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The unexpected finding that isotopomers (i.e., isotopic isomers) can be separated with high-resolution ion mobility spectrometry–mass spectrometry (IMS–MS) has raised new structural considerations affecting an ion's mobility, namely its center of mass (CoM) and moments of inertia (MoI). Unfortunately, thus far, no studies have attempted to experimentally isolate either CoM or MoI, as they are intrinsically linked by their definitions, where MoI is calculated in relation to CoM. In this study, we designed and synthesized four isotopically labeled tetrapropyl-ammonium (TAA3) ions, each with a unique mass distribution. Three of the synthesized TAA3 ions were labeled symmetrically, thus having identical CoM but differing MoI, which we verified using density functional theory (DFT) calculations. Consequently, we were able to isolate the effect of MoI changes in high-resolution IMS–MS separations. Cyclic ion mobility spectrometry–mass spectrometry (cIMS–MS) separations of the isotopically labeled TAA3 variants revealed isotopic mobility shifts attributable solely to changes in MoI. A 60-m cIMS–MS separation demonstrated that two nominally isobaric TAA3 pseudo-isotopomers could be partially resolved, showcasing potential feasibility for isotopomer separations on commercially available IMS–MS platforms. With our previously established collision cross section (CCS) calibration protocol, we also quantified the relationship between MoI and CCS. Our results represent the first demonstration of IMS–MS separations based solely on MoI differences. We believe these findings will contribute important evidence to the growing body of literature on the physical nature of isotopic shifts in IMS–MS separations and work toward more accurate CCS predictions. [ABSTRACT FROM AUTHOR]

Anthropogenic pressure is increasing the variety and frequency of environmental disturbance events, limiting recovery and leading to long‐term declines in wild plant and animal populations. Coral reefs and associated fish assemblages are inherently dynamic due to their susceptibility to a host of disturbances, but regional‐scale nuances in the drivers of long‐term change frequently remain poorly resolved. Here, we examine the effects of multiple potential drivers of change in coral reef fish assemblages across 4 inshore regions of the Great Barrier Reef Marine Park (GBRMP), Australia, over 12–14 years (2007–2021). Each region had a unique disturbance history, in conjunction with long‐term changes in physical and habitat variables. Phases of recovery were apparent in the years between disturbance events at all locations, but these were not long enough to prevent substantial declines in reef fish density (by 33%–72%) and species richness (by 41%–75%) throughout the study period. The main drivers of change in fish assemblages varied among regions; however, the most rapid changes followed cyclone and flood events. Limited recovery periods resulted in temporal shifts in fish species composition from typically coral‐associated to algae‐associated. Most trophic groups declined in density except farmers, grazers, omnivores and parrotfish. No‐take marine reserves (NTMRs) had small and inconsistent effects on total fish assemblages, but delivered benefits for fishery‐targeted piscivores. Our findings suggest that coral reef responses to local stressors and cumulative escalating climate change impacts are highly variable at regional scales, and that small NTMRs are unlikely to mitigate the impacts of increasingly frequent climatic disturbances. Nearshore coral reefs worldwide are high‐value habitats that are either already degraded or vulnerable to degradation and the loss of important fish groups. Global efforts to reduce greenhouse gas emissions must be coupled with effective local management that can support the functioning and adaptive capacity of coral reefs. [ABSTRACT FROM AUTHOR]

Toxicology studies in early fish life stages serve an important function in measuring the impact of potentially harmful substances, such as crude oil, on marine life. Morphometric analysis of larvae can reveal the effects of such substances in retarding growth and development. These studies are labor intensive and time consuming, typically resulting in only a small number of samples being considered. An automated system for imaging and measurement of experimental animals, using flow-through imaging and an artificial neural network to allow faster sampling of more individuals, has been described previously and used in toxicity experiments. This study compares the performance of the automated imaging and analysis system with traditional microscopy techniques in measuring biologically relevant endpoints using two oil treatments as positive controls. We demonstrate that while the automated system typically underestimates morphometric measurements relative to analysis of manual microscopy images, it shows similar statistical results to the manual method when comparing treatments across most endpoints. It allows for many more individual specimens to be sampled in a shorter time period, reducing labor requirements and improving statistical power in such studies, and is noninvasive allowing for repeated sampling of the same population. [ABSTRACT FROM AUTHOR]

In traumatic brain injury patients (TBI) admitted to the intensive care unit (ICU), agitation can lead to accidental removal of catheters, devices as well as self-extubation and falls. Actigraphy could be a potential tool to continuously monitor agitation. The objectives of this study were to assess the feasibility of monitoring agitation with actigraphs and to compare activity levels in agitated and non-agitated critically ill TBI patients. Actigraphs were placed on patients' wrists; 24-hour monitoring was continued until ICU discharge or limitation of therapeutic efforts. Feasibility was assessed by actigraphy recording duration and missing activity count per day. Data from 25 patients were analyzed. The mean number of completed day of actigraphy per patient was 6.5 ± 5.1. The mean missing activity count was 20.3 minutes (±81.7) per day. The mean level of activity measured by raw actigraphy counts per minute over 24 hours was higher in participants with agitation than without agitation. This study supports the feasibility of actigraphy use in TBI patients in the ICU. In the acute phase of TBI, agitated patients have higher levels of activity, confirming the potential of actigraphy to monitor agitation. [ABSTRACT FROM AUTHOR]

Background: The goal of this systematic review was to examine the efficacy and safety of proton-pump inhibitors for stress ulcer prophylaxis in critically ill patients. Methods: We included randomized trials comparing proton-pump inhibitors versus placebo or no prophylaxis in critically ill adults, performed meta-analyses, and assessed certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluations approach. To explore the effect of proton-pump inhibitors on mortality based on disease severity, a subgroup analysis was conducted combining within-trial subgroup data from the two largest trials and assessed credibility using the Instrument for Assessing the Credibility of Effect Modification Analyses. Results: Twelve trials that enrolled 9533 patients were included. Proton-pump inhibitors were associated with a reduced incidence of clinically important upper gastrointestinal bleeding (relative risk [RR], 0.51 [95% confidence interval (CI), 0.34 to 0.76]; high certainty evidence). Proton-pump inhibitors may have little or no effect on mortality (RR, 0.99 [95% CI, 0.93 to 1.05]; low certainty). Within-trial subgroup analysis with intermediate credibility suggested that the effect of proton-pump inhibitors on mortality may differ based on disease severity. Subgroup results raise the possibility that proton-pump inhibitors may decrease 90-day mortality in less severely ill patients (RR, 0.89; 95% CI, 0.80 to 0.98) and may increase mortality in more severely ill patients (RR, 1.08; 95% CI, 0.96 to 1.20]. Proton-pump inhibitors may have no effect on pneumonia and little or no effect on Clostridioides difficile infection (low certainty). Conclusions: High certainty evidence supports the association of proton-pump inhibitors with decreased upper gastrointestinal bleeding. Proton-pump inhibitors may have little or no effect on mortality, although a decrease in mortality in less severely ill patients and an increase in mortality in more severely ill patients remain possible. (PROSPERO number CRD42023461695.) [ABSTRACT FROM AUTHOR]

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Cyclic peptides are an important class of molecules that gained significant attention in the field of drug discovery due to their unique pharmacological characteristics and enhanced proteolytic stability. Yet, gastrointestinal degradation remains a major hurdle in the discovery of orally bioavailable cyclic peptides. Soft spot identification (SSID) of the regions in the cyclic peptide sequence susceptible to amide hydrolysis by proteases is used in the discovery stage to guide medicinal chemistry design. SSID can be an arduous task, traditionally performed using liquid chromatography–tandem mass spectrometry (LC-MS/MS), often resulting in complex and time-consuming manual analysis, particularly when isomeric linear peptide metabolites chromatographically coelute. Here, we present an alternative orthogonal approach that entails a high-resolution ion mobility (HRIM) system based on Structures for Lossless Ion Manipulation (SLIM) technology interfaced with quadrupole time-of-flight (QTOF) mass spectrometry to address some of the challenges associated with SSID. Two strategies were used to resolve linear isomeric peptide metabolites: labeled and label-free, both utilizing the HRIM platform. The label-free strategy leverages negative polarity to ionize the isomers which achieves better separation of the gas phase ions in the ion mobility (IM) dimension as compared to positive polarity, which is a more conventional approach when studying proteins and peptides. The second approach uses an isotope-labeled dimethyl tag on the terminal amine group, acting as a "shift reagent" to influence the mobility of isomers in the positive mode. This method resulted in baseline separation for the isomers of interest and produced unique product ions in the fragmentation spectra for unambiguous soft spot identification. Both label-free and labeled strategies demonstrated the ability to solve the challenges associated with SSID for cyclic peptides. [ABSTRACT FROM AUTHOR]

Introduction: Therapeutic interventions for disorders of consciousness lack consistency; evidence supports non-invasive brain stimulation, but few studies assess neuromodulation in acute-to-subacute brain-injured patients. This study aims to validate the feasibility and assess the effect of a multi-session transcranial alternating current stimulation (tACS) intervention in subacute brain-injured patients on recovery of consciousness, related brain oscillations and brain network dynamics., Methods and Analyses: The study is comprised of two phases: a validation phase (n=12) and a randomised controlled trial (n=138). Both phases will be conducted in medically stable brain-injured adult patients (traumatic brain injury and hypoxic-ischaemic encephalopathy), with a Glasgow Coma Scale score ≤12 after continuous sedation withdrawal. Recruitment will occur at the intensive care unit of a Level 1 Trauma Centre in Montreal, Quebec, Canada. The intervention includes a 20 min 10 Hz tACS at 1 mA intensity or a sham session over parieto-occipital cortical sites, repeated over five consecutive days. The current's frequency targets alpha brain oscillations (8-13 Hz), known to be associated with consciousness. Resting-state electroencephalogram (EEG) will be recorded four times daily for five consecutive days: pre and post-intervention, at 60 and 120 min post-tACS. Two additional recordings will be included: 24 hours and 1-week post-protocol. Multimodal measures (blood samples, pupillometry, behavioural consciousness assessments (Coma Recovery Scale-revised), actigraphy measures) will be acquired from baseline up to 1 week after the stimulation. EEG signal analysis will focus on the alpha bandwidth (8-13 Hz) using spectral and functional network analyses. Phone assessments at 3, 6 and 12 months post-tACS, will measure long-term functional recovery, quality of life and caregivers' burden., Ethics and Dissemination: Ethical approval for this study has been granted by the Research Ethics Board of the CIUSSS du Nord-de-l'Île-de-Montréal (Project ID 2021-2279). The findings of this two-phase study will be submitted for publication in a peer-reviewed academic journal and submitted for presentation at conferences. The trial's results will be published on a public trial registry database (ClinicalTrials.gov)., Trial Registration Number: NCT05833568., Competing Interests: Competing interests: None declared., (© 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: Whether proton-pump inhibitors are beneficial or harmful for stress ulcer prophylaxis in critically ill patients undergoing invasive ventilation is unclear., Methods: In this international, randomized trial, we assigned critically ill adults who were undergoing invasive ventilation to receive intravenous pantoprazole (at a dose of 40 mg daily) or matching placebo. The primary efficacy outcome was clinically important upper gastrointestinal bleeding in the intensive care unit (ICU) at 90 days, and the primary safety outcome was death from any cause at 90 days. Multiplicity-adjusted secondary outcomes included ventilator-associated pneumonia, Clostridioides difficile infection, and patient-important bleeding., Results: A total of 4821 patients underwent randomization in 68 ICUs. Clinically important upper gastrointestinal bleeding occurred in 25 of 2385 patients (1.0%) receiving pantoprazole and in 84 of 2377 patients (3.5%) receiving placebo (hazard ratio, 0.30; 95% confidence interval [CI], 0.19 to 0.47; P<0.001). At 90 days, death was reported in 696 of 2390 patients (29.1%) in the pantoprazole group and in 734 of 2379 patients (30.9%) in the placebo group (hazard ratio, 0.94; 95% CI, 0.85 to 1.04; P = 0.25). Patient-important bleeding was reduced with pantoprazole; all other secondary outcomes were similar in the two groups., Conclusions: Among patients undergoing invasive ventilation, pantoprazole resulted in a significantly lower risk of clinically important upper gastrointestinal bleeding than placebo, with no significant effect on mortality. (Funded by the Canadian Institutes of Health Research and others; REVISE ClinicalTrials.gov number, NCT03374800.)., (Copyright © 2024 Massachusetts Medical Society.)