Impact of adverse events, treatment modifications, and dose intensity on survival among patients with advanced renal cell carcinoma treated with first‐line sunitinib: a medical chart review across ten centers in five European countries

Angiogenesis inhibitors have become standard of care for advanced and/or metastatic renal cell carcinoma (RCC), but data on the impact of adverse events (AEs) and treatment modifications associated with these agents are limited. Medical records were abstracted at 10 tertiary oncology centers in Europe for 291 patients ≥18 years old treated with sunitinib as first-line treatment for advanced RCC (no prior systemic treatment for advanced disease). Logistic regression models were estimated to compare dose intensity among patients who did and did not experience AEs during the landmark periods (18, 24, and 30 weeks). Cox proportional hazard models were used to explore the possible relationship of low-dose intensity (defined using thresholds of 0.7, 0.8, and 0.9) and treatment modifications during the landmark periods to survival. 64.4% to 67.9% of patients treated with sunitinib reported at least one AE of any grade, and approximately 10% of patients experienced at least one severe (grade 3 or 4) AE. Patients reporting severe AEs were statistically significantly more likely to have dose intensities below either 0.8 or 0.9. Dose intensity below 0.7 and dose discontinuation during all landmark periods were statistically significantly associated with shorter survival time. This study of advanced RCC patients treated with sunitinib in Europe found a significant relationship between AEs and dose intensity. It also found correlations between dose intensity and shorter survival, and between dose discontinuation and shorter survival. These results confirm the importance of tolerable treatment and maintaining dose intensity

Personal epistemologies and disciplinarity in the workplace: implications for international students in higher education

Workplace experiences for international students undertaking higher education programs are important aspects of their university experience. This is because many of the programs in which they are enrolled are directed towards particular occupations. Nevertheless, these workplace experiences can be both engaging and daunting for all, but perhaps no more so than for international students, who may be unfamiliar with Australian workplace mores and practices, and therefore less able to understand and negotiate with them than their domestic counterparts. Not only do international students have to become familiar with the requirements of their selected profession but also need to understand and negotiate unfamiliar cultural environments. These students often have to engage in complex and demanding learning processes when engaging in work placements, perhaps more so than their domestic peers. Because of these discipline-based and workplace environmental challenges, it is necessary for these students and their mentors or supervisors to try and effectively mediate their participation and learning in the work placements. If all of those involved in work placements are aware of these factors, then the experiences and outcomes should potentially be more beneficial for all parties (i.e., students, supervisors, university staff, and workplaces). These issues are explored in this chapter through the notions of disciplinarity, which attends to the epistemological nuances of particular study or knowledge areas and how students develop skills as disciplinary professionals. With a focus on international students, the elaborations of these issues are explored through consideration of interculturalisation and how both the experiences and experiencing of international students impacts upon the success of their work placements. Using these concepts as explanatory bases stands to permit the illumination and elaboration of the complexity of factors and processes occurring as these students learn about, and participate in, their selected professional discipline and the cultural environment of its practice

Angiogenesis inhibitor therapies for advanced renal cell carcinoma: Toxicity and treatment patterns in clinical practice from a global medical chart review

The aim of this study was to assess the treatment patterns and safety of sunitinib, sorafenib and bevacizumab in real-world clinical settings in US, Europe and Asia. Medical records were abstracted at 18 community oncology clinics in the US and at 21 tertiary oncology centers in US, Europe and Asia for 883 patients ≥18 years who had histologically/cytologically confirmed diagnosis of advanced RCC and received sunitinib (n=631), sorafenib (n=207) or bevacizumab (n=45) as first‑line treatment. No prior treatment was permitted. Data were collected on all adverse events (AEs) and treatment modifications, including discontinuation, interruption and dose reduction. Treatment duration was estimated using Kaplan-Meier analysis. Demographics were similar across treatment groups and regions. Median treatment duration ranged from 6.1 to 10.7 months, 5.1 to 8.5 months and 7.5 to 9.8 months for sunitinib, sorafenib and bevacizumab patients, respectively. Grade 3/4 AEs were experienced by 26.0, 28.0 and 15.6% of sunitinib, sorafenib and bevacizumab patients, respectively. Treatment discontinuations occurred in 62.4 (Asia) to 63.1% (US) sunitinib, 68.8 (Asia) to 90.0% (Europe) sorafenib, and 66.7 (Asia) to 81.8% (US) bevacizumab patients. Globally, treatment modifications due to AEs occurred in 55.1, 54.2 and 50.0% sunitinib, sorafenib and bevacizumab patients, respectively. This study in a large, global cohort of advanced RCC patients found that angiogenesis inhibitors are associated with high rates of AEs and treatment modifications. Findings suggest an unmet need for more tolerable agents for RCC treatment

Measurement of the open-charm contribution to the diffractive proton structure function

Production of D*+/-(2010) mesons in diffractive deep inelastic scattering has been measured with the ZEUS detector at HERA using an integrated luminosity of 82 pb^{-1}. Diffractive events were identified by the presence of a large rapidity gap in the final state. Differential cross sections have been measured in the kinematic region 1.5 < Q^2 < 200 GeV^2, 0.02 < y < 0.7, x_{IP} < 0.035, beta 1.5 GeV and |\eta(D*+/-)| < 1.5. The measured cross sections are compared to theoretical predictions. The results are presented in terms of the open-charm contribution to the diffractive proton structure function. The data demonstrate a strong sensitivity to the diffractive parton densities.Comment: 35 pages, 11 figures, 6 table

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

Designing stakeholder learning dialogues for effective global governance

A growing scholarship on multistakeholder learning dialogues suggests the importance of closely managing learning processes to help stakeholders anticipate which policies are likely to be effective. Much less work has focused on how to manage effective transnational multistakeholder learning dialogues, many of which aim to help address critical global environmental and social problems such as climate change or biodiversity loss. They face three central challenges. First, they rarely shape policies and behaviors directly, but work to ‘nudge’ or ‘tip the scales’ in domestic settings. Second, they run the risk of generating ‘compromise’ approaches incapable of ameliorating the original problem definition for which the dialogue was created. Third, they run the risk of being overly influenced, or captured, by powerful interests whose rationale for participating is to shift problem definitions or narrow instrument choices to those innocuous to their organizational or individual interests. Drawing on policy learning scholarship, we identify a six-stage learning process for anticipating effectiveness designed to minimize these risks while simultaneously fostering innovative approaches for meaningful and longlasting problem solving: Problem definition assessments; Problem framing; Developing coalition membership; Causal framework development; Scoping exercises; Knowledge institutionalization. We also identify six management techniques within each process for engaging transnational dialogues around problem solving. We show that doing so almost always requires anticipating multiple-step causal pathways through which influence of transnational and/or international actors and institutions might occur

Transparent Meta-Analysis of Prospective Memory and Aging

Prospective memory (ProM) refers to our ability to become aware of a previously formed plan at the right time and place. After two decades of research on prospective memory and aging, narrative reviews and summaries have arrived at widely different conclusions. One view is that prospective memory shows large age declines, larger than age declines on retrospective memory (RetM). Another view is that prospective memory is an exception to age declines and remains invariant across the adult lifespan. The present meta-analysis of over twenty years of research settles this controversy. It shows that prospective memory declines with aging and that the magnitude of age decline varies by prospective memory subdomain (vigilance, prospective memory proper, habitual prospective memory) as well as test setting (laboratory, natural). Moreover, this meta-analysis demonstrates that previous claims of no age declines in prospective memory are artifacts of methodological and conceptual issues afflicting prior research including widespread ceiling effects, low statistical power, age confounds, and failure to distinguish between various subdomains of prospective memory (e.g., vigilance and prospective memory proper)

Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.

PURPOSE: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

Elective cancer surgery in COVID-19-free surgical pathways during the SARS-CoV-2 pandemic: An international, multicenter, comparative cohort study

PURPOSE As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19–free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19–free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19–free surgical pathways. Patients who underwent surgery within COVID-19–free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19–free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score–matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19–free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION Within available resources, dedicated COVID-19–free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology