The decay of space charge in a glassy epoxy resin following voltage removal

The PEA technique is used to measure the distribution of space charge in an epoxy resin after polarisation for one week at an applied field of 7.14kV/mm over a range of temperatures. The decay of the space charge is followed for times up to 114 hours after removal of the voltage and analysed in terms of a number of alternative decay mechanisms. It is shown that the rate-determining stage of the decay mechanism is that of a thermally activated process that has been associated with charge de-trapping. At times greater than 102s the de-trapping process behaves as though the space charge field does not exist and the retention time of the space charge depends only upon the depth of the deepest occupied traps and the temperature

Comprehensive geriatric assessment in men aged 70 years or older with localised prostate cancer undergoing radical radiotherapy

Aims Treatment decisions for men aged 70 years or over with localised prostate cancer need to take into account the risk of death from competing causes and fitness for the proposed treatment. Objective assessments such as those included in a comprehensive geriatric assessment (CGA) might help to inform the decision-making process. The aim of this study was to describe the CGA scores of a cohort of older men with prostate cancer, evaluate potential screening tools in this population and assess whether any CGA component predicts significant acute radiotherapy toxicity. Materials and methods This was a prospective cohort study undertaking pretreatment CGA, Vulnerable Elders Survey (VES-13) and G8 assessment in patients aged 70 years and over with localised prostate cancer planned to undergo radical external beam radiotherapy. Results In total, 178 participants were recruited over a 3 year period and underwent a CGA. Fifty-five (30.1%) participants were defined as having health needs identified by their CGA. Both VES-13 and G8 screening tools showed a statistically significant association with CGA needs (P < 0.001 and X2 = 15.02, P < 0.001, respectively), but their sensitivity was disappointing. There was no association between a CGA (or its components) and significant acute radiotherapy toxicity. Conclusions Many older men with localised prostate cancer are vulnerable according to a CGA. The screening tools evaluated were not sufficiently sensitive to identify this group. CGA outcome does not predict for significant acute radiotherapy toxicity

The perceived effects of singing on the health and wellbeing of wives and partners of members of the British Armed Forces: a cross-sectional survey

Objectives A survey to explore the extent to which a choir programme associated with the British Armed Forces provides benefits of wives and partners and families of military personnel. Study design A cross-sectional survey. Method Online self-completion questionnaires to survey 464 choir members and 173 committee members who were also participants in the choirs. Results Large majorities of participants report personal and social benefits from their engagement in choirs, as well as benefits for their health and wellbeing. Challenges facing choirs were also identified associated with performance demands and inter-personal relationships within choirs. Conclusions Group singing generates a range of personal, social and health benefits for wives and partners of armed services personnel. The study reveals some challenges arising in all female choirs in military settings and suggests potential areas for further research

Face validity of four preference-weighted quality-of-life measures in residential aged care: a think-aloud study

Objective There is an increased use of preference-weighted quality-of-life measures in residential aged care to guide resource allocation decisions or for quality-of-care assessments. However, little is known about their face validity (i.e., how understandable, appropriate and relevant the measures are ‘on their face’ when respondents complete them). The aim of this study was to assess the face validity of four preference-weighted measures (i.e., EQ-5D-5L, EQ-HWB, ASCOT, QOL-ACC) in older people living in residential aged care. Methods Qualitative cognitive think-aloud interviews were conducted using both concurrent and retrospective think-aloud techniques. To reduce burden, each resident completed two measures, with the four measures randomised across participants. Audio recordings were transcribed and framework analysis was used for data analysis, based on an existing framework derived from the Tourangeau four-stage response model. Results In total, 24 interviews were conducted with residents living across three residential aged care facilities in Melbourne, Australia. Response issues were identified across all four measures, often related to comprehension and difficulty selecting a response level due to double-barrelled and ambiguous items that have different meanings in the residential aged care context. We also identified issues related to understanding instructions, non-adherence to the recall period, and noted positive responding that requires attention when interpreting the data. Conclusions Our findings provide further evidence on the appropriateness of existing measures, indicating numerous response issues that require further research to guide the selection process for research and practice

The impact of ADHD on the health and well-being of ADHD children and their siblings

Childhood attention-deficit/hyperactivity disorder (ADHD) has been associated with reduced health and well-being of patients and their families. The authors undertook a large UK survey-based observational study of the burden associated with childhood ADHD. The impact of ADHD on both the patient (N = 476) and their siblings (N = 337) on health-related quality of life (HRQoL) and happiness was quantified using multiple standard measures [e.g. child health utility-9D (CHU-9D), EuroQol-5D-Youth]. In the analysis, careful statistical adjustments were made to ensure a like-for-like comparison of ADHD families with two different control groups. We controlled for carers' ADHD symptoms, their employment and relationship status and siblings' ADHD symptoms. ADHD was associated with a significant deficit in the patient's HRQoL (with a CHU-9D score of around 6 % lower). Children with ADHD also have less sleep and were less happy with their family and their lives overall. No consistent decrement to the HRQoL of the siblings was identified across the models, except that related to their own conduct problems. The siblings do, however, report lower happiness with life overall and with their family, even when controlling for the siblings own ADHD symptoms. We also find evidence of elevated bullying between siblings in families with a child with ADHD. Overall, the current results suggest that the reduction in quality of life caused by ADHD is experienced both by the child with ADHD and their siblings

How to Appropriately Extrapolate Costs and Utilities in Cost-Effectiveness Analysis

Costs and utilities are key inputs into any cost-effectiveness analysis. Their estimates are typically derived from individual patient-level data collected as part of clinical studies the follow-up duration of which is often too short to allow a robust quantification of the likely costs and benefits a technology will yield over the patient’s entire lifetime. In the absence of long-term data, some form of temporal extrapolation—to project short-term evidence over a longer time horizon—is required. Temporal extrapolation inevitably involves assumptions regarding the behaviour of the quantities of interest beyond the time horizon supported by the clinical evidence. Unfortunately, the implications for decisions made on the basis of evidence derived following this practice and the degree of uncertainty surrounding the validity of any assumptions made are often not fully appreciated. The issue is compounded by the absence of methodological guidance concerning the extrapolation of non-time-to-event outcomes such as costs and utilities. This paper considers current approaches to predict long-term costs and utilities, highlights some of the challenges with the existing methods, and provides recommendations for future applications. It finds that, typically, economic evaluation models employ a simplistic approach to temporal extrapolation of costs and utilities. For instance, their parameters (e.g. mean) are typically assumed to be homogeneous with respect to both time and patients’ characteristics. Furthermore, costs and utilities have often been modelled to follow the dynamics of the associated time-to-event outcomes. However, cost and utility estimates may be more nuanced, and it is important to ensure extrapolation is carried out appropriately for these parameters

Anastrozole versus tamoxifen for the prevention of locoregional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in situ (IBIS-II DCIS): a double-blind, randomised controlled trial

Background Third-generation aromatase inhibitors are more effective than tamoxifen for preventing recurrence in postmenopausal women with hormone-receptor-positive invasive breast cancer. However, it is not known whether anastrozole is more effective than tamoxifen for women with hormone-receptor-positive ductal carcinoma in situ (DCIS). Here, we compare the efficacy of anastrozole with that of tamoxifen in postmenopausal women with hormone-receptor-positive DCIS. Methods In a double-blind, multicentre, randomised placebo-controlled trial, we recruited women who had been diagnosed with locally excised, hormone-receptor-positive DCIS. Eligible women were randomly assigned in a 1:1 ratio by central computer allocation to receive 1 mg oral anastrozole or 20 mg oral tamoxifen every day for 5 years. Randomisation was stratified by major centre or hub and was done in blocks (six, eight, or ten). All trial personnel, participants, and clinicians were masked to treatment allocation and only the trial statistician had access to treatment allocation. The primary endpoint was all recurrence, including recurrent DCIS and new contralateral tumours. All analyses were done on a modified intention-to-treat basis (in all women who were randomised and did not revoke consent for their data to be included) and proportional hazard models were used to compute hazard ratios and corresponding confidence intervals. This trial is registered at the ISRCTN registry, number ISRCTN37546358. Results Between March 3, 2003, and Feb 8, 2012, we enrolled 2980 postmenopausal women from 236 centres in 14 countries and randomly assigned them to receive anastrozole (1449 analysed) or tamoxifen (1489 analysed). Median follow-up was 7·2 years (IQR 5·6–8·9), and 144 breast cancer recurrences were recorded. We noted no statistically significant difference in overall recurrence (67 recurrences for anastrozole vs 77 for tamoxifen; HR 0·89 [95% CI 0·64–1·23]). The non-inferiority of anastrozole was established (upper 95% CI <1·25), but its superiority to tamoxifen was not (p=0·49). A total of 69 deaths were recorded (33 for anastrozole vs 36 for tamoxifen; HR 0·93 [95% CI 0·58–1·50], p=0·78), and no specific cause was more common in one group than the other. The number of women reporting any adverse event was similar between anastrozole (1323 women, 91%) and tamoxifen (1379 women, 93%); the side-effect profiles of the two drugs differed, with more fractures, musculoskeletal events, hypercholesterolaemia, and strokes with anastrozole and more muscle spasm, gynaecological cancers and symptoms, vasomotor symptoms, and deep vein thromboses with tamoxifen. Conclusions No clear efficacy differences were seen between the two treatments. Anastrozole offers another treatment option for postmenopausal women with hormone-receptor-positive DCIS, which may be be more appropriate for some women with contraindications for tamoxifen. Longer follow-up will be necessary to fully evaluate treatment differences

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease