Citations

Abstract The paradigm in the field of oncolytic virotherapy proposes that tumor cell killing by an oncolytic virus (OV) culminates in the priming of antitumor CD8+ T cells. However, this ignores the impact a highly immunodominant antiviral response against the OV has on the subdominant antitumor response, particularly with regard to the naturally low affinity of tumor antigens to their cognate T-cell receptors. To investigate this experimentally, we first studied the interaction between the two responses in B16 and MC38 tumor models, both expressing ovalbumin (OVA). Contrary to the accepted paradigm, the inflammatory vesicular stomatitis virus (VSV) failed to expand OVA-specific T cells in vivo unless armed with tumor-associated antigen (TAA). In fact, treatment with the control VSV led to the ablation of antitumor T cells and a shift toward dysfunction as determined by the upregulation of markers, including LAG3 and CD39, correlating with lower rates of survival. Combination with anti–PD-1 immune checkpoint blockade therapy significantly improved survival only when VSV expressed TAA. VSV-expressing altered peptide ligand variants of tumor antigens, which evade mechanisms of central tolerance, expanded near self-antigen–specific T cells with the ability to cross-react with tolerized tumor antigens, thus providing an antitumor effector population capable of proliferating in the presence of a potent antiviral response. Taken together, these findings offer a rational approach to OV design which preserves acute antitumor therapy provided by antiviral innate and T-cell responses while promoting the induction of tumor-specific T cells. Significance: Oncolytic viruses can induce an antiviral T-cell response that occludes an antitumor response, challenging the paradigm in the field and elucidating strategies to optimize the efficacy of oncolytic viroimmunotherapy.

Abstract Background: Clostridium ramosum ( C. ramosum ) is an anaerobic gram-positive bacillus of the human intestine and a rare cause of bacteremia. This retrospective cohort study evaluated clinical characteristics and outcomes of a multicenter cohort of adults with C. ramosum bacteremia. Methods: This multicenter retrospective cohort included adults (≥ 18 years) with true C. ramosum bacteremia at Mayo Clinic hospitals in Arizona, Florida, Minnesota, and Wisconsin from September 1, 2012, through December 31, 2025. Data were collected through search for C. ramosum in microbiological culture records. Clinical characteristics assessed included immune status, source of bacteremia, presence of sepsis, neutropenic fever, monomicrobial vs. polymicrobial bacteremia, antimicrobial resistance patterns, antimicrobial therapy, length of stay and 30-day all cause mortality. Exploratory odds ratios (ORs) with 95% confidence intervals (CIs) were reported. Results: Among 90 patients with a positive C. ramosum blood culture, 17 were classified as contaminants and 73 comprised the study cohort. Median age was 66.0 years (IQR, 56.0–75.0); 44 (60.3%) were male and 33 (45.2%) were immunocompromised (including 26 with active malignancy, while the remaining 7 were received biologic immunosuppression). The most common infection sources were gastrointestinal (32/73, 43.8%) and central line-related (8/73, 11%). At presentation, 50.7% of patients met criteria for sepsis and 15/73 (20.5%), were in septic shock. Of 73 isolates tested, 31/73 (44.3%) were clindamycin resistant and 9/73 (12.9%) tested intermediate. Anaerobic-active antimicrobial therapy was received by 53/73 (72.6%). Thirty-day mortality was 11/73 (15.1%). Mortality was 30.0% (6/20) with therapy without reliable anaerobic activity and 9.4% (5/53) with anaerobic-active antimicrobial therapy (OR, 4.02; 95% CI, 0.88–19.46; P = 0.060). The median hospital LOS was 8.0 days. Among 30-day survivors, anaerobic active antimicrobial therapy was associated with a shorter median LOS compared to therapy without reliable anaerobic activity (8.5 vs. 12.0 days). Immunocompromised patients had higher odds of monomicrobial C. ramosum bacteremia than immunocompetent patients (OR 3.16, 95% CI 1.19–8.39; p = 0.03). Patients with polymicrobial bacteremia had higher odds of sepsis (OR, 3.89; 95% CI, 1.43–10.55; P = 0.008) and septic shock (OR, 5.66; 95% CI, 1.17–27.36; P = 0.020). Patients with malignancy or neutropenia demonstrated significantly lower odds of presenting in septic shock (p = 0.018; p = 0.029 retrospectively). Microbiological clearance was achieved in 91.3% (42/46) of evaluable cases. Conclusions: This largest reported cohort defines the clinical and microbiological profile of C. ramosum bacteremia. Frequent clindamycin nonsusceptibility is clinically actionable. Several clinical associations found on univariable analysis should be further investigated in larger studies.

ABSTRACT Introduction/Aims Phrenic nerve conduction studies (NCS) are regularly used in the evaluation of neuromuscular respiratory dysfunction; however, the impact of body mass index (BMI) on phrenic compound muscle action potential (CMAP) amplitudes remains poorly characterized. We evaluated the relationship between BMI and phrenic CMAP amplitudes in patients without evidence of neuromuscular diaphragmatic dysfunction. Methods We performed a retrospective secondary analysis of patients derived from two previously published cohorts from Mayo Clinic (Rochester, Minnesota) and the University of Alberta (Edmonton, Alberta) evaluating diaphragm ultrasound in suspected neuromuscular respiratory insufficiency. Patients without evidence of neuromuscular disease affecting the diaphragm who underwent bilateral phrenic NCS and diaphragm ultrasound were included. Results Seventy‐nine patients met inclusion criteria, including 36 with BMI ≥ 30 kg/m 2 . Median phrenic CMAP amplitudes were significantly lower in patients with BMI ≥ 30 kg/m 2 compared to BMI < 30 kg/m 2 (0.25 mV [ IQR 0.10–0.38] vs. 0.50 mV [0.30–0.65], p < 0.001). Low phrenic CMAP amplitudes (< 0.3 mV ) were more common in patients with obesity (58% vs. 21%, p < 0.001). BMI demonstrated a moderate negative correlation with phrenic CMAP amplitude ( ρ = −0.50, p < 0.001). Diaphragm thickness at functional residual capacity did not differ significantly between BMI groups, while diaphragm thickening ratio was modestly lower in obesity. Discussion Elevated BMI is associated with lower phrenic CMAP amplitudes in patients without evidence of neuromuscular diaphragmatic dysfunction. Reduced phrenic CMAP amplitudes in obesity may reflect technical recording limitations rather than clinically meaningful diaphragmatic dysfunction. Low‐amplitude phrenic responses in patients with obesity should be interpreted cautiously and alongside adjunctive assessments such as diaphragm ultrasound.

Abstract Objective Low back pain (LBP) is a leading cause of pain and disability worldwide. Recent studies demonstrate a vertebrogenic model involving the basivertebral nerve (BVN) as a cause of chronic LBP. Vertebral endplates are highly innervated by the BVN, and literature shows type 1 and 2 Modic changes at vertebral endplates are a source of vertebrogenic low back pain (VBP). As a result, intraosseous radiofrequency ablation of the BVN is a minimally invasive outpatient procedure used to treat VBP. We conducted a retrospective review of 1,145 patients that have undergone BVN ablation to assess for safety and complication management. Methods Chart reviews were conducted to obtain demographic and pre-procedural information regarding patient gender, age at the time of BVN ablation, duration of LBP, and BMI. Post-procedure information derived from chart notes included vertebral levels ablated and post-BVN ablation complications, which were categorized as increased LBP &gt; 7 days, increased radicular pain &gt; 7 days, lower extremity weakness, infection, vertebral compression fracture, superficial bleeding, spinal or epidural hematoma, serious neurological injury, visit to the ER, and deep vein thrombosis/clot. Results 1,145 patient charts were reviewed showing an overall complication rate of 3.2% (37 complications). Increased radicular pain was the most common complication at 2.2% (25 complications) and resolved completely in all but one patient. The overall complication rate fell to 1.1% (13 complications) when the 24 cases of transient radicular pain were not counted as adverse events. Conclusions In this multicenter retrospective review, the overall rate of complications related to BVN ablation was low (3.2%). The most common complication was temporary radicular pain that resolved with conservative care. These findings suggest that BVN ablation is a safe treatment for VBP in real-world clinical settings.

Abstract The development of biocompatible and biologically responsive scaffolds remains a key challenge for bone tissue engineering. Here, we report an enzyme-degradable, metal-free click-cross-linked organic–inorganic nanohybrid (Enz-Deg-Click-ON) scaffold with high biocompatibility for bone repair. The formulation was synthesized using a cyclooctyne-functionalized poly(propylene fumarate) polyphosphoester (PPF-poly(PE-BCN)) and azide-terminated dendritic polycaprolactone (PCL) with a polyhedral oligomeric silsesquioxane core (POSS-PCL-N3) via strain-promoted alkyne-azide cycloaddition (SPAAC) bioorthogonal click chemistry. The incorporation of phosphate-containing linkages enabled alkaline phosphatase (ALP)-responsive degradation. The scaffold exhibited rapid catalyst-free crosslinking, tunable swelling, and suitable mechanical properties. In vitro studies demonstrated excellent cytocompatibility, robust stem cell proliferation, and enhanced osteogenic differentiation with an elevated level of ALP and Runx2 expression. Enzyme-triggered degradation was confirmed in the presence of ALP. In the in vivo rat calvarial defect model, the scaffold significantly improved bone regeneration, as shown by an increased bone volume, mineral density, and defect coverage. Histological and immunofluorescence analyses revealed enhanced collagen deposition, angiogenesis, and osteogenesis. These results indicate that the Enz-Deg-Click-ON system provides a dynamic, bioresponsive platform for bone repair.

ABSTRACT Background Mobility functional status is inconsistently recorded in electronic health records. Recent advances in Large Language Models (LLMs) enable automated extraction of functional information from unstructured clinical notes. Leveraging a validated functional LLM with high performance in mobility extraction, we aimed to study the association between LLM‐derived mobility functional status and clinical outcomes, including emergency department (ED) visits, hospitalizations, and mortality. Methods Individuals aged 60 years and older enrolled in the Mayo Clinic Study of Aging, with documented clinical notes in 2022 were included. Individuals without any identifiable functional information were excluded. The LLM‐derived mobility functional status categorized mobility as impaired or unimpaired, across the five mobility domains as classified by International Classification of Functioning, Disability, and Health. Clinical outcomes in 2023 were extracted from the Rochester Epidemiology Project database. Logistic regression models assessed associations between mobility impairment and outcomes, adjusted for age, sex, Elixhauser comorbidity index, and education. Results Three thousand three hundred thirty‐seven individuals were screened, of whom three hundred forty‐three had no functional information. Two thousand nine hundred ninety‐four individuals were analyzed. 79.4% had at least one mobility impairment. Higher mobility impairment is associated with older age and greater Elixhauser comorbidity. Individuals with 3 or more impairments had an increased adjusted odds of ED visits (Adjusted Odds Ratio (aOR): 2.18 (1.64, 2.90)) and hospitalizations (aOR: 2.35 (1.51, 3.65)) compared to unimpaired individuals ( p < 0.001), while mortality did not demonstrate a significant association with mobility impairment. Conclusion LLM‐derived mobility functional status assessment was associated with ED visits and hospitalization, but not with all‐cause mortality after adjustment. Prospective validation and evaluation of incremental discrimination, calibration, and clinical utility are needed before clinical implementation.

Background Neurofibromatosis type 1 (NF1) is a genetic disorder in which plexiform neurofibromas (PNs) develop in approximately 30% to 50% of affected individuals, often causing substantial morbidity. Treatment of NF1-associated PNs is challenging due to disease variability and tumor complexity. Observations In the Phase 2b ReNeu trial (NCT03962543), mirdametinib, a mitogen-activated protein kinase kinase 1/2 (MEK) inhibitor, demonstrated efficacy and a manageable safety profile in children and adults with symptomatic PNs, achieving confirmed objective responses in 52% of children and 41% of adults, with substantial reductions in target tumor PN volume and improvements in patient- and parent proxy-reported outcomes. However, dermatologic adverse events (AEs) are common with MEK inhibitors, including mirdametinib, and can impact adherence and quality of life. While the ReNeu protocol included supportive care considerations for skin reactions associated with mirdametinib, some investigators recognized a need for more detailed guidance. The ReNeu Scientific Steering Committee, in collaboration with oncology and oncodermatology experts, developed expert-driven recommendations for the proactive management of mirdametinib-related skin AEs. Conclusions These strategies emphasize early recognition, individualized care, and timely intervention to help reduce the severity of mirdametinib-related skin AEs, minimize dose modifications, and support treatment continuity and long-term treatment goals. Although these recommendations were specifically developed for mirdametinib based on ReNeu trial experience, they may also provide practical guidance for managing skin AEs associated with other MEK inhibitors in clinical practice.

Summary: Bone defects are among the most challenging problems treated by limb reconstruction surgeons and orthopaedic traumatologists. Bone transport is a biological reconstruction technique which harnesses distraction osteogenesis to create new bone in critical bone defect. This technique has been successfully performed with a variety of internal and external solutions. This work introduces a newly available technology which provides a fully implantable, all-internal solution (eg, without the need for external fixation) for bone transport with the option to simultaneously address residual limb length discrepancy.