Beyond FEV1 in COPD: a review of patient-reported outcomes and their measurement

Abstract: Patients with chronic obstructive pulmonary disease (COPD) present with a variety of symptoms and pathological consequences. Although primarily viewed as a respiratory disease, COPD has both pulmonary and extrapulmonary effects, which have an impact on many aspects of physical, emotional, and mental well-being. Traditional assessment of COPD relies heavily on measuring lung function, specifically forced expiratory volume in 1 second (FEV1). However, the evidence suggests that FEV1 is a relatively poor correlate of symptoms such as breathlessness and the impact of COPD on daily life. Furthermore, many consequences of the disease, including anxiety and depression and the ability to perform daily activities, can only be described and reported reliably by the patient. Thus, in order to provide a comprehensive view of the effects of interventions in clinical trials, it is essential that spirometry is accompanied by assessments using patient-reported outcome (PRO) instruments. We provide an overview of patient-reported outcome concepts in COPD, such as breathlessness, physical functioning, and health status, and evaluate the tools used for measuring these concepts. Particular attention is given to the newly developed instruments emerging in response to recent regulatory guidelines for the development and use of PROs in clinical trials. We conclude that although data from the development and validation of these new PRO instruments are emerging, to build the body of evidence that supports the use of a new instrument takes many years. Furthermore, new instruments do not necessarily have better discriminative or evaluative properties than older instruments. The development of new PRO tools, however, is crucial, not only to ensure that key COPD concepts are being reliably measured but also that the relevant treatment effects are being captured in clinical trials. In turn, this will help us to understand better the patient's experience of the disease

Who Gets the Carrot and Who Gets the Stick? Evidence of Gender Disparities in Executive Remuneration

notes: Earlier versions of the paper appeared as http://papers.ssrn.com/sol3/papers.cfm?abstract_id=1526948 - TILEC Discussion Paper No. 2009-046 and http://papers.ssrn.com/sol3/papers.cfm?abstract_id=1526948 - CentER Discussion Paper Series No. 2010-02This paper offers a new explanation of the gender pay gap in leadership positions by examining the relationship between managerial bonuses and company performance. Drawing on findings of gender studies, agency theory, and the leadership literature, we argue that the gender pay gap is a context-specific phenomenon that results partly from the fact that company performance has a moderating impact on pay inequalities. Employing a matched sample of 192 female and male executive directors of U.K.-listed firms, we corroborate the existence of the gender pay disparities in corporate boardrooms. In line with our theoretical predictions, we find that bonuses awarded to men are not only larger than those allocated to women, but also that managerial compensation of male executive directors is much more performance-sensitive than that of female executives. The contribution of attributional and expectancy-related dynamics to these patterns is highlighted in line with previous work on gender stereotypes and implicit leadership theories such as the romance of leadership. Gender differences in risk taking and confidence are also considered as potential explanations for the observed pay disparities. The implications of organizations' indifference to women's performance are examined in relation to issues surrounding the recognition and retention of female talent. Copyright © 2010 John Wiley & Sons, Ltd

Psychometric validation of the German translation of the Gastrointestinal Symptom Rating Scale (GSRS) and Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaire in patients with reflux disease

BACKGROUND: Symptoms of heartburn has an impact on health-related quality of life (HRQL). When a questionnaire is translated into a new language, a linguistic validation is necessary but not sufficient unless the psychometric characteristics have been verified. The aim is to document the psychometric characteristics of the German translation of the Gastrointestinal Symptom Rating Scale (GSRS) and Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaire. METHODS: 142 patients with symptoms of heartburn (Age: M = 47.5, ± 14.6; Males = 44.4%) completed the German translation of GSRS, the QOLRAD, the Short-Form-36 (SF-36) and the Hospital Anxiety and Depression (HAD) scale. RESULTS: The internal consistency reliability of GSRS ranged from 0.53–0.91 and of QOLRAD from 0.90–0.94, respectively. The test-retest reliability of GSRS ranged from 0.49–0.73 and of QOLRAD from 0.70–0.84. The relevant domains of the GSRS and QOLRAD domain scores significantly correlated. GSRS domains of Abdominal Pain and Constipation correlated (negatively) with most of the domains of the SF-36. The relevant QOLRAD domains significantly correlated with all SF-36 domains. CONCLUSIONS: The psychometric characteristics of the German translation of GSRS and QOLRAD were found to be good, with satisfactory reliability and validity. The reliability of the GSRS Abdominal Pain domain was moderate

Исследование биосенсорной реакции клеточных субстанций на излучение импульсного газоразрядного генератора для информацинно-волновой терапии

У роботі запропоновано використовувати в якості індикатора електромагнітного випромінювання міліметрового діапазону наднизької інтенсивності біологічну реакцію клітин в умовах in vitro. Об'єктом дослідження була суспензія клітин кісткового мозку щурів у фізіологічному розчині. Показано принципову можливість побудови біосенсорів на основі клітинних структур для реєстрації надслабкого випромінювання міліметрового діапазону.Introduction. The biological effects are characterized by a range of millimeter waves in the spectrum of electromagnetic radiation of high frequency. This is due to the fact that the membranes of living cells with dipole oscillate in the millimeter frequency range. The aim. The aim is cell structures using as biosensors of natural electromagnetic radiation in millimeter range with extremely low intensity for the energy and spectral characteristics evaluation of the discharge pulse generator for information-wave therapy. The experimental technique. The study was conducted «in vitro». The suspension of bone marrow cells of rats in saline was the object of irradiation. One of the cell suspensions was seen, as a control and the other three parts were subjected to irradiation of 10, 20 and 30 minutes. The relative number of dead cells was determined in the control sample and the sample irradiated at 30, 60 and 90 minutes as the characteristics of biosensor response. Results of the study. The relative number of dead cells in the irradiated sample is almost twice lower than for the control for all three exposures. Thus, the impact generated electro-magnetic radiation enhances the viability of bone marrow cells of rats. Conclusions. The experiments indirectly support the structure of the frequency spectrum of electromagnetic radiation discharge pulse generator. Also the theoretical possibility of biosensors constructing based on cell structures can be mentioned for registration superweak radiation in millimeter range.В работе предложено использовать в качестве индикатора электромагнитного излучения миллиметрового диапазона сверхнизкой интенсивности биологическую реакцию клеток в условиях in vitro. Объектом исследования была суспензия клеток костного мозга крыс в физиологическом растворе. Показано принципиальную возможность построения биосенсоров на основе клеточных структур для регистрации сверхслабого излучения миллиметрового диапазона

Reliability and validity of the Gastrointestinal Symptom Rating Scale (GSRS) and Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaire in dyspepsia: A six-country study

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Age-related differences in socio-demographic and behavioral determinants of HIV testing and counseling in HPTN 043/NIMH Project Accept

Youth represent a large proportion of new HIV infections worldwide, yet their utilization of HIV testing and counseling (HTC) remains low. Using the post-intervention, cross-sectional, population-based household survey done in 2011 as part of HPTN 043/NIMH Project Accept, a cluster-randomized trial of community mobilization and mobile HTC in South Africa (Soweto and KwaZulu Natal), Zimbabwe, Tanzania and Thailand, we evaluated age-related differences among socio-demographic and behavioral determinants of HTC in study participants by study arm, site, and gender. A multivariate logistic regression model was developed using complete individual data from 13,755 participants with recent HIV testing (prior 12 months) as the outcome. Youth (18–24 years) was not predictive of recent HTC, except for high-risk youth with multiple concurrent partners, who were less likely (aOR 0.75; 95% CI 0.61–0.92) to have recently been tested than youth reporting a single partner. Importantly, the intervention was successful in reaching men with site specific success ranging from aOR 1.27 (95% CI 1.05–1.53) in South Africa to aOR 2.30 in Thailand (95% CI 1.85–2.84). Finally, across a diverse range of settings, higher education (aOR 1.67; 95% CI 1.42, 1.96), higher socio-economic status (aOR 1.21; 95% CI 1.08–1.36), and marriage (aOR 1.55; 95% CI 1.37–1.75) were all predictive of recent HTC, which did not significantly vary across study arm, site, gender or age category (18–24 vs. 25–32 years)

The spectrum of rare central nervous system (CNS) tumors with EWSR1-non-ETS fusions: experience from three pediatric institutions with review of the literature

The group of CNS mesenchymal (non-meningothelial) and primary glial/neuronal tumors in association with EWSR1-non-ETS rearrangements comprises a growing spectrum of entities, mostly reported in isolation with incomplete molecular profiling. Archival files from three pediatric institutions were queried for unusual cases of pediatric (≤21 years) CNS EWSR1-rearranged tumors confirmed by at least one molecular technique. Extra-axial tumors and cases with a diagnosis of Ewing sarcoma (EWSR1-ETS family fusions) were excluded. Additional studies, including anchored multiplex-PCR with next-generation sequencing and DNA methylation profiling, were performed as needed to determine fusion partner status and brain tumor methylation class, respectively. Five cases (median 17 years) were identified (M:F of 3:2). Location was parenchymal (n = 3) and undetermined (n = 2) with topographic distributions including posterior fossa (n = 1), frontal (n = 1), temporal (n = 1), parietal (n = 1) and occipital (n = 1) lobes. Final designation with fusion findings included desmoplastic small round cell tumor (EWSR1-WT1; n = 1) and tumors of uncertain histogenesis (EWSR1-CREM, n = 1; EWSR1-CREB1, n = 1; EWSR1-PLAGL1, n = 1; and EWSR1-PATZ1, n = 1). Tumors showed a wide spectrum of morphology and biologic behavior. For EWSR1-CREM, EWSR1-PLAGL1 and EWSR1-PATZ1 tumors, no significant methylation scores were reached in the known brain tumor classes. Available outcome (4/5) was reported as favorable (n = 2) and unfavorable (n = 2) with a median follow-up of 30 months. In conclusion, we describe five primary EWSR1-non-ETS fused CNS tumors exhibiting morphologic and biologic heterogeneity and we highlight the clinical importance of determining specific fusion partners to improve diagnostic accuracy, treatment and monitoring. Larger prospective clinicopathological and molecular studies are needed to determine the prognostic implications of histotypes, anatomical location, fusion partners, breakpoints and methylation profiles in patients with these rare tumors

TP53-PTEN-NF1 Depletion in Human Brain Organoids Produces a Glioma Phenotype

Glioblastoma (GBM) is fatal and the study of therapeutic resistance, disease progression, and drug discovery in GBM or glioma stem cells is often hindered by limited resources. This limitation slows down progress in both drug discovery and patient survival. Here we present a genetically engineered human cerebral organoid model with a cancer-like phenotype that could provide a basis for GBM-like models. Specifically, we engineered a doxycycline-inducible vector encoding shRNAs enabling depletion of the TP53, PTEN, and NF1 tumor suppressors in human cerebral organoids. Designated as inducible short hairpin-TP53-PTEN-NF1 (ish-TPN), doxycycline treatment resulted in human cancer-like cerebral organoids that effaced the entire organoid cytoarchitecture, while uninduced ish-TPN cerebral organoids recapitulated the normal cytoarchitecture of the brain. Transcriptomic analysis revealed a proneural GBM subtype. This proof-of-concept study offers a valuable resource for directly investigating the emergence and progression of gliomas within the context of specific genetic alterations in normal cerebral organoids

Multiple imputation for estimating hazard ratios and predictive abilities in case-cohort surveys

<p>Abstract</p> <p>Background</p> <p>The weighted estimators generally used for analyzing case-cohort studies are not fully efficient and naive estimates of the predictive ability of a model from case-cohort data depend on the subcohort size. However, case-cohort studies represent a special type of incomplete data, and methods for analyzing incomplete data should be appropriate, in particular multiple imputation (MI).</p> <p>Methods</p> <p>We performed simulations to validate the MI approach for estimating hazard ratios and the predictive ability of a model or of an additional variable in case-cohort surveys. As an illustration, we analyzed a case-cohort survey from the Three-City study to estimate the predictive ability of D-dimer plasma concentration on coronary heart disease (CHD) and on vascular dementia (VaD) risks.</p> <p>Results</p> <p>When the imputation model of the phase-2 variable was correctly specified, MI estimates of hazard ratios and predictive abilities were similar to those obtained with full data. When the imputation model was misspecified, MI could provide biased estimates of hazard ratios and predictive abilities. In the Three-City case-cohort study, elevated D-dimer levels increased the risk of VaD (hazard ratio for two consecutive tertiles = 1.69, 95%CI: 1.63-1.74). However, D-dimer levels did not improve the predictive ability of the model.</p> <p>Conclusions</p> <p>MI is a simple approach for analyzing case-cohort data and provides an easy evaluation of the predictive ability of a model or of an additional variable.</p