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Abstract 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 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.

This case report describes the death of a 73-year-old man who suffered a fatal myocardial infarction following pulmonary vein isolation (PVI) for the treatment of atrial fibrillation. Post-mortem examination and imaging revealed the presence of an atrioesophageal fistula (AEF) leading to gas embolism at various sites of the heart including the right coronary artery. Atrioesophageal fistulas are rare complications of pulmonary vein isolation with high mortality rates.

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 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.

A 61-year-old man was found dead on the terrace in front of his house. The body showed external signs of advanced (Grade 4) putrefaction. Routine post-mortem computed tomography (PMCT) was conducted prior to the forensic autopsy showing a radiological alteration index (RAI) of 100. Due to a suspicious hyperdense brain lesion seen in PMCT, additional post-mortem magnetic resonance imaging (PMMR) of the head was performed for research purpose. Compared to PMCT, the lesion appeared considerably more detailed in PMMR with a slightly hyperintense and focal hypointense signal in T2w images and an isointense and focal hyperintense signal in T1w images. Autoptic assessment of the brain lesion was considerably complicated due to softening and partial liquefaction of the brain. Considering post-mortem imaging and autopsy results, the lesion was determined as an acute brain hemorrhage. Case findings indicate that PMMR may be superior to autopsy in terms of diagnosis and localization of cerebral hemorrhage in putrefied brains.

Abstract 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.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has placed a tremendous strain on healthcare services. This study, prepared by a large international panel of stroke experts, assesses the rapidly growing research and personal experience with COVID-19 stroke and offers recommendations for stroke management in this challenging new setting: modifications needed for prehospital emergency rescue and hyperacute care; inpatient intensive or stroke units; posthospitalization rehabilitation; follow-up including at-risk family and community; and multispecialty departmental developments in the allied professions. SUMMARY: The severe acute respiratory syndrome coronavirus 2 uses spike proteins binding to tissue angiotensin-converting enzyme (ACE)-2 receptors, most often through the respiratory system by virus inhalation and thence to other susceptible organ systems, leading to COVID-19. Clinicians facing the many etiologies for stroke have been sobered by the unusual incidence of combined etiologies and presentations, prominent among them are vasculitis, cardiomyopathy, hypercoagulable state, and endothelial dysfunction. International standards of acute stroke management remain in force, but COVID-19 adds the burdens of personal protections for the patient, rescue, and hospital staff and for some even into the postdischarge phase. For pending COVID-19 determination and also for those shown to be COVID-19 affected, strict infection control is needed at all times to reduce spread of infection and to protect healthcare staff, using the wealth of well-described methods. For COVID-19 patients with stroke, thrombolysis and thrombectomy should be continued, and the usual early management of hypertension applies, save that recent work suggests continuing ACE inhibitors and ARBs. Prothrombotic states, some acute and severe, encourage prophylactic LMWH unless bleeding risk is high. COVID-19-related cardiomyopathy adds risk of cardioembolic stroke, where heparin or warfarin may be preferable, with experience accumulating with DOACs. As ever, arteritis can prove a difficult diagnosis, especially if not obvious on the acute angiogram done for clot extraction. This field is under rapid development and may generate management recommendations which are as yet unsettled, even undiscovered. Beyond the acute management phase, COVID-19-related stroke also forces rehabilitation services to use protective precautions. As with all stroke patients, health workers should be aware of symptoms of depression, anxiety, insomnia, and/or distress developing in their patients and caregivers. Postdischarge outpatient care currently includes continued secondary prevention measures. Although hoping a COVID-19 stroke patient can be considered cured of the virus, those concerned for contact safety can take comfort in the increasing use of telemedicine, which is itself a growing source of patient-physician contacts. Many online resources are available to patients and physicians. Like prior challenges, stroke care teams will also overcome this one. Key Messages: Evidence-based stroke management should continue to be provided throughout the patient care journey, while strict infection control measures are enforced.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting 1% of the population above sixty years. It is caused by an interaction between genetic and environmental risk factors. Loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) is pathologically characterizing the disease and responsible for the cardinal motor symptoms, most notably, bradykinesia, rest tremors, rigidity, and loss of postural reflexes. Non-motor signs such as olfactory deficits, cognitive impairment, sleep behavior disorders, and gastrointestinal disturbances are reflecting disturbances in the non-dopaminergic system. They precede dopaminergic neuronal degenerations by 5–10 years and are considered the main contributors to patients’ disability, particularly after the successful implementation of levodopa (L-dopa) treatment of motor symptoms. The present general review aimed to briefly update non-motor signs and their underlying pathophysiology in PD.

Objective: This study aimed to reveal the antitumor effects of Chinese herbal formulae and the underlying mechanisms in treating colorectal cancer, with a focus on developing traditional Chinese medicine (TCM) as a supplement and alternative therapeutic method for cancers. Materials and Methods: Human colon cancer SW480 cells were treated with three Chinese herbal formulae, Bu Zhong Yi Qi Decoction, Fuzi Lizhong Decoction, and Pulsatilla Decoction at different concentrations (50–600 μg/mL) for 24, 36, and 48 h, respectively. Cell viability was determined using the resazurin reduction assay, and cell survival rate was evaluated using a colony formation assay. After treatment with different concentrations (50–600 μg/mL) of these three formulae for 48 h, the effects of the Chinese herbal formulae on cell apoptosis were investigated using Hoechst/propidium iodide (PI) staining. The positive PI-stained cells were investigated using an EnSpire multilabel plate reader and the positive Hoechst-stained cells were observed under a fluorescence microscope for morphological changes. Results: Bu Zhong Yi Qi Decoction, Fuzi Lizhong Decoction, and Pulsatilla Decoction inhibited SW480 cell proliferation in a dose-and time-dependent manner and induced cell apoptosis. Conclusion: Chinese herbal formulae with a special prescription form of TCM with antitumor effects bring a new perspective in line with the principles of TCM in cancer treatment.

Abstract 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).

Movements on surfaces of centered Euclidean spheres and changes between those with different radii mean complex multiplication in R3. 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.

Mutations in the PARK2 gene are associated with early onset Parkinsonism. The Park2 -/- mouse, however, does not exhibit neurodegeneration or other Parkinsons disease (PD) phenotypes. Previously, we discovered that translation of Mcl-1, a pro-survival factor, is upregulated in the Park2 -/- mouse, suggesting a compensatory mechanism during development. Here we generated the Park2 -/- Mcl-1 +/- mouse and show that by reducing Mcl-1 gene dosage by 50%, the Park2 -/- genotype is sensitized, conferring both dopaminergic neuron loss and motor impairments. We propose that this murine model could be a useful tool for dissecting PD etiology and developing treatment strategies against this neurodegenerative disease.

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]

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.

Magnesium as biodegradable biomaterial could serve as bone augmentation material in implant dentistry. The knowledge about the predictability of the biodegradation process is essential as this process needs to go hand in hand with the formation of new bone to gradually replace the augmentation material. Therefore, this work aimed to assess if the electrochemistry (EC) measurements of the corrosion process correlate with the surface features at various time points during the surface degradation, in order to describe the degradation process of Mg and Mg alloys more reliably, under the assumption that differences in EC behavior can be detected and related to specific patterns on the surface.In this test setup, a special optical chamber was used for electrochemical measurements on Mg and Mg-alloys (Mg2Ag, Mg4Ag, and Mg6Ag). Specimens were investigated using different circulating cell culture solutions as electrolytes, these were minimum essential medium (MEM), Hank's Balanced Salt Solution (HBSS), and MEM+ (MEM with added sodium hydrogen carbonate) at 37 °C. Open circuit potential measurements (OCP) over 30 min followed by cyclic polarization were performed. The electrochemistry data, including OCP, exchange current density and corrosion potential, were compared with visible changes at the surface during these treatments over time. The results show that the addition of silver (Ag) leads to a “standardization” of the degradation regardless of the selected test medium. It is currently difficult to correlate the visible microscopic changes with the data taken from the measurements. Therefore, further investigations are necessary.

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.

The growth and microscopic characterization of two-dimensional germania films is presented. Germanium oxide monolayer films were grown on Ru(0001) by physical vapor deposition and subsequent annealing in oxygen. We obtain a comprehensive image of the germania film structure by combining intensity-voltage low-energy electron diffraction (I/V-LEED) and ab initio density functional theory (DFT) analysis with atomic-resolution scanning tunneling microscopy (STM) imaging. For benchmarking purposes, the bare Ru(0001) substrate and the (2×2)3O covered Ru(0001) were analyzed with I/V-LEED with respect to previous reports. STM topographic images of the germania film reveal a hexagonal network where the oxygen and germanium atom positions appear in different imaging contrasts. For quantitative LEED, the best agreement has been achieved with DFT structures where the germanium atoms are located preferentially on the top and fcc hollow sites of the Ru(0001) substrate. Moreover, in these atomically flat germania films, local site geometries, i.e., tetrahedral building blocks, ring structures, and domain boundaries, have been identified, indicating possible pathways towards two-dimensional amorphous networks.

Background: Well-developed assessment methods have a positive impact on students’ performance, and higher education institutes are usually encouraged to establish and use effective assessment methods that effectively enhance the learning process. Objectives: This study was designed to compare students’ performance in multiple choice questions (MCQs) including best single answer (BSA) and multiple true and false (MTF) types, and very short answer (VSA) questions, and to evaluate gender differences and feedback from students and faculty. Materials and methods: A test containing three different types of questions, BSA, MTF and VSA questions (10 each), was delivered to eight groups of veterinary pathology students (3rd level, Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt) in April 2022. Students’ performance, test reliability and gender differences as well as feedback from students and faculty were evaluated. Results: Students did a significant higher performance in BSA and MTF questions compared to VSA questions. The reliability of BSA, MTF and VSA questions between different groups of students were 0.53, 0.52 and 0.13, respectively. Girl students achieved a higher performance in the whole test compared to boy students. Both boy and girl students showed nearly similar performance in BSA and MTF questions. However, girl students got significant higher score in VSA questions compared to boy students. Students’ and faculty opinions were in favor of BSA and MTF questions. Conclusion: Students did much better in MCQs than VSA questions. BSA and MTF questions are preferentially favored by students and faculty.

Abstract 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.

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.

Im Titelinterview mit „Monitor Versorgungsforschung“ erklärt Prof. Dr. med. Wolf-Dieter Ludwig, der langjährige Vorsitzende der Arzneimittelkommission der deutschen Ärzteschaft, sehr detailliert, auf welcher Studienbasis die vier bisher verfügbaren Covid-19-Vakzine zugelassen wurden und was eine 95 Prozent relative Wirksamkeit tatsächlich bedeutet – „eigentlich recht wenig“. Zudem war seiner Ansicht nach die „bisher erfolgte Kommunikation in der Öffentlichkeit zur Wirksamkeit und Sicherheit der Impfstoffe gegen SARS-CoV-2 unzureichend“, wie Ludwig im Interview zu Protokoll gibt. Auch die ursprünglichen Preisvorstellungen von BioNTech/Pfizer hält er angesichts der Milliarden an zu impfenden Menschen für „unseriös“.

Abstract Age-related macular degeneration (AMD) is the predominant cause of vision loss in the elderly with a major impact on ageing societies and healthcare systems. A major challenge in AMD management is the difficulty to determine the disease stage, the highly variable progression speed and the risk of conversion to advanced AMD, where irreversible functional loss occurs. In this study we developed an optical coherence tomography (OCT) imaging based spatio-temporal reference frame to characterize the morphologic progression of intermediate age-related macular degeneration (AMD) and to identify distinctive patterns of conversion to the advanced stages macular neovascularization (MNV) and macular atrophy (MA). We included 10,040 OCT volumes of 518 eyes with intermediate AMD acquired according to a standardized protocol in monthly intervals over two years. Two independent masked retina specialists determined the time of conversion to MNV or MA. All scans were aligned to a common reference frame by intra-patient and inter-patient registration. Automated segmentations of retinal layers and the choroid were computed and en-face maps were transformed into the common reference frame. Population maps were constructed in the subgroups converting to MNV (n=135), MA (n=50) and in non-progressors (n=333). Topographically resolved maps of changes were computed and tested for statistical significant differences. The development over time was analysed by a joint model accounting for longitudinal and right-censoring aspect. Significantly enhanced thinning of the outer nuclear layer (ONL) and retinal pigment epithelium (RPE)–photoreceptorinner segment/outer segment (PR-IS/OS) layers within the central 3 mm and a faster thinning speed preceding conversion was documented for MA progressors. Converters to MNV presented an accelerated thinning of the choroid and appearance changes in the choroid prior to MNV onset. The large-scale automated image analysis allowed us to distinctly assess the progression of morphologic changes in intermediate AMD based on conventional OCT imaging. Distinct topographic and temporal patterns allow to prospectively determine eyes with risk of progression and thereby greatly improving early detection, prevention and development of novel therapeutic strategies.

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]

Introducción. El cianoacrilato de n-butilo (BCA) y su polímero, el policianoacrilato de n-buti- lo (PBCA) poseen excelentes propiedades adhesivas, biocompatibles y biodegradables para aplicaciones médicas. Este trabajo presenta nuevos métodos para producir BCA de alta pu- reza y micro/nanofibras de PBCA como potenciales productos farmacéuticos. Métodos. La radiación de microondas se utilizó para producir BCA y la técnica de electro-hilado para las micro/nanofibras de PBCA, cuyas propiedades química-físicas, mecánicas, biológicas y de transportación de fármacos fueron evaluadas. Resultados. El tiempo del proceso para la producción del BCA se redujo de 3 veces a 5 veces al emplear la radiación de microondas respecto al baño de aceite. El electro-hilado a disoluciones de PBCA con distintas masas moleculares produjo fibras libres de defectos con diámetros de 400 nm a 5 mm. Se deter- minaron valores del módulo de Young y de tensión máxima de 0,7 MPa a 1,9 MPa y de 0,05 MPa a 0,12 MPa respectivamente. La degradación térmica de las nanofibras de PBCA y las cargadas con 15 % de 5-fluorouracilo ocurrió de 110 oC a 241 oC y de 100 oC a 309 oC con sus respectivos máximos en 186 oC y 203 oC. El citostático 5-fluorouracilo se distribuyó homogéneamente en las fibras de PBCA, liberándose el 20 % en 7 días y el resto de forma gradual (hasta 96 días) en medio fisiológico. Los fibroblastos humanos proliferaron sobre las nanofibras de PBCA. Como conclusiones, la radiación de microondas reduce significativa- mente el tiempo de síntesis del BCA. El electro-hilado del PBCA produce mallas constituidas por micro/nanofibras, que pudieran utilizarse como sistemas transportadores de fármacos y para ingeniería de tejidos.

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.

Background and ObjectiveThe cochlear implant (CI) electrode insertion process is a key step in CI surgery. One of the aims of advances in robotic-assisted CI surgery (RACIS) is to realize better cochlear structure preservation and to precisely control insertion. The aim of this literature review is to gain insight into electrode selection for RACIS by acquiring a thorough knowledge of electrode insertion and related complications from classic CI surgery involving a manual electrode insertion process.MethodsA systematic electronic search of the literature was carried out using PubMed, Scopus, Cochrane, and Web of Science to find relevant literature on electrode tip fold over (ETFO), electrode scalar deviation (ESD), and electrode migration (EM) from both pre-shaped and straight electrode types.ResultsA total of 82 studies that include 8,603 ears implanted with a CI, i.e., pre-shaped (4,869) and straight electrodes (3,734), were evaluated. The rate of ETFO (25 studies, 2,335 ears), ESD (39 studies, 3,073 ears), and EM (18 studies, 3,195 ears) was determined. An incidence rate (±95% CI) of 5.38% (4.4–6.6%) of ETFO, 28.6% (26.6–30.6%) of ESD, and 0.53% (0.2–1.1%) of EM is associated with pre-shaped electrodes, whereas with straight electrodes it was 0.51% (0.1–1.3%), 11% (9.2–13.0%), and 3.2% (2.5–3.95%), respectively. The differences between the pre-shaped and straight electrode types are highly significant (p < 0.001). Laboratory experiments show evidence that robotic insertions of electrodes are less traumatic than manual insertions. The influence of round window (RW) vs. cochleostomy (Coch) was not assessed.ConclusionConsidering the current electrode designs available and the reported incidence of insertion complications, the use of straight electrodes in RACIS and conventional CI surgery (and manual insertion) appears to be less traumatic to intracochlear structures compared with pre-shaped electrodes. However, EM of straight electrodes should be anticipated. RACIS has the potential to reduce these complications.