Category: 8. Health

The burgeoning interest in psychedelic-assisted therapies for depression has propelled psilocybin to the forefront of psychiatric research and policy debate. Although granted FDA breakthrough therapy designation for treatment-resistant depression (TRD) in 2018 and major depressive disorder (MDD) in 2019, psilocybin has faced scrutiny for the methodological challenges it presents in clinical trials, particularly regarding blinding and patient expectancy.¹

In a recent meta-analysis published in JAMA Network Open, Hieronymus et al explored these concerns by examining whether control group outcomes in psilocybin trials differ meaningfully from those in trials of 2 more established treatments: selective serotonin reuptake inhibitors (SSRIs) and esketamine (Spravato; Janssen Pharmaceutical).² The findings have broad implications for clinicians, payers, and regulators seeking to interpret antidepressant efficacy claims in a postpandemic mental health landscape that has become increasingly receptive to psychedelic interventions.

Objective and Rationale

Psilocybin has demonstrated acute antidepressant efficacy in several clinical trials, with standardized effect sizes often exceeding those of conventional therapies. However, concerns have been raised about the degree to which these results may be influenced by “functional unblinding,” where the psychoactive effects of psilocybin make it obvious to participants and clinicians who is receiving the active treatment. This can compromise the integrity of control conditions and inflate treatment effects via expectancy bias or nocebo responses in control participants. To probe this issue, Hieronymus et al compared standardized mean changes (SMCs) and standardized mean differences (SMDs) across 17 randomized controlled trials (RCTs) using the Montgomery-Åsberg Depression Rating Scale (MADRS) as the primary outcome measure.

Meta-Analytic Comparison Across Three Drug Classes

Hieronymus et al synthesized data from 4 psilocybin trials (n=373), 2 esketamine trials (n=573), and 11 SSRI trials (n=4014). Eligible trials were selected based on predefined criteria including adult patient populations aged 18 to 65 years, use of the MADRS scale, double-blind design, and trial durations of 2 weeks or longer. Control treatments included inert placebo, low-dose psilocybin, or niacin in psilocybin trials; oral antidepressant plus intranasal placebo in esketamine trials; and placebo pills in SSRI trials.

Data extraction focused on within-group changes (baseline to end point) and between-group differences. Effect sizes were calculated using raw score standardization. To test whether the type of study population (psilocybin, SSRI, or esketamine) moderated outcomes, the authors used the Omnibus Test of Moderators (QM) and calculated the proportion of variance explained (R²).

Key Findings: Psilocybin Control Outcomes Lag Behind

The most striking finding was that control group outcomes in psilocybin trials were significantly worse than in SSRI and esketamine trials:

• Control group SMCs were 0.50 (SE = 0.15) for psilocybin, compared with 1.00 (SE = 0.08) for SSRIs and 1.12 (SE = 0.17) for esketamine.
• Active treatment SMCs were comparable across drug classes: 1.21 for psilocybin, 1.28 for SSRIs, and 1.43 for esketamine.
• Between-group SMDs were 0.70 (psilocybin), 0.30 (esketamine), and 0.27 (SSRIs), suggesting that psilocybin trials reported the largest apparent treatment effects, largely because of poorer control arm outcomes.

Importantly, study population type was a significant moderator for both between-group effect sizes (QM = 10.7; P = .005) and control treatment SMCs (QM = 10.4; P = .005), but not for active treatment SMCs (QM = 1.21; P = .55). In other words, the differences in trial results were driven by how well control participants fared, and not by differences in how well the active treatments performed.

Response and Attrition Rates

When looking at response rates (defined as ≥50% reduction in MADRS scores from baseline), only 19% of control participants in psilocybin trials responded, compared with 33% in SSRI trials and 42% in esketamine trials. Active treatment response rates were more consistent across drug classes as well at 48% (psilocybin), 46% (SSRIs), and 52% (esketamine).

Dropout rates also varied substantially. SSRI trials had the highest attrition, with 32% and 35% dropout in active and control arms, respectively. Psilocybin (5% active; 11% control) and esketamine (12% active; 8% control) trials reported much lower dropout rates, likely reflecting their shorter duration and more intensive participant engagement.

Interpreting Psilocybin’s Effect Size in Context

These findings suggest that the apparent superiority of psilocybin in clinical trials may be due in part to underperformance in control conditions. This could reflect either methodological bias (eg, inadequate blinding) or sampling bias (eg, enrolling patients with unusually low responsiveness to control treatments). The authors note that functional unblinding is more difficult to avoid with psychedelic interventions in which psychoactive effects are both immediate and conspicuous.

Importantly, while esketamine shares some administration similarities with psilocybin—including being given under supervision and causing acute perceptual effects—it did not exhibit the same level of control group underperformance. This implies that psilocybin trials may be uniquely vulnerable to expectancy-related biases.

Methodological Limitations and Heterogeneity

The primary limitation of the study is its inability to determine the causes behind the observed differences in control group outcomes across the 3 drug classes—psilocybin, esketamine, and SSRIs. While the meta-analysis clearly demonstrated that participants in psilocybin trials experienced significantly less improvement in depression scores in the control arms compared with those in SSRI and esketamine trials, the reasons for this disparity remain unresolved. Contributing to this uncertainty is the limited and heterogeneous nature of the psilocybin literature available; there are only 4 psilocybin trials available for analysis, compared with 11 SSRI trials and 2 esketamine trials.

Although the comparator groups (SSRIs and esketamine) are not exhaustive of all antidepressant options, their control group outcomes—SMC of 1.00 for SSRIs and 1.12 for esketamine—were consistent with previous meta-analytic findings. One notable methodological consideration was the inclusion of study findings from Carhart-Harris et al, which compared 25 mg of psilocybin with a combined regimen of 1 mg psilocybin plus the SSRI escitalopram (Lexapro; Forest Laboratories, Inc), rather than an inert placebo.^2,3 Hieronymus et al noted that this study was retained in the analysis for 2 reasons: first, because escitalopram is expected to be at least as effective as a placebo; and second, because the control group in this trial showed the largest pre- to posttreatment improvement among the 4 psilocybin studies.² Furthermore, excluding this trial would have resulted in an even lower pooled control group effect size for psilocybin. Importantly, sensitivity analyses that omitted this trial did not materially change the overall results, reinforcing the robustness of the findings.

The meta-analysis also excluded studies involving older adults or those with acute suicidality, which limits generalizability. Notably, a post hoc analysis of 3 esketamine trials in patients with suicidal ideation showed an unusually high control group response (SMC = 1.87), supporting the idea that baseline severity and acuity may modulate placebo responsiveness.

Conclusion

As enthusiasm grows for psychedelic-assisted treatments in mental health care, the findings of this meta-analysis underscore the importance of critically assessing the methodological context in which psilocybin’s antidepressant efficacy has been evaluated. While psilocybin continues to show promise in reducing depressive symptoms, Hieronymus et al explain that its large observed effect sizes may be partially driven by unusually poor outcomes in control groups rather than superior performance of the active intervention itself. Specifically, control participants in psilocybin trials demonstrated significantly lower response rates (19%) and smaller symptom improvements (SMC = 0.50) compared with those in SSRI (SMC = 1.00) and esketamine (SMC = 1.12) trials, suggesting a unique vulnerability to expectancy bias and functional unblinding.

These findings raise caution for stakeholders considering broad clinical or formulary adoption of psilocybin. For regulators and payers, they highlight the need for more rigorous trial designs—particularly those that minimize unblinding and address patient expectations—to ensure that efficacy signals are not overstated. Additionally, the limited number and heterogeneity of psilocybin trials to date underscore the need for further research using diverse and representative patient populations. Until such evidence emerges, claims about psilocybin’s broad effectiveness in depression should be interpreted with careful attention to trial context and control group performance.

REFERENCES
1. Heal DJ, Smith SL, Belouin SJ, Henningfield JE. Psychedelics: threshold of a therapeutic revolution. Neuropharmacology. 2023;236:109610. doi:10.1016/j.neuropharm.2023.109610

2. Hieronymus F, López E, Werin Sjögren H, Lundberg J. Control group outcomes in trials of psilocybin, SSRIs, or esketamine for depression: a meta-analysis. JAMA Netw Open. 2025;8(7):e2524119. doi:10.1001/jamanetworkopen.2025.24119

3. Carhart-Harris R, Giribaldi B, Watts R, et al. Trial of psilocybin versus escitalopram for depression. N Engl J Med. 2021;384(15):1402-1411. doi:10.1056/NEJMoa2032994

Regular walks may be a simple but effective way to protect thinking and memory, especially for people who have a gene that increases their risk of Alzheimer’s disease.

“Exercise is a great way to improve cognitive function — how we think and remember things — and in this study, the benefit seemed to be greater in APOE e4 carriers, though everyone benefited to some extent,” says the senior study author, Cindy Barha, PhD, an assistant professor of neuroscience at the University of Calgary and the Canada Research chair in neuroscience, brain health, and exercise.

How Do Genes Affect Alzheimer’s Risk?

Everyone carries some variant of the APOE (apolipoprotein E) gene, which plays a role in transporting cholesterol and other types of fat in the bloodstream. Breakdowns in this system are thought to contribute to the development of Alzheimer’s.

Tuberculosis (TB) is a persistent public health challenge in India; the country accounts for 28 percent of the global TB burden. The risk of TB transmission poses a particular challenge in urban poor community environments, where overcrowding, poor sanitation, inadequate nutrition, and limited access to health care services elevate the risk of TB infection by nearly five-fold. Reaching people in these communities requires fit-for-purpose solutions that are responsive to community needs and preferences.

Some of the best resources to combat TB can be found within communities themselves. In India, there are multiple frontline health care worker (FLHCW) cadres who are trusted by the community and well-positioned to provide care and referrals. These include Community Health Officers, Auxiliary Nurse Midwives, Accredited Social Health Activists (ASHAs), informal providers, and private-sector pharmacists. In some areas in India, FLHCWs serve as the initial point of care for roughly two-thirds of individuals with TB symptoms.

Additionally, vulnerable youth aged 18–34 represent an important group who can contribute to TB prevention and care. They account for 27 percent of India’s population, but bear 38 percent of the TB burden. Youth have enormous potential and energy to engage their communities and influence their peers. In one survey, nearly one-third of youth respondents said they were interested in volunteering in TB prevention activities.

Both FLHCWs and youth, however, frequently lack knowledge about TB and the specific actions they can take to connect people to care and combat TB stigma. This can limit the potential of both groups to impact the TB epidemic.

In response, the “Take Charge Against TB” project was designed and implemented to achieve TB-free urban poor communities through the dual activation of FLHCWs and youth populations, who are well placed to raise TB awareness and link people with symptoms to care. This project, a public health initiative of Johnson & Johnson in collaboration with PATH and TB Alert India, and in strategic partnership with India’s National TB Elimination Programme, was implemented across the three cities of Delhi, Hyderabad, and Pune from January–June 2025.

The “Take Charge Against TB” goals were to strengthen health system capacity by upskilling FLHCWs to accelerate early diagnosis, and to improve health care seeking and linkage to care by mobilizing youth populations to support FLHCWs in these efforts.

Cardiovascular disease remains a crisis in the United States, and at a recent webinar from The American Journal of Managed Care^® in association with the American Society of Preventive Cardiology, researchers and clinicians confronted the persistent gaps in prevention. Watch the full recording of the discussion.

The discussion, moderated by Viet Le, PA-C, associate professor of research at Intermountain Health, revealed a field in transition that includes a new understanding of the interconnected risks for cardiovascular disease from kidney health and metabolic dysfunction.

“Cardiovascular disease itself…has this long fuse,” Le said. “I think of that, because the question always is, how do we have patients understand [the importance of] lifestyle changes, etc, and it can be hard to see those risks when that fuse is so long, so far ahead.”

Martha Gulati, MD, MS, FACC, FAHA, FASPC, FESC, Cedars-Sinai Medical Center

While clinicians have appreciated the interconnectedness of cardiovascular-kidney-metabolic health for a while, an exciting change has been the development of drugs to change this risk, explained Martha Gulati, MD, MS, FACC, FAHA, FASPC, FESC, cardiologist at the Cedars-Sinai Medical Center Schmidt Heart Institute, professor of cardiology and associate director of the Barbra Streisand Women’s Heart Center, and director of cardiovascular disease prevention.

Addressing prevention of cardiovascular disease takes more of a team effort now, with cardiologists working with endocrinologists, nephrologists, and liver specialists instead of treating patients in silos, she said.

“I do think that all cardiologists need to be identifying who’s at risk. Whether everybody’s going to be comfortable with treating this disease is a completely different discussion,” Gulati said. “Because I think what, hopefully, will happen, given the evolution of this field, is that preventive cardiologists are going to be more appreciated. I think it is really becoming a specialty unto itself.”

She added that training people as preventive cardiologists means thinking about the disease in a new way, such as watching patients with calcium in their coronary arteries or aorta, because this now puts them into a stage that can progress.

Alison Bailey, MD, FACC, FASPC, of Centennial Heart

Starting on prevention for patients who are at risk runs into 2 main barriers: inaction and lack of access to care. Alison Bailey, MD, FACC, FASPC, chief of cardiology at Centennial Heart and a physician director of cardiovascular disease for HCA Healthcare, explained that often cardiologists will meet patients after they have an event or have already been dealing with uncontrolled hypertension or lipids for 2 decades.

“Instead of meeting these people up front, when we really could make more of a profound impact, we’re meeting them sort of on the tail end, after they have established disease,” she said. “I would say it’s never too early to get a referral…”

As someone who works in the South, Bailey often sees how big the challenge of access to care is in rural areas. Not only do these patients have trouble finding a physician or care team to go see, but they may also lack insurance or be underinsured, which are big barriers when dealing with lifetime, chronic disease.

Cardiovascular Risk Factors

Lipoprotein(a) (Lp[a]) is an emerging risk factor that has become a hot topic in the preventive cardiovascular space in recent years because it is 6 times more atherogenic—meaning it contributes to the development of atherosclerosis and cardiovascular disease—than low-density lipoprotein (LDL). However, a very small number of patients actually get tested for Lp(a).¹

Nathan Wong, PhD, MPH, FACC, FAHA, FNLA, FASPC, of University of California, Irvine

However, updated guidelines from the National Lipid Association² call for adults to get tested at least once in their lifetime, which should help raise awareness, said Nathan Wong, PhD, MPH, FACC, FAHA, FNLA, FASPC, professor and director of the Heart Disease Prevention Program at the Mary & Steve Wen Cardiovascular Division and codirector of the Center for Global Cardiometabolic Health and Nutrition at the University of California, Irvine.

“We know that people who get tested—there’s some data published showing that this does seem to motivate greater initiation of lipid-lowering therapy and other preventive practices,” he said.

For children with a family history of cardiovascular disease or familial hypercholesterolemia, they should get tested in later childhood or adolescence, Wong said. Gulati added that while most people only need to be checked once in their life, women should get rechecked if they were borderline once they go through menopause, because there is an increase in Lp(a).

Bailey noted that some people don’t want to check Lp(a) at all because they think it’s not actionable, but she thinks it is even if there aren’t specific therapies available, but there are multiple therapies on the horizon.

The urine albumin-creatinine ratio is another emerging risk factor. It looks at protein in urine, and there are therapies that can be initiated if it is elevated, she explained. Coronary calcium is also a marker of future risk, which can be modified with statin therapy.

However, risk assessments are limiting, and it’s important to personalize risk assessments to the person in front of you, Gulati said. She sees a lot of young women, and “regardless of the tool I use, if you’re under 40 [years old], you’re low risk. It just doesn’t matter. You can plug in the worst numbers for every risk factor, and they will still be low risk.”

Addressing Risk Factors

Patients with cardiovascular risk factors mostly know the right things to do and want to do the right things, such as eat healthy and exercise. However, there are many reasons why patients cannot exercise or eat healthy, and they may get overwhelmed when they’re told to make lifestyle changes and also start medication.

“We might be able to say things like, ‘Eat less, move more,’ but are we as good at prescribing it?” wondered Gulati. “Are we really good at making people understand the diet and how they should be focusing and how to implement exercise?”

Telling a patient that they need to do 150 minutes of exercise may sound like too much, but they could start with just 5 minutes every day and build from there. It’s also important to give them additional resources, such as going to a dietitian or an exercise physiologist or finding a community program they can join. Clinicians cannot change a patient’s environment or create safe places, but they can find what does exist and how it can benefit the patient.

However, these preventions are not always covered by insurance. Cardiac rehab for patients with cardiovascular disease who meet certain criteria could be covered, and Gulati said she’s had success getting a dietitian covered. Getting trainers and referrals to exercise physiologists that are covered for primary prevention is harder.

“I always tell people to go back and talk, call their insurer, and say, ‘What do you cover in terms of my wellness?’ You’ll be surprised,” she said. “There’s more of that these days than there was, but it’s still lacking.”

Wong noted there’s a need to get medical nutrition therapy better covered, and he has hope that legislation could expand it beyond mostly just patients with diabetes.

A lot of health savings accounts will cover gym membership or trainers, though, Bailey said. She also recommends patients utilize health apps more to track their activity and stay accountable. She echoed Gulati’s point that 5 minutes of exercise daily is better than zero minutes.

“Optimal should never, ever be the opposite of what is achievable and what we can do today,” Bailey said. “And you know, when we’re looking at population health…if we can get that group of people who does zero minutes of activity, doing 10 [minutes of] activity, we probably would make way more [progress] to our goal of preventing disease than getting people going from 20 [minutes] to 30 [minutes], or 30 [minutes] to 50 [minutes], or 50 [minutes] to 75 [minutes], and so I think those small changes are important.”

References

1. Bansal A, Cho L. Prevalence of lipoprotein(a) testing in a contemporary cohort. Circulation. 2025;151(9):649-651. doi:10.1161/CIRCULATIONAHA.124.070361

2. Koschinsky ML, Bajaj A, Boffa MB, et al. A focused update to the 2019 NLA scientific statement on use of lipoprotein(a) in clinical practice. J Clin Lipidol. 2024;18(3):e308-e319. doi:10.1016/j.jacl.2024.03.001

A notable association between chronic kidney disease (CKD) and gastroesophageal reflux disease (GERD) has been identified by a comprehensive meta-analysis involving over 4 million individuals.

The study, published in the Saudi Journal of Gastroenterology, showed a higher prevalence of GERD among people living with CKD, supporting the need for increased awareness and potential screening in this population.¹

Patients with CKD commonly experience upper gastrointestinal dysfunction—including delayed gastric emptying and reduced small bowel secretions and absorption—likely linked to gut barrier disruption and endotoxemia rather than disease severity or hydration status.²

Researchers conducted a systematic review and meta-analysis of 9 studies. These studies, which included cross-sectional and case-control designs, encompassed a total of 4,650,709 participants. The objective was to evaluate the prevalence of GERD in people with CKD and to determine the strength of the association between the 2 conditions.

The systematic search spanned major databases from their inception up to November 2024. After an initial identification of 1821 studies and subsequent thorough screening, 9 studies met the inclusion criteria for the qualitative and quantitative synthesis. The included studies were geographically diverse, originating from the US, India, Taiwan, China, Iran, and the Philippines. The diagnosis of GERD in these studies was confirmed through various methods, including endoscopy, validated questionnaires, or official health databases.

Key findings from the meta-analysis revealed a pooled prevalence of GERD among people with CKD of 18% (95% CI, 10%-26%). This figure, while varying across individual studies, consistently pointed to a presence of GERD within the CKD community. For instance, prevalence rates ranged from 36.8% in a Korean study to 16% in an Indian study.

Furthermore, the analysis demonstrated a statistically significant association between CKD and GERD. The pooled crude OR for this association was calculated to be 2.53 (95% CI, 1.30-4.92). When adjusted for potential confounders, the pooled adjusted OR was 1.48 (95% CI, 1.05-2.08), indicating that people with CKD were nearly 1.5 times more likely to experience GERD compared with those without CKD.

While the exact pathophysiological mechanisms linking CKD and GERD remain an area for further research, the study’s discussion highlighted several proposed contributing factors. These included delayed gastric emptying, which can lead to prolonged exposure of the esophagus to stomach acid, and uremia, a condition associated with impaired kidney function. Other potential factors discussed were altered gastrointestinal motility, elevated gastrin levels, electrolyte imbalances, and endocrine disorders such as hyperparathyroidism.

The researchers acknowledged limitations in their study, particularly the high heterogeneity among the included studies, which suggested variations in diagnostic methods or study designs. They also noted the inherent risk of bias in observational studies, where certain confounding variables might not have been fully controlled. Despite these limitations, the authors concluded that the meta-analysis confirmed a marginally significant association between CKD and GERD.

The study author called for health care practitioners to consider screening for GERD symptoms in individuals diagnosed with CKD. This proactive approach could facilitate early detection and intervention, ultimately aiming to improve the quality of life for people living with chronic kidney disease. The authors emphasized the need for additional prospective studies to further elucidate the underlying mechanisms and to inform targeted interventions.

The authors concluded, “Given these findings, healthcare practitioners are advised to consider screening for GERD symptoms in individuals diagnosed with CKD. This facilitates the early detection of GERD and emphasizes the necessity for ongoing research to inform targeted interventions and improve quality of life of individuals with CKD.”

References

1. Chaponan-Lavalle A, Godoy A, Estrada-Grossmann JM, et al. Relationship between gastroesophageal reflux and chronic kidney disease: a meta-analysis of 4 million patients. Saudi J Gastroenterol. 2025;31(4):206-211. doi:10.4103/sjg.sjg_133_25

2. Grant CJ, Harrison LE, Hoad CL, et al. Patients with chronic kidney disease have abnormal upper gastro-intestinal tract digestive function: a study of uremic enteropathy. J Gastroenterol Hepatol. 2017 Feb;32(2):372-377. doi:10.1111/jgh.13458

New study findings presented at the Society of NeuroInterventional Surgery’s (SNIS) 22nd Annual Meeting assessed whether glucagon-like peptide-1 (GLP-1) receptor agonists could lessen the impacts of stroke and related brain injuries or ultimately reduce the risk of stroke. If confirmed, treatment with common GLP-1s like semaglutide (Ozempic; Novo Nordisk) could aid the impacts of stroke and related brain injuries.¹

“More research is certainly needed, but seeing the potential protection offered by these medications is a fascinating finding,” said Ahmed Elbayomy, MD, a research fellow and data scientist in the Department of Neurological Surgery at the University of Wisconsin–Madison and primary author of 2 of these studies, in a news release.¹

Overview of GLP-1s

GLP-1s are commonly used to help lower blood sugar levels and promote weight loss in individuals with type 2 diabetes and obesity. Commonly used GLP-1s that are FDA approved for weight management include semaglutide (Ozempic; Novo Nordisk), dulaglutide (Trulicity; Eli Lilly and Company), and tirzepatide (Mounjaro; Eli Lilly and Company), which is a GLP-1 and gastric inhibitory polypeptide (GIP) receptor agonist.²

GLP-1s Used for Stroke Risk

Study 1

In the first study, researchers from the University of Wisconsin-Madison included data from patients at the medical center at the university and a global health collaborative. Together, the researchers aimed to assess whether patients using semaglutide who experience strokes have better outcomes compared with individuals who are not treated with semaglutide.¹

A total of 2,021,704 individuals who had strokes were included, with 43,338 of those individuals also on semaglutide from the global dataset. The University of Wisconsin medical center dataset included 13,510 individuals who presented strokes, with 190 of those individuals on semaglutide.¹

The results demonstrated that in both study groups, death from stroke was lower among individuals who were treated with semaglutide. Specifically, in the global dataset, 5.26% of semaglutide users faced mortality from their strokes compared to 21.6% of individuals who were not treated with semaglutide. For the medical center database, 5.6% of semaglutide users died from strokes compared with 26.57% of non-users. Also from the global database, researchers noted that 77.5% of semaglutide users had a chance of surviving strokes long term compared to 30.95% of nonusers.¹

Study 2

The second study was also from the University of Wisconsin-Madison, including a large nationwide sample of emergency department records from individuals who had strokes and individuals who were likely being treated with semaglutide. While full data was not explored, the study authors noted that they noticed a trend in a reduced odds of stroke among individuals who were potentially being treated with semaglutide. However, they noted that further research evaluating data directly from pharmacies to confirm semaglutide users would enhance the findings.¹

Study 3

In the third study from the University of Texas Medical Branch in Galveston, researchers evaluated if GLP-1s could improve outcomes for individuals after brain hemorrhages and strokes. The research focused on both spontaneous bleeds and those due to brain aneurysm rupture. After reviewing patient records from 6 months and 12 months after each brain hemorrhage and 1 year and 2 years after each stroke, they found that the use of GLP-1s was linked to a reduced risk of cognitive adverse effects, seizures, future brain hemorrhages, and death.¹

The findings suggest that GLP-1s could aid stroke prevention and reduce brain injury-related complications. However, further research is needed to confirm the findings.¹

“This research could introduce a new perspective to the discussion of preventing and mitigating the devastating effects of stroke and related brain injuries,” Matias Costa, MD, from the neurosurgery department at the University of Texas Medical Branch and author of the third study, concluded in the news release.¹

REFERENCES

1. Weight loss drugs like Ozempic may help prevent stroke and reduce brain injury-related complications, studies show. EuerkAlert! News release. July 17, 2025. Accessed July 31, 2025. https://www.eurekalert.org/news-releases/1091021

2. GLP-1 Agonists. Cleveland Clinic. News release. July 3, 2025. Accessed July 31, 2025. https://my.clevelandclinic.org/health/treatments/13901-glp-1-agonists

Hereditary hearing loss continues to affect millions, with over 150 genes implicated in congenital or early-onset deafness. Gene therapy holds promise to treat hereditary hearing loss, but while there has been progress, challenges remain, according to the authors of a recent review published in Sensory Neuroscience.¹

Three major gene therapy approaches to address underlying disease mechanisms include gene replacement, in which functional copies of mutant genes are delivered via viral vectors, most commonly AAV (adeno‑associated virus) vectors; gene suppression, which uses RNA interference or antisense oligonucleotides to down‑regulate dominant or toxic alleles; and gene editing, which uses CRISPR/Cas‑based or base editing to correct specific pathogenic mutations.

These approaches are each matched to underlying disease mechanisms. For example, gene replacement is used for recessive loss-of-function mutations, gene suppression for dominant-negative variants, and gene editing where precise correction is feasible.

“Although cochlear implants can significantly improve hearing, there is currently no drug therapy capable of restoring natural hearing in hereditary hearing loss,” the authors wrote. “In recent years, gene therapy has emerged as a promising strategy for addressing inner ear dysfunction.”

Preclinical studies in rodent models have shown promise, with the authors highlighting an example of base editing in the OTOF gene (a frequent cause of DFNB9 deafness), which restored otoferlin protein expression in approximately 88% of inner hair cells and resulted in sustained auditory response recovery for more than 1.5 years in mice without detectable off‑target effects.

Early-phase clinical trials are also in progress, with AAV-mediated OTOF gene replacement being applied unilaterally and bilaterally in pediatric patients with DFNB9, resulting in improved auditory brainstem responses and speech perception thresholds within weeks to months post-injection.²

Gene suppression strategies using RNA interference or antisense therapies have also shown potential to slow progression in dominant‑negative TMC1 mouse models, and gene editing platforms like CRISPR/Cas offer precise correction or allele-specific targeting in preclinical research.¹

Despite the promise, important challenges remain. Efficient therapy delivery to the inner and outer hair cells is one challenge, especially in mature cochleae. Optimized viral vectors and surgical methods are needed to achieve safe transduction, the authors explained.

Treatment timing is another issue, as animal studies have mostly been conducted early in development. However, human inner ear development happens prenatally, and this gap must be bridged to ensure therapies will also be effective in developed ears. Another challenge is ensuring safety and minimizing off-target effects of gene therapy. Long-term efficacy is a main goal of these therapies, but unintended effects such as off-target editing or immune responses are ongoing concerns.

From the manufacturing perspective, there are significant barriers to bringing a gene therapy to market, including producing good‑manufacturing‑practice viral vectors, characterizing therapy dosing, and navigating regulatory approval. “A comprehensive understanding of treatment side effects, including lifespan assessment and immune response evaluation, is essential for advancing gene therapy in this field,” the authors wrote.

With multiple gene therapies now transitioning into clinical testing and substantial preclinical data in animal models, gene therapy appears to be a promising approach for a subset of genetic deafness, the authors concluded. Still, standardizing protocols, ensuring safety, and expanding applicability beyond the most common genes will be critical next steps.

References

1. He W, Han S, Liu X, et al. Update on gene therapy in the treatment of hereditary hearing loss. Sensory Neuroscience. Published online May 7, 2025. doi:10.1002/sen2.70004

2. Wang H, Chen Y, Lv J, et al. Bilateral gene therapy in children with autosomal recessive deafness 9: single-arm trial results. Nat Med. 2024;30(7):1898-1904. doi:10.1038/s41591-024-03023-5

The emergence of the SARS-CoV-2 Omicron JN.1 lineage, classified as part of the KP.2 subvariant family, prompted urgent regulatory and public health responses to ensure continued protection against evolving COVID-19 viral threats.¹ In late 2024, updated mRNA vaccines targeting this lineage were authorized in the United States and Europe for use in the 2024-2025 booster campaign. Despite regulatory endorsement, real-world safety data on these variant-specific vaccines remained limited. To address this gap, a Danish cohort study conducted by Andersson et al and published in JAMA Network Open provides a comprehensive evaluation of 29 serious adverse events (AEs) following administration of JN.1-containing mRNA COVID-19 vaccines.²

This population-based study provides critical insights for clinicians, policy makers, and payers tasked with navigating vaccination strategies amid ongoing viral evolution and persistent vaccine hesitancy. By assessing safety outcomes in a large, at-risk population under real-world conditions, the findings can help to contextualize benefit-risk assessments and inform future immunization campaigns.

Study Design and Cohort Characteristics

This retrospective cohort study leveraged Denmark’s national health data infrastructure, linking records from the Danish Civil Registration System, Danish Vaccination Register, and the National Patient Register to monitor vaccine safety. The study population included all adults 18 years and older who met government criteria for receiving a JN.1-containing booster—specifically individuals 65 years and older or those categorized as high-risk due to comorbidities. To be eligible, participants were also required to have received at least 3 prior COVID-19 vaccine doses before the study start on May 1, 2024.

Of the 1,585,883 eligible adults, 1,012,400 received the updated JN.1 vaccine during the follow-up period ending March 31, 2025. The mean age of vaccinated individuals was 73.5 years, and the cohort was slightly more female (54.4%) than male. The majority (86.7%) were prioritized due to age rather than underlying high-risk conditions. Common comorbidities included chronic cardiac disorders (20.3% of vaccinated individuals), autoimmune conditions (8.5%), diabetes (6.4%), and malignancy (9.9%).

Outcomes and Statistical Methodology

The investigators focused on 29 predefined serious AEs of special interest (AESIs), compiled from sources including the Brighton Collaboration and FDA’s Biologics Effectiveness and Safety Initiative. These AESIs included cardiovascular conditions (eg, ischemic cardiac events, myocarditis), thrombotic events (eg, pulmonary embolism, deep vein thrombosis), neurological syndromes (eg, Guillain-Barré syndrome, seizures), autoimmune and inflammatory conditions (eg, type 1 diabetes, uveitis), and organ-specific failures (eg, acute liver failure, acute kidney injury).

Vaccination status was treated as a time-varying covariate. Each individual contributed person-time to both the “risk period” (the 28 days post vaccination) and “reference period” (person-time outside the 28-day window, beginning either at study start or ≥43 days after any vaccine dose). A 14-day buffer period (days 29-42) was excluded from analysis to mitigate time-related confounding.²

Outcomes were measured as the first recorded hospital contact for each AE. Poisson regression models were used to estimate adjusted incidence rate ratios (IRRs) comparing risk and reference periods. Models were adjusted for sex, age, region, vaccination priority status, calendar time, and number of comorbidities. Statistical significance was defined as a 95% CI not overlapping 1.

Key Study Findings

The central conclusion of the study is that no statistically significant increases in AE rates were observed in the 28 days following vaccination with the JN.1-containing mRNA vaccines. In fact, several IRRs suggested lower event rates during the risk period relative to the reference period, though causality should not be inferred from these associations, according to the study authors.

Notable results include the following:

• Ischemic cardiac events: IRR of 0.84 (95% CI, 0.76-0.94), suggesting a modest reduction in risk
• Cerebrovascular events: IRR of 0.84 (95% CI, 0.77-0.92), including a similar trend for transient ischemic attacks and infarctions
• Pulmonary embolism: IRR of 0.75 (95% CI, 0.62-0.90)
• Acute kidney injury: IRR of 0.67 (95% CI, 0.59-0.77)
• Myocarditis: IRR of 1.12 (95% CI, 0.41-3.10), not statistically significant, indicating no detectable increased risk
• Pericarditis: IRR of 0.42 (95% CI, 0.20-0.89), with fewer observed cases post-vaccination

Only a few outcomes, such as erythema multiforme and subacute thyroiditis, yielded wide CIs due to very low event counts, resulting in limited statistical precision. For 3 outcomes—cerebral venous thrombosis, transverse myelitis, and narcolepsy—no events occurred in the risk period, precluding estimation of IRRs. Importantly, the upper bounds of the CIs for 19 of the 29 AEs were inconsistent with even moderate (≥1.5-fold) increases in risk, reinforcing the conclusion that large safety signals are unlikely.

Contextualizing the Findings

These results build upon prior evaluations of earlier Omicron-adapted vaccines, including those targeting the BA.1, BA.4/5, and XBB.1.5 lineages, which similarly demonstrated no elevated risks for serious AEs. The JN.1 lineage, which rose to dominance globally in late 2024, shares spike protein mutations associated with immune escape, raising concerns about the need for vaccine updates. This study offers reassurance that updating vaccine composition to address antigenic drift has not compromised the safety profile of mRNA platforms.

From a managed care and public health perspective, these findings are crucial. As vaccination fatigue and hesitancy continue to impact booster uptake, particularly among older and high-risk populations, robust safety data remain vital to maintaining trust in public immunization programs. In Denmark, the timely rollout of updated boosters was guided by transparent national registry infrastructure and comprehensive eligibility criteria, enabling efficient pharmacovigilance and coverage estimation.

Recent preclinical research by Ao et al further supports the rationale for JN.1-specific updates, demonstrating that a JN.1-mRNA vaccine elicited robust, long-lasting humoral and cellular immune responses in animal models, with enhanced neutralizing activity against JN.1 and KP.3 variants. These findings highlight the adaptability of mRNA platforms and underscore the importance of timely reformulation to match emerging SARS-CoV-2 subvariants.³

Study Limitations

Andersson et al acknowledge several important limitations that may affect the interpretation of findings.² First, residual confounding remains a concern despite the use of within-individual comparisons to mitigate bias. Unmeasured factors, such as differences in health care–seeking behavior or temporal shifts in baseline health status, may still influence outcomes. Second, the study was underpowered to assess the safety of very rare events. For adverse outcomes such as transverse myelitis or Guillain-Barré syndrome, the low number of cases limited the statistical precision and precluded definitive risk estimation. Third, the relatively short follow-up period of 28 days after vaccination may not capture AEs with longer latency periods or delayed clinical onset. Finally, because the study population was restricted to adults eligible for Denmark’s national JN.1 booster program—primarily older individuals and those at high risk—the findings may not be generalizable to younger, healthier populations or those in different health care settings.

Conclusion

In the context of ongoing SARS-CoV-2 evolution and the need for variant-specific immunization strategies, this large-scale, real-world analysis offers timely and clinically meaningful reassurance about the safety of JN.1-updated mRNA COVID-19 vaccines. The absence of increased risk for any of the 29 serious AEs evaluated—including myocarditis, ischemic cardiac events, and thromboembolic conditions—reinforces the favorable safety profile of mRNA technology, even as antigenic targets evolve. These findings hold particular relevance for managed care organizations, public health authorities, and policymakers who must weigh the risks and benefits of updated booster campaigns amid growing public skepticism and pandemic fatigue.

REFERENCES

1. Ma KC, Castro J, Lambrou AS, et al. Genomic surveillance for SARS-CoV-2 variants: Circulation of omicron XBB and JN.1 lineages – United States, May 2023-September 2024. MMWR Morb Mortal Wkly Rep. 2024;73(42):938-945. doi:10.15585/mmwr.mm7342a1
2. Andersson NW, Thiesson EM, Hviid A. Safety of JN.1-updated mRNA COVID-19 vaccines. JAMA Netw Open. 2025;8(7):e2523557. doi:10.1001/jamanetworkopen.2025.23557
3. Ao D, Peng D, He C, et al. A promising mRNA vaccine derived from the JN.1 spike protein confers protective immunity against multiple emerged omicron variants. Mol Biomed. 2025;6(1):13. doi:10.1186/s43556-025-00258-7