Pet Stem Cell Therapy

A Referendum on Anti-Amyloid and Promising New Therapeutic Targets at AAIC – BioSpace

August 13, 2022 admin Pet Stem Cell Therapy

If a tree falls in a forest and nobody is around to hear it, does it make a sound? Similarly, if the U.S. Food and Drug Administration ultimately votes to approve Eli Lillys donanemab or Eisais lecanemab both anti-amyloid beta (A) antibodies will it make an impact on Alzheimers disease (AD)?

The stupid question is: if I have Alzheimer's disease and my plaque is gone, but I still have Alzheimer's disease, do I care? Maria Maccecchini, Ph.D., founder, president and CEO of Annovis Bio asked during an interview with BioSpace.

On Thursday, Maccecchini participated in a panel discussion, Integrative Systems Biology of Alzheimers Disease, at the Alzheimers Association International Conference (AAIC), addressing this very question. The panel, hosted by renowned AD researcher Dr. Jeffrey Cummings, M.D., and KristaLanctt,Ph.D. of Sunnybrook Research Institute, also looked at integrative approaches being taken to treat the disease.

The Battered Anti-Amyloid Theory

As anti-A therapeutics continue to fail, allegations recently broke calling into question seminal research behind the hypothesis. While looking into claims of misconduct by AD drug developer Cassava Sciences, Vanderbilt neuroscientist and physician Matthew Schrag made a discovery: It appeared to Schrag that the pioneering research of Sylvain Lesn and Karen Ashe possibly contained tampered images of Western blots, a laboratory technique used to visualize proteins. This data formed the backbone of the argument that A*56 - an oligomer of amyloid- proteins - is responsible for the AD hallmark of memory loss. The 2006 paper has been cited by some 2,300 other studies over the past 16 years.

Despite the failure of these drugs (Biogens Aduhelm is a possible though highly-scrutinized exception), the pharmaceutical industry continues to cling to the theory. Its no wonder why, given the astronomical resources that have been devoted to it. In 2021 alone, anti-amyloid research received nearly $300 million in support from the National Institutes of Health.

I had thought that amyloid was dying 10 years ago, Maccecchini said. It does not die. Maccecchini was perusing the booths at AAIC when she came across an Eli Lilly representative. She asked the individual why, with all of the failures in the space, she was still working in it. Her response? Because Lilly is the only employer in town.

When you have put billions into something, unless that person resigns or dies, they're not going to admit being wrong, Maccecchini said.

She was unwavering in her position on anti-A antibodies. I would not use an antibody in an elderly person with an impaired brain if my life depended on it. It's toxic. You're killing these people earlier. She also noted the perils of PET scans, which she said kills nerve cells.

The RNA-based Approach

Instead, Berwyn, PA-based Annovis is developing buntanetap, a small molecule that inhibits multiple neurotoxic proteins tau, aSynuclein, TDP-43 and amyloid beta at once. These proteins, she explained, are regulated by the same homologous region in messenger RNA (mRNA). This region, and only this region, binds to iron regulatory protein 1, a storage protein in the cytoplasm.

When it's bound, the mRNA is not translated; when it's free, the mRNA is translated, Maccecchini said. When the mRNA gets over-translated, (leading to the aggregation of these proteins), our drug stops it because it keeps it bound.

Buntanetap is currently being assessed in Phase III trials for Parkinsons disease, and Annovis plans to kick off a Phase II/III trial in AD this Fall. The company also intends to file a grant to study the drug in Lewy body dementia, with potential grants for both Huntingtons disease and amyotrophic lateral sclerosis (ALS) also under consideration.

While Maccecchini believes buntanetap will be effective in stopping the progression of AD, shes aiming higher.

If you already have dementia, stopping it is nice, but you would like to get better, right? she said. Eventually, while it is not possible today, Maccecchini envisions buntanetap being combined with stem cell therapy. Even if we figure out how to make (stem cells) become neurons, they'll diebecause the brain has Alzheimers. But if our drug stops them from getting Alzheimer's, then we can actually improve cognition.

The HGF-MET Approach

In Bothell, Washington, Athira Pharma is developing fosgonimeton, a small molecule designed to enhance the activity of hepatocyte growth factor (HGF) and its receptor, Met, with the aim of impacting neurodegeneration and regenerating brain tissue.

Athira Chief Medical Officer Hans Moebius, M.D., Ph.D. explained that the origin of plaques is inside of neurons and that this is why anti-A antibodies havent been effective to date.

This is a lysosomal overload with amyloid fibrils and it originates inside neurons, he told BioSpace. These monoclonal antibodiesare entering the brain only to a minuscule fraction, about one percent. From this percent of monoclonal antibodies, I maintain that zero percent enter neurons. You cannot rescue neurons by hoping you can get your monoclonal antibody into the neuron.

He shared that this mechanistic consideration has long led him to be critical of the amyloid hypothesis.

It is amazing to me to see that we are following Einsteins bon mot that repeating an experiment and hoping for a different outcome is the definition of stupidity, he said. At least what we should do is open our eyes a little bit and look with a different view on the disease. In Moebius view, Alzheimers is probably a family of diseasesand there are many pathophysiological processes ongoing.

Moebius referred to HGF-Met as being a key neurotrophic system to maintain homeostasis in the brain. First discovered in the liver, HGF is now known to be ubiquitous.

In Alzheimer's disease, we know that in predilection areas like the frontal cortex and the hippocampus, we have a depletion of Met expression, he said.

So, Athira is developing a pipeline of small molecules that aim to enter the brain and positively modulate the HGF-Met system. Importantly, these small molecules are not agonists; they are modulators. We are not overruling the natural regulation; we can only boost the natural signal. That, Moebius said, is a key point for safety.

Last week, Athira presented data from the Phase II proof-of-concept trial of fosgonimeton in mild-to-moderate AD. While the primary analysis did not meet statistical significance in the primary endpoint (event related potential (ERP) P300 latency), the company said the data gave meaningful insights into the drugs potential effects. These include a statistically significant reduction in plasma levels of the validated neurodegeneration biomarker neurofilament light chain (NfL) in a pre-specified subgroup of monotherapy patients. This data will inform the larger LIFT-AD study, which has already enrolled 300 patients.

The Metabolic Hypothesis

For John Didsbury,Ph.D., president and CEO of T3D Therapeutics, amyloid could be part of the answer but only part of it.

North Carolina-based T3D approaches AD as a brain-specific form of diabetes type 3 diabetes where aberrant metabolism is causing brain starvation, leading to loss of brain functions such as cognition. But, Didsbury said, The metabolic hypothesis is not antithetical to the amyloid hypothesis. They're highly interrelated and they perpetuate each other.

Didsbury told BioSpace that three main causes of AD are interconnected in a massive positive feedback loop. These causes are metabolic changes, structural change (plaques and tangles) and stress.

Insulin, Didsbury said, is the single most important regulator of brain functions, including cognitive function. Resistance to insulin precedes seeing Alzheimer's symptoms, he noted.

T3D set out to find a potential drug target that can bypass or correct the dysfunctional insulin signaling pathways causing this resistance. The companys research culminated in T3D-959, which aims to break this positive feedback cycle by correcting these metabolic defects.

The drug acts to correct dysfunctional glucose energy metabolism and dysfunctional lipid metabolism found in the brains of Alzheimers patients. It targets multiple abnormalities, as opposed to just plaques and tangles. T3D-959 is currently being assessed in a Phase II clinical trial of mild-to-moderate AD patients.

While the company is currently blinded to the data, We have encouraging results that are pointing to potential improvement, not just a slowing of decline, but potential improvement in cognitive performance and function and in executive function, Didsbury shared. T3D anticipates reporting top-line results in early April 2023.

He added that these results seem to go against the "recently perpetuated mantra that you can never treat AD effectively if you're at a mild-to-moderate stage.

We vehemently disagree with that, he continued. Coming from large pharma, I believe that this new mantra that you have to go early before symptoms to treatwas brought on by large pharma as [a way of] rationalizing their failures.

With anti-A antibodies, Didsbury said, at best, you are seeing just a slowing in decline.

Is there still hope that anti-amyloid is the answer? Are we just targeting it the wrong way? More likely, it seems, Alzheimers is a complex disease process that requires an integrative approach.

See the original post here:
A Referendum on Anti-Amyloid and Promising New Therapeutic Targets at AAIC - BioSpace

RCMP Investigating After Woman Attacked With Crow Bar – q961.com

The RCMP is asking the public's help to locate a person of interest after a woman was assaulted with a crow bar in Nerepis, N.B.

Members of the Grand Bay-Westfield RCMP and Ambulance New Brunswick responded to a report Tuesday afternoon of an assault with a weapon at a residence on Birch Street, according to Cpl. Jullie Rogers-Marsh.A 33-year-old woman had been struck over the head with a crow bar in the front yard of the residence, Rogers-Marsh said. She was transported to hospital and treated for injuries that were not considered life-threatening. RCMP said Thursday that the woman has since been released from hospital.

In the course of their investigation, police learned that a man fled the scene in a vehicle before police arrived. The man is considered a person of interest in the investigation.

The suspect is described as 58 tall (173 centimeters) with a skinny build. He is believed to be between 25 and 28 years old with short buzzed dirty blond hair. At the time of the alleged attack, the man was wearing a black hooded sweatshirt, jeans and white sunglasses, Rogers-Marsh said.

The vehicle of interest is described as a black four-door car with a tinted back window and tinted rear windows. Through the investigation, police obtained surveillance video footage of the vehicle and believe it to be a 2016-2020 model Honda Civic. It appears to have a spoiler on the back.

The RCMP hopes that information from the public may help provide additional clues to further their investigation. Police are looking to speak with anyone who was around Britain Road, Crandall Road or Birch Crescent in Nerepis between 2:00 and 2:45 p.m. on Tuesday, July 26.

Anyone who may have witnessed the incident, seen the vehicle of interest, or has any information about the incident, is asked to contact the Grand Bay-Westfield RCMP at (506) 757-1020. Information can also be provided anonymously through New Brunswick Crime Stoppers online or by calling 1-800-222-TIPS (8477).

To prepare yourself for a potential incident, always keep your vet's phone number handy, along with an after-hours clinic you can call in an emergency. The ASPCA Animal Poison Control Center also has a hotline you can call at (888) 426-4435 for advice.

Even with all of these resources, however, the best cure for food poisoning is preventing it in the first place. To give you an idea of what human foods can be dangerous, Stacker has put together a slideshow of 30 common foods to avoid. Take a look to see if there are any that surprise you.

Read this article:
RCMP Investigating After Woman Attacked With Crow Bar - q961.com

Treating Multiple Myeloma Following Quadruplet Induction Therapy and ASCT – Targeted Oncology

CASE SUMMARY

A 54-year-oldwoman presented with Revised International Staging System stage II multiple myeloma, based on evaluations that showed a hemoglobin level of 7.0 g/dL, 2-microglobulin of 6 mg/dl, albumin 3.2 g/dL, calcium 11.3 mg/dL, lactate dehydrogenase of 200 U/L, and creatinine clearance of 45 mL/min. Bone marrow showed 22% clonal plasma cells. Serum kappa free light chains were 24 mg/dL. She had no cytogenetic abnormalities and an ECOG performance score of 1. A PET/CT scan showed multiple bone lesions in the vertebrae. She had no extramedullary disease. She was diagnosed with IgG-kappa myeloma and was considered transplant eligible.

Daratumumab (Darzalex), bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (Dara-VRd) induction therapy was initiated. She achieved a very good partial response (VGPR) post induction therapy. She underwent stem cell mobilization and 2 months later underwent autologous stem cell transplant (ASCT). Her post-ASCT response was a VGPR.

DISCUSSION QUESTIONS

CAITLIN COSTELLO, MD: This patient did get a quadruplet regimen with dara-VRd. She achieved a VGPR post-induction, had stem cells mobilized, underwent her transplant, and post-transplant her response is a VGPR. What would you do next?

THOMAS DEKKER, MD: Consolidation with CAR [chimeric antigen receptor] T-cell therapy.

COSTELLO: With CAR T cell, sure. Youre going for it; I like it. This patient is post-transplant, they have a VGPR. The GRIFFIN study [NCT02874742] would give these patients consolidation with dara-VRd.

PREETI CHAUDHARY, MD: I would not do CAR T-cell therapy.

COSTELLO: What would you do?

CHAUDHARY: In my opinion, in multiple myeloma, patients do a maximum of 11 months with CAR T-cell therapy. It has a good response, but I dont think thats sustainable.

COSTELLO: I appreciate throwing ideas out there. That is not something we have an option to do right now. Its an interesting option, and something we can talk about; but yes, I agree with you. I think for the meantime, short of trials that are looking at doing CAR T-cell therapyparticularly for those patients who have not had an adequate response to transplant or consolidation, or patients who relapse shortly after their transplantI think the standard of care as it stands now is doing consolidation or trying to find a maintenance regimen to get them to minimal residual disease [MRD] negativity.

With all that being said, what are we going to do now for these patients? Weve talked about what these transplant eligible patients are getting consolidation and maintenance; weve talked about maintenance approaches for these patients who get quadruplets, to put them on doublets. Seeing all those deep response rates, is anyone getting cold on transplants? If we are going to get 90% remission rates, does anyone reconsider the role of transplant here?

PAMELA MIEL, MD: I dont make that call, meaning I still send patients to the transplant doctors to see if theyre going to proceed with the transplant or not. But, if theyre transplant eligible, they get referred.

COSTELLO: As a transplanter, I thank you for that. We want to see these patients, make the decisions, have the discussion with the patients so we can look at their risk/benefit profile, and understand their responses to their current therapy. So, please still send them in their third cycle, if not earlier, so we can have those discussions and make plans.

There are a lot of maintenance regimens that are out there, and different things to choose from; a whole other conversation in and of itself. Lenalidomide is the mainstay where we have an overall survival benefit, where we dont have it in any other maintenance regimens.1 But it does allow for the option of continued doublets. I think we will soon see daratumumab and lenalidomide as a doublet get added on to that maintenance therapy once we have some of these randomized trials that are going on that show the continued benefit of patients to get daratumumab in the maintenance setting if they did not receive it in the up-front setting.

DISCUSSION QUESTION

How likely are you to change your practice with respect to management of transplant eligible newly diagnosed myeloma?

DEKKER: I already use quadruplet.

MILAN SHETH, MD: I feel that we still need a lot of long-term data to get a better sense of what it is that were achieving with the quadruplet therapy. Im still not convinced everybody needs quadruplet therapy. I think somebody else had already said that we know were going to get better responses because were using great drugs, but do we need to use everything up-front? I feel like theres still a lot of unanswered questions here.

MIEL: Ive been wanting to put patients on quadruplet treatment. I dont know if you know Nina Shah, MD, over at UC San Francisco, but Ive attended some of her talks, and shes pushing for the quadruplet treatment. The only thing that changed my mind was that when I spoke to the transplant doctor at UC San Diego, he said, If its not very high-risk disease, Id go with VRd [bortezomib, lenalidomide, and dexamethasone]. So, I put the patient on VRd. But I probably would want to put someone on dara-VRd, given the chance.

COSTELLO: Yes. I think that my takeaway from the data has been that we would, of course, love long-term data to come out, butwe have to wait a long time for it. While were waiting for some of these phase 3 studies to go on, which are happening now to look at real randomized data, to play out, I find that this is just too intriguing to not do quadruplets for everybody now.

Since [these data were presented at [the 2021 American Society of Hematology annual meeting], Ive transitioned just about everyone whos at least transplant eligible over to quadruplet regimens now.2 Any patients who are on the fence, where Im not sure if theyre going to be eligible for transplant, I still will try and give them the benefit of a quadruplet regimen, and very quickly drop the bortezomib if I get worried about them, and end up with dara-Vd [daratumumab, lenalidomide, dexamethasone]. But I think these MRD negativity rates are just too good, and if that is going to be the true surrogate end point that were all aiming for, dara-VRd has been my go-to for the last 6-plus months or so for these patients, until someone tells me otherwise.

References

1. Ho M, Zanwar S, Kapoor P, et al. The effect of duration of lenalidomide maintenance and outcomes of different salvage regimens in patients with multiple myeloma (MM).Blood Cancer J. 2021;11(9):158. doi:10.1038/s41408-021-00548-7

2. Laubach JP, Kaufman JL, Sborov DW, et al. Daratumumab (DARA) plus lenalidomide, bortezomib, and dexamethasone (RVd) in patients (pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): updated analysis of GRIFFIN after 24 months of maintenance. Blood. 2021;138(Suppl_1):79. doi:10.1182/blood-2021-149024

See more here:
Treating Multiple Myeloma Following Quadruplet Induction Therapy and ASCT - Targeted Oncology

Twenty-Five Years After My House Call To Dolly: What Have We Learned About Cloning And How Did We Learn It? – Forbes

Nearly twenty-five years ago, the scientific breakthrough of mammalian cloning marked a monumental moment in medicine and science. Anticipating the collision it would have with ethical decision making in medicine, I, the only physician-scientist in the U.S. Senate at the time, journeyed to the University of Edinburgh in Scotland to personally visit Sir Ian Wilmut at his research lab at the Roslin Institute.

My house call to Dolly in 1997: I stand with Dolly, the first ever mammal to be cloned from an adult ... [+] somatic cell, during my journey to visit her creator and caretaker, Sir Ian Wilmut.

Professor Wilmut just months before in 1996 had cloned a sheep from an adult somatic cell, shocking the world. This was the first successful attempt of its kind. All over the world people were wondering: would we be cloning a human being next? We talked science, we talked ethics, and we talked about his creations potential impact on altering the course of human history. I also met and examined the cloned sheep, Dolly, in her stall.

Dolly, named after Tennessees own Dolly Parton, was a Finnish Dorset sheep cloned from a single, adult mammary gland cell. Her creation, birth, and short life were scientific feats that immediately sparked global concern and discourse on the increasingly complex moral and ethical dilemmas posed by a sudden discovery of life-manipulating science.

Wilmut and colleagues published their achievement in February 1997, having kept Dolly secret for seven months. We, as a society, were quickly forced to answer difficult, probing questions. A few months later on the Senate floor, I borrowed a question that the Washington Post editorial board had posed a few years before: Is there a line that should not be crossed even for scientific or other gain, and if so where is it?

Here are my remarks in the Senate chamber in 1998:

So it is vital that our public debate and reflection on scientific developments keep pace, and even anticipate and prepare for new scientific knowledge. The moral and ethical dilemmas inherent in the cloning of human beings may well be our greatest test to date. We do not simply seek knowledge, but the wisdom to apply that knowledge. As with each of the mind-boggling scientific advances of the last century, we know that there is the potential for both good and evil in this technology. Congressional Record February 2, 1998

Years removed, I now reflect back on the confusion, questions, and status quo that Dolly challenged.

Dolly was the first mammal to be successfully cloned from an adult somatic cell, which is any type of bodily cell that is not a reproductive germ cell. The process Wilmut developed is technically called somatic cell nuclear transfer, colloquially known as cloning. It is the process of transferring the nuclear DNA of a donor somatic cell into an enucleated oocyte, followed by embryo development and then transfer to a surrogate recipient, followed by live birth.

Dollys creation in a test tube and eventual birth marked a major milestone in scientific research, suggesting that an animal could be cloned to create an exact replica using genetic material derived from theoretically any type of body cell. It opened the world to staggering new possibilities in reproductive cloning and therapeutic cloning.

Soon after Dollys birth, another parallel and similarly monumental finding was made: in 1998 embryonic stem cells were discovered. These cells are a highly unique type of unprogrammed somatic cell with the exceptional ability to both reproduce unlimited exact copies of themselves and develop into more specialized cell types, such as heart, lung, kidney or skin cells. And though seemingly miraculous in potential, these cells could not be created or programmed from any other type of cell and could only be collected from embryos an ethical dilemma because collection for research required destruction of the embryo itself.

Dolly changed this. Her successful creation paved the way for future scientists to develop a technique to independently produce equally powerful pluripotent stem cells by reprogramming other adult somatic cells, revolutionizing genetic therapy, and completely nullifying the ethical dilemma of collecting embryonic stem cells from embryos. Similarly, Dolly also highlighted the potential for scientists to create new tissues and organs for diseased patients, and to preserve the genetic material of endangered species.

But, along with these positive contributions came widespread concern about the ethics of cloning, especially around potential attempts to clone another human being. Many, including myself, feared this type of technology, if left unregulated, would be misused and abused. Indeed, cloning evoked great scientific power that demanded even greater ethical responsibility, and there were no established ethical guardrails at the time to monitor this duty.

In retrospect, these fears have diminished in part due to proactive measures and to the inherent complexities of the human genome (cloning an entire human being is, after all, a large jump from cloning a sheep). Importantly, legislative and scientific communities have been resolute and unified in their opposition to cloning human beings.

Though a human embryo was indeed successfully cloned in 2013, no known progress has been made when it comes to attempts to clone a human being. Yet the technique to create Dolly has been repurposed widely and has led to numerous scientific innovations.

In 2003, six years after her birth, Dolly became sick and was euthanized. Her decline in health was due to the development of tumors in her chest; some examinations of her cells suggested that she was also aging prematurely.

Despite her relatively short life (the average sheep lifespan is ~10-12 years), Dollys influence on the scientific community has been profound. Not only did she force scientists and researchers to redefine the ethics of their field, but she also laid the foundation for other significant scientific advancements in the fast-evolving new field we know today as regenerative medicine.

One powerful example is gene therapy and editing, where specific genes are targeted, edited, and repaired to protect against disease, cancer, autoimmune disorders, and even rewiring immune system cells for treatment-resistant cancer patients. This revolutionary innovation is made possible by CRISPR technology (the same technology that enabled rapid vaccine development for COVID-19), which is currently celebrating its 10-year anniversary.

Genetic cloning was also made possible thanks to Dolly. This is a type of cloning where scientists create copies of genes within DNA segments to combine with plasmid DNA, or self-replicating genetic material, and then place this new plasmid into a host organism, such as a bacterium, yeast, or mammal cell. This process is used to develop vaccines and antigen tests and is also used to identify useful genetic traits in plants, which can be replicated on a larger scale through the genetic modification of seeds.

Further, cloning techniques have also helped to advance agricultural practices. Farmers can use cloning technology to quickly introduce favored characteristics of prize livestock (such as the ability to produce large amounts of high-quality milk) into a herd by cloning and breeding. These livestock will then further reproduce using traditional breeding or assisted reproductive technology.

Despite advances in genetic cloning and agricultural practices, cloning especially the additional attempts at cloning whole organisms remains variable and highly inefficient.

Successful attempts have been made by companies like Sooam Biotech Research and ViaGen Pets to clone dogs and kittens for wealthy pet owners. But, even today, the success rate of animal cloning is estimated to be less than 30%. In fact, many animal rights activists oppose the practice citing animal welfare. In 2015, the European Union banned the practice of livestock cloning.

Overall interest in cloning slowed as advances in adult stem cell research gained traction in the 2000s. This resulted primarily from scientists newfound ability to take adult human cells, for example skin cells, and reprogram them back into an earlier, more primitive but more powerful embryonic-like, pluripotent cells.

This technique was pioneered by Japanese scientist Shinya Yamanaka in 2006, for which he was awarded the 2012 Nobel Prize in Physiology or Medicine. Yamanakas discovery of reprogramming already specialized adult cells to create induced pluripotent stem cells (IPS) took the ethical issue of destroying embryos for research off the table. Some scientists continue to look to cloning as a way to develop genetically unique stem cells that can be used to reduce the risk of triggering an immune response.

Notes taken shortly after my visit with Dolly.

We have come a long way since my exploratory journey from the Senate floor in Washington, DC, to the stall and research laboratory that housed Dolly in Edinburgh in 1997.

For all the controversy that Dolly sparked during her short life, her contributions to society have been nothing short of remarkable. She forced thought leaders, researchers, and policymakers around the world to confront the ethics of cloning. And, she encouraged us, as a society, to weigh in and engage on the ethical considerations of increasingly frequent scientific discoveries.

On all of these fronts, we worked tirelessly to instill and adhere to a strong scientific code, focusing on the bettering of science, innovation, and technology for societal good. Cloning gave us that first glimpse into the future.

As I said on the floor of the Senate on February 3, 1998:

This cloning debate, I think, maybe for the first time in the history of this body [the US Senate], forces us to address what is inevitable as we look to the future, and that is a rapid-fire, one-after-another onslaught of new scientific technological innovation that has to be assimilated into our ethical-social fabric. Congressional Record February 3, 1998

What I said then still holds true today, Science and ethics must march hand in hand. Congressional Record February 11, 1998

Read the rest here:
Twenty-Five Years After My House Call To Dolly: What Have We Learned About Cloning And How Did We Learn It? - Forbes

Theyre here to save your travel plans this summer… – The Sun

IF you havent finalised your holiday plans, these ten top companies are your summer superheroes.

Theyre here to help with great holiday hacks and ideas, whether youre looking for a thrill-filled family trip or a chill-out break for two.

Surprising destinations, high-tech solutions to help you capture great memories, or simply a hay fever-free holiday: whatever you need, youll find it here.

The world of vlogging is highly competitive, so you need to grab any chance to stand out from the crowd.

Enter the Z 30, part of Nikons revolutionary Z series of mirrorless cameras and compatible with all NIKKOR Z lenses.

This innovative, compact and lightweight camera is packed with features to help ramp up your creativity and produce the kind of next-level content that simply isnt possible on a smartphone.

The Z 30 records up to 125 minutes of uninterrupted video in Full HD and approximately 35 minutes 4K UHD (ideal for tutorial vlogs) and lets you capture time-lapse movies or smooth slow motion in full HD.

The vari-angle touchscreen monitor makes shooting first-person vlogs or selfies a breeze, and exceptional vibration reduction ensures crystal-clear results every time.

There are 20 in-camera filters, all customisable in real time, and once youve created your content, you can upload it instantaneously, thanks to the Bluetooth and Wi-Fi functions.

Find out more about how to up your game with the impressive Z 30 at nikon.co.uk/en.

From a lagoon-view room at Hilton Garden Inn Snowdonia, you can enjoy the unlikely sight of people surfing or paddle boarding in the north Wales mountains.

The hotel is located in the heart of Adventure Parc Snowdonia, an outdoor playground filled with nature-inspired adventures, where the whole family can share thrilling activities in the great outdoors.

As well as testing yourself on the worlds first inland surf lagoon, you can go ziplining, whizz around on a bike on the pump track, try skate-bowl, or enjoy vigorous off-site experiences such as gorge walking and coasteering.

Even on rainy days, the fun doesnt stop: indoor adrenaline-pumping adventures include climbing walls, extreme slides, high ropes courses and caving.

Theres also a soft play zone for younger children.

After all the excitement, you can relax in the hotel, with its spa, modern, well-equipped rooms and relaxed bar/restaurant, or enjoy rustic outdoor living in a simple wooden camping pod.

Organise your family adventure now at adventureparcsnowdonia.com.

A magical family day out, this fairy tale theme park the largest in the Netherlands and third largest in Europe is open 365 days a year, packed with rides, attractions and shows, and surrounded by acres of natural woodland.

Theres something for every taste and age here, from high-adrenaline roller coasters such as Baron 1898 and water rides like Piraa, to a Fairytale Forest thats filled with characters from classic childrens stories, and a spectacular show of water, light and fire - Aquanura.

This year, expect even more fun as Efteling marks its 70th anniversary.

Special celebrations include Efteling Wonderland, a temporary fairytale that takes you through a rabbit hole into a scene inspired by Alices Adventures in Wonderland.

Easy to reach from the UK by ferry, train and air, the park offers a great choice of accommodation, from lakeside cabins and woodland cottages to fairy tale-themed hotel suites.

To experience a wonderful day at Efteling visit efteling.com.

If youve ever spent a summer suffering from hay fever, youll understand what a nuisance it can be.

However, there is a way that could help stop this all-too-common allergy from taking over your life: Allevia hay fever-relief tablets, now available over the counter.

Thanks to their key ingredient, fexofenadine (previously only available on prescription), Allevia has been designed to help provide relief from itchy, red, watery eyes, sneezing and a blocked or runny nose that hay fever sufferers know all too well.

Within an hour of taking a one-a-day tablet you can feel it taking effect, and the relief is reported to last for up to 24 hours.

Allevia are confident that no tablet is stronger for hay fever relief* and nothing works faster for 24-hour relief.

No wonder fexofenadine is the number one prescribed antihistamine by GPs in England*.

Live your life, not your allergy learn more at alleviaallergy.co.uk

Disclaimer: Allevia 120mg tablets contain fexofenadine. For the symptomatic relief of hay fever. Always read the label.

*For verification, email uk-medicalinformation@sanofi.com

Foreign travel can be a truly transformative experience. Thats certainly the case for hair loss sufferers who take a trip to Dr Karaaltin Hair Clinic in Istanbul.

This centre of excellence in hair restoration and hair transplantation treatments is in a well-equipped modern hospital and staffed by highly qualified professionals.

There are three staff anaesthesiologists and plastic surgeons who plan and manage your whole procedure, headed by plastic surgery professor Dr Mehmet Veli Karaaltin.

It claims to be the only clinic in the world that can combine hair transplantation with stem cell therapy, and provides an online lifestyle and aftercare programme of consultation.

It also invests in scientific research in its specialist field.

Treatments are carried out using the highest quality instruments and latest technology, and performed under local anaesthesia and intravenous sedation so that patients feel no discomfort.

The attention to patient comfort extends to providing VIP accommodation and transfer services.

While youre there, take the chance to explore the fascinating city of Istanbul the clinic is located close to Taksim Square, in the heart of the city.

Find out more and book an appointment at drkaraaltinhair.com.

If the mention of Wookey Hole conjures up images of the hairy Star Wars sidekick Chewbacca, think again.

This tiny Somerset village is famed for breathtakingly beautiful caves that were formed over millions of years.

Today, the magical world of Wookey Hole, rich in legends and adventures, is ideal for a family day out, with a host of attractions inside and out.

As well as exploring the spectacular caverns that once provided shelter for ancient hyenas, cave bears and Neanderthals, you can discover vintage penny arcades, museums, soft play zones and adventure golf, along with a cheese tunnel and dinosaur grove.

Oh, and keep an eye out for the famous witch of Wookey Hole.

Theres also a 4D cinema, the only place in the UK showing The Bear and The Squirrel, a new film from the Aardman group (Wallace and Gromit, Shaun the Sheep).

And, as the attraction is owned by the Cottle circus family you can enjoy summer performances by the Wookey Hole Circus School.

Plan your visit now at wookey.co.uk.

The best way to experience the Norfolk Broads National Park is by water.

So when you visit Britains largest protected wetland, make your first port of call Herbert Woods, a leader in the field of Norfolk Broads boat hire.

The regions largest independent hire boat marina, it has a fleet of more than 130 cruisers, with something to suit every budget and every type of holidaymaker, from romantic couples to groups of family and friends.

The cruisers sleep between two and 12 passengers and come in a variety of layouts, but all are light, airy and luxuriously kitted out with all the home comforts.

All are pet-friendly and self-drive, so you can explore at your own pace, completely in control of where you go maybe spotting otters and kingfishers along the River Ant, exploring the historic attractions of Norwich or venturing along the River Bure for some seaside fun in Great Yarmouth.

To book your Norfolk Broads boating holiday, visit herbertwoods.co.uk.

It may be one of the newer arrivals on the Cornish tourism scene, but Bodmin Jail has already clocked up awards, including Best Themed Entertainment and Attractions Project of the Year in the 2021 National AV Awards.

After a multimillion-pound investment, this immersive visitor experience opened in October 2020, using state-of-the-art technology and theatrical effects to bring the past vividly to life.

You can take a Dark Walk through Cornwalls murkier history, join a paranormal tour and get a feel for what it was like to live behind bars in this 18th-century prison on the edge of Bodmin Moor.

These days, an overnight stay is far more appealing.

Part of the handsome, Grade II listed building has been transformed into a boutique hotel, with 70 luxuriously styled rooms, a champagne bar and a fine-dining restaurant in the awe-inspiring surroundings of the former prison chapel.

For tickets, accommodation and restaurant reservations, visit bodminjail.org.

Banish any memories of the bad old days of self-tanning.

The trick to achieving a natural-looking sun-kissed glow without actually seeing any sun is to arm yourself with a bottle of Watermans Browned Off self-tanning foam.

Made in the UK (by a company that recently won a prestigious Queens Award for Enterprise), the mousse is easy to apply and quick to dry, and has a light, non-sticky formula.

Theres none of that odd biscuity smell you might associate with fake tans, just an appealingly tropical coconut scent, and its enriched with aloe vera and vitamin E, to aid absorption and hydration.

In just a few minutes, it delivers a flawless, streak-free finish and the more layers you apply, the deeper the tan.

Find out more, and shop for self-tanning products, at watermanshair.com.

If you have a fondness for heritage rail rides, youll love South Devon Railway, with its handsomely restored vintage locomotives and coaches.

This award-winning steam railway takes visitors on regular scenic trips along the beautiful valley of the River Dart between Buckfastleigh and Totnes, hugging the River Dart for much of the way.

If you fancy making a full day of it, take advantage of the 3 Great Attractions, 1 Amazing Day joint ticket.

This includes not just the return train trip but also admission to two other attractions: Dartmoor Otters and Buckfast Butterflies at one end of the line, and Totnes Rare Breeds Farm at the other.

Back on the tracks, there are some special attractions coming up later this year, including a Day Out With Thomas (every young childs favourite train) from 23-25 September and, from mid-November until Christmas, the chance to take a festive ride aboard the Polar Express.

Find out more at southdevonrailway.co.uk.

Follow Checklist

Enjoyed reading this article?

If you are interested in more inspiration on everything from food and drink, and health and wellbeing, to family life, why not follow Checklist on Facebook, Twitter and Instagram, or sign up to the newsletter?

Checklist is dedicated to providing the best free online competitions.

Plus discover amazing new services and products whenyou visit the website today.

See the original post:
Theyre here to save your travel plans this summer... - The Sun

5 Ways to Save on Your Pet’s Healthcare – The Motley Fool

Image source: Getty Images

Part of loving a pet is paying for care when they need it.

Most of us consider our pets to be family, and there are few things worse than not being able to pay for care when those furry (or feathered, or scaly) family members are in need. Here, we lay out some of the ways you can provide for your pet's health care without draining your bank account.

You may find some of these methods a little "out there," but hopefully, one or two will work for you.

This suggestion may sound insultingly simple, but when my husband and I were young, in college, and broke we looked around for places that provided low-cost vaccinations for our dog. Fortunately, a pet store not far from our apartment provided just such a service. We regularly got in line with other pet owners to have a vet look our dog over and give her the vaccinations she was due. We held on to her vaccination record like it was a passport and made sure she stayed up to date. She lived a long, healthy life.

To ensure that's still "a thing," I just did a quick online search. Our local animal shelter provides low-cost spay and neuter services, as well as free rabies vaccines. There's also an organization that provides discounted vaccination packages for pets of all ages. SNAP recipients get an even deeper discount.

Do not be discouraged if you don't find something right away. Expand your search parameter to include the entire county or call your local humane society to ask about programs not listed online.

No one likes going into debt, but if your pet is sick or injured, applying for a line of credit through a company like Scratchpay or CareCredit can help you cover an emergency situation.

Let's say your pet has a serious condition. CoFund My Pet allows you to upload a picture of your pet and explain why they need veterinary care. When people donate, they know that all funds collected through this crowdfunding site can only be spent at veterinary clinics and won't go to another cause.

There's a good chance you have something sitting around your house that you have no more use for. Or, clean out your basement or attic and sell a whole bunch of stuff. Whether you host a virtual garage sale online or an old-school tag sale in your front yard, all those things you no longer need or use are sure to be of use to someone else. And the money can go to vet bills, or into a savings account for future care.

I suspect that the last thing you want to hear right now is, "You ought to have pet insurance," especially if your pet has an immediate need. However, as someone who has had pets with and without insurance, I need you to know how much it can help. Let's say you have a cat you adore. For less than $10 a month you can buy a policy that will help you pay for whatever may go wrong. It won't cover the entire bill but will pay for 70% to 90% of medical care, depending on the policy you choose.

I have two middle-aged dogs and pay less than $52 per month to cover them both ($26 each). You could easily find a less expensive monthly premium, but this policy pays for everything -- from surgery to chemotherapy, all the way to stem cell replacement. If it sounds excessive, it's because I've made a medical decision on behalf of a dog based, in part, on how much treatment was going to cost and I promised myself (and that dog) I would never do it again.

No matter what, if your pet is suffering, don't give up. If you can't find help locally, contact an organization that specializes in this realm. Some examples include:

Veterinary care is expensive. Fortunately, there are a lot of good people in this world willing to help cover the costs.

If you don't currently have a plan in place to pay for pet healthcare, today is the day to decide what you'll do if your pet is sick or injured. Waiting until your pet is in pain will only add to your stress.

More here:
5 Ways to Save on Your Pet's Healthcare - The Motley Fool

Westin and Sehn Carve Out the Role of CAR T-Cell Therapy and Transplant in Primary Refractory DLBCL – OncLive

CAR T-cell therapy, autologous stem cell transplant (ASCT), and novel agents each have a role to play in the second-line management of patients with primary refractory diffuse large B-cell lymphoma (DLBCL), according to Jason Westin, MD, MS, FACP, and Laurie H. Sehn, MD, MPH, who provided perspective on the optimal use of each modality during a case-based presentation at the 2022 Pan Pacific Lymphoma Conference.1,2

Westin, director, Lymphoma Clinical Research, section chief, Aggressive Lymphoma, and associate professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, started the session by presenting a case of a 70-year-old man with a failure to thrive with progressive bowel obstruction. The man had decreased urine output, a performance status of 1, rising lactate dehydrogenase (LDH) of 1.5 x the upper limit of normal, and an International Prognostic Index (IPI) of 4. A biopsy confirmed high-grade double-hit DLBCL with MYC and BCL2 translocations.

The patient was started with dose-adjusted R-EPOCH and although his gastrointestinal (GI) symptoms improved during the first cycle of chemotherapy, he developed worsening shoulder pain in weeks 2 and 3 of cycle 2 of treatment. An interim PET scan performed after 2 cycles of treatment confirmed a significant improvement in tumor burden but persistent hypermetabolic lesion in the right humerus and a standardized uptake value of 7.

There is a lot of controversy in our field about how we interpret an interim positive PET [result], Westin said. We know the negative predictive value is strong, but the positive predictive value is rather poor.

As such, a bone biopsy was performed on the lesion in the humerus, confirming CD10-positive B-cell lymphoma. Westin argued that the patient was unlikely to achieve a complete response (CR) at the end of treatment, and as such, alternative regimens should then be considered. However, patients with refractory disease have poor outcomes with salvage chemotherapy, which led Westin to consider a clinical trial.

[ZUMA-12 (NCT03761056)] was the clinical trial we had open at the time, which Ill argue is something we should consider for our patients who have high-risk disease in the frontline setting: an early switch to a CAR T-cell therapy, Westin said.

The phase 2 trial enrolled patients with high-grade double-hit or triple-hit B-cell lymphoma and large B-cell lymphoma with an IPI score of at least 3.3 Patients had to have a positive interim PET scan following 2 cycles of an anti-CD20 monoclonal antibody and anthracycline-containing regimen.

Patients underwent leukapheresis and optional nonchemotherapy bridging therapy followed by conditioning chemotherapy consisting of 30 mg/m2 of intravenous (IV) fludarabine and 500 mg/m2 of IV cyclophosphamide on days 5, 4, and 3. They subsequently received a single IV infusion of axicabtagene ciloleucel (axi-cel; Yescarta) at 2 x 106 CAR T cells/kg on day 0.

The CR rate achieved with the CAR T-cell therapy was impressive, according to Westin, at 78% (n = 29) and benefit was consistent across subgroups. The 1-year event-free survival rate with axi-cel was 72.5% (95% CI, 53.1%-84.9%).

In terms of safety, cytokine release syndrome (CRS) occurred in all patients, but the rate of grade 3 CRS was low, at 8%, Westin said.

Westin acknowledged that although axi-cel could be saved for relapse, findings presented at the 2021 ASH Annual Meeting and Exposition comparing the populations in ZUMA-12 and ZUMA-1 (NCT02348216) showed better CAR T-cell expansion in patients who had received less chemotherapy.4

With this in mind, the patient was enrolled to ZUMA-12. He developed late, low-grade CRS and immune effector cellassociated neurotoxicity syndrome (ICANS) but went on to achieve a CR with treatment.

Hes more than 2 years out now without any relapse or any late toxicities, Westin said. Should you switch all patients with a positive interim PET? No. However, if you have circulating tumor DNA or a positive biopsy, its reasonable to consider switching to a different therapy. Having a non-chemotherapy option for chemorefractory disease makes treatment switch more attractive.

Laurie H. Sehn, MD, MPH, a clinical associate professor in the division of medical oncology at the University of British Columbia and the British Columbia Cancer Agency, subsequently presented a case of a 66-year-old man with stage IVB DLBCL with lymphadenopathy above and below the diaphragm. He had a large bowel mass that was biopsied, confirming germinal center B-cell DLBCL and was negative for MYC, BCL2, and BCL6 on fluorescence in situ hybridization.

The patient was treated with 6 cycles of R-CHOP and achieved a CR; however, 6 months later, the patient developed GI bleeding and was found to have recurrent DLBCL of the GI tract. He was started on 2 cycles of R-GDP and achieved a CR, with the intention of heading to ASCT.

Our longstanding management for relapsed/refractory DLBCL has been to take patients down the ASCT route, Sehn stated. However, only approximately half of patients will respond to salvage chemotherapy and proceed to transplant, making the decision on what to pursue a difficult one, Sehn explained.

The 3 randomized trials that have evaluated second-line CAR T-cell therapyZUMA-7 (NCT03391466), TRANSFORM (NCT03575351), and BELINDA (NCT03570892)have yet to show an overall survival (OS) benefit, supporting the rationale to opt for a stepwise approach.

Sehn noted that although all 3 trials demonstrated that CAR T-cell therapy would be the preferred approach in the second-line setting in the intent-to-treat population, they do not provide insight into the preferred approach for patients who respond to salvage chemotherapy.

This is a scenario we all face because most people do receive bridging therapy prior to going on to CAR T-cell therapy, even if your intention is to give it in the second-line setting, Sehn said. As such, we all face this question.

Although not randomized data, Sehn highlighted findings from a Center for International Blood and Marrow Transplant Research retrospective registry analysis which showed that patients in partial remission after salvage chemotherapy had a lower rate of relapse and disease progression (P = .010), as well as improved OS (P = .007).5

Moreover, supplementary findings from the ZUMA-7 trial demonstrated a comparable duration of response among responders, regardless of whether they were randomized to axi-cel or standard of care (HR, 0.763; 95% CI, 0.488-1.108).6

Additionally, Sehn stated that the one-size-fits-all design of the CAR T-cell therapy trials is not likely to hold up in the real world because not everyone will benefit from cellular therapy. Sehn cited data published in Blood Advances showing that predictive factors, including at least 2 extranodal sites, total metabolic tumor volume greater than 80 mL, and elevated LDH, is associated with poor outcomes following CAR T-cell therapy.7

In the CAR T trials, everybody went to CAR T based on an intent-to-treat approach, and even though those arms did better, most patients did relapse or progress subsequently, Sehn said. Just blindly taking everyone on to CAR T is probably not going to be feasible in most clinical settings.

In addition, the short- and long-term toxicities associated with CAR T-cell therapy are worth considering, said Sehn, who highlighted CRS, ICANS, prolonged cytopenias, hypogammaglobulinemia, CD19 loss, and B-cell aplasia in particular, which was present in 34% of patients on the ZUMA-7 trial up to 18 months after infusion.5

For patients who are not candidates to receive CAR T-cell therapy or ASCT, Sehn highlighted the potential of novel agents such as polatuzumab vedotin-piiq (Polivy) plus bendamustine and rituximab (Rituxan) and the combination of tafasitamab-cxix (Monjuvi) and lenalidomide (Revlimid), which have shown responses of 40.2% and 60%, and a median progression-free survival of 5.1 months and 11.6 months, respectively.7,8

For patients with primary refractory or early relapsing DLBCL, the data do argue for CAR T-cell therapy as the preferred potential second-line therapy. However, theres still a role for ASCT; [this approach] still might be suitable for patients who respond to salvage or bridging therapy, Sehn concluded. One of the main things we need to figure out is who shouldnt go to CAR T-cell therapy, as its unlikely to work for patients with fully uncontrollable disease. As far as the novel agents go, there are encouraging data to suggest that these [drugs] will improve outcomes in the refractory setting, although we do need predictive markers to figure out which option to select for which patient.

Read the rest here:
Westin and Sehn Carve Out the Role of CAR T-Cell Therapy and Transplant in Primary Refractory DLBCL - OncLive

Codex Beauty Labs Introduces Shaant: A Collection of Four Microbiome-Supporting Products for Oily and Acne-Prone Skin – Yahoo Finance

SAN JOSE, Calif., July 25, 2022 /PRNewswire/ -- Codex Beauty Labs, Silicon Valley's plant-based biotech skincare company launched its third collection called Shaant, that addresses oily and acne-prone skin by helping to reduce sebum production, exfoliate, encourage skin turnover and soothe irritation. Shaant, meaning "peace" and "calm" in Hindi, is often paired with "connectedness" in Ayurvedic philosophy.

Logo

"Increasing levels of stress in our society, stress, poor quality sleep, rising pollution, as well as unhealthy eating and alcohol habits have all contributed to increased acne in both teenagers and adults. Through Ayurvedic plant databases in India, we have identified actives that address two root causes, namely sebum overproduction, and accumulation of dead skin cells in pores," says Dr. Barb Paldus, Founder and CEO of Codex Beauty Labs. "Shaant also leverages our patented PreservX preservation system that supports microbiome health so we are proud that Shaant is the first MyMicrobiome-certified collection for acne-prone skin."

The Shaant products were formulated in partnership with Dr. Raja Sivamani, an integrative dermatologist and certified Ayurvedic practitioner, and leverage biotech-manufactured plant stem cells from Indian plants long valued by Ayurvedic healers for their calming, soothing and balancing properties.

"I am committed to individualizing patient care and my passion for practical research. By integrating concepts from Ayurvedic medicine, plant sciences, and food sciences, I look to push the boundaries of integrative therapies to make them better for our patients and to better educate those around me. This is the philosophy behind the Shaant skincare collection for acne-prone skin: Ayurvedic plants, such as gotu kola or patchouli, that have been vetted with Western scientific tools, like their effect on gene expression in skin cells and clinical tests on patients with acne." Dr. Sivamani added, "I always love to try to bridge the Ayurvedic principles into the western principles. The way Ayurveda looks at the body is slightly different, but actually it really beautifully integrates with the western approach when you start building these bridges. Shaant is a great example of this confluence."

Story continues

The collection will launch in two phases:

The collection harnesses the patent-pending ShaantComplex, a proprietary blend of derived from terrestrial and marine plants that help control oiliness, shed dead skin cells, reduce pore diameter, and help reduce redness. Each plant addresses the acne inflammasome in distinct yet synergistic ways. The ShaantComplex is supplemented by other Ayurvedic plants or fruits that are known for their analgesic, anti-inflammatory, and skin tone improving properties.

The first four Shaant products are certified MyMicrobiome, Vegan, Leaping Bunny, and EWG Verified. The cleanser and toner are also certified EcoCert COSMOS natural.

Everyproduct in the Shaant collection undergoes efficacy testing at a third-party clinical facility. Measurements are made on a statistically meaningful population using instrumentation accepted by dermatologists for quantifying specific skin parameters. This data is summarized in an efficacy panel that provides a transparent snapshot of product performance to the consumer. The entire collection, including future OTC products, is undergoing an IRB clinical trial under the supervision of Dr. Sivamani.

All products are manufactured in a high-tech cosmetic cGMP (ISO22716) facility to deliver the highest quality. All products contain sustainably sourced ingredients housed inplant-based polyethylene tubes or 50% PCR PET bottles, which reduce each product's carbon footprint from about 50% to 100%.

About Codex Beauty Labs

Based in Silicon Valley and led by scientist Dr. Barb Paldus, Codex Beauty Labs is committed to creating the highest standard in sustainable skincare and biotech plant-based alternatives to restore and protect the skin barrier and support a healthy microbiome. The products address key skincare concerns and conditions including eczema, psoriasis, sensitive, dry, and inflamed skin. The brand has been heralded by dermatologists for creating effective, clinically proven skincare that brings a new data-driven and transparent approach to beauty. Codex Beauty Labs is also dedicated to protecting biodiversity to ensure it flourishes for future generations. All products contain sustainably sourced ingredients from the forests of Patagonia to the bogs of Ireland packaged in plant-based polyethylene tubes, while reducing carbon footprint across all touchpoints. The products are sold around the world in over 15 countries and territories.

Codex Beauty Labs Shaant Collection

Cision

View original content to download multimedia:https://www.prnewswire.com/news-releases/codex-beauty-labs-introduces-shaant-a-collection-of-four-microbiome-supporting-products-for-oily-and-acne-prone-skin-301591871.html

SOURCE Codex Beauty Labs

View original post here:
Codex Beauty Labs Introduces Shaant: A Collection of Four Microbiome-Supporting Products for Oily and Acne-Prone Skin - Yahoo Finance

Global Animal Health Market To Be Driven By The Increasing Pet Ownership In The Forecast Period Of 2022-2027 This Is Ardee – This Is Ardee