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Evidence-based practices for reducing opioid-related overdose deaths include overdose education and naloxone distribution, the use of medications for the treatment of opioid use disorder, and prescription opioid safety. Data are needed on the effectiveness of a community-engaged intervention to reduce opioid-related overdose deaths through enhanced uptake of these practices. In this community-level, cluster-randomized trial, we randomly assigned 67 communities in Kentucky, Massachusetts, New York, and Ohio to receive the intervention (34 communities) or a wait-list control (33 communities), stratified according to state. The trial was conducted within the context of both the coronavirus disease 2019 (Covid-19) pandemic and a national surge in the number of fentanyl-related overdose deaths. The trial groups were balanced within states according to urban or rural classification, previous overdose rate, and community population. The primary outcome was the number of opioid-related overdose deaths among community adults. During the comparison period from July 2021 through June 2022, the population-averaged rates of opioid-related overdose deaths were similar in the intervention group and the control group (47.2 deaths per 100,000 population vs. 51.7 per 100,000 population), for an adjusted rate ratio of 0.91 (95% confidence interval, 0.76 to 1.09; P = 0.30). The effect of the intervention on the rate of opioid-related overdose deaths did not differ appreciably according to state, urban or rural category, age, sex, or race or ethnic group. Intervention communities implemented 615 evidence-based practice strategies from the 806 strategies selected by communities (254 involving overdose education and naloxone distribution, 256 involving the use of medications for opioid use disorder, and 105 involving prescription opioid safety). Of these evidence-based practice strategies, only 235 (38%) had been initiated by the start of the comparison year. In this 12-month multimodal intervention trial involving community coalitions in the deployment of evidence-based practices to reduce opioid overdose deaths, death rates were similar in the intervention group and the control group in the context of the Covid-19 pandemic and the fentanyl-related overdose epidemic. (Funded by the National Institutes of Health; HCS ClinicalTrials.gov number, NCT04111939.).

Several phenyl alkyl bonded phases for liquid chromatography were synthesized and characterized by liquid chromatography, gas chromatography and ('13)C nuclear magnetic resonance (NMR) spectroscopy. The chromatographic physical parameters investigated include a quantitative determination of the mobile phase volume and the stationary phase volume. The stationary phase volume was determined to be a function of the bonded moiety chain length and the chromatographic solvent system employed. The interpretation of the stationary phase volume is discussed in terms of the porous nature of the silica gel support. The chemical parameters determined include a quantitative determination of the mobile phase and stationary phase composition (which were different from each other). The selectivity of the chromatographic separations was dependent on the chemical composition and the volume of both the stationary and mobile phases. Carbon 13 NMR spectroscopy provided information about the environment of the bonded moiety in the stationary phase. The liquid-like nature of the bonded moiety was influenced by the chain length of the attached species, the choice of organic modifier, and the chemical composition of the solvents. Temperature did not appear to play a role in the line widths under the experimental conditions examined. The separation of several peptide diastereoisomers on different commercially available hydrocarbon bonded adsorbents is also reported. Select diastereoisomers of arginine vasopressin and oxytocin are extremely sensitive to differences in the composition of the stationary phase. The selectivity and elution order were dependent upon the choice of adsorbent and solvent system employed. The addition of a second organic modifier provided a method for the dynamic modification of the stationary phase. The ability to dynamically modify the stationary phase can enhance the selectivity for the separation of selected peptide diastereoisomers.

Zaeem et al discuss the case study of a 36-year-old man with fulminant multiple sclerosis. The man has a 9-year history of stable, relapsing-remitting multiple sclerosis (MS) who presented to the emergency department with a 1-week history of blurred vision, vertigo, perioral numbness, difficulty walking, aggression and confusion. Symptoms persisted despite the patient having started prednisolone 3 days before presentation. Several months previously, he had discontinued his maintenance therapy for MS--dimethyl fumarate, a nuclear factor erythroid 2-reIated factor 2 activator--owing to severe diarrhea.

Quantitative susceptibility mapping (QSM) measures bulk susceptibilities in the brain, which can arise from many sources. In iron-rich subcortical gray matter (GM), non-heme iron is a dominant susceptibility source. We evaluated the use of QSM for iron mapping in subcortical GM by direct comparison to tissue iron staining. We performed in situ or in vivo QSM at 4.7T combined with Perls' ferric iron staining on the corresponding extracted subcortical GM regions. This histochemical process enabled examination of ferric iron in complete slices that could be related to susceptibility measurements. Correlation analyses were performed on an individual-by-individual basis and high linear correlations between susceptibility and Perls' iron stain were found for the three multiple sclerosis (MS) subjects studied (R2=0.75, 0.62, 0.86). In addition, high linear correlations between susceptibility and transverse relaxation rate (R2*) were found (R2=0.88, 0.88, 0.87) which matched in vivo healthy subjects (R2=0.87). This work validates the accuracy of QSM for brain iron mapping and also confirms ferric iron as the dominant susceptibility source in subcortical GM, by demonstrating high linear correlation of QSM to Perls' ferric iron staining. [Display omitted] •In situ or in vivo QSM is compared with Perls' iron stain in subcortical gray matter.•Full slice Perls' iron staining enabled spatial maps of ferric iron to relate directly to MRI.•High linear correlations are found between QSM and Perls' iron stain in postmortem subjects with multiple sclerosis.•High linear correlations are also found between QSM and R2* for both postmortem and in vivo subjects.

IntroductionThe COVID-19 pandemic brought an urgent need to discover novel effective therapeutics for patients hospitalised with severe COVID-19. The Investigation of Serial studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis (ISPY COVID-19 trial) was designed and implemented in early 2020 to evaluate investigational agents rapidly and simultaneously on a phase 2 adaptive platform. This manuscript outlines the design, rationale, implementation and challenges of the ISPY COVID-19 trial during the first phase of trial activity from April 2020 until December 2021.Methods and analysisThe ISPY COVID-19 Trial is a multicentre open-label phase 2 platform trial in the USA designed to evaluate therapeutics that may have a large effect on improving outcomes from severe COVID-19. The ISPY COVID-19 Trial network includes academic and community hospitals with significant geographical diversity across the country. Enrolled patients are randomised to receive one of up to four investigational agents or a control and are evaluated for a family of two primary outcomes—time to recovery and mortality. The statistical design uses a Bayesian model with ‘stopping’ and ‘graduation’ criteria designed to efficiently discard ineffective therapies and graduate promising agents for definitive efficacy trials. Each investigational agent arm enrols to a maximum of 125 patients per arm and is compared with concurrent controls. As of December 2021, 11 investigational agent arms had been activated, and 8 arms were complete. Enrolment and adaptation of the trial design are ongoing.Ethics and disseminationISPY COVID-19 operates under a central institutional review board via Wake Forest School of Medicine IRB00066805. Data generated from this trial will be reported in peer-reviewed medical journals.Trial registration numberNCT04488081.

( ) causes a variety of disease states including fatal bacterial pneumonia. Our previous finding that introduction of into an animal with ongoing influenza virus infection resulted in a CD8 T cell population with reduced effector function gave rise to the possibility of direct regulation by pneumococcal components. Here, we show that treatment of effector T cells with lysate derived from resulted in inhibition of IFNγ and tumor necrosis factor α production as well as of cytolytic granule release. aminopeptidase N (PepN) was identified as the inhibitory bacterial component and surprisingly, this property was independent of the peptidase activity found in this family of proteins. Inhibitory activity was associated with reduced activation of ZAP-70, ERK1/2, c-Jun N-terminal kinase, and p38, demonstrating the ability of PepN to negatively regulate TCR signaling at multiple points in the cascade. These results reveal a novel immune regulatory function for a bacterial aminopeptidase.