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The objective of this review was to investigate the available qualitative evidence to enhance understanding of the experiences of children and young adults living with juvenile idiopathic arthritis, and their carers, in any setting.Juvenile idiopathic arthritis is the most common chronic rheumatic disease in childhood. Despite the availability of effective treatments, persistent pain, growth retardation, physical disability, and psychological problems can occur. This may reduce the quality of life for patients with juvenile idiopathic arthritis by negatively affecting their family, educational, and social well-being. Patient-centered management and care for patients with juvenile idiopathic arthritis requires increasing attention to their self-reported quality of life and experiences, in addition to clinically measured disease activity. Furthermore, caring for children with juvenile idiopathic arthritis may have negative impacts on the lives of their carers and families. The experiences of carers have been poorly understood and studied. This review describes experiences and perspectives from patients and carers in order to inform the needs of families throughout their juvenile idiopathic arthritis journey.Studies describing the experiences of patients aged21 years who have been diagnosed with juvenile idiopathic arthritis according to the International League of Associations for Rheumatology criteria, as well as the experiences of their carers, have been considered.A comprehensive search using PubMed, CINAHL, Embase, PsycINFO, Web of Science, and Google Scholar, as well as relevant conference proceedings of the American College of Rheumatology (2018-2019), the European Pediatric Rheumatology Congress 2018, the European League Against Rheumatism (2018-2019), and the Asia Pacific League of Associations for Rheumatology (2018-2019), was undertaken in December 2020 to identify pertinent published and unpublished studies. Studies published in English from 2001 to 2020 were included. The JBI approach to study selection, critical appraisal, data extraction, and data synthesis was used.Ten studies were included in this review. A total of 61 findings were extracted and aggregated to form 12 categories. From the 12 categories, five synthesized findings were developed: i) Self-management of juvenile idiopathic arthritis requires pain management, medication management, and the acquisition of knowledge and professional support; ii) A promising relationship with health care professionals but unbalanced access to services; iii) Parental financial burden and their adjustment to maintain family happiness; iv) Patients and parents support the web-based approach to communicate and develop self-management skills and acknowledge the importance of clinical trials; v) Desire to live a normal life without prejudice from school, social settings, and the workplace.This review has provided a comprehensive overview of experiences and perceptions of patients juvenile idiopathic arthritis and their parents. It is important to understand what they need to know about the disease. This review also highlights the importance of appropriate web-based programs, career counseling, infrastructures, and school facilities. Findings in this review can guide future policy and practice in order to improve care for families and children with juvenile idiopathic arthritis. Further research is required to develop management strategies for medication intolerance and to evaluate the longitudinal benefits of relevant juvenile idiopathic arthritis programs.PROSPERO CRD42019133165.

OBJECTIVE The objective of this review was to investigate the available qualitative evidence to enhance understanding of the experiences of children, young adults, and their carers living with Juvenile Idiopathic Arthritis in any setting. INTRODUCTION Juvenile Idiopathic Arthritis is the most common chronic rheumatic disease in childhood. Despite the availability of effective treatments, persistent pain, growth retardation, physical disability, and psychological problems can occur. This may reduce the quality of life for Juvenile Idiopathic Arthritis patients by negatively affecting their family, educational, and social well-being. Patient-centered management and care for Juvenile Idiopathic Arthritis patients requires increasing attention to their self-reported quality of life and experiences, in addition to clinically measured disease activity. Furthermore, taking care of children with Juvenile Idiopathic Arthritis may have negative impacts on the lives of their carers and families. The experiences of carers have been poorly understood and studied. This review describes experiences and perspectives from patients and carers in order to inform the needs of families throughout their Juvenile Idiopathic Arthritis journey. INCLUSION CRITERIA Studies describing the experiences of patients aged

Objective Many meta-analyses have provided synthesised likelihood ratio data to aid clinical decision-making. However, much less has been published on how to safely combine clinical information in practice. We aimed to explore the benefits and risks of pooling clinical information during the ED assessment of suspected acute coronary syndrome. Methods Clinical information on 1776 patients was collected within a randomised trial conducted across five South Australian EDs between July 2011 and March 2013. Bayes theorem was used to calculate patient-specific post-test probabilities using age- and gender-specific pre-test probabilities and likelihood ratios corresponding to the presence or absence of 18 clinical factors. Model performance was assessed as the presence of adverse cardiac outcomes among patients theoretically discharged at a post-test probability less than 1%. Results Bayes theorem-based models containing high-sensitivity troponin T (hs-troponin) outperformed models excluding hs-troponin, as well as models utilising TIMI and GRACE scores. In models containing hs-troponin, a plateau in improving discharge safety was observed after the inclusion of four clinical factors. Models with fewer clinical factors better approximated the true event rate, tended to be safer and resulted in a smaller standard deviation in post-test probability estimates. Conclusions We showed that there is a definable point where additional information becomes uninformative and may actually lead to less certainty. This evidence supports the concept that clinical decision-making in the assessment of suspected acute coronary syndrome should be focused on obtaining the least amount of information that provides the highest benefit for informing the decisions of admission or discharge.

The primary immune role of B cells is to produce antibodies, but they can also influence T cell function via antigen presentation and, in some contexts, immune regulation. Whether their roles in tumour immunity are similar to those in other chronic immune responses such as autoimmunity and chronic infection, where both pro- and anti-inflammatory roles have been described, remains controversial. Many studies have aimed to define the role of B cells in antitumor immune responses, but despite this considerable body of work, it is not yet possible to predict how they will affect immunity to any given tumour. In many human cancers, the presence of tumour-infiltrating B cells and tumour-reactive antibodies correlates with extended patient survival, and this clinical observation is supported by data from some animal models. On the other hand, T cell responses can be adversely affected by B cell production of immunoregulatory cytokines, a phenomenon that has been demonstrated in humans and in animal models. The isotype and concentration of tumour-reactive antibodies may also influence tumour progression. Recruitment of B cells into tumours may directly reflect the subtype and strength of the anti-tumour T cell response. As the response becomes chronic, B cells may attenuate T cell responses in an attempt to decrease host damage, similar to their described role in chronic infection and autoimmunity. Understanding how B cell responses in cancer are related to the effectiveness of the overall anti-tumour response is likely to aid in the development of new therapeutic interventions against cancer.

Low-range troponin elevations without clear coronary manifestations remain a major diagnostic challenge. We sought to determine if troponin velocity could allow for early identification of patients without an obvious cardiac diagnosis and who are at increased risk for cardiac-specific events.All patients presenting to South Australian public hospitals between 1 September 2011 and 30 September 2012, with at least two troponin measurements during the first 6h after ED presentation were included. Diagnoses were classified as 'coronary', 'non-coronary cardiac', and 'non-cardiac' using the International Classification of Diseases 10 codes. The relationship between troponin velocity and cardiac-specific mortality and combined cardiac outcome (death and myocardial infarction) was assessed using Fine and Gray competing risk models in patients with an initial troponin52 ng/L. Sensitivity analyses were performed using different initial and maximum troponin cut-off values. In total, 7300 patients were identified. A troponin velocity of 2.5 ng/L/h or greater in the non-cardiac (n=2793) patient group was significantly associated with an increased risk for 12-month cardiac mortality (sub-hazard ratio [SHR] 2.90, 95% CI 1.33-6.34) and combined cardiac outcome (SHR 2.08, 95% CI 1.01-4.27). This association was consistent for coronary (n=3835) and non-coronary cardiac (n=672) patient groups, and remained after sensitivity analyses.The significant association observed across all patient groups suggests that troponin velocity could be used for early risk stratification of patients with low-range troponin elevations without clear cardiac symptoms. These results may help guide future clinical trials aimed at assessing the utility of cardiac-targeted interventions in this challenging patient population.

Bronchiolitis is one of the leading causes of hospitalisation in infancy, with highly variable clinical presentations ranging from mild disease safely managed at home to severe disease requiring invasive respiratory support. Identifying immune biomarkers that can predict and stratify this variable disease severity has important implications for clinical prognostication/disposition. A systematic literature search of the databases Embase, PubMed, ScienceDirect, Web of Science, and Wiley Online Library was performed. English language studies that assessed the association between an immune biomarker and bronchiolitis disease severity among children aged less than 24 months were included. 252 distinct biomarkers were identified across 90 studies. A substantial degree of heterogeneity was observed in the bronchiolitis definitions, measures of disease severity, and study designs. 99 biomarkers showed some significant association with disease severity, but only 18 were significant in multiple studies. However, all of these candidate biomarkers had comparable studies that reported conflicting results. Conclusion: The heterogeneity among included studies and the lack of a consistently significant biomarker highlight the need for consensus on bronchiolitis definitions and severity measures, as well as further studies assessing their clinical utility both in isolation and in combination.

Background The aim of this study was to characterise the interaction between ACS- and non-ACS-risk on the benefits of invasive management in patients presenting with acute coronary syndrome (ACS). Methods Consecutive patients admitted to a tertiary hospital's Cardiac Care Unit in the months of July–December, 2003–2011 with troponin elevation (>30 ng/L) were included. “ACS-specific-risk” was estimated using the GRACE score and “non-ACS-risk” was estimated using the Charlson-Comorbidity-Index (CCI). Inverse-probability-of-treatment weighting was used to adjust for baseline differences between patients who did or did not receive invasive management. A multivariable flexible parametric model was used to characterise the time-varying hazard. Results In total, 3057 patients were included with a median follow-up of 9.0 years. Based on CCI, 1783 patients were classified as ‘low-non-ACS risk’ (CCI ≤ 1; invasive management 81%; 12-month mortality 5%), 820 as ‘medium-non-ACS risk’ (CCI 2–3; invasive management 68%; 12-month mortality 13%), and 468 as ‘high-non-ACS risk’ (CCI ≥ 4; invasive management 47%; 12-month mortality 29%). After adjustment, invasive management was associated with a significant reduction in one-year overall-mortality in the ‘low-risk’ and ‘medium-risk’ groups (HR = 0.38, 95%CI:0.26–0.56; HR = 0.46, 95%CI:0.32–0.67); but not in the ‘high-risk’ group (HR = 1.02, 95%CI:0.67–1.56). The absolute benefit of invasive management was greatest with higher baseline ACS-risk, with a non-linear interaction between ACS- and non-ACS-risk. Conclusions There is a complex interaction between ACS- and non-ACS-risk on the benefit of invasive management. These results highlight the need to develop robust methods to objectively quantify risk attributable to non-ACS comorbidities in order to make informed decisions regarding the use of invasive management in individuals with numerous comorbidities.

Preterm infants are uniquely susceptible to late-onset sepsis that is frequently caused by the skin commensal Staphylococcus epidermidis. Innate immune responses, particularly from monocytes, are a key protective mechanism. Impaired cytokine production by preterm infant monocytes is well described, but few studies have comprehensively assessed the corresponding monocyte transcriptional response. Innate immune responses in preterm infants may be modulated by inflammation such as prenatal exposure to histologic chorioamnionitis which complicates 40-70% of preterm pregnancies. Chorioamnionitis alters the risk of late-onset sepsis, but its effect on monocyte function is largely unknown. Here, we aimed to determine the impact of exposure to chorioamnionitis on the proportions and phenotype of cord blood monocytes using flow cytometry, as well as their transcriptional response to live S. epidermidis. RNA-seq was performed on purified cord blood monocytes from very preterm infants (

Viral bronchiolitis is one of the most common hospital presentations in infancy and as such represents a major healthcare burden worldwide. However despite this, there are currently no effective targeted therapies nor can those infants at highest risk for developing severe disease or subsequent respiratory morbidity be predicted on initial hospital presentation. Current definitions of bronchiolitis in the published literature vary significantly in terms of the age range at presentation, specific clinical symptoms, causative virus, and the inclusion or exclusion of infants with previous presentations and/or various comorbidities. In this review, we highlight how this heterogeneity among definitions contributes to a lack of clarity on this condition and its likely multiple endotypes. We argue that without a new universal consensus definition or sets of definitions, progress into bronchiolitis will continue to be stalled.

Background Sepsis involves aberrant immune responses to infection, but the exact nature of this immune dysfunction remains poorly defined. Bacterial endotoxins like lipopolysaccharide (LPS) are potent inducers of inflammation, which has been associated with the pathophysiology of sepsis, but repeated exposure can also induce a suppressive effect known as endotoxin tolerance or cellular reprogramming. It has been proposed that endotoxin tolerance might be associated with the immunosuppressive state that was primarily observed during late-stage sepsis. However, this relationship remains poorly characterised. Here we clarify the underlying mechanisms and timing of immune dysfunction in sepsis. Methods We defined a gene expression signature characteristic of endotoxin tolerance. Gene-set test approaches were used to correlate this signature with early sepsis, both newly and retrospectively analysing microarrays from 593 patients in 11 cohorts. Then we recruited a unique cohort of possible sepsis patients at first clinical presentation in an independent blinded controlled observational study to determine whether this signature was associated with the development of confirmed sepsis and organ dysfunction. Findings All sepsis patients presented an expression profile strongly associated with the endotoxin tolerance signature (p, Highlights • Addresses sepsis that affects up to 18 million persons annually with up to 5 million deaths worldwide. • Describes an endotoxin tolerance gene expression signature associated with consecutive treatments with endotoxin and reflecting cellular reprogramming. • Using a meta-analysis of the literature demonstrates the statistically significant association (p

Many meta-analyses have provided synthesised likelihood ratio data to aid clinical decision-making. However, much less has been published on how to safely combine clinical information in practice. We aimed to explore the benefits and risks of pooling clinical information during the ED assessment of suspected acute coronary syndrome.Clinical information on 1776 patients was collected within a randomised trial conducted across five South Australian EDs between July 2011 and March 2013. Bayes theorem was used to calculate patient-specific post-test probabilities using age- and gender-specific pre-test probabilities and likelihood ratios corresponding to the presence or absence of 18 clinical factors. Model performance was assessed as the presence of adverse cardiac outcomes among patients theoretically discharged at a post-test probability less than 1%.Bayes theorem-based models containing high-sensitivity troponin T (hs-troponin) outperformed models excluding hs-troponin, as well as models utilising TIMI and GRACE scores. In models containing hs-troponin, a plateau in improving discharge safety was observed after the inclusion of four clinical factors. Models with fewer clinical factors better approximated the true event rate, tended to be safer and resulted in a smaller standard deviation in post-test probability estimates.We showed that there is a definable point where additional information becomes uninformative and may actually lead to less certainty. This evidence supports the concept that clinical decision-making in the assessment of suspected acute coronary syndrome should be focused on obtaining the least amount of information that provides the highest benefit for informing the decisions of admission or discharge.

The 4th universal definition of myocardial infarction (MI) differentiated MI from myocardial injury. We compared the temporal course of excess hazard associated with MI and myocardial injury. We drew upon the state administrative and pathology reporting systems to assimilate a dataset of all

Summary The dendritic cell (DC) lineage is remarkably heterogeneous. It has been postulated that specialized DC subsets have evolved in order to select and support the multitude of possible T cell differentiation pathways. However, defining the function of individual DC subsets has proven remarkably difficult, and DC subset control of key T cell fates such as tolerance, T helper cell commitment and regulatory T cell induction is still not well understood. While the difficulty in assigning unique functions to particular DC subsets may be due to sharing of functions, it may also reflect a lack of appropriate physiological in-vivo models for studying DC function. In this paper we review the limitations associated with many of the current DC models and highlight some of the underlying difficulties involved in studying the function of murine DC subsets.

OBJECTIVES: Current guidelines recommend topical steroids as first-line treatment for patients with eosinophilic esophagitis (EoE). However, the evidence for this approach has been inconsistent in earlier reports. This meta-analysis aimed to clarify the efficacy of topical steroid treatment in active EoE using updated evidence. METHODS: CENTRAL, MEDLINE and EMBASE databases were searched for randomized controlled trials (RCTs) published up to May 2014 that compared topical steroids with control treatments for active EoE. Study bias was assessed using the Cochrane Collaboration Tool, and outcomes were pooled using random effects models. The primary outcome was the mean change in eosinophil counts. Secondary outcomes were symptom responses and adverse events. RESULTS: In total, seven RCTs (226 patients) were included. Topical steroids were associated with a significant reduction in esophageal mucosal eosinophil counts compared with control therapy although substantial heterogeneity between studies was observed (weighted mean difference (WMD) −27.2, 95% confidence interval (CI) −45.3 to −9.1, I2=56.2%). Subgroup analysis indicated the reduction in eosinophil counts was only present in studies where a proton pump inhibitor (PPI) trial was used to exclude other diagnoses (WMD −46.3, 95% CI −61.3 to −31.4, I2=0.0%). Subdivision of studies on the use of a PPI trial also accounted for the majority of heterogeneity among RCTs. No clear trends in symptom resolution were observed. Eleven out of 127 patients who received topical steroids developed asymptomatic esophageal candidiasis. CONCLUSIONS: These data provide updated high-quality evidence that support current guidelines for first-line EoE treatment with topical steroids after an initial PPI trial to exclude non-EoE pathologies (PROSPERO ID: CRD42014008828).

Occupational lung cancers represent a major health burden due to their increasing prevalence and poor long-term outcomes. While wood dust is a confirmed human carcinogen, its association with lung cancer remains unclear due to inconsistent findings in the literature. We aimed to clarify this association using meta-analysis. We performed a search of 10 databases to identify studies published until June 2014. We assessed the lung cancer risk associated with wood dust exposure as the primary outcome and with wood dust-related occupations as a secondary outcome. Random-effects models were used to pool summary risk estimates. 85 publications were included in the meta-analysis. A significantly increased risk for developing lung cancer was observed among studies that directly assessed wood dust exposure (RR 1.21, 95% CI 1.05 to 1.39, n=33) and that assessed wood dust-related occupations (RR 1.15, 95% CI 1.07 to 1.23, n=59). In contrast, a reduced risk for lung cancer was observed among wood dust (RR 0.63, 95% CI 0.39 to 0.99, n=5) and occupation (RR 0.96, 95% CI 0.95 to 0.98, n=1) studies originating in Nordic countries, where softwood dust is the primary exposure. These results were independent of the presence of adjustment for smoking and exposure classification methods. Only minor differences in risk between the histological subtypes were identified. This meta-analysis provides strong evidence for an association between wood dust and lung cancer, which is critically influenced by the geographic region of the study. The reasons for this region-specific effect estimates remain to be clarified, but may suggest a differential effect for hardwood and softwood dusts.

The lymphatics system has many diverse roles in the human body. These range from regulating fluid balance and fatty acid transport to serving as a conduit for leukocyte entry into lymphoid organs. While stromal cell populations are becoming increasingly recognised as important components of the immune response, the peripheral lymphatics are still commonly perceived as a passive conduit for immune cells. In contrast to this paradigm, the lymphatics are capable of responding to a wide range of pathogenic stimuli and secondary immune mediators, activating diverse, functional and stimulus dependant programs to these, with subsequent regulation of the effector function of multiple immune cell populations. In this review, we highlight papers that support the peripheral lymphatics as a crucial and active player in the immune response. We also interpret this evidence in the context of human disease pathogenesis and the potential for lymphatic-targeted therapeutic interventions.

The lymphatic system consists of a network of vessels connecting peripheral tissues and secondary lymphoid organs. The lymphatics vasculature is involved in the transport of fluid, fatty acids/cholesterol, local waste products, peripheral antigens, and immune molecules and cells throughout the body, and therefore plays critical roles in fluid, lipid, and immune homeostasis. However, while the lymphatic system was initially identified close to 400 years ago, the immune-roles for the lymphatics have only recently been appreciated, following the identification of lymphatic-specific markers. However, the lymphatics are still often perceived as a passive, inert conduit for immune cells and mediators rather than a tightly integrated and active component of the immune system. In addition, the lymphatics are often underrepresented or overlooked in immune studies of human disease.

Dendritic cells (DCs) are critical for regulating CD4 and CD8 T cell immunity, controlling Th1, Th2, and Th17 commitment, generating inducible Tregs, and mediating tolerance. It is believed that distinct DC subsets have evolved to control these different immune outcomes. However, how DC subsets mount different responses to inflammatory and/or tolerogenic signals in order to accomplish their divergent functions remains unclear. Lipopolysaccharide (LPS) provides an excellent model for investigating responses in closely related splenic DC subsets, as all subsets express the LPS receptor TLR4 and respond to LPS in vitro. However, previous studies of the LPS-induced DC transcriptome have been performed only on mixed DC populations. Moreover, comparisons of the in vivo response of two closely related DC subsets to LPS stimulation have not been reported in the literature to date. We compared the transcriptomes of murine splenic CD8 and CD11b DC subsets after in vivo LPS stimulation, using RNA-Seq and systems biology approaches. We identified subset-specific gene signatures, which included multiple functional immune mediators unique to each subset. To explain the observed subset-specific differences, we used a network analysis approach. While both DC subsets used a conserved set of transcription factors and major signalling pathways, the subsets showed differential regulation of sets of genes that ‘fine-tune’ the network Hubs expressed in common. We propose a model in which signalling through common pathway components is ‘fine-tuned’ by transcriptional control of subset-specific modulators, thus allowing for distinct functional outcomes in closely related DC subsets. We extend this analysis to comparable datasets from the literature and confirm that our model can account for cell subset-specific responses to LPS stimulation in multiple subpopulations in mouse and man.

Novel therapies to target lung inflammation are predicted to improve the lives of people with cystic fibrosis (CF) but specific antiinflammatory targets have not been identified. The goal of this study was to establish whether TLR5 signaling is the key molecular pathway mediating lung inflammation in CF, and to determine whether strategies to inhibit TLR5 can reduce the damaging inflammatory response. The innate immune responses were analyzed in both airway epithelial cells and primary PBMCs from CF patients and matched controls. Additionally, 151 clinical isolates of Pseudomonas aeruginosa from CF patients were assessed for motility and capacity to activate TLR5. Blood and airway cells from CF patients produced significantly more proinflammatory cytokine than did control cells following exposure to the CF pathogens P. aeruginosa and Burkholderia cepacia complex (p < 0.001). Stimulation with pure TLR ligands demonstrated that TLR signaling appears to mediate the excessive cytokine production occurring in CF. Using complementary approaches involving both neutralizing Ab targeting TLR5 and flagellin-deficient bacteria, we established that inhibition of TLR5 abolished the damaging inflammatory response generated by CF airway cells following exposure to P. aeruginosa (p < 0.01). The potential therapeutic value of TLR5 inhibition was further supported by our demonstration that 75% of clinical isolates of P. aeruginosa retained TLR5 activating capacity during chronic CF lung infection. These studies identify the innate immune receptor TLR5 as a novel antiinflammatory target for reducing damaging lung inflammation in CF.