Super-Speedy Diagnosis of Rare Genetic Diseases

About a year ago, Matthew Kunzman’s heart was failing, despite doctors’ best attempts to bolster it with every pump and gadget they could think of. But the 14-year-old has bounced back in large part due to super-speedy genetic sequencing that pinpointed the cause of his disease and helped doctors decide how to treat it — in just 11 and a half hours. That speedy diagnosis — faster than any other medical team has previously reported — resulted from a new approach to DNA sequencing to help patients with deadly and rare diseases. On Wednesday, a team of Stanford researchers and collaborators published a letter in the New England Journal of Medicine reporting that they had sequenced 12 seriously ill patients and successfully diagnosed five of them (including Matthew). In all five cases, the information led to tangible changes in how patients were treated.

Typical turnaround time for diagnosis was around eight hours and as short as seven hours and eighteen minutes – less than half the current record. And the scientists are convinced they can cut that in half yet again. Such speed could be life-saving for critically ill patients, according to Euan Ashley, a Stanford cardiologist and the study’s senior author.

You can not only make care better, and help patients more, but do it cheaper, save money, save the system money,” Ashley said. “It seems like a win, win, win all around.”

There’s a lot to be learned by exploring your genetic code, which influences everything from your height and eye color to your likelihood of developing certain diseases. For doctors, knowing whether a patient’s symptoms are linked to specific DNA mutations — and, if so, which ones — can help them determine what treatments and surgical procedures to try and which ones to avoid. But it typically takes weeks to run, process, and interpret sequencing results. That’s time some patients don’t have. And hospital stays spent chasing down the cause of an unknown disease can cost tens of thousands of dollars.

Ashley wanted to see how quickly he could speed things up. He and his team enrolled a dozen seriously ill patients admitted at Stanford, taking about half a teaspoon of blood from each of them for genetic sequencing. The participants, who ranged in age from 3 months to 57 years old, suffered from everything from seizures to cardiac arrest. Throughout the six-month study, which kicked off in December 2020, researchers tweaked nearly every step of the sequencing process, from having someone run samples from the hospital to the lab to shortening the time needed to prep DNA for sequencing. It was round-the-clock work.

Source: https://www.statnews.com/

Machine Learning Predicts Heart Failure

Every year, roughly one out of eight U.S. deaths is caused at least in part by heart failure. One of acute heart failure’s most common warning signs is excess fluid in the lungs, a condition known as “pulmonary edema.” A patient’s exact level of excess fluid often dictates the doctor’s course of action, but making such determinations is difficult and requires clinicians to rely on subtle features in X-rays that sometimes lead to inconsistent diagnoses and treatment plans.

To better handle that kind of nuance, a group led by researchers at MIT’s Computer Science and Artificial Intelligence Lab (CSAIL) has developed a machine learning model that can look at an X-ray to quantify how severe the edema is, on a four-level scale ranging from 0 (healthy) to 3 (very, very bad). The system determined the right level more than half of the time, and correctly diagnosed level 3 cases 90 percent of the time.

Working with Beth Israel Deaconess Medical Center (BIDMC) and Philips, the team plans to integrate the model into BIDMC’s emergency-room workflow this fall.

This project is meant to augment doctors workflow by providing additional information that can be used to inform their diagnoses as well as enable retrospective analyses,” says PhD student Ruizhi Liao, who was the co-lead author of a related paper with fellow PhD student Geeticka Chauhan and MIT professors Polina Golland and Peter Szolovits.

The team says that better edema diagnosis would help doctors manage not only acute heart issues, but other conditions like sepsis and kidney failure that are strongly associated with edema.

As part of a separate journal article, Liao and colleagues also took an existing public dataset of X-ray images and developed new annotations of severity labels that were agreed upon by a team of four radiologists. Liao’s hope is that these consensus labels can serve as a universal standard to benchmark future machine learning development.

An important aspect of the system is that it was trained not just on more than 300,000 X-ray images, but also on the corresponding text of reports about the X-rays that were written by radiologists. “By learning the association between images and their corresponding reports, the method has the potential for a new way of automatic report generation from the detection of image-driven findings,says Tanveer Syeda-Mahmood, a researcher not involved in the project who serves as chief scientist for IBM’s Medical Sieve Radiology Grand Challenge. “Of course, further experiments would have to be done for this to be broadly applicable to other findings and their fine-grained descriptors.”

Chauhan, Golland, Liao and Szolovits co-wrote the paper with MIT Assistant Professor Jacob Andreas, Professor William Wells of Brigham and Women’s Hospital, Xin Wang of Philips, and Seth Berkowitz and Steven Horng of BIDMC.

Source: https://news.mit.edu/

Gene Therapy Combats Efficiently Age-related Diseases

As we age, our bodies tend to develop diseases like heart failure, kidney failure, diabetes, and obesity, and the presence of any one disease increases the risk of developing others. In traditional drug development, a drug usually only targets one condition, largely ignoring the interconnectedness of age-related diseases, such as obesity, diabetes, and heart failure, and requiring patients to take multiple drugs, which increases the risk of negative side effects.

A new study from the Wyss Institute for Biologically Inspired Engineering at Harvard University and Harvard Medical School (HMS) reports that a single administration of an adeno-associated virus (AAV)-based gene therapy delivering combinations of three longevity-associated genes to mice dramatically improved or completely reversed multiple age-related diseases, suggesting that a systems-level approach to treating such diseases could improve overall health and lifespan. The research is reported in PNAS.

The AAV-based gene therapy improved the function of the heart and other organs in mice with various age-related diseases, suggesting that such an approach could help maintain health during aging.

The results we saw were stunning, and suggest that holistically addressing aging via gene therapy could be more effective than the piecemeal approach that currently exists,” said first author Noah Davidsohn, Ph.D., a former Research Scientist at the Wyss Institute and HMS who is now the Chief Technology Officer of Rejuvenate Bio. “Everyone wants to stay as healthy as possible for as long as possible, and this study is a first step toward reducing the suffering caused by debilitating diseases.

The study was conducted in the lab of Wyss Core Faculty member George Church, Ph.D. as part of Davidsohn’s postdoctoral research into the genetics of aging. Davidsohn, Church, and their co-authors honed in on three genes that had previously been shown to confer increased health and lifespan benefits when their expression was modified in genetically engineered mice: FGF21, sTGFβR2, and αKlotho. They hypothesized that providing extra copies of those genes to non-engineered mice via gene therapy would similarly combat age-related diseases and confer health benefits.

The team created separate gene therapy constructs for each gene using the AAV8 serotype as a delivery vehicle, and injected them into mouse models of obesity, type II diabetes, heart failure, and renal failure both individually and in combination with the other genes to see if there was a synergistic beneficial effect.

Source; https://wyss.harvard.edu/

One Pill A Day Reduces Heart Attack Risk By One Third

A cheap, single pill taken once a day that combines four common drugs is safe and reduces the risk of events such as heart attacks, strokes and sudden death in people over the age of 50, research has found. The study, the first large-scale trial to date, looked at the effectiveness of a so-called polypill – a four-in-one therapy containing drugs to lower cholesterol and blood pressure that was first proposed more than 15 years ago. The researchers found those taking the polypill had a more than 30% lower risk of serious heart problems than those just offered advice.

While different formulations have been studied, previous trials have only been conducted in small groups of people and over short periods of time. These studies have primarily looked at the impacts of cholesterol on blood pressure, relying on models to predict the impact on cardiovascular events such as strokes – meaning the full potential of the polypill has remained unclear. The latest study tackled both of these problems.

There has been a lot of talk about using this simple, fixed-dose combination drug for prevention of cardiovascular disease and I think we have shown that as a strategy it can work,” said Prof Tom Marshall, a co-author of the study from the University of Birmingham, adding that the pills might cost as little as a few pence per day. The new study involved more than 6,800 participants aged 50-75 from rural Iran – an area where almost 34% of premature deaths are down to coronary heart disease, and 14% are caused by strokes.

Writing in the Lancet, researchers from the UK, US and Iran reported that 3,417 people were given only minimum care, such as help with controlling blood pressure or cholesterol if needed, as well as lifestyle advice on topics such as diet, exercise and smoking. A similar number of people were, in addition to this, also given the polypill. More than 90% of those involved in the study did not have cardiovascular disease at the outset. Participants were followed up for five years. Over that time, 202 people taking the polypill had a major cardiovascular event, such as heart attack, heart failure, or stroke, compared with 301 in the “advice” group.

The authors say that translated as a 34% lower risk of having such an event, compared with the “advice” group, once factors including age, sex, diabetes and high blood pressure were taken into account.

There were also signs that, at least early on, the polypill reduced some aspects of high blood pressure, while it also led to a small fall in “bad” cholesterol. Both groups showed similar low levels of problematic events including internal bleeding and peptic ulcers. Overall, the results suggested that two major cardiovascular events would be avoided for every 69 people taking the tablet for 5 years. The polypill includes aspirin, which the team acknowledge is controversial as it can increase the risk of bleeding: the latest trial did not include people who were at high risk of such problems.

Source: https://www.theguardian.com/

First 3D Printed Heart

Researchers at Tel Aviv University have managed to 3D print a heart using a patient’s cells and biological materials — a first. Scientists have previously built synthetic hearts and bio-engineered tissues using a patient’s cells. But the latest feat is the first time scientists have created a complex organ with biological materials.

This is the first time anyone anywhere has successfully engineered and printed an entire heart replete with cells, blood vessels, ventricles and chambers,” lead researcher Tal Dvir, a material scientist and professor of molecular cell biology at TAU, said in a news release.

The proof-of-concept feat could pave the way for a new type of organ transplant. For patients with late stage heart failure, a heart transplant is the only solution. But there is a lack of heart donors.

This heart is made from human cells and patient-specific biological materials. In our process these materials serve as the bioinks, substances made of sugars and proteins that can be used for 3D printing of complex tissue models,” Dvir said. “Our results demonstrate the potential of our approach for engineering personalized tissue and organ replacement in the future.”

The heart scientists printed couldn’t be used in a human transplant operation. Though completely vascularized, it’s too small at about the size of a rabbit heart. “But larger human hearts require the same technology.” Dvir said.

Researchers detailed their breakthrough this week in the journal Advanced Science.

Source: https://www.upi.com/