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Family members carrying the same SCN1A variant often exhibit differences in the clinical severity of epilepsy. This variable expressivity suggests that other factors aside from the primary sodium channel variant influence the clinical manifestation. However, identifying such factors has proven challenging in humans.We perform whole exome sequencing (WES) in a large family in which an SCN1A variant (p.K1372E) is segregating that is associated with a broad spectrum of phenotypes ranging from lack of epilepsy, to febrile seizures and absence seizures, to Dravet syndrome. We assessed the hypothesis that the severity of the SCN1A-related phenotype was affected by alternate alleles at a modifier locus (or loci).One of our top candidates identified by WES was a second variant in the SCN1A gene (p.L375S) that was shared exclusively by unaffected carriers of the K1372E allele. To test the hypothesized that L375S variant nullifies the loss-of-function effect of K1372E, we transiently expressed Nav1.1 carrying the two variants in HEK293T cells and compared their biophysical properties with the wild-type (WT) variant, and then co-expressed WT with K1372E or L375S with K1372E in equal quantity and tested the functional consequence. The data demonstrated that co-expression of the L375S and K1372E alleles reversed the loss-of-function property brought by the K1372E variant, whereas WT-K1372E co-expression remained partial loss-of-function.These results support the hypothesis that L375S counteracts the loss-of-function effect of K1372E such that individuals carrying both alleles in trans do not present epilepsy-related symptoms. We demonstrate that monogenic epilepsies with wide expressivity can be modified by additional variants in the disease gene, providing a novel framework for the gene-phenotype relationship in genetic epilepsies.

Understanding the precise genetic -basis of disease is one of the critical developments in medicine in the twenty-first century. Genetic testing has revolutionized the diagnosis and treatment of neurological diseases in children. Whole-genome and whole-exome sequencing have particularly been useful in understanding the genetic basis of childhood epileptic encephalopathies characterized by early-onset seizures with significant developmental impairment and regression. In this review we describe the identification of a new epileptic encephalopathy caused by a de novo mutation in the SCN8A gene, which encodes for NaV1.6, a vital sodium channel in the central nervous system. SCN8A variants in patients with epilepsy result primarily in gain-of-function in Nav1.6 and hyperexcitability of neurons in the central nervous system. Following the original discovery in 2012 of a de novo mutation in a child with developmental and epileptic encephalopathy (DEE), more than 400 individuals with SCN8A-related disorders have been identified. Clinical manifestations range from movement disorders or intellectual disability only to severe DEE, which includes epileptic encephalopathy with intractable multivariate seizure types, developmental impairment and regression, intellectual disability, and other neurological manifestations. Gain-of-function of the Nav1.6 channel predicts effectiveness of sodium channel-blocking agents in the treatment of seizures, which has been corroborated by clinical experience. Nevertheless, treatment options remain limited and adverse effects are common. However, with the availability of a growing database of genetic and clinical data along with transfected cell lines and mouse models, more efficacious, targeted, and selective treatments may soon be feasible.

The human microbiome is strongly interwoven with human health and disease. Besides bacteria, viruses and eukaryotes, numerous archaea are located in the human gastrointestinal tract and are responsible for methane production, which can be measured in clinical methane breath analyses. Methane is an important readout for various diseases, including intestinal methanogen overgrowth. Notably, the archaea responsible for methane production are largely overlooked in human microbiome studies due to their non-bacterial biology and resulting detection issues. As such, their importance for health and disease remains largely unclear to date, in particular as not a single archaeal representative has been deemed to be pathogenic. In this Perspective, we discuss the current knowledge on the clinical relevance of methanogenic archaea. We explain the archaeal unique response to antibiotics and their negative and positive effects on human physiology, and present the current understanding of the use of methane as a diagnostic marker.

INTRODUCTION: 13 C-breath tests are valuable, noninvasive diagnostic tests that can be widely applied for the assessment of gastroenterological symptoms and diseases. Currently, the potential of these tests is compromised by a lack of standardization regarding performance and interpretation among expert centers. METHODS: This consensus-based clinical practice guideline defines the clinical indications, performance, and interpretation of 13 C-breath tests in adult and pediatric patients. A balance between scientific evidence and clinical experience was achieved by a Delphi consensus that involved 43 experts from 18 European countries. Consensus on individual statements and recommendations was established if ≥ 80% of reviewers agreed and

The digital era offers many opportunities to the wind energy industry and research community and digitalisation is one of the key drivers for reducing project costs and risks. The WeDoWind framework has been developed in order to address one of the main challenges to a successful exploitation of digitalisation in wind energy - data sharing and collaboration. The main innovation of this framework is the way it creates tangible incentives to motivate different types of people to actually share data and knowledge in practice. In this work, we carry out a detailed analysis of the strengths and weaknesses of the WeDoWind framework based on a survey filled out by participants of two use case studies and observations from the WeDoWind development team. The results show that the framework successfully enhances collaboration and data sharing in the sector. The results allowed a set of practical data sharing recommendations for the wind energy sector to be developed, which are being continuously improved based on our experience with the WeDoWind framework. They can be applied by anyone wishing to share data effectively and efficiently.

Background and ObjectivesPathogenic variants at the voltage-gated sodium channel gene,SCN8A, are associated with a wide spectrum of clinical disease outcomes. A critical challenge for neurologists is to determine whether patients carry gain-of-function (GOF) or loss-of-function (LOF) variants to guide treatment decisions, yet in vitro studies to infer channel function are often not feasible in the clinic. In this study, we develop a predictive modeling approach to classify variants based on clinical features present at initial diagnosis.MethodsWe performed an exhaustive search for individuals deemed to carry SCN8A GOF and LOF variants by means of in vitro studies in heterologous cell systems, or because the variant was classified as truncating, and recorded clinical features. This resulted in a total of 69 LOF variants: 34 missense and 35 truncating variants, including 9 nonsense, 13 frameshift, 6 splice site, 6 indels, and 1 large deletion. We then assembled a truth set of variants with known functional effects, excluding individuals carrying variants at other loci associated with epilepsy. We then trained a predictive model based on random forest using this truth set of 45 LOF variants and 45 GOF variants randomly selected from a set of variants tested by in vitro methods.ResultsPhenotypic categories assigned to individuals correlated strongly with GOF or LOF variants. All patients with GOF variants experienced early-onset seizures (mean age at onset = 4.5 ± 3.1 months) while only 64.4% patients with LOF variants had seizures, most of which were late-onset absence seizures (mean age at onset = 40.0 ± 38.1 months). With high accuracy (95.4%), our model including 5 key clinical features classified individuals with GOF and LOF variants into 2 distinct cohorts differing in age at seizure onset, development of seizures, seizure type, intellectual disability, and developmental and epileptic encephalopathy.DiscussionThe results support the hypothesis that patients withSCN8AGOF and LOF variants represent distinct clinical phenotypes. The clinical model developed in this study has great utility because it provides a rapid and highly accurate platform for predicting the functional class of patient variants duringSCN8Adiagnosis, which can aid in initial treatment decisions and improve prognosis.

Nonnative invasive plant species are a major cause of ecosystem degradation and impairment of ecosystem service benefits in the United States. Forested riparian areas provide many ecosystem service benefits and are vital to maintaining water quality of streams and rivers. These systems are also vulnerable to natural disturbances and invasion by nonnative plants. We assessed whether planting native trees on disturbed riparian sites may increase biotic resistance to invasive plant establishment in central Vermont in the northeastern United States. The density (stems per square meter) of invasive stems was higher in non-planted sites (x̄ = 4.1 stems m−2) compared with planted sites (x̄ = 1.3 stems m−2). More than 90% of the invasive plants were Japanese knotweed [Fallopia japonica (Houtt.) Ronse Decr.; syn. Polygonum cuspidatum Siebold & Zucc.]. There were no significant differences in total stem density of native vegetation between planted and non-planted sites. Other measured response variables such as native tree regeneration, species diversity, soil properties, and soil function showed no significant differences or trends in the paired riparian study sites. The results of this case study indicate that tree planting in disturbed riparian forest areas may assist conservation efforts by minimizing the risk of invasive plant colonization.

Background: Chronic diarrhea is defined as more than 3 bowel movements per day, or loose stools, or stool weight >200 g/day for at least 4 weeks. Accompanying symptoms may include urgency, abdominal pain, or cramps. Summary: A number of causes have to be considered, including inflammatory, neoplastic, malabsorptive, infective, vascular, and functional gastrointestinal diseases. Other causes include food intolerances, side effects of drugs, or postsurgical conditions. Diarrhea may also be symptom of a systemic disease, like diabetes or hyperthyroidism. Special patient groups, like the very elderly and immunocompromised patients, pose special challenges. This review follows a question-answer style and addresses questions raised on the intersection of primary and secondary care. What do you mean by diarrhea? Why is it important to distinguish between acute or chronic diarrhea? How shall the patient with chronic diarrhea be approached? How can history and physical exam help? How can routine laboratory tests help in categorizing diarrhea? Which additional laboratory tests may be helpful? How to proceed in undiagnosed or intractable diarrhea? What are the treatment options in patients with chronic diarrhea? Key Messages: Acute diarrhea is usually of infectious origin with the main treatment goal of preventing water and electrolyte disturbances. Chronic diarrhea is usually not of infectious origin and may be the symptom of a large number of gastrointestinal and general diseases or drug side effects. In undiagnosed or intractable diarrhea, the question shall be raised whether the appropriate tests have been performed and interpreted correctly.

Introduction: The development of a clinical guideline is a challenging process. National and international organizations have established a variety of approaches, grading systems, evaluation scales, and voting modes; however, a practical description which illustrates all steps from starting the initiative to publication and dissemination of the guideline is usually not provided. We describe a structured guideline procedure that can be adjusted to the requirements of other multinational guidelines. Methods: A group of European specialist gastroenterological societies and national societies initiated a guideline for the use of breath tests in gastroenterology. A balance between scientific evidence and clinical experience was achieved by involving European specialist societies and physicians from 18 European countries. For persons contributing to the guideline process, different levels of involvement were defined. The tasks were assigned to different groups of persons, which formed scientific institutions. Results: We describe organizational structures and institutions, the stepwise approach, and illustrate the multistep guideline development procedure in a flowchart diagram that shows workflow and assigned responsibilities and provides details for the execution of each step, including timelines. The process is split into 4 phases: foundation, preparation, voting, and publication. Discussion: This structured procedure of a gastroenterological clinical practice guideline can serve as a blueprint for future multinational guideline initiatives and may aid future attempts to standardize and harmonize guideline development processes in gastroenterology and in other medical fields. Although the described procedure is for a diagnostic guideline, it may also be appropriate for therapeutic guidelines by adjusting the acceptance criteria for recommendations.

OBJECTIVES Carbohydrate intolerances may affect a majority of the worlds-population but there is no validated, test-specific assessment of carbohydrate-induced symptoms during breath tests. We aimed to develop and validate a questionnaire for evaluation and quantification of carbohydrate intolerance. METHODS A visual analog scale-questionnaire with five complaints (pain, nausea, bloating, flatulence, and diarrhea) was designed. The time frame of symptoms was 'current' (for baseline symptoms) and 'since filling out the last questionnaire'. Validity was determined in focus-group style interviews and during breath tests in an original (n = 342) and follow-up patient groups (n = 338). RESULTS The questionnaire had good face validity, content validity ratio according to Lawshe was 1. Intraclass correlation coefficients (n = 195; 30-min' interval) demonstrated excellent reliability (P

It is hypothesized that the heat transfer in microgravity bubbly flow boiling can be computed through a single-flow simulation that accounts for the acceleration of the liquid as bubbles form since...

Aims To compare diabetes patients with hyperglycaemic hyperosmolar state (HHS), diabetic ketoacidosis (DKA), and patients without decompensation (ND). Methods In total, 500,973 patients with type 1 or type 2 diabetes of all ages registered in the diabetes patient follow-up (DPV) were included. Analysis was stratified by age (≤ / > 20 years) and by manifestation/follow-up. Patients were categorized into three groups: HHS or DKA—during follow-up according to the most recent episode—or ND. Results At onset of diabetes, HHS criteria were met by 345 (68.4% T1D) and DKA by 9824 (97.6% T1D) patients. DKA patients had a lower BMI(-SDS) in both diabetes types compared to ND. HbA1c was higher in HHS/DKA. During follow-up, HHS occurred in 1451 (42.2% T1D) and DKA in 8389 patients (76.7% T1D). In paediatric T1D, HHS/DKA was associated with younger age, depression, and dyslipidemia. Pump usage was less frequent in DKA patients. In adult T1D/T2D subjects, metabolic control was worse in patients with HHS/DKA. HHS and DKA were also associated with excessive alcohol intake, dementia, stroke, chronic kidney disease, and depression. Conclusions HHS/DKA occurred mostly in T1D and younger patients. However, both also occurred in T2D, which is of great importance in the treatment of diabetes. Better education programmes are necessary to prevent decompensation and comorbidities.

Frequently occurring diseases of disordered gut-brain interactions are the irritable bowel syndrome and functional dyspepsia. Breath tests are noninvasive and are used to monitor a variety of gastrointestinal functions or conditions. Their general principle is the oral application of a test substance, the metabolism of which results in a substrate that can be measured in expiratory air. Clinically used breath tests use carbohydrates or stable

To study the affinities of Siberian populations and to address hypotheses on the origin of the Samoyed peoples, 567,096 autosomal genome-wide single-nucleotide polymorphisms (SNPs) and 147 Y-chromosome data from 15 Siberian and 12 reference populations were examined. For several analyses, we used the intersection of our data with publicly available ancient Siberian samples. To examine genetic relatedness among populations, PCA, FST, TreeMix, and ADMIXTURE analyses were applied. The distribution of runs of homozygosity (ROH) and identical by descent (IBD) sharing within populations were studied to explore the potential effect of demography and evolutionary processes on the population structure. Analyses of autosomal and Y-chromosome data revealed high differentiation of the Siberian groups. A substantial level of variation among Samoyedic-speaking populations alone did not differ significantly from the whole of Siberia. Several populations (i.e., Nganasans, Evenks, Yukagirs, and Koryaks) did not appear to have experienced admixture with other Siberian populations (i.e., producing only positive f3), while for the other tested populations the composition of mixing sources always included Nganasans or Evenks. The Nganasans from the Taymyr Peninsula demonstrated the greatest level of shared shorter ROH and IBD with nearly all other Siberian populations. Autosomal SNP and Y-chromosome data demonstrate that Samoyedic populations differ significantly in their genetic composition. Genetic relationship is observed only between Forest and Tundra Nentsi. Selkups are affiliated with the Kets from the Yenisey River, while the Nganasans are separated from their linguistic neighbors, showing closer affinities with the Evenks and Yukagirs.

The underrepresentation of non-Europeans in human genetic studies so far has limited the diversity of individuals in genomic datasets and led to reduced medical relevance for a large proportion of the world’s population. Population-specific reference genome datasets as well as genome-wide association studies in diverse populations are needed to address this issue. Here we describe the pilot phase of the GenomeAsia 100K Project. This includes a whole-genome sequencing reference dataset from 1,739 individuals of 219 population groups and 64 countries across Asia. We catalogue genetic variation, population structure, disease associations and founder effects. We also explore the use of this dataset in imputation, to facilitate genetic studies in populations across Asia and worldwide., Using whole-genome sequencing data from 1,739 individuals, the GenomeAsia 100K Project catalogues genetic variation, population structure and disease associations to facilitate genetic studies in Asian populations and increase representation in genetics studies worldwide.

Objective To characterize a cohort of patients with SCN8A-related epilepsy and to perform analyses to identify correlations involving the acquisition of neurodevelopmental skills. Methods We analyzed patient data (n = 91) submitted to an online registry tailored to characteristics of children with SCN8A variants. Participants provided information on the history of their child's seizures, medications, comorbidities, and developmental skills based on the Denver II items. Spearman rank tests were utilized to test for correlations among a variety of aspects of seizures, medications, and neurodevelopmental progression. Results The 91 participants carried 71 missense variants (41 newly reported) and three truncating variants. Ages at seizure onset ranged from birth to >12 months of age (mean ± SD = 5 months 21 days ± 7 months 14 days). Multiple seizure types with multimodal onset times and developmental delay were observed as general features of this cohort. We found a positive correlation between a developmental score based upon percentage of acquired skills and the age at seizure onset, current seizure freedom, and initial febrile seizures. Analyses of cohort subgroups revealed clear distinctions between patients who had a single reported variant in SCN8A and those with an additional variant reported in a gene other than SCN8A, as well as between patients with different patterns of regression before and at seizure onset. Significance This is the first study of an SCN8A patient cohort of this size and for which correlations between age at seizure onset and neurodevelopment were investigated. Our correlation studies suggest that variants of uncertain significance should be considered in assessing children with SCN8A-related disorders. This study substantially improves the characterization of this patient population and our understanding of the neurodevelopmental effects associated with seizures for SCN8A patients, and provides a clinical context at initial presentation that may be prognostic for developmental outcome.

Interpreting the scaling relations measured by recent large kinematic surveys of $z < 1$ galaxies has remained hampered by large observational scatter. We show that the observed ISM and morpho-dynamical properties along the average $z \sim 0.6$ major merger describe a very self-consistent picture in which star formation is enhanced during first passage and fusion as a result of gravitational perturbations due to the interaction, while the gas velocity dispersion is simultaneously enhanced through shocks that convert kinematic energy associated with bulk orbital motions into turbulence at small scales. Angular momentum and rotation support in the disc are partly lost during the most perturbing phases, resulting in a morphologically compact phase. The fractions of present-day E/S0 versus later type galaxies can be predicted within only a few per cent, confirming that roughly half of local discs were reformed in the past 8-9 Gyr after gas-rich major mergers. Major mergers are shown to strongly scatter scaling relations involving kinematic quantities (e.g. the Tully-Fisher or Fall relations). Selecting high-z discs relying only on $V/{\sigma}$ turns out to be less efficient than selecting discs from multiple criteria based on their morpho-kinematic properties, which can reduce the scatter of high-z scaling relations down to the values measured in local galaxy samples., Comment: 18 pages, 7 figures, 2 tables; accepted for publication in MNRAS

Subcooled flow boiling measurements using HFE-7000 were obtained in a vertical 6 mm ID sapphire tube during upward and downward flow at various gravity levels including hypergravity and microgravity. Temperature sensitive paint (TSP) applied to the inside of the tube was used to measure time and space resolved temperature and heat transfer distributions at the wall–fluid interface, and this data along with flow visualization were used to characterize the heat transfer for different flow patterns. Time-averaged heat transfer coefficients were compared at nine gravity levels, four mass fluxes, six heat fluxes, and two subcoolings. The average heat transfer coefficient typically increased with heat flux, mass flux, and absolute gravity level. In microgravity, the lack of mixing at low heat fluxes due to the absence of natural convection and bubble slip velocity resulted in a decrease in heat transfer coefficient compared to downward and upward conditions. The heat transfer was strongly dependent on the flow regime, causing certain data points at high mass flux or low gravity to deviate from the typical trends due to deactivation of nucleation sites. The heat transfer coefficient became less dependent on gravity as the mass flux and heat flux increased. Flow regimes were very sensitive to the competition between buoyancy and inertial forces, which in turn affected the heat transfer. Mechanisms by which heat is transferred under various conditions are discussed.

13 C-gastric emptying breath tests (13 C-GEBT) are validated, reliable, and non-invasive tools for measurement of gastric emptying (GE) velocity of solids and liquids without radiation exposure or risk of toxicity. They are recommended and routinely used for clinical purposes in adult as well as pediatric patients and can be readily performed onsite or even at the patient's home. However, the underlying methodology is rather complex and test results can be influenced by dietary factors, physical activity, concurrent diseases, and medication. Moreover, epidemiological factors can influence gastric emptying as well as production and exhalation of 13 CO2 , which is the ultimate metabolic product measured for all 13 C-breath tests. Accordingly, in this issue of Neurogastroenterology & Motility, Kovacic et al. report performance of the 13 C-Spirulina breath test in a large group of healthy children and show significant effects of gender, pubertal status, and body size on test results. The purpose of this mini-review is to evaluate the clinical use of 13 C-GEBT in adults and children, exploring available protocols, analytical methods, and essential prerequisites for test performance, as well as the role of GE measurements in the light of the current discussion on relevance of delayed GE for symptom generation.

Introduction 13C‐breath tests are valuable, noninvasive diagnostic tests that can be widely applied for the assessment of gastroenterological symptoms and diseases. Currently, the potential of these tests is compromised by a lack of standardization regarding performance and interpretation among expert centers. Methods This consensus‐based clinical practice guideline defines the clinical indications, performance, and interpretation of 13C‐breath tests in adult and pediatric patients. A balance between scientific evidence and clinical experience was achieved by a Delphi consensus that involved 43 experts from 18 European countries. Consensus on individual statements and recommendations was established if ≥ 80% of reviewers agreed and

The hosts of long duration gamma-ray bursts (GRBs) are predominantly starburst galaxies at subsolar metallicity. At redshifts z < 1, this implies that most of them are low-mass galaxies similar to the populations of blue compact dwarfs and dwarf irregulars. What triggers the massive star-formation needed for producing a GRB progenitor is still largely unknown, as are the resolved gas properties and kinematics of these galaxies and their formation history. Here we present a sample of six spatially resolved GRB hosts at z < 0.3 observed with 3D spectroscopy at high spectral resolution (R = 8000-13 000) using FLAMES/VLT. We analyzed the resolved gas kinematics of the full sample and the abundances in a subsample with strong enough emission lines. Only two galaxies show a regular disk-like rotation field, another two are dispersion-dominated, and the remaining ones have two narrow emission components associated with different parts of the galaxy but no regular rotation field, which might indicate a recent merger. All galaxies show evidence for broad components underlying the main emission peak with σ of 50-110 km s-1. This broad component is more metal-rich than the narrow components, it is blueshifted in most cases, and it follows a different velocity structure. We find a weak correlation between the star-formation rate and the width of the broad component, its flux compared to the narrow component, and the maximum outflow velocity of the gas, but we do not find any correlation with the star-formation density, metallicity or stellar mass. We hence associate this broad component with a metal-rich outflow from star-forming regions in the host. The GRB is not located in the brightest region of the host, but is always associated with some star-forming region showing a clear wind component. Our study shows the great potential of 3D spectroscopy to study the star-formation processes and history in galaxies hosting extreme transients, the need for high signal-To-noise, and the perils using unresolved or only partially resolved data for these kinds of studies. © ESO 2021., CT and AdUP acknowledge support from AYA2017-89384-P, CT and AdUP also from a Ramón y Cajal fellowships RyC-2012-09984 and RyC-2012-09975, LI from a Juan de la Cierva Integración fellowship IJCI-2016-30940. DAK acknowledges support from the Spanish National Research Project RTI2018-098104-J-I00 (GRBPhot). JFAF acknowledges support from the Spanish Ministerio de Ciencia, Innovación y Universidades through the grant PRE2018-086507. SDV acknowledges support from the French National Research Agency (ANR) under contract ANR-16-CE31-0003. LC is supported by YDUN grant DFF 4090-00079. Ground based observations were collected at the VLT under program 092.D-0389(A)., With funding from the Spanish government through the Severo Ochoa Centre of Excellence accreditation SEV-2017-0709.

Dumping syndrome is a common but underdiagnosed complication of gastric and oesophageal surgery. We initiated a Delphi consensus process with international multidisciplinary experts. We defined the scope, proposed statements and searched electronic databases to survey the literature. Eighteen experts participated in the literature summary and voting process evaluating 62 statements. We evaluated the quality of evidence using grading of recommendations assessment, development and evaluation (GRADE) criteria. Consensus (defined as >80% agreement) was reached for 33 of 62 statements, including the definition and symptom profile of dumping syndrome and its effect on quality of life. the panel agreed on the pathophysiological relevance of rapid passage of nutrients to the small bowel, on the role of decreased gastric volume capacity and release of glucagon-like peptide 1. Symptom recognition is crucial, and the modified oral glucose tolerance test, but not gastric emptying testing, is useful for diagnosis. An increase in haematocrit >3% or in pulse rate >10 bpm 30 min after the start of the glucose intake are diagnostic of early dumping syndrome, and a nadir hypoglycaemia level, Methusalem grant from KULeuven; Methusalem grant from Leuven University, J.T. is supported by a Methusalem grant from KULeuven. T.V. is a senior clinical investigator from the Flanders research foundation (FWO Vlaanderen). the Delphi process was supported by a Methusalem grant from Leuven University to J.T.

Whole exome sequencing (WES) of matched tumor-normal pairs in rare tumors has the potential to identify genome-wide mutations and copy number alterations (CNAs). We evaluated 27 rare cancer patients with tumor-normal matching by WES and tumor-only next generation sequencing (NGS) as a comparator. Our goal was to: 1) identify known and novel variants and CNAs in rare cancers with comparison to common cancers, 2) examine differences between germline and somatic variants and how that functionally impacts rare tumors, 3) detect and characterize alleles in biologically relevant genes-pathways that may be of clinical importance but not represented in classical cancer genes. We identified 3343 germline single nucleotide variants (SNVs) and small indel variants&mdash, 1670 in oncogenes and 1673 in tumor suppressor genes&mdash, generating an average of 124 germline variants/case. The number of somatic SNVs and small indels detected in all cases was 523:306 in oncogenes and 217 in tumor suppressor genes. Of the germline variants, six were identified to be pathogenic or likely pathogenic. In the 27 analyzed rare cancer cases, CNAs are variable depending on tumor type, germline pathogenic variants are more common. Cell fate pathway mutations (e.g., Hippo, Notch, Wnt) dominate pathogenesis and double hit (mutation + CNV) represent ~18% cases.

Variants implicated in childhood epilepsy have been identified in all four voltage-gated sodium channels that initiate action potentials in the central nervous system. Previous research has focused on the functional effects of particular variants within the most studied of these channels (NaV1.1, NaV1.2 and NaV1.6); however, there have been few comparative studies across channels to infer the impact of mutations in patients with epilepsy. Here we compare patterns of variation in patient and public databases to test the hypothesis that regions of known functional significance within voltage-gated sodium (NaV) channels have an increased burden of deleterious variants. We assessed mutational burden in different regions of the Nav channels by (1) performing Fisher exact tests on odds ratios to infer excess variants in domains, segments, and loops of each channel in patient databases versus public "control" databases, and (2) comparing the cumulative distribution of variant sites along DNA sequences of each gene in patient and public databases (i.e., independent of protein structure). Patient variant density was concordant among channels in regions known to play a role in channel function, with statistically significant higher patient variant density in S4-S6 and DIII-DIV and an excess of public variants in SI-S3, DI-DII, DII-DIII. On the other hand, channel-specific patterns of patient burden were found in the NaV1.6 inactivation gate and NaV1.1 S5-S6 linkers, while NaV1.2 and NaV1.6 S4-S5 linkers and S5 segments shared patient variant patterns that contrasted with those in NaV1.1. These different patterns may reflect different roles played by the NaV1.6 inactivation gate in action potential propagation, and by NaV1.1 S5-S6 linkers in loss of function and haploinsufficiency. Interestingly, NaV1.2 and NaV1.6 both lack amino acid substitutions over significantly long stretches in both the patient and public databases suggesting that new mutations in these regions may cause embryonic lethality or a non-epileptic disease phenotype.

// Shariful Islam 1 , Andrew L. Paek 2 , Michael Hammer 3 , Savithri Rangarajan 4 , Robert Ruijtenbeek 4 , Laurence Cooke 5 , Eric Weterings 6 and Daruka Mahadevan 5 1 Cancer Biology GIDP, University of Arizona Cancer Center, Tucson, AZ, USA 2 Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ, USA 3 Division of Biotechnology, University of Arizona Cancer Center, Tucson, AZ, USA 4 PamGene International B.V., 's-Hertogenbosch, The Netherlands 5 Department of Medicine, University of Arizona Cancer Center, Tucson, AZ, USA 6 Department of Radiation Oncology, University of Arizona, Tucson, AZ, USA Correspondence to: Daruka Mahadevan, email: dmahadevan@uacc.arizona.edu Keywords: DLBCL; aurora kinase; aneuploidy-polyploidy; TPX2; RanGAP1 Received: August 22, 2018 Accepted: October 06, 2018 Published: November 13, 2018 ABSTRACT Double-hit (DH) or double-expresser (DE) lymphomas are high-grade diffuse large B-cell lymphomas (DLBCL) that are mostly incurable with standard chemo-immunotherapy due to treatment resistance. The generation of drug-induced aneuploid/polyploid (DIAP) cells is a common effect of anti-DLBCL therapies (e.g. vincristine, doxorubicin). DIAP cells are thought to be responsible for treatment resistance, as they are capable of re-entering the cell cycle during off-therapy periods. Previously we have shown that combination of alisertib plus ibrutinib plus rituximab can partially abrogate DIAP cells and induce cell death. Here, we provide evidence that DIAP cells can re-enter the cell cycle and escape cell death during anti-DLBCL treatment. We also discuss MYC/BCL2 mediated molecular mechanism that underlie treatment resistance. We isolated aneuploid/polyploid populations of DH/DE-DLBCL cells after treatment with the aurora kinase (AK) inhibitor alisertib. Time-lapse microscopy of single polyploid cells revealed that following drug removal, a subset of these DIAP cells divide and proliferate by reductive cell divisions, including multipolar mitosis, meiosis-like nuclear fission and budding. Genomic, proteomic, and kinomic profiling demonstrated that alisertib-induced aneuploid/polyploid cells up-regulate DNA damage, DNA replication and immune evasion pathways. In addition, we identified amplified receptor tyrosine kinase and T-cell receptor signaling, as well as MYC-mediated dysregulation of the spindle assembly checkpoints RanGAP1, TPX2 and KPNA2 . We infer that these factors contribute to treatment resistance of DIAP cells. These findings provide opportunities to develop novel DH/DE-DLBCL therapies, specifically targeting DIAP cells. Key Points MYC mediated upregulation of TPX2, KPNA2 and RanGAP1 dysregulate the spindle assembly checkpoint in drug-induced polyploid cells. Drug-induced polyploid cells re-enter the cell cycle via multipolar mitosis, fission or budding, a mechanism of disease relapse.

Single nucleotide polymorphisms (SNPs) in commercial arrays have often been discovered in a small number of samples from selected populations. This ascertainment skews patterns of nucleotide diversity and affects population genetic inferences. We propose a demographic inference pipeline that explicitly models the SNP discovery protocol in an Approximate Bayesian Computation (ABC) framework. We simulated genomic regions according to a demographic model incorporating parameters for the divergence of three well-characterized HapMap populations and recreated the SNP distribution of a commercial array by varying the number of haploid samples and the allele frequency cut-off in the given regions. We then calculated summary statistics obtained from both the ascertained and genomic data and inferred ascertainment and demographic parameters. We implemented our pipeline to study the admixture process that gave rise to the present-day Mexican population. Our estimate of the time of admixture is closer to the historical dates than those in previous works which did not consider ascertainment bias. Although the use of whole genome sequences for demographic inference is becoming the norm, there are still underrepresented areas of the world from where only SNP array data are available. Our inference framework is applicable to those cases and will help with the demographic inference.

EAGEN is one of the 7 founding sisters and an ordinary member society of UEG. EAGEN members have contributed significantly to the development of UEG in leading positions within UEG. The significant impact of UEG board members on science, education, and organization of European gastroenterology is demonstrated by the remarkable list of EAGEN board members who have received major UEG awards or prizes. The focus of EAGEN within UEG has been on postgraduate education. In this function, EAGEN has developed educational formats which after their establishment were handed over to UEG. EAGEN has established itself as an important provider of education in gastroenterology including pancreatic-biliary diseases, GI oncology, endoscopic procedures, nutrition, and intestinal microbiology. EAGEN has the goal to identify educational needs, fill existing gaps in medical education, and advance the quality of education. To fulfill these tasks, EAGEN is in close cooperation with the UEG education committee and UEG member societies. EAGEN puts a focus on reduction of pan-European health inequalities, provision of equal opportunity, promotion of young talent, and improvement of clinical standards and guidelines.

Novel modelling was utilised in the present study to reveal significant relationships between the abundance of the Australian freshwater stream-specialist fish Galaxias olidus and metrics defining ...