Medicine (RMH) - Research Publications
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ItemSub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals(CELL PRESS, 2021-06-03)Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.
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ItemVagus nerve stimulation therapy in people with drug-resistant epilepsy (CORE-VNS): rationale and design of a real-world post-market comprehensive outcomes registry(BMJ PUBLISHING GROUP, 2021-12)INTRODUCTION: The Vagus Nerve Stimulation Therapy System (VNS Therapy) is an adjunctive neuromodulatory therapy that can be efficacious in reducing the frequency and severity of seizures in people with drug-resistant epilepsy (DRE). CORE-VNS aims to examine the long-term safety and clinical outcomes of VNS in people with DRE. METHODS AND ANALYSIS: The CORE-VNS study is an international, multicentre, prospective, observational, all-comers, post-market registry. People with DRE receiving VNS Therapy for the first time as well as people being reimplanted with VNS Therapy are eligible. Participants have a baseline visit (prior to device implant). They will be followed for a minimum of 36 months and a maximum of 60 months after implant. Analysis endpoints include seizure frequency (average number of events per month), seizure severity (individual-rated categorical outcome including very mild, mild, moderate, severe or very severe) as well as non-seizure outcomes such as adverse events, use of antiseizure medications, use of other non-pharmacological therapies, quality of life, validated measures of quality of sleep (Pittsburgh Sleep Quality Index or Children's Sleep Habit Questionnaire) and healthcare resource utilisation. While the CORE-VNS registry was not expressly designed to test hypotheses, subgroup analyses and exploratory analysis that require hypothesis testing will be conducted across propensity score matched treatment groups, where possible based on sampling. ETHICS AND DISSEMINATION: The CORE-VNS registry has already enrolled 823 participants from 61 centres across 15 countries. Once complete, CORE-VNS will represent one of the largest real-world clinical data sets to allow a more comprehensive understanding of the management of DRE with adjunctive VNS. Manuscripts derived from this database will shed important new light on the characteristics of people receiving VNS Therapy; the practical use of VNS across different countries, and factors influencing long-term response. TRAIL REGISTRATION NUMBER: NCT03529045.
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ItemPractical Considerations for Ketogenic Diet in Adults With Super-Refractory Status Epilepticus(LIPPINCOTT WILLIAMS & WILKINS, 2021-10)PURPOSE OF REVIEW: Ketogenic diet therapy can be used as an adjuvant treatment of super-refractory status epilepticus (SRSE). However, the drug and metabolic interactions with concomitant treatments present a challenge for clinicians. In this review, we focus on the practical considerations of implementing ketogenic dietary therapy in the acute setting, including the dietary composition, potential drug-diet interactions, and monitoring during ketogenic treatment. RECENT FINDINGS: This report describes the ketogenic diet therapy protocol implemented for the treatment of SRSE and a review of the current evidence to support clinical practice. SUMMARY: The control of SRSE is critical in reducing morbidity and mortality. There is emerging evidence that ketogenic diet may be a safe and effective treatment option for these patients.
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ItemLetter: improved parsimony of genetic risk scores for coeliac disease through refined HLA modelling(WILEY, 2021-03)LINKED CONTENT This article is linked to Sharp et al paper. To view this article, visit https://doi.org/10.1111/apt.15826
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ItemMeander Thin-Film Biosensor Fabrication to Investigate the Influence of Structural Parameters on the Magneto-Impedance Effect(MDPI, 2021-10)Thin-film magneto-impedance (MI) biosensors have attracted significant attention due to their high sensitivity and easy miniaturization. However, further improvement is required to detect weak biomagnetic signals. Here, we report a meander thin-film biosensor preparation to investigate the fabrication parameters influencing the MI effect. Specifically, we hypothesized that an optimal film thickness and sensing area size ratio could be achieved to obtain a maximum MI ratio. A meander multilayer MI biosensor based on a NiFe/Cu/NiFe thin-film was designed and fabricated into 3-, 6-, and 9-turn models with film thicknesses of 3 µm and 6 µm. The 9-turn biosensor resembled the largest sensing area, while the 3- and 6-turn biosensors were designed with identical sensing areas. The results indicated that the NiFe film thickness of 6 µm with a sensing area size of 14.4 mm2 resembling a 9-turn MI biosensor is the optimal ratio yielding the maximum MI ratio of 238%, which is 70% larger than the 3- and 6-turn structures. The 3- and 6-turn MI biosensors exhibited similar characteristics where the MI ratio peaked at a similar value. Our results suggest that the MI ratio can be increased by increasing the sensing area size and film thickness rather than the number of turns. We showed that an optimal film thickness to sensing area size ratio is required to obtain a high MI ratio. Our findings will be useful for designing highly sensitive MI biosensors capable of detecting low biomagnetic signals.
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ItemRisk of Post-stroke Epilepsy Following Stroke-Associated Acute Symptomatic Seizures.(Frontiers Media SA, 2021)Objective: Post-stroke epilepsy (PSE) is associated with increased morbidity and mortality. Stroke-associated acute symptomatic seizures are an important risk factor: 20.8-34.3% of these patients will go on to develop PSE. Identifying these "high risk" individuals may result in earlier PSE diagnosis, treatment, and avoidance of seizure-related morbidity. This study was to identify predictors of PSE development in patients with stroke-associated acute symptomatic seizures. Participants and Methods: This was a retrospective cohort study of 167 patients with stroke-associated acute symptomatic seizures admitted to the Neurology Department of a tertiary Hospital of China, from 1 May 2006 to 30 January 2020. Both those with primary ischemic stroke and intracerebral hemorrhage were included in the study. Patient demographics, medical history, stroke-associated, and seizure-related variables were evaluated with univariable analysis and multivariable Cox regression analysis. PSE was defined as unprovoked seizures occurring > 7 days post-stroke. Data points were extracted from medical records and supplemented by tele-interview. Results: Of the 167 patients with stroke-associated acute symptomatic seizures, 49 (29.3%) developed PSE. NIHSS score > 14 [hazard ratio (HR) 2.98, 95% CI 1.57-5.67], longer interval from stroke to acute symptomatic seizures (days 4-7 post-stroke) (HR 2.51, 95% CI 1.37-4.59) and multiple acute symptomatic seizures (HR 5.08, 95% CI 2.58-9.99) were independently associated with PSE development. This association remained in the sub-analysis within the ischemic stroke cohort. In the sub-analysis of the hemorrhagic stroke cohort, multilobar involvement (HR 4.80, 95% CI 1.49-15.39) was also independently associated with development of PSE. Further, we developed a nomogram to predict individual risk of developing PSE following stroke-associated acute symptomatic seizures. The nomogram showed a C-index of 0.73. Conclusion: More severe neurofunctional deficits (NIHSS score > 14), longer interval from stroke to acute symptomatic seizures (days 4-7 post-stroke), and multiple acute symptomatic seizures were independently associated with development of PSE in patients with stroke-associated acute symptomatic seizures. This knowledge may increase clinical vigilance for development of PSE, facilitating rapid diagnosis and treatment initiation, and subsequently reduce seizure-related morbidity.
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ItemggVolcanoR: A Shiny app for customizable visualization of differential expression datasets(ELSEVIER, 2021)Volcano and other analytical plots (e.g., correlation plots, upset plots, and heatmaps) serve as important data visualization methods for transcriptomic and proteomic analyses. Customizable generation of these plots is fundamentally important for a better understanding of dysregulated expression data and is therefore instrumental for the ensuing pathway analysis and biomarker identification. Here, we present an R-based Shiny application, termed ggVolcanoR, to allow for customizable generation and visualization of volcano plots, correlation plots, upset plots, and heatmaps for differential expression datasets, via a user-friendly interactive interface in both local executable version and web-based application without requiring programming expertise. Compared to currently existing packages, ggVolcanoR offers more practical options to optimize the generation of publication-quality volcano and other analytical plots for analyzing and comparing dysregulated genes/proteins across multiple differential expression datasets. In addition, ggVolcanoR provides an option to download the customized list of the filtered dysregulated expression data, which can be directly used as input for downstream pathway analysis. The source code of ggVolcanoR is available at https://github.com/KerryAM-R/ggVolcanoR and the webserver of ggVolcanoR 1.0 has been deployed and is freely available for academic purposes at https://ggvolcanor.erc.monash.edu/.
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ItemComparative analysis of loop-mediated isothermal amplification (LAMP)-based assays for rapid detection of SARS-CoV-2 genes(NATURE PORTFOLIO, 2021-11-18)The COVID-19 pandemic caused by SARS-CoV-2 has infected millions worldwide, therefore there is an urgent need to increase our diagnostic capacity to identify infected cases. Although RT-qPCR remains the gold standard for SARS-CoV-2 detection, this method requires specialised equipment in a diagnostic laboratory and has a long turn-around time to process the samples. To address this, several groups have recently reported the development of loop-mediated isothermal amplification (LAMP) as a simple, low cost and rapid method for SARS-CoV-2 detection. Herein we present a comparative analysis of three LAMP-based assays that target different regions of the SARS-CoV-2: ORF1ab RdRP, ORF1ab nsp3 and Gene N. We perform a detailed assessment of their sensitivity, kinetics and false positive rates for SARS-CoV-2 diagnostics in LAMP or RT-LAMP reactions, using colorimetric or fluorescent detection. Our results independently validate that all three assays can detect SARS-CoV-2 in 30 min, with robust accuracy at detecting as little as 1000 RNA copies and the results can be visualised simply by color changes. Incorporation of RT-LAMP with fluorescent detection further increases the detection sensitivity to as little as 100 RNA copies. We also note the shortcomings of some LAMP-based assays, including variable results with shorter reaction time or lower load of SARS-CoV-2, and false positive results in some experimental conditions and clinical saliva samples. Overall for RT-LAMP detection, the ORF1ab RdRP and ORF1ab nsp3 assays have faster kinetics for detection but varying degrees of false positives detection, whereas the Gene N assay exhibits no false positives in 30 min reaction time, which highlights the importance of optimal primer design to minimise false-positives in RT-LAMP. This study provides validation of the performance of LAMP-based assays as a rapid, highly sensitive detection method for SARS-CoV-2, which have important implications in development of point-of-care diagnostics for SARS-CoV-2.
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ItemPractical considerations of dietary therapies for epilepsy in adults(SPRINGERNATURE, 2021-07-30)Abstract Despite the increasing number of anti-seizure medications becoming available, the proportion of patients with drug-resistant epilepsy remains unchanged. Dietary therapy for epilepsy is well-established practice in paediatric care, but relatively underutilised in adults. Recently, international recommendations have been published to guide the treatment of adults receiving dietary therapy for epilepsy. This review focuses on the specific aspects of care unique to the management of adults receiving dietary therapy for epilepsy, including patient selection, diet composition, initiation, monitoring and cessation of dietary treatment. We emphasise the need for a multidisciplinary team approach with appropriately trained neurologists and dietitians to provide holistic care while the patients are receiving dietary therapy. Future research should focus on the optimal diet composition and meeting the psychosocial needs of adults with epilepsy to maximise efficacy and adherence to dietary treatment.
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ItemAssociation Between Psychiatric Comorbidities and Mortality in Epilepsy(LIPPINCOTT WILLIAMS & WILKINS, 2021-10)OBJECTIVE: To explore the impact of psychiatric comorbidities on all-cause mortality in adults with epilepsy from a cohort of patients admitted for video-EEG monitoring (VEM) over 2 decades. METHODS: A retrospective medical record audit was conducted on 2,709 adults admitted for VEM and diagnosed with epilepsy at 3 Victorian comprehensive epilepsy programs from 1995 to 2015. A total of 1,805 patients were identified in whom the record of a clinical evaluation by a neuropsychiatrist was available, excluding 27 patients who died of a malignant brain tumor known at the time of VEM admission. Epilepsy and lifetime psychiatric diagnoses were determined from consensus opinion of epileptologists and neuropsychiatrists involved in the care of each patient. Mortality and cause of death were determined by linkage to the Australian National Death Index and National Coronial Information System. RESULTS: Compared with the general population, mortality was higher in people with epilepsy (PWE) with a psychiatric illness (standardized mortality ratio [SMR] 3.6) and without a psychiatric illness (SMR 2.5). PWE with a psychiatric illness had greater mortality compared with PWE without (hazard ratio 1.41, 95% confidence interval 1.02-1.97) after adjusting for age and sex. No single psychiatric disorder by itself conferred increased mortality in PWE. The distribution of causes of death remained similar between PWE with psychiatric comorbidities and those without. CONCLUSION: The presence of comorbid psychiatric disorders in adults with epilepsy is associated with increased mortality, highlighting the importance of identifying and treating psychiatric comorbidities in these patients.