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Abstract Aortic dissections (ADs) are serious conditions of the main artery of the human body, where a tear in the inner layer of the aortic wall leads to the formation of a new blood flow channel, named false lumen. ADs affecting the aorta distally to the left subclavian artery are classified as a Stanford type B aortic dissection (type B AD). This is linked to substantial morbidity and mortality, however, the course of the disease for the individual case is often unpredictable. Computed tomography angiography (CTA) is the gold standard for the diagnosis of type B AD. To advance the tools available for the analysis of CTA scans, we provide a CTA collection of 40 type B AD cases from clinical routine with corresponding expert segmentations of the true and false lumina. Segmented CTA scans might aid clinicians in decision making, especially if it is possible to fully automate the process. Therefore, the data collection is meant to be used to develop, train and test algorithms.

Abstract Aims Chronic heart failure is associated with a bone‐catabolic state and increases the risk of osteoporosis and fractures. Prospective studies investigating the clinical relevance of bone disease in heart failure are lacking. We aimed to assess the prevalence and prognostic impact of osteoporosis and vertebral fractures (VFs) in chronic heart failure with reduced ejection fraction (HFrEF). Methods and results Symptomatic outpatients with chronic heart failure and a previous diagnosis of overtly reduced left ventricular ejection fraction

Objective: To systematically review and summarize the existing evidence related to the influence of the menstrual cycle (MC) and hormonal contraceptive (HC) use on V˙O2max in physically active women. Methods: This systematic review and meta-analysis conforms to the PRISMA statement guidelines. Four (sub-)meta-analyses were performed. Two focused on longitudinal studies examining the same women several times to compare the V˙O2max during the different menstrual phases or oral contraceptive (OC) use and withdrawal. Two meta-analyses examined if there is a difference in V˙O2max between OC users and normally menstruating women by analyzing cross-sectional studies assigning physically active women to one of these two groups as well as intervention-based studies (cross-over studies, randomized controlled trials considering only the data of the intervention group) comparing women intra-individually with and without OCs. Results: Nine of the included studies (107 women) evaluated the influence of the MC, five studies (69 women) the impact of OCs on V˙O2max, and six studies investigated both topics (88 women). A mean difference of V˙O2max −0.03 ml/kg/min (95%CI –1.06 to 1.01) between the early follicular and luteal menstrual phase was observed. Between the active and inactive phases of OCs, a mean difference of −0.11 ml/kg/min (95%CI –2.32 to 2.10) was found. The inter-individual comparison of naturally menstruating women and OC users showed a mean difference in V˙O2max of 0.23 ml/kg/min (95% CI –2.33 to 2.79) in favor of OC use. The intra-individual comparison of the same women showed a mean decrease in V˙O2max of −0.84 ml/kg/min (95% CI –2.38 to 0.70) after a new start with OCs. Conclusions: Our meta-analyses showed no effects of the MC or the OCs on V˙O2max. More high-quality studies are needed determining the MC phases more precisely, including OCs with the current standard formulations and comparing the influence of different progestins.

ObjectiveGuidelines for previous negative biopsy (PNB) cohorts with a suspicion of prostate cancer (PCa) after positive multiparametric (mp) magnetic-resonance-imaging (MRI) often favour the fusion-guided targeted prostate-biopsy (TB) only approach for Prostate Imaging-Reporting and Data System (PI-RADS) ≥3 lesions. However, recommendations lack direct biopsy performance comparison within biopsy naïve (BN) vs. PNB patients and its prognostication of the whole mount pathology report (WMPR), respectively. We suppose, that the combination of TB and concomitant TRUS-systematic biopsy (SB) improves the PCa detection rate of PI-RADS 2, 3, 4 or 5 lesions and the International Society of Urological Pathology (ISUP)-grade predictability of the WMPR in BN- and PNB patients.MethodsPatients with suspicious mpMRI, elevated prostate-specific-antigen and/or abnormal digital rectal examination were included. All PI-RADS reports were intramurally reviewed for biopsy planning. We compared the PI-RADS score substratified TB, SB or combined approach (TB/SB) associated BN- and PNB-PCa detection rate. Furthermore, we assessed the ISUP-grade variability between biopsy cores and the WMPR.ResultsAccording to BN (n = 499) vs. PNB (n = 314) patients, clinically significant (cs) PCa was detected more frequently by the TB/SB approach (62 vs. 43%) than with the TB (54 vs. 34%) or SB (57 vs. 34%) (all p

Clostridioides difficile infections cause severe symptoms ranging from diarrhea to pseudomembranous colitis due to the secretion of AB-toxins, TcdA and TcdB. Both toxins are taken up into cells through receptor-mediated endocytosis, autoproteolytic processing and translocation of their enzyme domains from acidified endosomes into the cytosol. The enzyme domains glucosylate small GTPases such as Rac1, thereby inhibiting processes such as actin cytoskeleton regulation. Here, we demonstrate that specific pharmacological inhibition of Hsp70 activity protected cells from TcdB intoxication. In particular, the established inhibitor VER-155008 and the antiemetic drug domperidone, which was found to be an Hsp70 inhibitor, reduced the number of cells with TcdB-induced intoxication morphology in HeLa, Vero and intestinal CaCo-2 cells. These drugs also decreased the intracellular glucosylation of Rac1 by TcdB. Domperidone did not inhibit TcdB binding to cells or enzymatic activity but did prevent membrane translocation of TcdB’s glucosyltransferase domain into the cytosol. Domperidone also protected cells from intoxication with TcdA as well as CDT toxin produced by hypervirulent strains of Clostridioides difficile. Our results reveal Hsp70 requirement as a new aspect of the cellular uptake mechanism of TcdB and identified Hsp70 as a novel drug target for potential therapeutic strategies required to combat severe Clostridioides difficile infections.

AimWe aimed to investigate a correlation between PE severity and Lp(a) levels.MethodsWe 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.ResultsWe 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).ConclusionThe current findings suggest no correlation between PE severity and Lp(a) levels.

Abstract Aims Cardiac involvement in myopathies that primarily affect the skeletal muscle is variable and may be subtle, necessitating sensitive diagnostic approaches. Here, we describe the prevalence of cardiac abnormalities in a cohort of patients with skeletal muscle disease presenting at a tertiary care neuromuscular centre. Methods and results We systematically investigated patients with skeletal myopathies and comprehensively analysed their cardiac phenotype including 24 h electrocardiogram, echocardiography with strain analyses, contrast‐enhanced cardiac magnetic resonance imaging, and, if at increased risk of coronary artery disease, computed tomography coronary angiography. We prospectively screened 91 patients with diverse skeletal myopathies and enrolled 73 patients. The most pronounced cardiac involvement was present in patients with dystrophic myopathies (cardiac abnormalities in 59% of patients). We analysed myotonic dystrophies (n = 29) in more detail and found prolonged QRS (99.4 ± 15.6 vs. 91.5 ± 10.3 ms; P = 0.027) and QTc times (441.1 ± 28.1 vs. 413.0 ± 23.3 ms; P

The high-frequency (HF) machine data is retrieved from the Spinner U5-630 milling machine via an Edge Device. Unlike cloud computing, an Edge Device refers to distributed data processing of devices in proximity that generate data, which can thereby be used for analysis [1,2]. This data has a sampling rate of 2ms and hence, a frequency of 500Hz. The HF machine data is from various experiments performed. There are 2 experiments performed (parts 1 and 2). The experimented part 1 has 12 .json data files and part 2 has 11 .json files. In total, there are 23 files of HF machine data from 23 experiments. The HF machine data has vast potential for analysis as it contains all the information from the machine during the machining process. One part of the information was used in our case to calculate the energy consumption of the machine. Similarly, the data can be used for retrieving information of torque, commanded and actual speed, NC code, current, etc.

Background: Right ventricular (RV) function predicts survival in numerous cardiac conditions, including left heart disease. The reference standard for non-invasive assessment of RV function is cardiac magnetic resonance imaging (CMR). The aim of this study was to investigate the association between pre-procedural CMR-derived RV functional parameters and mortality in patients undergoing transcatheter aortic valve implantation (TAVI).Methods: Patients scheduled for TAVI were recruited to undergo pre-procedural CMR. Volumetric function and global longitudinal and circumferential strain (GLS and GCS) of the RV and left ventricle (LV) were measured. The association with the primary endpoint (1-year all-cause mortality) was analyzed with Cox regression.Results: Of 133 patients undergoing CMR, 113 patients were included in the analysis. Mean age was 81.8 ± 5.8 years, and 65% were female. Median follow-up was 3.9 [IQR 2.3–4.7] years. All-cause and cardiovascular mortality was 14 and 12% at 1 year, and 28 and 20% at 3 years, respectively. One-year all-cause mortality was significantly predicted by RV GLS [HR = 1.109 (95% CI: 1.023–1.203); p = 0.012], RV ejection fraction [HR = 0.956 (95% CI: 0.929–0.985); p = 0.003], RV end-diastolic volume index [HR = 1.009 (95% CI: 1.001–1.018); p = 0.025], and RV end-systolic volume index [HR = 1.010 (95% CI: 1.003–1.017); p = 0.005]. In receiver operating characteristic (ROC) analysis for 1-year all-cause mortality, the area under the curve was 0.705 (RV GLS) and 0.673 (RV EF). Associations decreased in strength at longer follow-up. None of the LV parameters was associated with mortality.Conclusions: RV function predicts intermediate-term mortality in TAVI patients while LV parameters were not associated with outcomes. Inclusion of easily obtainable RV GLS may improve future risk scores.

The evaluation and management of severe asthma patients require collection of comprehensive information, which is often a challenge in a busy outpatient clinic. The Danish Severe Asthma Register (DSAR) was designed as an electronic patient record form that captures operational clinical data and provides a clinical overview of the severe asthma patient. DSAR is a nationwide register; all patients in Denmark who are treated with biologics for severe asthma are included, and data are as a minimum entered at start of biological treatment, after four and 12 months of treatment, and hereafter annually. Currently, there are data from 621 treatment courses with biologics included in DSAR, with 71% of patients treated with anti-IL-5 drugs and 29% with an anti-IgE drug. Patients enter Patient Reported Outcome Measures electronically on tablets when they arrive in the outpatient clinic and their answers are immediately available to the clinician during the consultation. Nurses and doctors enter clinical data into DSAR during the consultation. DSAR offers immediate access to well-presented longitudinal overview and automatically creates a journal output that can be copy-pasted into the hospital’s existing health record form. DSAR is also currently expanding with an app, to be used for monitoring of home-treatment. In addition to serving as an electronic patient record form, DSAR will also provide opportunities to monitor the real-life efficacy of biological treatment for severe asthma in Denmark, and it will be a valuable research platform that will aid in answering important research questions on severe asthma in the future.

Abstract Binary enterotoxins Clostridium (C.) botulinum C2 toxin, C. perfringens iota toxin and C. difficile toxin CDT are composed of a transport (B) and a separate non-linked enzyme (A) component. Their B-components mediate endocytic uptake into mammalian cells and subsequently transport of the A-components from acidic endosomes into the cytosol, where the latter ADP-ribosylate G-actin resulting in cell rounding and cell death causing clinical symptoms. Protein folding enzymes, including Hsp90 and peptidyl-prolyl cis/trans isomerases facilitate transport of the A-components across endosomal membranes. Here, we identified Hsp70 as a novel host cell factor specifically interacting with A-components of C2, iota and CDT toxins to facilitate their transport into the cell cytosol. Pharmacological Hsp70-inhibition specifically prevented pH-dependent trans-membrane transport of A-components into the cytosol thereby protecting living cells and stem cell-derived human miniguts from intoxication. Thus, Hsp70-inhibition might lead to development of novel therapeutic strategies to treat diseases associated with bacterial ADP-ribosylating toxins.

Supercritical CO2 loading of preformed 3D printed drug carriers with active pharmaceutical ingredients (APIs) shows great potential in the development of oral dosage forms for future personalized medicine. We designed 3D printed scaffold like drug carriers with varying pore sizes made from polylactic acid (PLA) using a fused deposition modelling (FDM) 3D printer. The 3D printed drug carriers were then loaded with Ibuprofen as a model drug, employing the controlled particle deposition (CPD) process from supercritical CO2. Carriers with varying pore sizes (0.027–0.125 mm) were constructed and loaded with Ibuprofen to yield drug-loaded carriers with a total amount of 0.83–2.67 mg API (0.32–1.41% w/w). Dissolution studies of the carriers show a significantly decreasing dissolution rate with decreasing pore sizes with a mean dissolution time (MDT) of 8.7 min for the largest pore size and 128.2 min for the smallest pore size. The API dissolution mechanism from the carriers was determined to be Fickian diffusion from the non-soluble, non-swelling carriers. Using 3D printing in combination with the CPD process, we were able to develop dosage forms with individually tailored controlled drug release. The dissolution rate of our dosage forms can be easily adjusted to the individual needs by modifying the pore sizes of the 3D printed carriers.

BackgroundMultiple studies have shown that an NO‐induced activation of vascular smooth muscle BK channels contributes to the NO‐evoked dilation in many blood vessels. In vivo, NO is released continuously. NO attenuates vessel constrictions and, therefore, exerts an anticontractile effect. It is unknown whether the anticontractile effect of continuously present NO is mediated by BK channels. Methods and ResultsThis study tested the hypothesis that BK channels mediate the vasodilatory effect of continuously present NO. Experiments were performed on rat and mouse tail and rat saphenous arteries using isometric myography and FURA‐2 fluorimetry. Continuously present NO donors, as well as endogenous NO, attenuated methoxamine‐induced vasoconstrictions. This effect was augmented in the presence of the BK channel blocker iberiotoxin. Moreover, the contractile effect of iberiotoxin was reduced in the presence of NO donors. The effect of the NO donor sodium nitroprusside was abolished by an NO scavenger and by a guanylyl cyclase inhibitor. In addition, the effect of sodium nitroprusside was reduced considerably by a protein kinase G inhibitor, but was not altered by inhibition of H2S generation. Sodium nitroprusside attenuated the intracellular calcium concentration response to methoxamine. Furthermore, sodium nitroprusside strongly reduced methoxamine‐induced calcium influx, which depends entirely on L‐type calcium channels. It did not affect methoxamine‐induced calcium release. ConclusionsIn summary, this study demonstrates the following: (1) continuously present NO evokes a strong anticontractile effect on rat and mouse arteries; (2) the iberiotoxin‐induced augmentation of the effect of NO is associated with an NO‐induced reduction of the effect of iberiotoxin; and (3) NO evoked a reduction of calcium influx via L‐type calcium channels.