Citations

Background and Aims: Screening for diseases can have psychological impacts, such as anxiety, and requires acceptability from the population to be effective. This study examined the perspectives on the benefits and harms of screening for metabolic dysfunction–associated steatotic liver disease (MASLD) among the general population to optimize screening practices. Approach and Results: A survey was sent to participants enrolled between 2020 and 2024 in a prospective MASLD screening study in Olmsted County, MN. The survey assessed participants' perceived anxiety, stigma, quality of life, preferred screening methods, financial concerns, and lifestyle impacts following screening and diagnosis. Of the 461 participants, 342 (74%) completed the survey. Overall, 14% of participants reported screening-related anxiety, and 14% were concerned about disclosing a potential MASLD diagnosis to others. Among those without a MASLD diagnosis, 99% felt reassured about their liver health, 48% reported an improved quality of life, and 25% made lifestyle changes pertaining to their diet, alcohol use, and physical activity. Of the 77 participants diagnosed with MASLD, 52% experienced some anxiety about their new diagnosis; however, 95% and 97% considered it important to receive an early MASLD diagnosis to mitigate the risk for cirrhosis and cardiovascular disease, respectively. Notably, 79% of diagnosed participants found the diagnosis beneficial in adopting healthier habits, with 30% achieving a >10% weight loss after screening. Conclusion: This population-based survey demonstrates that the perceived benefits of proactive MASLD screening, such as increased awareness, lifestyle changes, and early diagnosis, outweigh the harms. These findings highlight the importance of early screening through patient-centered protocols to improve health outcomes.

Abstract Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative for older adults with hematologic malignancies. Concerns on nonrelapse mortality (NRM) in older adults limit allo-HCT utilization. We executed a prospective, observational study BMT-CTN 1704 (Blood and Marrow Transplant Clinical Trials Network) enrolling allo-HCT recipients aged ≥60 years from 49 centers in the United States. We analyzed associations between 13 measurements of older adult health and NRM within 1 year to construct a comprehensive health assessment risk model (primary-CHARM) using multivariate Fine-Gray model and grouped penalized variable selection. Two machine learning (ML) models (Cox and pseudo-value boosting) were also explored. Models’ performances were compared using area under the curve (AUC), with bootstrap and cross-validation sampling to correct for optimism, decision curve analysis (DCA), calibration, and Brier scores. Among 1105 patients with median age of 67 (range, 60-82) years who received allo-HCT, NRM was 14.4% and overall survival (OS) 71.7% at 1 year. Factors statistically selected for inclusion in primary-CHARM were higher comorbidity burden, lower albumin, higher C-reactive protein, older age, higher weight-loss percentage, lower patient-reported performance score, and cognitive impairment. Primary-CHARM scores were independently associated with higher NRM (hazard ratio [HR], 2.72; P < .0001) and worse OS (HR, 2.09; P < .0001). Bootstrap bias–corrected AUC for primary-CHARM was 0.591. Comparing primary-CHARM with HCT-comorbidity index and 2 ML-CHARM models, calibration, Brier score, and DCA analysis favored primary-CHARM. Primary-CHARM, with mostly simple and readily available parameters, risk stratifies older adults for allo-HCT. Adopting primary-CHARM in practice may promote broader use of HCT by quantifying risk and enhance the design of strategies to improve outcomes. This trial was registered at www.ClinicalTrials.gov as #NCT03992352.

ABSTRACTBackground and AimsLeucine Zipper 4 (LUZP4)‐immunoglobulin G (IgG) is a novel antibody implicated in germ cell tumor‐related paraneoplastic neurologic syndrome. We report a case of painful, progressive tetraparesis associated with testicular seminoma and LUZP4‐IgG seropositivity.Case ReportA 51‐year‐old male presented with a 5‐week history of lower limb predominant progressive weakness. Nerve conduction studies (NCS) and electromyography (EMG) revealed a subacute axonal polyradiculoneuropathy. MRI lumbar spine showed thickening of the cauda equina and enhancement of the lower thoracic spinal cord/conus. Cerebrospinal fluid (CSF) showed a lymphocytic pleocytosis, three oligoclonal bands, and mildly elevated protein. Initial treatment with intravenous immunoglobulin (IVIG) and prednisone produced temporary improvement. CT targeted retroperitoneal lymph node biopsy revealed a seminoma, which was treated with orchiectomy and chemotherapy. The testicular tissue was consistent with a regressed germ cell tumor. His course was subsequently refractory to IVIG, prednisone, and plasma exchange. LUZP4 antibodies were detected in serum, prompting treatment with cyclophosphamide and prednisone. At the 4‐month follow‐up, the patient had significant improvement in hand strength and had transitioned from walker to cane.InterpretationLUZP4‐IgG seropositivity and identification of retroperitoneal seminoma confirmed a paraneoplastic neurologic syndrome, which is a CD8+ T‐cell‐mediated disorder. Aggressive immunotherapy was initiated, resulting in clinical improvement. This case underscores the importance of identifying specific serologic biomarkers that can inform therapeutic decisions and improve outcomes.

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 antitumor response which has been weakened by mechanisms of central tolerance. Here, we show that inflammatory Vesicular Stomatitis Virus (VSV) failed to prime an adoptively transferred, or pre-existing, population of tumor-reactive T cells.Combination with αPD1 immune checkpoint blockade therapy improved survival only when VSV expressed tumor associated antigens (TAA). These data show that, in this model, the highly inflammatory OV VSV alone actively outcompetes antitumor immunity. However, we also show that viral expression of a mutant near-self TAA can break central tolerance expanding heteroclitic self-reactive and near-self-reactive T cells, thus overcoming viral immunodominance by promoting tumor-specific T cell proliferation in parallel with expanding antiviral T cells.

Abstract Background Antibody responses to MF59-adjuvanted (MF59Flu) and high-dose (HDFlu) influenza vaccines have been well-characterized in older adults, yet corresponding cellular immune response data remain limited. Methods Blood samples were collected from 106 MF59Flu recipients and 112 HDFlu recipients at 4 time points: before vaccination (day 0) and on days 1, 8, and 28 postvaccination. Antibody responses were assessed in serum samples using a hemagglutination inhibition assay. Eight proinflammatory cytokines and chemokines, including IFN-α2a, IFN-γ, IP-10, MCP-1, MIP-1α, IL-1β, IL-6, and IL-8, were quantified from peripheral blood mononuclear cells using a multiplex assay. Associations between cytokine/chemokine secretion levels and antibody responses were examined, along with the effect of sex, age, body mass index (BMI), and cytomegalovirus infection status. Results Age was positively correlated with IL-8 levels on day 1 (r = 0.24, P < .001) and the change in IL-8 levels from day 0 to day 1 (r = 0.16, P = .021). Notably, the change in IL-8 levels was negatively associated with day 28 hemagglutination inhibition titers (r = −0.15, P = .026). Causal mediation analysis demonstrated that IL-8 exerted significant causal mediation effects on antibody responses at both day 8 (P = .046) and day 28 (P = .0045). No significant effects of other cytokines and chemokines, vaccine type, sex, or BMI on antibody responses were observed. Conclusions Our findings underscore IL-8 as a potential mediator of antibody responses to influenza vaccination in older adults, suggesting that IL-8 inhibition could serve as a molecular intervention to improve antibody responses in this high-risk population.

Abstract Objectives To determine the efficacy, safety and pharmacodynamics of belumosudil in patients with diffuse cutaneous systemic sclerosis (dcSSc) treated with background immunosuppressive therapies. Methods Eligible patients were randomised 1:1:1 to receive belumosudil 200 mg once daily (QD) or twice daily (BID), or placebo for 28 weeks (double-blind period). After unblinding, the patients who received belumosudil continued the same dose, whereas the patients who received placebo were re-randomised for one of the belumosudil doses for 24 weeks (open-label extension). Results Thirty-five and 31 patients were treated in the double-blind and open-label periods, respectively. The study was terminated prematurely, and target enrolment was not met. The primary end point, of CRISS score ≥0.60 at week 24, did not exhibit an efficacy signal in the belumosudil vs placebo groups [odds ratio: 1.06 (0.19–5.82; P = 0.9472) for the QD, and 0.39 (0.07–2.35; P = 0.3078) for the BID group]. Belumosudil was well tolerated and exhibited similar safety profiles in both double-blind and open-label periods. Tissue-based RNA sequencing analysis revealed FOXP3 upregulation and STAT3, IL23A and TGF-β downregulation in patients with CRISS score ≥0.60, which supported the mechanism of action of belumosudil. In blood and tissue samples, trends of decreased fibrosis biomarker levels were seen in the belumosudil-treated group vs placebo. Conclusion Efficacy signal for belumosudil could not be detected. Signalling pathway modulation analysis supported the mechanism of action of belumosudil. A trend for decreased fibrosis-related biomarkers was observed in the belumosudil-treated group. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov, NCT03919799.