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The optimal treatment for patients with asymptomatic carotid artery stenosis is under debate. Since best medical treatment (BMT) has improved over time, the benefit of carotid endarterectomy (CEA) or carotid artery stenting (CAS) is unclear. Randomised data comparing the effect of CEA and CAS versus BMT alone are absent. We aimed to directly compare CEA plus BMT with CAS plus BMT and both with BMT only. SPACE-2 was a multicentre, randomised, controlled trial at 36 study centres in Austria, Germany, and Switzerland. We enrolled participants aged 50–85 years with asymptomatic carotid artery stenosis at the distal common carotid artery or the extracranial internal carotid artery of at least 70%, according to European Carotid Surgery Trial criteria. Initially designed as a three-arm trial including one group for BMT alone (with a randomised allocation ratio of 2·9:2·9:1), the SPACE-2 study design was amended (due to slow recruitment) to become two substudies with two arms each comparing CEA plus BMT with BMT alone (SPACE-2a) and CAS plus BMT with BMT alone (SPACE-2b); in each case in a 1:1 randomisation. Participants and clinicians were not masked to allocation. The primary efficacy endpoint was the cumulative incidence of any stroke or death from any cause within 30 days or any ipsilateral ischaemic stroke within 5 years. The primary safety endpoint was any stroke or death from any cause within 30 days after CEA or CAS. The primary analysis was by intention-to treat, which included all randomly assigned patients in SPACE-2, SPACE-2a, and SPACE-2b, analysed using meta-analysis of individual patient data. We did two-step hierarchical testing to first show superiority of CEA and CAS to BMT alone then to assess non-inferiority of CAS to CEA. Originally, we planned to recruit 3640 patients; however, the study had to be stopped prematurely due to insufficient recruitment. This report presents the primary analysis at 5-year follow-up. This trial is registered with ISRCTN, number ISRCTN78592017. 513 patients across SPACE-2, SPACE-2a, and SPACE-2b were recruited and surveyed between July 9, 2009, and Dec 12, 2019, of whom 203 (40%) were allocated to CEA plus BMT, 197 (38%) to CAS plus BMT, and 113 (22%) to BMT alone. Median follow-up was 59·9 months (IQR 46·6–60·0). The cumulative incidence of any stroke or death from any cause within 30 days or any ipsilateral ischaemic stroke within 5 years (primary efficacy endpoint) was 2·5% (95% CI 1·0–5·8) with CEA plus BMT, 4·4% (2·2–8·6) with CAS plus BMT, and 3·1% (1·0–9·4) with BMT alone. Cox proportional-hazard testing showed no difference in risk for the primary efficacy endpoint for CEA plus BMT versus BMT alone (hazard ratio [HR] 0·93, 95% CI 0·22–3·91; p=0·93) or for CAS plus BMT versus BMT alone (1·55, 0·41–5·85; p=0·52). Superiority of CEA or CAS to BMT was not shown, therefore non-inferiority testing was not done. In both the CEA group and the CAS group, five strokes and no deaths occurred in the 30-day period after the procedure. During the 5-year follow-up period, three ipsilateral strokes occurred in both the CAS plus BMT and BMT alone group, with none in the CEA plus BMT group. CEA plus BMT or CAS plus BMT were not found to be superior to BMT alone regarding risk of any stroke or death within 30 days or ipsilateral stroke during the 5-year observation period. Because of the small sample size, results should be interpreted with caution. German Federal Ministry of Education and Research (BMBF) and German Research Foundation (DFG).

Introduction: Factor Xa (FXa) inhibitors are superior to vitamin K antagonists (VKAs) in terms of avoiding hemorrhagic complications. However, no robust data are available to date as to whether this also applies to the early phase after stroke. In this prospective registry study, we aimed to investigate whether anticoagulation with FXa inhibitors in the early phase after acute ischemic stroke or transient ischemic attack (TIA) is associated with a lower risk of major bleeding events compared with VKAs. Materials and methods: The Prospective Record of the Use of Dabigatran in Patients with Acute Stroke or TIA (PRODAST) study is a prospective, multicenter, observational, post-authorization safety study at 86 German stroke units between July 2015 and November 2020. Primary outcome was a major bleeding event during hospital stay. Secondary endpoints were recurrent strokes, recurrent ischemic strokes, TIA, systemic/pulmonary embolism, myocardial infarction, death and the composite endpoint of stroke, systemic embolism, life-threatening bleeding and death. Results: In total, 10,039 patients have been recruited. 5,874 patients were treated with FXa inhibitors and 1,050 patients received VKAs and were eligible for this analysis. Overall, event rates were low. We observed 49 major bleeding complications during 33,297 treatment days with FXa-inhibitors (rate of 14.7 cases per 10,000 treatment days) and 16 cases during 7,714 treatment days with VKAs (rate of 20.7 events per 10,000 treatment days), translating into an adjusted hazard ratio (aHR) of 0.70 (95% confidence interval (95% CI): 0.37–1.32) in favor of FXa inhibitors. Hazards for ischemic endpoints (63 vs 17 strokes, aHR: 0.96 (95% CI: 0.53–1.74), mortality (33 vs 6 deaths, aHR: 0.87 (95% CI: 0.33–2.34)) and the combined endpoint (154 vs 39 events, aHR: 0.99 (95% CI: 0.65–1.41) were not substantially different. Discussion and conclusion: This large real-world study shows that FXa inhibitors appear to be similarly effective in terms of bleeding events and ischemic endpoints compared to VKAs in the early post-stroke phase of hospitalization. However, the results need to be interpreted with caution due to the low precision of the estimates. Graphical abstract

The mechanical behavior of a Fe 80 Zr 10 Cr 10 alloy has been studied at ambient and high temperature. This Fe 80 Zr 10 Cr 10 alloy, whoose microstructure is formed by alternate lamellae of Laves phase and ferrite, constitutes a very simple example of an in situ CMA phase composite. The role of the Laves phase type was investigated in a previous study while the present work focuses on the influence of the microstructure length scale owing to a series of alloys cast at different cooling rates that display microstructures with Laves phase lamellae width ranging from ∼50 nm to ∼150 nm. Room temperature compression tests have revealed a very high strength (up to 2 GPa) combined with a very high ductility (up to 35%). Both strength and ductility increase with reduction of the lamella width. High temperature compression tests have shown that a high strength (900 MPa) is maintained up to 873 K. Microstructural study of the deformed samples suggests that the confinement of dislocations in the ferrite lamellae is responsible for strengthening at both ambient and high temperature. The microstructure scale in addition to CMA phase structural features stands then as a key parameter for optimization of mechanical properties of CMA in situ composites.

Die Entwicklung einer in-stentRestenose nach stent-geschutzter Angioplastie der carotis (sPAc) ist eine relativ seltene Komplikation, bei der noch keine einheitliche Empfehlung hinsichtlich des therapeutischen Vorgehens existiert. In einer retrospektiven Analyse unserer Daten von 176 Patienten behandelt mit carotis-stents zwischen 2009 und 2015 wurden in insgesamt 9 Patienten farbduplexsonografisch eine hochgradige Restenose diagnostiziert (mittleres Alter 66.0 Jahre, sD 11.7 Jahre, 6 Frauen und 3 Manner). Die mittels Us detektierten stenosen wurden angiographisch in allen Fallen bestatigt, und mittels drug-eluting balloon (DEb) in der gleichen sitzung behandelt. Ein Patient hatte eine bilaterale Erkrankung, und ein weiterer Patient benotigte eine wiederholte behandlung mittels Deb 19 Monate nach der Erstbehandlung; so dass insgesamt 11 Prozeduren an den 9 Patienten erfolgten. Die mediane Zeit zwischen carotis-stent und erster DEB betrug 9 Monate. In 3 der Prozeduren musste die DEB durch einen weiteren stent unterstutzt werden--in zwei Fallen bei einer Edge-stenose, in einem Fall bei einer Dissektion wahrend der Behandlung mittels DEB. Es traten keine periprozeduralen Komplikationen auf. Das 1 Jahres event-free-survival (EFs) betrug somit 100%, das 2, und 3 Jahres sowie das 5 Jahres EFs 83% hinsichtlich einer Re-stenose nach DEB. Zusammenfassend ist die DEB eine vielversprechende, effektive und sichere Behandlung fur Patienten mit einer hochgradigen Rezidivstenose nach sPAc. Aufgrund der potenziellen Notwendigkeit einer zusatzlichen stentimplantation erscheint eine Behandlung durch erfahrene neuroradiologische Interventionalisten angezeigt.

ObjectiveProspective evaluation of intestinal ultrasound (IUS) for disease monitoring of patients with ulcerative colitis (UC) in routine medical practice.DesignTRansabdominal Ultrasonography of the bowel in Subjects with IBD To monitor disease activity with UC (TRUST&UC) was a prospective, observational study at 42 German inflammatory bowel disease-specialised centres representing different care levels. Patients with a diagnosis of a proctosigmoiditis, left-sided colitis or pancolitis currently in clinical relapse (defined as Short Clinical Colitis Activity Index ≥5) were enrolled consecutively. Disease activity and vascularisation within the affected bowel wall areas were assessed by duplex/Colour Doppler ultrasonography.ResultsAt baseline, 88.5% (n=224) of the patients had an increased bowel wall thickness (BWT) in the descending or sigmoid colon. Even within the first 2 weeks of the study, the percentage of patients with an increased BWT in the sigmoid or descending colon decreased significantly (sigmoid colon 89.3%–38.6%; descending colon 83.0%–42.9%; p<0.001 each) and remained low at week 6 and 12 (sigmoid colon 35.4% and 32.0%; descending colon 43.4% and 37.6%; p<0.001 each). Normalisation of BWT and clinical response after 12 weeks of treatment showed a high correlation (90.5% of patients with normalised BWT had symptomatic response vs 9.5% without symptomatic response; p<0.001).ConclusionsIUS may be preferred in general practice in a point-of-care setting for monitoring the disease course and for assessing short-term treatment response. Our findings give rise to the assumption that monitoring BWT alone has the potential to predict the therapeutic response, which has to be verified in future studies.

The access to portal circulation is possible during the implantation of a transjugular intrahepatic portosystemic shunt (TIPS). [...]we characterised the circulating microbiome in portal vein (first venous outflow in gut–liver axis), liver outflow, central venous blood and peripheral venous blood from seven patients with decompensated liver cirrhosis receiving TIPS for either variceal bleeding (n=3) or refractory ascites (n=4) (mean Model for End-stage Liver Disease (MELD) 8.4 (range 6–13), Child-Pugh-Score (CHILD) A: n=4, CHILD B: n=3) (figure 1A). Blood microbiome phylum compositions identified in our study agreed with previous findings investigating the peripheral blood microbiome in buffy coat samples from patients with liver fibrosis2 as well as healthy individuals3 but differed from the gut microbiome measured in faecal samples, where Bacteroidetes and Firmicutes are predominant.2 SP110.1136/gutjnl-2018-316227.supp1 Supplementary data Figure 1. Bacterial infections are frequent in cirrhotics, often trigger acute-on-chronic liver failure and are associated with high mortality.5 A number of cytokines, which might show immune dysfunction, systemic inflammation and oxidative stress, have been linked to decompensation, acute-on-chronic liver failure and mortality.6–10 To elaborate on the relationship with systemic inflammation, we measured cytokine levels in serum of the same patients and compartments except central venous blood.

Early information on treatment response of HCC to local ablative therapy is crucial. Elastography as a non-invasive method has recently been shown to play a potential role in distinguishing between benign and malignant liver lesions. Elastography of hepatocellular carcinoma (HCC) in early response to local ablative therapy has not been studied to date. We prospectively included a cohort of 14 patients with diagnosis of HCC who were treated with local ablative therapy (transarterial chemoembolization, TACE and/or radiofrequency ablation, RFA). We used 2D shear-wave elastography (RT 2D-SWE) to examine stiffness of HCC lesion before and 3, 30 and 90 days after local ablative therapy. Contrast-enhanced imaging after 90 days was performed to evaluate treatment response. Primary endpoint was stiffness of HCC in response to local ablative therapy. Secondary end point was tumor recurrence. Stiffness of HCC nodules and liver showed no significant difference prior to local ablative therapy. As early as three days after treatment, stiffness of responding HCC was significantly higher compared to non-responding. Higher stiffness before treatment was significantly associated with tumor recurrence. Nodule stiffness in general and RT 2D-SWE in particular could provide a useful tool for early prediction of HCC response to local ablative therapy.

The interplay between corticotropin-releasing hormone (CRH) and the dopaminergic system has predominantly been studied in addiction and reward, while CRH–dopamine interactions in anxiety are scarcely understood. We describe a new population of CRH-expressing, GABAergic, long-range-projecting neurons in the extended amygdala that innervate the ventral tegmental area and alter anxiety following chronic CRH depletion. These neurons are part of a distinct CRH circuit that acts anxiolytically by positively modulating dopamine release.

The effective transverse relaxation rate (R 2 *) is sensitive to the microstructure of the human brain like the g-ratio which characterises the relative myelination of axons. However, the fibre-orientation dependence of R 2 * degrades its reproducibility and any microstructural derivative measure. To estimate its orientation-independent part (R 2,iso *) from single multi-echo gradient-recalled-echo (meGRE) measurements at arbitrary orientations, a second-order polynomial in time model (hereafter M2) can be used. Its linear time-dependent parameter, β 1 , can be biophysically related to R 2,iso * when neglecting the myelin water (MW) signal in the hollow cylinder fibre model (HCFM). Here, we examined the performance of M2 using experimental and simulated data with variable g-ratio and fibre dispersion. We found that the fitted β 1 can estimate R 2,iso * using meGRE with long maximum-echo time (TE max  ≈ 54 ms), but not accurately captures its microscopic dependence on the g-ratio (error 84%). We proposed a new heuristic expression for β 1 that reduced the error to 12% for ex vivo compartmental R 2 values. Using the new expression, we could estimate an MW fraction of 0.14 for fibres with negligible dispersion in a fixed human optic chiasm for the ex vivo compartmental R 2 values but not for the in vivo values. M2 and the HCFM-based simulations failed to explain the measured R 2 *-orientation-dependence around the magic angle for a typical in vivo meGRE protocol (with TE max  ≈ 18 ms). In conclusion, further validation and the development of movement-robust in vivo meGRE protocols with TE max  ≈ 54 ms are required before M2 can be used to estimate R 2,iso * in subjects.

Terahertz technologies for non-destructive testing (NDT) are continuing to find their way into the industrial sector in the context of very specific inspection tasks. Part of this development is the capability to adapt terahertz systems in such a way that they can meet the sometimes harsh challenges and requirements of real-world industrial scenarios. One such scenario is the inspection of components with limited available measurement space. In particular, we show here the terahertz NDT inspection of the mica insulation of generator bars of turbogenerators at power plants, where an early on-site detection of defects and cracks in the insulation can be crucial, but where only few centimeters of space between adjacent bars are available. To address this problem, we have developed a measurement system combining a 100 GHz all-electronic terahertz transceiver with a low-loss dielectric waveguide antenna with 90 degree tip. We achieve sub-wavelength image resolution by scanning the waveguide antenna's tip over the surface of the generator bars in a near-field measurement setup. Employing a frequency-modulated continuous wave technique, we obtain depth-resolved, volumetric terahertz images of the objects under test. We discuss here the implementation and performance of the implemented measurement system for terahertz NDT inspection. keywords: terahertz, non-destructive testing, dielectric waveguides, frequency-modulated continuous wave, millimeter waves, power generators