New diagnostic technologies in laboratory medicine: Potential benefits and challenges.

Laboratory tests play a central role in medicine, as they help to make diagnoses, assess prognosis, risk of disease, and monitor therapies, thus contributing to 70% of all medical decisions. This cross-sectional function offers great potential for technological and organizational innovation to influence healthcare 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 allows the determination of laboratory tests at the point-of-care and enables faster medical decisions. Recent devices allow for patient-centric blood sampling, which eliminates the need for painful blood draws, patient traveling, and the workload of healthcare professionals. Analytical techniques such as metabolomics, lipidomics or proteomics can identify biomarkers extremely sensitively, even down to individual cells. Pharmacogenomics allows the determination of genetic polymorphisms that predict the response to chemotherapeutic agents. Machine-learning approaches can handle large amounts of multi-layered 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 technology fields, discuss their medical potential and obstacles to their implementation. In addition, we present a methodological framework to support researchers, clinicians and authorities in the development and implementation of novel diagnostic approaches.

Safety and Efficacy of High-Dose Chemotherapy with TreoMel 200 vs. TreoMel 140 in Acute Myeloid Leukemia Patients Undergoing Autologous Stem Cell Transplantation.

(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/m2 combined with either melphalan 140 mg/m2 (TreoMel 140) or melphalan 200 mg/m2 (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/m2 and 200 mg/m2 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.

Efficacy of Subthreshold Micropulse Laser for Central Serous Chorioretinopathy.

PURPOSE: To evaluate the efficacy of a subthreshold micropulse laser (SML) in patients with central serous chorioretinopathy (CSCR). METHODS: Retrospective clinical study conducted at the Departments of Ophthalmology at a university and a municipal hospital in Zurich, Switzerland. We enrolled acute and chronic CSCR patients with persistent subretinal fluid (SRF) treated with SML. Two treatment protocols (fluorescein/indocyanine green angiography or optical coherence tomography guided) were evaluated for efficacy after 3 and 6 months. The primary outcomes of the study were reduction and percentage of eyes with complete resolution of SRF 3 and 6 months after SML treatment. Secondary endpoints included changes in central subfield thickness (CST) and visual acuity (VA) after 3 and 6 months. RESULTS: The study involved 37 eyes (35 patients, 48.6% chronic). A statistically significant reduction in SRF height and CST could be shown, irrespective of SRF duration, type of CSCR, or chosen guidance after 3 and 6 months: SRF - 40 µm (p < 0.01), CST - 52 µm (p < 0.01). Percentage of eyes with complete resolution of fluid at 3 and 6 months after SML were 24.3 and 21.6%, respectively. No statistically significant functional improvement (VA) could be shown. Multivariable regression and linear mixed regression analyses did not identify statistically significant differences in SRF reduction, CMT change, or VA improvement with respect to the type of CSCR or the treatment plan used (p > 0.05). CONCLUSION: The effectiveness of SML in CSCR is under continuous debate. Our study findings demonstrate structural but only little functional changes with SML. In view of the shortage of verteporfin for photodynamic therapy, SML remains an important therapeutic option for CSCR patients.

Proteomic profiling for biomarker discovery in heparin-induced thrombocytopenia.

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.

Accuracy of Diagnosing Heparin-Induced Thrombocytopenia.

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.

Low-Frequency PPM1D Gene Mutations Affect Treatment Response to CD19-Targeted CAR T-Cell Therapy in Large B-Cell Lymphoma.

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.

Determination of the Diagnostic Performance of Laboratory Tests in the Absence of a Perfect Reference Standard: The Case of SARS-CoV-2 Tests.

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.

Clinical Impact of Single Nucleotide Polymorphism in CD-19 on Treatment Outcome in FMC63-CAR-T Cell Therapy.

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.

Next-generation diagnostic instruments in haematology.

Gallo et al. assessed the impact of implementing a clinical decision support tool in a multi-hospital setting. This is one of three important points to unlock the capabilities of the next-generation of diagnostic instruments: (a) integrating diagnostic information from various sources, (b) ensuring accurate development and validation in well-designed clinical studies and (c) seamlessly integrating them into clinical practice. Commentary on: Gallo et al. Clinical decision support to reduce unnecessary diagnostic testing for heparin-induced thrombocytopenia. Br J Haematol 2023;202:1011-1017.

Limited concordance of heparin/platelet factor 4 antibody assays for the diagnosis of heparin-induced thrombocytopenia: an analysis of the TORADI-HIT study.

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 (rs) 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.

Role of intrapulmonary lymph nodes in patients with NSCLC and visceral pleural invasion. The VPI 1314 multicenter registry study protocol.

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.

Early Use of Corticosteroids following CAR T-Cell Therapy Correlates with Reduced Risk of High-Grade CRS without Negative Impact on Neurotoxicity or Treatment Outcome.

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.

A machine-learning model for reducing misdiagnosis in heparin-induced thrombocytopenia: A prospective, multicenter, observational study.

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).

Prognostic significance of lymph nodes assessment during pulmonary metastasectomy: a systematic review and meta-analysis.

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 I2 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; I2=26%; 95% prediction interval (PI): 0.70, 1.24]. Regarding DFS, the pooled HR 0.60 (95% CI: 0.44, 0.80; I2=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.

Secondary prevention of venous thromboembolism: Predictors and outcomes of guideline adherence in a long-term prospective cohort study.

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.

Current Knowledge on Factor V Leiden Mutation as a Risk Factor for Recurrent Venous Thromboembolism: A Systematic Review and Meta-Analysis.

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.

Long-Term Survival After Venous Thromboembolism: A Prospective Cohort Study.

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.

Comparative effectiveness and safety of anticoagulants for the treatment of heparin-induced thrombocytopenia.

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.

Image-derived mean velocity measurement for prediction of coronary flow reserve in a canonical stenosis phantom using magnetic particle imaging.

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.