Publications by Year: 2026

The stable reactive oxygen species (ROS) hydrogen peroxide (H2O2) acts as a key signaling molecule for many vital intracellular pathways. In diverse cell types, surface receptors control intracellular H2O2 levels by modulating the activity of NADPH oxidases (NOX), a family of enzymes responsible for ROS synthesis. Most NOX isoforms are regulated through the reversible assembly of protein subunits to form an active oligomeric complex. The NOX isoforms NOX2 and NOX4 are expressed in endothelial cells and generate H2O2 in response to activation of cell surface receptors. The GPCR agonist histamine activates NOX2 independently of NOX4, but the H2O2 response to activation of the receptor tyrosine kinase agonist vascular endothelial growth factor (VEGF) involves both NOX2 and NOX4 by unknown mechanisms [M. Waldeck-Weiermair et al., Redox Biol. 58, 102539 (2022); M. Waldeck-Weiermair et al., Redox Biol. 73, 103214 (2024)]. Here, we show that endothelial NOX4 is localized to the endoplasmic reticulum (ER). We define the redox states of various subcellular locales in the vascular endothelium and demonstrate that NOX2 is responsible for cytosolic H2O2 signaling, whereas NOX4 contributes to H2O2 generation in the endoplasmic reticulum. Using biochemical assays and structural modeling, we further identify a previously unrecognized regulatory interaction in which the NOX2 subunit p67 associates with NOX4. VEGF stimulation induces dynamic dissociation of p67 from NOX4, unveiling a "cross talk" between NOX isoforms that coordinates the activation of both NOX2 and NOX4 and thereby produces compartment-specific H2O2 signals. This mechanism underscores the pivotal roles of NOX2 and NOX4 subunit interactions in endothelial redox homeostasis controlling cell survival, proliferation, and migration.

Fifty years ago, at the remarkably young age of 37, David Baltimore received the Nobel Prize (with Howard Temin and Renato Dulbecco) for "discoveries concerning the interaction between tumor viruses and the genetic material of the cell." David was a prolific scientist whose work spanned many topics, but he was first and foremost a virologist. His recent passing invites us to reflect on a remarkable intellectual trajectory that began with seminal discoveries in virology, broadened to encompass major advances in cancer biology and immunology, and culminated in a legacy-sustained by the many scientists he trained-that will continue to shape modern biomedicine for years to come.

OBJECTIVE: To address previous inconsistencies in reports of differential adherence to diabetes medications, we examined medication adherence and evaluated treatment group differences in a substudy of participants in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).

RESEARCH DESIGN AND METHODS: GRADE participants (type 2 diabetes duration <10 years, HbA1c 6.8%-8.5%, on metformin alone) were randomly assigned to add insulin glargine, glimepiride, liraglutide, or sitagliptin. Adherence was measured semiannually for 3 years using a validated three-item scale (0-100, lowest to highest adherence) in a substudy (N = 1,739). Analyses included evaluation of adherence over time and testing treatment group differences in adherence and in the association between adherence and primary (HbA1c ≥7.0%) and secondary (HbA1c >7.5%) glycemic outcomes.

RESULTS: Overall mean ± SD adherence (average of participant-level mean ± SD) was high over 3 years of follow-up at 88.7 ± 10.01, on a scale of 0-100, and decreased slightly by 3 years relative to baseline (-2.0 ± 14.7; P < 0.0001). No intergroup differences were observed until 3 years, when adherence was 5% and 3% higher for the glimepiride and sitagliptin groups, respectively, than for liraglutide (both P < 0.05). Over follow-up and across groups, a 10-point decrease in adherence was associated with 15% and 19% increased risk of reaching primary (HbA1c ≥7.0%) and secondary (HbA1c >7.5%) glycemic outcomes (both P < 0.0001). Lower adherence was somewhat more predictive of the secondary outcome for those assigned to glargine or liraglutide, compared with glimepiride or sitagliptin (each P < 0.05). No other comparisons were significant.

CONCLUSIONS: Medication adherence was consistently high in GRADE. Observed treatment group differences were small and of unclear clinical significance. Overall, lower adherence robustly predicted worsening glycemic control, highlighting the importance of ongoing assessment.

OBJECTIVE: Pain sketches help visualize neuropathic pain patterns in amputees and may predict surgical outcomes following targeted muscle reinnervation (TMR). Current manual interpretation introduces subjectivity and potential bias. Machine learning offers potential for automated, objective classification of these sketches. Therefore, we aimed to develop and evaluate a machine learning approach for automated classification of pain sketches from lower extremity amputees who underwent targeted muscle reinnervation (TMR).

METHODS: Here, 588 pain sketches from 206 lower extremity amputees (2021-2024) were analyzed. Convolutional neural networks were trained to perform binary classifications between pain categories (focal, radiating, diffuse, and no pain). Unsupervised hierarchical clustering was used to identify novel pain distribution patterns.

RESULTS: Binary classification models achieved the highest performance distinguishing no pain versus diffuse pain (AUROC: 0.799). Other models showed AUROCs between 0.587-0.760. Hierarchical clustering revealed distinct pain distribution patterns based on anatomical location and extent, providing insights beyond traditional classification schemes.

CONCLUSIONS: Machine learning can effectively automate pain sketch classification in lower extremity amputees, offering potential clinical utility for preoperative planning. This approach may help standardize interpretation and improve surgical decision-making for TMR procedures.

LEVEL OF EVIDENCE: IV-Therapeutic.

Cancers of the endometrium, cervix, and anus are frequently treated with radiation therapy (RT), which carries a risk for secondary malignancies. RT causes vaginal atrophy, dryness, and increased mucosal friability, predisposing to ulcers. Here, we describe "atypical vulvovaginal postradiation vascular lesion" (AVPRVL), a benign post-RT vascular lesion that histologically mimics angiosarcoma. Fifteen cases were retrospectively identified in patients aged 44 to 77 years (median: 70 y) who presented 3 to 23 years post-RT (median: 14 y), usually with vaginal bleeding. Histologically, AVPRVL demonstrated papillary endothelial hyperplasia (Masson change), mild-to-moderate nuclear atypia, and direct juxtaposition to squamous epithelium. Atypical vessels were located in fibrin and were not distributed in the native lamina propria. MYC immunohistochemistry demonstrated only scattered, weak expression in 5 tested lesions. Fluorescence in situ hybridization was negative for MYC amplification in 11 tested lesions. Five sequenced lesions lacked recurrent pathogenic alterations or copy number changes. Clinical follow-up was available for 11 patients (73%; median length: 3.3 y; range: 1 to 21.7 y). None developed metastases. Six patients (55%) experienced persistent or recurrent lesions, although sometimes it was not possible to distinguish true recurrence from new lesions developing in the RT field. At the most recent follow-up, 9 patients were alive with no evidence of disease, and 2 were alive with recurrent lesions. Ultimately, most lesions resolved with excision or cautery. Unlike RT-associated angiosarcoma, AVPRVL lacked MYC amplification, showed indolent clinical behavior, and usually resolved with conservative management. Unlike cutaneous atypical postradiation vascular proliferation, AVPRVL did not show vessels distributed within native subepithelial tissue. Instead, it more closely resembled a Masson change with nuclear atypia. We conclude that AVPRVL represents a distinctive, benign, possibly reactive vascular proliferation of the vulvovaginal mucosa occurring years after pelvic RT. The distinction between AVPRVL and angiosarcoma is critical to avoid overtreatment.

Hearing loss is a risk factor for dementia, but dementia subtypes underlying this association and effect modifiers are unknown. Using data collected from 2000 Framingham Heart Study participants we found that hearing loss increases risk for Alzheimer's disease and vascular dementia in participants aged 60-70 years ("young-old") at time of hearing assessment (Alzheimer's disease: HR 1.46[CI 1.07-2.0] p = 0.017; vascular dementia: HR 2.08[CI 1.22-3.56] p = 0.007). Longer duration of hearing loss determines increased risk for Alzheimer's disease and vascular dementia, and screening and intervention for hearing loss from mid-life may help reduce dementia.

•AI-driven tools and multimodal biomarkers emerged as key for early VCID detection.•Novel neuroimaging, fluid, and retinal markers show promise for precision diagnostics.•BBB leakage and inflammation could early drive small vessel disease and VCID.•Clinical trials explore drug repurposing and hybrid lifestyle-pharmacological interventions.•Genetic insights into CADASIL reveal shared pathways with sporadic SVD.

OBJECTIVE: Assess current drive times to the nearest pre-exposure prophylaxis (PrEP) provider in each county in the contiguous United States (US) and examine changes since the last analysis (2017).

METHODS: PrEP provider data were obtained from PrEPLocator.org in March 2025. Geospatial analyses calculated one-way drive times from population-weighted county centroids to the nearest provider. Counties with drive times >30 min were defined as PrEP deserts. Linear regression assessed variation in drive times by urbanicity and region, adjusting for median income, small-area population estimates of men who have sex with men (MSM), and proportion of racial/ethnic minority populations.

RESULTS: In 2025, median drive time was 30.2 min, increasing with decreasing urbanicity (p < 0.05). Half of counties were PrEP deserts, accounting for 36 million residents and 4 % of PrEP-eligible MSM. Drive times in micropolitan/non-core counties were 5-8 times higher than in large metro counties. Between 2017 and 2025, the US South had the largest relative reduction in drive time: however, relative changes did not significantly differ by urbanicity.

CONCLUSIONS: While PrEP access has improved nationally, important geographic disparities remain. Programs and policies must prioritize expanding access to PrEP to less urban areas to end the HIV epidemic in the US.

BACKGROUND: Asthma remission has emerged as a potential therapeutic goal. However, definitions of remission have primarily focused on adult populations, with limited consensus on how remission should be defined in children.

OBJECTIVE: To comprehensively review how asthma remission has been defined in children and to evaluate consistency and applicability of these definitions.

METHODS: This scoping review was conducted following PRISMA-ScR guidelines. PubMed MEDLINE was searched for studies published between January 2010 and February 2024. Eligible studies included children with asthma and reported definitions of remission. Key remission criteria were extracted and categorized, and hierarchical cluster analysis was used to identify key patterns.

RESULTS: Twenty-nine studies met the inclusion criteria. Most (79.3%) defined paediatric asthma remission based on the absence of clinical symptoms. The most common remission timeframe ranged from 1 to 2 years. A medication-free criterion was used in 68.9% of studies. On-treatment remission was reported in the minority of studies, but it is increasingly acknowledged as a valid outcome. Objective assessments, such as normal lung function (21%) and absence of bronchial hyperresponsiveness (10.3%), were infrequently included. Cluster analysis revealed 3 main patterns for remission definition: symptom-based, event-based, and 1 including objective criteria.

CONCLUSION: Current definitions of asthma remission in paediatric populations are predominantly symptom-based, with limited inclusion of objective physiological measures. Establishing consensus-based definitions for remission tailored to paediatric populations is essential to ensure clinical relevance and alignment with real-world disease patterns.