Publications by Year: 2026

BACKGROUND: Maternal breast milk is the optimal nutrition for preterm infants, supporting immune and gut maturation. When unavailable, alternatives include infant formulas or pasteurized donor milk, the latter conferring greater protection against feeding intolerance and necrotizing enterocolitis. This study examined the impact of cow's milk-derived extensively hydrolyzed proteins (eHP), widely used in formulas and human milk fortifiers, on intestinal barrier function and gene expression in fetal human intestinal organoid-derived monolayers, modeling premature epithelium.

METHODS: Monolayers were exposed to free amino acids (AA), intact cow milk proteins (WP), or eHP at different concentrations, followed by inflammatory cytokines or commensal bacteria, to mimic physiologic gut conditions. Barrier integrity, permeability, and viability were measured using FITC-Dextran diffusion and LDH release. RNA-seq assessed transcriptional changes.

RESULTS: eHP at low and high concentrations decreased epithelial permeability at baseline, AA showed no effect, and WP only at high concentrations. Under inflammatory conditions, eHP significantly reduced epithelial barrier permeability; both eHP and AA improved cell viability at low concentrations. Transcriptomic analysis revealed modulation of proliferation- and regulation-related pathways, including NOTCH and WNT signaling.

CONCLUSION: In this gut model, eHP enhanced barrier function under baseline and inflammatory conditions, supporting their role in nutrition, though further validation is needed.

IMPACT: Extensively hydrolyzed proteins (eHP) derived from cow's milk improve intestinal barrier function and cell viability in a fetal organoid-derived model of premature human intestine. This is the first study to assess the functional and transcriptomic impact of eHP on primary intestinal epithelial cells derived from fetal organoids, a highly relevant model for preterm gut physiology. It demonstrates that eHP-unlike intact proteins or free amino acids-can mitigate inflammation-induced permeability and modulate pathways involved in epithelial proliferation and repair (e.g., NOTCH, WNT, E2F, G2M checkpoint). These findings highlight the potential of eHP as a nutritional strategy to enhance gut integrity and limit inflammatory damage in preterm infants, who are at high risk of intestinal complications such as NEC. This study paves the way for further mechanistic and clinical research on how peptide-based formulas might support immature gut function and reduce extraintestinal risks.

The International Neonatal Consortium Seizure Working Group of the Critical Path Institute provides an update to the original recommendations for design of clinical trials to treat neonatal seizures based on recent experiences from several trials and developments in the field. Although there aren't sufficient new data to inform definitions of optimal efficacy endpoints, the Working Group recommended inclusion of alternate measures of seizure burden reduction as secondary or exploratory endpoints, to elucidate clinically meaningful efficacy endpoints for future trials. It was recommended to include additional key covariates, such as timing of seizure onset/cessation, randomization, and ASM administration. There are new recommendations regarding potential for unmasked or single-masked trials, and reporting of concomitant medications and adverse events, and genetic testing. Importantly, specific recommendations were added regarding improved strategies for recruitment and consent, including the use of novel technologies and the involvement of patient advocacy groups. Recommendations regarding trial infrastructure and operational feasibility were included to facilitate trial initiation and conduct, given the many logistical challenges of conducting neonatal seizure treatment trials. Finally, the recommendations consider accommodations for local or national regulations and resources, to ensure that trials are conducted as appropriate to the setting in which the patients are treated. IMPACT: This review provides an update to the initial recommendations for neonatal seizure treatment trial design, with recommendations regarding: (1) exploratory endpoints to inform future trials, (2) additional key covariates to include, (3) considerations regarding masking of investigators, (3) inclusion of concomitant medications and adverse events, (4) genetic testing, (5) strategies for recruitment and consent, and (6) infrastructure and operational feasibility.

Waldenström macroglobulinemia (WM) is the most common malignancy associated with an IgM paraprotein, but in rare cases, a clonal IgM may be the result of IgM multiple myeloma (IgM-MM). Although there are some overlapping features associated with these two entities, there are specific characteristics that can help differentiate IgM-MM from WM. In each patient a thorough clinical, pathologic, and genomic evaluation is required to distinguish these conditions and allow for accurate diagnosis and appropriate treatment.

INTRODUCTION: In spinal muscular atrophy (SMA), irreversible loss of spinal motor neurons and progressive skeletal muscle atrophy cause continuous weakness and loss of motor function. Treatments that increase levels of survival motor neuron (SMN) protein in motor neurons have greatly improved prognoses for patients, but significant unmet needs remain. Myostatin is a protein secreted by skeletal muscle that acts as a negative regulator of muscle growth. Inhibition of the myostatin signaling pathway may improve motor function in SMA and other neuromuscular diseases.

AREAS COVERED: This article reviews the role of muscle in SMA and the potential for treatments that inhibit the myostatin signaling pathway in neuromuscular diseases. Preclinical and clinical trial data are discussed for these muscle-targeted treatments in development for SMA.

EXPERT OPINION: SMN-targeted disease-modifying treatments focus on motor neuron survival rather than muscle. Treated individuals nonetheless experience a range of persistent muscle weakness. Treatments that inhibit myostatin signaling represent a potential complementary pathway for direct muscle enhancement. In the evolving SMA treatment landscape, understanding how muscle-targeted treatment can be incorporated into clinical practice will facilitate individualized treatment decisions and identify outcomes that best encapsulate maintenance or improvement of motor function across the phenotypic spectrum of SMA.

Red blood cells (RBCs) play a crucial role in delivering oxygen to tissues with their distinctive shape. However, the mechanisms underlying cellular deformation and rupture due to stress, which lead to diseases such as acute renal failure, pulmonary hypertension, anemia, and gallstone formation, remain poorly understood. Here, we investigate the mechanism of membrane protrusion and present a highly effective method to restore the morphology and function of damaged RBCs. We propose ultrasound-triggered nanodroplets loaded with oxygen and glucose to increase the local concentrations of these substances around RBCs and facilitate the rapid release of their payloads to repair fatigued RBCs under ultrasound. We identify a critical membrane protrusion length threshold of one-third the cell's diameter, beyond which the skeleton structure fractures and prevents repair. Our findings demonstrate how nanodroplets can efficiently deliver oxygen and glucose to expose membrane connection and trigger cytoskeleton reorganization to repair cellular structure. In an in vitro extracorporeal membrane oxygenation (ECMO) model, our method reduces the percentage of abnormal RBCs to 5% and decreases free hemoglobin concentration by 50%. This work offers new insights into RBC rejuvenation and strongly supports the potential of ultrasound-triggered nanodroplets for revitalizing fatigued RBCs, contributing to long-term health and well-being.

SUMMARY: Uchimata is a toolkit for visualization of 3D structures of genomes. It consists of two packages: a Javascript library facilitating the rendering of 3D models of genomes, and a Python widget for visualization in Jupyter Notebooks. Main features include an expressive way to specify visual encodings, and filtering of 3D genome structures based on genomic semantics and spatial aspects. Uchimata is designed to be highly integratable with biological tooling available in Python.

AVAILABILITY AND IMPLEMENTATION: Uchimata is released under the MIT License. The Javascript library is available on NPM, while the widget is available as a Python package hosted on PyPI. The source code for both is available publicly on Github (https://github.com/hms-dbmi/uchimata and https://github.com/hms-dbmi/uchimata-py) and Zenodo (https://doi.org/10.5281/zenodo.17831959 and https://doi.org/10.5281/zenodo.17832045). The documentation with examples is hosted at https://hms-dbmi.github.io/uchimata/.

BACKGROUND: Antithrombotic therapy (ATT) is recommended for patients with symptomatic lower extremity peripheral arterial disease (PAD). Optimal management of "breakthrough" venous thromboembolic events (VTEs) in these patients remains unclear. This study aims to describe current ATT prescription patterns in PAD patients before, during, and after VTE (treatment) and subsequent clinical outcomes.

METHODS: Using Dutch nationwide data, this cohort study identified patients with a reimbursement code for PAD between 2013 and 2021. Within this source population, patients with an International Classification of Diseases-10 code for VTE were identified and followed from VTE date until end-of-study date or death, whichever occurred first. ATT prescriptions, determined from pharmacy records, were mapped in 3 timeframes: 3 months before VTE, during VTE treatment, and 4 to 12 months after VTE.

RESULTS: Patients with PAD (N = 1866) and a concurrent VTE were included, with a mean age of 71.7 years and a median survival of 3.8 years. Before the VTE, 64% used antiplatelet therapy only, in contrast to 12% after VTE treatment. During the VTE treatment period, direct oral anticoagulants were the most frequently dispensed ATT type (40%), whereas 27% received anticoagulation plus antiplatelet therapy during this time. The one-year cumulative incidences of arterial thromboembolic events and clinically relevant bleedings were 6.1% (95% CI: 4.9-7.3) and 1.8% (95% CI, 1.2-2.4), respectively.

CONCLUSION: Immediate treatment of VTE and long-term ATT use in PAD patients were heterogeneous in our cohort. A substantial proportion of patients had prescriptions for both antiplatelet therapy and anticoagulation during the VTE treatment period. Our findings highlight the need for consensus on this complex clinical dilemma.

BACKGROUND: Physicians prescribing antibiotics for common infections must weigh trade-offs across drug attributes such as efficacy, dosing, side effects, and resistance. Understanding these priorities can help inform drug development, regulatory decisions, and insurance coverage determinations.

METHODS: We conducted a discrete choice experiment between June 5 and 9 July 2024, among a national sample of US physicians who prescribed antibiotics for community-acquired pneumonia (CAP) or complicated urinary tract infections (UTIs) in the past year. Respondents evaluated paired hypothetical antibiotics varying by 5 attributes: time to symptom improvement, dosing frequency, risk of nonserious and serious side effects, and risk of future resistance to the patient. Preference weights and relative importance scores were estimated using conditional logistic models. Subgroup analyses were conducted by disease, care setting, and specialty.

RESULTS: Of 880 enrolled physicians, 756 (86%) completed the survey. Respondents had a mean age of 51.5 years; 60% were male, and most practiced general internal medicine (64%) or infectious disease (15%). The most influential attributes overall were symptom improvement (relative importance score: 28%) and dosing convenience (relative importance score: 27%). In inpatient settings, physicians prioritized symptom improvement (relative importance score: 33%), while outpatient physicians prioritized dosing frequency (relative importance score: 31%). Risk of future antibiotic resistance to the patient was consistently the least influential attribute (relative importance score: 7%-13%) across disease-types and clinical settings.

CONCLUSIONS: In this national survey study, physicians prioritized rapid symptom relief and dosing convenience over other drug attributes when prescribing antibiotics for CAP and UTIs. Understanding physician priorities can help inform stewardship strategies and clinician-facing decision support, and encourage regulators and sponsors to prioritize clinically meaningful trial endpoints.

INTRODUCTION: The PSEN1E280A mutation causes autosomal dominant Alzheimer's disease (ADAD) with predictable onset, enabling presymptomatic studies. Extracellular vesicles (EVs) are emerging biomarkers of cognitive decline, but their role in early ADAD is unclear. The rare apolipoprotein E (APOE3) Christchurch (APOE3Ch) variant delays disease onset, yet its effect on EVs is unknown.

METHODS: We analyzed plasma EVs from mild cognitive impairment (MCI) and non-MCI PSEN1E280A-APOE3 carriers and non-MCI PSEN1E280A-APOE3Ch carriers using flow cytometry, proteomics, and co-culture assays.

RESULTS: APOE3Ch-EVs showed reduced vascular activation and inflammatory cargo linked to β-catenin signaling, higher apoE levels, and enrichment in lipid-loaded EVs. They mimicked the protective effect of recombinant ApoE3Ch on endothelial integrity by restoring β-catenin nuclear localization. In contrast, EVs from non-MCI PSEN1E280A-APOE3 carriers displayed vascular and inflammatory signatures associated with poorer cognition and detrimental astrocyte-endothelium effects. These findings highlight APOE3Ch-EVs as modulators of vascular and inflammatory pathways with biomarker and therapeutic potential in ADAD.