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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.

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.

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]

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.

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 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.

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.

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.

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.

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.