Measuring disease-specific quality of life in rare populations: a practical approach to cross-cultural translation

<p>Abstract</p> <p>Background</p> <p>Disease-specific quality of life (QoL) measures have enhanced the capacity of outcome measures to evaluate subtle changes and differences between groups. However, when the specific disease is rare, the cohort of patients is small and international collaboration is often necessary to accomplish meaningful research. As many of the QoL measures have been developed in North American English, they require translation to ensure their usefulness in a multi-cultural and/or international society. Published guidelines provide formal methods to achieve cross-culturally comparable versions of a QoL tool. However, these guidelines describe a rigorous process that is not always feasible, particularly in rare disease groups. The objective of this manuscript is to describe the process that was developed to achieve accurate cross-cultural translations of a disease-specific QoL measure, to overcome the challenges of a small sample size, i.e. children with a rare disorder.</p> <p>Procedure</p> <p>A measurement study was conducted in the United Kingdom (UK), France, Germany and Uruguay, during which the validated measure was translated into the languages of the respective countries.</p> <p>Results</p> <p>This is a report of a modified, child-centric, cross-cultural translation and adaptation process in which culturally appropriate and methodologically valid translations of a disease-specific QoL measure, the Kids' ITP Tools (KIT), were performed in children with immune thrombocytopenic purpura (ITP). The KIT was translated from North American English into UK English, French, German, and Spanish.</p> <p>Conclusion</p> <p>This study was a successful international collaboration. The modified process through which culturally appropriate and methodologically valid translations of QoL measures may be achieved in a pediatric population with a relatively rare disorder is reported.</p

Using quantitative single molecule localization microscopy to optimize multivalent HER2-targeting ligands

IntroductionThe progression-free survival of patients with HER2-positive metastatic breast cancer is significantly extended by a combination of two monoclonal antibodies, trastuzumab and pertuzumab, which target independent epitopes of the extracellular domain of HER2. The improved efficacy of the combination over individual antibody therapies targeting HER2 is still being investigated, and several molecular mechanisms may be in play: the combination downregulates HER2, improves antibody-dependent cell mediated cytotoxicity, and/or affects the organization of surface-expressed antigens, which may attenuate downstream signaling.MethodsBy combining protein engineering and quantitative single molecule localization microscopy (qSMLM), here we both assessed and optimized clustering of HER2 in cultured breast cancer cells.ResultsWe detected marked changes to the cellular membrane organization of HER2 when cells were treated with therapeutic antibodies. When we compared untreated samples to four treatment scenarios, we observed the following HER2 membrane features: (1) the monovalent Fab domain of trastuzumab did not significantly affect HER2 clustering; (2) individual therapy with either trastuzumab or (3) pertuzumab produced significantly higher levels of HER2 clustering; (4) a combination of trastuzumab plus pertuzumab produced the highest level of HER2 clustering. To further enhance this last effect, we created multivalent ligands using meditope technology. Treatment with a tetravalent meditope ligand combined with meditope-enabled trastuzumab resulted in pronounced HER2 clustering. Moreover, compared to pertuzumab plus trastuzumab, at early time points this meditope-based combination was more effective at inhibiting epidermal growth factor (EGF) dependent activation of several downstream protein kinases.DiscussionCollectively, mAbs and multivalent ligands can efficiently alter the organization and activation of the HER2 receptors. We expect this approach could be used in the future to develop new therapeutics

Promising System for Selecting Healthy In Vitro–Fertilized Embryos in Cattle

Conventionally, in vitro–fertilized (IVF) bovine embryos are morphologically evaluated at the time of embryo transfer to select those that are likely to establish a pregnancy. This method is, however, subjective and results in unreliable selection. Here we describe a novel selection system for IVF bovine blastocysts for transfer that traces the development of individual embryos with time-lapse cinematography in our developed microwell culture dish and analyzes embryonic metabolism. The system can noninvasively identify prognostic factors that reflect not only blastocyst qualities detected with histological, cytogenetic, and molecular analysis but also viability after transfer. By assessing a combination of identified prognostic factors—(i) timing of the first cleavage; (ii) number of blastomeres at the end of the first cleavage; (iii) presence or absence of multiple fragments at the end of the first cleavage; (iv) number of blastomeres at the onset of lag-phase, which results in temporary developmental arrest during the fourth or fifth cell cycle; and (v) oxygen consumption at the blastocyst stage—pregnancy success could be accurately predicted (78.9%). The conventional method or individual prognostic factors could not accurately predict pregnancy. No newborn calves showed neonatal overgrowth or death. Our results demonstrate that these five predictors and our system could provide objective and reliable selection of healthy IVF bovine embryos

Updating the Canadian Hemophilia Outcomes–Kids’ Life Assessment Tool (CHO‐KLAT) in the era of extended half‐life clotting factor concentrates

Abstract Introduction The purpose of this study was to review and update the content of the Canadian Hemophilia Outcomes–Kids’ Life Assessment Tool version 2.0 (CHO‐KLAT), in the context of extended half‐life (EHL) factor concentrates (FCs) and to establish the validity and reliability of the updated CHO‐KLAT. Methods Focus groups were conducted with boys with hemophilia, their parents, and health care providers across Canada to review the CHO‐KLAT v2.0 and determine if any modifications were required. The validity of the revised CHO‐KLAT (version 3.0) was then determined in a sample of boys with hemophilia and their parents by calculating its correlation with the Pediatric Quality of Life Core Module (PedsQL‐Core). Test‐retest reliability was assessed using an intraclass correlation coefficient (ICC). Results Thirteen focus groups at 5 pediatric hemophilia treatment centers (HTCs) (n = 71) resulted in 19 changes to the CHO‐KLAT v2.0, generating a revised 40‐item CHO‐KLAT, the CHO‐KLAT v3.0. Thirty‐five boys with hemophilia (median age, 14; range, 7–17 years) and 47 parents participated in the validation of the CHO‐KLAT v3.0. There was a moderate correlation between the CHO‐KLAT v3.0 child self‐report and PedsQL‐Core (r = 0.56, P = .01), and a strong correlation between the CHO‐KLAT v3.0 parent‐proxy and PedsQL‐Core (r = .79, P = .0007). The test‐retest reliability ICC was 0.90 for the child self‐report CHO‐KLAT v3.0 and 0.68 for the parent‐proxy CHO‐KLAT v3.0. Conclusion The CHO‐KLAT v3.0 is a reliable and valid child‐centric tool that effectively measures health‐related quality of life in boys with hemophilia who are receiving standard half‐life or EHL FCs

Data_Sheet_1_Using quantitative single molecule localization microscopy to optimize multivalent HER2-targeting ligands.pdf

IntroductionThe progression-free survival of patients with HER2-positive metastatic breast cancer is significantly extended by a combination of two monoclonal antibodies, trastuzumab and pertuzumab, which target independent epitopes of the extracellular domain of HER2. The improved efficacy of the combination over individual antibody therapies targeting HER2 is still being investigated, and several molecular mechanisms may be in play: the combination downregulates HER2, improves antibody-dependent cell mediated cytotoxicity, and/or affects the organization of surface-expressed antigens, which may attenuate downstream signaling.MethodsBy combining protein engineering and quantitative single molecule localization microscopy (qSMLM), here we both assessed and optimized clustering of HER2 in cultured breast cancer cells.ResultsWe detected marked changes to the cellular membrane organization of HER2 when cells were treated with therapeutic antibodies. When we compared untreated samples to four treatment scenarios, we observed the following HER2 membrane features: (1) the monovalent Fab domain of trastuzumab did not significantly affect HER2 clustering; (2) individual therapy with either trastuzumab or (3) pertuzumab produced significantly higher levels of HER2 clustering; (4) a combination of trastuzumab plus pertuzumab produced the highest level of HER2 clustering. To further enhance this last effect, we created multivalent ligands using meditope technology. Treatment with a tetravalent meditope ligand combined with meditope-enabled trastuzumab resulted in pronounced HER2 clustering. Moreover, compared to pertuzumab plus trastuzumab, at early time points this meditope-based combination was more effective at inhibiting epidermal growth factor (EGF) dependent activation of several downstream protein kinases.DiscussionCollectively, mAbs and multivalent ligands can efficiently alter the organization and activation of the HER2 receptors. We expect this approach could be used in the future to develop new therapeutics.</p

Impact of prophylaxis on health-related quality of life of boys with hemophilia : An analysis of pooled data from 9 countries

Background: Prophylaxis reduces the frequency of bleeds in boys with severe hemophilia and is the standard care for their management in resource-abundant countries. The effect of prophylaxis on Health-Related Quality of Life (HRQoL) has not been established, because the sample sizes of most studies are too small to explore the relationship of multiple factors that influence HRQoL. Methods: The aim of this study was to assess the impact of hemophilia severity and treatment regimen on HRQoL and to establish the minimum important difference (MID) using the international level of score distributions. HRQoL data were pooled from 7 studies across 9 countries. HRQoL was measured using the Canadian Hemophilia Outcomes-Kids' Life Assessment Tool (CHO-KLAT). A mixed-effect linear regression analysis was employed to assess the impact of prophylaxis on the CHO-KLAT score. Results: Data from 401 boys with hemophilia were analyzed (57.6% severe hemophilia and 57.6% receiving prophylaxis). The model revealed that receiving prophylaxis was significantly associated with higher HRQoL (regression coefficient 8.5, 95% confidence interval [CI] 3.9-13.1). Boys with severe hemophilia had a significantly lower HRQoL as compared to boys with moderate and mild hemophilia whose CHO-KLAT scores were 7.0 and 6.6 points higher, respectively. There was a significant interaction between treatment and disease severity (P = 0.023), indicating prophylaxis has the most significant impact in boys with severe hemophilia. Based on these pooled data, the MID of the CHO-KLAT was established at 6.5. Conclusions: This study confirms the positive effect of prophylaxis on HRQoL in boys with hemophilia in a real-world setting and provides initial benchmarks for interpreting HRQoL scores based on use of the CHO-KLAT instrument