Impact of Different Active-Speech-Ratios on PESQ’s Predictions in Case of Independent and Dependent Losses (in Presence of Receiver-Side Comfort-Noise)

This paper deals with the investigation of PESQ’s behavior under independent and dependent loss conditions from an Active-Speech-Ratio perspective in presence of receiver-side comfort-noise. This reference signal characteristic is defined very broadly by ITU-T Recommendation P.862.3. That is the reason to investigate an impact of this characteristic on speech quality prediction more in-depth. We assess the variability of PESQ’s predictions with respect to Active-Speech-Ratios and loss conditions, as well as their accuracy, by comparing the predictions with subjective assessments. Our results show that an increase in amount of speech in the reference signal (expressed by the Active-Speech-Ratio characteristic) may result in an increase of the reference signal sensitivity to packet loss change. Interestingly, we have found two additional effects in this investigated case. The use of higher Active-Speech-Ratios may lead to negative shifting effect in MOS domain and also PESQ’s predictions accuracy declining. Predictions accuracy could be improved by higher packet losses

Interaction of hyperalgesia and sensory loss in complex regional pain syndrome type I (CRPS I)

Sensory abnormalities are a key feature of Complex Regional Pain Syndrome (CRPS). In order to characterise these changes in patients suffering from acute or chronic CRPS I, we used Quantitative Sensory Testing (QST) in comparison to an age and gender matched control group

The Human Phenotype Ontology in 2024: phenotypes around the world

\ua9 The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research. The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs

Polygenic burden in focal and generalized epilepsies

Rare genetic variants can cause epilepsy, and genetic testing has been widely adopted for severe, paediatric-onset epilepsies. The phenotypic consequences of common genetic risk burden for epilepsies and their potential future clinical applications have not yet been determined. Using polygenic risk scores (PRS) from a European-ancestry genome-wide association study in generalized and focal epilepsy, we quantified common genetic burden in patients with generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) from two independent non-Finnish European cohorts (Epi25 Consortium, n = 5705; Cleveland Clinic Epilepsy Center, n = 620; both compared to 20 435 controls). One Finnish-ancestry population isolate (Finnish-ancestry Epi25, n = 449; compared to 1559 controls), two European-ancestry biobanks (UK Biobank, n = 383 656; Vanderbilt biorepository, n = 49 494), and one Japaneseancestry biobank (BioBank Japan, n = 168 680) were used for additional replications. Across 8386 patients with epilepsy and 622 212 population controls, we found and replicated significantly higher GE-PRS in patients with generalized epilepsy of European-ancestry compared to patients with focal epilepsy (Epi25: P = 1.64 710-15; Cleveland: P = 2.85 710-4; Finnish-ancestry Epi25: P = 1.80 710-4) or population controls (Epi25: P = 2.35 710-70; Cleveland: P = 1.43 710-7; Finnish-ancestry Epi25: P = 3.11 710-4; UK Biobank and Vanderbilt biorepository meta-analysis: P = 7.99 710-4). FE-PRS were significantly higher in patients with focal epilepsy compared to controls in the non-Finnish, non-biobank cohorts (Epi25: P = 5.74 710-19; Cleveland: P = 1.69 710-6). European ancestry-derived PRS did not predict generalized epilepsy or focal epilepsy in Japanese-ancestry individuals. Finally, we observed a significant 4.6-fold and a 4.5-fold enrichment of patients with generalized epilepsy compared to controls in the top 0.5% highest GE-PRS of the two non-Finnish European cohorts (Epi25: P = 2.60 710-15; Cleveland: P = 1.39 710-2). We conclude that common variant risk associated with epilepsy is significantly enriched in multiple cohorts of patients with epilepsy compared to controls-in particular for generalized epilepsy. As sample sizes and PRS accuracy continue to increase with further common variant discovery, PRS could complement established clinical biomarkers and augment genetic testing for patient classification, comorbidity research, and potentially targeted treatment

Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

ÚDRŽBA JAKO NÁSTROJ ZVYŠOVÁNÍ VÝKONNOSTI CHEMICKO-TECHNOLOGICKÉHO VÝROBNÍHO PROCESU

Reliability, flexibility and speed belong among particularly valued parameters of contractor. In manufacturing companies, the achievement thereof is significantly limited by the reliability of production equipment. The aim of the article is to analyse an applied production equipment maintenance system with heavily utilized production equipment, and to define guidelines for its improvement. A content analysis of information obtained in a primary qualitative research and a comparison with theoretical approaches made it possible to define an adequate combination of various types of maintenance, including methods and tools that are not primarily intended for the examined type of manufacturing processes.Mimořádně ceněnými parametry dodavatele jsou spolehlivost, flexibilita a rychlost. Jejich dosažení je ve výrobních podnicích významně limitováno spolehlivostí výrobního zařízení. Zejména u velmi vytíženého výrobního zařízení je proto třeba věnovat trvalou pozornost managementu údržby a neustále hledat cesty jeho zlepšování, a to se zohledněním specifik konkrétního výrobního procesu. Cílem článku proto je analyzovat reálně aplikovaný systém údržby výrobního zařízení (v podniku chemického průmyslu), jehož kapacita je využívána na více než 95 % a na základě identifikovaných nedostatků vymezit hlavní směry jeho zlepšení. Obsahová analýza informací získaných primárním kvalitativním výzkumem a komparace s teoretickými přístupy k údržbě výrobního zařízení umožnila vymezit, že adekvátní systém údržby zkoumaného výrobního zařízení musí být založen na vhodné kombinaci jednotlivých typů údržby. Jako vhodné se jeví i využití metod a nástrojů, které nejsou primárně určeny pro zkoumaný typ výrobních procesů

Large area heavily boron doped nano-crystalline diamond growth by MW-LA-PECVD [Póster]

Diamond is a unique semiconductor with a wide bandgap which usually is easily doped with boron and is acknowledged as one of the best materials for electrochemical applications. Heavily boron doped, high quality single crystal synthetic diamond can reach electrical conductivity as high as 103 S.cm, whereas polycrystalline material usually reaches c.a. 102 S.cm. However, many potential applications are restricted by the deposition temperature and limited coating area of conventional MW PECVD systems. Deposition of boron doped nano-crystalline diamond (BNCD) layers using a microwave PECVD system with linear antenna delivery (MW-LA-PECVD), enabling large area coating, was first reported in 2014 [1]. However, layers showed lower electrical conductivity in comparison to BNCD layers deposited using conventional PECVD systems. In addition, deposition of BNCD by MW-LA-PECVD is complicated by the necessity for the addition of oxygen species, which are known to limit boron incorporation and the competitive growth of silicon carbide at low CO2 concentrations [2, 3]. In this work, we further study the effect of deposition conditions on the synthesis of BNCD using the MW-LA-PECVD technique. In order to produce highly conductive BNCD with a low sp2 fraction, we have investigated in greater detail the effect of deposition temperature, from 250 °C up to 750 °C, using temperature controlled substrate stages and the effect of precursor gas compositions

Radiosensitisation of Hepatocellular Carcinoma Cells by Vandetanib

Hepatocellular Carcinoma (HCC) is increasing in incidence worldwide and requires new approaches to therapy. The combination of anti-angiogenic drug therapy and radiotherapy is one promising new approach. The anti-angiogenic drug vandetanib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and RET proto-oncogene with radio-enhancement potential. To explore the benefit of combined vandetanib and radiotherapy treatment for HCC, we studied outcomes following combined treatment in pre-clinical models. Methods: Vandetanib and radiation treatment were combined in HCC cell lines grown in vitro and in vivo. In addition to 2D migration and clonogenic assays, the combination was studied in 3D spheroids and a syngeneic mouse model of HCC. Results: Vandetanib IC 50 s were measured in 20 cell lines and the drug was found to significantly enhance radiation cell kill and to inhibit both cell migration and invasion in vitro. In vivo, combination therapy significantly reduced cancer growth and improved overall survival, an effect that persisted for the duration of vandetanib treatment. Conclusion: In 2D and 3D studies in vitro and in a syngeneic model in vivo, the combination of vandetanib plus radiotherapy was more efficacious than either treatment alone. This new combination therapy for HCC merits evaluation in clinical trials

HCFC1 loss-of-function mutations disrupt neuronal and neural progenitor cells of the developing brain.

Both gain- and loss-of-function mutations have recently implicated HCFC1 in neurodevelopmental disorders. Here, we extend our previous HCFC1 over-expression studies by employing short hairpin RNA to reduce the expression of Hcfc1 in embryonic neural cells. We show that in contrast to over-expression, loss of Hcfc1 favoured proliferation of neural progenitor cells at the expense of differentiation and promoted axonal growth of post-mitotic neurons. To further support the involvement of HCFC1 in neurological disorders, we report two novel HCFC1 missense variants found in individuals with intellectual disability (ID). One of these variants, together with three previously reported HCFC1 missense variants of unknown pathogenicity, were functionally assessed using multiple cell-based assays. We show that three out of the four variants tested result in a partial loss of HCFC1 function. While over-expression of the wild-type HCFC1 caused reduction in HEK293T cell proliferation and axonal growth of neurons, these effects were alleviated upon over-expression of three of the four HCFC1 variants tested. One of these partial loss-of-function variants disrupted a nuclear localization sequence and the resulting protein displayed reduced ability to localize to the cell nucleus. The other two variants displayed negative effects on the expression of the HCFC1 target gene MMACHC, which is responsible for the metabolism of cobalamin, suggesting that these individuals may also be susceptible to cobalamin deficiency. Together, our work identifies plausible cellular consequences of missense HCFC1 variants and identifies likely and relevant disease mechanisms that converge on embryonic stages of brain developmentLachlan A. Jolly, Lam Son Nguyen, Deepti Domingo, Ying Sun, Simon Barry, Miroslava Hancarova, Pavlina Plevova, Marketa Vlckova, Marketa Havlovicova, Vera M. Kalscheuer, Claudio Graziano, Tommaso Pippucci, Elena Bonora, Zdenek Sedlacek, and Jozef Gec