In a study including just under 800,000 people, the investigators found that risk for early stroke events was 18-23% higher in men and women who had a birth weight under the median level than those with a higher birth weight.

Around 795,000 people in the U.S. have a stroke each year. Although it can affect people of any age, it is much more common in older individuals with estimates of prevalence suggesting that 0.9% of 18–44 year olds have strokes versus 3.8% of those in the 45–64 year age group and 7.7% of people aged 65 and over.

Low birth weight has been previously linked to an increased risk for stroke in several studies. Researchers think that low birth weight is an indicator of exposure to an adverse environment in the womb that may adversely affect the cardiovascular system of the fetus in a way that increases stroke risk—for example, by increasing the risk of high blood pressure.

Over the last 10-15 years, stroke prevalence has stayed the same in older adults but has gone up by 14-16% in 18-64 year-olds. Lina Lilja, a doctoral student at the University of Gothenburg, and colleagues aimed to investigate whether low birth weight increased the risk of stroke in younger adults.

They included 420,173 men and 348,758 women from Sweden who were born between 1973 and 1982 and followed up from birth until 2022. The researchers collected data on birth weight, gestational age, and body mass index in young adulthood, as well as information on first stroke and the type of stroke.

Overall, 2252 first stroke events were recorded at an average age of 36 years. Of these, 1624 were ischemic stroke (average age 37 years) and 588 were intracerebral hemorrhage (average age 33 years).

The results, which will be presented at the European Congress on Obesity in Istanbul later this year, showed that birth weight below the median (3.5kg) increased the risk for all stroke by 21%. The rates of stroke were slightly higher in men with a low birthweight at 23% versus women with a low birthweight at 18%.

Notably, gestational age at birth and young adult body mass index were not linked to stroke risk in this study.

The post Low Birthweight Increases Risk of Early Stroke appeared first on Inside Precision Medicine.

“We know a lot about how pancreatic tumors behave and look, but we don’t know how they become cancerous,” said lead author Megan Radyk, PhD, a former postdoc in the lab of Costas Lyssiotis, PhD, at the University of Michigan and now an assistant professor at Roswell Park Comprehensive Cancer Center. “We wanted to learn about what metabolic changes happen before you get an established tumor.”

PDAC is the most common form of pancreatic cancer and has a low five-year survival rate. The disease develops through a stepwise process that begins with acinar-to-ductal metaplasia (ADM), a reversible state in which pancreatic cells respond to injury or inflammation by adopting a duct-like phenotype. Under normal conditions, these cells can revert to their original state. However, in the presence of oncogenic KRAS mutations, this process is disrupted, leading to persistent ADM and progression to pancreatic intraepithelial neoplasia (PanIN), which can ultimately become PDAC.

NADPH’s normal role is in maintaining cellular homeostasis. It supports the synthesis of lipids, cholesterol, and nucleotides, and it aids antioxidant systems that regulate reactive oxygen species (ROS). Under normal conditions, NADPH helps neutralize ROS, preventing cellular damage. The current study, however, demonstrated that lower levels of NADPH impair antioxidant defenses, leading to increased ROS and lipid peroxidation, which in turn promote the formation of precancerous lesions.

The researchers identified two NADPH-producing enzymes for their work: glucose-6-phosphate dehydrogenase (G6PD) and malic enzyme 1 (ME1). Both enzymes support the production of the appropriate levels of NADPH needed for biosynthesis and ROS regulation.

Using a multimodal approach involving RNA sequencing, metabolomics, and mouse models with oncogenic KRAS mutations, the Michigan team studied how the loss of these two enzymes affects pancreatic tissue. They observed that deficiency in either G6PD or ME1 increased ROS levels and accelerated the formation of ADM and pancreatic intraepithelial neoplasia (PanIN) lesions. Antioxidant treatments, including glutathione and N-acetyl cysteine, reduced lesion formation, further bolstering the current understanding of the role of oxidative stress in early tumorigenesis. The team achieved similar results when these methods were applied to human pancreatic tissue samples.

But results from later in the study showed that the two enzymes played distinct roles in the later stages of PDAC. While they both contributed to early lesion formation, only the loss of ME1 promoted progression to PDAC. This suggests that although both enzymes regulate NADPH and oxidative stress, they have distinct roles in later metabolic demands of cancer cells.

The study builds on prior research showing that KRAS mutations drive metabolic reprogramming and ROS production in pancreatic cells. Previous work has also indicated that antioxidant pathways, including those regulated by NRF2, are activated during tumor initiation.

Clinically, these findings suggest that targeting metabolic pathways involved in NADPH production could provide a strategy to intercept pancreatic cancer before it fully develops. Measuring levels of G6PD, ME1, or related metabolites could also serve as biomarkers to identify patients at higher risk of lesions progressing to cancer.

“Our study can help the search for new biomarkers that can intercept pancreatic cancer before it progresses,” the researchers wrote.

Future research will focus on identifying additional enzymes that regulate NADPH levels and determining how these pathways can be targeted safely. The researchers also plan to study whether patients with mutations in G6PD, ME1, or related pathways have an increased risk of pancreatic disease.

The post Pancreatic Cancer Development Driven by NADPH Disruption appeared first on Inside Precision Medicine.

For millions of people worldwide, carrying the APOE4 gene variant means a significantly higher risk of developing Alzheimer’s disease. Yet one of the biggest unanswered questions has been when, and how, that risk begins to take hold in the brain.

New research from the Gladstone Institutes, published in Nature Aging, suggests that the effects of APOE4 emerge far earlier than previously understood. The study shows that subtle but important changes in brain activity occur long before memory loss begins, offering a potential window for early intervention.

Early changes in a seemingly healthy brain

Alzheimer’s disease is typically diagnosed after cognitive symptoms appear, but growing evidence suggests that the disease process begins decades earlier. The new study adds to this picture by demonstrating that brain circuits in young individuals carrying APOE4 are already functioning differently.

We found fundamental changes in brain circuits occurring in young mice that still had normal learning and memory, and importantly, that those changes predicted the development of cognitive deficits at older ages, ” said Misha Zilberter, PhD, principal staff research scientist at Gladstone and senior author of the study.

The researchers observed increased neuronal activity in the hippocampus, a brain region essential for learning and memory. Similar patterns of hyperactivity have been reported in human APOE4 carriers, even before clinical symptoms arise.

According to the scientists, this suggests that Alzheimer’s risk is not simply a matter of late-stage degeneration, but may instead involve long-term changes in how brain circuits are wired and function.

Smaller neurons, stronger signals

To understand what drives this early hyperactivity, the team examined individual brain cells. They found that neurons in key regions of the hippocampus were physically smaller in APOE4 carriers compared to those with the more common, lower-risk APOE3 variant.

While this might seem like a minor structural difference, it has functional consequences. Smaller neurons are more easily activated, meaning they fire more readily in response to stimuli. This heightened sensitivity can lead to persistent hyperactivity within neural circuits.

Over time, this imbalance may place stress on the brain and contribute to the gradual decline seen in Alzheimer’s disease.

A surprising source of dysfunction

For years, researchers believed that APOE4’s effects were primarily driven by astrocytes, support cells in the brain that produce most of the APOE protein. However, the new findings challenge this assumption.

The team discovered that the disruptive effects on brain activity were instead linked to APOE4 produced directly by neurons themselves. When APOE4 was removed from neurons, their size and activity returned to normal. Removing it from astrocytes, by contrast, had little effect.

This shift in understanding refocuses attention on neurons as key drivers of early disease processes, rather than passive victims of surrounding dysfunction.

A reversible pathway—and a new target

Perhaps the most striking finding of the study is that these early changes may not be permanent.

The researchers identified a protein called Nell2 as a central player in the process. Levels of Nell2 were elevated in APOE4 neurons and appeared to drive both the reduction in cell size and the increase in neuronal activity.

By reducing Nell2 levels in adult mice, the team was able to restore normal neuron structure and function—even after the changes had already occurred.

“What’s exciting about Nell2 is that we were able to reverse the disease manifestations in adult mice by lowering its level,” said Yadong Huang, co-senior author of the study. “That tells us the damage is not irreversible […].”

This raises the possibility of developing therapies that target Nell2, potentially slowing or preventing disease progression in individuals at high genetic risk.

Implications for early intervention

APOE4 is present in roughly one in four people and in the majority of Alzheimer’s patients. Despite this, current treatments largely focus on late-stage symptoms rather than early prevention.

The new findings suggest that intervening earlier, before cognitive decline begins, could be key. If brain circuit changes can be detected and corrected at an early stage, it may be possible to delay or even prevent the onset of Alzheimer’s disease.

The study also highlights the importance of understanding how genetic risk translates into functional changes in the brain. Rather than acting as a simple risk marker, APOE4 appears to actively reshape neural activity over time.

A shift in perspective

More broadly, the work reflects a growing shift in Alzheimer’s research, from focusing solely on hallmark features such as amyloid plaques and tau tangles to examining earlier, subtler changes in brain function.

By identifying a concrete pathway linking genetic risk to altered brain activity, the study provides a clearer framework for understanding how the disease develops.

“This study is a big breakthrough for the field of Alzheimer’s research,” Huang said. “It opens the door to a better understanding of how APOE4 alters the function of neurons at a young age to increase risk of cognitive decline, and to the development of therapies that could block the detrimental effects of APOE4 early on.”

While the findings are based on mouse models, they align closely with observations in humans and offer a strong foundation for future research. The next steps will involve determining whether targeting Nell2 or similar pathways can produce similar benefits in human patients.

If successful, such approaches could transform how Alzheimer’s disease is treated, not as an inevitable consequence of aging, but as a process that can be detected early and potentially reversed.

The post How an Alzheimer’s Risk Gene Rewires the Brain Decades Before Symptoms appeared first on Inside Precision Medicine.

The artificial intelligence model recognizes genetic sequences involved in defenses that act against bacteriophages—viral invaders that infect bacteria.

These anti-viral immune systems have already been repurposed into powerful gene-editing technology, such as CRISPR-Cas, that enable DNA sequences to be precisely cut, modified, or deleted within an organism.

The DefensePredictor tool, outlined in Science, is available as an open-source tool to enable the discovery of more prokaryotic immune systems.

“Identifying new antiphage defense systems may yield the next generation of precision molecular tools while also shedding important light on the ongoing arms race between bacteria and phages,” said MIT-based molecular biologist Michael Laub, PhD, and co-workers.

Intense selective pressure to evade or survive infection has driven the evolution of numerous antiphage defense mechanisms, including restriction enzymes and the CRISPR-Cas systems.

While antiphage immunity genes often cluster into “defense islands” in prokaryotic genomes, this does not always occur and many systems are dispersed or carried on mobile elements such as plasmids, prophages, and transposons.

In an attempt to create a model to identify antiphage proteins, Laub and team first looked at around 17,000 genomes of prokaryotic organisms.

They labelled homologs of known defense and nondefense genes and built representations of the proteins coded by these genes as well as their four nearest neighbors on the genome.

DefensePredictor was trained through this to distinguish whether a gene was involved in defense systems.

After performing well in silico, it was tested on 69 diverse Escherichia coli genes and identified 624 different proteins that it confidently predicted were involved in defense, including 154 that shared no detectable homology to known defense proteins.

Nearly half of the defense proteins identified were not encoded in plasmids, prophages, or defense islands, showing that the model was able to identify systems in a wide range of genomic contexts.

Of 94 predicted genes tested in the lab, 42 provided protection against at least one of 24 phages tested, giving a validation rate of around 45%.

Fifteen protein domains across these 42 systems had not previously been validated as defensive, suggesting new immune systems remain undiscovered.

Expanding the predictive capacity of DefensePredictor beyond E. coli to 1000 diverse prokaryotic genomes revealed more than 5000 predicted defense proteins that were not clear homologs of those already known.

Another Science research article in the same issue of the journal also showed how AI could uncover unexplored diversity in bacterial immunity.

Ernest Mordret, PhD, from the Pasteur Institute, and co-workers demonstrated how deep-learning frameworks could lead to the large-scale discovery of antiphage and a vast atlas of bacterial antiviral immunity.

The team developed three complementary deep-learning models to predict antiphage proteins by leveraging genomic context (ALBERTDF), amino acid sequence (ESMDF), or both (GeneCLRDF).

Twelve newly predicted antiphage systems were then experimentally validated in Escherichia coli and Streptomyces albus.

When applied to more than 30,000 bacterial genomes, the models predict 2.39 million antiphage proteins, 85% of which had no previously known link to immunity, corresponding to approximately at least 23,000 predicted antiphage operon families.

All predictions have been made freely available through an interactive antiphage atlas.

“We developed deep learning models to predict antiphage systems,” the authors summarized.

“These methods extract cues about the “defensiveness” of a protein from two seemingly orthogonal sources: its genomic context across thousands of genomes, and its own amino acid sequence.

“By combining these complementary signals, we move from a fragmented, incomplete view of bacterial immunity toward a more resolved and quantitative understanding of its repertoire.”

The post Bacteria Defense Insights Could Revolutionize Genetic Editing appeared first on Inside Precision Medicine.

Researchers at Karolinska Institutet have found that people with long COVID face an increased risk of developing cardiovascular disease even if their initial infection did not require hospital care. The population-based study, published in eClinicalMedicine, shows that conditions such as cardiac arrhythmias and coronary artery disease occur more frequently in individuals diagnosed with long COVID compared with those without the condition.

Over a follow-up period of up to four years, 18.2% of women and 20.6% of men with long COVID experienced a cardiovascular event, compared with 8.4% and 11.1%, respectively, among those without long COVID. After adjusting for demographic and clinical factors, women with long COVID had just over twice the risk of cardiovascular disease, while men had approximately one-third third higher risk.

“We found that cardiac arrhythmias and coronary artery disease were more common among both women and men with long COVID. In women, there was also an increased risk of heart failure and peripheral vascular disease. However, no clear association was found between long COVID and stroke,” said lead author Pia Lindberg of Karolinska Institutet.

The research was conducted using the Multimorbidity Integrated Registry Across Care Levels in Stockholm (MIRACLE-S), which includes data from around 2.5 million residents. Investigators identified more than 1.2 million individuals aged 18 to 65, including nearly 9,000 diagnosed with long COVID between October 2020 and January 2025. To isolate the effects of long COVID, the study excluded individuals who had been hospitalized during acute infection or who had pre-existing cardiovascular disease. The researchers then applied Cox proportional hazards models to estimate the risk of major cardiovascular outcomes, including myocardial infarction, heart failure, arrhythmias, stroke, and peripheral arterial disease, adjusting for demographic, lifestyle, and mental health factors.

The decision to focus on non-hospitalized individuals reflects a gap in earlier research. Previous studies have largely concentrated on patients with severe COVID-19 requiring hospital or intensive care, leaving uncertainty about risks among those with milder infections managed in the community. Because hospitalized and non-hospitalized individuals differ in baseline cardiovascular risk, disease severity, and care pathways, the researchers aimed to examine these groups separately. This approach allowed them to assess whether long COVID itself is associated with increased cardiovascular risk independent of acute disease severity.

Prior evidence had suggested a link between COVID-19 and cardiovascular complications, including myocardial infarction, stroke, arrhythmias, and heart failure. Large cohort studies reported elevated rates of these outcomes following infection, with risks persisting for up to a year. However, many of these studies combined hospitalized and non-hospitalized populations or focused on severe cases, limiting insight into community-managed long COVID. The researchers wrote, “Long COVID has emerged as a global health challenge, with increasing evidence of cardiovascular sequelae. Most previous studies have focused on hospitalized cohorts, whereas cardiovascular risk in community-managed long COVID cases remains less explored.”

This study adds to the literature by providing population-based evidence that long COVID is associated with increased cardiovascular risk even after mild-to-moderate infection. By restricting the cohort to individuals without prior cardiovascular disease and analyzing outcomes separately by sex, the findings highlight differences in risk patterns. Cardiac arrhythmias showed the largest increase, particularly among women, while coronary artery disease was elevated in both sexes. Heart failure and peripheral arterial disease were increased among women only. The researchers wrote, “Long COVID is associated with increased risk of incident cardiovascular disease, particularly cardiac arrhythmias, heart failure, and coronary artery disease. These findings underscore the need for systematic follow-up and integration of long COVID into cardiovascular risk assessment.”

The mechanisms underlying these associations remain under investigation, but proposed explanations include endothelial dysfunction, chronic inflammation, thrombogenicity, and immune-mediated injury. The persistence of elevated risk over a follow-up period extending up to 40 months suggests that long COVID may involve sustained physiological changes rather than a short-term post-viral effect. The researchers wrote, “This population-based cohort study demonstrates that individuals who developed long COVID after mild-to-moderate infection have an elevated risk of future cardiovascular disease analyzed as a composite outcome.”

Clinically, the findings indicate that long COVID should be considered a risk factor for cardiovascular disease beyond hospitalized populations. The data support more systematic monitoring of individuals with long COVID, particularly in primary care settings where many cases are managed. Sex-specific differences observed in the study suggest that risk assessment and follow-up strategies may need to account for variation in presentation and outcomes between women and men. The results also highlight the potential for under-recognition of cardiovascular complications in patients who were not hospitalized during acute infection.

The researchers noted that while absolute risks remain modest, the relative increases are comparable to established cardiovascular risk factors. This has implications for integrating long COVID into existing risk assessment frameworks and for planning healthcare services. Future work will focus on further clarifying mechanisms, validating findings in other populations, and refining strategies for early detection and prevention of cardiovascular disease in people with long COVID.

The post Long COVID Linked to Higher Cardiovascular Risk in Non-Hospitalized Patients appeared first on Inside Precision Medicine.

“This study is a huge wake-up call because traditionally, physicians have tended to look at the total amount of alcohol consumed, not how it is consumed, when determining the risk to the liver,” said Brian Pei Lim Lee, MD, hepatologist and liver transplant specialist at Keck Medicine of USC and senior author of the study. “Our research suggests that the public needs to be much more aware of the danger of occasional heavy drinking and should avoid it even if they drink moderately the rest of the time.”  

Lee and colleagues focused on individuals with dysfunction-associated steatotic liver disease (MASLD), the most common form of chronic liver disease, affecting one in every three people. Although MASLD is often asymptomatic, over time it can lead to the development of more serious liver diseases such as alcohol-associated liver disease (ALD), which is currently the leading condition for liver transplantation in the U.S. 

Currently, average alcohol consumption is taken into account to classify MASLD patients and evaluate their prognosis. However, this classification does not take into account drinking patterns. In the current study, people with MASLD who consume alcohol heavily on occasion, for instance on weekends but not during the week, were found to have a much higher risk of advanced liver fibrosis. 

Using data from the National Health and Nutrition Examination Survey, Lee and colleagues looked at 8,000 adults whose data was collected between 2017 and 2023. Among them, nearly 4,000 had MASLD, and 16% reported episodic heavy drinking, which was defined as at least four drinks for women and five drinks for men on any given day, at least once per month. 

Compared to individuals with MASLD with the same average alcohol intake, those who engaged in episodic heavy drinking were three times more likely to develop advanced liver fibrosis. These results highlight that patterns of alcohol use should be taken into account when screening for alcohol use in MASLD patients to improve liver risk stratification, enabling targeted treatment and interventions designed to address alcohol use. 

Lee and colleagues hypothesise that, in addition to causing direct damage to the liver, occasional heavy drinking may be indirectly affecting MASLD patients by increasing rates of cardiometabolic risk factors that amplify the risk of liver disease, such as high blood pressure, high cholesterol or type II diabetes. 

“Although this study focused on patients with MASLD, these findings may also be pertinent to a broader patient population,” said Lee. “With more than half of adults reporting some episodic heavy drinking, this issue deserves further attention from both physicians and researchers to help better understand, prevent, and treat liver disease.” 

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Before, her son Aidan was much like any other six-year-old—healthy, energetic, thriving. Nothing in his early years hinted at what was coming. “He met all his milestones. He did really well in school. He played all the sports,” Seeger told me.

Then came subtle changes: vision problems that required a series of specialist visits, and finally, a precautionary MRI. At first, the neurologist did not suspect anything was seriously wrong with Aidan on his physical checkup, Seeger said. But then he requested an MRI. “That was the first time we heard about Adrenoleukodystrophy (ALD),” Seeger recalled.

ALD is a rare genetic condition that damages the brain and adrenal glands. Left untreated, it is often fatal. But caught early, it can be managed, even halted, through interventions like adrenal hormone replacement or a hematopoietic stem cell transplant (HSCT). Unfortunately, Aidan’s diagnosis came too late.

After Aidan qualified for a transplant, the Seeger family relocated to North Carolina for treatment. But by then, the disease had already ravaged his brain. “He spent the last ten months of his life living in the hospital,” Seeger said. “He lost all his abilities. His ability to see, to hear, to walk, and to talk—all his abilities—were gone.”

Aidan died in April 2012.

In the months leading up to his death, Seeger searched relentlessly for anything that might have changed his outcome. What she found reshaped her grief into a mission. “I came across the fact that there was a newborn screening test for this condition,” she said, “but not one state was putting it to use.”

That discovery revealed a devastating truth: Aidan’s life might have been saved, not by a breakthrough drug or experimental therapy but by a simple test at birth. “I knew at that moment this would be the difference between life and death,” she said, “not only for him but for thousands of boys across the country.”

Earlier this month, more than a decade since the loss of her son, Seeger co-founded the Surge to Save Newborns Coalition, an alliance of rare disease advocacy groups and industry partners aimed at eliminating disparities in state newborn screening panels. Along with the launch, Manatt Health released a study that fueled the coalition’s call for a one-time, $173-million increase in federal funding to test all newborns for a Recommended Uniform Screening Panel (RUSP) disease—40 core conditions and 26 secondary conditions as of December 2025—to prevent untreated rare disease deaths and disabilities.

A law born from loss

In hospitals across the United States, newborns routinely undergo screening within hours of birth. A nurse pricks the baby’s heel (i.e., the classic Guthrie heel prick test) and collects five drops of blood on a card. That sample is sent to a state lab, where it is tested for a panel of conditions. The panel, however, is not uniform.

Each state decides which conditions to screen for, with several omitting diseases that are included in the RUSP—conditions for which early detection can save lives or prevent severe disability. “The newborn screening that they’re receiving in Texas, for example, is vastly different than what they’re getting in Washington state,” Seeger explained.

For families, this variability is invisible until it isn’t. “Most parents would have no idea,” she adds. “The parents and the families end up bearing the brunt of that reality when they learn that there was a screening available that could have enabled early intervention, but it wasn’t available in their state.”

In late 2012, months after Aidan’s death, Seeger founded the ALD Alliance (formerly the Aidan Jack Seeger Foundation), which would become a national advocacy effort.

Within a year, she achieved what once seemed impossible: legislation and implementation. In 2013, New York signed Aidan’s Law, which requires all newborns in the state to undergo ALD screening—typically a test that measures very long-chain fatty acids (VLCFAs) first, followed by genetic testing of the ABCD1 gene. “That’s when I realized newborn screening is one of the most successful health programs in the country,” she said.

Yet Seeger still saw newborn screening on the nationwide level to be a broken system, leading her to a simple but stark question: What about everybody else across the country?

What followed was a state-by-state campaign that would stretch over more than a decade. “As of today, we are in 48 states,” Seeger said. “You can see the lag time there from 2013 to 2026. We’re still at 48 states. It’s been a very slow process.”

Seeger began to describe the problem in stark terms: survival determined by geography. “Eradication of death by ZIP code,” Seeger said bluntly.

“I believe every baby born in this country should have the same chance at a normal, healthy life. Imagine knowing that your child didn’t live just because you lived in… North Dakota instead of New York. It’s just unfathomable to me.”

The phrase has since become a rallying cry for a broader movement that extends beyond ALD to dozens of other conditions. Diseases like Krabbe disease require immediate treatment at birth. Others, including ALD, require early monitoring to intervene before irreversible damage occurs. Still others, like Pompe disease or other mucopolysaccharidoses (MPS), have therapies that significantly improve outcomes if started early. Yet even after being added to the federal panel, implementation can take years or more than a decade. “Pompe disease (MPS I) … was added to the RUSP in 2015,” Seeger noted. “We’re still not in 50 states, and that’s 11 years later.”

The economics of prevention

At the heart of the problem is a structural gap: the federal government recommends but does not require. “There is no time frame for states to implement,” Seeger explained, “and there is no mandate. States can either opt to do it or not to do it.”

Even when states do move forward, the process is slow. Adding a new condition requires funding, laboratory upgrades, training, and administrative changes. For under-resourced public health systems, those barriers can stall progress for years.

Funding, Seeger said, is the central obstacle. “We’ve realized funding is the number one issue, which is why states cannot implement a condition,” she said. “And that’s leading to the really long ten years or more time to implementation.”

In early 2026, Seeger and a coalition of advocates, researchers, and policymakers launched a new initiative: the Surge to Save Newborns Coalition. Backed by a report published in March 2026 by Manatt Health and supported by partners including Travere Therapeutics, the coalition set out to answer a straightforward question: What would it cost to fix the system?

The answer: $173 million.

Spread over five years, that amounts to roughly $35 million annually, a figure advocates argue is modest compared to the human and financial costs of delayed diagnosis. “With that funding, we should have all states screening for all of those conditions,” Seeger said.

The proposal would provide targeted federal funding to help states implement all RUSP conditions and even anticipate future additions. The goal is ambitious but concrete: cut implementation time in half, from a decade or more to five years or less.

For Seeger, the argument is not just moral but also economic. Aidan’s medical bills were almost $5 million/year as an inpatient. By contrast, the cost of adding ALD screening in New York, a state with about 250,000 births annually, was approximately $500,000. “One late diagnosis as opposed to the testing… could have just prevented that long hospital stay and the millions of dollars in health care costs and saved a life,” she said.

The math is difficult to ignore. Small upfront investments can avert massive downstream costs, both financial and human.

The limits of innovation

I spoke with Seeger in late February, coinciding with the 18th recognized Rare Disease Day. Despite its importance, newborn screening remains largely invisible to parents. “I had two children,” Seeger said. “I knew they took drops of blood from my baby’s heel, but nobody said to me, ‘This is what we’re testing for.’”

That lack of awareness compounds the problem. Without public pressure, policy change moves slowly. Seeger says people are often confused as to why she has been pursuing this cause for more than a decade and why it hasn’t been done yet. “Because it just seems so… common sense,” she said.

Seeger continues to hear from families whose stories echo her own. A woman from Alabama called to talk about her son, who, like Aidan was also diagnosed at age six. “She said to me, ‘Well, doesn’t Alabama have newborn screening?’ And they do. But they didn’t start screening until after her son was born.”

The difference between life and death, once again, came down to timing and geography. “How do you tell a family that?” Seeger asked. “There are thousands of those stories… It’s heartbreaking. And I relive that all over again.”

Every year, millions of babies are born in the United States. Each one will undergo newborn screening but not necessarily the same screening. That gap is what the Surge to Save Newborns coalition aims to close. The stakes are measured not just in policy timelines but in lives. “The main message is: early diagnosis saves lives,” Seeger said.

As genomic technologies continue to advance, whole genome sequencing is poised to replace traditional newborn screening. Several commercial genomic tests are already available for newborns, and non-invasive prenatal testing, such as those using cell-free DNA (cfDNA), now allow pregnancy-specific assessment of fetal risk for recessive conditions, aneuploidies (e.g., Down’s syndrome), and more. These prenatal tests have also paved the way for in utero treatments, such as recent stem cell therapy administered before birth to six children with spina bifida, far more complex than adrenal hormone replacement or even HSCT for newborns with ALD.

But Seeger is pragmatic, advocating for the simple heel prick as the most effective, scalable tool. “I think [WGS] too preliminary at the moment,” she said. “And… it would not take the place of newborn screening.”

For Seeger, the issue is not abstract. It is deeply personal and urgently practical. “We are spending this little bit of money to save lives and millions and millions in health care costs,” she said. “If someone just looked at this and said, ‘Oh, that makes sense!’”

More than a decade after Aidan’s death, that is still the hope: that common sense and a few drops of blood can finally align. “And yeah,” Seeger said quietly, “just save lives. That’s the message.”

The post ‘Death by ZIP Code’: Newborn Screening and the Geographic Screening Lottery appeared first on Inside Precision Medicine.

The treatment in question, called renizgamglogene autogedtemcel (reni-cel), employs CRISPR/Cas12a gene editing to modify hematopoietic stem cells from the patient’s own bone marrow. The editing targets the HBG1 and HBG2 promoters to reactivate the production of fetal hemoglobin, whose production otherwise naturally halts after birth. This form of hemoglobin is known to improve symptoms and reduce the rate of painful crises caused by sickle cell disease, where misshapen red blood cells can interfere with normal blood flow.

“We have seen that a benefit of this CRISPR/Cas12a gene editing technology is that there is no rejection, so it’s different from traditional bone marrow transplants, which is standard treatment for sickle cell patients currently,” said Rabi Hanna, MD, lead author of the study and chair of the Pediatric Hematology – Oncology & Blood and Bone Marrow Transplant Division at Cleveland Clinic Children’s. “Our aim has been to achieve a functional cure to help prevent any future damage caused by sickle cell disease, and these latest results are compelling.”

The clinical trial involved 28 patients with severe sickle cell disease, all of which had suffered at least two severe vaso-occlusive events per year in the previous two years. Their stem cells were collected for gene editing, followed by a course of chemotherapy to remove their bone marrow. The engineered cells were then reinfused to regrow the bone marrow with cells that produce fetal hemoglobin.

Only in one of the patients, the transplanted cells failed to engraft, resulting in two severe crises after treatment. In all other participants, blood cell production was restored within a month and average hemoglobin levels rose by 40% after six months, with no crises reported in two years of follow up. On average, levels of fetal hemoglobin were 48%, which remained stable over time. 

Despite positive efficacy and safety results, Editas Medicine terminated the RUBY trial early to instead pursue an in vivo approach where the gene editing happens within the patient rather than externally. This could make treatment easier to administer and more affordable, giving the company a competitive edge over other gene and cell therapies available for sickle cell disease. 

Last year, Editas reported positive preclinical data in humanized mice and non-human primates with this in vivo approach, which also targets the HBG1 and HBG2 promoters to treat both sickle cell disease and transfusion-dependent β-thalassemia. A single dose of the CRISPR-based therapy achieved high levels of editing that nearly doubled the threshold required to see a therapeutic benefit.

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An incomplete map of breast cancer variants

BRCA1, BRCA2, CHEK2, and PALB2 are linked to inherited risk, but they explain only a fraction of cases, especially early-life cases, even as rates of early-onset breast cancer (before age 50) have been rising. Furthermore, the incidence of early-onset breast cancer has been linked to ancestry. For instance, non-Hispanic Black women have the highest incidence of early-onset BRCA under 40. Understanding the genetic drivers behind these cases is critical for improving screening and prevention.

Previously, Baylor College of Medicine researchers Asmussen, Yi Li, PhD, Lawrence A. Donehower, PhD, and Olivier Lichtarge, MD, PhD, investigated combining evolutionary action (EA) with machine learning and statistical algorithms to address this challenge. This score estimates how much a mutation disrupts protein function, scoring from zero to 100 with higher values indicating greater consequences, based on how conserved that position is across evolution and how drastic the amino acid change is. The researchers used EA scores to identify de novo genetic drivers of Alzheimer’s, myocardial infarction, autism, and somatic tumors. 

After demonstrating that EA scores outperform other variant impact scores in distinguishing gain- versus loss-of-function mutations, Asmussen, Li, Donehower, and Lichtarge developed “EA-Pathways.” Instead of comparing patients to healthy controls, EA-Pathways analyzes only affected individuals from ultra-rare genetic variants—mutations found in one person in a dataset—to find genes and biological pathways where these rare, high-impact mutations may occur more often. Because it does not require a control group, the method can analyze large biobank datasets without population biases.

Pinning down breast cancer accelerating variants

Asmussen researchers found 131 potential risk genes by using EA-Pathways on ultra-rare variants of 16,837 BRCA-affected women from the UK Biobank. These encompassed recognized susceptibility genes like BRCA1 and BRCA2, as well as numerous previously undervalued candidates. Importantly, these genes clustered into biologically meaningful pathways already implicated in cancer, including DNA repair, cell cycle regulation, and cell adhesion. Subsequent analyses validated that these genes are not random. They are enriched for known pathogenic mutations, closely connected to established breast cancer genes in protein interaction networks, and linked to cancer-related traits in animal models. Crucially, the pattern of damaging mutations in these genes was specific to women with breast cancer and not seen in cancer-free individuals.

One of the study’s most significant findings is the link between certain genetic pathways and earlier age of diagnosis. The researchers identified eight pathways—primarily involved in DNA repair (especially homology-directed repair), TP53 signaling, and a cellular recycling process called pexophagy—where women carrying rare, high-impact variants were diagnosed about two years earlier on average. When expanded to a larger set of 59 genes across these pathways, about 14% of patients carried such variants and showed a similar trend toward earlier diagnosis. This suggests that these mutations may act as modifiers, accelerating disease onset even in the absence of classic high-risk genes.

Ancestry-specific genetic drivers of cancer

To test whether these findings apply broadly, the team analyzed data from the All of Us Research Program, which includes more diverse populations. The results largely held across ancestries—but with notable differences. Women of European ancestry showed about a two-year earlier diagnosis, while those of admixed American ancestry showed a four-year difference. In women of African ancestry, the effect emerged only when considering slightly more common variants, highlighting the importance of ancestry-specific genetic patterns.

The study found that some risk genes have ancestry-specific effects. For example, variants in the gene TOP3A, involved in DNA repair, were associated with earlier diagnosis in African ancestry populations and were much more common in these groups. Other genes, such as SEM1 and SQSTM1, emerged as potential new risk factors in specific populations, suggesting previously unrecognized biological mechanisms.

The researchers also identified a subset of genes that appear to drive especially early onset, with some linked to diagnoses up to nine years earlier in certain groups. Notably, more than half of these genes showed ancestry-specific effects, underscoring the need for tailored genetic screening strategies.

Too hot for MAGMA

Beyond its findings, EA-Pathways represents a methodological advance. It outperformed a widely used gene-set analysis tool (MAGMA) in identifying known breast cancer genes and worked effectively even in smaller sample sizes. By incorporating the functional impact of mutations rather than just their presence, it captures subtle but meaningful genetic signals that other approaches may miss.

Overall, the study expands the landscape of breast cancer genetics, particularly for early-onset disease. It highlights the role of rare, functionally significant mutations across multiple biological pathways and emphasizes the importance of considering genetic ancestry in risk assessment. These insights could pave the way for more precise screening strategies, helping identify women at higher risk earlier and tailoring interventions accordingly.

The post Ultra Rare Breast Cancer Variants Show Ancestry-Specific Links to Early Onset appeared first on Inside Precision Medicine.

“This raises the intriguing possibility of harnessing such pathways to durably ‘re-educate’ and restore core functional pathways of dysfunctional immune cells like Tregs,” said co-senior author Pingchang Yang, MD, PhD, a professor of immunology at Shenzen University School of Medicine.

Allergic asthma is characterized by immune dysregulation partially driven by an imbalance in pro-inflammatory and anti-inflammatory Tregs. Tregs are defined by expression of the transcription factor FOXP3 and their ability to suppress inflammation through cytokines such as IL-10. Previous research the both the number of Tregs, and their function, are reduced in asthma and are connected to disease severity. While this correlation is known, the mechanisms behind immune impairment has not been characterized. Other evidence has suggested that chronic inflammation, such as that seen in asthma, can induce a senescence-like state in Tregs that alters their function metabolism.

To see if it is possible to reverse this state in Tregs, the investigators isolated Tregs from allergic asthma patients and discovered the showed signs of this senescence-like state. This state was marked by shortened telomeres, increased senescence-associated β-galactosidase activity, and increased apoptosis. Additionally, these Tregs showed a shift toward pro-inflammatory cytokine production.

The team focused on the Dectin-1 receptor on Tregs. This is a C-type lectin receptor known for recognizing fungal β-glucans and mediating innate immune responses. Recent studies have indicated that Dectin-1 may also influence adaptive immunity, including T-cell function. Tregs express Dectin-1, and its activation can trigger intracellular signaling pathways that influence gene expression. The researchers hypothesized that targeting Dectin-1 could reverse Treg dysfunction by reprogramming key regulatory genes.

To test this, they used a fungal polysaccharide-derived peptide, KQS-1, which binds Dectin-1 with high affinity. In vitro experiments showed that KQS-1 treatment restored FOXP3 and IL-10 expression in patient-derived Tregs. This was linked to epigenetic changes including increased activating histone marks, reduced DNA methylation, and chromatin remodeling. These changes were driven by a Dectin-1–dependent signaling pathway involving Raf-1 and reactive oxygen species (ROS). “This functional rescue centered on these two core Treg signature genes was dependent on Dectin-1 binding and a downstream Raf-1/ROS signaling axis,” the researchers wrote. The team also found that CRISPR-mediated deletion of Dectin-1 eliminated the beneficial effects of KQS-1, which demonstrated that the receptor is required for this process.

Building on this information, the team then tested human Tregs treated with KQS-1 in mouse models and showed that it reduced airway hyperresponsiveness, inflammation, and tissue remodeling. Based on this, the researchers concluded that Treg dysfunction in asthma involves a reversible, senescence-like state centered on loss of FOXP3 and IL-10 activity. “This study identifies the acquisition of a senescence-like and dysfunctional phenotype in Tregs as a pivotal mechanism in the pathogenesis of allergic asthma and unveils a novel therapeutic strategy to reverse this defect,” they wrote.

The could potentially lead to new therapeutic strategies that reprogram immune cells, as opposed to current approaches that broadly suppress inflammation. By targeting Dectin-1, it could be possible to selectively restore Treg function and improve immune regulation in asthma and other immune-mediated diseases.

The research team will now study the safety, dosing, and pharmacokinetics of KQS-1. They will also look to discover if its effects extend beyond FOXP3 and IL10 to broader Treg lineage stability.

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