The potential impact of genotype-driven precision medicine for children with epilepsy

Introduction: The development and application of next generation sequencing (NGS) technology has led to an exponential rise in the number of genes and genetic variants associated with epilepsy. The detection of highly penetrant and damaging variants in some patients can be sufficient to provide an adequate explanation for the entire disease process. Particularly high yields from such diagnostic genetic testing are observed in cohorts of children who present with early onset seizures. Obtaining a genetic diagnosis can be helpful to families in terms of informing further reproductive decisions, providing answers, and preventing further costly investigations. Evidence is emerging that certain anti-epileptic therapies may be more effective than others in specific genetic epilepsies. Aim: The aim of this thesis is to explore the potential for genetically-guided therapy for children with epilepsy. This will be primarily achieved through describing the epidemiology of the genetic epilepsies of childhood, and through researching the evidence-base for gene-specific therapy. Methods: This is a mixed methods study. In chapter 5 The epidemiology of early childhood genetic epilepsy is described using a prospective whole Scotland population based national cohort. This includes all children presenting under three years of age presenting with new onset epilepsy over a defined time period (May 2014 to May 2017, n =315). These children were tested on a panel of 104 epilepsy-associated genes. In chapter 6 the potential for Whole Genome Sequencing (WGS) to identify further genetic diagnoses in deeply-phenotyped families is then explored in a separate cohort of children presenting in the West of Scotland with severe or drug-resistant epilepsy (n = 79). In chapter 4, a systematic review approach is used to identify any epilepsy-associated genes for which evidence exists to support a specific therapeutic approach. The results from this review considered in both cohorts. Chapter 7 describes a new genetic epilepsy due to SMC1A truncation and explores the potential for specific therapy in this condition. Chapter 8 evaluates whether sub-analysis of genetic data within a randomised controlled trial can be harnessed to identify patients most likely to respond to therapy. Key results: Epilepsy affects 1 per 383 children before their third birthday. In 22% of these children a single-gene cause can be identified. For 80% per cent of single-gene diagnoses in this group of patients there is some evidence to support a specific therapeutic approach. Evidence is variable in quality and nature. Between 1 in 2,000 and 1 in 2,300 of all children born are likely to have a genetically determined epilepsy for which there is currently available some evidence for a specific treatment choice. The majority of currently achievable genetic diagnoses are concentrated in a small number of genes, with genetic diagnoses beyond the 20 most common being extremely individually rare. Evidence to support specific therapeutic approaches is generally lacking in these rarer genetic epilepsies, particularly in those not associated with ion channel dysfunction. A stronger evidence base is required, and to generate this this will demand wide collaboration, and rigorous study design, and open access to pharmacogenomic data

Rates, causes and predictors of all-cause and avoidable mortality in 163 686 children and young people with and without intellectual disabilities:A record linkage national cohort study

Objectives: To investigate mortality rates and associated factors, and avoidable mortality in children/young people with intellectual disabilities. Design: Retrospective cohort; individual record-linked data between Scotland’s 2011 Census and 9.5 years of National Records for Scotland death certification data. Setting: General community. Participants: Children and young people with intellectual disabilities living in Scotland aged 5–24 years, and an age-matched comparison group. Main outcome measures: Deaths up to 2020: age of death, age-standardised mortality ratios (age-SMRs); causes of death including cause-specific age-SMRs/sex-SMRs; and avoidable deaths. Results: Death occurred in 260/7247 (3.6%) children/young people with intellectual disabilities (crude mortality rate=388/100 000 person-years) and 528/156 439 (0.3%) children/young people without intellectual disabilities (crude mortality rate=36/100 000 person-years). SMRs for children/young people with versus those without intellectual disabilities were 10.7 for all causes (95% CI 9.47 to 12.1), 5.17 for avoidable death (95% CI 4.19 to 6.37), 2.3 for preventable death (95% CI 1.6 to 3.2) and 16.1 for treatable death (95% CI 12.5 to 20.8). SMRs were highest for children (27.4, 95% CI 20.6 to 36.3) aged 5–9 years, and lowest for young people (6.6, 95% CI 5.1 to 8.6) aged 20–24 years. SMRs were higher in more affluent neighbourhoods. Crude mortality incidences were higher for the children/young people with intellectual disabilities for most International Statistical Classification of Diseases and Related Health Problems, 10th Revision chapters. The most common underlying avoidable causes of mortality for children/young people with intellectual disabilities were epilepsy, aspiration/reflux/choking and respiratory infection, and for children/young people without intellectual disabilities were suicide, accidental drug-related deaths and car accidents. Conclusion: Children with intellectual disabilities had significantly higher rates of all-cause, avoidable, treatable and preventable mortality than their peers. The largest differences were for treatable mortality, particularly at ages 5–9 years. Interventions to improve healthcare to reduce treatable mortality should be a priority for children/young people with intellectual disabilities. Examples include improved epilepsy management and risk assessments, and coordinated multidisciplinary actions to reduce aspiration/reflux/choking and respiratory infection. This is necessary across all neighbourhoods

'To live and die [for] Dixie': Irish civilians and the Confederate States of America

Around 20,000 Irishmen served in the Confederate army in the Civil War. As a result, they left behind, in various Southern towns and cities, large numbers of friends, family, and community leaders. As with native-born Confederates, Irish civilian support was crucial to Irish participation in the Confederate military effort. Also, Irish civilians served in various supporting roles: in factories and hospitals, on railroads and diplomatic missions, and as boosters for the cause. They also, however, suffered in bombardments, sieges, and the blockade. Usually poorer than their native neighbours, they could not afford to become 'refugees' and move away from the centres of conflict. This essay, based on research from manuscript collections, contemporary newspapers, British Consular records, and Federal military records, will examine the role of Irish civilians in the Confederacy, and assess the role this activity had on their integration into Southern communities. It will also look at Irish civilians in the defeat of the Confederacy, particularly when they came under Union occupation. Initial research shows that Irish civilians were not as upset as other whites in the South about Union victory. They welcomed a return to normalcy, and often 'collaborated' with Union authorities. Also, Irish desertion rates in the Confederate army were particularly high, and I will attempt to gauge whether Irish civilians played a role in this. All of the research in this paper will thus be put in the context of the Drew Gilpin Faust/Gary Gallagher debate on the influence of the Confederate homefront on military performance. By studying the Irish civilian experience one can assess how strong the Confederate national experiment was. Was it a nation without a nationalism

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

POLR3B is associated with a developmental and epileptic encephalopathy with myoclonic‐atonic seizures and ataxia

Objective: POLR3B encodes the second largest subunit of RNA polymerase III, which is essential for transcription of small non-coding RNAs. Biallelic pathogenic variants in POLR3B are associated with an inherited hypomyelinating leukodystrophy. Recently, de novo heterozygous variants in POLR3B were reported in six individuals with ataxia, spasticity, and demyelinating peripheral neuropathy. Three of these individuals had epileptic seizures. The aim of this article is to precisely define the epilepsy phenotype associated with de novo heterozygous POLR3B variants. Methods: We used online gene-matching tools to identify 13 patients with de novo POLR3B variants. We systematically collected genotype and phenotype data from clinicians using two standardized proformas. Results: All 13 patients had novel POLR3B variants. Twelve of 13 variants were classified as pathogenic or likely pathogenic as per American College of Medical Genetics (ACMG) criteria. Patients presented with generalized myoclonic, myoclonic-atonic, atypical absence, or tonic-clonic seizures between the ages of six months and 4 years. Epilepsy was classified as epilepsy with myoclonic-atonic seizures (EMAtS) in seven patients and “probable EMAtS” in two more. Seizures were treatment resistant in all cases. Three patients became seizure-free. All patients had some degree of developmental delay or intellectual disability. In most cases developmental delay was apparent before the onset of seizures. Three of 13 cases were reported to have developmental stagnation or regression in association with seizure onset. Treatments for epilepsy that were reported by clinicians to be effective were: sodium valproate, which was effective in five of nine patients (5/9) who tried it; rufinamide (2/3); and ketogenic diet (2/3). Additional features were ataxia/incoordination (8/13); microcephaly (7/13); peripheral neuropathy (4/13), and spasticity/hypertonia (6/13). Significance: POLR3B is a novel genetic developmental and epileptic encephalopathy (DEE) in which EMAtS is the predominant epilepsy phenotype. Ataxia, neuropathy, and hypertonia may be variously observed in these patients

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Penilaian Kinerja Keuangan Koperasi di Kabupaten Pelalawan

This paper describe development and financial performance of cooperative in District Pelalawan among 2007 - 2008. Studies on primary and secondary cooperative in 12 sub-districts. Method in this stady use performance measuring of productivity, efficiency, growth, liquidity, and solvability of cooperative. Productivity of cooperative in Pelalawan was highly but efficiency still low. Profit and income were highly, even liquidity of cooperative very high, and solvability was good

Juxtaposing BTE and ATE – on the role of the European insurance industry in funding civil litigation

One of the ways in which legal services are financed, and indeed shaped, is through private insurance arrangement. Two contrasting types of legal expenses insurance contracts (LEI) seem to dominate in Europe: before the event (BTE) and after the event (ATE) legal expenses insurance. Notwithstanding institutional differences between different legal systems, BTE and ATE insurance arrangements may be instrumental if government policy is geared towards strengthening a market-oriented system of financing access to justice for individuals and business. At the same time, emphasizing the role of a private industry as a keeper of the gates to justice raises issues of accountability and transparency, not readily reconcilable with demands of competition. Moreover, multiple actors (clients, lawyers, courts, insurers) are involved, causing behavioural dynamics which are not easily predicted or influenced. Against this background, this paper looks into BTE and ATE arrangements by analysing the particularities of BTE and ATE arrangements currently available in some European jurisdictions and by painting a picture of their respective markets and legal contexts. This allows for some reflection on the performance of BTE and ATE providers as both financiers and keepers. Two issues emerge from the analysis that are worthy of some further reflection. Firstly, there is the problematic long-term sustainability of some ATE products. Secondly, the challenges faced by policymakers that would like to nudge consumers into voluntarily taking out BTE LEI

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years