Citations

Abstract Introduction Revascularization to prevent limb loss is not feasible or represents a very high risk in a significant proportion of patients with chronic limb-threatening ischaemia (CLTI). No standard definition currently exists to define this population of patients. The aim of this study was to develop a consensus-based, multidomain definition to improve clinical assessment and reporting of studies in people with ‘no option’ (NO) or ‘poor option’ (PO) CLTI. Methods A modified Delphi process was conducted with 164 specialists from 30 countries. Two iterative survey rounds were used to reach consensus, defined as ≥70% agreement with a score of ≥7 on a nine-point scale. Results Some 164 international vascular specialists participated in the study, averaging 19 years of experience. A multidomain framework including arterial disease anatomy, biology, risk, function, and context (ABRFC) achieved 83% consensus. A ‘desert foot’ was defined as the absence of distal arterial revascularization targets on advanced non-invasive imaging, invasive digital subtraction angiography, and at least one failed endovascular revascularization attempt (81.6% agreement). Inadequate autogenous bypass conduit was defined as the lack of usable autologous vein across all four limbs (85% agreement). Patients were classified as NO for revascularization if they present with ‘desert foot’, prohibitive medical risk, a non-functional limb, or in those patients who refused arterial revascularization. PO revascularization patients combined factors such as severe infection, lack of autologous vein, or treatment non-compliance (72.1% agreement). Conclusion This consensus study established a structured, expert-validated definition of no option or poor option for revascularisation of patients with CLTI. The multidomain ABRFC framework provides a foundation for standardized clinical assessment, trial design, and future guideline development.

Abstract Background & Aims Stricturing Crohn’s disease (CD) is a significant problem, and no selective anti-fibrotic therapies are available. Anti-inflammatory approaches are the mainstay of medical treatment. However, data on the efficacy of ustekinumab (USTE) in ileal stricturing CD are lacking. Our aim was to assess its efficacy in this setting. Methods We performed an international multicenter observational cohort study evaluating adult CD patients who received USTE within 6 months of imaging-confirmed symptomatic stricturing small bowel disease. Outcomes were rates of endoscopic balloon dilation (EBD), surgery, intervention (defined as the composite need for EBD or surgery), recurrent obstructive symptoms, and USTE persistence. Results Fifty-seven patients were included (51% female, median age 43 years). Median follow-up was 17 months. Intervention rates were 35%, 45%, and 69% of patients, at 12, 24, and 48 months, respectively. USTE persistence was 78%, 76%, and 52% at 12, 24, and 48 months. Estimated obstructive symptoms rates were 31% and 49% at 12 and 24 months, respectively. EBD within 6 months prior to starting USTE was associated with an increased risk of intervention. Increased bowel wall thickness on imaging, prior biologic use, and obstructive symptom duration were associated with USTE discontinuation. Occurrence of obstructive symptoms during treatment was associated with prior biologic use, EBD within 6 months of starting USTE, and a lower BMI. Conclusions USTE appears to be an appropriate medical option in biologic-experienced CD patients with ileal strictures. Further prospective data are needed to better define outcomes and predictors of response in this setting.

Abstract Myocardial infarction (MI) triggers a systemic neutrophil response, yet the roles of distinct neutrophil subsets in cardiac remodeling remain unclear. Studying this requires murine models that accurately mirror human neutrophil dynamics. Here, we show that a minimally invasive intact-chest MI model is more pathophysiologically relevant than the standard open-chest approach for investigating post-MI immune responses. In the open-chest model, surgical trauma disrupts bone marrow homeostasis, releases large numbers of immature neutrophils, and masks MI-specific immune mechanisms. In contrast, the intact-chest model preserves bone marrow integrity and induces only a modest rise in circulating immature neutrophils, closely reflecting MI patient profiles. We further demonstrate that accumulation of immature neutrophils in the infarcted heart exacerbates cardiac dysfunction. Beyond neutrophils, the overall cardiac immune landscape differs markedly between both models. Collectively, our findings establish the intact-chest model as superior for studying post-MI inflammation and reveal immature neutrophils as mediators of adverse cardiac remodeling.

Abstract The human X chromosome accounts for ∼5% of the genome. Despite its size, the role of X-chromosomal variants in human diseases is not well understood, mainly due to its distinct inheritance pattern and the frequent omission of sex chromosomes from genome-wide association studies. This study used whole-genome sequencing data from 888 multiple system atrophy (MSA) cases and 7128 controls to perform an X-chromosome-wide common variant association study. Our analyses revealed two sex-differential risk loci: one located at Xq28, associated with increased risk for MSA in females [index variant: rs4898389, odds ratio (OR) = 1.69, 95% confidence interval (CI) = 1.40–2.03, P-value = 2.43 × 10⁻⁸], and another at Xp22.2 within the TBL1X gene, identified in males (index variant: rs6638956, OR = 1.48, 95%CI = 1.26–1.73, P-value = 9.92 × 10⁻⁷). In the Xq28 locus, colocalization analyses pointed to FAM3A and PLXNA3 as genes of interest. These findings emphasize the vital role of sex-differential genetic factors in the pathogenesis of MSA.

Abstract Glioblastomas exhibit low immunogenicity and a highly immunosuppressive tumor microenvironment (TME) mediated by both tumor cells and tumor associated microglia/macrophages (TAMs). However, biomarkers that allow for specific detection, monitoring and therapy response assessment of the TAM phenotype in glioblastoma are still lacking. To address this gap, we characterized the dynamics of TAM clusters in the TME of experimental SB28 glioblastoma using single-cell RNA sequencing, immunofluorescence, and molecular imaging and identified Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) as a dynamic TAM-specific target. Consequently, we investigated a novel 64 Cu-labeled TREM2 radiotracer with a blood-brain barrier transport vehicle for translational mapping of TAMs in the TME of glioblastoma. We found strong and highly myeloid cell-specific PET signals that followed the trajectory of TREM2 gene expression from early- towards late-stage tumors. Transient myeloid cell depletion via CSF1R inhibition showed a reduction of TREM2 PET signals compared to placebo and prolonged survival in SB28 glioblastoma mice, while TREM2 stimulation led to increased TREM2 PET signals. Translation into a pilot cohort of patients with glioblastoma revealed strong TREM2 PET signals predominantly at lesion edges and high heterogeneity across individuals, matching with immunohistochemistry. In summary, TREM2 PET imaging has strong potential as an immune cell-specific biomarker for personalized assessment of the TAM phenotype in the TME of patients with glioblastoma.