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The diffraction efficiencies of modified sinusoidal and blazed gratings are investigated in the high spatial frequency regime by rigorous numerical methods and are compared to experimentally manufactured gratings. The introduced modifications take actual technological induced variations of the profile geometries, such as specific corner rounding, into account. The high spatial frequency regime (resonance regime) is characterized by a local grating period, g, to wavelength, λ, ratio of 0.7 ≤ g/λ ≤ 4 and shows an important relevance for applications in spectroscopy and diffractive imaging. The investigations are carried out for both reflection on metallic surfaces and transmission of dielectric structures over a broad range of grating periods and incidence angles. It was found that near the grating resonance, the more simply producible sine gratings can compete in diffraction efficiency with sawtooth structures. Additionally, for certain application conditions, holographically modified sine structures achieve higher efficiencies than the ideal sine profile. It is also shown that holographic sinusoidal-like profiles measured by AFM can be fitted to a super-Gaussian shape, which is then used to inversely reconstruct the structure profiles from efficiency data.

Given a finite subset A of a distributive lattice, its total orderization to(A) is a natural transformation of A into a totally ordered set. Recently, the author showed that multivariate maps on distributive lattices which remain invariant under total orderizations generalize various maps on vector lattices, including bounded orthosymmetric multilinear maps and finite sums of bounded orthogonally additive polynomials. Therefore, a study of total orderization invariant maps on distributive lattices provides new perspectives for maps widely researched in vector lattice theory. However, the unwieldy notation of total orderizations can make calculations extremely long and difficult. In this paper we resolve this complication by providing considerably simpler characterizations of total orderization maps. Utilizing these easier representations, we then prove that a lattice multi-homomorphism on a distributive lattice is total orderization invariant if and only if it is symmetric, and we show that the diagonal of a symmetric lattice multi-homomorphism is a lattice homomorphism, extending known results for orthosymmetric vector lattice homomorphisms. [ABSTRACT FROM AUTHOR]

We provide two new characterizations of bounded orthogonally additive polynomials from a uniformly complete vector lattice into a convex bornological space using separately two polynomial identities of Kusraeva involving the root mean power and the geometric mean. Furthermore, it is shown that a polynomial on a vector lattice is orthogonally additive whenever it is orthogonally additive on the positive cone. These results improve recent characterizations of bounded orthogonally additive polynomials by G. Buskes and the author. [ABSTRACT FROM AUTHOR]

A letter to the editor on human food preferences which are associated with a 5-HT2A serotonergic receptor polymorphism is presented.

O objetivo deste trabalho é investigar a associação entre fatores de risco e morbidade cardiovascular com mortalidade em idosos longevos. Noventa e um por cento da população com idade superscript three 80 anos (n = 193) de Veranópolis, Rio Grande do Sul, no ano de 1996, foram avaliados para a detecção de fatores de risco e morbidade cardiovascular. Acompanhou-se esta população durante 3 anos e registraram-se os casos de óbitos. Os dados foram analisados por análise univariada e multivariada por regressão logística. Ocorreram 41 (21%) óbitos (20 homens e 21 mulheres). As mortes foram distribuídas ao longo do período estudado como se segue: 3 (7,3%) no primeiro ano, 8 (19,5%) no segundo ano e 30 (73,2%) no terceiro ano. Observou-se associação significativa de óbito com as seguintes características: pressão arterial diastólica (PAD), colesterol total (CT), LDL-C, ApoA-I, acidente vascular encefálico prévio (AVC), bloqueio do ramo direito (BRD) e hipertrofia ventricular esquerda (HVE) ao ECG. Os sobreviventes apresentaram níveis mais elevados de PAD, CT, LDL-C e ApoA-I. AVC, BRD e HVE. A análise multivariada mostrou que as variáveis eram fatores de risco independentes. Os fatores de risco cardiovascular parecem atuar de forma diferenciada em longevos.

OBJECTIVE: To establish the allelic and genotypic frequencies related to apolipoprotein E (ApoE) polymorphism and association of the genotypes with risk factors and cardiovascular morbidity in an elderly population with longevity. METHODS: We analyzed 70 elderly patients aged 80 years or more who were part of the Projeto Veranópolis. We used the gene amplification technique through the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and cleavage with the restriction enzyme Hha I to identify the ApoE genotypes. The most frequent genotypes were compared considering biological variables and cardiovascular risks and morbidity. RESULTS: The frequencies of the E2, E3, and E4 alleles were 0.05, 0.84, and 0.11, respectively, and of the genotypes were as follows: E3E3 (0.70), E3E4 (0.22), E2E3 (0.06), and E2E2 (0.02). Individuals with the E3E4 had a mean age greater than those with the E3E3. No association was observed between the genotypes and the variables analyzed, except for obesity, which was associated with the E3E3 genotype. Individuals with the E3E4 genotype had high levels of LDL-cholesterol and fibrinogen as compared with those with the E3E3 genotype. CONCLUSION: The results suggest that the E4E4 genotype may be associated with early mortality. A balance between the protective or neutral factors and the cardiovascular risk factors may occur among the individuals with different genotypes, attenuating the negative effects of the E4 allele.

Implementation strategies for pharmacogenetic testing have been largely limited to major academic medical centers and large health systems, threatening to exacerbate healthcare disparities for rural and tribal populations. There exists a need in Montana (United States)-a state where two-thirds of the population live in rural areas and with a large proportion of tribal residents-to develop novel strategies to make pharmacogenetic testing more broadly available. We established partnerships between University of Montana (UM) and three early adopter sites providing patient-centered care to historically neglected populations. We conducted 45 semi-structured interviews with key stakeholders at each site and solicited participant feedback on the utility of a centralized pharmacogenetic service at UM offering consultations to patients and providers statewide via telehealth. For settings serving rural patients-tribal and non-tribal-participants described healthcare facilities without adequate infrastructure, personnel, and funding to implement pharmacogenetic services. Participants serving tribal communities stressed the need for ethical practices for collecting biospecimens and returning genetic results to patients, largely due to historical and contemporary traumas experienced by tribal populations with regard to genetic research. Participants expressed that pharmacogenetic testing could benefit patients by achieving therapeutic benefit sooner, reducing the risk of side effects, and improving adherence outcomes for patients with limited access to follow-up services in remote areas. Others expressed concern that financial barriers to pharmacogenetic testing for patients of lower socioeconomic status would further exacerbate inequities in care. Participants valued the role of telehealth to deliver pharmacogenetic consults from a centralized service at UM, describing the ability to connect providers and patients to resources and expertise as imperative to driving successful pharmacogenetic implementation. Our results support strategies to improve access to pharmacogenetic testing for neglected patient populations and create opportunities to reduce existing healthcare inequities. By exploring critical challenges for pharmacogenetic implementation focused on serving underserved communities, this work can help guide equitable frameworks to serve as a model for other resource-limited settings looking to initiate pharmacogenetic testing., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Leitch, Killam, Brown, Katseanes, George, Schwanke, Loveland, Elias, Haney, Krebsbach, Muzquiz, Trinidad and Woodahl.)

Background & Aims: We evaluated the effectiveness of sofosbuvir/velpatasvir (SOF/VEL) in difficult-to-treat PWIDs with presumed high risk for non-adherence to antiviral therapy using an innovative concept involving their opioid agonist therapy (OAT) facility., Methods: N = 221 patients (m/f: 168/53; median age: 44.7 years (IQR 16.9); HCV-genotype 3: 45.2%; cirrhosis: 33.9%) treated with SOF/VEL were included. PWIDs at high risk for non-adherence to DAA therapy (n = 122) received HCV treatment alongside OAT under the supervision of medical staff ("directly observed therapy", DOT). These patients were compared to patients with presumed excellent drug compliance, who were treated in a "standard setting" (SS) of SOF/VEL prescription at a tertiary care center (n = 99)., Results: DOT-patients (n = 122/221; 55.2%) were younger than SS-patients (median age: 41.3 vs. 53.0 years), all had psychiatric comorbidities and most had a poor socioeconomic status. 83/122 (68.0%) reported ongoing intravenous drug use. Within the DOT-group, SVR12 was achieved in 99.1% (95% CI: 95.0-100; n = 109/110) with one patient experiencing treatment failure, while n = 12/122 (9.8%) patients were excluded due to loss of follow-up (FU). 5 patients showed HCV reinfection after achieving SVR12. SS-patients achieved SVR in 96.6% (95% CI: 90.3-99.3%; n = 84/87) after exclusion of 10/99 (10.1%) patients who were lost to FU and 2 patients who died prior to SVR12 due to reasons not related to DAA therapy., Conclusions: SOF/VEL given as DOT along with OAT in PWIDs at high risk of non-adherence to antiviral therapy including those with ongoing intravenous drug use resulted in excellent SVR rates similar to patients with presumed "excellent compliance" under standard drug intake., Competing Interests: C. Schmidbauer (schmidbauer.c@gmail.com): received travel support from Gilead, Abbvie and Gebro; and speaking honoraria from Abbvie. M. Schwarz (michael.schwarz@wienkav.at): received travel support from MSD, Sandoz, BMS and Abbvie; and speaking honoraria from BMS. A. Schütz (angelika.schuetz@suchthilfe.at): is employed by Suchthilfe Wien gGmbH and has no conflicts of interest. R. Schubert (raphael.schubert@outlook.at): is employed by Suchthilfe Wien gGmbH and received travel support from Gilead. C. Schwanke (cornelia.schwanke@suchthilfe.at): is employed by Suchthilfe Wien gGmbH and has no conflicts of interest. E. Gutic (enisa.gutic@extern.wienkav.at): received travel support from Gilead and Abbvie. R. Pirker (roxana.pirker@aon.at): no conflicts of interest. T. Lang (tobiaslang1904@gmail.com): no conflicts of interest. T. Reiberger (thomas.reiberger@meduniwien.ac.at): received grant support from Abbvie, Boehringer- Ingelheim, Gilead, MSD, Philips Healthcare, Gore; speaking honoraria from Abbvie, Gilead, Gore, Intercept, Roche, MSD; consulting/advisory board fees from Abbvie, Bayer, Boehringer-Ingelheim, Gilead, Intercept, MSD, Siemens; and travel support from Boehringer-Ingelheim, Gilead and Roche. H. Haltmayer (hans.haltmayer@suchthilfe.at): is employed by Suchthilfe Wien gGmbH and has no conflicts of interest. M. Gschwantler (michael.gschwantler@wienkav.at): received grants from Abbvie, Gilead, MSD; speaking honoraria from Abbvie, Gilead, MSD, Janssen, Roche, Intercept; consulting/advisory board fees from Abbvie, Gilead, MSD, Janssen, Roche, Intercept. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Congenital disorders of glycosylation (CDG) are a growing group of inborn metabolic disorders with multiorgan presentation. SLC39A8-CDG is a severe subtype caused by biallelic mutations in the manganese transporter SLC39A8, reducing levels of this essential cofactor for many enzymes including glycosyltransferases. The current diagnostic standard for disorders of N-glycosylation is the analysis of serum transferrin. Exome and Sanger sequencing were performed in two patients with severe neurodevelopmental phenotypes suggestive of CDG. Transferrin glycosylation was analyzed by high-performance liquid chromatography (HPLC) and isoelectric focusing in addition to comprehensive N-glycome analysis using matrix-assisted laser desorption ionization time of flight (MALDI-TOF) mass spectrometry (MS). Atomic absorption spectroscopy was used to quantify whole blood manganese levels. Both patients presented with a severe, multisystem disorder, and a complex neurological phenotype. Magnetic resonance imaging (MRI) revealed a Leigh-like syndrome with bilateral T2 hyperintensities of the basal ganglia. In patient 1, exome sequencing identified the previously undescribed homozygous variant c.608T>C [p.F203S] in SLC39A8. Patient 2 was found to be homozygous for c.112G>C [p.G38R]. Both individuals showed a reduction of whole blood manganese, though transferrin glycosylation was normal. N-glycome using MALDI-TOF MS identified an increase of the asialo-agalactosylated precursor N-glycan A2G1S1 and a decrease in bisected structures. In addition, analysis of heterozygous CDG-allele carriers identified similar but less severe glycosylation changes. Despite its reliance as a clinical gold standard, analysis of transferrin glycosylation cannot be categorically used to rule out SLC39A8-CDG. These results emphasize that SLC39A8-CDG presents as a spectrum of dysregulated glycosylation, and MS is an important tool for identifying deficiencies not detected by conventional methods., (© 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Background: Directly acting antivirals (DAA) against hepatitis C virus (HCV) infection have facilitated sustained virologic response (SVR) rates >90% in clinical studies. Yet, real life data regarding DAA treatment in people who inject drugs (PWIDs) are scarce. We evaluated the effectiveness of glecaprevir/pibrentasvir (G/P) in difficult-to-treat PWIDs with presumed high risk of non-adherence to DAA therapy using the concept of directly observed therapy involving their opioid substitution therapy (OST) facility., Methods: N = 145 patients (m/f: 91/54; median age: 41.1 (IQR 19.5) years; HCV-genotype (GT) 1/2/3/4: 82/1/56/5, GT3: 38.6%; cirrhosis: n = 6; 4.1%) treated with G/P were included. PWIDs at high risk for non-adherence to DAA therapy received HCV treatment together with their OST under the supervision of medical staff ("directly observed therapy", DOT). The effectiveness of G/P given as DOT in PWIDs with presumed high risk of non-adherence to DAA therapy was compared to patients with suspected "excellent compliance" in the "standard setting" (SS) of G/P prescription at a tertiary care center and self-managed G/P intake at home. Treatment duration was 8-16 weeks according to the G/P drug label., Results: DOT-patients (n = 74/145; 51.0%) were younger than SS-patients (median 38.7, IQR 12.5 vs. median 50.6, IQR 20.3 years), all had psychiatric co-morbidities and most had a poor socioeconomic status. 50/74 (67.6%) reported ongoing intravenous drug use (IDU). SVR was achieved in n = 70/74 (94.6%) patients with n = 3 being lost to follow-up (FU) and n = 1 showing nonresponse to therapy. SS-patients achieved SVR in 97.2% (69/71) with n = 1 patient being lost to FU and n = 1 patient with GT3 showing HCV relapse., Conclusion: G/P given as DOT along with OST in PWIDs with high risk of non-adherence to DAA therapy resulted in similarly high SVR rates (94.6%) as in patients with presumed "excellent compliance" under standard drug intake., Competing Interests: Competing Interests: C. Schmidbauer (schmidbauer.c@gmail.com): received travel support from Gilead, Abbvie and Gebro. R. Schubert (raphael.schubert@suchthilfe.at): is employed by Suchthilfe Wien gGmbH and received travel support from Gilead. A. Schütz (angelika.schuetz@suchthilfe.at): is employed by Suchthilfe Wien gGmbH and has no conflicts of interest. C. Schwanke (cornelia.schwanke@suchthilfe.at): is employed by Suchthilfe Wien gGmbH and has no conflicts of interest. J. Luhn (julian.luhn@suchthilfe.at): is employed by Suchthilfe Wien gGmbH and has no conflicts of interest. E. Gutic (enisa.gutic@extern.wienkav.at): received travel support from Gilead and Abbvie. R. Pirker (roxana.pirker@aon.at): no conflicts of interest. T. Lang (tobiaslang1904@gmail.com): no conflicts of interest. T. Reiberger (thomas.reiberger@meduniwien.ac.at): received grant support from Abbvie, Boehringer-Ingelheim, Gilead, MSD, Philips Healthcare, Gore; speaking honoraria from Abbvie, Gilead, Gore, Intercept, Roche, MSD; consulting/advisory board fees from Abbvie, Bayer, Boehringer-Ingelheim, Gilead, Intercept, MSD, Siemens; and travel support from Boehringer-Ingelheim, Gilead and Roche. H. Haltmayer (hans.haltmayer@suchthilfe.at): is employed by Suchthilfe Wien gGmbH and has no conflicts of interest. M. Gschwantler (michael.gschwantler@wienkav.at): received grants from Abbvie, Gilead, MSD; speaking honoraria from Abbvie, Gilead, MSD, Janssen, Roche, Intercept; consulting/advisory board fees from Abbvie, Gilead, MSD, Janssen, Roche, Intercept. Suchthilfe Wien gGmbH represents a governmental non-profit organization financed by the City of Vienna and the Austrian Ministry of Health. Suchthilfe Wien gGmbH did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors’ salaries. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Suchthilfe Wien gGmbH provided support in the form of salaries for authors [Raphael Schubert, Angelika Schütz, Cornelia Schwanke, Julian Luhn, Hans Haltmayer], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.“

Objectives: In vitro fertilization (IVF) has been linked to an increased risk for imprinting disorders in offspring. The data so far have predominantly been retrospective, comparing the rate of IVF conceptions in affected patients with controls. We describe a series of fetuses with omphalocele that were tested for Beckwith-Wiedemann syndrome (BWS) and subsequently ascertained as to whether pregnancies were conceived by assisted reproductive technologies (ART)., Methods: Fetuses were tested for BWS by Southern blot, PCR based methods, and methylation analysis to identify the imprinting status at primarily the IC2 locus, KCNQ1OT1, as well as IC1, H19/IGF-2. Some fetuses were also tested for uniparental disomy of chromosome 11p., Results: We tested 301 fetuses with omphalocele for BWS. Forty samples were positive. Sixteen were from IVF pregnancies, for an overall rate of 40%. Such as high proportion of IVF pregnancies in a series of BWS-positive fetuses has not been described previously. Possible factors such as twinning and ascertainment bias are discussed., Conclusion: We found about a 20-fold overrepresentation of IVF cases in fetuses with BWS/omphalocele when compared with the rate of ART pregnancies in the USA (p < .0001). Our series provides support for an association of IVF and BWS. Patients should be counseled about these risks and made aware of the availability of prenatal diagnosis for detection.

Deletion and truncation mutations in the X-linked gene CASK are associated with severe intellectual disability (ID), microcephaly and pontine and cerebellar hypoplasia in girls (MICPCH). The molecular origin of CASK-linked MICPCH is presumed to be due to disruption of the CASK-Tbr-1 interaction. This hypothesis, however, has not been directly tested. Missense variants in CASK are typically asymptomatic in girls. We report three severely affected girls with heterozygous CASK missense mutations (M519T (2), G659D (1)) who exhibit ID, microcephaly, and hindbrain hypoplasia. The mutation M519T results in the replacement of an evolutionarily invariant methionine located in the PDZ signaling domain known to be critical for the CASK-neurexin interaction. CASK M519T is incapable of binding to neurexin, suggesting a critically important role for the CASK-neurexin interaction. The mutation G659D is in the SH3 (Src homology 3) domain of CASK, replacing a semi-conserved glycine with aspartate. We demonstrate that the CASK G659D mutation affects the CASK protein in two independent ways: (1) it increases the protein's propensity to aggregate; and (2) it disrupts the interface between CASK's PDZ (PSD95, Dlg, ZO-1) and SH3 domains, inhibiting the CASK-neurexin interaction despite residing outside of the domain deemed critical for neurexin interaction. Since heterozygosity of other aggregation-inducing mutations (e.g., CASK W919R ) does not produce MICPCH, we suggest that the G659D mutation produces microcephaly by disrupting the CASK-neurexin interaction. Our results suggest that disruption of the CASK-neurexin interaction, not the CASK-Tbr-1 interaction, produces microcephaly and cerebellar hypoplasia. These findings underscore the importance of functional validation for variant classification.

Introduction: In the era of direct-acting antivirals, hepatitis C virus (HCV) genotype (GT) 3 remains as the most difficult-to-treat HCV-GT. Currently, data on the efficacy of ledipasvir/sofosbuvir plus ribavirin (SOF/LDV+RBV) in GT3-infected patients are limited. We investigated the efficacy of this regimen in a real-life cohort from Austria., Patients and Methods: A total of 55 patients with HCV-GT3 and compensated liver disease (20% treatment-experienced, 33% with cirrhosis, 7% with HIV coinfection) from four Austrian hepatitis centers received treatment with SOF/LDV+RBV for 12 weeks. The primary endpoint was sustained virological response 12 weeks after end of therapy (SVR12)., Results: In the modified intention-to-treat analysis - excluding patients lost to follow-up - the overall SVR12 rate was 94% (95% confidence interval: 84-99%). In treatment-naive and treatment-experienced patients, SVR12 rates were 95 and 89%, respectively. SVR12 rate was 91% in patients without cirrhosis and 100% in patients with cirrhosis. There were no serious adverse events. Viral sequencing did not show the presence of any resistance-associated substitutions in any of the three relapsed patients., Conclusion: Despite a very weak antiviral activity of ledipasvir against HCV-GT3 in vitro, a 12-week course of SOF/LDV+RBV was highly effective, with a 94% SVR12 rate in our cohort of compensated HCV-GT3-infected patients. Thus, if pangenotypic NS5A inhibitors are not available or not reimbursed by insurances, SOF/LDV+RBV seems to be an effective alternative in patients with HCV-GT3 infection.