Publications by Year: 2026

Deep brain stimulation (DBS) of the subthalamic nucleus improves motor symptoms in patients with Parkinson's disease. Using functional MRI, optimal DBS response networks have been characterized. However, neural activity associated with Parkinsonian symptoms is magnitudes faster than what can be resolved by this method. Although both spatial and temporal domains of these networks appear crucial, no single study has yet investigated both domains simultaneously. Here, we aimed at closing this gap by analysing electrophysiological data from a total of n = 127 hemispheres. Using subthalamic local field potentials that were recorded concurrently alongside whole-brain magnetoencephalography in a multi-centre cohort of patients who underwent subthalamic DBS for the treatment of Parkinson's disease (n = 100 hemispheres), we analysed the DBS response network in both spatial and temporal domains. In every cortical vertex, cortico-subthalamic coupling was correlated with stimulation outcomes. This network spatially resembled functional MRI-based findings (R = 0.40, P = 0.039) and explained significant amounts of variance in clinical outcomes (βstd = 0.30, P = 0.002), whereas theta-alpha and low beta coupling did not show significant associations with DBS response (theta-alpha: βstd = -0.02, P = 0.805; low beta: βstd = -0.08, P = 0.426). The 'optimal' high beta coupling map was robust when subjected to various cross-validation designs (10-fold cross-validation: R = 0.29, P = 0.009; split-half design: R = 0.31, P = 0.026) and was able to predict outcomes across DBS centres [R = 0.74; P(1) = 8.9 × 10-5]. We identified a DBS response network that resembles the previously defined MRI network and operates in the high beta band. Maximal connectivity to this network was associated with optimal DBS outcomes and was able to cross-predict clinical improvements across DBS surgeons and centres.

When using real-world data to construct an external comparator arm for a single-arm trial, there may be differences in how and when patients are assessed for disease between trial and real-world settings. Such differences can generate outcome measurement error when comparing time to event endpoints and lead to biased findings. Recent methods have been developed to mitigate measurement error bias in real-world endpoints; however, they rely on the existence of a validation sample, ie, data on a set of patients where both the "true" trial-like and "mis-measured" real-world measures are collected. We demonstrate how novel statistical methods can be leveraged as quantitative bias analyses (QBA) to contextualize real-world evidence findings when outcome measurement error is of concern, but validation samples are infeasible to collect. QBA allows researchers to set plausible ranges for the amount of error when not directly measurable. We highlight how to conduct QBA with two recent methods, Cumulative Incidence Curve Correction and Survival Regression Calibration, and illustrate how to generate plausible parameter values through simulation. We provide an illustrative QBA example in a cohort of real-world patients with Newly Diagnosed Multiple Myeloma and provide practical guidance to apply QBA for outcome measurement error and interpret results.

BACKGROUND: Animal models suggest a role of epigenetic mechanisms, including DNA methylation, in neural tube closure; however, studies characterizing DNA methylation profiles in nervous system tissue from humans with spina bifida are limited. In this study, we assessed DNA methylation profiles in dural tissue of infants with spina bifida, collected at the time of surgical closure of the defect, and examined whether whole blood or buccal swab are appropriate surrogate tissues, as they are more practical to collect in large-scale epidemiological studies. DNA methylation was measured in dural tissue, buccal swab, and whole blood samples collected from 27 unique infants using the Illumina Infinium MethylationEPIC BeadChip array.

RESULTS: Correlation analysis for each CpG site comparing DNA methylation from all participants in dural tissue to DNA methylation in whole blood DNA or buccal swab DNA yielded 1555 statistically significant associations for the whole blood analysis and 920 significant associations for the buccal swab analysis at the Bonferroni threshold of significance. We also performed paired analysis, calculating differences between tissues within each individual and then averaging differences across individuals. After accounting for multiple hypothesis testing using the FDR adjustment, 33% of CpG sites assessed were not significantly differentially methylated between dural tissue and whole blood samples, compared to the 27% of sites not differentially methylated between dural tissue and buccal swab samples.

CONCLUSIONS: These results suggest that in the absence of dural tissue, both whole blood and buccal swab samples may be considered as surrogates for dural tissue. The study warrants replication in larger groups to validate findings and may assist researchers restricted to more accessible biospecimens (i.e., blood) to further characterize epigenetic contributors to neural tube defect etiology.

BACKGROUND: Complex tibial plateau fractures continue to pose a significant challenge for surgeons. In recent years, the widespread use of CT imaging has led to new insights leading to novel classifications that facilitate 360° stabilization techniques. Visualization in 3D has improved both fracture reduction and surgical outcomes. This study investigated whether preoperative planning of complex tibial plateau fracture fixation via finite element modeling (FEM) could enhance the fixation performance achieved by experienced surgeons and potentially improve outcomes for less experienced surgeons.

METHODS: In twelve left cadaveric fresh-frozen human knees with intact soft tissue reproducible Schatzker type IV fractures with lateral depression were created. The samples were paired on the basis of bone mineral density and then randomly allocated into two groups. Six senior surgeons with extensive experience in the operative treatment of tibial plateau fractures performed two procedures: one using standard preoperative planning and one using FEM-optimized fixation planning. All fractures were stabilized with a medial locking plate and supplemental single screws when needed. The operation time, radiation dose and implant usage were documented. Surgeon mental workload was measured by the NASA task load index. Finally, the samples were biomechanically tested over four quasistatic load ramps from 10 to 200 N, followed by a cyclic sinusoidal load with increasing load level until failure. Failure was defined as either ≥ 5° varus/valgus malalignment or a vertical impression of the condyles ≥ 3 mm. The initial stiffness and load to failure were assessed via a 3D motion tracking system. Statistical analysis was conducted using Student's t-tests.

RESULTS: No significant differences were observed in terms of operative time or intraoperative radiation exposure. However, the NASA-TLX mental demand test revealed a statistically significant advantage for the FEM-planned group (33 ± 12.4 vs. 49 ± 8.6 (p = 0.043)), indicating a reduced cognitive load. Additionally, the FEM group exhibited superior biomechanical performance, with a higher load to failure of 1050 ± 535 N vs. 442 ± 226 N (p = 0.041).

CONCLUSION: This biomechanical feasibility study demonstrated that FEM-based preoperative planning is feasible and easy to implement for complex tibial plateau fractures. This planning supports specialized surgeons in challenging operations and can improve the stability of osteosynthesis.

BACKGROUND AND OBJECTIVES: Alzheimer's disease and related dementias (ADRDs) are prevalent conditions that are stressful and elevate emotional distress in couples after diagnosis. Without treatment, emotional distress may become chronic and negatively affect couples' quality of life. We report results from an NIH Stage 1A open pilot of Resilient Together for Dementia (RT-ADRD), a novel, dyadic, skills-based intervention aimed at preventing chronic emotional distress in couples early after diagnosis. We describe results from our mixed-methods single arm feasibility study, including preliminary feasibility and acceptability of the intervention, and qualitative feedback from exit interviews. We also present exploratory analyses for change in outcomes and mechanisms of action.

METHODS: Six couples (N = 12 individuals) were recruited within six months of ADRD diagnosis by their diagnosing providers. Participants completed baseline assessments, participated in weekly RT-ADRD sessions together, then completed post-intervention assessments and one 60-min exit interview together.

RESULTS: RT-ADRD exceeded all a-priori feasibility and acceptability benchmarks (> 70%). Feedback from exit interviews suggested that participants had favorable impressions of the program and found the skills useful and relevant. Participants also offered perspectives on barriers and facilitators of engagement and program enhancement. In exploratory analyses, persons living with dementia exhibited significant reductions in perceived stress at post-intervention (p < .05; Cohens d > 0.8). Both persons living with dementia and their care partners exhibited statistically significant improvements in positive dyadic interactions measured by the Dyadic Relationship Scale (ps < .05); Cohens ds > 0.8).

CONCLUSIONS: RT-ADRD shows promise as a feasible and acceptable dyadic intervention delivered early after diagnosis. Results support a future NIH Stage 1B trial of RT-ADRD to establish definitive feasibility markers of both intervention and control before formal efficacy testing.

TRIAL REGISTRATION: This open pilot was registered on ClinicalTrials.gov (NCT06421545) on 05/20/2024.

OBJECTIVE: To synthesize magnetic resonance imaging (MRI) features and their reported diagnostic performance that differentiate benign from malignant soft-tissue tumors in alignment with the 2020 World Health Organization classification.

MATERIALS AND METHODS: A systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Embase, Scopus, and the Cochrane Central Register of Controlled Trials were searched through July 2024. Eligible studies reported MRI feature frequencies or diagnostic accuracy for common soft-tissue tumor subtypes. Reviews, case reports, duplicates, non-English publications, and studies outside the scope were excluded. Quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2).

RESULTS: Seventy-six studies met inclusion criteria. In lipomatous tumors, homogeneous fat signal and thin septa supported lipoma, whereas thick or nodular septa and enhancement favored atypical or well-differentiated liposarcoma. Myxofibrosarcoma often demonstrated an infiltrative fascial "tail." Vascular lesions included angioleiomyoma with a reticular T2 pattern and glomus tumor with marked T2 hyperintensity and avid enhancement. In peripheral nerve sheath tumors, lower apparent diffusion coefficient values and peritumoral edema favored malignancy. Heterogeneity in imaging protocols precluded meta-analysis; results were summarized descriptively by subtype.

CONCLUSION: Consolidated MRI patterns-such as septal morphology in lipomatous tumors, the fascial tail in myxofibrosarcoma, characteristic T2 patterns in vascular lesions, and diffusion and edema cues in nerve sheath tumors-support differentiation of benign and malignant entities, enhance reader confidence, and inform biopsy and management. Standardized prospective studies are needed to validate these thresholds and improve generalizability.

Pulsed field ablation (PFA) has proven to be a safe and effective non-thermal ablation modality for the treatment of atrial fibrillation (AF), but little outcome data beyond 1 year have been reported. Here we present results from the ADVENT-LTO study, which provides extended follow-up of the ADVENT trial, the first randomized trial comparing PFA with conventional thermal ablation. In ADVENT-LTO, 364 patients with paroxysmal AF (183 PFA, 181 thermal; 237 men, 127 women) participated and were followed for 1,332 ± 147 days. For the primary endpoint of 4-year treatment success, PFA demonstrated preserved effectiveness compared to thermal ablation (72.8% PFA, 64.3% thermal; P = 0.12). Moreover, there was a trend favoring PFA as compared to thermal ablation for the prespecified outcome of freedom from hospital-based arrhythmia intervention (85.6% PFA, 78.6% thermal; hazard ratio (HR) = 0.64, 95% confidence interval (CI): 0.38-1.05), including fewer repeat ablations (10.4% PFA, 17.7% thermal; P = 0.04) as well as a trend favoring PFA as compared to thermal ablation for the prespecified outcome of progression to persistent AF (2.6% PFA, 4.6% thermal; HR = 0.55, 95% CI: 0.16-1.88). Taken together, these data demonstrate that the favorable outcomes of PFA are maintained over the course of 4 years. Coupled with the safety advantages of PFA over thermal ablation, these long-term data support widespread adoption of PFA for the treatment of AF. ClinicalTrials.gov registration: NCT06526546 .

Microvascular dysfunction plays a pivotal role in numerous diseases, often preceding clinical symptoms and structural changes. Ultrasound localization microscopy (ULM) is an emerging ultrasound imaging modality that enables in vivo visualization of microvascular structures with unprecedented resolution. This narrative review aimed to examine the recent clinical applications of ULM and its role in biomarker development. It was conducted following PRISMA 2020 guidelines and included 33 articles published up to November 2025, focusing on ULM in human studies. Inclusion criteria targeted studies evaluating ULM's clinical applications and biomarkers. Data extraction encompassed imaging protocols, biomarkers and outcomes, with study quality assessed using the Newcastle-Ottawa Scale. ULM demonstrates significant promise across various organs. In kidney applications, ULM and its novel variant, sensing ULM, identified glomeruli and microvascular density as biomarkers for kidney disease and allograft dysfunction. In the brain, transcranial ULM enabled microvascular mapping with a resolution of 25 μm, aiding the evaluation of Moyamoya disease. ULM has also shown potential in detecting inflammatory changes in the carotid artery, myocardial microcirculation and testicular vascular architecture. Oncology applications include monitoring tumor vascularity and therapy response, revealing early microvascular changes undetectable by conventional imaging. Future technical improvements, such as higher-frame-rate clinical scanners, real-time data processing and clinical 3D imaging capabilities, are necessary to overcome current limitations. To conclude, ULM is on the verge of clinical translation, offering significant potential for developing microvascular biomarkers across various tissues and diseases. The medical community must now adopt and refine ULM applications and establish their role in routine clinical practice.

Patients with multiple myeloma (MM) often use cardiovascular medications due to their increased risk of cardiovascular diseases. This study investigated the associations of baseline use of these drugs with survival and adverse events in MM patients initiating daratumumab, lenalidomide, or bortezomib combination treatments. Data from Phase III trials (CASTOR, MAIA, and POLLUX) were analysed, focusing on beta-blockers, calcium channel blockers, ACE inhibitors (ACEI), angiotensin II receptor blockers (ARBs), diuretics, and statins. Cox proportional hazard analysis and logistic regression were used to assess associations with survival and grade ≥ 3 adverse events. Among 1804 patients, ACEI/ARBs were most common (31%), followed by beta-blockers (23%), statins (21%), calcium channel blockers (17%), and diuretics (16%). ACEI/ARBs was associated with better progression-free survival (adjusted hazard ratio (aHR) [95% CI] = 0.84 [0.71-0.99], P = 0.034) but also higher odds of grade ≥ 3 adverse events (adjusted odds ratio (aOR) = 1.45 [1.06-1.97], P = 0.019). Diuretics were similarly associated with grade ≥ 3 adverse events (aOR = 1.53 [1.01-2.34], P = 0.047). Other cardiovascular drugs showed no significant associations. While ACEI/ARBs may improve progression-free survival, they pose safety concerns. It is reassuring that other cardiovascular drugs were not significantly associated with MM treatment outcomes. Further research is essential to fully understand the implications of these medications.