release.

()(NASDAQ:MTP) hiked 24% to 3.4 on the back of positive results from additional studies on its MTD201 cancer drug.

The analysis revealed the candidate can be delivered via an injection under the skin rather than into the muscle.

It is a key advantage paving the way for approval, while a pivotal study is planned for later in the first half with preparations already underway.

PLC () topped the losers list with a 21% stumble to 65.35p as the mineral resource estimate for its Asacha Gold Mine was reduced after further analysis.

As of 20 December, the asset is estimated to hold 312,558 ounces of gold, as opposed to 553,052 ounces a year before.

The AIM-listed miner is now undertaking a new drilling campaign to upgrade the resources, while formal guidance for the current year will be published shortly.

Travelex owner () was not doing much better with a 16% fall to 130p after updating on the Sodinokibi Windows ransomware attack.

The FTSE 250-listed firm was asked to pay US$6m (4.6m) to restore the customer data they claimed to have swiped from Travelexs systems, or else they would sell it on the dark web.

Finablr said there was no evidence that personal customer data has been encrypted and no evidence that any data has been exfiltrated, adding that Travelex has successfully contained the spread of the ransomware.

() lost 14% to 2.5p after announcing the process for listing on the Hong Kong Stock Exchange is taking longer than expected.

The AIM-listed engineering and technology solutions provider to the bioenergy sector said admission to trades will occur in the first half of 2020.

Management added trading in the second half of 2019 remained strong and is optimistic for the current period.

Asimilar Group PLC (LON:ASLR) jumped 25% higher to 40.66p in early morning trade on Wednesdayafter launching a placing at a premium to Tuesday's closing share price, hot on the heels of last months change of name from YOLO Leisure.

The AIM-listed big data and Internet of Things firm raised 6.8mln by placing 17mln new shares at a price of 40p each withexisting and new investors, a 15% premium to Tuesdays closing price of 33.8p.

Chairman John Taylor said in a release the proceeds will be used to pursue potentially bold and transformative investment options.

() was also onthe gainers list with a 5% push upwards to 247.9p after announcing full-year profit before tax will be comfortably ahead of market expectations.

The financial services provider and retailer mentioned strong trading during the Christmas period, when the jewellery segment recorded double-digit revenue growth.

The company noted that a high gold price boosted profits in the precious metals segment while its pawnbroking and foreign currency divisions continued to produce good results.

() also nudged higher, up 4% to 18.25p as it set up a joint venture with Korean firm Daewoong Pharmaceutical Co.

The firms will develop new cell and gene therapies using Avactas Affimer proteins which will specifically target the development of a new class of mesenchymal stem cells (MSCs), for the treatment of autoimmune and inflammatory diseases.

The AIM-listed company said its research and development costs for these targets will be fully covered by the joint venture which is funded by Daewoong.

() has confirmed that it has received a premium-priced takeover offer from (), and, it is now in advanced talks with the FTSE 100-listed miner. The offer is pitched at 5.5p per share, which is a 34.1% premium to yesterdays closing price of 4.1p. In a statement released after the market close on Tuesday, Siriuss management team said it would be prepared to recommend an offer at that price.

() (NASDAQ:MTP) has hailed the positive results from a study assessing the potential to deliver one of its drugs via an injection under the skin rather than into the muscle. MTD201, which is being developed to treat carcinoid cancer and the growth hormone condition acromegaly, was able to maintain the correct levels of plasma octreotide over six to eight weeks using this subcutaneous method, researchers found.

() has signed an exclusive agreement worth up to US$63mln for its iron deficiency treatment Feraccru to be sold in China. The deal with ASK Pharm (Beijing Aosaikang Pharmaceutical), covers China, Hong Kong, Macau and Taiwan and will involve an upfront payment of US$11.4mln and up to US$51.4mln in milestone and royalties. ASK Pharm will also pay for the marketing authorisation process and commercialising of Feraccru, which is branded as Accrufer in the US.

() has set up a joint venture to develop new cell and gene therapies using its Affimer proteins. The new JV with Daewoong Pharmaceutical Co will specifically target the development of a new class of mesenchymal stem cells (MSCs), multipotent cells where functions can include being agents for the treatment of autoimmune and inflammatory diseases.

() has signed a one-year exclusive evaluation agreement with Corteva Agriscience. The American giant, valued at US$21bn, wants to assess the potential of the UK biopesticides specialists encapsulation technology, focusing on formulations for seed treatments.

() said it has now completed the fundraising it announced on 30 September 2019, which in total raised approximately 412,000, with the final stage raising 150,360 via an issue of 2,148,000 new ordinary shares at a price of 7p each to Zark Capital Limited. Following the issue, Zark will hold 6,000,000 ordinary shares, representing 9.7% of ADMs issued share capital.

() is to trial its graphene-enhanced asphalt Gipave at Romes Fiumicino airport. Gipave will be tested for six months on the airports Alpha taxiway, which handles intercontinental aircraft such as Boeing 777s and Airbus A380s.

() said it has won two large contracts for delivery of Knowledge Capture, part of its information management suite of products, with a minimum combined contract value of 0.9mln over their minimum term. In a statement, the leading global big data technology company noted that the latest contract wins add to a growing list of multi-national clients for both the group's RAPid supply chain analytics and information management solutions, adding 200,000 to the company's annual recurring revenue.

() announced that it has delivered network services to more than 100 hospital and specialist care sites as part of a government contract with the NHS. AdEPT was contracted in 2018 to improve network and bandwidth capacity, to allow for financial savings and better access to clinical systems, after the previous connection managed by () was deemed obsolete.

Group PLC () has seen strong inflows of new money in the first three months of its current year. The sustainable investment specialist said funds under management rose 7% to 16.1bn in the quarter to December with 771mln of new funds and a 289mln gain from market movements.

() has sold its UK B2C business for 200,000 as part of its restructuring plans. In an announcement after the close on Tuesday, the online gaming platform operator said the B2C business was sold by administrators to Grace Media Limited, and the firm had now entered a B2B partnership with Grace Media to facilitate continued delivery of its B2C services to its white label partners, through which it will receive monthly royalties

() on Wednesday confirmed the receipt of US$6.7mln in oil payments from the Kurdistan Regional Government (KRG). In a statement, the Iraq-based crude producer reported that the partners in the Taq oil field were paid US$6.7mln gross for oil sales in August 2019, and, its 44% net share amounted to US$3.6mln.

() has released a statement informing investors that it has received notice of a potential claim against the company from a former energy advisor, Askell Limited. In a brief statement, the small cap oiler said: AAOG believes the Askell claim is without merit and the company intends to defend the claim vigorously.

() has announced the appointment of Oscar Marin Garcia as a non-executive director of the company with immediate effect. The group noted that Garcia has over 20 years' experience, specialising in retail business in the Extremadura region of Spain and managing family office investments, and is co-founder and CEO of Lider Aliment, SA, a 200mln sales family owned company. W resources pointed out that Garcia has a beneficial interest in 114,655,600 ordinary shares, representing approximately 1.8% of the companys share capital.

() said that, further to its announcement on 23 December 2019, the sale of its Malaysian business to AAA Management Science Academy PLT for a total cash consideration of MYR 400,000 (approximately 75,000), payable over a 13 month period, has duly completed. Sam Malafeh, CEO of Malvern, commented: "We are delighted to have completed this transaction, as we can now bring greater focus to growing our UK and Singapore operations."

() said it, has collaborated with BMW Group to integrate its FOVIO driver monitoring technology into the BMW i Interaction EASE. It noted that this integration will be featured at the CES 2020 technology show in Las Vegas at the BMW booth Tech East Outside Area. The firm noted that BMW i Interaction EASE leverages Seeing Machines' technology as a component of their innovative HMI (Human-Machine Interface) concept, visualized through a windshield projected Head-up Display (HUD). It added that Seeing Machines' SVP of Fleet and Human Factors, Dr Mike Lenn, will also be conducting daily presentations on BMW's CES booth from Wednesday through Friday.

() announced that it has terminated its broker services agreement with GMP . Shore Capital Stockbrokers Limited is now the company's sole broker and Strand Hanson Limited continues to act as the company's Nominated & Financial Adviser, the group said.

Bluebird Merchant Ventures () announced that its Annual General Meeting, held on 28 December 2019 in Jersey, all resolutions were duly passed.

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CLS Holdings dips over acquisition, sale - Proactive Investors UK

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