Assessing glucocorticoid toxicity: Are the measures sensitive enough?

The Glucocorticoid Toxicity Index (GTI) is a composite instrument designed to capture change in glucocorticoid-related morbidity over time.1 It was developed through consensus methods and multi-criteria decisions among 19 medical specialists, with relative domain weights decided via clinician consensus.2 The GTI has now been used in more than 45 studies, including 12 phase 3 clinical trials.1The GTI comprises eight domains: body mass index, blood pressure, glucose tolerance, lipid metabolism, glucocorticoid myopathy, skin toxicity, neuropsychiatric effects and infections. Two overall scores are calculated: the cumulative worsening score (CWS), which includes transient and permanent GC toxicity from baseline to specific time points, and the Aggregate Improvement Score (AIS), which accounts for improvement as well as worsening GC-toxicity.1 In The Lancet Rheumatology, Naomi Patel and colleagues3 present an analysis of domain scores of the GTI using data from the phase 3 ADVOCATE trial.4 In a clinical trial context where the GTI is used to produce repeated measures to demonstrate differences between (and within) groups of patients taking different dosages of glucocorticoids, and to measure the impact of steroid sparing agents, it is expected to have a high level of measurement validity and reliability

Comment on: Benchmarking tocilizumab use for giant cell arteritis

It is with great interest we read the editorial on tocilizumab (TCZ) use in giant cell arteritis (GCA) published on 9th May, 2022 by Conway et al [1]. We write to share some of our data to add weight to the views expressed, particularly in relation to use of TCZ beyond one yearin refractory cases with visual involvement

The OMERACT emerging leaders program: The good, the bad, and the future

The Journal of Rheumatology Copyright © 2019. All rights reserved. Objective. To describe the experience of the first OMERACT Emerging Leaders Program (ELP). Methods. A Delphi process identified positive aspects, areas for improvement, and future directions. Core items were defined as essential if they received ≥ 70% ratings. Results. Participants valued relatable/accessible mentors (100%), including an OMERACT Executive mentor (100%), and a support network of peers (90%). Key items for future development were funding support (100%) and developing knowledge about OMERACT processes (90%) and politics (80%). Conclusion. The ELP has the potential to provide targeted training for early career researchers to develop relevant skills for future leadership roles within OMERACT

Patient perceptions of health-related quality of life in giant cell arteritis: International development of a disease-specific patient-reported outcome measure

Objectives: GCA is a large vessel vasculitis (LVV) presenting with headache, jaw claudication, musculoskeletal and visual involvement. Current treatment is glucocorticoids and anti-IL-6 tocilizumab in refractory disease. The objective of this study was to explore the impact of GCA and its treatment on people's health-related quality of life (HRQoL), to inform the development of a disease-specific patient-reported outcome measure (PROM) for use in clinical trials and practice. Methods: Participants from the UK and Australia, with biopsy- or imaging-confirmed GCA, were interviewed to identify salient aspects of HRQoL in relation to GCA and its treatment. Purposive sampling included a range of demographic and disease features (cranial, LVV-GCA and visual involvement). Inductive analysis identified individual themes of importance, then domains. Candidate questionnaire items were developed from the individual themes, refined by piloting, cognitive interviews and a linguistic translatability assessment. Results: Thirty-six interviews were conducted to saturation with participants with GCA from the UK (25) and Australia (11). Mean age was 74 years, 23 (63.9%) were female, 13 (36.1%) had visual loss and 5 (13.9%) had LVV-GCA. Thirty-nine individual themes within five domains were identified: physical symptoms; activity of daily living and function; participation; psychological impact; and impact on sense of self and perception of health. Sixty-nine candidate items were developed from individual themes; piloting and refinement resulted in a 40-item draft questionnaire. Conclusion: This international qualitative study underpins the development of candidate items for a disease-specific PROM for GCA. The draft questionnaire is now ready for psychometric testing

The Atacama Cosmology Telescope: Data Characterization and Map Making

We present a description of the data reduction and mapmaking pipeline used for the 2008 observing season of the Atacama Cosmology Telescope (ACT). The data presented here at 148 GHz represent 12% of the 90 TB collected by ACT from 2007 to 2010. In 2008 we observed for 136 days, producing a total of 1423 hours of data (11 TB for the 148 GHz band only), with a daily average of 10.5 hours of observation. From these, 1085 hours were devoted to a 850 deg^2 stripe (11.2 hours by 9.1 deg) centered on a declination of -52.7 deg, while 175 hours were devoted to a 280 deg^2 stripe (4.5 hours by 4.8 deg) centered at the celestial equator. We discuss sources of statistical and systematic noise, calibration, telescope pointing, and data selection. Out of 1260 survey hours and 1024 detectors per array, 816 hours and 593 effective detectors remain after data selection for this frequency band, yielding a 38% survey efficiency. The total sensitivity in 2008, determined from the noise level between 5 Hz and 20 Hz in the time-ordered data stream (TOD), is 32 micro-Kelvin sqrt{s} in CMB units. Atmospheric brightness fluctuations constitute the main contaminant in the data and dominate the detector noise covariance at low frequencies in the TOD. The maps were made by solving the least-squares problem using the Preconditioned Conjugate Gradient method, incorporating the details of the detector and noise correlations. Cross-correlation with WMAP sky maps, as well as analysis from simulations, reveal that our maps are unbiased at multipoles ell > 300. This paper accompanies the public release of the 148 GHz southern stripe maps from 2008. The techniques described here will be applied to future maps and data releases.Comment: 20 pages, 18 figures, 6 tables, an ACT Collaboration pape

Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 x 10(53)). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 x 10(-20)). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management

The neighbourhood social environment and alcohol use among urban and rural Scottish adolescents

Funding for the Scottish Health Behaviour in School-aged Children was provided by NHS Scotland. This work was also supported by the 600th Anniversary Ph.D. Scholarship which was awarded to Gina Martin by the University of St Andrews.Objectives This research examined the relationship between neighbourhood social environmental characteristics and drinking outcomes among a sample of urban and rural adolescents. Methods From a sample of 1558 Scottish secondary schoolchildren, surveyed as part of the 2010 Health Behaviour in School-aged Children study, we modelled three drinking outcomes on a variety of neighbourhood conditions, including social cohesion, disorder, alcohol outlet density, deprivation, and urban/rurality. Nested and cross-classified multilevel logistic regressions were specified. Results An urban-to-rural gradient was found with non-urban adolescents exhibiting higher odds of having ever drank. Neighbourhood social cohesion related to having ever drank. Among drinkers, those living in accessible small towns had higher odds of weekly drinking and drunkenness compared to urban areas. Higher odds of drunkenness were also found in remote rural areas. Those residing in the least deprived areas had lower odds of weekly drinking. Conclusions In Scotland, inequalities exist in adolescent alcohol use by urban/rurality and neighbourhood social conditions. Findings support regional targeting of public health efforts to address inequalities. Future work is needed to develop and evaluate intervention and prevention approaches for neighbourhoods at risk.Publisher PDFPeer reviewe

A study exploring learners' informal learning space behaviors, attitudes, and preferences

What makes a successful informal learning space is a topic in need of further research. The body of discourse on informal space design is drawn from learning theory, placemaking and architecture, with a need for understanding of the synergy between the three. Findings from a longitudinal, quantitative and qualitative study at Sheffield Hallam University, explore learners' behaviours, attitudes and preferences towards informal learning spaces in higher education, within and outside of the context of the academic library. The learning spaces study contributes to the discourse on informal learning spaces design by producing a typology of nine learning space preference attributes which address aspects of learning theory, placemaking and architecture. The typology can be used to evaluate existing spaces and inform redevelopment of informal learning spaces in higher education institutions. Implementing the typology will be subject to localised conditions, but at Sheffield Hallam University the key conclusions have included developing a portfolio of discrete, interrelated learning environments, offering spaces with a clear identity and encouraging students to translate their learning preferences into space selection

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations