Mindsets set in concrete? Exploring the perspectives of domestic travellers on New Zealand's (auto-)mobility culture

Tourism trips in New Zealand are strongly car-dominated. Research suggests that such car use practices do not only emerge from purely rational economic considerations but also result from symbolic and affective motives, institutionalized mobility cultures, and habitualized mobility practices that have developed and materialized in spatial structures over decades. This paper explores the notion of automobility and its influence on the domestic tourism mobilities of Christchurch residents. It does so by applying Q methodology, an inherently mixed method that involves participants structuring statements by their level of agreement, followed by a range of qualitative post-sorting questions. The statements draw on insights from the study of tourism mobilities, mobility cultures and classical mode choice research, allowing this study to provide novel insights into the under-researched field of urban-rural tourism mobility. The juxtaposition of quantitative Q and the qualitative interview results reveals influential factors at the personal, interpersonal, societal/political and infrastructural level. The results then feed into a conceptualisation of influential factors of tourism mobility choices using an embedded, interlinked structure that captures the dynamics of social interactions (i.e., feedback-loops). Policy implications are discussed with regards to possible sustainability pathways in line with New Zealand's decarbonisation strategy

Fluid restriction reduces pulmonary edema in a model of acute lung injury in mechanically ventilated rats

Experimental acute lung injury models are often used to increase our knowledge on the acute respiratory distress syndrome (ARDS), however, existing animal models often do not take into account the impact of specific fluid strategies on the development of lung injury. In contrast, the current literature strongly suggests that fluid management strategies have a significant impact on clinical outcome of patients with ARDS. Thus, it is important to characterize the role of fluid management strategies in experimental models of lung injury. In this study we investigated the effect of two different fluid strategies on commonly used outcome variables in a short-term model of acute lung injury, in relation to age. Infant (2–3 weeks) and adult (3–4 months) Wistar rats received intratracheal instillations of lipopolysaccharide and 24 hours later were mechanically ventilated for 6 hours. During mechanical ventilation, rats from both age groups were randomized to either a standard or conservative intravenous fluid strategy. We found that the hemodynamic response in infant and adult rats was similar in both fluid strategies. Lung wet-to-dry ratios were lower in adult, but not in infant rats receiving the conservative fluid strategy as compared to the standard fluid strategy. There were age-related differences in markers of alveolar capillary barrier disruption and alveolar fluid clearance, yet these were unaffected by fluid strategy. Finally, we found significantly higher IL-1β and TNF-α concentrations in the adult rats treated with the conservative as compared to the standard fluid regimen. In conclusion, the choice of fluid strategy in mechanically ventilated rats with experimental LPS-induced acute lung injury has a significant effect on pulmonary extravascular water, an important and well-recognized lung injury marker, and on the local pro-inflammatory cytokine profiles. We advocate the use of a more uniform, conservative, fluid strategy regimen in experimental models of acute lung injury

Between-trial heterogeneity in ARDS research

Purpose: Most randomized controlled trials (RCTs) in patients with acute respiratory distress syndrome (ARDS) revealed indeterminate or conflicting study results. We aimed to systematically evaluate between-trial heterogeneity in reporting standards and trial outcome. Methods: A systematic review of RCTs published between 2000 and 2019 was performed including adult ARDS patients receiving lung-protective ventilation. A random-effects meta-regression model was applied to quantify heterogeneity (non-random variability) and to evaluate trial and patient characteristics as sources of heterogeneity. Results: In total, 67 RCTs were included. The 28-day control-group mortality rate ranged from 10 to 67% with large non-random heterogeneity (I 2 = 88%, p < 0.0001). Reported baseline patient characteristics explained some of the outcome heterogeneity, but only six trials (9%) reported all four independently predictive variables (mean age, mean lung injury score, mean plateau pressure and mean arterial pH). The 28-day control group mortality adjusted for patient characteristics (i.e. the residual heterogeneity) ranged from 18 to 45%. Trials with significant benefit in the primary outcome reported a higher control group mortality than trials with an indeterminate outcome or harm (mean 28-day control group mortality: 44% vs. 28%; p = 0.001). Conclusion: Among ARDS RCTs in the lung-protective ventilation era, there was large variability in the description of baseline characteristics and significant unexplainable heterogeneity in 28-day control group mortality. These findings signify problems with the generalizability of ARDS research and underline the urgent need for standardized reporting of trial and baseline characteristics

Between-trial heterogeneity in ARDS research

Purpose: Most randomized controlled trials (RCTs) in patients with acute respiratory distress syndrome (ARDS) revealed indeterminate or conflicting study results. We aimed to systematically evaluate between-trial heterogeneity in reporting standards and trial outcome. Methods: A systematic review of RCTs published between 2000 and 2019 was performed including adult ARDS patients receiving lung-protective ventilation. A random-effects meta-regression model was applied to quantify heterogeneity (non-random variability) and to evaluate trial and patient characteristics as sources of heterogeneity. Results: In total, 67 RCTs were included. The 28-day control-group mortality rate ranged from 10 to 67% with large non-random heterogeneity (I 2 = 88%, p < 0.0001). Reported baseline patient characteristics explained some of the outcome heterogeneity, but only six trials (9%) reported all four independently predictive variables (mean age, mean lung injury score, mean plateau pressure and mean arterial pH). The 28-day control group mortality adjusted for patient characteristics (i.e. the residual heterogeneity) ranged from 18 to 45%. Trials with significant benefit in the primary outcome reported a higher control group mortality than trials with an indeterminate outcome or harm (mean 28-day control group mortality: 44% vs. 28%; p = 0.001). Conclusion: Among ARDS RCTs in the lung-protective ventilation era, there was large variability in the description of baseline characteristics and significant unexplainable heterogeneity in 28-day control group mortality. These findings signify problems with the generalizability of ARDS research and underline the urgent need for standardized reporting of trial and baseline characteristics

Incidence, Clinical Characteristics and Outcomes of Early Hyperbilirubinemia in Critically Ill Patients: Insights From the MARS Study

OBJECTIVE: To investigate the incidence, clinical characteristics and outcomes of early hyperbilirubinemia in critically ill patients. DESIGN AND SETTING: This is a post hoc analysis of a prospective multicenter cohort study. PATIENTS: Patients with measured bilirubin levels within the first 2 days after ICU admission were eligible. Patients with liver cirrhosis were excluded. ENDPOINTS: The primary endpoint was the incidence of early hyperbilirubinemia, defined as bilirubin ≥33 μmol/L within 2 days after ICU admission. Secondary endpoints included clinical characteristics of patients with versus patients without early hyperbilirubinemia, and outcomes up to day 30. RESULTS: Of 4,836 patients, 559 (11.6%) patients had early hyperbilirubinemia. Compared to patients without early hyperbilirubinemia, patients with early hyperbilirubinemia presented with higher severity of illness scores, and higher incidences of sepsis and organ failure. After adjustment for confounding variables, early hyperbilirubinemia remained associated with mortality at day 30 (odds ratio, 1.31 [95%-confidence interval 1.06-1.60]; P = 0.018). Patients with early hyperbilirubinemia and thrombocytopenia (interaction P-value = 0.005) had a higher likelihood of death within 30 days (odds ratio, 2.61 [95%-confidence interval 2.08-3.27]; P < 0.001) than patients with early hyperbilirubinemia and a normal platelet count (odds ratio, 1.09 [95%-confidence interval 0.75-1.55]; P = 0.655). CONCLUSIONS: Early hyperbilirubinemia occurs frequently in the critically ill, and these patients present with higher disease severity and more often with sepsis and organ failures. Early hyperbilirubinemia has an association with mortality, albeit this association was only found in patients with concomitant thrombocytopenia

Bosutinib prevents vascular leakage by reducing focal adhesion turnover and reinforcing junctional integrity

Endothelial barrier dysfunction leads to edema and vascular leak, causing high morbidity and mortality. Previously, Abl kinase inhibition has been shown to protect against vascular leak. Using the distinct inhibitory profiles of clinically available Abl kinase inhibitors, we aimed to provide a mechanistic basis for novel treatment strategies against vascular leakage syndromes. We found that the inhibitor bosutinib most potently protected against inflammation-induced endothelial barrier disruption. In vivo, bosutinib prevented lipopolysaccharide (LPS)-induced alveolar protein extravasation in an acute lung injury mice model. Mechanistically, mitogen-activated protein 4 kinase 4 (MAP4K4) was identified as important novel mediator of endothelial permeability, which signaled via ezrin, radixin and moesin proteins to increase turnover of integrin-based focal adhesions. The combined inhibition of MAP4K4 and Abl-related gene (Arg, also known as ABL2) by bosutinib preserved adherens junction integrity and reduced turnover of focal adhesions, which synergistically act to stabilize the endothelial barrier during inflammation. We conclude that MAP4K4 is an important regulator of endothelial barrier integrity, increasing focal adhesion turnover and disruption of cell-cell junctions during inflammation. Because it inhibits both Arg and MAP4K4, use of the clinically available drug bosutinib might form a viable strategy against vascular leakage syndromes