Discriminative characteristics of marginalised novel psychoactive users: A transnational study

New psychoactive substances (NPS) continue to be considered as a major public health concern in many European countries. The study was implemented within the framework of a transnational project of six European countries (Germany, Hungary, Ireland, Netherlands, Poland, Portugal). Our aim here is to report on the distinct and differentiating characteristics of marginalised NPS users. Three subgroups of a total of 3023 adult NPS users (socially marginalised, night life, online community) were examined regarding their socio-demographic characteristics, substance use, and external motives towards NPS use. Poland and Hungary reported higher rates of NPS use in comparison to traditional controlled drugs. The external/contextual motives did not play a central role in the background of NPS use, the least important motives were alleged legality and non-detectability of these substances. Marginalised (defined as those accessing low threshold harm reduction services) users’ substance use patterns are different from the other two groups in terms of showing more intense and riskier drug use. The most important variables which contributed to be categorised as a marginalised NPS user were lower level education, being older, having an unfavourable labour market position and using drugs intravenously. Contextual motives did not play a decisive role in being categorised as a marginalised user when drug use pattern was controlled. These identified discriminative features of marginalised drug users should inform policy makers to develop and implement tailor-made interventions targeting this user group to successfully tackle the elevated public health concerns associated with NPS use

Why do people use new psychoactive substances? Development of a new measurement tool in six European countries.

This study was supported by the European Union (New Psychoactive Substances: transnational project on different user groups, user characteristics, extent and patterns of use, market dynamics, and best practices in prevention [HOME/2014/JDRU/AG/DRUG/7077]), the Hungarian National Research, Development and Innovation Office (Grant number: KKP126835; NKFIH1157-8/2019-DT). The study was also supported for the realization of this international cofinanced science project in 2016-2017 by the Polish Ministry of Science and Higher Education. Máté Kapitány-Fövény acknowledges the support by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences and the support by the ÚNKP-19 New National Excellence Program of the Hungarian Ministry for Innovation and Technology. The funding institutions had no role in the study design or the collection, analysis and interpretation of the data, writing the manuscript, or the decision to submit the paper for publication

How and where to find NPS users: a cross national survey among current users of new psychoactive substances.

Use of new psychoactive substances (NPS) across Europe remains a public health challenge. The study describes potentials and limitations of methods in a transnational survey of recent marginalized, nightlife and online community NPS users in Germany, Hungary, Ireland, the Netherlands, Poland and Portugal (n=3023). In terms of demographic profile, drug use history and type of NPS, different methods reached different segments of the NPS-using population. Last year use of different NPS varied across countries and groups. Respondents used NPS in a variety of settings, with public spaces most common in marginalized group. The study suggests that prevalence rates can reveal a picture of the NPS market that significantly deviates from what law enforcement seizures indicate. Outreach in nightlife settings and peer education are recommended to inform users about health risks and to improve access to drug services and care

Biallelic inherited SCN8A variants, a rare cause of SCN8A‐related developmental and epileptic encephalopathy

ObjectiveMonoallelic de novo gain‐of‐function variants in the voltage‐gated sodium channel SCN8A are one of the recurrent causes of severe developmental and epileptic encephalopathy (DEE). In addition, a small number of de novo or inherited monoallelic loss‐of‐function variants have been found in patients with intellectual disability, autism spectrum disorder, or movement disorders. Inherited monoallelic variants causing either gain or loss‐of‐function are also associated with less severe conditions such as benign familial infantile seizures and isolated movement disorders. In all three categories, the affected individuals are heterozygous for a SCN8A variant in combination with a wild‐type allele. In the present study, we describe two unusual families with severely affected individuals who inherited biallelic variants of SCN8A.MethodsWe identified two families with biallelic SCN8A variants by diagnostic gene panel sequencing. Functional analysis of the variants was performed using voltage clamp recordings from transfected ND7/23 cells.ResultsWe identified three probands from two unrelated families with DEE due to biallelic SCN8A variants. Each parent of an affected individual carried a single heterozygous SCN8A variant and exhibited mild cognitive impairment without seizures. In both families, functional analysis demonstrated segregation of one allele with complete loss‐of‐function, and one allele with altered biophysical properties consistent with partial loss‐of‐function.SignificanceThese studies demonstrate that SCN8A DEE may, in rare cases, result from inheritance of two variants, both of which exhibit reduced channel activity. In these families, heterozygosity for the dominant variants results in less severe disease than biallelic inheritance of two variant alleles. The clinical consequences of variants with partial and complete loss of SCN8A function are variable and likely to be influenced by genetic background.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153117/1/epi16371_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153117/2/epi16371.pd

PEDIA: prioritization of exome data by image analysis

Purpose Phenotype information is crucial for the interpretation of genomic variants. So far it has only been accessible for bioinformatics workflows after encoding into clinical terms by expert dysmorphologists. Methods Here, we introduce an approach driven by artificial intelligence that uses portrait photographs for the interpretation of clinical exome data. We measured the value added by computer-assisted image analysis to the diagnostic yield on a cohort consisting of 679 individuals with 105 different monogenic disorders. For each case in the cohort we compiled frontal photos, clinical features, and the disease-causing variants, and simulated multiple exomes of different ethnic backgrounds. Results The additional use of similarity scores from computer-assisted analysis of frontal photos improved the top 1 accuracy rate by more than 20–89% and the top 10 accuracy rate by more than 5–99% for the disease-causing gene. Conclusion Image analysis by deep-learning algorithms can be used to quantify the phenotypic similarity (PP4 criterion of the American College of Medical Genetics and Genomics guidelines) and to advance the performance of bioinformatics pipelines for exome analysis

Health and social problems associated with recent Novel Psychoactive Substance (NPS) use amongst marginalised, nightlife and online users in six European countries.

Continued diversification and use of new psychoactive substances (NPS) across Europe remains a public health challenge. The study describes health and social consequences of recent NPS use as reported in a survey of marginalised, nightlife and online NPS users in the Netherlands, Hungary, Portugal, Ireland, Germany and Poland (n = 3023). Some respondents were unable to categorise NPS they had used. Use of ‘herbal blends’ and ‘synthetic cannabinoids obtained pure’ was most reported in Germany, Poland and Hungary, and use of ‘branded stimulants’ and ‘stimulants/empathogens/nootropics obtained pure’ was most reported in the Netherlands. Increased heart rate and palpitation, dizziness, anxiety, horror trips and headaches were most commonly reported acute side effects. Marginalised users reported substantially more acute side effects, more mid- and long-term mental and physical problems, and more social problems. Development of country-specific NPS awareness raising initiatives, health and social service needs assessments, and targeted responses are warranted

The Sail-Backed Reptile Ctenosauriscus from the Latest Early Triassic of Germany and the Timing and Biogeography of the Early Archosaur Radiation

Background Archosaurs (birds, crocodilians and their extinct relatives including dinosaurs) dominated Mesozoic continental ecosystems from the Late Triassic onwards, and still form a major component of modern ecosystems (>10,000 species). The earliest diverse archosaur faunal assemblages are known from the Middle Triassic (c. 244 Ma), implying that the archosaur radiation began in the Early Triassic (252.3–247.2 Ma). Understanding of this radiation is currently limited by the poor early fossil record of the group in terms of skeletal remains. Methodology/Principal Findings We redescribe the anatomy and stratigraphic position of the type specimen of Ctenosauriscus koeneni (Huene), a sail-backed reptile from the Early Triassic (late Olenekian) Solling Formation of northern Germany that potentially represents the oldest known archosaur. We critically discuss previous biomechanical work on the ‘sail’ of Ctenosauriscus, which is formed by a series of elongated neural spines. In addition, we describe Ctenosauriscus-like postcranial material from the earliest Middle Triassic (early Anisian) Röt Formation of Waldhaus, southwestern Germany. Finally, we review the spatial and temporal distribution of the earliest archosaur fossils and their implications for understanding the dynamics of the archosaur radiation. Conclusions/Significance Comprehensive numerical phylogenetic analyses demonstrate that both Ctenosauriscus and the Waldhaus taxon are members of a monophyletic grouping of poposauroid archosaurs, Ctenosauriscidae, characterised by greatly elongated neural spines in the posterior cervical to anterior caudal vertebrae. The earliest archosaurs, including Ctenosauriscus, appear in the body fossil record just prior to the Olenekian/Anisian boundary (c. 248 Ma), less than 5 million years after the Permian–Triassic mass extinction. These earliest archosaur assemblages are dominated by ctenosauriscids, which were broadly distributed across northern Pangea and which appear to have been the first global radiation of archosaurs

Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism

ANKRD17 is an ankyrin repeat-containing protein thought to play a role in cell cycle progression, whose ortholog in Drosophila functions in the Hippo pathway as a co-factor of Yorkie. Here, we delineate a neurodevelopmental disorder caused by de novo heterozygous ANKRD17 variants. The mutational spectrum of this cohort of 34 individuals from 32 families is highly suggestive of haploinsufficiency as the underlying mechanism of disease, with 21 truncating or essential splice site variants, 9 missense variants, 1 in-frame insertion-deletion, and 1 microdeletion (1.16 Mb). Consequently, our data indicate that loss of ANKRD17 is likely the main cause of phenotypes previously associated with large multi-gene chromosomal aberrations of the 4q13.3 region. Protein modeling suggests that most of the missense variants disrupt the stability of the ankyrin repeats through alteration of core structural residues. The major phenotypic characteristic of our cohort is a variable degree of developmental delay/intellectual disability, particularly affecting speech, while additional features include growth failure, feeding difficulties, non-specific MRI abnormalities, epilepsy and/or abnormal EEG, predisposition to recurrent infections (mostly bacterial), ophthalmological abnormalities, gait/balance disturbance, and joint hypermobility. Moreover, many individuals shared similar dysmorphic facial features. Analysis of single-cell RNA-seq data from the developing human telencephalon indicated ANKRD17 expression at multiple stages of neurogenesis, adding further evidence to the assertion that damaging ANKRD17 variants cause a neurodevelopmental disorder.Neurolog