Proinflammatory polarization strongly reduces human macrophage in vitro phagocytosis of tumor cells in response to CD47 blockade.

Antibody-based CD47 blockade aims to activate macrophage phagocytosis of tumor cells. However, macrophages possess a high degree of phenotype heterogeneity that likely influences phagocytic capacity. In murine models, proinflammatory (M1) activation increases macrophage phagocytosis of tumor cells, but in human models, results have been conflicting. Here, we investigated the effects of proinflammatory polarization on the phagocytic response of human monocyte-derived macrophages in an in vitro model. Using both flow cytometry-based and fluorescence live-cell imaging-based phagocytosis assays, we observed that mouse monoclonal anti-CD47 antibody (B6H12) induced monocyte-derived macrophage phagocytosis of cancer cells in vitro. Proinflammatory (M1) macrophage polarization with IFN-γ+LPS resulted in a severe reduction in phagocytic response to CD47 blockade. This reduction coincided with increased expression of the antiphagocytic membrane proteins LILRB1 and Siglec-10 but was not rescued by combination blockade of the corresponding ligands. However, matrix metalloproteinase inhibitors (TAPI-0 or GM6001) partly restored response to CD47 blockade in a dose-dependent manner. In summary, these data suggest that proinflammatory (M1) activation reduces phagocytic response to CD47 blockade in human monocyte-derived macrophages.

The effect of the 'Swim Reaper' program on water safety awareness, drowning mortality and morbidity among males aged 15-34 years in Aotearoa, New Zealand.

BACKGROUND AND OBJECTIVE: To increase water safety awareness among young males New Zealand introduced the Swim Reaper program in 2016. The program ran annually over summer and in 2018/19 an evaluation was conducted. The objective of this study was to evaluate the impact of the 2018/19 Swim Reaper social media-based campaign on self-reported water safety awareness and identify changes in fatal and nonfatal drowning rates for New Zealand resident males aged 15-34 years before and after the 2016 Swim Reaper program. METHODS: Online surveys pre (December-2018) and post (February-March-2019) Swim Reaper campaign were used to estimate water safety awareness post-campaign relative to pre-campaign using negative binomial regression adjusted for potential confounders. Interrupted time series (ITS) analysis, adjusted for seasonality, explored changes in drowning mortality, hospital admissions and Accident Compensation Corporation (ACC) claims pre and post program introduction (2016). RESULTS: A total of 518 males responded (50.6% post-campaign). There were significant improvements (post vs. pre-campaign) in self-reported water safety awareness. ITS analysis showed a reduction in drowning related hospital admissions post relative to pre-program (RR = 0.47; [95%CI: 0.24-0.90]; p = 0.02). DISCUSSION: Young males are an at-risk cohort for drowning and creating behavior change among this group can be challenging. Using a unique, humor-based approach the Swim Reaper program appears to be having some impact on self-reported water safety behaviors, as well as unintentional drowning-related hospitalization rates. Further evaluation, more clearly linked to campaign themes, is required to ascertain direct impact of the program. CONCLUSION: The novelty and reach of the campaign within the context of a prevailing downward trend in drownings may provide support for social media-based programs targeting this hard-to-reach demographic.

Young drivers' early access to their own car and crash risk into early adulthood: Findings from the DRIVE study.

INTRODUCTION: Car ownership at early licensure for young drivers has been identified as a crash risk factor, but for how long this risk persists is unknown. This study examined crash hazard rates between young drivers with their own vehicle and those who shared a family vehicle at early licensure over 13 years. METHODS: The DRIVE study, a 2003/04 survey of 20,806 young novice drivers in New South Wales, Australia was used to link to police crash, hospital and death records up to 2016. The first police-reported crash and crash resulting in hospitalisation/death was modelled via flexible parametric survival analysis by type of vehicle access at baseline (own vs. shared family vehicle). RESULTS: After adjusting for covariates, drivers with their own vehicle at early licensure had an almost 30 % increased hazard rate for any crash after one year (95 % CI:1.16-1.42) compared with those who only had access to a family car and this attenuated but remained significantly higher until year 7 (HR: 1.1, 95 % CI: >1.00-1.20). For crashes resulting in hospitalisation or death, an almost 15-times higher hazard (95 % CI: 1.40-158.17) was observed at the start of follow up, remaining 50 % to year 3 (95 % CI:1.01-2.18). CONCLUSIONS: Parents and young drivers should be aware of the increased risks involved in car ownership at early licensure. Development of poorer driving habits has been associated with less parental monitoring at this time. Graduated Driving Licensing educators, researchers and stakeholders should seek to address this and to identify improved safety management options.

Interpersonal Violence and Gender Inequality in Adolescents: A Systematic Analysis of Global Burden of Disease Data From 1990 to 2019.

PURPOSE: Interpersonal violence is a leading cause of adolescent deaths and disability. This study investigates sex differences in burden of interpersonal violence for adolescents and explores associations with gender inequality. METHOD: Using data from the 2019 Global Burden of Disease study, we report numbers, proportions, rates of interpersonal violence deaths and disability adjusted life years (DALYs) for all ages, and rate of change (from 1990 to 2019) in adolescents aged 10-24 years disaggregated by sex and geography. We explored associations with gender inequality using gender inequality index. RESULTS: One in four (24.8%) all-age interpersonal violence deaths are in adolescents. In 2019, the rate of deaths in adolescent males was almost six times higher than females (9.3 vs. 1.6 per 100,000); and since 1990, the rate of decline in DALYs for females was double than that for males (-28.9% vs. -12.7%). By contrast, the burden of sexual violence is disproportionately borne by adolescent females, with over double the rate than males (DALYs: 42.8 vs. 17.5 per 100,000). In countries with greater gender inequality, the male-to-female ratio (deaths and DALYs) was increased among older adolescents, pointing to benefits for males in more gender equal settings. DISCUSSION: Social identities, relationships, and attitudes to violence are established in adolescence, which is an inflection point marking the emergence of disproportionate burdens of interpersonal violence. Our findings affirm that global agendas must be expanded to address interrelated factors driving multiple forms of interpersonal violence experienced by adolescents and reverberating to the next generation.

Role of high­sensitivity C­reactive protein in patients with sarcoma.

Immunotherapy has shown promising results in lung cancer and melanomas; however, the responses have been poor in patients with sarcoma. Understanding the relationship between the immune system and sarcoma is essential to develop improved immunotherapy approaches. High-sensitivity C-reactive protein (hs-CRP) has been proposed as a prognostic marker in other cancer types; however, to the best of our knowledge, the association between hs-CRP levels and mortality in patients with sarcoma has not been investigated. The present prospective, non-randomised, non-interventional explorative study investigated the prognostic value of hs-CRP in patients with sarcoma. Patients referred to the sarcoma centre of Aarhus University Hospital (Aarhus, Denmark) were included between April 2014 and December 2020. Clinical data were obtained from the national quality sarcoma database and biomarkers other than hs-CRP were obtained from the clinical laboratory information system. The study cohort consisted primarily of patients with localised sarcoma. hs-CRP was significantly higher in patients with bone sarcoma (P=0.022) and soft tissue sarcoma (STS; P<0.001) compared with control patients. For STS, grade III tumours but not metastatic disease were associated with a higher hs-CRP level (P=0.0001). Elevated hs-CRP levels were associated with increased overall mortality [hazard ratio (HR), 1.91; 95% CI, 1.33-2.75; P=0.001]. Furthermore, elevated hs-CRP levels were also associated with decreased progression-free survival (HR, 1.64; 95% CI, 1.17-2.29; P=0.004). Furthermore, for patients with hs-CRP <8 mg/l, higher hs-CRP was associated with an increased risk of recurrent disease and reduced overall survival compared with those of patients with low hs-CRP. In conclusion, the present study demonstrated that hs-CRP was a prognostic factor for overall mortality and progression-free survival in patients with localised sarcoma at the time of diagnosis. Further studies are required to investigate the mechanism behind the association between hs-CRP and sarcoma prognosis and its potential use in clinical practice.

Navigating child product safety: Perspectives from experts on international challenges and priorities in regulation and research.

OBJECTIVE: To elicit and summarise collective expert opinion on contemporary child product safety risks, challenges and priorities. METHODS: An online survey targeted international experts from a cross-section of product safety fields. RESULTS: Fifty-five experts participated, representing 1,137 years of product safety experience, from a broad range of fields including industry risk management, product assessment and testing, policy and regulation, research, paediatric medicine, advocacy and product liability. Participants identified the leading product safety hazards across all age brackets as falls, drowning and chemical hazards, with variance in specific age brackets, particularly the threat to breathing hazards for infants. The leading products of concern to experts were electrical connection/distribution products, primarily button batteries and lithium-ion batteries, infant furnishing products and household furniture. Product safety priorities and challenges were identified under five themes: regulatory, surveillance, industry, consumer and product-specific. CONCLUSIONS: The gains in knowledge, insight and understanding from experts on contemporary child product safety risks and issues should inform policy and future research. IMPLICATIONS FOR PUBLIC HEALTH: There are significant consequences of unsafe consumer products on population health, and the results are timely as we face new product safety issues emerging from e-commerce, the digital transition and innovative product technologies.

Physical Activity and Depression and Anxiety Disorders: A Systematic Review of Reviews and Assessment of Causality.

Introduction: Globally, depressive and anxiety disorders are the leading contributors to mental ill health. Physical activity reduces symptoms of depression and anxiety and has been proposed as an adjunct treatment therapy for depression and anxiety. Prospective studies suggest that physical activity may reduce the incidence of depression and anxiety. We conducted a systematic review of reviews with the aim to provide a comprehensive overview of available epidemiologic evidence on the strength of the association between physical activity and incident cases of depression and anxiety and to assess the likelihood of these associations being causal. Methods: We searched Embase and PubMed databases for systematic reviews published between January 1, 2000 and March 19, 2020 that reported findings on the strength of association between physical activity and incidence of depression and anxiety. We updated this search to October 15, 2022. Two reviewers independently assessed the methodologic quality of the included reviews using the Assessment of Multiple Systematic Reviews rating scale. We carried out a narrative synthesis of the evidence. We used the Bradford Hill criteria to assess the likelihood of associations being causal. Results: The initial search yielded 770 articles, of which 4 remained for data extraction. Two of the included reviews were scored as high quality, and 2 were scored as low quality. From the 2 included reviews that reported pooled estimates, people with high physical activity levels were found to have a decreased risk of incident depression (adjusted RR=0.83, 95% CI=0.76, 0.90) and reduced odds of developing anxiety (adjusted OR=0.74,95% CI=0.62, 0.88) when compared with those with low physical activity levels. We assessed physical activity to be probably causally related to both depression and anxiety. Discussion: Our evidence is drawn from systematic reviews of observational data. Further high-quality studies, such as randomized control trials, would help to strengthen the evidence base of the associations between physical activity and depression and anxiety. Nonetheless, our findings provide empirical support for the consideration of physical activity in strategies for the prevention of mental ill health.

Physical Activity and Depression and Anxiety Disorders in Australia: A Lifetable Analysis.

Introduction: Mental disorders, in particular, depressive and anxiety disorders, are a leading cause of disability in Australia and globally. Physical activity may reduce the incidence of anxiety and depression, and this supports the inclusion of physical activity in strategies for the prevention of mental ill health. Policy makers need to know the potential impact and cost savings of such strategies. We aimed to quantify the impact of changes in physical activity on the burden of anxiety and depression and healthcare costs in Australia. Methods: We used a proportional multistate lifetable model to estimate the impact of changes in physical activity levels on anxiety and depression burdens for the 2019 Australian population (numbering 24.6 million) over their remaining lifetime. The changes in physical activity were modeled through 3 counterfactual scenarios informed by policy targets: attainment of the Australian Physical Activity Guidelines and achievement of the WHO Global Action Plan on Physical Activity targets of a 10% relative reduction in the prevalence of insufficient physical activity by 2025 and a 15% relative reduction by 2030. Results: If all Australians adhered to the recommended minimum physical activity levels, in 25 years' time, the burden of anxiety could be reduced by up to 6.4% (95% uncertainty intervals=2.5, 10.6), and that of depression could be reduced by 4.4% (95% uncertainty intervals=2.3, 6.5). Over the lifetime of the 2019 Australian population, the gains could add up to 640,592 health-adjusted life years for anxiety (26 health-adjusted life years per 1,000 persons), 523,717 health-adjusted life years for depression (21 health-adjusted life years per 1,000 persons), and healthcare cost savings of 5.4 billion Australian dollars for anxiety (220 Australian dollars per capita) and 5.8 billion for depression (237 Australian dollars per capita). Conclusions: Adherence to the Australian physical activity guidelines and achievement of the 2025 and 2030 global physical activity targets could lead to a substantial reduction of the burden of anxiety and depression. This study provides empirical support for the inclusion of physical activity in strategies for the prevention of mental ill health. Future studies should also assess the size and distribution of the benefits for different socioeconomic and ethnic groups.

Intervention targets for reducing mortality between mid-adolescence and mid-adulthood: a protocol for a machine-learning facilitated systematic umbrella review.

INTRODUCTION: A rise in premature mortality-defined here as death during the most productive years of life, between adolescence and middle adulthood (15-60 years)-is contributing to stalling life expectancy in high-income countries. Causes of mortality vary, but often include substance misuse, suicide, unintentional injury and non-communicable disease. The development of evidence-informed policy frameworks to guide new approaches to prevention require knowledge of early targets for intervention, and interactions between higher level drivers. Here, we aim to: (1) identify systematic reviews with or without meta-analyses focused on intervention targets for premature mortality (in which intervention targets are causes of mortality that can, at least hypothetically, be modified to reduce risk); (2) evaluate the review quality and risk of bias; (3) compare and evaluate each review's, and their relevant primary studies, findings to identify existing evidence gaps. METHODS AND ANALYSIS: In May 2023, we searched electronic databases (MEDLINE, PubMed, Embase, Cochrane Library) for peer-reviewed papers published in the English language in the 12 years from 2012 to 2023 that examined intervention targets for mortality. Screening will narrow these papers to focus on systematic reviews with or without meta-analyses, and their primary papers. Our outcome is death between ages 15 and 60 years; with potential intervention targets measured prior to death. A MeaSurement Tool to Assess systematic Reviews (AMSTAR 2) will be used to assess quality and risk of bias within included systematic reviews. Results will be synthesised narratively due to anticipated heterogeneity between reviews and between primary studies contained within included reviews. ETHICS AND DISSEMINATION: This review will synthesise findings from published systematic reviews and meta-analyses, and their primary reviewed studies, meaning ethics committee approval is not required. Our findings will inform cross-cohort consortium development, be published in a peer-reviewed journal, and be presented at national and international conferences. PROSPERO REGISTRATION NUMBER: CRD42022355861.

Learning With a Supervisor Who has Traffic Offences and Young Driver Crashes: The DRIVE Study 13-Year Follow-Up.

PURPOSE: Young learner drivers commonly must record substantial supervised practice driving before independent licensure. Supervisory driver requirements can be limited or highly regulated, yet research is lacking on the effectiveness of different approaches. The current objective was to explore whether young drivers who were mostly supervised by someone who they perceived had traffic offences versus no offences had different crash records over a period of 13 years postlicensing. METHODS: DRIVE is an Australian prospective cohort study of more than 20,000 drivers who were aged 17-24 years and newly licensed during 2003-2004. They completed detailed baseline questionnaires, including whether the person they identified as supervising their learner driving the most had perceived traffic offences in the past 12 months. Responses were linked to their state crash, hospitalization, and death records to 2016. A parametric survival model was created to calculate hazard ratios of time to crash for those reporting that their supervisor had 0 versus 1 and 0 versus 2+ perceived offences, adjusting for the participants' prior crash history and other covariates. RESULTS: After adjusting for covariates, 369 participants reporting supervisory drivers with 2+ perceived offences, compared to 15,451 participants reporting no such offences, had up to 1.67 (95% confidence interval 1.10-2.53 at 6 months) times the rate of any crash for the first 2.5 years and up to 2.01 (95% confidence interval 1.26-3.19 at 3.5 years) times the rate of crashes resulting in injury for 5.5 years. DISCUSSION: Although overall supervision by a driver with two or more perceived offences was low, further attention is needed to ensure improved supervised driving experiences, with mentoring programs and professional instructor partnerships worthy of exploration.

Monocyte phenotype and extracellular vesicles in HIV-1, HIV-2, and HIV-1/2 dual infection.

OBJECTIVE: AIDS-defining illness develops at higher CD4 + T-cell counts in individuals infected with HIV-2 compared with HIV-1-infected, which suggests that the two types of HIV may have different effects on other compartments of the immune system. We here investigate monocyte phenotype, activation and macrophage-derived extracellular vesicles in individuals with different HIV types. DESIGN: Cross-sectional. METHODS: ART-naive HIV-1 ( n  = 83), HIV-2 ( n  = 63), and HIV-1/2 dually positive ( n  = 27) participants were recruited in Bissau, Guinea-Bissau, together with HIV-negative controls ( n  = 26). Peripheral blood mononuclear cells (PBMCs) were isolated and analyzed by flow cytometry for monocyte phenotype and activation, and plasma was analyzed for extracellular vesicle forms of CD163 and CD206. RESULTS: Compared with HIV-negative controls, all groups of HIV-positive participants had a skewed monocyte phenotype with a higher proportion of intermediate monocytes, increased CD163 expression and elevated serum levels of the inflammatory biomarkers soluble (s)CD163 and sCD206. HIV-2-positive participants had lower CD163 monocyte expression than HIV-1-positive participants, regardless of HIV RNA or CD4 + cell count. Levels of sCD206 extracellular vesicles were increased in all HIV groups, and higher in HIV-1 compared with HIV-2-positive participants. CONCLUSION: The monocyte phenotype of HIV-2-positive participants deviated less from healthy controls than did HIV-1 participants. HIV-2-positive participants also had a lower concentration of extracellular CD206 vesicles compared with HIV-1-positive participants. This does not explain the difference in AIDS development.

Comparison of culture media reveals that non-essential amino acids strongly affect the phenotype of human monocyte-derived macrophages.

Macrophages are important innate immune cells with the ability to adapt their phenotype to environmental cues. Research on human macrophages often uses monocyte-derived macrophages cultured in vitro, but it is unclear if culture medium affects macrophage phenotype. The objective of this study was to determine the impact of culture medium composition on monocyte-derived macrophage phenotype. Monocyte-derived macrophages were generated in different formulations of culture media (RPMI 1640, DMEM, MEM, McCoy's 5a and IMDM). Viability, yield and cell size were monitored, and RT-qPCR, flow cytometry or ELISA was used to compare levels of phenotype markers (CD163, CD206, CD80, TNFα, IL-10, SIRPα, LILRB1 and Siglec-10). Yield, cell size, gene expression, membrane protein levels and release of soluble proteins were all affected by changes in culture medium composition. The most pronounced effects were observed after culture in DMEM, which lacks the non-essential amino acids asparagine, aspartic acid, glutamic acid and proline. Supplementation of DMEM with non-essential amino acids either fully or partly reversed most effects of DMEM on macrophage phenotype. The results suggest culture medium composition and amino acid availability affect the phenotype of human monocyte-derived macrophages cultured in vitro.

The Potential Impact of Physical Activity on the Burden of Osteoarthritis and Low Back Pain in Australia: A Systematic Review of Reviews and Life Table Analysis.

OBJECTIVE: The objectives were (1) to establish the strength of the association between incident cases of osteoarthritis (OA) and low back pain (LBP), and physical activity (PA) and to assess the likelihood of the associations being causal; and (2) to quantify the impact of PA on the burden of OA and LBP in Australia. METHODS: We conducted a systematic literature review in EMBASE and PubMed databases from January 01, 2000, to April 28, 2020. We used the Bradford Hill viewpoints to assess causality. We used a proportional multistate life table model to estimate the impact of changes in the PA levels on OA and LBP burdens for the 2019 Australian population (aged ≥ 20 y) over their remaining lifetime. RESULTS: We found that both OA and LBP are possibly causally related to physical inactivity. Assuming causality, our model projected that if the 2025 World Health Organization global target for PA was met, the burden in 25 years' time could be reduced by 70,000 prevalent cases of OA and over 11,000 cases of LBP. Over the lifetime of the current adult population of Australia, the gains could add up to approximately 672,814 health-adjusted life years (HALYs) for OA (ie, 27 HALYs per 1000 persons) and 114,042 HALYs for LBP (ie, 5 HALYs per 1000 persons). The HALY gains would be 1.4 times bigger if the 2030 World Health Organization global target for PA was achieved and 11 times bigger if all Australians adhered to the Australian PA guidelines. CONCLUSION: This study provides empirical support for the adoption of PA in strategies for the prevention of OA and back pain.

A systematic review of the evidence for effectiveness of interventions to address transport and other unintentional injuries among adolescents.

INTRODUCTION: Globally, injuries are a leading cause of mortality and morbidity for adolescents, which disproportionately affect the disadvantaged. To build an investment case for adolescent injury prevention, evidence is needed as to effective interventions. METHODS: A systematic review of peer-reviewed original research published between 2010-2022 was conducted. CINAHL, Cochrane Central, Embase, Medline and PsycINFO databases were searched for studies reporting the effectiveness of unintentional injury prevention interventions for adolescents (10-24 years), with assessment of study quality and equity (e.g., age, gender, ethnicity, socio-economic status). RESULTS: Sixty-two studies were included; 59 (95.2%) from high-income countries (HIC). Thirty-eight studies (61.3%) reported no aspect of equity. Thirty-six studies (58.1%) reported prevention of sports injuries (commonly neuromuscular training often focused on soccer-related injuries, rule changes and protective equipment). Twenty-one studies (33.9%) reported prevention of road traffic injury, with legislative approaches, commonly graduated driver licensing schemes, found to be effective in reducing fatal and nonfatal road traffic injury. Seven studies reported interventions for other unintentional injuries (e.g., falls). DISCUSSION: Interventions were strongly biased towards HIC, which does not reflect the global distribution of adolescent injury burden. Low consideration of equity in included studies indicates current evidence largely excludes adolescent populations at increased risk of injury. A large proportion of studies evaluated interventions to prevent sports injury, a prevalent yet low severity injury mechanism. Findings highlight the importance of education and enforcement alongside legislative approaches for preventing adolescent transport injuries. Despite drowning being a leading cause of injury-related harm among adolescents, no interventions were identified. CONCLUSION: This review provides evidence to support investment in effective adolescent injury prevention interventions. Further evidence of effectiveness is needed, especially for low- and middle-income countries, populations at increased risk of injury who would benefit from greater consideration of equity and for high lethality injury mechanisms like drowning.

Fungal translocation measured by serum 1,3-ß-D-glucan correlates with severity and outcome of liver cirrhosis-A pilot study.

BACKGROUND & AIMS: On a global scale, liver cirrhosis is attributable to ~1 million deaths per year. This systemic disease comes along with diverse sequelae, including microbiota alterations, increased gut permeability and translocation of microbial components into the systemic circulation. Alongside the extensively studied influence of bacterial translocation and its host-pathogen interactions, far less is known about the role and impact of fungal components once having crossed the intestinal barrier. METHODS: Including 70 patients with different aetiologies of liver cirrhosis, we investigated the relationship between fungal translocation, measured by 1,3-ß-D-glucan (BDG), and biomarkers of gut integrity, inflammation and severity/outcome of liver disease. RESULTS: Patients with cirrhosis Child-Pugh class (CPC)-B were more likely to have positive serum BDG (aOR 5.4, 95% CI 1.2-25.2) compared to patients with cirrhosis CPC-A. BDG showed a moderate positive correlation with several markers of inflammation (sCD206, sCD163, Interleukin 8, interferon-gamma-induced protein). Mortality differed significantly between patients with positive versus negative BDG (log-rank test, p = 0.015). The multivariable Cox regression model yielded an aHR of 6.8 (95% CI 1.8-26.3). DISCUSSION: We observed trends for increased fungal translocation depending on the severity of liver cirrhosis, an association of BDG with an inflammatory environment and the adverse effects of BDG on disease outcome. In order to gain more in-depth knowledge about (fungal-)dysbiosis and its detrimental consequences in the setting of liver cirrhosis, these trends need to be studied in more detail including prospective sequential testing in larger cohorts together with mycobiome analyses. This will further elucidate complex host-pathogen interactions and potentially introduce points of application for therapeutic interventions.

External causes of emergency department presentations: A missing piece to understanding unintentional childhood injury in Australia.

OBJECTIVE: To identify external causes of unintentional childhood injury presenting to Australian EDs. METHODS: Six major paediatric hospitals in four Australian states supplied de-identified ED data for 2011-2017 on age, sex, attendance time/date, presenting problem, injury diagnosis, triage category and mode of separation. Three hospitals supplied data on external cause and intent of injury. A machine classifier tool was used to supplement the missing external cause coding in the remaining hospitals to enable the compilation of a standardised dataset for childhood injury causes analysis. RESULTS: A total of 486 762 ED presentations for unintentional injury in children aged 0-14 years were analysed. The leading specified cause of ED presentations was low fall (35.0%) followed by struck/collision with an object (13.8%) with little sex difference observed. Males aged 10-14 years had higher rates of motorcycle, pedal cycle and fire/flame-related injury and lower rates of horse-related injury and drug/medicinal substance poisoning compared with females. The leading specified external cause resulting in hospitalisation was low fall (32.2%) followed by struck/collision with an object (11.1%). The injuries with the highest proportion of children being hospitalised were drownings (64.4%), pedestrian (53.4%), motorcycle (52.7%) and horse-related injuries (50.0%). CONCLUSIONS: This is the first large-scale study since the 1980s to explore external causes of unintentional childhood injury presenting to Australian paediatric EDs. It demonstrates a hybrid human-machine learning approach to create a standardised database to overcome data deficiencies. The results supplement existing knowledge of hospitalised paediatric injury to better understand the causes of childhood injury by age and sex, which require health service utilisation.

Neoehrlichia mikurensis-An emerging opportunistic tick-borne infection in immunosuppressed patients.

BACKGROUND: Neoehrlichia mikurensis (N. mikurensis) is a newly discovered tick-borne pathogen that can inflict life-threatening illness in immunocompromised patients. N. mikurensis infection is only detectable by polymerase chain reaction (PCR)-based methodologies. We describe three distinct clinical manifestations of N. mikurensis infection (neoehrlichiosis) in Danish patients receiving B-lymphocyte-depleting therapy, rituximab, for underlying hematological, rheumatological, or neurological disorders. All three patients went through a protracted pre-diagnostic period. METHODS: N. mikurensis DNA was detected and confirmed using two methods. Blood was tested by specific real-time PCR targeting the groEL gene and by 16S and 18S profiling followed by sequencing. Bone marrow was analyzed by 16S and 18S profiling. RESULTS: N. mikurensis was detected in blood samples in all three cases and in bone marrow from one of the three. The severity of the symptoms ranged from prolonged fever lasting more than 6 months to life-threatening hyperinflammation in the form of hemophagocytic lymphohistiocytosis (HLH). Interestingly, all patients presented with splenomegaly and two with hepatomegaly. After starting doxycycline therapy, symptoms were relieved within a few days, and biochemistry and organomegaly quickly normalized. CONCLUSION: We present three Danish patients recognized by the same clinician over a period of 6 months, strongly suggesting that many cases are going unrecognized. Second, we describe the first case of N. mikurensis-induced HLH and emphasize the potential severity of undetected neoehrlichiosis.

Macrophage Biomarkers sCD163 and sSIRPα in Serum Predict Mortality in Sarcoma Patients.

Most soft tissue sarcoma (STS) patients do not respond to traditional checkpoint inhibitor treatment, which may be due to infiltrating immunosuppressive tumour-associated macrophages. This study investigated the prognostic value of four serum macrophage biomarkers. Methods: Blood samples were taken from 152 patients with STS at the time of diagnosis; clinical data were prospectively collected. The concentrations of four macrophage biomarkers (sCD163, sCD206, sSIRPα, sLILRB1) were measured in serum, dichotomised based on median concentration, and evaluated either individually or when combined with established prognostic markers. Results: All macrophage biomarkers were prognostic of overall survival (OS). However, only sCD163 and sSIRPα were prognostic for recurrent disease (sCD163: hazard ratio (HR): 1.97 (95% CI: 1.10-3.51) and sSIRPα: HR: 2.09 (95% CI: 1.16-3.77)). A prognostic profile was made based on sCD163 and sSIRPα; it also included c-reactive protein and tumour grade. Patients with intermediate- or high-risk prognostic profiles (adjusted for age and tumour size) had a higher risk of recurrent disease compared to low-risk patients (HR: 2.64 (95% CI: 0.97-7.19)) and (HR 4.3 (95% CI: 1.62-11.47)), respectively. Conclusion: This study demonstrated that serum biomarkers of immunosuppressive macrophages were prognostic for OS; when combined with well-established markers of recurrence they allowed for a clinically relevant categorising of patients.

The association between soluble CD163, disease severity, and ursodiol treatment in patients with primary biliary cholangitis.

INTRODUCTION: The macrophage activation marker soluble (s)CD163 is associated with disease severity and prognosis in patients with primary biliary cholangitis (PBC). Ursodeoxycholic acid (UDCA) treatment attenuates fibrosis progression in PBC patients, but its effect on macrophage activation is unclear. We examined the effect of UDCA on macrophage activation, as determined by sCD163 levels. METHODS: We included 2 cohorts of PBC patients; 1 cohort with prevalent PBC patients, and 1 cohort of incident PBC patients before start of UDCA treatment and with follow-up after 4 weeks and 6 months. We measured sCD163 and liver stiffness in both cohorts. Further, we measured sCD163 and TNF-α shedding in vitro in monocyte-derived macrophages after UDCA and lipopolysaccharide incubation. RESULTS: We included 100 patients with prevalent PBC [93% women, median age 63 y (interquartile range: 51-70)] and 47 patients with incident PBC [77% women, median age 60 y (49-67)]. Prevalent PBC patients had a lower median sCD163 of 3.54 mg/L (2.77-4.72) than incident PBC patients with a median sCD163 of 4.33 mg/L (2.83-5.99) at inclusion. Patients with an incomplete response to UDCA and patients with cirrhosis had higher sCD163 than responders to UDCA and noncirrhosis patients. After 4 weeks and 6 months of UDCA treatment median sCD163 decreased by 4.6% and 9.0%, respectively. In in vitro experiments, UDCA attenuated shedding of TNF-α, but not sCD163, from monocyte-derived macrophages. CONCLUSION: In PBC patients, sCD163 levels correlated with liver disease severity and treatment response to UDCA. Further, after 6 months of UDCA treatment, we observed a decrease in sCD163, which may be related to the treatment.

Cerebrospinal fluid levels of the macrophage-specific biomarker sCD163 are diagnostic for Lyme neuroborreliosis: An observational cohort study.

OBJECTIVES: We aimed to investigate levels of the macrophage-specific marker, sCD163, in cerebrospinal fluid and plasma in patients with Lyme neuroborreliosis. We tested the diagnostic value of CSF-sCD163 and ReaScan-CXCL13 and analyzed if plasma-sCD163 could monitor treatment response. METHODS: An observational cohort study: Cohort 1-Cerebrospinal fluid from adults with neuroborreliosis (n = 42), bacterial meningitis (n = 16), enteroviral meningitis (n = 29), and controls (n = 33); Cohort 2-Plasma from 23 adults with neuroborreliosis collected at diagnosis, three, and six months. sCD163 was determined using an in-house sandwich ELISA. ReaScan-CXCL13 measured semiquantitative concentrations of CXCL13, cut-off ≥ 250 pg/ml diagnosed neuroborreliosis. Receiver Operating Characteristics analyzed the diagnostic strength. A linear mixed model including follow-up as categorical fixed effect analyzed differences in plasma-sCD163. RESULTS: CSF-sCD163 was higher in neuroborreliosis (643 µg/l) than in enteroviral meningitis (106 µg/l, p < 0.0001) and controls (87 µg/l, p < 0.0001), but not bacterial meningitis (669 µg/l, p = 0.9). The optimal cut-off was 210 µg/l, area under the curve (AUC) 0.85. ReaScan-CXCL13 had an AUC of 0.83. Combining ReaScan-CXCL13 with CSF-sCD163 increased AUC significantly to 0.89. Plasma-sCD163 showed little variation and was not elevated during the 6 months of follow-up. CONCLUSION: CSF-sCD163 is diagnostic for neuroborreliosis with an optimal cut-off of 210 µg/l. Combining ReaScan-CXCL13 with CSF-sCD163 increases AUC. Plasma-sCD163 cannot monitor treatment response.