Ultra-Rare Genetic Variation in the Epilepsies : A Whole-Exome Sequencing Study of 17,606 Individuals

Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABA(A) receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNAIG, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.Peer reviewe

Taming the terminological tempest in invasion science

Standardised terminology in science is important for clarity of interpretation and communication. In invasion science – a dynamic and rapidly evolving discipline – the proliferation of technical terminology has lacked a standardised framework for its development. The result is a convoluted and inconsistent usage of terminology, with various discrepancies in descriptions of damage and interventions. A standardised framework is therefore needed for a clear, universally applicable, and consistent terminology to promote more effective communication across researchers, stakeholders, and policymakers. Inconsistencies in terminology stem from the exponential increase in scientific publications on the patterns and processes of biological invasions authored by experts from various disciplines and countries since the 1990s, as well as publications by legislators and policymakers focusing on practical applications, regulations, and management of resources. Aligning and standardising terminology across stakeholders remains a challenge in invasion science. Here, we review and evaluate the multiple terms used in invasion science (e.g. ‘non-native’, ‘alien’, ‘invasive’ or ‘invader’, ‘exotic’, ‘non-indigenous’, ‘naturalised’, ‘pest’) to propose a more simplified and standardised terminology. The streamlined framework we propose and translate into 28 other languages is based on the terms (i) ‘non-native’, denoting species transported beyond their natural biogeographic range, (ii) ‘established non-native’, i.e. those non-native species that have established self-sustaining populations in their new location(s) in the wild, and (iii) ‘invasive non-native’ – populations of established non-native species that have recently spread or are spreading rapidly in their invaded range actively or passively with or without human mediation. We also highlight the importance of conceptualising ‘spread’ for classifying invasiveness and ‘impact’ for management. Finally, we propose a protocol for classifying populations based on (i) dispersal mechanism, (ii) species origin, (iii) population status, and (iv) impact. Collectively and without introducing new terminology, the framework that we present aims to facilitate effective communication and collaboration in invasion science and management of non-native species

Taming the terminological tempest in invasion science

Standardized terminology in science is important for clarity of interpretation and communication. In invasion science — a dynamic and quickly evolving discipline — the rapid proliferation of technical terminology has lacked a standardized framework for its language development. The result is a convoluted and inconsistent usage of terminology, with various discrepancies in descriptions of damages and interventions. A standardized framework is therefore needed for a clear, universally applicable, and consistent terminology to promote more effective communication across researchers, stakeholders, and policymakers. Inconsistencies in terminology stem from the exponential increase in scientific publications on the patterns and processes of biological invasions authored by experts from various disciplines and countries since the 1990s, as well as publications by legislators and policymakers focusing on practical applications, regulations, and management of resources. Aligning and standardizing terminology across stakeholders remains a prevailing challenge in invasion science. Here, we review and evaluate the multiple terms used in invasion science (e.g. 'non-native', 'alien', 'invasive' or 'invader', 'exotic', 'non-indigenous', 'naturalized, 'pest') to propose a more simplified and standardized terminology. The streamlined framework we propose and translate into 28 other languages is based on the terms (i) 'non-native', denoting species transported beyond their natural biogeographic range, (ii) 'established non-native', i.e. those non-native species that have established self-sustaining populations in their new location(s) in the wild, and (iii) 'invasive non-native' — populations of established non-native species that have recently spread or are spreading rapidly in their invaded range actively or passively with or without human mediation. We also highlight the importance of conceptualizing 'spread' for classifying invasiveness and 'impact' for management. Finally, we propose a protocol for classifying populations based on (1) dispersal mechanism, (2) species origin, (3) population status, and (4) impact. Collectively and without introducing new terminology, the framework that we present aims to facilitate effective communication and collaboration in invasion science and management of non-native species

Can feeling of incomplete bladder emptying reflect significant postvoid residual urine? Is it reliable as a symptom solely?

PURPOSE: The main objective of this study was to reveal the relationship between lower urinary tract symptoms (LUTS) and post-void residual (PVR) urine volume. MATERIALS AND METHODS: Between October 2014 and February 2015, older than 40 years patients were included in this study. Volunteers filled out a questionnaire consisted of demographic characteristics, comorbidities, medications, history of surgery and LUTS. Volunteers were undergone PVR measurement with transabdominal ultrasonography. The relationship between symptoms, demographic characteristics and PVR were analyzed. RESULTS: A total of 939 patients (756 men and 183 women) were enrolled in this study. There was a positive correlation between the sensation of incomplete bladder emptying and PVR volume in all age groups of women (p=0.0001). However such a relationship was found only over the age of 60 in the subgroup analysis of men (p=0.001). PVR volume increased in men by age (0.65 mL per year of age, p=0.011). In men, voiding symptoms and urgency were associated with a high PVR volume. In women, storage and voiding symptoms (except slow stream and terminal dribble) did not correlate with PVR volume. CONCLUSIONS: Our study showed that all men over the age of 60 years and all women with the complaint of feeling of incomplete emptying should undergone PVR measurement. Women with the complaint of poor stream and men mainly with voiding symptoms are other candidates in whom PVR measurement would be considered as an important tool in the clinical management and follow-up

Prognostic implications of aquaporin-4 antibody status in neuromyelitis optica patients.

Neuromyelitis optica (NMO) is an inflammatory/demyelinating disorder predominantly affecting the optic nerves and spinal cord. Recent findings showed an underlying humoral abnormality in NMO, characterized by a serum antibody against aquaporin-4 (Aqp-4-Ab). In this study, we evaluated the Aqp-4-Ab status among Turkish patients with NMO to determine the clinical and prognostic relevance. Serum samples from 35 consecutive patients with NMO followed at a single center and diagnosed according to the 2006 revised criteria, were evaluated for Aqp-4-Ab. All samples were obtained during a relapse prior to any immunosuppressive treatment. Aqp-4-Ab was positive in 21/35 (60%) patients. Among these cases, 11 had an EDSS of 6.0 or more, whereas only two patients in the seronegative group had such severe disability (p < 0.05). Overall, seropositive cases had a mean EDSS score of 5.1 ± 2.2 compared with 3.5 ± 1.7 in seronegative cases (p < 0.01). There were trends towards female predominance in seropositive cases and a monophasic course predominance in seronegative cases. Disease duration, age at onset, number of attacks and time to definite NMO did not differ between groups. Our findings in this single-center cohort suggest that the presence of Aqp-4-Ab might have a prognostic significance indicating a more severe disease course

Pregnancy management and outcome in patients with four different tetrahydrobiopterin disorders

IntroductionInborn errors of tetrahydrobiopterin (BH4) biosynthesis or recycling are a group of very rare neurometabolic diseases. Following growing awareness and improved availability of drug treatment the number of patients with BH4 disorders reaching adulthood is constantly increasing. Pregnancy care of patients with these disorders is therefore a new challenge for clinicians.MethodsThis retrospective study summarises for the first time clinical and biochemical monitoring data of 16 pregnancies in seven women with different disorders of BH4 metabolism and evaluates treatment regimens before and during pregnancy in relation to the obstetrical outcome and paediatric follow-up.ResultsWorsening of pre-existing neurological symptoms or occurrence of new symptoms during pregnancy was not observed in most of the cases. Treatment regimens remained mostly unchanged. Pregnancies were not complicated by disease-specific features. Organ abnormalities, miscarriage, prematurity, IUGR and chromosomal changes were occasionally reported, without showing any association with the standard drug treatment for BH4 deficiencies.ConclusionAlthough our data on 16 pregnancies in seven patients did notpresent any association of standard drug treatment with an increased rate of pregnancy complications, abnormal obstetrical or paediatric outcome, an intensive clinical and biochemical supervision by a multidisciplinary team before, during and after the pregnancy in any BH4 deficiency is essential since available data on pregnancies in patients with BH4 deficiencies is limited

The region that isn't: China, Russia and the failure of regional integration in Central Asia

The failure of regionalism in Central Asia is a puzzle. Whereas almost all world regions have seen a rise of regional organisations since the end of the Cold War, attempts to establish durable regional cooperation among Kazakhstan, Kyrgyzstan, Tajikistan, Turkmenistan and Uzbekistan proofed unsuccessful. Although some of the Central Asian countries participate in wider regional organisations like the Eurasian Economic Union (EAEU) and the Shanghai Cooperation Organisation (SCO), the genuine Central Asian Cooperation Organisation (CACO) was dissolved in 2005. Given the cultural, economic and political similarities between the five Central Asian countries, this lack of a regional organisation is surprising. In contrast to previous work, this paper argues that the failure of regionalism in Central Asia is not so much due to domestic political factors, but more to the extra-regional economic dependence of the regional economies and the impact of external powers within Central Asia. Challenged by the rise of China, Russia uses the EAEU in order to preserve its hegemonic influence over the former Soviet Republics. By joining the Russian dominated EAEU, Central Asia’s regional power Kazakhstan enjoys economic benefits which outweigh the potential gains of Central Asian cooperation within CACO by far. Consequently, Kazakhstan follows its extra-regional interests in closer cooperation with Russia at the cost of regional cooperation with its Central Asian neighbours. As a result, the Central Asian countries are unable to build up a unified regional block in relation to extra-regional powers like China or Russia