First Results on the Presence of Mycotoxins in the Liver of Pregnant Fallow Deer (Dama dama) Hinds and Fetuses.

Reproductive abnormalities have been observed in fallow deer populations in Hungary. We supposed mycotoxin contamination to be one of the possible causes because multi-mycotoxin contamination is known to be dangerous even at low toxin levels, especially for young animals. We investigated the spatial pattern of mycotoxin occurrences and the relationship between maternal and fetal mycotoxin levels. A total of 72 fallow deer embryos and their mothers were sampled in seven forested regions in Hungary in the 2020/2021 hunting season. We analyzed Aflatoxin (AF), Zearalenone (ZEA), Fumonizin B1 (FB1), DON, and T2-toxin concentrations in maternal and fetal livers by ELISA. AF was present in 70% and 82%, ZEA in 41% and 96%, DON in 90% and 98%, T2-toxin in 96% and 85%, and FB1 in 84% and 3% of hind and fetus livers, respectively. All mycotoxins passed into the fetus, but only Fumonizin B1 rarely passed. The individual variability of mycotoxin levels was extremely high, but the spatial differences were moderate. We could not prove a relation between the maternal and fetal mycotoxin concentrations, but we found an accumulation of ZEA and DON in the fetuses. These results reflect the possible threats of mycotoxins to the population dynamics and reproduction of wild fallow deer.

Computed Tomography to Exclude Cardiac Thrombus in Atrial Fibrillation-An 11-Year Experience from an Academic Emergency Department.

BACKGROUND: Computed tomography (CT) could be a suitable method for acute exclusion of left atrial appendage thrombus (LAAT) prior to cardioversion of atrial fibrillation (AF) and atrial flutter (AFL) at the emergency department. Our aim was to present our experiences with this modality in recent years. METHODS: This registry-based observational study was performed at the Department of Emergency Medicine at the Medical University of Vienna, Austria. We studied all consecutive patients with AF and AFL who underwent CT between January 2012 and January 2023 to rule out LAAT before cardioversion to sinus rhythm was attempted. Follow-ups were conducted by telephone and electronic medical records. The main variables of interest were the rate of LAAT and ischemic stroke at follow-up. RESULTS: A total of 234 patients (143 [61%] men; median age 68 years [IQR 57-76], median CHA2DS2-VASc 2 [IQR 1-4]) were analyzed. Follow-up was completed in 216 (92%) patients after a median of 506 (IQR 159-1391) days. LAAT was detected in eight patients (3%). A total of 163 patients (72%) in whom LAAT was excluded by CT were eventually successfully cardioverted to sinus rhythm. No adverse events occurred during their ED stay. All patients received anticoagulation according to the CHA2DS2-VASc risk stratification, and no patient had suffered an ischemic stroke at follow-up, resulting in an incidence risk of ischemic strokes of 0% (95% CI 0.0-1.2%). CONCLUSION: LAAT was rare in patients admitted to the ED with AF and AFL who underwent cardiac CT prior to attempted cardioversion. At follow-up, no patient had suffered an ischemic stroke. Prospective studies need to show whether this strategy is suitable for the acute treatment of symptomatic AF in the emergency setting.

Dynamic Perviousness Predicts Revascularization Success in Acute Ischemic Stroke.

BACKGROUND: The predictive value of thrombus perviousness in acute ischemic stroke (AIS), as measured by computed tomography (CT), has been intensively studied with conflicting results. In this study, we investigate the predictive potential of the novel concept of dynamic perviousness using three-dimensional (3D) volumetric evaluation of occlusive thrombi. METHODS: The full thrombus volume in 65 patients with a hyperdense artery sign on non-contrast CT (NCCT), who underwent mechanical thrombectomy (MT), was segmented. Perviousness maps were computed voxel-wise for the entire thrombus volume as thrombus attenuation increase (TAI) between NCCT and CT angiography (CTA) as well as between CTA and late venous phase CT (CTV). Perviousness was analyzed for its association with NIHSS at admission, Thrombolysis In Cerebral Infarction (TICI) score, and number of MT passes. RESULTS: The mean late-uptake TAI of thrombi with NIHSS scores greater than 21 at admission was approximately 100% higher than for lower scored NIHSS (p between 0.05 and 0.005). Concerning revascularization results, thrombi requiring less than four MT passes had ca. 80% higher group mean late-uptake TAI than clots requiring four or more passes (p = 0.03), and thrombi with TICI score III had ca. 95% higher group mean late-uptake TAI than thrombi with TICI II (p = 0.03). Standard perviousness showed no significant correlation with MT results. CONCLUSION: Standard thrombus perviousness of 3D clot volume is not associated with revascularization results in AIS. In contrast, dynamic perviousness assessed with a voxel-wise characterization of 3D thrombi volume may be a better predictor of MT outcomes than standard perviousness.

Effect of hormone-induced plasma membrane phosphatidylinositol 4,5-bisphosphate depletion on receptor endocytosis suggests the importance of local regulation in phosphoinositide signaling.

Phosphatidylinositol 4,5-bisphosphate (PIP2) has been shown to be critical for the endocytosis of G protein-coupled receptors (GPCRs). We have previously demonstrated that depletion of PIP2 by chemically induced plasma membrane (PM) recruitment of a 5-phosphatase domain prevents the internalization of the ß2 adrenergic receptor (ß2AR) from the PM to early endosomes. In this study, we tested the effect of hormone-induced PM PIP2 depletion on ß2AR internalization using type-1 angiotensin receptor (AT1R) or M3 muscarinic acetylcholine receptor (M3R). We followed the endocytic route of ß2ARs in HEK 293T cells using bioluminescence resonance energy transfer between the receptor and endosome marker Rab5. To compare the effect of lipid depletion by different means, we created and tested an AT1R fusion protein that is capable of both recruitment-based and hormone-induced depletion methods. The rate of PM PIP2 depletion was measured using a biosensor based on the PH domain of phospholipase Cδ1. As expected, ß2AR internalization was inhibited when PIP2 depletion was evoked by recruiting 5-phosphatase to PM-anchored AT1R. A similar inhibition occurred when wild-type AT1R was activated by adding angiotensin II. However, stimulation of the desensitization/internalization-impaired mutant AT1R (TSTS/4A) caused very little inhibition of ß2AR internalization, despite the higher rate of measurable PIP2 depletion. Interestingly, inhibition of PIP2 resynthesis with the selective PI4KA inhibitor GSK-A1 had little effect on the change in PH-domain-measured PM PIP2 levels but did significantly decrease ß2AR internalization upon either AT1R or M3R activation, indicating the importance of a locally synthetized phosphoinositide pool in the regulation of this process.

Role of Conformational Dynamics of Sulfotransferases SULT1A1 and SULT1A3 in Substrate Specificity.

Sulfotransferases (SULTs) are phase II metabolizing enzymes catalyzing the sulfoconjugation from the co-factor 3'-Phosphoadenosine 5'-Phosphosulfate (PAPS) to a wide variety of endogenous compounds, drugs and natural products. Although SULT1A1 and SULT1A3 share 93% identity, SULT1A1, the most abundant SULT isoform in humans, exhibits a broad substrate range with specificity for small phenolic compounds, while SULT1A3 displays a high affinity toward monoamine neurotransmitters like dopamine. To elucidate the factors determining the substrate specificity of the SULT1 isoenzymes, we studied the dynamic behavior and structural specificities of SULT1A1 and SULT1A3 by using molecular dynamics (MD) simulations and ensemble docking of common and specific substrates of the two isoforms. Our results demonstrated that while SULT1A1 exhibits a relatively rigid structure by showing lower conformational flexibility except for the lip (loop L1), the loop L2 and the cap (L3) of SULT1A3 are extremely flexible. We identified protein residues strongly involved in the recognition of different substrates for the two isoforms. Our analyses indicated that being more specific and highly flexible, the structure of SULT1A3 has particularities in the binding site, which are crucial for its substrate selectivity.

Feasibility and safety of cavotricuspid isthmus ablation using exclusive intracardiac echocardiography guidance: a proof-of-concept, observational trial.

Introduction: Catheter ablation is the preferred treatment for typical atrial flutter (AFl), but it can be challenging due to anatomical abnormalities. The use of 3D electroanatomical mapping systems (EAMS) has reduced fluoroscopy exposure during AFl ablation. Intracardiac echocardiography (ICE) has also shown benefits in reducing radiation exposure during AFl ablation. However, there is a lack of evidence on the feasibility of ICE-guided, zero-fluoroscopy AFl ablation without the use of EAMS. Methods: In this prospective study, we enrolled 80 patients with CTI-dependent AFl. The first 40 patients underwent standard fluoroscopy + ICE-guided ablation (Standard ICE group), while the other 40 patients underwent zero-fluoroscopy ablation using only ICE (Zero ICE group). Procedure outcomes, including acute success, procedure time, fluoroscopy time, radiation dose, and complications, were compared between the groups. Results: The acute success rate was 100% in both groups. Out of the 40 cases, the zero-fluoroscopy strategy was successfully implemented in 39 cases (97.5%) in the Zero ICE group. There were no significant differences in procedure time [55.5 (46.5; 66.8) min vs. 51.5 (44.0; 65.5), p = 0.50] and puncture to first ablation time [18 (13.5; 23) min vs. 19 (15; 23.5) min, p = 0.50] between the groups. The Zero ICE group had significantly lower fluoroscopy time [57 (36.3; 90) sec vs. 0 (0; 0) sec, p < 0.001] and dose [3.17 (2.27; 5.63) mGy vs. 0 (0; 0) mGy, p < 0.001] compared to the Standard ICE group. Total ablation time was longer in the Standard ICE group [597 (447; 908) sec vs. 430 (260; 750), p = 0.02], but total ablation energy [22,458 (14,836; 31,116) Ws vs. 17,043 (10,533; 29,302) Ws, p = 0.10] did not differ significantly. First-pass bidirectional conduction block of the CTI and acute reconnection rates were similar between the groups. No complications or recurrences were observed during the follow-up period. Conclusion: Our study suggests that zero-fluoroscopy CTI ablation guided solely by ICE for AFl is feasible and safe. Further investigation is warranted for broader validation.

Intracardiac Echocardiography Guidance Improves Procedural Outcomes in Patients Undergoing Cavotricuspidal Isthmus Ablation for Typical Atrial Flutter.

Atrial flutter (AFL) represents a prevalent variant of supraventricular tachycardia, distinguished by a macro-reentrant pathway encompassing the cavotricuspid isthmus (CTI). Radiofrequency (RF) catheter ablation stands as the favored therapeutic modality for managing recurring CTI-dependent AFL. Intracardiac echocardiography (ICE) has been proposed as a method to reduce radiation exposure during CTI ablation. This study aims to comprehensively compare procedural parameters between ICE-guided CTI ablation and fluoroscopy-only procedures. A total of 370 consecutive patients were enrolled in our single-center retrospective study. In 151 patients, procedures were performed using fluoroscopy guidance only, while 219 patients underwent ICE-guided CTI ablation. ICE guidance significantly reduced fluoroscopy time (73 (36; 175) s vs. 900 (566; 1179) s; p < 0.001), fluoroscopy dose (2.45 (0.6; 5.1) mGy vs. 40.5 (25.7; 62.9) mGy; p < 0.001), and total procedure time (70 (52; 90) min vs. 87.5 (60; 102.5) min; p < 0.001). Total ablation time (657 (412; 981) s vs. 910 (616; 1367) s; p < 0.001) and the time from the first to last ablation (20 (11; 36) min vs. 40 (25; 55) min; p < 0.01) were also significantly shorter in the ICE-guided group. Acute success rate was 100% in both groups, and no major complications occurred in either group. ICE-guided CTI ablation in patients with AFL resulted in shorter procedure times, reduced fluoroscopy exposure, and decreased ablation times, compared to the standard fluoroscopy-only approach.

Spatio-temporal classification for polyp diagnosis.

Colonoscopy remains the gold standard investigation for colorectal cancer screening as it offers the opportunity to both detect and resect pre-cancerous polyps. Computer-aided polyp characterisation can determine which polyps need polypectomy and recent deep learning-based approaches have shown promising results as clinical decision support tools. Yet polyp appearance during a procedure can vary, making automatic predictions unstable. In this paper, we investigate the use of spatio-temporal information to improve the performance of lesions classification as adenoma or non-adenoma. Two methods are implemented showing an increase in performance and robustness during extensive experiments both on internal and openly available benchmark datasets.

Identifying key mechanisms leading to visual recognition errors for missed colorectal polyps using eye-tracking technology.

BACKGROUND AND AIM: Lack of visual recognition of colorectal polyps may lead to interval cancers. The mechanisms contributing to perceptual variation, particularly for subtle and advanced colorectal neoplasia, have scarcely been investigated. We aimed to evaluate visual recognition errors and provide novel mechanistic insights. METHODS: Eleven participants (seven trainees and four medical students) evaluated images from the UCL polyp perception dataset, containing 25 polyps, using eye-tracking equipment. Gaze errors were defined as those where the lesion was not observed according to eye-tracking technology. Cognitive errors occurred when lesions were observed but not recognized as polyps by participants. A video study was also performed including 39 subtle polyps, where polyp recognition performance was compared with a convolutional neural network. RESULTS: Cognitive errors occurred more frequently than gaze errors overall (65.6%), with a significantly higher proportion in trainees (P = 0.0264). In the video validation, the convolutional neural network detected significantly more polyps than trainees and medical students, with per-polyp sensitivities of 79.5%, 30.0%, and 15.4%, respectively. CONCLUSIONS: Cognitive errors were the most common reason for visual recognition errors. The impact of interventions such as artificial intelligence, particularly on different types of perceptual errors, needs further investigation including potential effects on learning curves. To facilitate future research, a publicly accessible visual perception colonoscopy polyp database was created.

Computer-aided characterization of early cancer in Barrett's esophagus on i-scan magnification imaging: a multicenter international study.

BACKGROUND AND AIMS: We aimed to develop a computer-aided characterization system that could support the diagnosis of dysplasia in Barrett's esophagus (BE) on magnification endoscopy. METHODS: Videos were collected in high-definition magnification white-light and virtual chromoendoscopy with i-scan (Pentax Hoya, Japan) imaging in patients with dysplastic and nondysplastic BE (NDBE) from 4 centers. We trained a neural network with a Resnet101 architecture to classify frames as dysplastic or nondysplastic. The network was tested on 3 different scenarios: high-quality still images, all available video frames, and a selected sequence within each video. RESULTS: Fifty-seven patients, each with videos of magnification areas of BE (34 dysplasia, 23 NDBE), were included. Performance was evaluated by a leave-1-patient-out cross-validation method. In all, 60,174 (39,347 dysplasia, 20,827 NDBE) magnification video frames were used to train the network. The testing set included 49,726 i-scan-3/optical enhancement magnification frames. On 350 high-quality still images, the network achieved a sensitivity of 94%, specificity of 86%, and area under the receiver operator curve (AUROC) of 96%. On all 49,726 available video frames, the network achieved a sensitivity of 92%, specificity of 82%, and AUROC of 95%. On a selected sequence of frames per case (total of 11,471 frames), we used an exponentially weighted moving average of classifications on consecutive frames to characterize dysplasia. The network achieved a sensitivity of 92%, specificity of 84%, and AUROC of 96%. The mean assessment speed per frame was 0.0135 seconds (SD ± 0.006). CONCLUSION: Our network can characterize BE dysplasia with high accuracy and speed on high-quality magnification images and sequence of video frames, moving it toward real-time automated diagnosis.

Single-antiplatelet regimen in ruptured cerebral blood blister and dissecting aneurysms treated with flow-diverter stent reconstruction.

BACKGROUND: Flow diversion treatment of ruptured cerebral aneurysms remains challenging due to the need for double-antiplatelet therapy. We report our experience with flow-diverter stent (FDS) reconstruction with single-antiplatelet therapy of ruptured cerebral blood blister and dissecting aneurysms. METHODS: In this case series we performed a retrospective analysis of all patients with ruptured cerebral aneurysms who were treated with a phosphoryl-bonded FDS between 2019 and 2022 in a single center. Periprocedurally, all patients received weight-adapted eptifibatide IV and heparin IV. After 6-24 hours, eptifibatide was switched to oral prasugrel as monotherapy. We analyzed the rate of bleeding complications, thromboembolic events, occlusion rate and clinical outcome. RESULTS: Nine patients with subarachnoid hemorrhage were treated, eight within 24 hours of symptom onset. Seven patients were treated with one FDS and two patients received two FDS in a telescopic fashion. Two aneurysms were additionally coil embolized. Fatal re-rupture occurred in one case; eight patients survived and had no adverse events associated with the FDS. Six patients showed complete occlusion of the aneurysm after 3 months (n=2) and 1 year (n=4), respectively. Two patients showed subtotal occlusion of the aneurysm at the last follow-up after 3 months and 6 months, respectively. Favorable clinical outcome was achieved in five patients. CONCLUSIONS: Peri-interventional single-antiplatelet therapy with eptifibatide followed by prasugrel was sufficient to prevent thromboembolic events and reduce re-bleeding using an anti-thrombogenic FDS. FDS with single-antiplatelet therapy might be a viable option for ruptured blood blister and dissecting cerebral aneurysms.

Polyp characterization using deep learning and a publicly accessible polyp video database.

OBJECTIVES: Convolutional neural networks (CNN) for computer-aided diagnosis of polyps are often trained using high-quality still images in a single chromoendoscopy imaging modality with sessile serrated lesions (SSLs) often excluded. This study developed a CNN from videos to classify polyps as adenomatous or nonadenomatous using standard narrow-band imaging (NBI) and NBI-near focus (NBI-NF) and created a publicly accessible polyp video database. METHODS: We trained a CNN with 16,832 high and moderate quality frames from 229 polyp videos (56 SSLs). It was evaluated with 222 polyp videos (36 SSLs) across two test-sets. Test-set I consists of 14,320 frames (157 polyps, 111 diminutive). Test-set II, which is publicly accessible, 3317 video frames (65 polyps, 41 diminutive), which was benchmarked with three expert and three nonexpert endoscopists. RESULTS: Sensitivity for adenoma characterization was 91.6% in test-set I and 89.7% in test-set II. Specificity was 91.9% and 88.5%. Sensitivity for diminutive polyps was 89.9% and 87.5%; specificity 90.5% and 88.2%. In NBI-NF, sensitivity was 89.4% and 89.5%, with a specificity of 94.7% and 83.3%. In NBI, sensitivity was 85.3% and 91.7%, with a specificity of 87.5% and 90.0%, respectively. The CNN achieved preservation and incorporation of valuable endoscopic innovations (PIVI)-1 and PIVI-2 thresholds for each test-set. In the benchmarking of test-set II, the CNN was significantly more accurate than nonexperts (13.8% difference [95% confidence interval 3.2-23.6], P = 0.01) with no significant difference with experts. CONCLUSIONS: A single CNN can differentiate adenomas from SSLs and hyperplastic polyps in both NBI and NBI-NF. A publicly accessible NBI polyp video database was created and benchmarked.

Polyp detection on video colonoscopy using a hybrid 2D/3D CNN.

Colonoscopy is the gold standard for early diagnosis and pre-emptive treatment of colorectal cancer by detecting and removing colonic polyps. Deep learning approaches to polyp detection have shown potential for enhancing polyp detection rates. However, the majority of these systems are developed and evaluated on static images from colonoscopies, whilst in clinical practice the treatment is performed on a real-time video feed. Non-curated video data remains a challenge, as it contains low-quality frames when compared to still, selected images often obtained from diagnostic records. Nevertheless, it also embeds temporal information that can be exploited to increase predictions stability. A hybrid 2D/3D convolutional neural network architecture for polyp segmentation is presented in this paper. The network is used to improve polyp detection by encompassing spatial and temporal correlation of the predictions while preserving real-time detections. Extensive experiments show that the hybrid method outperforms a 2D baseline. The proposed architecture is validated on videos from 46 patients and on the publicly available SUN polyp database. A higher performance and increased generalisability indicate that real-world clinical implementations of automated polyp detection can benefit from the hybrid algorithm and the inclusion of temporal information.

A new artificial intelligence system successfully detects and localises early neoplasia in Barrett's esophagus by using convolutional neural networks.

BACKGROUND AND AIMS: Seattle protocol biopsies for Barrett's Esophagus (BE) surveillance are labour intensive with low compliance. Dysplasia detection rates vary, leading to missed lesions. This can potentially be offset with computer aided detection. We have developed convolutional neural networks (CNNs) to identify areas of dysplasia and where to target biopsy. METHODS: 119 Videos were collected in high-definition white light and optical chromoendoscopy with i-scan (Pentax Hoya, Japan) imaging in patients with dysplastic and non-dysplastic BE (NDBE). We trained an indirectly supervised CNN to classify images as dysplastic/non-dysplastic using whole video annotations to minimise selection bias and maximise accuracy. The CNN was trained using 148,936 video frames (31 dysplastic patients, 31 NDBE, two normal esophagus), validated on 25,161 images from 11 patient videos and tested on 264 iscan-1 images from 28 dysplastic and 16 NDBE patients which included expert delineations. To localise targeted biopsies/delineations, a second directly supervised CNN was generated based on expert delineations of 94 dysplastic images from 30 patients. This was tested on 86 i-scan one images from 28 dysplastic patients. FINDINGS: The indirectly supervised CNN achieved a per image sensitivity in the test set of 91%, specificity 79%, area under receiver operator curve of 93% to detect dysplasia. Per-lesion sensitivity was 100%. Mean assessment speed was 48 frames per second (fps). 97% of targeted biopsy predictions matched expert and histological assessment at 56 fps. The artificial intelligence system performed better than six endoscopists. INTERPRETATION: Our CNNs classify and localise dysplastic Barrett's Esophagus potentially supporting endoscopists during surveillance.

Computational drug repurposing against SARS-CoV-2 reveals plasma membrane cholesterol depletion as key factor of antiviral drug activity.

Comparing SARS-CoV-2 infection-induced gene expression signatures to drug treatment-induced gene expression signatures is a promising bioinformatic tool to repurpose existing drugs against SARS-CoV-2. The general hypothesis of signature-based drug repurposing is that drugs with inverse similarity to a disease signature can reverse disease phenotype and thus be effective against it. However, in the case of viral infection diseases, like SARS-CoV-2, infected cells also activate adaptive, antiviral pathways, so that the relationship between effective drug and disease signature can be more ambiguous. To address this question, we analysed gene expression data from in vitro SARS-CoV-2 infected cell lines, and gene expression signatures of drugs showing anti-SARS-CoV-2 activity. Our extensive functional genomic analysis showed that both infection and treatment with in vitro effective drugs leads to activation of antiviral pathways like NFkB and JAK-STAT. Based on the similarity-and not inverse similarity-between drug and infection-induced gene expression signatures, we were able to predict the in vitro antiviral activity of drugs. We also identified SREBF1/2, key regulators of lipid metabolising enzymes, as the most activated transcription factors by several in vitro effective antiviral drugs. Using a fluorescently labeled cholesterol sensor, we showed that these drugs decrease the cholesterol levels of plasma-membrane. Supplementing drug-treated cells with cholesterol reversed the in vitro antiviral effect, suggesting the depleting plasma-membrane cholesterol plays a key role in virus inhibitory mechanism. Our results can help to more effectively repurpose approved drugs against SARS-CoV-2, and also highlights key mechanisms behind their antiviral effect.

Arrhythmia Caused by a Giant Coronary Artery Aneurysm.

Giant coronary artery aneurysms (GCAAs) are rare cardiovascular malformations that necessitate a multimodal, interdisciplinary diagnostic and individualized interventional approach. This report describes the case of a young, healthy patient with an idiopathic GCAA with pseudoaneurysmal protrusion into the right atrium that caused syncope, cardiac decompensation, and arrhythmia, which subsided postoperatively.

Performance of artificial intelligence for detection of subtle and advanced colorectal neoplasia.

OBJECTIVES: There is uncertainty regarding the efficacy of artificial intelligence (AI) software to detect advanced subtle neoplasia, particularly flat lesions and sessile serrated lesions (SSLs), due to low prevalence in testing datasets and prospective trials. This has been highlighted as a top research priority for the field. METHODS: An AI algorithm was evaluated on four video test datasets containing 173 polyps (35,114 polyp-positive frames and 634,988 polyp-negative frames) specifically enriched with flat lesions and SSLs, including a challenging dataset containing subtle advanced neoplasia. The challenging dataset was also evaluated by eight endoscopists (four independent, four trainees, according to the Joint Advisory Group on gastrointestinal endoscopy [JAG] standards in the UK). RESULTS: In the first two video datasets, the algorithm achieved per-polyp sensitivities of 100% and 98.9%. Per-frame sensitivities were 84.1% and 85.2%. In the subtle dataset, the algorithm detected a significantly higher number of polyps (P < 0.0001), compared to JAG-independent and trainee endoscopists, achieving per-polyp sensitivities of 79.5%, 37.2% and 11.5%, respectively. Furthermore, when considering subtle polyps detected by both the algorithm and at least one endoscopist, the AI detected polyps significantly faster on average. CONCLUSIONS: The AI based algorithm achieved high per-polyp sensitivities for advanced colorectal neoplasia, including flat lesions and SSLs, outperforming both JAG independent and trainees on a very challenging dataset containing subtle lesions that could have been overlooked easily and contribute to interval colorectal cancer. Further prospective trials should evaluate AI to detect subtle advanced neoplasia in higher risk populations for colorectal cancer.

Synthetic T2-weighted images of the lumbar spine derived from an accelerated T2 mapping sequence: Comparison to conventional T2w turbo spin echo.

OBJECTIVES: To evaluate the diagnostic usefulness of synthetic T2-weighted images of the lumbar spine derived from ten-fold undersampled k-space data using GRAPPATINI, a combination of a model-based approach for rapid T2 and M0 quantification (MARTINI) extended by generalized autocalibrating partial parallel acquistion (GRAPPA). MATERIALS AND METHODS: Overall, 58 individuals (26 female, mean age 23.3 ± 8.1 years) were examined at 3 Tesla with sagittal and axial T2w turbo spin echo (TSE) sequences compared to synthetic T2-weighted contrasts derived at identical effective echo times and spatial resolutions. Two blinded readers graded disk degeneration and evaluated the lumbar intervertebral disks for present herniation or annular tear. One reader reassessed all studies after four weeks. Weighted kappa statistics were calculated to assess inter-rater and intra-rater agreement. Also, all studies were segmented manually by one reader to compute contrast ratios (CR) and contrast-to-noise ratios (CNR) of the nucleus pulposus and the annulus fibrosus. RESULTS: Overall, the CRT2w was 4.45 ± 1.80 and CRT2synth was 4.71 ± 2.14. Both correlated (rsp = 0.768;p < 0.001) and differed (0.26 ± 1.38;p = 0.002) significantly. The CNRT2w was 1.73 ± 0.52 and CNRT2synth was 1.63 ± 0.50. Both correlated (rsp = 0.875;p < 0.001) and differed (-0.10 ± 0.25;p < 0.001) significantly. The inter-rater agreement was substantial to almost perfect (κ = 0.808-0.925) with the intra-rater agreement also substantial to almost perfect (κ = 0.862-0.963). The area under the curve of the receiver operating characteristics assessing disk herniation or annular tear ranged from 0.787 to 0.892. CONCLUSIONS: This study concludes that synthetic images derived by GRAPPATINI can be used for clinical routine assessment with inter-rater and intra-rater agreements comparable to conventional T2w TSE.

Insights into the substrate binding mechanism of SULT1A1 through molecular dynamics with excited normal modes simulations.

Sulfotransferases (SULTs) are phase II drug-metabolizing enzymes catalyzing the sulfoconjugation from the co-factor 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to a substrate. It has been previously suggested that a considerable shift of SULT structure caused by PAPS binding could control the capability of SULT to bind large substrates. We employed molecular dynamics (MD) simulations and the recently developed approach of MD with excited normal modes (MDeNM) to elucidate molecular mechanisms guiding the recognition of diverse substrates and inhibitors by SULT1A1. MDeNM allowed exploring an extended conformational space of PAPS-bound SULT1A1, which has not been achieved up to now by using classical MD. The generated ensembles combined with docking of 132 SULT1A1 ligands shed new light on substrate and inhibitor binding mechanisms. Unexpectedly, our simulations and analyses on binding of the substrates estradiol and fulvestrant demonstrated that large conformational changes of the PAPS-bound SULT1A1 could occur independently of the co-factor movements that could be sufficient to accommodate large substrates as fulvestrant. Such structural displacements detected by the MDeNM simulations in the presence of the co-factor suggest that a wider range of drugs could be recognized by PAPS-bound SULT1A1 and highlight the utility of including MDeNM in protein-ligand interactions studies where major rearrangements are expected.

Vaccination by Two DerG LEAPS Conjugates Incorporating Distinct Proteoglycan (PG, Aggrecan) Epitopes Provides Therapy by Different Immune Mechanisms in a Mouse Model of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) can be initiated and driven by immune responses to multiple antigenic epitopes including those in cartilage proteoglycan (PG, aggrecan) and type II collagen. RA is driven by T helper 1 (Th1) or Th17 pro-inflammatory T cell responses. LEAPS (Ligand Epitope Antigen Presentation System) DerG peptide conjugate vaccines were prepared using epitopes from PG that elicit immune responses in RA patients: epitope PG70 (DerG-PG70, also designated CEL-4000) and the citrullinated form of another epitope (PG275Cit). The LEAPS peptides were administered alone or together in Seppic ISA51vg adjuvant to mice with PG G1 domain-induced arthritis (GIA), a mouse model of RA. Each of these LEAPS peptides and the combination modulated the inflammatory response and stopped the progression of arthritis in the GIA mouse model. Despite having a therapeutic effect, the DerG-PG275Cit vaccine did not elicit significant antibody responses, whereas DerG-PG70 (alone or with DerG-PG275Cit) induced both therapy and antibodies. Spleen T cells from GIA mice, vaccinated with the DerG LEAPS peptides, preferentially produced anti-inflammatory (IL-4 and IL-10) rather than pro-inflammatory (IFN-γ or IL-17) cytokines in culture. Similarly, cytokines secreted by CD4+ cells of unvaccinated GIA mice, differentiated in vitro to Th2 cells and treated with either or both DerG vaccine peptides, exhibited an anti-inflammatory (IL-4, IL-10) profile. These results suggest that the two peptides elicit different therapeutic immune responses by the immunomodulation of disease-promoting pro-inflammatory responses and that the combination of the two LEAPS conjugates may provide broader epitope coverage and, in some cases, greater efficacy than either conjugate alone.