Regulatory agencies have long adopted a three‐tier framework for risk assessment. We build on this structure to propose a tiered approach for resilience assessment that can be integrated into the ...existing regulatory processes. Comprehensive approaches to assessing resilience at appropriate and operational scales, reconciling analytical complexity as needed with stakeholder needs and resources available, and ultimately creating actionable recommendations to enhance resilience are still lacking. Our proposed framework consists of tiers by which analysts can select resilience assessment and decision support tools to inform associated management actions relative to the scope and urgency of the risk and the capacity of resource managers to improve system resilience. The resilience management framework proposed is not intended to supplant either risk management or the many existing efforts of resilience quantification method development, but instead provide a guide to selecting tools that are appropriate for the given analytic need. The goal of this tiered approach is to intentionally parallel the tiered approach used in regulatory contexts so that resilience assessment might be more easily and quickly integrated into existing structures and with existing policies.
We analyse ice flow and structural glaciology of Shackleton Glacier, a dendritic glacier with multiple icefalls in the Canadian Rockies. A major tributary-trunk junction allows us to investigate the ...potential of tributaries to alter trunk flow and structure, and the formation of bedrock steps at confluences. Multi-year velocity-stake data and structural glaciology up-glacier from the junction were assimilated with glacier-wide velocity derived from Radarsat-2 speckle tracking. Maximum flow speeds are 65 m a−1 in the trunk and 175 m a−1 in icefalls. Field and remote-sensing velocities are in good agreement, except where velocity gradients are high. Although compression occurs in the trunk up-glacier of the tributary entrance, glacier flux is steady state because flow speed increases at the junction due to the funnelling of trunk ice towards an icefall related to a bedrock step. Drawing on a published erosion model, we relate the heights of the step and the hanging valley to the relative fluxes of the tributary and trunk. It is the first time that an extant glacier is used to test and support such model. Our study elucidates the inherent complexity of tributary/trunk interactions and provides a conceptual model for trunk flow restriction by a tributary in surge-type glaciers.
IL-17, a major inflammatory cytokine plays a critical role in the pathogenesis of many autoimmune inflammatory diseases. In this study, we report a new function of RNA-binding protein HuR in ...IL-17-induced Act1-mediated chemokine mRNA stabilization. HuR deficiency markedly reduced IL-17-induced chemokine expression due to increased mRNA decay. Act1-mediated HuR polyubiquitination was required for the binding of HuR to CXCL1 mRNA, leading to mRNA stabilization. Although IL-17 induced the coshift of Act1 and HuR to the polysomal fractions in a sucrose gradient, HuR deficiency reduced the ratio of translation-active/translation-inactive IL-17-induced chemokine mRNAs. Furthermore, HuR deletion in distal lung epithelium attenuated IL-17-induced neutrophilia. In summary, HuR functions to couple receptor-proximal signaling to posttranscriptional machinery, contributing to IL-17-induced inflammation.
Interest has grown in using new screening technologies such as drones to search for methane leaks in hydrocarbon production infrastructure. Screening technologies may be less expensive and faster ...than traditional methods. However, including new technologies in emissions monitoring programs requires an accurate understanding of what leaks a system will detect and the resultant emissions mitigation. Here we examine source detection of a drone-based system with controlled releases. We examine different detection algorithm parameters to understand trade-offs between false positive rate and detection probability. Leak detection was poor under all conditions with an average detection probability of 0.21. Detection probability was not affected by emission rate, suggesting similar systems may commonly miss large leaks. Detection was best in moderate wind speeds and at 750–2000 m downwind from the source where the plume had diffused vertically above the minimum flight level of 40–50 m. Predicted concentration enhancement from a Gaussian plume model was a reasonable predictor of detection within the test suite. Enabling lower flight elevations may increase detection probability. Overall, the experiments suggest that controlled releases are useful and necessary to provide an understanding of detection probability of screening technologies for regulatory and deployment purposes, and the testing must be representative to support broad application.
Elucidating the mechanism of action of an antifungal or cytotoxic compound is a time‐consuming process. Yeast chemogenomic profiling provides a compelling solution to the problem but is ...experimentally complex. Here, we demonstrate the use of a highly simplified yeast chemical genetic assay comprising just 89 yeast deletion strains, each diagnostic for a specific mechanism of action. We use the assay to investigate the mechanism of action of two antifungal chalcone compounds, trans‐chalcone and 4′‐hydroxychalcone, and narrow down the mechanism to transcriptional stress. Crucially, the assay eliminates mechanisms of action such as topoisomerase I inhibition and membrane disruption that have been suggested for related chalcone compounds. We propose this simplified assay as a useful tool to rapidly identify common off‐target mechanisms.
Here, we demonstrate a simplified HIP HOP assay comprising 89 yeast deletion strains, each diagnostic for common cell inhibitory mechanisms of action. We test two chalcone compounds with unknown mechanisms, trans‐chalcone and 4′‐hydroxychalcone and show that both act through transcriptional stress. The assay is both easy and cheap to use and can help identify and eliminate common mechanisms of action.
Summary
Haematology patients receiving chemo‐ or immunotherapy are considered to be at greater risk of COVID‐19‐related morbidity and mortality. We aimed to identify risk factors for COVID‐19 ...severity and assess outcomes in patients where COVID‐19 complicated the treatment of their haematological disorder. A retrospective cohort study was conducted in 55 patients with haematological disorders and COVID‐19, including 52 with malignancy, two with bone marrow failure and one immune‐mediated thrombotic thrombocytopenic purpura (TTP). COVID‐19 diagnosis coincided with a new diagnosis of a haematological malignancy in four patients. Among patients, 82% were on systemic anti‐cancer therapy (SACT) at the time of COVID‐19 diagnosis. Of hospitalised patients, 37% (19/51) died while all four outpatients recovered. Risk factors for severe disease or mortality were similar to those in other published cohorts. Raised C‐reactive protein at diagnosis predicted an aggressive clinical course. The majority of patients recovered from COVID‐19, despite receiving recent SACT. This suggests that SACT, where urgent, should be administered despite intercurrent COVID‐19 infection, which should be managed according to standard pathways. Delay or modification of therapy should be considered on an individual basis. Long‐term follow‐up studies in larger patient cohorts are required to assess the efficacy of treatment strategies employed during the pandemic.
Summary Background Blockade of the endocannabinoid receptor reduces obesity and improves metabolic abnormalities such as triglycerides, HDL cholesterol, and fasting blood glucose. We assessed whether ...rimonabant would improve major vascular event-free survival. Methods This double-blind, placebo-controlled trial was undertaken in 974 hospitals in 42 countries. 18 695 patients with previously manifest or increased risk of vascular disease were randomly assigned to receive either rimonabant 20 mg (n=9381) or matching placebo (n=9314). Randomisation was stratified by centre, implemented with an independent interactive voice response system, and all study personnel and participants were masked to group assignment. The primary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke, as determined via central adjudication. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00263042. Findings At a mean follow-up of 13·8 months (95% CI 13·6–14·0), the trial was prematurely discontinued because of concerns by health regulatory authorities in three countries about suicide in individuals receiving rimonabant. All randomised participants were analysed. At the close of the trial (Nov 6, 2008), the composite primary endpoint of cardiovascular death, myocardial infarction, or stroke occurred in 364 (3·9%) patients assigned to rimonabant and 375 (4·0%) assigned to placebo (hazard ratio 0·97, 95% CI 0·84–1·12, p=0·68). With rimonabant, gastrointestinal (3038 33% vs 2084 22%), neuropsychiatric (3028 32% vs 1989 21%), and serious psychiatric side-effects (232 2·5% vs 120 1·3%) were significantly increased compared with placebo. Four patients in the rimonabant group and one in the placebo group committed suicide. Interpretation The premature termination of this trial has important lessons for drug development. A drug that was being marketed for weight loss, but being tested for improving cardiovascular outcomes, induced a level of serious neuropsychiatric effects that was deemed unacceptable by regulatory authorities, and both the drug and the trial were abruptly terminated. Funding Sanofi-Aventis.
The primary immunodeficiencies (PIDs), rare inherited diseases characterized by severe dysfunction of immunity, have been successfully treated by allogeneic hematopoietic stem cell transplantation ...(Allo-HSCT) in childhood. Controversy exists regarding optimal timing and use of Allo-HSCT in adults, due to lack of experience and previous poor outcomes. Twenty-nine consecutive adult patients, with a mean age at transplant of 24 years (range, 17-50 years), underwent Allo-HSCT. Reduced-intensity conditioning (RIC) included fludarabine (Flu)/melphalan/alemtuzumab (n = 20), Flu/busulfan (Bu)/alemtuzumab (n = 8), and Flu/Bu/antithymocyte globulin (n = 1). Stem cell donors were matched unrelated donors or mismatched unrelated donors (n = 18) and matched related donors (n = 11). Overall survival (OS), event-free survival, transplant-related mortality (TRM), acute and chronic graft-versus-host disease incidence and severity, time to engraftment, lineage-specific chimerism, immune reconstitution, and discontinuation of immunoglobulin replacement therapy were recorded. OS at 3 years for the whole cohort was 85.2%. The rarer PID patients without chronic granulomatous disease (CGD) achieved an OS at 3 years of 88.9% (n = 18), compared with 81.8% for CGD patients (n = 11). TRM was low with only 4 deaths observed at a median follow-up of 3.5 years. There were no cases of early or late rejection. In all surviving patients, either stable mixed chimerism or full donor chimerism were observed. At last follow-up, 87% of the surviving patients had no evidence of persistent or recurrent infections. Allo-HSCT is safe and effective in young adult patients with severe PID and should be considered the treatment of choice where an appropriate donor is available.
•Allo-HSCT with RIC is safe and effective in younger adults with severe PID.•Referral triggers should include severe infections, autoimmunity, malignancy, and disease progression despite conservative management.
Workers in the oil and gas industry are exposed to numerous health risks, ranging from poor health behaviours to the possibility of life-threatening injuries. Determining the most appropriate models ...of healthcare for the oil and gas industry is difficult, as strategies must be acceptable to multiple stakeholders, including employees, employers, and local communities. The purpose of this review was to broadly explore the health status and needs of workers in the oil and gas industry and healthcare delivery models relating to primary care and emergency responses. Database searches of PubMed, EMBASE, CINAHL, PsycINFO, and Scopus were conducted, as well as grey literature searches of Google, Google Scholar, and the International Association of Oil and Gas Producers website. Resource-sector workers, particularly those in ‘fly-in fly-out’ roles, are susceptible to poor health behaviours and a higher prevalence of mental health concerns than the general population. Evidence is generally supportive of organisation-led behaviour change and mental health-related interventions. Deficiencies in primary care received while on-site may lead workers to inappropriately use local health services. For the provision of emergency medical care, telehealth and telemedicine lead to favourable outcomes by improving patient health status and satisfaction and reducing the frequency of medical evacuations.
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