Objective:D-dimer testing is commonly used in emergency departments (EDs) to rule out thromboembolic events. However, elevated D-dimer levels may also be associated with an increased risk of mortality, independent of thromboembolism. Methods:This prospective observational study enrolled acutely ill medical ED patients. D-dimer measurements were conducted as part of biobanking at ED presentation. Survival at 30, 90, and 360 days was analyzed in relation to D-dimer, and Receiver operating characteristic (ROC) curves and logistic regressions were performed. Results:A total of 1035 patients were included (56% male; 61 years [IQR 46-74]). Median follow-up was 764 days (7.7% mortality). Elevated D-dimer (≥0.5 μg/mL) was observed in 46.4% of patients. Thirty-day mortality was 4.8% in patients with elevated D-dimer versus 0.2% with normal D-dimer levels (log-rank p < 0.001), while 360-day mortality was 13.5% versus 2.3% (p < 0.001), respectively. Among discharged patients, 360-day mortality was 9.2% with elevated D-dimer vs. 0.7% with normal values (log-rank p < 0.001).The ROC-derived optimal cut-off for both time points was 0.75 μg/mL (AUC 0.82 and 0.76 for 30- and 360-day mortality). Multivariable analysis adjusted for age, BMI, and comorbidities yielded elevated D-dimer to remain an independent predictor of mortality. Conclusion:In unselected ED patients, D-dimer independently predicts 30- and 360-day mortality. Beyond its diagnostic role for VTE, an elevated D-dimer-particularly in patients with no VTE and discharge from the ED-identifies individuals at increased short- and long-term risk. Incorporating D-dimer (e.g., ≥ 0.75 μg/mL) into routine risk stratification may support targeted follow-up and post-discharge management.

The presence of abnormal nailfold capillaries and antinuclear antibodies (ANA) is associated with increased all-cause mortality in patients presenting with incipient Raynaud’s phenomenon (RP). We conducted a retrospective analysis aiming to assess the association between abnormal nailfold capillaries, ANA, and mortality over a 20-year follow-up period. In 2958 patients with incipient RP without previously known connective tissue disease, nailfold capillaroscopies and laboratory tests for ANA and ANA-subsets were obtained. Of these, long-term follow-up data were available for 2922 patients. Over a median follow-up period of 23 (IQR 20.2–25.2) years, 832 patients died, of which 562 were women (25

Clascoterone is an androgen receptor inhibitor approved for the treatment of acne vulgaris in patients 12 years of age and older. Here, we report results of 5 phase 1 studies that assessed the pharmacokinetics (PK), safety, and skin irritation and sensitization potential of clascoterone cream 1% in healthy participants and patients with acne. Studies CB-03-01/02 (EudraCT: 2007-005064-28) and CB-03-01/04 (n = 24 each) assessed PK in healthy participants. Study 171-7151-203 (n = 8) assessed steady-state PK in patients with acne. Studies CB-03-01/05 (n = 36) and CB-03-01/32 (n = 250) assessed skin irritation and sensitization potential, respectively, in healthy participants. Systemic exposure to clascoterone was low after repeated daily application for up to 42 days of treatment. Clascoterone was excreted in urine as conjugated esters at a ≤1% fraction of the administered dose. Adverse events and local skin reactions were generally mild/moderate and reversible. No clinically relevant changes were observed in laboratory tests and vital signs. Skin irritation and sensitization with clascoterone treatment were minimal. Phase 1 study findings supported low systemic absorption of clascoterone and a favorable safety profile after topical application of clascoterone cream 1%, with no evidence of irritation or sensitization.

OBJECTIVE:Ankle-brachial index (ABI) and carotid-femoral pulse-wave velocity (cfPWV) are well-established surrogate markers of overall cardiovascular risk. However, their prognostic value towards short- and long-term mortality in an emergency medicine setting is yet unknown. APPROACH AND RESULTS:Acutely ill medical patients systematically underwent cfPWV and ABI measurements at the emergency department of a tertiary care hospital. Patients' survival was analysed in relation to their ABI and cfPWV values at initial presentation. In total, 1080 individuals (43.7% females; 59.6 ± 17.4 years old) were enrolled. Over a median follow-up period of 24.4 months, 112 (10%) deaths were observed. 30-day mortality was 4.9% in patients with a pathological ABI and 1.4% with a normal ABI (p = .003). There was also a significant difference over the entire observational period regarding cumulative mortality (p < .001). Thirty-day mortality was 2.4% in patients with a cfPWV ≥10 m/s and .7% with a cfPWV <10 m/s (p = .025), and cumulative mortality over the whole period differed between a cfPWV ≥10 m/s and <10 m/s as well (p < .001). CONCLUSION:In acutely ill medical patients, the noninvasive ABI and cfPWV assessment at triage level facilitates initial risk stratification in the emergency setting for short- and long-term mortality. Patients with pathological ABI and cfPWV values could thus be seen as a proxy of a sicker cohort with an overall worse polyvascular situation.

Background and Objectives: Cardiovascular diseases are prevalent entities, especially in emergency patients. Arterial stiffness is a known predictor of cardiovascular risk and mortality and is quantified by carotid-femoral pulse wave velocity (cfPWV). It is caused in part by vascular calcification, but exact details of the underlying mechanisms are yet to be elucidated, and current data suggest endocrine influences. This study thus aimed to assess the associations of endocrine parameters, particularly thyroid and parathyroid hormones, calcium, inorganic phosphate, and vitamin D, with cfPWV as a surrogate for arterial stiffness. Materials and Methods: Adults presenting to a single tertiary care emergency department in Vienna between 2018 and 2023 were prospectively enrolled. CfPWV was measured non-invasively, and levels of thyroid and parathyroid hormones and 25-hydroxyvitamin D, calcium, and inorganic phosphate were assessed. Results: In total, data from 827 patients, predominantly male (57%) and around 60 (47–72) years of age, were assessed. We observed a significant worsening of cfPWV with increasing parathyroid hormone levels (p < 0.001) and TSH levels (p = 0.03). No significant influences of calcium, inorganic phosphate, or 25-hydroxyvitamin D were observed. Conclusions: Thyroid and parathyroid hormone levels are associated with arterial stiffness in emergency department patients, suggesting a need for a comprehensive workup in patients at risk because of comorbidities and age. Additional prospective studies are needed to further elucidate the role of endocrinology in arterial stiffness and the subsequent relevance in emergency medicine.

Purpose: To report the occurrence of acute postrenal kidney failure caused by external ureteral obstruction after iliac venous stent placement. Case report: A 73-year-old male patient presented with a chronic swelling and feeling of heaviness of his right leg. The presence of venous thrombosis was excluded by duplex ultrasound (DUS). However, DUS revealed a high-grade non-thrombotic stenosis of the right external iliac vein which was confirmed by computed tomography venography. This stenosis was attributed to local scarring following prostatectomy, lymphadenectomy, and adjuvant radiation therapy for prostate cancer 7 years before. According to the clinical presentation, the patient underwent catheter-based revascularization by implantation of a dedicated venous stent in the external iliac vein. One day after this procedure, the patient experienced acute kidney failure, which was attributable to an incipient right-sided grade II hydronephrosis. Subsequent ureterorenoscopy demonstrated a stenotic lesion of the intermediate part of the ureter at the same level as the venous stent. Finally, ureteral stent placement resulted in the restoration of urinary drainage as well as resolution of acute kidney failure. This case report highlights the importance of considering nonvascular complications after venous stent placement and it stresses the importance of postprocedural clinical and laboratory surveillance and follow-up. Clinical impact In recent years the number of endovenous stent implantations has significantly increased. In patients with clinically relevant iliofemoral obstructions, endovenous stent placement potentially reduces related symptoms and improves quality of life. However, endovenous stent placement may have an impact on peri-vascular structures, such as the ureters. This case report highlights the awareness of potential nonvascular complications, which might be caused by iliofemoral stent implantation.

The current buildings of the Medical University of Vienna were mainly constructed between the eighteenth and twentieth centuries and reflect a multigenerational ambition to keeping up with the latest developments in medicine. The current comprehensive structural expansion of the Medical University of Vienna within about a decade represents a significant turning point. Following the construction of the old and the new Vienna General Hospital (AKH), the establishment of modern infrastructure by the preclinical "MedUni Campus Mariannengasse" (MCM), the Center for Translational Medicine (CTM), and Center for Precision Medicine (CPM)/"Eric Kandel Institute" represents another milestone for Austrian medicine and will accompany the next generations of Austrian physicians for many decades.

Background Data on the course of walking capacity after acute deep vein thrombosis (DVT) are scarce. Objectives The aim of this prospective observational study was to assess the course of walking impairment and venous claudication after DVT and the association with clinical characteristics and quality of life (QoL). Methods Walking capacity was assessed by standardized treadmill exercise tests (TETs) at DVT diagnosis and after 3 months. Pain-free walking distance (PWD) and maximum walking distance (MWD) were recorded. Venous claudication during TET was evaluated and documented by trained biomedical scientists according to a standardized protocol. QoL was evaluated with the EuroQoL Group 5-Dimension 5-Level and the VEnous INsufficiency Epidemiologic and Economic Study (VEINES-QoL/Sym) questionnaires. Results Seventy-three patients (30.1% women; median age, 53.8 years; IQR, 42.9-60.0 years) were included. PWD and MWD generally improved over time, with a median change of 305 m (IQR, 33-710 m) and 30 m (IQR, 0-258 m), respectively. However, 16 (28.1%) patients reported persistent venous claudication after 3 months. Patients with venous claudication after 3 months tended to have higher rates of suprainguinal DVT, higher body mass index, and higher rates of arterial hypertension and were admitted to the hospital at DVT diagnosis more often. Generic and disease-specific QoL improved overall, but patients with venous claudication had significantly lower QoL scores than those without. Conclusion Walking capacity generally improved after DVT, but about one-third of patients had persisting venous claudication after 3 months, which was associated with poorer QoL. Suprainguinal DVT, higher body mass index, arterial hypertension, and hospital admission at diagnosis were more common in patients with venous claudication 3 months after DVT.

Transfusion of platelet concentrates (PC) can be a life-saving measure in case of severe thrombocytopenia or thrombocytopathy, particularly in bleeding patients. Although acaryote, platelets are involved in several important functions including immunomodulation, but their most important function is in primary and secondary haemostasis. In this German review, apheresis and whole blood derived PC are compared and indications as well as transfusion triggers and dosage of PC are discussed. Apart from emergencies, transfusion of PC can only occur after informed consent. Therefore, the treating physician should be aware of the potential adverse events and their prophylaxis in order to best advise the patient. Eight of the most prevalent and/or clinically severe adverse events following PC transfusion and their handling and prevention are discussed. In addition, practical aspects of PC transfusion are depicted as well as the treating physician's choice of the appropriate PC including a flowchart for refractory patients.

Purpose: The purpose of this study was to report the closure of iliac arteriovenous fistulas associated with a post-thrombotic iliac vein occlusion by iliac venous stent recanalization. Case Report: An 80-year-old woman presented with a worsening painful swelling of her left leg after an iliofemoral deep vein thrombosis 6 months ago. Duplex ultrasound and magnetic resonance venography revealed a post-thrombotic obstruction of her iliac veins as well as several arteriovenous fistulas between branches of her left external and internal iliac arteries and adjacent diseased venous segments. In a first attempt, coil embolization did not sustainably close these iliac arteriovenous fistulas. Direct stent recanalization of the chronically diseased iliofemoral venous segment, however, resulted in an immediate closure of arteriovenous shunt flow and subsequent improvement of clinical symptoms. Six months after iliac vein stent recanalization, still no fistulas could be detected any more, venous stents were fully patent, and the patient was free of symptoms. Conclusion: Post-thrombotic iliofemoral obstructions might be associated with the development of arteriovenous fistulas. Direct stent recanalization of the chronically occluded veins results in closure of related arteriovenous fistulas. Clinical Impact This case suggests that the combined occurrence of post-thrombotic venous obstructions with arteriovenous fistulas, which are related to aforementioned venous lesions, should be evaluated for primary venous stent recanalization rather than fistula embolization.

Cenerimod is a sphingosine-1-phosphate receptor 1 modulator that reduces tissue availability of circulating lymphocytes. The compound is in Phase 3 development for the treatment of systemic lupus erythematosus. Its pharmacokinetic properties are characterized by slow absorption and multiphasic elimination with a long terminal half-life (t 1/2), potentially caused by enterohepatic circulation (EHC). In this trial in healthy participants, oral cenerimod 0.5 and 4 mg once daily was administered for 50 days, followed by oral administration of activated charcoal (ie, 50 mg every 12 h for 11 days, starting 24 h after the last cenerimod dose), to investigate the potential EHC of cenerimod and assess whether elimination of cenerimod can be accelerated. The multiple-dose pharmacokinetics, pharmacodynamics, safety, and tolerability of cenerimod were also evaluated. For both doses, peak plasma concentrations were reached 6 and 7 h after dosing. Cenerimod accumulated approximately eightfold and (near) steady-state conditions were reached after 50 doses, resembling clinically meaningful exposure to cenerimod. The t 1/2 following 0.5 and 4 mg of cenerimod was 767 and 799 h (ie, 32 and 33 days) and 720 and 780 h (ie, 30 and 33 days) with or without administration of charcoal, respectively, indicating no statistically significant difference. Therefore, charcoal did not accelerate cenerimod elimination suggesting that there is no EHC of cenerimod. A reversible, dose-dependent decrease in total lymphocyte count was observed. No safety concerns were identified; administration of charcoal was well tolerated.

Background: For primary Raynaud phenomenon (PRP), an otherwise unexplained vasospastic disposition is assumed. To test the hypothesis of an additional involvement of distinct ultrastructural microvascular alterations, we compared the nailfold capillary pattern of patients with PRP and healthy controls.Methods: A total of 120 patients with PRP (with a median duration of vasospastic symptoms of 60 [IQR: 3-120] months) were compared against 125 controls. In both groups, nailfold capillaroscopy was performed to record the presence of dilatations, capillary edema, tortuous capillaries, ramifications, hemorrhages, and reduced capillary density and to determine a semiquantitative rating score. Further, the capacity of finger skin rewarming was investigated by performing infrared thermography in combination with cold provocation.Results: Unspecific morphologic alterations were found in both, PRP, such as controls, whereby the risk for PRP was four times as high in the presence of capillary dilations (CI: 2.3-7.6) and five times as high if capillary density was reduced (CI: 1.9-13.5). Capillary density correlated with thermoregulatory capacity in both hands in the PRP group, but not in controls. In addition, a negative correlation between the microangiopathy score and the percentage degree of rewarming in both hands was found for patients with PRP only.Conclusion: We found specific differences within the microvascular architecture between patients with PRP and controls. As a conclusion, PRP may not be an entirely benign vasospastic phenomenon, but might be associated with subtle microcirculatory vasculopathy. In addition, we suggest that the implementation of a scoring system might serve as guidance in the diagnostic process at least of patients with long-standing PRP.

Circular RNAs (circRNAs) are covalently closed non-coding RNAs lacking the 5’ cap and the poly-A tail. Nevertheless, it has been demonstrated that certain circRNAs can undergo active translation. Therefore, aberrantly expressed circRNAs in human cancers could be an unexplored source of tumor-specific antigens, potentially mediating anti-tumor T cell responses. This study presents an immunopeptidomics workflow with a specific focus on generating a circRNA-specific protein fasta reference. The main goal of this workflow is to streamline the process of identifying and validating human leukocyte antigen (HLA) bound peptides potentially originating from circRNAs. We increase the analytical stringency of our workflow by retaining peptides identified independently by two mass spectrometry search engines and/or by applying a group-specific FDR for canonical-derived and circRNA-derived peptides. A subset of circRNA-derived peptides specifically encoded by the region spanning the back-splice junction (BSJ) are validated with targeted MS, and with direct Sanger sequencing of the respective source transcripts. Our workflow identifies 54 unique BSJ-spanning circRNA-derived peptides in the immunopeptidome of melanoma and lung cancer samples. Our approach enlarges the catalog of source proteins that can be explored for immunotherapy.

Background:Data on walking impairment during the acute phase of deep vein thrombosis (DVT) are limited. Objectives:This study aimed to assess the degree of walking impairment in patients with acute DVT, with a particular focus on the relation to the DVT's anatomical location. Methods:Patients with sonographically confirmed DVT were eligible for inclusion in this cohort study. Pain-free walking distance (PWD) and maximum walking distance (MWD) were determined using standardized treadmill ergometer tests and analyzed in relation to DVT location. The impact of previous DVT on walking capacity was evaluated in an exploratory analysis. Results:The study included 64 patients (31% women; median age, 55 years). The median (IQR) time from diagnosis to exercise test was 3 (1-5) days. Patients with suprainguinal DVT demonstrated significantly shorter median (IQR) MWD than those with infrainguinal DVT (130 (61-202) m vs 565 (128-750) m; P < .01), while PWD did not significantly differ (PWD: 20 (0-30) m vs 40 (0-222) m; P = .14). The proportion of patients who had to terminate treadmill tests prematurely was higher in patients with suprainguinal DVT (91.7% vs 57.7%; P = .04). PWD and MWD seemed to be similar in patients with and without a history of DVT. Premature test termination and suprainguinal DVT location were associated with reduced quality of life, as measured by the EuroQoL Group 5-Dimension 5-Level questionnaire and visual analog scale. Conclusion:Suprainguinal DVT was linked to a more pronounced walking impairment compared with infrainguinal DVT. Limited walking capacity was associated with a reduced quality of life.

BACKGROUND:Patient Blood Management (PBM) is a patient-centred, systematic, evidence-based approach to improve patient outcomes by managing and preserving a patient's own blood whilst promoting patient safety and empowerment. The effectiveness and safety of PBM over a longer period have not yet been investigated. METHODS:We performed a prospectively designed, multicentre follow-up study with non-inferiority design. Data were retrospectively extracted case-based from electronic hospital information systems. All in-hospital patients (≥18 yr) undergoing surgery and discharged between January 1, 2010 and December 31, 2019 were included in the analysis. The PBM programme focused on three domains: preoperative optimisation of haemoglobin concentrations, blood-sparing techniques, and guideline adherence/standardisation of allogeneic blood product transfusions. The outcomes were utilisation of blood products, composite endpoint of in-hospital mortality and postoperative complications (myocardial infarction/ischaemic stroke/acute renal failure with renal replacement therapy/sepsis/pneumonia), anaemia rate at admission and discharge, and hospital length of stay. RESULTS:A total of 1 201 817 (pre-PBM: n=441 082 vs PBM: n=760 735) patients from 14 (five university/nine non-university) hospitals were analysed. Implementation of PBM resulted in a substantial reduction of red blood cell utilisation. The mean number of red blood cell units transfused per 1000 patients was 547 in the PBM cohort vs 635 in the pre-PBM cohort (relative reduction of 13.9%). The red blood cell transfusion rate was significantly lower (P<0.001) with odds ratio 0.86 (0.85-0.87). The composite endpoint was 5.8% in the PBM vs 5.6% in the pre-PBM cohort. The non-inferiority aim (safety of PBM) was achieved (P<0.001). CONCLUSIONS:Analysis of >1 million surgical patients showed that the non-inferiority condition (safety of Patient Blood Management) was fulfilled, and PBM was superior with respect to red blood cell transfusion. CLINICAL TRIAL REGISTRATION:NCT02147795.

Purpose: To determine the diagnostic accuracy of preinterventional imaging modalities in patients being evaluated for iliocaval venous recanalization and stent placement. Methods: Consecutive patients with iliocaval postthrombotic obstructions or nonthrombotic iliac vein lesions (NIVL), who were scheduled for recanalization, underwent duplex ultrasound (DUS), magnetic resonance venography (MRV), multiplanar venography (MPV), and intravascular ultrasound (IVUS). The diagnostic accuracies of DUS, MRV, and MPV were analyzed using IVUS as reference. Results: A total of 216 limbs in 108 patients (80 patients with postthrombotic obstructions, 28 patients with NIVL) were examined. In patients with postthrombotic obstructions, the diagnostic sensitivities for the detection of lesions of the common femoral vein were 81% (95% CI 71–89%) for DUS, 76% (95% CI 65–85%) for MRV, and 86% (95% CI 76–93%) for MPV. The sensitivities for detecting lesions of the iliac veins were 96% (95% CI 89–99%) for DUS, 99% (95% CI 92–100%) for MRV, and 100% (95% CI 94–100%) for MPV. Regarding the inferior vena cava, the sensitivities were 44% (95% CI 24–65%) for DUS, 52% (95% CI 31–73%) for MRV, and 70% (95% CI 47–86%) for MPV. The sensitivities for detecting NIVL were 58% (95% CI 34–79%) for DUS, 90% (95% CI 68–97%) for MRV, and 95% (95% CI 73–99%) for MPV. Conclusion: In patients scheduled for recanalization of iliocaval postthrombotic obstructions, the sensitivities of DUS, MRV, and MPV were similar. In patients with suspected inferior vena cava involvement and in patients with NIVL, additional imaging with MR or conventional venography is required.

BACKGROUND:Postinterventional sonographic assessment of the femoral artery after transfemoral transcatheter aortic valve replacement (TF-TAVR) has the potential to identify several pathologies. We investigated the incidence and risk factors of femoral vessel complications in a modern TAVR collective using postinterventional sonography. METHODS:Between September 2017 and March 2022, 480 patients underwent TF-TAVR with postinterventional femoral sonography at a single center. Clinical outcomes and adverse events were analyzed after the Valve Academic Research Consortium 3 (VARC-3) criteria. RESULTS:In this cohort (51.2% male; age 80 ± 7.5 years, median EuroSCORE II 3.7) 74.8% (n = 359) were implanted with a self-expandable and 25.2% (n = 121) with a balloon-expandable valve. The main access (valve-delivery) was located right in 91.4% (n = 438), and the primary closure system was Proglide in 95% (n = 456). Vascular complications (VC) were observed in 29.16% (n = 140) of patients; 23.3% (n = 112) presented with minor- and 5.8% (n = 28) with major VC. Postinterventional femoral artery stenosis on the main access was observed in 9.8% (n = 47). Multivariable logistic regression analysis revealed female sex (p = .03, odds ratio [OR] 2.32, 95% confidence interval [CI] 1.09-4.89) and the number of used endovascular closure devices (p = .014, OR 0.11, 95%CI 0.02-0.64) as predictive factors for femoral artery stenosis. CONCLUSIONS:The incidence of postinterventional femoral artery stenosis following TF-TAVR was higher than expected with a number of used closure devices and female sex being independent risk factors. Considering the continuous advance of TAVR in low-risk patients with preserved physical activity, emphasis should be directed at the correct diagnosis and follow-up of these complications.

One key barrier to improving efficacy of personalized cancer immunotherapies that are dependent on the tumor antigenic landscape remains patient stratification. Although patients with CD3 + CD8 + T cell-inflamed tumors typically show better response to immune checkpoint inhibitors, it is still unknown whether the immunopeptidome repertoire presented in highly inflamed and noninflamed tumors is substantially different. We surveyed 61 tumor regions and adjacent nonmalignant lung tissues from 8 patients with lung cancer and performed deep antigen discovery combining immunopeptidomics, genomics, bulk and spatial transcriptomics, and explored the heterogeneous expression and presentation of tumor (neo)antigens. In the present study, we associated diverse immune cell populations with the immunopeptidome and found a relatively higher frequency of predicted neoantigens located within HLA-I presentation hotspots in CD3 + CD8 + T cell-excluded tumors. We associated such neoantigens with immune recognition, supporting their involvement in immune editing. This could have implications for the choice of combination therapies tailored to the patient’s mutanome and immune microenvironment.