Foam fractionation Tags (F-Tags) enabling surfactant-free, activity-preserving recovery of enzymes.

Enzymes have become important tools in many industries. However, the full exploitation of their potential is currently limited by a lack of efficient and cost-effective methods for enzyme purification from microbial production. One technology that could solve this problem is foam fractionation. In this study, we show that diverse natural foam-stabilizing proteins fused as F-Tags to ß-lactamase, penicillin G acylase, and formate dehydrogenase, respectively, are able to mediate foaming and recovery of the enzymes by foam fractionation. The catalytic activity of all three candidates is largely preserved. Under appropriate fractionation conditions, especially when a wash buffer is used, some F-Tags also allow nearly complete separation of the target enzyme from a contaminating protein. We found that a larger distance between the F-Tag and the target enzyme has a positive effect on the maintenance of catalytic activity. However, we did not identify any particular sequence motifs or physical parameters that influenced performance as an F-tag. The best results were obtained with a short helical F-Tag, which was originally intended to serve only as a linker sequence. The findings of the study suggest that the development of molecular tags that enable the establishment of surfactant-free foam fractionation for enzyme workup is a promising method. KEY POINTS: • Foam-stabilizing proteins mediate activity-preserving foam fractionation of enzymes • Performance as an F-Tag is not restricted to particular structural motifs • Separation from untagged protein benefits from low foam stability and foam washings.

Detecting Near-Surface Sub-Millimeter Voids in Additively Manufactured Ti-5V-5Al-5Mo-3Cr Alloy Using a Transmit-Receive Eddy Current Probe.

Additive Manufacturing (AM) Direct Laser Fabrication (DLF) of Ti-5Al-5V-5Mo-3Cr (Ti5553) is being developed as a method for producing aircraft components. The additive manufacturing process can produce flaws near the surface, such as porosity and material voids, which act as stress raisers, leading to potential component failure. Eddy current testing was investigated to detect flaws on or near the surface of DLF Ti5553 bar samples. For this application, the objective was to develop an eddy current probe capable of detecting flaws 500 µm in diameter, located 1 mm below the component's surface. Two initial sets of coil parameters were chosen: The first, based on successful experiments that demonstrated detection of a near surface flaw in Ti5553 using a transmit-receive array probe, and the second, derived from simulation by Finite Element Method (FEM). An optimized transmit receive coil design, based on the FEM simulations, was constructed. The probe was evaluated on Ti5553 samples containing sub-surface voids of the target size, as well as samples with side-drilled holes and samples with holes drilled from the opposing inspection surface. The probe was able to effectively detect 80% of the sub-surface voids. Limitations included the probe's inability to detect sub-surface voids near sample edges and a sensitivity to surface roughness, which produces local changes in lift-off. Multifrequency mixing improved signal-to-noise ratio when surface roughness was present on average by 22%. A probe based on that described in this paper could benefit quality assurance of additively manufactured aircraft components.

Early MOnitoring of REsponse (MORE) to Golimumab Therapy: Results of a Multicentre, Prospective Observational Trial.

BACKGROUND: The therapeutic goal of clinical remission in patients with moderate to severe ulcerative colitis (UC) is achieved after biological therapy only in 16-39%. Individualization of therapeutic intervention would benefit from prediction of early response. STUDY OBJECTIVE: The primary objective of our study was to assess golimumab (GLM) trough serum level of ≥2.5 µg/mL in combination with a reduction of faecal calprotectin (FC) of ≥50% at week 6 compared to baseline to predict clinical response at week 26 after regular GLM intake. METHODS: Patients with moderate to severe active UC and planned GLM treatment were recruited for a prospective, multicentre, observational study in Germany. Prediction of clinical response was assessed by FC and GLM trough level. Missing data were imputed as therapy failure according to the last observation carried forward method. RESULTS: Fifty nine patients have been enrolled. 54% of patients were anti-TNF naïve. Clinical response at week 6 was a significant predictor for achieving clinical response at week 26 (odds ratio [OR] 10.97, confidence interval [CI], 2.96-40.68; p < 0.001). Moreover, patients with a GLM trough level of ≥2.5 µg/mL and a ≥50% reduction of FC at week 6 had an OR of 5.33 (95% CI, 0.59-47.84) to achieve clinical response at week 26. CONCLUSION: Clinical response at week 6 is the best predictive marker for achieving clinical response at week 26. Consideration of significant reduction of FC and trough GLM serum levels could improve prediction of response.

[Inferior temporal electrodes in 24-h EEG]. / Subtemporale Elektroden im 24­Stunden-EEG.

BACKGROUND: To improve the sensitivity of the EEG in the diagnosis and classification of seizures or epilepsy, long-term recording with inferior temporal electrodes are recommended. MATERIAL AND METHODS: The spatial distribution of epileptiform discharges from 24­h EEG with 25 electrodes (10-20, extended by F9/F10, T9/T10, P9/P10) was retrospectively analyzed in 25 cases. RESULTS: Maximum negativity was located below the 10-20 electrodes in 84%. Epileptiform discharges were more clearly detected on inferior temporal electrodes in 64%. In the intention-to-test population of 77 patients the number needed to test with extra electrodes was estimated as 5. CONCLUSION: Recording EEG with 25 electrodes for 24 h improves the detection and localization of temporal epileptiform discharges also in geriatric patients with suspected nonlesional epilepsy.

Impact of the Microbial Origin and Active Microenvironment on the Shape of Biogenic Elemental Selenium Nanomaterials.

The shape of nanomaterials affects their colloidal properties, cellular uptake, and fate in the environment. The microbial origin and microenvironment can play a role in altering the shape of the nanomaterial. However, such studies have never been conducted. Here, we demonstrate that the selenium nanomaterials produced by Escherichia coli K-12 are stable and remain as BioSe-Nanospheres under thermophilic conditions, while those produced by anaerobic granular sludge transform to BioSe-Nanorods, due to a lower quantity of proteins coating these nanoparticles, which has been verified by proteomics analysis as well as using chemically synthesized selenium nanomaterials. Furthermore, the presence of Bacillus safensis JG-B5T transform the purified BioSe-Nanospheres produced by E. coli K-12 to BioSe-Nanorods, though they are not transformed in the absence of B. safensis JG-B5T. This is due to the production of peptidases by B. safensis JG-B5T that cleaves the protein coating the BioSe-Nanospheres produced by E. coli K-12, leading to their transformation to trigonal BioSe-Nanorods, which is the thermodynamically more stable state. These findings suggest that the fate of selenium and probably other redox-active elements released from the biological wastewater treatment units needs to be reevaluated and improved by including microbial criteria for better accuracy.

Profile of patients with inflammatory bowel disease in conjunction with unmet needs and decision-making for choosing a new biologic therapy: a baseline analysis of the VEDOIBD-Study.

PURPOSE: We characterized the profile of Crohn's disease (CD) or ulcerative colitis (UC) biologic-naïve patients (starting a new therapy with vedolizumab or TNFα-antagonists), their baseline disease activity predictors, and their perception of the quality of life (HRQoL). METHODS: The VEDOIBD-Study is a real-world study on the effectiveness of vedolizumab vs other biologics as induction and maintenance therapy for CD and UC. A total of 627 CD and 546 UC patients were enrolled from IBD-experienced centers across Germany. In both biologic-naïve vedolizumab (n=397) and anti-TNF (n=359) patients, CD and UC disease severity and HRQoL predictors were analyzed with logistic regression. The results were reported as odds ratio (OR) and 95% confidence interval (CI). RESULTS: When compared to biologic-naïve anti-TNF patients, a first biological therapy with vedolizumab was considered for older CD patients, with a less complicated though longer disease course, and with a history of comorbidities. No differences in (unmet) needs were observed among patients with UC. The presence of extra-intestinal manifestations in biologic-naïve anti-TNF patients with CD (OR (95% CI): 3.83 (1.69-8.68)) and, in both biologic-naïve groups of patients with UC, stool frequency (2.00 (1.25-3.19); 1.82 (1.10-3.02), respectively) and rectal bleeding (2.24 (1.20-4.18); 1.92 (1.19-3.11), respectively) emerged as the most important predictors of disease severity, which in turn were also significantly associated with a worse HRQoL. CONCLUSION: This study highlights the existence of unmet medical needs of patients with CD or UC, for whom a new biological therapy is planned as part of the VEDOIBD-Study, which considerably impacts their HRQoL.

[Effects of SARS-CoV-2 Infection on Symptoms and Therapy of Inflammatory Bowel Disease]. / Auswirkungen einer SARS-CoV-2-Infektion auf Symptomatik und Therapie chronisch-entzündlicher Darmerkrankungen.

INTRODUCTION: The influence of a SARS-CoV-2 infection on inflammatory bowel disease (IBD) has not yet been well characterized and it is unclear whether this requires an adaptation of the immunosuppressive therapy. METHODS: A national register was established for the retrospective documentation of clinical parameters and changes in immunosuppressive therapy in SARS-CoV-2 infected IBD patients. RESULTS: In total, only 3 of 185 IBD patients (1.6 %) were tested for SARS-CoV-2 infection because of abdominal symptoms. In the course of COVID-19 disease, 43.5 % developed diarrhea, abdominal pain or hematochezia (risk of hospitalization with vs. without abdominal symptoms: 20.0 % vs. 10.6 %, p < 0.01). With active IBD at the time of SARS-CoV-2 detection, there was an increased risk of hospitalization (remission 11.2 %, active IBD 23.3 % p < 0.05). IBD-specific therapy remained unchanged in 115 patients (71.4 %); the most common change was an interruption of systemic therapy (16.2 %). DISCUSSION: New abdominal symptoms often appeared in SARS-CoV-2 infected IBD patients. However, these only rarely led to SARS-CoV-2 testing. A high IBD activity at the time of SARS-CoV-2 detection was associated with an increased risk of hospitalization.

Perceived distress, personality characteristics, coping strategies and psychosocial impairments in a national German multicenter cohort of patients with Crohn's disease and ulcerative colitis.

BACKGROUND AND AIMS: This study examined differences in personality, psychological distress, and stress coping in inflammatory bowel disease (IBD) depending on type of disease and disease activity. We compared patients suffering from Crohn's disease (CD) and ulcerative colitis (UC) with controls. While the literature is replete with distinctive features of the pathogenesis of IBD, the specific differences in psychological impairments are not well studied. METHODS: In this German national multicenter study, participants were recruited from 32 centers. Two hundred ninety-seven questionnaires were included, delivering vast information on disease status and psychological well-being based on validated instruments with a total of 285 variables. RESULTS: CD patients were more affected by psychological impairments than patients suffering from UC or controls. Importantly, patients with active CD scored higher in neuroticism (p < 0.01), psychological distress (p < 0.001) and maladaptive stress coping (escape, p = 0.03; rumination, p < 0.03), but less need for social support (p = 0.001) than controls. In contrast, patients suffering from active UC showed psychological distress (p < 0.04) and maladaptive coping (avoidance, p < 0.03; escape, p = 0.01). Patients in remission seemed to be less affected. In particular, patients with UC in remission were not inflicted by psychological impairments. The group of CD patients in remission however, showed insecurity (p < 0.01) and paranoid ideation (p = 0.04). CONCLUSIONS: We identified specific aspects of psychological impairment in IBD depending on disease and disease activity. Our results underscore the need for psychological support and treatment particularly in active CD.

Stroke in right dorsal anterior insular cortex Is related to myocardial injury.

OBJECTIVE: Elevated levels of cardiac troponin, and especially their relative changes over time, indicate acute myocardial injury. They are also frequently observed after acute ischemic stroke (AIS), indicating poor functional outcome and increased mortality. However, recent evidence showed that, in most AIS patients, myocardial injury is not caused by coronary ischemia. Instead, stroke lesion location has been suggested to precipitate myocardial injury. METHODS: Voxel-based lesion-symptom mapping (VLSM) was used in 299 patients who had a magnetic resonance imaging-confirmed acute ischemic stroke within the anterior circulation and a high-sensitivity cardiac troponin T (hs-cTnT) acquired on the day of admission. Of these, 228 had a second troponin measurement during the acute phase. The absolute hs-cTnT levels above the 99th percentile of a healthy reference population (≥14ng/l) as well as their relative temporal changes were used as continuous variables of interest in the VLSM model, including a multiple regression analysis adjusted for confounding variables. RESULTS: The anterior insular cortex of the right hemisphere, in particular its dorsal subregion, was significantly associated with the relative temporal changes of hs-cTnT (p < 0.01, corrected for multiple comparisons). In contrast, the baseline hs-cTnT levels on admission were not related to lesion location anywhere within the anterior circulation. INTERPRETATION: Our results amplify recent evidence from functional neuroimaging, which suggests a prominent role of dorsal anterior insular cortex in the parasympathetic control of cardiac and autonomic function. Acute vascular damage of this insular subregion might lead to autonomic dysbalance and an upregulation of sympathetic function, thereby resulting in myocardial injury. Ann Neurol 2017;81:502-511.

EANM guideline for radionuclide therapy with radium-223 of metastatic castration-resistant prostate cancer.

Radium Ra-223 dichloride (radium-223, Xofigo®) is a targeted alpha therapy approved for the treatment of castration-resistant prostate cancer (CRPC) with symptomatic bone metastases and no known visceral metastatic disease. Radium-223 is the first targeted alpha therapy in this indication providing a new treatment option, with evidence of a significant survival benefit, both in overall survival and in the time to the first symptomatic skeletal-related event. The skeleton is the most common metastatic site in patients with advanced prostate cancer. Bone metastases are a clinically significant cause of morbidity and mortality, often resulting in bone pain, pathologic fracture, or spinal cord compression necessitating treatment. Radium-223 is selectively accumulated in the bone, specifically in areas of high bone turnover, by forming complexes with the mineral hydroxyapatite (the inorganic matrix of the bone). The alpha radiation generated during the radioactive decay of radium-223 produces a palliative anti-tumour effect on the bone metastases. The purpose of this guideline is to assist nuclear medicine specialists in evaluating patients who might be candidates for treatment using radium-223, planning and performing this treatment, understanding and evaluating its consequences, and improving patient management during therapy and follow-up.

The prognostic and predictive value of sstr2-immunohistochemistry and sstr2-targeted imaging in neuroendocrine tumors.

PURPOSE: Our aim was to assess the prognostic and predictive value of somatostatin receptor 2 (sstr2) in neuroendocrine tumors (NETs). METHODS: We established a tissue microarray and imaging database from NET patients that received sstr2-targeted radiopeptide therapy with yttrium-90-DOTATOC, lutetium-177-DOTATOC or alternative treatment. We used univariate and multivariate analyses to identify prognostic and predictive markers for overall survival, including sstr2-imaging and sstr2-immunohistochemistry. RESULTS: We included a total of 279 patients. In these patients, sstr2-immunohistochemistry was an independent prognostic marker for overall survival (HR: 0.82, 95 % CI: 0.67 - 0.99, n = 279, p = 0.037). In DOTATOC patients, sstr2-expression on immunohistochemistry correlated with tumor uptake on sstr2-imaging (n = 170, p < 0.001); however, sstr2-imaging showed a higher prognostic accuracy (positive predictive value: +27 %, 95 % CI: 3 - 56 %, p = 0.025). Sstr2-expression did not predict a benefit of DOTATOC over alternative treatment (p = 0.93). CONCLUSIONS: Our results suggest sstr2 as an independent prognostic marker in NETs. Sstr2-immunohistochemistry correlates with sstr2-imaging; however, sstr2-imaging is more accurate for determining the individual prognosis.

Surface Profiling and Core Evaluation of Aluminum Honeycomb Sandwich Aircraft Panels Using Multi-Frequency Eddy Current Testing.

Surface damage on honeycomb aircraft panels is often measured manually, and is therefore subject to variation based on inspection personnel. Eddy current testing (ECT) is sensitive to variations in probe-to-specimen spacing, or lift-off, and is thus promising for high-resolution profiling of surface damage on aluminum panels. Lower frequency testing also allows inspection through the face sheet, an advantage over optical 3D scanning methods. This paper presents results from the ECT inspection of surface damage on an approximately flat aluminum honeycomb aircraft panel, and compares the measurements to those taken using optical 3D scanning technology. An ECT C-Scan of the dented panel surface was obtained by attaching the probe to a robotic scanning apparatus. Data was taken simultaneously at four frequencies of 25, 100, 400 and 1600 kHz. A reference surface was then defined that approximated the original, undamaged panel surface, which also compensated for the effects of specimen tilt and thermal drift within the ECT instrument. Data was converted to lift-off using height calibration curves developed for each probe frequency. A damage region of 22,550 mm² area with dents ranging in depth from 0.13-1.01 mm was analyzed. The method was accurate at 1600 kHz to within 0.05 mm (2σ) when compared with 231 measurements taken via optical 3D scanning. Testing at 25 kHz revealed a 3.2 mm cell size within the honeycomb core, which was confirmed via destructive evaluation. As a result, ECT demonstrates potential for implementation as a method for rapid in-field aircraft panel surface damage assessment.

Imperceptible somatosensory stimulation alters sensorimotor background rhythm and connectivity.

Most sensory input to our body is not consciously perceived. Nevertheless, it may reach the cortex and influence our behavior. In this study, we investigated noninvasive neural signatures of unconscious cortical stimulus processing to understand mechanisms, which (1) prevent low-intensity somatosensory stimuli from getting access to conscious experience and which (2) can explain the associated impediment of conscious perception for additional stimuli. Stimulation of digit 2 in humans far below the detection threshold elicited a cortical evoked potential (P1) at 60 ms, but no further somatosensory evoked potential components. No event-related desynchronization was detected; rather, there was a transient synchronization in the alpha frequency range. Using the same stimulation during fMRI, a reduced centrality of contralateral primary somatosensory cortex (SI) was found, which appeared to be mainly driven by reduced functional connectivity to frontoparietal areas. We conclude that after subthreshold stimulation the (excitatory) feedforward sweep of bottom-up processing terminates in SI preventing access to conscious experience. We speculate that this interruption is due to a predominance of inhibitory processing in SI. The increase in alpha activity and the disconnection of SI from frontoparietal areas are likely correlates of an elevated perception threshold and may thus serve as a gating mechanism for the access to conscious experience.

Spot Sign in Acute Intracerebral Hemorrhage in Dynamic T1-Weighted Magnetic Resonance Imaging.

BACKGROUND AND PURPOSE: In computed tomographic imaging of acute intracerebral hemorrhage spot sign on computed tomographic angiography has been established as a marker for hematoma expansion and poor clinical outcome. Although, magnetic resonance imaging (MRI) can accurately visualize acute intracerebral hemorrhage, a corresponding MRI marker is lacking to date. METHODS: We prospectively examined 50 consecutive patients with acute intracerebral hemorrhage within 24 hours of symptom onset. The MRI protocol consisted of a standard stroke protocol and dynamic contrast-enhanced T1-weighted imaging with a time resolution of 7.07 s/batch. Stroke scores were assessed at admission and at time of discharge. Volume measurements of hematoma size and spot sign were performed with MRIcron. RESULTS: Contrast extravasation within sites of the hemorrhage (MRI spot sign) was seen in 46% of the patients. Patients with an MRI spot sign had a significantly shorter time to imaging than those without (P<0.001). The clinical outcome measured by the modified Rankin Scale was significantly worse in patients with spot sign compared with those without (P≤0.001). Hematoma expansion was observed in the spot sign group compared with the nonspot sign group, although the differences were not significant. CONCLUSIONS: Spot sign can be detected using MRI on postcontrast T1-weighted and dynamic T1-weighted images. It is associated with worse clinical outcome. The time course of contrast extravasation in dynamic T1 images indicates that these spots represent ongoing bleeding.

HEart and BRain interfaces in Acute ischemic Stroke (HEBRAS)--rationale and design of a prospective oberservational cohort study.

BACKGROUND: An effective diagnostic work-up in hospitalized patients with acute ischemic stroke is vital to optimize secondary stroke prevention. The HEart and BRain interfaces in Acute ischemic Stroke (HEBRAS) study aims to assess whether an enhanced MRI set-up and a prolonged Holter-ECG monitoring yields a higher rate of pathologic findings as compared to diagnostic procedures recommended by guidelines (including stroke unit monitoring for at least 24 h, echocardiography and ultrasound of brain-supplying arteries). METHODS/DESIGN: Prospective observational single-center study in 475 patients with acute ischemic stroke and without known atrial fibrillation. Patients will receive routine diagnostic care in hospital as wells as brain MRI, cardiac MRI, MR angiography of the brain-supplying arteries and Holter-monitoring for up to 10 days. Study patients will be followed up for cardiovascular outcomes at 3 and 12 months after enrollment. DISCUSSION: By comparing the results of routine diagnostic care to the study-specific MRI/ECG approach, the primary outcome of HEBRAS is the proportion of stroke patients with pathologic diagnostic findings. Predefined secondary outcomes are the association of stroke localization, autonomic dysbalance and cardiac dysfunction as well as the effect of impaired heart-rate-variability on long-term clinical outcome. The investigator-initiated HEBRAS study will assess whether an enhanced MRI approach and a prolonged ECG monitoring yield a higher rate of pathological findings than current standard diagnostic care to determine stroke etiology. These findings might influence current diagnostic recommendations after acute ischemic stroke. Moreover, HEBRAS will determine the extent and clinical impact of stroke-induced cardiac damage. TRIAL REGISTRATION: Clinicaltrials.gov NCT02142413.

Heart rate turbulence in acute ischemic stroke.

BACKGROUND: Heart rate turbulence (HRT), an ECG-based marker of autonomic cardiac regulation, has shown high prognostic value in patients with established cardiovascular diseases, while data in patients with acute ischemic stroke are scarce. PATIENTS AND METHODS: The HRT parameters turbulence onset and turbulence slope were analyzed using Holter-ECG recordings from patients with acute ischemic stroke, consecutively enrolled in the prospective observational HEBRAS study. HRT was categorized as normal (category 0; both parameters normal), abnormal (category 1; one parameter abnormal), or severely abnormal (category 2; both parameters abnormal). Outcomes of interest were functional outcome according to modified Rankin Scale (mRS) score at 3 months, mortality at 1 year, newly detected atrial fibrillation (AF), and evidence of focal myocardial fibrosis on cardiovascular MRI. RESULTS: HRT was assessed in 335 patients in sinus rhythm (median age 69 years, 37% female, median NIHSS score 2 on admission), including 262 (78%) with normal HRT, 47 (14%) with abnormal and 26 (8%) with severely abnormal HRT. Compared with normal HRT, severely abnormal HRT was associated with increased disability [higher mRS] at 3 months (adjusted odds ratio [aOR]: 2.9, 95% confidence interval [CI]: 1.3-6.6), new AF (aOR: 3.5, 95% CI: 1.1-10.6), MRI-detected myocardial fibrosis (aOR: 5.8, 95% CI: 1.3-25.9), but not with mortality at 1 year after stroke (aOR: 3.0, 95% CI: 0.7-13.9). Abnormal HRT was not associated with the analyzed outcomes. CONCLUSIONS: Severely abnormal HRT was associated with increased disability and previously unknown cardiac comorbidities. The potential role of HRT in selecting patients for extended AF monitoring and cardiac imaging should be further investigated.

Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial.

BACKGROUND: No effective standard treatment exists for patients with radioiodine-refractory, advanced differentiated thyroid carcinoma. We aimed to assess efficacy and safety of vandetanib, a tyrosine kinase inhibitor of RET, VEGFR and EGFR signalling, in this setting. METHODS: In this randomised, double-blind, phase 2 trial, we enrolled adults (aged ≥18 years) with locally advanced or metastatic differentiated thyroid carcinoma (papillary, follicular, or poorly differentiated) at 16 European medical centres. Eligible patients were sequentially randomised in a 1:1 ratio with a standard computerised scheme to receive either vandetanib 300 mg per day (vandetanib group) or matched placebo (placebo group), balanced by centre. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population based on investigator assessment. This study is registered with ClinicalTrials.gov, number NCT00537095. FINDINGS: Between Sept 28, 2007, and Oct 16, 2008, we randomly allocated 72 patients to the vandetanib group and 73 patients to the placebo group. By data cutoff (Dec 2, 2009), 113 (78%) patients had progressed (52 [72%] patients in the vandetanib group and 61 [84%] in the placebo group) and 40 (28%) had died (19 [26%] patients in the vandetanib group and 21 [29%] in the placebo group). Patients who received vandetanib had longer PFS than did those who received placebo (hazard ratio [HR] 0·63, 60% CI 0·54-0·74; one-sided p=0·008): median PFS was 11·1 months (95% CI 7·7-14·0) for patients in the vandetanib group and 5·9 months (4·0-8·9) for patients in the placebo group. The most common grade 3 or worse adverse events were QTc prolongation (ten [14%] of 73 patients in the vandetanib group vs none in the placebo group), diarrhoea (seven [10%] vs none), asthenia (five [7%] vs three [4%]), and fatigue (four [5%] vs none). Two patients in the vandetanib group and one in the placebo group died from treatment-related serious adverse events (haemorrhage from skin metastases and pneumonia in the vandetanib group and pneumonia in the placebo group). INTERPRETATION: Vandetanib is the first targeted drug to show evidence of efficacy in a randomised phase 2 trial in patients with locally advanced or metastatic differentiated thyroid carcinoma. Further investigation of tyrosine-kinase inhibitors in this setting is warranted. FUNDING: AstraZeneca.

Switching Vedolizumab from IV to SC Injection in Inflammatory Bowel Disease Patients with Active Disease: Real-World Experience from a German IBD Cohort.

BACKGROUND: Vedolizumab (VDZ) for subcutaneous (SC) injection was approved for use in Europe in 2020 and the US in 2023. Promising efficacy and tolerability have been proven in pivotal trials. However, real-world data on the SC use of VDZ, especially in patients with active disease, are still lacking. We aimed to determine treatment persistence and the drug's efficacy in inflammatory bowel disease (IBD) patients with active disease in comparison to patients in clinical remission. METHODS: Patients treated for IBD in a tertiary care center from July 2020 to December 2021 were included in this study. Clinical and biochemical parameters and data on treatment adherence were collected. VDZ trough levels and disease activity before and after the switch from intravenous (IV) to SC injections were monitored during routine checkups and were retrospectively analyzed. The patients were followed up until week 20. RESULTS: Eighty-two patients were included in the study. Of them, 35 patients had active disease (35/82 = 43%) at the time of the switch and 47 patients (47/82 = 57%) were in remission. In total, 10 patients experienced switch failure, 5 were switched back to IV VDZ, and 5 were swapped to a different biologic agent. We observed an increase in VDZ trough levels from the switch to week 8 and from the switch to week 20 in the remission group. Vedolizumab trough levels of 7.4, 51.4, and 33.45 ug/mL at the switch, week 8, and week 20 were identified to discriminate between remission and disease activity in our cohort. There was no new safety signal detected during the study period. CONCLUSIONS: The switch from IV to SC VDZ proved to be efficient, safe, and even capable of reducing residual disease activity.

Elevation of cardiac biomarkers in stroke is associated with pathological findings on cardiac MRI-results of the HEart and BRain interfaces in Acute Stroke study.

INTRODUCTION: Cardiac biomarkers, such as high-sensitivity cardiac troponin T (hs-cTnT), are frequently elevated in ischemic stroke patients but the mechanisms underlying this elevation are insufficiently understood. We determined the presence of cardiac damage, assessed using cardiac magnetic resonance imaging (CMR), in stroke patients with elevated hs-cTnT and brain natriuretic peptide (BNP). METHODS: This is a post hoc analysis of the prospective, investigator-initiated, cross-sectional HEart and BRain interfaces in Acute Stroke (HEBRAS) study. All patients underwent the measurement of hs-cTnT and BNP as well as gadolinium-enhanced CMR in the acute phase of ischemic stroke. We performed unadjusted and adjusted logistic regression models to assess the association between hs-cTnT and BNP elevation and the presence of pathological CMR findings. RESULTS: Two hundred and thirty-three stroke patients (median age 67 years, 33% female) were included, of whom 43 (21%) had elevated hs-cTnT and 109 (47%) had elevated BNP. Hundred of the 233 (43%) patients had pathological findings on CMR had focal fibrosis as detected by late-gadolinium enhancement (LGE) in 51 (23%), left-ventricular hypertrophy (LVH) in 38 (16%), reduced LVEF in 32 (14%), and left-atrial dilatation in 34 (15%). After adjustment for potential confounders, both hs-cTnT (adjOR 5.0 (95%CI 2.1-11.7), p < 0.001) and BNP (adjOR 4.1 (95%CI 2.3-7.3), p < 0.001) were significantly associated with pathological findings on CMR. Hs-cTnT was associated with LGE, LVEF, and LVH, whereas BNP was associated with left-atrial dilatation and LVEF, LVH. CONCLUSION: Elevated cardiac biomarkers in acute stroke including CMR are strongly associated with pathological findings on CMR. In acute stroke patients, the elevation of cardiac biomarkers may identify patients who require a more thorough cardiology work-up.

Real-world Comparative Effectiveness of Ustekinumab vs Anti-TNF in Crohn's Disease With Propensity Score Adjustment: Induction Phase Results From the Prospective, Observational RUN-CD Study.

BACKGROUND: In addition to randomized controlled trials (RCTs), real-world studies on the effectiveness of ustekinumab (UST) in Crohn's disease (CD) are required inasmuch as RCTs are usually confined to selected patients, which may not represent everyday clinical practice. Within the framework of the prospective real-world RUN-CD registry, a total of approximately 900 CD patients from 44 inflammatory bowel disease centers from all over Germany starting a new therapy with UST or other biologics were screened for a real-world evidence (RWE) comparison of CD patients with UST vs antitumor necrosis factor (TNF). METHODS: A total of 618 CD patients with a nonrandomized biological therapy were qualified for this induction phase effectiveness RUN-CD study of UST vs anti-TNF. To reduce selection bias in estimations of treatment effects, the propensity score with inverse probability of treatment weighting was implemented. The results were reported as odds ratio (OR) and 95% confidence interval (CI). RESULTS: A total of 339 UST and 279 anti-TNF patients were analyzed. The effectiveness of UST vs anti-TNF in terms of clinical remission (UST 65.4% vs anti-TNF 63.0%; OR, 1.11; 95% CI, 0.71-1.74) and steroid-free remission (UST 51.0% vs anti-TNF 53.8%; OR, 0.94; 95% CI, 0.60-1.47) was comparable at the end of induction therapy. Similar results were observed in the bio-naïve and bio-experienced UST vs anti-TNF groups. For both, the remission rates were higher in the bio-naïve than in the bio-experienced groups (P < .05). CONCLUSIONS: In this prospective, observational RUN-CD study, the RWE head-to-head comparison of UST vs anti-TNF showed similar induction effectiveness in both groups, remarkably higher than those found in prior RCTs.

The higher effectiveness outcome rates observed in patients treated with UST compared with pivotal studies in combination with its known favorable safety profile and an improved HRQoL support UST use as a first-line, advanced therapy in CD.