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Divalent metal transporter 1 (DMT1) cotransports ferrous iron and protons and is the primary mechanism for uptake of nonheme iron by enterocytes. Inhibitors are potentially useful as therapeutic agents to treat iron overload disorders such as hereditary hemochromatosis or ß-thalassemia intermedia, provided that inhibition can be restricted to the duodenum. We used a calcein quench assay to identify human DMT1 inhibitors. Dimeric compounds were made to generate more potent compounds with low systemic exposure. Direct block of DMT1 was confirmed by voltage clamp measurements. The lead compound, XEN602, strongly inhibits dietary nonheme iron uptake in both rats and pigs yet has negligible systemic exposure. Efficacy is maintained for >2 weeks in a rat subchronic dosing assay. Doses that lowered iron content in the spleen and liver by >50% had no effect on the tissue content of other divalent cations except for cobalt. XEN602 represents a powerful pharmacological tool for understanding the physiologic function of DMT1 in the gut. SIGNIFICANCE STATEMENT: This report introduces methodology to develop potent, gut-restricted inhibitors of divalent metal transporter 1 (DMT1) and identifies XEN602 as a suitable compound for in vivo studies. We also report novel animal models to quantify the inhibition of dietary uptake of iron in both rodents and pigs. This research shows that inhibition of DMT1 is a promising means to treat iron overload disorders.
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Sobrecarga de Hierro , Humanos , Ratas , Animales , Porcinos , Sobrecarga de Hierro/tratamiento farmacológico , Hierro/metabolismo , Transporte Biológico , Proteínas de Unión a Hierro/metabolismo , Modelos AnimalesRESUMEN
Background: Screening first-degree relatives (FDRs) of patients with premature coronary artery disease (CAD) is recommended but not routinely performed. Objectives: To assess the diagnostic yield and impact on clinical management of a clinical and imaging-based screening program of FDRs delivered in the setting of routine clinical care. Methods: We recruited FDRs of patients with premature CAD with no personal history of CAD and prospectively assessed for: 1) cardiovascular risk and presence of significant subclinical atherosclerosis (SA) defined as plaque on carotid ultrasound, stenosis >50% or extensive atherosclerosis on coronary computed tomography angiography, or coronary artery calcium scores >100 Agatston units or >75% percentile for age and sex; 2) utilization of preventive medications and lipid levels prior enrolment and after completion of the assessment. Results: We assessed 132 FDRs (60.6% females), mean (SD) age 47(17) years old. Cardiovascular risk was high in 38.2%, moderate in 12.2%, and low in 49.6% of FDRs. SA was present in 34.1% of FDRs, including 12.5% in low, 51.9% in moderate, and 55.0% in high calculated risk groups. After assessment, LLT was initiated in 32.6% of FDRs and intensified in 16.0% leading to mean (SD) LDL-C decrease of 1.07(1.10) mmol/L in patients with high calculated risk or SA. LLT was recommended to all patients with high calculated risk, but those with SA were more likely to receive the medications from pharmacies (93.3% vs 60.0%, p = 0.006). Conclusion: Screening the FDRs of patients with premature CAD is feasible, may have high diagnostic yield and impact risk factor management.
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Background: Heart disease is the leading cause of premature death for women in Canada. Ischemic heart disease is categorized as myocardial infarction (MI) with no obstructive coronary artery disease (MINOCA), ischemia with no obstructive coronary arteries (INOCA), and atherosclerotic obstructive coronary artery disease (CAD) with MI (MI-CAD) or without MI (non-MI-CAD). This study aims to study the prevalence of traditional and nontraditional ischemic heart disease risk factors and their relationships with (M)INOCA, compared to MI-CAD and non-MI-CAD in young women. Methods: This study investigated women who presented with premature (at age ≤ 55 years) vasomotor entities of (M)INOCA or obstructive CAD confirmed by coronary angiography, who are currently enrolled in either the Leslie Diamond Women's Heart Health Clinic Registry (WHC) or the Study to Avoid Cardiovascular Events in British Columbia (SAVEBC). Univariable and multivariable regression models were applied to investigate associations of risk factors with odds of (M)INOCA, MI-CAD, and non-MI-CAD. Results: A total of 254 women enrolled between 2015 and 2022 were analyzed, as follows: 77 with INOCA and 37 with MINOCA from the registry, and 66 with non-MI-CAD and 74 with MI-CAD from the study. Regression analyses demonstrated that migraines and preeclampsia or gestational hypertension were the most significant risk factors, with a higher likelihood of being associated with premature (M)INOCA, relative to obstructive CAD. Conversely, the presence of diabetes and a current or previous smoking history had the highest likelihood of being associated with premature CAD. Conclusions: The risk factor profiles of patients with premature (M)INOCA, compared to obstructive CAD, have significant differences.
Contexte: Au Canada, la cardiopathie est la principale cause de décès prématuré chez les femmes. La cardiopathie ischémique est catégorisée comme suit : infarctus du myocarde (IM) en l'absence de coronaropathie obstructive (MINOCA), ischémie sans obstruction des artères coronaires (INOCA) et athérosclérose coronaire obstructive accompagnée d'un IM ou sans IM. La présente étude vise à examiner la prévalence des facteurs de risque classiques et non classiques de cardiopathie ischémique et leurs liens avec le (M)INOCA, comparativement à l'athérosclérose coronaire obstructive accompagnée d'un IM ou sans IM chez les femmes jeunes. Méthodologie: Cette étude portait sur des femmes qui avaient prématurément (55 ans ou moins) souffert d'un (M)INOCA ou d'une coronaropathie obstructive confirmés par coronarographie et qui étaient inscrites au registre de la Leslie Diamond Women's Heart Health Clinic (WHC) ou qui participaient à l'étude visant à éviter les événements cardiovasculaires en Colombie-Britannique (Study toAvoid CardiovascularEvents inBC; SAVEBC). Des modèles de régression univariés et multivariés ont été utilisés pour explorer les associations entre les facteurs de risque et les probabilités de (M)INOCA, ainsi que d'athérosclérose coronaire obstructive accompagnée ou non d'un IM. Résultats: Au total, 254 femmes inscrites de 2015 à 2022 ont été recensées, soit 77 présentant une INOCA et 37, un MINOCA selon le registre WHC, et 66 présentant une athérosclérose coronaire obstructive sans IM et 74, une athérosclérose coronaire obstructive accompagnée d'un IM selon l'étude SAVEBC. Les analyses de régression ont démontré que les migraines et la prééclampsie ou l'hypertension gestationnelle étaient les facteurs de risque les plus importants associés à une probabilité la plus élevée de (M)INOCA comparativement à une coronaropathie obstructive. En revanche, la présence d'un diabète et d'un tabagisme actuel ou passé était associée à la probabilité la plus élevée de coronaropathie prématurée. Conclusions: Il existe d'importantes différences pour ce qui est des profils de facteurs de risque des patientes ayant prématurément souffert d'un (M)INOCA en comparaison d'une coronaropathie obstructive.
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Familial exudative vitreoretinopathy (FEVR) is a hereditary ocular disorder characterized by a failure of peripheral retinal vascularization. Loci associated with FEVR map to 11q13-q23 (EVR1; OMIM 133780, ref. 1), Xp11.4 (EVR2; OMIM 305390, ref. 2) and 11p13-12 (EVR3; OMIM 605750, ref. 3). Here we have confirmed linkage to the 11q13-23 locus for autosomal dominant FEVR in one large multigenerational family and refined the disease locus to a genomic region spanning 1.55 Mb. Mutations in FZD4, encoding the putative Wnt receptor frizzled-4, segregated completely with affected individuals in the family and were detected in affected individuals from an additional unrelated family, but not in normal controls. FZD genes encode Wnt receptors, which are implicated in development and carcinogenesis. Injection of wildtype and mutated FZD4 into Xenopus laevis embryos revealed that wildtype, but not mutant, frizzled-4 activated calcium/calmodulin-dependent protein kinase II (CAMKII) and protein kinase C (PKC), components of the Wnt/Ca(2+) signaling pathway. In one of the mutants, altered subcellular trafficking led to defective signaling. These findings support a function for frizzled-4 in retinal angiogenesis and establish the first association between a Wnt receptor and human disease.
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Neovascularización Patológica/genética , Proteínas/genética , Enfermedades de la Retina/genética , Vasos Retinianos/patología , Secuencia de Aminoácidos , Preescolar , Femenino , Receptores Frizzled , Marcadores Genéticos , Haplotipos , Humanos , Masculino , Datos de Secuencia Molecular , Mutación , Linaje , Polimorfismo Genético , Receptores de Superficie Celular , Receptores Acoplados a Proteínas G , Retina/patología , Enfermedades de la Retina/patología , Alineación de Secuencia , Transducción de SeñalRESUMEN
Background: Lipid-lowering therapy (LLT) is a central aspect of the treatment of patients with coronary artery disease (CAD), and the benefits of LLT accrue over time. However, there are limited real-world data on longitudinal lipid control in patients with premature CAD. Objectives: The purpose of this study was to assess longitudinal attainment of guideline-recommended lipid goals and outcomes in a contemporary cohort of patients with premature CAD. Methods: We enrolled males younger than 50 years and females younger than 55 years with coronary stenosis of >50% and examined achievement of lipid goals, LLT characteristics, and cardiovascular outcomes (major adverse cardiovascular event [MACE]). Results: Of 476 patients who presented with acute coronary syndrome (ST-elevation myocardial infarction, non-ST-segment elevation myocardial infarction, unstable angina) (68%), stable angina (28%), or other symptoms, 73.2% achieved low-density lipoprotein cholesterol (LDL-C) <1.8 mmol/L on at least 1 occasion, but only 27.3% consistently stayed in the target range for 3 years after diagnosis. Although 73.9% of patients received high-intensity LLT at the time of diagnosis, only 43.5% had good adherence over the following 3 years. In multivariable analysis, 1 mmol/L increase in time-weighted average exposure to LDL-C, but not the lowest achieved LDL-C, was associated with a higher risk of MACE, hazard ratio 2.02 (95% CI: 1.48-2.76), when adjusted for sex, age, hypertension, diabetes, and smoking. Conclusions: We found low rates of longitudinal lipid target achievement in patients with premature CAD. Cumulative LDL-C exposure, but not lowest achieved LDL-C, was associated with risk of MACE. This highlights the critical importance of longitudinal control of lipids levels and identifies opportunities to improve LLT and maximize the time-dependent benefits of lipid-lowering.
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Importance: Many patients with focal epilepsy experience seizures despite treatment with currently available antiseizure medications (ASMs) and may benefit from novel therapeutics. Objective: To evaluate the efficacy and safety of XEN1101, a novel small-molecule selective Kv7.2/Kv7.3 potassium channel opener, in the treatment of focal-onset seizures (FOSs). Design, Setting, and Participants: This phase 2b, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging adjunctive trial investigated XEN1101 over an 8-week treatment period from January 30, 2019, to September 2, 2021, and included a 6-week safety follow-up. Adults experiencing 4 or more monthly FOSs while receiving stable treatment (1-3 ASMs) were enrolled at 97 sites in North America and Europe. Interventions: Patients were randomized 2:1:1:2 to receive XEN1101, 25, 20, or 10 mg, or placebo with food once daily for 8 weeks. Dosage titration was not used. On completion of the double-blind phase, patients were offered the option of entering an open-label extension (OLE). Patients not participating in the OLE had follow-up safety visits (1 and 6 weeks after the final dose). Main Outcomes and Measures: The primary efficacy end point was the median percent change from baseline in monthly FOS frequency. Treatment-emergent adverse events (TEAEs) were recorded and comprehensive laboratory assessments were made. Modified intention-to-treat analysis was conducted. Results: A total of 325 patients who were randomized and treated were included in the safety analysis; 285 completed the 8-week double-blind phase. In the 325 patients included, mean (SD) age was 40.8 (13.3) years, 168 (51.7%) were female, and 298 (91.7%) identified their race as White. Treatment with XEN1101 was associated with seizure reduction in a robust dose-response manner. The median (IQR) percent reduction from baseline in monthly FOS frequency was 52.8% (P < .001 vs placebo; IQR, -80.4% to -16.9%) for 25 mg, 46.4% (P < .001 vs placebo; IQR, -76.7% to -14.0%) for 20 mg, and 33.2% (P = .04 vs placebo; IQR, -61.8% to 0.0%) for 10 mg, compared with 18.2% (IQR, -37.3% to 7.0%) for placebo. XEN1101 was generally well tolerated and TEAEs were similar to those of commonly prescribed ASMs, and no TEAEs leading to death were reported. Conclusions and Relevance: The efficacy and safety findings of this clinical trial support the further clinical development of XEN1101 for the treatment of FOSs. Trial Registration: ClinicalTrials.gov Identifier: NCT03796962.
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Epilepsias Parciales , Adulto , Femenino , Humanos , Masculino , Anticonvulsivantes/efectos adversos , Método Doble Ciego , Quimioterapia Combinada , Epilepsias Parciales/tratamiento farmacológico , Canales de Potasio/uso terapéutico , Convulsiones/tratamiento farmacológico , Resultado del TratamientoRESUMEN
BACKGROUND AND AIMS: Familial combined hyperlipidemia (FCHL) is one of the most common inherited lipid phenotypes, characterized by elevated plasma concentrations of apolipoprotein B-100 and triglycerides. The genetic inheritance of FCHL remains poorly understood. The goals of this study were to investigate the polygenetic architecture and cardiovascular risk associated with FCHL. METHODS AND RESULTS: We identified individuals with an FCHL phenotype among 349,222 unrelated participants of European ancestry in the UK Biobank using modified versions of 5 different diagnostic criteria. The prevalence of the FCHL phenotype was 11.44% (n = 39,961), 5.01% (n = 17,485), 1.48% (n = 5,153), 1.10% (n = 3,838), and 0.48% (n = 1,688) according to modified versions of the Consensus Conference, Dutch, Mexico, Brunzell, and Goldstein criteria, respectively. We performed discovery, case-control genome-wide association studies for these different FCHL criteria and identified 175 independent loci associated with FCHL at genome-wide significance. We investigated the association of genetic and clinical risk with FCHL and found that polygenic susceptibility to hypercholesterolemia or hypertriglyceridemia and features of metabolic syndrome were associated with greater prevalence of FCHL. Participants with an FCHL phenotype had a similar risk of incident coronary artery disease compared to participants with monogenic familial hypercholesterolemia (adjusted hazard ratio vs controls [95% confidence interval]: 2.72 [2.31-3.21] and 1.90 [1.30-2.78]). CONCLUSIONS: These results suggest that, rather than being a single genetic entity, the FCHL phenotype represents a polygenic susceptibility to dyslipidemia in combination with metabolic abnormalities. The cardiovascular risk associated with an FCHL phenotype is similar to that of monogenic familial hypercholesterolemia, despite being â¼5x more common.
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Enfermedades Cardiovasculares , Hiperlipidemia Familiar Combinada , Hiperlipidemias , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/genética , Estudio de Asociación del Genoma Completo , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Hiperlipidemia Familiar Combinada/diagnóstico , Hiperlipidemia Familiar Combinada/genética , Hiperlipidemias/diagnóstico , Hiperlipidemias/epidemiología , Hiperlipidemias/genética , Factores de RiesgoRESUMEN
PURPOSE: SCN8A developmental epileptic encephalopathy (SCN8A-DEE) is a rare and severe genetic epilepsy syndrome characterized by early-onset developmental delay, cognitive impairment, and intractable seizures. SCN8A gene variants are associated with a broad phenotypic spectrum and variable disease severity. A caregiver survey, solicited by the advocacy group The Cute Syndrome Foundation (TCSF), was conducted to gather information on the demographics/disease presentation, seizure history, and treatment of patients with SCN8A-related epilepsies. METHODS: A 36-question online survey was developed to obtain de-identified data from caregivers of children with SCN8A-related epilepsy. The survey included questions on genetic diagnosis, disease manifestations/comorbidities, seizure severity/type, current/prior use of antiseizure medicines (ASMs), and best/worst treatments per caregiver perception. RESULTS: In total, 116 survey responses (87 USA, 12 Canada, 12 UK, 5 Australia) were quantitatively analyzed. Generalized tonic/clonic was the most common seizure type at onset and time of survey; absence and partial/focal seizures were also common. Most patients (77%) were currently taking ≥2 ASMs; 50% had previously tried and stopped ≥4 ASMs. Sodium channel blockers (oxcarbazepine, phenytoin, lamotrigine) provided the best subjective seizure control and quality of life. CONCLUSION: The SCN8A-DEE patient population is heterogeneous in seizure characteristics and ASMs taken and is difficult to treat, with high seizure burden and multiple comorbidities. The high proportion of patients who previously tried and stopped ASMs indicates large unmet treatment need. Further collaboration between families, caregivers, patient advocates, clinicians, researchers, and industry can increase awareness and understanding of SCN8A-related epilepsies, improve clinical trial design, and potentially improve patient outcomes.
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Epilepsia Generalizada , Epilepsia , Discapacidad Intelectual , Cuidadores , Niño , Epilepsia/complicaciones , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Epilepsia Generalizada/complicaciones , Humanos , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/genética , Canal de Sodio Activado por Voltaje NAV1.6/genética , Calidad de Vida , Convulsiones/complicacionesRESUMEN
NBI-921352 (formerly XEN901) is a novel sodium channel inhibitor designed to specifically target NaV1.6 channels. Such a molecule provides a precision-medicine approach to target SCN8A-related epilepsy syndromes (SCN8A-RES), where gain-of-function (GoF) mutations lead to excess NaV1.6 sodium current, or other indications where NaV1.6 mediated hyper-excitability contributes to disease (Gardella and Møller, 2019; Johannesen et al., 2019; Veeramah et al., 2012). NBI-921352 is a potent inhibitor of NaV1.6 (IC500.051 µM), with exquisite selectivity over other sodium channel isoforms (selectivity ratios of 756 X for NaV1.1, 134 X for NaV1.2, 276 X for NaV1.7, and >583 Xfor NaV1.3, NaV1.4, and NaV1.5). NBI-921352is a state-dependent inhibitor, preferentially inhibiting inactivatedchannels. The state dependence leads to potent stabilization of inactivation, inhibiting NaV1.6 currents, including resurgent and persistent NaV1.6 currents, while sparing the closed/rested channels. The isoform-selective profile of NBI-921352 led to a robust inhibition of action-potential firing in glutamatergic excitatory pyramidal neurons, while sparing fast-spiking inhibitory interneurons, where NaV1.1 predominates. Oral administration of NBI-921352 prevented electrically induced seizures in a Scn8a GoF mouse,as well as in wild-type mouse and ratseizure models. NBI-921352 was effective in preventing seizures at lower brain and plasma concentrations than commonly prescribed sodium channel inhibitor anti-seizure medicines (ASMs) carbamazepine, phenytoin, and lacosamide. NBI-921352 waswell tolerated at higher multiples of the effective plasma and brain concentrations than those ASMs. NBI-921352 is entering phase II proof-of-concept trials for the treatment of SCN8A-developmental epileptic encephalopathy (SCN8A-DEE) and adult focal-onset seizures.
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Epilepsia , Canal de Sodio Activado por Voltaje NAV1.6 , Animales , Mutación con Ganancia de Función , Ratones , Mutación , Canal de Sodio Activado por Voltaje NAV1.6/genética , Neuronas/fisiología , Ratas , Sodio , Bloqueadores de los Canales de Sodio/farmacologíaRESUMEN
BACKGROUND: Familial hypercholesterolemia (FH), familial combined hyperlipidemia (FCHL), and elevated lipoprotein (a) (Lp[a]) increase risk of premature coronary artery disease (CAD). The objective of this study was to assess the prevalence of FH, FCHL, elevated Lp(a) and their impact on management in patients with premature CAD. METHODS: We prospectively recruited men ≤ 50 years and women ≤ 55 with obstructive CAD. FH was defined as Dutch Lipid Clinic Network scores ≥ 6. FCHL was defined as apolipoprotein B > 1.2 g/L, triglyceride and total cholesterol > 90th population percentile, and family history of premature cardiovascular disease. Lp(a) ≥ 50 mg/dL was considered to be elevated. RESULTS: Among 263 participants, 9.1% met criteria for FH, 12.5% for FCHL, and 19.4% had elevated Lp(a). Among patients with FH, 37.5% had FH-causing DNA variants. Patients with FH, but not other dyslipidemias, were more likely than nondyslipidemic patients to have received lipid-lowering therapy before presenting with CAD (33.3% vs 12.3%, P = 0.04) and combined lipid-lowering therapy after the presentation (41.7% vs 7.7%, P < 0.001). One year after presentation, 58.3%, 54.5%, and 58.8% of patients with FH, FCHL, and elevated Lp(a) had low-density lipoprotein cholesterol (LDL-C) < 1.8 mmol/L, respectively, compared with 68.0 % in reference group. Patients with FCHL were more likely to have non-high-density lipoprotein (HDL) and apolipoprotein B above recommended lipid goals (70.0% and 87.9%, respectively). CONCLUSIONS: FH, FCHL, and elevated Lp(a) are common in patients with premature CAD and have differing impact on treatment and achievement of lipid targets. Assessment for these conditions in patients with premature CAD provides valuable information for individualized management.
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Enfermedad de la Arteria Coronaria/epidemiología , Hiperlipidemia Familiar Combinada/epidemiología , Hiperlipoproteinemia Tipo II/epidemiología , Lipoproteína(a)/sangre , Adulto , Biomarcadores/sangre , Colombia Británica/epidemiología , Comorbilidad , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/diagnóstico , Femenino , Estudios de Seguimiento , Humanos , Hiperlipidemia Familiar Combinada/sangre , Hiperlipoproteinemia Tipo II/sangre , Masculino , Persona de Mediana Edad , Fenotipo , Prevalencia , Estudios Prospectivos , Factores de RiesgoRESUMEN
Literature review of patients with KCNQ2 developmental and epileptic encephalopathy (KCNQ2-DEE) reveals, based on 16 reports including 139 patients, a clinical phenotype that includes age- and disease-specific stereotyped seizures. The typical seizure type of KCNQ2-DEE, focal tonic, starts within 0-5 days of life and is readily captured by video-electroencephalography VEEG for clinical and genetic diagnosis. After initial identification, KCNQ2-DEE seizures are clinically apparent and can be clearly identified without the use of EEG or VEEG. Therefore, we propose that the 2019 recommendations from the International League against Epilepsy (ILAE), the Pediatric Epilepsy Research Consortium (PERC), for capturing and recording seizures for clinical trials (Epilepsia Open, 4, 2019, 537) are suitable for use in KCNQ2-DEEâassociated antiseizure medicine (ASM) treatment trials. The ILAE/PERC consensus guidance states that a caregiver-maintained seizure diary, completed by caregivers who are trained to recognize seizures using within-patient historical recordings, accurately captures seizures prospectively in a clinical trial. An alternative approach historically endorsed by the Food and Drug Administration (FDA) compares seizure counts captured on VEEG before and after treatment. A major advantage of the ILAE/PERC strategy is that it expands the numbers of eligible patients who meet inclusion criteria of clinical trials while maintaining accurate seizure counts (Epilepsia Open, 4, 2019, 537). Three recent phase 3 pivotal pediatric trials investigating ASMs to treat syndromic seizures in patients as young as 2 years of age (N Engl J Med, 17, 2017, 699; Lancet, 21, 2020, 2243; Lancet, 17, 2018, 1085); and ongoing phase 2 open-label pediatric clinical trial that includes pediatric epileptic syndromes as young as 1 month of age (Am J Med Genet A, 176, 2018, 773), have already used caregiver-maintained seizure diaries successfully. For determining the outcome of a KCNQ2-DEE ASM treatment trial, the use of a seizure diary to count seizures by trained observers is feasible because the seizures of KCNQ2-DEE are clinically apparent. This strategy is supported by successful precedent in clinical trials in similar age groups and has the endorsement of the international pediatric epilepsy community.
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Encefalopatías/genética , Síndromes Epilépticos/genética , Canal de Potasio KCNQ2/genética , Convulsiones , Grabación en Video , Ensayos Clínicos como Asunto , Diarios como Asunto , Electroencefalografía , Humanos , Lactante , Recién Nacido , Pediatría , Estudios Prospectivos , Convulsiones/clasificación , Convulsiones/diagnóstico , Convulsiones/genética , Estados UnidosRESUMEN
OBJECTIVES: Despite advances in screening and prevention, rates of premature coronary artery disease (CAD) have been stagnant. The goals of this study were to investigate the barriers to early risk detection and preventive treatment in patients with premature CAD. In particular, we: 1) assessed the performance of the latest versions of major international guidelines in detection of risk of premature CAD and eligibility for preventive treatment; and, 2) investigated real-life utilization of primary prevention with lipid-lowering therapies in these patients. METHODS: We included patients in the Study to Avoid cardioVascular Events in British Columbia (SAVE BC), an observational study of patients with premature (males â≤ â50 years, females â≤ â55 years) angiographically confirmed CAD. Eligibility for primary prevention and treatment received were assessed retrospectively based on information recorded prior to or at the index presentation with CAD. RESULTS: Of 417 patients (28.1% females) who met the criteria, 94.3% had at least one major cardiovascular risk factor. In the retrospective risk assessment, 41.7%, 61.4%, and 34.3% (p â< â0.001) of patients met criteria for initiation of statin therapy, and an additional 13.9%, 8.4%, and 46.8% may be considered for treatment using the American College of Cardiology/American Heart Association, Canadian Cardiovascular Society, and European Society of Cardiology guidelines, respectively. Only 17.1% of patients received statins and 11.0% achieved guideline-recommended lipid goals before presentation. Diabetes and elevated plasma lipid levels were positively associated with treatment initiation, while smoking was associated with non-treatment. CONCLUSIONS: The current versions of major guidelines fail to recognize many patients who develop premature CAD as being at risk. The vast majority of these patients, including patients who have guideline-directed indications, do not receive lipid-lowering therapy before presenting with CAD. Our findings highlight the need for more effective screening and prevention strategies for premature CAD.
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Background The incidence of atherosclerotic cardiovascular disease has declined in the past 2 decades. However, these benefits may not extend to young patients. The objective of this work was to assess temporal trends in the incidence, risk profiles, sex-related differences, and outcomes in a contemporary population of young patients presenting with coronary artery disease ( CAD ) in British Columbia, Canada. Methods and Results We used a provincial cardiac registry to identify young patients (men aged <50 years, women aged <55 years), with a first presentation of CAD between 2000 and 2016, who had either ≥50% stenosis of ≥1 coronary arteries on angiography or underwent coronary revascularization. A total of 12 519 patients (30% women) met our inclusion criteria. The incidence of CAD remained stable and was higher for men than women (46-53 versus 18-23 per 100 000). Of patients, 92% had at least one traditional cardiovascular risk factor and 67% had multiple risk factors. The prevalence of diabetes mellitus, obesity, and hypertension increased during the study period and was higher for women. Women had fewer emergent procedures and revascularizations. Mortality rates decreased by 31% between 2000 and 2007, then were stable for the remaining 9 years. Mortality was significantly higher for women aged <45 years compared with men. Conclusions The incidence of premature CAD has not declined, and the prevalence of 3 major cardiovascular risk factors increased between 2000 and 2016. The risk burden and mortality rates were worse for women. These data have important implications for the design of strategies to prevent CAD in young adults.
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Aterosclerosis/epidemiología , Estenosis Coronaria/epidemiología , Diabetes Mellitus/epidemiología , Hipertensión/epidemiología , Mortalidad/tendencias , Obesidad/epidemiología , Adulto , Colombia Británica/epidemiología , Enfermedad de la Arteria Coronaria/epidemiología , Humanos , Incidencia , Persona de Mediana Edad , Factores de Riesgo , Factores SexualesRESUMEN
OBJECTIVE: Transcranial magnetic stimulation (TMS) produces characteristic deflections in the EEG signal named TMS-evoked EEG potentials (TEPs), which can be used to assess drug effects on cortical excitability. TMS can also be used to determine the resting motor threshold (RMT) for eliciting a minimal muscle response, as a biomarker of corticospinal excitability. XEN1101 is a novel potassium channel opener undergoing clinical development for treatment of epilepsy. We used TEPs and RMT to measure the effects of XEN1101 in the human brain, to provide evidence that XEN1101 alters cortical excitability at doses that might be used in future clinical trials. METHODS: TMS measurements were incorporated in this Phase I clinical trial to evaluate the extent to which XEN1101 modulates TMS parameters of cortical and corticospinal excitability. TEPs and RMT were collected before and at 2-, 4-, and 6-hours post drug intake in a double-blind, placebo-controlled, randomized, two-period crossover study of 20 healthy male volunteers. RESULTS: Consistent with previous TMS investigations of antiepileptic drugs (AEDs) targeting ion channels, the amplitude of TEPs occurring at early (15-55 msec after TMS) and at late (150-250 msec after TMS) latencies were significantly suppressed from baseline by 20 mg of XEN1101. Furthermore, the RMT showed a significant time-dependent increase that correlated with the XEN1101 plasma concentration. INTERPRETATION: Changes from baseline in TMS measures provided evidence that 20 mg of XEN1101 suppressed cortical and corticospinal excitability, consistent with the effects of other AEDs. These results support the implementation of TMS as a tool to inform early-stage clinical trials.
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Anticonvulsivantes/farmacología , Excitabilidad Cortical/efectos de los fármacos , Compuestos Orgánicos/farmacología , Adulto , Encéfalo/efectos de los fármacos , Estudios Cruzados , Método Doble Ciego , Electroencefalografía , Potenciales Evocados Motores/efectos de los fármacos , Humanos , Masculino , Estimulación Magnética TranscranealRESUMEN
BACKGROUND: Optimal design of clinical programs for patients with premature atherosclerotic cardiovascular disease (ASCVD) (men aged ≤ 50 years, women aged ≤ 55 years) requires an understanding of their priorities. We aimed to explore patient and family priorities for services in clinical programs. METHODS: We co-designed this study with a Patient Partner Committee using a sequential exploratory mixed-methods design. In Phase I, we conducted semistructured interviews with participants from the Study to Avoid Cardiovascular Events in British Columbia (SAVE BC) (n = 15). In Phase II, we designed a questionnaire based on Phase I data and distributed it to all current SAVE BC participants. We collected close-ended responses (n = 116) and stratified data using participant category (index, family member), age, sex, and number of clinic visits. RESULTS: We identified 4 major priorities for services in clinical programs: social support (weight: 62.6%), patient education (weight: 83.5%), mental health (weight: 50.7%), and lifestyle changes (85.1%). To address these priorities, participants wanted ASCVD clinical programs to enable recruitment of their family members, establish a comprehensive education component (with research updates in research programs), deliver mental health screening and support after myocardial infarction, and provide longitudinal sessions to support maintenance of lifestyle modifications. These services were identified in Phase I and verified in Phase II. CONCLUSION: We identified 4 priorities for services in clinical programs designed for patients with premature ASCVD and their families. Further research should be done to elucidate their outcomes and most effective methods to provide these services.
INTRODUCTION: La conception optimale des programmes cliniques des patients atteints d'une maladie cardiovasculaire athéroscléreuse (ASCVD pour atherosclerotic cardiovascular disease) prématurée (hommes âgés ≤ 50 ans, femmes âgées ≤ 55 ans) exige une compréhension de leurs priorités. Nous avions pour objectif d'examiner les priorités des patients et de leur famille en matière de services dans les programmes cliniques. MÉTHODES: Nous avons conçu la présente étude en collaboration avec le Patient Partner Commitee à l'aide d'un devis séquentiel exploratoire en méthodes mixtes. À la Phase 1, nous avons réalisé des entrevues auprès de participants de la Study to Avoid Cardiovascular Events in British Columbia (SAVE BC) (n = 15). À la Phase II, nous avons conçu un questionnaire en nous basant sur les données de la Phase I et l'avons distribué à tous les participants actuels de la SAVE BC. Nous avons recueilli les réponses fermées (n = 116) et stratifié les données en utilisant la catégorie (indice, membre de la famille), l'âge, le sexe et le nombre de consultations des participants. RÉSULTATS: Nous avons défini les 4 grandes priorités en matière de services dans les programmes cliniques : le soutien social (62,6 %), l'éducation des patients (83,5 %), la santé mentale (50,7 %) et les changements au mode de vie (85,1 %). Pour répondre à ces priorités, les participants voulaient des programmes cliniques sur la ASCVD pour favoriser le recrutement des membres de leur famille, établir un volet d'éducation complet (avec les dernières informations sur les travaux de recherche des programmes de recherche), offrir le dépistage de la santé mentale et le soutien après l'infarctus du myocarde, et offrir des séances longitudinales qui assureront le maintien des modifications au mode de vie. Ces services ont été définis à la Phase I et vérifiés à la Phase II. CONCLUSION: Nous avons défini les 4 priorités en matière de services dans les programmes cliniques conçus pour les patients atteints d'une ASCVD prématurée et leur famille. D'autres recherches devraient être réalisées pour élucider leurs résultats et les méthodes les plus efficaces pour offrir ces services.
RESUMEN
Atherosclerotic cardiovascular disease (ASCVD) is highly heritable, particularly when it occurs at a young age. The screening of individuals with premature ASCVD, although often recommended, is not routinely performed. Strategies to address this gap in care are essential. We designed the Study to Avoid CardioVascular Events in British Columbia (SAVE BC) as a prospective, observational study of individuals with a new diagnosis of very premature ASCVD (defined as age ≤ 50 years in males and age ≤ 55 years in females) and their first-degree relatives (FDRs) and spouses. FDRs and spouses will undergo screening for cardiovascular (CV) risk factors and subclinical ASCVD using a structured screening algorithm. All subjects will be followed longitudinally for ≥10 years. The overall goal of SAVE BC is to evaluate the yield of a structured screening program for identifying individuals at risk of premature ASCVD. The primary objectives of SAVE BC are to identify and follow index cases with very premature ASCVD and their FDRs and to determine the diagnostic yield of a structured screening program for these individuals. We will collect data on CV risk factors, medication use, CV events, and healthcare costs in these individuals. SAVE BC will provide insight regarding approaches to identify individuals at risk for premature ASCVD with implications for prevention and treatment in this population.
Asunto(s)
Enfermedades Cardiovasculares/epidemiología , Tamizaje Masivo/métodos , Medición de Riesgo/métodos , Colombia Británica/epidemiología , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Morbilidad/tendencias , Estudios Prospectivos , Factores de RiesgoRESUMEN
OBJECTIVE: The objective was to evaluate the safety and efficacy of TV-45070 ointment, as a treatment for postherpetic neuralgia, and to explore the response in patients with the Nav1.7 R1150W gain-of-function polymorphism. MATERIALS AND METHODS: This was a randomized, placebo-controlled, 2-period, 2-treatment crossover trial. Patients with postherpetic neuralgia with moderate or greater pain received TV-45070 and placebo ointments, each applied twice daily for 3 weeks. The primary efficacy measure was the difference in change in mean daily pain score from baseline compared with the last week of placebo and active treatment. Secondary endpoints included responder rate analyses and a further exploratory analysis of response in carriers of the Nav1.7 R1150W polymorphism was conducted. RESULTS: Seventy patients were enrolled and 54 completed the study. TV-45070 was safe and well tolerated. No statistical difference was observed between treatments for the primary endpoint. However, the proportion of patients with ≥50% reduction in mean pain scores at week 3 was greater on TV-45070 than on placebo (26.8% vs. 10.7%, P=0.0039). Similarly, a greater proportion of patients on TV-45070 had a ≥30% reduction in mean pain scores at week 3 (39.3% on TV-45070 vs. 23.2% on placebo, P=0.0784). Of note, 63% of patients with the R1150W polymorphism versus 35% of wild-type carriers had a ≥30% reduction in mean pain score on TV-45070 at week 3 (no inferential analysis performed). CONCLUSIONS: The 50% responder analysis suggests a subpopulation may exist with a more marked analgesic response to TV-45070.The trend toward a larger proportion of responders within Nav1.7 R1150W carriers warrants further investigation.
Asunto(s)
Indoles/uso terapéutico , Canal de Sodio Activado por Voltaje NAV1.7/genética , Neuralgia Posherpética/tratamiento farmacológico , Neuralgia Posherpética/genética , Bloqueadores de los Canales de Sodio/uso terapéutico , Compuestos de Espiro/uso terapéutico , Administración Tópica , Estudios Cruzados , Femenino , Genotipo , Humanos , Indoles/efectos adversos , Indoles/sangre , Masculino , Persona de Mediana Edad , Prueba de Estudio Conceptual , Bloqueadores de los Canales de Sodio/efectos adversos , Bloqueadores de los Canales de Sodio/sangre , Compuestos de Espiro/efectos adversos , Compuestos de Espiro/sangre , Resultado del TratamientoRESUMEN
BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically heterogeneous condition caused by mutations in genes encoding desmosomal proteins in up to 60% of cases. The 40% of genotype-negative cases point to the need of identifying novel genetic substrates by studying genotype-negative ARVC families. METHODS AND RESULTS: Whole exome sequencing was performed on 2 cousins with ARVC. Validation of 13 heterozygous variants that survived internal quality and frequency filters was performed by Sanger sequencing. These variants were also genotyped in all family members to establish genotype-phenotype cosegregation. High-resolution melting analysis followed by Sanger sequencing was used to screen for mutations in cadherin 2 (CDH2) gene in unrelated genotype-negative patients with ARVC. In a 3-generation family, we identified by whole exome sequencing a novel mutation in CDH2 (c.686A>C, p.Gln229Pro) that cosegregated with ARVC in affected family members. The CDH2 c.686A>C variant was not present in >200 000 chromosomes available through public databases, which changes a conserved amino acid of cadherin 2 protein and is supported as the causal mutation by parametric linkage analysis. We subsequently screened 73 genotype-negative ARVC probands tested previously for mutations in known ARVC genes and found an additional likely pathogenic variant in CDH2 (c.1219G>A, p.Asp407Asn). CDH2 encodes cadherin 2 (also known as N-cadherin), a protein that plays a vital role in cell adhesion, making it a biologically plausible candidate gene in ARVC pathogenesis. CONCLUSIONS: These data implicate CDH2 mutations as novel genetic causes of ARVC and contribute to a more complete identification of disease genes involved in cardiomyopathy.
Asunto(s)
Antígenos CD/genética , Displasia Ventricular Derecha Arritmogénica/genética , Cadherinas/genética , Exoma , Mutación Missense , Adolescente , Adulto , Sustitución de Aminoácidos , Femenino , Humanos , MasculinoRESUMEN
OBJECTIVE: The association between polymorphisms in candidate genes related to lipoprotein metabolism and the reduction in plasma triglyceride (TG) in response to fenofibrate treatment was evaluated in subjects with type 2 diabetes treated with micronized fenofibrate (200 mg/day) for at least 3 years in the Diabetes Atherosclerosis Intervention Study. METHODS: The cholesteryl ester transfer protein Taq1B, LPL S447X, hepatic lipase -514 C-->T, peroxisome-proliferator-activated receptors alpha (PPARA) L162V and G/C intron 7 polymorphisms and the apolipoprotein E2/E3/E4 alleles were genotyped using PCR and restriction enzyme digestion. Subjects were divided into high TG-responders (with > 30% TG relative reduction after treatment) and low TG-responders. RESULTS: The frequency of the PPARA intron 7 G/G genotype was higher in high TG-responders than in low TG-responders (85% vs. 69%, P < 0.05). There was no significant difference between the percentage of high TG-responders and low TG-responders for any of the other genetic polymorphisms examined. In stepwise logistic regression, baseline TG and only the PPARA intron 7 polymorphism among the others were selected in the model as significant predictors of TG-response (odds ratio: 3.10, 95% CI: 1.28-7.52, P = 0.012 for PPARA polymorphism). With age, gender, body mass index, smoking status and HbA1c as additional factors, baseline TG (P< 0.0001), intron 7 (P = 0.013), body mass index (P = 0.040) and LPL-S447X (P = 0.084) were significant predictors of TG-response. CONCLUSION: These results indicate that elevated baseline TG levels and PPARA gene intron 7 G/G genotype were associated with TG reduction > 30% after fenofibrate treatment in patients with type 2 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Fenofibrato/uso terapéutico , Hipolipemiantes/uso terapéutico , PPAR alfa/genética , Polimorfismo Genético , Apolipoproteína E2 , Apolipoproteínas E/genética , Índice de Masa Corporal , Proteínas Portadoras/sangre , Colesterol/sangre , Proteínas de Transferencia de Ésteres de Colesterol , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Diabetes Mellitus Tipo 2/sangre , Femenino , Fenofibrato/administración & dosificación , Glicoproteínas/sangre , Humanos , Hipolipemiantes/administración & dosificación , Intrones , Lipoproteína Lipasa/sangre , Masculino , Persona de Mediana Edad , Triglicéridos/sangre , Triglicéridos/genética , Población BlancaRESUMEN
Mutations in the SCN9A gene leading to deficiency of its protein product, Na(v)1.7, cause congenital indifference to pain (CIP). CIP is characterized by the absence of the ability to sense pain associated with noxious stimuli. In contrast, the opposite phenotype to CIP, inherited erythromelalgia (IEM), is a disorder of spontaneous pain caused by missense mutations resulting in gain-of-function in Na(v)1.7 that promote neuronal hyperexcitability. The primary aim of this study was to demonstrate that Na(v)1.7 antagonism could alleviate the pain of IEM, thereby demonstrating the utility of this opposite phenotype model as a tool for rapid proof-of-concept for novel analgesics. An exploratory, randomized, double-blind, 2-period crossover study was conducted in 4 SCN9A mutation-proven IEM patients. In each treatment period (2days), separated by a 2-day washout period, patients were orally administered XEN402 (400mg twice daily) or matching placebo. In 3 patients, pain was induced by heat or exercise during each treatment arm. A fourth patient, in constant severe pain, required no induction. Patient-reported outcomes of pain intensity and/or relief were recorded, and the time taken to induce pain was measured. The ability to induce pain in IEM patients was significantly attenuated by XEN402 compared with placebo. XEN402 increased the time to maximal pain induction and significantly reduced the amount of pain (42% less) after induction (P=.014). This pilot study showed that XEN402 blocks Na(v)1.7-mediated pain associated with IEM, thereby demonstrating target engagement in humans and underscoring the use of rare genetic disorders with mutant target channels as a novel approach to rapid proof-of-concept.