This genetic risk score may help health care providers identify the risk of heart disease earlier and take preventive measures.

Vibhu Parcha, M.D., first author of this study and a clinical research fellow in the Division of Cardiovascular Diseases and the UAB Cardiogenomics Clinic. (Photography: Lexi Coon)According to the Centers for Disease Control and Prevention, more than 37 million Americans have diabetes, and approximately 90-95 percent of them have Type 2 diabetes. Individuals with Type 2 diabetes are at an increased risk of poor cardiovascular outcomes, leading to an estimated $37.3 billion a year in heart disease-associated care.

A new study involving two researchers from the University of Alabama at Birmingham Division of Cardiovascular Disease states that a genetic score can predict the likelihood of high blood pressure and its connection to poor cardiovascular outcomes in people with Type 2 diabetes.

The study, published today in the American Heart Associations peer-reviewed journal titled Hypertension, could play a pivotal role in guiding treatment for people who are newly diagnosed with Type 2 diabetes or those with prediabetes. In this study, researchers explored whether genetic variants linked with high blood pressure are connected to the risk of heart disease or stroke for people with Type 2 diabetes.

Identifying the genetic risk of high blood pressure among newly diagnosed patients with diabetes may help with more targeted efforts to prevent the development of heart-related events in the future, said Pankaj Arora, M.D., associate professor in the UAB Marnix E. Heersink School of Medicines Division of Cardiovascular Disease and the director of the UAB Cardiogenomics Clinic. In the current era of precision medicine, we want to find the individualized approach of understanding the risk of heart disease in a person newly diagnosed with diabetes. This allows focusing our clinical efforts in preventing the occurrence of fatal heart events through a personalized approach based on their genetic risk.

Researchers analyzed the health records of 6,335 participants from the Action to Control Cardiovascular Risk in Diabetes trial database. Thirty percent of participants were racial minorities, and 37 percent of participants were women. Each candidate had Type 2 diabetes and elevated blood pressure.

They reviewed multiple health factors including blood pressure, cholesterol and blood sugar levels all commonly used to determine a persons risk for heart disease and reviewed their age, sex, body mass index, medical history and genetic history, among other factors. Through their analysis, researchers established a genetic risk score, which estimates a persons chance of developing heart disease within the next 10 years.

To develop this risk score, researchers used a genetic variant map of more than 1,000 common genetic variants known to affect blood pressure and compared it to the DNA of study participants to determine their genetic risk. More matches between a participants DNA and these genetic variants would mean a higher genetic risk score.

Pankaj Arora, M.D., associate professor in the UAB Division of Cardiovascular Disease and the director of the UAB Cardiogenomics Clinic.(Photography: Andrea Mabry)Commonly occurring changes in our DNA form the composite genetic risk score for an individual, said Vibhu Parcha, M.D., first author of this study and a clinical research fellow in the Division of Cardiovascular Diseases and the UAB Cardiogenomics Clinic. Since we are born with these commonly occurring DNA changes, we carry the risk for heart conditions conferred by them throughout our lifetime. We were curious to understand whether a high genetic risk score for blood pressure would help us identify individuals with diabetes who are at a higher risk of fatal heart events.

Researchers found that the genetic risk score identified study participants with a higher risk of cardiovascular events. This genetic score may help identify the risks for diseases earlier and allow doctors to take preventive measures among people with Type 2 diabetes.

This study represents a step toward personalized medicine for heart disease that stems from Type 2 diabetes and high blood pressure, said David Goff, M.D., Ph.D., director of the Division of Cardiovascular Sciences at the National Heart, Lung, and Blood Institute, part of the National Institutes of Health.

Other authors involved in the study are Akhil Pampana, M.S.; Adam Bress, Pharm.D., M.S.; Marguerite R. Irvin, Ph.D.; and Garima Arora, M.D.

We look forward to future studies to confirm and build on these findings, said Goff, who is not a member of the current study team. Studies such as this with diverse populations could also help inform efforts to reduce health disparities associated with heart disease. Future studies might also test whether interventions guided by this type of knowledge are more effective than current strategies.

The UAB Cardiogenomics Clinic uses a patients genetic history to help develop a personalized cardiovascular treatment plan based on their genetic results. The clinic provides a broad spectrum of cardiology health care services for people of all ages and those with all types of heart diseases in the southeastern United States. Make an appointment today by visiting uabmedicine.org or calling 205-975-2313.

Research reported in this release was supported in part by the National Heart, Lung, and Blood Institute, part the National Institutes of Health, under grant numbers R01HL160982 and K23HL146887. The study includes data from the multiethnic ACCORD trial, which was sponsored by the NHLBI. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Researchers find that genetic scores may identify risk of heart disease for people with Type 2 diabetes - University of Alabama at Birmingham

The goal of reaching an era of individualized precision medicine will first require a closer look at the broader population.

The big picture: Large clinical trials and massive databases of de-identified genetic and other health information sometimes from generations of populations are offering scientists and doctors data to decipher why certain individuals have a higher risk of disease or different responses to treatments.

What's happening: There are many institutions gathering this data, including...

What's new: The COVID-19 pandemic led various groups to collectively create large-scale studies to seek safe and effective COVID treatments as rapidly as possible, such as the U.K.'s Recovery trial on more than 47,000 participants and the WHO's Solidarity Therapeutics Trial on 14,200 randomized hospitalized patients globally.

Growing awareness of the problems caused by a lack of diversity in clinical trials and in most genetic databases has led to other changes.

Reality check: Personalized medicine continues to face serious challenges, and has sometimes resulted in deadly missed targets. But many hope accumulating data from large, more diverse trials will help alleviate those issues.

Between the lines: Large cohort studies are one of the key "strategies to be able to understand the risk factors associated with cancer and with other diseases," says Marcia Cruz-Correa, physician-scientist at the University of Puerto Rico Comprehensive Cancer Center.

The bottom line: These massive datasets are expected to help tease out the biological and socioeconomic factors of disease, Oh says. "They're all tied together."

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The power of massive databases and trials to unlock precision medicine - Axios

Cancer is a difficult disease to treat. Figuring out exactly what chemotherapy or immunotherapy treatment will perform best for a specific cancer patient can be a difficult task for physicians. There is no sure fire way of knowing exactly how a patient will react to a certain type of anticancer drug. And, unfortunately, time usually isnt abundant to perform trial-and-error, especially in particularly aggressive types of cancer.

Genetic profiling has been the traditional approach in aiding physician decisions with limited success. Even if certain mutations in the cancer are identified, it still boils down to an educated guess based on previous patients. Its not quite the personalized medicine that physicians and scientists have been searching for.

However, scientists from Ohio State University have come up with a solution that could prove to truly be a personalized approach to knowing exactly how a patient will react to different cancer drugs. These scientists took cancer tissue from melanoma patients and created petri-dish versions of their bodies to test which drug would be most effective. Melanoma is a type of cancer that originates from mutations to pigment in our skin called melanin. It is an incredibly aggressive type of cancer that can quickly spread to other parts of the body.

But creating these test tube patients to experiment on was not an easy task. Our bodies are made up of intricate biochemical systems, most of which we still dont completely understand in terms of cancer progression. In order to create the best possible replication of cancer in our bodies, these scientists came up with a way to combine cancer tissue from patients and important immune cells found in their lymph nodes using a thick substance called extracellular matrix (ECM) hydrogel.

Every cell has an extracellular matrix that serves as a barrier between the cells and their environment. The hydrogel that these scientists used served to mimic this important barrier. The hydrogel was able to keep the cancer and lymph node tissue together, while still allowing for dynamic movement of the cancer drugs across the membrane to mimic what happens in our bodies own cells.

Once these synthetic organoids were made using tissues from each patient, they tested to see how long these organoids would maintain their ability to simulate the inside of the patient. After 7 days of the tissues sitting at around body temperature (99F) without any treatment, the scientist used a type of dye to see how alive these new tissues were.

These dyes work by binding to specific proteins on the outside and inside of the cell. If the cell is alive, the dye will react with proteins on the outside membrane and glow a fluorescent green. If the cell is dead, these dyes will be able to pass through the cell membrane and react with other proteins withinthe cell, tuning it bright red. Of the 10 tissue samples collected from 8 patients, 9 glowed green, meaning the cells were alive and could be used to test cancer treatment options.

The scientists treated each living specimen with 4 of the most common immunotherapy treatments for melanoma. They allowed the treatment and immune cells to interact for 3 days at body temperature, and then used the same staining techniques to see how effective each cancer drug was. They compared how many organoid cells were killed when treated with the cancer drug and how many were killed without treatment by looking at the dead (red) and green (alive) organoids. If most or all of the cells were killed only when treated with a certain drug, they predicted that this treatment would be effective inside the patient. Of the 7 patients with viable tissue samples, this technique was able to predict if each therapy would be effective in 6 of the cases (85%).

These scientists emphasize that while the number of patients used in the study was relatively small, it does show the potential for further investigation and even application in some hospitals. They were later able to create viable cell systems with appendix cancer cells that are ready to be tested using these techniques, which shows that these methods could be applied to other forms of cancer.

The authors of the paper also discuss possible cooperation between these experimental techniques and genetic profiling. The two ideas could work in unison, with genetic profiling predicting the probable effective treatments and these techniques testing each possible combination. With the growth in genetic medicine, combined with advances in biomaterials science, cancer patients could start to see a truly personalized approach to treatment.

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Simulating cancer patients' organs in the lab to test treatments - Sciworthy

ALAMEDA, Calif.--(BUSINESS WIRE)--Scribe Therapeutics Inc., a molecular engineering company creating the most advanced technologies for CRISPR-based genetic medicine, today announced its participation in the Goldman Sachs The New Guard: Privates Leading The Disruption In Healthcare conference.

Benjamin Oakes, CEO and co-founder of Scribe Therapeutics, will join the Gene Editing: Moving from Molecular Scissors to Pencils panel on Thursday, April 7, 2022 at 10 a.m. ET in New York, NY.

About Scribe Therapeutics

Scribe Therapeutics is a molecular engineering company focused on creating best-in-class in vivo therapies that permanently treat the underlying cause of disease. Founded by CRISPR inventors and leading molecular engineers Benjamin Oakes, Brett Staahl, David Savage, and Jennifer Doudna, Scribe is overcoming the limitations of current genome editing technologies by developing custom engineered enzymes and delivery modalities as part of a proprietary, evergreen platform for CRISPR-based genetic medicine. The company is backed by leading individual and institutional investors including Andreessen Horowitz, Avoro Ventures and Avoro Capital Advisors, OrbiMed Advisors, Perceptive Advisors, funds and accounts advised by T. Rowe Price Associates, Inc., funds managed by Wellington Management, RA Capital Management, and Menlo Ventures. To learn more about Scribes mission to engineer the future of genetic medicine, visit http://www.scribetx.com.

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Scribe Therapeutics to Participate in Upcoming Goldman Sachs The New Guard: Privates Leading the Disruption in Healthcare Investor Conference -...

- NT-proBNP, a biomarker of cardiac failure and independent predictor of mortality in ATTR-CM patients, was stable or improving throughout the study. At Month 30, median change from baseline in NT-proBNP was -437 pg/mL with 68% of participants observing NT-proBNP levels below their baseline

- Serum TTR levels were sustainably increased from baseline, with mean concentration rising from 21.55 mg/dL at baseline to 30.06 mg/dL at Month 30 (+41%)

- Acoramidis remained generally well-tolerated with no safety signals of clinical concern identified

- Topline data from ongoing Phase 3 trial of acoramidis in ATTR-CM (ATTRibute-CM) are expected in mid-2023

PALO ALTO, Calif., April 03, 2022 (GLOBE NEWSWIRE) -- BridgeBio Pharma, Inc. (Nasdaq: BBIO) (BridgeBio or the Company), a commercial-stage biopharmaceutical company focused on genetic diseases and cancers, today announced updated data from its ongoing Phase 2 open-label extension (OLE) study of acoramidis (AG10) in patients with symptomatic transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM). The results were featured in an oral presentation at the American College of Cardiology (ACC) Annual Scientific Session & Expo, taking place in Washington, D.C. on April 2 4, 2022.

An interim analysis of the ongoing Phase 2 OLE study was completed based on available data through August 31, 2021. This corresponds to a median of 38 months since Phase 2 enrollment in the first half of 2018 and 35 months of continuous acoramidis treatment in the OLE. Acoramidis was generally well-tolerated and resulted in sustained, near-complete TTR stabilization as measured by established ex vivo assays and increased serum TTR levels. Median N-terminal Pro-brain natriuretic peptide (NT-ProBNP) was stable or improving in trial participants throughout the OLE. In ATTR-CM patients, NT-ProBNP concentrations are strongly correlated with mortality and typically increase progressively in untreated patients.1 The Phase 2 OLE data continue to suggest long-term tolerability of acoramidis in ATTR-CM patients and a stabilization of disease progression in treated participants.

Over approximately three years in this study, acoramidis continued to be well tolerated and potently stabilize TTR. In patients with advanced symptomatic disease that would be expected to decline rapidly, participants remained remarkably stable or improved with respect to key cardiac biomarkers, said Ahmad Masri, M.D., MS, director of the Cardiac Amyloidosis Program at Oregon Health & Science University. These results provide additional optimism for the results of the ongoing Phase 3 study of acoramidis expected next year.

The ongoing OLE study enrolled 47 participants who had completed the 28-day randomized, placebo-controlled Phase 2 study of acoramidis in ATTR-CM patients with New York Heart Association (NYHA) class II or III symptoms. Participants received 800 mg of acoramidis hydrochloride twice daily during the OLE. An interim analysis of the ongoing Phase 2 OLE study was completed based on available data through August 31, 2021. The data demonstrated:

31 of 47 participants remained in the OLE study; of the 16 discontinuations,adverse events (AEs) with an outcome of death, cardiac transplant or transition to hospice were reported for 11 participantsAcoramidis remained generally well-tolerated with a pattern ofAEs consistent with underlying disease, progression of disease, concurrent illnesses, and age of participants. No safety signals of clinical concern were identifiedAcoramidis demonstrated near-complete TTR stabilization. Serum TTR levels were sustainably increased from baseline, with mean concentration rising from 21.55 mg/dL at baseline to 30.06 mg/dL at Month 30 (+41%). Near-complete stabilization was verified using established ex-vivo assays with mean stabilization of 102.5 8.9% at Month 30Median NT-proBNP were stable or improving in study participants. At Month 30, median change from baseline in NT-proBNP was -437 pg/mL (interquartile range: -950, 316). 68% of participants with available samples at Month 30 (15/22) had NT-proBNP levels below their baseline, suggesting an improvement in their heart failure severity

BridgeBios Phase 3 study investigating acoramidis in ATTR-CM (ATTRibute-CM) is ongoing with Month 30 topline data expected in mid-2023. In the Month 12 readout, no benefit of acoramidis relative to placebo was observed on the six-minute walk test, but improvements in the Kansas City Cardiomyopathy Questionnaire Overall Score, NT-proBNP, and serum TTR level were observed. The Company remains optimistic in the Month 30 primary endpoint, a hierarchical composite including all-cause mortality and cardiovascular hospitalizations.

The Phase 2 OLE data deepen our conviction in the Month 30 readout given the stability or improvement of NT-proBNP change from baseline in patients with an otherwise rapidly progressive disease, said Neil Kumar, Ph.D., founder and CEO of BridgeBio. We are committed to the ATTR community and hope to provide a new treatment option for ATTR-CM patients.

About Acoramidis Acoramidis (AG10) is an investigational, orally-administered small molecule designed to potently stabilize tetrameric transthyretin, or TTR, thereby halting at its outset the series of molecular events that give rise to TTR amyloidosis, or ATTR. Acoramidis is currently being evaluated in Phase 2 and Phase 3 studies in patients with ATTR. Acoramidis was designed to mimic a naturally-occurring variant of the TTR gene (T119M) that is considered a rescue mutation because it has been shown to prevent or minimize ATTR in individuals carrying pathogenic, or disease-causing, mutations in the TTR gene. For patients with ATTR, TTR stabilization offers the chance to both preserve the protective benefits of TTR and address the root cause of disease.

About Transthyretin Amyloidosis (ATTR) Likely affecting more than 400,000 patients globally, ATTR is an underdiagnosed and life-threatening disease with limited treatment options that can devastate the heart and nervous system. When the transthyretin (TTR) becomes unstable due to inherited variants or aging, it can accumulate as amyloid fibrils in various organs in the body, causing ATTR. TTR amyloid deposits predominantly in the heart and/or peripheral nerves, causing cardiomyopathy (ATTR-CM) and/or polyneuropathy (ATTR-PN). ATTR often dramatically impairs the quality of life, functional independence and life expectancy of patients, as well as impacting caregivers due to the progressive nature of the disease. If left untreated life expectancy from diagnosis is approximately four years.

References 1Lane, T. et al. Circulation. 2019;140:1626.

About BridgeBio Pharma, Inc. BridgeBio Pharma, Inc. (BridgeBio) is a commercial-stage biopharmaceutical company founded to discover, create, test and deliver transformative medicines to treat patients who suffer from genetic diseases and cancers with clear genetic drivers.BridgeBios pipeline of over 30 development programs ranges from early science to advanced clinical trials and its commercial organization is focused on delivering the companys first two approved therapies. BridgeBio was founded in 2015 and its team of experienced drug discoverers, developers and innovators are committed to applying advances in genetic medicine to help patients as quickly as possible. For more information visit bridgebio.com and follow us on LinkedIn and Twitter.

BridgeBio Pharma, Inc. Forward-Looking Statements This press release contains forward-looking statements. Statements we make in this press release may include statements that are not historical facts and are considered forward-looking within the meaning of Section 27A of the Securities Act of 1933, as amended (the Securities Act), and Section 21E of the Securities Exchange Act of 1934, as amended (the Exchange Act), which are usually identified by the use of words such as anticipates, believes, estimates, expects, intends, may, plans, projects, seeks, should, will, and variations of such words or similar expressions. We intend these forward-looking statements to be covered by the safe harbor provisions for forward-looking statements contained in Section 27A of the Securities Act and Section 21E of the Exchange Act and are making this statement for purposes of complying with those safe harbor provisions. These forward-looking statements, including statements relating to the timing and prospects of success for Part B results from the Phase 3 ATTRibute-CM Study, the market opportunity for AG10, and the timing, prospects of success and clinical trial results of our ongoing Phase 2 OLE study of AG10 in patients with symptomatic ATTR-CM, reflect our current views about our plans, intentions, expectations, strategies and prospects, and are based on the information currently available to us and on assumptions we have made and are not forecasts, promises nor guarantees. Although we believe that our plans, intentions, expectations, strategies and prospects as reflected in or suggested by these forward-looking statements are reasonable, we can give no assurance that the plans, intentions, expectations or strategies will be attained or achieved. Furthermore, actual results may differ materially from those described in the forward-looking statements and will be affected by a number of risks, uncertainties and assumptions, including, but not limited to, the success of our product candidates to treat genetically driven diseases and cancers with clear genetic drivers, our anticipated cash runway and our being fully funded through the completion of the ATTRibute-CM study and our ability to access additional funding upon achievement of portfolio milestones, as well as those risks set forth in the Risk Factors section of our most recent Annual Report on Form 10-K and BridgeBio Pharmas other SEC filings. Moreover, we operate in a very competitive and rapidly changing environment in which new risks emerge from time to time. Except as required by applicable law, we assume no obligation to update publicly any forward-looking statements, whether as a result of new information, future events or otherwise.

BridgeBio Contact: Grace Rauh Grace.rauh@bridgebio.com (917) 232-5478

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BridgeBio Pharma Presents Updated Results from Phase 2 Open-label Extension Study of Acoramidis ... - The Bakersfield Californian

Newswise LOS ANGELES (April 4, 2022) --Every Thursday, a panel of clinicians from Cedars-Sinai gathers on a video call to spend a full hour talking about a single patient. Each week, the patient is different, but all have one thing in common: No doctor has been able to figure out exactly what ails them.

The clinicians, whose specialties range from internal medicine, neurology and rheumatology to nephrology, gastroenterology, surgery and genetics, are part of theCenter for the Undiagnosed Patient, a specialty Cedars-Sinai clinic founded in 2017 to diagnose and treat patients whose conditions have defied identification.

In spite of efforts by multiple doctors, sometimes patients with chronic conditions are unable to get a diagnosis, saidLeon Fine, MD, professor of Medicine and Biomedical Sciences at Cedars-Sinai and medical director of the center. When we begin seeing a patient in our clinic, our commitment is to help them find a diagnosisor at least a way forwardand the way that we approach this is to take a unique team approach to the patient involving both generalists and specialists.

When a new patient reaches out for help,Jennifer Elad, DNP, ACNP, a founding member of the center, conducts a detailed review of the patients medical recordssometimes years worthand condenses hundreds of pages of doctors handwritten notes, typed reports, test results and other information into a concise report.

Elad also meets in person with every patient to discuss their history in detail and ask a series of questions related to their condition.

My job is to listen to their story, ask about symptoms, what makes things worse, what makes things better, diet, lifestyle, past traumas, medical test results, what treatments have been tried, and to gain an understanding of what the patient perceives to be going on and compare this with what is reflected in their medical records," Elad said. It is important to identify where gaps may exist.

Specialists from throughout the medical center then weigh in as needed to ponder the cases of patients with complaints ranging from pain and inflammation to tremors, balance issues, loss of vision, and even a flagging fastball.

Weve learned to merge our specialized lenses to look at the whole patient, Elad said. When a patient has a mysterious condition, this helps us put the pieces of the puzzle together.

A patient is only enrolled in the center if consulting clinicians believe they can help, sometimes by ruling out a condition the patient or one of their doctors believes is the source of their symptoms.

We have a very robust discussion, saidLawrence Maldonado, MD, co-lead internist. Even if we're not having any brilliant ideas right now, we try to form a plan for moving forward.

Joshua Mould, a 21-year-old studying computer science and statistics at Villanova University in Pennsylvania, had suffered from mysterious balance issues and tightness, called spasticity, in his leg muscles since junior high. When Mould was in eighth grade, these symptoms began interfering with his passion for baseball, and eventually sidelined him.

I wasn't very flexible, Mould said. I also wasn't getting stronger, and I wasnt gaining any velocity on my fastball even though I was lifting weights and working out at least three times a week.

Pitchers generate power through their legs, with the arm simply following through. I didnt have the flexibility to take a very long stride toward the plate, or the leg strength or stability to create much momentum, Mould said.

After a lackluster sophomore year, Mould trained throughout the offseason, even working with coaches from a top sports performance center in hope of making progress. But the next spring, we checked the velocity on my fastball, and it had dropped about 10 miles per hour, he said.

His trainer suggested he see a doctor, and a local neurologist ordered a genetic screening test that identified variations in both copies of his human 4-hydroxyphenylpiruvate dioxygenase-like (HPDL) gene, a gene that had never before been associated with disease. The neurologist connected him withTyler Pierson, MD, PhD, assistant professor of Pediatrics and Neurology at Cedars-Sinai and lead pediatrician at the center.

Over the years, Pierson had seen a few other patients with symptoms and a genetic variation similar to Moulds.

At the time, very little was known about this gene, Pierson said, so further research was needed to determine whether the variation was causing Joshs symptoms.

Pierson and collaborators put together a study involving nearly 50 institutions in the U.S. and abroad, looking at the cases of Mould and 30 others with the HPDL variation, and were able to describe a new disorder called HPDL deficiency (also called SPG83) and provide Mould and the others with a diagnosis.

Pierson said the diagnosis has value, even though HPDL deficiency doesnt yet have a cure, because it lets families know the symptoms came from a condition over which they had no control. It also gives the patient the opportunity to pursue genetic counseling before having children, and to seek information within the community of fellow patients.

It allows them to look for other people with the same diagnosis, whether thats a family research group or even just a Facebook group, said Pierson. They can connect and perhaps gain insight from other families.

Pierson continues to work to better understand HPDL deficiency in the hope of one day finding a therapy that halts or even reverses the progression of symptoms. And Mould takes medications to reduce the tightness in his legs, which he said is helping improve his balance.

Early in high school, it was really hard to deal with, Mould said of his condition. The diagnosis gives me a reason why my muscles arent listening to me, and that its not just my failure to work as hard as other people. And its been really important to me to know that.

Pediatric patients referred to the center are diagnosed most often with genetic conditions. Adult patients are more likely to have conditions that arose later in life, and they often have been to multiple specialists who haven't been able to explain their symptoms or test results.

One typical adult patient is 73-year-old Genevieve Crean, a native of Chino, California, who had always enjoyed good health as she raised two children with husband John and pursued a career as a marriage and family therapist.

Crean was working as a mental health counselor when she began experiencing mysterious abdominal pain. "I remember that first pain episode like it was yesterday even though it was 11 years ago," Crean said. "It was just excruciating, and that was the first of many ER visits we made."

The pain always came on quickly, for no apparent reason, and could last up to six hours, leaving Crean in a fetal position. At first, the episodes came every six months, but the frequency and intensity increased over time. Crean's local doctors were stumped and, over the next eight years, referred her to gastrointestinal specialists, OB-GYN specialists, hematologists, and small-vein specialists. Her gallbladder was removed, and she had four other laparoscopic surgeriesyet her painful episodes continued.

Doctors prescribed narcotics and Crean used meditation practices to help keep the pain at bay. Meanwhile, she and John retired, hiking the Rogue River in Oregon, taking a pilgrimage to Israel and staying active in their church.

"I always took my pain medication with me wherever I went, because when I didn't, I paid dearly for it," said Crean. "But eventually, the pain medication became less effective. I think I was building up a tolerance."

Crean was grateful that she still had many pain-free days, but she kept looking for a solution. Finally, a friend referred her to Cedars-Sinai.

The game-changing question we asked was, had she ever had a CT scan during a pain episode? Elad said. And Genevieve said no.

Not long after that, Crean experienced a pain episode lasting not the usual five or six hoursbut two full weeks. At her local hospital, she got the scan the Cedars-Sinai team needed.

It was very striking, saidEdward Phillips, MD, executive vice chair of the Department of Surgery and director of the Division of General Surgery at Cedars-Sinai, who consulted on Creans case. It was a eureka moment and we could see quite clearly that she had a femoral hernia.

A loop of Creans bowel had become trapped in the space where the artery and vein supplying blood to the leg pass through her pelvis. But the bowel wasnt completely stuck, which explained the intermittent nature of Creans pain.

Sometimes, she had a partial obstruction, sometimes no obstruction and sometimes complete obstruction, said Phillips. And that just confounded everything because the symptoms of those three things are all different.

To correct the problem, Phillips decided to do a laparoscopic, minimally invasive procedure where a small camera is inserted to view the area, and possibly to free the bowel. During the procedure, however, he discovered that the bowel was swollen and stuck firmly in place.

It was very delicate because it had been obstructed for a while, Phillips said. So, I made an incision overlying the femoral area. Working from both the inside and outside, I was able to free up the bowel without injuring it.

Phillips then repaired the area where the bowel had pushed through. It was a successful procedure. We knew immediately that it was going to help, he said.

After one night in the hospital, Crean went home. The pain hasnt come back, but her healing wasnt only physical. It was such an emotional relief, said Crean. As the days turned into weeks, turned into months, turned into years, I grew more and more confident.

Not all patients enrolled in the center are cured, or even diagnosed, but Maldonado said that most are helped in some way.

Sometimes that means ruling out a diagnosis the patient had been fearing. Sometimes it means helping the patient better manage their symptoms, or the anxiety and depression that can come with experiencing years of unexplained yet debilitating health issuesand perhaps feeling like the doctors treating them dont believe them or arent really trying to help.

Sometimes we explain to the patient that, while we dont have a cure or even a diagnosis for them, we do understand that their symptoms are real and troubling, Maldonado said. Because feeling anxious or depressed can make those symptoms feel 10 times worse, well connect them with a psychiatrist to see if there are some strategies to help them get at least a part of their life back.

Another potential avenue of help comes through theVan Eyk Laboratoryat Cedars-Sinai, whereJennifer Van Eyk, PhD, and her team collect patient data that might correlate with their symptoms.

Weve been building what's essentially a bio registry, Maldonado said. But one of our goals is to be able to analyze this information and come up with treatment strategies for some of these patients. We can tell patients this might one day make a meaningful difference for them and that they are also helping a number of future patients they may never meet.

Read more on the Cedars-Sinai Blog:Unlocking the Mysteries of Endometriosis

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Medical Mysteries Are Their Specialty - Newswise

image:An MRI of a patient with a cavernous angioma, showing the location of the angioma and the developmental venous anomaly attached to it view more

Credit: Image provided by Issam Awad, MD.

A rare type of brain blood vessel malformation known as a cavernous angioma affects more than one million Americans and carries a lifetime risk of stroke and seizures. Only around one-third of cases can be connected to inherited familial genetic mutations. The majority of cavernous angiomas are sporadic and until now their cause was unknown.

A new study by researchers at the University of Chicago Medicine, Duke University and the University of Pennsylvania has identified a set of sporadic genetic mutations that make it more likely a person will develop these lesions, along with additional mutations in the same area that fuel the lesions growth. Understanding the underlying causes of these brain malformations will be the key to identifying which patients are at risk for their development and finding effective treatments against the condition. The research was published March 14 in Nature Cardiovascular Research.

Weve known for more than two decades that there is a familial form of cavernous angiomas that is inherited via genes passed on from generation to generation, said Issam Awad, MD, the John Harper Seeley Professor of Neurological Surgery and Director of Neurovascular Surgery at UChicago Medicine. But in the majority of people with this type of brain bleeding, the lesion is not inherited. And until now, weve never known why some people randomly end up with this lesion.

The new research has identified a unique combination of mutations that occurs during the development of the brain that results in a cavernous angioma. First, a mutation in the gene PIK3CA leads to an abnormal pattern of vessels in the brain, known as a developmental venous anomaly, or DVA. The DVA alone is generally innocuous. But when a second mutation in one of several genes, such as MAP3K3, KRIT1, CCM2, or PDCD10, occurs in the area of the abnormal vein, a cavernous angioma develops.

Wed previously observed that often these lesions grow near a preexisting abnormal vein, said Awad. But these DVAs are actually very common about 6% to 10% of people have one, and the vast majority of them never have any problems. Rarely, those veins grow a cavernous angioma and weve never known why. In this study, we were finally able to use mutation analysis on the vein itself, to see why the vein seems predisposed to these angiomas.

The researchers were able to examine the genetics of both the angioma and its connected DVA, thanks to the delicate surgical method used to repair bleeding lesions. It requires removing small portions of the veins to detangle them from the cavernous angioma lesion. This led to the discovery of the mutation in PIK3CA in the vein, and the realization that the same mutation co-occurs with a second mutation within the angioma.

This is very novel, because we can now explain why the DVA forms in the first place, said Awad. Along with a second mutation, it is the genetic seed for the formation and growth of the cavernous angioma.

Not only does this provide a genetic mechanism for the formation of the DVA, but the Chicago team also discovered molecules circulating in the blood that are associated with the key brain mutation. This is the first time that a blood test for a focal somatic mutation in the brain has been described.

Now we can develop blood tests that can identify these mutations in the brain, and in the future, we can develop therapies that can inhibit the mechanisms that cause these lesions to form, Awad said. Some of the genes weve identified can be inhibited by drugs that are already on the market.

The researchers hope to translate these findings into additional research and, ultimately, more treatments to prevent and heal cavernous angiomas. The next steps include searching for biomarkers that might help distinguish benign DVAs from the ones that are destined to grow a cavernous angioma.

Ideally, well be able to tell with a simple blood test if you have a benign vein abnormality, or if it has the seed that will lead it to grow an angioma, said Awad. In addition, well be testing some of these pharmacologic inhibitors of the mutations weve identified to see if they will stabilize or even shrink the brain lesions.

A mechanism is not just about scientific curiosity, he continued. It should motivate us to change patient care. If we dont know the mechanism, we cant have a truly rational therapy.

The study, Developmental venous anomalies are a genetic primer for cerebral cavernous malformations, was supported by the National Institutes of Health (P01NS092521 and F31HL152738). Additional authors include Romuald Girard, Rhonda Lightle, Abhinav Srinath, Sharbel Romanos, Ying Li and Chang Chen of the University of Chicago; Daniel A. Snellings and Douglas A. Marchuk of Duke University; and Aileen A. Ren and Mark L. Kahn of the University of Pennsylvania.

##

About the University of Chicago Medicine & Biological Sciences

The University of Chicago Medicine, with a history dating back to 1927, is one of the nations leading academic health systems. It unites the missions of the University of Chicago Medical Center, Pritzker School of Medicine and the Biological Sciences Division. Twelve Nobel Prize winners in physiology or medicine have been affiliated with the University of Chicago Medicine. Its main Hyde Park campus is home to the Center for Care and Discovery, Bernard Mitchell Hospital, Comer Childrens Hospital and the Duchossois Center for Advanced Medicine. It also has ambulatory facilities in Orland Park, South Loop, Homewood and River East as well as affiliations and partnerships that create a regional network of care. UChicago Medicine offers a full range of specialty-care services for adults and children through more than 40 institutes and centers including an NCI-designated Comprehensive Cancer Center. Together with Harvey-based Ingalls Memorial, UChicago Medicine has 1,296 licensed beds, nearly 1,300 attending physicians, over 2,800 nurses and about 970 residents and fellows.

Visit UChicago Medicines health and science news blog at http://www.uchicagomedicine.org/forefront.Twitter @UChicagoMedFacebook.com/UChicagoMedFacebook.com/UChicagoMedComer

Nature Cardiovascular Research

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A perfect storm of genetic mutations is behind rare sporadic brain malformations that cause stroke, seizures - EurekAlert

When I was in my 20s I went out for quite a while with a man who had a disability that affected his ability to walk, and who had a son severely disabled by cerebral palsy he communicated non-verbally and would never be able to live independently. To go out with them was to have your eyes opened to just how much of disability is socially constructed. Which is the fancy way of saying that there wouldnt be half so many problems for loads of disabled people if shops would just bother putting ramps and lifts in, and if non-disabled people would stop staring in either disgust or fascination at anyone who deviates even slightly from the physical norm. And a special shout-out, even 20-odd years on, to the lady who advised us from a position of unassailable entitlement and fury to Stop breeding.

On the other hand, we as a group, and my boyfriend and his son as individuals were, for the bulk of the time, met with great kindness, generosity and practical help from the non-staring demographic. But it is inescapably the case that to live with any condition that marks you out from the herd is to live, to some degree, in a different world from most.

Ellie Simmonds: A World Without Dwarfism (BBC One) is presented by the multiple gold medal-winning Paralympian swimmer, who has achondroplasia a rare genetic condition which causes a type of dwarfism. The programme poses the question of how much we should expect (or wait for) society to change and how much, if medical science offers the chance, people with disabilities (or states classed as such in the public mind) should change themselves.

Vosoritide is a new drug, designed to mitigate the symptoms of achondroplasia. There are other drugs too, aimed at other forms of dwarfism, but vosoritide is in the final stages of its clinical trials and may be available on the NHS from 2023. If given as a daily injection to growing children it can give them straighter spines and legs (bowing is a common feature of achondroplasic dwarfism), help avoid various surgeries that are commonly needed, lessen pains that are commonly experienced by stressed joints and this seems to be where most of the focus is, for parents, patients, doctors and campaigners both for and against its introduction make them taller.

So what do you do? Is this, as the doctor leading the UK trials seems to believe, a wholly unproblematic field of endeavour for medicine, seeking to eradicate the genuine physical problems associated with dwarfism, but not dwarfism itself? Or is it, as put by an activist in the US where the drug is already approved an existential threat to dwarfism (and by extension, all other forms of difference)? Is it giving in to prejudice, or empowering individuals to live their best lives in an enduringly imperfect world?

Simmonds starts from a pretty much wholly anti-drug perspective but, as she gathers accounts from parents of children on the drug, the children themselves and people who have undergone other procedures, she is open and honest about how fortunate she has been in her upbringing and how much this has coloured her thinking. She was born to average-sized parents who immediately accepted her condition and ensured she was from the beginning in contact with those who shared it. Her sporting talent was discovered at a very young age and enabled her to grow up with the message, overwhelming any outside negativity, that her body was something special and could as indeed it did lead her to greatness.

It is perhaps not until she interviews her teammate Will Perry, who also has achondroplasia, that she realises her life experience is not representative even within the narrow confines of Paralympian-hood. Perry speaks with passion and great articulacy on the rage and misery of the prejudice he has encountered he is 50/50, he says, on whether he would swap his life for a normal one and is much less sure than Simmonds that he would not put his putative children on the drug. Simmonds is not a natural interviewer (she is particularly reluctant to push vosoritude-embracing parents on the wider implications of their decisions and she doesnt take on any of the people at a Silicon Valley convention for research into dwarfism All raising funds to cure me) but this frank discussion between friends left you wanting more of it.

There was little examination of other cultural issues that can be at play no consideration of how Perrys experience and outlook differ because he is a man and men are not supposed to be short, for example or comparisons with the effect medical interventions have had on other conditions (amniocentesis tests and Downs syndrome birthrates, perhaps). But it raised questions and awareness and hopefully there are more of both to come.

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Ellie Simmonds: A World Without Dwarfism review are drugs really the answer? - The Guardian

**Note: the release below is a special early release from the European Congress of Clinical Microbiology & Infectious Diseases (ECCMID 2022, Lisbon, 23-26 April). Please credit the conference if you use this story**

Healthy pet dogs and cats could be passing on antibiotic-resistant bacteria as well as genes that play a key role in bacterial resistance to their owners, according to new research to be presented at this years European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) in Lisbon, Portugal (23-26 April). The study is by Dr Juliana Menezes from the University of Lisbon in Portugal and Dr Sian Frosini from the Royal Veterinary College, UK, and colleagues.

Our findings verify not only the sharing of antibiotic resistant bacteria but also of resistance genes between companion animals and their owners in the community, underscoring the need for continuous local surveillance programmes to identify the potential risk to human health, says Dr Menezes from the University of Lisbon.

The role of companion animals as potential reservoirs of antimicrobial-resistant bacteria is a growing concern worldwide. Escherichia coli(E. coli) bacteria are common in the intestines of healthy people and animals. There are a number of different types and, while the majority are harmless, some can cause serious food poisoning and life-threatening infections, including blood poisoning, with over 40,000 cases each year in England alone.

Particularly important are infections caused by highly resistant strains with ESBL and AmpC-producing Enterobacteriaceae (AmpC-E) and Carbapenemase-producing Enterobacterales (CPE), which are resistant to multiple antibiotics including penicillin and cephalosporins.

In this study, researchers wanted to find out how these resistant bacteria are spread and whether there is a cross-over between healthy companion animals (ie, cats and dogs) and their owners.

The health of companion animals was evaluated by their vet when attending the Small Animal Veterinary Teaching Hospital at the University of Lisbon and the Royal Veterinary College Small Animal Veterinary Referral Service at the Royal Veterinary College in the UK. Only animals and their owners who had not experienced bacterial infections or taken antibiotics in the 3 months prior to the start of the study were recruited.

Stool samples were collected from 58 healthy people and the 18 cats and 40 dogs that lived with them from 41 households in Portugal, and from 56 healthy people and 45 dogs from 42 households in the UK.

Samples were collected at monthly intervals for four months, and genetic sequencing was used to identify both the species of bacteria in each sample, and the presence of drug resistance genes.

The researchers used Rep-PCR, a fast and simple to use molecular fingerprinting technique that helps to identify related strains of bacteria. Because it is not as sensitive as whole genome sequencing, they also sequenced the strains to confirm the possible sharing of resistant bacteria.

Between 2018 and 2020, 15 out of 103 (15%; 1 cat and 14 dogs) pets and 15 out of 114 (13%) household members from both countries were found to be carrying ESBL/AmpC-producing bacteria. Of these, almost half the cats and dogs (6 in Portugal and 1 in the UK), and a third of the household members (4 in Portugal and 1 in the UK), were colonised with at least one multidrug-resistant strain (see table 1 in notes to editors).

No carbapenem-resistant Enterobacterales or Acinetobacter spp were detected in any of the samples.

In four Portuguese households, the ESBL/pAMPc resistance genes found in pets matched those found in their owners stool samples. In three of these households, matched resistance genes were only recovered at one timepoint (see figure 2 in notes to editors), but in one household, sharing strains were noted at two consecutive timepoints suggesting a persistent colonisation of shared bacteria.

In addition, in two of the households, the microbes in pets matched E. coli strains found in their owners stool sample, but in the other two, there was no evidence of bacteria sharing (see figure 3 in notes to editors).

Sometimes the bacteria may not be shared, but their resistance genes can be, explains Dr Menezes. These genes are found in mobile bits of DNA, meaning that they can be transferred between different bacterial populations in animal and humans.

She continues, Even before the COVID-19 pandemic, antibiotic resistance was one of the biggest threats to public health because it can make conditions like pneumonia, sepsis, urinary tract and wound infections untreatable. Although the level of sharing from the households we have studied is low, healthy carriers can shed bacteria into their environment for months, and they can be a source of infection for other more vulnerable people and animals such as the elderly and pregnant women. Our findings reinforce the need for people to practice good hygiene around their pets and to reduce the use of unnecessary antibiotics in companion animals and people.

This is an observational study and cannot prove that close contact with pets causes colonisation with antibiotic resistant bacteria, but only suggest the possibility of such an effect. The authors point to several limitations, including that it involved a small number of families and the longitudinal follow up was limited.

For interviews with the report authors, please contact Dr Juliana Menezes, Centre of Interdisciplinary Investigation of Animal Health of the Faculty of Veterinary Medicine, University of Lisbon, Portugal E) julianamenezes@fmv.ulisboa.pt T)+351 935 130 316

Alternative contact in the ECCMID Press Room: Tony Kirby T) + 44(0)7834 385827 E) tony@tonykirby.com

Notes to editors:

This press release is based on an oral presentation 1375 at the European Congress of Clinical Microbiology & Infectious Diseases (ECCMID). All accepted abstracts have been extensively peer reviewed by the congress selection committee. There is no full paper at this stage, but the authors are happy to answer your questions. The research has not yet been submitted to a medical journal for publication.

The work was supported by JPIAMR/0002/2016 ProjectPET-Risk Consortium and by FCT Fundao para a Cincia e Tecnologia IP (UIDB/00276/2020); JM and JMS were supported by a PhD fellowship.

The authors declare no conflicts of interest.

The authors declare no conflicts of interest

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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Both antibiotic resistant bacteria and genes transmitted between healthy dogs and cats and their owners, finds study in UK and Portugal - EurekAlert

Copenhagen, Denmark 4 April 2022: When should patients and family members undergo genetic assessment for a heart condition? Find out in an international consensus document published in EP Europace,1 a journal of the European Society of Cardiology (ESC) and presented at EHRA 2022,2 a scientific congress of the ESC.

This is now the reference document that all clinicians should use to decide whether genetic testing is indicated for patients with inherited cardiac diseases and their relatives, said lead author Professor Arthur Wilde of the Academic Medical Centre, Amsterdam University Medical Centres, the Netherlands. We provide strict criteria on who should be assessed and recommend which genes should beexamined.

The aim of genetic testing in patients with an inherited cardiac disease is to determine the cause. In some conditions this helps clinicians make a precise diagnosis, provides information about prognosis, and determines the treatment. For example in long QT syndrome, which is potentially lethal but treatable, a normal electrocardiogram (ECG) does not exclude the condition and genetic testing is required to clarify the diagnosis. The specific genetic variant impacts both prognosis and therapeutic choices.

Once a genetic cause is identified in the patient, family members, including children, can be screened. The document outlines in which conditions relatives should receiving genetic testing. In long QT syndrome, for example, family members should be tested. Many of these conditions start with a cardiac arrest in a young individual who dies or almost dies, said Professor Wilde. The way to avoid that happening in a family members is by genetic testing in conjunction with clinical screening. Those who are affected can be treated, for example with medications or with a defibrillator to correct a fatal heart rhythm, and those who are unaffected can be reassured.

Genetic counselling is essential and should start even before clinical and genetic testing are performed. A diagnosis can be life-changing as it may provoke significant anxiety or aggressive treatment, states the document. Professor Wilde said that the consequences of a positive diagnosis should be explained before any examinations. For instance, if an individual has no symptoms but his or her sibling has a serious inherited cardiac disease, the first question should be do you want to know whether you have this condition, yes or no?, he said. A diagnosis may trigger difficulties with insurance, getting a mortgage, and so on. He or she needs to be informed before making any decisions.

The paper provides recommendations on genetic testing for four groups of heart conditions caused by genetic defects: inherited arrhythmia syndromes, cardiomyopathies, sudden cardiac death or survivors of unexplained cardiac arrest, and congenital heart disease. The most common of these is hypertrophic cardiomyopathy, which affects at least one in 500 individuals.

The chapter on congenital heart disease also provides detailed advice on genetic testing in pregnant women and offspring. Professor Wilde said: This is a rapidly moving field and genetic testing is recommended for conditions in which there is a high likelihood of identifying the cause. As for all genetic cardiac conditions, testing for congenital heart defects should be coordinated by cardiologists and clinical genetics specialists with support from genetic counsellors.

In addition to conditions caused by single genetic defects, the authors describe how genetics can play a role in the manifestation of more common heart conditions such as coronary artery disease and heart failure. Professor Wilde explained: These conditions are not caused by one genetic variant but in some patients there is a genetic component. Researchers are investigating how the combination of frequently occurring genetic variants may cause or influence susceptibility to disease. This is an emerging field and it is too early to make recommendations.

The international consensus statement on genetic testing for cardiac diseases was developed by the European Heart Rhythm Association (EHRA), a branch of the ESC; the Heart Rhythm Society (HRS); the Asia Pacific Heart Rhythm Society (APHRS); and the Latin American Heart Rhythm Society (LAHRS).3 It is also published in Heart Rhythm, the official journal of the HRS, Journal of Arrhythmia, the official journal of the APHRS, and Journal of Interventional Cardiac Electrophysiology, the official journal of the LAHRS.

ENDS

Authors: ESC Press Office

Mobile: +33 (0)7 8531 2036Email: press@escardio.org

Follow us on Twitter @ESCardioNews

Notes to editor

Funding: None.

Disclosures: Please see the supplementary material online.

References and notes

1Wilde A, Semsarian C, Mrquez MF, et al. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) expert consensus statement on state of genetic testing for cardiac diseases. EP Europace. 2022. doi:10.1093/europace/euac030.

2The paper will be presented during the session Expert consensus statement on state of genetic testing for cardiac diseases on 4 April at 14:05 to 15:05 CEST in Room 1.

3Preparation of the document was led by: Arthur Wilde (EHRA Chair), Elizabeth Kaufman (HRS Co-Chair), Christopher Semsarian (APHRS Co-Chair) and Manlio F Mrquez (LAHRS Co-Chair).

About the European Heart Rhythm Association

The European Heart Rhythm Association (EHRA) is a branch of the European Society of Cardiology (ESC). Its aim is to improve patients quality of life and reduce sudden cardiac death by limiting the impact of heart rhythm disturbances.

About the EHRA Congress #EHRA2022

EHRA 2022 is the annual congress of the European Heart Rhythm Association (EHRA) of the European Society of Cardiology (ESC).

About the European Society of Cardiology

The European Society of Cardiology brings together health care professionals from more than 150 countries, working to advance cardiovascular medicine and help people lead longer, healthier lives.

About the Heart Rhythm Society

The Heart Rhythm Society (HRS) is the international leader in science, education, and advocacy for cardiac arrhythmia professionals and patients, and the primary information resource on heart rhythm disorders. Its mission is to improve the care of patients by promoting research, education, and optimal health care policies and standards. Incorporated in 1979 and based in Washington, DC, it has a membership of more than 7,000 heart rhythm professionals in more than 90 countries around the world. For more information, visitwww.HRSonline.org.

About the Asia Pacific Heart Rhythm Society

The Asia Pacific Heart Rhythm Society (APHRS) is the international organisation specialising in science and education for cardiac arrhythmia professionals. For members, the society regularly offers various educational programmes at the state-of-the-art laboratories with excellent lectures. For more information, visit http://www.aphrs.org.

About the Latin American Heart RhythmSociety

TheLatin American Heart RhythmSociety (LAHRS) was founded in 2017 with the aim of continuing the mission started by Sociedad Latinoamericana de Estimulacin Cardaca y Electrofisiologa (SOLAECE) morethan twenty years ago, promoting the improvement of the quality of life and reducing mortality related to cardiac arrhythmias in the Latin American population. For more information, visithttp://www.lahrs.org.

Information for journalists about registration for EHRA 2022

EHRA 2022 takes 3 to 5 April at the Bella Center in Copenhagen, Denmark and online. Explore the scientific programme.

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Recommendations on genetic testing for inherited cardiac diseases published today - EurekAlert