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Abstract Background Delays in diagnostic and therapeutic processes are a potentially preventable cause of morbidity and mortality. Process improvement depends on accurate knowledge about as-is processes, historically collected from front-line workers and summarized in flowcharts. Such flowcharts can now be generated by process discovery algorithms supplied with chronological records from real-world cases. However, these algorithms may generate incomprehensible flowcharts when applied to complex unstructured processes, which are common in healthcare. The aim of this study is to evaluate methods for analysing data from real-world cases to determine causes of delay in complex healthcare processes. Methods Physician insurance claims and hospital discharge data were obtained for patients undergoing carotid endarterectomy at a single tertiary hospital between 2008 and 2014. All patients were recently symptomatic with vision loss. A chronological record of physician visits and diagnostic tests (activities) was generated for each patient using claims data. Algorithmic process discovery was attempted using the Heuristic Miner. The effect of activity selection on treatment delay was investigated from two perspectives: activity-specific effects were measured using linear regression, and patterns of activity co-occurrence were identified using K means clustering. Results Ninety patients were included, with a median symptom-to-surgery treatment time of 34 days. Every patient had a unique sequence of activities. The flowchart generated by the Heuristic Miner algorithm was uninterpretable. Linear regression models of waiting time revealed beneficial effects of emergency and neurology visits, and detrimental effects of carotid ultrasound and post-imaging follow-up visits to family physicians and ophthalmologists. K-means clustering identified two co-occurrence patterns: emergency visits, neurology visits and CT angiography were more common in a cluster of rapidly treated patients (median symptom to surgery time of 18 days), whereas family physician visits, carotid ultrasound imaging and post-imaging follow-up visits to eye specialists were more common in a cluster of patients with treatment delay (median time of 57 days). Conclusions Routinely collected data provided a comprehensive account of events in the symptom-to-surgery process for carotid endarterectomy. Linear regression and K-means clustering can be used to analyze real-world data to understand causes of delay in complex healthcare processes.

Abstract The arousal systems of the brainstem, specifically the locus coeruleus-noradrenaline system, respond “phasically” during decisions. These central arousal transients are accompanied by dilations of the pupil. Mechanistic attempts to understand the impact of phasic arousal on cognition would benefit from temporally precise experimental manipulations. Here, we evaluated a non-invasive candidate approach to manipulate arousal in humans: presenting task-irrelevant auditory stimuli at different latencies during the execution of a challenging task. Task-irrelevant auditory stimuli drive responses of brainstem nuclei involved in the control of pupil size, but it is unknown whether such sound-evoked responses mimic the central arousal transients evoked during cognitive computations. A large body of evidence has implicated central arousal transients in reducing bias during challenging perceptual decisions. We thus used challenging visual decisions as a testbed, combining them with task-irrelevant sounds of varying onset latency or duration. Across three experiments, the sounds consistently elicited well-controlled pupil responses that superimposed onto task-evoked responses. While we replicated a negative correlation between task-evoked pupil responses and bias, the task-irrelevant sounds had no behavioral effect. This dissociation suggests that cognitive task engagement and task-irrelevant sounds may recruit distinct neural systems contributing to the control of pupil size.

Abstract Objectives Gout is caused by the response of the innate immune system to monosodium urate (MSU) crystals. A recent gout GWAS identified a signal of genetic association at a locus encompassing IL1RN-IL1F10. Colocalisation analysis using Genotype Tissue Expression Database (GTEx) eQTL data showed that the signal overlaps with genetic control of IL1RN/IL1F10 gene expression. We assess the functional implications of IL1RN rs9973741, the lead gout-associated variant. Methods We conducted functional validation of IL1RN rs9973741 in patients with gout and controls. The transcription level of IL1RN/IL1F10 was investigated in unstimulated or MSU-crystal co-stimulated PBMCs. Ex vivo functional assays were performed in PBMCs stimulated with C16 + MSU crystals or LPS for 24 h. Cytokine levels were assessed by ELISA. Results In unstimulated PBMCs, no association of IL1RN rs9973741 (gout risk allele G) to IL1RN expression was observed while IL-1F10 was hindered by low expression at both transcriptional and protein levels. However, G allele carriers showed lower IL1RN expression in PBMCs stimulated with C16/MSU crystal and lower concentrations of circulating IL-1Ra in both controls and gout patients. PBMCs depicted less spontaneous IL-1Ra release in GG homozygous controls and lower IL-1Ra production in response to C16 + MSU crystal costimulation in patients with gout. The G allele was associated with elevated IL-1β cytokine production in response to C16 + MSU crystal stimulation in controls. Conclusions The gout risk allele G associates with lower circulating IL-1Ra, lower IL-1Ra production in PBMC assays and elevated IL-1β production in PBMCs challenged with C16 + MSU crystals but not in unchallenged cells. Our data indicate that the genetic signal that associates with gout at IL1RN-IL1F10 region functions to alter expression of IL-1Ra when stimulated by MSU crystals.

Abstract We first present a formalism that incorporates the input-output formalism and the linear response theory to employ cavity-magnon-polariton coupling as a spectroscopic tool for investigating strongly hybridized electro-nuclear spin excitations. A microscopic relation between the generalized susceptibility and the scattering parameter $$|S_{11}|$$ | S 11 | in strongly hybridized cavity-magnon-polariton systems has been derived without resorting to semi-classical approximations. The formalism is then applied to both analyze and simulate a specific systems comprising a model quantum Ising magnet ( $$\hbox {LiHoF}_4$$ LiHoF 4 ) and a high-finesse 3D re-entrant cavity resonator. Quantitative information on the electro-nuclear spin states in $$\hbox {LiHoF}_4$$ LiHoF 4 is extracted, and the experimental observations across a broad parameter range were numerically reproduced, including an external magnetic field traversing a quantum critical point. The method potentially opens a new avenue not only for further studies on the quantum phase transition in $$\hbox {LiHoF}_4$$ LiHoF 4 but also for a wide range of complex magnetic systems.

Background: Mass school shootings have created fear in the American public. The results of this fear have been the hardening of schools, lockdowns, and active shooter drills, yet the mass shootings have not ended. The goal of this study was to analyze the mental health awareness of K-12 public schools teachers in Texas with a goal to identify the connections between mental health awareness and school safety. Methods: Data were used from an archival database of K-12 teacher responses in the 2020 Texas Educators' Needs Assessment Regarding School Safety and Victims Services to assess the current state of student mental health concerns and the connection of these concerns to school safety. This needs assessment included one mixed methods survey that was collected from Texas K-12 educators and Texas educators working in higher education in 2020. The original study included 25,161 usable responses (6.1%). For the purpose of this study, only K-12 teacher responses were used in the analysis. The K-12 teacher participants (n = 19,888) included the following institutional levels: (a) special setting, 2,919 (14.7%); (b) elementary school, 6,813 (34.3%); (c) middle/intermediate school, 4,189 (21.1%); (d) high school, 5,864 (29.5%); and (e) district level, 103 (0.5%). A total of 8,053 participant's qualitative responses and 10 of the original quantitative survey questions from the archival data were used to identify all findings in the study. Results: Collected qualitative and quantitative participant responses' outlined a need to improve student mental health by strengthening the focus on supporting all stakeholders (e.g., teachers, parents, counselors, and students) in mental health awareness and education. Participant comments focused on the lack of training, counselor support, and community support regarding the mental health needs of their students. Conclusion: Recommendations to improve student mental health that were developed from this study identified key goals in school counselor role and responsibility to student mental health, increased involvement of community agencies, and improvement to in-school mental health counseling. Final recommendations of this study were focused on the need to improve student mental health if stakeholders want to develop a positive school environment. The failure to build an environment that is focused on student mental health will continue to affect the goal to improve overall school safety.

Abstract Ammonium fluoride (NH₄F) exhibits a variety of crystalline phases depending on temperature and pressure. By employing Raman spectroscopy and synchrotron X-ray diffraction beyond megabar pressures (up to 140 GPa), we have here observed a novel dense solid phase of NH₄F, characterised by the tetragonal P4/nmm structure also observed in other ammonium halides under less extreme pressure conditions, typically a few GPa. Using detailed ab-initio calculations and reevaluating earlier theoretical models pertaining to other ammonium halides, we examine the microscopic mechanisms underlying the transition from the low-pressure cubic phase (P-43m) to the newly identified high-pressure tetragonal phase (P4/nmm). Notably, NH₄F exhibits distinctive properties compared to its counterparts, resulting in a significantly broader pressure range over which this transition unfolds, facilitating the identification of its various stages. Our analysis points to a synergistic interplay driving the transition to the P4/nmm phase, which we name phase VIII. At intermediate pressures (around 40 GPa), a displacive transition of fluorine ions initiates a tetragonal distortion of the cubic phase. Subsequently, at higher pressures (around 115 GPa), every second ammonium ion undergoes a rotational shift, adopting an anti-tetrahedral arrangement. This coupled effect orchestrates the transition process, leading to the formation of the tetragonal phase.

The 2020 Texas Educators' Needs Assessment Regarding School Safety and Victims Services included responses from educators across the state of Texas regarding school safety. This needs assessment generated data that provided researchers with the unique opportunity to analyze the school safety issues in Texas (Fuller et al, 2020). The purpose of the study was to evaluate Texas K-12 educators responses to their school's preparedness for an active attack or shooter using data from that needs assessment. To build a strong analysis, the results were separated into three categories: educator role; Texas school regions; and urbanicity. Pearson chi square statistical analysis was used to create an understanding of the data. The results of this analysis revealed a trend that a majority of K-12 educators felt prepared for an active attack or shooter.

Summary: The increasing scarcity of organs and the significant morbidity linked to dialysis require the development of engineered kidney tissues from human-induced pluripotent stem cells. Integrative approaches that synergize scalable kidney organoid differentiation, tissue biomanufacturing, and comprehensive assessment of their immune response and host integration are essential to accomplish this. Here, we create engineered human kidney tissues composed of organoid building blocks (OBBs) and transplant them into mice reconstituted with allogeneic human immune cells. Tissue-infiltrating human immune cells are composed of effector T cells and innate cells. This immune infiltration leads to kidney tissue injury characterized by reduced microvasculature, enhanced kidney cell apoptosis, and an inflammatory gene signature comparable to kidney organ transplant rejection in humans. Upon treatment with the immunosuppressive agent rapamycin, the induced immune response is greatly suppressed. Our model is a translational platform to study engineered kidney tissue immunogenicity and develop therapeutic targets for kidney rejection.

Background: Elite football players are monitored daily to minimize injury risks and maximize performance. Objectives: The aim of the study was to investigate injury incidence differences between competition and training and differences in key external load indicators during 1-, 2-, 3- or 4-weeks prior to the injury (WPI) with respect to the season average week (SAW). Methods: Data of 224 unique players of five teams (1st, under-23, under-18, under-17, and under-16) were collected during 3.5 seasons of competition and training resulting in 467 player records in total. Collected data included kinematics from Global Positioning System tracking units (Viper Units, STATSports) and 528 injury incident records. External load was expressed in terms of acceleration counts (ACC), deceleration counts (DEC), total training time (TT), total distance (TD), and distance covered in high-speed zones: 14.4-19.7 km/h (Z4), 19.7-25.1 km/h (Z5), and >25.1 km/h (Z6). Injury incidence was derived as number of injuries per 1000 hours of exposure. Results: Incidence rate was on average 4-11 times higher during competition than training for all teams except under-16 (incidence rate: 2.5, p=.153). In the 1st Team, external load (i.e. ACC, TT, and TD) were significantly different between 1-, 2-, 3-, and 4-WPI and SAW (p=.041, p=.037, and p=.049 respectively). For ACC and TT, the 3-WPI loads, were significantly higher than during SAW (p=.044 and p=.038, respectively). Conclusion: These findings can assist professionals and scientists to improve their understanding of the relationship between external load indicators and injury incidence and consequently improve player health and performance.

Cumulative culture requires efficient learning mechanisms that can withstand environmental change across generations. We unify two competing theories of the learning mechanism supporting cumulative culture in a common computational framework, distinguishing model-based from model-free social learning. We describe and analyze evolutionary models that explain when and why model-based and model-free social learning are each optimal, and in particular how environmental volatility determines which strategy succeeds. Strikingly, we find that model-based social learning can succeed even in high-volatility environments. These results yield novel predictions concerning cultural variation in social learning mechanisms

Abstract Gout is a common autoinflammatory joint diseases characterized by deposition of monosodium urate (MSU) crystals which trigger an innate immune response mediated by inflammatory cytokines. IGF1R is one of the loci associated with both urate levels and gout susceptibility in GWAS to date, and IGF-1-IGF-1R signaling is implicated in urate control. We investigate the role of IGF-1/IGF1R signaling in the context of gouty inflammation. Also, we test the gout and urate-associated IGF1R rs6598541 polymorphism for association with the inflammatory capacity of mononuclear cells. For this, freshly isolated human peripheral blood mononuclear cells (PBMCs) were exposed to recombinant IGF-1 or anti-IGF1R neutralizing antibody in the presence or absence of solubilized urate, stimulated with LPS/MSU crystals. Also, the association of rs6598541 with IGF1R and protein expression and with ex vivo cytokine production levels after stimulation with gout specific stimuli was tested. Urate exposure was not associated with IGF1R expression in vitro or in vivo. Modulation of IGF1R did not alter urate-induced inflammation. Developing urate-induced trained immunity in vitro was not influenced in cells challenged with IGF-1 recombinant protein. Moreover, the IGF1R rs6598541 SNP was not associated with cytokine production. Our results indicate that urate-induced inflammatory priming is not regulated by IGF-1/IGF1R signaling in vitro. IGF1R rs6598541 status was not asociated with IGF1R expression or cytokine production in primary human PBMCs. This study suggests that the role of IGF1R in gout is tissue-specific and may be more relevant in the control of urate levels rather than in inflammatory signaling in gout.

Summary: Familial Mediterranean fever (FMF) is a periodic fever syndrome caused by variation in MEFV. FMF is known for IL-1β dysregulation, but the innate immune landscape of this disease has not been comprehensively described. Therefore, we studied circulating inflammatory proteins, and the function of monocytes and (albeit less extensively) neutrophils in treated FMF patients in remission. We found that monocyte IL-1β and IL-6 production was enhanced upon stimulation, in concordance with alterations in the plasma inflammatory proteome. We did not observe changes in neutrophil functional assays. Subtle differences in chromatin accessibility and transcriptomics in our small patient cohort further argued for monocyte dysregulation. Together, these observations suggest that the MEFV-mutation-mediated primary immune dysregulation in monocytes leads to chronic inflammation that is subsequently associated with counterregulatory epigenetic/transcriptional changes reminiscent of tolerance. These data increase our understanding of the innate immune changes in FMF, aiding future management of chronic inflammation in these patients.

Rebecca Ingenhoff,1,2 Nicole Robertson,3 Richard Munana,4,5 Benjamin E Bodnar,6 Ivan Weswa,5 Isaac Sekitoleko,7,8 Julia Gaal,1 Bruce J Kirenga,9 Robert Kalyesubula,5,10,11 Felix Knauf,1,11 Trishul Siddharthan12 1Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany; 2Charité Center for Global Health, Charité - Universitätsmedizin Berlin, Berlin, Germany; 3University of Kentucky College of Medicine, Lexington, KY, USA; 4School of Public Health, Makerere University College of Health Sciences, Makerere University, Kampala, Uganda; 5African Community Center for Social Sustainability, Nakaseke, Uganda; 6Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 7MRC/UVRI and LSHTM Uganda Research Unit, Kampala, Uganda; 8London School of Hygiene and Tropical Medicine, London, UK; 9Makerere University Lung Institute, Kampala, Uganda; 10Department of Physiology, Department of Internal Medicine, Makerere University College of Health Sciences, Kampala, Uganda; 11Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA; 12Department of Pulmonary, Critical Care and Sleep Medicine, University of Miami, Coral Gables, FL, USACorrespondence: Rebecca Ingenhoff, Email Rebecca.ingenhoff@charite.deBackground: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally. The burden of COPD is expected to increase in low- and middle-income countries (LMICs). COPD screening and diagnostics tools are often inaccessible in rural settings of LMICs. To contribute to the growing body of evidence on the effectiveness of Community Health Worker (CHW) interventions, this study aims to understand the facilitators and barriers of implementing a CHW-led COPD screening and referral program in rural Uganda.Methods: This qualitative study was conducted from September to October 2022 to explore Community Members, CHWs, and Healthcare Providers (HCPs) perceptions on the challenges of CHW-delivered COPD programming in Nakaseke, rural Uganda. In total, we held eight individual in-depth interviews with CHWs, ten in-depth interviews with HCPs and six focus group discussions with 34 Community Members. Research assistants audio-recorded and transcribed interviews verbatim. The implementation outcomes framework guided the thematic analysis.Results: Implementation acceptability was constrained by a lack of COPD awareness, a lack of perceived utility in COPD screening as well as stigma around the diagnostic process. Limited spirometry adoption was also attributed to Community Member accessibility and willingness to participate in the COPD diagnostic referral process. The high patient volume and the complex, time-consuming diagnostic and referral process hindered successful implementation. To enhance program sustainability, all participants suggested increasing CHW support, medication access, decentralizing COPD care and upscaling follow-up of Community Members by CHWs.Conclusion: CHW-led interventions remain a potentially critical tool to alleviate barriers to treatment and self-management in settings where access to care is limited. While community-based interventions can create sustainable infrastructure to improve health outcomes, formative assessments of the potential barriers prior to intervention are required. Evidence-based, localized approaches and sustained funding are imperative to achieve this.Keywords: community health workers, task shifting, screening and referral, chronic obstructive pulmonary disease, Uganda

Abstract Rice is more vulnerable to drought than maize, wheat, and sorghum because its water requirements remain high throughout the rice life cycle. The effects of drought vary depending on the timing, intensity, and duration of the events, as well as on the rice genotype and developmental stage. It can affect all levels of organization, from genes to the cells, tissues, and/or organs. In this study, a moderate water deficit was applied to two contrasting rice genotypes, IAC 25 and CIRAD 409, during their reproductive stage. Multi‐level transcriptomic, metabolomic, physiological, and morphological analyses were performed to investigate the complex traits involved in their response to drought. Weighted gene network correlation analysis was used to identify the specific molecular mechanisms regulated by each genotype, and the correlations between gene networks and phenotypic traits. A holistic analysis of all the data provided a deeper understanding of the specific mechanisms regulated by each genotype, and enabled the identification of gene markers. Under non‐limiting water conditions, CIRAD 409 had a denser shoot, but shoot growth was slower despite better photosynthetic performance. Under water deficit, CIRAD 409 was weakly affected regardless of the plant level analyzed. In contrast, IAC 25 had reduced growth and reproductive development. It regulated transcriptomic and metabolic activities at a high level, and activated a complex gene regulatory network involved in growth‐limiting processes. By comparing two contrasting genotypes, the present study identified the regulation of some fundamental processes and gene markers, that drive rice development, and influence its response to water deficit, in particular, the importance of the biosynthetic and regulatory pathways for cell wall metabolism. These key processes determine the biological and mechanical properties of the cell wall and thus influence plant development, organ expansion, and turgor maintenance under water deficit. Our results also question the genericity of the antagonism between morphogenesis and organogenesis observed in the two genotypes.

Type 2 diabetes mellitus has been referred to as being closely related to oxidative stress, which may affect brain functions and brain glucose metabolism due to its high metabolic activity and lipid-rich content. Na,K-ATPase is an essential enzyme maintaining intracellular homeostasis, with properties that can sensitively mirror various pathophysiological conditions such as diabetes. The goal of this study was to determine oxidative stress markers as well as Na,K-ATPase activities in the cerebellum of Zucker diabetic fatty (ZDF) rats depending on diabetes severity. The following groups of male rats were used: Wistar, ZDF Lean (fa/+), and ZDF (fa/fa) rats, arbitrarily divided according to glycemia into ZDF obese (ZO, less severe diabetes) and ZDF diabetic (ZOD, advanced diabetes) groups. In addition to basic biometry and biochemistry, oxidative stress markers were assessed in plasma and cerebellar tissues. The Na, K-ATPase enzyme activity was measured at varying ATP substrate concentrations. The results indicate significant differences in basic biometric and biochemical parameters within all the studied groups. Furthermore, oxidative damage was greater in the cerebellum of both ZDF (fa/fa) groups compared with the controls. Interestingly, Na,K-ATPase enzyme activity was highest to lowest in the following order: ZOD > ZO > Wistar > ZDF lean rats. In conclusion, an increase in systemic oxidative stress resulting from diabetic conditions has a significant impact on the cerebellar tissue independently of diabetes severity. The increased cerebellar Na,K-ATPase activity may reflect compensatory mechanisms in aged ZDF (fa/fa) animals, rather than indicating cerebellar neurodegeneration: a phenomenon that warrants further investigation.

The paraoxonase (PON) gene family (including PON1, PON2, and PON3), is known for its anti-oxidative and anti-inflammatory properties, protecting against metabolic diseases such as obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). In this study, the influence of common and rare PON variants on both conditions was investigated. A total of 507 healthy weight individuals and 744 patients with obesity including 433 with histological liver assessment, were sequenced with single-molecule molecular inversion probes (smMIPs), allowing the identification of genetic contributions to obesity and MASLD-related liver features. Polymorphisms rs705379 and rs854552 in the PON1 gene displayed significant association with MASLD stage and fibrosis, respectively. Additionally, rare PON1 variants were strongly associated with obesity. This study thereby reinforces the genetic foundation of PON1 in obesity and various MASLD-related liver features, by extending previous findings from common variants to include rare variants. Additionally, rare and very rare variants in PON2 were discovered to be associated with MASLD-related hepatic fibrosis. Notably, we are the first to report an association between naturally occurring rare PON2 variants and MASLD-related liver fibrosis. Considering the critical role of liver fibrosis in MASLD outcome, PON2 emerges as a possible candidate for future research endeavors including exploration of biomarker potential.