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A number of molecular typing methods have been developed for characterization of Staphylococcus aureus isolates. The utility of these systems depends on the nature of the investigation for which they are used. We compared two commonly used methods of molecular typing, multilocus sequence typing (MLST) (and its clustering algorithm, Based Upon Related Sequence Type [BURST]) with the staphylococcal protein A ( spa) typing (and its clustering algorithm, Based Upon Repeat Pattern [BURP]), to assess the utility of these methods for macroepidemiology and evolutionary studies of S. aureus in the United States. We typed a total of 366 clinical isolates of S. aureus by these methods and evaluated indices of diversity and concordance values. Our results show that, when combined with the BURP clustering algorithm to delineate clonal lineages, spa typing produces results that are highly comparable with those produced by MLST/BURST. Therefore, spa typing is appropriate for use in macroepidemiology and evolutionary studies and, given its lower implementation cost, this method appears to be more efficient. The findings are robust and are consistent across different settings, patient ages, and specimen sources. Our results also support a model in which the methicillin-resistant S. aureus (MRSA) population in the United States comprises two major lineages (USA300 and USA100), which each consist of closely related variants. [ABSTRACT FROM AUTHOR]

Monoacylglycerol lipase (MAGL) is a key enzyme involved in the metabolism of the endogenous signaling ligand 2-arachidonoylglycerol, a neuroprotective endocannabinoid intimately linked to central nervous system (CNS) disorders associated with neuroinflammation. In the quest for novel MAGL inhibitors, a focused screening approach on a Roche library subset provided a reversible benzoxazinone hit exhibiting high ligand efficiency. The subsequent design of the three-dimensional cis -hexahydro-pyrido-oxazinone ( cis -HHPO) moiety as benzoxazinone replacement enabled the combination of high MAGL potency with favorable ADME properties. Through enzymatic resolution an efficient synthetic route of the privileged cis -(4 R ,8 S ) HHPO headgroup was established, providing access to the highly potent and selective MAGL inhibitor 7o . Candidate molecule 7o matches the target compound profile of CNS drugs as it achieves high CSF exposures after systemic administration in rodents. It engages with the target in the brain and modulates neuroinflammatory processes, thus holding great promise for the treatment of CNS disorders.

The endocannabinoid system (ECS) is a critical regulatory network composed of endogenous cannabinoids (eCBs), their synthesizing and degrading enzymes, and associated receptors. It is integral to maintaining homeostasis and orchestrating key functions within the central nervous and immune systems. Given its therapeutic significance, we have launched a series of drug discovery endeavors aimed at ECS targets, including peroxisome proliferator-activated receptors (PPARs), cannabinoid receptors types 1 (CB1R) and 2 (CB2R), and monoacylglycerol lipase (MAGL), addressing a wide array of medical needs. The pursuit of new therapeutic agents has been enhanced by the creation of specialized labeled chemical probes, which aid in target localization, mechanistic studies, assay development, and the establishment of biomarkers for target engagement. By fusing medicinal chemistry with chemical biology in a comprehensive, translational end-to-end drug discovery strategy, we have expedited the development of novel therapeutics. Additionally, this strategy promises to foster highly productive partnerships between industry and academia, as will be illustrated through various examples., (Copyright 2024 Johannes Aebi, Kenneth Atz, Simon M. Ametamey, Jörg Benz, Julie Blaising, Stefania Butini, Giuseppe Campiani, Erick M. Carreira, Ludovic Collin, Eva de Lago, Thais Gazzi, Jürg Gertsch, Luca Gobbi, Wolfgang Guba, Javier Fernández-Ruiz, Jürgen Fingerle, Ahmed Haider, Yingfang He, Laura H. Heitman, Michael Honer, Daniel Hunziker, Bernd Kuhn, Mauro Maccarrone, Hans Peter Märki, Rainer E. Martin, Peter Mohr, Linjing Mu, Marc Nazaré, David F. Nippa, Sergio Oddi, Fionn O’Hara, Pal Pacher, Julian Romero, Stephan Röver, Arne C. Rufer, Roger Schibli, Gisbert Schneider, Antonia F. Stepan, David A. Sykes, Christoph Ullmer, Mario van der Stelt, Dmitry B. Veprintsev, Matthias B. Wittwer, Uwe Grether. License: This work is licensed under a Creative Commons Attribution 4.0 International License.)

Astrocytes express ionotropic receptors, including N-methyl-D-aspartate receptors (NMDARs). However, the contribution of NMDARs to astrocyte-neuron interactions, particularly in vivo, has not been elucidated. Here we show that a knockdown approach to selectively reduce NMDARs in mouse cortical astrocytes decreases astrocyte Ca 2+ transients evoked by sensory stimulation. Astrocyte NMDAR knockdown also impairs nearby neuronal circuits by elevating spontaneous neuron activity and limiting neuronal recruitment, synchronization, and adaptation during sensory stimulation. Furthermore, this compromises the optimal processing of sensory information since the sensory acuity of the mice is reduced during a whisker-dependent tactile discrimination task. Lastly, we rescue the effects of astrocyte NMDAR knockdown on neurons and improve the tactile acuity of the animal by supplying exogenous ATP. Overall, our findings show that astrocytes can respond to nearby neuronal activity via their NMDAR, and that these receptors are an important component for purinergic signaling that regulate astrocyte-neuron interactions and cortical sensory discrimination in vivo., (© 2024. The Author(s).)

Background and study aims Telemedicine has progressed significantly in recent years, with newer, more integrated information technology systems improving healthcare delivery. The development of the world's first cloud-based capsule platform could allow safe and timely virtual analysis of videos from a network of linked hospital centers. We aimed to assess the efficacy of Medtronic's PillCam Remote Reader System. Methods PillCam remote reader technical data were collected from the capsule endoscopy (CE) database over 8 months. User-reported performance was collect using an online survey. Outcomes included overall procedure success, video-upload/report-download rates and speeds, encryption/decryption rates, and user/reader satisfaction. Results Data from 377 studies encompassing seven different readers was collected (318 small bowel capsules, 59 colon capsules). Overall procedure success was 100% (all videos reported). Two upload delays occurred (< 24 hours). There were no encryption/decryption errors. Seven of seven respondents felt it easy to access and use vs one of seve for the old system. Six of seven respondents felt department efficiency increased. Benefits included off-site reading and multisite-conferences. Issues included offsite difficulty accessing other hospital systems. Conclusions PillCam remote reader is a reliable, secure, and effective capsule analysis platform and should be incorporated into any CE service development plan., Competing Interests: Conflict of Interest The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

This study aimed to evaluate ( R )-[ 18 F]YH134 as a novel PET tracer for imaging monoacylglycerol lipase (MAGL). Considering the ubiquitous expression of MAGL throughout the whole body, the impact of various MAGL inhibitors on ( R )-[ 18 F]YH134 brain uptake and its application in brain-periphery crosstalk were explored. Methods: MAGL knockout and wild-type mice were used to evaluate ( R )-[ 18 F]YH134 in in vitro autoradiography and PET experiments. To explore the impact of peripheral MAGL occupancy on ( R )-[ 18 F]YH134 brain uptake, PET kinetics with an arterial input function were studied in male Wistar rats under baseline and blocking conditions. Results: In in vitro autoradiography, ( R )-[ 18 F]YH134 revealed a heterogeneous distribution pattern with high binding to MAGL-rich brain regions in wild-type mouse brain slices, whereas the radioactive signal was negligible in MAGL knockout mouse brain slices. The in vivo brain PET images of ( R )-[ 18 F]YH134 in wild-type and MAGL knockout mice demonstrated its high specificity and selectivity in mouse brain. A Logan plot with plasma input function was applied to estimate the distribution volume ( V T ) of ( R F]YH134. 18 F]YH134. V T F]YH134 PET imaging data from the brain. R )-[ 18 F]YH134 PET imaging data from the brain. Conclusion: F]YH134 is a highly specific and selective PET tracer with favorable kinetic properties for imaging MAGL in rodent brain. Our results showed that blocking of the peripheral target influences brain uptake but not the R )-[ 18 F]YH134 is a highly specific and selective PET tracer with favorable kinetic properties for imaging MAGL in rodent brain. Our results showed that blocking of the peripheral target influences brain uptake but not the V F]YH134. ( T of ( R F]YH134 can be used for estimating the dose of MAGL inhibitor at half-maximal peripheral target occupancy.18 F]YH134. ( R )-[ 18 F]YH134 can be used for estimating the dose of MAGL inhibitor at half-maximal peripheral target occupancy., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Capsule retention is one of the major complications of capsule endoscopy, which range from 2.1 to 8.2% depending on the indication. Over the last few years, reported rates of retention have fallen due to better patient selection due to the recognition of risk factors for capsule retention as well as the introduction of the patency capsule. The patency capsule is a dissolvable capsule with the same dimensions as the functional capsule. It breaks down in the GI tract after approximately 30 h, reducing the risk of symptomatic retention. Failure to pass this patency capsule out of the small bowel results in the patient being excluded from capsule endoscopy. We performed a retrospective analysis of the patency capsules performed in our unit over a 12-month period. A total of 166 (14.7%) of 1,127 patients referred for capsule endoscopy were deemed to require patency assessment (45.8% men, mean age 48 years). Of those who passed the patency assessment and underwent capsule endoscopy, no capsule retention was seen. Indication for patency assessment was found to be appropriate in 87.0% ( n = 147). Overall, the failure rate at the patency assessment was 43.1%. The patency capsule remains an imperfect but useful tool in examining functional patency of the GI tract prior to capsule endoscopy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 O'Hara, Walker and McNamara.)

Aims: The primary aim of this study was to assess the reliability, intra- and inter-observer variation of the SPICE, Mucosal protrusion angle (MPA) and SHYUNG scores in differentiating a subepithelial mass (SEM) from a bulge., Methods: This retrospective multicentre study analysed the 3 scores, radiological studies, enteroscopy and/or surgical findings., Results: 100 patients with a potential SEM (mean age 57.6years) were recruited with 75 patients having pathology. In patients with a SEM the mean SPICE score was 2.04 (95% CI 1.82-2.26) as compared to 1.16 (95% CI 0.81-1.51) without any pathology (AUC 0.74, p<0.001), with a fair intra-observer agreement (Kappa 0.3, p<0.001) and slight inter-observer agreement (Kappa 0.14, p<0.05). SPICE had a 37.3% sensitivity and 92.0% specificity in distinguishing between a SEM and bulge, whereas MPA<90˚ had 58.7% and 76.0% respectively, with poor intra-observer(p = 0.05) and interobserver agreement (p = 0.64). The SHYUNG demonstrated a moderate intra-observer (Kappa 0.44, p<0.001) and slight inter-observer reliability (Kappa 0.18, p<0.001). The sensitivity of an elevated SHYUNG score (≥4) in identifying a SEM was 18.7% with a specificity of 92.0% (AUC 0.71, p = 0.002)., Conclusions: Though these scores are easy to use, they have, at best, slight to moderate intra and inter-observer agreement. Their overall diagnostic performances are limited., Competing Interests: Conflict of interest None declared., (Copyright © 2022. Published by Elsevier Ltd.)

Monoacylglycerol lipase (MAGL) is a serine hydrolase that plays an important role in the endocannabinoid degradation in the brain. It has recently emerged as a promising therapeutic target in the treatment of neuroinflammatory and neurodegenerative diseases, such as multiple sclerosis, Alzheimer's disease and Parkinson's disease. Development of MAGL-specific radioligands for non-invasive imaging by positron-emission tomography (PET) would deepen our knowledge on the relevant pathological changes in diseased states and accelerate drug discovery. In this study, we report the selection and synthesis of two morpholine-3-one derivatives as potential reversible MAGL PET tracer candidates based on their multiparameter optimization scores. Both compounds ([ 11 C]1, [ 11 C]2) were radiolabeled by direct [ 11 C]CO 2 fixation and the in vitro autoradiographic studies demonstrated their specificity and selectivity towards MAGL. Dynamic PET imaging using MAGL knockout and wild-type mice confirmed the in vivo specificity of [ 11 C]2. Our preliminary results indicate that morpholine-3-one derivative [ 11 C]2 ([ 11 C]RO7279991) binds to MAGL in vivo, and this molecular scaffold could serve as an alternative lead structure to image MAGL in the central nervous system., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The small bowel is the longest organ within the gastrointestinal tract. The emergence of small bowel capsule endoscopy (SBCE) over the last 20 years has revolutionized the investigation and diagnosis of small bowel pathology. Its utility as a non-invasive and well-tolerated procedure, which can be performed in an outpatient setting, has made it a valuable diagnostic tool. The indications for SBCE include obscure gastrointestinal bleeding, small bowel Crohn's disease, and, less frequently for screening in polyposis syndromes, celiac disease, or other small bowel pathology. Currently, there are several small bowel capsules on the market from different manufacturers; however, they share many technological features. The European Society of Gastrointestinal Endoscopy (ESGE) only recently developed a set of key quality indicators to guide quality standards in this area. Many of the technical aspects of capsule endoscopy still feature a degree of uncertainty in terms of optimal performance. Incomplete studies due to slow transit through the bowel, poor imaging secondary to poor preparation, and the risk of capsule retention remain frustrations in its clinical utility. Capsule review is a time-consuming process; however, artificial intelligence and machine learning offer opportunities to improve this. This narrative review examines our current standing in a number of these aspects and the potential to further the application of SBCE in order to maximize its diagnostic utility.

Background: Incomplete excretion rates are problematic for colon capsule endoscopy (CCE). Widely available booster regimens are suboptimal. Recently published data on one day preparation CCE protocol using castor oil appeared effective., Aim: To assess the impact of adding castor oil to a standard split-dose (2-d) preparation in an unselected Western patient cohort., Methods: All patients aged 18 or more referred to our unit for a CCE over a 5-mo period were prospectively recruited. Controls were retrospectively identified from our CCE database. All patients received split bowel preparation with Moviprep ® [polyethylene glycol (PEG)-3350, sodium sulphate, sodium chloride, potassium chloride, sodium ascorbate and ascorbic acid for oral solution; Norgine B. V, United States], a PEG-based solution used predominantly in our colonoscopy practice. Control booster regimen included Moviprep ® with 750 mL of water (booster 1) on reaching the small bowel. A further dose of Moviprep ® with 250 mL of water was given 3 h later and a bisacodyl suppository (Dulcolax ® ) 10 mg after 8 h, if the capsule was not excreted. In addition to our standard booster regimen, cases received an additional 15 mL of castor oil given at the time of booster 1. A nested case control design with 2:1 ratio (control:case) was employed. Basic demographics, completion rates, image quality, colonic transit time, diagnostic yield and polyp detection were compared between groups, using a student t or chi-square tests as appropriate., Results: One hundred and eighty-six CCEs [mean age 60 years (18-97), 56% females, n = 104], including 62 cases have been analysed. Indication breakdown included 96 polyp surveillance (51.6%), 42 lower gastrointestinal symptoms (22.6%), 28 due to incomplete colonoscopy (15%), 18 anaemia (9.7%) and 2 inflammatory bowel disease surveillance (1.1%). Overall, CCE completion was 77% (144/186), image quality was adequate/diagnostic in 91% (170/186), mean colonic transit time was 3.5 h (0.25-13), and the polyp detection rate was 57% (106/186). Completion rates were significantly higher with castor oil, 87% cases (54/62) vs 73% controls (90/124), P = 0.01. The number needed to treat with castor oil to result in an additional complete CCE study was 7, absolute risk reduction = 14.52%, 95% confidence interval (CI): 3.06- 25.97. This effect of castor oil on excretion rates was more significant in the over 60 s, P < 0.03, and in females, P < 0.025. Similarly, polyp detection rates were higher in cases 82% (51/62) vs controls 44% (55/124), P = 0.0001, odds ratio 5.8, 95%CI: 2.77-12.21. Colonic transit times were similar, 3.2 h and 3.8 h, respectively. Image quality was similar, reported as adequate/diagnostic in 90% (56/62) vs 92% (114/124)., Conclusion: In our capsule endoscopy centre, castor oil addition as a CCE booster significantly improved completion rates and polyp detection in an unselected Western cohort., Competing Interests: Conflict-of-interest statement: The authors declare no conflicts of interest for this article., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Huntington's disease (HD) is a genetic condition resulting in movement, behavioural and cognitive impairments. People with HD have low levels of physical activity which may be compounded by insufficient support from health-care professionals., Objective: To evaluate the initial acceptability of a co-designed tool used within a HD clinic to promote physical activity., Design: Co-design of a physical activity tool; acceptability evaluation., Setting and Participants: Co-design included people with HD and health-care professionals. Acceptability was evaluated in a HD clinic in the UK., Main Variables Studied: A physical activity tool was co-designed and used within a HD clinic., Main Outcome Measure: Acceptability as assessed by semi-structured interviews with members of the HD clinic., Results: Forty people visited the HD clinic; 19 were given physical activity advice. Themes around who, where and how promotion of physical activity could take place were identified; concepts of benefits and barriers were threads through each theme., Discussion: We describe for the first time the co-design of a HD specific physical activity tool. Our associated acceptability study emphasizes the importance of individualized planning of physical activities in complex neurodegenerative conditions. Perceived barriers were time and lack of knowledge of local resources., Conclusions: A simple tool can support conversations about physical activity with people with HD and is an aid to individualized goal setting. Exploring the use of PAT-HD within a community setting and development of support systems for health-care professionals and support workers who are in regular contact with people with HD is required., (© 2021 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Khat consumption is an under-recognised cause of hypertensive encephalopathy and intraparenchymal brain haemorrhage. We report the radiological findings of extensive periventricular, subcortical and brain stem white matter pathology of a patient who had consumed excessive amounts of Khat. The Khat plant contains cathinone, an amphetamine-like alkaloid which has been associated with chronic hypertensive end-organ damage, but is seldom considered a cause of cerebrovascular events in northern Europe.

A sequential CH functionalization strategy for the synthesis of the marine alkaloid dictyodendrin B is reported. Our synthesis begins from commercially available 4-bromoindole and involves six direct functionalizations around the heteroarene core as part of a gram-scale strategy towards the natural product., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)