Hitherto no therapeutic has received regulatory approval for the treatment of post-COVID-19 condition (PCC). Cognitive deficits, mood symptoms and significant reduction in health-related quality of life (HRQoL) are highly replicated and debilitating aspects of PCC. We sought to determine the impact of vortioxetine on the foregoing symptoms and HRQoL in persons living with PCC. An 8-week randomized, double-blind, placebo-controlled study of adults >= 18 years of age residing in Canada and who are experiencing symptoms of World Health Organization (WHO)-defined PCC, with a history of confirmed SARS-CoV-2 infection, was conducted. Recruitment began November 2021 and ended January 2023. Of the 200 participants enrolled (487 invited: 121 ineligible and 59 eligible but declined participation; 307 cleared pre-screening stage), a total of 149 participants were randomized (1:1) to receive either vortioxetine (5-20 mg, n = 75) or placebo (n = 74) daily for 8 weeks of double-blind treatment (i.e. end point). The primary outcome was the change from baseline-to-end point in the Digit Symbol Substitution Test. Secondary outcomes included the effect on depressive symptoms and HRQoL, as measured by changes from baseline-to-end point on the Quick Inventory of Depressive Symptomatology 16-item and WHO Wellbeing Scale 5-item, respectively. A total of 68 (90.7%) participants randomized to vortioxetine and 73 (98.6%) participants randomized to placebo completed all 8 weeks. Between-group analysis did not show a significant difference in the overall change in cognitive function [P = 0.361, 95% confidence interval (CI) (-0.179, 0.492)]. However, in the fully adjusted model, a significant treatment x time interaction was observed in favour of vortioxetine treatment with baseline c-reactive protein (CRP) as a moderator (P = 0.012). In addition, a significant improvement in Digit Symbol Substitution Test scores were observed in vortioxetine versus placebo treated participants in those whose baseline CRP was above the mean (P = 0.045). Moreover, significant improvement was obtained in measures of depressive symptoms [P < 0.001, 95% CI (-4.378, -2.323)] and HRQoL [P < 0.001, 95% CI (2.297, 4.647)] in vortioxetine-treated participants and between the treatment groups [depressive symptoms: P = 0.026, 95% CI (-2.847, -0.185); HRQoL: P = 0.004, 95% CI (0.774, 3.938)]. Although vortioxetine did not improve cognitive function in the unadjusted model, when adjusting for CRP, a significant pro-cognitive effect was observed; antidepressant effects and improvement in HRQoL in this debilitating disorder were also noted.

Friday, May 1April 14, 2020Free AccessEarly Stages of Lafora Progressive Myoclonus Epilepsy (5489)Antonio Delgado-Escueta, Viet-Huong Nguyen, Reyna M. Durón, Cesia W. Garrido, Alenoush Aramian, Julia N. Bailey, Deborah Holder, Arthur Partikian, Nancy Allison McNamara, and René Silva SomozaAuthors Info & AffiliationsApril 14, 2020 issue94 (15_supplement)https://doi.org/10.1212/WNL.94.15_supplement.5489 Letters to the Editor

We created an online platform to record clinical and genetic information of patients with epilepsy. The platform is helping a stablished community of neurologists to integrate their findings and to share information across borders. The application is designed in such way that it will allow scalability and maintainability in the future.

April 23, 2018April 10, 2018Free AccessAutophagy in Juvenile Myoclonic Epilepsy (JME) (P2.275)Miyabi Tanaka, Iris Martinez-Juarez, Reyna Duron, Viet-Huong Nguyen, Adriana Ochoa, Aurelio Jara-Prado, Maria Alonso, … Show All … , Minerva Lopez-Ruiz, Marco Medina, Laura Guilhoto, Marcia Yacubian, Rene Silva, Christopher Patterson, Julia Bailey, and Antonio Delgado-Escueta Show FewerAuthors Info & AffiliationsApril 10, 2018 issue90 (15_supplement)https://doi.org/10.1212/WNL.90.15_supplement.P2.275 Letters to the Editor

GAW20 provided a platform for developing and evaluating statistical methods to analyze human lipid-related phenotypes, DNA methylation, and single-nucleotide markers in a study involving a pharmaceutical intervention. In this article, we present an overview of the data sets and the contributions analyzing these data. The data, donated by the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) investigators, included data from 188 families (N = 1105) which included genome-wide DNA methylation data before and after a 3-week treatment with fenofibrate, single-nucleotide polymorphisms, metabolic syndrome components before and after treatment, and a variety of covariates. The contributions from individual research groups were extensively discussed prior, during, and after the Workshop in groups based on discussion themes, before being submitted for publication.

Objective: To design a new database platform for the clinical and genetic investigation of epilepsies under a document-oriented scheme that allow data re-update and reanalysis according to the new 2016 ILAE classification of seizures and epilepsies. Background: The Genetic Epilepsy Studies Consortium (GENESS) and collaborators have collected clinical and genetic information from families with epilepsy residing in Los Angeles, CA (USA), Mexico, Honduras, El Salvador, Guatemala, Peru, Brazil, Spain, France, and Japan. For more than four decades, such information has been stored in physical and electronic files. Design/Methods: We created a document-oriented database model using a MongoDB platform, which provides flexibility, scalability and high performance. Mongoose allows data object modeling and maps our models with the actual database in NodeJS, as well as with ReactJS, React-Redux and other modern development libraries for building user interface. We added security models like data encryption and authentication tokens to restrict access to the system. We included action log for future auditing, updating and reanalysis. Designed as a local solution, our pilot system can be converted to a cloud environment. Results: During data migration, weaknesses were discovered in data sources and intake forms. Hence, the database platform was redesigned according to the reality of information obtained and the new ILAE classification. Reanalysis according to the new ILAE classification of seizures and epilepsies in 600 probands and families with genetic generalized epilepsies registered by the GENESS Intake Form will be shown. The new platform improves organization of information, enhances ability to update and reclassify, manipulate information, perform basic statistics and export information for analyzes in complex statistical programs. Conclusions: Our information management tool is a novel contribution to research in epilepsy genetics that will necessarily require frequent reanalysis in seeking perfection. Whenever ILAE classifications change, our platform could strengthen the clinical and genetic analysis of families with inherited epilepsies. Study Supported by: National Institutes of Health (1R01NS055057), VA Merit Review (5I01CX000743) and UNITEC. Disclosure: Dr. Discua has nothing to disclose. Dr. Duron has nothing to disclose. Dr. Martinez has nothing to disclose. Dr. Nguyen has nothing to disclose. Dr. Patterson has nothing to disclose. Dr. Bailey has nothing to disclose. Dr. Tanaka has nothing to disclose. Dr. Ochoa has nothing to disclose. Dr. Jara-Prado has nothing to disclose. Dr. Alonso has nothing to disclose. Dr. Lopez Ruiz has nothing to disclose. Dr. Medina has nothing to disclose. Dr. Guilhoto has nothing to disclose. Dr. Targas Yacubian has nothing to disclose. Dr. Silva has nothing to disclose. Dr. Arias has nothing to disclose. Dr. Delgado-Escueta has nothing to disclose.

April 23, 2018April 10, 2018Free AccessAnalyzing Phenotypes Using Artificial Intelligence Tools in Subgroups of Absence and Myoclonic Epilepsies (P2.344)Reyna M. Durón, Carlos Arias, Iris E. Martínez-Juárez, Christopher Patterson, Julia N. Bailey, Miyabi Tanaka, Adriana Ochoa, Aurelio Jara-Prado, María Elisa Alonso, Marco T. Medina, Viet-Huong Nguyen, and Antonio V. Delgado-EscuetaAuthors Info & AffiliationsApril 10, 2018 issue90 (15_supplement)https://doi.org/10.1212/WNL.90.15_supplement.P2.344 Letters to the Editor

Our objective is to report the advances of the Lafora Epilepsy Cure Initiative (LECI) Clinical Center, whose mission is to cure Lafora Disease (LD).

Genetic Analysis Workshop 19 provided a platform for developing and evaluating statistical methods to analyze whole-genome sequence and gene expression data from a pedigree-based sample, as well as whole-exome sequence data from a large cohort of unrelated individuals. In this article we present an overview of the data sets, the GAW experience, and summaries of the contributions arranged into nine methodological themes.

PURPOSE:EFHC1 variants are the most common mutations in inherited myoclonic and grand mal clonic-tonic-clonic (CTC) convulsions of juvenile myoclonic epilepsy (JME). We reanalyzed 54 EFHC1 variants associated with epilepsy from 17 cohorts based on National Human Genome Research Institute (NHGRI) and American College of Medical Genetics and Genomics (ACMG) guidelines for interpretation of sequence variants. METHODS:We calculated Bayesian LOD scores for variants in coinheritance, unconditional exact tests and odds ratios (OR) in case-control associations, allele frequencies in genome databases, and predictions for conservation/pathogenicity. We reviewed whether variants damage EFHC1 functions, whether efhc1-/- KO mice recapitulate CTC convulsions and "microdysgenesis" neuropathology, and whether supernumerary synaptic and dendritic phenotypes can be rescued in the fly model when EFHC1 is overexpressed. We rated strengths of evidence and applied ACMG combinatorial criteria for classifying variants. RESULTS:Nine variants were classified as "pathogenic," 14 as "likely pathogenic," 9 as "benign," and 2 as "likely benign." Twenty variants of unknown significance had an insufficient number of ancestry-matched controls, but ORs exceeded 5 when compared with racial/ethnic-matched Exome Aggregation Consortium (ExAC) controls. CONCLUSIONS:NHGRI gene-level evidence and variant-level evidence establish EFHC1 as the first non-ion channel microtubule-associated protein whose mutations disturb R-type VDCC and TRPM2 calcium currents in overgrown synapses and dendrites within abnormally migrated dislocated neurons, thus explaining CTC convulsions and "microdysgenesis" neuropathology of JME.Genet Med 19 2, 144-156.

Juvenile myoclonic epilepsy ( JME ), the most common genetic epilepsy, remains enigmatic because it is considered one disease instead of several diseases. We ascertained three large multigenerational/multiplex JME pedigrees from Honduras with differing JME subsyndromes, including Childhood Absence Epilepsy evolving to JME ( CAE / JME ; pedigree 1), JME with adolescent onset pyknoleptic absence ( JME / pA ; pedigree 2), and classic JME ( cJME ; pedigree 3). All phenotypes were validated, including symptomatic persons with various epilepsies, asymptomatic persons with EEG 3.5–6.0 Hz polyspike waves, and asymptomatic persons with normal EEG s. Two‐point parametric linkage analyses were performed with 5185 single‐nucleotide polymorphisms on individual pedigrees and pooled pedigrees using four diagnostic models based on epilepsy/ EEG diagnoses. Haplotype analyses of the entire genome were also performed for each individual. In pedigree 1, haplotyping identified a 34 cM region in 2q21.2–q31.1 cosegregating with all affected members, an area close to 2q14.3 identified by linkage ( Z max = 1.77; pedigree 1). In pedigree 2, linkage and haplotyping identified a 44 cM cosegregating region in 13q13.3–q31.2 ( Z max = 3.50 at 13q31.1; pooled pedigrees). In pedigree 3, haplotyping identified a 6 cM cosegregating region in 17q12. Possible cosegregation was also identified in 13q14.2 and 1q32 in pedigree 3, although this could not be definitively confirmed due to the presence of uninformative markers in key individuals. Differing chromosome regions identified in specific JME subsyndromes may contain separate JME disease‐causing genes, favoring the concept of JME as several distinct diseases. Whole‐exome sequencing will likely identify a CAE / JME gene in 2q21.2–2q31.1, a JME / pA gene in 13q13.3–q31.2, and a cJME gene in 17q12.

OBJECTIVE To refine classification of Juvenile Myoclonic Epilepsy (JME) subsyndromes in 298 cases according to age at onset of absence seizures (ABS) and results of whole exome sequencing (WES). BACKGROUND The 2011 Avignon Workshop established the diagnostic criteria for JME as onset of awakening myoclonias and EEG 4-6Hz polyspike waves between 10-25 years of age. However, ABS with/without eyelid myoclonia (EM), astatic drop, and photosensitivity confound JME nosology. DESIGN/METHODS JME cases were regrouped according to age onset of ABS: early childhood (1-5 yr) [eCA/JME], childhood (6-11y) [CA/JME], adolescence [adolABS/JME] (12-21y), and JME with ABS in adulthood (22y+). WES of 12 large JME families followed linkage and haplotype analysis. Discovered epilepsy genes were then screened in the 298 cases. RESULTS Out of 298, 134 probands (45[percnt]) had classic JME (cJME), 60 (20[percnt]) had CA/JME, 70 (23[percnt]) had adolABS/JME, 20 (7[percnt]) had eCA/JME, 9 (3[percnt]) had astatic seizures with JME, and only 5 (2[percnt]) had adulthood ABS/JME. EFHC1 variants were genetically implicated in cJME (16 cases) and CA/JME (1 case), ICK variants in cJME (7 probands) and adolABS/JME (1 proband). IPO8 variants in photosensitive CA with/without EM evolving to JME (6 probands), JME with adolABS (2 probands), JME with absence and astatic seizures (1 proband), and JME with adult onset ABS (1 proband), and 7 cases of childhood ABS only from another cohort. PROSER1 variants were implicated adolABS/JME (6 probands) and one case with cJME. MYOFERLIN variant was implicated in a proband with photosensitive eCA/ JME. CONCLUSIONS EFHC1 and ICK variants are most common in cJME, while IPO8 and MYOFERLIN variants predominate in JME with eCA, adolABS, CA/JME and adult onset ABS. PROSER1 variants associated with pyknoleptic adolABS/JME. Finding variants of genes mean JME subsyndromes are true entities and separate diseases. Study supported by NIH R01NS055057, VACO Merit Review Grant, CIDR. Disclosure: Dr. Duron has nothing to disclose. Dr. Medina has nothing to disclose. Dr. Martinez-Juarez has received personal compensation for activities with commercial entities as a consultant. Dr. Jara-Prado has nothing to disclose. Dr. Ochoa has nothing to disclose. Dr. Lopez-Ruiz has nothing to disclose. Dr. Molina has nothing to disclose. Dr. Guilhoto has nothing to disclose. Dr. Yacubian has nothing to disclose. Dr. Wight has nothing to disclose. Dr. Nguyen has nothing to disclose. Dr. Lin has nothing to disclose. Dr. Bai has nothing to disclose. Dr. Tanaka has nothing to disclose. Dr. Patterson has nothing to disclose. Dr. Alonso has nothing to disclose. Dr. Bailey has nothing to disclose. Dr. Delgado-Escueta has nothing to disclose.

Objective:To evaluate knowlegde about Sudden Unexpected Death in Epilepsy (SUDEP) and first aid for seizures in health personnel, non-epilepsy patients, persons related to epilepsy patients, and general population in Olancho, HondurasBackground:SUDEP occurs in 1/1000 patients, but knowledge about it is still lacking in Honduras.Methods:We performed a descriptive study by using a 16-question-questionaire. Participants were invited as they consecutively visited a clinic at Santa Maria del Real and public locations in Catacamas, Olancho (mixed urban-rural Municipality at East Honduras). We evaluated demographics, personal connection to epilepsy, knowledge about risk of death in epilepsy, SUDEP and seizure first aid for seizures.Results:Of the 162 participants, 15[percnt] (n=25) were health personnel, 41[percnt] (n=66) were family members or friends of patients with epilepsy, 10[percnt] (n=16) were patients with other diseases, and 34[percnt] (n=55) were from the general population. On sudden death, 98[percnt] (n=158) of participants said that it can happen in cases of heart disease, but only 69[percnt] (n=111) said it can happen in epilepsy patients. Only 16[percnt] of health personnel, 18[percnt] of relatives/friends of epilepsy patients and 12[percnt] of general population had heard about the term SUDEP. Friends and relatives of epilepsy patients knew more about risk of death in epilepsy than the general population, but both groups listed inappropiate measures for first aid. Twelve doctors interviewed (100[percnt]) knew about premature death in epilepsy, only two of them knew specifically about SUDEP, few discussed with patients about these topics.ConclusionsMost participants knew about the risk of death related to epilepsy but not about SUDEP specifically. Most non-health-personnel participants listed inappropiate first aid measures during seizures. Education about prevention of morbity and mortality in epilepsy should be included in national comprehensive guidelines of epilepsy and continuing educational programs for doctors, patients and general population. Disclosure: Dr. Guifarro has nothing to disclose. Dr. Duron has nothing to disclose. Dr. Caceres has nothing to disclose. Dr. Nunez has nothing to disclose. Dr. Lagos has nothing to disclose. Dr. Bailey has nothing to disclose.

High-density genetic marker data, especially sequence data, imply an immense multiple testing burden. This can be ameliorated by filtering genetic variants, exploiting or accounting for correlations between variants, jointly testing variants, and by incorporating informative priors. Priors can be based on biological knowledge or predicted variant function, or even be used to integrate gene expression or other omics data. Based on Genetic Analysis Workshop (GAW) 19 data, this article discusses diversity and usefulness of functional variant scores provided, for example, by PolyPhen2, SIFT, or RegulomeDB annotations. Incorporating functional scores into variant filters or weights and adjusting the significance level for correlations between variants yielded significant associations with blood pressure traits in a large family study of Mexican Americans (GAW19 data set). Marker rs218966 in gene PHF14 and rs9836027 in MAP4 significantly associated with hypertension; additionally, rare variants in SNUPN significantly associated with systolic blood pressure. Variant weights strongly influenced the power of kernel methods and burden tests. Apart from variant weights in test statistics, prior weights may also be used when combining test statistics or to informatively weight p values while controlling false discovery rate (FDR). Indeed, power improved when gene expression data for FDR-controlled informative weighting of association test p values of genes was used. Finally, approaches exploiting variant correlations included identity-by-descent mapping and the optimal strategy for joint testing rare and common variants, which was observed to depend on linkage disequilibrium structure.

BACKGROUND:Adherence to medication is a worldwide problem and deserves country-specific attention. Honduras, like many other countries, has allopathic providers, traditional medicine (TM), and complementary and alternative medicine (CAM). Understanding a population's health behaviors is essential to satisfactory integration of these systems and successful patient care.STUDY OBJECTIVE:The objective was to identify factors that influence medication adherence in Honduras.DESIGN:The research team administered a cross-sectional, 25-item questionnaire to various neighborhoods based on national demographic statistics in order to obtain a quota sample. Setting • The survey took place in Tegucigalpa, Honduras, Central America.PARTICIPANTS:The research team surveyed 614 Hondurans, aged ≥ 18 y, within the general population of Tegucigalpa, the largest and capital city of Honduras, in neighborhoods representing areas where primarily the lower and middle classes lived.OUTCOME MEASURES:The primary outcome measure was a modified Medication Adherence Report Scale (MARS). Results • The research team collected 610 surveys that had complete answers to questions about adherence (610/614, 99.3%) total complete responses to other items varied. The prevalence of use of TM was 62.8% (381/607). Nearly one-half, 47.3% (287/607), of all the respondents had used herbs or teas for health in the prior year, and 26.1% (159/607) of all respondents had received a sobada (therapeutic rubbing). Respondents with daily private spiritual devotions (OR = 0.610, P = .018) and diabetes (OR = 0.154, P = .004) were less likely to report low adherence. Receiving a sobada and a history of fever were independently associated with low adherence (OR = 1.718, P = .017 and OR = 2.226, P < .001, respectively).CONCLUSIONS:Hondurans use both allopathic and TM. Although private spiritual devotion may help improve adherence to medication, only use of traditional massage therapy, the sobada, was associated with decreased adherence. Effective integration of alternative therapies in Central America will require proper counseling on how to combine multiple therapies to maximize the health benefits.