Gadofosveset-Trinatrium-Enhanced MR Angiography and MR Venography in the Diagnosis of Venous Thromboembolic Disease: A Single-Center Cohort Study.

BACKGROUND: The aim of this single-center combined prospective/retrospective cohort study was to analyze Gadolinium (Gd)-enhanced MRA (magnetic resonance angiography) and MRV (MR venography) for the diagnosis of pulmonary artery embolism and deep venous thrombosis. The gold standard methods result in major exposure to radiation and a high amount of nephrotoxic iodinated contrast media. This is the first larger contrast-enhanced MR imaging study of acute and chronic venous thromboembolic disease of various stages. METHODS: We prospectively examined 88 patients presenting clinical signs of deep vein thrombosis and/or pulmonary artery embolism. A single-session, one-stop shop Gd-enhanced MRA/MRV at 1.5 Tesla, using gradient echo sequences with very short repetition and echo times as well as low flip angles with subtraction and three-dimensional reconstruction, was performed. A diagnosis was made with the consensus of two experienced radiologists. RESULTS: We observed excellent MRA image quality in 87% and even higher diagnostic image quality of MRV in 90% of our examinations. Pulmonary artery embolism occurred with deep vein thrombosis in 22%. CONCLUSIONS: Gd-enhanced MRA/MRV provided excellent image quality for the diagnosis of venous thromboembolic disease in the majority of cases. It may be particularly useful to plan and follow-up filter implantation and retrieval in the inferior caval vein.

Lipoprotein(a) and Pulmonary Embolism Severity-A Retrospective Data Analysis.

AIM: We aimed to investigate a correlation between PE severity and Lp(a) levels. METHODS: We performed a retrospective data analysis from our medical records of PE patients admitted to the University Hospital Graz, Austria. Patients with an Lp(a) reading within a 1-year interval before and after PE diagnosis were included. In accordance with the 2019 ESC guidelines for the diagnosis and management of acute PE, severity assessment was carried out classifying patients into four groups: low risk (LR), intermediate low risk (IML), intermediate high risk (IMH) and high risk (HR). The study period of interest was between January 1, 2002 and August 1, 2020. RESULTS: We analyzed 811 patients with PE, of whom 323 (40%) had low-risk PE, 343 (42%) had intermediate-low-risk PE, 64 (8%) had intermediate-high-risk PE, and 81 (10%) had high-risk PE, respectively. We did not observe an association between PE severity and Lp(a) concentrations. In detail, median Lp(a) concentrations were 17 mg/dL [25-75th percentile: 10-37] in low-risk PE patients, 16 mg/dL [10-37] in intermediate-low-risk PE patients, 15mg/dL [10-48] in intermediate-high-risk PE patients, and 13mg/dL [10-27] in high-risk PE patients, respectively (Kruskal-Wallis p = 0.658, p for linear trend = 0.358). CONCLUSION: The current findings suggest no correlation between PE severity and Lp(a) levels.

Only Subclinical Alterations in the Haemostatic System of People with Diabetes after COVID-19 Vaccination.

People with diabetes have an increased risk of experiencing adverse COVID-19 outcomes. COVID-19 vaccination is, therefore, highly recommended. However, people with diabetes have an inherently elevated risk of thrombotic events and the impact of the vaccination on the coagulation system in this patient population remains to be elucidated. The aim of this study was to investigate the impact of COVID-19 vaccination on the haemostatic system in people with type 1 or type 2 diabetes. We evaluated the effects of COVID-19 vaccination (BioNTech Pfizer, Moderna, AstraZeneca) on standard coagulation parameters, whole blood coagulation (Thrombelastometry), platelet function (impedance aggregation), and thrombin generation (calibrated automated thrombography) in people with type 1 diabetes mellitus (n = 41) and type 2 diabetes mellitus (n = 37). Blood sampling points were prior to vaccination and two weeks after the respective vaccination. Thrombelastometry measurements indicated moderately increased clot formation post-vaccination in people with type 1, as well as with type 2, diabetes: "Clot formation times" were significantly shorter, and both "maximum clot firmness" and "alpha angles" were significantly higher, as compared to the respective pre-vaccination values. Therefore, TEM parameters were not altered after vaccination in patients receiving ASA. Moreover, platelet aggregation was enhanced in people with type 1 diabetes, and plasma levels of D-Dimer were increased in people with type 2 diabetes, following COVID-19 vaccination. All other standard coagulation parameters, as well as thrombin generation, were not affected by the vaccination. The coagulation responses of people with diabetes to COVID-19 vaccination were only subclinical and comparable to those observed in healthy individuals. Our findings suggest that people with diabetes do not face an increased activation of the coagulation post-vaccination.

Evaluation of Endothelial Dysfunction and Inflammatory Vasculopathy After SARS-CoV-2 Infection-A Cross-Sectional Study.

Background: Rising data suggest that COVID-19 affects vascular endothelium while the underlying mechanisms promoting COVID-19-associated endothelial dysfunction and inflammatory vasculopathy are largely unknown. The aim was to evaluate the contribution of COVID-19 to persisting vascular injury and to identify parameters linked to COVID-19-associated endothelial dysfunction and inflammatory vasculopathy. Methods: In a cross-sectional design, flow-mediated dilation (FMD), nitroglycerine-related dilation (NMD), pulse-wave velocity (PWV), augmentation index, intima-media thickness (IMT), compounds of the arginine and kynurenine metabolism, homocysteine, von Willebrand factor (vWF), endothelial microparticles (EMP), antiendothelial cell antibodies, inflammatory, and immunological parameters, as well as nailfold capillary morphology were measured in post-COVID-19 patients, patients with atherosclerotic cardiovascular diseases (ASCVD) and healthy controls without prior or recent SARS-CoV-2 infection. Results: Post-COVID-19 patients had higher values of PWV, augmentation index, IMT, asymmetric and symmetric dimethylarginine, vWF, homocysteine, CD31+/CD42b- EMP, C-reactive protein, erythrocyte sedimentation rate, interleukin-6, and ß-2-glycoprotein antibodies as well as lower levels of homoarginine and tryptophan compared to healthy controls (all with p < 0.05). A higher total number of pathologically altered inflammatory conditions and higher rates of capillary ramifications, loss, caliber variability, elongations and bushy capillaries with an overall higher microangiopathy evolution score were also observed in post-COVID-19 patients (all with p < 0.05). Most parameters of endothelial dysfunction and inflammation were comparably altered in post-COVID-19 patients and patients with ASCVD, including FMD and NMD. Conclusion: COVID-19 may affect arterial stiffness, capillary morphology, EMP and selected parameters of arginine, kynurenine and homocysteine metabolism as well as of inflammation contributing to COVID-19-associated endothelial dysfunction and inflammatory vasculopathy.

Soluble urokinase plasminogen activator receptor (suPAR) predicts critical illness and kidney failure in patients admitted to the intensive care unit.

Soluble urokinase plasminogen activator receptor (suPAR) is an inflammatory biomarker and risk factor for kidney diseases, with a potential prognostic value in critically ill patients. In this monocentric prospective study, we measured plasma suPAR levels immediately after ICU admission in unselected 237 consecutive patients using a turbidimetric assay. Primary objective was the prognostic value for ICU- and 28-day mortality. Secondary objectives were association with sequential organ failure assessment (SOFA) score, coagulation and inflammation markers, AKI-3 and differences in prespecified subgroups. Median suPAR levels were 8.0 ng/mL [25th-75th percentile 4.3-14.4], with lower levels in ICU survivors than non-survivors (6.7 vs. 11.6 ng/mL, p < 0.001). SuPAR levels were higher in COVID-19, kidney disease, moderate-to-severe liver disease, and sepsis. ICU mortality increased by an odds ratio (OR) of 4.7 in patients with the highest compared to lowest quartile suPAR. Kaplan-Meier overall survival estimates at 3 months were 63% and 49%, in patients with suPAR below/above 12 ng/mL (log-rank p = 0.027). Due to an observed interaction between SOFA score and suPAR, we performed a random forest method identifying cutoffs. ICU mortality was 53%, 17% and 2% in patients with a SOFA score > 7, SOFA ≤ 7 & suPAR > 8 ng/mL, and SOFA score ≤ 7 & suPAR ≤ 8 ng/mL, respectively. suPAR was a significant predictor for AKI-3 occurrence (OR per doubling 1.89, 95% CI: 1.20-2.98; p = 0.006). suPAR levels at ICU admission may offer additional value for risk stratification especially in ICU patients with moderate organ dysfunction as reflected by a SOFA score ≤ 7.

Triacetylfusarinine C: A urine biomarker for diagnosis of invasive aspergillosis.

OBJECTIVES: Early diagnosis of invasive aspergillosis (IA) remains challenging, with available diagnostics being limited by inadequate sensitivities and specificities. Triacetylfusarinine C, a fungal siderophore that has been shown to accumulate in urine in animal models, is a potential new biomarker for diagnosis of IA. METHODS: We developed a method allowing absolute and matrix-independent mass spectrometric quantification of TAFC. Urine TAFC, normalized to creatinine, was determined in 44 samples from 24 patients with underlying hematologic malignancies and probable, possible or no IA according to current EORTC/MSG criteria and compared to other established biomarkers measured in urine and same-day blood samples. RESULTS: TAFC/creatinine sensitivity, specificity, positive and negative likelihood ratio for probable versus no IA (cut-off ≥ 3) were 0.86, 0.88, 6.86, 0.16 per patient. CONCLUSION: For the first time, we provide proof for the occurrence of TAFC in human urine. TAFC/creatinine index determination in urine showed promising results for diagnosis of IA offering the advantages of non-invasive sampling. Sensitivity and specificity were similar as reported for GM determination in serum and bronchoalveolar lavage, the gold standard mycological criterion for IA diagnosis.

Low mean platelet volume is associated with critical limb ischemia in peripheral arterial occlusive disease.

Mean platelet volume (MPV) was recently published as a possible marker of coronary artery disease in patients at high risk for major adverse cardiac events. Because platelets play an important role in atherosclerosis, we examined the relationship between critical limb ischemia (CLI) and MPV in patients with peripheral arterial occlusive disease (PAOD). Our study comprised 2124 PAOD patients. Univariate logistic regression was performed to analyze potential predictors for CLI. Nagelkerke's R² is reported. Cross validation was performed using the leave-one-out principle. ROC analyses were performed to identify the best cut off value for MPV predicting CLI; to this end, Youden's index was calculated. For CLI diabetes (p < 0.001, OR 2.44, 95% CI 1.97-3.02), hsCRP (p < 0.001, OR 1.01, 95% CI 1.01-1.01), age (p < 0.001, OR 1.05, 95% CI 1.04-1.06), thrombocytosis (p = 0.025, OR 1.84, 95%CI 1.08-3.14), and MPV (p = 0.003, OR 0.84, 95% CI 0.75-0.94) were significant independent predictors for CLI. ROC analysis (AUC: 0.55, 95% CI 0.52-0.58, p < 0.001) showed ≤10.2 as the best cut off value for MPV to predict CLI. As there is a significant relationship between low MPV and a high risk for CLI in PAOD patients, MPV can be used to identify patients who are likely to develop CLI.

Platelet Inhibition and Bleeding in Patients Undergoing Non-Cardiac Surgery-The BIANCA Observational Study.

Nearly 20% of patients will need non-cardiac surgery within 1 year of coronary stenting and their management is complicated by concomitant antiplatelet therapy. Platelet function testing may optimize the timing of surgery in these patients. In this prospective observational study, we explored the association between platelet reactivity and bleeding in patients undergoing non-cardiac surgery treated with clopidogrel with or without aspirin within 7 days before surgery. The timing of surgery was at the surgeon's discretion. Blood was drawn at induction of anaesthesia and platelet reactivity assessed by light transmittance aggregometry (LTA), vasodilator stimulated phosphoprotein (VASP) assay, Multiplate Analyzer and Innovance PFA-200. The primary endpoint was surgery-related thrombolysis in myocardial infarction (TIMI) bleeding. Among 197 patients enrolled, 72 and 12% underwent surgery within 24 and 48 hours of the last dose of clopidogrel, respectively. The median (interquartile range [IQR]) for pre-operative maximal adenosine diphosphate (ADP)-induced aggregation was 33.0% (21.0-57.5%), for VASP-platelet reactivity index was 61.5% (40.1-75.4%), for Multiplate was 22.0 (14.5-36.0) U*min and for Innovance PFA-200 was 224 (101.0-300.0) seconds. TIMI bleeding, observed in 25% of patients, decreased with increasing tertiles of platelet reactivity to ADP assessed by LTA (p = 0.031). Additionally, in a multivariable logistic regression analysis, platelet reactivity to ADP assessed by LTA was significantly associated with TIMI bleeding, as were age and urgency of surgery. These results demonstrate that in clopidogrel-treated patients, pre-operative platelet reactivity to ADP is associated with surgical bleeding risk. An objective assessment of pre-operative platelet function may optimize the timing of non-cardiac surgery in these patients.

Early skin-to-skin contact after cesarean section: A randomized clinical pilot study.

OBJECTIVE: Early bonding by skin-to-skin contact (SSC) has been demonstrated to be beneficial for mothers and newborns following vaginal delivery. The aim of this study was to investigate the impact of intraoperative bonding (early SSC) after cesarean section on neonatal adaptation, maternal pain and stress response. STUDY DESIGN: This prospective, randomized-controlled pilot study was performed at a single academic tertiary hospital (Department of Obstetrics and Gynecology, Medical University of Graz, Austria) between September 2013 and January 2014. Women were randomly assigned to intraoperative ("early") SCC (n = 17) versus postoperative ("late") SCC (n = 18). Main variables investigated were neonatal transition (Apgar score, arterial oxygen saturation, heart rate and temperature), maternal pain perception and both maternal and neonatal stress response by measuring the stress biomarkers salivary free cortisol and salivary alpha amylase. RESULTS: There was no evidence for differences in parameters reflecting neonatal transition or stress response between the 'Early SSC Group' and the 'Late SSC Group'. Maternal salivary cortisol and alpha-amylase levels as well as maternal wellbeing and pain did not differ between the groups. However, the rise of maternal salivary alpha-amylase directly after delivery was higher in the 'Early SSC Group' compared to the 'Late SSC Group' (p = 0.004). CONCLUSIONS: This study did not reveal significant risks for the newborn in terms of neonatal transition when early SSC is applied in the operating room. Maternal condition and stress marker levels did not differ either, although the rise of maternal salivary alpha-amylase directly after delivery was higher in the 'Early SSC Group' compared to the 'Late SSC Group', which may indicate a stressor sign due to intensive activation of the sympathetic-adreno-medullary-system. This needs to be further evaluated in a larger prospective randomized trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT01894880.

Road and rail traffic noise induce comparable extra-aural effects as revealed during a short-term memory test.

To examine extraaural effects as induced by 20 min of road (ROAD) and 20 min of rail (RAIL) traffic noise with same loudness (75 dBA), a laboratory study was carried out. The study (N = 54) consisted of 28 high and 26 low-annoyed healthy individuals as determined by a traffic annoyance test. To control attention, all individuals performed a nonauditory short-term memory test during the noise exposures. A within-subject design, with phases of ROAD, RAIL, and CALM (memory test only), alternated by phases of rest, was defined. Heart rate (HR), systolic blood pressure (sBP), total peripheral resistance (TPR), as well as three autonomic variables, preejection period (PEP), 0.15-0.4 Hz high-frequency component of HR variability (HF), and salivary stress biomarker alpha amylase (sAA) were measured. In relation to CALM, HR increased (RAIL +2.1%, ROAD +2.5%), sBP tended to increase against the end of noise exposure, PEP decreased (RAIL -0.7%, ROAD -0.8%), HF decreased (RAIL -3.4%, ROAD -2.9%), and sAA increased (RAIL +78%, ROAD +69%). No differences were found between RAIL and ROAD, indicating that both noise stressors induced comparable extraaural effects. Factor annoyance showed significant during CALM. Here a reduced sympathetic drive (higher PEP values) combined with an increased vascular tone (higher TPR values) was found at the high-annoyed subgroup.

Does Platelet Reactivity Predict Bleeding in Patients Needing Urgent Coronary Artery Bypass Grafting During Dual Antiplatelet Therapy?

BACKGROUND: Up to 15% of patients require coronary artery bypass grafting (CABG) during dual antiplatelet therapy. Available evidence suggests an association between platelet reactivity and CABG-related bleeding. However, platelet reactivity cutoffs for bleeding remain elusive. We sought to explore the association between platelet reactivity and bleeding. METHODS: Patients on aspirin and a P2Y12 receptor inhibitor within 48 hours before isolated CABG (n = 149) were enrolled in this prospective study. Blood was drawn 2 to 4 hours preoperatively and platelet reactivity assessed by light transmittance aggregometry (LTA), vasodilator-stimulated phosphoprotein (VASP) assay, Multiplate analyzer and Innovance PFA2Y. The primary endpoint was calculated red blood cell loss computed as follows: (blood volume × preoperative hematocrit × 0.91) - (blood volume × hematocrit × 0.91 on postoperative day 5) + (mL of transfused red blood cells × 0.59). RESULTS: Preoperative platelet reactivity was low [median (interquartile range): LTA: 20 (9-28)%; VASP-PRI: 39 (15-73)%; Multiplate adenosine phosphate test: 16 (12-22) U∗min]. Innovance PFA2Y ≥300 seconds, 72%. Median (IQR) red blood cell loss in patients in first the LTA tertile was 1,449 (1,020 to 1,754) mL compared with 1,107 (858 to 1,512) mL and 1,075 (811 to 1,269) mL in those in the second and third tertiles, respectively (p < 0.004). Bleeding Academic Research Consortium (BARC)-4 bleeding differed between tertiles (62% versus 46% versus 36%; p = 0.037). In a multivariable linear regression model, aspirin dose ≥300 mg, cardiopulmonary bypass time, EuroSCORE, and tertile distribution of platelet reactivity were significantly associated with red blood cell loss. CONCLUSIONS: A gradual decrease in red blood cell loss and BARC-4 bleeding occurs with increasing platelet reactivity in patients on antiplatelet therapy undergoing CABG. Our findings support current guidelines to determine time of surgery based on an objective measurement of platelet function (Platelet Inhibition and Bleeding in Patients Undergoing Emergent Cardiac Surgery; clinicaltrials.gov NCT01468597).

Characterisation of Candida within the Mycobiome/Microbiome of the Lower Respiratory Tract of ICU Patients.

Whether the presence of Candida spp. in lower respiratory tract (LRT) secretions is a marker of underlying disease, intensive care unit (ICU) treatment and antibiotic therapy or contributes to poor clinical outcome is unclear. We investigated healthy controls, patients with proposed risk factors for Candida growth in LRT (antibiotic therapy, ICU treatment with and without antibiotic therapy), ICU patients with pneumonia and antibiotic therapy and candidemic patients (for comparison of truly invasive and colonizing Candida spp.). Fungal patterns were determined by conventional culture based microbiology combined with molecular approaches (next generation sequencing, multilocus sequence typing) for description of fungal and concommitant bacterial microbiota in LRT, and host and fungal biomarkes were investigated. Admission to and treatment on ICUs shifted LRT fungal microbiota to Candida spp. dominated fungal profiles but antibiotic therapy did not. Compared to controls, Candida was part of fungal microbiota in LRT of ICU patients without pneumonia with and without antibiotic therapy (63% and 50% of total fungal genera) and of ICU patients with pneumonia with antibiotic therapy (73%) (p<0.05). No case of invasive candidiasis originating from Candida in the LRT was detected. There was no common bacterial microbiota profile associated or dissociated with Candida spp. in LRT. Colonizing and invasive Candida strains (from candidemic patients) did not match to certain clades withdrawing the presence of a particular pathogenic and invasive clade. The presence of Candida spp. in the LRT rather reflected rapidly occurring LRT dysbiosis driven by ICU related factors than was associated with invasive candidiasis.

Chemotherapy-Induced Intestinal Mucosal Barrier Damage: a Cause of Falsely Elevated Serum 1,3-Beta-d-Glucan Levels?

Blood citrulline and intestinal fatty acid binding protein were determined as biomarkers for intestinal mucositis. Biomarker levels were correlated with corresponding serum 1,3-beta-D-glucan levels in 56 samples obtained from 33 cases with underlying hematological malignancies receiving induction chemotherapy. No correlation between biomarkers of intestinal mucositis and BDG levels was observed. (This study has been registered at ClinicalTrials.gov under registration no. NCT01576653.).

Prognostic potential of 1,3-beta-d-glucan levels in bronchoalveolar lavage fluid samples.

OBJECTIVES: The objective of this study was to investigate the prognostic potential of 1,3-beta-d-glucan (BDG) testing in bronchoalveolar lavage fluid (BALF) samples. METHODS: A total of 300 BALF samples from 252 patients were investigated for BDG (Fungitell(®) assay). Prognostic potential of BALF BDG was evaluated by using: i.) Kaplan-Meier analysis, and ii.) multivariable Cox hazard regression analyses. RESULTS: BALF BDG levels were found to be significantly higher in samples with Candida spp. colonization (p < 0.001). A total of 61/252 patients (24.2%) died within 90-days of BALF sampling (18.1% of patients with BALF BDG <200 pg/mL, 32.4% with BALF BDG ≥200 pg/mL). Kaplan-Meier analysis revealed that overall cumulative 90-day mortality was significantly higher in those with BALF BDG levels ≥200 pg/mL when compared to those with levels <200 pg/mL (log-rank p = 0.006, Breslow p = 0.005 and Tarone-Ware p = 0.005). The multivariable Cox regression analysis showed that BALF BDG levels were a strong predictor of 90-day overall mortality, with a hazard ratio of 1.048 (per 100 pg/mL increase of BALF BDG). CONCLUSION: False positive BALF BDG results in the presence of Candida spp. colonization of the lower respiratory tract may explain the limited diagnostic potential of BALF BDG testing. In contrast, prognostic potential of BALF BDG may be promising.