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We identified a syndrome characterized by a relatively isolated progressive impairment of reading words that the patient was able to understand and repeat but without other components of speech apraxia. This cluster of symptoms fits a new syndrome designated Progressive Verbal Apraxia of Reading. A right-handed man (AB) came with a 2.5-year history of increasing difficulties in reading aloud. He was evaluated twice, 2 years apart, using multimodal neuroimaging techniques and quantitative neurolinguistic assessment. In the laboratory, reading difficulties arose in the context of intact visual and auditory word recognition as well as intact ability to understand and repeat words he was unable to read aloud. The unique feature was the absence of dysarthria or speech apraxia in tasks other than reading. Initial imaging did not reveal statistically significant atrophy. Structural magnetic resonance and FDG-PET imaging at the second assessment revealed atrophy and hypometabolism in the right posterior cerebellum, in areas shown to be part of his language network by task-based functional neuroimaging at initial assessment. This syndromic cluster can be designated Progressive Verbal Apraxia of Reading, an entity that has not been reported previously to the best of our knowledge. We hypothesize a selective disconnection of the visual word recognition system from the otherwise intact articulatory apparatus, a disconnection that appears to reflect the disruption of multisynaptic cerebello-cortical circuits., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Mouse monoclonal antibody M4M was recently designed to block human TRPM4 channel. The polypeptide for generating M4M is composed of peptide A1 between the transmembrane segment 5 (S5) and the pore, and a second peptide A2 between the pore and the transmembrane segment 6 (S6). Using peptide microarray, a 4-amino acid sequence EPGF within the A2 was identified to be the binding epitope for M4M. Substitution of EPGF with other amino acids greatly reduced binding affinity. Structural analysis of human TRPM4 structure indicates that EPGF is located externally to the channel pore. A1 is close to the EPGF binding epitope in space, albeit separated by a 37-amino acid peptide. Electrophysiological study reveals that M4M could block human TRPM4, but with no effect on rodent TRPM4 which shares a different amino acid sequence ERGS for the binding motif. Our results demonstrate that M4M is a specific inhibitor for human TRPM4., (© 2022. The Author(s).)

Cytochrome P450 1A1 (CYP1A1) metabolizes estrogens, melatonin, and other key endogenous signaling molecules critical for embryonic/fetal development. The enzyme has increasing expression during pregnancy, and its inhibition or knockout increases embryonic/fetal lethality and/or developmental problems. Here, we present a virtual screening model for CYP1A1 inhibitors based on the orthosteric and predicted allosteric sites of the enzyme. Using 1001 reference compounds with CYP1A1 activity data, we optimized the decision thresholds of our model and classified the training compounds with 68.3% balanced accuracy (91.0% sensitivity and 45.7% specificity). We applied our final model to 11 known CYP1A1 orthosteric binders and related compounds, and found that our ranking of the known orthosteric binders generally agrees with the relative activity of CYP1A1 in metabolizing these compounds. We also applied the model to 22 new test compounds with unknown/unclear CYP1A1 inhibitory activity, and predicted 16 of them are CYP1A1 inhibitors. The CYP1A1 potency and modes of inhibition of these 22 compounds were experimentally determined. We confirmed that most predicted inhibitors, including drugs contraindicated during pregnancy (amiodarone, bicalutamide, cyproterone acetate, ketoconazole, and tamoxifen) and environmental agents suspected to be endocrine disruptors (bisphenol A, diethyl and dibutyl phthalates, and zearalenone), are indeed potent inhibitors of CYP1A1. Our results suggest that virtual screening may be used as a rapid tier-one method to screen for potential CYP1A1 inhibitors, and flag them out for further experimental evaluations., (© 2021. The Author(s).)

Objective: Endoscopic full-thickness resection (EFTR) has shown efficacy and safety in the colorectum. The aim of this analysis was to investigate whether EFTR is cost-effective in comparison with surgical and endoscopic treatment alternatives., Design: Real data from the study cohort of the prospective, single-arm WALL RESECT study were used. A simulated comparison arm was created based on a survey that included suggested treatment alternatives to EFTR of the respective lesions. Treatment costs and reimbursement were calculated in euro according to the coding rules of 2017 and 2019 (EFTR). R0 resection rate was used as a measure of effectiveness. To assess cost-effectiveness, the average cost-effectiveness ratio (ACER) and the incremental cost-effectiveness ratio (ICER) were determined. Calculations were made both from the perspective of the care provider as well as of the payer., Results: The cost per case was €2852.20 for the EFTR group, €1712 for the standard endoscopic resection (SER) group, €8895 for the surgical resection group and €5828 for the pooled alternative treatment to EFTR. From the perspective of the care provider, the ACER (mean cost per R0 resection) was €3708.98 for EFTR, €3115.10 for SER, €8924.05 for surgical treatment and €7169.30 for all pooled and weighted alternatives to EFTR. The ICER (additional cost per R0 resection compared with EFTR) was €5196.47 for SER, €26 533.13 for surgical resection and €67 768.62 for the pooled rate of alternatives. Results from the perspective of the payer were similar., Conclusion: EFTR is cost-effective in comparison with surgical and endoscopic treatment alternatives in the colorectum., Competing Interests: Competing interests: AS and KC received lecture fees and study grants from Ovesco Endoscopy, Tübingen, Germany. AK, JB, TB, BS, AM, HM, HN, DA, MB, AP, MF, TF, MG and RT have no conflicts of interest or financial ties to disclose., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: A recent prospective randomised controlled trial ('STING') showed superiority of over-the-scope clips compared to standard treatment in recurrent peptic ulcer bleeding. Cost-effectiveness studies on haemostasis with over-the-scope clips have not been reported so far., Objective: The aim of this study was to investigate whether the higher efficacy of the over-the-scope clips treatment outweighs the higher costs of the device compared to standard clips., Methods: For the analysis, the study population of the STING trial was used. Costs for the hospital stay in total as well as treatment-related costs were obtained. The average cost-effectiveness ratio, representing the mean costs per designated outcome, and the incremental cost-effectiveness ratio, expressing the additional costs of a new treatment strategy per difference in outcome were calculated. The designated outcome was defined as successful haemostasis without rebleeding within seven days, which was the primary endpoint of the STING trial. Average cost-effectiveness ratio and incremental cost-effectiveness ratio were calculated for total costs of the hospital stay as well as the haemostasis treatment alone. The cost-effectiveness analysis is taken from the perspective of the care provider. Results: Total costs and treatment-related costs per patient were 13,007.07 € in the standard group vs 12,808.56 € in the over-the-scope clip group ( p  = 0.812) and 2084.98 € vs 1984.71 € respectively ( p  = 0.663). The difference was not statistically significant. Total costs per successful haemostasis (average cost-effectiveness ratio) were 30,677.05 € vs 15,104.43 € and 4917.41 € vs 2340.46 € for the haemostasis treatment. The additional costs per successful haemostasis with over-the-scope clip treatment (incremental cost-effectiveness ratio) is -468.18 € for the whole treatment and -236.49€ for the haemostasis treatment., Conclusions: Over-the-scope clip treatment is cost-effective in recurrent peptic ulcer bleeding., (© Author(s) 2019.)

We reviewed our experience at the Western Reserve Care System with totally implantable drug delivery systems (IDDS) in cancer patients with vascular access problems. Fifty-one ports were placed in 50 patients. Forty-nine of the IDDS were placed under local anesthesia. One patient developed a hemothorax during placement. Two catheters were removed because of infection. Two catheters found to be occluded responded to flushing with streptokinase. All catheters remained functional up to the time of treatment completion or of the patient's death. The low morbidity and high success rates of IDDS should encourage placement early in the course of chemotherapy.