Case-control study developing Scottish Epilepsy Deaths Study score to predict epilepsy-related death

This study aims to develop a risk prediction model for epilepsy-related death in adults. In this age- and sex-matched case-control study, we compared adults (aged ≥16 years) who had epilepsy-related death between 2009-2016 to living adults with epilepsy in Scotland. Cases were identified from validated administrative national datasets linked to mortality records. ICD-10 cause-of-death coding was used to define epilepsy-related death. Controls were recruited from a research database and epilepsy clinics. Clinical data from medical records were abstracted and used to undertake univariable and multivariable conditional logistic regression to develop a risk prediction model consisting of four variables chosen a priori. A weighted sum of the factors present was taken to create a risk index - the Scottish Epilepsy Deaths Study Score (SEDS Score). Odds ratios (OR) were estimated with 95% confidence intervals (CIs). 224 deceased cases (mean age 48 years, 114 male) and 224 matched living controls were compared. In univariable analysis, predictors of epilepsy-related death were recent epilepsy-related accident and emergency (A&E) attendance (OR 5.1, 95% CI 3.2-8.3), living in deprived areas (OR 2.5, 95% CI 1.6-4.0), developmental epilepsy (OR 3.1, 95% CI 1.7-5.7), raised Charlson Comorbidity Index (CCI) score (OR 2.5, 95% CI 1.2-5.2), alcohol abuse (OR 4.4, 95% CI 2.2-9.2), absent recent neurology review (OR 3.8, 95% CI 2.4-6.1), and generalised epilepsy (OR 1.9, 95% CI 1.2-3.0). SEDS Score model variables were derived from the first four listed above, with CCI ≥2 given 1 point, living in the two most deprived areas given 2 points, having an inherited or congenital aetiology or risk factor for developing epilepsy given 2 points, and recent epilepsy-related A&E attendance given 3 points. Compared to having a SEDS Score of 0, those with a SEDS Score of 1 remained low risk, with OR 1.6 (95% CI 0.5-4.8). Those with a SEDS Score of 2-3 had moderate risk, with OR 2.8 (95% CI 1.3-6.2). Those with a SEDS Score of 4-5 and 6-8 were high risk, with OR 14.4 (95% CI 5.9-35.2) and 24.0 (95% CI 8.1-71.2), respectively. The SEDS Score may be a helpful tool for identifying adults at high risk of epilepsy-related death and requires external validation

Comparison of neurodevelopmental, educational and adulthood socioeconomic outcomes in offspring of women with and without epilepsy: A systematic review and meta-analysis

Background: Adequate pre-pregnancy counselling and education planning are essential to improve outcomes for offspring of women with epilepsy (OWWE). The current systematic review and meta-analysis aimed to compare outcomes for OWWE and offspring of women without epilepsy (OWWoE). Methods: We conducted a systematic review and meta-analysis. We searched MEDLINE, EMBASE, CINAHL, PsycINFO (database inception-1st January 2023), OpenGrey, GoogleScholar, and hand-searched journals and reference lists of included studies to identify eligible studies. We placed no language restrictions and included observational studies concerning OWWE and OWWoE. We followed the PRIMSA checklist for abstracting data. The Newcastle-Ottawa Scale for risk of bias assessment was conducted independently by two authors with mediation by a third. We report pooled unadjusted odds ratios (OR) or mean differences (MD) with 95% confidence intervals (95CI) from random (I2&gt;50%) or fixed (I2&lt;50%) effects meta-analyses. Outcomes of interest included offspring autism, attention deficit/hyperactive disorder, intellectual disability, epilepsy, developmental disorder, intelligence, educational, and adulthood socioeconomic outcomes. Results: Of 10,928 articles identified, we included 21 in meta-analyses. OWWE had increased odds of autism (2 articles, 4,502,098 offspring) OR [95CI] 1·67 [1·54, 1·82], attention-deficit/hyperactivity disorder (3 articles, 957,581 offspring) 1·59 [1·44, 1·76], intellectual disability (2 articles, 4,501,786 children) 2·37 [2·13, 2·65], having special educational needs (3 articles, 1,308,919 children) 2·60 [1·07, 6·34]. OWWE had worse mean scores for full-scale intelligence (5 articles, 989 children) -6·05 [-10·31, -1·79]. No studies were identified that investigated adulthood socioeconomic outcomes. Conclusions: Increased odds of poor outcomes are higher with greater anti-seizure medication burden including neurodevelopmental and educational outcomes. In fact, these two outcomes seem to be worse in OWWE compared to OWWoE, even if there was no ASM exposure during pregnancy, but further work is needed to take into account potential confounding factors. Key words: Epilepsy, pregnancy, mother, child, outcomes <br/

5-Hydroxyvitamin D concentration in paediatric cancer patients from Scotland:a prospective cohort study

Children with cancer are potentially at high risk of plasma 25-hydroxyvitamin D [25(OH)D] inadequacy and despite UK vitamin D supplementation guidelines their implementation remains inconsistent. Thus, we aimed to investigate 25(OH)D concentration and factors contributing to 25(OH)D inadequacy in paediatric cancer patients. A prospective cohort study of Scottish children aged <18 years, diagnosed with and treated for cancer (patients) between Aug 2010-Jan 2014 was performed, with control data from Scottish healthy children (controls). Clinical and nutritional data were collected at defined periods up to 24 months. 25(OH)D status was defined by the Royal College of Paediatrics and Child Health (2013); inadequacy [<50 nmol/L: deficiency (<25 nmol/L), insufficiency (25-50 nmol/L)], sufficiency (51-75 nmol/L), optimal (>75 nmol/L). Eighty-two patients [median(IQR) age 3.9(1.9-8.8); 56% males)] and 35 controls [median(IQR) age (6.2(4.8-9.1); 49% males] were recruited. 25(OH)D inadequacy was highly prevalent in the controls (63%; 22/35), and in the patients (64%; 42/65) at both baseline and during treatment (33-50%). Non-supplemented children had the highest prevalence of 25(OH)D inadequacy at every stage with 25(OH)D median(IQR) ranging from 32.0 (21.0-46.5) nmol/L to 45.0(28.0-64.5) nmol/L. Older age at baseline [R=-0.46; p<0.001], overnutrition (BMI ≥85th centile) at 3 months [p=0.005; RR=3.1] and not being supplemented at 6 months (p=0.04; RR=4.3) may have contributed to lower plasma 25(OH)D. Paediatric cancer patients are not at higher risk of 25(OH)D inadequacy than healthy children at diagnosis; however prevalence of 25(OH)D inadequacy is still high and non-supplemented children have a higher risk. Appropriate monitoring and therapeutic supplementation should be implemented

C. elegans serine-threonine kinase KIN-29 modulates TGFβ signaling and regulates body size formation

BACKGROUND: In C. elegans there are two well-defined TGFβ-like signaling pathways. The Sma/Mab pathway affects body size morphogenesis, male tail development and spicule formation while the Daf pathway regulates entry into and exit out of the dauer state. To identify additional factors that modulate TGFβ signaling in the Sma/Mab pathway, we have undertaken a genetic screen for small animals and have identified kin-29. RESULTS: kin-29 encodes a protein with a cytoplasmic serine-threonine kinase and a novel C-terminal domain. The kinase domain is a distantly related member of the EMK (ELKL motif kinase) family, which interacts with microtubules. We show that the serine-threonine kinase domain has in vitro activity. kin-29 mutations result in small animals, but do not affect male tail morphology as do several of the Sma/Mab signal transducers. Adult worms are smaller than the wild-type, but also develop more slowly. Rescue by kin-29 is achieved by expression in neurons or in the hypodermis. Interaction with the dauer pathway is observed in double mutant combinations, which have been seen with Sma/Mab pathway mutants. We show that kin-29 is epistatic to the ligand dbl-1, and lies upstream of the Sma/Mab pathway target gene, lon-1. CONCLUSION: kin-29 is a new modulator of the Sma/Mab pathway. It functions in neurons and in the hypodermis to regulate body size, but does not affect all TGFβ outputs, such as tail morphogenesis

Long-Term Survival, Safety and Tolerability with Selexipag in Patients with Pulmonary Arterial Hypertension: Results from GRIPHON and its Open-Label Extension

INTRODUCTION: In the event-driven GRIPHON randomised-controlled trial, the oral prostacyclin receptor agonist selexipag significantly reduced the risk of disease progression (composite primary endpoint of morbidity/mortality), compared with placebo, in patients with pulmonary arterial hypertension (PAH). The ongoing open-label extension study (GRIPHON OL) collects further data on long-term safety, tolerability, and survival of PAH patients treated with selexipag. METHODS: Patients randomised to selexipag or placebo in GRIPHON could enter GRIPHON OL either after experiencing a morbidity event during double-blind treatment or at the end of the study. Patients were followed for adverse events (AE) and survival from selexipag initiation up to 3&nbsp;days and 30&nbsp;days after end of treatment, respectively. Data are presented up to a cut-off date of 1 September 2019. RESULTS: Overall, 953 patients in GRIPHON and GRIPHON OL were treated with selexipag. At the time of selexipag initiation, 81.2% of patients were receiving background PAH therapy. Median (min, max) exposure to selexipag was 31.7&nbsp;months (0, 106), corresponding to a total of 3054.4 patient-years. The most frequently reported AEs were related to known prostacyclin-related effects or underlying disease. There were 305 (32.0%) patients who experienced an AE leading to treatment discontinuation. Survival during GRIPHON and GRIPHON OL was assessed for the 574 patients randomised to selexipag in GRIPHON. Kaplan-Meier survival estimates (95%CI) at 1, 3, 5 and 7&nbsp;years were 92.0% (89.4, 94.0), 79.3% (75.4, 82.6), 71.2% (66.5, 75.3) and 63.0% (57.4, 68.1), respectively. CONCLUSIONS: These results provide the longest follow-up period published to date for a PAH therapy. The safety profile of selexipag over this extended treatment period was consistent with that observed in GRIPHON. A large proportion of the population was receiving background therapy at selexipag initiation, providing further insight into the long-term safety of selexipag as part of a combination therapy regimen. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT01106014 and NCT01112306

risk assessment in pulmonary arterial hypertension insights from the griphon study

BACKGROUND Approaches to risk assessment in pulmonary arterial hypertension (PAH) include the noninvasive French risk assessment approach (number of low-risk criteria based on the European Society of Cardiology and European Respiratory Society guidelines) and Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) 2.0 risk calculator. The prognostic and predictive value of these methods for morbidity/mortality was evaluated in the predominantly prevalent population of GRIPHON, the largest randomized controlled trial in PAH. METHODS GRIPHON randomized 1,156 patients with PAH to selexipag or placebo. Post-hoc analyses were performed on the primary composite end-point of morbidity/mortality by the number of low-risk criteria (World Health Organization functional class I-II; 6-minute walk distance >440 m; N-terminal pro-brain natriuretic peptide RESULTS Both the number of low-risk criteria and the REVEAL 2.0 risk category were prognostic for morbidity/mortality at baseline and any time-point during the study. Patients with 3 low-risk criteria at baseline had a 94% reduced risk of morbidity/mortality compared to patients with 0 low-risk criteria and were all categorized as low-risk by REVEAL 2.0. The treatment effect of selexipag on morbidity/mortality was consistent irrespective of the number of low-risk criteria or the REVEAL 2.0 risk category at any time-point during the study. Selexipag-treated patients were more likely to increase their number of low-risk criteria from baseline to week 26 than placebo-treated patients (odds ratio 1.69, p = 0.0002); similar results were observed for REVEAL 2.0 risk score. CONCLUSIONS These results support the association between risk profile and long-term outcome and suggest that selexipag treatment may improve risk profile