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Transition of a Clinical Trial into Translational Research: The Prostate Cancer Prevention Trial Experience
Phyllis J. Goodman, Catherine M. Tangen, Alan R. Kristal, Ian M. Thompson, M. Scott Lucia, Elizabeth A. Platz, William D. Figg, Ashraful Hoque, Ann Hsing, Marian L. Neuhouser, Howard L. Parnes, Juergen K.V. Reichardt, Regina M. Santella, Cathee Till and Scott M. Lippman
Phyllis J. Goodman
Catherine M. Tangen
Alan R. Kristal
Ian M. Thompson
M. Scott Lucia
Elizabeth A. Platz
William D. Figg
Ashraful Hoque
Ann Hsing
Marian L. Neuhouser
Howard L. Parnes
Juergen K.V. Reichardt
Regina M. Santella
Cathee Till
Scott M. Lippman
DOI: 10.1158/1940-6207.CAPR-09-0256 Published December 2010
Large clinical trials provide a tremendous opportunity to integrate correlative, comprehensive biological studies with invaluable repositories of biospecimens and clinical and other data from the trial. The Prostate Cancer Prevention Trial (PCPT) was a phase III randomized, double-blind, placebo-controlled clinical trial of finasteride in 18,882 men. Clinical data and blood and tissue specimens were collected at baseline and throughout the study, offering an opportunity to create a program project to investigate hypotheses related to the biology underlying the PCPT findings as well as the etiology and risk of prostate cancer. The transition of the randomized PCPT into this translational and epidemiologic scientific investigation required extensive planning and coordination. Five individual but interrelated projects were brought together with the underlying program theme of the genetic, metabolic, and environmental factors associated with the risks of overall and high-grade prostate cancer and how these factors affected the efficacy of finasteride in preventing cancer. All projects with serum-based measures use a single, shared, nested case–control sample of participants so that each subject provides a more complete biomarker and genetic profile for the evaluation of joint effects of these factors. Strengths of this program include the following: 1) the control group contains only men who are negative for biopsy-detected cancer, 2) the statistical methods to evaluate associations of risk factors with disease are shared across all projects, 3) the large number of cancer cases with fully characterized genetic, metabolic, and behavioral exposures, 4) a central pathology core histopathologically classified the prostate cancer, and 5) cancer cases identified during the PCPT reflect the characteristics of cases currently being detected in the prostate-specific antigen screening era, leading to contemporary and highly relevant results. This article describes the comprehensive methodology and multidisciplinary collaborations, both national and international, essential to a major risk-modeling research program. We provide a framework for doing collaborative research in an international setting structured around a common theme of a clinical trial. Cancer Prev Res; 3(12); 1523–33. ©2010 AACR.
Prostate cancer is the most frequently diagnosed nonskin cancer and second leading cause of cancer death in U.S. men; 192,280 new diagnoses and 27,360 deaths are estimated to occur in 2009 despite advances in diagnosis and treatment (1). Furthermore, the absolute number of new cases of prostate cancer is expected to increase substantially in the years to come because of the aging male population. Research into improving control of this disease is progressing on many fronts including cancer prevention.
Although much has been learned in recent years about the molecular pathogenesis of prostate cancer, the only established risk factors are increased age, African American race, and family history of prostate cancer in a first-degree relative (2). Many questions remain about the etiologic roles of common genetic variants, inflammation, environmental carcinogens, and diet, obesity, and other lifestyle factors. Finasteride in the Prostate Cancer Prevention Trial (3–7) and dutasteride in the Reduction by Dutasteride of Prostate Cancer Events (8) trial reduced prostate cancer risk by 23% to 25%, but this reduction left many men in both studies who still developed prostate cancer while taking study medication. The development and implementation of strategies for more effective prevention, whether through more options or through larger risk reductions, requires advances in our understanding of prostate carcinogenesis and in prostate cancer risk assessment (9–12).
The Prostate Cancer Prevention Trial (PCPT) was a phase III randomized, double-blind, placebo-controlled clinical trial of a molecular targeted agent (3). Extensive clinical data, including clinical, lifestyle, behavioral, and anthropometric data, were collected at baseline and throughout the 7-year study, blood specimens were obtained annually for prostate-specific antigen (PSA) assessment, tissue from prostate biopsies and prostatectomies, and a special white blood cell (WBC) collection for the harvesting of DNA were stored in the PCPT biorepository. The clinical and biospecimen resources collected during the PCPT offered an opportunity to investigate hypotheses related both to the biology underlying the trial's findings and to the etiology of prostate cancer. This opportunity differs from that of a well-designed phase II trial, which would be more limited in the availability of data and biological samples and would not include a cancer endpoint for subsequent risk determinations. PCPT risk modeling also differs from population-based epidemiology, which is less controlled and more prone to the influence of confounding factors. With yearly blood samples, central pathology review, and definitive cancer endpoint data in a large prospective trial population that included clinically established controls (i.e., with no prostate cancer diagnosed), the PCPT is a unique resource for comprehensive risk modeling.
The overall goals of the program are to investigate hypotheses concerning a) the biological mechanisms underlying the results of the PCPT and b) the etiology of prostate cancer with an eye toward risk assessment and prevention strategies. The program encompasses 5 interrelated and interactive projects, biostatistical and pathology-genotyping teams, and 26 investigators. The strategy for accomplishing our research goals is to conduct interactive epidemiologic and molecular studies using the common PCPT database. Each projects ask 2 questions: (1) What are the associations of a purported risk factor with the risk of prostate cancer and high-grade prostate cancer, focusing on associations in the placebo arm? and (2) Do the effects of this purported risk factor on the risk of prostate cancer and high-grade prostate cancer differ for those taking finasteride? Interactions between projects are also investigated to determine the joint effects of genetic, metabolic, and environmental risk factors on the outcomes of the PCPT.
The project required extensive planning and coordination for the transition of a randomized clinical trial into a translational and epidemiologic scientific investigation. This article describes the comprehensive methodology and multidisciplinary collaborations, both national and international, which are essential components of this major risk-modeling research program. We provide a framework for doing collaborative research in an international setting structured around a common theme of a clinical trial.
The PCPT
The foundation of this risk-modeling program, the PCPT, was designed to establish whether finasteride, a 5α-reductase type II inhibitor, prevents prostate cancer. Between 1994 and 1997, a total of 18,882 men from 210 study sites located throughout the United States and Canada were randomized in the PCPT to either the finasteride or placebo arm and followed yearly with a digital rectal examination (DRE) and PSA determination. Men found to have abnormal DRE findings or elevated PSA levels were recommended for prostate biopsy. Following 7 years of study participation, men without a diagnosis of prostate cancer were recommended to undergo an end-of-study biopsy. The primary study endpoint was the 7-year period prevalence of prostate cancer. The results were published on July 17, 2003 (3).
At the final analysis, prostate cancer status, either a diagnosis or negative end-of-study biopsy, was available in 59.6% of the participants in the finasteride arm and 63.0% of those in the placebo arm. Prostate cancer was detected in 803 of 4,368 (18.4%) in the finasteride arm and in 1,147 of 4,692 (24.4%) in the placebo arm; a 24.8% lower risk of prostate cancer for men in the finasteride group compared with men in the placebo group (P <.001). However, despite the reduction in risk of prostate cancer overall, there was an increased risk of a diagnosis of high-grade disease, defined as Gleason score 7–10. High-grade tumors were found in 280 of the evaluated men in the finasteride group (6.4%) versus 237 men in the placebo group (5.1%).
Subsequent analyses over the next 5 years helped to put the overall and high-grade disease findings into perspective. There is now convincing evidence that the initial observation of an excess risk of high-grade disease on the intervention arm of PCPT was due, at least in part, to detection bias: finasteride has been shown to significantly increase the sensitivity of both PSA (13) and prostate biopsy (5) for high-grade cancers, thereby enhancing their detection in men taking finasteride. In addition, statistical modeling studies, which adjusted for the fact that the majority of men with a diagnosis of prostate cancer did not undergo prostatectomy (the gold standard for determining prostate cancer grade), suggest that the risk of Gleason score 7–10 cancer is either unchanged or even reduced by finasteride (5–7).
Prostate Carcinogenesis and Finasteride
The biological rationale for testing finasteride in the PCPT hinged largely on the nature of prostate cancer as an androgen-dependent disease (14, 15). Dihydrotestosterone (DHT) is the most biologically active androgen in the prostate and is synthesized through the irreversible reduction of testosterone (T) by the enzyme steroid 5α-reductase. The drug finasteride inhibits the type 2 isoenzyme of 5α-reductase, markedly decreasing the intraprostatic conversion of T to DHT (16). This rationale supported testing the preventive efficacy of finasteride in the PCPT. The initial results of the PCPT raised urgent questions regarding the use and activity of finasteride. A significant contribution of ongoing research based on PCPT will be to provide a better understanding of the precise role of hormone metabolism, with all its constitutional and somatic genetic variations, in prostate cancer risk and finasteride activity.
Genesis of the Program
In the program concept phase, which began in 1998, an executive scientific review committee received and evaluated proposals solicited from a widely circulated requests for applications (RFA) from investigators across the United States and Canada for studies of genetic factors and other variables that affect an individual's risk of prostate cancer and the effect of the intervention with finasteride. Proposals were evaluated for their scientific merit, relevance of the project to the original PCPT study hypotheses, judicious use of biospecimens from this unique population, and the previous scientific accomplishment and experience of the investigators. The proposals need not have been related to the planned secondary objectives of the PCPT, and other than hypotheses related to the grade of carcinoma and the role of diet, they were not. Because of a numerous common themes across the accepted proposals, they were assembled into a program project (P01) application rather than released for submission as independent R01 applications. Proposals that were not accepted as part of the P01 still had the potential to move forward but would need to do so under a separate funding source (R01). Another year was spent refining the projects, identifying laboratories, performing pilot studies, and assembling the final P01 application that was submitted to the National Cancer Institute. Ultimately, the application received a favorable score and the notice of funding was received in December 2004.
Risk-Modeling Program Theme
The theme unifying the 5 key areas (or "studies") within this project is the genetic, metabolic, and environmental factors associated with the risks of prostate cancer overall and high-grade prostate cancer specifically, and the effects of these factors on the efficacy of finasteride as a cancer preventive agent. The program also includes studies to better understand the mechanisms underlying these risk factor associations. Two major elements of this theme are (1) the study of genetic polymorphisms to identify molecular prostate cancer risk factors, from which we expect to determine pharmacogenetic profiles of men most likely to benefit from finasteride, and (2) the study of somatic mutations to discover the mechanisms underlying the increased risk of high-grade prostate cancer associated with finasteride use. Identifying factors or mutation that can distinguish aggressive or high-grade tumors in an era in which there is concern about the overdetection of prostate cancer will prove beneficial, and while the concern over the increase of high-grade disease in the finasteride arm has been tempered by subsequent research since the inception of this project, there is still interest in finding biologic results which support the detection bias finding.
Five Interrelated Research Projects
Each of the 5 projects constituting this collaborative risk-modeling program is outlined in Table 1, and fuller descriptions are provided in the following paragraphs.
Projects, PI, and serum and tissue measures
Project 1 ("Androgen Metabolism in the PCPT")
This project directly examines the mechanisms underlying the primary hypothesis of the PCPT: whether inhibiting conversion of T to DHT, the primary steroid-driving cell growth in the prostate, reduces the risk of prostate cancer. The overall project 1 hypothesis is that genetic variations in the steroid metabolic genes and variations in hormone levels are associated with both prostate cancer risk and the efficacy of finasteride in preventing prostate cancer. Project 1 exemplifies the new field of "preventive pharmacogenetics," or the study of genetic factors that account for interindividual variability in response to a preventive agent. Another hypothesis of project 1 is that long-term finasteride exposure, which results in a DHT-starved environment, selects for the growth of high-grade prostate cancer cells. This is being investigated by determining rates of somatic mutations in high-grade lesions to see whether they differ between the finasteride and placebo arms. Project 1 also examines whether rates of specific somatic mutations differ across normal and neoplastic prostate tissues. Finally, this project measures post–baseline finasteride concentrations in the intervention arm using LC/MS. These data will provide insight into the adherence to the intervention and will be used in secondary analyses.
Project 2 ("Diet and Diet-Related Factors in the PCPT")
This project improves the understanding of 1) the associations of diet and diet-related factors such as obesity with prostate cancer risk and 2) the role favorable dietary patterns or use of dietary supplements may play in enhancing the efficacy of finasteride as a prostate cancer preventive agent. This project investigates dietary factors that affect steroid hormone and insulin-like growth factor (IGF) metabolism, such as obesity, glycemic index, and dairy foods, as well as dietary factors that affect oxidative load through prooxidant, antioxidant, and anti-inflammatory effects, such as lycopene, ω-3 fatty acids, glucosinolates, and tocopherols.
Project 3 ("Insulin-like Growth Factor Axis and Insulin Resistance in the PCPT")
This project provides information regarding the hypothesis that circulating levels of IGF-1, IGF-2, IGF-BP3 (total and intact), IGF-BP2, leptin, and C-peptide, considered jointly as well as individually, are related to prostate cancer risk. The metabolic factors tested in project 3 are IGFs, peptide growth factors known to play important roles in regulating cell proliferation, differentiation, and death. Suggestive evidence from human population studies show that IGF-1 and insulin resistance increase risk for prostate cancer whereas IGF-BP3 decreases risk. Project 3 is also assessing whether IGFs and IGF signaling in prostate tissue is related to measures of cell renewal dynamics. If IGF-insulin receptor signaling is found to be associated with aggressive prostate cancer, one model to account for the PCPT results regarding increased risk of high-grade lesions in the finasteride arm is that the reduction of androgen receptor signaling associated with finasteride use results in selective pressure for neoplasms that are, at least in part, stimulated by growth factors other than androgens.
Project 4 ("Genotypic and Phenotypic Studies of Inflammation in the PCPT")
This project tests the hypothesis that inflammation and focal atrophy, possible environmental contributors (serum antibodies against infectious agents), and genetics (polymorphisms in genes involved in the innate and adaptive immune response) influence prostate cancer risk. Given that inflammation is a clear target for intervention, we anticipate that this work will have important implications for prostate cancer prevention. This study is the first to systematically examine focal atrophy lesions in men with and without prostate cancer. Prostate tissue is not typically available for middle-aged men who do not have an indication for biopsy, such as an elevated serum PSA. For this reason, it is unknown how the presence and extent inflammation correlate with the occurrence of prostate cancer. This study is the first to evaluate this association in a large sample of men with a known negative prostate cancer status.
Project 5 ("Oxidative Damage and DNA Repair in the PCPT")
This project evaluates hypotheses related to oxidative stress and DNA repair and prostate carcinogenesis. This study investigates whether variations in genes encoding enzymes that generate reactive oxygen species (ROS), neutralize ROS, and repair DNA damage are associated with risk of prostate cancer and high-grade cancer. Serum levels of oxidized proteins, a biomarker of oxidative damage, are measured to determine whether baseline levels of oxidative stress are elevated in those who go on to develop cancer and, if so, whether the association is modified by finasteride.
Cross-Project Interactions
Interactions among projects are motivated by the strategic incorporation of cross-project interactive specific aims within each project. Some examples of these aims are as follows:
Project 1 ("Androgen Metabolism in the PCPT") and project 2 ("Diet and Diet-Related Factors in the PCPT") : To investigate the joint associations of serum sex steroid hormones and obesity in relation to prostate cancer risk.
Project 2 ("Diet and Diet-Related Factors in the PCPT") and project 4 ("Genotypic and Phenotypic Studies of Inflammation in the PCPT") : To investigate the associations of dietary and serum phospholipid fatty acids with inflammation and focal atrophy in prostate biopsy tissue.
Project 3 ("Insulin-like Growth Factor Axis and Insulin Resistance in the PCPT") and project 5 ("Oxidative Damage and DNA Repair in the PCPT") : To assess how IGFs may influence the oxidative stress–prostate cancer risk association.
Project 4 ("Genotypic and Phenotypic Studies of Inflammation in the PCPT") and project 1 ("Androgen Metabolism in the PCPT") : To test whether the difference between prostate cancer cases and controls in the prevalence and extent of inflammation and atrophy varies by serum testosterone or estradiol.
Project 5 ("Oxidative Damage and DNA Repair in the PCPT") and project 2 ("Diet and Diet-Related Factors in the PCPT") : To test whether the associations of specific dietary factors with prostate cancer risk differ by polymorphisms in genes affecting oxidative load.
A final goal is to evaluate the joint effects of risk factors across the 5 projects, both in terms of predicting prostate cancer and predicting who may be the ideal candidates for the use of finasteride to prevent prostate cancer. This model spans all projects incorporating the key findings from each project and from the cross-project interactions and could include serum and tissue measures, pharmacokinetic assessment, and genotyping results. Finally, findings from this model could be used to enhance the prostate cancer risk model that was developed using data from the PCPT (2).
Biostatistics and Pathology-Genotyping
The biostatistics team supports the development of study design, manages data collection, and performs statistical analyses to test the research hypotheses. In the study design phase, biostatisticians assisted investigators in formulating studies that can feasibly address the questions of scientific interest, are amenable to analysis by statistical and data-mining methods, and will ultimately yield statistically valid and interpretable results.
An equally important role for the biostatistics team is the coordination of the clinical database and the accumulated results from analyses on serum, WBC, and tissue samples. Because the laboratory data are ultimately integrated into the overall PCPT database, the biostatistics team developed a quality control plan and worked with each laboratory to ensure quality sample processing and data handling. This includes the management of the overall data infrastructure for the entire program consisting of the maintenance of the clinical database, the secure electronic transfer of laboratory data, and ensuring the security and confidentiality of all data. Other key roles of the biostatistics team include the identification of the specific samples to be sent, verification that the appropriate material is sent to the correct laboratory at the correct time, the tracking of the laboratory analyses, and the overall progress of each project.
The pathology-genotyping team is responsible for 3 major areas with the overall goal of supporting and providing the foundation for the project. These include 1) archival biorepository management and distribution, 2) histopathology, laser capture microdissection, immunohistochemistry, and image analysis, and 3) specialized sample preparation (i.e., DNA) and genotyping. The 3 major areas are largely interrelated with the intent being to provide the highest quality samples prepared to meet the needs of the 5 research teams and coupled with high-quality standardized pathologic analysis and genotyping. The use of high-quality biological specimens that are handled, processed, and interpreted in a uniform manner and that can be directly linked to clinical information and outcome ensures that results across all projects are reliable and comparable.
Research Plan and Study Design
All projects with serum-based measurements use a single, shared, nested case–control sample of participants to evaluate associations of risk factors with the risk or prostate cancer so that each subject will provide a more complete biomarker and genetic profile for the evaluation of joint effects of these putative factors. In addition, several projects are using prostate tissue from the biopsy cores from both cases and controls and the prostatectomy tissue from cases. These studies use a variety of designs and laboratory methods to address questions about somatic mutation, inflammation, focal atrophy, proliferation, and growth factor signaling. In the following, we highlight features of the case–control study design, including the definition of cases and controls.
Selection of nested case–control design
Data from the PCPT, a randomized clinical trial, can be thought of as a prospective cohort, with data collected on exposures before diagnosis of cancer being used to predict prostate cancer risk. However, even though this is a cohort study, a time-to-event is inappropriate. Because the PCPT had interim events and the detection of the interim events was biased between the arms due to the enhanced sensitivity of PSA, DRE and needle biopsy in the finasteride group, the only method to determine whether a participant was prostate cancer free or not was an end-of-study biopsy that assessed the endpoint in an unbiased fashion.
As a result of this detection method, our endpoints are not time-to-event analysis; rather, they are simply the presence or absence of prostate cancer by the end of 7 years of follow-up, as it was unknown when many of the cancers would have been detected without the end-of-study biopsy. We therefore define the outcome in the cohort study as the 7-year period prevalence of prostate cancer found at either a for-cause procedure or an end-of-study biopsy. Because the tissue, serum, and genetic assays are expensive, the prospective nested case–control study design was selected to efficiently examine a sample of men without prostate cancer.
Definition of prostate cancer cases
The primary case definition for this program is biopsy-proven presence of prostate cancer. From an initial pool of 2,401 potential cases, cases for this project were excluded because the detection of the prostate cancer was after the trial was unblinded (n = 173) or was outside the established time frame of the 7-year end-of-study biopsy (n = 91) or an adequate baseline serum sample was not available (n = 328). This resulted in a total of 1,809 cases of prostate cancer with available baseline serum included in this project. Approximately 40% of our cases are interim and 60% are cases detected at the end-of-study biopsy. All analyses examining prostate cancer cases are stratified by Gleason score, defining high-grade cancer as Gleason score 7–10 (n = 498; 218 in placebo arm, 280 in finasteride arm) and low-grade cancer, defined as Gleason score 2–6 (n = 1,233; 782 in placebo arm, 451 in finasteride arm). Although the subsequent analyses, described earlier (4–7), have tempered concerns regarding the excess of high-grade cancer diagnosed in men receiving finasteride, all projects continue to examine high-grade cancers, given the clinical relevance of high-grade disease and the urgent need to develop markers of aggressive disease that go beyond Gleason score. In addition, given the relatively small numbers of Gleason score 8–10 cancers, it was not possible draw definitive conclusions regarding the potential of finasteride to affect this important subgroup.
Two endpoints often used in epidemiologic studies of prostate cancer, stage and prostate cancer–specific death, cannot be examined in the project research proposed because nearly all of the men with a diagnosis of prostate cancer in the PCPT had early-stage disease (i.e., 98% were T1 or T2). This is most likely due to the requirement for serum PSA levels of 3 ng/mL or less and normal DRE at randomization and annual PSA and DRE testing.
Definition of controls
Controls were randomly selected in a 1:1 ratio from men who completed the end-of-study prostate biopsy and had no evidence of prostate cancer. Controls include all eligible non-White men (primarily African Americans and Hispanics) to better support exploratory analyses in these subgroups. Remaining controls were frequency matched to cases by distributions of age at randomization, in 5-year intervals, first-degree family history of prostate cancer (established risk factors for prostate cancer), and intervention arm. By oversampling the non-White men and matching on the factors listed earlier, the estimated race-specific odds ratios for prostate cancer are not interpretable.
Because of the impossibility of sampling the entire prostate using needle biopsies, it is possible that some men with prostate cancer will be misclassified as controls. However, the controls in this program will yield a much lower misclassification of prostate cancer disease status than that typically seen in epidemiologic studies using cumulative incidence sampling of controls. This reduced misclassification is especially important when the expected associations for some of the research questions being addressed are in the small to moderate range [e.g., single-nucleotide polymorphisms (SNP) and prostate cancer].
The baseline demographics and potential prostate cancer risk factors [diabetes, body mass index (BMI), physical activity, and smoking status] for the cases and controls, as well as for those with noncancers in the PCPT who were eligible to be in the controls but were not chosen, are presented in Table 2. Also presented are the characteristics of the men in the PCPT who had an endpoint evaluated (i.e., either had an interim prostate cancer or had an end-of-study biopsy within the required time frame) and those who were not evaluated. As shown, the men who were evaluated for an endpoint were younger, more likely to have had a family history of prostate cancer, and tended to be Caucasian. Redman et al. reported that by accounting for the nonrandom missing biopsy results, the true rate of cancer would have been slightly less in both intervention arms, but the relative risk was minimally changed (4).
The baseline demographics and potential prostate cancer risk factors
Because the population to be studied in this project is frequency-matched case–control with specific oversampling of non-White race and positive family history, men in the project were older and have a higher baseline PSA than those men not in the project.
Overall analytical approach
The approach for the analysis of the primary aims for each of the projects is to apply the same methods across all projects when possible. This includes using the same set of cases and controls and definitions of exposure variables and endpoints. The preliminary analyses produce standard tables and refinements are made to address issues specific to individual projects and/or analyses. For the serum analyses, this has been relatively straightforward to implement once agreement among the investigators was achieved. Because the tissue analyses are done in differing subsets, the analyses are more project-specific.
Each biological analyte is assessed separately in each of the intervention (placebo and finasteride) groups. If there is no evidence of an interaction between the exposure analyte and intervention, the 2 arms are pooled. This increases the sample size and greatly increases the power to identify associations.
In the design phase, each investigator consulted with the statisticians to determine the achievable power for each of the primary and cross-project aims given a sample size of 1,809 cases and 1,809 controls and their prespecified, clinically meaningful differences. Power was calculated for the main effects, intervention interactions, and effect modification by genetic variation. Tables 3–5 provide some examples of the minimally detectable odds ratios with 80% power and a 2-sided α of 0.05.
Minimally detectable odds ratio
Minimum detectable interactionsa of intervention with an analyte of interest, pooled intervention groups
Minimum detectable odds ratios of prostate cancer and high-grade disease
Most cross-project interactive aims take the analytic form of tests of interactions: between genes, between genes and metabolic and behavioral measures, and between metabolic and behavioral measures. These cross-project collaborations are feasible because of both the large number of cases and the coordination of study designs (including sample selection) across projects. There is also reasonable power to detect statistically significant tests of cross-project aims. In general, if odds ratios comparing high to low quartiles of an exposure differ by a ratio of about 2 between 2 groups (e.g., by polymorphism), there is 80% power to detect such a difference.
Another focus of our analyses is to maximize the ability to address questions related to race/ethnicity and prostate cancer risk. African American men have an elevated risk of prostate cancer, and there is some evidence that this may be linked to genetic characteristics (e.g., short AR CAG repeat length, CYP3A4 polymorphisms) and higher serum androgen levels (17). Extensive efforts were made to recruit minorities into the PCPT; however, only 8% of participants were non-White and only 4% were African American. We have oversampled controls to include all non-White men, and race/ethnicity is used as a stratification variable in exploratory analyses. Although limited in power to address hypotheses stratified by race/ethnicity, this program includes the largest African American cohort (216 controls and 90 cases) we are aware of to have been included in comprehensive molecular epidemiologic studies of prostate cancer.
For the genetic aims, the program investigators are primarily using a candidate gene and SNP approach. Several criteria were used to select the specific genes and polymorphisms to be assayed in the different pathways of interest. Data on functional significance or data demonstrating a significant role in prostate or any other cancer were the primary criteria used for selection. Other criteria include SNPs that result in amino acid changes in the protein (i.e., nonsynonymous SNPs) and changes in promoter regions and splice sites. In general, variants with a minor allele frequency of 5% or higher were selected to have good statistical power. The major exception to this is SNPs in project 1, in which a number of variants at very low frequency will be studied in the SRD5A2 gene because of their known functional significance and relevance to the finasteride intervention. Additional genotyping will be done on tagging SNPs for key genes. Each project prioritized which tagging SNPs would be genotyped on the basis of their knowledge of the gene variants and the number that would be needed for coverage.
With extensive serum measurements and genotyping from several different projects, the program provides the opportunity to study the complexity of potential joint effects within and between projects. A number of methods will be explored including logistic regression adjusting for "upstream" effects and potential interactions, classification and regression trees (CART), or logic regression to identify prognostic groups based on combinations of SNPs or other biomarkers. Bayesian model averaging, which draws inferences about particular effects, taking into account the uncertainty about the correct model form, will also be used. A pharmacokinetic approach that attempts to use physiologically based representations of the biochemical pathways to statistically model the dependencies between factors and pathway analysis providing estimates of hypothesized causal connections between variables are other planned analytic methods. All of these methodologies rely on interdisciplinary collaboration. These models are useful not only to identify the complex joint effects on prostate cancer risk but also to identify groups of men who are either more or less likely to benefit from the chemopreventive effects of finasteride.
At the time of the development of this project, it was clear that the statistical analysis for genetic polymorphisms was a rapidly evolving field. Over the course of the project, improved and less expensive methods have become available, which have permitted SNP analyses to be conducted at lower cost while providing flexibility to select new candidate SNPs and haplotype tagging SNPs.
Methodologic Strengths of the Program
Sensitive and specific definition of cases and controls
This program is unique in that all cases in the study sample are identified and the control group contains only men who are negative for biopsy-detected cancer. Case–control studies to date have been based on control groups without definitive knowledge of cancer status. The PCPT demonstrated that a moderate prevalence of prostate cancer, including high-grade cancer, occurs even among men with low PSA levels (19). This prevalence is especially problematical for studies completed in the PSA era because they included early-stage, low-grade cancers in the case group and cannot rely on PSA screening to eliminate such cancers from the control group. This misclassification weakens studies attempting to understand the risk factors for early-stage cancer and may explain both inconsistent findings across studies and the apparent lack of associations of many risk factors with early-stage disease. This issue may be particularly important for studies in which the magnitude of effects may be small but population-attributable risk is potentially very high.
Parallel study designs and integrated selection of tissue and serum specimens across projects
The cases and controls, and the statistical methods to evaluate associations of risk factors with disease, are shared across all projects. The selection of prostate tissues and serum specimens is carefully integrated across projects to maximize the number of cases and controls for which genetic, metabolic, and histopathologic data are available, which will maximize the ability to complete cross-project interactive aims.
Large number of cancer cases with fully characterized genetic, metabolic, and behavior exposures
The number of cases in this program is based on a larger number of cases than most prospective studies, and this program is one of the largest prospective studies with access to prostate tissue and multiple serum samples collected throughout the follow-up period. The comprehensive set of data available on cases and controls allows this program to address many important questions in prostate cancer etiology and prevention.
Standardized histopathologic classification of disease
This program uses a central pathology core to histopathologically classify cancer and other abnormalities. While many studies have used clinical stage to identify aggressive disease, no large prevention studies have had access to uniform pathologic grading based on a central pathology facility using rigorously standardized protocols. This is especially important for studies of high-versus low-grade disease in which it is difficult to standardize results across different pathologists and laboratories.
Focus on comprehensive risk models
An overarching aim of this program is to examine joint associations among prostate cancer risk factors such as gene–gene and gene–environment interactions (diet, hormones, growth factors) that will be integrated into comprehensive risk models.
Relevance of the cases
The cases identified during the PCPT were mostly early, clinically localized prostate cancers. Although the PCPT has been criticized to prevent clinically insignificant cancers, the cancers detected reflect the characteristics of the current cases that are being detected and treated in the PSA screening era. Subsequent analysis has determined that many of the criticized end-of-study cancers are "clinically meaningful," using the most accepted definitions for classification based on biopsy pathology (18). The criteria for prostate biopsy have changed since the implementation of this trial, from a PSA cutoff of greater than 4.0 ng/mL to greater than 2.5 ng/mL. As a result, many of the cancers found on end-of-study biopsy would have been found during the course of the trial if this lower cutoff had been the threshold for biopsy.
Southwest Oncology Group Executive Committee Review
The selection of the projects and investigators for this program resulted from an open process of evaluating responses to widely distributed RFAs to use the PCPT biorepository and data set. This open and impartial review process continues and will continue into the future. The Southwest Oncology Group Executive Committee Review, independent from either PCPT or this program's leadership, is in place to evaluate new proposals to use the PCPT biospecimens. This review process provides no funding but only permission to include the formal approval to use PCPT specimens/data in applications for funding from other sources. The committee's review includes determining whether proposed future research will have potential conflicts (with respect to duplication, feasibility etc.) with the ongoing projects. In general, approval based on priority is given only to projects that address prostate cancer prevention and at least 1 of the following: 1) Questions related to understanding the PCPT clinical outcomes; 2) Questions that require the PCPT biorepository and cannot be addressed otherwise; and 3) Questions that expand and contribute to the ongoing risk-modeling program. Studies that do not address prostate cancer prevention but meet one of the other criteria will be considered on the basis of scientific merit and amounts and types of materials requested. The application can be accessed online at http://www.cancer.gov/pcpt.
The project described here is unparalleled in the combined biology and etiology of cancer in its access to the resources, in particular annual blood samples, from a large, placebo-controlled, randomized prevention trial with a definitive cancer primary endpoint. The program benefits from parallel study designs and integrated selection of tissue and serum specimens across projects; the selection of cases and controls and the statistical methods to evaluate associations of risk factors with disease are shared across all projects. Furthermore, the selection of prostate tissue and serum specimens is integrated across projects to maximize the number of cases and controls for which genetic, metabolic, and histopathologic data are available.
This project represents a unique opportunity to test biological hypotheses related to a clinical trial in a coordinated manner. The strengths of the program are multifold and include the wealth of biological samples, both in total quantity and in the multiple sources (blood, tissue, sputum) that represent and enable the biological basis for the project. Another key strength comes from the interdisciplinary approach that spans the 5 individual projects and the common set of methods used across studies, including the central repositories, sample distribution, and centralized genotyping that minimize variation across studies and permits the analysis of main effects in individual projects and joint effects across studies. Furthermore, the unified approach to the analysis, which incorporates a common set of definitions, cross-project aims and a cohesive analysis plan that addresses each of the individual projects, and ultimately an analysis that will span all of the projects, gives this program a strong and unique backbone.
The approach taken by this project does not come without challenges. The diverse locations of the 5 projects and biostatistics and pathology-genotyping centers can be cumbersome for coordination and communication and requires a commitment to open and effective communication. This is achieved through monthly teleconferences, twice yearly in-person meetings, and is augmented by focused discussion by phone and e-mail discussions that are topic-specific or related to specific analysis or procedural issues. Another challenge is in managing multiple laboratories with differing sample and data-handling capabilities. This challenge is managed by developing specific procedures within some laboratories, training, and close regulation of all steps of the laboratory process. Finally, the program was conceived prior to publication of the results of the PCPT. The results of the trial and the evolving interpretation based on subsequent analyses of the data have resulted in some of the hypotheses being modified and additional hypotheses developed.
The program entered its most productive period in mid-2009, with completion of the vast majority of laboratory analyses of serum and tissue. The initial round of genotyping has been completed and a second expanded round is in process. A number of papers are under review by the authors, submitted for publication, accepted, or already have been published. The topics of these reports cover some of the pilot work that was done to prepare for the program, methodologic issues, and results from specific projects.
This program represents a model for team science and the use of the biospecimens generated from a large clinical trial. One example is an ongoing SNP-based risk-modeling program nested within a randomized, placebo-controlled trial to prevent head and neck cancer–related second primary tumors (20). All large, definitive prevention trials could be designed with an eye toward the development of future programs that utilize their biorepositories. For example, the definitive Selenium and Vitamin E Cancer Prevention Trial (21) in 35,533 men was carefully designed with data and biological specimen collection methods and objectives that would facilitate follow-on risk-modeling and other molecular biological research. This approach assembles experts in a number of cancer research areas into a single collaborative effort. Although benefiting from the expertise, the approach has a cost in the learning curve to understand the study design, science, and procedures of the parent randomized, controlled trial, as illustrated by this program founded on the PCPT.
No potential conflicts of interest were disclosed.
This work was funded by the National Cancer Institute, National Institutes of Health (CA37429 and P01CA108964). The content of this work is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Received December 11, 2009.
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. Finasteride does not increase the risk of high-grade prostate cancer: a bias-adjusted modeling approach. Cancer Prev Res 2008; 1: 174–81.
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Finasteride and high-grade prostate cancer in the Prostate Cancer Prevention Trial. J Natl Cancer Inst 2007; 99: 1375–83.
Cohen YC,
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. Estimating rates of true high-grade disease in the Prostate Cancer Prevention Trial. Cancer Prev Res 2008; 1: 182–6.
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Cancer Prev Res December 1 2010 (3) (12) 1523-1533; DOI: 10.1158/1940-6207.CAPR-09-0256
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Rapture has an awesome development team that provides non-stop updates and improvements. The UI for QT wallet is always getting better which is awesome because I don't know about you but looking at an interface from 1995 isn't cutting it these days. The fonts and colors truly make for a more pleasant UX. There is now integration with Altcoin Wallet for sending and receiving $RAP on Android devices. Also, the iOS app has just been submitted for approval.
nice @veyeoshi . Looking forward to see the Android wallet !


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Home > NewsInferno > Tekturna Linked to Significant Number of Adverse Events
Tekturna Linked to Significant Number of Adverse Events
Independent watchdog group, the Institute for Safe Medical Practices (ISMP) reports a 90 percent increase in significant adverse drug event reports received by the U.S. Food & Drug Administration (FDA) over the past four years.
Among these, are events associated with Novartis' Tekturna (aliskiren). As we've explained, Novartis launched Tekturna in 2007 for the treatment of high blood pressure, conducting a number of trials to determine if Tekturna could protect vital organs when taken for longer periods.
ISMP explained that it observed a serious hypersensitivity reaction—angioedema, a sudden swelling that can impact the tongue, face, lips, or throat—that can take place at any time during treatment and could result in life-threatening problems if the patient's airway is obstructed. Also, a combination medication involving aliskiren and valsartan, an angiotensin receptor blocker, was withdrawn when a clinical trial revealed that treating patients with two drugs that are active in "the renin-angiotensin pathway" could harm some patients. Novartis told ISMP it was investigating the angioedema issue.
The FDA received 57,393 reports meeting ISMP's criteria for an adverse event, which was a 23.8 percent increase over the prior quarter, what ISMP described as "sustained and substantial growth" in adverse event reporting linked to new and existing medications. A 30.1 percent increase was seen in the same quarter of the prior year. Tekturna was among the top four medications in which adverse events were reported and was associated with 100 adverse event reports to the FDA in the first quarter, said Lawyers USA Online. ISMP's report, Quarter Watch, relies on FDA data, said Lawyers USA Online.
We recently wrote that Tektuma was scheduled to undergo a Canadian Safety Review after Novartis halted a clinical study over unexpected adverse reactions. " Tekturna is in a class of drugs known as direct rennin inhibitors, and is known generically as aliskiren, which is sold in Canada and elsewhere, under the brand name Rasilez.
When blood pressure increases to high levels, explained CBC News, the pressure forces the heart to work harder, increasing death risks from a number of causes, including heart disease and stroke. Tekturna is intended to reduce the body's production of the enzyme renin, which has been shown to increase blood pressure.
Novartis, announced it was halting the multinational clinical trial created to determine if adding Tektuma to tradition treatments in people diagnosed with Type 2 diabetes and kidney impairment could lower risks for cardiac and kidney problems, explained CBC News. Novartis also said it will stop marketing aliskiren for use with ACE-inhibitors and angiotensin receptor blockers until regulators determine if the aliskiren's marketing license needs to be amended.
The ceased trial—known as ALTITUDE—involved 8,606 Type 2 diabetes patients at increased risk for heart or kidney failure and who took Tekturna in addition to receiving traditional heart treatment. Participants came from 36 countries. The committee overseeing the study discovered greater-than-expected, unwanted adverse events once the drug was added to traditional treatments, including higher rates of nonfatal stroke, renal complications, and other problems. The committee also found the drug failed to prove more effective than a placebo.
Just prior, we wrote that Europe's key drug regulator, the European Medicines Agency (EMA) announced it was initiating a review of aliskiren's benefits and risks and had advised doctors to stop prescribing the medication to diabetic patients also taking older generation hypertension medications (ACE inhibitors, angiotensin receptor blockers).
We also previously wrote about a study published in the American Journal of Hypertension in 2007 that called into question the drug's efficacy. The study was conducted at Weill Medical College of Cornell University in New York.

redpajama_set_name: RedPajamaCommonCrawl


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When will the industry get their act together? (Image via Instagram)
Culture /// Thoughts x August 27, 2019
Does Disney+ Have What It Takes to Save Clint Barton?
Probably not. It'll take a lot to clean up Joss Whedon's mess.
By Emma Dailey Mitchell, Columbia College Chicago
Clint Barton's in trouble. He has been for years if we're being honest with ourselves. While trouble's nothing new for an Avenger, especially Clint Barton, few people have the power to save him. Is Disney+ one of them?
Hawkeye, Clint Barton's alter ego, is an underrated Marvel comic book character. But he was severely underestimated and underused in the Marvel Cinematic Universe. Even in the moments he was used, it wasn't the same Clint Barton fans know and love — depicted in the original comics and the animated shows.
This version of Clint Barton played by Jeremy Renner had potential in the first Avengers' movie, but as the actor said, Hawkeye spent most of the time being Loki's puppet. There's not much room for characterization when under mind control.
By the time "Avengers: Age of Ultron" rolled around, audiences were excited to see what would become of the archer after the trauma of the last film, as well as see who he was behind the bow. Of course, the pain of that was never explored and audiences learned something brand new about the character — probably something too new. The inclusion of the Barton family was a boulder in the path of Hawkeye storylines.
It effectively blocks character development and cuts off multiple different directions future creators could go with this character. It shifts the priorities for the character and with every upcoming movie audiences would have to ask, "Why isn't he with his family?"
Pixar's 'Soul' Serenades Its Way Right Into Our Homes
Settling down with a significant other and kids is the endgame for so many heroes, in fact, it was the end they intended for Tony Stark and Steve Rogers. Joss Whedon essentially sped up Clint Barton's story to fit his needs, sacrificing character and potential … for what?
A post shared by Avengers (@avengers)
They certainly couldn't explore the Hawkeye and Black Widow romance with his wife around. It worked to further damage Widow's characterization, or lack thereof. This pivot from the Hawkeye/Black Widow romantic relationship they were hinting at in "Avengers," to her relationship with the Hulk, caused a lot of confusion, even for the actors involved. Ultimately, it only served to hurt Black Widow's character, who was serving as the one and only female hero.
They couldn't explore any of his past romantic relationships, including his actual wife in the comics, Mockingbird. Creators to come can't take Barton's character on a journey for stability or make changes when the family must remain a constant.
A post shared by Marvel Entertainment (@marvel)
The family also adds layers to the character that aren't there in the comics or the cartoons, effectively changing Hawkeye until he's almost unrecognizable. It made him a family man, a stable presence as the rest of the Avengers struggled.
"I loved the idea that one Avenger had a secret, and that it was that he was a normal guy who is genuinely connected to the world in a way no other avenger is," Whedon wrote on his Tumblr. Perhaps it made him more relatable, but here's another big "secret": Hawkeye is already the most relatable character throughout the comics and the cartoons. He is just a regular guy, that's what makes his character incredible. He didn't need a secret family to prove it.
His wit enables him to make the humorous quips about the insane situations occurring, which audiences get a taste of in the later films. His lack of supernatural abilities may make him seem weaker compared to a rage monster, but his natural talent shows that humans can do great things and his strong will shows the average person could be a hero in their own right.
He is the only regular person on the team, given that he hasn't been exposed to dangerous chemicals or come from a different planet, and he's the most grounded given his past growing up in a circus instead of a mansion or a spy-training program.
As far as a secret goes, there are plenty in Clint Barton's sordid past he could have kept hidden. Hawkeye was originally introduced as a villain for Iron Man. His criminal and carnival history make for a much more interesting secret — as does his abusive parents. Including his brother would have opened several storylines.
'Clouds' on Disney+ Encourages Viewers To Live Life To the Fullest
If it had been his older brother's family, Clint Barton could still be a family man with a stable place for the Avengers to hide out while still maintaining his character's potential. It would have worked to increase the drama and possible conflicts because the relationship between the Barton brothers is strained and complex.
It opens a door into Barton's shadowed past, providing further depth to the character, while showing off the human side to him. In the comics, the humanity of Clint Barton is further explored because he suffers like so many of us from depression and, in many versions, is deaf.
That deaf representation is severely missing from the MCU and Hollywood in general, even though it helps to add those human layers to the character. The comics and cartoon versions of Hawkeye also all include incredible shots and really show off his survival skills even without a bow, while the MCU rarely gives him a chance to show off his talent, making him seem like a weaker Avenger even though he's not out there fighting with a suit of armor or any chemically enhanced abilities. Barton battles with his wits and his skills unlike the rest of the team who is aided by technology, chemicals and cosmic help.
Now Disney+ promises a chance for Clint Barton to show off all that he can do with his own "Hawkeye" series. However, they can't undo the mistakes Joss Whedon and previous creators made with the character. No matter when they set the show during his life, the audience will always know where he'll end up. His family will always be his endgame. Audiences will know he will always survive and that any romantic relationship that isn't with his wife will not last.
Disney+ claims that the show will be taking inspiration from the Matt Fraction run of "Hawkeye," which featured an extremely relatable Clint Barton. One who was a mess and just trying to get through the day, which is a far throw from the Clint Barton with a family. One could argue that everyone is a mess when they're a youth and eventually even out to have a family, but with Jeremy Renner attached to continue his role as Clint Barton, it is unlikely Disney will be diving terribly far back in Barton's past.
Live-Action 'Mulan' Releases to Disney+ for $30 Amid Controversy
Whedon's mistakes with Clint Barton cannot be undone as easily as the one's made with Black Widow, as the Barton family will probably always exist. Fans may never get the live-action Clint Barton they deserve, but that doesn't mean Hawkeye is completely screwed.
Hope exists in Kate Bishop, the second Hawkeye. In the comics, she takes up the mantle of Hawkeye after Clint Barton's death when Captain America gives her his bow. When it is revealed that he is alive and he returns, both Hawkeyes and their one-eyed dog help keep their section of New York safe.
He works to help train her, which is what the Disney+ show is rumored to feature. If Disney does right by her, her Hawkeye is the last chance fans have to see Hawkeye done right, and perhaps along the way Renner's Clint Barton will see some of his stories get the attention it deserves.
Disney cannot erase the mistakes they made with Clint Barton, but they have the chance to make it right with Kate Bishop.
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The 'Mulan' Remake Fails at Nuanced Asian Representation
A Look Back at Chadwick Boseman's Cultural Impact
'Phineas and Ferb' Allows Us To Vicariously Live Out Our Summer Dreams
The Send-Off to 'Agents of S.H.I.E.L.D.' Doesn't Have To Be the End
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Marvel's Lineup Is as Impressive as It Is Intimidating. Let's Break It Down
Marvel Phase Four Is Offering Some Promising New Releases
The Snyder Cut Could Restore the Original Vision of 2017's 'Justice League'


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Between December and February flights and trains in the north can be delayed due to fog, (but this just adds to the country's atmospheric vistas).
In the summer months it will get very hot. Be sure to drink lots of water, pack light cotton clothing and use adequate skin protection.
As we'll be walking through varying terrain in national parks, comfortable walking shoes are essential.
Use a free morning to delve further into the spiritual atmosphere of Varanasi, wander through the ghats or perhaps haggle with vendors in colourful bazaars. Return to Delhi by plane (about 1.5 hours) for a last chance to explore India's capital. Perhaps head to the legendary Connaught Place for some last-minute shopping. This evening, why not share one last meal with your group to reminisce about your travels before the trip come to an end.
Fly to Chennai for the second half of your trip. This flight is included in the cost of the trip.
Chennai (previously known as Madras) was the site of the first major settlement of the East India Company in 1639, and is now the fourth largest city in India. The town grew up around the Fort St George and along Mount Road and some interesting historic buildings can be seen here. It's true that it is busy, noisy and often extremely hot, but in many ways it is a surprisingly efficient and orderly place by Indian standards. The Government Museum is worth a visit if you're interested in the history of the city, and for motorcycle enthusiasts the Enfield Factory tour is a must - though it only runs on certain days of the week, so check days and times before you make the journey. You might prefer to just wander the streets and soak up the atmosphere, exploring the many temples and bustling local markets.
As this is a combination trip, your group leader and the composition of your group may change at this location. There will be a group meeting to discuss the next stage of your itinerary and you're encouraged to attend, as this is a great chance to meet your new fellow travellers.
Drive through rubber and pineapple plantations to Thekkady and explore the Periyar National Park and Tiger Reserve, perched lakeside in the ranges of the Western Ghats. The sanctuary surrounds a picturesque lake, which was formed as result of a dam that was built in 1895. It ambles through the contours of the wooded hills, and is a permanent source of water for local wildlife. This afternoon, take a tour of a local spice plantation. If you have time, perhaps attend a demonstration of Indian martial arts (kalaripayattu) at the Kadathanadan Kalari Centre.
In the morning, take a guided nature walk in the acclaimed Periyar Wildlife Sanctuary (approximately 3 hours). Encounters with animals in the wild are never guaranteed, and this is more of a jungle walk than an animal spotting tour, but look out for tiger tracks, spotted deer, Indian elephants or gaur – the world's largest species of buffalo. In the afternoon, unwind with an optional ayurvedic massage or just relax in this scenic setting.
There are currently no scheduled departures on our India Experience trip. If you are interested in other trips in the region visit one of the links below.
1. The internal flight from Delhi to Chennai is included in the price of your trip.
2. A Single Supplement is available on this trip. See under the Single Traveller section of your Trip Notes for more information.
3. An airport Arrival Transfer is included. Please provide your flight details at the time of booking.
4. This trip is a combination trip and as such the makeup of your group will change on day 9.


Mr. Leigh Brasington will conduct a 10-day silent meditation retreat in Japan, September 28th- October 9th, 2012. After having taught retreats in many countries, this will be Leigh`s first retreat in (and visit to!) Japan. We are privileged to receive these high-level theravadan Buddhist teachings in a location so easily accessible to Tokyo.
Location: Hinata Fureai Gakushu Center near Isehara City in Kanagawa Prefecture (about 50km from Tokyo). This rustic and cozy venue is nestled in a quiet, densely-treed mountain valley at the foot of Oyama Mountain, alongside freshwater streams. The region is excellent for hiking, onsen (hot spring baths) and historic Buddhist temple visits.
Teaching: The Jhanas, commonly called the meditative absorptions, are eight altered states of consciousness which can arise during periods of strong concentration. Their principle use in Buddhist meditation is to generate ever increasing levels of concentration, so that later when the meditative mind is turned to a wisdom practice, it can do that practice with far less distraction. This retreat will emphasize the teaching of this technique and will be held in Noble Silence with sitting and walking meditation, dharma talks, and personal interviews. There will also be an optional yoga session daily.
Language: Leigh will teach in English and this will be translated on the spot for Japanese-speaking participants.


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Under Virus, Netanyahu and Bitter Rival Gantz Enjoy Fleeting Moment of Solidarity
Deborah Brand
TEL AVIV – In an unlikely show of camaraderie, Prime Minister Benjamin Netanyahu and main rival Blue and White head Benny Gantz shared an affectionate moment on social media over a coronavirus post, prompting reluctant umpire President Reuven Rivlin to urge the two party heads to continue the solidarity offline as well.
Gantz on Tuesday shared a post written by Netanyahu regarding new restrictions for staying at home. "When it comes to people's lives, there's no politics. Israel comes before everything. Protect yourselves and your families and fully obey instructions," Gantz wrote.
Netanyahu then shared Gantz's own share, with the accompanying text, "Very important. Thanks, Benny."
Rivlin then shared the share chain and added, "Maybe we can continue with this at the cabinet table, friends?"
חשוב מאוד!תודה, בניבני גנץ – Benny Gantz
Posted by Benjamin Netanyahu – בנימין נתניהו on Wednesday, March 18, 2020
Rivlin called on Knesset speaker Yuli Edelstein to open the Knesset plenum and allow for MKs to debate setting up committees.
Edelstein closed the plenary over fighting regarding the committees only two days after the 23rd Knesset was sworn in.
"A frozen Knesset harms Israel's ability to act in a good and responsible way during an emergency," Rivlin told Edelstein.
"We cannot let this crisis, as bad as it is, harm the infrastructure of our democratic system. We need to do everything to deal with this crisis, but carefully, in order not to strike a fatal blow to our democratic infrastructure," he added.
Gantz said he would petition the High Court of Justice over Edelstein's decision.
"We have been working hard all day through different communication channels — including me meeting personally with MK Edelstein, who is refusing to let us congregate in the halls of democracy and work for the citizens and — above all else — tackle the challenge of corona," Gantz said.
"At this point — we have no choice but to turn to the Supreme Court," he added.
Edelstein blamed the Blue and White party for not agreeing to any of the terms for the committees and said the plenum would reopen Monday after negotiations.
He said he would allow the plenum to vote Monday on establishing an Arrangements Committee to begin parliamentary work.
Blue and White's leaders were behaving "ridiculously," Edelstein said.
A day earlier, Blue and White number 2, Yair Lapid, said the new coronavirus restrictions proved that Israel was "no longer a democracy."
Lapid blasted the government's use of digital tracking tools from cellphone data which Netanyahu said would be used to monitor the spread of the virus.
"It's possible that it doesn't really interest you with all this coronavirus in the air, but as of today, you no longer live in a democracy," Lapid said in a video posted to social media.
Lapid came under fire for his remarks, prompting him to post on Twitter Wednesday that "the instruction [not] to leave home is not the problem; the fact that it is given by an illegitimate government is definitely a problem."
Israel / Middle EastNational SecurityPoliticsBenjamin NetanyahuBenny GantzcoronavirusIsrael politicsKnessetreuven rivlinYuli Edelstein


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Q: UIWebView to WKWebView on youtube-ios-player-helper-swift My app uses the framework youtube-is-player-helper-swift, found here: https://github.com/malkouz/youtube-ios-player-helper-swift
It is an implementation of the original youtube-ios-player-helper, for Swift.
It is working fine, but it is based on UIWebView, deprecated in iOS 12.
I'm looking for a version of this framework using WKWebView or some help to change this one.
Anyone can point me to a possible solution?

A: You can use youtube helper
from hmhv. Which uses WKWebView instead of UIWebView.

redpajama_set_name: RedPajamaStackExchange


dun get shock.. cuz we finally sedar..
we quite serious at first..
we end up doing tis..
jessy in specs.. nice isn't she???
jessy n ongy with specs.. ^^ pretty neh?
always the sweet smile from her..
pretty, talented, sweet gal... wan her number??
but cuz of exam.. i got no time to blog bout it..
we did j3 shirt jux for fun n for the remembrance of our frenship..
will keep going without an ending..
ok la.. hereby i upload sum j3 shirt pic for u to c..
the back design of syn joe..
feel like doing one with ur fren or bf/gf??
find urself... if u really do wish to do..
with that i upload some photos of my new hair style..


Sometimes the realities of everyday carry are hard to accept. There are some places where guns are not allowed. So what do you do? Leave the gun at home, or lock it in the car? And then what do you have left? Bruce Flemings, a stay at home dad and gun writer, explains his EDC.
SeeCamp LWS-380 .380ACP Black Ships TODAY!
SeeCamp LWS-32 BLACK FREE LEATHER HOLSTER!


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Tuesday October 7, 2014
European Commission: new faces and new fears for environmental action
By: Agata Mrowiec
The ongoing public hearings of the future European Commissioners before the European Parliament pose many questions and many doubts.
Last week, we observed the grilling of both Karmenu Vella, a candidate Commissioner for Environment, Maritime Affairs and Fisheries and Miguel Cañete- for Climate Action and Energy.
"Sustainability", "green economy" and "competitiveness and jobs" were the buzz words coming from Karmenu Vella's opening statement. Mr Vella expressed his strong commitment to continue the outgoing Commisionner's –Maria Damanaki's- fight against illegal fishing (IUU) and to implement the Common Fisheries Policy. At the same time, he underlined the fact that science in the place of politics should guide annual fishing quotas, while decisions on issues like deep-sea mining should be taken only after a meticulous scientific and environmental analysis. Saying that, Mr Vella gave a rise of hope on the protection of Europe's marine resources. Also, he assured that Marine Protected Areas are an urgent matter that requires immediate action based on a regional approach.
However, his lack of concrete answers to questions is worrying, including the foreseen "modernization" of the Birds and Habitats Directive by Jean-Claude Juncker, President elect of the European Commission. Will the implementation of the EU law become the foundation of his future portfolio?
The nomination of Miguel Cañete has attracted a lot of controversy for his and his family links with the oil industry. Oceana is concerned about his conservative political stance on climate and his true motivation to fully engage the EU in the process of de-carbonization its economy and a definite commitment to renewables. In the current atmosphere of the social protest against his nomination, under the slogan "stop Cañete", the MEPs and the environmental organizations demonstrated last Thursday in front of the European Parliament. During his hearing, Mr Cañete remained evasive about important questions related to potential conflict of interests or on climate action commitment. While advocating for renewable energies and greater energy efficiency, MEPs did not forget his previous disastrous mandate as Spanish Minister for Environment.
We recognize the remarkable work of Connie Hedegaard, the outgoing EU Commissioner for Climate Action, and call on the new Commissioner to put climate change as priority on their agenda, especially at this difficult economic time in Europe. Oceana expects the newly chosen Commissioner for Climate Action and Energy will strongly oppose fossil-fuel energy and will make an ambitious commitment to energy efficiency and renewables, including marine renewable. Similarly, strict climate policy is needed to further reduce greenhouse gas emissions and integrate climate adaptation measures into other EU policies.
Kung Hei Fat Choi – but hold the shark fin soup, please!
Mercury rising: Seafood contamination and a consumer's right to know
Nemo at risk: Finding Nemo's marine friends in trouble
A Christmas Giveaway from Oceana - enter to win!
What lies beneath: Mysterious species in our fascinating oceans
10 things anyone can do to save the oceans!
Sabellaria reefs: ugly and fragile, yet incredibly important emblems of Dutch waters
¿Hay soluciones para la crisis de sobrepesca del Mediterráneo?
One more at-sea expedition
Until next time, Baltic Sea
13,5 Hours
Chile Becomes First South American Nation to Tax Carbon


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America in the 1800s: 19th Century Innovations - Paving the Way Ebook
Excite students as they learn more about the nineteenth century inventions that accelerated growth and change in the United States in the 1800s. With the 19th Century Innovations: Paving the Way e-Book, students...
America in the 1800s: Abolitionists - What We Need Is Action Ebook
Ignite a passion for history as students learn more about the abolitionists that organized during the early nineteen century to end slavery. The Abolitionists: What We Need Is Action e-Book offers an exciting...
America in the 1800s: Abraham Lincoln - Addressing a Nation Ebook
This fascinating biography focuses on "The Great Emancipator," the president who helped abolish slavery. With the Abraham Lincoln: Addressing a Nation e-Book, students will examine the life of the sixteenth...
America in the 1800s: American Indians in the 1800s - Right and Resistance Ebook
Spark a curiosity for past events with this nonfiction reader focusing on the lives of native people as pioneers began moving westward during the nineteenth century. With the American Indians in the 1800s: Right and...
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Provide an engaging nonfiction reader for your students as they explore some of the causes of the Civil War. With the Causes of the Civil War: A House Divided e-Book, students will examine the divisive events in...
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This nonfiction reader e-Book profiles some of the great leaders during the Civil War era. Students will examine the lives of these leaders that inspired others to fight bravely for the cause. It explores prominent figures...
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Engage students as they learn more about the "Father of the Constitution" with this fascinating biography that focuses on this important founding father. With the James Madison and the Making of the United...
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This fascinating biography profiles the life of Laura Ingalls Wilder and the events in her life that helped shape her beloved children's books. With the Laura Ingalls Wilder: Pioneer Woman e-Book, students will...
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Students will gain a deeper understanding of the exploration team that headed west to explore new territories. With the Lewis & Clark e-Book, this nonfiction reader focuses on the treacherous trek, including...
America in the 1800s: Reconstruction - Freedom Delayed Ebook
This nonfiction reader e-Book explores the steps the country took towards greater equality after the Civil War. Students will learn more about how many tried to counter racism and injustice, including Freedmen's Bureau,...
America in the 1800s: Settling and Unsettling the West Ebook
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The ratio of net operating income to the amount of money that is required to make regular debt payments. A DSCR of greater than one means that the project is taking in enough income to cover payments on loans. A number of less than one means that the project will have to dip into reserves or other financial resources to cover debt payments. Lending institutions generally frown on lending to projects that have a DSCR of less than one.
An amount of money borrowed and owed by one party to another is considered debt. For example: bonds, loans, and commercial paper. Equity is a term whose meaning depends very much on the context, but in general, it refers to ownership in any asset after all debts associated with that asset are paid off.
The process of dismantling a turbine and restoring the site to pre-project conditions.
Decommissioning as a permitting regulation refers to the process for removing a wind energy conversion system once the project has reached its end. There are a variety of methods used to regulate this area of wind development, from requiring a bond or financial guarantee before a permit is issued to simply requiring a written plan for removing the turbine and associated components.
The amount of electricity drawn from an electric system at a given time, measured in kilowatts.
As it pertains to the electricity industry, deregulation is the process of opening up electricity markets to competition between power producers with the notion that competition will help lower electricity rates for consumers.
1) The interest rate that an eligible depository institution is charged to borrow short-term funds directly from a Federal Reserve Bank. 2) The ineterest rate used in determining the present value of future cash flows.
A small-scale power generation technology that provides electric power at a site closer to customers than the central station generation. The term is commonly used to indicate non-utility sources of electricity, including facilities for self-generation.
An electric cooperative that purchases wholesale power and delivers it to consumer members.
The poles, wires, transformers, breakers, fuses, and other associated equipment, used to deliver electric energy from a bulk power supplier to the consumer. Typically, the distribution system is defined as power lines and associated equipment where the operating voltage is less than 69 kilovolts.
A dual line is a second, redundant transmission line connecting a turbine to the grid that allows your project to generate power even if the first line is taken out of service.
Do your homework! Due diligence means that you have looked at a particular investment from as many angles as possible to best understand the risks, rewards, and opportunity costs. Lenders, investors, contractors, and equipment suppliers will be much more willing to work with you if you can demonstrate that you know the lingo and understand the industry.


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Founders and well-known households: Philadelphia brings to existence the founding households' histories, a historical past of lives lived huge -- actually the who is Who (as good because the while and the place) of Philadelphia -- that after thought of jointly, made town of cohesion the nice city it really is today.
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For 8 centuries, the Texas frontier has obvious conquest, exploration, immigration, revolution and innovation, leaving to historical past a solid of interesting characters and desirable stories. Its old interval started in 1519 with Spanish exploration, yet there has been a prehistory lengthy sooner than, approximately fifteen thousand years past, with the coming of individuals to Texas.
The opposite house Race is a special examine the early U. S. area software and the way it either formed and was once formed through politics throughout the chilly battle. Eisenhower's "New glance" extended the function of the Air strength in nationwide protection, and finally allowed bold aerospace initiatives, specifically the "Dyna-Soar," a bomber built with nuclear guns that will function in house.
A Pictorial heritage of Lamar County, Georgia good points enormous quantities of infrequent and never-before released images of this quiet group from the nineteenth century via sleek times.
Western slavery is going again 10,000 years to Mesopotamia, today's Iraq, the place a male slave was once worthy an orchard of date fingers. woman slaves have been referred to as on for sexual prone, gaining freedom merely whilst their masters died. This e-book strains slavery from classical occasions to the current. It exhibits how the enforced circulation of greater than 12 million Africans directly to the Atlantic slave ships, and the scattering of extra eleven million survivors around the colonies of the Americas among the past due sixteenth and early nineteenth centuries, remodeled the face of the Americas.


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Washington Air National Guard members from the 194th Wing and Western Air Defense Sector received COVID-19 vaccines Jan. 8, 2021, on Camp Murray, Washington. The vaccine was made available to all WA ANG service members in early January on a voluntary basis.
NEWS | Jan. 11, 2021
COVID-19 vaccine available to Washington Air Guard members
By Master Sgt. Timothy Chacon 194th Wing
CAMP MURRAY, Wash. – Across Washington State, every Air National Guardsman is eligible to receive a COVID-19 vaccine on a voluntary basis, and many are choosing to do so.
On Jan. 8, several members of the 194th Wing and Western Air Defense Sector went through the vaccination process at Camp Murray. They were among the first few groups within the Washington Air National Guard to receive the vaccine.
"This is our path forward to getting back to a life without masks and social distancing," said Col. Kenneth Borchers, 194th Wing commander. "I understand people's hesitation, but I think this is the right way ahead, and as more information comes out on it, I think that will be proven true. I encourage people to seek out the information that is currently out there."
Air Guardsmen opted in for their reasons but most wanted to contribute to the collective effort needed to push back against the COVID-19 virus.
"I decided to volunteer because I want us to get back to some kind of normal," said Staff Sgt. Shayna Shon, a personnel specialist in the 225th Air Defense Group. "2020 was rough for me, so I think contributing to hopefully getting past the pandemic will make an impact for our country and improve my life personally."
Part of the process included a lengthy brief from medical personnel. They covered the vaccination process, to include the two-shot series for the Moderna variant they would be receiving. They went over the statistics for vaccines already administered, and ample time was given to answer questions. This was an important step for some.
"My biggest concern was for the long-term effects, but the more I researched, the benefits outweighed [possible] side effects," said Senior Master Sgt. Rebekah St. Romain, 225th Air Defense Group superintendent. "I'm hoping more people will get the vaccine, and they can see that it is OK. I feel it was the right decision. All the briefings and the info they provided helped alleviate my concerns."
The exposure to factual information about the vaccines was a common turning point for many in their decision process.
"Initially this was not something I planned on doing. I was nervous because I didn't know the facts," said Tech. Sgt. Courtney Lawson, 225th Air Defense Group base records manager. "But my leadership providing [the facts] and my husband getting it changed my mind."
According to the Food and Drug Administration, the COVID-19 vaccines have and are undergoing a rigorous development process that includes tens of thousands of study participants to generate the needed non-clinical, clinical, and manufacturing data.
The vaccines are being administered under an Emergency Use Act. An EUA is a mechanism to facilitate the availability and use of medical countermeasures, including vaccines, during public health emergencies, such as the current COVID-19 pandemic. For an EUA to be issued for a vaccine, the FDA must determine that the known and potential benefits outweigh the vaccine's known and potential risks.
The FDA says the COVID-19 vaccine has been developed so quickly because U.S. government agencies, international counterparts, academia, nonprofit organizations and pharmaceutical companies developed a coordinated strategy for prioritizing and speeding development of the most promising vaccines.
Brig. Gen. Gent Welsh, Washington Air National Guard commander, has made getting vaccines to those who want them his organization's highest priority. He was confident that a few hundred members would be vaccinated by Jan. 10 and has a plan in place to reach the rest of those wanting the vaccine in coming weeks.
Information is readily available for those who have questions about the vaccine and the process. The vaccine has a stellar track record with the more than 22 million people who had already received it as of Jan. 9.
"This is an optional vaccine. This is not mandatory at this time," said Borchers. "Whether to receive it or not is up to each of you. There's no negative consequence to opting out. We all need to make up our own minds based on what we know, what we're learning, and what new reliable information is made available."
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Have you wondered why your resume doesn't get noticed? Are you curious regarding how a recruiter "examines" your resume? Interested in the resume killers? Join career expert, motivator, and award-winning author Andrew LaCivita as he discusses how to get your resume noticed in 5 seconds guaranteed!
How do you review a resume?
Side note: If I can sum up my entire 28-year career in 26 words, you can summarize a 50-year career in two pages. If you think you can't, you are mistaken.
What's the 5-second magic pill!?
Check out the video for much more on this topic!
You can join the resume course + workshop here!
Free Job Interviewing WEBINAR: I'm offering a FREE WEBINAR titled 3 Keys to Ace Any Job Interview. It comes with great instruction and a nice workbook for note taking. Even more, I have an awesome giveaway when you attend. It's an eBook titled Ace Any Job Interview. There are several times available.
Hello Andrew. I enjoyed your videos, very informative. I wanted to offer a couple of suggestions that may make your video presentations a little better. Your videos are nicely lit, but motion such as a Fed Ex truck zipping past a window or tree branches blowing in the wind can distract your viewer from your presentation. It's the equivalent of an objective statement at the top of the resume! With regards to composition, the viewer can draw a vertical line through the center of your videos. It starts with your shirt button/zipper straight up to your nose and continues with the corner of the room up to the ceiling. When your face breaks that perfect alignment by naturally moving off center to one side or the other as you speak – it again becomes very distracting. So, watch for lines, or objects in the background that may look like they are poking out of your head when viewed on screen. Other than that, you have a good energy and a smooth flowing message. Keep up the good work! I'm off to re-design my resume.
Max, thank you for the kind words and glad you like the content. I will also keep in mind those suggestions about the movement in the background!!!
Hey Andrew – All of your videos have been beneficial- and on an upbeat tone, so THANKS! Question about the abridged resume style- how does that "handle" the new technology word scan that will filter OUT resumes that don't match over 80% optimization? Do we change the one or two bullet points – our HIGHLIGHTS- to get more word match with their job posting/requirements?
Again, hope you feel the appreciation from so many people that are just building a better life for themselves – and YOU have been a sometimes silent partner in it- so Thanks!
Hi Mike, thanks for the kind words! First point, would be I'm not recommending an abridged resume style. It's a full-out, complete resume. Check out exactly how I recommend that here (if you haven't seen this already): http://milewalk.com/mwblog/build-ultimate-professional-resume-andrew-lacivita/. I also have a workshop dedicated to this: https://www.milewalkacademy.com/p/build-your-ultimate-professional-resume-workshop. Second, if you are loading your resume into an ATS that might be sensitive to keyword matches (or even recruiters who are sensitive to keyword matches), you should check out https://www.jobscan.co/. That will help you determine the overall "keyword" match to see whether the computer feels you're in alignment. Hope that helps!!!