Milpirri: Jennifer Biddle in Discussion with Tracks Dance Company

Jennifer Biddle interviews the artistic directors of Tracks Dance Company, Tim Newth and David McMicken, about the company's ongoing involvement in the Milpirri festival

Milpirri: Jennifer Biddle in Discussion with Tracks Dance Company

Jennifer Biddle interviews the artistic directors of Tracks Dance Company, Tim Newth and David McMicken, about the company's ongoing involvement in the Milpirri festival

Decoupling global environmental pressure and economic growth: scenarios for energy use, materials use and carbon emissions

In recent decades economic growth and increased human wellbeing around the globe have come at the cost of fast growing natural resource use (including materials and energy) and carbon emissions, leading to converging pressures of declining resource security, rising and increasingly volatile natural resource prices, and climate change. We ask whether well-designed policies can reduce global material and energy use, and carbon emissions, with only minimal impacts on improvements in living standards. We use a novel approach of combined economic and environmental modelling to assess the potential for decoupling for 13 world regions and globally. We apply a production (territorial) and consumption approach to discuss regional differences in natural resource use and carbon emissions across three stylized policy outlooks: a reference case with no significant changes to environment and climate policies; a ‘high efficiency’ outlook involving a global carbon price rising from $50 to$236 (constant price) per tonne of CO2 between 2010 and 2050 and improvements in resource efficiency (rising from 1.5% historically to between 3.5% and 4.5% in the scenarios); and a ‘medium efficiency’ outlook midway between the ‘no change’ and ‘high’ outlooks. We find that global energy use will continue to grow rapidly under all three scenarios from 17 billion tonnes of oil equivalent (toe) in 2010 to between 30 and 36 billion toe. Carbon emissions would be considerably lower with a global carbon price, less than half the level of the reference case (29–37 billion tonnes of CO2 instead of 74 billion tonnes) and also material use would grow much more slowly under a carbon price and significant investment to increase resource efficiency (95 instead of 180 billion tonnes of materials). We find that OECD economies have significant potential to reduce their material throughput and carbon emissions with little impact on economic growth, and that developing economies such as China could expand their economies at much lower environmental cost. Globally, the effects of very strong abatement and resource efficiency policies on economic growth and employment until 2050 are negligible. Our study suggests that decarbonization and dematerialization are possible with well-designed policy settings and would not contradict efforts to raise human wellbeing and standards of living. The research demonstrates the usefulness of scenarios for unpacking environmental and economic outcomes of policy alternatives. The findings have important implications for future economic opportunities in a highly resource efficient and low carbon global economy to set human development and achieving the sustainable development goals on a more resilient path

Hyperferritinemic sepsis, macrophage activation syndrome, and mortality in a pediatric research network: a causal inference analysis

Abstract Background One of five global deaths are attributable to sepsis. Hyperferritinemic sepsis (> 500 ng/mL) is associated with increased mortality in single-center studies. Our pediatric research network’s objective was to obtain rationale for designing anti-inflammatory clinical trials targeting hyperferritinemic sepsis. Methods We assessed differences in 32 cytokines, immune depression (low whole blood ex vivo TNF response to endotoxin) and thrombotic microangiopathy (low ADAMTS13 activity) biomarkers, seven viral DNAemias, and macrophage activation syndrome (MAS) defined by combined hepatobiliary dysfunction and disseminated intravascular coagulation, and mortality in 117 children with hyperferritinemic sepsis (ferritin level > 500 ng/mL) compared to 280 children with sepsis without hyperferritinemia. Causal inference analysis of these 41 variables, MAS, and mortality was performed. Results Mortality was increased in children with hyperferritinemic sepsis (27/117, 23% vs 16/280, 5.7%; Odds Ratio = 4.85, 95% CI [2.55–9.60]; z = 4.728; P-value < 0.0001). Hyperferritinemic sepsis had higher C-reactive protein, sCD163, IL-22, IL-18, IL-18 binding protein, MIG/CXCL9, IL-1β, IL-6, IL-8, IL-10, IL-17a, IFN-γ, IP10/CXCL10, MCP-1/CCL2, MIP-1α, MIP-1β, TNF, MCP-3, IL-2RA (sCD25), IL-16, M-CSF, and SCF levels; lower ADAMTS13 activity, sFasL, whole blood ex vivo TNF response to endotoxin, and TRAIL levels; more Adenovirus, BK virus, and multiple virus DNAemias; and more MAS (P-value < 0.05). Among these variables, only MCP-1/CCL2 (the monocyte chemoattractant protein), MAS, and ferritin levels were directly causally associated with mortality. MCP-1/CCL2 and hyperferritinemia showed direct causal association with depressed ex vivo whole blood TNF response to endotoxin. MCP-1/CCL2 was a mediator of MAS. MCP-1/CCL2 and MAS were mediators of hyperferritinemia. Conclusions These findings establish hyperferritinemic sepsis as a high-risk condition characterized by increased cytokinemia, viral DNAemia, thrombotic microangiopathy, immune depression, macrophage activation syndrome, and death. The causal analysis provides rationale for designing anti-inflammatory trials that reduce macrophage activation to improve survival and enhance infection clearance in pediatric hyperferritinemic sepsis

Viral DNAemia and DNA Virus Seropositivity and Mortality in Pediatric Sepsis

IMPORTANCE: Sepsis is a leading cause of pediatric mortality. Little attention has been paid to the association between viral DNA and mortality in children and adolescents with sepsis. OBJECTIVE: To assess the association of the presence of viral DNA with sepsis-related mortality in a large multicenter study. DESIGN, SETTING, AND PARTICIPANTS: This cohort study compares pediatric patients with and without plasma cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus 1 (HSV-1), human herpesvirus 6 (HHV-6), parvovirus B19 (B19V), BK polyomavirus (BKPyV), human adenovirus (HAdV), and torque teno virus (TTV) DNAemia detected by quantitative real-time polymerase chain reaction or plasma IgG antibodies to CMV, EBV, HSV-1, or HHV-6. A total of 401 patients younger than 18 years with severe sepsis were enrolled from 9 pediatric intensive care units (PICUs) in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. Data were collected from 2015 to 2018. Samples were assayed from 2019 to 2022. Data were analyzed from 2022 to 2023. MAIN OUTCOMES AND MEASURES: Death while in the PICU. RESULTS: Among the 401 patients included in the analysis, the median age was 6 (IQR, 1-12) years, and 222 (55.4%) were male. One hundred fifty-four patients (38.4%) were previously healthy, 108 (26.9%) were immunocompromised, and 225 (56.1%) had documented infection(s) at enrollment. Forty-four patients (11.0%) died in the PICU. Viral DNAemia with at least 1 virus (excluding TTV) was detected in 191 patients (47.6%) overall, 63 of 108 patients (58.3%) who were immunocompromised, and 128 of 293 (43.7%) who were not immunocompromised at sepsis onset. After adjustment for age, Pediatric Risk of Mortality score, previously healthy status, and immunocompromised status at sepsis onset, CMV (adjusted odds ratio [AOR], 3.01 [95% CI, 1.36-6.45]; P = .007), HAdV (AOR, 3.50 [95% CI, 1.46-8.09]; P = .006), BKPyV (AOR. 3.02 [95% CI, 1.17-7.34]; P = .02), and HHV-6 (AOR, 2.62 [95% CI, 1.31-5.20]; P = .007) DNAemia were each associated with increased mortality. Two or more viruses were detected in 78 patients (19.5%), with mortality among 12 of 32 (37.5%) who were immunocompromised and 9 of 46 (19.6%) who were not immunocompromised at sepsis onset. Herpesvirus seropositivity was common (HSV-1, 82 of 246 [33.3%]; CMV, 107 of 254 [42.1%]; EBV, 152 of 251 [60.6%]; HHV-6, 253 if 257 [98.4%]). After additional adjustment for receipt of blood products in the PICU, EBV seropositivity was associated with increased mortality (AOR, 6.10 [95% CI, 1.00-118.61]; P = .049). CONCLUSIONS AND RELEVANCE: The findings of this cohort study suggest that DNAemia for CMV, HAdV, BKPyV, and HHV-6 and EBV seropositivity were independently associated with increased sepsis mortality. Further investigation of the underlying biology of these viral DNA infections in children with sepsis is warranted to determine whether they only reflect mortality risk or contribute to mortality

Derivation of four computable 24-hour pediatric sepsis phenotypes to facilitate personalized enrollment in early precise anti-inflammatory clinical trials

ABSTRACTObjectiveThrombotic microangiopathy induced Thrombocytopenia Associated Multiple Organ Failure and hyperinflammatory Macrophage Activation Syndrome are important causes of late pediatric sepsis mortality that are often missed or have delayed diagnosis. Our objective is to derive computable 24-hour sepsis phenotypes to facilitate enrollment in early precise anti-inflammatory trials targeting mortality from these conditions.DesignMachine learning analysis using consensus k-means clustering.SettingNine pediatric intensive care units.Patients404 children with severe sepsis.Interventions24-hour computable phenotypes derived using 25 bedside variables including C-reactive protein and ferritin.Measurements and Main ResultsFour computable phenotypes (PedSep-A, B, C, and D) are derived. Compared to the overall population mean, PedSep-A has the least inflammation (median C-reactive protein 7.3 mg/dL, ferritin 125 ng/mL), younger age, less chronic illness, and more respiratory failure (n = 135; 2% mortality); PedSep-B (median C-reactive protein 13.2 mg/dL, ferritin 225 ng/ mL) has organ failure with intubated respiratory failure, shock, and Glasgow Coma Scale score &lt; 7 (n = 102, 12% mortality); PedSep-C (median C-reactive protein 15.2 mg/dL, ferritin 405 ng/mL) has elevated ferritin, lymphopenia, more shock, more hepatic failure and less respiratory failure (n = 110; mortality 10%); and, PedSep D (median C-reactive protein 13.1 mg/dL ferritin 610 ng/mL), has hyperferritinemic, thrombocytopenic multiple organ failure with more cardiovascular, respiratory, hepatic, renal, hematologic, and neurologic system failures (n = 56, 34% mortality). PedSep-D has highest likelihood of Thrombocytopenia Associated Multiple Organ Failure (Adj OR 47.51 95% CI [18.83-136.83], p &lt; 0.0001) and Macrophage Activation Syndrome (Adj OR 38.63 95% CI [13.26-137.75], p &lt;0.0001), and an observed survivor interaction with combined methylprednisolone and intravenous immunoglobulin therapies (p &lt; 0.05).CONCLUSIONS AND RELEVANCEMachine learning identifies four computable phenotypes (www.pedsepsis.pitt.edu). Membership in PedSep-D appears optimal for enrollment in early anti-inflammatory trials targeting Thrombocytopenia Associated Multiple Organ Failure and Macrophage Activation Syndrome.Author’s CommentQuestionCan machine learning methods derive 24-hour computable pediatric sepsis phenotypes that facilitate early identification of patients for enrollment in precise anti-inflammatory therapy trials?FindingsFour distinct phenotypes (PedSep-A, B, C, and D) were derived by assessing 25 bedside clinical variables in 404 children with sepsis. PedSep-D patients had a thrombotic microangiopathy and hyperinflammatory macrophage activation biomarker response, and improved survival odds associated with combined methylprednisolone plus intravenous immunoglobulin therapy.MeaningFour novel computable 24-hour phenotypes are identifiable (www.pedsepsis.pitt.edu) that could potentially facilitate enrollment in early precise anti-inflammatory trials targeting thrombotic microangiopathy and macrophage activation in pediatric sepsis.</jats:sec

Prevalence of Pathogenic and Potentially Pathogenic Inborn Error of Immunity Associated Variants in Children with Severe Sepsis

Abstract Purpose: Our understanding of the inborn errors of immunity that cause immunodeficiencies is increasing however, their contribution to pediatric sepsis is unknown. Methods: We used whole exome sequencing to characterize variants previously reported in monogenic immunologic disorders in 330 children admitted to intensive care for severe sepsis. Candidate variants were restricted to novel null variants or rare variants classified as pathogenic or potentially pathogenic in Qiagen’s Human Genetic Mutation Database in a disease consistent inheritance pattern. Results: One in two children overall and two of three African American children had immunodeficiency-associated variants. Children with candidate variants had increased odds of isolating a blood or urinary pathogen (blood: OR 2.05, 95% CI 1.16 - 3.65, p- value = 0.014, urine: OR: 2.35, 95% CI 1.02 – 5.41, p- value = 0.04) and laboratory evidence of increased immune activation with increased odds of hyperferritinemia (ferritin ≥ 500 ng/ml, OR: 1.92, 95% CI: 1.16 – 3.20, p- value = 0.013) and lymphopenia (minimum lymphocyte count &lt;1000/µL, OR: 1.62, 95% CI: 1.03 – 2.55, p- value = 0.038). Conclusion: Herein, we describe the genetic findings in this pediatric sepsis cohort and their microbiologic and immunologic significance providing rationale for screening children with life-threatening infection for potential inborn errors of immunity.</jats:p

Machine learning derivation of four computable 24-h pediatric sepsis phenotypes to facilitate enrollment in early personalized anti-inflammatory clinical trials

Abstract Background Thrombotic microangiopathy-induced thrombocytopenia-associated multiple organ failure and hyperinflammatory macrophage activation syndrome are important causes of late pediatric sepsis mortality that are often missed or have delayed diagnosis. The National Institutes of General Medical Science sepsis research working group recommendations call for application of new research approaches in extant clinical data sets to improve efficiency of early trials of new sepsis therapies. Our objective is to apply machine learning approaches to derive computable 24-h sepsis phenotypes to facilitate personalized enrollment in early anti-inflammatory trials targeting these conditions. Methods We applied consensus, k-means clustering analysis to our extant PHENOtyping sepsis-induced Multiple organ failure Study (PHENOMS) dataset of 404 children. 24-hour computable phenotypes are derived using 25 available bedside variables including C-reactive protein and ferritin. Results Four computable phenotypes (PedSep-A, B, C, and D) are derived. Compared to all other phenotypes, PedSep-A patients (n = 135; 2% mortality) were younger and previously healthy, with the lowest C-reactive protein and ferritin levels, the highest lymphocyte and platelet counts, highest heart rate, and lowest creatinine (p &lt; 0.05); PedSep-B patients (n = 102; 12% mortality) were most likely to be intubated and had the lowest Glasgow Coma Scale Score (p &lt; 0.05); PedSep-C patients (n = 110; mortality 10%) had the highest temperature and Glasgow Coma Scale Score, least pulmonary failure, and lowest lymphocyte counts (p &lt; 0.05); and PedSep-D patients (n = 56, 34% mortality) had the highest creatinine and number of organ failures, including renal, hepatic, and hematologic organ failure, with the lowest platelet counts (p &lt; 0.05). PedSep-D had the highest likelihood of developing thrombocytopenia-associated multiple organ failure (Adj OR 47.51 95% CI [18.83–136.83], p &lt; 0.0001) and macrophage activation syndrome (Adj OR 38.63 95% CI [13.26–137.75], p &lt; 0.0001). Conclusions Four computable phenotypes are derived, with PedSep-D being optimal for enrollment in early personalized anti-inflammatory trials targeting thrombocytopenia-associated multiple organ failure and macrophage activation syndrome in pediatric sepsis. A computer tool for identification of individual patient membership (www.pedsepsis.pitt.edu) is provided. Reproducibility will be assessed at completion of two ongoing pediatric sepsis studies. </jats:sec

Prevalence of Pathogenic and Potentially Pathogenic Inborn Error of Immunity Associated Variants in Children with Severe Sepsis

Abstract Purpose: Our understanding of inborn errors of immunity is increasing however, their contribution to pediatric sepsis is unknown. Methods: We used whole exome sequencing to characterize variants in genes related to monogenic immunologic disorders in 330 children admitted to intensive care for severe sepsis. We defined candidate variants as rare variants classified as pathogenic or potentially pathogenic in Qiagen’s Human Genetic Mutation Database or novel null variants in a disease-consistent inheritance pattern. We investigated variant correlation with infection and inflammatory phenotype. Results: More than one in two children overall and three of four African American children had immunodeficiency-associated variants. Children with variants had increased odds of isolating a blood or urinary pathogen (blood: OR 2.82, 95% CI: 1.12 – 7.10, p = 0.023, urine: OR: 8.23, 95% CI: 1.06 – 64.11, p = 0.016) and demonstrating increased inflammation with hyperferritinemia (ferritin ng/mL, OR: 2.16, 95% CI: 1.28 – 3.66, p = 0.004), lymphopenia (lymphocyte count &lt;1000/µL, OR: 1.66, 95% CI: 1.06 – 2.60, p = 0.027), thrombocytopenia (platelet count &lt; 150,000/µL, OR: 1.76, 95% CI: 1.12 – 2.76, p = 0.013) and CRP greater than 10mg/dL (OR: 1.71, 95%CI: 1.10 – 2.68, p = 0.017). They also had increased odds of requiring extracorporeal membrane oxygenation (ECMO, OR: 4.19, 95%CI: 1.21 – 14.5, p = 0.019).Conclusion: Herein, we describe the genetic findings in this severe pediatric sepsis cohort and their microbiologic and immunologic significance, providing evidence for phenotypic effect of these variants and rationale for screening children with life-threatening infection for potential inborn errors of immunity.</jats:p

Additional file 1 of Hyperferritinemic sepsis, macrophage activation syndrome, and mortality in a pediatric research network: a causal inference analysis

Additional file 1. Supplemental Digital Content