Background
Women and their health care providers need a reliable answer to this important question: If a woman chooses to participate in regular mammography screening, then how much will this choice ...improve her chances of avoiding a death from breast cancer compared with women who choose not to participate?
Methods
To answer this question, we used comprehensive registries for population, screening history, breast cancer incidence, and disease‐specific death data in a defined population in Dalarna County, Sweden. The annual incidence of breast cancer was calculated along with the annual incidence of breast cancers that were fatal within 10 and within 11 to 20 years of diagnosis among women aged 40 to 69 years who either did or did not participate in mammography screening during a 39‐year period (1977‐2015). For an additional comparison, corresponding data are presented from 19 years of the prescreening period (1958‐1976). All patients received stage‐specific therapy according to the latest national guidelines, irrespective of the mode of detection.
Results
The benefit for women who chose to participate in an organized breast cancer screening program was a 60% lower risk of dying from breast cancer within 10 years after diagnosis (relative risk, 0.40; 95% confidence interval, 0.34‐0.48) and a 47% lower risk of dying from breast cancer within 20 years after diagnosis (relative risk, 0.53; 95% confidence interval, 0.44‐0.63) compared with the corresponding risks for nonparticipants.
Conclusions
Although all patients with breast cancer stand to benefit from advances in breast cancer therapy, the current results demonstrate that women who have participated in mammography screening obtain a significantly greater benefit from the therapy available at the time of diagnosis than do those who have not participated.
After 20 years of follow‐up, women who participate in mammography screening have a 47% lower risk of dying from breast cancer. Although all patients with breast cancer potentially can benefit from advances in breast cancer therapy, women who participate in mammography screening obtain a significantly greater benefit from the therapy available at the time of diagnosis than those who do not participate.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The International Council on Harmonization (ICH) S7B and E14 regulatory guidelines are sensitive but not specific for predicting which drugs are pro‐arrhythmic. In response, the Comprehensive In ...Vitro Proarrhythmia Assay (CiPA) was proposed that integrates multi‐ion channel pharmacology data in vitro into a human cardiomyocyte model in silico for proarrhythmia risk assessment. Previously, we reported the model optimization and proarrhythmia metric selection based on CiPA training drugs. In this study, we report the application of the prespecified model and metric to independent CiPA validation drugs. Over two validation datasets, the CiPA model performance meets all pre‐specified measures for ranking and classifying validation drugs, and outperforms alternatives, despite some in vitro data differences between the two datasets due to different experimental conditions and quality control procedures. This suggests that the current CiPA model/metric may be fit for regulatory use, and standardization of experimental protocols and quality control criteria could increase the model prediction accuracy even further.
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After multiple drugs were removed from the market secondary to drug‐induced torsade de pointes (TdP) risk, the International Council for Harmonisation (ICH) released guidelines in 2005 that focused ...on the nonclinical (S7B) and clinical (E14) assessment of surrogate biomarkers for TdP. Recently, Vargas et al. published a pharmaceutical‐industry perspective making the case that “double‐negative” nonclinical data (negative in vitro hERG and in vivo heart‐rate corrected QT (QTc) assays) are associated with such low probability of clinical QTc prolongation and TdP that potentially all double‐negative drugs would not need detailed clinical QTc evaluation. Subsequently, the ICH released a new E14/S7B Draft Guideline containing Questions and Answers (Q&As) that defined ways that double‐negative nonclinical data could be used to reduce the number of “Thorough QT” (TQT) studies and reach a low‐risk determination when a TQT or equivalent could not be performed. We review the Vargas et al. proposal in the context of what was contained in the ICH E14/S7B Draft Guideline and what was proposed by the ICH E14/S7B working group for a “stage 2” of updates (potential expanded roles for nonclinical data and details for assessing TdP risk of QTc‐prolonging drugs). Although we do not agree with the exact probability statistics in the Vargas et al. paper because of limitations in the underlying datasets, we show how more modest predictive value of individual assays could still result in low probability for TdP with double‐negative findings. Furthermore, we expect that the predictive value of the nonclinical assays will improve with implementation of the new ICH E14/S7B Draft Guideline.
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Breast cancer screening and overdiagnosis Bulliard, Jean‐Luc; Beau, Anna‐Belle; Njor, Sisse ...
International journal of cancer,
15 August 2021, Volume:
149, Issue:
4
Journal Article
Peer reviewed
Open access
Overdiagnosis is a harmful consequence of screening which is particularly challenging to estimate. An unbiased setting to measure overdiagnosis in breast cancer screening requires comparative data ...from a screened and an unscreened cohort for at least 30 years. Such randomised data will not become available, leaving us with observational data over shorter time periods and outcomes of modelling. This collaborative effort of the International Cancer Screening Network quantified the variation in estimated breast cancer overdiagnosis in organised programmes with evaluation of both observed and simulated data, and presented examples of how modelling can provide additional insights. Reliable observational data, analysed with study design accounting for methodological pitfalls, and modelling studies with different approaches, indicate that overdiagnosis accounts for less than 10% of invasive breast cancer cases in a screening target population of women aged 50 to 69. Estimates above this level are likely to derive from inaccuracies in study design. The widely discrepant estimates of overdiagnosis reported from observational data could substantially be reduced by use of a cohort study design with at least 10 years of follow‐up after screening stops. In contexts where concomitant opportunistic screening or gradual implementation of screening occurs, and data on valid comparison groups are not readily available, modelling of screening intervention becomes an advantageous option to obtain reliable estimates of breast cancer overdiagnosis.
What's new
The detection of breast cancer before symptoms arise greatly increases the chance of prolonging survival or even curing malignancy. However, the assumption that asymptomatic disease progresses to symptomatic disease is a major factor in breast cancer overdiagnosis. While estimates of overdiagnosis vary substantially, the present analysis of observational data and data from modelling studies shows that overdiagnosis accounts for less than 10 percent of invasive breast cancer cases among women ages 50 to 69. The findings reaffirm the idea that observational studies require careful design to avoid methodological pitfalls and highlight the value of insight gained from well‐calibrated modelling studies.
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Buprenorphine is a μ-opioid receptor (MOR) partial agonist used to manage pain and addiction. QTC prolongation that crosses the 10 msec threshold of regulatory concern was observed at a ...supratherapeutic dose in two thorough QT studies for the transdermal buprenorphine product BUTRANS®. Because QTC prolongation can be associated with Torsades de Pointes (TdP), a rare but potentially fatal ventricular arrhythmia, these results have led to further investigation of the electrophysiological effects of buprenorphine. Drug-induced QTC prolongation and TdP are most commonly caused by acute inhibition of hERG current (IhERG) that contribute to the repolarizing phase of the ventricular action potentials (APs). Concomitant inhibition of inward late Na+ (INaL) and/or L-type Ca2+ (ICaL) current can offer some protection against proarrhythmia. Therefore, we characterized the effects of buprenorphine and its major metabolite norbuprenorphine on cardiac hERG, Ca2+, and Na+ ion channels, as well as cardiac APs. For comparison, methadone, a MOR agonist associated with QTC prolongation and high TdP risk, and naltrexone and naloxone, two opioid receptor antagonists, were also studied. Whole cell recordings were performed at 37°C on cells stably expressing hERG, CaV1.2, and NaV1.5 proteins. Microelectrode array (MEA) recordings were made on human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). The results showed that buprenorphine, norbuprenorphine, naltrexone, and naloxone had no effect on IhERG, ICaL, INaL, and peak Na+ current (INaP) at clinically relevant concentrations. In contrast, methadone inhibited IhERG, ICaL, and INaL. Experiments on iPSC-CMs showed a lack of effect for buprenorphine, norbuprenorphine, naltrexone, and naloxone, and delayed repolarization for methadone at clinically relevant concentrations. The mechanism of QTC prolongation is opioid moiety-specific. This remains undefined for buprenorphine, while for methadone it involves direct hERG channel block. There is no evidence that buprenorphine use is associated with TdP. Whether this lack of TdP risk can be generalized to other drugs with QTC prolongation not mediated by acute hERG channel block warrants further study.
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Drug-induced Torsade-de-Pointes (TdP) has been responsible for the withdrawal of many drugs from the market and is therefore of major concern to global regulatory agencies and the pharmaceutical ...industry. The Comprehensive
Proarrhythmia Assay (CiPA) was proposed to improve prediction of TdP risk, using
models and
multi-channel pharmacology data as integral parts of this initiative. Previously, we reported that combining dynamic interactions between drugs and the rapid delayed rectifier potassium current (IKr) with multi-channel pharmacology is important for TdP risk classification, and we modified the original O'Hara Rudy ventricular cell mathematical model to include a Markov model of IKr to represent dynamic drug-IKr interactions (IKr-dynamic ORd model). We also developed a novel metric that could separate drugs with different TdP liabilities at high concentrations based on total electronic charge carried by the major inward ionic currents during the action potential. In this study, we further optimized the IKr-dynamic ORd model by refining model parameters using published human cardiomyocyte experimental data under control and drug block conditions. Using this optimized model and manual patch clamp data, we developed an updated version of the metric that quantifies the net electronic charge carried by major inward and outward ionic currents during the steady state action potential, which could classify the level of drug-induced TdP risk across a wide range of concentrations and pacing rates. We also established a framework to quantitatively evaluate a system's robustness against the induction of early afterdepolarizations (EADs), and demonstrated that the new metric is correlated with the cell's robustness to the pro-EAD perturbation of IKr conductance reduction. In summary, in this work we present an optimized model that is more consistent with experimental data, an improved metric that can classify drugs at concentrations both near and higher than clinical exposure, and a physiological framework to check the relationship between a metric and EAD. These findings provide a solid foundation for using
models for the regulatory assessment of TdP risk under the CiPA paradigm.
Over the past ten years, there has been a growing interest in integrating arts and humanities in medicine to increase learners' empathy and resilience; improve personal well-being, communication, and ...observational skills; enhance self-reflection; and promote professionalism. These desired skills and qualities are becoming increasingly important for the physicians of tomorrow. Parallel to curricular interventions of integrating arts and humanities to medical education, there has been an increasing research interest in investigating the impact of such interventions on medical students with respect to improving and sustaining students' empathy as they progress in their medical education and develop their professional identity. Research has yielded interesting findings on the types and effect of the interventions in the medical curriculum. The Association of the American Medical Colleges (AAMC), recognizing the unique and unrealized role of arts and humanities in preparing and equipping physicians for twenty-first-century challenges, proposed seven recommendations for advancing arts and humanities integration into medical education to improve the education, practice, and well-being of physicians and physician learners across the spectrum of medical education. Institutional initiatives of arts and humanities integration in the medical curriculum in response to the AAMC's recommendations afford health sciences librarians expansive opportunities and a new landscape of playing an important role in these initiatives. With their diverse educational background in arts, humanities, social sciences, and many other disciplines and fields, health sciences librarians are poised for meaningful contributions to their institutional goals in developing a humanistic, compassionate workforce of future physicians.
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Q-methodology is an approach to studying complex issues of human 'subjectivity'. Although this approach was developed in the early twentieth century, the value of Q-methodology in healthcare was not ...recognised until relatively recently. The aim of this review was to scope the empirical healthcare literature to examine the extent to which Q-methodology has been utilised in healthcare over time, including how it has been used and for what purposes.
A search of three electronic databases (Scopus, EBSCO-CINAHL Complete, Medline) was conducted. No date restriction was applied. A title and abstract review, followed by a full-text review, was conducted by a team of five reviewers. Included articles were English-language, peer-reviewed journal articles that used Q-methodology (both Q-sorting and inverted factor analysis) in healthcare settings. The following data items were extracted into a purpose-designed Excel spreadsheet: study details (e.g., setting, country, year), reasons for using Q-methodology, healthcare topic area, participants (type and number), materials (e.g., ranking anchors and Q-set), methods (e.g., development of the Q-set, analysis), study results, and study implications. Data synthesis was descriptive in nature and involved frequency counting, open coding and the organisation by data items.
Of the 2,302 articles identified by the search, 289 studies were included in this review. We found evidence of increased use of Q-methodology in healthcare, particularly over the last 5 years. However, this research remains diffuse, spread across a large number of journals and topic areas. In a number of studies, we identified limitations in the reporting of methods, such as insufficient information on how authors derived their Q-set, what types of analyses they performed, and the amount of variance explained.
Although Q-methodology is increasingly being adopted in healthcare research, it still appears to be relatively novel. This review highlight commonalities in how the method has been used, areas of application, and the potential value of the approach. To facilitate reporting of Q-methodological studies, we present a checklist of details that should be included for publication.
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The EarlyCDT‐Lung test is a blood‐based autoantibody assay intended to identify high‐risk individuals for low‐dose computed tomography lung cancer screening. However, there is a paucity of evidence ...on the performance of the EarlyCDT‐Lung test in ever‐smokers. We conducted a nested case‐control study within two prospective cohorts to evaluate the risk‐discriminatory performance of the EarlyCDT‐Lung test using prediagnostic blood samples from 154 future lung cancer cases and 154 matched controls. Cases were selected from those who had ever smoked and had a prediagnostic blood sample <3 years prior to diagnosis. Conditional logistic regression was used to estimate the association between EarlyCDT‐Lung test results and lung cancer risk. Sensitivity and specificity of the EarlyCDT‐Lung test were calculated in all subjects and subgroups based on age, smoking history, lung cancer stage, sample collection time before diagnosis and year of sample collection. The overall lung cancer odds ratios were 0.89 (95% CI: 0.34‐2.30) for a moderate risk EarlyCDT‐Lung test result and 1.09 (95% CI: 0.48‐2.47) for a high‐risk test result compared to no significant test result. The overall sensitivity was 8.4% (95% CI: 4.6‐14) and overall specificity was 92% (95% CI: 87‐96) when considering a high‐risk result as positive. Stratified analysis indicated higher sensitivity (17%, 95% CI: 7.2‐32.1) in subjects with blood drawn up to 1 year prior to diagnosis. In conclusion, our study does not support a role of the EarlyCDT‐Lung test in identifying the high‐risk subjects in ever‐smokers for lung cancer screening in the EPIC and NSHDS cohorts.
What's new?
Low‐dose computed tomography (LDCT) is a promising tool for the early detection of lung cancer. To improve its effectiveness, prescreening to identify individuals with high lung cancer risk may be necessary. Here, the authors examined the prescreening utility of the commercially available blood‐based autoantibody EarlyCDT®‐Lung test. Analysis of prediagnostic blood samples from cases and controls reveals low sensitivity for the EarlyCDT®‐Lung test, with limited evidence supporting an association between a positive test result and lung cancer risk. The results indicate that the EarlyCDT®‐Lung test is unlikely to be useful for identifying ever smokers with an elevated risk of lung cancer.
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The Comprehensive
Proarrhythmia Assay (CiPA) is a global initiative intended to improve drug proarrhythmia risk assessment using a new paradigm of mechanistic assays. Under the CiPA paradigm, the ...relative risk of drug-induced Torsade de Pointes (TdP) is assessed using an
model of the human ventricular action potential (AP) that integrates
pharmacology data from multiple ion channels. Thus, modeling predictions of cardiac risk liability will depend critically on the variability in pharmacology data, and uncertainty quantification (UQ) must comprise an essential component of the
assay. This study explores UQ methods that may be incorporated into the CiPA framework. Recently, we proposed a promising
TdP risk metric (qNet), which is derived from AP simulations and allows separation of a set of CiPA training compounds into Low, Intermediate, and High TdP risk categories. The purpose of this study was to use UQ to evaluate the robustness of TdP risk separation by qNet. Uncertainty in the model parameters used to describe drug binding and ionic current block was estimated using the non-parametric bootstrap method and a Bayesian inference approach. Uncertainty was then propagated through AP simulations to quantify uncertainty in qNet for each drug. UQ revealed lower uncertainty and more accurate TdP risk stratification by qNet when simulations were run at concentrations below 5× the maximum therapeutic exposure (C
). However, when drug effects were extrapolated above 10× C
, UQ showed that qNet could no longer clearly separate drugs by TdP risk. This was because for most of the pharmacology data, the amount of current block measured was <60%, preventing reliable estimation of IC
-values. The results of this study demonstrate that the accuracy of TdP risk prediction depends both on the intrinsic variability in ion channel pharmacology data as well as on experimental design considerations that preclude an accurate determination of drug IC
-values
. Thus, we demonstrate that UQ provides valuable information about
modeling predictions that can inform future proarrhythmic risk evaluation of drugs under the CiPA paradigm.
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