Therapeutic and Prognostic Implications of BRAF V600E in Pediatric Low-Grade Gliomas.

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively ( P \u3c .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy

Therapeutic and Prognostic Implications of BRAF V600E in Pediatric Low-Grade Gliomas

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively (P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy. (C) 2017 by American Society of Clinical Oncolog

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Greening the Wharfies: organisational learning for sustainability at Sydney Theatre Company

This thesis is an exploratory and explanatory study of organisational learning for sustainability at Sydney Theatre Company. The complex problem of sustainability relates to humankind's capacity to respond to the various environmental and social problems that we have created so that we can continue to live within the carrying capacity of the planet. Sustainability in organisations is often couched in terms of the triple bottom line, wherein an organisation must sustain itself financially while minimising environmental impacts and ensuring the sustainability of staff and other human stakeholders. To achieve this requires an organisation to undertake learning processes that shift it towards embracing sustainable practices. That shift should be evident in changes in policies and procedures as well as the work practices of staff. However, the sustainability imperative affects all of the contexts we occupy and learning in the workplace could be relevant to those other contexts. This raises the possibility that learnings from an organisational setting might translate to the non-work contexts occupied by staff. An examination of the literature revealed that organisational learning for sustainability is usually studied only at the level of the organisation. The nexus between personal and organisational learning had not been examined except in terms of drawing on theories of how people learn. This seemed to be an area worthy of exploration because it offered the possibility that an organisation could potentially influence the behaviour of staff in relation to sustainability in their non-work contexts. Greening the Wharf at Sydney Theatre Company (STC) was an environmental sustainability project that appeared to be an example of successful organisational learning for sustainability as showcased on their greeningthewharf. com website. I undertook a single in-depth case study to explore if organisational learning for sustainability was evident; how that learning had unfolded over time; what organisational learning features were evident and how the personal and organisational learning intersected with each other. I used the lens of complexity theory to explore the array of potential influences on the process and its impacts on staff. Using this conceptual framework, an organisation is a complex adaptive system that responds and adapt to its environment in ways that are difficult to predict due to the many sources of dynamic influence at play. Cause and effect relationships can be circular and difficult to identify. In such systems, small changes can lead to large outcomes or large changes may lead to outcomes that do not take hold. The individuals who work for an organisation come with their own complex backgrounds that inform the way they interact with the organisation and each other. They hold their perspectives cognitively and express them verbally and non-verbally as they communicate. To appreciate the differences in individual perspectives, I was attentive to the language used during interviews, particularly what participant utterances revealed about the way they framed their experiences and the metaphors they used in describing their experiences. In order to attain a deep and contextual understanding of the complexity of the Greening the Wharf project and its impacts beyond at STC, including its cognitive impacts on staff, I adopted an interpretivist/constructivist perspective with a grounded theory approach. I collected qualitative data from five sources – semi-structured interviews with staff, company documentation, press reports about STC, Greening the Wharf and relevant players over the period studied, photographs of STC and my own observations during site visits that I recorded in my research diary. I used MAXQDA 11.1.2 to support my data analysis and subsequent theorising. The research found that organisational learning for sustainability had taken place at STC by applying the Sustainability Phase Model to the organisation and determining that it had attained the status of a sustaining organisation (Benn et al., 2014). The learning emerged through a process with multiple dynamic influences, some of which created key enabling conditions that contributed to the success of the project. This included the personal environmental commitments of key staff, a collaborative organisational culture, an inclusive leadership team and a fertile socio-political climate at the time the project began. The organisation's ongoing commitments to making environmental sustainability part of business as usual ensured the learning became part of the each staff member's work practices and that facilitated the emergence of organisational learning for sustainability. The organisational learning that took place was characterised by a combination of double and single loop learning, underpinned by leadership that fostered learning that was distributed across the organisation to staff empowered to lead in their own learning at the team and individual level. The double loop learning occurred in response to the disruptive idea of greening theatre, something that STC had not considered previously. Once staff were convinced that it was an important thing to do, the first part of the project was characterised by the transformational metaphor of Greening the Wharf as theatre production and this allowed staff to engage in the project using skills and processes that were already familiar to them. Once the initial production of Greening the Wharf ended, STC continued its ecological sustainability journey, embedding behaviour change and continuing to seek improvements in organisational practices and processes. However, the success within the workplace did not automatically impact of the behaviour of staff in other contexts such as their homes. That is, despite it being relevant to multiple contexts, the staff did not make the connection between the sustainability behaviours in the workplace and sustainability behaviours outside the workplace for the most part. This exploratory and explanatory research has shown that taking a complexity theory perspective illuminated key sources of influence that were critical to the organisational learning for sustainability at STC which may have been missed had other conceptual approaches been used. It suggests that organisations attempting to become more ecologically sustainable may do well to attend to the human sustainability of their staff first, creating the right cultural conditions for such a change. It also suggests that an organisation might achieve learning that is more powerful if it finds ways to relate the new objective or vision for the organisation to existing work practices rather than trying to invent new practices. It also suggests that we cannot assume that learning in one context automatically transfers to other contexts

Paediatric COVID-19 mortality: a database analysis of the impact of health resource disparity

BackgroundThe impact of the COVID-19 pandemic on paediatric populations varied between high-income countries (HICs) versus low-income to middle-income countries (LMICs). We sought to investigate differences in paediatric clinical outcomes and identify factors contributing to disparity between countries.MethodsThe International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) COVID-19 database was queried to include children under 19 years of age admitted to hospital from January 2020 to April 2021 with suspected or confirmed COVID-19 diagnosis. Univariate and multivariable analysis of contributing factors for mortality were assessed by country group (HICs vs LMICs) as defined by the World Bank criteria.ResultsA total of 12 860 children (3819 from 21 HICs and 9041 from 15 LMICs) participated in this study. Of these, 8961 were laboratory-confirmed and 3899 suspected COVID-19 cases. About 52% of LMICs children were black, and more than 40% were infants and adolescent. Overall in-hospital mortality rate (95% CI) was 3.3% [=(3.0% to 3.6%), higher in LMICs than HICs (4.0% (3.6% to 4.4%) and 1.7% (1.3% to 2.1%), respectively). There were significant differences between country income groups in intervention profile, with higher use of antibiotics, antivirals, corticosteroids, prone positioning, high flow nasal cannula, non-invasive and invasive mechanical ventilation in HICs. Out of the 439 mechanically ventilated children, mortality occurred in 106 (24.1%) subjects, which was higher in LMICs than HICs (89 (43.6%) vs 17 (7.2%) respectively). Pre-existing infectious comorbidities (tuberculosis and HIV) and some complications (bacterial pneumonia, acute respiratory distress syndrome and myocarditis) were significantly higher in LMICs compared with HICs. On multivariable analysis, LMIC as country income group was associated with increased risk of mortality (adjusted HR 4.73 (3.16 to 7.10)).ConclusionMortality and morbidities were higher in LMICs than HICs, and it may be attributable to differences in patient demographics, complications and access to supportive and treatment modalities

Palaeoclimate constraints on the impact of 2 °C anthropogenic warming and beyond

Over the past 3.5 million years, there have been several intervals when climate conditions were warmer than during the pre-industrial Holocene. Although past intervals of warming were forced differently than future anthropogenic change, such periods can provide insights into potential future climate impacts and ecosystem feedbacks, especially over centennial-to-millennial timescales that are often not covered by climate model simulations. Our observation-based synthesis of the understanding of past intervals with temperatures within the range of projected future warming suggests that there is a low risk of runaway greenhouse gas feedbacks for global warming of no more than 2 °C. However, substantial regional environmental impacts can occur. A global average warming of 1–2 °C with strong polar amplification has, in the past, been accompanied by significant shifts in climate zones and the spatial distribution of land and ocean ecosystems. Sustained warming at this level has also led to substantial reductions of the Greenland and Antarctic ice sheets, with sea-level increases of at least several metres on millennial timescales. Comparison of palaeo observations with climate model results suggests that, due to the lack of certain feedback processes, model-based climate projections may underestimate long-term warming in response to future radiative forcing by as much as a factor of two, and thus may also underestimate centennial-to-millennial-scale sea-level rise

Paediatric COVID-19 mortality: a database analysis of the impact of health resource disparity

Background The impact of the COVID-19 pandemic on paediatric populations varied between high-income countries (HICs) versus low-income to middle-income countries (LMICs). We sought to investigate differences in paediatric clinical outcomes and identify factors contributing to disparity between countries.Methods The International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) COVID-19 database was queried to include children under 19 years of age admitted to hospital from January 2020 to April 2021 with suspected or confirmed COVID-19 diagnosis. Univariate and multivariable analysis of contributing factors for mortality were assessed by country group (HICs vs LMICs) as defined by the World Bank criteria.Results A total of 12 860 children (3819 from 21 HICs and 9041 from 15 LMICs) participated in this study. Of these, 8961 were laboratory-confirmed and 3899 suspected COVID-19 cases. About 52% of LMICs children were black, and more than 40% were infants and adolescent. Overall in-hospital mortality rate (95% CI) was 3.3% [=(3.0% to 3.6%), higher in LMICs than HICs (4.0% (3.6% to 4.4%) and 1.7% (1.3% to 2.1%), respectively). There were significant differences between country income groups in intervention profile, with higher use of antibiotics, antivirals, corticosteroids, prone positioning, high flow nasal cannula, non-invasive and invasive mechanical ventilation in HICs. Out of the 439 mechanically ventilated children, mortality occurred in 106 (24.1%) subjects, which was higher in LMICs than HICs (89 (43.6%) vs 17 (7.2%) respectively). Pre-existing infectious comorbidities (tuberculosis and HIV) and some complications (bacterial pneumonia, acute respiratory distress syndrome and myocarditis) were significantly higher in LMICs compared with HICs. On multivariable analysis, LMIC as country income group was associated with increased risk of mortality (adjusted HR 4.73 (3.16 to 7.10)).Conclusion Mortality and morbidities were higher in LMICs than HICs, and it may be attributable to differences in patient demographics, complications and access to supportive and treatment modalities