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This randomized, double-blind, single- and multiple-ascending dose study assessed the pharmacokinetics (PKs), pharmacodynamics, and safety of deucravacitinib (Sotyktu™), a selective and potent small-molecule inhibitor of tyrosine kinase 2, in 100 (75 active, 25 placebo) healthy volunteers (NCT02534636). Deucravacitinib was rapidly absorbed, with a half-life of 8-15 h, and 1.4-1.9-fold accumulation after multiple dosing. Deucravacitinib inhibited interleukin (IL)-12/IL-18-induced interferon (IFN)γ production ex vivo in a dose- and concentration-dependent manner. Following in vivo challenge with IFNα-2a, deucravacitinib demonstrated dose-dependent inhibition of lymphocyte count decreases and expression of 53 IFN-regulated genes. There were no serious adverse events (AEs); the overall frequency of AEs was similar in the deucravacitinib (64%) and placebo (68%) groups. In this first-in-human study, deucravacitinib inhibited IL-12/IL-23 and type I IFN pathways in healthy volunteers, with favorable PK and safety profiles. Deucravacitinib is a promising therapeutic option for immune-mediated diseases, including Crohn's disease, psoriasis, psoriatic arthritis, and systemic lupus erythematosus.

Mutations in the TMEM260 gene cause structural heart defects and renal anomalies syndrome, but the function of the encoded protein remains unknown. We previously reported wide occurrence of O-mannose glycans on extracellular immunoglobulin, plexin, transcription factor (IPT) domains found in the hepatocyte growth factor receptor (cMET), macrophage-stimulating protein receptor (RON), and plexin receptors, and further demonstrated that two known protein O-mannosylation systems orchestrated by the POMT1/2 and transmembrane and tetratricopeptide repeat-containing proteins 1-4 gene families were not required for glycosylation of these IPT domains. Here, we report that the TMEM260 gene encodes an ER-located protein O-mannosyltransferase that selectively glycosylates IPT domains. We demonstrate that disease-causing TMEM260 mutations impair O-mannosylation of IPT domains and that TMEM260 knockout in cells results in receptor maturation defects and abnormal growth of 3D cell models. Thus, our study identifies the third protein-specific O-mannosylation pathway in mammals and demonstrates that O-mannosylation of IPT domains serves critical functions during epithelial morphogenesis. Our findings add a new glycosylation pathway and gene to a growing group of congenital disorders of glycosylation.

Olivine is the most abundant mineral in Earth’s mantle, and its rheology is likely to control upper-mantle convection. While the rheology of olivine is widely studied, little is known about the rheology of olivine grain boundaries and their effect on deformation in the mantle. Forsterite bicrystals, synthesized by direct bonding of highly polished single-crystal plates, were tested in this study to investigate sliding along the single grain boundary at high temperature (1300°C). Prior to deformation, the bicrystals were polished and scratch markers were scribed perpendicular to the grain boundary to track grain-boundary sliding. Bicrystals were deformed in shear loading between two alumina pistons in a uniaxial creep apparatus at 1 atm with applied axial stress ranging from 1 to 30 MPa. The specimen deformation was measured in real time using a high-resolution (~1 μm) linear variable differential transducer. Each test was carried out until attainment of a quasi-steady state deformation rate to determine the creep parameters. Post-deformation microstructural analysis was conducted using a scanning electron microscope (SEM) and electron backscattered diffraction. Our study established that the creep-rate law for bicrystals is different than single and polycrystalline forsterite. Bicrystals are weaker and shows up to 1 order of magnitude higher deformation rates. SEM microstructures reveal the sliding of scratch markers, which is direct evidence of grain-boundary sliding in forsterite. However, the strain geometry is complex, and further experiments are necessary to determine the overall strain distribution in the sample. Here we present the rationale of our research, and we compare our results on grain-boundary sliding in forsterite with the earlier literature.

Lattice preferred orientation (LPO) of olivine crystals occurs due to deformation in the mantle. Different parts of the upper mantle can undergo a large variety of deformation paths. During simple processes, such as simple shearing below oceans due to the movement of tectonic plates, the LPO will reflect the direction of the movement of tectonic plates. On the other hand, in areas, such as around subduction zones, the mantle undergoes more complex deformation paths, resulting in a less easily predictable LPO. Seismic anisotropy has been used as a proxy for mantle flows and the LPO formed in the mantle. To interpret the seismic anisotropy observations more accurately, we need to understand how LPO forms in different regions of subduction.LPO has been implemented in many numerical modelling tools to predict seismic anisotropy, which places constraints on mantle dynamics. However, a few recent studies have linked olivine texture development to viscous anisotropy, resulted from the summed effect of individual crystals that are deforming anisotropically. Anisotropic viscosity can affect deformation and in turn the resulting LPO. To study the effect of anisotropic viscosity (AV) and LPO evolution in geodynamics processes, it is important to know the role of AV on LPO and the differences between the numerical methods that calculate them.We choose three methods of olivine texture development to examine in this study. D-Rex is a polycrystal LPO model that is relatively balanced in computational efficiency and accuracy. From previous studies, D-Rex has been shown to produce faster texture development and stronger texture compared to other methods, including our second choice, the modified director method (MDM). The MDM parameterizes the olivine LPO formation as relative rotation rates along the slip systems that participate in the rotation of olivine grains due to finite deformation. We also couple the MDM with a micromechanical model for olivine AV (which makes our third choice MDM+AV), to allow the anisotropic texture to modify the viscosity and in turn affect the formation of LPO.Here we compare the LPO evolution under subduction settings with a slowly advancing trench and a retreating trench, with and without the effect of AV. Since the mantle flow pattern in subduction zones is not homogeneous, different particles experience a variety of deformation paths. We place 60 particles in each subduction model around the slab to track the deformation and resulting olivine texture. We compute olivine texture using the above-mentioned three different methods (D-Rex, MDM, MDM+AV). With the particles, we can identify characteristic textures developed in key regions such as the mantle wedge, sub-slab area, and lateral slab edge. We then run a statistical analysis on the texture parameter and anisotropic properties of the particles from both retreating and advancing subduction models, to study where anisotropic viscosity has the largest effect on the mantle flow. We expect AV to have a larger effect in a retreating slab setting since the mantle flows feeding material to the sub-slab region is more intensive.

Transient creep controls the behavior of Earth’s mantle at human timescales. Transient creep occurs during postseismic creep, glacial isostatic adjustment, and tidal deformation of planetary interiors experiencing large tidal stresses, such as Jupiter’s moon Io or various identified exoplanets. Unfortunately, laboratory data of transient creep of olivine, the most abundant mineral in Earth’s upper mantle, remain limited, and at present we lack the microphysical understanding of transient creep required to extrapolate experimental data to geological grain sizes and time scales. Several mechanisms for transient creep have been proposed, both intergranular mechanisms such as plastic anisotropy and elastically or diffusionally-assisted grain boundary sliding, and intragranular mechanisms including long-range dislocation interactions and various other dislocation damping mechanisms. Each mechanism produces distinct rheological behavior, presenting a hurdle for modeling geodynamic processes occurring on timescales of hours to years.To distinguish among the various proposed microphysical mechanisms for transient creep, we performed compressional load-reduction experiments on cylindrical, isostatically hot-pressed aggregates of San Carlos olivine in a gas-medium Paterson apparatus at confining pressures of 300 MPa and temperatures of 1200°C. Samples were subjected to a constant differential stress of 200 MPa, which resulted in a steady-state strain rate of ~10-5 s-1. After steady state was achieved, the samples were subjected to a near-instantaneous load reduction of 10–70% of the original load. For load reductions exceeding ~50%, the samples exhibited a period of transient anelastic relaxation with zero or negative strain rate before continuing to strain at a positive strain rate lower than the previous steady state. The duration of relaxation increased with the magnitude of the load reduction. Multiple load reductions from the same steady-state strain rate were performed during a single experiment to test for reproducibility. We interpret our results to indicate that, at these conditions, the backstress stored in polycrystalline olivine is approximately half of the differential stress applied to the material. The magnitude of backstress is compatible with long-range dislocation interactions on the [100](010) and [100](001) or [001](100) slip systems previously observed for single crystals of olivine. If transient creep is controlled by such dislocation interactions then it may be inappropriate to apply the traditional Burgers rheology based exclusively on intergranular dissipation processes or power-law flow laws calibrated for steady-state creep to model transient creep and transient viscosity evolution in the upper mantle.

Dyslexia is a common learning disability exhibited as a delay in acquiring reading skills despite adequate intelligence, and reading single real words are impaired in many dyslexics. Reading disability or developmental dyslexia (DD) is a neurodevelopmental disorder affecting children globally, and the molecular mechanisms underlying it are largely underdetermined, while loci and susceptibility genes are suggested by genetic mapping in families or cohorts and by genome wide association studies (GWAS). To identify a possible genetic cause, we genotyped and performed genome wide linkage analysis employing the programs LIPED and SNP6-LINK of six multigenerational families with autosomal dominant inherited dyslexia. The linkage analyses resulted in informative haplotypes segregating with the dyslectic trait in all families and a LOD score of Z>4 at 13q12.3 and 19p13.3, and a LOD score of Z>3 at 15q23-q24.1, 18q11.21, and 21q22.3. The five mapped regions are supported by previous linkage or associations studies of dyslexia. Whole genome sequencing (WGS) of affected individuals in the six family’s revealed rare regulatory variants in the mapped regions.

Causes of suicide are complex indicating a nation's psycho-socio-economic well-being hence this population-based study explores whether USA suicides worsened compared to nineteen Other Western Countries (OWC) being possibly related to gun ownership in theTotal suicide data are drawn from the latest WHO Age-Standardised-Death-Rates per million (pm) controlled for age, sex, and population, along with suicides in the five age- bands 15-34 years to 75 + years. National gun ownership data from the international Small Arms Survey. Chi-square tests any significant difference between American and OWC suicides during the century. Spearman Rank Order correlations are used to determine comparability of suicides and gun ownership per thousand person rates over the period 2000-15.USA had the highest gun ownership, treble the rate of the next highest country. American Total suicides rose 27%, significantly more than eight other countries (The key finding is whilst most countries reduced suicides American rates rose substantially this century, raising questions about US society. Importantly the easy access to firearms in the USA makes Young Adult suicide more likely when facing psycho-social stress. This study exposes the vulnerability of distressed young American adults in a permissive gun culture, with its sequel, life-long grieving parents.HighlightsDuring 21st Century USA suicides rose substantially more than other Western nations.Only USA suicides rose20% amongst Total suicides and in those aged 15-to-74years.USA Young Adult suicides 150,099 in 21st century, 12,438 in 2015, 6,702 were gun-related.

In Schleswig-Holstein müssen die Mentoren und Mentorinnen als sogenannte Ausbildungslehrkräfte ein Zertifikat für die Ausbildungstätigkeit erwerben. Der Erwerb dieses Zertifikats bedingt Qualifikationen, die in speziellen Fortbildungen erworben werden. Damit entsteht ein Qualitätsmanagement zur Ausbildung, welches nicht der einzelnen Ausbildungslehrkraft überlassen wird, sondern insgesamt Maßstäbe setzt.

Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished cases). A Cux1+/− mouse model was used to analyze CUX1 expression in the brain and evaluate susceptibility to epilepsy. We describe 34 patients with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development, and intellectual disability. In Cux1+/− mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/− brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was also reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some patients, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. Furthermore, the balance of CUX1 isoform expression in the brain during development appears to be important for this favorable clinical course.

Background: The IMF fears the COVID-19 pandemic will create an economic down-turn matching the Great Depression. More recent recessions\ud have led to physical and mental health problems including suicide deaths of\ud young adults (15 - 34). We aim to identify risk patterns of mortality by age\ud from influenza and suicide mortality in peak years from 1979 to 2016 to see if\ud there are lessons to be learned for policy makers and psychiatric services.\ud Method: Using WHO mortality data for 1979-2016 peak years of influenza\ud deaths and suicides are identified in ten Western countries. Death rates per\ud million in each age-band are calculated for both sexes and the percentage of\ud the total deaths accruing in each of five age-bands for influenza and suicides.\ud Ratios of influenza to suicide by age in regard to rates and percentages of\ud deaths indicate differential risk mortality and morbidity patterns. Results: Of\ud the ten country’s average Influenza deaths, 95% occurred in people over 55,\ud including 80% - 85% for the over 75’s. Conversely it was 59% of suicides occurred in peoples aged

Negative psychotic symptoms are among the most disabling features of schizophrenia, and are strongly associated with relatively poor clinical and functional outcomes. However, there are no effective treatments for negative symptoms, and this represents a major unmet clinical need. Recent research has shown that negative symptoms are already present in many patients at illness onset. There is evidence that cariprazine may improve negative symptoms in patients with chronic schizophrenia. However, its utility in treating negative symptoms in the early stage of the disorder is unclear. Here, we report six cases of patients with first-episode psychosis who were treated with cariprazine.

The mechanics of olivine deformation play a key role in long-term planetary processes, such as the response of the lithosphere to tectonic loading or the response of the solid Earth to tidal forces, and in short-term processes, such as the evolution of roughness on oceanic fault surfaces or postseismic creep within the upper mantle. Many previous studies have emphasized the importance of grain-size effects in the deformation of olivine. However, most of our understanding of the role of grain boundaries in the deformation of olivine is inferred from comparison of experiments on single crystals to experiments on polycrystalline samples.To directly observe and quantify the mechanical properties of olivine grain boundaries, we use high-precision mechanical testing of synthetic forsterite bicrystals with well characterised interfaces. We conduct in-situ micropillar compression tests at high-temperature (700°C) on low-angle (13° tilt about [100] on (015)) and high-angle (60° tilt about [100] on (011)) grain boundaries. In these experiments, the boundary is contained within the micropillar and oriented at 45° to the loading direction to promote shear along the boundary. In these in-situ tests, we observe differences in deformation style between the pillars containing the grain boundary and the pillars in the crystal interior. In-situ observations and analysis of the mechanical data indicate that pillars containing the grain boundary consistently support elastic loading to higher stresses than pillars without a grain boundary. Moreover, only the pillars without a grain boundary display evidence of sustained plasticity and slip-band formation. Post-deformation advanced microstructural characterization (STEM) confirms that under the conditions of these deformation experiments, sliding did not occur along the grain boundary. These observations support the hypothesis that grain boundaries are stronger than the crystal interior. These experiments on small deformation volumes allow us to qualitatively explore the differences between the crystal interior and regions containing grain boundaries. Overall, the variation in strain and temperature in our small scale experiments allows fundamental investigation of the response of well characterised forsterite grain boundaries to deformation.

The development of olivine texture, or lattice preferred orientation (LPO), has been implemented in many numerical modelling tools to predict seismic anisotropy, which places constraints on mantle dynamics. However, a few recent studies have linked olivine texture development to its mechanical anisotropy, which in turn can affect deformation rates and also the resulting texture. To study the effect of anisotropic viscosity (AV) and LPO evolution in geodynamics processes, it is important to know the role of AV and LPO and the differences between the numerical methods that calculate them.The modified director method parameterizes the olivine LPO formation as relative rotation rates along the slip systems that participate in the rotation of olivine grains due to finite deformation. When it is coupled with a micromechanical model for olivine AV, it allows the anisotropic texture to modify the viscosity. We compare the olivine textures predicted by the modified director method both with and without a coupled micromechanical model and textures predicted by the D-Rex LPO evolution model. To do this, we recalculate the texture observed in simple 3D models such as a shear box model and two other well-understood models: a corner flow model and a subduction model. In general, we observed that the D-Rex models predict a stronger anisotropic texture compared to the texture predicted by the modified director method both with and without the micromechanical model, in agreement with previous studies. When including the micromechanical model, the anisotropic texture changes the observed strain rates, which allows for a slightly faster texture evolution that is more similar to the D-Rex predictions than it is to those produced by the modified director method alone. We found that even for the simplest settings there is an increase of 10~15% in strain rate during deformation until a strain of 2.5. When shearing the asthenosphere over ~10 Myr, such anisotropy could modify the effective viscosity of the mantle,causing an up to 40% increase in plate velocity for the same applied stress. The anisotropy can also induce deformation in planes other than the initial shear plane, which can change the direction of the primary deformation.Our ultimate goal is to understand the role of AV and LPO evolution in geodynamic processes by looking at deformation paths predicted by geodynamic models in ASPECTWith this initial test, we will gain a basic understanding of olivine AV behavior and LPO evolution under different deformation settings calculated with different numerical methods, which we will carry onto our next step of implementing anisotropic viscosity of olivine in 3D into ASPECT.

Increasingly, volcanologists model mature volcanic systems as being fed by stratified magma reservoirs, that is, small lenses of eruptible magma suspended within a larger volume of non-eruptible, crystal-rich mush. Erupted lavas record geochemical evidence for long-term deep storage of distinct magma bodies followed by their ascent and coalescence shortly before eruption. Conditions and flow mechanisms that allow deep-seated magmas to rise quickly in reservoirs despite the high viscosity and low permeability of crystal-rich mushes are a subject of debate. We present results of melt migration experiments conducted in a triaxial, gas-medium apparatus. We prepared multiple crystal-rich mushes by hot pressing crushed borosilicate glass mixed with different amounts of subrounded quartz sand (44-106 μm diameter). Prepared mushes have crystal fractions from 0.59 to 0.83. A single disk of mush is stacked on a disk of soda lime glass, representing the intruding crystal-free magma, then heated to 900°C (above the glass transitions) and pressurized to 100-300 MPa. The bottom and circumference of the mush experience the confining pressure, but the top is at room pressure, resulting in a pore pressure gradient (~33-100 MPa/mm) that could drive the underlying melt into the mush. After several hours samples are cooled, decompressed, cut and imaged to determine the distribution of the soda lime glass that migrated in to the mush while at the experimental conditions. High crystal fraction samples (>0.80; Hi X) have glass filling intergranular space. In low crystal fraction samples (-1.7 to 10-8.6). The observed increase in the amount of melt migration with decreasing crystal fraction is coincident with the onset of mush deformation. Applied to natural systems, these results suggest small changes in mush crystal fraction significantly influence the amount of melt migration that occurs and that melt migration in magma reservoirs peaks near the transition from deformable mush to partially-molten rock (i.e., at the rheologically critical melt fraction).

Aim: To assess the efficacy, safety and tolerability of cotadutide in patients with type 2 diabetes mellitus and chronic kidney disease.Materials and Methods: In this phase 2a study (NCT03550378), patients with body mass index 25-45 kg/m2, estimated glomerular filtration rate 30-59 ml/min/1.73 m2 and type 2 diabetes [glycated haemoglobin 6.5-10.5% (48-91 mmol/mol)] controlled with insulin and/or oral therapy combination, were randomized 1:1 to once-daily subcutaneous cotadutide (50-300 μg) or placebo for 32 days. The primary endpoint was plasma glucose concentration assessed using a mixed-meal tolerance test.Results: Participants receiving cotadutide (n = 21) had significant reductions in the mixed-meal tolerance test area under the glucose concentration-time curve (–26.71% vs. +3.68%, p Conclusions: We established the efficacy of cotadutide in this patient population, with significantly improved postprandial glucose control and reduced bodyweight versus placebo. Reductions in urinary albumin-to-creatinine ratios suggest potential benefits of cotadutide on kidney function, supporting further evaluation in larger, longer-term clinical trials.

Aims This pooled analysis of the DEPICT-1 and -2 trials aimed to evaluate the efficacy and safety of adjunct dapagliflozin therapy in patients with type 1 diabetes (T1D). Materials and methods DEPICT-1 and -2 were randomized, double-blind, parallel-group, 24-week studies, with 28-week extension periods. Adults with T1D and HbA1c 7.5-10.5% were randomized (1:1:1) to receive dapagliflozin 5, 10 mg or placebo. The short- and long-term efficacy and safety of dapagliflozin were examined in an exploratory pooled analysis of both studies. Results Efficacy analyses included 530, 529 and 532 and safety analysis included 548, 566 and 532 patients in the dapagliflozin 5 mg, 10 mg and placebo groups, respectively. Baseline characteristics were similar between treatment groups. At Week 24, reductions were seen with dapagliflozin 5 and 10 mg compared with placebo in HbA1c (-0.40%, -0.43% vs 0.00%) and body weight (-2.45, -2.91 vs 0.11 kg). HbA1c and body weight reductions versus placebo were also seen after 52 weeks of treatment. There was no imbalance in occurrence of severe hypoglycaemic events between groups. The proportion of patients experiencing definite diabetic ketoacidosis (DKA) was higher with dapagliflozin 5 mg (4.0%) and 10 mg (3.5%) compared with placebo (1.1%) over 52 weeks; most events were of mild or moderate severity, and all resolved with treatment. Conclusions Over 52 weeks, dapagliflozin provided glycaemic and weight benefits, with no increased frequency of severe hypoglycaemia compared with placebo. More DKA events were reported with dapagliflozin than placebo, highlighting the importance of appropriate patient selection, education and risk mitigation strategies. This article is protected by copyright. All rights reserved.

Primary microcephaly (MCPH) is characterized by reduced brain size and intellectual disability. The exact pathophysiological mechanism underlying MCPH remains to be elucidated, but dysfunction of neuronal progenitors in the developing neocortex plays a major role. We identified a homozygous missense mutation (p.W155C) in Ribosomal RNA Processing 7 Homolog A, RRP7A, segregating with MCPH in a consanguineous family with 10 affected individuals. RRP7A is highly expressed in neural stem cells in developing human forebrain, and targeted mutation of Rrp7a leads to defects in neurogenesis and proliferation in a mouse stem cell model. RRP7A localizes to centrosomes, cilia and nucleoli, and patient-derived fibroblasts display defects in ribosomal RNA processing, primary cilia resorption, and cell cycle progression. Analysis of zebrafish embryos supported that the patient mutation in RRP7A causes reduced brain size, impaired neurogenesis and cell proliferation, and defective ribosomal RNA processing. These findings provide novel insight into human brain development and MCPH., The RRP7A a gene is involved in ribosome biogenesis. Here the authors report a homozygous missense mutation segregating with primary microcephaly, and show that this occurs via functional defects in both nucleoli and primary cilia disrupting cell proliferation and neurogenesis.

Glycoside hydrolases (GHs) are found in all domains of life, and at least 87 distinct genes encoding proteins related to GHs are found in the human genome. GHs serve diverse functions from digestion of dietary polysaccharides to breakdown of intracellular oligosaccharides, glycoproteins, proteoglycans and glycolipids. Congenital disorders of GHs (CDGHs) represent more than 30 rare diseases caused by mutations in one of the GH genes. We previously used whole-exome sequencing of a homogenous Danish population of almost 2000 individuals to probe the incidence of deleterious mutations in the human glycosyltransferases (GTs) and developed a mutation map of human GT genes (GlyMAP-I). While deleterious disease-causing mutations in the GT genes were very rare, and in many cases lethal, we predicted deleterious mutations in GH genes to be less rare and less severe given the higher incidence of CDGHs reported worldwide. To probe the incidence of GH mutations, we constructed a mutation map of human GH-related genes (GlyMAP-II) using the Danish WES data, and correlating this with reported disease-causing mutations confirmed the higher prevalence of disease-causing mutations in several GH genes compared to GT genes. We identified 76 novel nonsynonymous single-nucleotide variations (nsSNVs) in 32 GH genes that have not been associated with a CDGH phenotype, and we experimentally validated two novel potentially damaging nsSNVs in the congenital sucrase-isomaltase deficiency gene, SI. Our study provides a global view of human GH genes and disease-causing mutations and serves as a discovery tool for novel damaging nsSNVs in CDGHs.

OBJECTIVE: To define the phenotypic spectrum of phosphatidylinositol glycan class A protein (PIGA)-related congenital disorder of glycosylation (PIGA-CDG) and evaluate genotype-phenotype correlations.METHODS: Our cohort encompasses 40 affected males with a pathogenic PIGA variant. We performed a detailed phenotypic assessment, and in addition, we reviewed the available clinical data of 36 previously published cases and assessed the variant pathogenicity using bioinformatical approaches.RESULTS: Most individuals had hypotonia, moderate to profound global developmental delay, and intractable seizures. We found that PIGA-CDG spans from a pure neurological phenotype at the mild end to a Fryns syndrome-like phenotype. We found a high frequency of cardiac anomalies including structural anomalies and cardiomyopathy, and a high frequency of spontaneous death, especially in childhood. Comparative bioinformatical analysis of common variants, found in the healthy population, and pathogenic variants, identified in affected individuals, revealed a profound physiochemical dissimilarity of the substituted amino acids in variant constrained regions of the protein.SIGNIFICANCE: Our comprehensive analysis of the largest cohort of published and novel PIGA patients broadens the spectrum of PIGA-CDG. Our genotype-phenotype correlation facilitates the estimation on pathogenicity of variants with unknown clinical significance and prognosis for individuals with pathogenic variants in PIGA.

At low-temperature and high-stress conditions, quartz deformation is controlled by the kinetics of dislocation glide, that is, low-temperature plasticity (LTP). To investigate the relationship between intracrystalline H2O content and the yield strength of quartz LTP, we have integrated spherical and Berkovich nanoindentation tests at room temperature on natural quartz with electron backscatter diffraction and secondary-ion mass spectrometry measurements of intracrystalline H2O content. Dry (, Geophysical Research Letters, 49 (2), ISSN:0094-8276, ISSN:1944-8007

PurposeDynamic radiostereometric analysis (dRSA) enables precise non-invasive three-dimensional motion-tracking of bones for assessment of joint kinematics. Hereby, the biomechanical effects of arthroscopic osteochondroplasty of the hip (ACH) can be evaluated in patients with femoroacetabular impingement (FAI).The aim was to investigate the pre- and postoperative range of motion (ROM) and the CT bone volume removed (BV) after ACH. We hypothesize increase in ROM 1 year after surgery.MethodsThirteen patients (6 female) with symptomatic FAI were included prospectively. The patient’s hips were CT-scanned and CT-bone models were created. Preoperative dRSA recordings were acquired during passive flexion to 90°, adduction, and internal rotation (FADIR). ACH was performed, CT and dRSA were repeated 3 months and 1 year postoperatively. Hip joint kinematics before, and 3 months and 1 year after ACH were compared pairwise. The bone volume removal was quantified and compared to change in ROM.ResultsMean hip internal rotation, adduction and flexion were all unchanged after ACH at 1-year follow-up (p > 0.84). HAGOS scores revealed improvement of quality of life (QOL) from 32 to 60 (p = 0.02). The BV was between 406 and 1783 mm3and did not correlate to post-operative ROM.ConclusionsACH surgery in FAI patients had no impact of ROM at 1-year follow-up. QOL improved significantly. This indicates that the positive clinical effects reported after ACH might be a result of reduced labral stress and cartilage pressure during end-range motion rather than increased ROM.Level of evidenceTherapeutic prospective cohort study, level II.

Aims: To examine whether increased neurological deaths during 21st Century are predominately due to elderly demographics, or major influences of interactive-multiple environmental contributory factors? We examine WHO Early-Adult-Deaths (55-74yearolds), which is below Western life-expectancy, and total Age-Standardised-Death-Rates (ASDR) controlled by age, sex, and population, to challenge the demographic assumption. Method. Based upon WHO latest global neurological mortality categories, Nervous-Disease-Deaths and Alzheimer’s & Other Dementias, which provides the Combined Neurological Death, rates per million (pm), for the twenty-one West-Developed-Nations (WDN) over the period. Early-Adult-Death rates based upon numbers of deaths, divided by 55-74 population and WHO total ASDR during the 21st Century. Increases between Over 75’s population and Over 75’s neurological mortality is compared using Odds Ratios. Numbers of deaths are indicative of family and services pressures. Results: Every country’s 55-74yearolds Nervous-Disease-Deaths rates were higher than Alzheimer’s & Dementia Deaths, ten countries Nervous-Disease-Deaths rose higher than Alzheimer’s & Dementias during Century. Highest Combined Deaths and increases were Finland 1006 per million (pm) up 44%, USA 710pm, rose 39% and UK 653pm a rise of 32%, countries average of 25%, though Belgium, Canada and France rates fell. Highest ASDR were Finland 973pm, up 104%, USA 592pm, rose 76%, UK 553pm, increase 170%. Lowest were Japan 112pm, yet up 90%, Greece 184pm, rose 64% and Austria 214pm increased 102%, average nation’s 62%. Belgium at 387pm up 34%, Canada 401pm, increased 13% and France ASDR 336pm up 11%. Population compared with total neurological amongst Early-Adult-Deaths and Over 75’s, ratios of change, were respectively 1:1.34 and 1:2.21, yielding an Odds ratios of 1:1.65 French total neurological numbers were 40,594 rose to 71,543, up 76%, UK 24,601 to 103,550 increased 321% and the USA 174,708 to 436,438 rising 150%. Discussion: We reject the hypothesis that neurological increases were mainly dues to demographics. Our results support by new studies across the continents, with their findings of significant causal multiple-interactive-environmental pollutants, including, endocrine disruptive chemicals, air pollution, organophosphates, plastics, petrochemicals, impact of low ubiquitous prolonged electro-magnetism, etc, associated with neuro-degenerative disease, especially Early-Onset-Dementia, below Western life-expectancy. Conclusions: Governments should seek urgent research to explain this new epidemic.

Worldwide, there are now three marketed dopamine D2 partial agonists: aripiprazole, brexpiprazole and cariprazine. These three drugs share a number of properties other than their action at D2 receptors. Pharmacologically, they are 5HT2 antagonists and D3 and 5HT1A partial agonists but with little or no alpha-adrenergic, anticholinergic or antihistaminic activity. They also share a long duration of action. Clinically, D2 partial agonists are effective antipsychotics and generally have useful antimanic and antidepressant activity. They are usually well tolerated, causing akathisia and insomnia only at the start of treatment, and are non-sedating. These drugs also share a very low risk of increased prolactin and of weight gain and accompanying metabolic effects. They may also have a relatively low risk of tardive dyskinesia. There is some evidence that they are preferred by patients to dopamine antagonists. Individual dopamineD2 partial agonists have much in common and as a group they differ importantly from dopamine D2 antagonists. Dopamine D2 partial agonists should be considered a distinct class of antipsychotics.Key pointsD2 partial agonists share many pharmacological and clinical propertiesD2 partial agonists differ in several important respects from D2 antagonistsD2 partial agonists should be considered a discrete class of antipsychotics D2 partial agonists share many pharmacological and clinical properties D2 partial agonists differ in several important respects from D2 antagonists D2 partial agonists should be considered a discrete class of antipsychotics

Background: Cotadutide is a GLP1/glucagon receptor dual agonist under development for the treatment of nonalcoholic steatohepatitis and type 2 diabetes (T2D) with diabetic kidney disease. Early-phase clinical studies show that cotadutide achieves clinically significant weight loss. We aimed to establish mechanistically to what extent this effect is mediated via changes in energy intake (EI) or energy expenditure (EE). Methods: We conducted a phase 2a single-center randomized double-blind placebo-controlled trial in overweight/obese adults (BMI 27-40 kg/m2) with T2D (HbA1c 6.5-8%). Participants underwent a 16-day single-blind placebo run-in and were randomized to double-blind 42-day cotadutide or placebo. Cotadutide was given subcutaneously, up to 300 µg daily. Primary outcome: % weight change from day 17 to day 59. Secondary outcomes: % and absolute changes in EI (ad libitum lunch), and EE (indirect calorimetry). Results: A total of 19 (63%) cotadutide and 9 (78%) placebo participants completed the study. Least-squares (LS) mean weight change was -3.98% (90% CI -4.85%, -3.10%) and -1.40% (90% CI -2.66%, -0.13%) for cotadutide and placebo, respectively, p= 0.011 between groups. The cotadutide group had a striking 35% lower EI vs. placebo: LS mean -35.0% (90% CI -61.8%, -8.2%), p=0.037. Total EE (kJ/kg lean mass) after cotadutide treatment decreased vs. placebo: -6.0% vs. 0.3%, p Conclusions: Weight loss caused by cotadutide is predominantly due to reduced EI rather than increased EE. Transient preservation of EE in the early phases of cotadutide treatment may reflect glucagon receptor engagement. Disclosure R. Golubic: None. M. Evans: Advisory Panel; Self; Pila Pharma, Zucara Therapeutics Inc., Other Relationship; Self; Abbott Diabetes, Medtronic, Novo Nordisk, Research Support; Self; AstraZeneca, Imcyse. J. Kennet: None. V. E. Parker: Employee; Self; AstraZeneca, Stock/Shareholder; Self; AstraZeneca. D. Robertson: Employee; Self; AstraZeneca, Employee; Spouse/Partner; GlaxoSmithKline plc., Stock/Shareholder; Self; AstraZeneca. D. Luo: None. L. Hansen: Employee; Self; AstraZeneca. L. Jermutus: Employee; Self; AstraZeneca, Stock/Shareholder; Self; AstraZeneca. P. Ambery: Employee; Self; AstraZeneca. A. Park: Other Relationship; Self; Novo Nordisk.

Background: Cotadutide, a dual glucagon-like peptide (GLP-1) and glucagon receptor agonist, is in development for NASH and T2DM with DKD. GLP-1 receptor agonists have been shown to delay the onset of macroalbuminuria in DKD. The glycemic and renal effects of cotadutide were assessed in a phase 2a, randomized, controlled trial (NCT03550378). Methods: The trial enrolled 41 patients with T2DM (HbA1c 6.5-10.5%) and CKD stage 3 (eGFR 30-59 mL/min/1.73 m2), on insulin and/or oral glucose-lowering therapy and BMI 25-45 kg/m2. Patients were randomized to once-daily subcutaneous cotadutide (n = 21) titrated up to 300 µg or placebo (PBO; n = 20) for 32 days. Endpoints included glucose response during a mixed meal tolerance test (MMTT), time spent within a target glucose range over a 7-day period on continuous glucose monitoring (CGM) and body weight. Exploratory measures included eGFR, UACR, C-peptide and NT-proBNP. Results: After 32 days, cotadutide compared with PBO reduced MMTT glucose AUC (-26.7%; 90% CI -34.6% to -18.8%; 7-day mean glucose -47.9 mg/dL vs. PBO) and increased CGM time spent in target range over 32 days by 36.0% vs. PBO to 78.7% (both p ≤ 0.003). Cotadutide was associated with 35.2% reduction in insulin dose, 0.88 µg/L increase in C-peptide and 3.7% reduction in body weight (all p ≤ 0.012). There was no change in eGFR. In patients with baseline micro- or macroalbuminuria (n = 18), UACR was reduced by 50.6% (p = 0.0504 vs. PBO). In addition, NT-proBNP level was reduced with cotadutide vs. PBO (-79.7 ng/L vs. -9.42 ng/L, p = 0.040). Safety and tolerability findings were consistent with the known mechanism of action of GLP-1 receptor agonists. There were no episodes of severe hypoglycemia, and CGM time < 54 mg/dL was 1.65% with cotadutide vs. 0.82% with PBO. Conclusion: In patients with T2DM and DKD, short term treatment with cotadutide had robust effects on glucose lowering. The reduction in albuminuria suggests that cotadutide has renoprotective potential in DKD, but further evaluation is warranted. Disclosure V. E. Parker: Employee; Self; AstraZeneca, Stock/Shareholder; Self; AstraZeneca. P. Ambery: Employee; Self; AstraZeneca. H. L. Heerspink: Consultant; Self; AbbVie Inc., Astellas Pharma Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Chinook, CSL Behring, Fresenius Medical Care, Gilead Sciences, Inc., Janssen Research & Development, LLC, Merck & Co., Inc., Mitsubishi Corporation Life Sciences Limited, Mundipharma International, Novo Nordisk, Retrophin, Inc., Research Support; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Janssen Research & Development, LLC. R. J. Mccrimmon: Advisory Panel; Self; Novo Nordisk Inc., Sanofi-Aventis, Board Member; Self; Novo Nordisk Foundation, Research Support; Self; AstraZeneca. L. Jermutus: Employee; Self; AstraZeneca, Stock/Shareholder; Self; AstraZeneca. T. Hoang: None. H. Schlichthaar: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk. F. W. Gibb: Speaker’s Bureau; Self; Abbott Diabetes. B. Wenzel: None. M. G. Posch: None. Y. Chang: None. M. Petrone: None. L. Hansen: Employee; Self; AstraZeneca.

Introduction Lurasidone is an atypical antipsychotic that was approved in Europe in 2014 for the treatment of schizophrenia in adults aged ≥ 18 years. Clinical experience with lurasidone in Europe is currently limited, and there is therefore a need to provide practical guidance on using lurasidone for the treatment of adults with schizophrenia. Methods A panel of European psychiatrists with extensive experience of prescribing lurasidone was convened to provide recommendations on using lurasidone to treat adults with schizophrenia. Results Extensive evidence from clinical trials and the panel’s clinical experience suggest that lurasidone is as effective as other atypical agents, with the possible exception of clozapine. Lurasidone is associated with a lower propensity for metabolic side effects (in particular, weight gain) and hyperprolactinaemia than most other atypical antipsychotics and has a relatively benign neurocognitive side effect profile. Patients switching to lurasidone from another antipsychotic may experience weight reduction and/or improvements in the ability to focus/concentrate. Most side effects with lurasidone (such as somnolence) are transitory, easily managed and/or ameliorated by dose adjustment. Akathisia and extrapyramidal symptoms may occur in a minority of patients, but these can be managed effectively with dose adjustment, adjunctive therapy and/or psychosocial intervention. Conclusions Given the crucial importance of addressing the physical as well as mental healthcare needs of patients, lurasidone is a rational therapeutic choice for adults with schizophrenia, both in the acute setting and over the long term. Funding Sunovion Pharmaceuticals Europe Ltd. Electronic supplementary material The online version of this article (10.1007/s40120-019-0138-z) contains supplementary material, which is available to authorized users.

Aim: the current study aimed to explore the effects of organized befriending for an Early Intervention in Psychosis (EIP) population.Methods: participants were randomly assigned to control or intervention groups. Those in the befriending arm were paired based on a shared interests questionnaire. Qualitative and quantitative methods were planned to assess experience and impact of the intervention across clinical and recovery outcomes. We aimed to recruit 60 participants, however only 16 participants completed the trial.Results: the study was unsuccessful due to issues with recruitment and retention of participants. We gathered feedback from those who withdrew, to understand this better.Conclusions: we offer our observations to other clinicians who may be considering similar research. A more assertive researcher-led approach over the first few meetings between matched pairs is likely to have been more effective in retaining participants' engagement in the study.

Mucin-type O-glycosylation involves the attachment of glycans to an initial O-linked N-acetylgalactosamine (GalNAc) on serine and threonine residues on proteins. This process in mammals is initiated and regulated by a large family of 20 UDP-GalNAc: polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts) (EC 2.4.1.41). The enzymes are encoded by a large gene family (GALNTs). Two of these genes, GALNT2 and GALNT3, are known as monogenic autosomal recessive inherited disease genes with well characterized phenotypes, whereas a broad spectrum of phenotypes is associated with the remaining 18 genes. Until recently, the overlapping functionality of the 20 members of the enzyme family has hindered characterizing the specific biological roles of individual enzymes. However, recent evidence suggests that these enzymes do not have full functional redundancy and may serve specific purposes that are found in the different phenotypes described. Here, we summarize the current knowledge of GALNT and associated phenotypes.

Mucins are a large family of heavily O-glycosylated proteins that cover all mucosal surfaces and constitute the major macromolecules in most body fluids. Mucins are primarily defined by their variable tandem repeat (TR) domains that are densely decorated with different O-glycan structures in distinct patterns, and these arguably convey much of the informational content of mucins. Here, we develop a cell-based platform for the display and production of human TR O-glycodomains (~200 amino acids) with tunable structures and patterns of O-glycans using membrane-bound and secreted reporters expressed in glycoengineered HEK293 cells. Availability of defined mucin TR O-glycodomains advances experimental studies into the versatile role of mucins at the interface with pathogenic microorganisms and the microbiome, and sparks new strategies for molecular dissection of specific roles of adhesins, glycoside hydrolases, glycopeptidases, viruses and other interactions with mucin TRs as highlighted by examples., Mucins play critical roles in maintaining the human microbiome, with their O-glycosylated tandem repeats (TRs) providing important cues for microbiota. Here, the authors develop a cellular platform for producing TRs with defined O-glycan structures to dissect the functions of TR O-glycosylation.

A hydropower station is under construction at Sikfors, northern Sweden and will be completed in 1991. The rock construction comprises a powerhouse in a rock shaft with 37 metres high walls, two intake shafts, two headrace tunnels, a surge gallery, a tailrace tunnel with an area of 210 m2 and a 43 m high vertical outlet shaft. The tailrace tunnel, the surge gallery and the outlet shaft are unlined. During the construction, several faults were encountered in the tunnels. In one case, special temporary support measures had to be taken and a set of steeply dipping fault planes caused some changes in the design of the outlet shaft. The different behaviour of the faults has corresponded to differences in grain-size distribution of the matrix and absence or presence of swelling clay and water. The encountered faults have been divided into three types with regard to their matrix: stable, pseudostable and unstable. The pseudostable fault type has not caused any excavation problems, but has been subject to comprehensive permanent support measures in order to prevent future damage.

Background and Aims: Previously, cotadutide demonstrated significant glucose- and body weight-lowering effects in doses up to 300 µg. We examined the safety and efficacy of cotadutide in doses up to 600 µg in patients with T2DM. Methods: In this double-blind, phase 2a study, 20 adults with T2DM (HbA1c ≤8.5%) were randomized to receive QD SC cotadutide (n=15) or placebo (n=5) for 77 days. A dose-escalation committee approved titrations >400 µg and ≤600 µg following a safety data review. Patients underwent continuous glucose monitoring. Results: The adverse event profile suggests that the highest clinically tolerated dose has not been identified. Nausea was reported by 3 (20%) patients treated with cotadutide, with one episode of vomiting. There was a significant reduction from baseline in the 7-day average glucose levels (Figure). By day 77, 76.9% of patients in the cotadutide group achieved a >5% body weight loss. A significant reduction in least-squares mean from baseline in ALT level with cotadutide versus placebo was reported (-7.17 U/L, 90% CI: -12.21, -2.14). Conclusions: Cotadutide was well-tolerated at doses up to 600 µg and reduced hyperglycemia, with clinically significant weight loss and beneficial effects on liver enzymes. Disclosure D. Robertson: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. L. Hansen: Employee; Self; AstraZeneca. M. Jain: Employee; Self; CSL Behring. Stock/Shareholder; Self; AstraZeneca. M. Petrone: Employee; Self; AstraZeneca. T. Wang: Employee; Self; AstraZeneca. T. Heise: Advisory Panel; Self; Mylan, Novo Nordisk A/S. Research Support; Self; ADOCIA, Aerami, Becton, Dickinson and Company, Biocon, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Gan & Lee Pharmaceuticals, MedImmune, Merck KGaA, Mylan, Nordic Bioscience, Novo Nordisk A/S, Poxel SA, Sanofi, Xeris Pharmaceuticals, Inc., Zealand Pharma A/S. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S. L. Jermutus: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. Funding AstraZeneca

Background and Aims: Cotadutide, a dual receptor agonist with glucagon-like peptide-1 (GLP-1) and glucagon activity, is being researched for the potential treatment of nonalcoholic steatohepatitis. Given the known effects of glucagon on hepatic glycogen and lipid metabolism, the aim of this phase 2a study was to investigate the effect of cotadutide on hepatic glycogen. Methods: In this double-blind, placebo-controlled study, 21 overweight or obese adults with type 2 diabetes mellitus (HbA1c ≤ 8%) were randomized to receive once-daily subcutaneous cotadutide (n = 12) or placebo (n = 9) for 28 days. Following 48 hours of standardized meals, serial magnetic resonance spectroscopy scans relying on signals from naturally abundant 13C were performed to measure glycogen, and liver fat was also estimated. Fasting amino acid and ketone levels were also assessed. Results: Significant reductions from baseline in postprandial hepatic glycogen content were observed with cotadutide (-100.2 mmol/L; 90% CI: -150.2, -50.1) vs. placebo (+5.5 mmol/L; 90% CI: -47.2, 58.3; P = 0.023). Statistically significant reductions in hepatic glycogen content were observed across serial measures and after a 14-hour fast (P < 0.05), with an overall change in glycogen AUC24h of -27.3% (P = 0.003) vs. placebo. In addition, a relative reduction in liver fat of 33.2% vs. placebo was reported (P = 0.006), and significant reductions in fasting alanine, glutamate, glycine, lysine, and threonine levels were also observed with cotadutide vs. placebo (all P ≤ 0.05). Beta-hydroxybutyrate and acetoacetate levels were not significantly different between the two arms. Conclusions: Cotadutide promoted a generalized reduction in hepatic glycogen and selected amino acid levels. Substantial reductions in liver fat were also observed with cotadutide, suggesting glucagon receptor engagement. Disclosure D. Robertson: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. L. Hansen: Employee; Self; AstraZeneca. P. Ambery: Employee; Self; AstraZeneca. R.L. Esterline: Employee; Self; AstraZeneca. L. Jermutus: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. Y. Chang: None. M. Petrone: Employee; Self; AstraZeneca. E. Johansson: None. L. Johansson: Employee; Self; Antaros Medical AB. Stock/Shareholder; Self; Antaros Medical AB. F.B. Sjöberg: None. V. Parker: None. Funding AstraZeneca

Antigorite is a key constituent of subducted slabs, and its dehydration is thought to be responsible for the generation of intermediate-depth earthquakes. The mechanical behaviour of antigorite at elevated pressure and temperature remains difficult to constrain experimentally: intracrystalline slip systems are hard to activate under typical laboratory timescales and microstructures do not always provide unambiguous evidence for dislocation creep. Here, we present recent laboratory data showing that antigorite might deform due to intracrystalline frictional slip and delamination, at least in the low temperature regime (

Congenital disorders of glycosylation are a growing group of rare genetic disorders caused by deficient protein and lipid glycosylation. Here, we report the clinical, biochemical, and molecular features of seven patients from four families with GALNT2-congenital disorder of glycosylation (GALNT2-CDG), an O-linked glycosylation disorder. GALNT2 encodes the Golgi-localized polypeptide N-acetyl-d-galactosamine-transferase 2 isoenzyme. GALNT2 is widely expressed in most cell types and directs initiation of mucin-type protein O-glycosylation. All patients showed loss of O-glycosylation of apolipoprotein C-III, a non-redundant substrate for GALNT2. Patients with GALNT2-CDG generally exhibit a syndrome characterized by global developmental delay, intellectual disability with language deficit, autistic features, behavioural abnormalities, epilepsy, chronic insomnia, white matter changes on brain MRI, dysmorphic features, decreased stature, and decreased high density lipoprotein cholesterol levels. Rodent (mouse and rat) models of GALNT2-CDG recapitulated much of the human phenotype, including poor growth and neurodevelopmental abnormalities. In behavioural studies, GALNT2-CDG mice demonstrated cerebellar motor deficits, decreased sociability, and impaired sensory integration and processing. The multisystem nature of phenotypes in patients and rodent models of GALNT2-CDG suggest that there are multiple non-redundant protein substrates of GALNT2 in various tissues, including brain, which are critical to normal growth and development.

Polypeptide GalNAc-transferase T3 (GalNAc-T3) regulates fibroblast growth factor 23 (FGF23) by O-glycosylating Thr178 in a furin proprotein processing motif RHT178R↓S. FGF23 regulates phosphate homeostasis and deficiency in GALNT3 or FGF23 results in hyperphosphatemia and familial tumoral calcinosis. We explored the molecular mechanism for GalNAc-T3 glycosylation of FGF23 using engineered cell models and biophysical studies including kinetics, molecular dynamics and X-ray crystallography of GalNAc-T3 complexed to glycopeptide substrates. GalNAc-T3 uses a lectin domain mediated mechanism to glycosylate Thr178 requiring previous glycosylation at Thr171. Notably, Thr178 is a poor substrate site with limiting glycosylation due to substrate clashes leading to destabilization of the catalytic domain flexible loop. We suggest GalNAc-T3 specificity for FGF23 and its ability to control circulating levels of intact FGF23 is achieved by FGF23 being a poor substrate. GalNAc-T3’s structure further reveals the molecular bases for reported disease-causing mutations. Our findings provide an insight into how GalNAc-T isoenzymes achieve isoenzyme-specific nonredundant functions., We thank ARAID, MEC (grant no. CTQ2013-44367-C2-2-P, BFU2016-75633-P and RTI2018-099592-B-C21), the National Institutes of Health (grant no. GM113534 and instrument grant no. GM113534-01S), the Danish National Research Foundation (grant no. DNRF107), the FCT-Portugal (grant no. UID/Multi/04378/2013) and Gobierno de Aragón (grant nos. E34_R17, E35_17R and LMP58_18) with FEDER (grant no. 2014-2020) funds for ‘Building Europe from Aragón’ for financial support. I.C. thanks the Universidad de La Rioja for the FPI grant. F.M. and H.C. thank FCT-Portugal for IF Investigator (IF/00780/2015), PTDC/BIA-MIB/31028/2017 and UID/Multi/04378/2019 projects, and PTNMR (grant no. ROTEIRO/0031/2013 and PINFRA/22161/2016). P.B. acknowledges support from the Labex EpiGenMed, an ‘Investissements d’avenir’ program (grant no. ANR-10-LABX-12-01). The CBS (Montpellier) is a member of France-BioImaging (FBI, ANR-10-INBS-04-01) and the French Infrastructure for Integrated Structural Biology (FRISBI, ANR-10-INBS-05). The research leading to these results has also received funding from the FP7 (2007–2013) under BioStruct-X (grant agreement nos. 283570 and BIOSTRUCTX_5186).

Introduction The aim of this study was to evaluate the short-term cost-utility of insulin degludec (degludec) versus insulin glargine 100 units/mL (glargine U100) for the treatment of type 2 diabetes in the basal–bolus subgroup of the head-to-head cardiovascular (CV) outcome trial, DEVOTE. Methods A cost-utility analysis was conducted over a 2-year time horizon using a decision analytic model to compare costs in patients receiving once daily degludec or glargine U100, both as part of a basal–bolus regimen, in addition to standard care. Clinical outcomes and patient characteristics were taken exclusively from DEVOTE, whilst health-related quality of life utilities and UK-specific costs (expressed in 2016 GBP) were obtained from the literature. The analysis was conducted from the perspective of the National Health Service. Results Degludec was associated with mean cost savings of GBP 28.78 per patient relative to glargine U100 in patients with type 2 diabetes at high CV risk. Cost savings were driven by the reduction in risk of diabetes-related complications with degludec, which offset the higher treatment costs relative to glargine U100. Degludec was associated with a mean improvement of 0.0064 quality-adjusted life-years (QALYs) compared with glargine U100, with improvements driven predominantly by lower rates of severe hypoglycemia with degludec versus glargine U100. Improvements in quality-adjusted life expectancy combined with cost neutrality resulted in degludec being dominant over glargine U100. Sensitivity analyses demonstrated that the incremental cost-utility ratio was stable to variations in the majority of model inputs. Conclusion The present short-term modeling analysis found that for the basal–bolus subgroup of patients in DEVOTE, with a high risk of CV events, degludec was cost neutral (no additional costs) compared with glargine U100 over a 2-year time horizon in the UK setting. Furthermore, there were QALY gains with degludec, particularly due to the reduction in the risk of severe hypoglycemia. Funding Novo Nordisk A/S. Trial Registration ClinicalTrials.gov identifier, NCT01959529. Electronic supplementary material The online version of this article (10.1007/s13300-018-0430-4) contains supplementary material, which is available to authorized users.

Dieser Beitrag illustriert anhand der Gestaltung einer mitarbeiterorientierten Fuhrungskultur, wie der Design Thinking (DT)-Ansatz im Rahmen einer Organisationsentwicklung genutzt werden kann. Unterstutzt durch eine rahmengebende Prozessbegleitung entwickelten vier selbstgesteuerte Teams, bestehend aus Mitarbeitenden der Daimler Group Services Berlin GmbH (DGSB), in einem DT-Prozess Konzepte zur Steigerung der Mitarbeiterzufriedenheit. In der Falldarstellung beschreiben wir die Herausforderungen, denen sich die DGSB gegenubersah und welche Zielvorgaben von Seiten der Geschaftsleitung in Bezug auf die Prozessdurchfuhrung gestellt wurden. Basierend auf diesen Vorgaben wurde ein zehnwochiges DT-Konzept entwickelt, dessen Kern drei Prasenzveranstaltungen bildete. Die Inhalte, Ziele und Ergebnisse dieses Vorgehens werden im Rahmen dieses Beitrags prasentiert, gefolgt von Optimierungsmoglichkeiten unseres DT-Konzeptes. Abschliesend diskutieren wir auf Basis unserer Beobachtungen, warum kritische Teaminteraktionen in einem DT-Prozess ein Team bei der Entwicklung einer guten Idee behindern konnen. Von diesen Uberlegungen ausgehend leiten wir Forschungsfragen ab, deren Untersuchung dazu beitragen kann, den Erfolg von Organisationsentwicklungen weiter zu steigern.

BMS-823778 is a potent and selective inhibitor of 11β-HSD1, an enzyme that regulates tissue-specific intracellular glucocorticoid metabolism and is a compelling target for the treatment of metabolic diseases. Metabolism of BMS-823778 was mediated mainly by polymorphic CYP2C19, with minor contributions from CYP3A4/5 and UGT1A4. The clinical pharmacokinetics (PK) of BMS-823778 was first investigated in healthy volunteers after single and multiple ascending doses. BMS-823778 was rapidly absorbed after the oral dose, and systemic exposure at steady state increased proportionally to the dose. Large intersubject variability in BMS-823778 exposure was likely because of the polymorphism of metabolic enzymes. The impact of genetic polymorphism of CYP2C19, UGT1A4, and CYP3A5 on BMS-823778 PK was assessed in healthy Chinese and Japanese subjects, as well as in a human absorption, distribution, metabolism, and excretion study in which all subjects were genotyped either before or after treatment. A clear trend of high exposure and low clearance was seen in poor metabolizers (PMs) of CYP2C19 compared with extensive (EM) and intermediate metabolizer (IM) subjects. The impact of UGT1A4 or CYP3A5 polymorphism on BMS-823778 PK was statistically not significant in CYP2C19 EM and IM subjects; however, in a subject with predicted CYP2C19 PM phenotype, the PK of BMS-823778 was affected significantly by UGT1A4 polymorphism. Overall, BMS-823778 was safe and well tolerated in healthy subjects after single or multiple oral doses. The PK of BMS-823778 was characterized by rapid absorption, and the systemic clearance directly correlated with the genetic polymorphism of CYP2C19.