Publications by Year: 2025

BackgroundBasilar artery occlusion (BAO) is a rare stroke type, with subtypes like vertebrobasilar tandem occlusion (VBTO), complicating treatment. Mechanical thrombectomy (MT) is increasingly used, but evidence on its safety and effectiveness in VBTO compared to isolated BAO (iBAO) remains limited.MethodsPubMed, Cochrane Central, Embase, Web of Science, and ScienceDirect were searched till May 2025. The risk ratios (RR) were pooled along with 95% Confidence intervals (CI) under the random effects model using Review Manager. The Newcastle Ottawa Scale and GRADE assessment were used to assess the quality of studies and certainty of evidence. Successful recanalization was defined as a Thrombolysis in Cerebral Infarction (TICI) score of ≥2b. The modified Rankin Scale (mRS) is a scale used to assess the severity of stroke, with functional independence defined as an mRS score of 0-2. Publication bias was assessed using funnel plots and Egger's regression test.ResultsNine studies, pooling a total of 737 patients, were included in this analysis. MT showed no significant difference in functional independence in the VBTO group compared to the iBAO group (RR = 1.25; 95% CI: 0.73, 2.12; p = .42). The successful recanalization was also comparable between the VBTO and iBAO arms when MT was performed (RR = 0.96; 95%CI 0.81, 1.13; p = .60). The risk of symptomatic intracerebral hemorrhage (sICH) was significantly increased when MT was performed in the VBTO arm compared to the iBAO group (RR = 2.20; 95%CI : 1.09, 4.46]; p = .03). The mortality rates were also comparable between the two groups (RR = 1.28; 95% CI 0.78, 2.10; p = .33). Also, in the VBTO patients, the successful recanalization rate showed no significant difference between the clean and dirty road techniques (RR = 1.04; 95% CI 0.90, 1.20; p = .63).ConclusionWhen MT was performed on VBTO and iBAO patients, the efficacy endpoints-such as functional independence and successful recanalization-and the safety endpoint of mortality were comparable. However, the risk of sICH was higher in the VBTO group.

BACKGROUND: Fimepinostat, an oral dual inhibitor of histone deacetylase (HDAC) and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), has shown activity in preclinical models of Myc-driven pediatric malignancies. This Phase 1 trial aimed to determine the recommended pediatric Phase 2 dose (RPP2D), describe the toxicity profile, and evaluate the pharmacokinetics of fimepinostat in children with relapsed and refractory solid and central nervous system (CNS) tumors.

METHODS: This multicenter, Phase 1 study enrolled patients ages 1-21 years with relapsed or refractory solid tumors, CNS tumors, or lymphoma. The dose-escalation phase followed a 3 + 3 design, starting at 27.5 mg/m2 and escalating to 45 mg/m2. Following dose escalation, three expansion cohorts were opened including cohorts for patients with Myc(n)-driven neuroblastoma, Myc-driven extracranial solid tumors, and diffuse large B-cell lymphoma or Burkitt lymphoma. The pharmacokinetics of fimepinostat and its metabolites were studied after the first dose.

RESULTS: Twenty-six patients were enrolled, with 25 receiving treatment. The median age was 13.6 years (range: 4.1-20.9). In the dose-escalation phase, 12 patients were evaluable for DLT assessment. The RPP2D was initially determined to be 45 mg/m2 but was revised to 35 mg/m2 after observing DLTs in the dose-expansion phase. Treatment-related adverse events were primarily hematologic and gastrointestinal. No objective responses were observed in 23 evaluable patients. Three patients had stable disease for over four cycles, including a patient with MYCN amplified neuroblastoma with stable disease for 24 cycles. Pharmacokinetic analysis showed significant interpatient variability and rapid conversion of fimepinostat to its metabolites.

CONCLUSION: Fimepinostat was tolerable at a dose of 35 mg/m2 in children with relapsed and refractory solid and CNS tumors, but lacked significant clinical activity. Discovery of drugs to target Myc continues to be a high priority for childhood cancers.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02909777.

BACKGROUND AND AIMS: Diabetes is associated with increased risk of cardiovascular and renal disease. This study investigated the role of peptidylarginine deiminase 4 (PAD4), neutrophil extracellular traps (NETs), and inflammasome activation in diabetic cardiomyopathy (DCM) and kidney disease (DKD).

METHODS: Endomyocardial biopsies (EMB) from heart failure (HF) patients (n = 20) with or without diabetes were stained for NETs. Wild-type (WT) and PAD4⁻/⁻ mice were subjected to streptozotocin (STZ)-induced diabetes and cardiac function, blood glucose, body weight, and exercise tolerance were assessed longitudinally. NETosis and ASC specks were evaluated in mouse and human neutrophils. Cardiac and renal fibrosis was assessed by Sirius Red/Fast Green staining. Confocal microscopy, ELISA, and flow cytometry were used to quantify NETs, IL-1β, von Willebrand factor (VWF), cytokine transforming growth factor beta-1 (TGF-β1), and neutrophil infiltration.

RESULTS: Myocardial NET burden was increased in HF patients with diabetes. High glucose triggered inflammasome activation in human neutrophils. After STZ, PAD4⁻/⁻ and WT mice developed hyperglycaemia and weight loss, yet only WT neutrophils showed increased NETosis and ASC speck formation. Only diabetic WT mice exhibited elevated IL-1β and VWF levels, impaired cardiac function, reduced exercise tolerance, and pulmonary oedema; PAD4⁻/⁻ mice were protected. Wild-type diabetic hearts and kidneys showed greater fibrosis, neutrophil infiltration, NETs, and TGF-β1 levels. Kidney injury in WT mice was reflected by albuminuria and renal fibrosis, whereas PAD4⁻/⁻ mice preserved renal function.

CONCLUSIONS: Diabetes promotes neutrophil inflammasome activation and NETosis, driving cardiac and renal inflammation and fibrosis. Peptidylarginine deiminase 4 deficiency prevents heart failure and preserves kidney function in experimental diabetes.

Deep learning has revolutionized neuroimage analysis by delivering unprecedented speed and accuracy. However, the narrow scope of many training datasets constrains model robustness and generalizability. This challenge is particularly acute in magnetic resonance imaging (MRI), where image appearance varies widely across pulse sequences and scanner hardware. A recent domain-randomization strategy addresses the generalization problem by training deep neural networks on synthetic images with randomized intensities and anatomical content. By generating diverse data from anatomical segmentation maps, the approach enables models to accurately process image types unseen during training, without retraining or fine-tuning. It has demonstrated effectiveness across modalities including MRI, computed tomography, positron emission tomography, and optical coherence tomography, as well as beyond neuroimaging in ultrasound, electron and fluorescence microscopy, and X-ray microtomography. This tutorial paper reviews the principles, implementation, and potential of the synthesis-driven training paradigm. It highlights key benefits, such as improved generalization and resistance to overfitting, while discussing trade-offs such as increased computational demands. Finally, the article explores practical considerations for adopting the technique, aiming to accelerate the development of generalizable tools that make deep learning more accessible to domain experts without extensive computational resources or machine learning knowledge.

Dysregulated transcription is a defining hallmark of cancer. Recently, novel chemically induced proximity approaches have enabled the rewiring of transcriptional machinery to drive expression of pro-apoptotic genes using bivalent small molecules. In this work, we demonstrate that this strategy is amenable to relocalizing DNA bound transcriptional machinery, such as fusion transcription factors that commonly drive pediatric malignancies. Targeting fusion transcription factors, such as EWSR1::FLI1 in Ewing sarcoma, with these bivalent compounds may open new therapeutic avenues. Here, we develop a small molecule, EB-TCIP, that recruits FKBP12F36V-tagged EWSR1::FLI1 to DNA sites bound by the transcriptional regulator BCL6, leading to rapid chromatin remodeling and expression of BCL6 target genes. This proof-of-concept study demonstrates that DNA binding proteins with pioneering transcription factor activity, such as EWSR1::FLI1, can be relocalized on chromatin to induce expression of repressed genes. Insights herein will guide the development of future bivalent molecules that rewire DNA binding transcriptional machinery.

The human gut microbiome is essential for maintaining health, as it substantially impacts immune regulation and overall balance within the body. Accordingly, disruptions in this microbial community are associated with various diseases. Probiotics offer a promising solution, but their effectiveness is often hampered by challenges related to gastrointestinal delivery. To overcome the issue of probiotic survival in the gastrointestinal system, researchers have explored various encapsulation techniques. However, traditional coarse encapsulation techniques lack precision and effective targeting, limiting the delivery of viable organisms to the colon. Current methods face challenges such as inadequate particle size control, leakage, and poor survival in complex gastrointestinal environments. This research introduces a novel approach for encapsulating individual bacteria to create single-bacterium microgels, utilizing gas-shearing technology to enhance the survival and targeting capabilities of probiotics. This approach also demonstrates the capability to coat multiple microbial species, including bacteria and fungi, while ensuring good biocompatibility and mechanical support. Focusing on Escherichia coli Nissle 1917, we demonstrate that this method significantly improves therapeutic efficacy in treating inflammatory bowel disease compared to unencapsulated strains. Our results suggest that gas-shearing encapsulation represents a promising strategy for the fabrication of single-bacterium microgels, facilitating the development of effective probiotic therapies with potential applications in both biomedical and nutraceutical fields.

BACKGROUND: Sulfonylureas (SU) are widely used for diabetes management in older adults but can cause hypoglycemia, which may be worsened by drug interactions. We applied high-throughput data mining to identify medications that could increase hypoglycemia risk when taken with SU.

METHODS: Using Medicare, MarketScan, and Optum Clinformatics (2003-2022), we identified patients aged ≥ 65 years who experienced a severe hypoglycemic event after at least 90 days on SU. We evaluated all medications dispensed in the 90 days before the event using a case-crossover (CCO) design. We adjusted for time-varying confounding and direct effect of the evaluated medications (precipitant) using a case-case time-control (CCTC) approach and metformin as control. We computed odds ratios (ORs) for its association with hypoglycemia. The false discovery rate (FDR) was controlled at 0.05 to adjust for multiple testing. To reduce confounding from other diabetes medications, we analyzed non-diabetes and diabetes medications separately.

RESULTS: Among 1607 candidate drugs received before experiencing hypoglycemia, 86 non-diabetes medications showed a CCO OR ≥ 1.00. With metformin as control, sulfamethoxazole/trimethoprim (CCTC OR 1.76, p < 0.01, FDR q < 0.01) and metronidazole (CCTC OR 2.17, p < 0.01, FDR q = 0.04) were associated with severe hypoglycemia. Among 10 diabetes medications, insulin showed increased association (CCO OR 1.22, p < 0.01); however, once adjusted for the drug's direct effects, CCTC OR was 1.03 (p = 0.47, FDR q = 0.47).

CONCLUSIONS: Using a high-throughput data mining approach, we identified two antibiotics (sulfamethoxazole/trimethoprim and metronidazole) that may increase hypoglycemia risk in older adults on sulfonylureas. Given the exploratory nature of this study, these findings warrant further investigation.

BACKGROUND: The causes of individual headache attacks are commonly sought, yet the multiple potential influences make this task difficult. Information theory provides a framework for addressing this challenge by quantifying how unexpected an exposure is through surprisal. Prior research has shown that higher surprisal scores predict migraine onset, but the extent to which this relationship generalizes to tension-type headache remains unknown.

AIMS: This study aimed to determine whether surprisal is associated with incident tension-type headache attacks among individuals with episodic migraine.

METHODS: This secondary analysis proceeded from a prospective daily diary study in which 109 participants with migraine recorded potential triggers, headache activity, and symptoms twice daily for up to 28 days. Surprisal values were computed from person-specific probability distributions of diary responses, aggregated to yield average surprisal scores per diary entry. Associations between current surprisal and the onset of headache attacks within 12- and 24-hour intervals were evaluated. Analyses were conducted for all headaches combined and separately for migraine-only and tension-type headache-only attack sets.

RESULTS: Headache attacks occurred in 1,345 of 4,530 (29.7%) of 12-hour and 2,122 of 4,947 (42.9%) of 24-hour windows. Stratified analyses showed a strong association for migraine attacks, OR: 2.18 (95%CI: 1.15 - 4.14) at 12 hours and OR: 2.88 (95%CI: 1.77 - 4.69) at 24 hours. In contrast, associations with tension-type headache were weak and nonsignificant, OR: 1.01 (95%CI: 0.45 - 2.23) at 12 hours and OR: 1.40 (95%CI: 0.69 -2.86) at 24 hours. Exploratory nonlinear and contextual analyses within the tension-type headache subset revealed no consistent gradients or effect modification by prior-day surprisal.

CONCLUSIONS: Surprisal was associated with migraine but not tension-type headache attacks in this cohort. These findings suggest that migraine may be more sensitive to contextual unpredictability in the environment than tension-type headache. Future research should examine surprisal in populations with primary tension-type headache diagnoses to clarify whether the absence of association reflects true diagnostic differences or misclassification of attacks.

BACKGROUND: The US Food and Drug Administration (FDA)-mandates Risk Evaluation and Mitigation Strategy (REMS) programs for certain drugs with serious side effects help ensure that the benefits of use outweigh the risks. REMS materials-including enrollment forms, fact sheets, and medication guides-inform patients and caregivers about drug risks and program requirements.

OBJECTIVE: To explore how effectively REMS materials communicate drug risk information and program requirements to patients and caregivers and to identify patients' and caregivers' preferences for risk communication.

METHODS: Interviews with patients and caregivers of patients prescribed REMS-covered drugs focused on REMS materials. Transcripts were coded manually, with answers to closed-ended questions tabulated in Excel.

RESULTS: The study included 43 patients and six caregivers across eight REMS-covered drugs: alemtuzumab, ambrisentan, clozapine, isotretinoin, lenalidomide, pegvaliase, pomalidomide, and sodium oxybate. Most participants were female (N = 42, 86%), white/non-Hispanic (N = 40, 82%), and college educated (N = 37, 76%). The average age was 40 years, with 27 (55%) having annual family incomes over $100,000. Most participants learned about REMS-covered drugs via printed information (N = 36, 73%), mostly REMS materials; conversations with providers about drug risks and benefits (N = 29, 59%); and websites found on their own (N = 42, 86%). Nearly all participants (N = 47, 96%) felt well-informed about drug risks and benefits, and most participants taking self-administered drugs (N = 28, 67%) reported understanding safe use "very well." However, knowledge gaps emerged around REMS-related risks and reasons for safe use measures; some participants misunderstood REMS enrollment forms as legal protections, not safety measures. Patients also widely varied in their valuations of REMS materials, with some feeling informed and empowered and others confused or intimidated. Preferences for risk communication varied; most participants (N = 36, 73%) wanted to receive information verbally from providers, with several wanting visual aids, summaries, and other resources.

DISCUSSION: Gaps in patients' and caregivers' understanding of REMS programs and drug risks highlight the merits of reviewing communication materials and strategies. Clear, concise, and comprehensive educational documents could promote understanding and adherence to REMS requirements.