Rocky digital health funding market post-SVB

 This year was shaping up to be a rebound year for digital health funding before the collapse of Silicon Valley Bank in March and the subsequent collapse of similar banks threw the future of digital health funding back into disarray.

Digital health startups are holding tight to liquid assets and capitalizing on existing resources as 2023 funding looks poised to drop below pre-pandemic levels, according to a new report from Rock Health.

In the first quarter, digital health companies in the U.S. brought in $3.4 billion in funding across 132 deals, the report found. The amount tops both the third and fourth quarters of 2022, but isn’t enough to signal a new “bull run,” according to the report.

If funding in the next three quarters matches the average funding in the prior three, 2023 is on pace to see the lowest level of digital health funding since 2019.

Rebecca Pifer/Healthcare Dive; Rock Health data

 

Megadeals, or funding rounds that net over $100 million, made up 40% of overall dollars in the quarter. The amount of megadeals suggests that the current market is being driven by a small number of large transactions from deep-pocketed investors, and doesn’t foreshadow a sector rebound, Rock Health found.

Six megadeals occurred during the first quarter: a $375 million funding round for value-based provider Monogram Health; a $300 million round for health staffing startup ShiftKey; a $203 million Series A for clinical trial tech platform Paradigm; a $200 million funding round for health workforce manager ShiftMed; a $179 million equity investment in health benefits company Gravie; and a $100 million round for provider enablement platform Vytalize Health.

The rapid and unexpected collapse of SVB — a major lender to digital health startups — was a reckoning moment in March. The bank’s fall nearly set off a liquidity crisis, and halted any funding momentum from January and February in its tracks, the report said. Startups were left with the question of who to bank with next. Many companies are turning to bigger banks after the collapse of the regional lenders, which could hamper access to quick, short-term cash.

In addition, foreign startups and those with nascent teams may need to turn to more restrictive and expensive alternatives for financial operations and loans, according to Rock Health.

The next few quarters of startup financing are likely to be more conservative, the report said. Some companies may look for buyers as a result as cash runs out, while others will face pressure to fundraise due to inflation concerns.

“It’s hard to overstate just how supportive SVB was of the startup ecosystem, and the full ramifications of its closure and acquisition on technology innovation may not be felt until quarters later,” analysts said.

Digital health companies continued not to seek public market exits in the first quarter, continuing a trend from late last year, as startups remained fearful of low initial public offering prices. To seek out cash, startups will either turn to private funders —  deals which can involve valuation adjustments or operational reorganizations — or pursue alternative exit avenues, like becoming a public benefit corporation. Startups might also turn to debt financing, or sell assets in exchange for capital.

But such strategies won’t work for everyone, Rock Health said, reiterating warnings from prominent investors that startups need to be conservative and disciplined to make it through the next few quarters.

“Either by personal choice or business requirements, we are likely to see some startups give in to turbulent waters—seeking out buyers or shutting down completely over the next several months,” analysts said.

https://www.healthcaredive.com/news/rocky-digital-health-funding-market-post-svb-collapse/646902/

Tackling major obstacle to stem-cell heart repair

 Researchers at the University of Washington School of Medicine in Seattle have engineered stem cells that do not generate dangerous arrhythmias, a complication that has to date thwarted efforts to develop stem-cell therapies for injured hearts.

“We have found what we have to tackle to make these cells safe,” said Silvia Marchiano, a postdoctoral fellow in the laboratory of Chuck Murry at the UW Medicine Institute for Stem Cell and Regenerative Medicine. Marchiano is the lead author of a paper describing the findings published Thursday, April 6, in the journal Cell Stem Cell. The work was done in collaboration with the Seattle company Sana Biotechnology.

In previous studies, Murry’s team used heart muscle cells created from stem cells to repair heart muscle damage caused by myocardial infarction. This type of heart attack occurs when blood flow to the heart muscle is blocked, thereby causing heart cells to die. Heart cells do not regenerate, so the affected muscle is replaced by scar tissue. This weakens the heart and impairs its ability to pump blood. Severe damage can lead to heart failure and death.

To create their therapeutic heart cells, the Seattle researchers used pluripotent stem cells. Unlike adult stem cells, which have specialized to become specific cell types, pluripotent stem cells can become any type of cell in the body. 

From 2012 to 2018 the Seattle team successfully injected pluripotent stem cells into damaged heart walls to create new muscle to replace that lost during an infarction. In animal studies, they showed that the grafted cells would integrate with the heart muscle, beat in synchrony with the other heart cells and improve the heart’s contractility. These findings demonstrated that stem cell therapy could potentially be used to rescue damaged hearts.

But there was one major complication. During the early weeks of engraftment, the hearts tended to beat at a dangerously high rate. Unless a way could be found to prevent or suppress this problem, stem cells could not become a safe treatment for myocardial infarction and heart failure.

“Our goal is to create working contractile cells that would not try to set their own pace,” Murry said.

In the mature heart, the heart rate is regulated by specialized cells called pacemaker cells.These cells generate electric signals at regular intervals that induce the other heart cells to contract.

In pacemaker cells, the voltage cycles back and forth from negative (hyperpolarized) to positive (depolarized). Murry compares it to a metronome with positive ions swooshing in and out of the cell through these channels. The rate at which this cycle of repolarization and depolarization occurs determines the heart rate. 

In early embryonic hearts, however, this system, in which relatively few cells have become specialized pacemaker cells while the rest have become quiescent contractile cells, has not developed. All the cells are pacemakers. Murry and his colleagues suspected that the engrafted stem cells were behaving like early embryonic cells chaotically generating signals and causing the dangerous heart rhythms. 

To sort out what was causing these cells to behave this way, the researchers used a technique called RNA-sequencing to find out which ion channels were being made at different times as the cells matured. The sequencing revealed that some types of ion channels appear early in development and then disappear as the cell matures while other types of ion channels appear later in development. Like an unfolding mystery, this gave the researchers their list of suspects.

To determine which ion channels were the culprits carrying the arrhythmia-causing current, the scientists used CRISPR-based genome editing to systematically knock out depolarizing genes or to activate repolarizing genes. This proved surprisingly complex. They had hypothesized that there would be a single ion channel causing the arrhythmia, but none of the single-gene edits eliminated the rapid heart rhythms. The researchers then undertook a painstaking process of “playing the combinations” by performing double and triple gene edits. Vexingly, none of these edits eliminated the arrhythmia, and some seemed to make it worse.

Finally, the scientists created a stem cell line in which three depolarizing genes were knocked out and one repolarizing gene was activated. That did the trick. Cardiac muscle cells generated from these stem cells were electrically quiescent, like adult heart muscle, but they contracted when given an electrical signal to mimic a natural pacemaker. The researchers termed these cells “MEDUSA” (for modifying electrophysiological DNA to understand and suppress arrhythmias). The MEDUSA cardiomyocytes engraft in the heart, mature into adult cells, electrically integrate into heart muscle, and beat in sync with natural pacemaking, all without generating dangerous heart rates. This, Murry says, is the sine qua non for heart regeneration.

Murry cautions that additional testing with the engineered cells will need to be done, but, he adds, “I think we’ve overcome the biggest roadblock to regenerating the human heart.”

 

---

JOURNAL

Cell Stem Cell

DOI

10.1016/j.stem.2023.03.010 

METHOD OF RESEARCH

Experimental study

SUBJECT OF RESEARCH

Animals

ARTICLE TITLE

Gene editing to prevent ventricular arrhythmias associated with cardiomyocyte cell therapy

ARTICLE PUBLICATION DATE

6-Apr-2023

https://www.eurekalert.org/news-releases/985266

Why do so many dementia treatments fail? Questioning mouse models of tau accumulation

 To date, the search for effective treatments for dementia has yielded only disappointments. Many recent drug candidates target the tau protein, which aggregates and forms tangles in patients' brain tissue and is involved in 75% of all dementias. While tau-targeting drugs have looked promising in mouse models, they've failed in clinical trials.

A recent study published in Molecular Neurodegeneration led by Kathrin Wenger, a Ph.D. student in the lab of Judith Steen, Ph.D., at Boston Children's, suggests one reason: The available tau-based mouse models don't correspond well with tau pathology in late-stage, symptomatic human dementia.

"We don't think these mice are the right models," Wenger says.

Tracking tau dynamics

Previous research in the Steen Lab, part of the F.M. Kirby Neurobiology Center, found that the tau protein changes during the course of Alzheimer's disease as it gets chemically modified. In the new study, Wenger and colleagues analyzed tau in its aggregated form in brain samples from the two most common mouse models. Known as P301S and P301L, these models are based on genetic mutations of tau identified in patients with frontotemporal dementia.

In collaboration with the Proteomics Center at Boston Children's, Wenger systematically mapped modifications of tau protein at different disease stages, then compared the findings to tau samples from people with Alzheimer's disease and people with dementia and P301L mutations.

"We took an unbiased approach with quantitative proteomics, looking at all possible chemical modifications of tau over time, and quantified them," says Wenger. "We are the only group with the technology to quantify modifications comprehensively across a given protein. Other groups focus on one or two chemical modifications previously suspected to played a role in disease, and are not able to quantify these modifications."

Through meticulous experiments, the Steen team showed that, in both mouse models, the chemical process of phosphorylation drives tau accumulation. The same was true in people with early stage Alzheimer's disease or dementia with P301L tau mutations. However, in symptomatic human disease and late-stage human Alzheimer's disease, ubiquitination and acetylation of tau are important, and these were not represented in the mouse models.

Better dementia models needed

The team concludes that the mouse models may be suitable for testing drugs meant to intervene in the early, pre-symptomatic stages of dementia, when phosphorylation is the main tau modification, but not in symptomatic or later-stage disease.

Steen also notes that better models are needed to account for factors such as lifestyle, genetics, environment, comorbidities such as diabetes, and infections that can contribute to human dementia—particularly non-familial Alzheimer's disease, which makes up more than 90% of all Alzheimer's disease cases.

"We grow mice in optimal conditions, with healthy diets and no stressors or infections," Steen says. "But human Alzheimer's disease is the product of multiple biological insults over a lifetime. We need a model that reflects insults people sustain over a lifetime."

More information: Kathrin Wenger et al, Common mouse models of tauopathy reflect early but not late human disease, Molecular Neurodegeneration (2023). DOI: 10.1186/s13024-023-00601-y

https://medicalxpress.com/news/2023-04-dementia-treatments-mouse-tau-accumulation.html

2 different regulatory T cell populations

 A regulatory class of human T cells descends from two different origins, one that relates to autoimmunity and one that relates to protective immunity, according to a new study led by Children's Hospital of Philadelphia (CHOP). The findings, published today in Science Immunology, could pave the way for new treatments for autoimmune diseases that target the immune system selectively.

"When it comes to autoimmunity, the prevailing wisdom has been that the only way to stop inflammation is to suppress the immune system broadly, making patients more susceptible to infection," said senior author Neil D. Romberg, MD, an attending physician in the Division of Allergy and Immunology at Children's Hospital of Philadelphia. "However, that is only true if all T cells come from the same place. What this study shows is that there are two different T cell lineages, which means you might be able to have your cake and eat it too—suppressing inflammation due to autoimmunity while allowing T cells that fight infection to thrive."

Germinal centers (GCs) are spherical collections of cells inside tonsils, lymph nodes, and the spleen that orchestrate interactions between T follicular helper (Tfh) cells and B cells. The action within these GCs is locally governed by FOXP3+ T follicular regulatory (Tfr) cells. Although the proper function of Tfr cells is likely important to immunologic health—and their dysfunction a potential contributor to various disease states—few studies have assessed the biologic roles of human Tfr cells and none have addressed where they come from or how they develop within tissues.

To solve this problem, the researchers, led by Carole Le Coz, Ph.D., a former postdoctoral researcher in the Romberg Lab, used a combination of computational, in vitro, and in vivo techniques to describe the origins, functions, and positions of Tfr cells within GCs. Since GCs are located in secondary lymphoid tissues like lymph nodes, spleens, and tonsils, the researchers analyzed tonsils that had been removed from healthy donor patients.

Using an interlocking suite of single cell technologies, the researchers were able to show that there is one subpopulation of Tfr cells that is induced by Tfh cells, which they called iTfrs, and another subpopulation that were "naturally" derived from Tregs, a subpopulation of T cells that are responsible for moderating the immune system, which they called nTfrs. In doing so, the demonstrated that there are two developmental trajectories: Treg-to-nTfr and Tfh-to-iTfr.

Once the researchers identified these two subpopulations of Tfr cells, they analyzed whether these two regulatory T cells express the surface protein CD38 differently. They found that iTfr cells express CD38, whereas nTfr cells do not. They were also able to catalog the precise location of these different subpopulations within the GCs, in addition to demonstrating their developmental path and ability so support B cell function.

"This study raises the question of whether we could selectively deplete iTfr cells through anti-CD38 treatments, while leaving nTfrs intact—using a silver bullet rather than a bomb to target specific T cells," Dr. Romberg said. "A similar approach could also potentially be used in a therapeutic context to boost immunity in patients with weakened immune systems."

More information: Carole Le Coz et al, Human T follicular helper clones seed the germinal center-resident regulatory pool, Science Immunology (2023). DOI: 10.1126/sciimmunol.ade8162. www.science.org/doi/10.1126/sciimmunol.ade8162

https://medicalxpress.com/news/2023-04-regulatory-cell-populations.html

Predicting mRNA degradation to improve vaccine stability

 Messenger Ribonucleic Acid (mRNA) as a therapeutic approach is gaining momentum due to its ability to be rapidly manufactured and its promising outcomes. mRNA-based vaccines, for instance, played a crucial role in the fight against COVID-19 in many parts of the world.

However, mRNA-based therapeutics can face challenges due to their thermal instability, which makes them susceptible to chemical degradation. As a result, mRNA vaccines require stringent conditions for manufacturing, storage and worldwide delivery. To make mRNA vaccines more broadly accessible, it is critical to understand and improve their stability.

Dr. Qing Sun, a professor in the Artie McFerrin Department of Chemical Engineering at Texas A&M University, and a team of graduate students have created an effective and interpretable model architecture using deep-learning techniques that can predict RNA degradation more accurately than previous best methods, such as Degscore models, RNA folding algorithms and other machine-learning models.

Their model was tested to show its efficiency, and the findings were recently published in Briefings in Bioinformatics.

"mRNA's inherent thermal instability has hampered the distribution of mRNA vaccines worldwide due to in-line hydrolysis, a chemical degradation reaction," said Sun. "For this reason, our research seeks to understand and predict mRNA degradations."

To combat this problem, Sun and her team turned to deep-learning techniques, in which they developed the RNAdegformer—a deep-learning-based model powered by artificial neural networks capable of extracting data and using these insights to make predictions.

According to Sun, the RNAdegformer processes RNA sequences with self-attention and convolutions, two deep-learning techniques that have proved dominant in the fields of computer vision and natural language processing while utilizing the biophysical features of RNA secondary structure features and base pairing probabilities.

"The RNAdegformer outperforms previous best methods at predicting degradation properties at the nucleotide level, which are like letters of a sentence that combine to form mRNA," said Sun. "We can make predictions about each nucleotide in COVID-19 mRNA vaccines. RNAdegformer predictions also exhibit improved correlation with RNA in vitro half-life compared with previous best methods."

Additionally, the research shows how direct visualization of self-attention maps assists informed decision-making. According to Shujun He, a graduate student in Sun's group and the paper's first author, attention maps show how the model "thinks" using input information, which assists in informed decision-making based on model predictions.

Further, their model reveals essential features in determining mRNA degradation rates.

The team worked with Rhiju Das, an associate professor of biochemistry at Stanford University whose high-quality mRNA degradation data served as a starting point for this study.

"With our research, we hope we will be able to design more stable mRNA vaccines using our model to allow more equity and more broad usage of mRNA therapeutics," said Sun.

More information: Shujun He et al, RNAdegformer: accurate prediction of mRNA degradation at nucleotide resolution with deep learning, Briefings in Bioinformatics (2023). DOI: 10.1093/bib/bbac581

https://medicalxpress.com/news/2023-04-mrna-degradation-vaccine-stability.html

4 ways avian flu must evolve to become a human pandemic

 An outbreak of avian flu at a Spanish mink farm in October 2022 and several other reported cases of the virus's spread to mammals sparked concern of its transmission to humans. But experts say it will take a lot for avian flu to become a full-fledged human pandemic, Science reported.

Human cases of avian flu are deadly, but historically rare, according to the CDC. A few have cropped up across the globe in places like China, Cambodia and Chile throughout the past year, but largely from direct contact with infected birds or animals — not from human-to-human transmission. 

The H5N1 strain of avian flu has been the one responsible for a majority of human cases to date, but for the flu to become a full-scale, concerning human pandemic, experts say a few key things must happen first: 

1. Several of the strain's proteins must evolve to "become adept at spreading between mammals," Science reported.
   
   
2. The strain must undergo significant "changes in hemagglutinin," which would allow it to better attach to host cells.
   
   
3. The hemagglutinin must also experience a "a pH-dependent shape change" after attaching to a cell and being transported to a vesicle that is more acidic, which would allow it to be more easily transmissible via air. 
   
   
4. The virus may also need to evolve and become able to "evade an intracellular protein called MxA," which alerts the body's immune system of influenza. 

"With the virus spreading so furiously around the globe, it has more opportunities to hit the right combination than ever before," according to Science. "In the past, H5N1 outbreaks have faded, but this time, the virus is probably here to stay in wild birds in Europe and the Americas."

https://www.beckershospitalreview.com/public-health/4-ways-avian-flu-must-evolve-to-become-a-human-pandemic.html

Don’t Let Biden Gaslight You About The Jobs Situation

 After the Bureau of Labor Statistics report today about job growth and the unemployment rate, you can bet that President Joe Biden will use it as an opportunity to brag about his superb handling of the economy. The one thing Biden is good at is lying with statistics.

Biden will probably claim that he’s overseen a record number of new jobs – the most in history. The press will dutifully regurgitate White House talking points.

But the numbers getting bandied about these days about job growth and unemployment are wildly misleading because they ignore important bits of context. Such as:

1. The pace of job growth slowed considerably once Biden started “rescuing” the economy.
2. It took just nine months under President Donald Trump for the economy to regain 57% of the 22 million jobs lost during the COVID lockdowns. It took 17 months under Biden to regain the other 43%.
3. The economy was adding jobs at an average of 1.3 million a month in Trump’s last nine months in office. In the first nine months of Biden’s term, job growth averaged 620,000.
4. As a result, job growth is now behind the pace set by most recoveries since 1948, according to the Minneapolis Federal Reserve Bank. Nearly three years after the COVID recession officially ended, we are still just 2% ahead of the previous employment peak. At the same point after the 1981 recession, there were 3.5% more jobs. Three years after the 1969 recession, the job market was 5.7% bigger.
5. The jobs picture would be far worse had it not been for Republican-run states that defied the Biden administration’s intrusive COVID policies. By mid-2022, red states were 350,000 ahead of their pre-COVID highs, while blue states were still 1.3 million jobs short of where they were before the COVID lockdowns.

But what about the low unemployment rate Biden brags about?

In February 2020, just before the COVID insanity struck, unemployment had fallen to a 50-year low of 3.5%. Then it shot up to 14.7%. The March 2023, the unemployment rate was back down to 3.5%.

Surely that is good news, right?

Not so fast.

Over those same three years, the working-age population grew by 6.6 million. For unemployment to be back down to 3.5%, you’d think there’d be 6.6 million new jobs created.

But the number of people employed went up by only 2.1 million over the past three years.

So where did the other 4.5 million people go? Most of them simply dropped out of the labor force. They don’t have a job, and they aren’t looking for one.

And because the unemployment rate counts only those who are actively looking for work, the more labor-force dropouts there are, the lower the official unemployment number is.

If those millions of people hadn’t given up looking for work, they would be counted as unemployed, and today’s unemployment rate would be 5%, not 3.5%.

That’s not terrible, but it’s hardly anything to brag about. And it’s Biden’s policies that have suffocated what would have been a much stronger jobs recovery.

The first thing Biden did when taking office was to hand out wads of cash, extend unemployment bonuses, expand Obamacare subsidies, and strip away welfare work requirements, while throwing the job market into chaos with his vaccine mandates and regulatory onslaught.

Put simply, he paid people not to work, often handsomely, while punishing job creators.

A recent analysis by the Committee to Unleash Prosperity found that in nearly half the states, unemployment benefits and enhanced Obamacare subsidies added up to more than the median household income. Why work, when staying home pays better?

To make matters worse, those with jobs have been getting pay cuts thanks to the high inflation rates that Biden’s $2 trillion “rescue plan” unleashed. While real average hourly earnings went up under Trump, they’ve been steadily falling ever since, and are now 4% below where they were when Biden took office.

This is the reality of the job market today. It’s not pretty. It’s not what Biden and the mainstream media want you to hear. But it’s what families are struggling with every day.

https://issuesinsights.com/2023/04/07/dont-let-biden-gaslight-you-about-the-jobs-situation/