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We review comprehensive observations of electromagnetic ion cyclotron (EMIC) wave-driven energetic electron precipitation using data collected by the energetic electron detector on the Electron Losses and Fields InvestigatioN (ELFIN) mission, two polar-orbiting low-altitude spinning CubeSats, measuring 50-5000 keV electrons with good pitch-angle and energy resolution. EMIC wave-driven precipitation exhibits a distinct signature in energy-spectrograms of the precipitating-to-trapped flux ratio: peaks at >0.5 MeV which are abrupt (bursty) (lasting ∼17 s, or ΔL∼0.56) with significant substructure (occasionally down to sub-second timescale). We attribute the bursty nature of the precipitation to the spatial extent and structuredness of the wave field at the equator. Multiple ELFIN passes over the same MLT sector allow us to study the spatial and temporal evolution of the EMIC wave - electron interaction region. Case studies employing conjugate ground-based or equatorial observations of the EMIC waves reveal that the energy of moderate and strong precipitation at ELFIN approximately agrees with theoretical expectations for cyclotron resonant interactions in a cold plasma. Using multiple years of ELFIN data uniformly distributed in local time, we assemble a statistical database of ∼50 events of strong EMIC wave-driven precipitation. Most reside at L∼5-7 at dusk, while a smaller subset exists at L∼8-12 at post-midnight. The energies of the peak-precipitation ratio and of the half-peak precipitation ratio (our proxy for the minimum resonance energy) exhibit an L-shell dependence in good agreement with theoretical estimates based on prior statistical observations of EMIC wave power spectra. The precipitation ratio's spectral shape for the most intense events has an exponential falloff away from the peak (i.e., on either side of ∼1.45 MeV). It too agrees well with quasi-linear diffusion theory based on prior statistics of wave spectra. It should be noted though that this diffusive treatment likely includes effects from nonlinear resonant interactions (especially at high energies) and nonresonant effects from sharp wave packet edges (at low energies). Sub-MeV electron precipitation observed concurrently with strong EMIC wave-driven >1 MeV precipitation has a spectral shape that is consistent with efficient pitch-angle scattering down to ∼ 200-300 keV by much less intense higher frequency EMIC waves at dusk (where such waves are most frequent). At ∼100 keV, whistler-mode chorus may be implicated in concurrent precipitation. These results confirm the critical role of EMIC waves in driving relativistic electron losses. Nonlinear effects may abound and require further investigation.

The Electron Loss and Fields Investigation with a Spatio-Temporal Ambiguity-Resolving option (ELFIN-STAR, or heretoforth simply: ELFIN) mission comprises two identical 3-Unit (3U) CubeSats on a polar (∼93∘ inclination), nearly circular, low-Earth (∼450 km altitude) orbit. Launched on September 15, 2018, ELFIN is expected to have a >2.5 year lifetime. Its primary science objective is to resolve the mechanism of storm-time relativistic electron precipitation, for which electromagnetic ion cyclotron (EMIC) waves are a prime candidate. From its ionospheric vantage point, ELFIN uses its unique pitch-angle-resolving capability to determine whether measured relativistic electron pitch-angle and energy spectra within the loss cone bear the characteristic signatures of scattering by EMIC waves or whether such scattering may be due to other processes. Pairing identical ELFIN satellites with slowly-variable along-track separation allows disambiguation of spatial and temporal evolution of the precipitation over minutes-to-tens-of-minutes timescales, faster than the orbit period of a single low-altitude satellite (Torbit ∼ 90 min). Each satellite carries an energetic particle detector for electrons (EPDE) that measures 50 keV to 5 MeV electrons with Δ E/E < 40% and a fluxgate magnetometer (FGM) on a ∼72 cm boom that measures magnetic field waves (e.g., EMIC waves) in the range from DC to 5 Hz Nyquist (nominally) with 1 MeV. This broad energy range of precipitation indicates that multiple waves are providing scattering concurrently. Many observed events show significant backscattered fluxes, which in the past were hard to resolve by equatorial spacecraft or non-pitch-angle-resolving ionospheric missions. These observations suggest that the ionosphere plays a significant role in modifying magnetospheric electron fluxes and wave-particle interactions. Routine data captures starting in February 2020 and lasting for at least another year, approximately the remainder of the mission lifetime, are expected to provide a very rich dataset to address questions even beyond the primary mission science objective.

This report documents the physics case for building a 2 MW, 8 GeVsuperconducting linac proton driver at Fermilab.

The Cryogenic Underground Observatory for Rare Events (CUORE) is the first cryogenic experiment searching for neutrinoless double-beta (0vßß) decay that has been able to reach the one-ton scale. The detector, located at the Laboratori Nazionali del Gran Sasso in Italy, consists of an array of 988 TeO2 crystals arranged in a compact cylindrical structure of 19 towers. Following the completion of the detector construction in August 2016, CUORE began its first physics data run in 2017 at a base temperature of about 10 mK. Following multiple optimization campaigns in 2018, CUORE is currently in stable operating mode. In 2019, CUORE released its 2nd result of the search for 0vßß with a TeO2 exposure of 372.5 kg·yr and a median exclusion sensitivity to a 130Te 0vßß decay half-life of 1.7 · 1025 yr. We find no evidence for 0vßß decay and set a 90% C.I. (credibility interval) Bayesian lower limit of 3.2 · 1025 yr on the 130Te 0vßß decay half-life. In this work, we present the current status of CUORE's search for 0vßß, as well as review the detector performance. Finally, we give an update of the CUORE background model and the measurement of the 130Te two neutrino double-beta (2vßß) decay half-life.

The initial Point of View: Directions for Research (Neurorehabilitation and Neural Repair, 2007;21:3-13) identified confounders that might limit the impact that rehabilitation multicenter clinical trials may have upon altering practice patterns. Part of that viewpoint addressed the Extremity Constraint Induced Therapy Evaluation (EXCITE) Trial and highlighted some of its perceived strengths and limitations. The present Point of View expands upon factors worthy of consideration in planning and executing clinical trials in neurorehabilitation based upon experiences encountered by the EXCITE team. Cost factors and patient attributes, both of which profoundly influence the ability of clinical researchers to execute the ideal study, are among these factors. In particular, the costs associated with large trials necessitate compromise in study design or implementation, resulting in a dichotomy between what should be undertaken and what can be accomplished. [ABSTRACT FROM AUTHOR]

Objective: To examine the effect of leg rotation on the vastus medialis oblique/vastus lateralis (VMO/VL) electromyogram (EMG) activity ratio during two closed chain knee extension exercises prescribed for patellofemoral pain syndrome (PFPS). Design and Setting: Subjects performed step-up/stepdown (SUSD) and modified wall-slide (MWS), exercises with the leg neutral (SUSD/N, MWS/N), internally rotated (SUSD/I, MWS/I), and externally rotated (SUSD/E, MWS/E), respectively, for determination of root mean square EMG. Subjects: Six athletically active females symptomatic for PFPS and nine athletically active asymptomatic female control subjects. Measurements: The EMG activity of the VMO and the VL was collected while the subjects performed the exercises. Root mean square EMG was determined and then normalized to the subjects' maximal voluntary isometric contractions for calculation and analysis of the VMO/VL activity ratio. Results: Leg rotation had no effect on the VMO/VL activity ratio for the symptomatic group. The SUSD/E produced a lower VMO/VL activity ratio compared with the SUSD/N to (p < .01) and the SUSD/I (p < .01) in the control group. Similarly, the VMO/VL activity ratio for the MWWS/E was lower than for the MWS/I (p < 0.01). Conclusions. These results suggest that external rotation of the leg may affect VMO/VL activity ratio during closed chain knee extension exercises in individuals without PFPS but not in individuals symptomatic for PFPS. [ABSTRACT FROM AUTHOR]

Cell migration during many fundamental biological processes including metastasis requires cells to traverse tissue with heterogeneous mechanical cues that direct migration as well as determine force and energy requirements for motility. However, the influence of discrete structural and mechanical cues on migration remains challenging to determine as they are often coupled. Here, we decouple the pro-invasive cues of collagen fiber alignment and tension to study their individual impact on migration. When presented with both cues, cells preferentially travel in the axis of tension against fiber alignment. Computational and experimental data show applying tension perpendicular to alignment increases potential energy stored within collagen fibers, lowering requirements for cell-induced matrix deformation and energy usage during migration compared to motility in the direction of fiber alignment. Energy minimization directs migration trajectory, and tension can facilitate migration against fiber alignment. These findings provide a conceptual understanding of bioenergetics during migration through a fibrous matrix., 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.)

Abstract: Allogeneic hematopoietic cell transplantation is a life-saving procedure used to treat a variety of devastating diseases. It requires hematopoietic stem cells collected via filgrastim-mobilized peripheral blood stem cells (PBSCs) or bone marrow (BM) harvest from volunteer unrelated donors (URDs). There is a paucity of safety data regarding donors' long-term adverse events. This prospective, observational study combined PBSC donors enrolled in the NMDP Investigational New Drug trial and BM donors between 1 July 1999 and 30 September 2015. The primary objective was to describe the long-term incidence of myeloid malignancies. The secondary objectives included describing the long-term incidence of lymphoid malignancies, nonhematologic malignancies, autoimmune disorders, and thrombotic events. A total of 21 643 donors (14 530 PBSCs and 7123 BM) were included. The incidence rate of myeloid disorders per 100 000 person-years in donors of PBSCs was 2.53 (95% confidence interval [CI], 0.82-7.84) and in donors of BM, it was 4.13 (95% CI, 1.33-12.8). The incidence rate ratio of PBSCs/BM donors was 0.61 (95% CI, 0.12-3.03; P = .55). The incidence of other malignancies, autoimmunity, and thrombosis did not differ between the donor types. This comprehensive study of the long-term effects of filgrastim in URDs of PBSCs provides strong evidence that donors who receive filgrastim are not at an increased risk of these events compared with BM donors. It also provides reassurance to current donors undergoing stem cell mobilization as well as individuals considering joining stem cell registries, such as NMDP., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Homelessness is associated with significant health disparities. Conventional health services often fail to address the unique needs and lived experience of homeless individuals and fail to include participatory design when planning health services. This scoping review aimed to examine areas of patient experience that are most frequently reported by people experiencing homelessness when seeking and receiving healthcare, and to identify existing surveys used to measure patient experience for this cohort., Methods: A scoping review was undertaken reported according to the PRISMA-ScR 2020 Statement. Databases were searched on 1 December 2022: MEDLINE, EMBASE, APA PsychINFO and CINAHL. Included studies focused on people experiencing homelessness, healthcare services and patient experience, primary research, published in English from 2010. Qualitative papers and findings were extracted and synthesized against a modified framework based on the National Institute for Health and Care Excellence guidelines for care for people experiencing homelessness, the Institute of Medicine Framework and Lachman's multidimensional quality model. People with lived experience of homelessness were employed as part of the research team., Results: Thirty-two studies were included. Of these, 22 were qualitative, seven quantitative and three mixed methods, from the United States of America (n = 17), United Kingdom (n = 5), Australia (n = 5) and Canada (n = 4). Health services ranged from primary healthcare to outpatient management, acute care, emergency care and hospital based healthcare. In qualitative papers, the domains of 'accessible and timely', 'person-centred', and values of 'dignity and respect' and 'kindness with compassion' were most prevalent. Among the three patient experience surveys identified, 'accessible and timely' and 'person-centred' were the most frequent domains. The least frequently highlighted domains and values were 'equitable' and 'holistic'. No questions addressed the 'safety' domain., Conclusions: The Primary Care Quality-Homeless questionnaire best reflected the priorities for healthcare provision that were highlighted in the qualitative studies of people experiencing homelessness. The most frequently cited domains and values that people experiencing homelessness expressed as important when seeking healthcare were reflected in each of the three survey tools to varying degrees. Findings suggest that the principles of 'Kindness and compassion' require further emphasis when seeking feedback on healthcare experiences and the domains of 'safety', 'equitable', and 'efficiency' are not adequately represented in existing patient experience surveys., (© 2024. The Author(s).)

Introduction: Preoperative anxiety and depression symptoms among older surgical patients are associated with poor postoperative outcomes, yet evidence-based interventions for anxiety and depression have not been applied within this setting. We present a protocol for randomised controlled trials (RCTs) in three surgical cohorts: cardiac, oncological and orthopaedic, investigating whether a perioperative mental health intervention, with psychological and pharmacological components, reduces perioperative symptoms of depression and anxiety in older surgical patients., Methods and Analysis: Adults ≥60 years undergoing cardiac, orthopaedic or oncological surgery will be enrolled in one of three-linked type 1 hybrid effectiveness/implementation RCTs that will be conducted in tandem with similar methods. In each trial, 100 participants will be randomised to a remotely delivered perioperative behavioural treatment incorporating principles of behavioural activation, compassion and care coordination, and medication optimisation, or enhanced usual care with mental health-related resources for this population. The primary outcome is change in depression and anxiety symptoms assessed with the Patient Health Questionnaire-Anxiety Depression Scale from baseline to 3 months post surgery. Other outcomes include quality of life, delirium, length of stay, falls, rehospitalisation, pain and implementation outcomes, including study and intervention reach, acceptability, feasibility and appropriateness, and patient experience with the intervention., Ethics and Dissemination: The trials have received ethics approval from the Washington University School of Medicine Institutional Review Board. Informed consent is required for participation in the trials. The results will be submitted for publication in peer-reviewed journals, presented at clinical research conferences and disseminated via the Center for Perioperative Mental Health website., Trial Registration Numbers: NCT05575128, NCT05685511, NCT05697835, pre-results., 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.)

Introduction: Previously published studies have hypothesized that total hip arthroplasty (THA) requires the surgeon to expend more energy that total knee arthroplasty (TKA). However, techniques for performing these procedures have evolved. Therefore, we sought to compare if primary THA had increased energy expenditure compared to primary TKA., Methods: We prospectively recorded the heart rate, respiratory rate, minute ventilation, cadence, and energy expenditure of a single fellowship-trained arthroplasty surgeon while performing primary THA and TKA on 372 patients. Patient demographics and operative records were reviewed to evaluate differences in the physical demands of each surgical case. Age (64.3 versus 65.9 years, p = 0.1) and gender (54.8% versus 51.0% female, p = 0.5) were similar between THA and TKA, but TKAs had a higher body mass index (31.1 versus 28.7 kg/m 2 , p < 0.001). Chi-square and independent-samples t-tests were used to compare cohorts. Significance was set at p < 0.05., Results: THA tended to have 1.1 times longer operative time than TKA (102.2 versus 88.9 min, p < 0.001). THA had a statistically higher heart rate compared to TKA, although this is unlikely to be clinically significant (82.5 versus 80.7 beats/minute, p < 0.001). Respiratory Rate was 1.1 times higher (15.9 versus 14.9 respirations/minute, p < 0.001) and minute ventilation was 1.2 times higher (19.6 versus 16.9 L/min, p < 0.001) when performing THA. Cadence was 1.5 times higher when performing TKA (4.2 versus 2.8 steps/minute, p < 0.001). THA had a 1.2 times higher energy expenditure/patient (378.8 versus 312.0 Calories/patient, p < 0.001) and a 1.1 times higher energy expenditure/minute (3.7 versus 3.5 Calories/minute, p = 0.01) compared to TKA., Discussion: THA is associated with longer operative time and increased energy expenditure per compared to TKA. Despite THA and TKA procedures becoming more efficient, arthroplasty surgery continues to have heavy physical burden on the surgeon. Further research is needed to understand ways to decrease surgeon energy expenditure and promote career longevity., Competing Interests: Journal of Orthopaedic Experience & Innovation: Editorial or governing board. Astra-Zeneca: Employee. DJ Orthopaedics: IP royalties; Paid consultant., (© 2024 Professor P K Surendran Memorial Education Foundation. Published by Elsevier B.V. All rights reserved.)

Forchlorfenuron (FCF) is a widely used plant cytokinin that enhances fruit quality and size in agriculture. It also serves as a crucial pharmacological tool for the inhibition of septins. However, the precise target of FCF has not yet been fully determined. This study reveals a novel target of FCF and elucidates its downstream signaling events. FCF significantly impairs mitochondrial respiration and mediates metabolic shift toward glycolysis, thus making cells more vulnerable to glycolysis inhibition. Interestingly, FCF's impact on mitochondrial function persists, even in cells lacking septins. Furthermore, the impaired mitochondrial function leads to the degradation of HIF-1α, facilitated by increased cellular oxygen. FCF also induces AMPK activation, suppresses Erk1/2 phosphorylation, and reduces the expression of HER2, β-catenin, and PD-L1. Endometrial cancer is characterized by metabolic disorders such as diabetes and aberrant HER2/Ras-Erk1/2/β-catenin signaling. Thus, FCF may hold promise as a potential therapeutic in endometrial cancer.

Prenatal exposure to heightened maternal inflammation has been associated with adverse neurodevelopmental outcomes, including atypical brain maturation and psychiatric illness. In mothers experiencing socioeconomic disadvantage, immune activation can be a product of the chronic stress inherent to such environmental hardship. While growing preclinical and clinical evidence has shown links between altered neonatal brain development and increased inflammatory states in utero, the potential mechanism by which socioeconomic disadvantage differentially impacts neural-immune crosstalk remains unclear. In the current study, we investigated associations between socioeconomic disadvantage, gestational inflammation, and neonatal white matter microstructure in 320 mother-infant dyads over-sampled for poverty. We analyzed maternal serum levels of four cytokines (IL-6, IL-8, IL-10, TNF-α) over the course of pregnancy in relation to offspring white matter microstructure and socioeconomic disadvantage. Higher average maternal IL-6 was associated with very low socioeconomic status (SES; INR < 200% poverty line) and lower neonatal corticospinal fractional anisotropy (FA) and lower uncinate axial diffusivity (AD). No other cytokine was associated with SES. Higher average maternal IL-10 was associated with lower FA and higher radial diffusivity (RD) in corpus callosum and corticospinal tracts, higher optic radiation RD, lower uncinate AD, and lower FA in inferior fronto-occipital fasciculus and anterior limb of internal capsule tracts. SES moderated the relationship between average maternal TNF-α levels during gestation and neonatal white matter diffusivity. When these interactions were decomposed, the patterns indicated that this association was significant and positive among very low SES neonates, whereby TNF-α was inversely and significantly associated with inferior cingulum AD. By contrast, among the more advantaged neonates (lower-to-higher SES [INR ≥ 200% poverty line]), TNF-α was positively and significantly associated with superior cingulum AD. Taken together, these findings suggest that the relationship between prenatal cytokine exposure and white matter microstructure differs as a function of SES. These patterns are consistent with a scenario where gestational inflammation's effects on white matter development diverge depending on the availability of foundational resources in utero., (© 2024. The Author(s).)

Health disparities are driven by underlying social disadvantage and psychosocial stressors. However, how social disadvantage and psychosocial stressors lead to adverse health outcomes is unclear, particularly when exposure begins prenatally. Variations in the gut microbiome and circulating proinflammatory cytokines offer potential mechanistic pathways. Here, we interrogate the gut microbiome of mother-child dyads to compare high-versus-low prenatal social disadvantage, psychosocial stressors and maternal circulating cytokine cohorts (prospective case-control study design using gut microbiomes from 121 dyads profiled with 16 S rRNA sequencing and 89 dyads with shotgun metagenomic sequencing). Gut microbiome characteristics significantly predictive of social disadvantage and psychosocial stressors in the mothers and children indicate that different discriminatory taxa and related pathways are involved, including many species of Bifidobacterium and related pathways across several comparisons. The lowest inter-individual gut microbiome similarity was observed among high-social disadvantage/high-psychosocial stressors mothers, suggesting distinct environmental exposures driving a diverging gut microbiome assembly compared to low-social disadvantage/low-psychosocial stressors controls (P = 3.5 × 10 -5 for social disadvantage, P = 2.7 × 10 -15 for psychosocial stressors). Children's gut metagenome profiles at 4 months also significantly predicted high/low maternal prenatal IL-6 (P = 0.029), with many bacterial species overlapping those identified by social disadvantage and psychosocial stressors. These differences, based on maternal social and psychological status during a critical developmental window early in life, offer potentially modifiable targets to mitigate health inequities., (© 2023. Springer Nature Limited.)

Background: Prior randomized clinical trials have reported benefit of fluvoxamine ≥200 mg/d vs placebo for patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)., Methods: This randomized, double-blind, placebo-controlled, fully remote multisite clinical trial evaluated whether fluvoxamine prevents clinical deterioration in higher-risk outpatients with acute coronavirus disease 2019 (COVID-19). Between December 2020 and May 2021, nonhospitalized US and Canadian participants with confirmed symptomatic infection received fluvoxamine (50 mg on day 1, 100 mg twice daily thereafter) or placebo for 15 days. The primary modified intent-to-treat (mITT) population included participants who started the intervention within 7 days of symptom onset with a baseline oxygen saturation ≥92%. The primary outcome was clinical deterioration within 15 days of randomization, defined as having both (1) shortness of breath (severity ≥4 on a 0-10 scale or requiring hospitalization) and (2) oxygen saturation <92% on room air or need for supplemental oxygen., Results: A total of 547 participants were randomized and met mITT criteria (n = 272 fluvoxamine, n = 275 placebo). The Data Safety Monitoring Board recommended stopping early for futility related to lower-than-predicted event rates and declining accrual concurrent with vaccine availability in the United States and Canada. Clinical deterioration occurred in 13 (4.8%) participants in the fluvoxamine group and 15 (5.5%) participants in the placebo group (absolute difference at day 15, 0.68%; 95% CI, -3.0% to 4.4%; log-rank P = .91)., Conclusions: This trial did not find fluvoxamine efficacious in preventing clinical deterioration in unvaccinated outpatients with symptomatic COVID-19. It was stopped early and underpowered due to low primary outcome rates., Clinical Trials Registration: ClinicalTrials.gov Identifier: NCT04668950., Competing Interests: Potential conflicts of interest. A.M.R. and E.J.L. are listed on a patent application that includes use of sigma-1 receptor agonists for treatment of COVID-19. C.F.Z. is on the Scientific Advisory Board of Sage Therapeutics and has stock in the company. Sage was not involved in any of this work. R.B.I. consulted for SeaGen, AbbVie, and Resverlogix and received research support through her institution from Novartis and Ascentage unrelated to this research. R.H. serves on a data safety and monitoring board for Astellas Pharmaceuticals unrelated to the current work. E.J.L. consulted for Prodeo, Merck, IngenioRx, Boehringer-Ingelheim, and Pritikin ICR and received research support through his institution from Janssen and PCORI. T.R.G. consulted for Pritikin ICR. J.T.R. has received funding for schizophrenia trials unrelated to this work. M.W.R. receives support from the NIH, but none of these grants are relevant to the current study. All other authors report no potential conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Small-molecule inhibitors of PD-L1 are postulated to control immune evasion in tumors similar to antibodies that target the PD-L1/PD-1 immune checkpoint axis. However, the identity of targetable PD-L1 inducers is required to develop small-molecule PD-L1 inhibitors. In this study, using chromatin immunoprecipitation (ChIP) assay and siRNA, we demonstrate that vitamin D/VDR regulates PD-L1 expression in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cells. We have examined whether a VDR antagonist, MeTC7, can inhibit PD-L1. To ensure that MeTC7 inhibits VDR/PD-L1 without off-target effects, we examined competitive inhibition of VDR by MeTC7, utilizing ligand-dependent dimerization of VDR-RXR, RXR-RXR, and VDR-coactivators in a mammalian 2-hybrid (M2H) assay. MeTC7 inhibits VDR selectively, suppresses PD-L1 expression sparing PD-L2, and inhibits the cell viability, clonogenicity, and xenograft growth of AML cells. MeTC7 blocks AML/mesenchymal stem cells (MSCs) adhesion and increases the efferocytotic efficiency of THP-1 AML cells. Additionally, utilizing a syngeneic colorectal cancer model in which VDR/PD-L1 co-upregulation occurs in vivo under radiation therapy (RT), MeTC7 inhibits PD-L1 and enhances intra-tumoral CD8 + T cells expressing lymphoid activation antigen-CD69. Taken together, MeTC7 is a promising small-molecule inhibitor of PD-L1 with clinical potential.

Background: Obesity is common in individuals with severe mental illness (SMI), contributing to a significantly shortened lifespan when compared to the general population. Available weight loss treatments have attenuated efficacy in this population, underscoring the importance of prevention and early intervention., Objective: Here, we describe a type 1 hybrid study design for adapting and pilot-testing an existing mobile health intervention for obesity prevention in individuals with early SMI and Class I or early-stage obesity, defined as a BMI of 30-35., Methods: An existing, evidence-based interactive obesity treatment approach using low-cost, semiautomated SMS text messaging was selected for adaptation. Community mental health clinics and Clubhouse settings in Eastern Missouri and South Florida were identified to participate. This study has the following 3 aims. First, using the Enhanced Framework for Reporting Adaptations and Modifications to Evidence-based interventions, contextual aspects of the clinical and digital treatment environments are identified for adaptation, considering 5 main stakeholder groups (clinical administrators, prescribing clinicians, case managers, nurses, and patients). Following a 2-week trial of unadapted SMS text messaging, Innovation Corps methods are used to discover needed intervention adaptations by stakeholder group and clinical setting. Second, adaptations to digital functionality and intervention content will be made based on themes identified in aim 1, followed by rapid usability testing with key stakeholders. A process for iterative treatment adaptation will be developed for making unplanned modifications during the aim 3 implementation pilot study. Individuals working in partner community mental health clinics and Clubhouse settings will be trained in intervention delivery. Third, in a randomized pilot and feasibility trial, adults with 5 years or less of treatment for an SMI diagnosis will be randomized 2:1 to 6 months of an adapted interactive obesity treatment approach or to an attentional control condition, followed by a 3-month extension phase of SMS text messages only. Changes in weight, BMI, and behavioral outcomes, as well as implementation challenges, will be evaluated at 6 and 9 months., Results: Institutional review board approval for aims 1 and 2 was granted on August 12, 2018, with 72 focus group participants enrolled; institutional review board approval for aim 3 was granted on May 6, 2020. To date, 52 participants have been enrolled in the study protocol., Conclusions: In this type 1 hybrid study design, we apply an evidence-based treatment adaptation framework to plan, adapt, and feasibility test a mobile health intervention in real-world treatment settings. Resting at the intersection of community mental health treatment and physical health promotion, this study aims to advance the use of simple technology for obesity prevention in individuals with early-stage mental illness., Trial Registration: ClinicalTrials.gov NCT03980743; https://clinicaltrials.gov/ct2/show/NCT03980743., International Registered Report Identifier (irrid): DERR1-10.2196/42114., (©Ginger E Nicol, Madeline O Jansen, Amanda R Ricchio, Julia A Schweiger, Katie E Keenoy, J Philip Miller, Elaine H Morrato, Zhaohua Guo, Bradley A Evanoff, Joseph J Parks, John W Newcomer. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 09.06.2023.)

Background: Race is commonly used as a proxy for multiple features including socioeconomic status. It is critical to dissociate these factors, to identify mechanisms that affect infant outcomes, such as birth weight, gestational age, and brain development, and to direct appropriate interventions and shape public policy., Methods: Demographic, socioeconomic, and clinical variables were used to model infant outcomes. There were 351 participants included in the analysis for birth weight and gestational age. For the analysis using brain volumes, 280 participants were included after removing participants with missing magnetic resonance imaging scans and those matching our exclusion criteria. We modeled these three different infant outcomes, including infant brain, birth weight, and gestational age, with both linear and nonlinear models., Results: Nonlinear models were better predictors of infant birth weight than linear models ( R 2  = 0.172 vs. R 2  = 0.145, p  = .005). In contrast to linear models, nonlinear models ranked income, neighborhood disadvantage, and experiences of discrimination higher in importance than race while modeling birth weight. Race was not an important predictor for either gestational age or structural brain volumes., Conclusions: Consistent with the extant social science literature, the findings related to birth weight suggest that race is a linear proxy for nonlinear factors related to structural racism. Methods that can disentangle factors often correlated with race are important for policy in that they may better identify and rank the modifiable factors that influence outcomes., (© 2023 The Authors.)

Background: Triage implementation in resource-limited emergency departments (EDs) has traditionally relied on intensive in-person training. This study sought to evaluate the impact of a novel digital-based learning strategy focused on the Interagency Integrated Triage Tool, a three-tier triage instrument recommended by the World Health Organization., Methods: A mixed methods study utilising pre-post intervention methods was conducted in two EDs in Papua New Guinea. The primary outcome was the mean change in knowledge before and after completion of a voluntary, multimodal training program, primarily delivered through a digital learning platform accessible via smartphone. Secondary outcomes included the change in confidence to perform selected clinical tasks, and acceptability of the learning methods., Findings: Among 136 eligible ED staff, 91 (66.9%) completed the digital learning program. The mean knowledge score on the post-training exam was 87.5% (SD 10.4), a mean increase of 12.9% (95% CI 10.7-15.1%, p < 0.0001) from the pre-training exam. There were statistically significant improvements in confidence for 13 of 15 clinical tasks, including undertaking a triage assessment and identifying an unwell patient.In an evaluation survey, 100% of 30 respondents agreed or strongly agreed the online learning platform was easy to access, use and navigate, and that the digital teaching methods were appropriate for their learning needs. In qualitative feedback, respondents reported that limited internet access and a lack of dedicated training time were barriers to participation., Interpretation: The use of digital learning to support triage implementation in resource-limited EDs is feasible and effective when accompanied by in-person mentoring. Adequate internet access is an essential pre-requisite., Funding: Development of the Kumul Helt Skul learning platform was undertaken as part of the Clinical Support Program (Phase II), facilitated by Johnstaff International Development on behalf of the Australian Government Department of Foreign Affairs and Trade through the PNG-Australia Partnership. RM is supported by a National Health and Medical Research Council Postgraduate Scholarship and a Monash Graduate Excellence Scholarship, while PC is supported by a Medical Research Future Fund Practitioner Fellowship. Funders had no role in study design, results analysis or manuscript preparation., Competing Interests: RM, SB, JPM, TC, AE and CB declare that they received consulting fees for their contributions to the Clinical Support Program., (© 2023 The Author(s).)

Background: It has been well established that socioeconomic status is associated with mental and physical health as well as brain development, with emerging data suggesting that these relationships begin in utero. However, less is known about how prenatal socioeconomic environments interact with the gestational environment to affect neonatal brain volume., Methods: Maternal cortisol output measured at each trimester of pregnancy and neonatal brain structure were assessed in 241 mother-infant dyads. We examined associations between the trajectory of maternal cortisol output across pregnancy and volumes of cortisol receptor-rich regions of the brain, including the amygdala, hippocampus, medial prefrontal cortex, and caudate. Given the known effects of poverty on infant brain structure, socioeconomic disadvantage was included as a moderating variable., Results: Neonatal amygdala volume was predicted by an interaction between maternal cortisol output across pregnancy and socioeconomic disadvantage (standardized β = -0.31, p < .001), controlling for postmenstrual age at scan, infant sex, and total gray matter volume. Notably, amygdala volumes were positively associated with maternal cortisol for infants with maternal disadvantage scores 1 standard deviation below the mean (i.e., less disadvantage) (simple slope = 123.36, p < .01), while the association was negative in infants with maternal disadvantage 1 standard deviation above the mean (i.e., more disadvantage) (simple slope = -82.70, p  = .02). Individuals with disadvantage scores at the mean showed no association, and there were no significant interactions in the other brain regions examined., Conclusions: These data suggest that fetal development of the amygdala is differentially affected by maternal cortisol production at varying levels of socioeconomic advantage., (© 2023 The Authors.)

Background: Access to providers and programs that provide medications for opioid use disorder (MOUD) remains a systemic barrier for patients with opioid use disorder (OUD), particularly if they live in rural areas. The Rural Access to Medication Assisted Treatment (MAT) in Pennsylvania Project (Project RAMP) addressed this problem with a multisystem partnership that recruited, trained, and supported rural primary care providers to provide MOUD and implement an integrated care model (ICM) for patients with OUD. Given the demonstrated efficacy of Project RAMP, this article summarizes our recruitment strategies, including feasibility concerns for further expansion into other regions., Methods: The approach for recruiting implementation sites included two phases: partner outreach and site identification. Once recruited, the Systems Transformation Framework guided planning and implementation activities. Recruitment and implementation activities were assessed with implementation trackers and evaluated by providers via key informant interviews (KIIs)., Results: Project RAMP recruited 26 primary care practices from 13 counties, including nine health systems and two private practice groups-exceeding the original target of 24 sites. There was a median of 49 days from first contact to project onboarding. A total of 108 primary care practices spanning 22 health systems declined participation. Findings from the KIIs highlighted the value of engaging PCPs by connecting to a shared vision (i.e., improving the quality of patient care) as well as addressing perceived participation barriers (e.g., offering concierge technical assistance to address lack of training or resources)., Conclusion: Findings highlight how successful recruitment activities should leverage the support of health system leadership. Findings also emphasize that aiding recruitment and engagement efforts successfully addressed prescribers' perceived barriers to providing MOUD as well as facilitating better communication among administrators, PCPs, behavioral health professionals, care managers, and patients. Plain Language Summary: Opioid use disorder (OUD) is one of the leading causes of preventable illness and death. The standard of care for OUD is the provision of medications for opioid use disorder (MOUD) and the application of an integrative integrated care model (ICM) where behavioral health is blended with specialized medical services. Unfortunately, access to providers and healthcare facilities that provide MOUD or apply an ICM remains a systemic barrier for patients with OUD, particularly if they live in rural areas. Although there is no one-size-fits-all approach to implementing MOUD in primary care, findings from Project The Rural Access to Medication Assisted Treatment (MAT) in Pennsylvania Project (Project RAMP) highlight strategies that may improve future MOUD and ICM implementation efforts in similar rural contexts. Specifically, future efforts to increase MOUD capacity by recruiting new providers should be prepared to leverage health system leadership, address provider barriers via training and expert consultation, and facilitate connections to local behavioral health providers. This approach may be helpful to others recruiting health systems and primary care practices to implement new care models to use MOUD in treating patients with OUD., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Early life adversity (social disadvantage and psychosocial stressors) is associated with altered microstructure in fronto-limbic pathways important for socioemotional development. Understanding when these associations begin to emerge may inform the timing and design of preventative interventions. In this longitudinal study, 399 mothers were oversampled for low income and completed social background measures during pregnancy. Measures were analyzed with structural equation analysis resulting in two latent factors: social disadvantage (education, insurance status, income-to-needs ratio [INR], neighborhood deprivation, and nutrition) and psychosocial stress (depression, stress, life events, and racial discrimination). At birth, 289 healthy term-born neonates underwent a diffusion MRI (dMRI) scan. Mean diffusivity (MD) and fractional anisotropy (FA) were measured for the dorsal and inferior cingulum bundle (CB), uncinate, and fornix using probabilistic tractography in FSL. Social disadvantage and psychosocial stress were fitted to dMRI parameters using regression models adjusted for infant postmenstrual age at scan and sex. Social disadvantage, but not psychosocial stress, was independently associated with lower MD in the bilateral inferior CB and left uncinate, right fornix, and lower MD and higher FA in the right dorsal CB. Results persisted after accounting for maternal medical morbidities and prenatal drug exposure. In moderation analysis, psychosocial stress was associated with lower MD in the left inferior CB among the lower-to-higher socioeconomic status (SES) (INR ≥ 200%) group, but not the extremely low SES (INR < 200%) group. Increasing access to social welfare programs that reduce the burden of social disadvantage and related psychosocial stressors may be an important target to protect fetal brain development in fronto-limbic pathways.

Background: The Coronavirus Disease 2019 (COVID-19) pandemic in early 2020 has resulted in an unprecedented level of uncertainty and challenge for the stem cell donor registries. To address these challenges, rapid strategies were implemented by the National Marrow Donor Registry (NMDP) and its network partners. Herein, we aim to report the impact of the COVID-19 pandemic on the collection, utilization of grafts, and short-term outcomes of patients who received stem cell products from COVID-19-positive donors., Methods: NMDP data during the early phase (1 March 2020 through 1 May 2020) of the pandemic were compared to the later phase (1 March 2021 through 1 May 2021). Odds ratios were calculated to determine the impact of the pandemic on graft sources requested by transplant centers (TCs). The Kruskal-Wallis test was used to test the effect of the pandemic on the disease indication, volume of searches, and number of products not infused., Results: Although there was an initial decline in overall donor searches during the early phase of the pandemic, these numbers increased reaching pre-pandemic levels during the later phase. Urgent malignant diseases remained the most common indication for transplant in 2021. The pandemic necessitated cryopreservation of stem cell products due to transportation restrictions as well as clinical uncertainties in managing the virus. Cryopreserved grafts remained the most common requested grafts throughout the pandemic. In the later phase of the pandemic, the total numbers of requests for fresh grafts increased, mostly due to the increase in requests for fresh bone marrow (BM) grafts. As the pandemic continued, TCs became more accepting of cryopreservation, resulting in a reduction in the number of products not infused. Lastly, no short-term deleterious outcomes were noted among the patients who had stem cell products infused from a SARS-CoV-2-positive donor., Conclusion: Throughout the pandemic, the NMDP and TCs worked tirelessly to ensure that patients would receive lifesaving grafts when needed. The data reported here, although limited by small numbers, illustrate that transplantation from donors with COVID-19 is feasible and safe., Competing Interests: JNe, JNo, JB, EN, JO, MC, HP, JA, JM, SD and HS are employees of the National Marrow Donor Program. The remaining author declares 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 Farhadfar, Newman, Novakovich, Barten, Ndifon, Oakes, Cody, Pham, Auletta, Miller, Devine and Stefanski.)

Introduction: Cauda equina syndrome (CES) is most caused by lumbar disc herniation, and the associated treatment involves prompt surgical decompression. Rarer causes of CES include perineural (Tarlov) cysts., Clinical Presentation: A 62-year-old female with history of rheumatoid arthritis, hip and knee replacements, and chronic low back pain presented with worsening back pain, left leg weakness and pain for 6 weeks, and bowel/bladder incontinence with diminished sensation in the perianal region for 24 h prior to presentation. MRI demonstrated severe spinal stenosis at L4-S1, central disc herniation at L5-S1, and compression of the cauda equina, consistent with CES. A lumbar decompression was performed. Patient did well at 2-week follow up, but presented 5 weeks post-discharge with increased left leg pain/weakness and genitalia anesthesia. Imaging was unremarkable. Two months later, the patient presented with diminished sensation in the buttocks and bilateral lower extremities and bowel/bladder incontinence. Imaging demonstrated a large cystic presacral mass with involvement of the left sciatic foramen and S3 neural foramen. A team of plastic, orthopedic, and neurological surgeons performed an S3 sacral laminectomy, foraminotomy, partial sacrectomy, and S3 rhizotomy, and excision of the large left hemorrhagic pudendal mass. Final pathology demonstrated a perineural cyst with organizing hemorrhage. On follow-up, the patient's pain and weakness improved., Conclusion: CES-like symptoms were initially attributed to a herniated disk. However, lumbar decompression did not resolve symptoms, prompting further radiographic evaluation at two separate presentations. This represents the first reported case of a pudendal tumor causing symptoms initially attributed to a herniated disc., (© 2022. The Author(s), under exclusive licence to International Spinal Cord Society.)

Background: Depression and anxiety frequently coexist with chronic musculoskeletal pain and can negatively impact patients' responses to standard orthopedic treatments. Nevertheless, mental health is not routinely addressed in the orthopedic care setting. If effective, a digital mental health intervention may be a feasible and scalable method of addressing mental health in an orthopedic setting., Objective: We aimed to compare 2-month changes in mental and physical health between orthopedic patients who received a digital mental health intervention in addition to usual orthopedic care, those who received usual orthopedic care only (without a specific mental health intervention), and those who received in-person care with a psychologist as part of their orthopedic treatment plan., Methods: In this single-center retrospective cohort study involving ancillary analysis of a pilot feasibility study, 2-month self-reported health changes were compared between a cohort of orthopedic patients who received access to a digital mental health intervention (Wysa) and 2 convenience sample comparison cohorts (patients who received usual orthopedic care without a specific mental health intervention and patients who received in-person care with a psychologist as part of their orthopedic treatment plan). All patients were 18 years or older and reported elevated symptoms of depression or anxiety at an orthopedic clinic visit (Patient-Reported Outcomes Measurement Information System [PROMIS] Depression or Anxiety score ≥55). The digital intervention was a multi-component mobile app that used chatbot technology and text-based access to human counselors to provide cognitive behavioral therapy, mindfulness training, and sleep tools, among other features, with an emphasis on behavioral activation and pain acceptance. Outcomes of interest were between-cohort differences in the 2-month longitudinal changes in PROMIS Depression and Anxiety scores (primary outcomes) and PROMIS Pain Interference and Physical Function scores (secondary outcomes)., Results: Among 153 patients (mean age 55, SD 15 years; 128 [83.7%] female; 51 patients per cohort), patients who received the digital mental health intervention showed clinically meaningful improvements at the 2-month follow-up for all PROMIS measures (mean longitudinal improvement 2.8-3.7 points; P≤.02). After controlling for age and BMI, the improvements in PROMIS Depression, Pain Interference, and Physical Function were meaningfully greater than longitudinal changes shown by patients who received usual orthopedic care (mean between-group difference 2.6-4.8 points; P≤.04). Improvements in PROMIS Physical Function were also meaningfully greater than longitudinal changes shown by patients who received in-person psychological counseling (mean between-group difference 2.4 points; P=.04)., Conclusions: Patients who received a digital mental health intervention as part of orthopedic care reported greater 2-month mean improvements in depression, pain interference, and physical function than patients who received usual orthopedic care. They also reported a greater mean improvement in physical function and comparable improvements in depression, anxiety, and pain interference compared with orthopedic patients who received in-person psychological counseling., (©Ashwin J Leo, Matthew J Schuelke, Devyani M Hunt, J Philip Miller, Patricia A Areán, Abby L Cheng. Originally published in JMIR Formative Research (https://formative.jmir.org), 04.05.2022.)

Importance: Exposure to early-life adversity alters the structural development of key brain regions underlying neurodevelopmental impairments. The association between prenatal exposure to adversity and brain structure at birth remains poorly understood., Objective: To examine whether prenatal exposure to maternal social disadvantage and psychosocial stress is associated with neonatal global and regional brain volumes and cortical folding., Design, Setting, and Participants: This prospective, longitudinal cohort study included 399 mother-infant dyads of sociodemographically diverse mothers recruited in the first or early second trimester of pregnancy and their infants, who underwent brain magnetic resonance imaging in the first weeks of life. Mothers were recruited from local obstetric clinics in St Louis, Missouri from September 1, 2017, to February 28, 2020., Exposures: Maternal social disadvantage and psychosocial stress in pregnancy., Main Outcomes and Measures: Confirmatory factor analyses were used to create latent constructs of maternal social disadvantage (income-to-needs ratio, Area Deprivation Index, Healthy Eating Index, educational level, and insurance status) and psychosocial stress (Perceived Stress Scale, Edinburgh Postnatal Depression Scale, Everyday Discrimination Scale, and Stress and Adversity Inventory). Neonatal cortical and subcortical gray matter, white matter, cerebellum, hippocampus, and amygdala volumes were generated using semiautomated, age-specific, segmentation pipelines., Results: A total of 280 mothers (mean [SD] age, 29.1 [5.3] years; 170 [60.7%] Black or African American, 100 [35.7%] White, and 10 [3.6%] other race or ethnicity) and their healthy, term-born infants (149 [53.2%] male; mean [SD] infant gestational age, 38.6 [1.0] weeks) were included in the analysis. After covariate adjustment and multiple comparisons correction, greater social disadvantage was associated with reduced cortical gray matter (unstandardized β = -2.0; 95% CI, -3.5 to -0.5; P = .01), subcortical gray matter (unstandardized β = -0.4; 95% CI, -0.7 to -0.2; P = .003), and white matter (unstandardized β = -5.5; 95% CI, -7.8 to -3.3; P < .001) volumes and cortical folding (unstandardized β = -0.03; 95% CI, -0.04 to -0.01; P < .001). Psychosocial stress showed no association with brain metrics. Although social disadvantage accounted for an additional 2.3% of the variance of the left hippocampus (unstandardized β = -0.03; 95% CI, -0.05 to -0.01), 2.3% of the right hippocampus (unstandardized β = -0.03; 95% CI, -0.05 to -0.01), 3.1% of the left amygdala (unstandardized β = -0.02; 95% CI, -0.03 to -0.01), and 2.9% of the right amygdala (unstandardized β = -0.02; 95% CI, -0.03 to -0.01), no regional effects were found after accounting for total brain volume., Conclusions and Relevance: In this baseline assessment of an ongoing cohort study, prenatal social disadvantage was associated with global reductions in brain volumes and cortical folding at birth. No regional specificity for the hippocampus or amygdala was detected. Results highlight that associations between poverty and brain development begin in utero and are evident early in life. These findings emphasize that preventive interventions that support fetal brain development should address parental socioeconomic hardships.

The cercal sensory system of cricket mediates the detection, localization, and identification of air current signals generated by predators, mates, and competitors. This mechanosensory system has been used extensively for experimental and theoretical studies of sensory coding at the cellular and system levels. It is currently thought that sensory interneurons (INs) in the terminal abdominal ganglion extract information about the direction, velocity, and acceleration of the air currents in the animal's immediate environment and project a coarse-coded representation of those parameters to higher centers. All feature detection is thought to be carried out in higher ganglia by more complex, specialized circuits. We present results that force a substantial revision of current hypotheses. Using multiple extracellular recordings and a special sensory stimulation device, we demonstrate that four well-studied interneurons in this system respond with high sensitivity and selectivity to complex dynamic multidirectional features of air currents that have a spatial scale smaller than the physical dimensions of the cerci. The INs showed much greater sensitivity for these features than for unidirectional bulk-flow stimuli used in previous studies. Thus, in addition to participating in the ensemble encoding of bulk airflow stimulus characteristics, these interneurons are capable of operating as feature detectors for naturalistic stimuli. In this sense, these interneurons are encoding and transmitting information about different aspects of their stimulus environment; they are multiplexing information. Major aspects of the stimulus-response specificity of these interneurons can be understood from the dendritic anatomy and connectivity with the sensory afferent map. NEW & NOTEWORTHY A set of sensory interneurons that have been studied for over 30 years by several different research groups were discovered to have previously unknown encoding characteristics. As well as encoding the direction of bulk airflow with a coarse-coding scheme as shown in previous studies, these interneurons are also responsive to very small-scale, directionally complex air current waveforms. This feature sensitivity can be understood in terms of the cells' complex dendritic branching patterns.

We describe and apply novel methodology for whole-brain analysis of resting state fMRI functional connectivity data, combining conventional multi-channel Pearson correlation with covariance analysis. Unlike correlation, covariance analysis preserves signal amplitude information, which feature of fMRI time series may carry physiological significance. Additionally, we demonstrate that dimensionality reduction of the fMRI data offers several computational advantages including projection onto a space of manageable dimension, enabling linear operations on functional connectivity measures and exclusion of variance unrelated to resting state network structure. We show that group-averaged, dimensionality reduced, covariance and correlation matrices are related, to reasonable approximation, by a single scalar factor. We apply this methodology to the analysis of a large, resting state fMRI data set acquired in a prospective, controlled study of mindfulness training and exercise in older, sedentary participants at risk for developing cognitive decline. Results show marginally significant effects of both mindfulness training and exercise in both covariance and correlation measures of functional connectivity., 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 Snyder, Nishino, Shimony, Lenze, Wetherell, Voegtle, Miller, Yingling, Marcus, Gurney, Rutlin, Scott, Eyler and Barch.)

Understanding the etiology and treatment approaches in schizophrenia is challenged in part by the heterogeneity of this disorder. One encouraging progress is the growing evidence that there are subtypes of schizophrenia. Recent in vitro findings of messenger ribonucleic acid (mRNA) gene expression on postmortem dorsolateral prefrontal cortex (DLPFC) showed that schizophrenia has two subtypes, those with a relatively normal DLPFC transcriptome (Type 1) and those with differentially expressed genes (Type 2). Sphingosine-1-phosphate receptor-1 (S1PR1) is one of the genes that was highly upregulated in Type 2 compared to Type 1 and controls. The impact of that finding is limited because it only can be confirmed through analysis of autopsy tissue, and the clinical characteristics such as symptoms severity or illness duration except for cause of death was not available from that Medical Examiner based autopsy study. However, S1PR1 has great potential because it is a target gene that can be accessed via positron emission tomography (PET) in vivo using specific radioligands (starting with [ 11 C]CS1P1) successfully developed at our center in human brain imaging. As a preliminary study to validate this PET target in schizophrenia, S1PR1 protein expression was assessed by receptor autoradiography (ARG) using [ 3 H]CS1P1 and immunohistochemistry (IHC) in the DLPFC from patients with schizophrenia classified as Type 1 or Type 2 based on their DLPFC transcriptomes and from controls. Our analyses demonstrate that ARG S1PR1 protein expression is significantly higher in Type 2 compared to Type 1 ( p < 0.05) and controls ( p < 0.05), which was consistent with previous mRNA S1PR1. These findings support the possibility that PET S1PR1 can be used as a future imaging biomarker to distinguish these subgroups of schizophrenic patients during life with obvious implications for both patient management and the design of clinical trials to validate novel pharmacologic therapies., Competing Interests: CR is employed by Neurodex Inc. 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 © 2022 Chand, Jiang, Miller, Rhodes, Tu and Wong.)