Soluble CD46 as a diagnostic marker of hepatic steatosis

Background The increasing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) incurs substantial morbidity, mortality and healthcare costs. Detection and clinical intervention at early stages of disease improves prognosis; however, we are currently limited by a lack of reliable diagnostic tests for population screening and monitoring responses to therapy. To address this unmet need, we investigated human invariant Natural Killer T cell (iNKT) activation by fat-loaded hepatocytes, leading to the discovery that circulating soluble CD46 (sCD46) levels accurately predict hepatic steatosis. Methods sCD46 in plasma was measured using a newly developed immuno-competition assay in two independent cohorts: Prospective living liver donors (n = 156; male = 66, female = 90) and patients with liver tumours (n = 91; male = 58, female = 33). sCD46 levels were statistically evaluated as a predictor of hepatic steatosis. Findings Interleukin-4-secreting (IL-4+) iNKT cells were over-represented amongst intrahepatic lymphocytes isolated from resected human liver samples. IL-4+ iNKT cells preferentially developed in cocultures with a fat-loaded, hepatocyte-like cell line, HepaRG. This was attributed to induction of matrix metalloproteases (MMP) in fat-loaded HepaRG cells and primary human liver organoids, which led to indiscriminate cleavage of immune receptors. Loss of cell-surface CD46 resulted in unrepressed differentiation of IL-4+ iNKT cells. sCD46 levels were elevated in patients with hepatic steatosis. Discriminatory cut-off values for plasma sCD46 were found that accurately classified patients according to histological steatosis grade. Interpretation sCD46 is a reliable clinical marker of hepatic steatosis, which can be conveniently and non-invasively measured in serum and plasma samples, raising the possibility of using sCD46 levels as a diagnostic method for detecting or grading hepatic steatosis

Virus-specific memory T cell responses unmasked by immune checkpoint blockade cause hepatitis

Treatment of advanced melanoma with combined PD-1/CTLA-4 blockade commonly causes serious immune-mediated complications. Here, we identify a subset of patients predisposed to immune checkpoint blockade-related hepatitis who are distinguished by chronic expansion of effector memory CD4+ T cells (TEM cells). Pre-therapy CD4+ TEM cell expansion occurs primarily during autumn or winter in patients with metastatic disease and high cytomegalovirus (CMV)-specific serum antibody titres. These clinical features implicate metastasis-dependent, compartmentalised CMV reactivation as the cause of CD4+ TEM expansion. Pre-therapy CD4+ TEM expansion predicts hepatitis in CMV-seropositive patients, opening possibilities for avoidance or prevention. 3 of 4 patients with pre-treatment CD4+ TEM expansion who received αPD-1 monotherapy instead of αPD-1/αCTLA-4 therapy remained hepatitis-free. 4 of 4 patients with baseline CD4+ TEM expansion given prophylactic valganciclovir and αPD-1/αCTLA-4 therapy remained hepatitis-free. Our findings exemplify how pathogen exposure can shape clinical reactions after cancer therapy and how this insight leads to therapeutic innovations

Total joint arthroplasty versus resection-interposition arthroplasty for thumb carpometacarpal arthritis: a randomized controlled trial

Background and purpose: Thumb carpometacarpal (TCMC) osteoarthritis is a common condition that causes pain and functional limitations. We compared the outcomes of 2 surgical procedures for TCMC osteoarthritis, the Epping resection-suspension arthroplasty and the double-mobility TCMC prosthesis, and focused on pain relief, functional outcomes, and patient quality of life. Patients and methods: Over a 7-year period a randomized controlled trial including 183 cases of TCMC osteoarthritis was conducted comparing a double mobility TCMC prosthesis (Moovis, Stryker, Kalamazoo, MI, USA) with the Epping resection-suspension arthroplasty. Pre- and postoperative examinations included the range of motion (ROM), SFMcGill score, visual analogue scale (VAS), the disabilities of the arm, shoulder and hand questionnaire (DASH), and the hospital anxiety and depression scale (HADS). Results: At the 6-week postoperative follow-up, significant differences were found in VAS: Epping median 4.0 (interquartile range [IQR] 2.0–5.0) vs. TCMC prosthesis 2.0 (IQR 0.25–4.0), p = 0.03, effect size (area under the curve [AUC]) 0.64 (95% confidence interval [CI] 0.55–0.73), in DASH score: Epping 61 (IQR 43–75) vs. TCMC prosthesis 45 (IQR 29–57), p < 0.001, AUC 0.69 (CI 0.61– 0.78), and in radial abduction: Epping 55 (IQR 50–60) vs. TCMC prosthesis 62 (IQR 60–70), p = 0.001, AUC 0.70 (CI 0.61–0.79). No significant group differences were found at the 6- and 12-months follow-up. During the follow-up period, 3 of 82 prostheses had to be revised but there was no revision in the Epping group. Conclusion: The double mobility TCMC prosthesis had superior outcomes compared with the Epping procedure at 6 weeks; however, there were no significant differences in outcomes at 6 months and 1 year postoperatively. The implant survival rate of 96% after 12 months was acceptabl

Combined serum biomarker analysis shows no benefit in the diagnosis of periprosthetic joint infection

Purpose In many cases, the diagnosis of a periprosthetic joint infection (PJI) consisting of the clinical appearance, laboratory tests, and other diagnostic tools remains a difficult task. Single serum biomarkers are easy to collect, are suitable for periodical assessment, and are a crucial tool in PJI diagnosis, but limited sensitivity or specificity is reported in literature. The aim of this study was to combine the best-performing single serum biomarkers into a multi-biomarker model aiming to improve the diagnostic properties. Methods Within a 27-month period, 124 surgical procedures (aseptic or septic revision total knee arthroplasty (TKA) or total hip arthroplasty (THA)) were prospectively included. The serum leukocyte count, C-reactive protein (CRP), interleukin-6, procalcitonin, interferon alpha, and fibrinogen were assessed 1 day prior to surgery. Logistic regression with lasso-regularization was used for the biomarkers and all their ratios. After randomly splitting the data into a training (75%) and a test set (25%), the multi-biomarker model was calculated and validated in a cross-validation approach. Results CRP (AUC 0.91, specificity 0.67, sensitivity 0.90,pvalue 0.03) and fibrinogen (AUC 0.93, specificity 0.73, sensitivity 0.94,pvalue 0.02) had the best single-biomarker performances. The multi-biomarker model including fibrinogen, CRP, the ratio of fibrinogen to CRP, and the ratio of serum thrombocytes to CRP showed a similar performance (AUC 0.95, specificity 0.91, sensitivity 0.72,pvalue 0.01). Conclusion In this study, multiple biomarkers were tested for their diagnostic performance, with CRP and fibrinogen showing the best results regarding the AUC, accuracy, sensitivity, and specificity. It was not possible to further increase the diagnostic accuracy by combining multiple biomarkers using sophisticated statistical methods