Costs and health-related quality of life in patients with NMO spectrum disorders and MOG-antibody-associated disease: CHANCE(NMO) study

OBJECTIVE: To evaluate costs and health-related quality of life (HRQoL) of neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein-antibody associated disease (MOGAD).MethodsIn this multicenter cross-sectional study, data on consumption of medical and non-medical resources and work ability were assessed via patient questionnaires. Costs were analyzed in EUR for 2018 from the societal perspective. HRQoL was captured by the EuroQoL EQ-5D-5L questionnaire. Clinical data were retrieved from the Neuromyelitis Optica Study Group (NEMOS) database. RESULTS: Two hundred twelve patients (80% women; median age 50 [19-83] years; median disease duration 7 [0-43] years; median Expanded Disability Status Scale [EDSS] 3.5 [0-8.5]; 66% Aquaporin-4 IgG, 22% MOG IgG positive, 12% double seronegative) were analyzed. The mean total annual per capita cost of illness accounted for EUR (Euro) 59 574 (95% CI 51 225 to 68 293; USD [United States dollars] 70 297, 95% CI 60 445 to 80 586), and the mean index value of the EQ-5D-5L was 0.693 (95% CI 0.65 to 0.73). The most important cost drivers were informal care costs (28% of total costs), indirect costs (23%) and drugs (16%), especially immunotherapeutics. Costs showed a positive correlation with disease severity (ρ=0.56, 95% CI 0.45 to 0.65); in the EDSS 6.5-8.5 subgroup the mean annual costs were EUR 129 687 (95% CI 101 946 to 160 336; USD 153 031, 95% CI 120 296 to 189 196). The HRQoL revealed a negative correlation to disease severity (ρ=-0.69, 95% CI -0.76 to -0.61); in the EDSS 6.5-8.5 subgroup the EQ-5D-5L mean index value was 0.195 (95% CI 0.13 to 0.28). Neither antibody status nor disease duration influenced the total annual costs or HRQoL. CONCLUSION: These German data from the era without approved preventive immunotherapies show enormous effects of the diseases on costs and quality of life. An early and cost-effective therapy should be provided to prevent long-term disability and preserve quality of life

DSC studies of the conformational stability of barstar wild-type.

The temperature induced unfolding of barstar wild-type of bacillus amyloliquefaciens (90 residues) has been characterized by differential scanning microcalorimetry. The process has been found to be reversible in the pH range from 6.4 to 8.3 in the absence of oxygen. It has been clearly shown by a ratio of delta HvH/delta Hcal near 1 that denaturation follows a two-state mechanism. For comparison, the C82A mutant was also studied. This mutant exhibits similar reversibility, but has a slightly lower transition temperature. The transition enthalpy of barstar wt (303 kJ mol-1) exceeds that of the C82A mutant (276 kJ mol-1) by approximately 10%. The heat capacity changes show a similar difference, delta Cp being 5.3 +/- 1 kJ mol-1 K-1 for the wild-type and 3.6 +/- 1 kJ mol-1 K-1 for the C82A mutant. The extrapolated stability parameters at 25 degrees C are delta G0 = 23.5 +/- 2 kJ mol-1 for barstar wt and delta G0 = 25.5 +/- 2 kJ mol-1 for the C82A mutant

Crystal structures of the human neurokinin 1 receptor in complex with clinically used antagonists

Neurokinins (or tachykinins) are peptides that modulate a wide variety of human physiology through the neurokinin G protein-coupled receptor family, implicated in a diverse array of pathological processes. Here we report high-resolution crystal structures of the human NK receptor (NKR) bound to two small-molecule antagonist therapeutics - aprepitant and netupitant and the progenitor antagonist CP-99,994. The structures reveal the detailed interactions between clinically approved antagonists and NKR, which induce a distinct receptor conformation resulting in an interhelical hydrogen-bond network that cross-links the extracellular ends of helices V and VI. Furthermore, the high-resolution details of NKR bound to netupitant establish a structural rationale for the lack of basal activity in NKR. Taken together, these co-structures provide a comprehensive structural basis of NKR antagonism and will facilitate the design of new therapeutics targeting the neurokinin receptor family

High-resolution crystal structure of parathyroid hormone 1 receptor in complex with a peptide agonist

Parathyroid hormone 1 receptor (PTH1R) is a class B multidomain G-protein-coupled receptor (GPCR) that controls calcium homeostasis. Two endogenous peptide ligands, parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP), activate the receptor, and their analogs teriparatide and abaloparatide are used in the clinic to increase bone formation as an effective yet costly treatment for osteoporosis. Activation of PTH1R involves binding of the peptide ligand to the receptor extracellular domain (ECD) and transmembrane domain (TMD), a hallmark of class B GPCRs. Here, we present the crystal structure of human PTH1R in complex with a peptide agonist at 2.5-Å resolution, allowing us to delineate the agonist binding mode for this receptor and revealing molecular details within conserved structural motifs that are critical for class B receptor function. Thus, this study provides structural insight into the function of PTH1R and extends our understanding of this therapeutically important class of GPCRs

Short range versus long range structure in Cu In,Ga Se2, Cu In,Ga 3Se5, and Cu In,Ga 5Se8

The Cu poor phases Cu In,Ga 3Se5 and Cu In,Ga 5Se8 play an important role both for understanding the Cu In,Ga Se material system and for growing high efficiency Cu In,Ga Se2 thin film solar cells. Using extended X ray absorption fine structure spectroscopy, we have studied the element specific short range structure of Cu In,Ga Se2, Cu In,Ga 3Se5, and Cu In,Ga 5Se8 alloys spanning the entire compositional range. The materials feature different local atomic arrangements and the element specific average bond lengths remain nearly constant despite significant changes of the lattice constants with increasing In to Ga ratio and decreasing Cu content. In particular, the average bond lengths of Cu Se and Ga Se are almost identical while the average In Se bond length is significantly longer in all three phases. The distance between lattice sites with mixed site occupation therefore corresponds to the weighted average of different element specific bond lengths rather than to the individual bond lengths themselves. Furthermore, the increasing number of vacancies with decreasing Cu content lead to both a significant unit cell contraction and a slight bond length expansion. The crystallographic long range structure and the element specific short range structure thus describe different structural aspects that are certainly interrelated but obviously not identica

Discrepancy between integral and local composition in off stoichiometric Cu2ZnSnSe4 kesterites A pitfall for classification

High efficiency kesterite based thin film solar cells typically feature Cu poor, Zn rich absorbers although secondary phases occur easily in non stoichiometric Cu2ZnSnSe4. We therefore applied high resolution X ray fluorescence analysis using a synchrotron nanobeam to study the local composition of a CZTSe cross section lamella cut from a sample with an integral composition of Zn Sn 1.37 and Cu Zn Sn 0.55. We find submicrometer sized ZnSe , SnSe SnSe2 , and even CuSe Cu2Se like secondary phases, while the local compositions of the kesterite are highly Zn rich yet barely Cu poor with 1.5 Zn Sn 2.2 and Cu Zn Sn 1.0. Consequently, great care must be taken when relating the integral composition to other material properties including the device performanc

Discrepancy between integral and local composition in off-stoichiometric Cu2ZnSnSe4 kesterites: a pitfall for classification

High-efficiency kesterite-based thin film solar cells typically feature Cu-poor, Zn-rich absorbers although secondary phases occur easily in non-stoichiometric CuZnSnSe. We therefore applied high-resolution X-ray fluorescence analysis using a synchrotron nanobeam to study the local composition of a CZTSe cross section lamella cut from a sample with an integral composition of Zn/Sn = 1.37 and Cu/(Zn+Sn) = 0.55. We find submicrometer-sized ZnSe-, SnSe/SnSe-, and even CuSe/CuSe-like secondary phases, while the local compositions of the kesterite are highly Zn-rich yet barely Cu-poor with 1.5 ≤ Zn/Sn ≤ 2.2 and Cu/(Zn+Sn) ∼ 1.0. Consequently, great care must be taken when relating the integral composition to other material properties including the device performance.This work was funded by ESRF, DFG (Deutsche Forschungsgemeinschaft) under Grant No. SCHN 1283/2-1, BMBF (Bundesministerium für Bildung und Forschung) under the “nano@work” project (Grant No. 05 K16SJ1), KESTCELLS 316488, FP7-PEOPLE-2012 ITN, Multi-ITN project, and MINECO (Ministerio de Economía y Competitividad de España) under the NASCENT Project (ENE2014-56237-C4-1-R). S.G. thanks the Government of Spain for the FPI fellowship (BES-2014-068533) and E.S. for the “Ramón y Cajal” fellowship (RYC-2011-09212)

Rubidium segregation at random grain boundaries in Cu(In,Ga)Se2 absorbers

Solar cells based on Cu(In,Ga)Se absorbers are the most efficient ones among all thin film photovoltaics. The current world record efficiency was attained by applying a rubidium fluoride (RbF) post deposition treatment (PDT) to the absorber. However, it is still not clear why the introduced Rb improves the solar cell performance. In order to investigate the beneficial effect of Rb, a Cu(In,Ga)Se absorber was grown on a Mo coated alkali free substrate and subjected to a RbF PDT. This pure RbF PDT without any additional alkalis from the substrate leads to a strong increase in solar cell efficiency. A thin cross sectional lamella was cut out of the layer stack and investigated via a combination of electron microscopy and high resolution synchrotron based methods. This combinatory approach provides clear indications of the origin of the beneficial effect of Rb. It is evident that Rb agglomerates at detrimental random high angle grain boundaries and dislocation cores, where it likely passivates defects, which would otherwise lead to a recombination of carriers. In contrast, Rb does not agglomerate at benign Σ3 twin boundaries. Additionally, Rb segregates at the interface between the absorber and the MoSe layer.This work was financially supported by the German Federal Ministry for Economic Affairs and Energy under the speedCIGS project (contract number: 0324095E)