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The underlying mechanisms of plasma metabolite signatures of human aging and age-related diseases are not clear but telomere attrition and dysfunction are central to both. Dyskeratosis congenita (DC) is associated with mutations in the telomerase enzyme complex (TERT, TERC, and DKC1) and progressive telomere attrition. We analyzed the effect of telomere attrition on senescence-associated metabolites in fibroblast-conditioned media and DC patient plasma. Samples were analyzed by gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry. We showed extracellular citrate was repressed by canonical telomerase function in vitro and associated with DC leukocyte telomere attrition in vivo, leading to the hypothesis that altered citrate metabolism detects telomere dysfunction. However, elevated citrate and senescence factors only weakly distinguished DC patients from controls, whereas elevated levels of other tricarboxylic acid cycle (TCA) metabolites, lactate, and especially pyruvate distinguished them with high significance. The DC plasma signature most resembled that of patients with loss of function pyruvate dehydrogenase complex mutations and that of older subjects but significantly not those of type 2 diabetes, lactic acidosis, or elevated mitochondrial reactive oxygen species. Additionally, our data are consistent with further metabolism of citrate and lactate in the liver and kidneys. Citrate uptake in certain organs modulates age-related disease in mice and our data have similarities with age-related disease signatures in humans. Our results have implications for the role of telomere dysfunction in human aging in addition to its early diagnosis and the monitoring of anti-senescence therapeutics, especially those designed to improve telomere function.

This study investigated whether anthropometric and physical abilities explained variance in match collision performance among international female rugby union players. Physical performance and anthropometric data for fifty-one international female rugby union players, and collision actions categorised as "effort" or "performance" variables, from 20 international matches, were analysed using partial least squares regression. Among forwards, variance in carries/min was explained (R

Following the startling Prussian victory in the Austro-Prussian War of 1866, European observers sought to understand the war’s lessons and to apply them to future conflict. This article traces the way in which commentators in Britain, France, Prussia, Austria, and the various secondary states of Germany evaluated tactical developments resulting from the war. It highlights the transnational community of interest in military affairs, and how some imperfections in military learning from the war were nationally specific while others transcended borders. Understandings of the war’s battlefield implications were often slow to develop, and imperfectly anticipated conditions in the subsequent Franco-Prussian War.

Publisher Copyright: © 2023 by the authors. The ‘as-a-Service’ (aaS) concept of the IT sector is suggested to reduce upfront and ongoing costs, enable easier scaling, and make for simpler system upgrades. The concept is explored in relation to the domain of land administration, with a view to examining its relevance, application, and potential adaptation. Specifically, these aspects are analysed against the long-standing problem of land administration system maintenance. Two discrete literature reviews, a comparative analysis, and final modelling work constitute the research design. Of the 35 underlying land administration maintenance issues identified, aaS is found to directly respond to 15, indirectly support another 15, and provide no immediate benefit to 5. Most prominent are the ability of aaS to support issues relating to financial sustainability, continuous innovation, and human capacity provision. The approach is found to be already in use in various country contexts. It is articulated by the UNECE as one of four scenarios for future land administration development. In terms of adaptation, the 4-tier framework from Enterprise Architecture—consisting of Business, Application, Information, and Technology layers—is used to model and describe five specific aaS approaches: (i) On Premises; (ii) Basic Outsourcing; (iii) Public Private Partnership; (iv) Fully Privatised; and (v) Subscription. Several are more theoretical in nature but may see future adoption. Each requires further development, including case analyses, to support more detailed definitions of the required underlying legal frameworks, financial models, partnerships arrangements, data responsibilities, and so on. Decisions on the appropriate aaS model, and the application of aaS more generally, are entirely dependent on the specific country context. Overall, this work provides a platform for land administration researchers and practitioners to analyse the relevance and implementation options of the aaS concept.

The aims of this study were to: i) identify performance indicators associated with match outcomes in the United Rugby Championship; ii) compare the efficacy of isolated and relative datasets to predict match outcome; and iii) investigate whether reduced statistical models can reproduce predictive accuracy.Retrospective analysis of key performance indicators in the United Rugby Championship.Twenty-seven performance indicators were selected from 96 matches (2020-21 United Rugby Championship). Random forest classification was completed on isolated and relative datasets, using a binary match outcome (win/lose). Maximum relevance and minimum redundancy performance indicator selection was utilised to reduce models. In addition, models were tested on 53 matches from the 2021-22 season to ascertain prediction accuracy.Within the 2020-21 datasets, the full models correctly classified 83% of match performances for the relative dataset and 64% for isolated data, the equivalent reduced models classified 85% and 66% respectively. The reduced relative model successfully predicted 90% of match performances in the 21-22 season, highlighting that five performance indicators were significant: kicks from hand, metres made, clean breaks, turnovers conceded and scrum penalties.Relative performance indicators were more effective in predicting match outcomes than isolated data. Reducing features used in random forest classification did not degrade prediction accuracy, whilst also simplifying interpretation for practitioners. Increased kicks from hand, metres made, and clean breaks compared to the opposition, as well as fewer scrum penalties and turnovers conceded were all indicators of winning match outcomes within the United Rugby Championship.

Per - and polyfluoroalkyl substances (PFAS) are a group of environmental contaminants, that are dispersed throughout the world. A number of areas have been affected by their persistence and biomagnification. PFAS remediation of contaminated material requires extensive knowledge of the species involved. A method to simplify the study of the thermal degradation of PFAS is presented in this paper, providing a solution to experimental and analytical challenges. A three-zone furnace allowed manipulation of both reaction temperature and gas flowrate (and consequently residence time). The PFAS compound could be charged and vaporised in a separate zone. Adopting this experimental methodology, a kinetic model describing the decomposition of the PFAS can be devised. When reacting under an inert nitrogen atmosphere, perfluorooctanoic acid (PFOA) degraded at temperatures above 450 °C. The products observed were found to be hydrofluoric acid (HF) and carbon dioxide (CO2), along with a perfluoro-1-heptene species. Additional products of 1H-perfluorohexane or 1H-perfluoroheptane were also observed when residence times were increased. The effect of water vapour was also investigated, with similar behaviour to pyrolysis being observed, where a significantly higher concentration of HF was detected under otherwise similar reaction conditions. These preliminary results suggest water vapour accelerates the rate of PFAS decomposition.

Background Meal regularity is associated with many aspects of mental health. However, few studies have examined whether a relationship exists between meal regularity and self-esteem in children. Objectives The objective of this study was to determine whether an association exists between meal regularity and self-esteem in grade 5 children. Methods Among 4009 grade 5 students (mean age = 11.0 years ± SEM = 0.006) from the 2011 Children's Lifestyle and School Performance Study (CLASS-II; Nova Scotia, Canada), cross-sectional meal regularity survey data (family supper, supper in front of the television, supper alone, skipping breakfast, and skipping lunch) were collected using the Harvard Youth/Adolescent Food Frequency Questionnaire and examined in relation to self-esteem. Multilevel mixed-effects logistic regression was used to determine the ORs and 95% CIs associated with low self-esteem. Analyses were stratified by sex and adjusted for sociodemographic and lifestyle covariates. Results Compared to children who ate supper in front of the television or alone either never or less than once/week, children had greater odds of low self-esteem if 5 or more times/week they ate supper in front of the television (OR = 1.85; 95% CI, 1.40-2.43) or alone (OR = 4.23; 95% CI, 2.58-6.95). Compared to children who ate family supper 5 or more times/week, children who ate family supper never or less than once/week had greater odds of low self-esteem (OR: 1.97; 95% CI, 1.51-2.56). Skipping breakfast and skipping lunch were associated with greater odds of low self-esteem [OR = 2.92 (95% CI, 1.87-4.57) and OR = 4.82 (95% CI, 2.14-10.87) respectively]. Conclusions In our study of grade 5 children, all 5 indicators of meal regularity tested are significantly and consistently associated with self-esteem.

SUMMARYUnderlying mechanisms of plasma metabolite signatures of human ageing and age-related diseases are not clear but telomere attrition and dysfunction are central to both. Dyskeratosis Congenita (DC) is associated with mutations in the telomerase enzyme complex (TERT, TERC, DKC1) and progressive telomere attrition. We show extracellular citrate is repressed by canonical telomerase function in vitro and associated with DC leukocyte telomere attrition in vivo; leading to the hypothesis that altered citrate metabolism detects telomere dysfunction. However, citrate and senescence factors only weakly distinguished DC patients from controls, whereas other tricarboxylic acid cycle metabolites, lactate and especially pyruvate distinguished them with high significance, consistent with further metabolism of citrate and lactate in the liver and kidneys. Citrate uptake in certain organs modulates age-related disease in mice and our data has similarities with age-related disease signatures in humans. Our results have implications for the early diagnosis of telomere dysfunction and anti-senescence therapeutics.HighlightsExtracellular citrate is regulated by telomere function in vitro and in vivo.Dyskeratosis Congenita (DC) is a human disease characterized by systemic telomere attrition, which showed an age-related plasma energetic profile, distinct from age-related disease and that of centenarians.The DC profile strikingly out-performed senescence factors in discriminating DC from controls, and pyruvate associated with a low lactate:pyruvate ratio is potentially a useful and cheap minimally invasive diagnostic aid for DC and telomere dysfunction.Mechanistically DC systemic metabolism is indicative of a shift to reduced pyruvate dehydrogenase activity, glycolysis and/or increased citrate and lactate production followed by further metabolism in the kidneys and liver.

The COVID-19 pandemic in 2020 has resulted in widespread training disruption in many sports. Some athletes have access to facilities and equipment, while others have limited or no access, severely limiting their training practices. A primary concern is that the maintenance of key physical qualities (e. g. strength, power, high-speed running ability, acceleration, deceleration and change of direction), game-specific contact skills (e. g. tackling) and decision-making ability, are challenged, impacting performance and injury risk on resumption of training and competition. In extended periods of reduced training, without targeted intervention, changes in body composition and function can be profound. However, there are strategies that can dramatically mitigate potential losses, including resistance training to failure with lighter loads, plyometric training, exposure to high-speed running to ensure appropriate hamstring conditioning, and nutritional intervention. Athletes may require psychological support given the challenges associated with isolation and a change in regular training routine. While training restrictions may result in a decrease in some physical and psychological qualities, athletes can return in a positive state following an enforced period of rest and recovery. On return to training, the focus should be on progression of all aspects of training, taking into account the status of individual athletes.

The landmark 2016 Minimal Invasive Extracorporeal Technologies International Society (MiECTiS) position paper promoted the creation of a common language between cardiac surgeons, anesthesiologists and perfusionists which led to the development of a stable framework that paved the way for the advancement of minimal invasive perfusion and related technologies. The current expert consensus document offers an update in areas for which new evidence has emerged. In the light of published literature, modular minimal invasive extracorporeal circulation (MiECC) has been established as a safe and effective perfusion technique that increases biocompatibility and ultimately ensures perfusion safety in all adult cardiac surgical procedures, including re-operations, aortic arch and emergency surgery. Moreover, it was recognized that incorporation of MiECC strategies advances minimal invasive cardiac surgery (MICS) by combining reduced surgical trauma with minimal physiologic derangements. Minimal Invasive Extracorporeal Technologies International Society considers MiECC as a physiologically-based multidisciplinary strategy for performing cardiac surgery that is associated with significant evidence-based clinical benefit that has accrued over the years. Widespread adoption of this technology is thus strongly advocated to obtain additional healthcare benefit while advancing patient care.

The mitotic count (MC) is an important histological parameter for prognostication of malignant neoplasms. However, it has inter- and intraobserver discrepancies due to difficulties in selecting the region of interest (MC-ROI) and in identifying or classifying mitotic figures (MFs). Recent progress in the field of artificial intelligence has allowed the development of high-performance algorithms that may improve standardization of the MC. As algorithmic predictions are not flawless, computer-assisted review by pathologists may ensure reliability. In the present study, we compared partial (MC-ROI preselection) and full (additional visualization of MF candidates and display of algorithmic confidence values) computer-assisted MC analysis to the routine (unaided) MC analysis by 23 pathologists for whole-slide images of 50 canine cutaneous mast cell tumors (ccMCTs). Algorithmic predictions aimed to assist pathologists in detecting mitotic hotspot locations, reducing omission of MFs, and improving classification against imposters. The interobserver consistency for the MC significantly increased with computer assistance (interobserver correlation coefficient, ICC = 0.92) compared to the unaided approach (ICC = 0.70). Classification into prognostic stratifications had a higher accuracy with computer assistance. The algorithmically preselected hotspot MC-ROIs had a consistently higher MCs than the manually selected MC-ROIs. Compared to a ground truth (developed with immunohistochemistry for phosphohistone H3), pathologist performance in detecting individual MF was augmented when using computer assistance (F1-score of 0.68 increased to 0.79) with a reduction in false negatives by 38%. The results of this study demonstrate that computer assistance may lead to more reproducible and accurate MCs in ccMCTs.

Despite the significant and explicit focus on the United Nations Sustainable Development Goals (SDGs), much of the world’s land rights remain unrecorded and outside formal government systems. Blame is often placed on land administration processes that are considered slow, expensive, and expertise-dependent. Fit-For-Purpose Land Administration (FFPLA) has been suggested as an alternative, time and cost-effective approach. Likewise, the UN endorsed Framework for Effective Land Administration (FELA) demands attention to worldwide tenure insecurity by directly linking it to responsible land administration. Implementation of FFPLA and FELA is country-context dependent, and there are now many lessons of execution from various jurisdictions. Undertaken in 2022, this study synthesizes a review of experiences to provide a further update on the best global FFPLA implementation practices and inform approaches for future FFPLA projects. A systematic review is adopted as the research methodology, and contemporary articles from the internationally recognized land administration discourse are examined. The studies focus on FFPLA implementation practices and innovative approaches for delivering land tenure security. A checklist is developed, based on the FELA strategic pathways and the FFPLA fundamental framework principles and characteristic elements, to identify best implementation practices. Success stories across the globe show that the FFPLA characteristic elements and the FELA pathway goals are achieved through effective execution of the FFPLA framework key principles. As a result, the study identified successful FFPLA implementation practices in Asia and Africa, which can be synthesized and extended to realize tenure security in rapidly urbanizing areas. However, further study is necessary to determine the efficacy, practicability, innovativeness, and transferability of the best practices to other land administration scenarios.

The mitotic count (MC) is an important histological parameter for prognostication of malignant neoplasms. However, it has inter- and intra-observer discrepancies due to difficulties in selecting the region of interest (MC-ROI) and in identifying/classifying mitotic figures (MFs). Recent progress in the field of artificial intelligence has allowed the development of high-performance algorithms that may improve standardization of the MC. As algorithmic predictions are not flawless, the computer-assisted review by pathologists may ensure reliability. In the present study we have compared partial (MC-ROI preselection) and full (additional visualization of MF candidate proposal and display of algorithmic confidence values) computer-assisted MC analysis to the routine (unaided) MC analysis by 23 pathologists for whole slide images of 50 canine cutaneous mast cell tumors (ccMCTs). Algorithmic predictions aimed to assist pathologists in detecting mitotic hotspot locations, reducing omission of MF and improving classification against imposters. The inter-observer consistency for the MC significantly increased with computer assistance (interobserver correlation coefficient, ICC = 0.92) compared to the unaided approach (ICC = 0.70). Classification into prognostic stratifications had a higher accuracy with computer assistance. The algorithmically preselected MC-ROIs had a consistently higher MCs than the manually selected MC-ROIs. Compared to a ground truth (developed with immunohistochemistry for phosphohistone H3), pathologist performance in detecting individual MF was augmented when using computer assistance (F1-score of 0.68 increased to 0.79) with a reduction in false negatives by 38%. The results of this study prove that computer assistance may lead to a more reproducible and accurate MCs in ccMCTs.

Aim: The purpose of this study is to determine the readiness of occupational therapy clinics to address the occupations their clients’ may be interested in. Methods: A quantitative survey s...

Density of mitotic figures in histologic sections is a prognostically relevant characteristic for many tumours. Due to high interpathologist variability, deep learning-based algorithms are a promising solution to improve tumour prognostication. Pathologists are the gold standard for database development, however, labelling errors may hamper development of accurate algorithms. In the present work we evaluated the benefit of multi-expert consensus (n = 3, 5, 7, 9, 11) on algorithmic performance. While training with individual databases resulted in highly variable F1 scores, performance was notably increased and more consistent when using the consensus of three annotators. Adding more annotators only resulted in minor improvements. We conclude that databases by few pathologists and high label precision may be the best compromise between high algorithmic performance and time investment.

Background Skipping meals is an increasingly common practice to lose weight among North American adults. However, the long-term effect of this practice on incident type 2 diabetes mellitus (T2DM) remains unknown. We assessed whether skipping meals to lose weight is associated with T2DM risk and whether this association is modified by cardiometabolic risk factors. Methods Skipping meals to lose weight was assessed by questionnaire in 2,288 adults from the 1995 Nova Scotia Health Survey and was linked to administrative health databases to determine T2DM incidence in the following 23 years. Multivariable-adjusted Cox proportional hazards models estimated hazard ratios (aHRs) and 95% confidence intervals (CIs) for T2DM. Results During follow up, 378 T2DM cases were diagnosed. Compared with participants who did not skip meals to lose weight, those who did (2.2%) had a 125% higher risk of T2DM (aHR, 2.25; 95% CI, 1.31 to 3.86). This association was no longer present after further adjustment for baseline body mass index (BMI) (aHR, 1.66; 95% CI, 0.96 to 2.85). Skipping meals to lose weight was associated with T2DM among participants who were men (n=1,135; aHR, 2.09; 95% CI, 1.09 to 4.02) or had a BMI Conclusions Skipping meals to lose weight may be a predictive modifiable risk factor for developing T2DM over time, potentially working in connection with other T2DM risk factors.

Introduction: Skipping meals is an increasingly common practice to lose weight among North American adults of all bodyweights. However, due to a lack of long-term studies, the long-term effect of skipping meals to lose weight on cardiometabolic health outcomes such as a diagnosis of type 2 diabetes mellitus (T2DM) or incident coronary heart disease (CHD) remains unknown, although previous short-term studies of skipping meals and risk factors for T2DM and CHD have suggested plausible biological pathways for a relationship to exist in either direction, protective or harmful. Hypothesis: We assessed the hypotheses that skipping meals to lose weight was associated with long-term risk of incident T2DM and CHD in the Canadian 1995 Nova Scotia Health Survey (NSHS95), and that these associations were influenced by cardiometabolic risk factors. Methods: Skipping meals to lose weight was assessed via questionnaire in a cohort of 2,898 adults in the NSHS95 and was linked to population-based health care administrative databases to determine incidence of T2DM and/or CHD in the following 23 years. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for T2DM and CHD. Results: During 23 years of follow-up, 430 incident cases of T2DM and 632 incident cases of CHD were diagnosed. Compared to participants who did not skip meals to lose weight, those who did skip meals to lose weight (2.7%) had an 87% higher risk of T2DM (multivariable-adjusted HR=1.87, 95% CI: 1.11-3.17). This association was no longer present after adjustment for baseline body mass index (BMI) (HR=1.42, 0.83-2.42). After stratification by BMI, skipping meals was associated with T2DM among participants who had BMI 2 (n=1,030; HR=4.42, 1.01-19.30) but not among participants with BMIs of 25-29.9 kg/m 2 (n=1,123; HR=1.07, 0.39-2.96) or 30+ kg/m 2 (n=586; HR=1.21, 0.61-2.39). The multivariable-adjusted (including BMI) association was also present within participants with elevated cholesterol (n=1,450; HR=1.88, 1.00-3.53) and high blood pressure (n=1,363; HR=2.07, 1.11-3.85), but not among those without. No significant association was observed between skipping meals to lose weight and CHD risk before (HR=1.14, 0.67-1.96) or after adjustment for BMI (HR=1.05, 0.61-1.81), or within subgroups. Conclusion: These findings suggest that skipping meals to lose weight may be a predictive modifiable risk factor for developing T2DM over time, especially among people with a BMI 2 , potentially working in connection or iteration with other T2DM risk factors. With the growing number of popular diets that include skipping meals, future studies are warranted to understand perturbations of potential metabolic consequences.

Introduction: Despite low mortality, cardiac surgery patients may experience serious life-threatening post-operative complications, often due to extracorporeal circulation and reperfusion. Miniaturised cardiopulmonary bypass (minimally invasive extracorporeal circulation) has been developed aiming to reduce the risk of post-operative complications arising with conventional extracorporeal circulation. Methods: The COMICS trial is a multi-centre, international, two-group parallel randomised controlled trial testing whether type II, III or IV minimally invasive extracorporeal circulation is effective and cost-effective compared to conventional extracorporeal circulation in patients undergoing elective or urgent coronary artery bypass grafting, aortic valve replacement or coronary artery bypass grafting + aortic valve replacement. Randomisation (1:1 ratio) is concealed and stratified by centre and surgical procedure. The primary outcome is a composite of 12 serious complications, objectively defined or adjudicated, 30 days after surgery. Secondary outcomes (at 30 days) include other serious adverse events (primary safety outcome), use of blood products, length of intensive care and hospital stay and generic health status (also at 90 days). Status of the trial: Two centres started recruiting on 08 May 2018; 10 are currently recruiting and 603 patients have been randomised (11 May 2020). The recruitment rate from 01 April 2019 to 31 March 2020 was 40-50 patients/month. About 80% have had coronary artery bypass grafting only. Adherence to allocation is good. Conclusions: The trial is feasible but criteria for progressing to a full trial were not met on time. The Trial Steering and Data Monitoring Committees have recommended that the trial should currently continue.

In the month approaching the 2014 Scottish Independence referendum, we tested the Identity‐Deprivation‐Efficacy‐Action‐Subjective Well‐Being model using an electorally representative survey of Scottish adults (N = 1,156) to predict voting for independence and subjective well‐being. Based on social identity theory, we hypothesized for voting intention that the effects of collective relative deprivation, group identification, and collective efficacy, but not personal relative deprivation (PRD), should be fully mediated by social change ideology. Well‐being was predicted to be associated with PRD (negatively) and group identification (positively and, indirectly, negatively). Unaffected by demographic variables and differences in political interest, nested structural equation model tests supported the model, accounting for 82% of the variance in voting intention and 31% of the variance in subjective well‐being. However, effects involving efficacy depended on its temporal framing. We consider different ways that social identification can simultaneously enhance and diminish well‐being and we discuss ramifications of the model for collective mobilization and separatist nationalism. Findings also suggest new directions for research on social identity, collective efficacy, and collective action.

This article explores how perceived inefficiencies and inadequacies in the militia were reflected in contemporary works of fiction and satire. The militia's public image was consistently poor: half-trained battalions, staffed by inefficient senior officers, chronically short of subalterns and recruiting from the very worst elements of the working class. It suffered from the combined flaws of both regulars and volunteers, but was unable to benefit from either the Christian ‘civilizing mission’ of the former or the earnest patriotic enthusiasm of the latter. This negative image contributed to the ease with which the force was abolished after the Boer War.

Significance Tissues are viscoelastic in nature and their physical properties play a fundamental role in development, tumorigenesis, and wound healing. Cell response to matrix elasticity is well understood through a “molecular clutch” which engages when stiffness is sufficiently high to expose binding sites in mechanosensitive proteins. Here we show that cell response to pure viscous surfaces (i.e., with no elastic component) can be explained through the same molecular clutch. Mechanisms used by cells to sense rigidity are more universal and can be used to unveil cell interaction with complex viscoelastic environments. The research presents a tool to understand cells within tissues and in turn opens new avenues to incorporate viscosity into the design of synthetic cellular microenvironments., Cell response to matrix rigidity has been explained by the mechanical properties of the actin-talin-integrin-fibronectin clutch. Here the molecular clutch model is extended to account for cell interactions with purely viscous surfaces (i.e., without an elastic component). Supported lipid bilayers present an idealized and controllable system through which to study this concept. Using lipids of different diffusion coefficients, the mobility (i.e., surface viscosity) of the presented ligands (in this case RGD) was altered by an order of magnitude. Cell size and cytoskeletal organization were proportional to viscosity. Furthermore, there was a higher number of focal adhesions and a higher phosphorylation of FAK on less-mobile (more-viscous) surfaces. Actin retrograde flow, an indicator of the force exerted on surfaces, was also seen to be faster on more mobile surfaces. This has consequential effects on downstream molecules; the mechanosensitive YAP protein localized to the nucleus more on less-mobile (more-viscous) surfaces and differentiation of myoblast cells was enhanced on higher viscosity. This behavior was explained within the framework of the molecular clutch model, with lower viscosity leading to a low force loading rate, preventing the exposure of mechanosensitive proteins, and with a higher viscosity causing a higher force loading rate exposing these sites, activating downstream pathways. Consequently, the understanding of how viscosity (regardless of matrix stiffness) influences cell response adds a further tool to engineer materials that control cell behavior.

Systemic juvenile idiopathic arthritis (SJIA) is a severe childhood arthropathy with features of autoinflammation. Monocytes and macrophages in SJIA have a complex phenotype with both pro- and anti-inflammatory properties that combine features of several well characterized in vitro conditions used to activate macrophages. An important anti-inflammatory phenotype is expression of CD163, a scavenger receptor that sequesters toxic pro-inflammatory complexes that is highly expressed in both active SJIA and macrophage activation syndrome (MAS). CD163 is most strongly up-regulated by IL-10 (M(IL-10)), and not by other conditions that reflect features seen in SJIA monocytes such as M(LPS+IC). MicroRNA plays key roles in integrating cellular signals such as those in macrophage polarization, and as such we hypothesize microRNAs regulate macrophage functional responses in SJIA including CD163 expression. We find that 2 microRNAs previously found to be elevated in active SJIA, miR-125a-5p and miR-181c, significantly reduced macrophage CD163 expression through 2 distinct mechanisms. Neither microRNA was elevated in M(IL-10) with robust CD163 expression, but were instead induced in M(LPS+IC) where they restricted CD163 mRNA expression. Mir-181 species directly targeted CD163 mRNA for degradation. In contrast, miR-125a-5p functions indirectly, as transcriptome analysis of miR-125a-5p overexpression identified “cytokine-cytokine receptor interactions” as the most significantly repressed gene pathway, including decreased IL10RA, required for IL-10-mediated CD163 expression. Finally, overexpression of miR-181c inhibited CD163 anti-inflammatory responses to hemoglobin or high mobility group box 1 (HMGB1) complexes. Together, these data show that microRNA utilizes multiple mechanisms to integrate well-characterized polarization phenotypes and regulate macrophage functional properties seen in SJIA.