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Background & Aims: Chronic liver diseases pose a serious public health issue. Identifying patients at risk for advanced liver fibrosis is crucial for early intervention. The Fibrosis-4 score (FIB-4), a simple non-invasive test, classifies patients into three risk groups for advanced fibrosis. This study aimed to estimate the prevalence of patients at risk for advanced hepatic fibrosis at a Swiss tertiary care hospital by calculating the FIB-4 score in routine blood analysis., Methods: A retrospective study was conducted using data from 36,360 patients who visited outpatient clinics at eight main clinics of the University Hospital Bern in Switzerland. The data collection period ran from January 1st to December 31st, 2022. Patients attending the hepatology outpatient clinic were excluded. We then calculated the overall and clinic-specific prevalence of patients falling into the high risk category for advanced fibrosis according to FIB-4., Results: Among the 36,360 patients, 26,245 (72.2%) had a low risk of advanced fibrosis (FIB-4 <1.3), whereas 3913 (10.8%) and 2597 (7.1%) patients were flagged to have a high risk of advanced fibrosis (FIB-4 >2.67 and FIB-4 >3.25 respectively). Geriatrics and Cardiology had the highest proportions of patients at risk for advanced fibrosis over all clinics., Conclusions: This study demonstrates a high prevalence of high FIB-4 score in a Swiss tertiary care hospital. The implementation of the automatically generated FIB-4 score in daily practice, not only in primary care, but also within tertiary care hospitals, could be crucial for early identification of outpatients at high risk of advanced liver fibrosis requiring further hepatological investigations., Competing Interests: I have read the journal’s policy, and the authors of this article declare the following competing interests: Petra Strajhar was a Master of Public Health student at the time this work was completed and an employee of Alexion AstraZeneca. Alexion AstraZeneca was not involved in or did not fund this work. This does not alter our adherence to PLOS ONE’s policies on sharing data and materials., (Copyright: © 2025 Strajhar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Early detection and diagnosis of venous thromboembolism are vital for effective treatment. To what extent methodological shortcomings exist in studies of diagnostic tests and whether this affects published test performance is unknown., Objectives: We aimed to assess the methodological quality of studies evaluating diagnostic tests for venous thromboembolic diseases and quantify the direction and impact of design characteristics on diagnostic performance., Methods: We conducted a literature search using Medline and Embase databases for systematic reviews summarizing diagnostic accuracy studies for five target disorders associated with venous thromboembolism. The following data were extracted for each primary study: methodological characteristics, the risk of bias scored by the QUADAS QUADAS-2 instrument, and numbers of true-positives, true-negatives, false-positives, and false-negatives. In a meta-analysis, we compared diagnostic accuracy measures from studies unlikely to be biased with those likely to be biased., Results: Eighty-five systematic reviews comprising 1'818 primary studies were included. Adequate quality assessment tools were used in 43 systematic reviews only (51%). The risk of bias was estimated to be low for all items in 23% of the primary studies. A high or unclear risk of bias in particular domains of the QUADAS/QUADAS-2 tool was associated with marked differences in the reported sensitivity and specificity., Conclusions: Significant limitations in the methodological quality of studies assessing diagnostic tests for venous thromboembolic disorders exist, and studies at risk of bias are unlikely to report valid estimates of test performance. Established guidelines for evaluation of diagnostic tests should be more systematically adopted., Systematic Review Registration: PROSPERO (CRD 42021264912)., Competing Interests: MN has received research grants, material support, or lecture fees from Siemens healthineers, Bühlmann laboratories, Pentapharm, Euroimmun, Technoclone, Werfen, Abbott, and Roche diagnostics. LF and LB is employed by Medignition Inc., WW has received research grants, lecture fees, and consultant fees from Roche Diagnostics, St. Jude Medical, Pfizer, Novo Nordisk, MEDA Pharma, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, and sanofi-avensis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Boschetti, Nilius, Ten Cate, Wuillemin, Faes, Bossuyt, Bachmann and Nagler.)

Introduction: The growing body of evidence around sexual and gender dimorphism in medicine, particularly in oncology, has highlighted differences in treatment response, outcomes, and side effects between males and females. Differences in drug metabolism, distribution, and elimination, influenced by factors like body composition and enzyme expression, contribute to these variations., Methods: We retrospectively analyzed data of 112 multiple myeloma (MM) patients treated with first-line high-dose chemotherapy (HDCT) with treosulfan and melphalan (TreoMel) followed by autologous stem cell transplantation (ASCT) at a single academic center between January 2020 and August 2022. We assessed response rate, progression-free survival (PFS), overall survival (OS), and toxicities in relation to gender and treosulfan exposure., Results: Our analysis revealed significant gender-specific differences in treosulfan exposure. Females had higher peak levels (343.8 vs. 309.0 mg/L, p = 0.0011) and area under the curve (AUC) (869.9 vs. 830.5 mg*h/L, p = 0.0427) compared to males. Higher treosulfan exposure was associated with increased mortality in females but not in males. Females with treosulfan AUC > 900 mg*h/L had significantly shorter overall survival, while PFS was unaffected by treosulfan exposure., Conclusion: Our study demonstrates that female patients undergoing TreoMel HDCT have higher treosulfan exposure than males and that females with higher levels are at increased risk for toxicity and adverse outcomes. These data suggest that higher treosulfan doses do not confer a benefit in terms of better outcomes for females. Therefore, exploring lower treosulfan doses for female MM patients undergoing TreoMel HDCT may be warranted to mitigate toxicity and improve outcomes.

Laboratory tests play a central role in medicine, as they help to make diagnoses, assess prognosis and risk of disease, and monitor therapies, thus contributing to 70% of all medical decisions. This cross‑sectional function offers great potential for technologic and organizational innovation to influence health care as a whole. In recent years, a variety of technologies have emerged and entered the field of medical research, or even medical care. A new generation of biosensors enables laboratory tests to be carried out at the point of care and allows for faster medical decisions. Modern devices allow for patient‑centric blood sampling, which eliminates the need for painful blood draws, patient traveling, and limits the workload of health care professionals. Analytical techniques, such as metabolomics, lipidomics, or proteomics can identify biomarkers extremely sensitively, even down to individual cells. Pharmacogenomics allows for determination of genetic polymorphisms that predict a response to chemotherapeutic agents. Machine‑learning approaches can handle large amounts of multilayered data for diagnostic applications. However, this enormous diagnostic potential is far from being utilized and only very few applications have been implemented in clinical practice. Why is this the case? In this article, we describe the key technologic fields, discuss their medical potential, and list obstacles to their implementation. In addition, we present a methodologic framework to support researchers, clinicians, and authorities in development and implementation of novel diagnostic approaches.

Multiple myeloma (MM) first-line treatment algorithms include immuno-chemotherapy (ICT) induction, high-dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT) consolidation, followed by lenalidomide maintenance. After these initial therapies, most patients suffer a disease relapse and require subsequent treatment lines including ICT, additional HDCT and ASCT, or novel immunotherapies. The presence of somatic mutations in peripheral blood cells has been associated with adverse outcomes in a variety of hematological malignancies. Nonsense and frameshift mutations in the PPM1D gene, a frequent driver alteration in clonal hematopoiesis (CH), lead to the gain-of-function of Wip1 phosphatase, which may impair the p53-dependent G1 checkpoint and promote cell proliferation. Here, we determined the presence of PPM1D gene mutations in peripheral blood cells of 75 subsequent myeloma patients in remission after first or second HDCT/ASCT. The prevalence of truncating PPM1D gene mutations emerged at 1.3% after first HDCT/ASCT, and 7.3% after second HDCT/ASCT, with variant allele frequencies (VAF) of 0.01 to 0.05. Clinical outcomes were inferior in the PPM1D -mutated ( PPM1D mut) subset with median progression-free survival (PFS) of 15 vs. 37 months ( p = 0.0002) and median overall survival (OS) of 36 vs. 156 months ( p = 0.001) for the PPM1D mut and PPM1D wt population, respectively. Our data suggest that the occurrence of PPM1D gene mutations in peripheral blood cells correlates with inferior outcomes after ASCT in patients with multiple myeloma.

Abstract: New analytical techniques can assess hundreds of proteins simultaneously with high sensitivity, facilitating the observation of their complex interplay and role in disease mechanisms. We hypothesized that proteomic profiling targeting proteins involved in thrombus formation, inflammation, and the immune response would identify potentially new biomarkers for heparin-induced thrombocytopenia (HIT). Four existing panels of the Olink proximity extension assay covering 356 proteins involved in thrombus formation, inflammation, and immune response were applied to randomly selected patients with suspected HIT (confirmed HIT, n = 32; HIT ruled out, n = 38; and positive heparin/platelet factor 4 [H/PF4] antibodies, n = 28). The relative difference in protein concentration was analyzed using a linear regression model adjusted for sex and age. To confirm the test results, soluble P-selectin was determined using enzyme-linked immunosorbent assay (ELISA) in above mentioned patients and an additional second data set (n = 49). HIT was defined as a positive heparin-induced platelet activation assay (washed platelet assay). Among 98 patients of the primary data set, the median 4Ts score was 5 in patients with HIT, 4 in patients with positive H/PF4 antibodies, and 3 in patients without HIT. The median optical density of a polyspecific H/PF4 ELISA were 3.0, 0.9, and 0.3. Soluble P-selectin remained statistically significant after multiple test adjustments. The area under the receiver operating characteristic curve was 0.81 for Olink and 0.8 for ELISA. Future studies shall assess the diagnostic and prognostic value of soluble P-selectin in the management of HIT., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

(1) Background: Treosulfan and melphalan (TreoMel)-based high-dose chemotherapy (HDCT) has shown promising safety and efficacy as a conditioning regimen for acute myeloid leukemia (AML) patients undergoing autologous stem cell transplantation (ASCT). However, despite intensive first-line induction treatment and upfront consolidation with HDCT and ASCT, AML relapse rates are still high, and further efforts are needed to improve patient outcomes. The aim of this study was to compare two melphalan dose schedules in regard to the safety of TreoMel HDCT and patient outcomes. (2) Methods: We retrospectively analyzed the safety and efficacy of two melphalan dose schedules combined with standard-dose treosulfan in AML patients undergoing HDCT and ASCT at the University Hospital of Bern, Switzerland, between August 2019 and August 2023. Patients received treosulfan 42 g/m 2 combined with either melphalan 140 mg/m 2 (TreoMel 140) or melphalan 200 mg/m 2 (TreoMel 200). Co-primary endpoints were progression-free survival (PFS), overall survival (OS), as well as safety profile. (3) Results: We included a total of 51 AML patients: 31 (60.8%) received TreoMel 140 and 20 (39.2%) TreoMel 200. The patients' basal characteristics were comparable between both cohorts. No significant differences in the duration of hospitalization or the adverse event profile were identified. There were no statistically significant differences in relapse (0.45 vs. 0.30, p = 0.381) and mortality rates (0.42 vs. 0.15, p = 0.064) between the melphalan 140 mg/m 2 and 200 mg/m 2 cohorts, nor for PFS (HR: 0.81, 95% CI: 0.29-2.28, p = 0.70) or OS (HR: 0.70, 95% CI: 0.19-2.57, p = 0.59) for the TreoMel 140 vs. TreoMel 200 cohort. (4) Conclusions: A higher dose of melphalan (TreoMel 200) was well tolerated overall. No statistically significant differences for patient outcomes could be observed, possibly due to the relatively small patient cohort and the short follow-up. A longer follow-up and prospective randomized studies would be required to confirm the safety profile and clinical benefit.

Importance: Heparin-induced thrombocytopenia (HIT) is a life-threatening condition that requires urgent diagnostic clarification. However, knowledge of the diagnostic utility of the recommended diagnostic tests is limited in clinical practice., Objective: To evaluate the current diagnostic practice for managing the suspicion of HIT., Design, Setting, and Participants: This prospective diagnostic study was conducted from January 2018 to May 2021 among consecutive patients with suspected HIT from 11 study centers in Switzerland, Germany, and the United States. Detailed clinical data and laboratory information were recorded. Platelet factor 4/heparin antibodies were quantified using an automated chemiluminescent immunoassay (CLIA). A washed-platelet heparin-induced platelet activation (HIPA) test was used as a reference standard to define HIT., Exposures: Suspicion of HIT., Main Outcomes and Measures: The primary outcome was the diagnostic accuracy of the 4Ts score, the CLIA, and the recommended algorithm serially combining both tests., Results: Of 1448 patients included between 2018 and 2021, 1318 were available for the current analysis (median [IQR] age, 67 [57-75] years; 849 [64.6%] male). HIPA was positive in 111 patients (prevalence, 8.4%). The most frequent setting was intensive care unit (487 [37.0%]) or cardiovascular surgery (434 [33.0%]). The 4Ts score was low risk in 625 patients (46.8%). By 2 × 2 table, the numbers of patients with false-negative results were 10 (9.0%; 4Ts score), 5 (4.5%; CLIA), and 15 (13.5%; recommended diagnostic algorithm). The numbers of patients with false-positive results were 592 (49.0%; 4Ts score), 73 (6.0%; CLIA), and 50 (4.1%; recommended diagnostic algorithm), respectively., Conclusions and Relevance: In this diagnostic study of patients suspected of having HIT, when the recommended diagnostic algorithm was used in clinical practice, antibody testing was required in half the patients. A substantial number of patients were, however, still misclassified, which could lead to delayed diagnosis or overtreatment. Development of improved diagnostic algorithms for HIT diagnosis should be pursued.

Background: Lung metastasectomy is an accepted treatment modality worldwide. Whether the addition of lymph node dissection to the procedure is useful remains, however, unknown., Methods: We performed a systematic review of the literature analyzing MEDLINE, Embase, until 31st October 2021. We included all studies which met the inclusion criteria aiming to determine if the addition of lymph node tissue dissection/sampling to lung metastasectomy offers survival benefits when compared to patients who do receive lymph node tissue dissection. Secondary outcomes were 3- and 5-year overall survival (OS) and disease-free survival (DFS). Each study was assessed for risk of bias. The data collected from the included studies were pooled using reconstruction of individual-level patient data and pooling of reported 5-year odds ratios (ORs). Interstudy heterogeneity was estimated with visual inspection of forest plots and calculation of the I 2 inconsistency statistic., Results: We found 11 eligible studies that included a total of 3,310 patients. The most common primary tumor type was colorectal cancer (1,740 patients) and the most commonly performed operative procedure was wedge resection (57%) followed by lobectomy (39%). When resection status was reported, R0 resection was achieved in 90% of the cases. Nine studies did not show a statistically significant effect of lymph nodes dissection or sampling on the 5-year OS with a pooled hazard ratio (HR) of 0.94 [95% confidence interval (CI): 0.82, 1.08; I 2 =26%; 95% prediction interval (PI): 0.70, 1.24]. Regarding DFS, the pooled HR 0.60 (95% CI: 0.44, 0.80; I 2 =31%; 95% PI: 0.12, 2.09)., Conclusions: The addition of lymph node tissue dissection during lung metastasectomy was not associated with a significant benefit in OS and showed a slight tendency towards a better DFS., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-769/coif). The authors have no conflicts of interest to declare., (2023 Journal of Thoracic Disease. All rights reserved.)

Chimeric antigen receptor T (CAR T)-cell therapy has become a standard treatment option for patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL). Mutations in the PPM1D gene, a frequent driver alteration in clonal hematopoiesis (CH), lead to a gain of function of PPM1D/Wip1 phosphatase, impairing p53-dependent G1 checkpoint and promoting cell proliferation. The presence of PPM1D mutations has been correlated with reduced response to standard chemotherapy in lymphoma patients. In this study, we analyzed the impact of low-frequency PPM1D mutations on the safety and efficacy of CD19-targeted CAR T-cell therapy in a cohort of 85 r/r DLBCL patients. In this cohort, the prevalence of PPM1D gene mutations was 20% with a mean variant allele frequency (VAF) of 0.052 and a median VAF of 0.036. CAR T-induced cytokine release syndrome (CRS) and immune effector cell-associated neuro-toxicities (ICANS) occurred at similar frequencies in patients with and without PPM1D mutations. Clinical outcomes were globally worse in the PPM1D mutated (PPM1Dmut) vs. PPM1D wild type (PPM1Dwt) subset. While the prevalent treatment outcome within the PPM1Dwt subgroup was complete remission (56%), the majority of patients within the PPM1Dmut subgroup had only partial remission (60%). Median progression-free survival (PFS) was 3 vs. 12 months ( p = 0.07) and median overall survival (OS) was 5 vs. 37 months ( p = 0.004) for the PPM1Dmut and PPM1Dwt cohort, respectively. Our data suggest that the occurrence of PPM1D mutations in the context of CH may predict worse outcomes after CD19-targeted CAR T-cell therapy in patients with r/r DLBCL.

Background: Currently, assessing the diagnostic performance of new laboratory tests assumes a perfect reference standard, which is rarely the case. Wrong classifications of the true disease status will inevitably lead to biased estimates of sensitivity and specificity., Objectives: Using Bayesian' latent class models (BLCMs), an approach that does not assume a perfect reference standard, we re-analyzed data of a large prospective observational study assessing the diagnostic accuracy of an antigen test for the diagnosis of SARS-CoV-2 infection in clinical practice., Methods: A cohort of consecutive patients presenting to a COVID-19 testing facility affiliated with a Swiss University Hospital were recruited (n = 1465). Two real-time PCR tests were conducted in parallel with the Roche/SD Biosensor rapid antigen test on nasopharyngeal swabs. A two-test (PCR and antigen test), three-population BLCM was fitted to the frequencies of paired test results., Results: Based on the BLCM, the sensitivities of the RT-PCR and the Roche/SD Biosensor rapid antigen test were 98.5% [95% CRI 94.8;100] and 82.7% [95% CRI 66.8;100]. The specificities were 97.7% [96.1;99.7] and 99.9% [95% CRI 99.6;100]., Conclusions: Applying the BLCM, the diagnostic accuracy of RT-PCR was high but not perfect. In contrast to previous results, the sensitivity of the antigen test was higher. Our results suggest that BLCMs are valuable tools for investigating the diagnostic performance of laboratory tests in the absence of perfect reference standard.

Background: Anecdotal reports suggest that the correlation between heparin/platelet factor 4 (PF4) antibody assays for the diagnosis of heparin-induced thrombocytopenia (HIT) is limited., Objectives: To investigate the correlation between widely used assays and examine possible factors contributing to variability., Methods: This is a large, prospective cohort study with 10 participating tertiary care hospitals including 1393 patients with suspected HIT in clinical practice. HIT was defined by a positive heparin-induced platelet activation (HIPA) assay (washed platelet reference standard test). Three different immunoassays were used to measure heparin/PF4 antibodies: chemiluminescent immunoassay, enzyme-linked immunosorbent assay, and particle gel immunoassay. Various factors that could influence the assays were examined: sex (male or female), age (<65 years or ≥65 years), unfractionated heparin exposure, presence of thrombosis, cardiovascular surgery, and intensive care unit. Spearman's correlation coefficients were calculated. Z-scores and diagnostic odds ratios were determined in the aforementioned subgroups of patients., Results: Among 1393 patients, 119 were classified as HIT-positive (prevalence, 8.5%). The median 4Ts score was 5 (IQR, 4-6) in patients with HIT compared with 3 (IQR, 2-4) in patients without HIT. Correlations (r s ) between immunoassays were weak (0.53-0.65). Inconsistencies between immunoassays could not be explained by further analyses of z-scored test results and diagnostic odds ratios in subgroups of patients., Conclusion: The correlation between widely used heparin/PF4 antibody assays was weak, and key factors could not explain this variability. Standardization of immunoassays is requested to improve comparability., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Chimeric antigen receptor (CAR)-T cell therapy is effective in patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) with response rates of 63-84% and complete response observed in 43-54%. Common germline variants of the target antigen CD19 may elicit different responses to CAR-T cell therapy. The CD19 gene single nucleotide polymorphism rs2904880 encoding leucine or valine at amino acid position 174 of the CD19 antigen was prevalent in 51% of the studied DLBCL patients. In a retrospective comparative analysis of clinical outcome, there were significant differences in CD19 L174 versus V174 carriers: the median time of progression-free survival was 22 vs. 6 months ( p = 0.06), overall survival was 37 vs. 8 months ( p = 0.11), complete response rates were 51% vs. 30% ( p = 0.05), and refractory disease rates were 14% vs. 32% ( p = 0.04). The single nucleotide polymorphism in CD19 was shown to influence the treatment outcome in FMC63-anti-CD19-CAR-T cell therapy, and the CD19 minor allele L174 predicted a favorable treatment outcome.

Background: In the lung cancer classification (TNM), the involvement of thoracic lymph nodes is relevant from a diagnostic and prognostic point of view. Even if imaging modality could help in selecting patients who should undergo surgery, a systematic lymph node dissection during lung surgery is mandatory to identify the subgroup of patients who can benefit from an adjuvant treatment., Methods: Patients undergoing elective lobectomy/bilobectomy/segmentectomy) for non-small cell lung cancer and lymphadenectomy with lymph nodes station 10-11-12-13-14 sampling that meet the inclusion and exclusion criteria will be recorded in a multicenter prospective database. The overall incidence of N1 patients (subclassified in: Hilar Lymph nodes, Lobar Lymph nodes and Sublobar Lymph nodes) will be examined as well as the incidence of visceral pleural invasion., Discussion: The aim of this multicenter prospective study is to evaluate the incidence of intrapulmonary lymph nodes metastases and the possible relation with visceral pleural invasion. Identifying patients with lymph node station 13 and 14 metastases and/or a link between visceral pleural invasion and presence of micro/macro metastases in intrapulmonary lymph nodes may have an impact on decision-making process., Trial Registration: ClinicalTrials.gov ID: NCT05596578., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Minervini et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Chimeric antigen receptor T-cell therapy (CAR T-cell therapy) is associated with potentially life-threatening toxicities, most commonly cytokine release syndrome (CRS) and immune-effector-cell-associated neurotoxicity syndrome (ICANS). These frequent adverse events are managed with the IL-6 receptor antagonist tocilizumab and/or corticosteroids. The prophylactic and early use of corticosteroids for CRS and ICANS have previously been reported, but eventual negative impacts on CAR T-cell efficacy are feared., Methods: Retrospective comparative analysis of two patient cohorts with hematological malignancies treated with CAR T-cell therapy: 43 patients received early administration of 10 mg dexamethasone preceding each dose of tocilizumab ("early corticosteroid/ tocilizumab", EcsTcz cohort) vs. 40 patients who received tocilizumab alone ("tocilizumab alone", Tcz cohort) for treatment of low-grade CRS., Results: Despite overall higher CRS incidence (91% vs. 70%; p = 0.0249), no high-grade CRS was observed (0% vs. 10%; p = 0.0497) among patients receiving early corticosteroids in combination with tocilizumab. In terms of neurotoxicity, no worsening regarding incidence of ICANS (30% vs. 33%; p = 0.8177) or high-grade ICANS (20% vs. 14%; p = 0.5624) was observed in the EcsTcz cohort. Moreover, overall response rates (80% vs. 77%; p = 0.7936), complete response rates (50% vs. 44%; p = 0.6628), progression-free survival ( p = 0.6345) and overall survival ( p = 0.1215) were comparable for both cohorts., Conclusions: Our study suggests that the early use of corticosteroids in combination with the standard tocilizumab schedule for low-grade CRS following CAR T-cell therapy may significantly reduce the risk of high-grade CRS without negative impact on neurotoxicity or treatment outcome.

Background: Diagnosing heparin-induced thrombocytopenia (HIT) at the bedside remains challenging, exposing a significant number of patients at risk of delayed diagnosis or overtreatment. We hypothesized that machine-learning algorithms could be utilized to develop a more accurate and user-friendly diagnostic tool that integrates diverse clinical and laboratory information and accounts for complex interactions., Methods: We conducted a prospective cohort study including 1393 patients with suspected HIT between 2018 and 2021 from 10 study centers. Detailed clinical information and laboratory data were collected, and various immunoassays were conducted. The washed platelet heparin-induced platelet activation assay (HIPA) served as the reference standard., Findings: HIPA diagnosed HIT in 119 patients (prevalence 8.5%). The feature selection process in the training dataset (75% of patients) yielded the following predictor variables: (1) immunoassay test result, (2) platelet nadir, (3) unfractionated heparin use, (4) CRP, (5) timing of thrombocytopenia, and (6) other causes of thrombocytopenia. The best performing models were a support vector machine in case of the chemiluminescent immunoassay (CLIA) and the ELISA, as well as a gradient boosting machine in particle-gel immunoassay (PaGIA). In the validation dataset (25% of patients), the AUROC of all models was 0.99 (95% CI: 0.97, 1.00). Compared to the currently recommended diagnostic algorithm (4Ts score, immunoassay), the numbers of false-negative patients were reduced from 12 to 6 (-50.0%; ELISA), 9 to 3 (-66.7%, PaGIA) and 14 to 5 (-64.3%; CLIA). The numbers of false-positive individuals were reduced from 87 to 61 (-29.8%; ELISA), 200 to 63 (-68.5%; PaGIA) and increased from 50 to 63 (+29.0%) for the CLIA., Interpretation: Our user-friendly machine-learning algorithm for the diagnosis of HIT (https://toradi-hit.org) was substantially more accurate than the currently recommended diagnostic algorithm. It has the potential to reduce delayed diagnosis and overtreatment in clinical practice. Future studies shall validate this model in wider settings., Funding: Swiss National Science Foundation (SNSF), and International Society on Thrombosis and Haemostasis (ISTH)., Competing Interests: AC has served as a consultant for Synergy; has received authorship royalties for UpToDate; and his institution has received research support on his behalf from Alexion, Bayer, Novartis, Novo Nordisk, Pfizer, Sanofi, Spark, and Takeda. The institution of BG received grant support and CME support from Pfizer, Thermo Fisher Scientific, Axonlab, Sanofi, Alnylam, Bayer, BMS, Daiichi-Sankyo, Octapharma, Takeda, SOBI, Janssen, Novo Nordisk, Mitsubishi Taneba, outside of the current work. The institution of JKH received grant support, consultancy fees, or honoraria from SNSF, Baxter/Takeda, Bayer, CSL-Behring, NovoNordisk, Octapharma, Roche, SOBI, Roche, Sanofi, FOPH, and Swiss Hemophilia Society, outside of the current work. MN received research grants from Bayer Healthcare, Roche diagnostics, Siemens healthineers, Pentapharm, and Bühlmann laboratories, outside of the current work. Dr. Greinacher reports personal fees from Aspen, grants from Ergomed, grants from Boehringer Ingelheim, personal fees from Bayer Vital, grants from Rovi, grants from Sagent, personal fees from Chromatec, personal fees from Instrumentation Laboratory, grants and personal fees from Macopharma, grants from Portola, grants from Biokit, personal fees from Sanofi-Aventis, grants from Fa. Blau Farmaceutics, grants from Prosensa/Biomarin, grants and other from DRK-BSD NSTOB, grants from DRK-BSD Baden-Würtemberg/Hessen, personal fees from Roche, personal fees from GTH e.V., grants from Deutsche Forschungsgemeinschaft, grants from Deutsche Forschungsgemeinschaft, grants from Deutsche Forschungsgemeinschaft, grants from Robert-Koch-Institut, non-financial support from Veralox, grants from Dilaflor, non-financial support from Vakzine Projekt Management GmbH, grants from GIZ Else-Körner-Stiftung, grants from GIZ Else-Körner-Stiftung, non-financial support from AstraZeneca, non-financial support from Janssen Vaccines & Prevention B.V., personal fees from Takeda Pharma, personal fees from Falk Foundation e.V., grants from European Medicines Agency, outside the submitted work; In addition, AG has a patent Screening Methods for transfusion related acute lung injury (TRALI) with royalties paid to EP2321644, 18.05.2011. TM reports grant support, consultancy fees, honoraria, or support for attending meetings from DFG, Stiftung Transfusionsmedizin und Immunhämatologie e.V, DRK Blutspendedienst, Deutsche Herzstiftung, Ministerium für Wissenschaft, Forschung und Kunst Baden Würtemberg, Gesellschaft für Thrombose-und Hämostaseforschung, Berufsverband Deutscher Internisten, CoaChrom Diagnostica GmbH, Robert Bosch GmbH, Ergomed, Bayer, Bristol-Myers Squibb, Doctrina Med AG, Leo Pharma GmbH, Schöchl medical education GmbH, Mitsubishi Tanabe GmbH, Novo Nordisk GmbH, Swedish Orphan Biovitrium GmbH. All other authors declare that no conflict of interest exists., (© 2022 The Author(s).)

Background: Prevention of recurrent venous thromboembolism (VTE) is considered a main goal of VTE management. However, the extent to which physicians adhere to the recommendations from evidence-based guidelines is unknown., Aim: From a large, prospective clinical cohort, we aimed to (1) quantify the adherence of treatment recommendations to evidence-based guidelines and establish its predictors, and (2) estimate its impact on clinical outcomes and costs in patients with VTE., Methods: We included 6'243 consecutive patients with VTE treated at the university outpatient unit. Detailed clinical characteristics and treatment recommendations were recorded. Adherence of treatment recommendations to evidence-based guidelines at risk assessment was assessed in terms of duration of anticoagulant treatment. Data on death were obtained from the Swiss Central Compensation Office. Health care claims data recorded between 2014 and 2019 were retrieved from Helsana, one of the largest Swiss health insurance companies., Results: The adherence to evidence-based guidelines was 36.1%. Among patients with non-adherence, overtreatment was present in 70.1%. Significant patient-related predictors of guideline adherence were (a) age above 50 years, (b) male sex, (c) pulmonary embolism, (d) unprovoked VTE, (e) multiple VTE, (f) laboratory tests not ordered, and (g) various cardiovascular comorbidities. Non-adherence was not significantly associated with mortality, hospitalization, admission to nursing home, and costs., Conclusions: The adherence to evidence-based guidelines was low, and several unrelated predictors appeared. Although these results need to be confirmed in other settings, they highlight the need for implementation of evidence-based guidelines in clinical practice., Competing Interests: This study received funding from an unrestricted research grant of Bayer Healthcare. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. EB reports grants from Novartis, grants from MSD, grants from Vifor, grants from Bayer, grants from Swiss Cancer Research Foundation, outside the submitted work. JK reports grants from Baxalta US Inc., member of the Takeda group of companies, personal fees from Shire, member of the Takeda group of companies, personal fees from Ablynx, now part of Sanofi, personal fees from Roche, from SOBI, from Federal Office of Public Health, Switzerland, outside the submitted work; and The Hemophilia Comprehensive Care Center (HCCC) is part of the Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, which receives third party funds for the project “Interprofessional Hemophilia Care” by Bayer, CSL-Behring, Octapharma, Novo Nordisk, Roche, and Sobi. All fees or honoraria go to JK's institution Insel Gruppe AG, Inselspital, Bern University Hospital. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mertins, Nilius, Boss, Knuchel, Signorell, Huber, Blozik, Kremer Hovinga, Bachmann and Nagler.)

Background: Thrombophilia screening is widely done in clinical practice, and it is claimed that the extent of venous thromboembolism (VTE) recurrence risk in patients with common defects is still not fully understood., Aim: We aimed to summarize data of all observational studies prospectively assessing the association of heterozygous factor V Leiden (FVL) mutation and recurrent VTE in patients with VTE, and to calculate pooled relative risks (RR), overall and in various subgroups., Methods: We searched MEDLINE and EMBASE databases for cohort studies prospectively assessing VTE recurrence in patients with and without FVL mutation (PROSPERO: CRD42021182800). Data were extracted on cohort and study-level. The methodological quality was assessed using the Newcastle-Ottawa Scale (NOS). RR were calculated overall and in subgroups using a random-effects model., Results: From 31 cohorts, 24 studies were finally included summarizing 13,571 patients. Heterozygous FVL mutation was identified in 2,840 individuals (21%). The methodological quality was estimated to be high in 20 studies (83%). The overall RR was 1.46 (95% CI: 1.31, 1.64), consistent across subgroups., Conclusions: Pooling all high-quality epidemiological data, the risk of recurrent VTE was increased by 46% in patients with heterozygous FVL mutation. Against the background of established risk factors, the FVL mutation plays only a marginal role in the risk assessment for recurrent VTE., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Eppenberger, Nilius, Anagnostelis, Huber and Nagler.)

Background: Little is known about long-term survival after the initial treatment of venous thromboembolism (VTE). In a prospective cohort study, we aimed to assess the long-term mortality and key predictor variables relating to disease severity, treatment intensity, and comorbidities. Materials and Methods: Between 1988 and 2018, 6,243 consecutive patients with VTE from a University outpatient unit were prospectively included and followed until December 2019; clinical characteristics, measures of disease severity, and treatment details were recorded. Dates of death were retrieved from the Swiss Central Compensation Office. Results: Overall, 254 deaths occurred over an observation period of 57,212 patient-years. Compared to the Swiss population, the standardized mortality ratio was 1.30 (95% CI: 1.14, 1.47; overall mortality rate: 4.44 per 1,000 patient-years). The following predictors were associated with increased mortality: Unprovoked VTE (hazard ratio [HR]: 5.06; 95% CI: 3.29, 7.77), transient triggering risk factors (HR: 3.46; 95% CI: 2.18, 5.48), previous VTE (HR: 2.05; 95% CI: 1.60, 2.62), pulmonary embolism (HR: 1.45, 95% CI: 1.10, 1.89), permanent anticoagulant treatment (HR: 3.14; 95% CI: 2.40, 4.12), prolonged anticoagulant treatment (7-24 months; HR: 1.70; 95% CI: 1.16, 2.48), and cardiovascular comorbidities. Unprovoked VTE, previous VTE, permanent and prolonged anticoagulation remain independent risk factors after adjustment for age, sex, and comorbidities. Conclusion: Survival after VTE was significantly reduced compared to the Swiss general population, especially in patients with more severe disease, cardiovascular comorbidities, and longer anticoagulant treatment., Competing Interests: This study received funding from an unrestricted research grant of Bayer Healthcare. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. EB reports grants from Novartis, grants from MSD, grants from Vifor, grants from Bayer, grants from Swiss Cancer Research Foundation, outside the submitted work. JK reports grants from Baxalta US Inc., member of the Takeda group of companies, personal fees from Shire, member of the Takeda group of companies, personal fees from Ablynx, now part of Sanofi, personal fees from Roche, from SOBI, from Federal Office of Public Health, Switzerland, outside the submitted work; and The Hemophilia Comprehensive Care Center (HCCC) is part of the Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, which receives third party funds for the project “Interprofessional Hemophilia Care” by Bayer, CSL-Behring, Octapharma, Novo Nordisk, Roche, and Sobi. All fees or honoraria go to JK's institution (Insel Gruppe AG, Inselspital, Bern University Hospital). SE reports personal fees from Bayer, personal fees from Pfizer, personal fees from Daiichi-Sankyo, personal fees from Boehringer-Ingelheim, personal fees from BMS, personal fees from CSL-Behring, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Nilius, Mertins, Boss, Knuchel, Blozik, Kremer Hovinga, Eichinger and Nagler.)

Background: The effectiveness and safety of non-heparin anticoagulants for the treatment of heparin-induced thrombocytopenia (HIT) are not fully established, and the optimal treatment strategy is unknown. In a systematic review and meta-analysis, we aimed to determine precise rates of platelet recovery, new or progressive thromboembolism (TE), major bleeding, and death for all non-heparin anticoagulants and to study potential sources of variability., Methods: Following a detailed protocol (PROSPERO: CRD42020219027), EMBASE and Medline were searched for all studies reporting clinical outcomes of patients treated with non-heparin anticoagulants (argatroban, danaparoid, fondaparinux, direct oral anticoagulants [DOAC], bivalirudin, and other hirudins) for acute HIT. Proportions of patients with the outcomes of interest were pooled using a random-effects model for each drug. The influence of the patient population, the diagnostic test used, the study design, and the type of article was assessed., Results: Out of 3194 articles screened, 92 studies with 119 treatment groups describing 4698 patients were included. The pooled rates of platelet recovery ranged from 74% (bivalirudin) to 99% (fondaparinux), TE from 1% (fondaparinux) to 7% (danaparoid), major bleeding from 1% (DOAC) to 14% (bivalirudin), and death from 7% (fondaparinux) to 19% (bivalirudin). Confidence intervals were mostly overlapping, and results were not influenced by patient population, diagnostic test used, study design, or type of article., Discussion: Effectiveness and safety outcomes were similar among various anticoagulants, and significant factors affecting these outcomes were not identified. These findings support fondaparinux and DOACs as viable alternatives to conventional anticoagulants for treatment of acute HIT in clinical practice., (© 2021 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Introduction: Aim of this study is to evaluate whether magnetic particle imaging (MPI) is capable of measuring velocities occurring in the coronary arteries and to compute coronary flow reserve (CFR) in a canonical phantom as a preliminary study., Methods: For basic velocity measurements, a circulation phantom was designed containing replaceable glass tubes with three varying inner diameters, matching coronary-vessel diameters. Standardised boluses of superparamagnetic-iron-oxide-nanoparticles were injected and visualised by MPI. Two image-based techniques were competitively applied to calibrate the respective glass tube and to compute the mean velocity: full-duration-at-half-maximum (FDHM) and tracer dilution (TD) method. For CFR-calculation, four necessary settings of the circulation model of a virtual vessel with an inner diameter of 4 mm were generated using differently sized glass tubes and a stenosis model. The respective velocities in stenotic glass tubes were computed without recalibration., Results: On velocity level, comparison showed a good agreement (rFDHM = 0.869, rTD = 0.796) between techniques, preferably better for 4 mm and 6 mm inner diameter glass tubes. On CFR level MPI-derived CFR-prediction performed considerably inferior with a relative error of 20-44%., Conclusions: MPI has the ability to reliably measure coronary blood velocities at rest as well as under hyperaemia and therefore may be suitable for CFR calculation. Calibration-associated accuracy of CFR-measurements has to be improved substantially in further studies., Competing Interests: The authors have declared that no competing interests exist.