ABSTRACT Accurate assessment of anti-respiratory syncytial virus (RSV)-specific antibodies has gained importance following the introduction of RSV vaccines and long-acting monoclonal antibody prophylaxis. However, the analytical performance and interchangeability of commercially available RSV−ELISAs remain insufficiently defined, leaving uncertainty about their reliability for clinical diagnostic practice. We performed a head-to-head comparison of the widely used commercial Euroimmun− and Virotech‒ELISA for detection of total anti-RSV‒IgG and IgA in 462 sera from four cohorts: healthy adults ( n = 100), pregnant women ( n = 59), children ( n = 101), and vaccinated transplant recipients ( n = 101; baseline and day + 30). Prefusion-F (pre-F)-specific IgG was quantified to infer functionally relevant antibody responses. Qualitative agreement, quantitative bias, correlations, and age-dependent patterns were assessed. Qualitative concordance in anti-RSV‒IgG detection was high (83.8%) between assays. However, the Virotech‒ELISA systematically yielded higher IgG detection rates and quantitative values ( P < 0.001). Total anti-RSV‒IgG correlated significantly with pre-F‒IgG in all cohorts, with strongest correlations in children (r s = 0.92) and vaccinated transplant recipients (r s = 0.79). Anti-RSV‒IgA was detected infrequently (6%–11%), with moderate (79.4%) inter-assay concordance. IgG‒IgA correlations were weak in healthy adults and pregnant women (r s < 0.25), but moderate in children and vaccinated transplant recipients (r s ≥ 0.40). The Euroimmun− and Virotech‒ELISAs are not analytically interchangeable and exhibit systematic assay-dependent differences. Integrated analysis of total anti-RSV‒IgG, pre-F‒IgG, and IgA across clinically relevant populations emphasizes the need for assay- and population-aware interpretation to support reliable use of RSV serology in seroepidemiological studies and diagnostic laboratory practice. IMPORTANCE With the recent introduction of espiratory syncytial virus (RSV) vaccines and infant monoclonal antibody prophylaxis, serological testing is gaining relevance in vaccine immunogenicity trials, post-licensure evaluations, and population-based serosurveillance. Although commercial ELISAs offer the potential to harmonize antibody testing, their appropriate application requires a detailed understanding of assay-specific performance and calibration characteristics. Inadequate validation can limit inter-laboratory comparability, such that identical samples yield different quantitative results across centers, thereby complicating longitudinal antibody monitoring and harmonized analysis in multicenter surveillance and vaccine studies. In this context, the present study provides a systematic cross-comparison of two widely used RSV−ELISAs and demonstrates that, despite good qualitative agreement, they are not quantitatively interchangeable and exhibit systematic differences in IgG and IgA measurements across populations and immune contexts. By characterizing the performance of total IgG, pre-F−specific IgG, and IgA in diverse clinical settings, this work supports informed assay selection and interpretation of RSV serology in clinical diagnostic practice.

Preoperative anemia and non-anemic iron deficiency are common in cardiac surgery patients. Both are frequently caused by absolute iron deficiency or are associated with chronic diseases and inflammation. Multiple studies have shown an association between preoperative anemia and increased RBC transfusion, prolonged intensive care unit and hospital length of stay, and higher postoperative morbidity and mortality. The impact of preoperative non-anemic iron deficiency on postoperative adverse outcome is less clear, but worsened postoperative outcomes have been suggested. Accordingly, treatment for anemia and iron deficiency is a primary goal in preoperative optimization in cardiac surgery patients. Several guidelines recommend timely supplementation with modern oral iron formulation as first-line intervention, followed by intravenous iron administration in case of patient intolerance or time restriction. In patients with non-pure iron deficiency or in ultra-short treatment strategies, the combined therapy of intravenous iron and erythropoiesis-stimulating agents seems safe and most efficacious to increase red blood mass before surgery. However, the positive effects of preoperative interventions in anemic or iron-deficient patients were mostly limited to reduced transfusion of red blood cells, whereas lower morbidity and mortality were shown in limited studies only. It is also important to note that allogeneic blood products are a limited resource, and preoperative oral iron supplementation showed the best cost-effectiveness.

Chimeric antigen receptor (CAR) T-cell therapy has improved outcomes for patients with chemotherapy-resistant B-cell malignancies. However, CAR T-cell treatment of patients with solid cancers has been more difficult, in part because of the heterogeneous expression of tumor-specific cell surface antigens. In this study, we describe the generation of a fully human CAR targeting altered glycosylation in secretory epithelial cancers. The expression of the target antigen-the truncated, sialylated O-glycan Sialyl-Thomsen-nouveau (STn) antigen-was studied with a highly STn-specific antibody across various different tumor tissues. Strong expression was found in a high proportion of gastrointestinal cancers, including pancreatic cancers, and in gynecologic cancers, in particular ovarian and endometrial tumors. T cells expressing anti-STn CAR were tested in vitro and in vivo. Anti-STn CAR T cells showed activity in mouse models, as well as in assays with primary ovarian cancer samples. No considerable toxicity was observed in mouse models although some intraluminal expression of STn was found in gastrointestinal mouse tissue. Taken together, this fully human anti-STn CAR construct shows promising activity in preclinical tumor models, supporting its further evaluation in early clinical trials.

The blood donor population has great potential to serve as a sentinel system for the general population. The data presented in this study of a survey of the seroprevalence of Anti-SARS-CoV-2 antibodies in Switzerland are an illustrative example of this possibility. From March 2020 to January 2021, the increase in antibody seroprevalence for both Anti-NCP and Anti-S was only very moderate, up to ~17%. In May/June 2021, the Anti-NCP seroprevalence was 21.6% and the S-seroprevalence 59.4%, respectively, indicating only a moderate natural infection rate. The Anti-seroprevalence rate was in good agreement with the first vaccination campaign launched in winter 2020/21. The dramatic increase in the antibodies against the NCP protein (74.6%) since November/December 2021 to June–August 2022 was simultaneous with the appearance and rapid spread of the Omicron SARS-CoV-2 variant in Switzerland and the abolition of compulsory mask wearing in public spaces. At the end of 2022, 99.0% of the blood donor population already developed antibodies against the S protein and 83.9% against the NCP. One year later, after the official termination of the pandemic, these seroprevalences were even higher, 99.8% for the Anti-S and 95.0% for Anti-NCP. This increase for both of them was in accordance with the vaccination campaigns, the abolition of mask wearing, and the spread of the Omicron variant. These data show how the blood donor population can be used to represent the infection surveillance of the general population of a region or country.

In the original publication [...].

PURPOSE OF THE REVIEW:In this narrative review, we evaluate the recent evidence for benefits, cost-effectiveness, and ethical considerations of patient blood management (PBM) programs. RECENT FINDINGS:PBM programs are able to reduce the amount of red blood cell transfusion by 20-40% and the risk of reoperation. Lower morbidity and mortality due to PBM implementation were only shown in retrospective studies with a before-and-after design but not in randomized controlled trials. PBM is very likely to be cost-effective when reduced blood transfusion can be accomplished through low-cost interventions, such as administration of oral iron or antifibrinolytics. Further, cost-efficacy can also be achieved by reducing postoperative morbidity and length of hospital stay. Of note, cost-efficacy of PBM interventions might be better in patients at high bleeding risk. Finally, aiming to improve patient's outcome while minimizing transfusion-induced complications, PBM seems highly ethical. SUMMARY:PBM is an important concept as it promotes the rational use of allogeneic blood products and reduces transfusion and wastage of precious and limited blood products.

INTRODUCTION AND OBJECTIVES:It is unclear whether applying sex-specific rather than uniform upper reference limits (URLs) for high-sensitivity cardiac troponin I (hs-cTnI) improves diagnostic equity between women and men with suspected myocardial infarction (MI). We compared the diagnostic performance of these 2 approaches. METHODS:In an international, prospective, multicenter study of patients presenting with suspected MI, the final diagnosis was centrally adjudicated twice by 2 independent cardiologists using all available information, including serial measurements of hs-cTnI-Architect, once using the uniform URL (26.2 ng/L) and once using sex-specific URLs (women: 15.6 ng/L; men: 34.2 ng/L). The primary outcome was the diagnostic performance of uniform vs sex-specific URLs at presentation for MI. RESULTS:Among 7137 eligible patients, 2434 were women (34%), median age 65 years, and 4703 were men (66%), median age 59 years. Using the uniform URL, 348 women and 880 men were adjudicated as having MI. At presentation, the sensitivity and specificity of hs-cTnI were high and similar in women (77%; 95%CI, 72-81, and 93%; 95%CI, 92-94, respectively) and men (79%; 95%CI, 77-82, and 94%; 95%CI, 93-94). Using sex-specific URLs, the sensitivity and specificity were 85% (95%CI, 81-89) and 91% (95%CI, 89-92) in women vs 74% (95%CI, 71-77), and 95% (95%CI, 94-95) in men (P<.001). Using sex-specific URLs, diagnostic reclassification occurred in 27 patients, 12 women (upgrade to MI) and 15 men (downgrade from MI), representing 0.4%, (95%CI, 0.3-0.6) of all patients. CONCLUSIONS:Using a uniform URL for hs-cTnI provides high and similar diagnostic sensitivity and specificity in women and men. Contrary to expectations, sex-specific URLs introduced sex-related disparities. These findings support the use of a uniform rather than sex-specific URL in the diagnosis of MI.

INTRODUCTION: Quantifying antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and neutralising antibodies may help to understand protection at the individual and population levels. Determination of neutralising antibodies using classical virus neutralisation tests (VNT) is considered the gold standard, but they are costly and time-intensive. Enzyme-linked immunosorbent assay (ELISA)-based surrogate VNTs (sVNT) or anti-SARS-CoV-2 spike protein receptor binding domain immunoglobulins (anti-S-RBD Ig) may be suitable alternatives to VNTs. We aimed to (a) explore the correlations between anti-S-RBD Ig, VNT, and sVNT measurements and (b) describe humoral immunity against SARS-CoV-2 after vaccination, natural infection, and vaccine breakthrough infection in healthy blood donors. METHODS: We measured total anti-SARS-CoV-2 Ig in 5714 serum samples from 2748 healthy individuals visiting the Swiss Red Cross Blood Donation Centre in Basel from 03/2020 to 04/2022. We used the Elecsys® Anti-SARS-CoV-2 immunoassay (Roche) against the N- and S-receptor binding domain (RBD) proteins. In a subset of 548 samples from 123 donors, we conducted sVNTs against the Wuhan wild-type SARS-CoV-2 (SARS-CoV-2 Neutralizing Antibodies Detection Kit; Adipogen™). In 100 samples from 40 donors, we correlated sVNT and VNTs against the wild-type (D614G WU1) virus. Surveys were sent to the blood donors to collect data on their SARS-CoV-2 infection and vaccination status. Using this data, donors were categorised as “vaccination only”, “infection before vaccination”, “post-vaccine breakthrough infection”, and “natural infection only”. RESULTS: Our longitudinal observation study cohort consisted of 50.7% males with a median age of 31 years (range 18–75 y). Anti-SARS-CoV-2 N protein positivity rates per month indicate 57.1% (88/154) of the cohort was infected up to 04/2022. No differences in seropositivity were found between sexes, age groups, blood types (AB0 or RhD), and cytomegalovirus serostatus. We observed a high correlation between anti-S-RBD Ig and inhibition percentage (Spearman’s ρ = 0.92, Kendall’s τ = 0.77, p <0.0001). We determined the sensitivity and specificity for the manufacturers’ thresholds for detecting virus-neutralising effects and computed the “best” cut-off based on our real-world data. We categorised 722/1138 (63.5%) donors as vaccination only (82.3%), post-vaccine breakthrough infection (7.8%), infection before vaccination (5.8%), and natural infection only (4.2%). We observed a lower inhibition percentage in the natural infection-only group than in all other vaccinated groups. The infection before vaccination group had higher anti-S-RBD Ig titres after the first vaccine dose than the other vaccinated groups. CONCLUSION: In total, 57.1% of healthy blood donors were infected with SARS-CoV-2, but natural infection without evidence of vaccination seems to result in substantially lower neutralising antibody levels. An estimate of antibody neutralisation may be helpful to assess reinfection risk. Total anti-S-RBD Ig correlates with surrogate virus neutralisation test results, a surrogate for neutralisation; therefore, we suggest that total anti-S-RBD Ig may estimate the level of neutralising antibodies. The threshold for protection from an unfavourable clinical outcome must be evaluated in prospective clinical cohorts.

Aim Pathogen inactivation (PI) is a globally recognized method for enhancing the safety of platelet concentrates and plasma. This publication examines the necessity and potential benefits of implementing PI for platelet concentrates in Germany. Method The analysis includes data on the current blood supply, infection risks associated with platelet concentrates, and existing safety standards, also in international comparison. Results The results show that PI improves safety by inactivating known and unknown pathogens, extends shelf life, expands the donor pool, and reduces the number of discarded platelet concentrates. This stabilizes supply and reduces costs. Conclusion The integration of PI into the German hemotherapy guideline and accelerated approval processes are recommended.

Zusammenfassung Zielsetzung Die Pathogeninaktivierung (PI) ist ein weltweit anerkanntes Verfahren zur Verbesserung der Sicherheit von Thrombozytenkonzentraten und Plasma. Diese Arbeit untersucht die Notwendigkeit und potenziellen Vorteile der Implementierung der PI für Thrombozytenkonzentrate in Deutschland. Methodik Analysiert werden sowohl Daten zur aktuellen Blutversorgung als auch zu Infektionsrisiken von Thrombozytenkonzentraten sowie bestehender Sicherheitsstandards auch im interationalen Vergleich. Ergebnisse Die Ergebnisse zeigen, dass PI die Sicherheit durch die Inaktivierung bekannter und unbekannter Pathogene verbessert, die Haltbarkeit verlängert, den Spenderkreis erweitert und die Anzahl verworfener Thrombozytenkonzentrate reduziert. Dies stabilisiert die Versorgung und senkt Kosten. Schlussfolgerung Eine Integration der PI in die deutschen Hämotherapie-Richtlinien und beschleunigte Zulassungsverfahren werden empfohlen.

BackgroundElevated serum ferritin with/without HFE variants in asymptomatic persons leads frequently to referral for blood donation. Hemochromatosis (p.C282Y/p.C282Y) only requires treatment. We evaluated safety and feasibility of iron removal in healthy persons with elevated ferritin and HFE variants using blood donation procedures.Materials and methodsThirty subjects with ferritin >200 ng/mL (women) or >300 ng/mL (men) with p.C282Y/p.C282Y, p.C282Y/p.H63D or p.H63D/p.H63D were randomized to weekly phlebotomy (removal of 450 mL whole blood) or erythrapheresis (removal of 360 mL red blood cells) every 14 days. The ferritin target was <100 ng/mL. A full blood count and ferritin were measured at each visit. Hemoglobin (Hb) ≥140 g/L was required at inclusion. If Hb dropped to <120 g/L (women) or <130 g/L (men), procedures were postponed (7 or 14 days). Primary endpoint was the number of procedures needed to the ferritin target; secondary objectives were duration of treatment and compliance. The treatment effect was tested with Poisson regression; number of procedures and treatment duration were compared between study arms with the Kruskal–Wallis test.ResultsTwenty-five of 30 participants were men (83%); mean age was 47 years (SD 10.5), mean BMI 26.6 kg/m2 (SD 3.6); 17 had p.C282Y/p.C282Y, nine p.C282Y/p.H63D, four p.H63D/p.H63D. Median baseline Hb was 150 g/L (IQR 144, 1,559), median ferritin 504 ng/mL (IQR 406,620). Twenty-seven subjects completed the study. Treatment arm (p < 0.001) and HFE variant (p = 0.007) influenced the primary endpoint significantly. To ferritin levels <100 ng/mL, a median number of 7.5 (IQR 6.2, 9.8) phlebotomies and 4.0 (IQR 3.0, 5.8) erythraphereses (p = 0.001) was needed during a median of 66.5 days (IQR 49,103) and 78.5 days (IQR 46139), respectively (p = 0.448). Low Hb was the principal reason for protocol violation; anemia occurred in 13 participants (48%). Immediate complications were infrequent; fatigue was reported after 25% of phlebotomies and 45% of erythraphereses. Thirty-five procedures were postponed because of low Hb and 15 for non-medical reasons. The median interval was 7.0 (IQR 7.7) and 14.0 (IQR 14, 20) days between phlebotomies and erythraphereses, respectively.ConclusionBlood donation procedures remove iron effectively in HC, but frequent treatments cause Hb decrease and fatigue that can impair feasibility.

Supplementary Figure 7. MHC I expression on tumor cells in lesion used for expansion of the TIL product and the progressing lung metastasis.

Background: Von Willebrand factor (vWF) is an important part of blood coagulation since it binds platelets to each other and to endothelial cells. In traumatic and surgical haemorrhage, both blood cells and plasmatic factors are consumed, leading to consumption coagulopathy and fluid resuscitation. This often results in large amounts of crystalloids and blood products being infused. Additional administration of vWF complex and platelets might mitigate this problem. We hypothesize that administration of vWF concentrate additionally to platelet concentrates reduces blood loss and the amount of blood products (platelets, red blood cells [RBC], fresh frozen plasma [FFP]) administered. Methods: We conducted a monocentric 6-year retrospective data analysis of cardiac surgery patients. Included were all patients receiving platelet concentrates within 48 h postoperatively. Patients who additionally received vWF concentrates were allocated to the intervention group and all others to the control group. Groups were compared in mixed regression models correcting for known confounders, based on nearest neighbour propensity score matching. Primary endpoints were loss of blood (day one and two) and amount of needed blood products on day one and two (platelets, RBC, FFP). Secondary endpoints were intensive care unit (ICU) and in-hospital length of stay, ICU and in-hospital mortality, and absolute difference of platelet counts before and after treatment. Results: Of 497 patients analysed, 168 (34%) received vWF concentrates. 121 patients in both groups were considered for nearest neighbour matching. Patients receiving additional vWF were more likely to receive more blood products (RBC, FFP, platelets) in the first 24 h after surgery and had around 200 mL more blood loss at the same time. Conclusion: In this retrospective analysis, no benefit in additional administration of vWF to platelet concentrates on perioperative blood loss, transfusion requirement (platelets, RBC, FFP), length of stay, and mortality could be found. These findings should be verified in a prospective randomized controlled clinical trial (www.clinicaltrials.gov identifier NCT04555785).

Background and Purpose Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) is a personalized immunotherapy. The efficacy of TIL-ACT has been demonstrated prospectively in patients with advanced melanoma but is not limited to melanoma patients. However, many patients are refractory to TIL-ACT, or their cancer becomes resistant. Combining anti-PD-1 with TIL-ACT to antagonize the immunosuppressive tumor microenvironment may synergize to enhance the anti-tumor potential. Material and Methods We set up the BaseTIL trial (NCT04165967), a single-center investigator-initiated phase I trial to test feasibility and safety of TIL-ACT followed by PD-1 blockade in patients with advanced cutaneous melanoma with disease progression after at least one line of anti-PD-1. TIL-ACT included tumor collection, ex vivo TIL expansion, lymphodepletion with cyclophosphamide and fludarabine, TIL transfer and in vivo TIL stimulation with interleukin-2 (125’000 IE/kg, 10 days). TIL-ACT was followed by nivolumab treatment for a maximum of 2 years. Nine patients were planned for inclusion. Results Between 2020 and 2022, we enrolled 11 patients and 9 underwent a TIL transfer (median transfused cell number: 66.25 x109). Two patients did not start lymphodepletion. Nine patients received at least 1 dose of interleukin-2 (median number: 10; range, 1-10), 7 started nivolumab (median number: 5; range, 2-23). All patients had hematologic adverse events (AEs). Most common non-hematologic AEs were fever and cytokine-release syndrome. No nivolumab-associated AEs of ≥ grade 2 occurred. The objective response rate to TIL-ACT was 22% (2/9, 2 partial remission). Conclusions TIL-ACT with nivolumab is feasible and safe. Larger trials are needed to further determine the efficacy of this combination.

Abstract Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) is effective in patients with melanoma, although long-term responses seem restricted in patients who have complete remissions. Many patients develop secondary resistance to TIL-ACT but the involved mechanisms are unclear. In this study, we describe a case of secondary resistance to TIL-ACT possibly due to intratumoral heterogeneity and selection of a resistant tumor cell clone by the transferred T cells. To the best our knowledge, this is the first case of clonal selection of a pre-existing nondominant tumor cell clone; this report demonstrates the mechanism involved in secondary resistance to TIL-ACT that can potentially change current clinical practice because it advocates for T-cell collection from multiple tumor sites and analysis of tumor heterogeneity before treatment with TIL-ACT.

Introduction: Cardiac complications after major noncardiac surgery are common and associated with high morbidity and mortality. How preoperative use of beta-blockers may impact perioperative cardiac complications remains unclear. Methods: In a multicentre prospective cohort study, preoperative beta-blocker use was ascertained in consecutive patients at elevated cardiovascular risk undergoing major noncardiac surgery. Cardiac complications were prospectively monitored and centrally adjudicated by two independent experts. The primary endpoint was perioperative myocardial infarction or injury attributable to a cardiac cause (cardiac PMI) within the first three postoperative days. The secondary endpoints were major adverse cardiac events (MACE), defined as a composite of myocardial infarction, acute heart failure, life -threatening arrhythmia, and cardiovascular death and all -cause death after 365 days. We used inverse probability of treatment weighting to account for differences between patients receiving beta-blockers and those who did not. Results: A total of 3839/10 272 (37.4%) patients (mean age 74 yr; 44.8% female) received beta-blockers before surgery. Patients on beta-blockers were older, and more likely to be male with established cardiorespiratory and chronic kidney disease. Cardiac PMI occurred in 1077 patients, with a weighted odds ratio of 1.03 (95% confidence interval [CI] 0.94 - 1.12, P = 0.55) for patients on beta-blockers. Within 365 days of surgery, 971/10 272 (9.5%) MACE had occurred, with a weighted hazard ratio of 0.99 (95% CI 0.83 - 1.18, P = 0.90) for patients on beta-blockers. Conclusion: Preoperative use of beta-blockers was not associated with decreased cardiac complications including cardiac perioperative myocardial infarction or injury and major adverse cardiac event. Additionally, preoperative use of betablockers was not associated with increased all -cause death within 30 and 365 days. Clinical trial registration: NCT02573532.

Background Point-of-care (POC) high-sensitivity cardiac troponin assays may further accelerate the diagnosis of myocardial infarction (MI). Objectives This study sought to assess the clinical and analytical performance of the novel high-sensitivity cardiac troponin I (hs-cTnI)-SPINCHIP POC test. Methods Adult patients presenting with acute chest discomfort to the emergency department were enrolled in an international, diagnostic, multicenter study. The final diagnosis was centrally adjudicated by 2 independent cardiologists using all clinical information. We compared the discriminatory performance of hs-cTnI-SPINCHIP with current established central laboratory assays and derived an assay-specific hs-cTnI-SPINCHIP 0/1-hour algorithm. Secondary analyses included sample type comparisons (whole blood, fresh/frozen plasma, and capillary finger prick) and precision analysis. Results MI was the adjudicated final diagnosis in 214 (19%) of 1,102 patients. Area under the receiver-operating characteristic curve was 0.94 (95% CI: 0.92-0.95) for hs-cTnI-SPINCHIP vs 0.94 (95% CI: 0.92-0.95) for hs-cTnI-Architect (P = 0.907) and 0.93 (95% CI: 0.91-0.95) for high-sensitivity cardiac troponin T Elecsys (P = 0.305). A cutoff <7 ng/L at presentation (if chest pain onset was >3 hours) or <7 ng/L together with a 0/1-hour delta of <4 ng/L ruled out 51% with a sensitivity and negative predictive value of 100% (95% CI: 97.7%-100%) and 100% (95% CI: 99.0%-100%), respectively. A hs-cTnI-SPINCHIP concentration ≥36 ng/L or a 0/1-hour delta ≥11 ng/L ruled in 27% with a specificity and positive predictive value of 90.9% (95% CI: 88.3%-92.9%) and 72.9% (95% CI: 66.4%-78.6%), respectively. Bootstrap internal validation confirmed excellent diagnostic performance. High agreement was observed between different sample types. Conclusions The SPINCHIP hs-cTnI POC test has very high diagnostic accuracy. Its assay-specific 0/1-hour algorithm achieved very high sensitivity/negative predictive value and specificity/positive predictive value for rule-out/in MI. (Advantageous Predictors of Acute Coronary Syndromes Evaluation [APACE] Study [APACE]; NCT00470587)