Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension

BACKGROUND: Inflammation is a feature of pulmonary arterial hypertension (PAH), and increased circulating levels of cytokines are reported in patients with PAH. However, to date, no information exists on the significance of elevated cytokines or their potential as biomarkers. We sought to determine the levels of a range of cytokines in PAH and to examine their impact on survival and relationship to hemodynamic indexes. METHODS AND RESULTS: We measured levels of serum cytokines (tumor necrosis factor-alpha, interferon-gamma and interleukin-1beta, -2, -4, -5, -6, -8, -10, -12p70, and -13) using ELISAs in idiopathic and heritable PAH patients (n=60). Concurrent clinical data included hemodynamics, 6-minute walk distance, and survival time from sampling to death or transplantation. Healthy volunteers served as control subjects (n=21). PAH patients had significantly higher levels of interleukin-1beta, -2, -4, -6, -8, -10, and -12p70 and tumor necrosis factor-alpha compared with healthy control subjects. Kaplan-Meier analysis showed that levels of interleukin-6, 8, 10, and 12p70 predicted survival in patients. For example, 5-year survival with interleukin-6 levels of >9 pg/mL was 30% compared with 63% for patients with levels < or = 9 pg/mL (P=0.008). In this PAH cohort, cytokine levels were superior to traditional markers of prognosis such as 6-minute walk distance and hemodynamics. CONCLUSIONS: This study illustrates dysregulation of a broad range of inflammatory mediators in idiopathic and familial PAH and demonstrates that cytokine levels have a previously unrecognized impact on patient survival. They may prove to be useful biomarkers and provide insight into the contribution of inflammation in PAH

Developing core outcomes sets: methods for identifying and including patient-reported outcomes (PROs)

BACKGROUND: Synthesis of patient-reported outcome (PRO) data is hindered by the range of available PRO measures (PROMs) composed of multiple scales and single items with differing terminology and content. The use of core outcome sets, an agreed minimum set of outcomes to be measured and reported in all trials of a specific condition, may improve this issue but methods to select core PRO domains from the many available PROMs are lacking. This study examines existing PROMs and describes methods to identify health domains to inform the development of a core outcome set, illustrated with an example. METHODS: Systematic literature searches identified validated PROMs from studies evaluating radical treatment for oesophageal cancer. PROM scale/single item names were recorded verbatim and the frequency of similar names/scales documented. PROM contents (scale components/single items) were examined for conceptual meaning by an expert clinician and methodologist and categorised into health domains. A patient advocate independently checked this categorisation. RESULTS: Searches identified 21 generic and disease-specific PROMs containing 116 scales and 32 single items with 94 different verbatim names. Identical names for scales were repeatedly used (for example, ‘physical function’ in six different measures) and others were similar (overlapping face validity) although component items were not always comparable. Based on methodological, clinical and patient expertise, 606 individual items were categorised into 32 health domains. CONCLUSION: This study outlines a methodology for identifying candidate PRO domains from existing PROMs to inform a core outcome set to use in clinical trials

Developing core outcomes sets: Methods for identifying and including patient-reported outcomes (PROs)

Background: Synthesis of patient-reported outcome (PRO) data is hindered by the range of available PRO measures (PROMs) composed of multiple scales and single items with differing terminology and content. The use of core outcome sets, an agreed minimum set of outcomes to be measured and reported in all trials of a specific condition, may improve this issue but methods to select core PRO domains from the many available PROMs are lacking. This study examines existing PROMs and describes methods to identify health domains to inform the development of a core outcome set, illustrated with an example.Methods: Systematic literature searches identified validated PROMs from studies evaluating radical treatment for oesophageal cancer. PROM scale/single item names were recorded verbatim and the frequency of similar names/scales documented. PROM contents (scale components/single items) were examined for conceptual meaning by an expert clinician and methodologist and categorised into health domains. A patient advocate independently checked this categorisation.Results: Searches identified 21 generic and disease-specific PROMs containing 116 scales and 32 single items with 94 different verbatim names. Identical names for scales were repeatedly used (for example, 'physical function' in six different measures) and others were similar (overlapping face validity) although component items were not always comparable. Based on methodological, clinical and patient expertise, 606 individual items were categorised into 32 health domains.Conclusion: This study outlines a methodology for identifying candidate PRO domains from existing PROMs to inform a core outcome set to use in clinical trials

Translating patient reported outcome measures: Methodological issues explored using cognitive interviewing with three rheumatoid arthritis measures in six European languages

© The Author 2016. Objective. Cross-cultural translation of patient-reported outcome measures (PROMs) is a lengthy process, often performed professionally. Cognitive interviewing assesses patient comprehension of PROMs. The objective was to evaluate the usefulness of cognitive interviewing to assess translations and compare professional (full) with non-professional (simplified) translation processes. Methods. A full protocol used for the Bristol RA Fatigue Multi-dimensional Questionnaire and Numerical Rating Scale (BRAF-MDQ, BRAF-NRS) was compared with a simplified protocol used for the RA Impact of Disease scale (RAID). RA patients in the UK, France, the Netherlands, Germany, Spain and Sweden completed the PROMs during cognitive interviewing (BRAFs in the UK were omitted as these were performed during development). Transcripts were deductively analysed for understanding, information retrieval, judgement and response options. Usefulness of cognitive interviewing was assessed by the nature of problems identified, and translation processes by percentage of consistently problematic items (≥40% patients per country with similar concerns). Results. Sixty patients participated (72% women). For the BRAFs (full protocol) one problematic item was identified (of 23 items × 5 languages, 1/115 = 0.9%). For the RAID (simplified protocol) two problematic items were identified (of 7 items × 6 languages, 2/42 = 4.8%), of which one was revised (Dutch). Coping questions were problematic in both PROMs. Conclusion. Conceptual and cultural challenges though rare were important, as identified by formal evaluation, demonstrating that cognitive interviewing is crucial in PROM translations. Proportionately fewer problematic items were found for the full than for the simplified translation procedure, suggesting that while both are acceptable, professional PROM translation might be preferable. Coping may be a particularly challenging notion cross-culturally

Reliability and sensitivity to change of the bristol rheumatoid arthritis fatigue scales

Objective. To examine the reliability (stability) and sensitivity of the Bristol Rheumatoid Arthritis Fatigue scales (BRAFs) and patient-reported outcome measures (PROMs) developed to capture the fatigue experience. The Multi-Dimensional Questionnaire (BRAF-MDQ) has a global score and four subscales (Physical Fatigue, Living with Fatigue, Cognitive Fatigue and Emotional Fatigue), while three numerical rating scales (BRAF-NRS) measure fatigue Severity, Effect and Coping. Methods. RA patients completed the BRAFs plus comparator PROMs. Reliability (study 1): 50 patients completed questionnaires twice. A same-day test-retest interval (minimum 60 min) ensured both time points related to the same 7 days, minimizing the capture of fatigue fluctuations. Reliability (study 2): 50 patients completed the same procedure with a re-worded BRAF-NRS Coping. Sensitivity to change (study 3): 42 patients being given clinically a single high dose of i.m. glucocorticoids completed questionnaires at weeks 0 and 2.Results. The BRAF-MDQ, its subscales and the BRAF-NRS showed very strong reliability (r = 0.82-0.95). BRAF-NRS Coping had lower moderate reliability in both wording formats (r = 0.62, 0.60). The BRAF-MDQ, its subscales and the BRAF-NRS Severity and Effect were sensitive to change, with effect sizes (ESs) of 0.33-0.56. As hypothesized, the BRF-NRS Coping was not responsive to the pharmaceutical intervention (ES 0.05). Preliminary exploration suggests a minimum clinically important difference of 17.5% for improvement and 6.1% for fatigue worsening. Conclusion. The BRAF scales show good reliability and sensitivity to change. The lack of BRAF-NRS Coping responsiveness to medication supports the theory that coping with fatigue is a concept distinct from severity and effect that is worth measuring separately. © The Author 2013. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved

The revised Bristol Rheumatoid Arthritis Fatigue measures and the Rheumatoid Arthritis Impact of Disease scale: Validation in six countries

© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. Objective. To evaluate the Bristol Rheumatoid Arthritis Fatigue Multidimensional Questionnaire (BRAFMDQ), the revised Bristol Rheumatoid Arthritis Numerical Rating Scales (BRAF-NRS V2) and the Rheumatoid Arthritis Impact of Disease (RAID) scale in six countries. Methods. We surveyed RA patients in France, Germany, The Netherlands, Spain, Sweden and the UK, including the HAQ, 36-item Short Form Health Survey (SF-36) and potential revisions of the BRAF-NRS coping and Spanish RAID coping items. Factor structure and internal consistency were examined by factor analysis and Cronbach's α and construct validity by Spearman's correlation. Results. A total of 1276 patients participated (76% female, 25% with a disease duration < 5 years, median HAQ 1.0). The original BRAF-MDQ four-factor structure and RAID single-factor structure were confirmed in every country with ≥66% of variation in items explained by each factor and all item factor loadings of 0.71-0.98. Internal consistency for the BRAF-MDQ total and subscales was a Cronbach's α of 0.75-0.96 and for RAID, 0.93-0.96. Fatigue construct validity was shown for the BRAF-MDQ and BRAF-NRS severity and effect scales, correlated internally with SF-36 vitality and with RAID fatigue (r = 0.63-0.93). Broader construct validity for the BRAFs and RAID was shown by correlation with each other, HAQ and SF-36 domains (r = 0.46-0.82), with similar patterns in individual countries. The revised BRAF-NRS V2 Coping item had stronger validity than the original in all analyses. The revised Spanish RAID coping item performed as well as the original. Conclusion. Across six European countries, the BRAF-MDQ identifies the same four aspects of fatigue, and along with the RAID, shows strong factor structure and internal consistency and moderate-good construct validity. The revised BRAF-NRS V2 shows improved construct validity and replaces the original

Using viral vectors as gene transfer tools (Cell Biology and Toxicology Special Issue: ETCS-UK 1 day meeting on genetic manipulation of cells)

In recent years, the development of powerful viral gene transfer techniques has greatly facilitated the study of gene function. This review summarises some of the viral delivery systems routinely used to mediate gene transfer into cell lines, primary cell cultures and in whole animal models. The systems described were originally discussed at a 1-day European Tissue Culture Society (ETCS-UK) workshop that was held at University College London on 1st April 2009. Recombinant-deficient viral vectors (viruses that are no longer able to replicate) are used to transduce dividing and post-mitotic cells, and they have been optimised to mediate regulatable, powerful, long-term and cell-specific expression. Hence, viral systems have become very widely used, especially in the field of neurobiology. This review introduces the main categories of viral vectors, focusing on their initial development and highlighting modifications and improvements made since their introduction. In particular, the use of specific promoters to restrict expression, translational enhancers and regulatory elements to boost expression from a single virion and the development of regulatable systems is described