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Background: Whereas the beneficial effect of antiplatelet therapy for recurrent stroke prevention has been well established, uncertainties remain regarding the optimal antithrombotic regimen for recently symptomatic carotid stenosis. We sought to explore the approaches of stroke physicians to antithrombotic management of patients with symptomatic carotid stenosis. Methods: We employed a qualitative descriptive methodology to explore the decision-making approaches and opinions of physicians regarding antithrombotic regimens for symptomatic carotid stenosis. We conducted semi-structured interviews with a purposive sample of 22 stroke physicians (11 neurologists, 3 geriatricians, 5 interventional-neuroradiologists, and 3 neurosurgeons) from 16 centers on four continents to discuss symptomatic carotid stenosis management. We then conducted thematic analysis on the transcripts. Results: Important themes revealed from our analysis included limitations of existing clinical trial evidence, competing surgeon versus neurologist/internist preferences, and the choice of antiplatelet therapy while awaiting revascularization. There was a greater concern for adverse events while using multiple antiplatelet agents (e.g., dual-antiplatelet therapy (DAPT)) in patients undergoing carotid endarterectomy compared to carotid artery stenting. Regional variations included more frequent use of single antiplatelet agents among European participants. Areas of uncertainty included antithrombotic management if already on an antiplatelet agent, implications of nonstenotic features of carotid disease, the role of newer antiplatelet agents or anticoagulants, platelet aggregation testing, and timing of DAPT. Conclusion: Our qualitative findings can help physicians critically examine the rationale underlying their own antithrombotic approaches to symptomatic carotid stenosis. Future clinical trials may wish to accommodate identified variations in practice patterns and areas of uncertainty to better inform clinical practice.

The protein kinases PAK4, PAK5 and PAK6 comprise a family of ohnologues. In multiple cancers including melanomas PAK5 most frequently carries non-synonymous mutations; PAK6 and PAK4 have fewer; and PAK4 is often amplified. To help interpret these genomic data, initially we compared the cellular regulation of the sister kinases and their roles in melanoma cells. In common with many ohnologue protein kinases, PAK4, PAK5 and PAK6 each have two 14-3-3-binding phosphosites of which phosphoSer99 is conserved. PAK4 localises to the leading edge of cells in response to phorbol ester-stimulated binding of 14-3-3 to phosphoSer99 and phosphoSer181, which are phosphorylated by two different PKCs or PKDs. These phosphorylations of PAK4 are essential for its phorbol ester-stimulated phosphorylation of downstream substrates. In contrast, 14-3-3 interacts with PAK5 in response to phorbol ester-stimulated phosphorylation of Ser99 and epidermal growth factor-stimulated phosphorylation of Ser288; whereas PAK6 docks onto 14-3-3 and is prevented from localising to cell–cell junctions when Ser133 is phosphorylated in response to cAMP-elevating agents via PKA and insulin-like growth factor 1 via PKB/Akt. Silencing of PAK4 impairs viability, migration and invasive behaviour of melanoma cells carrying BRAFV600E or NRASQ61K mutations. These defects are rescued by ectopic expression of PAK4, more so by a 14-3-3-binding deficient PAK4, and barely by PAK5 or PAK6. Together these genomic, biochemical and cellular data suggest that the oncogenic properties of PAK4 are regulated by PKC–PKD signalling in melanoma, while PAK5 and PAK6 are dispensable in this cancer.

To describe longitudinal trends in patients with obesity and Metabolic Syndrome (MetS) undergoing total knee arthroplasty (TKA) and the impact on complications.We identified primary TKA patients between 2006 and 2017 within the National Surgical Quality Improvement Program database. We recorded patient demographics and 30-day complications. We labeled those with an obese Body Mass Index (BMI ≥30), hypertension, and diabetes as having MetS. We used regression to evaluate trends in BMI and complications over time and variables associated with the odds of complication.We identified 270,846 TKA patients, 63.71% of which were obese (n = 172,333), 15.21% morbidly obese (n = 41,130), and 12.37% met the criteria for MetS (n = 33,470). Mean BMI increased by 0.03 per year (0.02-0.05). Despite this, the odds of adverse events in obese patients decreased: major complications by 0.94 (0.93-0.96) and minor complications by 0.94 (0.93-0.95). The proportion of patients with MetS remained stable; however, we found improvements in major (0.94 [0.91-0.97]) and minor complications (0.97 [0.94-1.00]) over time. MetS components (hypertension, diabetes, and BMI ≥40) were associated with major and minor complications in obese patients, while neuraxial anesthesia lowered the odds of major complications in obese patients (0.87 [0.81-0.92]).Mean BMI in primary TKA patients increased from 2006 to 2017. MetS components diabetes and hypertension elevated the odds of complications in obese patients. Rates of complications in patients with obesity and MetS exhibited a longitudinal decline. These findings may reflect increased awareness and improved management of these patients.

In 2020, the Australian and New Zealand flux research and monitoring network, OzFlux, celebrated its 20th anniversary by reflecting on the lessons learned through two decades of ecosystem studies on global change biology. OzFlux is a network not only for ecosystem researchers, but also for those ‘next users’ of the knowledge, information and data that such networks provide. Here, we focus on eight lessons across topics of climate change and variability, disturbance and resilience, drought and heat stress and synergies with remote sensing and modelling. In distilling the key lessons learned, we also identify where further research is needed to fill knowledge gaps and improve the utility and relevance of the outputs from OzFlux. Extreme climate variability across Australia and New Zealand (droughts and flooding rains) provides a natural laboratory for a global understanding of ecosystems in this time of accelerating climate change. As evidence of worsening global fire risk emerges, the natural ability of these ecosystems to recover from disturbances, such as fire and cyclones, provides lessons on adaptation and resilience to disturbance. Drought and heatwaves are common occurrences across large parts of the region and can tip an ecosystem's carbon budget from a net CO2 sink to a net CO2 source. Despite such responses to stress, ecosystems at OzFlux sites show their resilience to climate variability by rapidly pivoting back to a strong carbon sink upon the return of favourable conditions. Located in under-represented areas, OzFlux data have the potential for reducing uncertainties in global remote sensing products, and these data provide several opportunities to develop new theories and improve our ecosystem models. The accumulated impacts of these lessons over the last 20 years highlights the value of long-term flux observations for natural and managed systems. A future vision for OzFlux includes ongoing and newly developed synergies with ecophysiologists, ecologists, geologists, remote sensors and modellers.

This paper is one in a series reporting results from small telescope observations of variable young stars. Here, we study the repeating outbursts of three likely Be stars based on long-term optical, near-infrared, and mid-infrared photometry for all three objects, along with follow-up spectra for two of the three. The sources are characterised as rare, truly regularly outbursting Be stars. We interpret the photometric data within a framework for modelling light curve morphology, and find that the models correctly predict the burst shapes, including their larger amplitudes and later peaks towards longer wavelengths. We are thus able to infer the start and end times of mass loading into the circumstellar disks of these stars. The disk sizes are typically 3-6 times the areas of the central star. The disk temperatures are ~40%, and the disk luminosities are ~10% of those of the central Be star, respectively. The available spectroscopy is consistent with inside-out evolution of the disk. Higher excitation lines have larger velocity widths in their double-horned shaped emission profiles. Our observations and analysis support the decretion disk model for outbursting Be stars., Comment: Accepted for publication by MNRAS. 20 pages, 11 figures, 2 tables

PDF file - 232K, Immunohistochemical analysis of P-Erk, P-Akt, P-S6, and beta-catenin in tumors arising in K5-tTR::tet-Kras mice

The RAS genes are the most commonly mutated oncogenes in human cancer and present a particular therapeutic dilemma, as direct targeting of Ras proteins by small molecules has proved difficult. Signaling pathways downstream of Ras, in particular Raf/Mek/Erk and PI3K/Akt/mTOR, are dominated by lipid and protein kinases that provide attractive alternate targets in Ras-driven tumors. As p21-activated kinase 1 (Pak1) has been shown to regulate both these signaling pathways and is itself upregulated in many human cancers, we assessed the role of Pak1 in Ras-driven skin cancer. In human squamous cell carcinoma (SCC), we found a strong positive correlation between advanced stage and grade and PAK1 expression. Using a mouse model of Kras-driven SCC, we showed that deletion of the mouse Pak1 gene led to markedly decreased tumorigenesis and progression, accompanied by near total loss of Erk and Akt activity. Treatment of KrasG12D mice with either of two distinct small molecule Pak inhibitors (PF3758309 and FRAX597) caused tumor regression and loss of Erk and Akt activity. Tumor regression was also seen in mice treated with a specific Mek inhibitor, but not with an Akt inhibitor. These findings establish Pak1 as a new target in KRAS-driven tumors and suggest a mechanism of action through the Erk, but not the Akt, signaling pathway. Cancer Res; 72(22); 5966–75. ©2012 AACR.

PDF file - 99K, Immunostaining for Pak1 and Pak2 in mouse skin

PDF file - 60K, Schematic presentation of Ras-mediated Pak1 signaling

PDF file - 162K, Proliferation and apoptosis in drug-treated animals

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PDF file - 289K, Immunostaining of Pak1 and proliferative signaling markers in SCC

PDF file - 126K, Activity of FRAX-597 against group A and group B Paks

PDF file - 58K, Specificity of Pak inhibitors

PDF file - 219K, Immunostaining for Pak1 and Pak2 in mouse skin

PDF file - 131K