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Global trade is plagued by slow and inefficient manual processes associated with physical documents. Firms are constantly looking for new ways to improve transparency and increase the resilience of their supply chains. This can be solved by the digitalisation of supply chains and the automation of document- and information-sharing processes. Blockchain is touted as a solution to these issues due to its unique combination of features, such as immutability, decentralisation and transparency. A lack of business cases that quantify the costs and benefits causes uncertainty regarding the truth of these claims. This paper explores how the costs and benefits of a blockchain-based solution for digitalising and automating documentation flows in cross-border supply chains compare to a conventional centralised relational database solution. The research described in this paper uses primary data collected through semi-structured interviews with industry experts, as well as secondary data from literature. Two models based on existing services were developed and the costs and benefits compared and then analysed using the Architecture Trade-off Analysis Method (ATAM) and the Analytic Network Process (ANP). Findings from the analysis show that a consortium blockchain solution like TradeLens is the favourable solution for digitalising and automating information flows in cross-border supply chains. [ABSTRACT FROM AUTHOR]

The authors present the case of a 58-year-old man found hanging from a radiator by his shoelaces. The time of death was approximately 6 h before the body was discovered. An autopsy was performed approximately 24 h after the body was found, which revealed hemorrhages in the thoracic aorta at the junctions of the posterior intercostal arteries. Before autopsy, a routine whole-body CT scan was performed. Histologic examination of the aorta and the posterior intercostal arteries revealed a fresh hemorrhage into the tunica adventitia of the aorta. To our knowledge, there is no case description of such findings in hanged persons in the literature. Conclusion: Hemorrhages into the tunica adventitia of the junction of the posterior costal arteries may occur in association with suicidal hanging. The significance of these hemorrhages as a sign of vitality may be debated. [ABSTRACT FROM AUTHOR]

Objective: To analyze medical device reports (MDR) submitted to the Food and Drug Administration's (FDA) Manufacturer and User Device Facility Experience (MAUDE) database to identify adverse events (AEs) in patients implanted with novel active bone conduction hearing implants (BCIs). Methods: We conducted a search of the FDA MAUDE database on the newest generation of BCIs. Data were collected concerning device malfunctions, patient injuries, factors triggering these incidents, and the subsequent actions taken. Results: In total, 93 (16.7%) device malfunctions and 465 (83.3%) patient injuries with 358 subsequent interventions were identified, resulting in 558 AEs. Although the absolute AE number per device cannot be identified, the following trends were detected: Among the 494 AEs associated with OSI200, 55 (11.1%) reported device malfunctions and 454 (88.9%) cited patient injuries. Out of the 64 AEs linked to BCI602, 28 (59.4%) were associated with malfunctions, whereas 26 (40.6%) involved patient injuries. The most frequently reported particular AEs for the OSI200 were infection (n = 171, 34.6%), extrusion of the device (n = 107, 21.7%), and pain (n = 51, 10.3%). Conversely, no device output (n = 20, 31.3%) and loss of osseointegration (n = 7, 10.9%) were the most reported AEs for the BCI602. Various AEs led to 214 explanations and 77 revision surgeries. Sixty‐seven AEs reported conservative treatment. Conclusion: The current study provides an overview of the most commonly reported complications with new active BCIs. Although providing an overview, given the limitations of the FDA MAUDE database, our results have to be interpreted with caution. Level of Evidence: 4. [ABSTRACT FROM AUTHOR]

With the approval of the first two substances for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration (AMD), a standardized monitoring of patients treated with complement inhibitors in clinical practice is needed. Optical coherence tomography (OCT) provides high-resolution access to the retinal pigment epithelium (RPE) and neurosensory layers, such as the ellipsoid zone (EZ), which further enhances the understanding of disease progression and therapeutic effects in GA compared to conventional fundus autofluorescence (FAF). In addition, artificial intelligence-based methodology allows the identification and quantification of GA-related pathology on OCT in an objective and standardized manner. The purpose of this study was to comprehensively evaluate automated OCT monitoring for GA compared to reading center-based manual FAF measurements in the largest successful phase 3 clinical trial data of complement inhibitor therapy to date. Automated OCT analysis of RPE loss showed a high and consistent correlation to manual GA measurements on conventional FAF. EZ loss on OCT was generally larger than areas of RPE loss, supporting the hypothesis that EZ loss exceeds underlying RPE loss as a fundamental pathophysiology in GA progression. Automated OCT analysis is well suited to monitor disease progression in GA patients treated in clinical practice and clinical trials. [ABSTRACT FROM AUTHOR]

Neuraminic acid synthases are an important yet underexplored group of enzymes. Thus, in this research, we performed a detailed kinetic and stability analysis and a comparison of previously known neuraminic acid synthase from Neisseria meningitidis, and a novel enzyme, PNH5, obtained from a metagenomic library. A systematic analysis revealed a high level of similarity of PNH5 to other known neuraminic acid synthases, except for its pH optimum, which was found to be at 5.5 for the novel enzyme. This is the first reported enzyme from this family that prefers an acidic pH value. The effect of different metal cofactors on enzyme activity, i.e. Co2+, Mn2+ and Mg2+, was studied systematically. The kinetics of neuraminic acid synthesis was completely elucidated, and an appropriate kinetic model was proposed. Enzyme stability study revealed that the purified enzyme exhibits changes in its structure during time as observed by differential light scattering, which cause a drop in its activity and protein concentration. The operational enzyme stability for the neuraminic acid synthase from N. meningitidis is excellent, where no activity drop was observed during the batch reactor experiments. In the case of PNH5, some activity drop was observed at higher concentration of substrates. The obtained results present a solid platform for the future application of these enzymes in the synthesis of sialic acids. Key points: • A novel neuraminic acid synthase was characterized. • The effect of cofactors on NeuS activity was elucidated. • Kinetic and stability characterization of two neuraminic acid synthases was performed. [ABSTRACT FROM AUTHOR]

Background: This longitudinal prospective study aimed to assess orthodontic patients' immune system response to metal ion release in saliva. Methods: Thirty adult patients (18–35 years) were equally divided into three groups: groups at the end (G1) and beginning (G2) of multibracket appliances (MBA) treatment and a non-treated control group (G3). Participants were evaluated at four timepoints within 21 days, with saliva samples being analyzed for metal ion concentrations and blood for the lymphocyte transformation test (LTT). Results: There were no significant differences between groups or timepoints for saliva. LTT analyses revealed hypersensitivity in one-third of all patients and 50% of G2 for nickel, with three developing sensitizations after MBA insertion. All nickel-sensitized patients exhibited varying elevated saliva nickel concentrations. The most nickel-sensitized patients had low ion saliva loads. In borderline nickel-sensitization cases, saliva ion concentrations were up to 20 times higher than the reference. Hypersensitivity to palladium, gold, and mercury was also observed. Conclusions: These findings indicate that increased MBA ion release was not inherently linked to the immune response (Type-IV sensitization), as reactions occurred even with ion levels below thresholds. This underlines the need for a comprehensive evaluation of the immune response to metal ion release in orthodontic patients. [ABSTRACT FROM AUTHOR]

Objective: The bone conduction implant (BCI) 602 is a new transcutaneous BCI with smaller dimensions. However, limited patient numbers restrict the statistical power and generalizability of the current studies. The present systematic review and meta‐analysis summarize early audiological and medical outcomes of adult and pediatric patients implanted with the BCI 602 due to mixed or conductive hearing loss. Data Source: Following the Preferred Reporting items for Systematic Reviews and Meta‐analyses guidelines, 108 studies were reviewed, and 6 (5.6%) were included in the meta‐analysis. Review Method: The data on study and patient characteristics, surgical outcomes, and audiological test results were extracted from each article. Meta‐analysis employed the fixed‐effect and random‐effects models to analyze the mean differences (MDs) between pre‐ and postoperative performances. Results: In total, 116 patients were evaluated, including 64 (55%) adult and 52 (45%) pediatric patients. No intraoperative adverse events were reported, while postoperative complications were reported in 2 (3.1%) adult and 2 (3.8%) pediatric patients. Studies consistently showed significant improvements in audiological outcomes, quality of life, and sound localization in the aided condition. In the meta‐analysis, we observed a significant difference in the unaided compared to the aided condition in sound field thresholds (n = 112; MD, −27.05 dB; P < 0.01), signal‐to‐noise ratio (n = 96; MD, −6.35 dB; P < 0.01), and word recognition scores (n = 96; MD, 68.89%; P < 0.01). Conclusion: The implantation of the BCI 602 was associated with minimal surgical complications and excellent audiological outcomes for both the pediatric and the adult cohort. Therefore, our analysis indicates a high level of safety and reliability. Further research should focus on direct comparisons with other BCIs and long‐term functional outcomes. [ABSTRACT FROM AUTHOR]

Objective: To assess the accuracy of CT and MRI reports of alert patients presenting after non-self-inflicted strangulation (NSIS) and evaluate the appropriateness of these imaging modalities in NSIS. Material and methods: The study was a retrospective analysis of patient characteristics and strangulation details, with a comparison of original radiology reports (ORR) to expert read-outs (EXR) of CT and MRI studies of all NSIS cases seen from 2008 to 2020 at a single centre. Results: The study included 116 patients (71% women, p <.001, χ2), with an average age of 33.8 years, mostly presenting after manual strangulation (97%). Most had experienced intimate partner violence (74% of women, p <.001, χ2) or assault by unknown offender (88% of men, p < 0.002 χ2). Overall, 132 imaging studies (67 CT, 51% and 65 MRI, 49%) were reviewed. Potentially dangerous injuries were present in 7%, minor injuries in 22%, and no injuries in 71% of patients. Sensitivity and specificity of ORR were 78% and 97% for MRI and 30% and 98% for CT. Discrepancies between ORR and EXR occurred in 18% of all patients, or 62% of injured patients, with a substantial number of unreported injuries on CT. Conclusions: The results indicate that MRI is more appropriate than CT for alert patients presenting after non-self-inflicted strangulation and underline the need for radiologists with specialist knowledge to report these cases in order to add value to both patient care and potential future medico-legal investigations. Clinical relevance statement: MRI should be preferred over CT for the investigation of strangulation related injuries in alert patients because MRI has a higher accuracy than CT and does not expose this usually young patient population to ionizing radiation. Key Points: • Patients presenting after strangulation are often young women with a history of intimate partner violence while men typically present after assault by an unknown offender. • Expert read-outs of CT and MRI revealed potentially dangerous injuries in one of 14 patients. • MRI has a significantly higher sensitivity than CT and appears to be more appropriate for the diagnostic workup of alert patients after strangulation. [ABSTRACT FROM AUTHOR]

Copyright of Leviathan: Zeitschrift für Sozialwissenschaft (Nomos Verlagsgesellschaft mbH & Co. KG) is the property of Nomos Verlagsgesellschaft mbH & Co. KG and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Movements on surfaces of centered Euclidean spheres and changes between those with different radii mean complex multiplication in R 3 . Here, the Euclidean norm, which generates the spheres, is replaced with an inhomogeneous functional and a product is introduced in a geometric analogy. Because a change in the radius now leads to a change in the shape of the sphere, a three-dimensional dynamic complex structure is created. Statements about invariant probability densities, generalized uniform distributions on generalized spheres, geometric measure representations, and dynamic ball numbers associated with this structure are also presented. [ABSTRACT FROM AUTHOR]

Based upon the vector representation of complex numbers and the vector exponential function, we introduce the vector representation of characteristic functions and consider some of its elementary properties such as its polar representation and a vector power expansion. [ABSTRACT FROM AUTHOR]

We recently reported that the transketolase from Geobacillus stearothermophilus (TKgst) upon acyl transfer to nitrosoarenes generates N‐aryl hydroxamic acids (HA). The latter are metal chelating compounds that in the presence of Fe(III) ions form deep‐red complexes. Here, we applied this principle to the development of a colorimetric assay in both solid‐ and liquid‐phase formats for the high‐throughput screening of TKgst and its variants. Screening a set of positive hits from a L382X/D470X library validated the specificity and sensitivity of the assays. The solid surface assay allows a clear distinction between positive and negative colonies by the naked eye in qualitative mode, and further also to measure activity in semi‐quantitative fashion in the liquid‐phase format. The assay will be important for engineering the TKgst enzyme towards improved conversion of aromatic aldehydes by their close structural analogy to nitrosoarenes. [ABSTRACT FROM AUTHOR]

The AGFAD (Arbeitsgemeinschaft für Forensische Alterdiagnostik, Study Group on Forensic Age Diagnostics) has published several recommendations regarding both technical aspects of computed tomography (CT) of the medial clavicular epiphysis (MCE) and the process of reading and interpreting the CT images for forensic age estimations (FAE). There are, however, no published recommendations regarding CT scan protocols and no dose reference values for CT of the MCE. The objective of this analysis was to assess adherence to AGFAD recommendations among practitioners of FAE and analyse reported dose-relevant CT scan parameters with the objective of helping to establish evidence-based dose reference values for FAE. A systematic literature search was conducted in PubMed and in Google Scholar with specific MeSH terms to identify original research articles on FAE with CT of the MCE from 1997 to 2022. A total of 48 studies were included. Adherence to AGFAD recommendations among practitioners of FAE is high regarding the use of Schmeling main stages (93%), bone window (79%), ≤ 1 mm CT slices (67%), axial/coronal CT images (65%), and Kellinghaus sub-stages (59%). The reporting of CT technique and CT dose-relevant scan parameters is heterogeneous and often incomplete in the current literature. Considering the success achieved by the AGFAD in creating standards of practice of FAE in living subjects, there is potential for the AGFAD to establish standards for radiation protection in FAE as well. [ABSTRACT FROM AUTHOR]

Background: Effective dental plaque removal is essential for oral health. Different toothbrush parameters including head-size, filament-diameter and interdent-height and different brushing movements like horizontal, rotating and vertical may affect plaque removal efficacy. The purpose of the study was to examine plaque removal efficacy of different design parameters of manual toothbrushes. Methods: Eight manual toothbrushes were tested using a validated robot test to examine efficacy of toothbrush on replicated human teeth. Characteristics tested were: (i) head-size, (ii) filament-diameter, (iii) cutting-height, (iv) hardness, (v) interdental-height. Each test ran five times in horizontal, rotating, vertical movements. Simulated Plaque removal was evaluated using automated plaque planimetry: 30 fields/tooth, 13 areas representing buccal, lingual, proximal tooth sites. The Kolmogorov-Smirnov-test was applied to test tooth surface variables for normal distribution of plaque removal values. Parameters were analysed by independent two-sample t-test to assess mean differences. Where null hypothesis of normality was rejected, the Wilcoxon-Mann-Whitney-U-test was used. Results: Plaque removal was significantly better with toothbrush having smaller head-size (compact vs. full-size); smaller filament-diameter (0.12 mm vs. 0.15 mm); larger cutting-height (12 mm vs. 9 mm); softer filaments (0.15 or 0.18 mm vs. 0.23 mm) and greater interdent-height difference (8.5/11 mm vs. 10/11 mm). Conclusions: Manual brushes allowing filaments free to flex with longer, softer and/or having a difference in filament length overall removed significantly more simulated plaque as compared to more standard flat trim, stiff brushes with shorter, harder bristles and a larger head size. While limited by the in vitro nature of the study design, this indicates that the advances in toothbrush design can further enhance plaque removal. [ABSTRACT FROM AUTHOR]

Objective: Recently, the Bonebridge 602 implant was introduced. Its smaller dimensions facilitate implantation even in surgically demanding cases. However, in extreme anatomical conditions, implant lifts are still required. We intended to report on the medical and audiological outcomes of all patients implanted with the implant with a secondary focus on the safety, efficacy, and feasibility of the use of 1‐mm lifts. Study Design: Retrospective cohort study. Setting: Tertiary academic center. Methods: We retrospectively analyzed all patients implanted with the Bonebridge 602. Patient demographics and surgically‐specific data were collected from the medical charts. Furthermore, audiological results were assessed. Outcomes were compared between implantations with versus without lifts. Results: Twenty‐one devices were implanted during the study period. Satisfactory audiological results were observed, while no intra‐ or postoperative adverse events occurred. The majority of patients were daily users at the end of the observation period (n = 20/21, 95.2%), and one patient (n = 1/21, 4.8%) was a nonuser after 6 months of use because of subjective dissatisfaction. Due to anatomical considerations, 1‐mm lifts were used in 4 implantations (19.0%). The application of lifts did not result in prolonged surgical times, complications, or shorter time of use, nor did it negatively affect audiometric results. Conclusion: Implantations with the new and smaller Bonebridge were associated with gratifying medical and audiological outcomes. Still, in extreme anatomical conditions, 1‐mm lifts are necessary. Nonetheless, surgical placement with the help of lifts seems safe, effective, and feasible, and is a viable option in cases with challenging anatomies due to previous surgeries or anomalies. [ABSTRACT FROM AUTHOR]

Copyright of Die Ophthalmologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Idiopathic pulmonary fibrosis (IPF) is one of the most common forms of interstitial lung disease, characterized by progressive parenchymal fibrosis and respiratory failure. In a model of bleomycin-induced pulmonary fibrosis, the antifibrotic and anti-inflammatory activity of Longidaze (Bovhyaluronidase Azoxymer), which contains a conjugate of the hyaluronidase enzyme with a high molecular weight synthetic carrier azoxymer bromide, was investigated. Experiments were conducted in male C57BL/6 mice. Longidaze was administered at different doses by intranasal and intramuscular routes. Histology, hematology, and enzyme-linked immunosorbent assay were used in the study. The use of Longidaze reduced pulmonary fibrosis, as evidenced by an improvement in histopathologic damage to the lungs, a decrease in the area of connective tissue, and the levels of profibrotic factors (TGF-β1, hydroxyproline, collagen I) in lung tissue. In addition, Longidaze inhibited the inflammatory response in pulmonary fibrosis, and decreased the levels of IL-6, TNF-α, and hyaluronic acid in lung tissue and the recruitment of inflammatory cells into lung tissue. The highest therapeutic efficacy was observed with the use of Longidaze at doses of 120 and 1200 U/kg intramuscularly, which was superior to that of the reference drug pirfenidone axunio. The data presented in this study suggest that Longidaze is a new and promising drug for the treatment of IPF that warrants further investigation in patients with fibrotic interstitial lung disease. [ABSTRACT FROM AUTHOR]

Purpose Whereas most human genes encode multiple mRNA isoforms with distinct function, clinical workflows for assessing this heterogeneity are not readily available. This is a substantial shortcoming, considering that up to 25% of disease-causing gene variants are suspected of disrupting mRNA splicing or mRNA abundance. Long-read sequencing can readily portray mRNA isoform diversity, but its sensitivity is relatively low due to insufficient transcriptome penetration. Methods We developed and applied capture-based target enrichment from patient RNA samples combined with Oxford Nanopore long-read sequencing for the analysis of 123 hereditary cancer transcripts (capture and ultradeep long-read RNA sequencing (CAPLRseq)). Results Validating CAPLRseq, we confirmed 17 cases of hereditary non-polyposis colorectal cancer/Lynch syndrome based on the demonstration of splicing defects and loss of allele expression of mismatch repair genes MLH1, PMS2, MSH2 and MSH6. Using CAPLRseq, we reclassified two variants of uncertain significance in MSH6 and PMS2 as either likely pathogenic or benign. Conclusion Our data show that CAPLRseq is an automatable and adaptable workflow for effective transcriptome-based identification of disease variants in a clinical diagnostic setting. [ABSTRACT FROM AUTHOR]

In time series analyses, the auto-regressive (AR) modelling of zero mean data is widely used for system identification, signal decorrelation, detection of outliers and forecasting. An AR process of order p is uniquely defined by p coefficients and the variance in the noise. The roots of the characteristic polynomial can be used as an alternative parametrization of the coefficients, which can be used to construct a continuous covariance function of the AR process or to verify that the AR process is stationary. In a previous study, we introduced an AR process of time variable coefficients (TVAR process) in which the movement of the roots was specified as a polynomial of order one. Until now, this method was analytically derived only for TVAR processes of orders one and two. Thus, higher-level processes had to be assembled by the successive estimation of these process orders. In this contribution, the analytical solution for a TVAR(3) process is derived and compared to the successive estimation using a TVAR(1) and TVAR(2) process. We will apply the proposed approach to a GNSS time series and compare the best-fit TVAR(3) process with the best-fit composition of TVAR(2) and TVAR(1) process. [ABSTRACT FROM AUTHOR]

Two‐dimensional oxide films are potentially useful for future technological applications, but also important objects to study model catalyst systems on the more fundamental side. Here we study silica, germania, and mixed silica‐germania films supported on a metal single crystal surface Ru(0001). Those mixed films are interesting objects to systematically modify the properties of silica films, which may be used as membranes or covers for model studies in confined space, due to the modification of the rather stiff silica layers by incorporating germanium atoms replacing silicon atoms. Here we report a combined experimental and theoretical study of such layers, where we show how X‐ray photoelectron spectroscopy in combination with LEED and I/V LEEM measurements allow us to judge the formation of such mixed films. [ABSTRACT FROM AUTHOR]

Enterotoxigenic Escherichia coli (ETEC) is a diarrhoeal pathogen associated with high morbidity and mortality especially among young children in developing countries. At present, there is no vaccine for ETEC. One candidate vaccine antigen, EtpA, is a conserved secreted adhesin that binds to the tips of flagellae to bridge ETEC to host intestinal glycans. EtpA is exported through a Gram-negative, two-partner secretion system (TPSS, type Vb) comprised of the secreted EtpA passenger (TpsA) protein and EtpB (TpsB) transporter that is integrated into the outer bacterial membrane. TpsA proteins share a conserved, N-terminal TPS domain followed by an extensive C-terminal domain with divergent sequence repeats. Two soluble, N-terminal constructs of EtpA were prepared and analysed respectively including residues 67 to 447 (EtpA67-447) and 1 to 606 (EtpA1-606). The crystal structure of EtpA67-447 solved at 1.76 Å resolution revealed a right-handed parallel β-helix with two extra-helical hairpins and an N-terminal β-strand cap. Analyses by circular dichroism spectroscopy confirmed the β-helical fold and indicated high resistance to chemical and thermal denaturation as well as rapid refolding. A theoretical AlphaFold model of full-length EtpA largely concurs with the crystal structure adding an extended β-helical C-terminal domain after an interdomain kink. We propose that robust folding of the TPS domain upon secretion provides a template to extend the N-terminal β-helix into the C-terminal domains of TpsA proteins. [ABSTRACT FROM AUTHOR]

eIF3, whose subunits are frequently overexpressed in cancer, regulates mRNA translation from initiation to termination, but mRNA‐selective functions of individual subunits remain poorly defined. Using multiomic profiling upon acute depletion of eIF3 subunits, we observed that while eIF3a, b, e, and f markedly differed in their impact on eIF3 holo‐complex formation and translation, they were each required for cancer cell proliferation and tumor growth. Remarkably, eIF3k showed the opposite pattern with depletion promoting global translation, cell proliferation, tumor growth, and stress resistance through repressing the synthesis of ribosomal proteins, especially RPS15A. Whereas ectopic expression of RPS15A mimicked the anabolic effects of eIF3k depletion, disruption of eIF3 binding to the 5′‐UTR of RSP15A mRNA negated them. eIF3k and eIF3l are selectively downregulated in response to endoplasmic reticulum and oxidative stress. Supported by mathematical modeling, our data uncover eIF3k‐l as a mRNA‐specific module which, through controlling RPS15A translation, serves as a rheostat of ribosome content, possibly to secure spare translational capacity that can be mobilized during stress. Are there mRNA‐selective functions of individual eIF3 subunits? Here, multiomic profiling upon acute depletion of eIF3 subunits uncovers eIF3k‐l as an mRNA‐specific module that serves as a rheostat of ribosome content, securing spare translational capacity that can be mobilized during stress. Acute depletion of eIF3 subunits has subunit‐selective impact on holo‐eIF3 architecture.eIF3k depletion uniquely causes increased tumor growth and ribosome content.eIF3k depletion boosts the translation of RPS15A mRNA through an eIF3‐binding site in the 5′‐UTR.eIF3k and eIF3l are selectively downregulated by cellular stress, thus promoting cell survival. [ABSTRACT FROM AUTHOR]

Instability of simple DNA repeats has been known as a common cause of hereditary ataxias for over 20 years. Routine genetic diagnostics of these phenotypically similar diseases still rely on an iterative workflow for quantification of repeat units by PCR-based methods of limited precision. We established and validated clinical nanopore Cas9-targeted sequencing, an amplification-free method for simultaneous analysis of 10 repeat loci associated with clinically overlapping hereditary ataxias. The method combines target enrichment by CRISPR–Cas9, Oxford Nanopore long-read sequencing and a bioinformatics pipeline using the tools STRique and Megalodon for parallel detection of length, sequence, methylation and composition of the repeat loci. Clinical nanopore Cas9-targeted sequencing allowed for the precise and parallel analysis of 10 repeat loci associated with adult-onset ataxia and revealed additional parameter such as FMR1 promotor methylation and repeat sequence required for diagnosis at the same time. Using clinical nanopore Cas9-targeted sequencing we analysed 100 clinical samples of undiagnosed ataxia patients and identified causative repeat expansions in 28 patients. Parallel repeat analysis enabled a molecular diagnosis of ataxias independent of preconceptions on the basis of clinical presentation. Biallelic expansions within RFC1 were identified as the most frequent cause of ataxia. We characterized the RFC1 repeat composition of all patients and identified a novel repeat motif, AGGGG. Our results highlight the power of clinical nanopore Cas9-targeted sequencing as a readily expandable workflow for the in-depth analysis and diagnosis of phenotypically overlapping repeat expansion disorders. [ABSTRACT FROM AUTHOR]

Geographic atrophy (GA) represents a late stage of age-related macular degeneration, which leads to irreversible vision loss. With the first successful therapeutic approach, namely complement inhibition, huge numbers of patients will have to be monitored regularly. Given these perspectives, a strong need for automated GA segmentation has evolved. The main purpose of this study was the clinical validation of an artificial intelligence (AI)-based algorithm to segment a topographic 2D GA area on a 3D optical coherence tomography (OCT) volume, and to evaluate its potential for AI-based monitoring of GA progression under complement-targeted treatment. 100 GA patients from routine clinical care at the Medical University of Vienna for internal validation and 113 patients from the FILLY phase 2 clinical trial for external validation were included. Mean Dice Similarity Coefficient (DSC) was 0.86 ± 0.12 and 0.91 ± 0.05 for total GA area on the internal and external validation, respectively. Mean DSC for the GA growth area at month 12 on the external test set was 0.46 ± 0.16. Importantly, the automated segmentation by the algorithm corresponded to the outcome of the original FILLY trial measured manually on fundus autofluorescence. The proposed AI approach can reliably segment GA area on OCT with high accuracy. The availability of such tools represents an important step towards AI-based monitoring of GA progression under treatment on OCT for clinical management as well as regulatory trials. [ABSTRACT FROM AUTHOR]

Aim: This European multicentric study aimed to prove safety and performance of the Bonebridge BCI 602 in children and adults suffering from either conductive hearing loss (CHL), mixed hearing loss (MHL), or single-sided sensorineural deafness (SSD). Methods: 33 patients (13 adults and 10 children with either CHL or MHL and 10 patients with SSD) in three study groups were included. Patients were their own controls (single-subject repeated measures), comparing the unaided or pre-operative to the 3-month post-operative outcomes. Performance was evaluated by sound field thresholds (SF), word recognition scores (WRS) and/or speech reception thresholds in quiet (SRT) and in noise (SNR). Safety was demonstrated with a device-specific surgical questionnaire, adverse event reporting and stable pure-tone measurements. Results: The Bonebridge BCI 602 significantly improved SF thresholds (+ 25.5 dB CHL/MHL/SSD), speech intelligibility in WRS (+ 68.0% CHL/MHL) and SRT in quiet (− 16.5 dB C/MHL) and in noise (− 3.51 dB SNR SSD). Air conduction (AC) and bone conduction (BC) thresholds remained stable over time. All adverse events were resolved, with none unanticipated. Mean audio processor wearing times in hours [h] per day for the CHL/MHL group were ~ 13 h for adults, ~ 11 h for paediatrics and ~ 6 h for the SSD group. The average surgical length was 57 min for the CHL/MHL group and 42 min for the SSD group. The versatility of the BCI 602 (reduced drilling depth and ability to bend the transition for optimal placement) allows for treatment of normal, pre-operated and malformed anatomies. All audiological endpoints were reached. Conclusions: The Bonebridge BCI 602 significantly improved hearing thresholds and speech understanding. Since implant placement follows the patient's anatomy instead of the shape of the device and the duration of surgery is shorter than with its predecessor, implantation is easier with the BCI 602. Performance and safety were proven for adults and children as well as for the CHL/MHL and SSD indications 3 months post-operatively. [ABSTRACT FROM AUTHOR]

Purpose: The objective of the study was to evaluate the proposed cochlear duct length estimation based on the cochlear 'A value'. Furthermore, we assessed the interobserver variability between radiology and otolaryngology attending physicians and otolaryngology trainees. Methods: Thirteen pediatric cochlear implant candidates were retrospectively analyzed by three otolaryngology physicians (attending physician, second year, and fourth year trainees) and a radiology attending. The cochlear duct length was calculated based on the formula of Grover et al. The differences in acquired measurements between observers were compared using the Wilcoxon matched signed-rank test. Results: The differences in measurements between the attending otolaryngologist and radiologist were not statistically different, while several significant differences were observed with regard to measurements of attending doctors compared to both residents. In particular, a significant difference between the second year otolaryngology resident and otolaryngology and radiology attending was observed for one side (right ear p = 0.034 and p = 0.012, respectively). Moreover, the fourth year resident calculated significantly different cochlear duct measurements when compared to the attending otolaryngologist (left ear p = 0.014) and radiologist (right ear p = 0.047). Interestingly, differently experienced otolaryngology residents provided significantly different measurements for both ears. Conclusions: Based on these results, cochlear duct length measurement according to the proposed method may be a reliable and cost-effective method. Indeed, otolaryngology training may be sufficient to provide measurements comparable to radiologists. On the other hand, additional efforts should be invested during otolaryngology training in terms of the evaluation of radiological imaging which may increase the capabilities of otolaryngology residents in this regard. [ABSTRACT FROM AUTHOR]

Purpose: To identify correlations between the vascular characteristics of macular neovascularization (MNV) obtained by optical coherence tomography angiography (OCTA) and distinct retinal fluid volumes in neovascular age‐related macular degeneration (nAMD). Methods: In this prospective interventional study, 54 patients with treatment‐naïve type 1 or 2 nAMD were included and treated with intravitreal aflibercept. At baseline and month 1, each patient underwent a SD‐OCT volume scan and volumetric flow scan using a swept‐source OCTA. A deep learning algorithm was used to automatically detect and quantify fluid in OCT scans. Angio Tool, a National Cancer Institute algorithm, was used to skeletonize MNV properties and quantify lesion size (LS), vessel area (VA), vessel density (VD), total number of endpoints (TNE), total number of junctions (TNJ), junction density (JD), total vessel length (TVL), average vessel length (AVL) and mean‐e‐lacunarity (MEL). Subsequently, linear regression models were used to investigate a correlation between OCTA parameters and fluid quantifications. Results: The median amount of fluid within the central 6‐mm EDTRS ring was 173.7 nl at baseline, consisting of 156.6 nl of subretinal fluid (SRF) and 2.3 nl of intraretinal fluid (IRF). Fluid decreased significantly in all compartments to 1.76 nl (SRF) and 0.64 nl (IRF). The investigated MNV parameters did not change significantly after the first treatment. There was no significant correlation between MNV parameters and relative fluid decrease after anti‐VEGF treatment. Baseline fluid correlated statistically significant but weakly with TNE (p = 0.002, R2 = 0.17), SRF with TVL (p = 0.04, R2 = 0.08), VD (p = 0.046, R2 = 0.08), TNE (p = 0.001, R2 = 0.20) and LS (p = 0.033, R2 = 0.09). IRF correlated with VA (p = 0.042, R2 = 0.08).The amount of IRF at month 1 correlated significantly but weakly with VD (p = 0.036, R2 = 0.08), JD (p = 0.019, R2 = 0.10) and MEL (p = 0.005, R2 = 0.14). Conclusion: Macular neovascularization parameters at baseline and month 1 played only a minor role in the exudation process in nAMD. None of the MNV parameters were correlated with the treatment response. [ABSTRACT FROM AUTHOR]

New monolithic multi-layered zirconia restorations are gaining popularity due to their excellent aesthetic properties. However, current knowledge of these newest multi-layer ceramics in terms of mechanical properties is scarce. Three monolithic, multi-layered zirconia materials (Katana, Kuraray Noritake, Japan) were selected for comparison: High Translucent Multi-layered zirconia (HTML), Super Translucent Multi-layered zirconia (STML) and Ultra Translucent Multi-layered zirconia (UTML). Fifteen specimens per group were cut from pre-sintered blocs in each of the four layers (L1, L2, L3, L4) and in different thicknesses (0.4 mm, 0.8 mm and 1.2 mm). Critical fracture load (Fcf) was recorded in 3-point-bending. Flexural strength (σ) in MPa, Vickers hardness (HV) in N/mm2, fracture toughness (KIc) in MPa*m1/2, Weibull Modulus (m) and characteristic Weibull strength (σw) in MPa were assessed. Statistical analysis was performed using ANOVA analysis. FS and KIc were significantly higher (p < 0.05) for Katana™ HTML (652.85 ± 143.76–887.64 ± 118.95/4.25 ± 0.43–5.01 ± 0.81) in comparison to Katana™ STML (280.17 ± 83.41–435.95 ± 73.58/3.06 ± 0.27–3.84 ± 0.47) and UTML (258.25 ± 109.98–331.26 ± 56.86/2.35 ± 0.31–2.94 ± 0.33), with no significant differences between layers and layer thicknesses. The range of indications should be carefully considered when selecting the type of monolithic zirconia for fabrication of dental restorations, as materials widely differ in mechanical properties. [ABSTRACT FROM AUTHOR]

Based upon a new general vector-valued vector product, generalized complex numbers with respect to certain positively homogeneous functionals including norms and antinorms are introduced and a vector-valued Euler type formula for them is derived using a vector valued exponential function. Furthermore, generalized Cauchy–Riemann differential equations for generalized complex differentiable functions are derived. For random versions of the considered new type of generalized complex numbers, moments are introduced and uniform distributions on discs with respect to functionals of the considered type are analyzed. Moreover, generalized uniform distributions on corresponding circles are studied and a connection with generalized circle numbers, which are natural relatives of π , is established. Finally, random generalized complex numbers are considered which are star-shaped distributed. [ABSTRACT FROM AUTHOR]

A platform to help clinicians ensure that hearing device candidates are informed about the benefits and drawbacks of their recommended treatment option would be of clinical counselling benefit because it could help each candidate form realistic expectations about life with their treatment option. Following the World Café approach, 54 participants (surgeons, audiologist, and researchers) generated lists of the benefits and drawbacks of each treatment option for single-sided deafness (SSD) and bone conduction (BC) solutions. They then prioritized the benefits and drawbacks. After the World Café, literature research was performed on each topic to check if the statements (on benefits and drawbacks) are supported by quality peer-reviewed publications. Each participant was surveyed to ensure a collective agreement was reached. The HEARRING Counselling 1.0 Platform was developed. Thus far, sections for SSD and BC solutions have been completed. Initial feedback has been highly positive. The platform will be expanded to cover middle ear implant solutions and cochlear implants. A plan is in place to ensure the information continues to be timely. The HEARRING Counselling 1.0 helps clinicians provide comprehensive information to candidates about their treatment option and thereby helps establish that candidates have realistic expectations about the benefits and drawbacks of device use. [ABSTRACT FROM AUTHOR]

Background: Long-term prescriptions of strong opioids for chronic noncancer pain—which are not supported by scientific evidence—suggest miscalibrated risk perceptions among those who prescribe, dispense, and take opioids. Because risk perceptions and behaviors can differ depending on whether people learn about risks through description or experience, we investigated the effects of descriptive versus simulated-experience educative formats on physicians' risk perceptions of strong opioids and their prescription behavior for managing chronic noncancer pain. Methods: Three hundred general practitioners and 300 pain specialists in Germany—enrolled separately in two independent exploratory randomized controlled online trials—were randomly assigned to either a descriptive format (fact box) or a simulated-experience format (interactive simulation). Primary endpoints: Objective risk perception (numerical estimates of opioids' benefits and harms), actual prescriptions of seven therapy options for managing chronic pain. Secondary endpoint: Implementation of intended prescriptions of seven therapy options for managing chronic pain. Results: Both formats improved the proportion of correct numerical estimates of strong opioids' benefits and harms immediately after intervention, with no notable differences between formats. Compared to description, simulated experience led to significantly lower reported actual prescription rates for strong and/or weak opioids, and was more effective at increasing prescription rates for non-drug-based therapies (e.g., means of opioid reduction) from baseline to follow-up for both general practitioners and pain specialists. Simulated experience also resulted in a higher implementation of intended behavior for some drug-based and non-drug-based therapies. Conclusions: The two formats, which recruit different cognitive processes, may serve different risk-communication goals: If the goal is to improve exact risk perception, descriptive and simulated-experience formats are likely to be equally suitable. If, however, the goal is to boost less risky prescription habits, simulated experience may be the better choice. Trial registration: DRKS00020358 (German Clinical Trials Register, first registration: 07/01/2020). [ABSTRACT FROM AUTHOR]

This study aimed to discover expert opinion on the surgical techniques and materials most likely to achieve maximum postoperative residual hearing preservation in cochlear implant (CI) surgery and to determine how these opinions have changed since 2010. A previously published questionnaire used in a study published in 2010 was adapted and expanded. The questionnaire was distributed to an international group of experienced CI surgeons. Present results were compared, via descriptive statistics, to those from the 2010 survey. Eighteen surgeons completed the questionnaire. Respondents clearly favored the following: round window insertion, slow array insertion, and the peri- and postoperative use of systematic antibiotics. Insertion depth was regarded as important, and electrode arrays less likely to induce trauma were preferred. The usefulness of dedicated soft-surgery training was also recognized. A lack of agreement was found on whether the middle ear cavity should be flushed with a non-aminoglycoside antibiotic solution or whether a sheath or insertion tube should be used to avoid contaminating the array with blood or bone dust. In conclusion, this paper demonstrates how beliefs about CI soft surgery have changed since 2010 and shows areas of current consensus and disagreement. [ABSTRACT FROM AUTHOR]

Purpose Approximately 20% of patients with clinical familial adenomatous polyposis (FAP) remain unsolved after molecular genetic analysis of the APC and other polyposis genes, suggesting additional pathomechanisms. Methods We applied multidimensional genomic analysis employing chromosomal microarray profiling, optical mapping, long- read genome and RNA sequencing combined with FISH and standard PCR of genomic and complementary DNA to decode a patient with an attenuated FAP that had remained unsolved by Sanger sequencing and multigene panel next- generation sequencing for years. Results We identified a complex 3.9 Mb rearrangement involving 14 fragments from chromosome 5q22.1q22.3 of which three were lost, 1 reinserted into chromosome 5 and 10 inserted into chromosome 10q21.3 in a seemingly random order and orientation thus fulfilling the major criteria of chromothripsis. The rearrangement separates APC promoter 1B from the coding ORF (open reading frame) thus leading to allele-specific downregulation of APC mRNA. The rearrangement also involves three additional genes implicated in the APC--Axin--GSK3B--β-catenin signalling pathway. Conclusions Based on comprehensive genomic analysis, we propose that constitutional chromothripsis dampening APC expression, possibly modified by additional APC--Axin--GSK3B--β-catenin pathway disruptions, underlies the patient's clinical phenotype. The combinatorial approach we deployed provides a powerful tool set for deciphering unsolved familial polyposis and potentially other tumour syndromes and monogenic diseases. [ABSTRACT FROM AUTHOR]

Background: DFNB28, a recessively inherited nonsyndromic form of deafness in humans, is caused by mutations in the TRIOBP gene (MIM #609761) on chromosome 22q13. Its protein TRIOBP helps to tightly bundle F‐actin filaments, forming a rootlet that penetrates through the cuticular plate into the cochlear hair cell body. Repeat motifs R1 and R2, located in exon 7 of the TRIOBP‐5 isoform, are the actin‐binding domains. Deletion of both repeat motifs R1 and R2 results in complete disruption of both actin‐binding and bundling activities, whereas deletion of the R2 motif alone retains F‐actin bundling ability in stereocilia rootlets. Methods: Target sequencing, using a custom capture panel of 180 known and candidate genes associated with sensorineural hearing loss, bioinformatics processing, and data analysis were performed. Genesis 2.0 was used for variant filtering based on quality/score read depth and minor allele frequency (MAF) thresholds of 0.005 for recessive NSHL, as reported in population‐based sequencing databases. All variants were reclassified based on the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines together with other variant interpretation guidelines for genetic hearing loss. Candidate variants were confirmed via Sanger sequencing according to standard protocols, using the ABIPRISM 3730 DNA Analyzer. DNA sequence analysis was performed with DNASTAR Lasergene software. Results: Candidate TRIOBP variants identified among 94 indigenous sub‐Saharan African individuals were characterized through segregation analysis. Family TS005 carrying variants c.572delC, p.Pro191Argfs*50, and c.3510_3513dupTGCA, p.Pro1172Cysfs*13, demonstrated perfect cosegregation with the deafness phenotype. On the other hand, variants c.505C > A p.Asp168Glu and c.3636 T > A p.Leu1212Gln in the same family did not segregate with deafness and we have classified these variants as benign. A control family, TS067, carrying variants c.2532G > T p.Leu844Arg, c.2590C > A p.Asn867Lys, c.3484C > T p.Pro1161Leu, and c.3621 T > C p.Phe1187Leu demonstrated no cosegregation allowing us to classify these variants as benign. Together with published TRIOBP variants, the results showed that genotypes combining two truncating TRIOBP variants affecting repeat motifs R1 and R2 or R2 alone lead to a deafness phenotype, while a truncating variant affecting repeat motifs R1 and R2 or R2 alone combined with a missense variant does not. Homozygous truncating variants affecting repeat motif R2 cosegregate with the deafness phenotype. Conclusion: While a single intact R1 motif may be adequate for actin‐binding and bundling in the stereocilia of cochlear hair cells, our findings indicate that a truncated R2 motif in cis seems to be incompatible with normal hearing, either by interfering with the function of an intact R1 motif or through another as yet unknown mechanism. Our study also suggests that most heterozygous missense variants involving exon 7 are likely to be tolerated. [ABSTRACT FROM AUTHOR]

ATAs engineered for having an enlarged small binding pocket were applied for the synthesis of enantiomerically pure (R)‐benzo[1,3]dioxol‐5‐yl‐butylamine, a chiral component of human leukocyte elastase inhibitor DMP 777 (L‐694,458). Kinetic resolution of the racemic amine was performed by using the L59A variant of the (S)‐selective ATA from Chromobacterium violaceum (Cv‐ATA), providing the residual (R)‐enantiomer in excellent yield and >99% ee. At moderate enzyme loading and absence of co‐solvent, high volumetric productivity of 0.22 mol L−1 h−1 (42.5 g L−1 h−1) was achieved. Complementarily, the (S)‐enantiomer was generated via kinetic resolution using the (R)‐selective ATA‐117‐Rd11 from Arthrobacter sp. with acetone as the amino acceptor. In an alternative approach, we employed ATA‐117‐Rd11 for the asymmetric amination of the prochiral ketone precursor, which at 86% conversion gave the (R)‐benzo[1,3]dioxol‐5‐yl‐butylamine with excellent >99% ee. We further evaluated the utility of Cv‐ATA L59A for the asymmetric synthesis of pharmaceutically relevant (S)‐1‐phenylbutan‐1‐amine, a chiral component of the deubiquitinase inhibitor degrasyn (WP1130). The enzyme showed good tolerance to high concentrations of isopropylamine, producing (S)‐1‐phenylbutan‐1‐amine in enantiomerically pure form (>99% ee). [ABSTRACT FROM AUTHOR]

For dimensions two, three and four, we derive hyperbolic complex algebraic structures on the basis of suitably defined vector products and powers which allow in a standard way a series definitions of the hyperbolic vector exponential function. In doing so, we both modify arrow multiplication, which, according to Feynman, is fundamental for quantum electrodynamics, and we give a geometric explanation of why in a certain situation it is natural to define random vector products. Through the interplay of vector algebra, geometry and complex analysis, we extend a systematic approach previously developed for various other complex algebraic structures to the field of hyperbolic complex numbers. We discuss a quadratic vector equation and the property of hyperbolically holomorphic functions of satisfying hyperbolically modified Cauchy–Riemann differential equations and also give a proof of an Euler type formula based on series expansion. [ABSTRACT FROM AUTHOR]

The depletion of fossil fuels, associated pollution, and resulting health hazards are of concern worldwide. Woody biomass constitutes an alternative source of cleaner and renewable energy. The efficient use of woody biomass depends on xylan depolymerisation as the endo-β-1,4-xylopyranosyl homopolymer is the main component of hemicellulose, the second most abundant component of wood. Xylan depolymerisation is achieved by hemicellulolytic xylanases of glycoside hydrolase (GH) families 5, 8, 10, 11, 30 and 43 of the CAZY database. We analysed a multidomain xylanase (Xyl) from the hindgut metagenome of the snouted harvester termite Trinervitermes trinervoides that releases xylobiose and xylotriose from beech and birch xylan and wheat arabinoxylan. The four domains of Xyl include an N-terminal GH11 xylanase domain, two family 36-like carbohydrate-binding domains CBM36-1 and 2, and a C-terminal CE4 esterase domain. Previous analyses indicated that CBM36-1 deletion slightly increased GH11 catalysis at low pH whereas removal of both CBMs decreased xylanase activity at 60°C from 90 to 56%. Possible cooperativity between the domains suggested by these observations was explored. A crystal structure of the two-domain construct, GH11-CBM36-1, confirmed the structure of the GH11 domain whereas the CBM36-1 domain lacked electron density, possibly indicating a random orientation of the CBM36-1 domain around the GH11 domain. Isothermal titration calorimetry (ITC) experiments similarly did not indicate specific interactions between the individual domains of Xyl supporting a "beads-on-a-string" model for Xyl domains. [ABSTRACT FROM AUTHOR]

A time span of 60 years covers the detection of catecholamines in the brain, their function in movement and correlation to Parkinson's disease (PD). The clinical findings that orally given l-DOPA can alleviate or even prevent akinesia gave great hope for the treatment of PD. Attention focused on the role of tyrosine hydroxylase (TH) as the rate-limiting enzyme in the formation of catecholamines. It became evident that the enzyme driven formation is lowered in PD. Such results could only be obtained from studying human brain samples demonstrating the necessity for human brain banks. Originally, a TH enzyme deficiency was suspected in PD. Studies were conducted on the enzyme properties: its induction and turnover, the complex regulation starting with cofactor requirements as tetrahydrobiopterin and ferrous iron, and the necessity for phosphorylation for activity as well as inhibition by toxins or regulatory feedback inhibition by catecholamines. In the course of time, it became evident that neurodegeneration and cell death of dopaminergic neurons is the actual pathological process and the decrease of TH a cophenomenon. Nevertheless, TH immunochemistry has ever since been a valuable tool to study neuronal pathways, neurodegeneration in various animal models of neurotoxicity and cell cultures, which have been used as well to test potential neuroprotective strategies. [ABSTRACT FROM AUTHOR]

Acknowledging previous reports with abnormal findings in sensory nerve conduction studies in up to 20% of patients with ALS [[6]] and earlier morphological findings in sensory nerve biopsies suggesting loss of sensory root ganglion neurons [[7]], an involvement of pathological I RFC1 i expansions as additional monogenic form or at least genetic risk factor for ALS might be discussed. However, one must admit, that we cannot differentiate an association of pathological I RFC1 i expansions with a combined phenotype of ALS and sensory neuro(no)pathy in our patient from a bare coincidence of ALS with a beginning CANVAS phenotype due to I RFC1 i pathology. In conclusion, the presented case with a concomitant sensory neuro(no)pathy and proven I RFC1 i expansion in addition to ALS should prompt a more systematical search for I RFC1 i expansion in larger patient cohorts with ALS and unexplained sensory involvement in order to disentangle a possible role of I RFC1 i pathology in ALS. [Extracted from the article]

Cochlear implant, minimally invasive surgery, robotic cochlear implant surgery, image-guided surgery, keyhole access Adaption of the planning procedure by increasing the milling depth enables robotic cochlear implant surgery in ossified basal cochlear turns. Keywords: cochlear implant; image-guided surgery; keyhole access; minimally invasive surgery; robotic cochlear implant surgery EN cochlear implant image-guided surgery keyhole access minimally invasive surgery robotic cochlear implant surgery 504 507 4 04/22/22 20220501 NES 220501 Key Points Robotic cochlear implant surgery is a new and safe technique. Current challenges in robotic CI surgery include prolonged duration of the surgery compared to conventional techniques and exclusion of children. [Extracted from the article]

In mass spectrometry-based proteomics, heavy internal standards are used to validate target peptide detections and to calibrate peptide quantitation. Here, we report light contamination present in heavy labelled synthetic peptides of high isotopic enrichment. Application of such peptides as assay-internal standards potentially compromises the detection and quantitation especially of low abundant cellular peptides. Therefore, it is important to adopt guidelines to prevent false-positive identifications of endogenous light peptides as well as errors in their quantitation from biological samples. [ABSTRACT FROM AUTHOR]

Iron plays a crucial role in many physiological processes of the human body, but iron is continuously deposited in the brain as we age. Early studies found iron overload is directly proportional to cognitive decline in Alzheimer's disease (AD). Amyloid precursor protein (APP) and tau protein, both of which are related to the AD pathogenesis, are associated with brain iron metabolism. A variety of iron metabolism-related proteins have been found to be abnormally expressed in the brains of AD patients and mouse models, resulting in iron deposition and promoting AD progression. Amyloid β (Aβ) and hyperphosphorylated tau, two pathological hallmarks of AD, can also promote iron deposition in the brain, forming a vicious cycle of AD development-iron deposition. Iron deposition and the subsequent ferroptosis has been found to be a potential mechanism underlying neuronal loss in many neurodegenerative diseases. Iron chelators, antioxidants and hepcidin were found useful for treating AD, which represents an important direction for AD treatment research and drug development in the future. The review explored the deep connection between iron dysregulation and AD pathogenesis, discussed the potential of new hypothesis related to iron dyshomeostasis and ferroptosis, and summarized the therapeutics capable of targeting iron, with the expectation to draw more attention of iron dysregulation and corresponding drug development. [ABSTRACT FROM AUTHOR]