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A breakthrough medical technology can save the lives of children with heart defects. Scientists have developed the first-ever heart valve that grows with the child, reducing the need for risky heart surgeries in the future.

Children with congenital heart disease who need valve replacement often undergo multiple surgeries because the valve cannot grow as the child's heart grows. They need multiple heart surgeries to change the heart valve to accommodate the growing size of the heart. However, these surgeries are risky and pose a threat to the child's health.

To solve this problem, a team of scientists from Boston Children's Hospital developed a prosthetic valve that mimics the geometry of the human venous valve. Composed of polymeric leaflets attached to a stainless-steel stent, the valve can be expanded by a minimally invasive balloon catheter procedure, reducing invasive open-heart surgeries.

The doctors can use keyhole surgery to insert a rubber tube attached to a deflated balloon in the valve. They can inflate it depending on the child's heart size.

The valve replacement expanding to accommodate different lengths in implanted sheep. This material relates to a paper that appeared in the Feb. 19, 2020, issue of Science Translational Medicine, published by AAAS. The paper, by S.C. Hofferberth at Boston Children's Hospital in Boston, MA; and colleagues was titled, "A geometrically adaptable heart valve replacement." Image Credit: S.C. Hofferberth et al., Science Translational Medicine (2020)

Multiple heart surgeries

Congenital heart valve disease is life-threatening, and children with this condition may need valve replacement early in their lives. However, children grow, and the artificial heart valve may not be able to accommodate the heart's increasing size.

Many children with this condition face high-risk and multiple open-heart surgeries to remove the valves and replace then with bigger ones.

The scientists used computational modeling to predict how their valve replacement expanded to deal with the stress of blood flow. This material relates to a paper that appeared in the Feb. 19, 2020, issue of Science Translational Medicine, published by AAAS. The paper, by S.C. Hofferberth at Boston Children's Hospital in Boston, MA; and colleagues was titled, "A geometrically adaptable heart valve replacement." Credit: S.C. Hofferberth et al., Science Translational Medicine (2020)

For the first time, the new valve, a biomimetic prosthetic valve, adapts to accommodate growth and structural asymmetries within the heart. In previous heart valve models, they contain three leaflet-like flaps providing a one-way inlet or outlet for blood flow. However, in the new heart valve, it only has two flaps, with a geometry designed to maintain closure, and a one-way flow even when the veins expand in diameter.

"Veins carry approximately 70 percent of our blood volume. The vein dimensions can change dramatically depending on body position, yet the valves must remain functional. We mimicked the geometric profile of the human venous valve to design a bi-leaflet valve of programmed dimensions that is adaptable to growth without loss of one-way flow control," Dr.  Sophie C. Hofferberth, a surgical resident at Brigham and Women's Hospital and lead researcher at Boston Children's Hospital, said.

New artificial heart valve on the way

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The new heart valve has been tested in large animal models, computer simulations, and benchtop studies, demonstrating that it works across a broad range of sizes. What is more, it retains functionality and efficacy when it is expanded through a balloon catheter procedure.

The team tested the prosthetic heart valve in growing young lambs. When implanted on the animals, it exhibited good performance without the blockage of blood flow. In another test in other lambs, the valves stayed functional for ten weeks without causing inflammation or injury to the heart tissues.

Though the study requires human testing and longer-follow up times, there is more work needed to validate the design. If it passes through rigorous testing, it can help more than 1.35 million children across the globe who were born with a congenital heart valve disorder.

The researchers also found that the new prosthetic valve promotes favorable blood flow through the valve, reducing the risk for blood clot formation, which is often observed in existing valve replacement devices. With the invasive heart valve device, there are fewer complications that may endanger the life of the child.

The study was published in the journal Science Translational Medicine.

What is congenital heart valve disease?

The heart pumps blood throughout the body throughout the day, and it contains valves that are responsible for keeping the blood from flowing backward. As a result, the blood flow is controlled, and the oxygenated and non-oxygenated blood will not mix.

A congenital heart valve disease happens if one or more of the valves in the heart do not work well, leading to problems such as regurgitation, stenosis, and atresia. Usually, this occurs when a heart's valves do not develop before birth, causing a defect that keeps the valve from closing completely.

Regurgitations happen when the blood backflows because the valve does not close tightly or adequately. The most common cause of blood backflow is a valve prolapse.

Stenosis happens when the flaps become thick, stiff, or fuse, resulting in the inability of the valve to open fully. Stenosis leads to blockage of blood flow. Atresia pertains to a condition when the valve does not have an opening for the blood to pass through.

All these conditions lead to a wide range of heart problems and can endanger the life of the child. Over time, these problems can strain the heart because it works double-time to compensate for the valve defect. It can cause serious problems such as aortic aneurysm, dilated cardiomyopathy, and heart failure.

Source:

National Heart, Lung, and Blood Institute. (2020). Heart Valve Disease. https://www.nhlbi.nih.gov/health-topics/heart-valve-disease.

Journal reference:

Hofferberth, S., Saeed, M., Tomholt, Fernandes, M., Payne, C., Price, K., Marx, G., Esch, J., Brown, J. et al. (2020). A geometrically adaptable heart valve replacement. Science Translational Medicine. https://stm.sciencemag.org/content/12/531/eaay4006?rss=1.

In a study of patients with kidney failure and atrial fibrillation, racial/ethnic minorities experienced higher rates of stroke compared with non-Hispanic White patients, and they were less likely to fill prescriptions of stroke-preventive medications. The findings, which appear in an upcoming issue of JASN, indicate that equalizing the distribution of such prescriptions may help address stroke-related disparities among patients.

Because patients with kidney failure and atrial fibrillation, or an irregular heartbeat, are at risk of developing strokes, they may benefit from taking blood thinners as a preventive measure. Prior studies of patients with atrial fibrillation, with or without kidney failure, have reported that minority racial/ethnic groups face a higher risk of stroke compared with Whites.

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To investigate the potential causes of such disparities, a team led by Paul L. Kimmel, MD (National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health) examined information from a national registry of patients with kidney failure.

For the study, the researchers analyzed information from the United States Renal Data System to identify patients with kidney failure who initiated hemodialysis from 2006 to 2013, and then they identified those with a subsequent atrial fibrillation diagnosis and Medicare Part A/B/D insurance coverage.

Among 56,587 patients who were followed for one year, the number of strokes per 1,000 people were 84, 94, 97, and 102 in non-Hispanic White, Black, Hispanic White, and Asian patients, respectively.

Black, Hispanic White, and Asian patients filled prescriptions of the blood-thinner warfarin less often than non-Hispanic White patients, and they were more likely to experience stroke. Specifically, Black, Hispanic White, and Asian patients were 10%, 17%, and 28% less likely than non-Hispanic Whites to fill a warfarin prescription, respectively, and they were 13%, 15%, and 16% more likely to experience stroke. (The database did not provide information on whether patients were prescribed drugs, only whether they filled prescriptions.)

Analyses suggested that equalizing the warfarin distribution to that in the non-Hispanic White patient population would prevent 7%, 10%, and 12% of the stroke disparity among Black, Hispanic White, and Asian patients, respectively.

Institutional features and medical choices may play key roles underlying differences between prescriptions received by members of different groups. Our estimates suggest equalization of prescription of warfarin, a relatively inexpensive anticoagulant medication, across all ethnic/racial groups would be associated with decreased stroke rates in Black, Asian, and Hispanic White patients on hemodialysis."

Dr. Paul L. Kimmel, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health

Source:

American Society of Nephrology

Journal reference:

Waddy, S.P., et al. (2020) Racial/Ethnic Disparities in Atrial Fibrillation Treatment and Outcomes among Dialysis Patients in the United States. JASN. doi.org/10.1681/ASN.2019050543.

After 50 years of research and the testing of over 1,000 drugs, there is new hope for preserving brain cells for a time after stroke. Treating acute ischemic stroke patients with an experimental neuroprotective drug, combined with a surgical procedure to remove the clot improves outcomes as shown by clinical trial results published today in The Lancet.

The multi-center, double-blinded, randomized trial, led by a team at the Cumming School of Medicine's (CSM) Hotchkiss Brain Institute and Alberta Health Services, investigates the use of the neuroprotective drug nerinetide, developed by NoNO Inc, in two scenarios in the same trial. In one scenario, nerinetide is given to patients in addition to the clot-busting drug alteplase. In the second scenario, patients who were not suitable for alteplase received only nerinetide. Both groups of patients had concurrent endovascular treatment (EVT) to remove the clot.

"Compared to placebo, almost 20 per cent more patients who received nerinetide along with endovascular treatment, but did not receive alteplase, recovered from a devastating stroke – a difference between paralysis and walking out of the hospital," says Dr. Michael Hill, MD, a neurologist at Foothills Medical Centre (FMC) and professor in the departments of Clinical Neurosciences and Radiology at the CSM. "In the patients who received both drugs, the alteplase negated the benefits of the nerinetide."

Hill says the study provides evidence of a biological pathway that protects brain cells from dying when they are deprived of blood flow. Nerinetide targets the final stage of the brain cell's life by stopping the production of nitric oxide within the cell.

"We really believe this is a new scientific observation," says Hill. "There is evidence nerinetide promotes brain cell survival, offering neuroprotection until we can extract the clot. It opens the door to a new way of treating stroke."

Images of patients' brains from the study show the expected size of the damage from the stroke is sizeably reduced when nerinetide is administered and EVT is performed among patients not concurrently receiving alteplase.

After so many studies investigating neuroprotective drugs failed, we are extremely excited by these results. While nerinetide is not approved for use yet, it shows the potential of a new tool to promote recovery from stroke."

Dr. Mayank Goyal, MD, PhD, neuroradiologist at the FMC, and clinical professor in the Department of Radiology at the CSM

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Worldwide, 15 million people suffer a stroke each year – that's one every nine minutes in Canada and every 90 seconds in the United States. The results can be devastating. Ischemic stroke, the most common, is caused by a clot in a blood vessel in the brain. The sudden loss of blood flow causes brain cells to die, which can permanently affect speech, vision, balance and movement.

The international trial enrolled 1,105 patients between March 2017 and August 2019 at centres in North America, Europe, Australia, and Asia – a global academic collaboration bringing together scientists, clinicians, funding agencies, and industry.

"The collaboration between NoNO Inc., the University of Calgary and investigators at 48 leading stroke hospitals around the world has shown how effective such an academic-industry partnership can be in running high-quality, foundational stroke trials that can lead to positive changes in clinical practice," says Dr. Michael Tymianski, MD, PhD, CEO of NoNO Inc. and the inventor of nerinetide.

The results in the current study, called the ESCAPE-NA1 Trial, build on the success of the ESCAPE trial, in which the Calgary Stroke Program proved that a clot retrieval procedure known as EVT can dramatically improve patient outcomes after an acute ischemic stroke. During the procedure, a catheter is inserted in the groin and guided through blood vessels into the brain. A tiny metal mesh device is used to grab the clot and pull it out. The current study investigates whether administering nerinetide in addition to clot retrieval improves the patient's ability to recover.

Source:

University of Calgary

Journal reference:

Hill, M.D, et al. (2020) Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial. The Lancet. doi.org/10.1016/S0140-6736(20)30258-0.

When you're facing a cancer diagnosis with an average survival span of 12 to 18 months, every milestone is a victory. That makes each wedding invitation, graduation announcement and birthday photo that UCI neuro-oncologist Dr. Daniela Bota receives from her patients a cherished validation of her 12 years of groundbreaking research on glioblastoma multiforme, the most aggressive form of brain cancer. "Because of our work, these people have been able to move on with their lives," she says.

Bota has pushed the boundaries of innovation in her quest to increase the survival rates of individuals with brain tumors, especially glioblastomas. The esteemed physician-scientist has taken a truly comprehensive approach to battling this rare disease, which has a five year survival rate of only 10 percent and claimed the lives of U.S. Sens. Ted Kennedy and John McCain. Bota has conducted clinical trials of multiple cutting-edge treatments that are improving the quantity as well as the quality of life for glioblastoma patients at UCI and beyond.

'So much potential, so much growth'

Bota grew up in Romania, in a family of engineers. It was assumed she'd follow them into the profession – she was a national mathematics champion in her youth – but Bota had another path in mind. "I wanted to make a more significant contribution," she says. "I wanted to combine my analytical side with a place where I could help others. I ended up becoming an M.D.-Ph.D. to blend both."

At USC, Bota earned a doctorate in molecular biology, focusing on neural degeneration. She then went to the University of Kansas for medical school and a residency in neurology. During her shifts, Bota found herself caring for people with brain tumors – and discovered a new direction for her medical career.

The generosity and gratitude of brain tumor patients make it so rewarding to care for them. I see it again and again at UCI. Many of these patients have a terminal diagnosis, but they're volunteering their time and energy to participate in our clinical trials to help us build a better treatment and, hopefully, in the future, a cure."

Dr. Daniela Bota, UCI neuro-oncologist

After a neuro-oncology fellowship at Duke University, Bota joined the faculty of UCI's School of Medicine and the Chao Family Comprehensive Cancer Center in November 2007. "Both my career and UCI in general have grown so tremendously over the dozen years since," says Bota, who's now co-director of the UCI Health Comprehensive Brain Tumor Program. "There has been so much potential, so much growth, so many changes and so much scientific revolution helping us move forward in so many different directions. It's a very exciting time."

A comprehensive approach

The word "comprehensive" carries significant weight in the realm of cancer care centers. The "comprehensive" designation from the National Cancer Institute recognizes an added depth and breadth of research that bridges multiple scientific areas. Just 51 cancer centers in the U.S. carry the designation; the Chao Family Comprehensive Cancer Center is the only one in Orange County. "We offer one of the most innovative and complex portfolios of clinical trials anywhere in the world," Bota says.

Her own multipronged attack against glioblastoma multiforme reflects the center's comprehensive approach. Bota's work on the experimental drug marizomib has generated significant attention and hope. Unlike traditional chemotherapy drugs, marizomib can penetrate the blood-brain barrier – the filtering mechanism that prevents many blood-borne substances from passing into brain tissues – and inhibit cancer growth without causing damage to other parts of the brain.

Over the past 12 years, Bota has shepherded marizomib from preclinical development all the way through a 700-person international phase III clinical trial now underway. "We have a number of patients from our clinical trials who are surviving this tumor for longer periods of time than usually expected," she says.

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Amanda Johnson, a 32-year-old freelance writer in Mission Viejo, has been receiving marizomib for two years under Bota's care. Her large glioblastoma tumor – which straddled both sides of her brain – has shrunk so much that it's no longer measurable. She has returned to work on her novel and even joined a gym. "I feel so happy just to be alive," Johnson says.

Larry Johnson, her father, told Fox News, "I don't think [Amanda] has come to realize how important her survival is to other people and families who are going to find themselves in a similar situation."

Bota strives to reach a point where such cases will be so commonplace that they don't make the news. "That's what success looks like – not having a prominent publication or being part of a game-changing discovery," she says. "It's having patients like Amanda still be here and doing well."

Vaccine trials and right to try

To achieve that goal, Bota tenaciously pursues multiple avenues of treatment. She has been a leader in the use of Optune, a device worn on the head that generates an electrical field that disrupts the growth of cancer cells. "We were among the first in the country to explore and use this technology," Bota says. "Now we're working with physicians from other countries to help them adopt it in their practices."

She is also spearheading two clinical trials on cancer vaccines. "Brain tumors hide behind the blood-brain barrier, so the body doesn't recognize them as not being a normal part of the body," Bota explains. "With our vaccines, we extract cellular markers from the patient's tumor and inject them back into the patient to stimulate the immune system to recognize those tumors, attack them and, if possible, eliminate them."

She adds: "Both studies have been well-received in our neuro-oncological community, which is highly promising. And a significant benefit is that the vaccines function with minimal or no toxicity."

In January 2019, one of Bota's patients who was ineligible for both clinical trials was able to access one of the vaccines through the first successful application of the national Right to Try Act. Passed in May 2018, it allows people with terminal illnesses, in consultation with their doctors, to seek treatment with experimental drugs not yet approved by the Food and Drug Administration directly from pharmaceutical companies. "The law puts patients in charge of their care; they initiate contact with the manufacturer and request therapy," Bota says. "It gives patients who don't qualify for clinical trials another option."

"We offer one of the most innovative and complex portfolios of clinical trials anywhere in the world."

Sharing her expertise

Bota eagerly offers her knowledge beyond the doors of the Chao Family Comprehensive Cancer Center. Whenever she and her husband, Robert, a local psychiatrist, travel back to their home country of Romania, she consults with medical colleagues there, as there are no certified neuro-oncologists in the nation. On days when the couple work on their farm in the Transylvanian Alps, locals come to them – often on foot – for medical advice. The two hope to eventually establish a clinic in the area. "I want to make sure that Romania also benefits from my medical expertise," Bota says.

Back on campus, in her capacity as senior associate dean for clinical research, she uses her vast clinical trial experience to help colleagues in UCI's School of Medicine advance their own research projects into the clinical arena.

"I'm excited by the ability to impact the lives of so many people through this role," Bota says. "Whether it's for burns or vascular disorders or other conditions, people come to UCI for the same reason: We can offer what community hospitals cannot. Being able to make that happen, to create new options for our patients, is what wakes me up in the morning."

Source:

University of California, Irvine

A new simple blood test for brain tumors that could be used by GPs in primary care is being developed thanks to funding of nearly £500,000 by Cancer Research UK. Around 60,000 patients in the UK are living with a brain tumor but only 20 per cent of patients are still alive five years after diagnosis, partly because they present late with large inoperable tumors.

The University of Bristol-led research project to develop an affordable, point of care blood test to diagnose brain tumors earlier using fluorescent carbon dots and nanophotonics will be headed by Dr. Kathreena Kurian, Associate Professor in Brain Tumour Research and Dr. Sabine Hauert, Senior Lecturer in Robotics in collaboration with co-investigators: Professors Carmen Galan and Richard Martin at the University of Bristol; Dr. Neciah Dorh at FluoretiQ Limited and Dr. Helen Bulbeck at Brainstrust.

The cross-disciplinary research project brings together medical practitioners, along with experts in population health, nanoparticle engineering and detection, as well as computational modeling.

Dr. Kathreena Kurian, Head of the Brain Tumour Research Centre at the University of Bristol, said:

A simple blood test carried out by GPs would help decision-making and early diagnosis. This would revolutionize care by speeding up diagnosis, reducing costs to the NHS, anxiety of unnecessary scans and reducing the number of patients presenting with inoperable large brain tumors.

Additionally, this test could be used as an early monitor of brain tumor recurrence. Our work will be followed by a multicentre cohort biomarker study to determine the effectiveness of the test in a real-world setting."

Dr. Sabine Hauert from the Department of Engineering Mathematics and Bristol Robotics Laboratory (BRL), added: "Nanoparticles have shown promise in early detection of cancer by fluorescent labeling of very low levels of biomarkers in blood samples and other fluids."

Dr. Alexis Webb, Cancer Research UK's senior early detection funding manager, said:

At the moment the number of people who survive after a brain tumor diagnosis remains low and little has changed in over a generation. We're proud to support this innovative project and funding brain tumor research remains a priority for the charity. We need better techniques to diagnose brain tumors earlier, when more treatment options are available, to secure a future for more people affected by the disease."

Professor Carmen Galan, Professor of Organic and Biological Chemistry in the School of Chemistry, who has developed the fluorescent carbon-based nanomaterials that form the basis for the project, explained: "The fluorescent nanoprobes are produced by low-cost renewable routes and we have shown that we can decorate them with different biomolecules to target specific biomarkers in physiological conditions, which is really exciting."

Dr. Neciah Dorh, CEO of FluoretiQ Limited, stated:

As a diagnostics company, we are passionate about creating technology that can improve people's lives and we see this project as natural extension of the work that we are currently doing in infectious disease."

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In the UK in 2013, 38 percent of brain tumor patients visited their GP five times or more before being referred for diagnosis by imaging MRI/CT scan and neurosurgical biopsy, because the symptoms such as headache are non-specific, so there is an urgent need to develop new tests for brain tumors to help GPs diagnose brain tumors earlier.

There is a pressing need for the discovery of new blood biomarkers for brain cancer and state-of-the-art technology that allows for its sensitive detection. The aims of the research project are:

  • discover novel biomarkers, in addition to known markers such as Glial fibrillary acidic protein (GFAP), which will be used as a baseline;
  • implement a computational model to predict biomarker levels in blood;
  • develop a fluorescent nanoparticle that can label this marker in blood;
  • work with Bristol-based start-up FluoretiQ towards an affordable near patient testing solution.

Glioblastoma is the most common type of malignant brain tumor among adults and it is usually very aggressive, which means it can grow fast and spread quickly. It is characterized by abnormal blood vessels following a leaky blood-brain barrier (BBB). GFAP is unique to the brain and not present in blood that circulates throughout the body. Antibodies in GFAP are used to diagnose gliomas in tissue samples. There is evidence that GFAP crosses the leaky BBB and is an early non-specific peripheral blood biomarker which predates the clinical diagnosis of glioblastoma.

However, GFAP levels are too low for routine detection by routine protein detection tests such as ELISA. The research team has already identified other novel potential protein biomarkers of brain tumours using the epidemiological method, Mendelian Randomization, which may be present in low levels in the blood.

Fluorescent carbon dots (FCDs), also known as nanoparticles, are cheap and easy to create using a three-minute synthesis. FCDs can be readily attached to ligands such as antibodies targeting specific protein markers. FCDs labeling biomarkers can then be detected using nanophotonic technology, which has been developed by FluoretiQ, for rapid, sensitive, and low-cost diagnosis. Computational modeling will then be used to predict tumor size given biomarker availability in blood and establish the theoretical limits of the detection.

Source:

University of Bristol