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Low renal nitric oxide (NO) bioavailability contributes to the development and maintenance of chronic hypertension. We investigated whether impaired L-arginine transport contributes to low renal NO bioavailability in hypertension. Responses of renal medullary perfusion and NO concentration to renal arterial infusions of the L-arginine transport inhibitor L-lysine (10 μmol.kg-1.min-1; 30 min) and subsequent superimposition of L-arginine (100 μmol.kg-1.min-1; 30 min), the NO synthase inhibitor NG-nitro-L-arginine (2.4 mg/kg; iv bolus), and the NO donor sodium nitroprusside (0.24 μg.kg-1.min-1) were examined in Sprague-Dawley rats (SD) and spontaneously hypertensive rats (SHR). Renal medullary perfusion and NO concentration were measured by laser-Doppler flowmetry and polarographically, respectively, 5.5 mm below the kidney surface. Renal medullary NO concentration was less in SHR (53 ± 3 nM) compared with SD rats (108 ± 12 nM; P = 0.004). L-Lysine tended to reduce medullary perfusion (-15 ± 7%; P = 0.07) and reduced medullary NO concentration (-9 ± 3%; P = 0.03) while subsequent superimposition of L-arginine reversed these effects of L-lysine in SD rats. In SHR, L-lysine and subsequent superimposition of L-arginine did not significantly alter medullary perfusion or NO concentration. Collectively, these data suggest that renal L-arginine transport is impaired in SHR. Renal L-[3H]arginine transport was less in SHR compared with SD rats (P = 0.01). Accordingly, we conclude that impaired arginine transport contributes to low renal NO bioavailability observed in the SHR kidney. [ABSTRACT FROM AUTHOR]

A new series of [Co III -CF 3 ] n + complexes supported by a bidentate redox-active ligand is presented. The cationic [Co-CF 3 ] + complex was first obtained by reacting [CpCo( t BuUrea opda)] (Cp = cyclopentadienyl, opda = o -phenylenediamide) with an electrophilic trifluoromethyl source, for which the redox-active phenylenediamide ligand serves as a 2e - reservoir to generate [CpCp( t BuUrea bqdi)(CF 3 )] + (bqdi = benzoquinonediimine). Electrochemical studies of [Co-CF 3 ] + revealed two reversible 1e - reductions. Chemical reduction with 1 or 2 equiv. reducing agent enabled isolation of the neutral and anionic complexes, respectively, where the [Co III -CF 3 ] bond remains intact in all three oxidation states ( n = +1, 0, -1). Structural analysis shows systematic changes to the redox-active ligand backbone upon reduction, consistent with sequential ligand-centered electron transfer in the series [bqdi] 0 to [s-bqdi]˙ - to [opda] 2- . In contrast, the reaction of [CpCo( t BuUrea opda)] with alkyl triflates resulted in ligand-centered alkylation at the ureayl groups instead of the targeted Co-alkyl bond formation, suggesting less favorable bond formation at cobalt and greater nucleophilic accessibility of the ligand compared to the metal center.

Introduction: Remote monitoring technologies (RMTs) can measure cognitive and functional decline objectively at-home, and offer opportunities to measure passively and continuously, possibly improving sensitivity and reducing participant burden in clinical trials. However, there is skepticism that age and cognitive or functional impairment may render participants unable or unwilling to comply with complex RMT protocols. We therefore assessed the feasibility and usability of a complex RMT protocol in all syndromic stages of Alzheimer's disease and in healthy control participants., Methods: For 8 weeks, participants (N = 229) used two activity trackers, two interactive apps with either daily or weekly cognitive tasks, and optionally a wearable camera. A subset of participants participated in a 4-week sub-study (N = 45) using fixed at-home sensors, a wearable EEG sleep headband and a driving performance device. Feasibility was assessed by evaluating compliance and drop-out rates. Usability was assessed by problem rates (e.g., understanding instructions, discomfort, forgetting to use the RMT or technical problems) as discussed during bi-weekly semi-structured interviews., Results: Most problems were found for the active apps and EEG sleep headband. Problem rates increased and compliance rates decreased with disease severity, but the study remained feasible., Conclusions: This study shows that a highly complex RMT protocol is feasible, even in a mild-to-moderate AD population, encouraging other researchers to use RMTs in their study designs. We recommend evaluating the design of individual devices carefully before finalizing study protocols, considering RMTs which allow for real-time compliance monitoring, and engaging the partners of study participants in the research., Competing Interests: JC is an employee and shareholder of Novartis. AD is supported by the Welcome Trust [223100/Z/21/Z]. Research of Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting Steun Alzheimercentrum Amsterdam. DA has received research support and/or honoraria from Astra-Zeneca, H. Lundbeck, Novartis Pharmaceuticals, Biogen, and GE Health, and served as paid consultant for H. Lundbeck, Eisai, Heptares, Mentis Cura, and Roche Diagnostics. IK declares support for this work through the National Institute of Health Research (personal award and Oxford Health Biomedical Research Centre) and the Medical Research Council (Dementias Platform UK grant), and is a paid medical advisor for digital healthcare technology companies (Five Lives SAS and Cognetivity Ltd). All other authors declare that there is no conflict of interest., (© The Author(s) 2024.)

Intestinal motility is governed in part by bioelectrical slow-waves and spike-bursts. Mesenteric ischemia is a substantial clinical challenge, but its electrophysiological and contractile mechanisms are not well understood. Simultaneous high-resolution bioelectrical and video mapping techniques were used to capture the changes in slow-waves, spike-bursts, and contractile activity during baseline, ischemia, and reperfusion periods. Experiments were performed on anesthetized pigs where intestinal contractions were quantified using surface strain and diameter measurements, while slow-wave and spike-bursts were quantified using frequency and amplitude. Slow-waves entrainment within the ischemic region diminished during ischemia, resulting in irregular slow-wave activity and a reduction in the frequency from 12.4 ± 3.0 cycles-per-minute (cpm) to 2.5 ± 2.7 cpm (p = 0.0006). At the end of the reperfusion period, normal slow-wave entrainment was observed at a frequency of 11.5 ± 2.9 cpm. There was an increase in spike-burst activity between the baseline and ischemia periods (1.1 ± 1.4 cpm to 8.7 ± 3.3 cpm, p = 0.0003) along with a spasm of circumferential contractions. At the end of the reperfusion period, the frequency of spike-bursts decreased to 2.7 ± 1.4 cpm, and contractions subsided. The intestine underwent tonal contraction during ischemia, with the diameter decreasing from 29.3 ± 2.6 mm to 21.2 ± 6.2 mm (p = 0.0020). At the end of the reperfusion period, the intestinal diameter increased to 27.3 ± 3.9 mm. The decrease in slow-wave activity, increase in spike-bursts, and tonal contractions can objectively identify ischemic segments in the intestine. It is anticipated that the use of electrophysiological slow-wave and spike-burst biomarkers, along with contractile measures, could identify mesenteric ischemia in surgical settings and allow an objective biomarker for successful revascularization., (© 2023. The Author(s) under exclusive licence to Biomedical Engineering Society.)

Introduction: Clinical research with remote monitoring technologies (RMTs) has multiple advantages over standard paper-pencil tests, but also raises several ethical concerns. While several studies have addressed the issue of governance of big data in clinical research from the legal or ethical perspectives, the viewpoint of local research ethics committee (REC) members is underrepresented in the current literature. The aim of this study is therefore to find which specific ethical challenges are raised by RECs in the context of a large European study on remote monitoring in all syndromic stages of Alzheimer's disease, and what gaps remain., Methods: Documents describing the REC review process at 10 sites in 9 European countries from the project Remote Assessment of Disease and Relapse-Alzheimer's Disease (RADAR-AD) were collected and translated. Main themes emerging in the documents were identified using a qualitative analysis approach., Results: Four main themes emerged after analysis: data management, participant's wellbeing, methodological issues, and the issue of defining the regulatory category of RMTs. Review processes differed across sites: process duration varied from 71 to 423 days, some RECs did not raise any issues, whereas others raised up to 35 concerns, and the approval of a data protection officer was needed in half of the sites., Discussion: The differences in the ethics review process of the same study protocol across different local settings suggest that a multi-site study would benefit from a harmonization in research ethics governance processes. More specifically, some best practices could be included in ethical reviews across institutional and national contexts, such as the opinion of an institutional data protection officer, patient advisory board reviews of the protocol and plans for how ethical reflection is embedded within the study., Competing Interests: The authors have read the journal’s policy and have the following competing interests: IK is a paid medical advisor for digital healthcare technology companies Five Lives SAS and Cognetivity Ltd., outside the submitted work. CA has received honoraria as speaker from F. Hoffmann-La Roche Ltd, Zambon, Nutricia, Schwabe Farma Ibérica S.A.U, outside of the submitted work. CA is a member of the Board of Directors of the Lewy Body Dementia Association, outside the submitted work. DA has received research support and/or honoraria from Astra-Zeneca, H. Lundbeck, Novartis Pharmaceuticals, Biogen, and GE Health, and served as paid consultant for H. Lundbeck, Eisai, Heptares, Mentis Cura, and Roche Diagnostics, outside the submitted work. MB is an employee of the Ace Alzheimer Center and an advisory board member for Grifols, Roche, Eli Lilly, Araclon Biotech, Merck, Zambon, Biogen, Novo Nordisk, Bioiberica, Eisai, Servier, and Schwabe Pharma, outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors have declared that no competing interests exist. There are no patents, products in development or marketed products associated with this research to declare., (Copyright: © 2023 Muurling 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.)

Alzheimer's disease (AD) and other neurodegenerative diseases such as Parkinson's disease (PD) and Huntington's disease (HD) are associated with progressive cognitive, motor, affective and consequently functional decline considerably affecting Activities of Daily Living (ADL) and quality of life. Standard assessments, such as questionnaires and interviews, cognitive testing, and mobility assessments, lack sensitivity, especially in early stages of neurodegenerative diseases and in the disease progression, and have therefore a limited utility as outcome measurements in clinical trials. Major advances in the last decade in digital technologies have opened a window of opportunity to introduce digital endpoints into clinical trials that can reform the assessment and tracking of neurodegenerative symptoms. The Innovative Health Initiative (IMI)-funded projects RADAR-AD ( Remote assessment of disease and relapse-Alzheimer's disease ), IDEA-FAST ( Identifying digital endpoints to assess fatigue, sleep and ADL in neurodegenerative disorders and immune-mediated inflammatory diseases ) and Mobilise-D ( Connecting digital mobility assessment to clinical outcomes for regulatory and clinical endorsement ) aim to identify digital endpoints relevant for neurodegenerative diseases that provide reliable, objective, and sensitive evaluation of disability and health-related quality of life. In this article, we will draw from the findings and experiences of the different IMI projects in discussing (1) the value of remote technologies to assess neurodegenerative diseases; (2) feasibility, acceptability and usability of digital assessments; (3) challenges related to the use of digital tools; (4) public involvement and the implementation of patient advisory boards; (5) regulatory learnings; and (6) the significance of inter-project exchange and data- and algorithm-sharing., Competing Interests: AP received grant support from Ministry of Health (MINSAL) and Ministry of Education, Research and University (MIUR), from Airalzh Foundation, LIMPE-DSIMOV society and MI H2020 initiative (MI2-2018-15-06); he received speaker honoraria from Abbvie, Bial, Biomarin, Roche and Zambon Pharmaceuticals. W-FN has consulted for Novartis, GlaxoSmithKline, Abbvie, BMS, Sanofi, MedImmune, Janssen, Resolve Therapeutics and UCB. LR receives consultancy from MJ Fox Foundation and grant support from the EU, NIHR, MRC, PDUK, Dunhill Medical Trust, Cure Parkinson’s Trust, EPSRC, MJ Fox Foundation. DA has received research support and/or honoraria from Astra-Zeneca, H. Lundbeck, Novartis Pharmaceuticals, Evonik, Roche Diagnostics, and GE Health, and served as paid consultant for H. Lundbeck, Eisai, Heptares, Mentis Cura, Eli Lilly, Cognetivity, Enterin, Acadia, EIP Pharma, and Biogen. JC was employed by Novartis Institutes for Biomedical Research (NIBR), Basel, Switzerland and GE was employed by Novartis Pharmaceuticals Corporations, Cambridge, MA, United States. The remaining 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 Brem, Kuruppu, de Boer, Muurling, Diaz-Ponce, Gove, Curcic, Pilotto, Ng, Cummins, Malzbender, Nies, Erdemli, Graeber, Narayan, Rochester, Maetzler, Aarsland and on behalf of the RADAR-AD Consortium.)

The prevalence of dementia is increasing and poses a health challenge for individuals and society. Despite the desire to know their risks and the importance of initiating early therapeutic options, large parts of the population do not get access to memory clinic-based assessments. Remote memory clinics facilitate low-level access to cognitive assessments by eschewing the need for face-to-face meetings. At the same time, patients with detected impairment or increased risk can receive non-pharmacological treatment remotely. Sensor technology can evaluate the efficiency of this remote treatment and identify cognitive decline. With remote and (partly) automatized technology the process of cognitive decline can be monitored but more importantly also modified by guiding early interventions and a dementia preventative lifestyle. We highlight how sensor technology aids the expansion of assessments beyond cognition and to other domains, e.g., depression. We also illustrate applications for aiding remote treatment and describe how remote tools can facilitate health education which is the cornerstone for long-lasting lifestyle changes. Tools such as transcranial electric stimulation or sleep-based interventions have currently mostly been used in a face-to-face context but have the potential of remote deployment-a step already taken with memory training apps. Many of the presented methods are readily scalable and of low costs and there is a range of target populations, from the worried well to late-stage dementia., 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 © 2022 Owens, Krebs, Kuruppu, Brem, Kowatsch, Aarsland and Klöppel.)

Background/aims: High-resolution extracellular mapping has improved our understanding of bioelectric slow-wave and spike-burst activity in the small intestine. The spatiotemporal correlation of electrophysiology and motility patterns is of critical interest to intestinal function but remains incompletely defined., Methods: Intestinal jejunum segments from in vivo pigs and rabbits were exteriorized, and simultaneous high-resolution extracellular recordings and video recordings were performed. Contractions were quantified with strain fields, and the frequencies and velocities of motility patterns were calculated. The amplitudes, frequencies, and velocities of slow-wave propagation patterns and spike-bursts were quantified and visualized. In addition, the duration, size and energy of spike-burst patches were quantified., Results: Slow-wave associated spike-bursts activated periodically at 10.8 ± 4.0 cycles per minute (cpm) in pigs and 10.2 ± 3.2 cpm in rabbits, while independent spike-bursts activated at a frequency of 3.2 ± 1.8 cpm. Independent spike-bursts had higher amplitude and longer duration than slow-wave associated spike-bursts (1.4 ± 0.8 mV vs 0.1 ± 0.1 mV, P < 0.001; 1.8 ± 1.4 seconds vs 0.8 ± 0.3 seconds, P < 0.001 in pigs). Spike-bursts that activated as longitudinal or circumferential patches were associated with contractions in the respective directions. Spontaneous peristaltic contractions were elicited by independent spike-bursts and travelled slower than slow-wave velocity (3.7 ± 0.5 mm/sec vs 10.1 ± 4.7 mm/sec, P = 0.007). Cyclic peristaltic contractions were driven by slow-wave associated spike-bursts and were coupled to slow-wave velocity and frequency in rabbit (14.2 ± 2.3 mm/sec vs 11.5 ± 4.6 mm/sec, P = 0.162; 11.0 ± 0.6 cpm vs 10.8 ± 0.6 cpm, P = 0.970)., Conclusions: Motility patterns were dictated by patterns of spike-burst patches. When spike-bursts were coupled to slow-waves, periodic motility patterns were observed, while when spike-bursts were not coupled to slow-waves, spontaneous aperiodic motility patterns were captured.

Objective: To develop a method to quantify strain fields from in vivo intestinal motility recordings that mitigate accumulation of tracking error., Methods: The deforming geometry of the intestine in video sequences was modeled by a biquadratic B-spline mesh. Green-Lagrange strain fields were computed to quantify the surface deformations. A nonlinear optimization scheme was applied to mitigate the accumulation of tracking error associated with image registration., Results: The optimization scheme maintained the RMS strain error under 1% and reduced the rate of strain error by 97% during synthetic tests. The algorithm was applied to map 64 segmental, 12 longitudinal, and 23 propagating circular contractions in the jejunum. Coordinated activity of the two muscle layers could be identified and the strain fields were able to map and quantify the anisotropic contractions of the intestine. Frequency and velocity were also quantified, from which two types of propagating circular contractions were identified: (i) [Formula: see text] strain contractions that originated spontaneously and propagated at [Formula: see text] mm/s in two pigs, and (ii) cyclic propagating contractions of [Formula: see text] strain occurred at [Formula: see text] cpm and propagated at [Formula: see text] mm/s in a rabbit., Conclusion: The algorithm simultaneously mapped the circular, longitudinal activity of the intestine with high spatial resolution and quantified anisotropic contractions and relaxations., Significance: The proposed algorithm can now be used to define the interactions of muscle layers during motility patterns. It can be integrated with high-resolution bioelectrical recordings to investigate the regulatory mechanisms of motility.

The National Institutes of Health (NIH) Stimulating Peripheral Activity to Relieve Conditions (SPARC) program seeks to accelerate the development of therapeutic devices that modulate electrical activity in nerves to improve organ function. SPARC-funded researchers are generating rich datasets from neuromodulation research that are curated and shared according to FAIR (Findable, Accessible, Interoperable, and Reusable) guidelines and are accessible to the public on the SPARC data portal. Keeping track of the utilization of these datasets within the larger research community is a feature that will benefit data-generating researchers in showcasing the impact of their SPARC outcomes. This will also allow the SPARC program to display the impact of the FAIR data curation and sharing practices that have been implemented. This manuscript provides the methods and outcomes of SPARClink, our web tool for visualizing the impact of SPARC, which won the Second prize at the 2021 SPARC FAIR Codeathon. With SPARClink, we built a system that automatically and continuously finds new published SPARC scientific outputs (datasets, publications, protocols) and the external resources referring to them. SPARC datasets and protocols are queried using publicly accessible REST application programming interfaces (APIs, provided by Pennsieve and Protocols.io) and stored in a publicly accessible database. Citation information for these resources is retrieved using the NIH reporter API and National Center for Biotechnology Information (NCBI) Entrez system. A novel knowledge graph-based structure was created to visualize the results of these queries and showcase the impact that the FAIR data principles can have on the research landscape when they are adopted by a consortium., Competing Interests: Competing interests: NIH SPARC is the primary funder for the publication of this research article., (Copyright: © 2022 Soundarajan S et al.)