Risk factors predicting the need for intensive care unit admission within forty-eight hours of emergency department presentation: A case-control study.

BACKGROUND: Patients admitted from the emergency department to the wards, who progress to a critically unwell state, may require expeditious admission to the intensive care unit. It can be argued that earlier recognition of such patients, to facilitate prompt transfer to intensive care, could be linked to more favourable clinical outcomes. Nevertheless, this can be clinically challenging, and there are currently no established evidence-based methods for predicting the need for intensive care in the future. OBJECTIVES: We aimed to analyse the emergency department data to describe the characteristics of patients who required an intensive care admission within 48 h of presentation. Secondly, we planned to test the feasibility of using this data to identify the associated risk factors for developing a predictive model. METHODS: We designed a retrospective case-control study. Cases were patients admitted to intensive care within 48 h of their emergency department presentation. Controls were patients who did not need an intensive care admission. Groups were matched based on age, gender, admission calendar month, and diagnosis. To identify the associated variables, we used a conditional logistic regression model. RESULTS: Compared to controls, cases were more likely to be obese, and smokers and had a higher prevalence of cardiovascular (39 [35.1%] vs 20 [18%], p = 0.004) and respiratory diagnoses (45 [40.5%] vs 25 [22.5%], p = 0.004). They received more medical emergency team reviews (53 [47.8%] vs 24 [21.6%], p < 0.001), and more patients had an acute resuscitation plan (31 [27.9%] vs 15 [13.5%], p = 0.008). The predictive model showed that having acute resuscitation plans, cardiovascular and respiratory diagnoses, and receiving medical emergency team reviews were strongly associated with having an intensive care admission within 48 h of presentation. CONCLUSIONS: Our study used emergency department data to provide a detailed description of patients who had an intensive care unit admission within 48 h of their presentation. It demonstrated the feasibility of using such data to identify the associated risk factors to develop a predictive model.

IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses.

Polymorphisms in the gene encoding the transcription factor IRF5 that lead to higher mRNA expression are associated with many autoimmune diseases. Here we show that IRF5 expression in macrophages was reversibly induced by inflammatory stimuli and contributed to the plasticity of macrophage polarization. High expression of IRF5 was characteristic of M1 macrophages, in which it directly activated transcription of the genes encoding interleukin 12 subunit p40 (IL-12p40), IL-12p35 and IL-23p19 and repressed the gene encoding IL-10. Consequently, those macrophages set up the environment for a potent T helper type 1 (T(H)1)-T(H)17 response. Global gene expression analysis demonstrated that exogenous IRF5 upregulated or downregulated expression of established phenotypic markers of M1 or M2 macrophages, respectively. Our data suggest a critical role for IRF5 in M1 macrophage polarization and define a previously unknown function for IRF5 as a transcriptional repressor.

Financial toxicity experienced by rural Australian families with chronic kidney disease.

AIM: Chronic kidney disease (CKD) and its treatment places a financial burden on healthcare systems and households worldwide, yet little is known of its financial impact, on those who reside in rural settings. We aimed to quantify the financial impacts and out-of-pocket expenditure experienced by adult rural patients with CKD in Australia. METHODS: A web based structured survey was completed between November 2020 and January 2021. English speaking participants over 18 years of age, diagnosed with CKD stages 3-5, those receiving dialysis or with a kidney transplant, who lived in a rural location in Australia. RESULTS: In total 77 (69% completion rate) participated. The mean out of pocket expenses were 5056 AUD annually (excluding private health insurance costs), 78% of households experienced financial hardship with 54% classified as experiencing financial catastrophe (out-of-pocket expenditure greater than 10% of household income). Mean distances to access health services for all rural and remote classifications was greater than 50 kilometres for specialist nephrology services and greater than 300 kilometres for transplanting centres. Relocation for a period greater than 3 months to access care was experienced by 24% of participants. CONCLUSION: Rural households experience considerable financial hardship due to out-of-pocket costs in accessing treatment for CKD and other health-related care, raising concerns about equity in Australia, a high-income country with universal healthcare.

Interferon-ß production via Dectin-1-Syk-IRF5 signaling in dendritic cells is crucial for immunity to C. albicans.

Type I interferon (IFN) is crucial during infection through its antiviral properties and by coordinating the immunocompetent cells involved in antiviral or antibacterial immunity. Type I IFN (IFN-α and IFN-ß) is produced after virus or bacteria recognition by cytosolic receptors or membrane-bound TLR receptors following the activation of the transcription factors IRF3 or IRF7. IFN-ß production after fungal infection was recently reported, although the underlying mechanism remains controversial. Here we describe that IFN-ß production by dendritic cells (DCs) induced by Candida albicans is largely dependent on Dectin-1- and Dectin-2-mediated signaling. Dectin-1-induced IFN-ß production required the tyrosine kinase Syk and the transcription factor IRF5. Type I IFN receptor-deficient mice had a lower survival after C. albicans infection, paralleled by defective renal neutrophil infiltration. IFN-ß production by renal infiltrating leukocytes was severely reduced in C. albicans-infected mice with Syk-deficient DCs. These data indicate that Dectin-induced IFN-ß production by renal DCs is crucial for defense against C. albicans infection.

Sex differences in the likelihood of pre-emptive living donor kidney transplantation, and outcomes after kidney transplantation in children and adolescents.

BACKGROUND: Data on sex-based disparities in children with kidney failure and outcomes after kidney transplantation are relatively sparse. This study examined the association between sex differences and the odds of receiving a pre-emptive living donor kidney transplantation, and post-transplant outcomes in children and adolescents. METHODS: We studied all patients (aged <20 years) who commenced kidney replacement therapy (KRT) between 2002 and 2017 using data from the ANZDATA Registry. Factors associated with graft loss and acute rejection after transplantation were assessed using multivariable Cox regression model. Differences in the odds of receiving a pre-emptive live donor transplant between sexes were assessed using adjusted logistic regression. RESULTS: Of the 757 children transplanted during the study period, 497 (65.7%) received a live donor kidney (163, 21.5% pre-emptive). In total, 168 (22.2%) patients experienced graft loss and 213 (28.1%) patients experienced a first episode of acute rejection during the median follow-up period of 6.9 years (IQR 3.5-11.5 years). There were no differences in the rates of graft loss or acute rejection by sex. Compared with boys, the adjusted hazard ratios (aHR) (95% confidence interval) for graft loss and acute rejection in girls were 0.97 (0.71-1.33) and 1.09 (0.82-1.44), respectively. Among children who received living donor kidney transplants, there were no sex differences in the odds of receiving a pre-emptive transplant (adjusted odds ratio (aOR) 0.90 (95% CI 0.56-1.45)). CONCLUSIONS: No sex differences were observed in the odds of receiving a pre-emptive living donor kidney transplant or outcomes after kidney transplantation.

Cognitive and academic outcomes in children with chronic kidney disease.

BACKGROUND: Few data exist on the cognitive and academic functioning of children with chronic kidney disease (CKD) over the trajectory of their illness. We aimed to determine the association between CKD stages and cognitive and academic performance in children over time. METHODS: We included 53 participants (aged 6-18 years) with CKD stages 1-5 (n = 37), on dialysis (n = 3), or with functioning kidney transplant (n = 22) from three units in Australia from 2015 to 2019. Participants undertook a series of psychometric tests and were invited for repeated assessments annually. We used linear regression and linear mixed models to investigate the effect of CKD stage, adjusted for socioeconomic status. RESULTS: At baseline, full-scale intelligence quotient (FSIQ) (95%CI) of children on kidney replacement therapy (KRT) was in the low average range (87: 78, 96) and average (101: 95, 108) for children with CKD 1-5. Mean (95%CI) FSIQ, word reading, numerical operations, and spelling scores for children on KRT were 14.3 (- 25.3, - 3.3), 11 (- 18.5, - 3.6), 8.5 (- 17.6, 0.76), and 10 (- 18.6, - 1.3) points lower than children with CKD Stages 1-5. Spelling and numerical operations scores declined by 0.7 (- 1.4, - 0.1) and 1.0 (- 2.0, 0.2) units per year increase in age, regardless of CKD stage. CONCLUSIONS: Children treated with KRT have low average cognitive abilities and lower academic performance for numeracy and literacy compared to both children with CKD 1-5 and to the general population. However, the rate of decline in academic performance over time is similar for children across the full spectrum of CKD. A higher resolution version of the Graphical abstract is available as Supplementary information.

Association between socioeconomic status and academic performance in children and adolescents with chronic kidney disease.

BACKGROUND: Lower socioeconomic status (SES) is associated with lower academic achievement; however, this relationship is understudied in children with chronic kidney disease (CKD). This study examined the relationship between SES and academic performance in children and adolescents with CKD. METHODS: A total of 377 participants aged 6-18 years with CKD stages 1-5 (n = 199), on dialysis (n = 43) or with a kidney transplant (n = 135) were recruited. Five SES measures and a composite SES index were examined for associations with parent-rated average or above average academic performance in numeracy and literacy using multivariable logistic regression. RESULTS: Participants' median age was 12.6 years (IQR 8.9-15.5). Adjusted odds ratios (aOR) (95%CI) for better performance in numeracy and literacy, respectively, were 0.71 (0.44-1.15) and 0.75 (0.45-1.23) for children whose caregivers had lower educational attainment; 0.46 (0.26-0.80) and 0.53 (0.30-0.93) for lower household income; 0.52 (0.32-0.85) and 0.44 (0.26-0.73) for caregivers who were unemployed; 0.68 (0.41-1.12) and 0.59 (0.35-1.00) for caregivers with poor self-rated financial status; and 0.93 (0.53-1.64) and 1.00 (0.56-1.79) for caregivers who did not own their own home. Compared with the highest SES index quartile, the aORs for better performance by SES quartile in descending order were 1.24 (0.60-2.54), 0.76 (0.37-1.58), and 0.39 (0.18-0.86) for numeracy and 0.88 (0.41-1.85), 0.77 (0.35-1.66), and 0.32 (0.14-0.72) for literacy. No interactions were identified between SES and CKD stage, child age, or gender. CONCLUSIONS: Across all CKD stages, children from lower SES families are less likely to perform well in literacy and numeracy than those from higher SES households. A higher resolution version of the Graphical abstract is available as Supplementary information.

A practical guide to multiple imputation of missing data in nephrology.

Health data are often plagued with missing values that can greatly reduce the sample size if only complete cases are considered for analysis. Furthermore, analyses that ignore missing data have the potential to introduce bias in the parameter estimates. Multiple imputation techniques have been developed to recover the information that would otherwise be lost when excluding observations with missing data and to help minimize bias. However, the validity of analyses using imputed data relies on the imputation model having been correctly specified. The aim of this guide is to aid the reader in the decision-making process when conducting an analysis with multiply imputed data in the context of nephrology research. We discuss (i) missing mechanism assumption, (ii) imputation method, (iii) imputation model, (iv) derived variables, (v) the number of imputed data sets, (vi) diagnostic checks, (vii) analysis and pooling of results, and (viii) reporting the results. This process is demonstrated using data from the National Health and Nutrition Examination Survey to explore the association between hypertension and kidney disease in adults from the general population. Example code is provided for SAS software and the mice package in R.

Conspicuous animal signals avoid the cost of predation by being intermittent or novel: confirmation in the wild using hundreds of robotic prey.

Social animals are expected to face a trade-off between producing a signal that is detectible by mates and rivals, but not obvious to predators. This trade-off is fundamental for understanding the design of many animal signals, and is often the lens through which the evolution of alternative communication strategies is viewed. We have a reasonable working knowledge of how conspecifics detect signals under different conditions, but how predators exploit conspicuous communication of prey is complex and hard to predict. We quantified predation on 1566 robotic lizard prey that performed a conspicuous visual display, possessed a conspicuous ornament or remained cryptic. Attacks by free-ranging predators were consistent across two contrasting ecosystems and showed robotic prey that performed a conspicuous display were equally likely to be attacked as those that remained cryptic. Furthermore, predators avoided attacking robotic prey with a fixed, highly visible ornament that was novel at both locations. These data show that it is prey familiarity-not conspicuousness-that determine predation risk. These findings replicated across different predator-prey communities not only reveal how conspicuous signals might evolve in high predation environments, but could help resolve the paradox of aposematism and why some exotic species avoid predation when invading new areas.

The emergence and characteristics of the Australian Mamil.

BACKGROUND: The Mamil (middle-aged man in Lycra) appears to be an emergent cycling-focused species. OBJECTIVES: To explore the nature and distribution of the Mamilian species; to determine whether rates of cycling by middle-aged men in Australia have changed since the pre-Mamilian era. SETTING: Secondary analysis of representative population-based datasets. National sport participation data from the Exercise, Recreation and Sport (2002-2004, 2008-2010) and Ausplay surveys (2016) were analysed to assess trends in recreational and exercise-related cycling, including by middle-aged men (45-64 years of age). Data from New South Wales Population Health Surveys (2006, 2010, 2014) and Australian censuses (2006, 2011, 2014) were analysed to assess trends in cycling to work. MAIN OUTCOME MEASURES: Cycling participation rates (at least once or at least once a week in the past 12 months); rates of cycling to work. RESULTS: The proportion of middle-aged men who cycled for exercise or recreational purposes at least once a week during the previous year increased from 6.2% (95% CI, 5.5-7.0%) during 2002-2004 to 13.2% (95% CI, 11.9-14.6%) in 2016. The prevalence of Mamils in the most affluent residential areas has more than doubled since 2002-2004, and is twice as high as in the least advantaged locations. Media reports of "Mamils" corroborate these temporal trends. DISCUSSION: Mamils in Australia are socially graded, and also grade themselves according to bicycle-related expenditure and hill gradients overcome. They often form cohesive and supportive groups, but may not reflect a population-wide social movement to increase physical activity among adult Australians.

IRF5 controls both acute and chronic inflammation.

Whereas the importance of macrophages in chronic inflammatory diseases is well recognized, there is an increasing awareness that neutrophils may also play an important role. In addition to the well-documented heterogeneity of macrophage phenotypes and functions, neutrophils also show remarkable phenotypic diversity among tissues. Understanding the molecular pathways that control this heterogeneity should provide abundant scope for the generation of more specific and effective therapeutics. We have shown that the transcription factor IFN regulatory factor 5 (IRF5) polarizes macrophages toward an inflammatory phenotype. IRF5 is also expressed in other myeloid cells, including neutrophils, where it was linked to neutrophil function. In this study we explored the role of IRF5 in models of acute inflammation, including antigen-induced inflammatory arthritis and lung injury, both involving an extensive influx of neutrophils. Mice lacking IRF5 accumulate far fewer neutrophils at the site of inflammation due to the reduced levels of chemokines important for neutrophil recruitment, such as the chemokine (C-X-C motif) ligand 1. Furthermore we found that neutrophils express little IRF5 in the joints and that their migratory properties are not affected by the IRF5 deficiency. These studies extend prior ones suggesting that inhibiting IRF5 might be useful for chronic macrophage-induced inflammation and suggest that IRF5 blockade would ameliorate more acute forms of inflammation, including lung injury.

Cross-species analysis reveals evolving and conserved features of the nuclear factor κB (NF-κB) proteins.

NF-κB is a key regulator of immune gene expression in metazoans. It is currently unclear what changes occurred in NF-κB during animal evolution and what features remained conserved. To address this question, we compared the biochemical and functional properties of NF-κB proteins derived from human and the starlet sea anemone (Nematostella vectensis) in 1) a high-throughput assay of in vitro preferences for DNA sequences, 2) ChIP analysis of in vivo recruitment to the promoters of target genes, 3) a LUMIER-assisted examination of interactions with cofactors, and 4) a transactivation assay. We observed a remarkable evolutionary conservation of the DNA binding preferences of the animal NF-κB orthologs. We also show that NF-κB dimerization properties, nuclear localization signals, and binding to cytosolic IκBs are conserved. Surprisingly, the Bcl3-type nuclear IκB proteins functionally pair up only with NF-κB derived from their own species. The basis of the differential NF-κB recognition by IκB subfamilies is discussed.

IL-17 receptor adaptor protein Act1/CIKS plays an evolutionarily conserved role in antiviral signaling.

Double-stranded RNA-induced antiviral gene expression in mammalian cells requires activation of IFN regulatory factor 3 (IRF3). In this study, we show that the IL-17R adaptor protein Act1/CIKS is involved in this process. Small interfering RNA-mediated knockdown of Act1 in primary human skin fibroblasts specifically attenuates expression of IFN-ß and IFN-stimulated antiviral genes induced by a synthetic viral mimic, polyinosinic-polycytidylic acid. Ectopic expression of Act1 potentiates the IRF3-driven expression of a synthetic reporter construct as well as the induction of antiviral genes. We demonstrate that this effect is dependent on the ability of Act1 to functionally and physically interact with IκB kinase ε (IKKε), a known IRF3 kinase, and IRF3: 1) Act1 binds IKKε and IRF3; 2) Act1-induced IRF3 activation can be blocked specifically by coexpression of a catalytically inactive mutant of IKKε; and 3) mutants of IRF3, either lacking the C terminus or mutated at the key phosphorylation sites, important for its activation by IKKε, do not support Act1-dependent IRF3 activation. We also show that a zebrafish Act1 protein is able to trigger antiviral gene expression in human cells, which suggests an evolutionarily conserved function of vertebrate Act1 in the host defense against viruses. On the whole, our study demonstrates that Act1 is a component of antiviral signaling.

Pneumococcal vaccination and primary care presentations for acute respiratory tract infection and antibiotic prescribing in older adults.

BACKGROUND: While the 23-valent pneumococcal polysaccharide vaccine (PPV23) has demonstrated its role in preventing severe pneumococcal disease, its impact on more non-specific conditions like acute respiratory tract infection (ARI) and lower respiratory tract infections (LRTI) remains unclear. We aimed to investigate the role of PPV23 in prevention of presentations for ARI and LRTI and related antibiotic prescriptions among older adults in primary care. METHODS: Using a nationwide general practice dataset, we followed a cohort of regularly attending patients aged ≥65 years from 1 January 2014 until 31 December 2018 for presentations for ARI, LRTI, and related antibiotic prescriptions. Associations between PPV23 receipt and each outcome were assessed using a multiple failures survival model to estimate hazard ratios (HR) adjusted for age, sex, socioeconomic status, and various health measures. RESULTS: A cohort of 75,264 patients aged ≥65 years (mean 75.4, 56% female) in 2014 was followed. The incidence of presentations for ARI, ARI-related antibiotic prescription, LRTI, and LRTI-related antibiotic prescription was 157.6, 76.0, 49.6, and 24.3 per 1000 person-years, respectively. Recent PPV23 vaccine receipt was associated with a small reduction in ARI presentations (adjusted HR vaccinated vs. unvaccinated 0.96; 95%CI 0.94-0.98; p = 0.002); however, there was no reduction in ARI-related antibiotic prescription, LRTI presentation, nor LRTI-related antibiotic prescription (adjusted HR were 0.99[95%CI 0.96-1.03], 1.04[95%CI 0.99-1.09], 1.07[95%CI 1.00-1.14]). CONCLUSION: PPV23 vaccination in older adults may result in a small reduction in the incidence of total ARI presentations in primary care. However, the effect is small and residual confounding cannot be excluded.

Attitudes and behaviors of maternal Tdap vaccination in Panama, Peru, and Colombia: An international cross-sectional study.

INTRODUCTION: Despite a recommendation by PAHO for Tdap vaccination in pregnant women since 2019, uptake remains suboptimal across Latin America. This study evaluated the knowledge and attitudes of women towards maternal Tdap vaccination in Colombia, Peru, and Panama to identify the critical behavioral and social drivers of Tdap vaccine uptake during pregnancy. METHODS: A cross-sectional online survey was undertaken between December 8, 2022, and January 11, 2023, targeting women in Colombia, Peru, or Panama with a child 12 months or under. We collected data on respondents' demographics, social and behavioral determinants of vaccine acceptance, determinants of vaccine uptake (using the validated 5As taxonomy), and previous vaccination experience. RESULTS: In the 938 respondents who completed the survey (Panama, n = 325; Peru, n = 305; Colombia, n = 308), 73-80 % had received the influenza vaccine, whereas only 30-39 % had received a Tdap vaccine. Significant correlates of Tdap vaccine uptake common to all three countries included a health professional recommendation, knowledge of the vaccine and location of vaccination, perceived vulnerability to pertussis infection, perceived importance of immunization, and receipt of a reminder. In specific countries, nonvaccinated women were more likely to cite issues with ease of access (Panama, Colombia), affordability (opportunity costs; Peru, Colombia), and understanding the rationale for vaccination in pregnancy (Panama, Colombia). CONCLUSION: To increase maternal Tdap vaccine uptake, health professionals should be encouraged to recommend vaccination consistently, and pregnant women should receive reminders explaining why and where to be vaccinated.

Examining the influence of community leaders and other community actors on immunisation practices in Australia: A national cross-sectional study.

BACKGROUND: Variation in COVID-19 vaccination coverage and increasing vaccine hesitancy are well documented, especially amongst ethnic minority populations and current channels of vaccine and communication have been found to be inadequate. It has been suggested that more be done to utilise community-led pathways to improve vaccine readiness in ethnic minority communities in Australia. The study aimed to explore receptiveness towards the role of different actors and methods of communication about immunisation. METHODS: A cross-sectional survey of 1,227 adults in Australia was conducted to examine the roles of various actors in promoting vaccine uptake. Chi-square analyses and independent samples t-tests were used to identify significant associations between sociodemographic characteristics, vaccine practices, and vaccine information-seeking behaviours and (1) COVID-19 vaccine uptake (at least one dose) and (2) speaking a language other than English. RESULTS: At the time of the survey, 93% of respondents had received at least one dose of the COVID-19 vaccine. There were significant associations between COVID-19 vaccine uptake and: perceived capacity to locate accurate and timely vaccine information; receiving the COVID-19 vaccination information from a Nurse or Pharmacist; and receiving a vaccine recommendation by a GP. Additionally, respondents who spoke a language other than English reported were significantly more likely to have received information from family, friends, workplaces, local councils, religious centres, community leaders, and religious leaders than those who only spoke English. CONCLUSION: Significant variations in vaccine practices and vaccine information-seeking behaviours were found, especially in those who speak a language other than English. To enhance vaccine uptake and to address vaccine hesitancy in Australia, vaccine promotion strategies and health communication efforts require significant consideration of information accessibility and communication source preferences.

FOXO3 as a new IKK-ε-controlled check-point of regulation of IFN-ß expression.

Cell survival transcription factor FOXO3 has been recently implicated in moderating pro-inflammatory cytokine production by dendritic cells (DCs), but the molecular mechanisms are unclear. It was suggested that FOXO3 could antagonize NF-κB activity, while IKK-ß was demonstrated to inactivate FOXO3, suggesting a cross-talk between the two pathways. Therefore, FOXO3 activity must be tightly regulated to allow for an appropriate inflammatory response. Here, we show that in human monocyte-derived DCs (MDDCs), FOXO3 is able to antagonize signaling intermediates downstream of the Toll-like receptor (TLR) 4, such as NF-κB and interferon regulatory factors (IRFs), resulting in inhibition of interferon (IFN)-ß expression. We also demonstrate that the activity of FOXO3 itself is regulated by IKK-ε, a kinase involved in IFN-ß production, which phosphorylates and inactivates FOXO3 in response to TLR4 agonists. Thus, we identify FOXO3 as a new IKK-ε-controlled check-point of IRF activation and regulation of IFN-ß expression, providing new insight into the role of FOXO3 in immune response control.

IL-17 boosts proinflammatory outcome of antiviral response in human cells.

Excessive inflammation during bacterial and viral infections is destructive to the host and involves elevated production of proinflammatory cytokines. It is especially deleterious in organs with space constraints such as lung and the CNS. Indeed, a number of viruses that infect lungs, such as avian influenza virus, SARS-associated coronavirus, and respiratory syncytial virus, elicit a very high level of proinflammatory cytokines; however, it is unclear what triggers their production. In this study, we show that IL-17 commonly produced during viral infection specifically augments a proinflammatory response by directly synergizing with antiviral signaling. Costimulation of primary human fibroblasts with IL-17 greatly enhanced respiratory syncytial virus-induced or synthetic dsRNA-based viral mimic polyinosinic:polycytidylic acid-induced expression of proinflammatory genes without affecting expression of IFN-ß-stimulated or IFN-stimulated genes. Knockdown of expression of known mediators of the antiviral signaling pathway revealed that the IL-17-poly(I:C) synergy depends on the presence of the transcriptional factors RelA and IFN regulatory factor 3 and IκB kinases. Moreover, this synergy was blocked by an IκB kinase inhibitor, BAY 11-7082. These findings shed light on the molecular mechanisms behind IL-17-dependent immunopathology observed in viral infections.

IRF5 is a specific marker of inflammatory macrophages in vivo.

Macrophages are an integral part of the innate immune system and key players in pathogen clearance and tissue remodelling. Both functions are accomplished by a pivotal network of different macrophage subtypes, including proinflammatory M1 and anti-inflammatory M2 macrophages. Previously, our laboratory identified the transcription factor interferon regulatory factor 5 (IRF5) as the master regulator of the M1 macrophage polarisation. IRF5 was found to be highly expressed in human M1 compared to M2 macrophages. Furthermore, IRF5 dictates the expression of proinflammatory genes such as IL12b and IL23a whilst repressing anti-inflammatory genes like IL10. Here we show that murine bone marrow derived macrophages differentiated in vitro with GM-CSF are also characterised by high levels of IRF5 mRNA and protein and express proinflammatory cytokines upon LPS stimulation. These macrophages display characteristic expression of M1-marker MHC II but lack the M2-marker CD206. Significantly, we develop intracellular staining of IRF5- expressing macrophages and utilise it to recapitulate the in vitro results in an in vivo model of antigen-induced arthritis, emphasising their physiological relevance. Thus, we establish the species-invariant role of IRF5 in controlling the inflammatory macrophage phenotype both in vitro and in in vivo.

Body composition and body mass index measures from 8 to 18 years old in children with cystic fibrosis.

BACKGROUND: Historically, body mass index (BMI) >50th percentile has represented optimal nutritional status in children with cystic fibrosis (CF) due to its positive association with lung function. Body composition parameters including fat-free mass index (FFMI) have been suggested as a more physiological nutrition benchmark. AIMS: (1) describe changes in body composition with age and gender; (2) assess the correlation between measures of nutritional status (FFMI-z, FMI-z, BMI-z) and lung function (forced expiratory volume in one second predicted; FEV1pp). METHODS: This retrospective, mixed cross-sectional and serial measures study consisted of children with CF (8 to 18 years) attending Sydney Children's Hospital (2007-2020). FFMI and fat mass index (FMI) were taken from biennial dual energy x-ray absorptiometry (DXA) scans. Z-scores were derived using Well's reference population [1]. Repeated measures correlation analyses assessed correlations between FFMI-z, FMI-z, and BMI-z with FEV1pp. RESULTS: 339 DXA reports were analysed from 137 patients. There were slight downwards trends in BMI-z and FMI-z, and an upwards trend in FFMI-z with increasing age and across both genders. Females had higher FMI-z and FFMI-z than males from 12.5 years. There was a weak, positive correlation between FEV1pp and BMI-z (r = 0.14, p = 0.04), and FFMI-z (r = 0.25, p<0.001). FMI-z had no correlation with FEV1pp (r=-0.06, p = 0.41). CONCLUSION: Deficits in FFMI exist despite increasing trends with age. FFMI-z and BMI-z had a weak, positive correlation with FEV1pp. In contemporary cohorts, nutritional status (reflected by surrogate markers such as FFMI and BMI) may be less influential upon lung function than in previous decades. [1]: Wells, J.C., et al. Body-composition reference data for simple and reference techniques and a 4-component model: a new UK reference child. Am. J. Clin. Nutr.96, 1316-1326 (2012).