The analysis drew on 24,117,949 adverse-event reports available in FAERS during the study period. Records were identified under the generic names givinostat and givinostat hydrochloride and the trade name Duvyzat, and only reports assigning givinostat the primary-suspect role were included. Investigators removed duplicate records using the database case identifier and coded events with Medical Dictionary for Regulatory Activities preferred terms. The resulting series was highly concentrated geographically, with 306 reports, or 95.3%, coming from the United States. Patients were predominantly male: 308 of 321 cases, or 96.0%, were male, while one was female and 12 had missing sex. Ages were broadly distributed, but 72 reports, or 22.4%, lacked age information, and outcome data were absent in 257 cases, or 80.1%. These features constrain subgroup analysis and make the distinction between a genuinely non-serious event and an event for which no serious outcome was documented especially important.

At the system-organ-class level, investigations had the strongest reporting-odds signal, with a reporting odds ratio of 5.54 and a 95% confidence interval of 4.71 to 6.53. Gastrointestinal disorders followed with a reporting odds ratio of 4.09, with a 95% confidence interval of 3.48 to 4.80, while blood and lymphatic system disorders had a ratio of 3.43, with a 95% confidence interval of 2.51 to 4.71. The Bayesian information components for these three categories had lower 95% confidence bounds above zero, meeting the study’s signal threshold. Investigators also applied the proportional reporting ratio, Bayesian Confidence Propagation Neural Network and Multi-item Gamma Poisson Shrinker. A preferred term was considered a signal if it met the criteria of at least three of the four methods, allowing signal detection to depend on consistency across frequentist and Bayesian approaches. Twenty preferred-term signals were identified by all four methods, including platelet count decreased, thrombocytopenia, diarrhoea, nausea and increased blood triglycerides. These statistics describe reporting disproportionality relative to the FAERS background; they are not incidence rates or direct measures of a drug’s clinical risk.

At the preferred-term level, blood triglycerides increased produced the strongest signal by reporting odds ratio: 341.3, with a 95% confidence interval of 253.18 to 460.10. It appeared in 47 reports, representing 14.64% of the givinostat series. Platelet count decreased was the most frequently reported term, occurring in 96 reports, or 29.91%, and had a reporting odds ratio of 91.7, with a 95% confidence interval of 73.97 to 113.68. Diarrhoea occurred in 62 reports, or 19.31%, with a reporting odds ratio of 8.29 and a 95% confidence interval of 6.39 to 10.75. Abdominal discomfort appeared in 31 reports, or 9.66%, and thrombocytopenia in 30, or 9.35%. Nausea and vomiting were reported in 27 and 23 cases, respectively. The contrast between frequency and disproportionality was notable: decreased platelet count was the most common reported event, whereas increased triglycerides had the largest relative reporting signal. Product dose omission issue and off-label use were also identified but excluded as operational or recording-related signals rather than pharmacological safety events.

The investigators analyzed platelet count decreased and thrombocytopenia separately because MedDRA distinguishes a reduced platelet-count laboratory finding, categorized under investigations, from a clinician-coded diagnosis of thrombocytopenia, categorized under blood and lymphatic system disorders. When both terms appeared in one report, the case was retained in both term-specific analyses and the overlap was quantified; the terms were not combined into a composite endpoint. Seriousness was based solely on FAERS outcome codes for death, hospitalization, life-threatening events or other serious outcomes. Sixty-four reports, or 19.9% of the series, contained at least one such coded outcome. The other 257 reports, or 80.1%, were operationally grouped as having no documented serious outcome. They were not confirmed non-serious events, and some reports could contain more than one serious outcome, so total outcome codes can exceed the number of reports.

Unadjusted analyses suggested different seriousness patterns for laboratory and clinical platelet terms. Among the 30 reports containing thrombocytopenia, 53.33% had a documented serious outcome and 46.67% did not, whereas among the 96 reports containing platelet count decreased, 14.58% had a documented serious outcome and 85.42% did not. These are proportions within each preferred-term group, not the proportion of all serious reports in which each event occurred. Pyrexia also showed a higher documented-seriousness proportion within its own group, at 63.64%, while blood triglycerides increased had a documented-seriousness proportion of 14.89%. After a likelihood ratio analysis with Benjamini–Hochberg false-discovery-rate correction, platelet count decreased was the only preferred term that differed significantly from the overall preferred-term-entry baseline of 30.07% documented serious outcomes, with an adjusted p value of 0.024. Thrombocytopenia had an adjusted p value of 0.071, blood triglycerides increased had 0.151 and pyrexia had 0.132, meaning those nominally significant unadjusted differences did not survive correction. Their estimates remained imprecise because of the small number of reports.

Time-to-onset analysis suggested that gastrointestinal and platelet-related events could emerge at different stages after treatment began, although only 124 of the 321 reports, or 38.6%, had complete and plausible dates for calculating onset. Among non-serious diarrhoea reports, the median time to onset was 3.5 days, with an interquartile range of 0.25 to 18.25 days. Non-serious platelet count decreased had a median onset of 15.5 days, with an interquartile range of 14.25 to 32.5 days, while thrombocytopenia had a median onset of 17 days and an interquartile range of 2 to 24 days. Across evaluable adverse events, 50.79% were reported within the first 30 days. Serious platelet count decreased had a descriptive median onset of 63 days, but that group contained only four reports, compared with six non-serious reports, and the comparison was not adjusted for multiple testing. The authors therefore did not treat the timing difference as evidence that serious platelet changes consistently occur later.

Regression models did not identify age, weight or corticosteroid use as independent predictors of a documented serious outcome. The complete-case analysis included 185 reports, of which 51, or 27.6%, had a documented serious outcome. Reports involving patients aged 18 or older had a serious-outcome proportion of 35.6%, compared with 23.8% among those younger than 18, but the adjusted odds ratio was 1.64, with a 95% confidence interval of 0.79 to 3.37 and an adjusted p value of 0.182. Patients weighing more than 45 kilograms had an adjusted odds ratio of 1.21, with a 95% confidence interval of 0.60 to 2.45, while reported corticosteroid use had an adjusted odds ratio of 1.66, with a 95% confidence interval of 0.87 to 3.22. No preferred term significantly modified the reporting profile across age, weight or time-to-onset subgroups after correction. These null findings do not prove that the factors have no association: the sample was small, confidence intervals were wide and the severe missingness reduced statistical power.

In an exploratory active-comparator analysis, givinostat had a reporting odds ratio of 91.70, with a 95% confidence interval of 73.97 to 113.68, for platelet count decreased and 23.76, with a 95% confidence interval of 16.48 to 34.24, for thrombocytopenia. Vamorolone had a positive disproportionality signal for platelet count decreased, with a reporting odds ratio of 2.39 and a 95% confidence interval of 1.38 to 4.12, but not for thrombocytopenia, for which its ratio was 0.17, with a 95% confidence interval of 0.02 to 1.19. Stable reporting-odds-ratio estimates were unavailable for prednisone and deflazacort because of insufficient reports, so the analysis did not establish that givinostat had stronger platelet-related signals than either drug. Comparator results were also not head-to-head risk estimates. The exceptionally large triglyceride signal may reflect givinostat, underlying disease activity, concomitant glucocorticoid-associated metabolic effects, more intensive lipid surveillance or a combination of these factors, rather than givinostat alone.

Overall, the FAERS analysis points to platelet-related and metabolic events as the clearest reporting signals following givinostat’s launch, with platelet count decreased particularly frequent and increased blood triglycerides particularly disproportionate in the database. The adjusted seriousness result adds a nuance: a laboratory finding of decreased platelets was common but had a lower documented-seriousness proportion than the overall preferred-term-entry baseline, while clinically coded thrombocytopenia appeared more serious but did not remain significant after multiple-testing correction. Missing exposure denominators, under-reporting, stimulated reporting, incomplete outcome fields, heavy use of concomitant corticosteroids and the predominance of 2024 reports prevent the study from estimating how often these events occur or whether givinostat caused them. The authors identified platelet and lipid monitoring during early treatment as targets for structured follow-up, but the signals require validation in registries or electronic health records with more complete exposure, laboratory and clinical-outcome data before they can be treated as definitive safety estimates.

Subject of Research: Retrospective pharmacovigilance analysis of givinostat adverse-event reports for Duchenne muscular dystrophy

Article Title: A disproportionality analysis of adverse event reports for givinostat in the FDA adverse event reporting system (FAERS) database

Article References: Chen, L., Zhang, H., Wang, Y., Feng, X., Hou, Y., & Su, Q. (2026). A disproportionality analysis of adverse event reports for givinostat in the FDA adverse event reporting system (FAERS) database. Frontiers in Pharmacology, 17, Article 1954821. https://doi.org/10.3389/fphar.2026.1954821

Image Credits: AI Generated

DOI: 10.3389/fphar.2026.1954821

Keywords: givinostat, Duchenne muscular dystrophy, FAERS, pharmacovigilance, thrombocytopenia, platelet count decreased, hypertriglyceridemia, adverse-event reporting, disproportionality analysis, drug safety, time to onset, disproportionality

In musculoskeletal studies, results are commonly reported either as shear modulus in kilopascals or as shear-wave speed in metres per second. The review stresses that these units describe related biomechanical properties but cannot be treated as interchangeable when comparing results from different studies or devices. SWE is non-invasive and provides real-time assessment of anatomical structures, allowing researchers to investigate how the mechanical properties of musculoskeletal tissue vary with health, movement, training, injury and treatment.

The researchers registered the review protocol in PROSPERO as CRD42023468863 and followed PRISMA 2020 reporting guidance. They searched PubMed/MEDLINE, Scopus, Web of Science and selected resources accessed through Ovid SP and EBSCOhost, beginning in October and November 2023 and updating the search in May 2026. Two reviewers independently screened titles, abstracts and full texts, extracted study data and assessed risk of bias with tools selected for randomised, non-randomised and diagnostic studies.

Of 1,834 records identified, 99 underwent full-text assessment and 67 met the eligibility criteria. The included publications dated from 2012 to 2026, with most appearing between 2021 and 2023. Skeletal muscle was by far the most frequently examined tissue, while smaller numbers of studies investigated tendons, nerves, the temporomandibular joint disc, annulus fibrosus, adipose tissue, deep fascia and skin.

The most common participant groups were children with cerebral palsy, typically developing children, athletes, children with Duchenne muscular dystrophy and infants with congenital muscular torticollis. Other populations included children with scoliosis, Osgood–Schlatter disease, Fukuyama muscular dystrophy, bruxism, juvenile idiopathic arthritis, intoeing gait, paediatric carpal tunnel syndrome associated with mucopolysaccharidosis, nocturnal enuresis and type 1 diabetes. The range of applications demonstrates broad exploration, but the evidence varies considerably in depth and quality across conditions and anatomical sites.

Twenty-two studies assessed the reliability of SWE, reporting intraclass correlation coefficients that ranged from near zero to approximately 0.99. Reliability therefore extended from poor to excellent and depended on the structure and examination conditions. Sonographer experience was associated with measurement consistency, while probe compression, movements of adjacent organs or the chest, patient positioning, anatomical location and transducer orientation could affect results.

The review notes that increasing probe pressure can increase measured muscle stiffness. To improve repeatability, the authors advise standardising the anatomical site, patient position and acquisition procedure, averaging multiple measurements from the same structure, and maintaining the same system, transducer and protocol during longitudinal comparisons whenever possible. Among children with cerebral palsy, several studies reported higher gastrocnemius or soleus stiffness than in typically developing peers, although findings varied by muscle, resting state and passive stretching.

One investigation found higher lateral gastrocnemius shear modulus across all tested ankle positions, while another detected higher medial gastrocnemius shear-wave velocity but no significant soleus difference. A further study found no group difference at rest but higher medial gastrocnemius stiffness during passive stretching. SWE measurements were also associated with the Modified Ashworth Scale, Modified Tardieu Scale, ankle range of motion and Reimers’ hip migration index.

These findings show potential for complementary quantitative assessment, but the review concludes that evidence remains insufficient to support routine SWE use in managing paediatric neurological disease. Duchenne muscular dystrophy was another major focus of the evidence. Comparisons with healthy controls commonly showed higher muscle stiffness in affected children, with the most consistent differences involving the gastrocnemius, rectus femoris and vastus lateralis.

One study reported significantly higher shear modulus in tibialis anterior, gastrocnemius medialis, vastus lateralis, biceps brachii and triceps brachii in children with Duchenne muscular dystrophy, while another found higher shear-wave velocity in both rectus femoris and medial gastrocnemius muscles. Findings for tibialis anterior were less consistent. The included studies interpreted variations in muscle elasticity as potentially reflecting a mixture of fibrosis and fatty degeneration, but only one study followed children for one year.

A proposal that SWE may detect early elasticity changes more sensitively than magnetic resonance imaging remains unconfirmed. Intervention studies showed that SWE can register some changes over time, although several effects were short-lived. After botulinum toxin injections for spastic cerebral palsy, studies most often reported lower gastrocnemius shear modulus at early follow-up around three weeks or one month; these changes commonly diminished or became non-significant by three months.

One study also found lower tibialis anterior shear modulus after a gastrocnemius injection. Extracorporeal shockwave therapy was associated with decreased soleus shear modulus, with the largest predicted effect around the thirteenth week, while a very small study linked anti-gravity treadmill training with changes in contrast, entropy and shear-wave velocity. Stretching findings were inconsistent: five minutes of static stretching reduced rectus femoris shear modulus in adolescent athletes but two minutes did not, and a high-intensity passive stretching session improved dorsiflexion without consistently changing gastrocnemius stiffness.

Scoliosis, sports medicine and congenital muscular torticollis supplied additional possible applications. Differences in paraspinal muscle elasticity depended on where the transducer was positioned, while intercostal and lateral abdominal muscles often showed no significant group differences. In congenital muscular torticollis, the affected sternocleidomastoid was generally less elastic than the healthy side or control tissue, and the technique could be used from the earliest days of life.

Athlete studies suggested possible uses for identifying tissue asymmetry and monitoring training or injury-related changes, but small samples and the absence of validated thresholds limited interpretation. The review’s central conclusion is that paediatric SWE has demonstrated research potential rather than an established diagnostic or prognostic role. Only two included studies were randomised, and both raised concerns about bias in outcome assessment.

Many intervention studies lacked control groups, most observational studies had concerns, often involving absent blinding, and samples were frequently small. Long-term observational studies were scarce, while inconsistent terminology, equipment, body and limb positioning, probe orientation and compression limited comparison among results. Robust paediatric reference values that account for age, growth, body size and developmental stage are also unavailable for most structures.

SWE may ultimately provide a complementary quantitative assessment, but current evidence supports further standardization and validation rather than its use as a standalone diagnostic method or direct transfer of measurements between devices, centres or patients.

Subject of Research: Systematic review of paediatric musculoskeletal shear-wave elastography for tissue stiffness assessment and monitoring

Article Title: Musculoskeletal shear-wave elastography in the paediatric population: a systematic review

Article References: Domin, M., Pałac, M., & Linek, P. (2026). Musculoskeletal shear-wave elastography in the paediatric population: a systematic review. Pediatric Radiology. https://doi.org/10.1007/s00247-026-06816-7

Image Credits: AI Generated

DOI: 10.1007/s00247-026-06816-7

Keywords: shear-wave elastography, paediatric ultrasound, muscle stiffness, cerebral palsy, Duchenne muscular dystrophy, adolescent idiopathic scoliosis, congenital muscular torticollis, sports medicine, treatment monitoring, measurement reliability, Musculoskeletal, shear-wave

The non-interventional, web-based study was conducted from July to December 2025 and included 53 healthcare professionals across Spain: 37 pediatric neurologists, 11 rehabilitation physicians and five hospital pharmacists. Most worked in tertiary referral hospitals, and roughly half used dedicated neuromuscular consultations. Fewer than 20% of respondents had participated in clinical trials, while 35.1% of pediatric neurologists reported prior clinical experience with gene therapy. The researchers used ad hoc questionnaires, validated psychometric instruments and multivariable logistic regression to assess technical knowledge, attitudes, perceived usefulness, behavioral intent, barriers and facilitators. Pediatric neurologists also completed measures of openness to evidence-based practice, care-related regret, empathy, work engagement and burnout.

The treatment in focus is delandistrogene moxeparvovec, a recombinant adeno-associated virus therapy that delivers a functional micro-dystrophin gene assembly directly to target muscle tissue. The source article describes it as the sole gene therapy available for Duchenne muscular dystrophy at the time of publication, although following an unfavorable European Medicines Agency opinion it lacked European approval and remained restricted to clinical trials. Its administration nevertheless exposes hospitals to requirements that differ substantially from those of conventional medicines, including viral-vector cold-chain storage, dedicated infusion facilities, acute monitoring capacity and coordination among neurology, pharmacy, rehabilitation, cardiology, immunology and intensive-care services. The regulatory position made the survey a measure of anticipated implementation rather than experience with routine European prescribing.

Pediatric neurologists were optimistic about the treatment’s anticipated clinical value. A total of 78.4% considered gene therapy at least moderately effective for improving overall outcomes, and 81.0% considered it at least moderately useful for slowing progressive muscle weakness. Almost all anticipated a positive effect on health-related quality of life, and 89.2% agreed that introducing disease-modifying therapies would have significant clinical value in routine practice. Overall, 91.9% expressed high openness to adoption in their own practice, and 89.2% reported being enthusiastic or extremely enthusiastic about changing the standard of care. Seventy-three percent agreed that clinical benefits would outweigh potential risks. These were assessments of expected benefit and hypothetical intent, not measurements of efficacy in treated patients.

Despite that optimism, 67.6% of pediatric neurologists rated the complete delivery pathway—including hospital logistics, multidisciplinary coordination and mandatory long-term surveillance—as challenging or extremely challenging, and only 54.0% anticipated smooth workflow integration. Ranked responses identified acute post-infusion safety problems as the most clinically important barrier, with a mean relevance score of 2.30, where lower values denote greater importance. Uncertainty about long-term efficacy ranked second at 2.70, followed by high cost and reimbursement constraints at 3.38. Administrative and institutional burden, lack of formal clinical guidelines, possible resistance from patients or caregivers and the operational burden of infusion were perceived as less prominent barriers. The underlying concern extends beyond whether a therapy can be administered to whether hospitals can manage immune-mediated toxicities, establish standardized surveillance and sustain follow-up over many years. The article describes serious potential complications including hepatotoxicity, myocarditis, thrombotic microangiopathy and treatment-related mortality.

The strongest reported facilitator was access to more robust clinical-trial evidence, selected by 86.5% of pediatric neurologists. Formal guidance from scientific societies was chosen by 78.4%, reduction of institutional administrative workloads by 59.5%, accessible patient-friendly educational materials by 51.4% and positive recommendations from colleagues by 45.9%. Even when hypothetically confronted with high administrative burden, 91.9% of the neurologists said they were likely or extremely likely to adopt or recommend gene therapy; 94.6% gave the same response to a scenario involving substantial economic impact. These figures measure stated intent rather than observed prescribing, so they do not establish how treatment would actually be used once costs, staffing and safety procedures become concrete. The contrast between high stated willingness and low confidence in the delivery system nevertheless identifies a practical gap between clinical interest and organizational execution.

Functional measurement was the only measured factor independently associated with high adoption intent. A total of 52 of the 53 participants recognized the Six-Minute Walk Test, or 6MWT, and pediatric neurologists rated it alongside the North Star Ambulatory Assessment as among the most relevant and feasible motor instruments in routine care. Ninety-six percent of neurologists with high adoption willingness regarded the 6MWT as both objective and sensitive to change, compared with 41.7% of those with lower willingness. In the multivariable model, this perception was the sole independent predictor of high adoption intent, with an odds ratio of 15.23 and a wide 95% confidence interval of 1.58 to 146.67. The result supports an association between assessment confidence and stated willingness in this sample; it does not establish that confidence in one test causes adoption. The broad interval also cautions against treating the precise odds ratio as a stable population estimate.

The 6MWT records the distance a patient can walk in six minutes, offering a quantifiable baseline and a way to track subsequent function. Yet more than 45% of pediatric neurologists answered “no opinion” when asked about the formal sensitivity to change and specificity of functional scales, revealing limited confidence in the technical properties of the measurement system. The authors warn that over-reliance on a single metric can overlook effort dependence and non-linear disease trajectories. A multidimensional assessment framework, using multiple complementary measures rather than dependence on one test, may therefore be important for clinical trials, long-term follow-up and reimbursement decisions. The survey did not evaluate which specific clinical endpoints, such as delayed loss of ambulation or respiratory preservation, clinicians considered most persuasive. Familiarity was also uneven across instruments: more than 90% of clinicians recognized the NSAA and 6MWT, while awareness of secondary tools among pediatric neurologists ranged from 78.4% to 83.8%.

The study also tested whether professional experience, attitudes or working conditions predicted readiness, and found no statistically significant links. Years managing DMD, neuromuscular specialization, patient volume, care-related regret, empathy, work engagement, burnout and openness to innovation did not distinguish neurologists with high and low adoption intent. Burnout was reported by 27.0%, and the mean evidence-based practice attitude score was 1.8 on a scale running from zero to four, but these measures did not explain therapeutic willingness. Descriptive differences in perceived utility or quality-of-life impact among pediatricians with higher and lower evidence-based practice scores were not statistically significant determinants in the model. The findings instead connect stated readiness with technical confidence in clinical assessment, while larger organizational determinants—such as budgets, leadership priorities and resource allocation—remained largely outside the survey’s scope.

Several limitations constrain what can be concluded. Recruitment through national professional societies and the predominance of tertiary hospitals likely favored clinicians working in relatively well-resourced settings, so the sample may not represent Spain’s full care network. Its modest size limited statistical power, especially for comparisons among professional groups, and the web-based design captured self-reported perceptions and hypothetical intentions rather than audited practice. Genetic counsellors, nurse coordinators, clinical geneticists, patient families and hospital executives were not included, and institutional budget allocation, organizational priorities and executive support were not directly evaluated. The study was funded by Roche Farma, Spain; several authors were company employees, and the principal author disclosed speaker honoraria and advisory roles involving Roche and other pharmaceutical companies, although the funder reported no role in study design, analysis, interpretation, writing or submission. The evidence therefore supports a picture of high theoretical receptivity accompanied by unresolved safety, logistical, financial and measurement gaps—not proof that widespread deployment is ready or inevitable.

Subject of Research: Healthcare-professional readiness, barriers and facilitators for adopting gene therapy in Duchenne muscular dystrophy

Article Title: Willingness to adopt gene therapy for Duchenne muscular dystrophy: barriers, facilitators, and multidisciplinary readiness

Article References: García-Uzquiano, R., Branas-Pampillón, M., Medina-Cantillo, J., García-Palop, B., Ruiz-Beato, E., Maurino, J., & Poveda-Andrés, J. L. (2026). Willingness to adopt gene therapy for Duchenne muscular dystrophy: barriers, facilitators, and multidisciplinary readiness. Frontiers in Medicine, 13, 1985172. https://doi.org/10.3389/fmed.2026.1985172

Image Credits: AI Generated

DOI: 10.3389/fmed.2026.1985172

Keywords: Duchenne muscular dystrophy, gene therapy, adeno-associated virus, healthcare readiness, patient safety, Six-Minute Walk Test, functional outcomes, health economics, multidisciplinary care, clinical implementation, Willingness, adopt

Duchenne muscular dystrophy is an X-linked recessive disorder caused by deletions, duplications or point mutations in the dystrophin gene. Dystrophin is a core component of the muscle-fiber cytoskeleton, and its functional absence leads to repeated cycles of muscle-fiber necrosis and regeneration. Eventually, failed regeneration is accompanied by replacement with fibrotic tissue and fat infiltration, as well as involvement of the heart and respiratory muscles.

The study describes a global incidence of approximately one in 3,500 to 5,000 male live births and a prolonged disease course associated with severe functional decline, contractures and scoliosis in advanced stages. Diagnosis currently relies on clinical symptom assessment, serum muscle-enzyme assays, muscle biopsy and genetic testing. Genetic testing and muscle biopsy are regarded in the source article as diagnostic gold standards.

Genetic testing is particularly important because it can guide targeted therapies, but the investigators note that it is resource-intensive and may not be readily accessible as a first-line screening tool in every clinical setting. Muscle biopsy is technically challenging in children and, according to the study background, has low parental acceptance. The investigators reasoned that HFUS and SWE could provide complementary information.

HFUS was used to quantify muscle morphology, including thickness and cross-sectional area, while SWE measured tissue stiffness through shear-wave velocity. The study focused on the biceps brachii, a superficial upper-limb muscle, and the quadriceps femoris, a lower-limb group known from MRI and histological studies to undergo earlier and more severe fibrofatty change. Their superficial location also permits reproducible ultrasound imaging.

The researchers included 1,140 muscle sites and analyzed 3,420 parameters across 53 children with genetically or pathologically confirmed DMD and 61 age- and sex-matched healthy controls. Participants were recruited at West China Second University Hospital in China between January 2019 and September 2024. The control boys had normal physical examinations and no neuromuscular or other diseases.

Exclusion criteria included intellectual disability that prevented cooperation, current hormonal treatment or use within the previous six months, physical training for at least one month during the preceding three months, orthopedic surgery within the previous six months, and other conditions that clearly affected physical fitness. These restrictions reduced some sources of variation in muscle properties but also narrowed the population represented by the results. The groups did not differ significantly in age, weight or body-mass index, although children with DMD were shorter on average.

All examinations were performed with a Mindray Resona 7 system and a 5–14 MHz high-frequency linear-array probe. A certified sonographer with more than five years of experience in pediatric neuromuscular imaging examined the bilateral biceps brachii and quadriceps femoris while the children lay supine, relaxed, with their arms neutral and legs extended. HFUS was performed first, followed by SWE.

The sonographer assessed internal echogenicity, texture, blood-flow signals and space-occupying lesions, and measured muscle thickness and cross-sectional area. Mean shear-wave velocity, expressed in meters per second, was used to characterize stiffness. Standardized anatomical landmarks defined the measurement sites, and the entire muscle belly was included in cross-sectional-area measurements while surrounding fascia was excluded.

Two pediatric radiologists, each with more than 10 years of experience, independently analyzed the images without knowing participants’ clinical status or group allocation. Their measurements were averaged. Inter-observer reliability was generally high: intraclass correlation coefficients for muscle thickness, cross-sectional area and shear-wave velocity commonly ranged from 0.92 to 0.98.

The authors described these findings as evidence that the measurements were reproducible. For the HFUS model, principal component analysis reduced the number of morphological variables. The first four components had eigenvalues above 1, and the first two entered a multivariable logistic regression after univariate testing.

This model produced an AUC of 0.875, with a 95% confidence interval of 0.807 to 0.943, 88.9% sensitivity and 81.9% specificity. A Hosmer–Lemeshow test indicated good calibration. The separate SWE model was constructed through univariate and multivariable logistic regression.

Independent predictors included mean shear-wave velocity in the right biceps brachii, right vastus lateralis and left vastus intermedius. Their odds ratios were 0.170, 3.836 and 2.844, with 95% confidence intervals of 0.063 to 0.460, 1.623 to 9.070 and 1.002 to 8.075, respectively. The full SWE model achieved an AUC of 0.846, with a 95% confidence interval of 0.763 to 0.909.

The abstract reports 69.8% sensitivity and 75.4% specificity. A direct comparison found no statistically significant difference between the standalone HFUS and SWE models, with P = 0.494. Several individual measurements differed between the DMD and control groups.

Significant HFUS differences included selected thickness or cross-sectional-area measurements in the right biceps brachii and quadriceps muscles. Significant SWE differences occurred in the right biceps brachii, right vastus lateralis, left vastus medialis and left vastus intermedius. In every muscle with a significant SWE difference, shear-wave velocity was lower in the DMD group, indicating lower measured stiffness.

The authors interpret this pattern as consistent with the replacement of contractile muscle by softer adipose and connective tissue. They also note that the reduction differs from the increased stiffness reported in spastic conditions such as cerebral palsy. Left-right differences among homologous muscles were interpreted as compatible with an asymmetric and patchy disease process.

Combining the two models produced the study’s largest improvement in discrimination. The HFUS-SWE model reached an AUC of 0.947, with a 95% confidence interval of 0.885 to 0.981, and significantly outperformed both standalone models, with P < 0.001 for each comparison. Its sensitivity was 82.2%, while specificity reached 95.1%.

At the prevalence observed in this cohort, the combined model had a positive predictive value of 94.3% and a negative predictive value of 84.8%. Decision-curve analysis indicated a greater net benefit from the combined model across all tested threshold probabilities. The authors attribute its performance to complementary information: HFUS captures macroscopic morphology, including reduced muscle dimensions and architectural disruption, whereas SWE samples biomechanical properties such as tissue stiffness.

The findings remain preliminary because this was a small, single-center retrospective study, and the authors explicitly position the imaging approach as adjunctive. The cohort’s DMD prevalence was 46.5%, far above the global incidence of roughly one in 3,500 to 5,000 male births, so the reported predictive values cannot be assumed to apply to general screening populations. In a much lower-prevalence setting, the positive predictive value would be expected to be substantially lower and the negative predictive value higher.

Differences in height between the groups may also have influenced muscle biomechanics, although the authors argue that standardized measurement sites and relative ratios reduced this concern. Subcutaneous fat was considered as a possible confounder but could not be quantified because of its compressibility. Larger prospective, multicenter studies are needed to validate and refine the models, assess their performance in lower-prevalence populations and determine whether the approach can reliably support clinical triage or longitudinal monitoring.

Subject of Research: Evaluation of combined high-frequency ultrasound and shear-wave elastography models for adjunctive diagnosis of pediatric Duchenne muscular dystrophy.

Article Title: Non-invasive adjunctive diagnostic models incorporating high-frequency ultrasound and shear wave elastography for pediatric Duchenne muscular dystrophy

Article References: Qiang, K.-K., Zhang, S.-R., Luo, H., & Song, Q.-Y. (2026). Non-invasive adjunctive diagnostic models incorporating high-frequency ultrasound and shear wave elastography for pediatric Duchenne muscular dystrophy. Frontiers in Genetics, 17, Article 1912996. https://doi.org/10.3389/fgene.2026.1912996

Image Credits: AI Generated

DOI: 10.3389/fgene.2026.1912996

Keywords: Duchenne muscular dystrophy, Pediatric neuromuscular disease, High-frequency ultrasound, Shear-wave elastography, Diagnostic modeling, Muscle stiffness, Muscle morphology, Medical imaging, Non-invasive diagnosis, Non-invasive, adjunctive, diagnostic

Researchers used a video platform compliant with 21 Code of Federal Regulations Part 11 to compare live telehealth with asynchronous at-home videos and to compare live with recorded telehealth scoring. NSAA-certified physical therapists double-scored the assessments. The clinical trial number was listed as not applicable.

Mean NSAA scores were 25.8 for telehealth and 25.1 for asynchronous assessment, a difference of 0.82 points. This difference met the study’s two one-sided tests for equivalence within margins of plus or minus three standard errors of the mean, with p less than 0.001. Live and recorded telehealth scores differed by 0.23 points and were also reported as equivalent, with p less than 0.001. Inter-rater mean absolute differences were 1.87 points overall, comprising 1.61 points for telehealth and 2.15 points for asynchronous video; the abstract states that these values were below the study’s minimum clinically important difference threshold.

Based on the available abstract, the authors characterized remote NSAA administration and scoring as feasible, reliable and clinically comparable across the methods evaluated, supporting decentralized follow-up and data collection in Duchenne muscular dystrophy. The findings are bounded by the sample of 18 participants and the limited information available in the abstract, which does not describe recruitment, attrition, clinical characteristics beyond mean age, or the basis and magnitude of the clinically important difference threshold. Consequently, the abstract alone does not establish the precision or generalizability of the results across broader patient populations.

Subject of Research: Remote administration and scoring of the North Star Ambulatory Assessment in Duchenne muscular dystrophy

Article Title: Use of telehealth and at-home video for remote administration of the North Star Ambulatory Assessment (NSAA): a comparative methods study

Article References: Kane, A. S., Foreman, N., Lazzaro, E. C., Lastra, J. D., Gothier, J. D., Posner, N., & Jones, C. (2026). Use of telehealth and at-home video for remote administration of the North Star Ambulatory Assessment (NSAA): a comparative methods study. BMC Health Services Research. https://doi.org/10.1186/s12913-026-15496-w

Image Credits: AI Generated

DOI: 10.1186/s12913-026-15496-w

Keywords: Duchenne muscular dystrophy, North Star Ambulatory Assessment, telehealth, at-home video, remote assessment, physical therapy, equivalence testing, clinical comparability, at-home, video, remote, administration

The DMD gene is the largest known protein-coding gene in the human genome, and it does not produce a single protein but a family of them. In muscle, the full-length dystrophin Dp427 anchors the dystrophin-glycoprotein complex, a transmembrane linker between laminin and actin that stabilizes muscle fibers during contraction. In the brain, however, the picture is far more complex. Several dystrophin isoforms are expressed in neural tissue, including Dp427 itself, the shorter Dp140, and the tiny Dp71, each with its own developmental timing and cellular localization. Dp427 appears in neurons, particularly in the postsynaptic density of excitatory synapses in the hippocampus and cortex, where it helps organize receptor clusters. Dp140 is expressed in developing fetal brain and in glial cells, while Dp71 is found in astrocytes and other macroglial cells, where it anchors aquaporin-4 channels and potassium channels critical for water and ion homeostasis. Mutations in the DMD gene can therefore disrupt one or several of these brain dystrophins depending on where the genetic lesion falls, producing a spectrum of cognitive and neuropsychiatric comorbidities that range from mild learning difficulties to intellectual disability, autism spectrum features, attention deficit hyperactivity disorder and anxiety.

The review synthesizes imaging findings across magnetic resonance imaging, diffusion tensor imaging, positron emission tomography, single-photon emission computed tomography and magnetic resonance spectroscopy, applied both to patients and to animal models including mdx mice, DMD rats and DE50-MD dogs. One of the most consistent findings is the presence of mild cortical atrophy, particularly in frontal regions, together with slight modifications in the volumes of specific brain structures. Studies of boys with Duchenne muscular dystrophy have shown reduced cerebral gray matter and altered white matter compared with typically developing controls, and voxel-based morphometric analyses in Becker muscular dystrophy patients reveal similar though generally milder structural changes. In the motor cortex specifically, decreased gray matter concentration and reduced local synchronization of spontaneous neural activity have been documented, suggesting that the brain regions controlling movement are affected in parallel with the muscles they command.

Beyond gross anatomy, the imaging evidence points to profound alterations in brain physiology. Cerebral blood flow is decreased in patients with Duchenne muscular dystrophy, with frontal lobe-dominant reductions that appear to be progressive over time according to longitudinal observations in Japanese patient cohorts. Brain hypometabolism has been detected through positron emission tomography studies showing altered regional glucose metabolism, and magnetic resonance spectroscopy has revealed abnormalities in brain biochemistry, including changes in phosphorus-31 and proton spectra that suggest disturbed energy metabolism and neuronal integrity. Animal models reinforce these observations: mdx mice show abnormal cerebral diffusion and perfusion in vivo, and the DMD rat exhibits measurable disruptions in both microstructure and neurochemistry. The review also highlights an abnormal cerebral response to stress, with recent work demonstrating that brain glucose metabolism serves as a neuronal substrate of the abnormal behavioral response to stress in the mdx mouse, providing a biological explanation for the heightened anxiety and stress reactivity frequently reported in patients.

White matter microstructure alterations emerge as another central theme. Diffusion tensor imaging studies in children with Duchenne muscular dystrophy consistently show abnormal fractional anisotropy and diffusivity in major white matter tracts, indicating disrupted myelination or axonal organization. This aligns with cellular evidence from mdx mice, where myelination is delayed during postnatal brain development and oligodendrogenesis is defective, with persistent hypomyelination observed even in adult animals. Advanced diffusion approaches probing the diffusion of water and metabolites have further refined the assessment of white matter microstructure in patients, suggesting that the alterations reflect genuine tissue-level changes rather than artifacts of image processing. The review notes that these white matter changes may underlie some of the cognitive profiles seen in patients, particularly difficulties with executive function and processing speed that depend on efficient long-range communication between brain regions.

Functional connectivity disturbances add yet another dimension to the imaging picture. Resting-state functional MRI has revealed altered default-mode network functional connectivity in Duchenne muscular dystrophy patients, and connectomic analyses in patients with mild cognitive impairment show broader large-scale network disturbances. Interestingly, the review draws parallels with connectivity patterns observed in other neurodevelopmental and psychiatric conditions, including attention deficit hyperactivity disorder, obsessive-compulsive disorder and autism, where both hypoconnectivity and hyperconnectivity of specific networks have been documented. This suggests that the loss of brain dystrophins may produce network-level imbalances that resemble, at least partially, the connectomic signatures of common neuropsychiatric disorders, providing a mechanistic bridge between the genetic lesion and the psychological symptoms that patients experience.

A crucial insight from the review concerns the genotype-phenotype relationship, particularly the role of Dp140. When mutations affect Dp427 alone, cognitive and neuropsychiatric consequences tend to be milder, but when Dp140 expression is also disrupted, severity increases substantially. This is consistent with the developmental timing of Dp140, which is expressed during fetal brain development and appears to play a critical role in glutamatergic transmission and social behaviour, as demonstrated in the mdx52 mouse model that lacks Dp140. Studies comparing patients with mutations at different locations along the DMD gene have confirmed that the risk of cognitive impairment correlates with mutation location, and that Dp71 disruption contributes to the severity of intellectual disability. The review emphasizes that the variable severity of cerebral disorders depends on which combination of brain dystrophins is lost, making the DMD gene a remarkable example of a single gene producing multiple phenotypes through its family of protein products.

The question of progression remains one of the most clinically important aspects of the review. Some correlations between imaging parameters and cognitive or psychological impairments have been reported, but the authors caution that these remain to be confirmed in larger cohorts. Evidence for progression comes from longitudinal observations showing that frontal lobe-dominant cerebral blood flow reduction and atrophy can worsen over time in Duchenne muscular dystrophy, raising the possibility that cerebral involvement is not static but evolves alongside the muscular disease. However, other spectroscopy studies indicate preserved cerebral biochemical composition in some patient groups, suggesting that the trajectory may be more nuanced than simple deterioration. The review calls for standardized longitudinal imaging protocols that would allow researchers to track cerebral changes across the lifespan of patients, from early childhood through adulthood, and to determine whether therapeutic interventions targeting the muscle disease also benefit the brain.

The implications of this work extend well beyond academic interest. As exon-skipping therapies, gene replacement strategies and gene-editing approaches advance through clinical trials for Duchenne muscular dystrophy, the question of whether these treatments restore brain dystrophins becomes paramount. Many current therapies are designed primarily with muscle in mind, and the blood-brain barrier poses a significant challenge for delivering dystrophin-restoring treatments to the central nervous system. The imaging biomarkers catalogued in this review, from cortical atrophy to cerebral blood flow, white matter microstructure, brain metabolism and functional connectivity, provide a toolkit for evaluating whether future therapies reach the brain and produce measurable benefits. Without such biomarkers, it would be impossible to know whether a treatment that improves muscle strength also improves learning, memory or emotional regulation.

The review ultimately reframes dystrophinopathies as genuine brain diseases with muscular consequences rather than the reverse. The convergence of structural, physiological, metabolic and connectomic imaging evidence, replicated across species and imaging modalities, establishes that the loss of brain dystrophins produces real and measurable cerebral alterations. While the correlations between imaging findings and cognitive or psychological symptoms await confirmation in larger studies, the biological plausibility is strong, supported by cellular and molecular evidence of dystrophin function in neurons, glia and the neurovascular unit. As the authors conclude, cerebral imaging has shed new light on the impact of dystrophinopathies on brain structure, function and connectivity, and this light now guides the search for therapies that address the full spectrum of what it means to live with a dystrophin mutation.

Subject of Research: Neuroscience

Article Title: Brain imaging in dystrophinopathies

Article References: Lancien, M., Leboucq, N., Desguerre, I., Rivier, F., & Vaillend, C. (2026). Brain imaging in dystrophinopathies. Journal of Neurology, 273(11), Article 669. https://doi.org/10.1007/s00415-026-14215-z

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14215-z

Keywords: Duchenne muscular dystrophy, Becker muscular dystrophy, brain imaging, dystrophin, MRI, cognitive impairment, Brain, imaging, dystrophinopathies, scientific research

The modification in question is isonicotinylation, abbreviated Kinic, a recently discovered post-translational mark in which an isonicotinyl group is attached to proteins. It was first described in liver cancer, where it modifies histones to boost oncogenic protein expression and activate the PI3K–AKT signaling pathway. Subsequent work showed that Kinic can also modify non-histone proteins, driving epithelial–mesenchymal transition and invasion in liver cells, and an independent artificial intelligence study suggested that Kinic signatures could support risk stratification and drug design in hepatocellular carcinoma. What remained unclear was whether this modification plays any role in the immune system—and, by extension, in immune-mediated diseases such as DMD.

Mast cells, meanwhile, have long been suspected participants in muscular dystrophy. These inflammatory cells are recruited to damaged muscle, where they can promote progressive myofiber necrosis and sustain chronic inflammation. Earlier studies in dystrophin-deficient humans, dogs, and mice, including double-mutant mdx mice with exaggerated mast cell activity, correlated mast cell burden with disease severity. But whether the balance of mast cell activity could serve as a measurable indicator for DMD patients had never been systematically tested. The research team, led by investigators from hospitals in Zhejiang and Jiangsu, China, set out to close both gaps at once by asking how Kinic-related biology and mast cell behavior intersect in dystrophic muscle.

Methodologically, the study is a tour de force of modern bioinformatics. The researchers drew on four publicly available bulk gene expression datasets from the Gene Expression Omnibus—GSE38417, GSE109178, GSE6011, and GSE32720—covering a total of 98 muscle samples from DMD patients and healthy controls. After normalizing the data and correcting for batch effects using the sva and limma packages, they applied gene set variation analysis to quantify Kinic pathway activity, the CIBERSORT algorithm to estimate immune cell infiltration, and weighted gene co-expression network analysis to identify gene modules correlated with each feature. In GSE38417, the black module correlated most strongly with Kinic activity (R = 0.49) and negatively with DMD pathology (R = −0.86); in GSE109178, the green module tracked mast cell signatures (R = −0.63) and disease status (R = 0.91). Intersecting these modules yielded nine shared genes, which the team designated KM-related differentially expressed genes—KM standing for the combined Kinic and mast cell axis.

Functional enrichment revealed that these nine genes were principally involved in maintaining intracellular homeostasis, a finding that hints at how a protein-modification program and an immune cell population might converge on a shared cellular vulnerability. Using consensus clustering on the GSE6011 training cohort, the researchers then split DMD patients into two molecular subgroups, C1 and C2, based on the expression patterns of these KM-related genes. The subgroups differed in molecular function, gene expression, and immune infiltration profiles, suggesting that the KM axis captures biologically meaningful variation among patients rather than statistical noise.

The heart of the diagnostic effort lay in an ensemble machine learning pipeline. The team systematically combined twelve machine learning algorithms with multiple feature selection and preprocessing strategies, generating 132 candidate models, each trained on GSE6011 with ten-fold cross-validation and then tested on the independent validation set GSE32720. The winning combination—random forest paired with stepwise generalized linear modeling, abbreviated RF + Stepglm—achieved favorable discrimination in both cohorts, as assessed by receiver operating characteristic and precision–recall analyses, and its accuracy was further confirmed through nomogram and calibration plots. To interpret which genes drove the model’s decisions, the researchers applied SHAP analysis, a game-theoretic approach for quantifying each feature’s contribution to predictions. The verdict was unambiguous: USP18, a gene encoding a ubiquitin-specific protease, emerged as the dominant contributor.

USP18’s credentials made the finding compelling. The enzyme is known to regulate ubiquitination and has been implicated in muscular disorders, including as an ISG15 activator promoting inflammation in dermatomyositis muscle with perifascicular atrophy and in juvenile inflammatory myopathies. In the new study, USP18 expression was consistently upregulated in DMD samples across all four bulk datasets, and single-gene pathway analysis in GSE6011 tied it to inflammatory signaling. Crucially, the team also found that high USP18 expression was negatively correlated with mast cell activation, suggesting a regulatory relationship between the two. To validate these patterns experimentally, the researchers engineered human mast cell lines using CRISPR–Cas9: one line (DMDI) carried a deletion of exon 52 of the DMD gene, and another (DMDII) carried a stop codon introduced within exon 52. Quantitative PCR and Western blotting confirmed the USP18 expression patterns observed computationally, anchoring the bioinformatic predictions in wet-lab measurements.

To place USP18 in its cellular context, the team turned to single-cell transcriptomics. They analyzed a DMD mouse muscle dataset (GSE213925) comprising 382,392 cells, which resolved into 24 clusters and 10 cell types after quality control and dimensionality reduction. Mast cells represented a relatively small fraction of this landscape, but AUCELL scoring showed that Kinic activity was comparatively enriched within them, and Usp18 was distributed in mast cells specifically. Using the scTenifoldKnk package, the researchers performed an in silico knockout: they constructed a gene regulatory network from the single-cell data via tensor decomposition, virtually set Usp18 expression to zero, and recomputed the network to identify genes whose regulatory connections changed significantly. The perturbed targets were enriched for molecules involved in maintaining muscular function and linked to muscular disease. Pseudotime trajectory analysis with monocle2 further revealed five differentiation trajectories along which Usp18 expression correlated with mast cell maturation, and cell–cell communication and metabolic profiling rounded out the atlas.

The therapeutic arm of the study was equally computational. Using the DrugReflector platform—a multi-omics drug repositioning database integrating transcriptomic, proteomic, and protein–protein interaction data—the team scored compounds against the GSE6011 signature using a Drug–Target Association Score that weighs gene expression similarity, chemical structure similarity, known drug–target interactions, and network topology. The deep learning pipeline flagged BRD-K10482608 as the top candidate. In parallel, network pharmacology based on the molecular perturbations caused by virtual USP18 knockout identified finafloxacin, an antibiotic, as a USP18-targeted agent. Molecular docking using AlphaFold2-predicted protein structures, AutoDock Vina simulations, and visualization in PyMOL and MOE showed favorable binding affinity between finafloxacin and USP18, with defined hydrogen bond and hydrophobic interactions at the binding interface. Together, the two compounds represent computationally derived starting points for DMD drug development.

The authors are careful to frame their conclusions within clear limitations. The Kinic signal was inferred from a transcriptomic gene signature rather than measured directly by mass spectrometry or antibody-based detection, so the findings should be read as signature-based associations rather than direct biochemical proof. The in vitro work quantified USP18 expression but did not dissect how Kinic modification of USP18 might function mechanistically. The single-cell cohort comprised only two DMD mouse samples, which may not capture the full heterogeneity of mast cell states across the disease spectrum, and the bulk datasets, despite batch correction, may retain unmodeled technical and biological variability. The drug candidates, identified entirely in silico, will require rigorous preclinical testing to confirm efficacy, dosing, and muscle tissue penetration. Still, the study offers something DMD research has lacked: a unified, data-driven framework linking a novel protein modification, a specific immune cell type, and a druggable target, with a validated diagnostic model that could support molecular stratification of patients. If future multi-center trials bear out the model’s predictive power and the therapeutic candidates’ promise, the convergence of artificial intelligence, multi-omics, and targeted validation demonstrated here could reshape how this relentless disease is diagnosed and treated.

Subject of Research: Isonicotinylation and mast cell-associated gene signatures in Duchenne muscular dystrophy identified through ensemble machine learning and in vitro validation

Article Title: Deciphering isonicotinylation and mast cell-associated pathogenic patterns in Duchenne muscular dystrophy: evidence from ensemble learning-driven multi-omics and in vitro validation

Article References: Yu, S., Xu, D., Hua, Y., Mo, H., & Liu, Y. (2026). Deciphering isonicotinylation and mast cell-associated pathogenic patterns in Duchenne muscular dystrophy: evidence from ensemble learning-driven multi-omics and in vitro validation. Frontiers in Molecular Biosciences, 13, Article 1853169. https://doi.org/10.3389/fmolb.2026.1853169

Image Credits: AI Generated

DOI: 10.3389/fmolb.2026.1853169

Keywords: Duchenne muscular dystrophy, isonicotinylation, mast cells, USP18, machine learning, multi-omics, single-cell RNA sequencing, drug repositioning, post-translational modification, biomarkers, CRISPR, inflammation

Duchenne muscular dystrophy is an X-linked childhood disease caused by loss of dystrophin, the protein that stabilizes muscle fibers during contraction. Delandistrogene moxeparvovec attempts to compensate by using an AAVrh74 viral vector to ferry a miniaturized micro-dystrophin gene into heart and skeletal muscle. Five FDA-approved gene therapies now rely on intravenous recombinant adeno-associated virus (rAAV), but the enormous doses needed to transduce enough tissue have produced serious adverse events and even deaths in clinical practice, making a detailed understanding of the body’s systemic reaction to these infusions a pressing safety concern.

The new study, led by researchers at the University of Florida Myology Institute, examined plasma and urine samples banked from four young boys in the NCT03375164 trial, all between four and eight years old. These participants received 2.0 × 10¹⁴ vector genomes per kilogram of rAAVrh74 carrying the micro-dystrophin transgene, and all four experienced effective muscle expression, multiyear functional improvement, and no serious adverse events. That makes them, in the researchers’ words, among the best representatives of a successful micro-dystrophin gene therapy, and therefore an ideal case study of what a favorable response looks like at the molecular level.

Using digital PCR to count viral genomes and immunoblotting to detect capsid proteins, the team found extraordinarily high levels of circulating vector one day after infusion, exceeding 10¹² vector genomes per milliliter of plasma. By day 7, plasma titers had dropped more than a thousandfold, to roughly 10⁹ vector genomes per milliliter or below. Urinary shedding was minimal and highly variable; two participants showed undetectable levels at every time point, while the highest value observed was 6 × 10⁶ vector genomes per milliliter in a single day 1 urine sample.

Critically, the circulating virus was not just inert debris. DNase pretreatment experiments showed that most of the detected genomes were protected inside intact capsids, and when day 1 plasma was added to cultured AC16 human cardiomyocytes, the particles successfully transduced the cells, proving that at least some of the vector remained biologically active a full day after infusion. This finding also addressed a recent concern in the field: laboratory studies have suggested AAV particles can spontaneously eject their genomes at body temperature, but the new data indicate genome ejection is not a prominent feature of systemic AAVrh74 therapy in humans.

The proteomic analysis told a more dramatic story. Using the SomaScan platform, which measures more than 5,000 circulating proteins with DNA-aptamer reagents, the researchers found 287 protein targets significantly altered across the treatment time course, and 99 targets changing at a stricter statistical threshold. Pathway analysis revealed that these changes were overwhelmingly concentrated in immune and infection-related programs: iron regulation, collagen biosynthesis, interleukin-6 signaling, complement and coagulation cascades, and ferroptosis all ranked among the most enriched pathways, even though none of the boys developed serious clinical complications.

The temporal pattern suggested an acute, self-limiting innate antiviral response. Interferon-stimulated genes such as MX1, IFIT3, IFI16, and TLR5 spiked sharply at day 7, coinciding with vector clearance, and largely returned to baseline by day 14. Macrophage markers like HMOX1, LST1, and MARCKSL1, along with neutrophil proteins including MPO, LCP1, and EZR, followed the same trajectory. Complement activation markers C3d, C1QTNF1, and C1S also peaked at day 7, while C1q components dropped at day 14, consistent with consumption during cascade activation. Notably, IL1R1 rose later, peaking at days 60 to 90 during the glucocorticoid taper, suggesting a rebound of interleukin-1 signaling as steroid suppression wore off rather than a direct effect of the virus.

Muscle biomarkers painted a nuanced picture of treatment effect. Sustained declines in TNNI3, a cardiac troponin, and MYL6B, a slow-fiber myosin light chain, hint at protection of heart and slow skeletal muscle. But a striking day 1 spike in titin, TTN, suggested transient muscle damage at the moment of infusion, and the classic damage markers fast troponin, cardiac troponin T, and creatine kinase showed no significant change at all. A newly proposed marker, the ubiquitin-conjugating enzyme UBE2S, declined steadily across the study and may reflect reduced muscle turnover as the transgene takes hold. Meanwhile, organ injury markers HAVCR1, FBP1, and IGFBP7 all peaked at days 60 to 90, and GDF15, a tissue stress signal, rose from day 7 and stayed elevated for at least three months, possibly explaining the vomiting that all participants experienced, since GDF15 is now linked to nausea in pregnancy and chemotherapy.

To test whether these immune signatures translate across species, the team injected dystrophic D2.mdx mice with a matching systemic rAAV dose and examined their livers a week later. Genes central to viral sensing and interferon signaling, including Ifit3, Ifnb, and Mavs, were significantly elevated, confirming that the antiviral response seen in human plasma also occurs in dystrophic liver tissue. The mouse work offers a tractable model for dissecting mechanisms and testing interventions, though the top human hit, MX1, only trended upward in mice, likely because inbred mouse strains carry nonfunctional Mx1 mutations.

The findings establish that robust immune activation is a natural and probably universal consequence of high-dose rAAV therapy, not merely a warning sign of impending toxicity. The key clinical question is what separates the transient, self-limiting response observed here from the sustained immune pathology seen in patients who develop hepatotoxicity, thrombotic microangiopathy, or fatal outcomes. By providing a detailed molecular reference point from a best-case scenario, the study gives clinicians a benchmark for monitoring future patients and points toward interventions, including complement control and anti-GDF15 strategies, that could make systemic gene therapy safer for the children who need it.

Subject of Research: Systemic immune and viral dynamics following intravenous rAAV micro-dystrophin gene therapy in boys with Duchenne muscular dystrophy

Article Title: Systemic responses to intravenous rAAV administration in boys with Duchenne muscular dystrophy

Article References: Harris, B. E., Seldin, B. M., Towne, S. C., Hobson, O. R., Zerpa, E., Prima, V., Sweeney, H. L., & Hammers, D. W. (2026). Systemic responses to intravenous rAAV administration in boys with Duchenne muscular dystrophy. Frontiers in Molecular Medicine, 6, Article 1953867. https://doi.org/10.3389/fmmed.2026.1953867

Image Credits: AI Generated

DOI: 10.3389/fmmed.2026.1953867

Keywords: rAAV gene therapy, Duchenne muscular dystrophy, micro-dystrophin, delandistrogene moxeparvovec, AAVrh74, SomaScan proteomics, interferon response, complement activation, digital PCR, vector dynamics, GDF15, immune response biomarkers

Mary Ellen Avery’s legacy provides the intellectual template for this kind of work. In the 1950s, Avery demonstrated that respiratory distress syndrome in premature newborns was caused by a deficiency of pulmonary surfactant, the lipoprotein mixture that keeps the tiny air sacs of the lung from collapsing with each breath. That insight, derived from careful basic science, eventually produced surfactant replacement therapy, one of the most consequential interventions in modern neonatology. The lesson embedded in her career is that a mechanistic discovery, pursued patiently over decades, can be converted into a system delivered to every infant who needs it. It is precisely that conversion, from knowledge to infrastructure, that the award celebrates.

Chung’s own work sits at the intersection of genetics, pediatrics, and public health. As a human geneticist who has led large-scale genomic medicine initiatives, she has focused on a question that sounds simple but is operationally formidable: which conditions should be looked for in every newborn, and how should the results be delivered to families in a way that changes outcomes rather than merely generating anxiety? The answer determines whether a diagnosis arrives in time to alter the course of a disease or only in time to explain it retrospectively.

The clearest recent example comes from spinal muscular atrophy, a genetic disorder that was, until recently, the leading inherited cause of infant mortality. SMA is caused by loss or mutation of the SMN1 gene, which produces a protein survival motor neurons require. Infants with the most severe form lose motor neurons progressively in the first months of life, and before effective therapy existed, most died of respiratory failure before their second birthday. The disease, however, has a crucial property that makes it an ideal target for newborn screening: intervention is dramatically more effective when it begins before symptoms appear, because motor neurons that have not yet been lost can be preserved.

The therapeutic landscape changed with the development of disease-modifying treatments, most prominently nusinersen, an antisense oligonucleotide that alters splicing of the related SMN2 gene so that it produces more functional survival motor neuron protein. The pivotal randomized trial published in the New England Journal of Medicine in 2017 showed that infants treated with nusinersen had significantly better motor-function outcomes than those receiving a sham control procedure. Suddenly, a fatal diagnosis became a treatable condition, but only if it was identified early enough. Screening became the bottleneck: without systematic detection at birth, infants would still present with established weakness, at which point the therapeutic window had narrowed.

Chung and colleagues addressed this directly in New York State, where a pilot study of population-based newborn screening for spinal muscular atrophy demonstrated that molecular screening could be integrated into existing public health infrastructure. The technical approach relies on detecting the homozygous deletion of SMN1 in dried blood spots, the same heel-prick specimens already collected from every newborn for dozens of metabolic and genetic conditions. The pilot study, published in Genetics in Medicine, established feasibility, laboratory workflow, and the clinical pathway connecting a positive screen to confirmatory testing and rapid treatment initiation. New York subsequently moved from pilot to universal screening, and the model has since been adopted across a growing number of states and countries.

The same logic has been extended to Duchenne muscular dystrophy, another severe neuromuscular condition in which early identification may enable earlier access to emerging therapies. A two-year pilot study of newborn screening for Duchenne in New York, reported in Annals of Clinical and Translational Neurology, evaluated the performance of screening for elevated creatine kinase and confirmatory genetic testing in dried blood spots. These pilots illustrate a recurring pattern in Chung’s career: rigorous, unglamorous implementation science that determines whether a screening concept can actually function at population scale, with acceptable rates of false positives, clear follow-up protocols, and equitable reach across diverse communities.

Chung’s most ambitious project in this space is the GUARDIAN study, a genomic newborn screening program conducted in New York that screened tens of thousands of infants for hundreds of genetic conditions, many of which are actionable in early childhood. Unlike traditional newborn screening, which targets a fixed panel of biochemical markers, genomic screening reads the infant’s DNA directly, allowing a single platform to detect conditions ranging from metabolic disorders to hearing loss to cardiac arrhythmia syndromes. The study received in-kind contributions from GeneDx and Illumina, and its results are shaping the debate over how much genetic information should be gathered at birth and how families should be counseled about findings that range from urgently actionable to uncertain.

The GUARDIAN study also raises the ethical and logistical questions that any system of universal early care must confront. Screening an entire population inevitably identifies infants with variants of uncertain significance, conditions that may never cause symptoms, and incidental findings unrelated to the reason for testing. The design of the program, with defined gene panels focused on childhood-onset, actionable conditions, reflects an attempt to balance the promise of early intervention against the risks of overdiagnosis and medicalization of healthy infancy. Chung’s framing of the work, as building systems of care rather than simply tests, emphasizes that a screen is only as valuable as the clinical pathway behind it: confirmatory diagnostics, genetic counseling, treatment access, and long-term follow-up.

The deeper argument of the Avery Award lecture is historical and structural. Medicine tends to organize itself around the sick patient who arrives at the clinic, but the greatest gains in pediatric health have come from systems that reach children before illness declares itself: vaccination schedules, congenital hypothyroidism screening, hearing screening, pulse oximetry for critical congenital heart disease, and now genomic screening. Each of these required decades of persistence, coalition-building among scientists, public health officials, advocacy groups, and families, and a willingness to demonstrate value through pilot data before universal implementation. Chung’s career, from her leadership in identifying the genetic basis of conditions to her role in designing and executing population screening programs, exemplifies the long gestational period that careers in physician science often require before the birth of innovation reaches patients. In honoring that journey, the Society for Pediatric Research signals to the next generation of pediatrician-scientists that the highest-impact work may not be a single discovery but the patient construction of systems that ensure every child, starting at birth, benefits from what medicine already knows.

Subject of Research: Newborn screening and systems of early pediatric care, including genomic screening for treatable genetic conditions

Article Title: The journey to establishing systems of care for all children, starting at birth: the Society for Pediatric Research’s 2026 Mary Ellen Avery award

Article References: Chung, W. K. (2026). The journey to establishing systems of care for all children, starting at birth: the Society for Pediatric Research’s 2026 Mary Ellen Avery award. Pediatric Research. https://doi.org/10.1038/s41390-026-05580-6

Image Credits: AI Generated

DOI: 10.1038/s41390-026-05580-6

Keywords: newborn screening, spinal muscular atrophy, Mary Ellen Avery, Wendy Chung, GUARDIAN study, genomic medicine, nusinersen, Duchenne muscular dystrophy, pediatric research, public health, SMN1, early intervention

The essay, published on 12 October 2026 under the title Family reflections: the questions we learn to ask, offers a parent’s perspective on living alongside Duchenne muscular dystrophy for nearly twenty years. Smith, who is affiliated with Harrison’s Fund in Surrey, United Kingdom, uses the piece to trace how his understanding of scientific inquiry evolved from a simple transactional model, in which researchers produced cures and families waited, to something far more collaborative, iterative and emotionally demanding. The reflection appears in a journal primarily read by paediatric researchers and clinicians, a placement that is itself part of its argument: that the people who live with a disease day after day hold knowledge that laboratory science cannot generate on its own.

Duchenne muscular dystrophy is among the most common and severe inherited muscle disorders of childhood. It is caused by mutations in the DMD gene, the largest known protein-coding gene in the human genome, which sits on the X chromosome and carries the instructions for dystrophin, a structural protein essential for keeping muscle fibres intact during contraction. Because the gene is X-linked, the condition predominantly affects boys, who have only a single X chromosome. Without functional dystrophin, skeletal and cardiac muscle suffer progressive damage; the resulting degeneration typically manifests in early childhood as delayed walking, frequent falls and difficulty rising from the floor, and advances relentlessly through loss of ambulation, weakening of the respiratory muscles and deterioration of the heart muscle.

The technical biology of the disease explains why the diagnosis was so disorienting for Smith and his family. Dystrophin acts as a molecular shock absorber, linking the internal cytoskeleton of each muscle fibre to the surrounding extracellular matrix through a protein complex at the cell membrane. When that linkage fails, the microscopic tearing that occurs during every normal muscle contraction can no longer be repaired efficiently, and fibres die and are replaced by fat and connective tissue. The result is a condition in which the very act of using a muscle contributes to its destruction, a paradox that has shaped decades of research into corticosteroid treatment, exon-skipping therapies, gene transfer approaches and, more recently, base and prime editing strategies designed to correct or bypass mutations in the DMD gene itself.

Against that backdrop, Smith’s reflection asks a deceptively simple question: what do families actually need from research, and what do they have to give it? His opening conviction, that research equals answers, is one that many patient advocates describe outgrowing. In the years following the diagnosis, he writes, the questions changed. Instead of asking when a cure would arrive, he learned to ask how trials were designed, who was included in them, what outcomes were being measured, and whether the endpoints chosen by scientists reflected what mattered to the children and families living with the condition. Those questions, he suggests, are ones that families learn to ask gradually, and that the research community needs to hear.

This shift mirrors a broader transformation in how rare-disease research is conducted. Over the past two decades, patient organisations have moved from the margins of biomedical science to its centre, funding early-stage research, building patient registries, and pressing regulators to accept outcome measures that capture changes in daily function rather than laboratory markers alone. In Duchenne specifically, parent-led foundations have been credited with accelerating the development of standards of care, driving the creation of natural-history datasets that made clinical trials feasible, and sustaining momentum during long periods when commercial interest in an ultra-rare paediatric condition was limited. Smith’s essay situates his own experience within that movement, presenting the family not as a passive recipient of scientific progress but as a participant in it.

The nearly twenty-year arc that Smith describes also captures the uneven rhythm of translational science in neuromuscular disease. A child diagnosed in 2011 grew up in a period when the first antisense oligonucleotide therapies designed to skip exons in the DMD gene were moving through clinical development, when ataluren was being evaluated in Europe, and when gene-transfer trials were beginning to test whether a microdystrophin construct, a shortened but functional version of the gene packaged into an adeno-associated virus vector, could slow the disease’s progression. Each of these advances arrived wrapped in caveats: modest effects, contested endpoints, regulatory debates over surrogate markers, and the persistent gap between statistical significance and meaningful change in a child’s life. Families lived through those debates from the inside, weighing enrolment decisions and eligibility criteria while their children continued to grow weaker.

Smith’s central insight, as framed by the essay’s title, is that the questions a family learns to ask are themselves a form of knowledge worth recording. Early questions tend to be urgent and personal: what is the prognosis, what can be done now, what will happen next year. Later questions become structural and critical: why does this trial exclude children with certain mutations, how was this outcome measure validated, who decided that this was the primary endpoint, and how will the results be communicated to the people who volunteered for the study. The progression, he implies, is not merely a parent’s education in clinical science; it is a critique of how science communicates, and a reminder that the language of research, like the vocabulary of dystrophin and degeneration that replaced ordinary conversation on the day of diagnosis, has to be learned by families who never asked to enrol in that education.

For the readership of Pediatric Research, the value of such a perspective lies in its specificity. Reflection pieces of this kind occupy a small but significant niche in medical journals, offering clinicians and scientists a view of their work from the other side of the consulting-room door. Smith’s account, grounded in a single date, a single diagnosis and a single child, resists generalisation while making a general point: that research on childhood disease is conducted on families as much as in them, and that the quality of that research depends partly on how seriously the lived experience of patients is treated as evidence. The essay’s publication in a peer-reviewed paediatric journal signals an institutional willingness to count that experience as part of the scientific record.

The piece closes, in effect, where it began, but with the terms reversed. The father who once thought research was about finding answers now frames it as an ongoing conversation in which the questions matter as much as the results, and in which families, clinicians and scientists each hold fragments of the truth. Nearly two decades after a folder of incomprehensible information left a paediatrician’s office in January 2011, the vocabulary of dystrophin and muscle degeneration has become familiar, but the most important questions, Smith suggests, are still being learned, and they are questions that no single participant in the research enterprise can ask alone.

Subject of Research: A parent's perspective on living alongside Duchenne muscular dystrophy and family engagement with pediatric research

Article Title: Family reflections: the questions we learn to ask

Article References: Smith, A. (2026). Family reflections: the questions we learn to ask. Pediatric Research. https://doi.org/10.1038/s41390-026-05533-z

Image Credits: AI Generated

DOI: 10.1038/s41390-026-05533-z

Keywords: Duchenne muscular dystrophy, dystrophin, Pediatric Research, patient advocacy, rare disease, genetics, clinical trials, parent perspective, muscle degeneration, X-linked inheritance, gene therapy, family reflections