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Bin blending is one of the main steps in pharmaceutical production processes. Commercial-scale production of expensive products typically does not allow to perform a large number of experiments in order to optimize the process. Alternatively, Discrete Element Method (DEM) simulations can be used to evaluate the powder behavior (flow and blending pattern) during blending, identify the risks (e.g., segregation), and provide solutions to mitigate them. In this work, DEM simulations are used to investigate the blending of two granulated powders in commercial-scale cone and cylindrical (hoop) blenders. The DEM contact model parameters were calibrated based on the experimental compression and ring shear tests for both granulated powders to mimic the bulk powder behavior in the simulations. The model's output was compared to the experiments in one of the blending cases. The blending efficiency in the cone blenders was evaluated considering the fill levels, the presence of baffles, the rotating directions, the filling order, and the bin sizes. Furthermore, for the hoop blenders, the effects of blender's angle, rotation speed, and filling order were addressed. The main findings of the work were that, in cone blenders, the blending can be improved by introducing baffles and changing in the rotational direction frequently. In hoop blenders, blending can be improved by increasing the inclination angle from the horizontal plane and the rotational speed., (Copyright © 2024. Published by Elsevier B.V.)

Background and Aims: We aimed to evaluate the feasibility, safety and efficacy of endoscopic submucosal dissection for recurrent rectal neoplastic lesions after transanal microsurgery of superficial rectal neoplasms., Methods: Multicenter retrospective study., Main Outcomes: recurrence at first endoscopic follow-up, En bloc, R0 and curative resections., Results: 39 patients were included. 71 % percent of lesions were located in the lower rectum, 57 % reached the pectineal line. 67 % were laterally spreading tumor granular type, 33 % were protruding lesions. Median size was 41 mm (IQR 30 - 60). Median operation time was 70 min (IQR 35 - 97). 92 % were successfully resected en bloc. R0 and curative resection rates were 77 % and 71 %, respectively. Perirectal fat was visualized in 10 patients, none of them required surgery. One significant hematochezia (3 %), two stenosis (6 %) and one untreatable anal incontinence (3 %) occurred. Median hospital stay after endoscopic submucosal dissection was 2 days (IQR 1-2). Median period for the first endoscopy follow-up was 6 months (IQR 4-8). A single post endoscopic submucosal dissection recurrence adenoma was found during follow-up (3 %), occurring after a non-en bloc resection., Conclusion: Endoscopic submucosal dissection is a good option for safely achieving high rates of complete en bloc resection in cases of recurrent superficial rectal tumor after transanal microsurgery., Competing Interests: Conflict of interest - Ali Jaafar has no conflict of interest. - Xavier Dray is co-founder and shareholder of Augmented Endoscopy. He has received consultant fees from Norgine and Provepharm. He has received lecture fees from Fujifilm, Medtronic, MSD, Norgine, Pfizer and Sandoz. - Jeremie Jacques has received workshop fees from Olympus, Fujifilm, Erbe, Pentax and Boston. He has received hospitality from Janssen and Abbvie. - Romain Legros has received workshop fees from Olympus, Fujifilm, Erbe, Pentax and Boston. - Sarah Leblanc has received workshop fees from Olympus and Boston. She has received congresses fees from Fujifilm. She is laboratory board for Alfasigma. - Vincent Lepilliez has received workshops fees from Olympus. He has refunded fees from Medtronic on JFHOD 2023. - Arthur Berger has received fees from Fujifilm, Norgine, Creo medical and Janssen. - Edouard Chabrun has received workshops fees from Norgine. - Yann Le Baleur is expert training consultant for Ovesco Endoscopy and Duomed. - Mathieu Pioche is co-founder of A-TRACT. He has received ESD formation fees from Olympus, Pentax and Erbe. He has received formation fees from Norgine and Provepharm. - Maximilien Barret is consulting for Medtronic, Sanofi and Fujifilm. He has participated in boards for Norgine and Ambu. He has received interventions fees from Dr. Falk Pharma. He organized training sessions for Olympus. He participated in research funding for Pentax - Timothee Wallenhorst, Thibault Degand and Felix Corre had no conflict of interest. - Marion Schaefer has received lecture and workshops fees from Boston scientific, workshop fees from Duomed Endoscopy and Erbe, lecture fees from Norgine, Alfasigma and Ferring. She is consulting for Abbvie. She has received hospitality from Cook, Olympus, Janssen, MSD, Pfizer, Cousin, Ipsen and Takeda., (Copyright © 2024 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background and Aims: EUS-guided hepaticogastrostomy (EUS-HGS) is an effective biliary drainage technique for patients with altered anatomy or duodenal strictures. EUS-guided hepaticojejunostomy (EUS-HJS) can be used to create a fistula between the left hepatic duct and the jejunum in patients with a history of total gastrectomy. No specific data on this technique have been published. The aim of this study was to assess the feasibility and safety of EUS-HJS in patients with a history of total gastrectomy., Methods: This retrospective multicenter study included all adult patients who underwent EUS-HJS at 3 tertiary French centers and 1 tertiary Swiss center between May 2011 and February 2023. The primary outcome was clinical success, which was defined as the disappearance of pruritus, jaundice, and/or cholangitis. An improvement in bilirubin >30% within the first week and/or bilirubin normalization within 1 month after the procedure were also considered indicators of clinical success. Secondary outcomes were technical success, rate of adverse events, need for endoscopic revision, possibility of resuming anticancer treatment, median survival, and technical differences compared with EUS-HGS., Results: Twenty-one patients with history of complete gastrectomy who underwent EUS-HJS were included. Technical success was achieved in 100% of patients (95% confidence interval [CI], 85-100). Clinical success was achieved in 80% of patients (95% CI, 58-92). The incidence of recorded adverse events was 33% (95% CI, 17-55), with cholangitis being the most frequent adverse event. Seven patients (39%) were able to benefit from anticancer treatment after the procedure. Median survival time was 6 months (interquartile range, 1.5-12)., Conclusions: EUS-HJS is an effective and feasible procedure for patients whose anatomy has been altered by total gastrectomy., Competing Interests: Disclosure The following authors disclosed financial relationships: M. Schaefer: Consultant for Boston Scientific and AbbVie; instructor for Erbe, Boston Scientific, and Duomed Endoscopy; speaker for Alfasigma, Norgine, and Ferring. E. Perez-Cuadrado-Robles: Consultant for Boston Scientific. J.-B. Chevaux: Consultant for Norgine. M. Giovannini: Consultant for Pentax and Cook Medical. All other authors disclosed no financial relationships., (Copyright © 2025 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

RF-amide peptide receptors including the neuropeptide FF receptor 1 (NPFFR1) are G protein-coupled receptors (GPCRs) that modulate diverse physiological functions. High conservation of endogenous ligands and receptors makes the identification of selective ligands challenging. Previously identified antagonists mimic the C-terminus of peptide ligands and lack selectivity towards the closely related neuropeptide FF receptor 2 (NPFFR2) or the neuropeptide Y 1 receptor (Y 1 R). In a high-throughput screening, we identified the pentacyclic triterpenoid hederagenin (1) as a novel selective antagonist for the NPFFR1. Hederagenin (1) is a natural product isolated from Hedera helix (ivy). We characterized its mode of activity using in vitro and in silico methods, revealing an overlapping binding site of the small molecule with the orthosteric peptide agonists. Despite the high similarity of the orthosteric binding pockets of NPFFR1 and NPFFR2, hederagenin (1) shows strong subtype selectivity, particularly caused by slight differences in the shape of the binding pockets and the rigidity of the small molecule. Several residues inhibiting the activity of hederagenin (1) at the NPFFR2 were identified. As NPFFR1 antagonists are discussed as potential candidates for the treatment of chronic pain, these insights into the structural determinants governing subtype specificity will facilitate the development of next-generation analgesics with improved safety and efficacy., (© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Background: To investigate the association between the development of incident interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA) and the disease activity of RA with its various components, especially C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)., Methods: We analysed data from RA patients, observed in the German biologics register RABBIT between 2001 and 2021. In a nested case-control study, patients with a reported incident ILD diagnosis during follow-up were matched 1:5 to patients without ILD. Matching criteria were sex, age, RA duration, date of enrolment and observation time. Defined by a directed acyclic graph (DAG), we adjusted the conditional logistic regression models for rheumatoid factor, smoking, chronic obstructive pulmonary disease and tuberculosis/chronic viral infections to investigate the impact of disease activity/systemic inflammation. Mean and categorized values were analysed within 12 months prior to ILD and during the entire observation time. Additionally, two sensitivity analyses were performed, using validated ILD cases only and considering ILD cases with an observation time of more than 12 months., Results: We identified 139 RA patients with incident ILD and matched them to 686 controls. In 94 cases the diagnosis could be validated, and 98 cases had a follow-up of > 12 months. The averaged DAS28 composite score (including ESR or CRP) was not associated with developing RA-ILD (odds ratios 1.16 [95% confidence interval: 0.97-1.40] and 1.06 [0.86-1.29], respectively). However, single measures of inflammation, log ESR (1.86 [1.35-2.57]) and log CRP (1.55 [1.21-1.97]), were significantly associated with an increased RA-ILD risk. A higher risk for ILD was also revealed for persistently high inflammation. Other DAS28 components showed no significant associations with RA-ILD. These results were consistent for values over the entire observation time of a patient and within 12 months prior to the ILD. Sensitivity analyses confirmed these findings., Conclusion: Higher levels of systemic inflammation, as indicated by ESR and CRP, but not joint counts or patient's global assessment, were significantly associated with the occurrence of incident ILD in patients with RA. As possible predictor for the development of RA-ILD, systemic inflammation should be monitored closely and independently of joint count results., Competing Interests: Declarations. Ethics approval and consent to participate: The study protocol was approved by the ethics committee of the Charité University Medicine Berlin, Germany (EA4/123/21). Participants gave written informed consent to participate in the study prior to enrolment. Consent for publication: No applicable. Competing interests: RR: Support for attending meetings and/or travel: AlfaSigma, Lilly, UCB; All support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.): RABBIT* is supported by a joint, unconditional grant from AbbVie, Amgen, BMS, Celltrion, Fresenius Kabi, Galapagos, Hexal, Lilly, MSD, Pfizer, Samsung Bioepis, Sanofi Aventis, Viatris Sante, and UCB, and previously Roche. TR: no competing interest. RA: Consulting fees: Abbvie, AlfaSigma, Amgen, Biogen, BMS, Celltrion, Chugai, Galapagos, Gilead, Hexal, Janssen, Lilly, Mylan/Viatris, Novartis, Pfizer, Roche, UCB; Payment or honoraria for speakers bureaus or similar: Abbvie, AlfaSigma, Amgen, Biogen, BMS, Celltrion, Chugai, Galapagos, Gilead, Hexal, Janssen, Lilly, Mylan/Viatris, Novartis, Pfizer, Roche, UCB; Support for attending meetings and/or travel: Abbvie, AlfaSigma, Amgen, Biogen, BMS, Celltrion, Chugai, Galapagos, Gilead, Hexal, Janssen, Lilly, Mylan/Viatris, Novartis, Pfizer, Roche, UCB. AK: Consulting fees: AbbVie, Gilead, Boehringer Ingelheim, Novartis, Janssen, UCB, Lilly; Payment or honoraria for speakers bureaus or similar: AbbVie, Gilead, Boehringer Ingelheim, Roche, Novartis, Janssen, UCB, Lilly; Support for attending meetings and/or travel: AbbVie, Boehringer Ingelheim; Participation on a Data Safety Monitoring Board or Advisory Board: Pfizer; Leadership or fiduciary role: German society for rheumatology. MSchneider: Grants or contracts from any entity: GSK, AstraZeneca; Consulting fees: AstraZeneca, GSK, Otsuka, UCB; Payment or honoraria for speakers bureaus or similar: AstraZeneca, Pfizer, GSK, BMS; Support for attending meetings and/or travel: Abbvie; Leadership or fiduciary role: Guidelines DGRh. MSchaefer: Grants or contracts from any entity: PI of the RABBIT* registry. AS: Grants or contracts from any entity: PI of the RABBIT* registry; Honoraria for lectures: AbbVie, Pfizer, Galapagos, Takeda, Janssen, Lilly, Samsung Bioepis; Participation on a Data Safety Monitoring Board or Advisory Board: Unpaid role as DMC-Chair of the BADBIR register, UK, Unpaid member of the DMC Board of the Lupus Best Study. YM: Honoraria for lectures: Lilly, Pfizer., (© 2024. The Author(s).)

Background: End-stage renal disease is a growing global health issue, disproportionately impacting low- and middle-income countries. While kidney transplantation remains the best treatment for end-stage renal disease, access to this treatment modality is limited by chronic donor organ shortages. To address this critical need, we are developing transplantable bioengineered kidney grafts., Methods: Podocyte differentiation was achieved in adherent monoculture through Wnt and TGF-β inhibition with IWR-1 and SB431542, respectively. Podocytes along with endothelial cells were then used to recapitulate glomeruli within decellularized porcine kidney scaffolds to generate bioengineered kidneys grafts. These bioengineered kidney grafts were functionally assessed via normothermic perfusion which compared kidney grafts recellularized with only endothelial cells as a control to bi-culture kidney grafts comprised of endothelial cells and podocytes. Heterotopic implantation further tested bi-culture kidney graft function over 3 successive implant sessions with 1-2 grafts per session., Results: We demonstrate the ability to source primary human podocytes at scale. Decellularized porcine kidney grafts repopulated with podocytes and endothelial cells exhibit native glomerular structure and display blood filtration capabilities during normothermic perfusion testing. Extending these findings to a clinically relevant model, bioengineered kidneys produce urine with indices of filtration when heterotopically implanted in pigs., Conclusions: Our results showcase a human-scale, transplantable bioengineered kidney capable of performing requisite filtration function. This study reinforces the possibility for the bioengineering of transplantable human kidneys, which could someday provide increased and more equitable access to kidney grafts for the treatment of end-stage renal disease., Competing Interests: Competing interests: The authors declare the following competing interests: D.Y.L., M.A.S., M.S., J.I.W., E.J.V., U.A., C.D.L., K.M., P.H., E.C.B., and J.J.R. are or were employees of Miromatrix Inc., a subsidiary of United Therapeutics. United Therapeutics is a publicly funded company and owns the exclusive patent rights for the perfusion decellularization and recellularization technologies utilized in this study. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Background: U.S. policy intervention to increase methadone treatment accommodations during COVID did not result in national adoption of the new patient-centered treatment practices. Staff-level interventions may facilitate adoption of these treatment practices, but this will depend upon knowledge about staff level characteristics and beliefs. Currently, the role of clinic staff characteristics, beliefs about patient-centeredness, and perceptions about the need for treatment practice change is unknown. This study explored the relationship between opioid treatment program staff characteristics, work roles and staff beliefs to identify opportunities for future staff-level treatment practice change interventions., Methods: Staff of three Arizona opioid treatment programs were surveyed (n = 40) from April 11-22, 2023 using a hybrid online survey method. The 161 survey items required less than 30 min to complete. Pearson point biserial correlation coefficients assessed the covariation between staff beliefs, staff characteristics and staff work roles. Perception of the clinic as person-centered was a potential proxy indicator for staff awareness of discontinuity between the clinic's person-centeredness and person-centered approaches to methadone treatment., Results: Among staff, 47.5% reported lived substance use disorder experience and 27.5% reported lived opioid use disorder experience. Most staff (70%) held at least 1 prior clinic role at the current clinic and 5% had had more than 4 prior roles. Rotation was observed with roles that did not require licensure or degrees. Staff with lived experience with substance use disorder or opioid use disorder treatment reported having more prior roles at the clinic than those without such experience. Abstinence-oriented views were significantly associated with reporting vicarious (work related) trauma symptoms. Those who rated the clinic as significantly more person-centered were staff with lived substance use disorder experience who also held abstinence-oriented views, staff with trauma exposure, and staff with lived opioid use disorder treatment experience who held harm reduction beliefs. In contrast, staff without substance use disorder experience who held harm reduction beliefs perceived the clinic as less person-centered., Conclusions: Staff beliefs, personal and work characteristics are likely factors in the recognition of need for clinic practice change. How these characteristics function in a clinic culture may also be influenced by clinic staffing patterns. A patient-to-provider pipeline with role cycling was observed and this staffing pattern may also influence shared beliefs of trauma-informed care or clinic person-centeredness. Vicarious trauma may also be an important factor. Larger studies should examine these relationships further to understand mechanisms associated with recognition of need for clinic practice change in order to inform staff-level interventions to increase opioid treatment program patient-centeredness., Competing Interests: Declarations. Ethics approval and consent to participate: Ethics approval was provided by the University of Arizona Institutional Review Board (STUDY00002531). The participant consent process involved prospective participants voluntarily accessing the online landing page for the study, reviewing the study information and providing assent (online agreement) to proceed with the survey. If ‘agree’ was selected by the participant, they would be led to the anonymous survey instrument for completion. If ‘disagree’ was selected, they were led to a ‘thank you for considering the study’ message. Consent for publication: All authors provide publication consent for this manuscript. Competing interests: Meyerson, Linde-Krieger, Carter, Huff, Brady, Crosby, and De La Rosa have nothing to declare. Allison, Barakat, Ergurrola, Pava and Schaefer are employees of the opioid treatment program company from which the staff sample was drawn., (© 2024. The Author(s).)

Competing Interests: The authors declare that they have no conflict of interest.

Objectives: Although pediatric cancer often causes significant stress for families, most childhood cancer survivors are resilient and do not exhibit severe or lasting psychopathology. Research demonstrates some survivors may report benefit-finding or positive outcomes following this stressful life event. However, considerably less research has included families of children who are unlikely to survive their illness. Thus, this study investigated benefit-finding among parents and their children with advanced cancer, as well as associated demographic and medical factors., Methods: Families ( N = 72) of children with advanced cancer (ages 5-25) were recruited from a large pediatric hospital. Advanced cancer was defined as relapsed or refractory disease, an estimated prognosis of <60%, or referral to end-of-life care. Participants completed a demographic survey and the Benefit Finding Scale at enrollment., Results: Children, mothers, and fathers reported moderate to high benefit-finding scores. Correlations between family members were weak and non-significant. Children reported significantly higher benefit-finding than fathers. Demographic and medical factors were not associated with benefit-finding in children, mothers, or fathers., Significance of Results: Families of children with advanced cancer reported moderate to high benefit-finding regardless of background or medical factors. Children identified benefits of their cancer experience independent of the experiences of their mothers and fathers. Larger studies should continue to examine factors associated with positive and negative outcomes in the context of childhood cancer to inform interventions.

A core function of the olfactory system is to determine the valence of odors. In humans, central processing of odor valence perception has been shown to take form already within the olfactory bulb (OB), but the neural mechanisms by which this important information is communicated to, and from, the olfactory cortex (piriform cortex, PC) are not known. To assess communication between the 2 nodes, we simultaneously measured odor-dependent neural activity in the OB and PC from human participants while obtaining trial-by-trial valence ratings. By doing so, we could determine when subjective valence information was communicated, what kind of information was transferred, and how the information was transferred (i.e., in which frequency band). Support vector machine (SVM) learning was used on the coherence spectrum and frequency-resolved Granger causality to identify valence-dependent differences in functional and effective connectivity between the OB and PC. We found that the OB communicates subjective odor valence to the PC in the gamma band shortly after odor onset, while the PC subsequently feeds broader valence-related information back to the OB in the beta band. Decoding accuracy was better for negative than positive valence, suggesting a focus on negative valence. Critically, we replicated these findings in an independent data set using additional odors across a larger perceived valence range. Combined, these results demonstrate that the OB and PC communicate levels of subjective odor pleasantness across multiple frequencies, at specific time points, in a direction-dependent pattern in accordance with a two-stage model of odor processing., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Nordén et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: The environmental impact of endoscopy is a topic of growing interest. This study aimed to compare the carbon footprint of performing an esogastroduodenoscopy (EGD) with a reusable (RU) or with a single-use (SU) disposable gastroscope., Methods: SU (Ambu aScope Gastro) and RU gastroscopes (Olympus, H190) were evaluated using life cycle assessment methodology (ISO 14040) including the manufacture, distribution, usage, reprocessing and disposal of the endoscope. Data were obtained from Edouard Herriot Hospital (Lyon, France) from April 2023 to February 2024. Primary outcome was the carbon footprint (measured in Kg CO 2 equivalent) for both gastroscopes per examination. Secondary outcomes included other environmental impacts. A sensitivity analysis was performed to examine the impact of varying scenarios., Results: Carbon footprint of SU and RU gastroscopes were 10.9 kg CO 2 eq and 4.7 kg CO 2 eq, respectively. The difference in carbon footprint equals one conventional car drive of 28 km or 6 days of CO 2 emission of an average European household. Based on environmentally-extended input-output life cycle assessment, the estimated per-use carbon footprint of the endoscope stack and washer was 0.18 kg CO 2 eq in SU strategy versus 0.56 kg CO 2 eq in RU strategy. According to secondary outcomes, fossil eq depletion was 130 MJ (SU) and 60.9 MJ (RU) and water depletion for 6.2 m 3 (SU) and 9.5 m 3 (RU), respectively., Conclusion: For one examination, SU gastroscope have a 2.5 times higher carbon footprint than RU ones. These data will help with the logistics and planning of an endoscopic service in relation to other economic and environmental factors., Competing Interests: Competing interests: ERdS: Olympus Educational activity and advisory work, Apollo Endosurgery Educational activity, Norgine Conference fees and educational activity, Casen Conference fees. MP: Consultant for Olympus, trainer for Olympus, Pentax, Norgine, Boston, Cook. Other authors have nothing to disclose., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The ileocecal valve (ICV) is considered to be one of the most difficult locations for endoscopic submucosal dissection (ESD). The objective of this study was to evaluate the efficacy and safety of traction-assisted ESD in this situation., Methods: All patients who underwent traction-assisted ESD for an ICV lesion at three centers were identified from a prospective ESD database. En bloc and R0 rates were evaluated. Factors associated with non-R0 resection were explored., Results: 106 patients with an ICV lesion were included. The median lesion size was 50 mm (interquartile range 38-60) and 58.5% (62/106) invaded the terminal ileum. The en bloc and R0 resection rates were 94.3% and 76.4%, respectively. Factors associated with non-R0 resection were lesions covering ≥75% of the ICV (odds ratio [OR] 0.21. 95%CI 0.06-0.76; P=0.02), and involving the anal lip (OR 0.36, 95%CI 0.13-0.99; P=0.04) or more than two sites on the ICV (OR 0.27, 95%CI 0.07-0.99; P=0.03)., Conclusion: Traction-assisted ESD for treatment of ICV lesions was a safe and feasible option. Large lesions and anal lip involvement appeared to be factors predictive of difficulty., Competing Interests: C. Yzet is a consultant and lecturer for Abbvie, Takeda, Jansen, Amgen, and Galapagos. T. Wallenhorst has received honoraria for ESD training sessions from Olympus and Fujifilm, and lectures for Mayoli. J. Jacques has provided ESD training sessions for Olympus, Fuji, Erbe, Pentax Medical, and Lumendi, and lectures for Abbvie, Janssen, and Norgine. J. Rivory has received honoraria for training sessions in endoscopy and endoscopic resection from Olympus and Cook Medical. M. Schaefer has received honoraria for training session from Boston Scientific, and has received invitations to congresses from Olympus, Cook, Cousin Medical, Boston, Pentax, Abbvie, MSD, Amgen, and Norgine. M. Pioche has received honoraria for training sessions in endoscopy and endoscopic resection from Olympus, Cook Medical, Boston Scientific, and Pentax Medical; honoraria for training sessions in endoscopic characterization from Norgine and Provepharm; invitation to UEGW from AlfaSigma; and owns a patent for the Hospices Civils de Lyon IPEFIX device. M. Figueiredo, F. Rostain, L.J. Masgnaux, J. Grimaldi, R. Legros, P. Lafeuille, J. Albouys, and F. Subtil declare that they have no conflict of interest., (Thieme. All rights reserved.)

Several studies suggest that breathing entrains neural oscillations and thereby improves visual detection and memory performance during nasal inhalation. However, the evidence for this association is mixed, with some studies finding no, minor, or opposite effects. Here, we tested whether nasal breathing phase influences memory of repeated images presented in a rapid serial visual presentation (RSVP) task. The RSVP task is ideal for studying the effects of respiratory-entrained oscillations on visual memory because it engages critical aspects of sensory encoding that depend on oscillatory activity, such as fast processing of natural images, repetition detection, memory encoding, and retrieval. It also enables the presentation of a large number of stimuli during each phase of the breathing cycle. In two separate experiments (n = 72 and n = 142, respectively) where participants were explicitly asked to breathe through their nose, we found that nasal breathing phase at target presentation did not significantly affect memory performance. An exploratory analysis in the first experiment suggested a potential benefit for targets appearing approximately 1 s after inhalation. However, this finding was not replicated in the pre-registered second experiment with a larger sample. Thus, in two large sample experiments, we found no measurable impact of breathing phase on memory performance in the RSVP task. These results suggest that the natural breathing cycle does not have a significant impact on memory for repeated images and raise doubts about the idea that visual memory is broadly affected by the breathing phase., (© 2024 The Authors. Psychophysiology published by Wiley Periodicals LLC on behalf of Society for Psychophysiological Research.)

PURPOSE OF REVIEW: This health technology assessment aimed to systematically assess the efficacy and safety of yoga as therapy for burnout. Economic, ethical, legal, social and organizational aspects were considered as well. RECENT FINDINGS: Yoga as a therapy has been shown to have positive effects on a range of symptoms, including stress, anxiety and depression. Regarding work-related stress and burnout, the effects of yoga have mainly been examined in a preventative context. Meta-analyses revealed no effects on burnout severity comparing yoga with passive controls in general. Compared with passive controls, yoga had a positive effect on subjective stress. Compared to active control, yoga had an effect on the burnout subscale depersonalization on individual study level. Yoga may have positive effects on burnout, but the results are mixed. Common definitions and standardized diagnostic tools are necessary to improve research and further assess yoga as therapy for burnout. TRIAL REGISTRATION: The HTA is registered with PROSPERO, CRD42022299405, on 6th February 2022., (© 2024. The Author(s).)

Obesity is a major public health problem worldwide. Different approaches are known to face this problem, for example, dieting, surgery, or drug interventions. It has also been shown that placebos may help to reduce weight and hunger feelings, but the use of placebos is linked to problems with respect to the patient-healthcare-provider relationship. However, recent studies demonstrated that even placebos without deception (open-label placebos) affect symptoms such as pain, anxiety, or emotional distress. Here we aimed to examine whether an open-label placebo may help to lose weight in obesity. Our study included fifty-seven overweight and obese patients who aimed to lose weight using a combination of diet and sports. Patients were randomly divided into two groups. Participants in the open-label placebo group received two placebos each day. A treatment-as-usual group received no pills. Primary outcome included changes of body weight. Secondary outcomes were change of eating behavior and self-management abilities. After 4 weeks we found that participants in the open-label placebo condition lost more weight than the treatment-as-usual group. Furthermore, OLP treatment affected eating behavior. No effects for self-management abilities were found. Although further research is necessary, open-label placebos might help individuals to lose weight., (© 2024. The Author(s).)

Small molecular kinase inhibitors play a key role in modern cancer therapy. Protein kinases are essential mediators in the growth and progression of cancerous tumors, rendering involved kinases an increasingly important target for therapy. However, kinase inhibitors are almost insoluble in water because of their hydrophobic aromatic nature, often lowering their availability and pharmacological efficacy. Direct drug functionalization with polar groups represents a simple strategy to improve the drug solubility, availability, and performance. Here, we present a strategy to functionalize secondary amines with oligoethylene glycol (OEG) phosphate using a one-pot synthesis in three exemplary kinase inhibiting drugs Ceritinib, Crizotinib, and Palbociclib. These OEG-prodrug conjugates demonstrate superior solubility in water compared to the native drugs, with the solubility increasing up to 190-fold. The kinase inhibition potential is only slightly decreased for the conjugates compared to the native drugs. We further show pH dependent hydrolysis of the OEG-prodrugs which releases the native drug. We observe a slow release at pH 3, while the conjugates remain stable over 96 h under physiological conditions (pH 7.4). Using confocal microscopy, we verify improved cell uptake of the drug-OEG conjugates into the cytoplasm of HeLa cells, further supporting our universal solubility approach., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

A key prerequisite for the successful application of protein crystallography in drug discovery is to establish a robust crystallization system for a new drug-target protein fast enough to deliver crystal structures when the first inhibitors have been identified in the hit-finding campaign or, at the latest, in the subsequent hit-to-lead process. The first crucial step towards generating well folded proteins with a high likelihood of crystallizing is the identification of suitable truncation variants of the target protein. In some cases an optimal length variant alone is not sufficient to support crystallization and additional surface mutations need to be introduced to obtain suitable crystals. In this contribution, four case studies are presented in which rationally designed surface modifications were key to establishing crystallization conditions for the target proteins (the protein kinases Aurora-C, IRAK4 and BUB1, and the KRAS-SOS1 complex). The design process which led to well diffracting crystals is described and the crystal packing is analysed to understand retrospectively how the specific surface mutations promoted successful crystallization. The presented design approaches are routinely used in our team to support the establishment of robust crystallization systems which enable structure-guided inhibitor optimization for hit-to-lead and lead-optimization projects in pharmaceutical research., (open access.)

Background: Computational simulation of biological processes can be a valuable tool for accelerating biomedical research, but usually requires extensive domain knowledge and manual adaptation. Large language models (LLMs) such as GPT-4 have proven surprisingly successful for a wide range of tasks. This study provides proof-of-concept for the use of GPT-4 as a versatile simulator of biological systems., Methods: We introduce SimulateGPT, a proof-of-concept for knowledge-driven simulation across levels of biological organization through structured prompting of GPT-4. We benchmarked our approach against direct GPT-4 inference in blinded qualitative evaluations by domain experts in four scenarios and in two quantitative scenarios with experimental ground truth. The qualitative scenarios included mouse experiments with known outcomes and treatment decision support in sepsis. The quantitative scenarios included prediction of gene essentiality in cancer cells and progression-free survival in cancer patients., Results: In qualitative experiments, biomedical scientists rated SimulateGPT's predictions favorably over direct GPT-4 inference. In quantitative experiments, SimulateGPT substantially improved classification accuracy for predicting the essentiality of individual genes and increased correlation coefficients and precision in the regression task of predicting progression-free survival., Conclusion: This proof-of-concept study suggests that LLMs may enable a new class of biomedical simulators. Such text-based simulations appear well suited for modeling and understanding complex living systems that are difficult to describe with physics-based first-principles simulations, but for which extensive knowledge is available as written text. Finally, we propose several directions for further development of LLM-based biomedical simulators, including augmentation through web search retrieval, integrated mathematical modeling, and fine-tuning on experimental data., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Christoph Bock reports a relationship with Myllia Biotechnology and Neurolentech that includes: board membership., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The adoption of colorectal endoscopic submucosal dissection (ESD) is still limited in the West. A recent randomized trial showed that ESD is more effective and only slightly riskier than piecemeal endoscopic mucosal resection; reproducibility outside expert centers was questioned. We evaluated the results according to the annual case volume in a multicentric prospective cohort., Methods: Between September 2019 and September 2022, colorectal ESD was consecutively performed at 13 participating centers classified as low volume (LV), middle volume (MV), and high volume (HV). The main procedural outcomes were assessed. Multivariate and propensity score matching analyses were performed., Results: Three thousand seven hundred seventy ESDs were included. HV centers treated larger and more often colonic lesions than MV and LV centers. En bloc , R0, and curative resection rates were 95.2%, 87.4%, and 83.2%, respectively, and were higher at HV than at MV and LV centers. HV centers also achieved a faster dissection speed. Delayed bleeding and surgery for complications rates were 5.4% and 0.8%, respectively, without significant differences. The perforation rate (overall: 9%) was higher at MV than at LV and HV centers. Lesion characteristics, but not volume center, were independently associated with both R1 resection and perforation. However, after propensity score matching, R0 rates were significantly higher at HV than at LV centers, and perforation rates were significantly higher at MV than at HV centers., Discussion: Colorectal ESD can be successfully implemented in the West, even in nonexpert centers. However, difficult lesions must still be referred to experts., (Copyright © 2024 by The American College of Gastroenterology.)

The basal and glucose-induced insulin secretion from pancreatic beta cells is a tightly regulated process that is triggered in a Ca 2+ -dependent fashion and further positively modulated by substances that raise intracellular levels of adenosine 3',5'-cyclic monophosphate (cAMP) or by certain antidiabetic drugs. In a previous study, we have temporally resolved the subplasmalemmal [Ca 2+ ] i dynamics in beta cells that are characterized by trains of sharply delimited spikes, reaching peak values up to 5 µM. Applying total internal reflection fluorescence (TIRF) microscopy and synaptopHluorin to visualize fusion events of individual granules, we found that several fusion events can coincide within 50 to 150 ms. To test whether subplasmalemmal [Ca 2+ ] i microdomains around single or clustered Ca 2+ channels may cause a synchronized release of insulin-containing vesicles, we applied simultaneous dual-color TIRF microscopy and monitored Ca 2+ fluctuations and exocytotic events in INS-1 cells at high frame rates. The results indicate that fusions can be triggered by subplasmalemmal Ca 2+ spiking. This, however, does account for a minority of fusion events. About 90 %-95 % of fusion events either happen between Ca 2+ spikes or incidentally overlap with subplasmalemmal Ca 2+ spikes. We conclude that only a fraction of exocytotic events in glucose-induced and tolbutamide- or forskolin-enhanced insulin release from INS-1 cells is tightly coupled to Ca 2+ microdomains around voltage-gated Ca 2+ channels., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: In 2017, three brick and mortar supervised consumption sites (SCS) opened in Montreal, Canada. Opponents argued the sites would attract people who use drugs and reduce local real estate prices., Methods: We used interrupted time series and hedonic price models to evaluate the effects of Montreal's SCS on local real estate prices. We linked the Quebec Professional Association of Real Estate Brokers' housing sales data provided by Centris Inc. with census tract data and gentrification scores. Homes sold within 200 m of the SCS locations between 1 January 2014 and 31 December 2021 were included. We adjusted for internal (e.g., number of bed/bathrooms, unit size) and external attributes (e.g., neighbourhood demographics), and included a spatio-temporal lag to account for correlation between sales. For sensitivity analysis we used site-specific dummy variables to better account for unmeasured neighbourhood differences, and repeated analyses using 500 m and 1000 m radii., Results: We observed a price shock after the opening of the first two SCS in June 2017 (level effect: -10.5%, 95% CI: -19.1%, -1.1%) but prices rose faster month-to-month (trend effect: 1.1%, 95% CI: 0.7%, 1.6%) after implementation. Following the implementation of the third site in November 2017 there was no immediate impact (level effect: 2.4%, 95% CI: -10.4%, 17.0%) but once more prices roses faster (0.9%, 95% CI: 0.4%, 1.5%) thereafter. When we replaced neighbourhood attributes with a site-specific dummy variable, we observed the same pattern. Sales' prices dropped (level effect: -9.6%, 95% CI: -15.0%, -3.8%) but rose faster month-to-month (trend effect: 0.9%, 95% CI: 0.6%, 1.2%) following June 2017's SCS implementations, with no level effect (4.9%, 95% CI: -7.3%, 18.6%) and a positive trend (0.9%, 95% CI: 0.5%, 1.3%) after November 2017's SCS opening. In most 500 m and 1000 m radii models, there were no immediate shocks following SCS opening, however, positive trend effects persisted in all models., Conclusion: Our models suggest homes sold near SCS may experience a price shock immediately post-implementation, with evidence of market recovery in the months that follow., Competing Interests: We declare no competing interests., (© 2024 The Authors.)

Objectives: To investigate the impact of disease activity and treatment with disease-modifying antirheumatic drugs (DMARDs) on all-cause mortality in patients with rheumatoid arthritis and prevalent interstitial lung disease (RA-ILD)., Methods: Patients with RA-ILD were selected from the biologics register Rheumatoid Arthritis: Observation of Biologic Therapy (RABBIT). Using time-varying Cox regression, the association between clinical measures and mortality was investigated. The impact of DMARDs was analysed by (1) Cox regression considering cumulative exposure (ie, treatment months divided by total months) and (2) time-varying Cox regression as main approach (treatment exposures at monthly level)., Results: Out of 15 566 participants, 381 were identified as RA-ILD cases with 1258 person-years of observation and 2.6 years median length of follow-up. Ninety-seven patients (25.5%) died and 34 (35.1%) of these were not receiving DMARD therapy at the time of death. Higher inflammatory biomarkers but not swollen and tender joint count were significantly associated with mortality. Compared with tumour necrosis factor inhibitors (TNFi), non-TNFi biologic DMARDs (bDMARDs) exhibited adjusted HRs (aHRs) for mortality below 1, lacking statistical significance. This finding was stable in various sensitivity analyses. Joint aHR for non-TNFi biologics and JAKi versus TNFi was 0.56 (95% CI 0.33 to 0.97). Receiving no DMARD treatment was associated with a twofold higher mortality risk compared with receiving any DMARD treatment, aHR 2.03 (95% CI 1.23 to 3.35)., Conclusions: Inflammatory biomarkers and absence of DMARD treatment were associated with increased risk of mortality in patients with RA-ILD. Non-TNFi bDMARDs may confer enhanced therapeutic benefits in patients with RA-ILD., Competing Interests: Competing interests: AK: consulting fees: AbbVie, Gilead, Boehringer Ingelheim, Novartis, Janssen, UCB, Lilly and payment for lectures, presentations: AbbVie, Gilead, Boehringer Ingelheim, Roche, Novartis, Janssen, UCB, Lilly and support for attending meetings and/or travel: AbbVie, Boehringer Ingelheim and participation on a Data Safety Monitoring Board or Advisory Board: Pfizer and leadership or fiduciary role in other board, society, commitee or advocacy group, paid or unpaid: German Society for Rheumatology. CK: payment for lectures, presentations: AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Celltrion, Galapagos, GSK, Hexal, Janssen, Lilly, Medical School Hamburg, MSD, Novartis, Pfizer, Roche, Sanofi, UCB and participation on a Data Safety Monitoring Board or Advisory Board: Boehringer Ingelheim, Novartis. H-ML: grants or contracts from any entity: Pfizer, Novartis and consulting fees: AbbVie, AstraZeneca, Actelion, Amgen, Bayer Vital, Boehringer Ingelheim, BMS, Celgene, GSK, Gilead/Galapagos, Janssen, Lilly, Medac, MSD, Novartis, Pfizer, Roche/Chugai, Sanofi, UCB and payment for lectures, presentations: AbbVie, AstraZeneca, Actelion, Amgen, Bayer Vital, Boehringer Ingelheim, BMS, Celgene, GSK, Gilead/Galapagos, Janssen, Lilly, Medac, MSD, Novartis, Pfizer, Roche/Chugai, Sanofi, UCB and support for attending meetings and/or travel: AbbVie, AstraZeneca, Boehringer Ingelheim, BMS, Celgene, GSK, Gilead/Galapagos, Janssen, Lilly, MSD, Novartis, Pfizer, Roche/Chugai, Sanofi, USB and participation on a Data Safety Monitoring Board or Advisory Board: AbbVie, AstraZeneca, Amgen, Boehringer Ingelheim, BMS, Celgene, GSK, Gilead/Galapagos, Janssen, Lilly, Medac, MSD, Novartis, Pfizer, Roche/Chugai, Sanofi, UCB. AS: lecture honoraria from AbbVie, Amgen, BMS, Celltrion, MSD, Lilly, Pfizer, Roche, UCB., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Recent studies have indicated that breathing shapes the underlying oscillatory brain activity critical for episodic memory, potentially impacting memory performance. However, the literature has presented conflicting results, with some studies suggesting that nasal inhalation enhances visual memory performance, while others have failed to observe any significant effects. Furthermore, the specific influence of breathing route (nasal vs. mouth) and the precise phase of the respiratory cycle during which stimuli are presented have remained elusive. To address this, we employed a visual recognition memory (VRM) and electroencephalography paradigm in which stimuli presentation was phase-locked to either inhalation or exhalation onset, using a within-subject design where participants performed the memory task while engaging in separate sessions of nose and mouth breathing. We show that neither breathing route nor breathing phase has a significant impact on VRM performance as measured by d-prime, with the data supporting the null hypothesis. However, we did find an effect of breathing phase on response bias, with participants adopting a more conservative decision criterion during exhalation. Moreover, we found that breathing phase during memory encoding shaped the late parietal effect (LPE) amplitude, while the Frontal Negative Component (FN400) and LPE during recognition were less impacted. While our study demonstrates that breathing does not shape VRM performance, it shows that it influences brain activity, reinforcing the importance of further research to elucidate the extent of respiratory influence on perception, cognition, and behavior., (© 2023 The Authors. Psychophysiology published by Wiley Periodicals LLC on behalf of Society for Psychophysiological Research.)

The study objective was to estimate the efficacy and safety of chlormethiazole in older adults experiencing insomnia (sleep disorder). We therefore systematically searched Medline, Scopus, the Cochrane Library, PsycINFO, Ovid, ZB MED and PMC through December 2021 for randomized-controlled trials including patients > 60 years old with insomnia treated with chlormethiazole. Standardized mean differences or odds ratios with 95% confidence intervals were calculated for the main outcome parameters: sleep duration, onset of sleep, quality of sleep, adverse events or drop-out rates compared with placebo and other drugs. Risk of bias was assessed using the Cochrane tool. Eight randomized-controlled trials with 424 patients were included. Chlormethiazole significantly increased the duration of sleep when compared with placebo (standardized mean difference = 0.61; 95% confidence interval = 0.11-1.11; p = 0.02). More patients receiving chlormethiazole had adequate quality of sleep than those receiving other drugs (odds ratio = 1.44; 95% confidence interval = 1.04-1.98; p = 0.03). No differences were found regarding the onset of sleep (standardized mean difference = 1.07; 95% confidence interval = 0.79-1.46; p = 0.65). Drop-out rates were significantly lower under chlormethiazole treatment when compared with other drugs (odds ratio = 0.51; 95% confidence interval = 0.26-0.99; p = 0.05) and did not differ from placebo treatment (odds ratio = 1.37; 95% confidence interval = 0.23-8.21; p = 0.73). Side-effects such as "hangover" and daytime drowsiness occurred less frequently during chlormethiazole treatment compared with other drugs in three out of four studies, but differences were not significant (odds ratio = 0.24; 95% confidence interval = 0.04-1.48; p = 0.12). In conclusion, chlormethiazole showed significant effects on the duration and the quality of sleep with better tolerability if compared with other drugs in older adults with insomnia., (© 2023 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Passing the driving school test can be very challenging, especially in big cities, where up to 52% of all students fail this test. Consequently, many learner drivers experience stress and anxiety. For some learner drivers these feelings can be extreme and negatively affect the performance in the driving test. Different strategies to face anxiety and stress are known, including, for example, psychological or pharmacological approaches and even placebo pills. Recent intriguing findings have also demonstrated that placebos without deception, so-called open-label placebos, successfully reduce anxiety. Here we aimed to test effects of this novel treatment for learner drivers. We investigated whether open-label placebos affect test performance and feelings of anxiety in learner drivers. Sixty-eight healthy participants (mean age 21.94 years, 26 females) were randomized into two groups. The open-label placebo group received placebo pills two weeks before the driving test (two pills each day). The control group received no treatment. Results revealed that the open-label placebo group experienced significantly less anxiety than the control group before the test (measured with the State-Trait-Anxiety-Inventory, STAI-S, and the German Test Anxiety Inventory, PAF). Moreover, in the open-label placebo group less learner drivers failed the driving test (29.41% vs. 52.95%). The results suggest that open-label placebos may provide an ethical unproblematic way to experience less anxiety and might also enhance the probability to pass the driving test. We discuss possible mechanisms of open-label placebos and limitations of our findings., (© 2024. The Author(s).)

Background and Aims: The muscle retracting sign (MRS) can be present during endoscopic submucosal dissection (ESD) of macronodular colorectal lesions. The prevalence of MRS and its pathologic and clinical implications is unclear. This study evaluated the effect of MRS on the technical and clinical outcomes of ESD., Methods: All patients referred for ESD of protruding lesions or granular mixed lesions with >10 mm macronodule granular mixed laterally spreading tumors (LST-GMs) in 2 academic centers from January 2017 to October 2022 were prospectively included. Size of the macronodule was analyzed retrospectively. The primary outcome was the curative resection rate according to MRS status. Secondary outcomes were R0 resection, perforation, secondary surgery rate, and risk factors for MRS., Results: Of 694 lesions, 84 (12%) had MRS (MRS+). The curative resection rate was decreased by MRS (MRS+ 41.6% vs lesions without MRS [MRS-] 81.3%), whereas the perforation (MRS+ 22.6% vs MRS- 9.2%), submucosal cancer (MRS+ 34.9% vs MRS- 9.2%), and surgery (MRS+ 45.2% vs MRS- 6%) rates were increased. The R0 resection rate of MRS+ colonic lesions was lower than that of rectal lesions (53% vs 74.3%). In multivariate analysis, protruding lesions (odds ratio, 2.47; 95% confidence interval, 1.27-4.80) and macronodules >4 cm (odds ratio, 4.24; 95% confidence interval, 2.23-8.05) were risk factors for MRS., Conclusions: MRS reduces oncologic outcomes and increases the perforation rate. Consequently, procedures in the colon should be stopped if MRS is detected, and those in the rectum should be continued due to the morbidity of alternative therapy., Competing Interests: Disclosure The following authors disclosed financial relationships: J. Albouys: support for meeting from Amgen; consulting for Boston Scientific; remunerated lecture for Fujifilm; and ESD training for Erbe. M. Schaefer: Consultant for AbbVie; honoraria from Alfasigma, Boston Scientific, Duomed Endoscopy, Erbe Medical, Ferring, and Norgine; and meeting support from Boston Scientific, Cook, Cousin Endoscopy, Erbe, Ipsen, Janssen, Medtronic, Olympus, MSD, and Takeda R. Legros: training event for Pentax Medical, Fujifilm, Erbe, Olympus; and consulting for Boston Scientific. P. Leclercq: speaker fee and advisory board for Medtronic; speaker fee for Erbe; and travel grant from Olympus. M. Dahan: remunerated lecture for MSD; meeting support from Amgen; and training event for Fujifilm. A. Guyot: remunerated lecture for MSD. P. Carrier: consulting for AbbVie; support for meeting from Ipsen; and remunerated lecture for Gilead. V. Loustaud-Ratti: consulting for AbbVie and Gilead; and remunerated lecture for Ipsen. H. Lepetit: remunerated lecture for Fujifilm; and ESD training for Erbe. S. Geyl: remunerated lecture for AbbVie, Galapagos, and Ipsen; and support for meeting from Janssen and Takeda. T. Wallenhorst: training event for Fujifilm and Olympus; and support for meeting from AbbVie. M. Pioche: training event for Olympus, Fujifilm, and Viatris; and educational purposes for Boston Scientific, Olympus, Norgine, and AlfaSigma. J. Jacques: training event for Pentax Medical, Fujifilm, Erbe, and Olympus; and consulting for Boston Scientific. All other authors disclosed no financial relationships., (Copyright © 2024. Published by Elsevier Inc.)

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background and Aims: We aimed to compare the long-term outcomes of patients with high-risk T1 colorectal cancer (CRC) resected endoscopically who received either additional surgery or surveillance., Methods: We used data from routine care to emulate a target trial aimed at comparing 2 strategies after endoscopic resection of high-risk T1 CRC: surgery with lymph node dissection (treatment group) versus surveillance alone (control group). All patients from 14 tertiary centers who underwent an endoscopic resection for high-risk T1 CRC between March 2012 and August 2019 were included. The primary outcome was a composite outcome of cancer recurrence or death at 48 months., Results: Of 197 patients included in the analysis, 107 were categorized in the treatment group and 90 were categorized in the control group. From baseline to 48 months, 4 of 107 patients (3.7%) died in the treatment group and 6 of 90 patients (6.7%) died in the control group. Four of 107 patients (3.7%) in the treatment group experienced a cancer recurrence and 4 of 90 patients (4.4%) in the control group experienced a cancer recurrence. After balancing the baseline covariates by inverse probability of treatment weighting, we found no significant difference in the rate of death and cancer recurrence between patients in the 2 groups (weighted hazard ratio, .95; 95% confidence interval, .52-1.75)., Conclusions: Our study suggests that patients with high-risk T1 CRC initially treated with endoscopic resection may not benefit from additional surgery., Competing Interests: Disclosure J Albouys: Consultant for Boston Scientific; speaker for Mayoly; ESD training program for Fujifilm and Erbe; conference funding from Amgen. V Lepilliez: Consultant for and endoscopic training from Olympus. G Rahmi: Consultant for Medtronic, Fujifilm, and Apollo Endosurgery. M Barret: Endoscopic training sessions for Olympus; consultant for Fujifilm; research grant from Pentax. All other authors disclosed no financial relationships., (Copyright © 2024 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

The matrix metalloprotease ADAMTS7 has been identified by multiple genome-wide association studies as being involved in the development of coronary artery disease. Subsequent research revealed the proteolytic function of the enzyme to be relevant for atherogenesis and restenosis after vessel injury. Based on a publicly known dual ADAMTS4/ADAMTS5 inhibitor, we have in silico designed an ADAMTS7 inhibitor of the catalytic domain, which served as a starting point for an optimization campaign. Initially our inhibitors suffered from low selectivity vs MMP12. An X-ray cocrystal structure inspired us to exploit amino acid differences in the binding site of MMP12 and ADAMTS7 to improve selectivity. Further optimization composed of employing 5-membered heteroaromatic groups as hydantoin substituents to become more potent on ADAMTS7. Finally, fine-tuning of DMPK properties yielded BAY-9835, the first orally bioavailable ADAMTS7 inhibitor. Further optimization to improve selectivity vs ADAMTS12 seems possible, and a respective starting point could be identified.

Objectives: Adolescents with cancer often experience significant symptom burden and aggressive treatment near end-of-life. Increased adolescent involvement in care and decision-making may benefit health outcomes. Limited research has examined factors associated with adolescents' involvement in care in the context of advanced disease. Thus, we examined the impact of background factors and decision-making perceptions on both adolescents' involvement in care and their desired change in involvement., Methods: Adolescents with advanced cancer (<60% survival or refractory/relapsed disease), ages 10-23 ( n = 41; M age = 15.37), were recruited approximately 1 month after diagnosis to complete measures of decision-making perceptions and their family role. Hierarchical regressions examined the contributions of background factors and decision-making perceptions to adolescents' frequency and desired involvement in their care. Qualitative interviews regarding decision-making were analyzed using deductive analysis., Results: The model examining frequency of involvement in care was significant, F (5,34) = 3.12, p = .02, R 2 = .31. Older age was the only significant predictor ( β = .13, p = .003). The model examining desired involvement was non-significant, F (5,34) = 2.22, p = .075. Qualitative analysis indicated that (1) older adolescents have more involvement in decision-making, (2) collaborative decision-making occurred between the adolescent and extended family, and (3) adolescents trusted others to make decisions. Integration of qualitative and quantitative data revealed congruence in findings., Significance of Results: Adolescents with advanced cancer, who consider how decisions directly impact them and prefer greater autonomy, may be more involved in their medical care. Research is needed to identify other longitudinal predictors of decision-making and involvement in care. Providers should consider encouraging families to communicate their preferences and engage in shared decision-making.

Objective: Approximately one third of individuals worldwide have not received a COVID-19 vaccine. Although studies have investigated risk factors linked to severe COVID-19 among unvaccinated people with rheumatic diseases (RDs), we know less about whether these factors changed as the pandemic progressed. We aimed to identify risk factors associated with severe COVID-19 in unvaccinated individuals in different pandemic epochs corresponding to major variants of concern., Methods: Patients with RDs and COVID-19 were entered into the COVID-19 Global Rheumatology Alliance Registry between March 2020 and June 2022. An ordinal logistic regression model (not hospitalized, hospitalized, and death) was used with date of COVID-19 diagnosis, age, sex, race and/or ethnicity, comorbidities, RD activity, medications, and the human development index (HDI) as covariates. The main analysis included all unvaccinated patients across COVID-19 pandemic epochs; subanalyses stratified patients according to RD types., Results: Among 19,256 unvaccinated people with RDs and COVID-19, those who were older, male, had more comorbidities, used glucocorticoids, had higher disease activity, or lived in lower HDI regions had worse outcomes across epochs. For those with rheumatoid arthritis, sulfasalazine and B-cell-depleting therapy were associated with worse outcomes, and tumor necrosis factor inhibitors were associated with improved outcomes. In those with connective tissue disease or vasculitis, B-cell-depleting therapy was associated with worse outcomes., Conclusion: Risk factors for severe COVID-19 outcomes were similar throughout pandemic epochs in unvaccinated people with RDs. Ongoing efforts, including vaccination, are needed to reduce COVID-19 severity in this population, particularly in those with medical and social vulnerabilities identified in this study., (© 2023 American College of Rheumatology.)

Introduction: When initial resection of rectal neuroendocrine tumors (r-NETs) is not R0, persistence of local residue could lead to disease recurrence. This study aimed to evaluate the interest of systematic resection of non-R0 r-NET scars., Methods: Retrospective analysis of all the consecutive endoscopic revisions and resections of the scar after non-R0 resections of r-NETs., Results: A total of 100 patients were included. Salvage endoscopic procedure using endoscopic submucosal dissection or endoscopic full-thickness resection showed an R0 rate of near 100%. Residual r-NET was found in 43% of cases., Discussion: In case of non-R0 resected r-NET, systematic scar resection by endoscopic full-thickness resection or endoscopic submucosal dissection seems necessary., (Copyright © 2023 by The American College of Gastroenterology.)

Malignant distal biliary obstructions are becoming increasingly common, especially in patients with cancers of the pancreatic head, despite progress in medical oncology research. ERCP is the current gold standard for management of such strictures, but the emergence of EC-LAMS has rendered EUS-CDS both safe and efficient. It is a "game changer"; originally intended for ERCP failure, two randomised clinical trials recently proposed EUS-CDS as a first-intent procedure in palliative settings. For resectable diseases, the absence of iatrogenic pancreatitis associated with a lower rate of postsurgical adverse events (compared with ERCP) leads us to believe that EUS-CDS might be used in first-intent as a pre-operative endoscopic biliary drainage.

Background: Endoscopic resection of adenomas prevents colorectal cancer, but the optimal technique for larger lesions is controversial. Piecemeal endoscopic mucosal resection (EMR) has a low adverse event (AE) rate but a variable recurrence rate necessitating early follow-up. Endoscopic submucosal dissection (ESD) can reduce recurrence but may increase AEs., Objective: To compare ESD and EMR for large colonic adenomas., Design: Participant-masked, parallel-group, superiority, randomized controlled trial. (ClinicalTrials.gov: NCT03962868)., Setting: Multicenter study involving 6 French referral centers from November 2019 to February 2021., Participants: Patients with large (≥25 mm) benign colonic lesions referred for resection., Intervention: The patients were randomly assigned by computer 1:1 (stratification by lesion location and center) to ESD or EMR., Measurements: The primary end point was 6-month local recurrence (neoplastic tissue on endoscopic assessment and scar biopsy). The secondary end points were technical failure, en bloc R0 resection, and cumulative AEs., Results: In total, 360 patients were randomly assigned to ESD ( n  = 178) or EMR ( n  = 182). In the primary analysis set ( n  = 318 lesions in 318 patients), recurrence occurred after 1 of 161 ESDs (0.6%) and 8 of 157 EMRs (5.1%) (relative risk, 0.12 [95% CI, 0.01 to 0.96]). No recurrence occurred in R0-resected cases (90%) after ESD. The AEs occurred more often after ESD than EMR (35.6% vs. 24.5%, respectively; relative risk, 1.4 [CI, 1.0 to 2.0])., Limitation: Procedures were performed under general anesthesia during hospitalization in accordance with the French health system., Conclusion: Compared with EMR, ESD reduces the 6-month recurrence rate, obviating the need for systematic early follow-up colonoscopy at the cost of more AEs., Primary Funding Source: French Ministry of Health., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-1812.

Globally, 6 million coral reef fishers provide ~25% of emergent countries' catch, but species have low value. The marine aquarium trade (MAT) targets high-value biodiversity, but missing data amplify draconian governance and demand for international prohibition. To stimulate sustainability and reef conservation investment, we generate a fiscal baseline using the first global analysis of numbers, diversity, and biomass of MAT-traded organisms. Each year, ~55 million organisms worth US$2.15 billion at retail are traded comparable with major fisheries, e.g., tuna. A sustainable MAT also requires overexploitation assessments. We identify 25 species/genera with "Extremely High" risk ratios and place the Indonesian and Sulu-Celebes Seas in the highest exploitation category. Despite predicted hobbyist number increases, unabated reef degradation and low governance will transform the MAT into an aquaculture-dominated industry decoupled from communities (i.e., culture located in importing countries). A "MAT-positive" future requires evidence-based management/governance, consumer education, and sustainable practice incentivization but can address the biodiversity and social and economic inequality crises.

Competing Interests: The authors declare that they have no conflict of interest.

Competing Interests: M. Schaefer and J. Jacques have received honoraria from ERBE Medical for educational purposes.

Chagas disease (CD), caused by Trypanosoma cruzi ( T. cruzi ) protozoa, is a complicated parasitic illness with inadequate medical measures for diagnosing infection and monitoring treatment success. To address this gap, we analyzed changes in the metabolome of T. cruzi -infected mice via liquid chromatography tandem mass spectrometry of clinically accessible biofluids: saliva, urine, and plasma. Urine was the most indicative of infection status across mouse and parasite genotypes. Metabolites perturbed by infection in urine include kynurenate, acylcarnitines, and threonylcarbamoyladenosine. Based on these results, we sought to implement urine as a tool for the assessment of CD treatment success. Strikingly, it was found that mice with parasite clearance following benznidazole antiparasitic treatment had an overall urine metabolome comparable to that of mice that failed to clear parasites. These results provide a complementary hypothesis to explain clinical trial data in which benznidazole treatment did not improve patient outcomes in late-stage disease, even in patients with successful parasite clearance. Overall, this study provides insights into new small-molecule-based CD diagnostic methods and a new approach to assess functional responses to treatment.

INTRODUCTION : Residual colorectal neoplasia (RCN) after previous endoscopic mucosal resection is a frequent challenge. Different management techniques are feasible including endoscopic full-thickness resection using the full-thickness resection device (FTRD) system and endoscopic submucosal dissection (ESD). We aimed to compare the efficacy and safety of these two techniques for the treatment of such lesions. METHODS : All consecutive patients with RCN treated either using the FTRD or by ESD were retrospectively included in this multicenter study. The primary outcome was the R0 resection rate, defined as an en bloc resection with histologically tumor-free lateral and deep margins. RESULTS : 275 patients (median age 70 years; 160 men) who underwent 177 ESD and 98 FTRD procedures for RCN were included. R0 resection was achieved in 83.3 % and 77.6 % for ESD and FTRD, respectively ( P  = 0.25). Lesions treated by ESD were however larger than those treated by FTRD ( P  < 0.001). The R0 rates for lesions of 20-30 mm were 83.9 % and 57.1 % in the ESD and FTRD groups, respectively, and for lesions of 30-40 mm were 93.6 % and 33.3 %, respectively. On multivariable analysis, ESD procedures were associated with statistically higher en bloc and R0 resection rates after adjustment for lesion size ( P  = 0.02 and P  < 0.001, respectively). The adverse event rate was higher in the ESD group (16.3 % vs. 5.1 %), mostly owing to intraoperative perforations. CONCLUSION:  ESD is effective in achieving R0 resection for RCN whatever the size and location of the lesions. When residual lesions are smaller than 20 mm, the FTRD is an effective alternative., Competing Interests: C. Yzet has received consultancy and lecture fees from Abbvie, Takeda, Jansen, Amgen, and Galapagos. Y. Le Baleur has provided training sessions for Ovesco Endoscopy AG. J. Jacques has provided ESD training sessions for Olympus, Fuji, Erbe, Pentax, and Lumendi and has received lecture fees from Abbvie, Janssen, and Norgine. M. Barret is on the boards of Norgine and Ambu, and has received research grants from Pentax. M. Shaefer has provided training sessions for Boston Scientific, and has received congress invitations from Olympus, Cook, Cousin Medical, Boston Scientific, Pentax, Abbvie, MSD, Amgen, and Norgine. S. Leblanc has received consulting and lecture fees from Norgine, Olympus, Alfasigma, and Ovesco. J. Rivory has provided training sessions in endoscopy and endoscopic resection for Olympus, and Cook Medical.E. Coron had a speaker's and consultancy agreement with Fujifilm. G. Vanbiervliet has provided consultancy for Boston Scientific, Cook Medical, Fujifilm Inc., and Ambu, and has provided expert lectures/medical training for Boston Scientific, Cook Medical, Mayloy Spindler, Pentax Inc., Fujifilm Inc., and Tillotts. M. Pioche has provided training sessions in endoscopy and endoscopic resection for Olympus, Cook Medical, Boston Scientific, and Pentax Medical, and in endoscopic characterization with Norgine and Provepharm; he received an invitation to UEGW from AlfaSigma; he holds a patent with his institution, Hospices civils de Lyon, for the IPEFIX device.J. Albouys, P. Mandengue, E. Abou Ali, J.-B. Chevaux, V. Lepillez, J. Privat, T. Degand, T. Wallenhorst, U. Chaput, A. Berger, K. Aziz, G. Rahmi, E. Kull, L. Caillo, S. Koch, and F. Subtil declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background and Purpose: In macrophages, transient receptor potential vanilloid 2 (TRPV2) channel contributes to various cellular processes such as cytokine production, differentiation, phagocytosis and migration. Due to a lack of selective pharmacological tools, its function in immunological processes is not well understood and the identification of novel and selective TRPV2 modulators is highly desirable., Experimental Approach: Novel and selective TRPV2 modulators were identified by screening a compound library using Ca 2+ influx assays with human embryonic kidney 293 (HEK293) cells heterologously expressing rat TRPV2. Hits were further characterized and validated with Ca 2+ influx and electrophysiological assays. Phagocytosis and migration of macrophages were analysed and the contribution of TRPV2 to the generation of Ca 2+ microdomains was studied by total internal reflection fluorescence microscopy (TIRFM)., Key Results: The compound IV2-1, a dithiolane derivative (1,3-dithiolan-2-ylidene)-4-methyl-5-phenylpentan-2-one), is a potent inhibitor of heterologously expressed TRPV2 channels (IC 50  = 6.3 ± 0.7 μM) but does not modify TRPV1, TRPV3 or TRPV4 channels. IV2-1 also inhibits TRPV2-mediated Ca 2+ influx in macrophages. IV2-1 inhibits macrophage phagocytosis along with valdecoxib and after siRNA-mediated knockdown. Moreover, TRPV2 inhibition inhibits lipopolysaccharide-induced migration of macrophages whereas TRPV2 activation promotes migration. After activation, TRPV2 shapes Ca 2+ microdomains predominantly at the margin of macrophages, which are important cellular regions to promote phagocytosis and migration., Conclusions and Implications: IV2-1 is a novel TRPV2-selective blocker and underline the role of TRPV2 in macrophage-mediated phagocytosis and migration. Furthermore, we provide evidence that TRPV2 activation generates Ca 2+ microdomains, which may be involved in phagocytosis and migration of macrophages., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Objectives: Children with congenital heart disease (CHD) undergoing cardiac surgery on cardiopulmonary bypass (CPB) are at risk for systemic inflammation leading to endothelial dysfunction associated with increased morbidity. Bioactive adrenomedullin (bio-ADM) is a peptide regulating vascular tone and endothelial permeability. The aim of this study was to evaluate the dynamics of plasma bio-ADM in this patient cohort and its role in capillary leak., Methods: Plasma samples from 73 pediatric CHD patients were collected for bio-ADM measurement at five different timepoints (TP) in the pre-, intra-, and post-operative period. The primary endpoint was a net increase in bio-ADM levels after surgery on CPB. Secondary endpoints included association of bio-ADM levels with clinical signs for endothelial dysfunction., Results: Bio-ADM levels increased after surgery on CPB from pre-operative median of 12 pg/mL (IQR [interquartile range] 12.0-14.8 pg/mL) to a maximum post-operative median of 48.8 pg/mL (IQR 34.5-69.6 pg/mL, p<0.001). Bio-ADM concentrations correlated positively with post-operative volume balance, (r=0.341; p=0.005), increased demand for vasoactive medication (duration: r=0.415; p<0.001; quantity: TP3: r=0.415, p<0.001; TP4: r=0.414, p<0.001), and hydrocortisone treatment for vasoplegia (bio-ADM median [IQR]:129.1 [55.4-139.2] pg/mL vs. 37.9 [25.2-64.6] pg/mL; p=0.034). Patients who required pleural effusion drainage revealed higher bio-ADM levels compared to those who did not (median [IQR]: 66.4 [55.4-90.9] pg/mL vs. 40.2 [28.2-57.0] pg/mL; p<0.001)., Conclusions: Bio-ADM is elevated in children after cardiac surgery and higher levels correlate with clinical signs of capillary leakage. The peptide should be considered as biomarker for endothelial dysfunction and as potential therapeutic target in this indication., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Background and Aims: Endoscopic submucosal dissection (ESD) is challenging for appendicular lesions. We report the outcomes of ESD in this context., Methods: We collected data of ESD procedures for appendiceal neoplasia in a multicenter prospective registry. Main study endpoints were R0, en-bloc, and curative resection rates and adverse event rate., Results: One hundred twelve patients were included, 47 (42%) with previous appendectomy. Fifty-six (50%) were Toyonaga type 3 lesions (15 [13.4%] postappendectomy). En-bloc and R0 resection rates were 86.6% and 80.4%, respectively, with no significant difference associated with different grades of appendiceal invasion (P = .9 and P = .4, respectively) or previous appendectomy (P = .3 for both). The curative resection rate was 78.6%. Additional surgery was performed in 16 cases (14.3%), including 10 (62.5%) Toyonaga type 3 lesions (P = .04). This included the treatment of 5 cases (4.5%) of delayed perforation and 1 acute appendicitis., Conclusions: ESD for appendicular lesions is a potentially safer and effective alternative to surgery for a significant proportion of patients., (Copyright © 2023 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)