Late diagnoses of Dravet syndrome: How many individuals are we missing?

We report new genetic diagnoses of Dravet syndrome in a group of adults with complex epilepsy of unknown cause, under follow up at a tertiary epilepsy centre. Individuals with epilepsy and other features of unknown cause from our unit underwent whole genome sequencing through the 100,000 Genomes Project. Virtual gene panels were applied to frequency-filtered variants based on phenotype summary. Of 1078 individuals recruited, 8 (0.74%) were identified to have a pathogenic or likely pathogenic variant in SCN1A. Variant types were: nonsense (stopgain) in five (62.5%) and missense in three (37.5%). Detailed review of childhood history confirmed a phenotype compatible with Dravet syndrome. Median age at genetic diagnosis was 44.5 years (range 28-52 years). Tonic-clonic seizures were ongoing in all despite polytherapy including valproate. All had a history of fever sensitivity and myoclonic seizures, which were ongoing in two (25%) and three (37.5%) individuals, respectively. Salient features of Dravet syndrome may be less apparent in adulthood, making clinical diagnosis difficult. Regardless of age, benefits of a genetic diagnosis include access to syndrome-specific treatment options, avoidance of harmful drugs, and monitoring for common complications

Ecological correlates of elevational range shifts in tropical birds

Globally, birds have been shown to respond to climate change by shifting their elevational distributions. This phenomenon is especially prevalent in the tropics, where elevational gradients are often hotspots of diversity and endemism. Empirical evidence has suggested that elevational range shifts are far from uniform across species, varying greatly in the direction (upslope vs. downslope) and rate of change (speed of elevational shift). However, little is known about the drivers of these variable responses to climate change, limiting our ability to accurately project changes in the future. Here, we compile empirical estimates of elevational shift rates (m/yr) for 421 bird species from eight study sites across the tropics. On average, species shifted their mean elevations upslope by 1.63 ± 0.30 m/yr, their upper limits by 1.62 m ± 0.38 m/yr, and their lower limits by 2.81 ± 0.42 m/yr. Upslope shift rates increased in smaller-bodied, less territorial species, whereas larger species were more likely to shift downslope. When considering absolute shift rates, rates were fastest for species with high dispersal ability, low foraging strata, and wide elevational ranges. Our results indicate that elevational shift rates are associated with species’ traits, particularly body size, dispersal ability, and territoriality. However, these effects vary substantially across sites, suggesting that responses of tropical montane bird communities to climate change are complex and best predicted within the local or regional context

Clinical trial protocol: PRednisolone in early diffuse cutaneous Systemic Sclerosis (PRedSS)

Background: Many of the painful, disabling features of early diffuse cutaneous systemic sclerosis have an inflammatory component and are potentially treatable with corticosteroid therapy. These features include painful and itchy skin, fatigue and musculoskeletal involvement. Yet many clinicians are understandably reluctant to prescribe corticosteroids because of the concern that these are a risk factor for scleroderma renal crisis. The aim of PRedSS (PRednisolone in early diffuse cutaneous Systemic Sclerosis) is to evaluate the efficacy and safety of moderate dose prednisolone in patients with early diffuse cutaneous systemic sclerosis, specifically whether moderate dose prednisolone is (a) effective in terms of reducing pain and disability, and improving skin score and (b) safe, with particular reference to renal function. Methods: PRedSS is a Phase II, multicentre, double-blind randomised controlled trial which aims to recruit 72 patients with early diffuse cutaneous systemic sclerosis. Patients are randomised to receive either prednisolone (dosage approximately 0.3 mg/kg) or placebo therapy for 6 months. The two co-primary outcome measures are the difference in mean Health Assessment Questionnaire Disability Index at 3 months and the difference in modified Rodnan skin score at 3 months. Secondary outcome measures include patient reported outcome measures of itch, hand function, anxiety and depression, and helplessness. Results: Recruitment commenced in December 2017 and after a slow start (due to delays in opening centres) 25 patients have now been recruited. Conclusion: PRedSS should help to answer the question as to whether clinicians should or should not prescribe prednisolone in early diffuse cutaneous systemic sclerosis

The minimum clinically important difference of the incremental shuttle walk test in bronchiectasis: a prospective cohort study.

The incremental shuttle walk test (ISW) is an externally-paced field walking test that measures maximal exercise capacity1 and is widely used in patients with chronic obstructive pulmonary disease (COPD) undergoing pulmonary rehabilitation (PR). Its psychometric properties, including reliability, construct validity2 and responsiveness to intervention,2-5 have been demonstrated in patients with bronchiectasis, but little data exist on the minimum clinically important difference (MCID). Although two studies have investigated the MCID of ISW in patients with bronchiectasis, the generalisability of these data is limited because of the study sample characteristics,6 or did not involve an exercise-based intervention.2 The MCID enables clinicians and researchers to understand the clinical significance of change data and forms an important part of the evidence required by regulatory agencies for approval for use in clinical trials. Accordingly, the aim of this study was to provide MCID estimates of the ISW in response to intervention, namely PR, in patients with bronchiectasis

Factors associated with crisis pregnancies in Ireland: Findings from three nationally representative sexual health surveys

Background: Findings on the demographic and sexual health characteristics associated with the experience of a crisis pregnancy is important to inform the public health policy of a country, including Ireland. Findings from other jurisdictions have suggested that certain demographic groups are at risk for unintended pregnancies and the disparity between the groups have been growing in recent years. Ireland is a country which experienced much economic and societal change in the first decade of the 21st century, changes which are likely to have affected demographic variables pertaining to sexual health. The current study had two aims: to investigate changes in the socioeconomic characteristics associated with crisis pregnancies over a seven year period [2003 to 2010], and to investigate the recent [2010] socioeconomic risk factors associated with crisis pregnancies in Ireland. Methods: The study compared the results from 18-45 year old women using data from three broadly similar nationally representative Irish sexual health surveys carried out in 2003, 2004-2006 and 2010. Chi square analysis compared of the socioeconomic characteristics across the seven year period and found that a higher proportion of women with two or more children and women for whom religion was not important reported a crisis pregnancy in 2010 compared with earlier years. A logistic regression then investigated the sexual health history and socioeconomic factors associated with the experience of a recent crisis pregnancy using the most recent 2010 data. Results: Receipt of sex education and contraception use at first sex significantly predicted the experiencing of a recent crisis pregnancy. Younger women and those with a lower level of education were more likely to report having experienced a recent crisis pregnancy. Conclusion: Similar demographic groups are at risk for experiencing a crisis pregnancy in Ireland compared with international research, yet the disparities between demographic groups who have experienced a crisis pregnancy appear to be decreasing rather than increasing over a seven year period. Recommendations are made with regard to the provision of continued sex education throughout the lifespan, particularly for those women who are at an increased risk of experiencing a crisis pregnancy

Applying a genetic risk score for prostate cancer to men with lower urinary tract symptoms in primary care to predict prostate cancer diagnosis : a cohort study in the UK Biobank

Background Prostate cancer is highly heritable, with >250 common variants associated in genome-wide association studies. It commonly presents with non-specific lower urinary tract symptoms that are frequently associated with benign conditions. Methods Cohort study using UK Biobank data linked to primary care records. Participants were men with a record showing a general practice consultation for a lower urinary tract symptom. The outcome measure was prostate cancer diagnosis within 2 years of consultation. The predictor was a genetic risk score of 269 genetic variants for prostate cancer. Results A genetic risk score (GRS) is associated with prostate cancer in symptomatic men (OR per SD increase = 2.12 [1.86-2.41] P = 3.5e-30). An integrated risk model including age and GRS applied to symptomatic men predicted prostate cancer (AUC 0.768 [0.739-0.796]). Prostate cancer incidence was 8.1% (6.7-9.7) in the highest risk quintile. In the lowest quintile, prostate cancer incidence was Conclusions This study is the first to apply GRS in primary care to improve the triage of symptomatic patients. Men with the lowest genetic risk of developing prostate cancer could safely avoid invasive investigation, whilst those identified with the greatest risk could be fast-tracked for further investigation. These results show that a GRS has potential application to improve the diagnostic pathway of symptomatic patients in primary care.Peer reviewe

Are your covariates under control? How normalization can re-introduce covariate effects

Many statistical tests rely on the assumption that the residuals of a model are normally distributed. Rank-based inverse normal transformation (INT) of the dependent variable is one of the most popular approaches to satisfy the normality assumption. Studies regularly adjust for covariates and then normalize the residuals. This study investigated the effect of regressing covariates against the dependent variable and then applying rank-based INT to the residuals. The correlation between the dependent variable and covariates at each stage of processing was assessed. An alternative approach was tested of applying rank-based INT to the dependent variable before regressing covariates was tested. Analyses based on both simulated and real data examples demonstrated that applying rank-based INT to the dependent variable residuals after regressing out covariates re-introduces a linear correlation between the dependent variable and covariates in almost all situations. This will increase type-1 errors and reduce power. Our proposed alternative approach, where rank-based INT was applied prior to controlling for covariate effects, gave residuals that were normally distributed and linearly uncorrelated with covariates. This approach is therefore recommended