Citations

Oral nimodipine is the only drug approved for aneurysmal subarachnoid hemorrhage (aSAH). However, bioavailability is poor and peak plasma concentrations fluctuate widely, leading to dose‐limiting hypotension. Administration is problematic in patients who cannot swallow. An enteral liquid formulation exists but causes severe diarrhea. GTX‐104 is an intravenous (IV) nimodipine formulation that has 100% bioavailability and is not affected by swallowing, gastrointestinal absorption and first pass effects. When administered in pharmacokinetically‐equivalent doses to oral nimodipine in healthy humans, GTX‐104 has more consistent plasma concentrations and causes less hypotension than oral nimodipine. To conduct a randomized, open label, blinded endpoint study to determine the safety and tolerability of GTX‐104 compared with oral nimodipine in patients with aSAH We conducted a multicenter, prospective, randomized, open‐label safety and tolerability study of GTX‐104 compared to oral nimodipine in aSAH. Inclusion/exclusion criteria matched prescribing information for oral nimodipine and included adults with aSAH of all Hunt/Hess grades. Subjects were randomized 1:1 to GTX‐104 or oral nimodipine. The primary endpoint was the proportion of subjects with clinically significant hypotension (hypotension requiring treatment, with a reasonable likelihood of being due to study drug, as determined by an independent, blinded committee). Secondary endpoints included all episodes of hypotension, adverse events, EQ‐5D‐3L and modified Rankin scale within 90 days of aSAH. 102 subjects were randomized at 24 sites in the USA. Demographics reflected those of aSAH. There was a 20% relative reduction in clinically significant hypotension with GTX‐104 compared to oral nimodipine (28% versus 35%). 54% of GTX‐104 subjects got >95% of the prescribed dose compared to 8% on oral nimodipine. Favorable outcome (90‐day mRS 0‐2) was more common in the GTX‐104 group compared with oral nimodipine (62% versus 48%). Fewer patients on GTX‐104 (36% versus 48% oral nimodipine) had serious adverse events. There were no safety issues with GTX‐104. GTX‐104, an IV formulation of nimodipine that can be administered through central or peripheral veins, is safer and potentially more efficacious than oral nimodipine.

Three previously uncharacterized bacterial species, designated strains BD586 T , BD613 T and BD626 T , isolated from human clinical specimens, were identified at Mayo Clinic, Rochester, Minnesota, USA. Initial identification efforts using matrix-assisted laser desorption ionization-time-of-flight MS and partial 16S rRNA gene sequencing proved inconclusive. Comprehensive analysis involving phenotypic characterization, biochemical assays and whole-genome sequencing was undertaken. The isolates were Gram-negative, motile, facultatively anaerobic rods, occurring singly, in pairs and in short chains; BD613 T additionally formed small aggregates. The isolates tested positive for catalase and negative for oxidase. Their colonies appeared smooth, white, opaque and non-haemolytic. Growth was observed at 35 °C under aerobic, anaerobic and CO₂-enriched conditions, as well as in media with NaCl concentrations up to 10% and at pH 7-9. Phylogenetic relationships were inferred from core gene alignments, average nucleotide identity and digital DNA–DNA hybridization comparisons. Results confirmed the placement of BD586 T , BD613 T and BD626 T within the recently established Dryocola genus, while also indicating their novelty as distinct species. The major cellular fatty acids were C 16:0 and C 17:0 cyclo. Based on these findings, a formal description of three new species, Dryocola mayonis sp. nov. (type strain BD586 T =TSD 474 T , =NCTC 15089 T , =DSM 119465 T ), Dryocola sharpae sp. nov. (type strain BD613 T =TSD 475 T , =NCTC 15090 T , =DSM 119466 T ) and Dryocola baronae sp. nov. (type strain BD626 T =TSD 476 T , =NCTC 15091 T , =DSM 119479 T ), is proposed, and the genus description of Dryocola is emended to refine its genomic, morphological and chemotaxonomic boundaries.

Glioblastoma (GBM), the most common primary malignant brain tumor in adults, has a median survival of 14–15 months despite aggressive treatment. Monitoring relies on MRI, but differentiating tumor progression from pseudo-progression or radiation necrosis remains difficult. Plasma extracellular vesicles (EVs) are emerging as promising non-invasive biomarkers due to their molecular cargos and accessibility. This review evaluates studies that specifically isolated plasma EVs for molecular profiling in GBM diagnosis and monitoring. Biomarkers (miRNA, RNA, DNA, proteins), EV characterization methods, and advancements in enriching tumor-derived EV subpopulations and assessing their diagnostic and prognostic potential are highlighted. Plasma EVs carry diverse cargos, including miRNAs (e.g., miR-21, miR-15b-3p), mRNAs (e.g., EGFRvIII), circRNAs, and proteins (e.g., CD44, GFAP). Composite molecular signatures have achieved sensitivities of 87–100% and specificities of 73–100% for GBM diagnosis. Tumor-derived EVs, enriched using techniques like SEC-CD44 immunoprecipitation, microfluidic platforms, or 5-ALA-induced PpIX fluorescence, enhance biomarker detection. Non-tumor-derived EVs may also reflect GBM’s systemic effects. Challenges include EV heterogeneity, non-EV contamination, and variable biomarker expression across studies. Plasma-EV-based liquid biopsies offer significant potential for GBM monitoring, with advanced enrichment methods improving tumor-specific biomarker detection. Standardizing isolation protocols and validating biomarkers in larger cohorts are critical for clinical translation.

BACKGROUND: Cavotricuspid isthmus (CTI) ablation is frequently performed either as a standalone procedure or in combination with pulmonary vein isolation. With the rapid adoption of pulsed field ablation for atrial fibrillation, it is essential to delineate the utility of this modality in treating CTI-dependent atrial flutter (AFL). This study aims to evaluate the procedural and clinical outcomes of CTI ablation using pulsed field energy. METHODS: We conducted a retrospective analysis of consecutive patients who underwent pulsed field ablation for CTI-dependent AFL between January 2024 and March 2025. The primary end points were acute procedural success, periprocedural complications, and CTI-dependent AFL recurrence during follow-up. RESULTS: A total of 132 patients underwent CTI nonthermal ablation. The median age was 69.5 years, and 27.3% were female. The Farawave catheter was used in 93.9% of cases, PulseSelect in 4.5%, and Sphere-9 in 1.5%. Acute block was achieved in 99.2% of patients, although 8 required adjunctive radiofrequency ablation to complete the line. Periprocedural complications included transient ST-segment elevation in 2 patients and transient conduction disturbances in 3. During a median follow-up of 114 days (n=131), 5 patients (3.8%) experienced recurrence of typical AFL. The 6-month typical AFL-free survival estimate was 93.6%. CONCLUSIONS: Pulsed field ablation appears to be a feasible and effective strategy for CTI-dependent AFL. However, anatomic variability may limit its universal applicability with current catheter designs. Although acute procedural success is high, the long-term durability of the CTI block and its comparative efficacy versus conventional thermal ablation remain areas requiring further investigation.

PURPOSE STELLAR (ClinicalTrials.gov identifier: NCT02796261 ) was a phase III, randomized, open-label trial of eflornithine + lomustine versus lomustine monotherapy in patients with recurrent grade 3 astrocytoma. METHODS At trial initiation, eligibility criteria included: age ≥18 years, anaplastic astrocytoma (2016 WHO CNS Tumor classification [WHO CNS4]), first recurrence ≥6 months after radiation and temozolomide (TMZ), Karnofsky performance status ≥70, and no imaging findings consistent with grade 4 glioblastoma. Random assignment (1:1) was stratified by isocitrate dehydrogenase ( IDH ) mutation, age, resection extent, and geography. Patients received eflornithine (2.8 g/m 2 orally, every 8 hours [2 weeks on, 1 week off]) + lomustine (90 mg/m 2 orally, once every 6 weeks), or lomustine monotherapy (110 mg/m 2 once every 6 weeks). The primary end point was overall survival (OS). RESULTS Among 343 patients randomly assigned across 74 sites in eight countries, there was no difference in survival between eflornithine + lomustine and lomustine monotherapy (median OS 23.4 v 20.3 months, hazard ratio [HR], 0.94). Following changes in classification and grading in the 2021 WHO CNS5, a subset analysis of patients with IDH- mutant, grade 3 astrocytoma (n = 196), defined in 2024, before unblinding, showed clinically meaningful improvements in median OS with eflornithine + lomustine versus lomustine monotherapy (34.9 v 23.5 months, HR, 0.64) and median progression-free survival (PFS, 15.8 v 7.2 months, HR, 0.57). No differences were observed among patients with CNS grade 4 disease. Grade ≥3 treatment-emergent adverse events of relevance were related to reversible myelosuppression (eflornithine + lomustine 42% v lomustine monotherapy 29% of patients) and hearing impairment (24% v 0%). No new safety signals were identified. CONCLUSION Clinically meaningful improvements were observed; eflornithine + lomustine doubled PFS and improved OS in patients with recurrent IDH -mutant, grade 3 astrocytoma, but not grade 4 tumors, after prior radiotherapy and TMZ, consistent with its cytostatic mechanism of action.

ABSTRACT The Mayo Foundation Special Purpose Processor Development Group has been supporting a serial link development effort. In order to characterize serial link performance, two versions of a multi-chip module (MCM) test vehicle were assembled to study the effects of the substrate and the integrated circuit input/output buffer technologies on basic signal integrity performance parameters at data rates of 2.5 GHz. The difference between the test vehicles was the substrate technology used: ceramic and laminate. This paper describes the steps taken to develop an assembly process for the ceramic version of the test vehicle. The ceramic test vehicle consisted of a high thermal coefficient of expansion ceramic substrate, 2 CMOS chips with IBM high lead content (hereafter: “high lead”) bumps, 16 surface mount (SMT) capacitors, and an interposer. Assembly processes needed to be developed for SMT attach of the capacitors, flip-chip attach of the chips, and ball grid array (BGA) attach of the interposer. Based on Mayo's suite of assembly equipment, three process flows could have been used to attach the capacitors and the chips to the substrate: High lead attach of the capacitors and chips; Eutectic attach of capacitors, high lead attach of chips; Eutectic attach of the capacitors and chips. Assembly process flow 1 required the least number of steps. Therefore, it was initially selected as the process flow. However, this process flow was found to be unsatisfactory due to problems with flux charring around the capacitors and a high incidence of chip to substrate opens. Assembly process flow 2 was then evaluated. Assembly process flow 3 was considered the least desirable because eutectic solder paste had to be coated on the substrate die pads and Mayo did not have capability to do this. In order to develop the capacitor and die attach processes and to set up the interposer attach process, two assembly test vehicles were built on glass substrates. A capacitor attach process was devised that involved stenciling the eutectic solder paste, placing the capacitors, and then reflowing the assembly. The flip-chip attach process development required greater effort. Experimental matrices were run that allowed an assessment of bond strength as a function of flux quantity, bond force, and reflow temperature and time. Water-soluble flux was used for the chip attach process, so a de-fluxing process had to be developed. The chips then needed to be underfilled. The underfill dispense pattern and substrate heating were evaluated. The interposer was attached using eutectic solder paste stenciled on the back of the substrate. A BGA style attach process was set up to do this. The result of this process development activity was the successful assembly of 21 modules with no defects. Lessons were learned during the assembly process development regarding the difficulties associated with attaching components with high lead solder.