Publications by Year: 2026

BACKGROUND: The 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America heart failure (HF) classification incorporates cardiac biomarkers to identify early risk of HF. The HF stages may also guide the prognosis and management of cardiovascular and kidney-related events.

METHODS: SCORED (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk) was a randomized trial in diabetes with kidney disease comparing sotagliflozin versus placebo on cardiovascular death, HF hospitalizations, and urgent HF visits. SCORED participants were grouped by HF stage post hoc. Stage A: no HF, normal biomarkers (NT-proBNP [N-terminal pro-B-type natriuretic peptide] <125 pg/mL; high sensitivity cardiac troponin T [hs-cTnT] <14 ng/L), and normal cardiac structure/function. Stage B (pre-HF): no HF but elevated NT-proBNP, hs-cTnT, or abnormal cardiac structure/function. Stage C/D: symptomatic HF. End points include the primary composite (cardiovascular death and HF-related events), major adverse cardiovascular events, and kidney-related composites (≥50% decline in estimated glomerular filtration rate, kidney failure, or kidney death). Using competing-risk proportional hazards models, we examined the association between HF stage and these end points, and the effect of sotagliflozin versus placebo by HF stage.

RESULTS: There were 741 patients (7%) in stage A, 6560 (62%) in stage B (pre-HF), and 3283 (31%) in stage C/D (established HF). The median NT-proBNP and hs-cTnT increased with HF stage. Increasing HF stage was associated with a 2- to 4-fold increase in the primary outcome/major adverse cardiovascular events in the placebo group. The kidney-specific composite was 5-fold higher in stage B (pre-HF) versus stage A but similar in stages B and C/D. The effect of sotagliflozin versus placebo was similar, irrespective of HF stage (primary outcome: hazard ratio, 0.74 [95% CI, 0.63-0.88]; Pinteraction=1.00), with higher absolute benefit in each HF stage (P-trendIRR=0.002). The absolute benefit for the kidney-specific end point was comparable for stages B and C/D.

CONCLUSIONS: Increasing HF stage is associated with a higher risk of HF, major adverse cardiovascular events, and kidney events. Asymptomatic stage B (pre-HF) increased cardiovascular and renal events by >2- and 5-fold, respectively. The benefits of sotagliflozin are consistent, irrespective of HF stage.

IMPORTANCE: Bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) are leading causes of morbidity and mortality in premature infants.

OBJECTIVE: To determine whether images obtained as part of retinopathy of prematurity (ROP) screening might contain features associated with BPD and PH in infants and whether a multimodal model integrating imaging features with demographic risk factors might outperform a model based on demographic risk alone.

DESIGN, SETTING, AND PARTICIPANTS: A deep learning model was used to study retinal images collected from patients enrolled in the multi-institutional Imaging and Informatics in Retinopathy of Prematurity (i-ROP) study. The analysis included infants at risk for ROP undergoing routine ROP screening examinations from 2012 to 2020. Infants were recruited from 7 neonatal intensive care units. Images were limited to 34 weeks' or less postmenstrual age (PMA) so as to precede the clinical diagnosis of BPD or PH. The dataset included the period from June 2015 to April 2020. Data were analyzed from April to June 2025.

EXPOSURES: BPD was diagnosed by the presence of an oxygen requirement at 36 weeks' PMA, and PH was diagnosed by echocardiogram at 34 weeks. A support vector machine model was trained to predict BPD or PH diagnosis using (1) image features alone (extracted using ResNet18), (2) demographics alone, or (3) image features concatenated with demographics. To reduce the possibility of confounding with ROP, secondary models were trained using only images without clinical signs of ROP.

MAIN OUTCOMES AND MEASURES: For both BPD and PH, performance was reported on a held-out test set and assessed by the area under receiver operating characteristic curve (AUROC).

RESULTS: A total of 493 infants (mean [SD] gestational age, BPD, 25.7 [1.8] weeks; normal, 27.3 [1.8] weeks; 267 male [54.2%]) were included in this analysis. Performance was reported on a held-out test set (99 patients from the BPD cohort and 37 patients from the PH cohort). For BPD, the multimodal model showed higher accuracy (AUC, 0.82; 95% CI, 0.72-0.90) than demographics-only (0.72; ∆AUC, 0.1; 95% CI, -0.008 to 0.21; P = .07) or imaging-only (0.72; ∆AUC, 0.1; 95% CI, 0.04-0.16; P = .002) models. For PH, multimodal AUC was 0.91 vs the demographics-only 0.68 (∆AUC, 0.14; 95% CI, 0.006-0.27; P = .04) and imaging-only 0.91 (∆AUC, -0.09; 95% CI, -0.3 to 0.12; P = .40) models. Results persisted when trained on images lacking clinical ROP signs.

CONCLUSIONS AND RELEVANCE: Results suggest that retinal images obtained during ROP screening may be used to predict the diagnosis of BPD and PH in preterm infants, which may lead to earlier diagnosis and avoid the need for invasive diagnostic testing in the future.

IMPORTANCE: Recurrence rates for locally advanced human papillomavirus (HPV)-independent head and neck squamous cell carcinoma (HNSCC) are high. Circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) assays have shown promise to improve management and surveillance in several tumor types, but their clinical utility in HPV-independent HNSCC remains understudied.

OBJECTIVE: To evaluate the performance of a tumor-informed ctDNA-based MRD assay in patients with newly diagnosed locally advanced HNSCC.

DESIGN, SETTING, AND PARTICIPANTS: Between December 2020 and March 2022, among patients newly diagnosed with locally advanced HNSCC treated with surgery followed by risk-adjusted adjuvant treatment at a large referral center specializing in treatment of HNSCC, ctDNA was assessed before surgery, before the start of adjuvant treatment, within 6 weeks of completion of treatment, and during surveillance. Patients were followed up for at least 12 months after treatment completion. Kaplan-Meier survival analyses were used to compare recurrence-free survival (RFS) and overall survival (OS) between patients who were MRD positive and those who were MRD negative during each time window. Multivariable Cox hazard regressions were used to assess the association between MRD status and outcomes while controlling for established risk factors. Data were analyzed from August 2024 to March 2025.

INTERVENTION: Tumor-informed ctDNA-based MRD testing.

MAIN OUTCOMES AND MEASURES: RFS and OS.

RESULTS: Of 40 included patients, 29 (73%) were male, 38 (95%) had HPV-independent disease, and the median (IQR) age at diagnosis was 63 (28-85) years. A total of 142 samples from 40 patients. A total of 20 patients (50%) experienced recurrence. The presurgery ctDNA detection rate was 97% (35 of 36). MRD positivity within 6 weeks of completion of treatment was associated with worse OS (hazard ratio [HR], 7.15; 95% CI, 1.44-35.34) and RFS (HR, 5.39; 95% CI, 1.98-21.07). MRD positivity during surveillance was associated with worse RFS (HR, 8.27; 95% CI, 2.03-33.64). The median (range) time from first MRD detection to clinical detection of recurrence was 5 (0.2-21.6) months. In multivariable analyses, MRD positivity was associated with worse RFS (HR, 13.84; 95% CI, 2.92-65.68) and worse OS (HR, 18.93; 95% CI, 2.27-157.70).

CONCLUSIONS AND RELEVANCE: In this study, tumor-informed ctDNA MRD positivity was associated with worse RFS and OS in patients with HNSCC. MRD testing could serve as a noninvasive, prognostic biomarker in patients with HPV-independent HNSCC.

OBJECTIVE: Cognitive dysfunction (CD) is a prevalent symptom in childhood-onset systemic lupus erythematosus (cSLE). This study aimed to investigate the neurobehavioral basis of CD in cSLE.

METHODS: Patients with cSLE (N=20) and age- and sex-matched healthy controls (HCs, N=20) completed questionnaires and multiple neurocognitive tests. The Systemic Lupus Erythematosus Disease Activity Index 2000 and laboratory markers were used to monitor patients' clinical status. Neuroimaging assessments included functional near-infrared spectroscopy (fNIRS), functional magnetic resonance imaging (fMRI), and structural MRI.

RESULTS: cSLE patients demonstrated moderate disease activity with high inflammation and immune dysregulation, alongside low medication adherence. Relative to HCs, cSLE patients showed worse cognitive functioning, higher emotional distress and more physical symptoms. fNIRS revealed higher prefrontal cortex activity in cSLE vs. HCs during the color-word Stroop task, suggesting impaired cognitive flexibility. fMRI performed during the N-back working memory task revealed altered frontal cortex and cerebellum activity, while modulations in resting-state fronto-cerebellar connectivity in the cSLE cohort were observed. Patients with cSLE were characterized by reduced gray matter morphological properties in frontal cortex and cerebellar subdivisions (e.g., crus II) alongside altered white matter structural connectivity among these cognitive processing hubs. K-means clustering analysis delineated three subgroups within the cSLE cohort based on neuroimaging profiles, where subgroups varied based on cognitive and emotional health.

CONCLUSION: This study provides evidence of fronto-cerebellar abnormalities and their associations with CD in cSLE. This investigation underscores the need for multidisciplinary research efforts to further elucidate the neurobiological underpinnings of CD in cSLE.

Accurate fetal brain tissue segmentation and biometric measurement are essential for monitoring neurodevelopment and detecting abnormalities in utero. The Fetal Tissue Annotation (FeTA) Challenges have established robust multi-center benchmarks for evaluating state-of-the-art segmentation methods. This paper presents the results of the 2024 challenge edition, which introduced three key innovations. First, we introduced a topology-aware metric based on the Euler characteristic difference (ED) to overcome the performance plateau observed with traditional metrics like Dice or Hausdorff distance (HD), as the performance of the best models in segmentation surpassed the inter-rater variability. While the best teams reached similar scores in Dice (0.81-0.82) and HD95 (2.1-2.3 mm), ED provided greater discriminative power: the winning method achieved an ED of 20.9, representing roughly a 50% improvement over the second- and third-ranked teams despite comparable Dice scores. Second, we introduced a new 0.55T low-field MRI test set, which, when paired with high-quality super-resolution reconstruction, achieved the highest segmentation performance across all test cohorts (Dice=0.86, HD95=1.69, ED=6.26). This provides the first quantitative evidence that low-cost, low-field MRI can match or surpass high-field systems in automated fetal brain segmentation. Third, the new biometry estimation task exposed a clear performance gap: although the best model reached a mean average percentage error (MAPE) of 7.72%, most submissions failed to outperform a simple gestational-age-based linear regression model (MAPE=9.56%), and all remained above inter-rater variability with a MAPE of 5.38%. Finally, by analyzing the top-performing models from FeTA 2024 alongside those from previous challenge editions, we identify ensembles of 3D nnU-Net trained on both real and synthetic data with both image- and anatomy-level augmentations as the most effective approaches for fetal brain segmentation. Our quantitative analysis reveals that acquisition site, super-resolution strategy, and image quality are the primary sources of domain shift, informing recommendations to enhance the robustness and generalizability of automated fetal brain analysis methods.

BACKGROUND: Hallucinations are underrecognized neuropsychiatric complications after cardiac surgery. Data on incidence and type-specific predictors in coronary artery bypass grafting (CABG) and valvular surgery are limited.

METHODS: We conducted a multicenter prospective cohort study (September 2022 to May 2025) across West Bank cardiac surgery centers. A total of 1332 adults (997 CABG, 335 valve) were assessed daily for 7 days postoperatively using the Questionnaire for Psychotic Experiences. Predictors of visual and auditory hallucinations evaluated with Cox proportional hazards models.

RESULTS: Visual hallucinations occurred in 11.5 % of CABG patients and 10.0 % of valve surgery patients, while auditory hallucinations were reported in 7.0 % and 5.0 %, respectively. In the CABG group, the multivariable Cox regression models stratified by hospital showed that auditory hallucinations were significantly associated with lower left ventricular ejection fraction (HR = 1.05 per 1 % decrease; 95 % CI 1.01-1.09), longer aortic cross-clamp time (HR = 1.01 per minute; 95 % CI1.0004-1.02), and immunosuppressive therapy (HR = 4.81; 95 % CI 1.13-20.53). Postoperative blood transfusion was associated with an increased risk of visual hallucinations in univariate analysis (HR = 1.87; 95 % CI 1.05-3.33), but the association became borderline after adjustment (HR = 1.97; 95 % CI 0.95-4.09). Among the valve surgery cohort, the hospital-stratified models indicated that prolonged postoperative ventilation was independently protective against visual hallucinations (adjusted HR = 0.78; 95 % CI 0.68-0.90), whereas noradrenalin use (adjusted HR = 6.07; 95 % CI 2.18-16.93) and immunosuppressive therapy (adjusted HR = 5.13; 95 % CI 1.14-23.09) markedly increased the risk. For auditory hallucinations in valve surgery patients, adrenaline exposure emerged as a significant independent predictor (adjusted HR = 3.40; 95 % CI 1.21-9.54).

CONCLUSIONS: Postoperative hallucinations affected ∼1 in 10 patients; visual hallucinations were more frequent, auditory hallucinations linked to stress and medications, with risks varying by surgery type, supporting tailored monitoring and prevention.

BACKGROUND: The purpose of this study was to report the outcome of primary localized pleomorphic rhabdomyosarcoma (P-RMS).

PATIENTS AND METHODS: Patients with primary localized P-RMS, aged >40 years, and surgically treated with curative intent from January 2013 to December 2023 were enrolled from 25 institutions across 12 countries. Pathological inclusion criteria were predefined by expert pathologists per established World Health Organization guidelines. Primary endpoint was overall survival (OS). Secondary endpoints were disease-free survival (DFS), crude cumulative incidence (CCI) of local recurrence (LR), CCI of distant metastases (DM), post-relapse OS, and post-metastasis OS.

RESULTS: A total of 93 patients were eligible and included in the present study. At a median follow-up of 39.8 months (interquartile range 22.83-85.69 months), 32/93 (34%) patients died and 53/93 (57%) recurred. The corresponding 5-year OS and DFS were 57.7% [95% confidence interval (CI) 46.7% to 71.2%] and 35.8% (95% CI 26.3% to 48.9%), respectively. Younger age, R0 surgical margins, and administration of radiotherapy were positive prognostic factors in multivariable analysis for DFS. LR and DM were developed in 14/93 (15%) and 39/93 (42%) patients, respectively. The corresponding 3-year CCI-LR and DM were 16% (95% CI 8.9% to 25%) and 44% (95% CI 33% to 55%). Post-metastasis median OS was 14.3 months (95% CI 9.4 months-not reached).

CONCLUSIONS: While P-RMS is known to be an aggressive histologic sarcoma subtype, one-third of patients with primary localized disease may be cured. The contribution of chemotherapy and radiotherapy to the cure rate remains unclear. Post-metastatic outcomes mirror those observed in other sarcomas.

The Food and Drug Administration recently announced a plan to phase out animal-testing requirements for drug assessments based on advances in new approach methodologies, including human organ-on-a-chip (Organ Chip) microfluidic culture technology. Although Organ Chips are being explored in many pharmaceutical laboratories, they have not yet been integrated into drug-development pipelines. Here, I review challenges that must be overcome to bridge this gap and new opportunities that will emerge. I also discuss additional work that will be required for Organ Chips to reduce animal use, lower drug costs, meet regulatory goals, and improve clinical success in the future.

BACKGROUND: There is limited experience of the all-oral 6-month regimens containing bedaquiline, delamanid, linezolid and levofloxacin/clofazimine (BDLLfx/BDLCfz) in pregnant women with MDR/RR-TB. We report maternal treatment, pregnancy, and infant outcomes to 12 months of age in a cohort of pregnant women treated with these regimens.

METHODS: We included pregnant women treated for MDR/RR-TB from September 2023 to January 2025 in KwaZulu-Natal, South Africa in a prospective observational study. Outcomes were collected through ongoing record reviews. Infant clinical assessments were conducted at six weeks, six and 12 months.

RESULTS: Of 25 pregnant women with MDR/RR-TB, 21 received BDLLfx/BDLCfz; 12 (57%) were living with HIV. Although 10/21 (48%) of the women developed anaemia, 18 (86%) had favourable treatment outcomes. All 21 infants were born alive; median gestational age 39 weeks (interquartile range [IQR]:38-40) and median birth weight 3160g (IQR: 2818-3308). Three women had unfavourable pregnancy outcomes, with infants born prematurely, two with low birth weight, one of whom developed respiratory distress syndrome. Of the 18 infants evaluated at 12 months, ten (56%) had possible or confirmed unfavourable outcomes. Two infants had confirmed congenital anomalies and three possible congenital anomalies, but only one had first-trimester drug exposure. One infant died, another was diagnosed with MDR/RR-TB and started on treatment, and three infants had signs/symptoms of TB necessitating referral for care.

CONCLUSIONS: These limited data suggests that in pregnant women, the BDLLfx/BDLCfz regimens have improved treatment and pregnancy outcomes compared to prior regimens. However, there is a high prevalence of unfavourable infant outcomes.

Transitions of cancer cells between distinct cell states, which are typically driven by transcription reprogramming, fuel tumor plasticity, metastasis, and therapeutic resistance. Whether the transitions between cell states can be therapeutically targeted remains unknown. Here, using the epithelial-to-mesenchymal transition (EMT) as a model, we show that the transcription reprogramming during a cell-state transition induces genomic instability through R-loops and transcription-replication conflicts, and the cell-state transition cannot occur without the ATR kinase, a key regulator of the replication stress response. ATR inhibition during EMT not only increases transcription- and replication-dependent genomic instability but also disrupts transcription reprogramming. Unexpectedly, ATR inhibition elevates R-loop-associated DNA damage at the SNAI1 gene, a key driver of the transcription reprogramming during EMT, triggering ATM- and Polycomb-mediated transcription repression of SNAI1. Beyond SNAI1, ATR also suppresses R-loops and antagonizes repressive chromatin at a subset of EMT genes. Importantly, inhibition of ATR in tumors undergoing EMT reduces tumor growth and metastasis, suggesting that ATR inhibition eliminates cancer cells in transition. Thus, during EMT, ATR not only protects genome integrity but also enables transcription reprogramming, revealing that ATR is a safeguard of cell-state transitions and a target to suppress tumor plasticity.