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Reporter’s Notebook: The Day the Scientific Debate Died

When the news broke on May 5 that U.S. Food and Drug Administration (FDA) officials had blocked the publication of two major COVID-19 vaccine safety studies in 2025 after being accepted for publication in medical journals, many researchers saw more than a scientific dispute. They saw it as further evidence that America’s most powerful public health agencies were devolving into ideological warfare, institutional instability, and political distrust.

By the time FDA commissioner Martin Makary, MD, resigned a week later on May 12, 2026, there was a growing conflict among scientists, political appointees, public health officials, and outside activists not only over vaccines and public health policy but also over something even more fundamental: who gets to determine what constitutes legitimate science and whether scientific disagreement itself would still be permitted to occur in public.  

A decade in the making 

Makary’s departure came amid a broader transformation of the FDA and HHS from relatively stable, technocratic agencies into politicized institutions shaped by pandemic-era conflicts. Under Obama-era leaders Robert Califf, MD, and Margaret Hamburg, MD, the FDA emphasized regulatory continuity and evidence-based policymaking, while the Department of Health and Human Services (HHS) focused largely on healthcare administration and implementing the Affordable Care Act. 

That changed during the first Trump administration and accelerated during COVID-19, when disputes over vaccines, masking, emergency authorizations, and therapeutics turned the FDA into a political flashpoint. Leadership turnover has increased, tensions between political appointees and career scientists have deepened, and public trust has fractured along ideological lines.  

The Biden administration attempted to restore institutional stability by returning Califf to the FDA and appointing lawyer and politician Xavier Becerra, JD, to HHS, but the agencies remained mired in conflicts over pandemic policy and public health authority. Under HHS Secretary Robert F. Kennedy Jr. in the second Trump administration, those tensions intensified further through staffing and funding cuts, ideological battles over vaccines and food policy, and growing distrust inside federal health agencies.  

Makary initially aligned with parts of the administration’s “Make America Healthy Again” (MAHA) agenda, particularly on food reform and criticism of segments of the pharmaceutical industry. But reports suggest he became caught between competing pressures from the White House, HHS leadership, industry groups, conservative activists, and public-health officials. He ultimately resigned amid disputes over vaping regulation, drug approvals, and broader public health policy during a sweeping restructuring of federal health agencies. Reports also indicated he was already at risk of removal and that his departure was not directly tied to controversy over the blocked COVID publication.  

Instead, the move signals the White House’s continued support for Robert F. Kennedy Jr., “MAHA,” and a shift toward more centralized control over food-safety strategy, inspections, and outbreak response—changes that could affect how aggressively the FDA enforces nutrition standards and responds to contamination events. More broadly, the episode has done little to ease concerns among scientists and public-health experts that political considerations are increasingly shaping regulatory decisions and narrowing the space for independent scientific debate within federal health agencies. 

Seeing double(think) 

One of the two was posted online as a medRxiv preprint in 2025 by lead author Joann F. Gruber, PhD, and senior author Steven A. Anderson, PhD, and examined updated Covid-19 vaccines in adults over 65, the population most vulnerable to severe disease and death from the virus. The analysis drew on data from 7.6 million Medicare FFS beneficiaries who received a COVID-19 vaccination in 2023–2024—either the Pfizer-BioNTech (3.68 million) or Moderna (3.84 million) mRNA vaccine or the Novavax protein-based vaccine (30,000)—and found no new vaccine safety signals. 

But before the study could move through peer review, publication was halted by the FDA, according to a spokesperson for the HHS. As reported by the New York Times, an HHS spokesperson said the studies were withdrawn “because the authors drew broad conclusions that were not supported by the underlying data. The FDA acted to protect the integrity of its scientific process and ensure that any work associated with the agency meets its high standards.”  

Both Gruber, whose work with the FDA’s Center for Biologics Evaluation and Research (CBER) began in 2017, and Anderson, a veteran of CBER having joined in 2001, left the FDA at some point in 2025. It’s worth noting that Anderson’s team posted a second preprint on influenza vaccines that mirrored the COVID-19 vaccines study, using the same patient population, on the same day, which was also posted online as a medRxiv preprint on January 5, 2025, and was accepted in the peer-reviewed journal Vaccine on March 25, 2025, and made available online April 8, 2025. 

On June 25, 2025, Makary and former CBER director Vinay Prasad, MD, PhD, in conjunction with manufacturers, added class safety warnings for myocarditis and pericarditis to COVID-19 mRNA vaccines’ prescribing information. The exact timing of when the accepted Gruber and Anderson study was pulled from publication has yet to be reported. That it occurred before June 2025 to prevent contradiction with Makary’s and Prasad’s safety update to the COVID-19 mRNA vaccine is entirely possible. Anderson’s team posted a second preprint on influenza vaccines that mirrored the COVID-19 vaccines study, using the same patient population, on the same day, which was also posted online as a medRxiv preprint on January 5, 2025, and was accepted in the peer-reviewed journal Vaccine on March 25, 2025, and made available online April 8, 2025. 

Both Gruber, whose work with the FDA’s Center for Biologics Evaluation and Research (CBER) began in 2017, and Anderson, a veteran of CBER having joined in 2001, no longer work at the FDA. According to their LinkedIn profiles, Gruber left in June 2025 and Anderson in December 2024. 

Gold-standard science 

I spoke with several leading epidemiologists to assess whether there was substance to the HHS statement. All immediately noted the lack of specificity in the agency’s criticism, particularly the vague references to “gold-standard science.” 

An epidemiologist with experience conducting vaccine safety studies, requesting anonymity, told Inside Precision Medicine, “If someone wants to criticize the study, there should either be a very clear articulation of what exactly they mean when they invoke terms like ‘gold-standard science’—specifically, which methods are acceptable, which are not, and why—or they should bring to the table the scientific credibility that would justify dismissing this kind of work outright. Frankly, neither of those things has happened. Broad, nonspecific attacks like these actually undermine the critique itself.”  

The epidemiologists I spoke to emphasized that the study’s methods were not novel but reflected established approaches used in vaccine surveillance and prior scientific work, including self-controlled case series and cohort studies. A Harvard University researcher familiar with the study said the framework was specifically designed for this purpose. “The system/infrastructure (FDA BEST), data source, study design, and analytic approach are all fit-for-purpose for the study question,” the Harvard researcher told me. “Self-controlled designs are robust and control for non-time-varying factors, especially in adults.” 

Céline Gounder, MD, an infectious disease specialist, epidemiologist, and editor-at-large for public health at KFF Health News, said the report used one of the strongest available methods for post-market vaccine surveillance. “This study used one of the best methods we have to check if vaccines cause side effects, and it found that the updated COVID vaccines are safe,” Gounder told me. “Pulling this study from publication doesn’t protect good science. It’s not radical transparency, and it’s not gold-standard science.” 

Gounder also noted that the study analyzed data from more than seven million people and found no new safety concerns. “That’s a careful conclusion backed by solid data,” she said. “Blocking a study because you don’t like the answer is censorship.” 

Indeed, the consensus among interviewees was that the study appeared adequately powered and appropriately cautious in its conclusions. “This study includes a large number of people, and from what I can see, it appears adequately powered for the conclusions they’re making,” said the epidemiologist with vaccine expertise. “Importantly, the authors are framing the findings appropriately. They are not claiming more than the data support. Their framing is essentially ‘No new safety signals identified.’ That’s a careful and reasonable way to present findings like this.” 

The study also openly acknowledged limitations, including possible outcome misclassification and residual uncertainty, while describing how these issues were addressed in the analysis. “Seasonality can be a concern with the study design, but it was adjusted for in the study,” said the Harvard researcher. “Claims data are well equipped for studying the exposure and outcomes of interest… In this study, misclassification was accounted for.”

Steven Goodman, MD, PhD, associate dean of clinical and translational research and professor of epidemiology and population health and medicine at Stanford University, told Inside Precision Medicine the study was informative and aligned with broader evidence supporting the low-risk profile of COVID vaccines in adults over 65. Goodman also highlighted the restraint of the authors’ interpretations. “They do not make a statement about the risk-benefit balance, which they can’t because they didn’t study the benefit, but they note that the FDA felt that the balance was positive,” he said. “Their main conclusion was, ‘Our study contributes to growing evidence on the safety of COVID-19 vaccines.’ It is hard to argue with that.” 

Goodman added, “All studies have strengths and limitations, i.e., none establish a scientific truth all by themselves. But this is fundamentally good science that adds valuable information to the COVID vaccine safety picture in adults >65.” 

The epidemiologists stressed that vaccine safety science depends on cumulative evidence across multiple studies, methods, and datasets. “Public health surveillance has always operated this way,” the Harvard University researcher said. “No single study claims to be the final word on a topic. You accumulate evidence across multiple studies, multiple methods, and multiple datasets and then interpret the totality of evidence together.” 

The Harvard researcher added, “The results are consistent with what has been reported by others, including in other countries. There is no clear scientific reason for this work being pulled from publication.” 

Truth welcomes questions 

Further, many of the epidemiologists I interviewed stressed that publication does not imply unquestioned acceptance. Instead, they argued that publication serves as the mechanism through which scientific claims challenge, refine, or overturn one another.   

Goodman emphasized that the unpublished manuscript was intended for scientific scrutiny and peer review and said imperfections in such work are neither unusual nor disqualifying. “Is it perfect? No, but this is a preprint, and usually the peer review and editing process improves the analyses, exploring robustness to various assumptions, the reporting, and the interpretation,” he said. “I would presume that the final version would have come out with some more qualifications, limitations, sensitivity analyses and caveats.” 

The experts I contacted emphasized how suppressing publication interrupts the ordinary process through which scientific consensus develops. “This study should be out there, clearly labeled as one piece of evidence among many, with all the necessary caveats attached,” said the epidemiologist. “Then additional studies come in, more data accumulate, and eventually the field interprets the evidence in totality.” 

The unnamed epidemiologist added, “For 250 years, this country has benefited from exactly that: reasonable people openly disagreeing about difficult issues. So why not say, ‘Fine, publish the study,’ and then publish an editorial alongside it explaining the caveats, limitations, and alternative interpretations? That’s how science is supposed to work. You respond to speech you disagree with by adding more speech, not by suppressing speech and certainly not by suppressing scientific speech.” 

Several of the epidemiologists argued that blocking the manuscript conflicts with repeated public calls for open scientific debate from directors at agencies under the purview of HHS, notably Jay Bhattacharya, PhD, Director of the National Institutes of Health (NIH). 

Goodman said that how the FDA handled this study “contrasted with Dr. Bhattacharya’s many public remarks stressing the criticality of open discussion of scientific results and his objections to suppressing science whose results one doesn’t like. The forced withdrawal of this manuscript prevented that process from occurring, shutting down the open discussion Dr. Bhattacharya has called for in innumerable forums.” 

Goodman added that if officials believe the study contains fatal flaws, they should articulate those concerns publicly and subject them to scientific scrutiny, “letting the authors respond and the scientific community decide… Their own critique should be subjected to peer review.” 

The fundamental process of science encourages that disputes over evidence should unfold transparently in scientific journals and public debates. “If someone has objections, they should make those objections publicly and specifically in the scientific literature where others can critique them, evaluate them, or even prove them right,” said the epidemiologist. “That’s how science advances. That’s what real science looks like: gold-, platinum-, titanium-, or whatever rare metal metaphor people want to use for standards. The scientific enterprise in this country has succeeded because ideas are tested openly, criticized openly, and refined openly. This kind of amateur hour behavior at regulatory agencies doesn’t help anybody.” 

Nostrums, not normalcy 

The culling of FDA scientists, be it via resignations or firings in 2025–2026, has continued since Makary’s resignation. Tracy Beth Hoeg, MD, PhD, the head of the FDA’s Center for Drug Evaluation and Research (CDER), was fired Friday (according to a social media post reported by Reuters on Sunday) and replaced by Michael Davis, MD, PhD, who had served as deputy director of CDER for about a year. 

There is no concrete evidence connecting the FDA’s blocking publication of two studies accepted into medical journals to Makary’s departure. But the contradictory messaging within the agency on COVID-19 mRNA vaccines—the product of Operation Warp Speed, considered a signature accomplishment of the first Trump administration—is obvious. The collapse of confidence within institutions that once relied on scientific independence as their organizing principle. Increasingly, senior scientists and regulators appear unwilling to publicly defend decisions, studies, or processes they privately regarded as scientifically sound. That shift matters more than any single resignation. 

The appointment of Kyle Diamantas as acting head of the FDA, however, is far from a course correction, marking another sharp turn away from independent scientific leadership at America’s top health regulator. A former corporate lawyer for Abbott Laboratories with no medical or research background, Diamantas rose through the agency by advancing the “MAHA” food agenda and cultivating ties to politically aligned health influencers rather than the scientific establishment. A close friend of Donald Trump Jr., the appointment of the 38-year-old Diamantas only reinforces concerns that ideological loyalty is increasingly outweighing scientific expertise inside the FDA. 

For decades, FDA and HHS leadership operated with relative continuity, assuming that disputes would be resolved through open scientific debate. That assumption now appears badly weakened. The blocked vaccine safety study became symbolic not merely because of the substance of the research but also because even many scientists who believed the work was rigorous hesitated to say so publicly. When experts become reluctant to attach their names to conclusions that they consider obvious or well-supported, the problem extends beyond politics or personnel. It reflects a deeper institutional fear inside the scientific establishment itself. 

Makary’s resignation earlier this month therefore represented more than another leadership change in Washington. It exposed how federal health agencies have been pulled into a culture where scientific judgments are increasingly filtered through ideological loyalty, political risk, and reputational self-preservation. The larger danger is not only instability at the FDA or HHS, but the emergence of a scientific culture in which silence becomes safer than candor. Institutions built to evaluate evidence cannot function for long under those conditions.  

The post Reporter’s Notebook: The Day the Scientific Debate Died appeared first on Inside Precision Medicine.

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Microbiome Therapy Could Help Drug-Resistant Melanoma Patients

Microbiotica, a microbiome-focused biotech based in Cambridge in the U.K., has achieved good Phase Ib results in a trial of its microbiome therapy for patients with advanced melanoma skin cancer.

The therapy, currently known as MB097, is designed to be given to patients who have not previously responded to immunotherapy in addition to a checkpoint inhibitor pembrolizumab. MB097 was developed to reverse the drug resistance seen in these patients and is based on research looking into the gut microbiome of melanoma patients who do respond to this kind of immunotherapy.

The primary endpoint of the trial, which included 41 patients from the U.K., France, Italy, and Spain, who had previously shown resistance to anti-PD-1 drugs, was safety and tolerability of MB097. Several secondary endpoints including response rate, duration of response, and overall survival were also included. The therapy, which contains nine beneficial strains of gut bacteria, met both its primary and secondary endpoints in the study, according to the company, although precise details will be released at a scientific conference later this year.

“There is increasing evidence that the microbiome plays a crucial role in patients’ response to immune checkpoint inhibitors. Clinical benefit has been reported with fecal microbiota transplantations, while MB097 capsules taken orally each day affords an easy and reproducible way of modifying the microbiome,” said the national coordinating investigator for the study, Pippa Corrie, MD, PhD, a clinician and researcher from Cambridge University Hospitals NHS Foundation Trust, in a press statement.

“The MELODY-1 study results show that MB097 is well tolerated, with encouraging early signs of efficacy in a very difficult to treat metastatic melanoma patient population with primary resistance to anti-PD-1 based immunotherapy, in whom there is a significant unmet need.”

Up to half of all advanced melanoma patients fail to respond to anti-PD-1 immunotherapy, leaving them with very few options. A growing body of research, including a 2021 study showing fecal transplant can overcome resistance to anti-PD-1 immunotherapy, shows that the gut microbiome plays an important role in whether a patient’s immune system mounts an effective anti-tumor response when given these therapies.

The make-up of MB097 is based on detailed research looking at strains of bacteria linked to effective response to immunotherapy. Preclinical work showed that the bacteria in the therapy directly activate cytotoxic T cells and counter immunosuppressive tumor macrophages. If larger controlled trials confirm these initial results MB097 could become a standard add-on to immunotherapy.

Microbiotica has another clinical program in ulcerative colitis, which also reported good results earlier this year in another Phase Ib trial. In total, 63% of those in the treatment group achieved clinical disease remission versus 30% in the placebo group and all were also taking standard therapy for the autoimmune disease.

The company now plans to move both its programs to larger controlled studies with a view to moving closer to market approval with both therapies.

The post Microbiome Therapy Could Help Drug-Resistant Melanoma Patients appeared first on Inside Precision Medicine.

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<![CDATA[Learn more about medication use in pregnancy and postpartum, including risks and benefit analysis.]]>
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<![CDATA[Planning for prevention of perinatal psychiatric relapse with safer medication options. ]]>
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Preclinical and Emerging Clinical Evidence Supporting the Translational Potential of GLP-1 Receptor Agonists for Treating Psychostimulant and Nicotine Use Disorders

Psychostimulant use disorder (PSUD) and nicotine use disorder (NUD) affect tens of millions of people worldwide, yet no clinically-approved medications exist for PSUD and existing NUD treatments have limited long-term efficacy. Recent preclinical evidence suggests that glucagon-like peptide-1 receptor (GLP-1R) agonists could be repurposed for treating PSUD and NUD. This review summarizes the current literature investigating the efficacy of GLP-1R agonists to reduce psychostimulant and nicotine-mediated behaviors in animal models of PSUD and NUD, respectively.

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RAGE Implicated in Worsening Breast Cancer Mortality with Age

Researchers at Georgetown’s Lombardi Comprehensive Cancer Center have identified a mechanism that may help to explain why older people experience worse outcomes from breast cancer. The study in different mouse breast cancer models and in human breast cancers implicates RAGE (receptor for advanced glycation end-products), a cell surface receptor that amplifies inflammatory signaling, and which also becomes increasingly active with metastatic progression. The study findings in addition suggested that inhibiting RAGE may offer a well-tolerated adjunctive breast cancer therapy in older patients.

“Our study addresses a major gap by showing that aging dramatically increases breast cancer metastasis and that this effect depends on RAGE, a receptor on the surface of cells that fuels inflammation,” said Barry Hudson, PhD, associate professor of oncology at Georgetown Lombardi. “Most laboratory studies rely on young mice, which has limited our understanding of how aging itself alters the host environment, including immune function and chronic inflammatory states that, in turn, influence cancer behavior.” Hudson is corresponding author of the researchers’ Communications Biology published paper titled “Aging promotes a RAGE-dependent increase in breast cancer metastasis.” In their paper the authors concluded that their findings “… identify RAGE as a mechanistic link between aging and metastasis and a potential therapeutic target in older patients.” They say the findings will also be featured in the Nature portfolio special collection, Cancer and Aging.

Age is the primary risk factor for the development of adult cancers, including breast cancer, with almost half of new breast cancer diagnoses and more than half of breast cancer-specific deaths occurring in women aged 65 years and older, the authors wrote. And while advances in screening and therapy have improved survival, older women continue to have higher breast cancer-specific mortality. “Despite accumulating evidence that metastasis in murine breast cancer models increases with advancing host age, the mechanisms underlying this have not been elucidated, highlighting the need for further mechanistic studies,” the team continued.

And while breast cancer is more prevalent in older women, most cancer research in mouse models has used young, 2–3-month-old adult mice, which are about equivalent in age to 15–20-year-old humans. Timing and chance presented Hudson and colleagues with opportunities to carry out their newly reported study. During COVID, when there was reduced laboratory activity, some of the research team’s mouse colonies aged longer than originally planned. This created a rare opening to study cancer in these older animals—normally a difficult and expensive endeavor—giving the scientists the ability to directly compare how tumors behave in younger versus older mice.

RAGE is a proinflammatory molecule that is being considered as a therapeutic target in multiple aging-related diseases, including various cancers, cardiovascular and neurodegenerative diseases.

Using three different mouse models of triple-negative breast cancer (TNBC), the researchers discovered that aged mice developed substantially more lung metastases than younger mice, despite similar primary tumor growth. The team then showed that genetic deletion of RAGE in mice almost completely eliminated this age-related surge in metastasis.

Through their studies, the team demonstrated that aging increased levels of inflammatory molecules that activate RAGE. These included the proteins S100 and HMGB1, found in both primary tumors and at metastatic sites. These changes made it easier for cancer cells to invade and spread. “These findings show that aging doesn’t just increase cancer risk—it actively changes the body in ways that help tumors spread,” said Hudson. “RAGE appears to be a key mediator of these harmful age-related pathways.” In their paper the authors stated that their data “… suggest that aging promotes multiple prometastatic processes within the tumor and its microenvironment, and that RAGE is required for the induction of these inflammatory and tumor-promoting pathways in aged hosts.“

The team also analyzed breast cancer data from more than 1,000 patients and found that higher expression of AGER (the gene encoding RAGE) and related inflammatory gene signatures were associated with worse outcomes in patients, supporting the clinical relevance of their findings. They noted, “… in human breast cancers, high AGER expression, as well as enrichment for mouse tumor-derived aging- and RAGE-associated gene signatures, predicted poorer outcomes, particularly in older women …Together, these data indicate that in older individuals with breast cancer, intratumor RAGE overexpression amplifies aging-associated transcriptional programs, linking age-dependent inflammation to promote metastatic progression.”

RAGE is already being explored as a therapeutic target in several age-related diseases, highlighting its potential relevance in cancer. In prior work, the researchers had shown that the RAGE inhibitor TTP488 (azeliragon) can suppress breast cancer metastasis in preclinical models. In the current study, they also tested the drug in the lab and found that TTP488 was able to reduce tumor cell invasiveness that was induced by blood sera from aged mice.” Pharmacologic inhibition of RAGE by TTP488 (PF-04494700 or azeliragon) suppressed migration and invasion towards aged serum, further supporting the requirement of RAGE signaling for age-dependent metastasis,” the team noted.

A clinical study is underway at Lombardi evaluating TTP488 in breast cancer patients receiving chemotherapy, with a focus on safety and cognitive outcome. The drug has demonstrated a favorable safety profile in people, making it an optimal choice for further study. “TTP488 has demonstrated an excellent safety profile in Phase I/II clinical studies in older adults with Alzheimer’s disease, supporting its potential for repurposing,” the authors wrote. “Therapeutic RAGE inhibition may provide a well-tolerated means to counteract inflammaging and improve cancer outcomes in the elderly, who often face limited treatment options due to toxicity,” the investigators wrote.

“This study highlights the importance of the host environment in cancer,” Hudson added. “While cancer is often viewed as driven primarily by mutations intrinsic to tumor cells, systemic factors such as aging and inflammation play a critical role in shaping how cancers behave,” said Hudson. “Most deaths due to cancer occur because tumors spread to other organs, so understanding these influences may help identify new strategies to limit metastasis.”

The post RAGE Implicated in Worsening Breast Cancer Mortality with Age appeared first on GEN – Genetic Engineering and Biotechnology News.

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PPG-Derived Digital Biomarker Developed for Peripheral Artery Disease Detection

A research team at the University of California, San Diego has developed a machine learning-based screening approach for peripheral artery disease (PAD) that uses a light-based technology called photoplethysmography (PPG) that can measure changes in blood volume in tissue. The researchers reported that short-duration PPG recordings in a patient’s toe, analyzed by machine learning models, identified PAD with a high degree of accuracy and may provide the basis for a scalable digital screening tool that could eventually be deployed through smartphones, pulse oximeters, and wearable devices. The team’s findings are published in npj Digital Medicine.

“PPG works by shining a light into tissue, in our case, the toe,” said co-first author Ava J. Fascetti, a PhD student in the digital health technology lab of senior author Edward J. Wang, PhD. “A photosensor measures how much light is reflected back, allowing us to detect tiny changes in blood volume: what we call the PPG signal.”

PAD is caused by plaque buildup in arteries that restricts blood flow, particularly to the legs and lower extremities. The disease affects an estimated 12 million Americans and 200 million adults worldwide. PAD substantially increases the risk of limb loss and major cardiovascular events, yet many patients are not diagnosed until later stages of disease progression. The researchers noted that the condition disproportionately affects underserved populations and is underdiagnosed in part because the current standard diagnostic, ankle-brachial index (ABI), requires specialized equipment, staff, and clinic visits.

“There exists a glaring unmet clinical need to develop technology to meet the demands of modern practice,” the researchers wrote. Further, ABI testing, introduced about 60 years ago, has has remained largely unchanged and has long-standing barriers to widespread use in primary care and under-resourced settings.

The current study originated from discussions between co-first author Mattheus Ramsis, MD, and assistant professor of medicine and medical director of cardiology informatics, and co-author Elsie G. Ross, MD, an associate professor of surgery in vascular and endovascular surgery, who noted that vascular labs conducting ABI testing often also collected toe PPG waveforms.

“The light-bulb went off for me at that moment,” Ramsis said.

PPG works by shining light into tissue and measuring backscattered light associated with blood volume changes. PPG has previously been used to identify cardiovascular and metabolic conditions including diabetes and atrial fibrillation. Earlier research efforts to use PPG for PAD detection had relied on small datasets, long recordings and less interpretable deep-learning approaches.

For their approach, the UCSD team assembled a dataset containing more than 10,000 toe PPG recordings from more than 3,500 patients who underwent ABI testing at UC San Diego Health between 2020 and 2025. Using these data, the researchers extracted 78 waveform features from the PPG signals that correlated significantly with ABI measurements. Those features were then used to train an explainable support vector machine model designed to identify PAD from PPG data alone.

Ramsis said the model correctly distinguished PAD cases approximately 83% of the time using only PPG data, compared with roughly 60% to 65% performance typically achieved using clinical risk-factor assessments alone. Incorporating smoking status of the patients further improved the performance of the new method.

Importantly, the model performed consistently across Black, Hispanic, and White patient populations, and among patients with diabetes, coronary artery disease, and end-stage renal disease. The researchers also reported similar performance across two UC San Diego Health campuses that used different equipment and staff.

The investigators noted that the physiologic basis for their findings align with established vascular biology. In PAD, reduced blood flow and arterial stiffness alter the morphology of PPG waveforms. Healthier patients demonstrated steeper systolic upstrokes and narrower waveform widths, while patients with PAD showed more dampened signals.

“Our findings support the existence of a reproducible PPG-derived digital biomarker that captures peripheral vascular pathophysiology relevant to ABI-defined PAD,” the researchers wrote.

The researchers said they don’t think their new model should replace ABI testing. Instead, they envision PPG screening as a complementary tool that could serve to identify patients earlier that might need further vascular evaluation.

The team said prospective deployment studies are already underway to evaluate performance in clinical settings and across additional reference standards, including toe pressure measurements, ultrasound imaging, and angiography. Additional research will also gauge performance in consumer-grade environments, including smartphones and wearable devices, and assess how the screening tool functions in broader patient populations outside specialized vascular clinics.

“If we can catch PAD early enough to prevent a limb amputation, that would be the ultimate impact: preserving limb function, reducing mortality, and addressing barriers in underserved populations,” Ramsis said.

The post PPG-Derived Digital Biomarker Developed for Peripheral Artery Disease Detection appeared first on Inside Precision Medicine.

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Antibody-Drug Conjugate Shows Activity in Hard-to-Treat Uterine Cancer

A Phase II clinical trial led by researchers at Yale School of Medicine and Yale Cancer Center has found that the antibody-drug conjugate sacituzumab govitecan, also known as Trodelvy, demonstrated encouraging clinical activity in patients with recurrent uterine cancer who had already exhausted several standard treatment options.

The findings, published in Clinical Cancer Research, suggest the therapy could become an important new option for patients with advanced endometrial cancer after chemotherapy and immunotherapy stop working.

A difficult disease to treat after relapse

Endometrial cancer is the most common gynecologic cancer in the United States, and rates continue to rise worldwide. While recent advances in immunotherapy have improved treatment for some patients, options remain limited once the disease returns after platinum-based chemotherapy or checkpoint inhibitor therapy.

Patients with recurrent disease often face poor outcomes, particularly those with aggressive tumor types such as uterine serous carcinoma and carcinosarcoma. Standard second-line chemotherapies typically produce modest response rates and short-lived disease control.

Researchers therefore wanted to investigate whether sacituzumab govitecan could improve outcomes in this challenging setting.

How the drug works

Sacituzumab govitecan belongs to a newer class of targeted therapies known as antibody-drug conjugates, or ADCs. These drugs combine an antibody that recognizes cancer cells with a chemotherapy payload designed to destroy them.

In this case, the therapy targets Trop-2, a protein commonly overexpressed in several aggressive cancers, including many uterine tumors. Attached to the antibody is SN-38, the active metabolite of irinotecan, a well-known chemotherapy drug.

By delivering chemotherapy directly to Trop-2–expressing cancer cells, researchers hope to increase anti-tumor activity while limiting damage to healthy tissue.

The drug is already approved for metastatic breast cancer and urothelial cancer, but remains investigational in uterine cancer.

Trial included heavily pretreated patients

The study enrolled 50 patients with recurrent or persistent endometrial cancer between 2020 and 2024. All participants had previously received platinum-based chemotherapy, and many had also undergone treatment with immune checkpoint inhibitors such as pembrolizumab or dostarlimab.

The study population represented a particularly difficult-to-treat group. Most patients had aggressive tumor histologies, including serous carcinoma, carcinosarcoma, or grade 3 endometrioid disease. Patients had received a median of two prior treatment regimens, with some undergoing as many as four lines of therapy before entering the study.

Encouraging responses and survival data

The trial met its primary endpoint, achieving an objective response rate of 28%. Two patients experienced complete responses with no detectable cancer remaining, while another 12 patients achieved partial responses with substantial tumor shrinkage.

In total, more than 70% of evaluable patients experienced some degree of tumor reduction during treatment. The study also reported durable responses, with a median response duration of 9.3 months. Several patients were still responding at the time of analysis.

Median progression-free survival reached 5.5 months, while median overall survival was 17.5 months in this heavily pretreated population.

Researchers also noted that responses were observed across multiple tumor subtypes rather than being limited to one specific histology.

“The results of our Investigator Initiated Trial complement and extend the TROPiCS-03 Trial results by demonstrating significant clinical activity of SG not only against the most common histological types of uterine cancer (endometrioid tumors) but also in patients harboring biologically aggressive endometrial tumors such as uterine serous carcinoma and carcinosarcoma,” said Alessandro Santin, MD, the study’s lead author.

Side effects remained manageable

As expected with potent cancer therapies, treatment-related side effects were common. The most frequent severe toxicities included neutropenia, anemia, fatigue, diarrhea, and febrile neutropenia.

However, investigators reported that most adverse events were manageable using supportive care measures such as growth factor support, anti-diarrheal medications, hydration, and dose adjustments. No treatment-related deaths were reported during the trial.

Looking ahead

The researchers cautioned that the study was relatively small and lacked a randomized comparison arm. Nevertheless, the results add to growing evidence supporting sacituzumab govitecan in advanced endometrial cancer, particularly for patients who have limited options remaining after standard therapies fail.

A larger international Phase III study is already underway to compare the drug directly against standard chemotherapy in patients with recurrent endometrial cancer following platinum chemotherapy and immunotherapy.

The team also highlighted future possibilities for combining the therapy with immunotherapy approaches, particularly because the drug’s chemotherapy payload may help stimulate anti-tumor immune responses.

“This is a major bench-to-bedside accomplishment for patients with uterine cancer,” Santin said.

 

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