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MedRxiv : the Preprint Server For... Jun 2024Low power is a problem in many fields, as underpowered studies that find a statistically significant result will exaggerate the magnitude of the observed effect size. We...
UNLABELLED
Low power is a problem in many fields, as underpowered studies that find a statistically significant result will exaggerate the magnitude of the observed effect size. We quantified the statistical power and magnitude error of studies of epilepsy surgery outcomes. The median power across all studies was 14%. Studies with a median sample size or less (n<=56) and a statistically significant result exaggerated the true effect size by a factor of 5.4 (median odds ratio 9.3 vs. median true odds ratio 1.7), while the Bayesian estimate of the odds ratio only exaggerated the true effect size by a factor of 1.6 (2.7 vs. 1.7). We conclude that Bayesian estimation of odds ratio attenuates the exaggeration of significant effect sizes in underpowered studies. This approach could help improve patient counseling about the chance of seizure freedom after epilepsy surgery.
SHORT SUMMARY
We estimated the statistical power of studies predicting seizure freedom after epilepsy surgery. We exacted data from a Cochrane meta-analysis. The median power across all studies was 14%. Studies with a median sample size or less (n<=56) and a statistically significant result exaggerated the true effect size by a factor of 5.4, while the Bayesian estimate of the odds ratio only exaggerated the true effect size by a factor of 1.6. We conclude that Bayesian estimation of odds ratios attenuates the exaggeration of significant effect sizes in underpowered studies. This result could improve patient counseling regarding epilepsy surgery.
PubMed: 38947027
DOI: 10.1101/2024.06.21.24309313 -
MedRxiv : the Preprint Server For... Jun 2024Propranolol, a non-selective beta-blocker, is commonly used for migraine prevention, but its impact on stroke risk among migraine patients remains controversial. Using...
BACKGROUND
Propranolol, a non-selective beta-blocker, is commonly used for migraine prevention, but its impact on stroke risk among migraine patients remains controversial. Using two large electronic health records-based datasets, we examined stroke risk differences between migraine patients with- and without- documented use of propranolol.
METHODS
This retrospective case-control study utilized EHR data from the Vanderbilt University Medical Center (VUMC) and the All of Us Research Program. Migraine patients were first identified based on the International Classification of Headache Disorders, 3rd edition (ICHD-3) criteria using diagnosis codes. Among these patients, cases were defined as those with a primary diagnosis of stroke following the first diagnosis of migraine, while controls had no stroke after their first migraine diagnosis. Logistic regression models, adjusted for potential factors associated with stroke risk, assessed the association between propranolol use and stroke risk, stratified by sex and migraine subtype. A Cox proportional hazards regression model was used to estimate the hazard ratio (HR) for stroke risk at 1, 2, 5, and 10 years from baseline.
RESULTS
In the VUMC database, 378 cases and 15,209 controls were identified, while the All of Us database included 267 cases and 6,579 controls. Propranolol significantly reduced stroke risk in female migraine patients (VUMC: OR=0.52, p=0.006; All of Us: OR=0.39, =0.007), but not in males. The effect was more pronounced for ischemic stroke and in females with migraines without aura (MO) (VUMC: OR=0.60, p=0.014; All of Us: OR=0.28, p=0.006). The Cox model showed lower stroke rates in propranolol-treated female migraine patients at 1, 2, 5, and 10 years (VUMC: HR=0.06-0.55, p=0.0018-0.085; All of Us: HR=0.23, p=0.045 at 10 years).
CONCLUSIONS
Propranolol is associated with a significant reduction in stroke risk, particularly ischemic stroke, among female migraine without aura patients. These findings suggest that propranolol may benefit stroke prevention in high-risk populations.
PubMed: 38946982
DOI: 10.1101/2024.06.11.24308801 -
Research Square Jun 2024Spastic cerebral palsy, the most common pediatric-onset disabling condition with an estimated prevalence of 0.2% in children, is a complex condition characterized by...
Spastic cerebral palsy, the most common pediatric-onset disabling condition with an estimated prevalence of 0.2% in children, is a complex condition characterized by stiff movement, muscle contractures, and abnormal gait that can diminish quality of life. Spastic CP accounts for approximately 83% of all CP cases and frequently co-occurs with other complex conditions, like epilepsy. An estimated 42% of spastic CP cases have co-occurring epilepsy. Unfortunately, CP is often difficult to diagnose. Although most children with CP are born with it or acquire it immediately after birth, many are not identified until after 19 months of age with CP diagnosis often not confirmed until 5 years of age. New bioinformatic approaches to identify CP earlier are needed. Recent studies indicate that altered DNA methylation patterns associated with CP may have diagnostic value. The potential confounding effects of co-occurrent epilepsy on these patterns are not known. We evaluated machine learning classification of CP patients with or without co-occurring epilepsy. Whole blood samples were collected from 30 study participants diagnosed with epilepsy (n=4), spastic CP (n=10), both (n=8), or neither (n=8). A novel Support-Vector-Machine learning algorithm was developed to identify methylation loci that have ability to classify CP from controls in the presence or absence of epilepsy. This algorithm was also employed to measure classification ability of identified methylation loci. After preprocessing of data, isolation of important methylation loci was performed in a binary comparison between CP and controls, as well as in a 4-way scheme, encapsulating epilepsy diagnoses. The classification ability was similarly assessed. CP Classification performance wasevaluated with and without inclusion of epilepsy as a feature. Median F1 scoreswere 0.67 in 4-class comparison, and 1.0 in the binary classification, outperforming Linear-Discriminant-Analysis (0.57 and 0.86, respectively). This novel algorithm was able to classify study participants with spastic CPand/or epilepsy from controls with significant performance. The algorithm shows promise for rapid identification in methylation data of diagnostic methylation loci. In this model, Support Vector Machines outperformed Linear Discriminant Analysis in classification. In the evaluation of epigenetics-based diagnostics for CP, epilepsy may not be a significant confounding factor.
PubMed: 38946953
DOI: 10.21203/rs.3.rs-4560364/v1 -
MedRxiv : the Preprint Server For... Jun 2024Since the initial description of related hemiplegic migraine (HM), the phenotypic spectrum has expanded from mild episodes in neurotypical individuals to potentially...
INTRODUCTION
Since the initial description of related hemiplegic migraine (HM), the phenotypic spectrum has expanded from mild episodes in neurotypical individuals to potentially life-threatening events frequently seen in individuals with developmental and epileptic encephalopathies. However, the overall longitudinal course throughout childhood remains unknown.
METHODS
We analyzed HM and seizure history in individuals with -related HM, delineating frequency and severity of events in monthly increments through a standardized approach. Combining these data with medication prescription information, we assessed the response of HM to different agents.
RESULTS
Our cohort involved 15 individuals between 3 and 29 years (163 patient years) and included 11 unique and two recurrent variants (p.R1349Q and p.V1393M; both 2). The age of first confirmed HM ranged from 14 months to 13 years (average 3 years). 25% of all HM events were severe (lasting >3 days) and 73% of individuals had at least 1 severe occurrence. Spacing of HM events ranged from 1 month to 14 years and changes in HM severity over time of showed increases or decreases of >2 severity levels in 12/122 events. Eight individuals had epilepsy, but severity of epilepsy did not correlate with frequency and severity of HM events. While levetiracetam ( 6) and acetazolamide ( 5) were the most frequently used medications, they did not show efficacy in HM prevention or HM severity reduction. However, verapamil ( 3) showed efficacy in preventing HM episodes (OR 2.68, CI 1.39-5.67).
SIGNIFICANCE
The longitudinal course of -related HM lacks recognizable patterns for timing and severity of HM events or correlation with seizure patterns. Our data underscores the unpredictability of -related HM, highlighting the need for close surveillance for reoccurring HM events even in individuals with symptom-free periods.
KEY POINTS
24% of hemiplegic migraines (HM) in related disorders are severe, involving cerebral edema and greater than 4 days to recover Timing and severity of HM are unpredictable, with large changes in severity between events, and age of onset ranging from 1-13 yearsEpilepsy occurred in 53% of individuals, with neither the timing nor severity of seizures correlated with HM.
PubMed: 38946946
DOI: 10.1101/2024.06.14.24308953 -
Cell Biology International Jul 2024JRK is a DNA-binding protein of the pogo superfamily of transposons, which includes the well-known centromere binding protein B (CENP-B). Jrk null mice exhibit epilepsy,...
JRK is a DNA-binding protein of the pogo superfamily of transposons, which includes the well-known centromere binding protein B (CENP-B). Jrk null mice exhibit epilepsy, and growth and reproductive disorders, consistent with its relatively high expression in the brain and reproductive tissues. Human JRK DNA variants and gene expression levels are implicated in cancers and neuropsychiatric disorders. JRK protein modulates β-catenin-TCF activity but little is known of its cellular functions. Based on its homology to CENP-B, we determined whether JRK binds centromeric or other satellite DNAs. We show that human JRK binds satellite III DNA, which is abundant at the chromosome 9q12 juxtacentromeric region and on Yq12, both sites of nuclear stress body assembly. Human JRK-GFP overexpressed in HeLa cells strongly localises to 9q12. Using an anti-JRK antiserum we show that endogenous JRK co-localises with a subset of centromeres in non-stressed cells, and with heat shock factor 1 following heat shock. Knockdown of JRK in HeLa cells proportionately reduces heat shock protein gene expression in heat-shocked cells. A role for JRK in regulating the heat shock response is consistent with the mouse Jrk null phenotype and suggests that human JRK may act as a modifier of diseases with a cellular stress component.
PubMed: 38946594
DOI: 10.1002/cbin.12216 -
Epilepsia Open Jul 2024Epilepsy is a suitable target for gene panel sequencing because a considerable portion of epilepsy is now explained by genetic components, especially in syndromic cases....
OBJECTIVE
Epilepsy is a suitable target for gene panel sequencing because a considerable portion of epilepsy is now explained by genetic components, especially in syndromic cases. However, previous gene panel studies on epilepsy have mostly focused on pediatric patients.
METHODS
We enrolled adult epilepsy patients meeting any of the following criteria: family history of epilepsy, seizure onset age ≤ 19 years, neuronal migration disorder, and seizure freedom not achieved by dual anti-seizure medications. We sequenced the exonic regions of 211 epilepsy genes in these patients. To confirm the pathogenicity of a novel MTOR truncating variant, we electroporated vectors with different MTOR variants into developing mouse brains.
RESULTS
A total of 92 probands and 4 affected relatives were tested, and the proportion of intellectual disability (ID) and/or developmental disability (DD) was 21.7%. As a result, twelve probands (13.0%) had pathogenic or likely pathogenic variants in the following genes or regions: DEPDC5, 15q12-q13 duplication (n = 2), SLC6A1, SYNGAP1, EEF1A2, LGI1, MTOR, KCNQ2, MEF2C, and TSC1 (n = 1). We confirmed the functional impact of a novel truncating mutation in the MTOR gene (c.7570C > T, p.Gln2524Ter) that disrupted neuronal migration in a mouse model. The diagnostic yield was higher in patients with ID/DD or childhood-onset seizures. We also identified additional candidate variants in 20 patients that could be reassessed by further studies.
SIGNIFICANCE
Our findings underscore the clinical utility of gene panel sequencing in adult epilepsy patients suspected of having genetic etiology, especially those with ID/DD or early-onset seizures. Gene panel sequencing could not only lead to genetic diagnosis in a substantial portion of adult epilepsy patients but also inform more precise therapeutic decisions based on their genetic background.
PLAIN LANGUAGE SUMMARY
This study demonstrated the effectiveness of gene panel sequencing in adults with epilepsy, revealing pathogenic or likely pathogenic variants in 13.0% of patients. Higher diagnostic yields were observed in those with neurodevelopmental disorders or childhood-onset seizures. Additionally, we have shown that expanding genetic studies into adult patients would uncover new types of pathogenic variants for epilepsy, contributing to the advancement of precision medicine for individuals with epilepsy. In conclusion, our results highlight the practical value of employing gene panel sequencing in adult epilepsy patients, particularly when genetic etiology is clinically suspected.
PubMed: 38946282
DOI: 10.1002/epi4.12993 -
Iranian Biomedical Journal Apr 2024The growing threat of antibiotic resistance and Klebsiella pneumoniae infection in healthcare settings highlights the urgent need for innovative solutions, such as...
BACKGROUND
The growing threat of antibiotic resistance and Klebsiella pneumoniae infection in healthcare settings highlights the urgent need for innovative solutions, such as vaccines, to address these challenges. This study sought to assess the potential of using K. pneumoniae OmpA as a vaccine candidate through both in silico and in vivo analyses.
METHODS
The study examined the OmpA protein sequence for subcellular localization, antigenicity, allergenicity, similarity to the human proteome, physicochemical properties, B-cell epitopes, MHC binding sites, tertiary structure predictions, molecular docking, and immune response simulations. The ompA gene was cloned into the pET-28a (+) vector, expressed, purified and confirmed using Western blotting analysis. IgG levels in the serum of the immunized mice were measured using ELISA with dilutions ranging from 1:100 to 1:6400, targeting rOmpA and K. pneumoniae ATCC 13883. The sensitivity and specificity of the ELISA method were also assessed.
RESULTS
The bioinformatics analysis identified rOmpA as a promising vaccine candidate. The immunized group demonstrated significant production of specific total IgG antibodies against rOmpA and K. pneumoniae ATCC1 13883, as compared to the control group (p < 0.0001). The titers of antibodies produced in response to bacterial exposure did not show any significant difference when compared to the anti-rOmpA antibodies (p > 0.05). The ELISA test sensitivity was 1:3200, and the antibodies in the serum could accurately recognize K. pneumoniae cells.
CONCLUSION
This study is a significant advancement in the development of a potential vaccine against K. pneumoniae that relies on OmpA. Nevertheless, additional experimental analyses are required.
PubMed: 38946021
DOI: 10.61186/ibj.4023 -
BMC Biomedical Engineering Jul 2024This article aims to provide and implement a patient-specific seizure (for Intervention Time (IT) detection) prediction algorithm using non-invasive data to develop...
This article aims to provide and implement a patient-specific seizure (for Intervention Time (IT) detection) prediction algorithm using non-invasive data to develop warning devices to prevent further patient injury and reduce stress. Employing algorithms with high initial data volume and computations time to increase the accuracy is an important problem in prediction issues. Consequently, reduction of calculations is met by applying only two effective EEG signal channels without manual removal of artifacts by visual inspection as the algorithm's input. Autoregression (AR) modeling and Cepstrum detect changes due to IT period. We carry out the goal of higher accuracy by increasing sensitivity to interictal epileptiform discharges or artifacts and reduce errors caused by them, taking advantage of the discrete wavelet transform and the comparison of two channels epochs by applying the median filter. Averaging and positive envelope methods are introduced to patient-specific thresholds become more differentiated as soon as possible and can be lead to sooner prediction. We examined this method on a mathematical model of adult epilepsy as well as on 10 patients with EEG data. The results of our experiments confirm that performance of the proposed approach in accuracy and average false prediction rate is superior to other algorithms. Simulation results have been shown the robustness of our proposed method to artifacts and errors, which is a step towards the development of real-time alarm devices by non-invasive techniques.
PubMed: 38946007
DOI: 10.1186/s42490-024-00081-1 -
Seizure Jun 2024The highly heterogeneous population of elderly with epilepsy continues to increase as the incidence of epilepsy rises with increasing life expectancy. There are many... (Review)
Review
The highly heterogeneous population of elderly with epilepsy continues to increase as the incidence of epilepsy rises with increasing life expectancy. There are many aspects to consider in the treatment of elderly with epilepsy, e g comorbidities and the complexity of polypharmacy. The literature on quality-of-life (QoL) and patient-centered outcomes in elderly in general as well as in elderly with epilepsy is limited, most of the existing studies report results from quality-of-life surveys. No such QoL questionnaires have, however, in the validation process explored issues specific to the elderly. Seizure frequency, co-morbidities and depression predicted QoL in elderly with epilepsy and the energy/fatigue domain scored worst when QOLIE-31 was used. In the handful of qualitative interview studies identified in this review, a number of topics specific for elderly with epilepsy were explored. Some of these were difficulties with information gathering, the importance of maintaining normalcy, incongruence with provider goals and wanting to be more involved in the treatment. There is a need for further exploration of the specific concerns of elderly with epilepsy. This review provides a comprehensive overview of the studies and emphasizes the importance of involving elderly people with epilepsy in their own care.
PubMed: 38945798
DOI: 10.1016/j.seizure.2024.06.025 -
Nefrologia Jun 2024Sarcopenia and dynapenia are two terms associated with ageing that respectively define the loss of muscle mass and strength. In 2018, the European Working Group on...
Sarcopenia and dynapenia are two terms associated with ageing that respectively define the loss of muscle mass and strength. In 2018, the European Working Group on Sarcopenia in Older People (EWGSOP) introduced the EWGSOP2 diagnostic algorithm for sarcopenia, which integrates both concepts. It consists of 4 sequential steps: screening for sarcopenia, examination of muscle strength, assessment of muscle mass and physical performance; depending on these last 3 aspects sarcopenia is categorised as probable, confirmed, and severe respectively. In the absence of validation of the EWGSOP2 algorithm in various clinical contexts, its use in haemodialysis poses several limitations: (a) low sensitivity of the screening, (b) the techniques that assess muscle mass are not very accessible, reliable, or safe in routine clinical care, (c) the sequential use of the magnitudes that assess dynapenia and muscle mass do not seem to adequately reflect the muscular pathology of the elderly person on dialysis. We reflect on the definition of sarcopenia and the use of more precise terms such as "myopenia" (replacing the classic concept of sarcopenia to designate loss of muscle mass), dynapenia and kratopenia. Prospective evaluation of EWGSOP2 and its comparison with alternatives (i.e. assessment of kratopenia and dynapenia only; steps 2 and 4) is proposed in terms of its applicability in clinical routine, resource consumption, identification of at-risk individuals and impact on events.
PubMed: 38945744
DOI: 10.1016/j.nefroe.2023.08.007