To evaluate whether in juvenile localized scleroderma (JLS), non-invasive imaging can differentiate affected from non-affected skin and whether imaging correlates with a validated skin score [Localised Scleroderma Cutaneous Assessment Tool (LoSCAT)].
Randomised controlled trials in reproductive medicine are often subject to outcome truncation, where study outcomes are only defined in a subset of participants. Examples include birthweight (measurable only in the subgroup of participants who give birth) and miscarriage (which can only occur in participants who become pregnant). These are typically analysed by making a comparison between treatment arms within the subgroup (comparing birthweights in the subgroup who gave birth, or miscarriages in the subgroup who became pregnant). However, this approach does not represent a randomised comparison when treatment influences the probability of being observed (i.e. survival). The practical implications of this for reproductive trials are unclear. We developed a simulation platform to investigate the implications of outcome truncation for reproductive medicine trials. We used this to perform a simulation study, in which we considered the bias, Type 1 error, coverage, and precision of standard statistical analyses for truncated continuous and binary outcomes. Increasing treatment effect on the intermediate variable, strength of confounding between the intermediate and outcome variables, and interactions between treatment and confounder were found to adversely affect performance. However, within parameter ranges we would consider to be more realistic, the adverse effects were generally not drastic. For binary outcomes, the study highlighted that outcome truncation may lead to none of the participants in a study arm experiencing the outcome event. This was found to have severe consequences for inferences, and this may have implications for meta-analysis.
Patients with rheumatoid arthritis (RA) have increased cardiovascular (CV) and mortality risk. Patients with RA are also frequently prescribed glucocorticoids (GCs) which have been associated with increased risk of mortality. In addition, for patients who have concomitant diabetes mellitus (DM), GCs are known to worsen glycaemic control and hence may further increase CV and mortality risk. This study aimed to understand the relationship between GCs, DM and mortality in patients with RA.This was a retrospective cohort study of patients with incident RA identified from UK primary care electronic medical records. Patients with linkage to Office for National Statistics (ONS) for mortality data (N = 9085) were included. DM was identified through Read codes, prescriptions and blood tests, and GC use was identified through prescriptions. Mortality rate ratios (RR) and rate differences (RD) were calculated across the different exposure groups. Cox proportional hazards regression models were used to estimate interaction on the multiplicative and additive scales.In those without DM GC use had a 4.4-fold increased all-cause mortality RR (95% confidence interval (CI): 3.83 to 5.14) compared to non-use, whilst those with DM had a lower RR for GC use (3.02 (95% CI: 2.34, 3.90)). However, those with DM had a higher RD associated with GC use because of their higher baseline risk. In those with DM, GC use was associated with an additional 46.7 deaths/1000 person-years (pyrs) (95% CI: 34.1 to 59.3) compared to non-use, while in those without DM GC use was associated with an additional 36.2 deaths/1000 pyrs (95% CI: 31.6 to 40.8). A similar pattern was seen for CV mortality. The adjusted Cox proportional hazards model showed no evidence of multiplicative interaction, but additive interaction indicated a non-significant increased risk. For CV mortality there was no interaction on either scale.GC use was associated with higher mortality rates in people with comorbid DM compared to people without DM, despite apparently reassuring similar relative risks. Clinicians need to be aware of the higher baseline risk in patients with DM, and consider this when prescribing GCs in patients with RA and comorbid DM.
Glucocorticoids (GC) are widely used to treat rheumatoid arthritis (RA), however they are known to have risks associated with them. It has been shown that GCs increase the risk of diabetes mellitus (DM). A few studies have investigated the long-term effects of GC use on outcomes in DM, but not in RA specifically. As people with RA already have increased risk of cardiovascular (CV) disease, the additional burden of DM and GCs may be important. If the effect of GCs was dependent on DM we would say there is effect modification and this can be on the additive scale, corresponding to variation in the absolute treatment effect, e.g. the risk difference (RD), across DM status, or the multiplicative scale, corresponding to variation in the relative treatment effect e.g. the rate ratio (RR).1
Objectives
To examine in patients with RA 1) whether all-cause and CV mortality rates differ by GC and DM status, and 2) whether DM modifies the relationship between GC and all-cause and CV mortality on multiplicative and additive scales.
Methods
Patients with RA and linkage to mortality data were identified from the Clinical Practice Research Datalink (n=9085), a database of primary care electronic medical records in the UK. RR and RD for ever GC use were calculated by DM status. Cox proportional hazards (PH) regression models were fitted with an interaction term for DM and use of GC to assess multiplicative interaction. Additive interaction was measured with the Relative Excess Risk due to Interaction (RERI)2 where a value different from zero indicates a difference in the absolute effect of treatment.
Results
Those with DM and ever treated with GCs had a 3-fold increased all-cause mortality RR (95% CI: 2.27, 4.09) whilst those without DM had a slightly higher RR (3.46 (95% CI: 2.95, 4.07)). However those with DM had a higher RD: 36.46 deaths per 1000 patient years (pyrs) (95% CI: 27.5, 45.41) compared to those without DM: RD 22.83 deaths per 1000 pyrs (95% CI: 19.83, 25.82) because of higher baseline mortality rates. A similar pattern was seen for CV mortality. The adjusted Cox PH model for all-cause mortality showed no evidence of multiplicative interaction, but there was significant additive interaction (RERI 0.86 (95% CI: 0.18, 1.54)). For CV mortality there was no interaction on either scale.
Conclusions
Methodologically, this study showed assessing interaction on the additive and multiplicative scales can lead to different conclusions and should be considered carefully. In this study significant interaction was seen on additive scale but not on the multiplicative scale due to higher baseline rates in patients with DM. Clinically, this study provides some evidence that long-term GC therapy may be particularly harmful in patients with RA and DM.
References
[1] VanderWeele TJ, Knol MJ. A tutorial on interaction. Epidemiologic Methods2014;3(1):33–72. [2] Li R, Chambless L. Test for additive interaction in proportional hazards models. Annals of epidemiology2007Mar;17(3):227–236.
Abstract Background: It is well recognised that access and receipt of appropriate guideline recommended treatment with systemic anti-cancer therapies for secondary breast cancer is a key determinant in overall survival. Where there is disparity in access this may result in unwarranted variation and disparity in outcomes. Individual, clinical and wider contextual factors have been associated with these disparities, however this remains poorly understood for women with secondary breast cancer. The purpose of the review is to address this gap by bringing together the available quantitative and qualitative evidence to examine factors associated with access to systemic anti-cancer therapies for women with secondary breast cancer and explore barriers and facilitators in relation to women and clinicians experience of access. Methods: A mixed methods approach with a segregated design will be used to examine and explore factors which influence access to systemic anti-cancer therapies for women with secondary breast cancer. Quantitative and qualitative appraisal, analysis and syntheses will be conducted discretely prior to final integration of findings. The review will use a comprehensive search strategy to search published and gray literature. Titles and abstracts will be screened against the eligibility criteria and full text articles will be retrieved for all records that meet the inclusion criteria. A data extraction tool will be developed, piloted and refined prior to full data extraction. Methodological quality and risk of bias will be assessed using the Mixed Methods Appraisal Tool. Discussion: Understanding individual, clinical and wider contextual factors associated with access and receipt of systemic anti-cancer therapies for secondary breast cancer is a complex phenomenon. These will be examined to determine any association with access. Review findings will be used to guide future research in this area and the development of an evidence-based service level intervention designed to address unwarranted variation in access based upon the Medical Research Council (MRC) approach to the development, implementation and evaluation of complex interventions. Systematic review registration: The review protocol has been registered in PROSPERO CRD42020196490
Diet may affect susceptibility of the inner ear to noise and age-related effects that lead to tinnitus and hearing loss. This study used complementary single nutrient and dietary pattern analysis based on statistical grouping of usual dietary intake in a cross-sectional analysis of tinnitus and hearing difficulties in a large population study sample.The research was conducted using the UK Biobank resource. Tinnitus was based on report of ringing or buzzing in one or both ears that lasts more than five minutes at a time and is currently experienced at least some of the time. Identification of a hearing problem was based on self-reported difficulties with hearing. Usual dietary intake and dietary patterns (involving statistical grouping of intake to account for how foods are combined in real-life diets) were estimated based on between two and five administrations of the Oxford Web-Q 24-hour dietary recall questionnaire over the course of a year for 34,576 UK adult participants aged 40 to 69.In a multivariate model, higher intake of vitamin B12 was associated with reduced odds of tinnitus, while higher intakes of calcium, iron, and fat were associated with increased odds (B12, odds ratio [OR] 0.85, 95% confidence interval [CI] 0.75 to 0.97; Calcium, OR 1.20, 95% CI 1.08 to 1.34; Iron, OR 1.20, 95% CI 1.05 to 1.37; Fat, OR 1.33, 95% CI 1.09 to 1.62, respectively, for quintile 5 versus quintile 1). A dietary pattern characterised by high protein intake was associated with reduced odds of tinnitus (OR 0.90, 95% CI 0.82 to 0.99 for quintile 5 versus quintile 1). Higher vitamin D intake was associated with reduced odds of hearing difficulties (OR 0.90, 95% CI 0.81 to 1.00 for quintile 5 versus quintile 1), as were dietary patterns high in fruit and vegetables and meat and low in fat (Prudent diet: OR 0.89, 95% CI 0.83 to 0.96; High protein: OR 0.88, 95% CI 0.82 to 0.95; High fat: OR 1.16, 95% CI 1.08 to 1.24, respectively, for quintile 5 versus quintile 1).There were associations between both single nutrients and dietary patterns with tinnitus and hearing difficulties. Although the size of the associations was small, universal exposure for dietary factors indicates that there may be a substantial impact of diet on levels of tinnitus and hearing difficulties in the population. This study showed that dietary factors might be important for hearing health.
Pure-tone threshold audiometry is currently the standard test of hearing. However, in everyday life, we are more concerned with listening to speech of moderate loudness and, specifically, listening to a particular talker against a background of other talkers. FreeHear delivers strings of three spoken digits (0–9, not 7) against a background babble via three loudspeakers placed in front and to either side of a listener. FreeHear is designed as a rapid, quantitative initial assessment of hearing using an adaptive algorithm. It is designed especially for children and for testing listeners who are using hearing devices. In this first report on FreeHear, we present developmental considerations and protocols and results of testing 100 children (4–13 years old) and 23 adults (18–30 years old). Two of the six 4 year olds and 91% of all older children completed full testing. Speech reception threshold (SRT) for digits and noise colocated at 0° or separated by 90° both improved linearly across 4 to 12 years old by 6 to 7 dB, with a further 2 dB improvement for the adults. These data suggested full maturation at approximately 15 years old SRTs at 90° digits/noise separation were better by approximately 6 dB than SRTs colocated at 0°. This spatial release from masking did not change significantly across age. Test–retest reliability was similar for children and adults (standard deviation of 2.05–2.91 dB SRT), with a mean practice improvement of 0.04–0.98 dB. FreeHear shows promise as a clinical test for both children and adults. Further trials in people with hearing impairment are ongoing.
Abstract Study Objectives We sought to examine the impact of digital cognitive behavioral therapy (dCBT) for insomnia on both self-reported cognitive impairment and objective cognitive performance. Methods The Defining the Impact of Sleep improvement on Cognitive Outcomes (DISCO) trial was an online, two-arm, single-blind, randomized clinical trial of dCBT versus wait-list control. Participants were aged 25 years and older, met DSM-5 diagnostic criteria for insomnia disorder, and reported difficulties with concentration or memory. Assessments were carried out online at baseline, and 10 and 24 weeks post-randomization. The primary outcome measure was self-reported cognitive impairment, assessed with the British Columbia Cognitive Complaints Inventory (BC-CCI). Secondary outcomes included tests of cognitive performance, insomnia symptoms, cognitive failures, fatigue, sleepiness, depression, and anxiety. Results Four hundred and ten participants with insomnia were recruited and assigned to dCBT (N = 205) or wait-list control (N = 205). At 10 weeks post-randomization the estimated adjusted mean difference for the BC-CCI was −3.03 (95% CI: −3.60, −2.47; p < 0.0001, d = −0.86), indicating that participants in the dCBT group reported less cognitive impairment than the control group. These effects were maintained at 24 weeks (d = −0.96) and were mediated, in part, via reductions in insomnia severity and increased sleep efficiency. Treatment effects in favor of dCBT, at both 10 and 24 weeks, were found for insomnia severity, sleep efficiency, cognitive failures, fatigue, sleepiness, depression, and anxiety. We found no between-group differences in objective tests of cognitive performance. Conclusions Our study shows that dCBT robustly decreases self-reported cognitive impairment at post-treatment and these effects are maintained at 6 months.
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