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 Aims Religiosity and spirituality (R/S) are generally associated with a more favourable cardiovascular risk profile, but longitudinal evidence is limited. We examined whether multidimensional R/S predicts its future behavioural and biological components. Methods This prospective cohort study analysed 6,844 adults aged ≥50 (56% women; mean R/S score 2.1; 20% weekly attenders; 81% Christian) from waves 4–7 of the English Longitudinal Study of Ageing (ELSA). Behavioural outcomes included smoking, exercise, alcohol intake, and fruit and vegetable consumption; biological outcomes included blood pressure (BP), haemoglobin A1c (HbA1c), and the inflammatory risk markers C-reactive protein (CRP) and fibrinogen. R/S was assessed with four items from the Santa Clara Strength of Religious Faith Questionnaire. Hierarchical linear and logistic regressions adjusted for age, sex, wealth, education and ethnicity; biomarker models also adjusted for health behaviours and body mass index. Results Greater spirituality ( B =−0.019; 95%CI[−0.036,−0.003]), daily prayer/meditation ( B =−0.017; 95%CI[−0.032,−0.002]), participation in organized religion ( B =−0.017; 95%CI[−0.032,−0.002]), and importance of religious faith ( B =−0.017; 95%CI[−0.033,−0.002]) were independently associated with lower fibrinogen levels. Daily prayer/meditation also independently predicted higher fruit and vegetable intake ( B =0.004; 95%CI[0.000,0.008]). However, frequent attendance (OR=0.846; 95%CI[0.730,0.982]), the significance of faith (OR=0.935; 95%CI[0.879,0.994]), and religious purpose (OR=0.939; 95%CI[0.884,0.997]) independently reduced the odds of meeting exercise recommendations. Similarly, frequent attendance was associated with higher HbA1c ( B =0.002; 95%CI[0.000,0.005]). There were no independent associations with CRP or blood pressure. Conclusion R/S showed mixed prospective associations with the cardiovascular risk profile: favourable for fibrinogen and fruit and vegetable intake, unfavourable for physical activity and HbA1c. LAY SUMMARY We examined whether religious and spiritual involvement was related to later heart-related health behaviours and blood measurements in more than 6,800 English adults aged 50 and over. The associations ran in both directions, and the study cannot show that religion or spirituality causes these changes. Stronger religious and spiritual involvement was associated with lower fibrinogen, a blood protein linked to clotting. Daily prayer or meditation was associated with eating more fruit and vegetables. Regular attendance at religious services was associated with less physical activity and higher blood sugar. GRAPHICAL ABSTRACT

Abstract Purpose Failed stapes surgery presents a diagnostic challenge requiring high-resolution imaging to guide revision. Energy-integrating detector CT (EID-CT) is widely used but limited by spatial resolution and metal artifact. Photon-counting CT (PCCT) offers improved spatial resolution and reduced noise, with potential advantages in temporal bone imaging. The purpose of this study was to compare PCCT and EID-CT in identifying etiologies of failed primary stapes surgery, with emphasis on diagnostic accuracy, interobserver agreement, and interpreter confidence Methods In this retrospective study, 38 patients with failed primary stapes surgery who underwent successful revision surgery and pre-revision CT were included; 18 underwent PCCT and 20 underwent EID-CT. Three expert reviewers independently determined the cause of surgical failure, compared against the reference standard of intraoperative findings at revision. Diagnostic accuracy, interobserver agreement (Fleiss kappa), and reader confidence were compared between modalities. Results Overall interobserver agreement was substantially higher with PCCT (κ = 0.75; 95% CI, 0.60–0.90) than EID-CT (κ = 0.44; 95% CI, 0.30–0.59), with improved agreement observed across etiologies of failure; confidence intervals were non-overlapping for overall agreement and ossicular discontinuity. Consensus diagnostic accuracy was comparable between modalities (88.9% PCCT vs 85% EID-CT; p = 1.00), as was interpreter confidence (4.33 PCCT vs 4.17 EID-CT; p = 0.29). Conclusion In this small cohort, PCCT and EID-CT demonstrated similar diagnostic accuracy and reader confidence, whereas PCCT demonstrated significantly higher interobserver agreement, suggesting more reproducible assessment of failed stapes surgery and a potential role in supporting revision surgical planning.

Purpose To evaluate the association between myocardial infarction (MI) timing within 2 years prior to arthroscopic rotator cuff repair (aRCR) and postoperative cardiac, medical, and surgical complications. Methods The PearlDiver Mariner Database (2010‐2022) was queried to identify patients undergoing aRCR (CPT‐29827). Patients with an MI within 2 years before surgery were propensity matched 1:4 to controls without MI based on demographics and comorbidities. Subgroup analyses evaluated MI timing (0‐6, 6‐12, 12‐18, and 18‐24 months), MI type (type 1 vs type 2, ST‐elevation MI vs non‐ST‐elevation MI), percutaneous coronary intervention (PCI) status, guideline‐directed medical therapy, and infarct location. Primary outcomes included 90‐day medical and 2‐year surgical complications. Odds ratios with 95% confidence intervals were calculated. Results A total of 2886 patients with prior MI were matched to 10,613 controls. Prior MI increased the odds of postoperative MI (odds ratio, 3.48; 95% confidence interval, 2.13, 8.32). The highest risk of postoperative MI occurred when aRCR was performed within 6 months of MI (odds ratio, 7.55; 95% confidence interval, 4.38, 13.01), with no significant elevation beyond this window. Type 1 MI was associated with postoperative MI and mortality, whereas type 2 MI was associated with acute kidney injury, pneumonia, and readmission. Both ST‐elevation MI and non‐ST‐elevation MI were linked to increased postoperative MI risk. Patients without PCI showed broader postoperative complications, including mortality, acute kidney injury, and stiffness, compared with those who underwent PCI. Conclusions Recent MI is associated with increased postoperative risk of MI after aRCR, particularly when surgery is performed within 6 months. Patients without PCI experience additional vulnerability. Level of Evidence Level III, retrospective comparative study.

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.