Evaluation of the concomitant use of prophylactic treatments in patients with migraine under anti-calcitonin gene-related peptide therapies: The PREVENAC study.

BACKGROUND AND PURPOSE: Anti-calcitonin gene-related peptide (CGRP) therapies are recent preventive therapies approved for both episodic and chronic migraine. One of the measures of effectiveness is the withdrawal of other preventive treatments. The objective of this study is to quantify the impact of anti-CGRP drugs in concomitant preventive treatment in patients with migraine. METHODS: This was an observational, retrospective, multicenter cohort study with patients from nine national headache units. Patients with migraine undergoing treatment for at least 6 months with anti-CGRP antibodies, who were initially associated with some preventive treatment (oral and/or onabotulinumtoxinA) were included. Demographic and clinical variables were collected, as well as variables related to headache. Differences according to withdrawal or nonwithdrawal were evaluated. RESULTS: A total of 408 patients were included, 86.52% women, 48.79 (SD = 1.46) years old. Preventive treatment was withdrawn in 43.87% (179/408), 20.83% partially and 23.04% totally. In 27.45% (112/408), it was maintained exclusively due to comorbidity and in 28.6% (117/408) due to partial efficacy. The most frequent time of withdrawal was between 3 and 5 months after the start of treatment. The baseline characteristics associated with nonwithdrawal were comorbidities: insomnia, hypertension and obesity, chronic migraine, and medication overuse. In the multivariate analysis, the absence of high blood pressure, a greater number of preventive treatments at the start, and a lower number of migraine days/month after anti-CGRP treatment were independently associated with withdrawal of the treatment (p < 0.05). CONCLUSIONS: Anti-CGRP antibodies allow the withdrawal of associated preventive treatment in a significant percentage of patients, which supports its effectiveness in real-life conditions.

Identifying susceptibility genes for primary ovarian insufficiency on the high-risk genetic background of a fragile X premutation.

OBJECTIVE: To identify modifying genes that explains the risk of fragile X-associated primary ovarian insufficiency (FXPOI). DESIGN: Gene-based, case/control association study, followed by a functional screen of highly ranked genes using a Drosophila model. SETTING: Participants were recruited from academic and clinical settings. PATIENT(S): Women with a premutation (PM) who experienced FXPOI at the age of 35 years or younger (n = 63) and women with a PM who experienced menopause at the age of 50 years or older (n = 51) provided clinical information and a deoxyribonucleic acid sample for whole genome sequencing. The functional screen was on the basis of Drosophila TRiP lines. INTERVENTION(S): Clinical information and a DNA sample were collected for whole genome sequencing. MAIN OUTCOME MEASURES: A polygenic risk score derived from common variants associated with natural age at menopause was calculated and associated with the risk of FXPOI. Genes associated with the risk of FXPOI were identified on the basis of the P-value from gene-based association test and an altered level of fecundity when knocked down in the Drosophila PM model. RESULTS: The polygenic risk score on the basis of common variants associated with natural age at menopause explained approximately 8% of the variance in the risk of FXPOI. Further, SUMO1 and KRR1 were identified as possible modifying genes associated with the risk of FXPOI on the basis of an untargeted gene analysis of rare variants. CONCLUSIONS: In addition to the large genetic effect of a PM on ovarian function, the additive effects of common variants associated with natural age at menopause and the effect of rare modifying variants appear to play a role in FXPOI risk.

Identifying genetic factors that contribute to the increased risk of congenital heart defects in infants with Down syndrome.

Atrioventricular septal defects (AVSD) are a severe congenital heart defect present in individuals with Down syndrome (DS) at a > 2000-fold increased prevalence compared to the general population. This study aimed to identify risk-associated genes and pathways and to examine a potential polygenic contribution to AVSD in DS. We analyzed a total cohort of 702 individuals with DS with or without AVSD, with genomic data from whole exome sequencing, whole genome sequencing, and/or array-based imputation. We utilized sequence kernel association testing and polygenic risk score (PRS) methods to examine rare and common variants. Our findings suggest that the Notch pathway, particularly NOTCH4, as well as genes involved in the ciliome including CEP290 may play a role in AVSD in DS. These pathways have also been implicated in DS-associated AVSD in prior studies. A polygenic component for AVSD in DS has not been examined previously. Using weights based on the largest genome-wide association study of congenital heart defects available (2594 cases and 5159 controls; all general population samples), we found PRS to be associated with AVSD with odds ratios ranging from 1.2 to 1.3 per standard deviation increase in PRS and corresponding liability r2 values of approximately 1%, suggesting at least a small polygenic contribution to DS-associated AVSD. Future studies with larger sample sizes will improve identification and quantification of genetic contributions to AVSD in DS.

Bystro: rapid online variant annotation and natural-language filtering at whole-genome scale.

Accurately selecting relevant alleles in large sequencing experiments remains technically challenging. Bystro ( https://bystro.io/ ) is the first online, cloud-based application that makes variant annotation and filtering accessible to all researchers for terabyte-sized whole-genome experiments containing thousands of samples. Its key innovation is a general-purpose, natural-language search engine that enables users to identify and export alleles and samples of interest in milliseconds. The search engine dramatically simplifies complex filtering tasks that previously required programming experience or specialty command-line programs. Critically, Bystro's annotation and filtering capabilities are orders of magnitude faster than previous solutions, saving weeks of processing time for large experiments.

Stress transient hypertrophic cardiomyopathy and B-type natriuretic peptide role.

This report describes a transient hypertrophic cardiomyopathy with right-ventricle outlet tract obstruction (RVOTO) induced by perinatal stress due to a major surgical procedure in a female newborn with congenital abnormalities. On day 10, she presented with heart failure, abnormal B-type natriuretic peptide (BNP), and an echocardiogram showing normal wall thickness. An in-hospital follow-up echocardiogram showed biventricular hypertrophy and RVOTO. At discharge, the infant was asymptomatic, with a normal echocardiogram and BNP. Transient RVOTO triggered by surgical stress and abnormal BNP have not been reported previously. Pathophysiology, the role of BNP, and clinical characteristics are discussed.

Dominant ionic mechanisms explored in spiking and bursting using local low-dimensional reductions of a biophysically realistic model neuron.

The large number of variables involved in many biophysical models can conceal potentially simple dynamical mechanisms governing the properties of its solutions and the transitions between them as parameters are varied. To address this issue, we extend a novel model reduction method, based on "scales of dominance," to multi-compartment models. We use this method to systematically reduce the dimension of a two-compartment conductance-based model of a crustacean pyloric dilator (PD) neuron that exhibits distinct modes of oscillation--tonic spiking, intermediate bursting and strong bursting. We divide trajectories into intervals dominated by a smaller number of variables, resulting in a locally reduced hybrid model whose dimension varies between two and six in different temporal regimes. The reduced model exhibits the same modes of oscillation as the 16 dimensional model over a comparable parameter range, and requires fewer ad hoc simplifications than a more traditional reduction to a single, globally valid model. The hybrid model highlights low-dimensional organizing structure in the dynamics of the PD neuron, and the dependence of its oscillations on parameters such as the maximal conductances of calcium currents. Our technique could be used to build hybrid low-dimensional models from any large multi-compartment conductance-based model in order to analyze the interactions between different modes of activity.

Computational model of electrically coupled, intrinsically distinct pacemaker neurons.

Electrical coupling between neurons with similar properties is often studied. Nonetheless, the role of electrical coupling between neurons with widely different intrinsic properties also occurs, but is less well understood. Inspired by the pacemaker group of the crustacean pyloric network, we developed a multicompartment, conductance-based model of a small network of intrinsically distinct, electrically coupled neurons. In the pyloric network, a small intrinsically bursting neuron, through gap junctions, drives 2 larger, tonically spiking neurons to reliably burst in-phase with it. Each model neuron has 2 compartments, one responsible for spike generation and the other for producing a slow, large-amplitude oscillation. We illustrate how these compartments interact and determine the dynamics of the model neurons. Our model captures the dynamic oscillation range measured from the isolated and coupled biological neurons. At the network level, we explore the range of coupling strengths for which synchronous bursting oscillations are possible. The spatial segregation of ionic currents significantly enhances the ability of the 2 neurons to burst synchronously, and the oscillation range of the model pacemaker network depends not only on the strength of the electrical synapse but also on the identity of the neuron receiving inputs. We also compare the activity of the electrically coupled, distinct neurons with that of a network of coupled identical bursting neurons. For small to moderate coupling strengths, the network of identical elements, when receiving asymmetrical inputs, can have a smaller dynamic range of oscillation than that of its constituent neurons in isolation.