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Objective: Postoperative communication errors contribute to patient harm and excess costs. There are no existing standards for postoperative handoff to the acute care inpatient unit. We aimed to compare the experiences and preferences of pediatric hospitalists and surgeons about the content and timing of this handoff., Methods: We conducted a cross-sectional multisite survey of pediatric hospitalists and surgeons at 4 hospitals using a novel survey tool developed through a systematic 7-step process. We collected data on the perceived frequency of communication for 37 handoff elements and how essential each element was for an ideal handoff. We used 5-point Likert scales of communication frequency and essentialness. Respondents identified perceived and preferred handoff timing. Mention frequency and timing data were analyzed with the Mann-Whitney U test and Fisher's exact test, respectively., Results: Seventy hospitalists (61%) and 27 surgeons (25%) responded to the survey. Over half of both hospitalist and surgeon respondents rated 13 handoff elements a 5 on the essentialness Likert scale. Surgeons perceived that 33 handoff elements were mentioned significantly more frequently than perceived by hospitalists (P < .05). Of hospitalists, 58% preferred that handoff occur immediately before the patient leaves the postanesthesia care unit. Of surgeons, 60% preferred that handoff occur immediately postoperatively., Conclusions: The 13 core elements we identified may facilitate the development of a standardized handoff checklist for postoperative communication between surgeons and hospitalists on acute care units. Areas of future study could include checklist validation, audits of handoff practice, and qualitative research on handoff preferences., Competing Interests: CONFLICT OF INTEREST DICLOSURES: The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2024 by the American Academy of Pediatrics.)

Objective: Rheumatoid arthritis (RA) has a "pre-RA" period in which multiple autoantibodies, including antibodies to citrullinated (cit) proteins (ACPA), rheumatoid factor (RF), anti-peptidyl arginine deiminase (anti-PAD), among others, have been described; however, few studies have tested all autoantibodies in a single pre-RA cohort. This study aims to evaluate the prevalence of multiple autoantibodies in pre-RA and potentially identify an autoantibody profile in pre-RA that indicates imminent onset of clinical RA., Methods: We evaluated 148 individuals with two pre- and one post-RA diagnosis samples available from the Department of Defense Serum Repository and matched controls. Samples were tested for immuglobulin (Ig) G anti-cyclic cit peptide-3 (anti-CCP3), five ACPA fine specificities, five anti-PAD isoforms, as well as RF IgA and RF IgM using commercial platforms; cutoffs were determined using levels present in <1% of controls., Results: Positivity of anti-CCP3, RF IgA and RF IgM, anti-PAD1, anti-cit-vimentin 2, anti-cit-fibrinogen, and anti-cit-histone 1 increased over time in pre-RA, although anti-PAD and ACPA fine specificities were predominately present within anti-CCP3-positive individuals. Within anti-CCP3-positive samples from the pre-RA period, positivity for RFs as well as anti-PAD and ACPA fine specificities classified samples as being closer to the time of RA diagnosis., Conclusion: Multiple autoantibodies are present in pre-RA and increase in positivity as the time of RA diagnosis approaches. These results confirm previous findings predicting imminent RA and provide a pathway using commercial-grade assays to assess the risk for and timing of development of clinical RA., (© 2024 The Author(s). ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objectives: This project aims to determine the feasibility of predicting future critical care bed availability using data-driven computational forecast modelling and routinely collected hospital bed management data., Methods: In this proof-of-concept, single-centre data informatics feasibility study, regression-based and classification data science techniques were applied retrospectively to prospectively collect routine hospital-wide bed management data to forecast critical care bed capacity. The availability of at least one critical care bed was forecasted using a forecast horizon of 1, 7 and 14 days in advance., Results: We demonstrated for the first time the feasibility of forecasting critical care bed capacity without requiring detailed patient-level data using only routinely collected hospital bed management data and interpretable models. Predictive performance for bed availability 1 day in the future was better than 14 days (mean absolute error 1.33 vs 1.61 and area under the curve 0.78 vs 0.73, respectively). By analysing feature importance, we demonstrated that the models relied mainly on critical care and temporal data rather than data from other wards in the hospital., Discussion: Our data-driven forecasting tool only required hospital bed management data to forecast critical care bed availability. This novel approach means no patient-sensitive data are required in the modelling and warrants further work to refine this approach in future bed availability forecast in other hospital wards., Conclusions: Data-driven critical care bed availability prediction was possible. Further investigations into its utility in multicentre critical care settings or in other clinical settings are warranted., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Intracranial pressure (ICP) monitoring is a very commonly performed neurosurgical procedure but there is a wide variation in how it is reported, hindering analysis of it. The current study sought to generate consensus on the reporting of ICP monitoring recording data., Research Question: "What should be included in an ICP monitoring report?", Material and Methods: The exercise was completed via a modified eDelphi survey. An expert panel discussion was held from which themes were identified and used to produce a code to annotate the transcript of the discussion. Statements were generated for a further two rounds of electronic questionnaires distributed via the REDcap platform. A Likert scale was used to grade agreement with each statement in the survey. A statement was accepted if more than 70% agreement was achieved between respondents. Data was collated using Microsoft Excel and analysed using R., Results: 149 relevant statements were identified from the transcript and categorised into recording parameters, waveform characteristics or reporting. A total of 22 statements were generated for the first round of the survey which was answered by 39 respondents. Following the electronic round of surveys consensus was achieved for all but one statement regarding the acceptability of automating ICP reporting. This was put forward to a second round after which 79% agreement was reached., Discussion and Conclusion: The themes and statements from this eDelphi can be used as a framework to allow the standardisation of the reporting of intracranial pressure monitoring data., Competing Interests: 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., (© 2024 The Authors.)

Introduction: Numerous complex physiological models derived from intracranial pressure (ICP) monitoring data have been developed. More recently, techniques such as machine learning are being used to develop increasingly sophisticated models to aid in clinical decision-making tasks such as diagnosis and prediction. Whilst their potential clinical impact may be significant, few models based on ICP data are routinely available at a patient's bedside. Further, the ability to refine models using ongoing patient data collection is rare. In this paper we identify and discuss the challenges faced when converting insight from ICP data analysis into deployable tools at the patient bedside., Research Question: To provide an overview of challenges facing implementation of sophisticated ICP models and analyses at the patient bedside., Material and Methods: A narrative review of the barriers facing implementation of sophisticated ICP models and analyses at the patient bedside in a neurocritical care unit combined with a descriptive case study (the CHART-ADAPT project) on the topic., Results: Key barriers found were technical, analytical, and integrity related. Examples included: lack of interoperability of medical devices for data collection and/or model deployment; inadequate infrastructure, hindering analysis of large volumes of high frequency patient data; a lack of clinical confidence in a model; and ethical, trust, security and patient confidentiality considerations governing the secondary use of patient data., Discussion and Conclusion: To realise the benefits of ICP data analysis, the results need to be promptly delivered and meaningfully communicated. Multiple barriers to implementation remain and solutions which address real-world challenges are required., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Laura Moss reports financial support was provided by 10.13039/501100006041Innovate UK. Martin Shaw reports financial support was provided by 10.13039/501100006041Innovate UK. Ian Piper reports financial support was provided by 10.13039/501100006041Innovate UK. Christopher Hawthorne reports financial support was provided by 10.13039/501100006041Innovate UK., (© 2024 The Authors.)

Introduction: Intracranial pressure (ICP) monitoring is commonly used in investigating the aetiology of chronic paediatric neurological conditions. A series of high-amplitude spikes has been observed in overnight ICP recordings of some children, many of whom have hydrocephalus or craniosynostosis., Research Question: This clinical evaluation aimed to define the spike pattern, describe the patient group in which it is most likely to occur, and conduct high-resolution waveform analysis., Material and Methods: ICP waveforms from 40 patients aged 0-5 years (inclusive), recorded between 2017 and 2021 at the Royal Hospital for Children Glasgow, were retrospectively analysed. The pattern was defined through visual inspection of regions of interest by two reviewers. Patients were stratified using demographic and clinical data. R software was used to perform regression and high-resolution waveform analyses., Results: The spike pattern was defined as the presence of 2 consecutive spikes with an amplitude of at least 8 mmHg, with a gap of at least 30 min between spikes. In the adjusted Poisson regression, age was significantly associated with the number of spikes (IRR 0.8, 95% CI 0.70 to 0.92, p-value 0.001)., Discussion and Conclusion: Younger age was significantly associated with an increased number of spikes in this cohort. Investigation of clinical consequences of the spikes is warranted., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Amarah Saeed reports financial support was provided by Neuro Anaesthesia & Critical Care Society (via National Institute of Academic Anaesthesia). Amarah Saeed reports financial support was provided by 10.13039/501100000294Medical Research Scotland., (© 2024 The Authors.)

Objective: To investigate immune dysregulation in the peripheral blood that contributes to the pre-rheumatoid arthritis (RA) stage of RA development in anticitrullinated protein antibody (ACPA)+ individuals., Methods: Using 37 markers by mass cytometry, we investigated peripheral blood mononuclear cells (PBMCs) from ACPA+ at-risk individuals, ACPA+ early untreated patients with RA, and ACPA- controls in the Tokyo Women's Medical University cohort (n = 17 in each group). Computational algorithms, FlowSOM and Optimized t-Distributed Stochastic Neighbor Embedding, were employed to explore specific immunologic differences between study groups. These findings were further evaluated, and longitudinal changes were explored, using flow cytometry and PBMCs from the US-based Targeting Immune Responses for Prevention of RA cohort that included 11 ACPA+ individuals who later developed RA (pre-RA), of which 9 had post-RA diagnosis PBMCs (post-RA), and 11 ACPA- controls., Results: HLA-DR + peripheral helper T (Tph) cells, activated regulatory T cells, PD-1 hi CD8 + T cells, and CXCR5 - CD11c - CD38 + naive B cells were significantly expanded in PBMCs from at-risk individuals and patients with early RA from the Tokyo Women's Medical University cohort. Expansion of HLA-DR + Tph cells and CXCR5 - CD11c - CD38 + naive B cells was likewise found in both pre-RA and post-RA time points in the Targeting Immune Responses for Prevention of RA cohort., Conclusion: The expansion of HLA-DR + Tph cells and CXCR5 - CD11c - CD38 + naive B cells in ACPA+ individuals, including those who developed inflammatory arthritis and classified RA, supports a key role of these cells in transition from pre-RA to classified RA. These findings may identify a new mechanistic target for treatment and prevention in RA., (© 2024 American College of Rheumatology.)

Introduction: Partial pressure of brain tissue oxygen (PbtO2) has been shown to be a safe an effective monitoring modality to compliment intracranial pressure (ICP) monitoring. It is related to metabolic activity, disease severity and mortality., Research Question: Understanding the complex relationship between PbtO2 and ICP for patients with traumatic brain injury will enable better clinical decision making beyond simple threshold treatment strategies., Material and Methods: Patients with PbtO2 monitoring were identified from the BrainIT database, a multi-centre dataset, containing minute by minute PbtO2 and ICP readings. Missing data was imputed and a multi-level log-normal regression model with a compound symmetry correlation structure was built. This accounted for any increased correlation due to the repeated measurements. The model was adjusted for mean arterial pressure and the partial pressure of carbon dioxide. Non-linearity was assessed using analysis of deviance and trends using expected marginal means., Results: 11 subjects with over 82,000 readings were included. They had a median age of 38 (IQR: 37-47), 73% were male, a median length of stay of 11.8 (IQR: 6.6-19.7) days and a median extended Glasgow outcome scale of 7.00 (IQR: 5-8).There is a statistically significant (p < 0.001) non-linear effect of ICP on PbtO2. With an overall increase in PbtO2 of 5.2% (95% CI 4%-6.4%, p < 0.001) for a 10 mmHg increase in ICP below 22 mmHg and a decrease of 5.5% (95% CI 2.7%-8.3%, p=<0.001) in PbtO2 for a 10 mmHg increase in ICP above 22 mmHg. As well as a decrease of 40.9% (95% CI 2.3%-64.3%, p = 0.040) in PbtO2 per day in the intensive care unit., Discussion and Conclusion: This model demonstrates that there is a significant non-linear relationship between ICP and PbtO2, however, this is a small heterogeneous cohort and further validation will be required., Competing Interests: The authors declare that they have no competing interests.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., (© 2024 The Authors.)

The characteristics of a neighborhood's built environment may influence health-promoting behaviors, interactions between neighbors, and perceptions of safety. Although some research has reported on how youth in high-violence communities navigate danger, less work has investigated how these youth perceive the built environment, their desires for these spaces, and how these desires relate to their conceptions of safety and perceptions of other residents. To fill this gap, this study used focus group data from 51 youth ages 13-24 living in New Orleans, Louisiana. Four themes were developed using reflexive thematic analysis: community violence is distressing and disruptive, youth use and want to enjoy their neighborhood, systemic failure contributes to negative outcomes, and resources and cooperation create safety. This analysis indicates that young people desire to interact with the built environment despite the threat of community violence. They further identified built environment assets that facilitate socialization and recreation, such as local parks, and social assets in the form of cooperation and neighbor-led civic engagement initiatives. In addition, the youth participants demonstrated awareness of structural inequities that influence neighborhood health and violence-related outcomes. This study contributes to efforts to understand how youth with high levels of community violence exposure understand and interact with the built and social environments., (© 2024. The Author(s).)

Background: The use of anesthetics may result in depression of the hypoxic ventilatory response. Since there are no receptor-specific antagonists for most anesthetics, there is the need for agnostic respiratory stimulants that increase respiratory drive irrespective of its cause. The authors tested whether ENA-001, an agnostic respiratory stimulant that blocks carotid body BK-channels, could restore the hypoxic ventilatory response during propofol infusion. They hypothesize that ENA-001 is able to fully restore the hypoxic ventilatory response., Methods: In this randomized, double-blind crossover trial, 14 male and female healthy volunteers were randomized to receive placebo and low- and high-dose ENA-001 on three separate occasions. On each occasion, isohypercapnic hypoxic ventilatory responses were measured during a fixed sequence of placebo, followed by low- and high-dose propofol infusion. The authors conducted a population pharmacokinetic/pharmacodynamic analysis that included oxygen and carbon dioxide kinetics., Results: Twelve subjects completed the three sessions; no serious adverse events occurred. The propofol concentrations were 0.6 and 2.0 µg/ml at low and high dose, respectively. The ENA-001 concentrations were 0.6 and 1.0 µg/ml at low and high dose, respectively. The propofol concentration that reduced the hypoxic ventilatory response by 50% was 1.47 ± 0.20 µg/ml. The steady state ENA-001 concentration to increase the depressed ventilatory response by 50% was 0.51 ± 0.04 µg/ml. A concentration of 1 µg/ml ENA-001 was required for full reversal of the propofol effect at the propofol concentration that reduced the hypoxic ventilatory response by 50%., Conclusions: In this pilot study, the authors demonstrated that ENA-001 restored the hypoxic ventilatory response impaired by propofol. This finding is not only of clinical importance but also provides mechanistic insights into the peripheral stimulation of breathing with ENA-001 overcoming central depression by propofol., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Anesthesiologists.)

Purpose: The purpose of this study was to investigate the impact of the type of data capture on the time and help needed for collecting patient-reported outcomes as well as on the proportion of missing scores., Methods: In a multinational prospective study, thyroid cancer patients from 17 countries completed a validated questionnaire measuring quality of life. Electronic data capture was compared to the paper-based approach using multivariate logistic regression., Results: A total of 437 patients were included, of whom 13% used electronic data capture. The relation between data capture and time needed was modified by the emotional functioning of the patients. Those with clinical impairments in that respect needed more time to complete the questionnaire when they used electronic data capture compared to paper and pencil (OR adj 24.0; p = 0.006). This was not the case when patients had sub-threshold emotional problems (OR adj 1.9; p = 0.48). The odds of having the researcher reading the questions out (instead of the patient doing this themselves) (OR adj 0.1; p = 0.01) and of needing any help (OR adj 0.1; p = 0.01) were lower when electronic data capture was used. The proportion of missing scores was equivalent in both groups (OR adj 0.4, p = 0.42)., Conclusions: The advantages of electronic data capture, such as real-time assessment and fewer data entry errors, may come at the price of more time required for data collection when the patients have mental health problems. As this is not uncommon in thyroid cancer, researchers need to choose the type of data capture wisely for their particular research question., (© 2023. The Author(s).)

Antibody affinity maturation occurs in secondary lymphoid organs within germinal centers (GCs). At these sites, B cells mutate their antibody-encoding genes in the dark zone, followed by preferential selection of the high-affinity variants in the light zone by T cells. The strength of the T cell-derived selection signals is proportional to the B cell receptor affinity and to the magnitude of subsequent Myc expression. However, because the lifetime of Myc mRNA and its corresponding protein is very short, it remains unclear how T cells induce sustained Myc levels in positively selected B cells. Here, by direct visualization of mRNA and active transcription sites in situ, we found that an increase in transcriptional bursts promotes Myc expression during B cell positive selection in GCs. Elevated T cell help signals predominantly enhance the percentage of cells expressing Myc in GCs as opposed to augmenting the quantity of Myc transcripts per individual cell. Visualization of transcription start sites in situ revealed that T cell help promotes an increase in the frequency of transcriptional bursts at the Myc locus in GC B cells located primarily in the LZ apical rim. Thus, the rise in Myc , which governs positive selection of B cells in GCs, reflects an integration of transcriptional activity over time rather than an accumulation of transcripts at a specific time point.

Background: Radiotherapy is a standard treatment modality in cancer therapy, particularly for lung cancer. Diffusing alpha-emitters Radiation Therapy sources (hereafter, "Alpha DaRTs") are fixed with Ra-244 (half-life =3.6 days) that releases alpha-emitting atoms into the tumor tissue to an effective range of a few millimeters., Methods: The feasibility, usability, and safety of Alpha DaRTs deployment and implantation via bronchoscopy into the lung parenchyma and mediastinum in a big animal model of healthy swine was studied in two phases: (I) inert and (II) active Alpha DaRTs deployment. The Alpha DaRTs were inserted in both individual and cluster patterns based on a predefined plan. Swine health was monitored throughout the study. The usability of bronchoscopic deployment and implantation was evaluated using a user questionnaire. The movement and migration of the Alpha DaRTs were assessed. Necropsy was performed, and lungs were evaluated via gross pathology and histopathology., Results: A total of 158 Alpha DaRTs were inserted successfully in the lung parenchyma and mediastinum of five swine in two phases. It was possible to deliver and place the Alpha DaRTs in clusters of no more than 4 mm distance between the Alpha DaRTs. No adverse event or change in the health and general condition of animals was observed. Hematologic evaluation did not show any clinically significant abnormality related to the Alpha DaRTs. Histopathology demonstrated local mild inflammatory changes, minimal fibrosis, and dystrophic mineralization with giant cells. Minimal movement and no migration of Alpha DaRTs were observed., Conclusions: Bronchoscopic deployment of Alpha DaRTs in the lung parenchyma and mediastinum of the porcine animal is feasible, precise, and safe., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-639/coif). All authors report that this study was funded by Alpha Tau Medical. A.S. (Ali Sadoughi) has been compensated for the expenses of educational and training events by Merit Medical, Olympus, Siemens, AcuityMD and Boston Scientific, served on advisory board for Mauna Kea, received consulting fee from Alpha Tau Medical and Olympus, and has stock option at Alpha Tau. N.O. received research funds from AstraZeneca and Merck and received consulting fees from AstraZeneca, Genentech and Merck. The authors have no other conflicts of interest to declare., (2024 Translational Lung Cancer Research. All rights reserved.)

This study aimed to develop an efficient data collection and curation process for all drugs and natural health products (NHPs) used by participants to the Canadian Longitudinal Study on Aging (CLSA). The three-step sequential process consisted of (a) mapping drug inputs collected through the CLSA to the Health Canada Drug Product Database (DPD), (b) algorithm recoding of unmapped drug and NHP inputs, and (c) manual recoding of unmapped drug and NHP inputs. Among the 30,097 CLSA comprehensive cohort participants, 26,000 (86.4%) were using a drug or an NHP with a mean of 5.3 (SD 3.8) inputs per participant user for a total of 137,366 inputs. Of those inputs, 70,177 (51.1%) were mapped to the Health Canada DPD, 20,729 (15.1%) were recoded by algorithms, and 44,108 (32.1%) were manually recoded. The Direct algorithm correctly classified 99.4 per cent of drug inputs and 99.5 per cent of NHP inputs. We developed an efficient three-step process for drug and NHP data collection and curation for use in a longitudinal cohort.

This qualitative study explored the role of neglected properties and neighborhood environment characteristics on a sample of New Orleans, Louisiana residents' health and well-being, sense of community, sense of safety, and civic engagement. We hypothesized that residents would identify conditions of their neighborhood's physical environment, including neglected properties, as one factor that impacted their health and other aspects of well-being. Seventy-four (N = 74) participants, including women, men, youth, young adults, and community leaders, took part in 11 focus groups (n = 51) and 23 key informant interviews. Thematic content analysis through inductive and deductive coding cycles of interview transcripts revealed five main categories related to urban neighborhood-built and social environments: 1) health and well-being, 2) sense of community, 3) sense of safety, 4) civic engagement, and 5) youth and family violence. Ten themes were developed and included, for example, the role of neighborhoods in delineating access to health-promoting characteristics and resources; the role of neighborhood social networks as crime prevention strategies; resident-led decision-making in neighborhood improvements; the negative impact of neglected properties; and the role of the local government in improving physical infrastructure. These findings affirm that residents were aware of and impacted by the cyclical nature of built environment neglect on health and well-being, community violence, neighborhood cohesion, civic engagement, and youth violence. Participants recommended improving neighborhood conditions to shift resident mindsets about the health of neighborhoods, reduce violence, and improve quality of life., (© The Author(s) 2024.)

Background: Noradrenergic signaling declines in Parkinson's disease (PD) following locus coeruleus neurodegeneration. Epidemiologic studies demonstrate that β-acting drugs slow PD progression., Objective: The primary objective was to compare the safety and effects of 3 β-adrenoceptor (β-AR) acting drugs on central nervous system (CNS) function after a single dose in healthy volunteers (HVs) and evaluate the effects of multiple doses of β-AR acting drugs in HVs and PD-patients., Methods: In Part A, HVs received single doses of 32 mg salbutamol, 160μg clenbuterol, 60 mg pindolol and placebo administered in a randomized, 4-way cross-over study. In Part B (randomized cross-over) and Part C (parallel, 2:1 randomized), placebo and/or clenbuterol (20μg on Day 1, 40μg on Day 2, 80μg on Days 3-7) were administered. CNS functions were assessed using the NeuroCart test battery, including pupillometry, adaptive tracking and recall tests., Results: Twenty-seven HVs and 12 PD-patients completed the study. Clenbuterol improved and pindolol reduced the adaptive tracking and immediate verbal recall performance. Clenbuterol and salbutamol increased and pindolol decreased pupil-to-iris ratios. Clenbuterol was selected for Parts B and C. In Part B, clenbuterol significantly increased performance in adaptive tracking with a tendency toward improved performance in immediate and delayed verbal recall. In Part C trends toward improved performance in immediate and delayed verbal recall were observed in PD-patients. Typical cardiovascular peripheral β2-AR effects were observed with clenbuterol., Conclusions: This study demonstrates the pro-cognitive effects of clenbuterol in HVs with similar trends in PD-patients. The mechanism of action is likely activation of β2-ARs in the CNS.

Objectives: To assess the relationship between self-reported and serologic evidence of prior chlamydial infection, rheumatoid arthritis (RA)-related autoantibodies and risk of RA-development., Methods: This is a nested study within a prospective Swiss-based cohort including all first-degree relatives of RA patients (RA-FDR) who answered a question on past chlamydial infections. Primary outcome was systemic autoimmunity associated with RA (RA-autoimmunity) defined as positivity for anti-citrullinated peptide antibodies (ACPA) and/or rheumatoid factor (RF). Secondary outcomes were high levels of RA-autoimmunity, RA-associated symptoms and RA-autoimmunity, and subsequent seropositive RA diagnosis. We conducted a nested case-control analysis by measuring the serological status against Chlamydia trachomatis' major outer membrane protein. We replicated our analysis in an independent United States-based RA-FDR cohort., Results: Among 1231 RA-FDRs, 168 (13.6%) developed RA-autoimmunity. Prevalence of self-reported chlamydial infection was significantly higher in individuals with RA-autoimmunity compared with controls (17.9% vs 9.8%, OR = 2.00, 95%CI: 1.27-3.09, p < 0.01). This association remained significant after adjustments (OR = 1.91, 95%CI: 1.20-2.95). Stronger effect sizes were observed in later stages of RA development. There was a similar trend between a positive C. trachomatis serology and high levels of RA-autoimmunity (OR = 3.05, 95% CI: 1.10-8.46, p= 0.032). In the replication cohort, there were significant associations between chlamydial infection and RF positivity and incident RA, but not anti-CCP positivity., Conclusions: Self-reported chlamydial infections are associated with elevated RA-autoimmunity in at risk individuals. The differing association of chlamydial infections and ACPA/RF between cohorts will need to be explored in future studies but is consistent with a role of mucosal origin of RA-related autoimmunity., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Oliceridine (Olinvyk) is a μ-opioid receptor agonist that in contrast to conventional opioids preferentially engages the G-protein-coupled signaling pathway. This study was designed to determine the utility function of oliceridine versus morphine based on neurocognitive tests and cold pressor test., Methods: The study had a randomized, double-blind, placebo-controlled, partial block three-way crossover design. Experiments were performed in 20 male and female volunteers. The subjects received intravenous oliceridine (1 or 3 mg; cohorts of 10 subjects/dose), morphine (5 or 10 mg; cohorts of 10 subjects/dose), or placebo on three separate occasions. Before and after dosing, neurocognitive tests, cold pressor test, and plasma drug concentrations were obtained at regular intervals. Population pharmacokinetic-pharmacodynamic analyses served as the basis for construction of a utility function, which is an objective function of probability of benefit minus probability of harm. Antinociception served as the measure of benefit, and slowing of saccadic peak velocity and increased body sway as the measures of neurocognitive harm., Results: The oliceridine and morphine C50 values, i.e., the effect-site concentrations causing 50% effect, were as follows: antinociception, 13 ± 2 and 23 ± 7 ng/ml; saccadic peak velocity, 90 ± 14 and 54 ± 15 ng/ml; and body sway, 10 ± 2 and 5.6 ± 0.8 ng/ml, respectively. The ratio oliceridine/morphine of the therapeutic indices, C50(benefit)/C50(harm), were 0.34 (95% CI, 0.17 to 0.7; P < 0.01) for saccadic peak velocity and 0.33 (0.16 to 0.50; P < 0.01) for body sway. The oliceridine utility was positive across the effect-site concentration 5 to 77 ng/ml, indicative of a greater probability of benefit than harm. The morphine utility was not significantly different from 0 from 0 to 100 ng/ml. Over the concentration range 15 to 50 ng/ml, the oliceridine utility was superior to that of morphine (P < 0.01). Similar observations were made for body sway., Conclusions: These data indicate that over the clinical concentration range, oliceridine is an analgesic with a favorable safety profile over morphine when considering analgesia and neurocognitive function., (Copyright © 2023 American Society of Anesthesiologists. All Rights Reserved.)

Molecular markers of autoimmunity, such as antibodies to citrullinated protein antigens (ACPA), are detectable prior to inflammatory arthritis (IA) in rheumatoid arthritis (RA) and may define a state that is 'at-risk' for future RA. Here we present a cross-sectional comparative analysis among three groups that include ACPA positive individuals without IA (At-Risk), ACPA negative individuals and individuals with early, ACPA positive clinical RA (Early RA). Differential methylation analysis among the groups identifies non-specific dysregulation in peripheral B, memory and naïve T cells in At-Risk participants, with more specific immunological pathway abnormalities in Early RA. Tetramer studies show increased abundance of T cells recognizing citrullinated (cit) epitopes in At-Risk participants, including expansion of T cells reactive to citrullinated cartilage intermediate layer protein I (cit-CILP); these T cells have Th1, Th17, and T stem cell memory-like phenotypes. Antibody-antigen array analyses show that antibodies targeting cit-clusterin, cit-fibrinogen and cit-histone H4 are elevated in At-Risk and Early RA participants, with the highest levels of antibodies detected in those with Early RA. These findings indicate that an ACPA positive at-risk state is associated with multifaceted immune dysregulation that may represent a potential opportunity for targeted intervention., (© 2023. The Author(s).)

Intimate partner violence (IPV) among Black adolescents is a critical public health issue, as they report higher levels of IPV perpetration and victimization than their counterparts from other racial groups. Although practitioners frequently implement educational programs to reduce and prevent adolescent relationship violence among adolescents, the extent to which these interventions have been culturally tailored to Black youth is unclear. The purpose of this scoping review is to investigate the nature and effects of cultural tailoring in IPV interventions delivered to Black adolescent populations as well as any critical media literacy (CML) content therein. We conducted searches of three databases for peer-reviewed research published in the United States between 2000 and 2020 that evaluated an IPV-focused educational intervention with a predominantly Black adolescent sample. A total of eight original studies met our inclusion criteria. Findings showed that five of the articles mentioned some level of cultural tailoring for the participants. However, the level and nature of that tailoring ranged widely with regard to curriculum development, staffing, and other program elements. No studies included any elements of CML education. Overall results indicate positive effects of IPV interventions on adolescents and reduced acceptance of violence in romantic relationships. This scoping review highlights a lack of clarity on methods used for cultural tailoring of curriculum based IPV interventions, vague application of social learning theoretical frameworks, and the potential benefits of CML content.

Background: Borrelia persica causes tick-borne relapsing fever in Israel, the eastern Mediterranean basin, and Asia. Relapsing fever is associated with severe illness and potentially death in humans and animals. Since B. persica infection has rarely been described in wild animals, the aim of this study was to evaluate the prevalence of infection with B. persica in wild carnivores in Israel., Methods: Spleen and blood clot samples from wild carnivores, which underwent necropsy, were tested for the presence of Borrelia DNA by real-time polymerase chain reaction (PCR). PCR products were sequenced, and the spirochete loads were quantified using a specific quantitative PCR (qPCR)., Results: A total of 140 samples from 74 wild carnivores were analyzed for the presence of Borrelia DNA. Six out of the 74 (8.1%) animals were found positive for B. persica by PCR and sequencing of the flagellin B gene, of which 4/74 (5.4%) were also positive by PCR for the glycerophosphodiester phosphodiesterase (glpQ) gene. Positive samples were obtained from three European badgers, and one striped hyena, golden jackal, and red fox each. All B. persica-positive animals were young males (P < 0.0001). Quantifiable results were obtained from 3/5 spleen and 4/5 blood samples. The spirochete loads in the blood were significantly higher than those found in the spleen (P = 0.034)., Conclusions: The prevalence of B. persica infection found in wild carnivores brought for necropsy was unexpectedly high, suggesting that this infection is widespread in some wild animal species in Israel. This is the first report of B. persica infection in the European badger and striped hyena. These carnivores have a wide geographical range of activity, and the results of this survey raise the possibility that they may serve as reservoir hosts for B. persica., (© 2023. The Author(s).)

Thrombopoietin (THPO or TPO) is an essential cytokine for hematopoietic stem cell (HSC) maintenance and megakaryocyte differentiation. Here, we report the 3.4 Å resolution cryoelectron microscopy structure of the extracellular TPO-TPO receptor (TpoR or MPL) signaling complex, revealing the basis for homodimeric MPL activation and providing a structural rationalization for genetic loss-of-function thrombocytopenia mutations. The structure guided the engineering of TPO variants (TPO mod ) with a spectrum of signaling activities, from neutral antagonists to partial- and super-agonists. Partial agonist TPO mod decoupled JAK/STAT from ERK/AKT/CREB activation, driving a bias for megakaryopoiesis and platelet production without causing significant HSC expansion in mice and showing superior maintenance of human HSCs in vitro. These data demonstrate the functional uncoupling of the two primary roles of TPO, highlighting the potential utility of TPO mod in hematology research and clinical HSC transplantation., Competing Interests: Declaration of interests K.C.G., N.T., and I.S.H. are inventors on a United States provisional patent (63/519,687, filed 15 August 2023) related to the mutant TPO molecules described in the manuscript., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Magnetic resonance imaging scanner faults can be missed during routine quality assurance (QA) if they are subtle, intermittent, or the test being performed is insensitive to the type of fault. Coil element malfunction is a common fault within MRI scanners, which may go undetected for quite some time. Consequently, this may lead to poor image quality and the potential for misdiagnoses., Purpose: Daily QA typically consists of an automated signal to noise ratio test and in some instances this test is insensitive to coil element malfunction. Instead of relying on daily QA testing, it was proposed to utilize patient images in conjunction with a trained neural network to detect coil element malfunction, even when it presents as a very subtle defect. The advantage to using patient images over phantom testing is real-time monitoring can be achieved. This allows clinical staff to focus more on patient throughput without being burdened by daily testing., Methods: A neural network was trained using simulated coil failure in 3958 abdominal or pelvic images from 497 patients. The accuracy of the trained network was then tested on an unseen dataset of 109 images from which 44 patients which had coil element malfunction present. Five MRI radiographers were shown 249 images with and without real coil malfunction to assess their accuracy compared to the neural network in identifying the scanner fault., Results: The neural network achieved an accuracy of 91.74% in identifying coil element malfunction in the unseen data. Radiographers tasked with identifying coil element malfunction had an average accuracy of 59.99%. In the same test case, the neural network outperformed all radiographers with an accuracy of 91.56%., Conclusion: This work demonstrates that neural networks trained with artificial data can successfully identify MRI scanner coil element malfunction in clinical images. The method provided better accuracy than MRI radiographers (technologists) at identifying coil element malfunction and highlights the potential utility of AI methods as an alternative to support traditional QA. Further, our methodology of training neural networks with simulated data could potentially identify other faults, allowing centers to produce robust fault detection systems with minimal data., (© 2023 American Association of Physicists in Medicine.)

Purpose: The aim of this study was to validate the new European Organisation for Research and Treatment of Cancer Quality of Life Thyroid Cancer Module (EORTC QLQ-THY34). Methods: We enrolled 437 thyroid cancer patients from 17 countries. One group ( n  = 303), undergoing treatment or best supportive care, completed the questionnaires at three time points (before therapy [t1], 6 weeks later [t2], and 6 months after t2 [t3]). A second group (survivors ≥2 years after diagnosis, n  = 134) completed it at a random baseline time point and a second time 1 week later. We determined internal consistency (using Cronbach's alpha), the scale structure (with confirmatory factor analysis), and discriminant validity (using known-group comparisons). Group 1 data were used to assess responsiveness and group 2 data to determine test-retest reliability using intra-class correlations (ICC). Results: All 34 items fulfilled the criteria to be kept in the questionnaire. Cronbach's alpha was >0.70 in 8 of the 9 multi-item scales. All standardized factor loadings exceeded 0.40, confirming the proposed scale structure. The ICC was >0.70 in all scales expressing good test-retest reliability. Differences in scale scores between patients with different histology were >5 points in all scales. In all but one of the pre-specified scales ( Dry Mouth ), changes over time were ≥|4| points between at least two time points. Conclusion: The EORTC QLQ-THY34 with its 9 multi-item and 8 single-item scales is a reliable and valid tool to measure quality of life in thyroid cancer patients and can be used in future trials and studies.

Background: This survey-based study identified views on antiobesity medications in youth referred to a weight management program. Methods: One parent completed a 14-item Research Electronic Data Capture (REDcap) survey regarding openness to medication use in youth with obesity at their first visit in a weight management program. Medical data were extracted from the medical records of all responders. Results: Ninety-four percent (116/125) of parents approached completed the survey (youths' demographic: mean age = 14.1 years old, 46.8% female, 68.8% Hispanic). Results indicate that 75% of parents surveyed were open to medication use. There was no difference in sex, age, insurance, severity of obesity, or family history between parents who were and were not open to medication (all p  > 0.05). Hispanic ethnicity was associated with greater openness to medication use (odds ratio: 3.4, 95% confidence interval: 1.4-8.5, p  = 0.007). Conclusions: These results highlight the importance of parental perceptions of medication use for obesity treatment and suggest a need for improved education about the role of medication in the management of pediatric obesity.

Objectives: RESCUEicp studied decompressive craniectomy (DC) applied as third-tier option in severe traumatic brain injury (TBI) patients in a randomized controlled setting and demonstrated a decrease in mortality with similar rates of favorable outcome in the DC group compared to the medical management group. In many centers, DC is being used in combination with other second/third-tier therapies. The aim of the present study is to investigate outcomes from DC in a prospective non-RCT context., Methods: This is a prospective observational study of 2 patient cohorts: one from the University Hospitals Leuven (2008-2016) and one from the Brain-IT study, a European multicenter database (2003-2005). In thirty-seven patients with refractory elevated intracranial pressure who underwent DC as a second/third-tier intervention, patient, injury and management variables including physiological monitoring data and administration of thiopental were analysed, as well as Extended Glasgow Outcome score (GOSE) at 6 months., Results: In the current cohorts, patients were older than in the surgical RESCUEicp cohort (mean 39.6 vs. 32.3; p < 0.001), had higher Glasgow Motor Score on admission (GMS < 3 in 24.3% vs. 53.0%; p = 0.003) and 37.8% received thiopental (vs. 9.4%; p < 0.001). Other variables were not significantly different. GOSE distribution was: death 24.3%; vegetative 2.7%; lower severe disability 10.8%; upper severe disability 13.5%; lower moderate disability 5.4%; upper moderate disability 2.7%, lower good recovery 35.1%; and upper good recovery 5.4%. The outcome was unfavorable in 51.4% and favorable in 48.6%, as opposed to 72.6% and 27.4% respectively in RESCUEicp (p = 0.02)., Conclusion: Outcomes in DC patients from two prospective cohorts reflecting everyday practice were better than in RESCUEicp surgical patients. Mortality was similar, but fewer patients remained vegetative or severely disabled and more patients had a good recovery. Although patients were older and injury severity was lower, a potential partial explanation may be in the pragmatic use of DC in combination with other second/third-tier therapies in real-life cohorts. The findings underscore that DC maintains an important role in managing severe TBI., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Quality of life (QoL) assessment forms an integral part of modern cancer care and research. The aim of this study is to determine patients' preferences and willingness to complete commonly used head-and-neck cancer (HNC) QoL questionnaires (QLQs) in routine follow-up clinics., Methods: This is a randomised control trial of 583 subjects from 17 centres during follow-up after treatment for oral, oropharyngeal or laryngeal cancer. Subjects completed three structured validated questionnaires: EORTC QLQ-HN35; FACT-HN and UW-QOL, and an unstructured patient-generated list. The order of questionnaire presentation was randomised, and subjects were stratified by disease site and stage. Patients self-rated the questionnaires they found most helpful to communicate their health concerns to their clinicians., Results: Of the 558 respondents, 82% (457) found QLQs useful to communicate their health concerns to their clinician (OR = 15.76; 95% CI 10.83-22.94). Patients preferred the structured disease-specific instruments (OR 8.79; 95% CI 5.99-12.91), while the open list was the most disliked (OR = 4.25; 95% CI 3.04-5.94). There was no difference in preference by treatment modality. More women preferred the FACT-HN (OR = 3.01, 95% CI 1.05-8.62), and patients under 70 preferred EORTC QLQ-HN35 (OR = 3.14, 95% CI 1.3-7.59). However, only 55% of patients expressed preference to complete questionnaires routinely at the clinic., Conclusions: Most patients found QLQs helpful during their follow-up and 55% supported routine questionnaires in follow-up clinics. Males and people over 70 years old were the least willing to complete the routine questionnaires and preferred shorter questionnaires (e.g., UW-QOL). Women preferred FACT-HN, and younger patients preferred EORTC QLQ-HN35. Reasons for the reluctance to complete questionnaires require elucidation., (© 2023 The Authors. Clinical Otolaryngology published by John Wiley & Sons Ltd.)

Pyrolysis is the process whereby carbonaceous materials, such as biosolids, are heated between 400°C and 900°C in the absence of oxygen. Three main products are generated: a solid product called biochar, a py-liquid that consists of aqueous phase and non-aqueous phase liquid, and py-gas. The biochar holds value as a beneficial soil amendment and sequesters carbon. The py-liquid is potentially hazardous and needs to be dealt with (including potentially reducing it on-site via catalysis or thermal oxidation). Py-gas can be used on-site for energy recovery. Pyrolysis has gained recent interest due to concern over per- and polyfluoroalkyl substances (PFAS) in biosolids. Although pyrolysis can remove PFAS from biosolids, it has been shown to produce PFAS that reside in py-liquid, and the fate in py-gas remains a knowledge gap. More research is needed to help close the PFAS and fluorine mass balance through pyrolysis influent and effluent products because pyrolysis alone does not destroy all PFAS. The moisture content of biosolids substantially affects the energy balance for pyrolysis. Utilities that already produce a dried biosolids product are in a better position to install pyrolysis. Pyrolysis has both defined benefits (solids reduction, PFAS removal from biosolids, and biochar production) as well as remaining questions (the fate of PFAS in py-gas and py-liquid, mass balance on nutrients, and py-liquid handling options) that will be answered through more pilot and full-scale demonstrations. Regulations and local policies (such as carbon sequestration credits) could affect pyrolysis implementation. Pyrolysis should be considered as an option in the biosolids stabilization toolbox with application being based on individual circumstances of a utility (e.g., energy, moisture content of biosolids, PFAS). PRACTITIONER POINTS: Pyrolysis has known benefits but limited full-scale operational data. Pyrolysis removes PFAS from biochar, but PFAS fate in gas phase is unknown. Moisture content of influent feed solids affects energy balance of pyrolysis. Policy on PFAS, carbon sequestration, or renewable energy could impact pyrolysis., (© 2023 Water Environment Federation.)

Negative mental health outcomes have been associated with adverse childhood experiences (ACEs) and intimate partner violence (IPV); however, few studies have identified risk and protective factors across levels of the social ecology that mitigate the onset of psychological distress and suicide risk associated with trauma. This study examines the relationship between ACEs, IPV, and mental health (i.e., psychological distress, suicidal ideation, and suicide attempts) within racial sub-populations of Black American, Latinx, and White adults. An online, cross-section survey was administered to a general population sample of adults in Baltimore and New York City. ACEs, IPV, and mental health outcomes were assessed within racial sub-populations of Black American (N = 390), Latinx (N = 178), and White (N = 339) adults, while accounting for within-group demographic differences. Moderating effects of social support and neighborhood disconnection on the relationship between ACEs, IPV, and mental health outcomes were also assessed. IPV was associated with psychological distress and suicidal ideation for Black and Latinx adults, but not for White adults. ACEs were associated with increased psychological distress for all three groups, and increased odds for suicidal ideation among Black and Latinx adults.. A significant negative interaction effect for neighborhood disconnection was found in the relationship between ACEs and psychological distress for Black adults. Findings highlight the significant mental health burdens of ACEs and IPV within racial and ethnic groups. Neighborhood disconnection may exacerbate psychological distress associated with ACEs among populations most impacted by interpersonal violence and mental health inequalities., Competing Interests: Conflict of InterestThe authors did not obtain any monetary or non-monetary support for this paper and report no conflicts of interest., (© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Aims: Hypoplastic left heart syndrome (HLHS) survival relies on surgical reconstruction of the right ventricle (RV) to provide systemic circulation. This substantially increases the RV load, wall stress, maladaptive remodelling, and dysfunction, which in turn increases the risk of death or transplantation., Methods and Results: We conducted a phase 1 open-label multicentre trial to assess the safety and feasibility of Lomecel-B as an adjunct to second-stage HLHS surgical palliation. Lomecel-B, an investigational cell therapy consisting of allogeneic medicinal signalling cells (MSCs), was delivered via intramyocardial injections. The primary endpoint was safety, and measures of RV function for potential efficacy were obtained. Ten patients were treated. None experienced major adverse cardiac events. All were alive and transplant-free at 1-year post-treatment, and experienced growth comparable to healthy historical data. Cardiac magnetic resonance imaging (CMR) suggested improved tricuspid regurgitant fraction (TR RF) via qualitative rater assessment, and via significant quantitative improvements from baseline at 6 and 12 months post-treatment ( P < 0.05). Global longitudinal strain (GLS) and RV ejection fraction (EF) showed no declines. To understand potential mechanisms of action, circulating exosomes from intramyocardially transplanted MSCs were examined. Computational modelling identified 54 MSC-specific exosome ribonucleic acids (RNAs) corresponding to changes in TR RF, including miR-215-3p, miR-374b-3p, and RNAs related to cell metabolism and MAPK signalling., Conclusion: Intramyocardially delivered Lomecel-B appears safe in HLHS patients and may favourably affect RV performance. Circulating exosomes of transplanted MSC-specific provide novel insight into bioactivity. Conduct of a controlled phase trial is warranted and is underway.Trial registration number NCT03525418., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Shifts in normal aging set stage for neurodegeneration and dementia affecting 1 in 10 adults. The study demonstrates that lncRNA GAS5 is decreased in aged and Alzheimer's disease brain. The role and targets of lncRNA GAS5 in the aging brain were elucidated using a GAS5-targeting small molecule NPC86, a frontier in lncRNA-targeting therapeutic. Robust techniques such as molecular dynamics simulation of NPC86 binding to GAS5, in vitro functional assays demonstrating that GAS5 regulates insulin signaling, neuronal survival, phosphorylation of tau, and neuroinflammation via toll-like receptors support the role of GAS5 in maintaining healthy neurons. The study demonstrates the safety and efficacy of intranasal NPC86 treatment in aged mice to improve cellular functions with transcriptomic analysis in response to NPC86. In summary, the study demonstrates that GAS5 contributes to pathways associated with neurodegeneration and NPC86 has tremendous therapeutic potential to prevent the advent of neurodegenerative diseases and dementias., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Hypothesis: We hypothesized that Lomecel-B, an allogeneic medicinal signaling cell (MSC) therapeutic candidate for Alzheimer's disease (AD), is safe and potentially disease-modifying via pleiotropic mechanisms of action., Key Predictions: We prospectively tested the predictions that Lomecel-B administration to mild AD patients is safe (primary endpoint) and would provide multiple exploratory indications of potential efficacy in clinical and biomarker domains (prespecified secondary/exploratory endpoints)., Strategy and Key Results: Mild AD patient received a single infusion of low- or high-dose Lomecel-B, or placebo, in a double-blind, randomized, phase I trial. The primary safety endpoint was met. Fluid-based and imaging biomarkers indicated significant improvement in the Lomecel-B arms versus placebo. The low-dose Lomecel-B arm showed significant improvements versus placebo on neurocognitive and other assessments., Interpretation: Our results support the safety of Lomecel-B for AD, suggest clinical potential, and provide mechanistic insights. This early-stage study provides important exploratory information for larger efficacy-powered clinical trials., (© 2022 Longeveron Inc. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Wiley Periodicals LLC.)

Background: This prospective observational cohort study evaluates risk-stratified venous thromboembolism (VTE) screening in injured children. While the reported incidence of VTE is 6% to 10% among critically injured children, there is no standard for screening. Venous thromboembolism may have long-term sequelae in children, including postthrombotic syndrome., Methods: Patients admitted to a level 1 pediatric trauma center were risk stratified for VTE using a validated prediction algorithm. Children at high risk (risk scores ≥523; i.e., ≥1% risk) received screening duplex ultrasonography. Children at moderate risk (risk scores 410-522; i.e., 0.3-0.99% risk) were screened as a comparison/control., Results: Three-hundred fifty-five children were consecutively risk stratified from October 2019 to May 2021. Forty-seven children received screening duplex ultrasounds: 21 from a high-risk cohort and 26 from a moderate-risk cohort. Four children were diagnosed with VTE in the high-risk cohort compared with seven in the moderate-risk cohort ( p = 0.53). Total incidence of VTE among screened children was 23.4% (11 of 47). Asymptomatic VTE accounted for 81.8% of all events (9 of 11). Fifty-four percent (6 of 11) of VTE were central venous catheter associated. Venous thromboembolism in surviving children resolved by 3 to 6 months with no symptoms of postthrombotic syndrome after 1 year. No cases of VTE were identified in unscreened children, yielding an institutional VTE incidence of 3.1% (11 of 355)., Discussion: Risk-stratified screening demonstrates a significant incidence of asymptomatic VTE in injured children. These results may guide reevaluation of prediction algorithms developed from symptomatic VTE risk and longitudinal study of the sequelae of asymptomatic VTE., Level of Evidence: Prognostic and Epidemiological; Level III., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Neurocritical care patients are a complex patient population, and to aid clinical decision-making, many models and scoring systems have previously been developed. More recently, techniques from the field of machine learning have been applied to neurocritical care patient data to develop models with high levels of predictive accuracy. However, although these recent models appear clinically promising, their interpretability has often not been considered and they tend to be black box models, making it extremely difficult to understand how the model came to its conclusion. Interpretable machine learning methods have the potential to provide the means to overcome some of these issues but are largely unexplored within the neurocritical care domain. This article examines existing models used in neurocritical care from the perspective of interpretability. Further, the use of interpretable machine learning will be explored, in particular the potential benefits and drawbacks that the techniques may have when applied to neurocritical care data. Finding a solution to the lack of model explanation, transparency, and accountability is important because these issues have the potential to contribute to model trust and clinical acceptance, and, increasingly, regulation is stipulating a right to explanation for decisions made by models and algorithms. To ensure that the prospective gains from sophisticated predictive models to neurocritical care provision can be realized, it is imperative that interpretability of these models is fully considered., (© 2022. The Author(s).)

Background/purpose: In rheumatoid arthritis (RA) autoantibodies including antibodies to citrullinated protein antigens (ACPA) and rheumatoid factor (RF) can be predictive of incident clinical RA. However, there is limited understanding of how antibody changes over time impact prediction of the likelihood and timing of future clinical RA., Materials and Methods: We evaluated relationships between ACPA, the shared epitope (SE), RF isotypes and incident RA in a prospective cohort of 90 ACPA(+) individuals without baseline arthritis identified through health-fair testing (i.e. Healthfair). We also evaluated ACPA and RF isotypes and time-to-diagnosis of RA in a retrospective cohort of 215 individuals with RA from the Department of Defense Serum Repository (DoDSR)., Results: Twenty-six of 90 (29%) of ACPA(+) Healthfair participants developed incident RA. Baseline or incident dual RF-IgA and RF-IgM positivity was associated with increased risk for incident RA (HR 3.09; 95% CI 1.15 to 8.29) although RFs were negative in ~50% of individuals with incident RA. SE was associated with increased risk of RA (HR 2.87, 95% CI 1.22-6.76). In the DoDSR cohort, triple positivity for ACPA, RF-IgA and RF-IgM was present a median of 1-2 years prior to RA diagnosis, with some sex-specific differences., Conclusion: These findings can be used to counsel individuals at-risk for future RA and to design clinical trials for RA prevention. The findings also suggest that RF could be a surrogate outcome as a success of an immunologic intervention in RA prevention. Additional studies are needed to understand the biologic of different patterns of autoantibody elevations in RA evolution., Competing Interests: KD has received free materials for autoantibody testing from Inova Diagnostics, Inc., and he has also served as an advisor for Inova Diagnostics, 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 Bergstedt, Tarter, Peterson, Feser, Parish, Striebich, Demoruelle, Moss, Bemis, Norris, Holers, Edison, Thiele, Mikuls and Deane.)

BACKGROUNDPotent synthetic opioids, such as fentanyl, are increasingly abused, resulting in unprecedented numbers of fatalities from respiratory depression. Treatment with the high-affinity mu-opioid receptor partial agonist buprenorphine may prevent fatalities by reducing binding of potent opioids to the opioid receptor, limiting respiratory depression.METHODSTo characterize buprenorphine-fentanyl interaction at the level of the mu-opioid receptor in 2 populations (opioid-naive individuals and individuals who chronically use high-dose opioids), the effects of escalating i.v. fentanyl doses with range 0.075-0.35 mg/70 kg (opioid naive) and 0.25-0.70 mg/70 kg (chronic opioid use) on iso-hypercapnic ventilation at 2-3 background doses of buprenorphine (target plasma concentrations range: 0.2-5 ng/mL) were quantified using receptor association/dissociation models combined with biophase distribution models.RESULTSBuprenorphine produced mild respiratory depression, while high doses of fentanyl caused pronounced respiratory depression and apnea in both populations. When combined with fentanyl, buprenorphine produced a receptor binding-dependent reduction of fentanyl-induced respiratory depression in both populations. In individuals with chronic opioid use, at buprenorphine plasma concentrations of 2 ng/mL or higher, a protective effect against high-dose fentanyl was observed.CONCLUSIONOverall, the results indicate that when buprenorphine mu-opioid receptor occupancy is sufficiently high, fentanyl is unable to activate the mu-opioid receptor and consequently will not cause further respiratory depression in addition to the mild respiratory effects of buprenorphine.TRIAL REGISTRATIONTrialregister.nl, no. NL7028 (https://www.trialregister.nl/trial/7028)FUNDINGIndivior Inc., North Chesterfield, Virginia, USA.

Background: Inhalation of apomorphine could be a faster-acting and more user-friendly alternative to subcutaneous injection for treating off periods in Parkinson's disease (PD)., Objective: The aim of this study was to compare the safety and pharmacokinetics of inhaled apomorphine (AZ-009) with subcutaneous apomorphine (APO-go PEN) in healthy volunteers (HVs) and to examine the safety, pharmacokinetics, and efficacy of AZ-009 in patients with PD., Methods: In part A of this study, eight HVs received 1 mg AZ-009 and 2 mg subcutaneous apomorphine in a randomized crossover manner. In the subsequent single ascending dose parts in HVs (part B, n = 16) and patients with PD (part C, n = 25), participants were randomized to placebo or AZ-009 up to 4 mg. In patients, after medication withdrawal, Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III and on/off states were assessed predose and postdose., Results: AZ-009 was rapidly absorbed with peak plasma concentrations at 2 minutes, as compared to 30 minutes for subcutaneous apomorphine. Adverse events for AZ-009 were comparable to subcutaneous apomorphine, except for mild and transient throat irritation. Adverse events limited AZ-009 dose escalation in HVs to 3 mg. Patients tolerated up to 4 mg. In patients with PD, 2, 3, and 4 mg AZ-009 reduced mean Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III score (standard deviation) by 10.7 (13.6), 12.8 (7.9), and 10.3 (3.7) points, respectively, compared to 4.8 (4.9) after placebo at 10 minutes postdose. The percentage of patients achieving full on within 45 minutes postdose increased dose dependently: 0% (placebo), 17% (2 mg), 50% (3 mg), and 83% (4 mg)., Conclusions: AZ-009 appears to be a rapid-acting and reasonably well-tolerated formulation for treating off periods. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

The tumor microenvironment hosts antibody-secreting cells (ASCs) associated with a favorable prognosis in several types of cancer. Patient-derived antibodies have diagnostic and therapeutic potential; yet, it remains unclear how antibodies gain autoreactivity and target tumors. Here, we found that somatic hypermutations (SHMs) promote antibody antitumor reactivity against surface autoantigens in high-grade serous ovarian carcinoma (HGSOC). Patient-derived tumor cells were frequently coated with IgGs. Intratumoral ASCs in HGSOC were both mutated and clonally expanded and produced tumor-reactive antibodies that targeted MMP14, which is abundantly expressed on the tumor cell surface. The reversion of monoclonal antibodies to their germline configuration revealed two types of classes: one dependent on SHMs for tumor binding and a second with germline-encoded autoreactivity. Thus, tumor-reactive autoantibodies are either naturally occurring or evolve through an antigen-driven selection process. These findings highlight the origin and potential applicability of autoantibodies directed at surface antigens for tumor targeting in cancer patients., Competing Interests: Declaration of interests The antibodies reported in the article are in the process of being patented., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Randomized controlled trials of time restricted eating (TRE) in adults have demonstrated improvements in glucose variability as captured by continuous glucose monitors (CGM). However, little is known about the feasibility of CGM use in TRE interventions in adolescents, or the expected changes in glycemic profiles in response to changes in meal-timing. As part of a pilot trial of TRE in adolescents with obesity, this study aimed to 1) assess the feasibility of CGM use, 2) describe baseline glycemic profiles in adolescents with obesity, without diabetes, and 3) compare the difference between glycemic profiles in groups practicing TRE versus control., Methods: This study leverages data from a 12-week pilot trial (ClinicalTrials.gov Identifier: NCT03954223) of late TRE in adolescents with obesity compared to a prolonged eating window. Feasibility of CGM use was assessed by monitoring 1) the percent wear time of the CGM and 2) responses to satisfaction questionnaires. A computation of summary measures of all glycemic data prior to randomization was done using EasyGV and R. Repeat measures analysis was conducted to assess the change in glycemic variability over time between groups. Review of CGM tracings during periods of 24-hour dietary recall was utilized to describe glycemic excursions., Results: Fifty participants were enrolled in the study and 43 had CGM and dietary recall data available (16.4 + 1.3 years, 64% female, 64% Hispanic, 74% public insurance). There was high adherence to daily CGM wear (96.4%) without negative impacts on daily functioning. There was no significant change in the glycemic variability as measured by standard deviation, mean amplitude glycemic excursion, and glucose area under the curve over the study period between groups., Conclusions: CGM use appears to be a feasible and acceptable tool to monitor glycemic profiles in adolescents with obesity and may be a helpful strategy to confirm TRE dosage by capturing glycemic excursions compared to self-reported meal timing. There was no effect of TRE on glucose profiles in this study. Further research is needed to investigate how TRE impacts glycemic variability in this age group and to explore if timing of eating window effects these findings., 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 Naguib, Hegedus, Raymond, Goran, Salvy, Wee, Durazo-Arvizu, Moss and Vidmar.)

Competing Interests: RM is the cofounder/owner of Seizure Tracker, LLC and reports financial income to Seizure Tracker, LLC, from Neurelis, UCB, Greenwich Biosciences, Neuropace and the Tuberous Sclerosis Complex Alliance. SC is supported by the National Institute of Neurological Disorders and Stroke, National Institutes of Health (5R25NS070680-12). 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.

Background and Aims: Patients with differentiated thyroid cancer are often advised to follow a low iodine diet (LID) one to two weeks before radioiodine remnant ablation (RRA). We describe treatment practices and ablation success rates in centres (C1, C2, C3) in the UK with different approaches to LID advice., Methods: Historic cohort of patients with differentiated thyroid cancer treated with RRA in 2015/16 in C1 (n = 50, 1-week LID), C2 (n = 59, 2-week LID) and C3 (n = 108, no LID advice). Response to RRA was stratified as excellent, indeterminate, or incomplete by the adapted American Thyroid Association Dynamic Risk Stratification Score., Results: There was little difference in age, sex and staging between centres, but the percentage receiving 1.1 GBq vs higher administered activities differed (C1:22%, C2:44%, C3:15%, p < 0.001). Excellent response was recorded for: C1:48%, C2:36%, C3:49% (p = 0.61). Differences in RRA preparation and outcome assessment at C3 precluded comparison across all centres. Adjusted odds ratio for excellent response at C2 vs C1 was 0.57 (95%CI: 0.25,1.32), p = 0.19., Conclusions: There was no evidence that advising a LID for 2-weeks before RRA improves outcomes compared to 1-week. For definitive recommendations on LIDs prior to RRA, a prospective multi-centre study with a more homogenous approach to patient management or, randomised controlled trial, is needed., Competing Interests: Declaration of competing interest IHS is the lead and LM is a member of the UK Low Iodine Diet Working Group. The remaining authors have nothing to declare., (Copyright © 2021 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Background: There is limited guidance for using common drug therapies in the context of multimorbidity. In part, this is because their effectiveness for patients with specific comorbidities cannot easily be established using subgroup analyses in clinical trials. Here, we use simulations to explore the feasibility and implications of concurrently estimating effects of related drug treatments in patients with multimorbidity by partially pooling subgroup efficacy estimates across trials., Methods: We performed simulations based on the characteristics of 161 real clinical trials of noninsulin glucose-lowering drugs for diabetes, estimating subgroup effects for patients with a hypothetical comorbidity across related trials in different scenarios using Bayesian hierarchical generalized linear models. We structured models according to an established ontology-the World Health Organization Anatomic Chemical Therapeutic Classifications-allowing us to nest all trials within drugs and all drugs within anatomic chemical therapeutic classes, with effects partially pooled at each level of the hierarchy. In a range of scenarios, we compared the performance of this model to random effects meta-analyses of all drugs individually., Results: Hierarchical, ontology-based Bayesian models were unbiased and accurately recovered simulated comorbidity-drug interactions. Compared with single-drug meta-analyses, they offered a relative increase in precision of up to 250% in some scenarios because of information sharing across the hierarchy. Because of the relative precision of the approaches, a large proportion of small subgroup effects was detectable only using the hierarchical model., Conclusions: By assuming that similar drugs may have similar subgroup effects, Bayesian hierarchical models based on structures defined by existing ontologies can be used to improve the precision of treatment efficacy estimates in patients with multimorbidity, with potential implications for clinical decision making.

Background: Frailty in older adults is a rapidly growing unmet medical need. It is an aging-related syndrome characterized by physical decline leading to higher risk of adverse health outcomes., Objectives: To evaluate the efficacy of Lomecel-B, an allogeneic medicinal signaling cell (MSC) formulation, in older adults with frailty., Design: This multicenter, randomized, parallel-arm, double-blinded, and placebo-controlled phase 2b trial is designed to evaluate dose-range effects of Lomecel-B for frailty on physical functioning, patient-reported outcomes (PROs), frailty status, and biomarkers., Setting: Eight enrolling clinical research centers, including the Miami Veterans Affairs Medical Center., Participants: Target enrollment is 150 subjects aged 70-85 years of any race, ethnicity, or gender. Enrollment criteria include a Clinical Frailty Score of 5 ("mild") or 6 ("moderate"), a 6MWT of 200-400 m, and serum tumor necrosis factor-alpha (TNF-α) ≥2.5 pg/mL., Intervention: A single intravenous infusion of Lomecel-B (25, 50, 100, or 200 million cells) or placebo (N=30/arm). Patients are followed for 365 days for safety, and the efficacy assessments performed at 90, 180, and 270 days., Measurements: The primary endpoint is change in 6MWT in the Lomecel-B-treated arms versus placebo at 180 days post-infusion. Secondary and exploratory endpoints include change in: 6MWT and other physical function measures at all time points; PROs; frailty status; cognitive status; and an inflammatory biomarkers panel. A pre-specified sub-study examines vascular/endothelial biomarkers. Safety is evaluated throughout the trial., Results: The trial is conducted under a Food and Drug Administration Investigational New Drug (IND), with Institutional Review Board approval, and monitoring by an NIH-appointed independent Data Safety Monitoring Board., Conclusion: This clinical trial investigates the use of a regenerative medicine strategy for frailty in older adults. The results will further the understanding of the potential for Lomecel-B in the geriatric condition of frailty., Competing Interests: AAO, BH, LM-M, KNR, KY, LD, GAG and JMH are affiliated with Longeveron Inc. JMH is a co-founder, board member and paid consultant of Longeveron Inc. JMH is also inventor of technology licensed to Longeveron Inc. This relationship is reported to the University of Miami, and a management plan is in place. EV and JW are members of Longeveron’s Science Advisory Board, for which they receive personal fees (honoraria). The University of Miami is an equity owner in Longeveron, which has licensed intellectual property from the University of Miami.

Long-lasting immunity depends on the generation of protective antibodies through the germinal center (GC) reaction. N6-methyladenosine (m6A) modification of mRNAs by METTL3 activity modulates transcript lifetime primarily through the function of m6A readers; however, the physiological role of this molecular machinery in the GC remains unknown. Here, we show that m6A modifications by METTL3 are required for GC maintenance through the differential functions of m6A readers. Mettl3-deficient GC B cells exhibited reduced cell-cycle progression and decreased expression of proliferation- and oxidative phosphorylation-related genes. The m6A binder, IGF2BP3, was required for stabilization of Myc mRNA and expression of its target genes, whereas the m6A reader, YTHDF2, indirectly regulated the expression of the oxidative phosphorylation gene program. Our findings demonstrate how two independent gene networks that support critical GC functions are modulated by m6A through distinct mRNA binders., Competing Interests: Disclosures: The authors declare no competing interests exist., (© 2021 Grenov et al.)

Background: Following the shooting at Sandy Hook Elementary School, the Hartford Consensus produced the Stop the Bleed program to train bystanders in hemorrhage control. In our region, the police bureau delivers critical incident training to public schools, offering instruction in responding to violent or dangerous situations. Until now, widespread training in hemorrhage control has been lacking. Our group developed, implemented and evaluated a novel program integrating hemorrhage control into critical incident training for school staff in order to blunt the impact of mass casualty events on children., Methods: The staff of 25 elementary and middle schools attended a 90-minute course incorporating Stop the Bleed into the critical incident training curriculum, delivered on-site by police officers, nurses and doctors over a three-day period. The joint program was named Protect Our Kids. At the conclusion of the course, hemorrhage control kits and educational materials were provided and a four-question survey to assess the quality of training using a ten-point Likert scale was completed by participants and trainers., Results: One thousand eighteen educators underwent training. A majority were teachers (78.2%), followed by para-educators (5.8%), counselors (4.4%) and principals (2%). Widely covered by local and state media, the Protect Our Kids program was rated as excellent and effective by a majority of trainees and all trainers rated the program as excellent., Conclusions: Through collaboration between trauma centers, police and school systems, a large-scale training program for hemorrhage control and critical incident response can be effectively delivered to schools., (© 2021. The Author(s).)