Prognostic value of single-subject grey matter networks in early multiple sclerosis.

The identification of prognostic markers in early multiple sclerosis (MS) is challenging and requires reliable measures that robustly predict future disease trajectories. Ideally, such measures should make inferences at the individual level to inform clinical decisions. This study investigated the prognostic value of longitudinal structural networks to predict 5-year Expanded Disability Status Scale (EDSS) progression in patients with relapsing-remitting MS (RRMS). We hypothesized that network measures, derived from MRI, outperform conventional MRI measurements at identifying patients at risk of developing disability progression. This longitudinal, multicentre study within the Magnetic Resonance Imaging in MS (MAGNIMS) network included 406 patients with RRMS (mean age = 35.7 ± 9.1 years) followed up for 5 years (mean follow-up = 5.0 ± 0.6 years). EDSS was determined to track disability accumulation. A group of 153 healthy subjects (mean age = 35.0 ± 10.1 years) with longitudinal MRI served as controls. All subjects underwent MRI at baseline and again 1 year after baseline. Grey matter atrophy over 1 year and white matter lesion load were determined. A single-subject brain network was reconstructed from T1-weighted scans based on grey matter atrophy measures derived from a statistical parameter mapping-based segmentation pipeline. Key topological measures, including network degree, global efficiency and transitivity, were calculated at single-subject level to quantify network properties related to EDSS progression. Areas under receiver operator characteristic (ROC) curves were constructed for grey matter atrophy and white matter lesion load, and the network measures and comparisons between ROC curves were conducted. The applied network analyses differentiated patients with RRMS who experience EDSS progression over 5 years through lower values for network degree [H(2) = 30.0, P < 0.001] and global efficiency [H(2) = 31.3, P < 0.001] from healthy controls but also from patients without progression. For transitivity, the comparisons showed no difference between the groups [H(2) = 1.5, P = 0.474]. Most notably, changes in network degree and global efficiency were detected independent of disease activity in the first year. The described network reorganization in patients experiencing EDSS progression was evident in the absence of grey matter atrophy. Network degree and global efficiency measurements demonstrated superiority of network measures in the ROC analyses over grey matter atrophy and white matter lesion load in predicting EDSS worsening (all P-values < 0.05). Our findings provide evidence that grey matter network reorganization over 1 year discloses relevant information about subsequent clinical worsening in RRMS. Early grey matter restructuring towards lower network efficiency predicts disability accumulation and outperforms conventional MRI predictors.

Ultrafast Brain MRI with Deep Learning Reconstruction for Suspected Acute Ischemic Stroke.

Background Deep learning (DL)-accelerated MRI can substantially reduce examination times. However, studies prospectively evaluating the diagnostic performance of DL-accelerated MRI reconstructions in acute suspected stroke are lacking. Purpose To investigate the interchangeability of DL-accelerated MRI with conventional MRI in patients with suspected acute ischemic stroke at 1.5 T. Materials and Methods In this prospective study, 211 participants with suspected acute stroke underwent clinically indicated MRI at 1.5 T between June 2022 and March 2023. For each participant, conventional MRI (including T1-weighted, T2-weighted, T2*-weighted, T2 fluid-attenuated inversion-recovery, and diffusion-weighted imaging; 14 minutes 18 seconds) and DL-accelerated MRI (same sequences; 3 minutes 4 seconds) were performed. The primary end point was the interchangeability between conventional and DL-accelerated MRI for acute ischemic infarction detection. Secondary end points were interchangeability regarding the affected vascular territory and clinically relevant secondary findings (eg, microbleeds, neoplasm). Three readers evaluated the overall occurrence of acute ischemic stroke, affected vascular territory, clinically relevant secondary findings, overall image quality, and diagnostic confidence. For acute ischemic lesions, size and signal intensities were assessed. The margin for interchangeability was chosen as 5%. For interrater agreement analysis and interrater reliability analysis, multirater Fleiss κ and the intraclass correlation coefficient, respectively, was determined. Results The study sample consisted of 211 participants (mean age, 65 years ± 16 [SD]); 123 male and 88 female). Acute ischemic stroke was confirmed in 79 participants. Interchangeability was demonstrated for all primary and secondary end points. No individual equivalence indexes (IEIs) exceeded the interchangeability margin of 5% (IEI, -0.002 [90% CI: -0.007, 0.004]). Almost perfect interrater agreement was observed (P > .91). DL-accelerated MRI provided higher overall image quality (P < .001) and diagnostic confidence (P < .001). The signal properties of acute ischemic infarctions were similar in both techniques and demonstrated good to excellent interrater reliability (intraclass correlation coefficient, ≥0.8). Conclusion Despite being four times faster, DL-accelerated brain MRI was interchangeable with conventional MRI for acute ischemic lesion detection. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Haller in this issue.

Concurrent inflammation-related brain reorganization in multiple sclerosis and depression.

BACKGROUND: Neuroinflammation affects brain tissue integrity in multiple sclerosis (MS) and may have a role in major depressive disorder (MDD). Whether advanced magnetic resonance imaging characteristics of the gray-to-white matter border serve as proxy of neuroinflammatory activity in MDD and MS remain unknown. METHODS: We included 684 participants (132 MDD patients with recurrent depressive episodes (RDE), 70 MDD patients with a single depressive episode (SDE), 222 MS patients without depressive symptoms (nMS), 58 MS patients with depressive symptoms (dMS), and 202 healthy controls (HC)). 3 T-T1w MRI-derived gray-to-white matter contrast (GWc) was used to reconstruct and characterize connectivity alterations of GWc-covariance networks by means of modularity, clustering coefficient, and degree. A cross-validated support vector machine was used to test the ability of GWc to stratify groups according to their depression symptoms, measured with BDI, at the single-subject level in MS and MDD independently. FINDINGS: MS and MDD patients showed increased modularity (ANOVA partial-η2 = 0.3) and clustering (partial-η2 = 0.1) compared to HC. In the subgroups, a linear trend analysis attested a gradient of modularity increases in the form: HC, dMS, nMS, SDE, and RDE (ANOVA partial-η2 = 0.28, p < 0.001) while this trend was less evident for clustering coefficient. Reduced morphological integrity (GWc) was seen in patients with increased depressive symptoms (partial-η2 = 0.42, P < 0.001) and was associated with depression scores across patient groups (r = -0.2, P < 0.001). Depressive symptoms in MS were robustly classified (88 %). CONCLUSIONS: Similar structural network alterations in MDD and MS exist, suggesting possible common inflammatory events like demyelination, neuroinflammation that are caught by GWc analyses. These alterations may vary depending on the severity of symptoms and in the case of MS may elucidate the occurrence of comorbid depression.

Gender differences in self-assessed performance and stress level during training of basic interventional radiology maneuvers.

OBJECTIVES: Gender differences have been reported to influence medical training. We investigated gender differences encountered during training in interventional radiology maneuvers. METHODS: Catheter handling was analyzed under standardized conditions in 64 participants naïve to endovascular procedures (26 women, 38 men). Objective (e.g., catheter pathway, catheter movements, required time) and subjective parameters (stress level) were recorded. The NASA-Task Load Index (NASA-TLX; 1-20 points) was used to assess participants' stress levels and perceived workload. RESULTS: In the easier tasks, no significant differences between male and female participants regarding catheter handling were observed. In the most complex task, female participants took themselves more time (688 ± 363 vs. 501 ± 230 s; p = 0.02), asked for help more frequently (n = 19 vs. n = 8) and earlier than men (203 ± 94 vs. 305 ± 142 s; p = 0.049), whereas men stood out by more agitated catheter handling (6.0 ± 1.8 vs. 4.8 ± 1.6 movements/s; p = 0.005). Overall, female participants perceived tasks to be more difficult (11.5 ± 4.2 vs. 9.6 ± 3.3; p = 0.016), perceived higher stress levels (8.9 ± 4.9 vs. 6.3 ± 4.4; p = 0.037), and rated their own performance lower (9.12 ± 3.3 vs. 11.3 ± 3.3; p = 0.009). However, female participants were able to correlate self-assessed with objective parameters correctly (r between -0.555 and -0.469; p = 0.004-0.018), whereas male participants failed to correctly rate their performance (p between 0.34 and 0.73). Stress levels correlated with objective parameters in males (r between 0.4 and 0.587; p < 0.005), but not in female participants. CONCLUSION: Perceived stress levels, self-evaluation skills, and catheter handling differ greatly between untrained male and female participants trying to solve interventional radiological tasks. These gender-specific differences should be considered in interventional radiology training. CLINICAL RELEVANCE STATEMENT: As psychological aspects may influence individual working strategies gender-specific differences in self-perception while learning interventional radiology maneuvers could be essential regarding success in teaching and treatment outcomes. KEY POINTS: • After performing standardized training, 38 male and 26 female volunteers showed significant differences regarding objective and self-assessed performance, as well as in perceived workload while performing simulated endovascular catheter maneuvers. • After solving simulated endovascular radiological tasks, female participants were able to self-assess their objective performance much more accurately than male participants. • Women took more time to solve simulated endovascular tasks and asked earlier and more frequently for help than men.

Unveiling the Antiviral Efficacy of Forskolin: A Multifaceted In Vitro and In Silico Approach.

Coleus forskohlii (Willd.) Briq. is a medicinal herb of the Lamiaceae family. It is native to India and widely present in the tropical and sub-tropical regions of Egypt, China, Ethiopia, and Pakistan. The roots of C. forskohlii are edible, rich with pharmaceutically bioactive compounds, and traditionally reported to treat a variety of diseases, including inflammation, respiratory disorders, obesity, and viral ailments. Notably, the emergence of viral diseases is expected to quickly spread; consequently, these data impose a need for various approaches to develop broad active therapeutics for utilization in the management of future viral infectious outbreaks. In this study, the naturally occurring labdane diterpenoid derivative, Forskolin, was obtained from Coleus forskohlii. Additionally, we evaluated the antiviral potential of Forskolin towards three viruses, namely the herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), hepatitis A virus (HAV), and coxsackievirus B4 (COX-B4). We observed that Forskolin displayed antiviral activity against HAV, COX-B4, HSV-1, and HSV-2 with IC50 values of 62.9, 73.1, 99.0, and 106.0 µg/mL, respectively. Furthermore, we explored the Forskolin's potential antiviral target using PharmMapper, a pharmacophore-based virtual screening platform. Forskolin's modeled structure was analyzed to identify potential protein targets linked to its antiviral activity, with results ranked based on Fit scores. Cathepsin L (PDB ID: 3BC3) emerged as a top-scoring hit, prompting further exploration through molecular docking and MD simulations. Our analysis revealed that Forskolin's binding mode within Cathepsin L's active site, characterized by stable hydrogen bonding and hydrophobic interactions, mirrors that of a co-crystallized inhibitor. These findings, supported by consistent RMSD profiles and similar binding free energies, suggest Forskolin's potential in inhibiting Cathepsin L, highlighting its promise as an antiviral agent.

Single Infrared Spectrum Enables Simultaneous Identification of (Bio)Chemical Nature and Particle Size of Microorganisms and Synthetic Microplastic Beads.

Populations of nearly identical chemical and biological microparticles include the synthetic microbeads used in cosmetic, biomedical, agri-food, and pharmaceutical industries as well as the class of living microorganisms such as yeast, pollen, and biological cells. Herein, we identify simultaneously the size and chemical nature of spherical microparticle populations with diameters larger than 1 µm. Our analysis relies on the extraction of both physical and chemical signatures from the same optical spectrum recorded using attenuated total reflection (ATR)-Fourier transform infrared (FTIR) spectroscopy. These signatures are the spectral resonances caused by the microparticles, which depend on their size and the absorption peaks revealing their chemical nature. We validate the method first on separated and mixed groups of spherical microplastic particles of two different diameters, where the method is used to calculate the diameter of the microspherical particles. Then, we apply the method to correctly identify and measure the diameter of Saccharomyces cerevisiae yeast cells. Theoretical simulations to help in understanding the effect of size distribution and dispersion support our results.

Deep Learning Reconstruction for Accelerated Spine MRI: Prospective Analysis of Interchangeability.

Background Deep learning (DL)-based MRI reconstructions can reduce examination times for turbo spin-echo (TSE) acquisitions. Studies that prospectively employ DL-based reconstructions of rapidly acquired, undersampled spine MRI are needed. Purpose To investigate the diagnostic interchangeability of an unrolled DL-reconstructed TSE (hereafter, TSEDL) T1- and T2-weighted acquisition method with standard TSE and to test their impact on acquisition time, image quality, and diagnostic confidence. Materials and Methods This prospective single-center study included participants with various spinal abnormalities who gave written consent from November 2020 to July 2021. Each participant underwent two MRI examinations: standard fully sampled T1- and T2-weighted TSE acquisitions (reference standard) and prospectively undersampled TSEDL acquisitions with threefold and fourfold acceleration. Image evaluation was performed by five readers. Interchangeability analysis and an image quality-based analysis were used to compare the TSE and TSEDL images. Acquisition time and diagnostic confidence were also compared. Interchangeability was tested using the individual equivalence index regarding various degenerative and nondegenerative entities, which were analyzed on each vertebra and defined as discordant clinical judgments of less than 5%. Interreader and intrareader agreement and concordance (κ and Kendall τ and W statistics) were computed and Wilcoxon and McNemar tests were used. Results Overall, 50 participants were evaluated (mean age, 46 years ± 18 [SD]; 26 men). The TSEDL method enabled up to a 70% reduction in total acquisition time (100 seconds for TSEDL vs 328 seconds for TSE, P < .001). All individual equivalence indexes were less than 4%. TSEDL acquisition was rated as having superior image noise by all readers (P < .001). No evidence of a difference was found between standard TSE and TSEDL regarding frequency of major findings, overall image quality, or diagnostic confidence. Conclusion The deep learning (DL)-reconstructed turbo spin-echo (TSE) method was found to be interchangeable with standard TSE for detecting various abnormalities of the spine at MRI. DL-reconstructed TSE acquisition provided excellent image quality, with a 70% reduction in examination time. German Clinical Trials Register no. DRKS00023278 © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Hallinan in this issue.

Free-breathing Arterial Spin Labeling MRI for the Detection of Pulmonary Embolism.

Background Arterial spin labeling (ASL) MRI can be used to assess organ perfusion but has yet to be implemented for perfusion evaluation of the lung. Purpose To evaluate pseudo-continuous ASL (PCASL) MRI for the detection of acute pulmonary embolism (PE) and its potential as an alternative to CT pulmonary angiography (CTPA). Materials and Methods Between November 2020 and November 2021, 97 patients (median age, 61 years; 48 women) with suspected PE were enrolled in this prospective study. PCASL MRI was performed within a 72-hour period following CTPA under free-breathing conditions and included three orthogonal planes. The pulmonary trunk was labeled during systole, and the image was acquired during diastole of the subsequent cardiac cycle. Additionally, multisection, coronal, balanced, steady-state free-precession imaging was carried out. Two radiologists blindly assessed overall image quality, artifacts, and diagnostic confidence (five-point Likert scale, 5 = best). Patients were categorized as positive or negative for PE, and a lobe-wise assessment in PCASL MRI and CTPA was conducted. Sensitivity and specificity were calculated on a patient level with the final clinical diagnosis serving as the reference standard. Interchangeability between MRI and CTPA was also tested with use of an individual equivalence index (IEI). Results PCASL MRI was performed successfully in all patients with high scores for image quality, artifact, and diagnostic confidence (κ ≥ .74). Of the 97 patients, 38 were positive for PE. PCASL MRI depicted PE correctly in 35 of 38 patients with three false-positive and three false-negative findings, resulting in a sensitivity of 35 of 38 patients (92% [95% CI: 79, 98]) and a specificity of 56 of 59 patients (95% [95% CI: 86, 99]). Interchangeability analysis revealed an IEI of 2.6% (95% CI: 1.2, 3.8). Conclusion Free-breathing pseudo-continuous arterial spin labeling MRI depicted abnormal lung perfusion caused by acute pulmonary embolism and may be useful as a contrast material-free alternative to CT pulmonary angiography for selected patients. German Clinical Trials Register no. DRKS00023599 © RSNA, 2023.

Liquid-Liquid Phase Separation Induced by Vapor Transfer in Evaporative Binary Sessile Droplets.

Drying of binary sessile droplets consisting of ethanol and octamethyltrisiloxane on a high-energy surface is investigated. During the process of evaporation, the droplets undergo liquid-liquid phase separation, resulting in the appearance of microdroplets at the liquid-air interface, which subsequently violently burst. This phase separation is attributed to water vapor transfer into the droplet, which modifies the solubility and leads to the formation of a ternary mixture. The newly formed ternary mixture may undergo nucleation and growth or spinodal decomposition, depending on the droplet composition path. By control of the relative humidity of air, phase separation can be mitigated or even eliminated. The droplets also display high mobility and complex wetting behavior due to phase separation, with two contracting and two spreading stages. The mass loss experiments reveal that the droplets undergo three distinct drying stages with an enhanced evaporation rate observed during the phase separation stage. A modified diffusion-limited model was employed to predict the evaporation rate, accounting for the physiochemical changes during evaporation and proved to be consistent with experimental observations. The findings of this work enhance our understanding of a coupled fundamental process involving the evaporation of multicomponent mixtures, wetting, and phase separation.

Scalloped pattern deposition during the spreading and drying of polymer droplets.

Droplets containing polyvinylpyrrolidone (PVP) dissolved in ethanol display a distinctive scalloped pattern at the rim while spreading and drying on a high-energy surface. Two distinct spreading regimes are observed, leading to the formation of a thin film with a uniform height that extends from the original droplet. An experimental study indicates polymer accumulation at the edge containing trace water, resulting in a surface tension gradient across the droplet, enhancing the droplet's spreading. This fast-spreading film develops a ridge at the contact line and becomes unstable. The influence of evaporation within the droplet shows no significant effect on the wavelength of the instability. Instead, the magnitude of the surface tension gradient and the surface energy of the substrate emerge as the dominant factors influencing the instability. This observation is validated by saturating the environment surrounding the droplet with ethanol vapour to reduce evaporation or employing solvents with low vapour pressure. Additionally, PVP in ethanol droplets deposited on hydrophobic substrates demonstrate a stable and pinned contact line, contrasting the behaviour observed on high-energy surfaces. By identifying the critical overlap concentration of the polymer, the transitional threshold between the scalloped instability and ringlike morphology is determined. The scalloped instability can be suppressed by removing residual water from the solution, eliminating the surface tension gradient, indicating that Marangoni forces are the underlying cause of the observed instability. The long-wave evolution equation, assuming a constant Marangoni shear flow, accurately predicts the most unstable wavelength, demonstrating good agreement with experimental observations.

Oligomeric Proanthocyanidin Complex from Avocado Seed as A Promising α-glucosidase Inhibitor: Characteristics and Mechanisms.

Although considered an abundant source of agricultural by-products, avocado (Persea americana Mill.) seed, with several biological activities and bioactive components, might become a promising resource for phytopharmaceutical development. In this study, through bioassay-guided isolation of the main α-glucosidase inhibitors in avocado seed, we discovered the major α-glucosidase inhibitor to be avocado seed oligomeric proanthocyanidin complex (ASOPC). Thiolysis and UPLC-DAD-HRESIMS showed the presence of A- and B-type procyanidins, and B-type propelargonidin with (epi)afzelechin as extension unit. Mean degree of polymerization (mDP) of ASOPC was calculated as 7.3 ± 1. Furthermore, ASOPC appeared to be a strong, reversible, competitive inhibitor of α-glucosidase, with IC50 value of 0.1 µg/mL, which was significantly lower than Acarbose (IC50 = 75.6 µg/mL), indicated that ASOPC is a potential natural α-glucosidase inhibitor. These findings would contribute to the direction of utilizing avocado seed bioactive components with the possibility to be used as natural anti-diabetic agents.

Prospective intraindividual comparison of a standard 2D TSE MRI protocol for ankle imaging and a deep learning-based 2D TSE MRI protocol with a scan time reduction of 48.

PURPOSE: Magnetic resonance imaging (MRI) scan time remains a limited and valuable resource. This study evaluates the diagnostic performance of a deep learning (DL)-based accelerated TSE study protocol compared to a standard TSE study protocol in ankle MRI. MATERIAL AND METHODS: Between October 2020 and July 2021 forty-seven patients were enrolled in this study for an intraindividual comparison of a standard TSE study protocol and a DL TSE study protocol either on a 1.5 T or a 3 T scanner. Two radiologists evaluated the examinations regarding structural pathologies and image quality categories (5-point-Likert-scale; 1 = "non diagnostic", 5 = "excellent"). RESULTS: Both readers showed almost perfect/perfect agreement of DL TSE with standard TSE in all analyzed structural pathologies (0.81-1.00) with a median "good" or "excellent" rating (4-5/5) in all image quality categories in both 1.5 T and 3 T MRI. The reduction of total acquisition time of DL TSE compared to standard TSE was 49% in 1.5 T and 48% in 3 T MRI to a total acquisition time of 5 min 41 s and 5 min 46 s. CONCLUSION: In ankle MRI the new DL-based accelerated TSE study protocol delivers high agreement with standard TSE and high image quality, while reducing the acquisition time by 48%.

Feasibility of an accelerated 2D-multi-contrast knee MRI protocol using deep-learning image reconstruction: a prospective intraindividual comparison with a standard MRI protocol.

OBJECTIVES: The aim of this study was to evaluate the image quality and diagnostic performance of a deep-learning (DL)-accelerated two-dimensional (2D) turbo spin echo (TSE) MRI of the knee at 1.5 and 3 T in clinical routine in comparison to standard MRI. MATERIAL AND METHODS: Sixty participants, who underwent knee MRI at 1.5 and 3 T between October/2020 and March/2021 with a protocol using standard 2D-TSE (TSES) and DL-accelerated 2D-TSE sequences (TSEDL), were enrolled in this prospective institutional review board-approved study. Three radiologists assessed the sequences regarding structural abnormalities and evaluated the images concerning overall image quality, artifacts, noise, sharpness, subjective signal-to-noise ratio, and diagnostic confidence using a Likert scale (1-5, 5 = best). RESULTS: Overall image quality for TSEDL was rated to be excellent (median 5, IQR 4-5), significantly higher compared to TSES (median 5, IQR 4 - 5, p < 0.05), showing significantly lower extents of noise and improved sharpness (p < 0.001). Inter- and intra-reader agreement was almost perfect (κ = 0.92-1.00) for the detection of internal derangement and substantial to almost perfect (κ = 0.58-0.98) for the assessment of cartilage defects. No difference was found concerning the detection of bone marrow edema and fractures. The diagnostic confidence of TSEDL was rated to be comparable to that of TSES (median 5, IQR 5-5, p > 0.05). Time of acquisition could be reduced to 6:11 min using TSEDL compared to 11:56 min for a protocol using TSES. CONCLUSION: TSEDL of the knee is clinically feasible, showing excellent image quality and equivalent diagnostic performance compared to TSES, reducing the acquisition time about 50%. KEY POINTS: • Deep-learning reconstructed TSE imaging is able to almost halve the acquisition time of a three-plane knee MRI with proton density and T1-weighted images, from 11:56 min to 6:11 min at 3 T. • Deep-learning reconstructed TSE imaging of the knee provided significant improvement of noise levels (p < 0.001), providing higher image quality (p < 0.05) compared to conventional TSE imaging. • Deep-learning reconstructed TSE imaging of the knee had similar diagnostic performance for internal derangement of the knee compared to standard TSE.

Efficacy of Upadacitinib in a Randomized Trial of Patients With Active Ulcerative Colitis.

BACKGROUND & AIMS: We evaluated the efficacy and safety of upadacitinib, an oral selective inhibitor of Janus kinase 1, as induction therapy for ulcerative colitis (UC). METHODS: We performed a multicenter, double-blind, phase 2b study of 250 adults with moderately to severely active UC and an inadequate response, loss of response, or intolerance to corticosteroids, immunosuppressive agents, and/or biologic therapies. Patients were randomly assigned to groups that received placebo or induction therapy with upadacitinib (7.5 mg, 15 mg, 30 mg, or 45 mg, extended release), once daily for 8 weeks. The primary endpoint was the proportion of participants who achieve clinical remission according to the adapted Mayo score at week 8. No multiplicity adjustments were applied. RESULTS: At week 8, 8.5%, 14.3%, 13.5%, and 19.6% of patients receiving 7.5 mg, 15 mg, 30 mg, or 45 mg upadacitinib, respectively, achieved clinical remission compared with none of the patients receiving placebo (P = .052, P = .013, P = .011, and P = .002 compared with placebo, respectively). Endoscopic improvement at week 8, defined as endoscopic subscore of ≤ 1, was achieved in 14.9%, 30.6%, 26.9%, and 35.7% of patients receiving upadacitinib 7.5 mg, 15 mg, 30 mg, or 45 mg, respectively, compared with 2.2% receiving placebo (P = .033, P < .001, P < .001, and P < .001 compared with placebo, respectively). One event of herpes zoster and 1 participant with pulmonary embolism and deep venous thrombosis (diagnosed 26 days after treatment discontinuation) were reported in the group that received upadacitinib 45 mg once daily. Increases in serum lipid levels and creatine phosphokinase with upadacitinib were observed. CONCLUSION: In a phase 2b trial, 8 weeks of treatment with upadacitinib was more effective than placebo for inducing remission in patients with moderately to severely active UC. (ClinicalTrials.gov, Number: NCT02819635).

Efficacy and Safety of Upadacitinib in a Randomized Trial of Patients With Crohn's Disease.

BACKGROUND & AIMS: We evaluated the efficacy and safety of upadacitinib, an oral selective Janus kinase 1 inhibitor, in a randomized trial of patients with Crohn's disease (CD). METHODS: We performed a double-blind, phase 2 trial in adults with moderate to severe CD and inadequate response or intolerance to immunosuppressants or tumor necrosis factor antagonists. Patients were randomly assigned (1:1:1:1:1:1) to groups given placebo; or 3 mg, 6 mg, 12 mg, or 24 mg upadacitinib twice daily; or 24 mg upadacitinib once daily and were evaluated by ileocolonoscopy at weeks 12 or 16 of the induction period. Patients who completed week 16 were re-randomized to a 36-week period of maintenance therapy with upadacitinib. The primary endpoints were clinical remission at week 16 and endoscopic remission at week 12 or 16 using the multiple comparison procedure and modeling and the Cochran-Mantel-Haenszel test, with a 2-sided level of 10%. RESULTS: Among the 220 patients in the study, clinical remission was achieved by 13% of patients receiving 3 mg upadacitinib, 27% of patients receiving 6 mg upadacitinib (P < .1 vs placebo), 11% of patients receiving 12 mg upadacitinib, and 22% of patients receiving 24 mg upadacitinib twice daily, and by 14% of patients receiving 24 mg upadacitinib once daily, vs 11% of patients receiving placebo. Endoscopic remission was achieved by 10% (P < .1 vs placebo), 8%, 8% (P < .1 vs placebo), 22% (P < .01 vs placebo), and 14% (P < .05 vs placebo) of patients receiving upadacitinib, respectively, vs none of the patients receiving placebo. Endoscopic but not clinical remission increased with dose during the induction period. Efficacy was maintained for most endpoints through week 52. During the induction period, patients in the upadacitinib groups had higher incidences of infections and serious infections vs placebo. Patients in the twice-daily 12 mg and 24 mg upadacitinib groups had significant increases in total, high-density lipoprotein, and low-density lipoprotein cholesterol levels compared with patients in the placebo group. CONCLUSIONS: In a phase 2 trial of patients with CD, upadacitinib induced endoscopic remission in a significant proportion of patients compared with placebo. Upadacitinib's benefit/risk profile supports further development for treatment of CD. (Clinicaltrials.gov, Number: NCT02365649).

Contemporary results of open thoracic and thoracoabdominal aortic surgery in a single United Kingdom center.

OBJECTIVE: To report our outcomes and identify predictors of mortality after open descending thoracic aneurysm (DTA) and thoracoabdominal aortic aneurysm (TAAA) repair in a specialist aortic center. METHODS: This retrospective observational cohort study included consecutive patients who underwent surgery at our institution between October 1998 and December 2019. The main outcome measures were mortality and major morbidities. A multivariate analysis was used to identify predictors of mortality. RESULTS: There were 430 patients who underwent DTA (n = 157) and TAA (n = 273) repair; 151 underwent surgery nonelectively. Forty-eight patients (11%) died within 30 days of surgery. The 30-day mortality was lower after elective surgery (3.1% after DTA repair and 9.9% after TAAA repair), whereas nonelective surgery had a 30-day mortality of 17.9%. Fourteen additional patients died in hospital after 30 days, one after nonelective DTA repair and 13 after TAAA repair (10 elective), all but one extent II. In-hospital mortality for the whole cohort improved over time, as the activity volume increased, except for patients undergoing extent II TAAA repair. Predictors of in-hospital mortality were age ≥70 years (odds ratio [OR], 3.36; 95% confidence interval [CI], 1.79-6.32; P < .001), extent II repair (OR, 4.39; 95% CI, 2.34-8.21; P < .001), nonelective surgery (OR, 2.72; 95% CI, 1.44, 5.12; P = .002), out-of-hours surgery (OR, 8.17; 95% CI, 2.16-30.95; P = .002), a left ventricular ejection fraction of <30% (OR, 9.86; 95% CI, 1.91-50.86; P < .006), and surgery for a degenerative aneurysm (OR, 2.20; 95% CI, 1.12-4.31; P = .02). The incidence of stroke and paraplegia was 7.1% and 0% after DTA repair and 9.9% and 3.3% after TAAA repair. Hemodialysis was necessary in 5.1% of cases after DTA repair and 22.7% after TAAA repair. CONCLUSIONS: Open thoracoabdominal aortic surgery carries significant risk to life, which is related to age, extent of aortic replacement, timing of surgery, and left ventricular function. Morbidity is considerable. Understanding these risks is fundamental for patient selection and the consent process of potential candidates for surgery, particularly in the elderly.

Systematic approach to diagnosis and management of infected prosthetic grafts in the proximal aorta.

OBJECTIVES: Management of infected prosthetic aortic grafts in the ascending and or root is complex and multifaceted. We report our diagnostic pathway, management and outcomes, identifying successful strategies. METHODS: This was a retrospective, single center, observational study. Consecutive patients who underwent management of infected aortic grafts in the ascending and/or root at our institution between October 1998 and December 2019 were included. The main outcome measures were: discharge from hospital alive with at least 1 year survival, operative mortality and success of primary treatment strategy. RESULTS: Twenty-six patients presented with infection of proximal aortic grafts and were managed through a number of strategies with an overall hospital-survival of 81% and 1 year survival of 69%. Twenty of them ultimately underwent redo surgery with 25% operative mortality (within 24 h of surgery). Five patients underwent washout and irrigation of which two were successfully treated and cured with adjunctive antibiotics and two went on to have staged explant and definitive surgery. Interval between surgery and infection was 42.5 ± 35.8 months. All patients had at least one major criterion and three minor criterions with no diagnostic uncertainty. The commonest primary strategy was 3a (definitive surgery), (13/26, 50%). CONCLUSIONS: Adopting a systematic and flexible patient specific approach to the diagnosis and management of patients with proximal aortic graft infections results in reasonable overall 1 year survival. In the majority of patients surgery is ultimately required in an attempt to achieve a curative treatment; however this comes with high operative mortality risk.

COVID-19 and cardiac surgery: A perspective from United Kingdom.

The emergence of severe acute respiratory syndrome coronavirus 2 in December 2019, presumed from the city of Wuhan, Hubei province in China, and the subsequent declaration of the disease as a pandemic by the World Health Organization as coronavirus disease 2019 (COVID-19) in March 2020, had a significant impact on health care systems globally. Each country responded to this disease in different ways, however this was done broadly by fortifying and prioritizing health care provision as well as introducing social lockdown aiming to contain the infection and minimizing the risk of transmission. In the United Kingdom, a lockdown was introduced by the government on March 23, 2020 and all health care services were focussed to challenge the impact of COVID-19. To do so, the United Kingdom National Health Service had to undergo widespread service reconfigurations and the so-called "Nightingale Hospitals" were created de novo to bolster bed provision, and industries were asked to direct efforts to the production of ventilators. A government-led public health campaign was publicized under the slogan of: "Stay home, Protect the NHS (National Health Service), Save lives." The approach had a significant impact on the delivery of all surgical services but particularly cardiac surgery with its inherent critical care bed capacity. This paper describes the impact on provision for elective and emergency cardiac surgery in the United Kingdom, with a focus on aortovascular disease. We describe our aortovascular activity and outcomes during the period of UK lockdown and present a patient survey of attitudes to aortic surgery during COVID-19 pandemic.

[Primary treatment of prostate cancer using 1.5 T MR-linear accelerator]. / Stellenwert des 1,5-T-MR-Linearbeschleunigers für die primäre Therapie des Prostatakarzinoms.

BACKGROUND: Hybrid devices of MR-scanners and linear accelerators (MR-Linacs) represent a new and promising extension of radiotherapeutic options for prostate cancer. The potential advantage of magnetic resonance imaging (MRI) over computed tomography (CT) for soft tissue contrast is well-known and leads to more consistent and smaller target volumes and improved normal tissue sparing. OBJECTIVES: This article presents an overview of clinical experience, indications, advantages and challenges of utilizing a 1.5 T MR-Linac in the setting of radiotherapy of prostate cancer. RESULTS: All current indications for radiotherapy of prostate cancer can be treated with an MR-Linac. The advantages include daily MR-based imaging in treatment position and daily adaption of the treatment plan on current anatomy (adaptive radiotherapy). Additionally, functional MRI sequences might be exploited to enhance treatment individualization and response assessment. Ultimately treatment on an MR-Linac might further increase the therapeutic window. The limitations of using MR-Linac include treatment complexity and the duration of each session. CONCLUSIONS: MR-Linacs expand the spectrum of radiotherapeutic options for prostate cancer. Increased precision can be reached with daily MRI-based target volume definition and plan adaption. Clinical studies are necessary to identify patient groups who would benefit most from radiotherapy on a MR-Linac.

Upadacitinib in adults with moderate to severe atopic dermatitis: 16-week results from a randomized, placebo-controlled trial.

BACKGROUND: Atopic dermatitis is a chronic inflammatory skin disease characterized by pruritic skin lesions. OBJECTIVE: We sought to evaluate the safety and efficacy of multiple doses of the selective Janus kinase 1 inhibitor upadacitinib in patients with moderate to severe atopic dermatitis. METHODS: In the 16-week, double-blind, placebo-controlled, parallel-group, dose-ranging portion of this 88-week trial in 8 countries (ClinicalTrials.gov, NCT02925117; ongoing, not recruiting), adults with moderate to severe disease and inadequate control by topical treatment were randomized 1:1:1:1, using an interactive response system and stratified geographically, to once-daily upadacitinib oral monotherapy 7.5, 15, or 30 mg or placebo. The primary end point was percentage improvement in Eczema Area and Severity Index from baseline at week 16. Efficacy was analyzed by intention-to-treat in all randomized patients. Safety was analyzed in all randomized patients who received study medication, based on actual treatment. RESULTS: Patients (N = 167) enrolled from November 21, 2016, to April 20, 2017. All were randomized and analyzed for efficacy (each upadacitinib group, n = 42; placebo, n = 41); 166 were analyzed for safety (each upadacitinib group, n = 42; placebo, n = 40). The mean (SE) primary efficacy end point was 39% (6.2%), 62% (6.1%), and 74% (6.1%) for the upadacitinib 7.5-, 15-, and 30-mg groups, respectively, versus 23% (6.4%) for placebo (P = .03, <.001, and <.001). Serious adverse events occurred in 4.8% (2 of 42), 2.4% (1 of 42), and 0% (0 of 42) of upadacitinib groups (vs 2.5% [1 of 40] for placebo). CONCLUSIONS: A dose-response relationship was observed for upadacitinib efficacy; the 30-mg once-daily dose showed the greatest clinical benefit. Dose-limiting toxicity was not observed.