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Morphological alterations at the kidney filtration barrier increase intrinsic capillary wall permeability resulting in albuminuria. However, automated, quantitative assessment of these morphological changes has not been possible with electron or light microscopy. Here we present a deep learning-based approach for segmentation and quantitative analysis of foot processes in images acquired with confocal and super-resolution fluorescence microscopy. Our method, Automatic Morphological Analysis of Podocytes (AMAP), accurately segments podocyte foot processes and quantifies their morphology. AMAP applied to a set of kidney diseases in patient biopsies and a mouse model of focal segmental glomerulosclerosis allowed for accurate and comprehensive quantification of various morphometric features. With the use of AMAP, detailed morphology of podocyte foot process effacement was found to differ between categories of kidney pathologies, showed detailed variability between diverse patients with the same clinical diagnosis, and correlated with levels of proteinuria. AMAP could potentially complement other readouts such as various omics, standard histologic/electron microscopy and blood/urine assays for future personalized diagnosis and treatment of kidney disease. Thus, our novel finding could have implications to afford an understanding of early phases of kidney disease progression and may provide supplemental information in precision diagnostics.

A randomized inter-group trial comparing more intensive treatment strategies to a common standard arm 3 + 7 (CSA) was conducted in patients with non-M3 AML. Untreated patients ≥ 60 years were allocated to the CSA (n = 132) or to the study group arms (n = 1154) of the AMLCG (TAD/HAM versus HAM/HAM ± G-CSF followed by TAD and maintenance) and the OSHO (intermediate-dose ara-C/mitoxantrone followed by ara-C/mitoxantrone). Median age of the 1147 eligible patients was 69 (range 60–87) years. CR/CRi status at 90 days was not significantly different between the CSA (54% (95%CI: 45–64)) and the study group arms (53% (95%CI: 47–60) and 59% (95%CI: 58–63)). The five-year event-free survival (EFS) probability (primary endpoint) was 6.2% (95%CI: 2.7–14.0) in the CSA, 7.6% (95%CI: 4.5–12.8) in study group A and 11.1% (95%CI: 9.0–13.7) in B. The 5-year OS was 17.2% (95%CI: 11.0–26.9), 17.0% (95%CI: 2.0–23.9), and 19.5% (95%CI: 16.7–22.8) in CSA, study group A and B, respectively. Neither study group differed significantly from the CSA regarding EFS, OS, or relapse-free survival. In multivariate analyses, allocation to the treatment strategy was not significantly associated with the time-to-event endpoints. The evaluation of more intensive treatment strategies did not show clinically relevant outcome differences when compared to CSA.

ZusammenfassungDie Hyperglykämie ist wesentlich an der Entstehung der Spätkomplikationen bei an Diabetes mellitus Typ 2 erkrankten Patienten/Patientinnen beteiligt. Während Lebensstilmaßnahmen die Eckpfeiler jeder Diabetestherapie bleiben, benötigen im Verlauf die meisten Patienten/Patientinnen mit Typ 2 Diabetes eine medikamentöse Therapie. Bei der Definition individueller Behandlungsziele stellen die Therapiesicherheit, die Effektivität sowie substanzspezifische, kardiovaskuläre Effekte der Therapie die wichtigsten Faktoren dar. In dieser Leitlinie haben wir die rezenten evidenzbasierten Daten für die klinische Praxis zusammengestellt.

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Aims/hypothesis Sodium–glucose cotransporter 2 (SGLT2) inhibitors are widely used in the treatment of type 2 diabetes, heart failure and chronic kidney disease. Their role in the prevention of diet-induced metabolic deteriorations, such as obesity, insulin resistance and fatty liver disease, has not been defined yet. In this study we set out to test whether empagliflozin prevents weight gain and metabolic dysfunction in a mouse model of diet-induced obesity and insulin resistance. Methods C57Bl/6 mice were fed a western-type diet supplemented with empagliflozin (WDE) or without empagliflozin (WD) for 10 weeks. A standard control diet (CD) without or with empagliflozin (CDE) was used to control for diet-specific effects. Metabolic phenotyping included assessment of body weight, food and water intake, body composition, hepatic energy metabolism, skeletal muscle mitochondria and measurement of insulin sensitivity using hyperinsulinaemic–euglycaemic clamps. Results Mice fed the WD were overweight, hyperglycaemic, hyperinsulinaemic and insulin resistant after 10 weeks. Supplementation of the WD with empagliflozin prevented these metabolic alterations. While water intake was significantly increased by empagliflozin supplementation, food intake was similar in WDE- and WD-fed mice. Adipose tissue depots measured by MRI were significantly smaller in WDE-fed mice than in WD-fed mice. Additionally, empagliflozin supplementation prevented significant steatosis found in WD-fed mice. Accordingly, hepatic insulin signalling was deteriorated in WD-fed mice but not in WDE-fed mice. Empagliflozin supplementation positively affected size and morphology of mitochondria in skeletal muscle in both CD- and WD-fed mice. Conclusions/interpretation Empagliflozin protects mice from diet-induced weight gain, insulin resistance and hepatic steatosis in a preventative setting and improves muscle mitochondrial morphology independent of the type of diet. Graphical abstract

Objective Embouchure dystonia (ED) is a task-specific movement disorder that leads to loss of fine motor control of the embouchure and tongue muscles in wind musicians. In contrast to musicians’ hand dystonia, no validated severity rating for ED exists, posing a major obstacle for structured assessment in scientific and clinical settings. The aim of this study is to validate an ED severity rating scale (EDSRS) allowing for a standardized estimation of symptom severity in ED.Methods The EDSRS was set up as a composite score of six items evaluating audio-visual disease symptoms during the performance of three standardized musical tasks (sustained notes, scales, and fourths) separately for each body side. For validation, 17 musicians with ED underwent standardized audiovisual recordings during performance. Anonymized and randomized recordings were assessed by two experts in ED (raters). Statistical analysis included metrics of consistency, reliability, and construct validity with the fluctuation of the fundamental frequency of the acoustic signal (F0) (extracted in an audio analysis of the sustained notes).Results The EDSRS showed high internal consistency (Cronbach’s α = 0.975−0.983, corrected item-total correlations r = 0.90−0.96), interrater reliability (intraclass correlation coefficient [ICC] for agreement/consistency = 0.94/0.96), intrarater reliability over time (ICC per rater = 0.93/0.87) and good precision (standard error of measurement = 2.19/2.65), and correlated significantly with F0 variability (r = 0.55–0.60, p = 0.011–0.023).Conclusion The developed EDSRS is a valid and reliable tool for the assessment of ED severity in the hands of trained expert raters. Its easy applicability makes it suitable not only for routine clinical practice but also for scientific studies.

In the recent past, lots of efforts have been put into further developing SiC power MOSFETs. In addition to optimization of device geometry, i.e., vertical device structure, various post-oxidation anneals have been studied to improve carrier mobility by reducing trap density. Nevertheless, a considerable number of traps remain, which are the central origin for dynamic changes in the threshold voltage of up to several volts during DC and AC operation. To explain the threshold voltage instability, an effective two-state defect model has been recently applied. In this work, we give an overview of modeling efforts to explain the impact of defects on the device threshold voltage and discuss the hysteresis of voltage sweep and bias temperature instabilities in SiC transistors. Based on the combination of measurements and computer simulations, a list of potential defect candidates responsible for the observed threshold voltage instabilities is discussed.

As leishmanioses são doenças infecto-parasitárias endêmicas e estão entre as antropozoonoses de maior prevalência em todo mundo. São causadas por protozoários do gênero Leishmania, e os responsáveis pela transmissão são dípteros da (família Psychodidae, subfamília Phlebotominae), conhecidos como flebotomíneos. O presente estudo teve como objetivo identificar a fauna de flebotomíneos no ambiente florestal no interior do estado do Amazonas. Os insetos foram capturados com armadilhas luminosas tipo Center for Disease Control (CDC), instaladas em seis pontos amostrais compreendendo três diferentes ecótopos: borda da floresta, interior da floresta e peridomicílio, em uma floresta ombrófila densa de planície de terra firme. As armadilhas foram alojadas nesses ecótopos das 19h às 5h, totalizando um esforço de captura de 60 horas. Foram coletados um total de 637 espécimes pertencentes a 10 gêneros e 25 espécies. Os gêneros mais abundantes foram Trichophoromyia (51,96%), Psychodopygus (20,37%) e Nyssomyia (8.97%). Considerando apenas os flebotomíneos devidamente identificados, as espécies mais abundantes foram Th. ubiquitalis (42,43%), Ps. davisi (11,21%) e Lu. sherlocki (5.98%). Quando analisada a média horária (MH) por ecótopo, o interior da floresta apresentou a maior média com MH=15. O ambiente estudado apresentou uma fauna diversificada de flebotomíneos, incluindo espécies de interesse na saúde única. O fato do ambiente apresentar espécies já incriminadas como vetores de leishmanioses, bem como a circulação de pessoas e a proximidade de moradias, pode, no futuro, indicar a alta transmissão de Leishmania nesta comunidade.

Digital media are becoming increasingly influential in society, especially among the younger generation. Therefore, an augmented reality (AR) app was developed that simulates experiments with radioactive sources. The app runs experiments on the range and penetration power of alpha, beta and gamma radiation. It assigns virtual radiation sources, shielding materials or a detector to printed image markers, and superimposes their 3D images on the camera image. Alpha, beta and gamma radiation are clearly distinguishable by choosing different visualizations. The detector displays the measured count rates. At school, the app can be used in different ways. A concept for a teaching unit in Grade 10 was developed and tested in several classes based on a prototype of the app. The learning progress from the AR experiments was examined. Furthermore, an evaluation of the app was carried out. The most recent version of the app can be found here: https://seafile.projekt.uni-hannover.de/d/dd033aaaf5df4ec18362/

BACKGROUND AND AIMS Porto-sinusoidal vascular liver disorder (PSVD) is a rare disease that occasionally requires liver transplantation (LT), despite usually presenting preserved liver function. There remains a paucity of data pertaining to LT in PSVD. The aim was to identify features associated with post-LT outcomes in PSVD. METHODS Retrospective multicentre study of 79 patients who received LT for PSVD. RESULTS Median post-LT follow-up was 37 (range 1-261) mo. Refractory ascites 24 (30%), hepatic encephalopathy 16 (20%), and hepatopulmonary syndrome 13 (16.3%) were the most frequent indications for LT. Hepatocellular carcinoma was the indication in only 2 patients. Twenty-four patients died, 7 due to liver and 17 to non-liver related causes. Post-LT survival was 82.2%, 80.7%, and 68.6% at 1, 2, and 5 y, respectively. Post-LT survival was significantly better in patients without (n = 58) than in those with a persistent severe PSVD-associated condition (n = 21). Pre-LT hyperbilirubinemia levels and creatinine >100 µmol/L were also independently associated with poor survival. Six patients (7.6%) required a second LT. Recurrence of PSVD was confirmed by liver biopsy in only 1 patient and in 3 further patients it was likely. CONCLUSIONS LT in PSVD is associated with an acceptable outcome in the absence of associated severe conditions. However, persistence of a severe associated condition, pre-LT high bilirubin levels, or creatinine >100 µmol/L impact outcome, and these are features that should be considered when evaluating PSVD patients for LT. PSVD recurrence is possible after LT and needs to be explored, at least, in cases of posttransplant portal hypertension.

We compute the spin torque acting on elongated magnetic layers inrecently proposed ultra-scaled STT-MRAM devices. For thispurpose we evaluate the non-equilibrium spin accumulation bysolving the coupled spin and charge transport equations. This goesbeyond the Slonczewski torque approximation which describestorques localized at the interface of the tunnel barrier and themagnetic free layer as well as the Zhang-Li torque approximationmodeling the torque acting on a magnetic texture (a domain wall)in the layer’s bulk. We show that the torque contributions frominterface and bulk are not independent from each other and ourgeneralized approach is necessary to accurately model the torquein the presence of a magnetic domain wall inside the magnetic freelayer. We implemented a numerical solution of the spin and chargetransport equations in a finite element-based framework.

This paper examined the type of relationship existing between wealth accumulation ( and /or human development), and natural gas energy consumption (NGC) in Nigeria using the Human Development Index (HDI1 and HDI2) as proxies for human development and wealth accumulation. We employed the theoretical pedestal of natural gas energy consumption-growth nexus in our empirical review, and econometric model specification, and in evaluating the resultant estimates of this relationship. Annual time series data for the selected indicators were extracted for several years. Our results indicated that in the long-run, natural gas energy consumption does not facilitate human development and wealth accumulation vice versa in Nigeria. Furthermore, our results suggest that natural gas energy is consumed or utilized in Nigeria for non-wealth accumulation and non-human development purposes. We recommend that gas energy should be consumed and/or redirected to a more purposeful wealth and human development facilitating consumption. Keywords: Natural Gas Energy, Growth, Nigeria, ARDL Bounds Tests. JEL Classification Code:C50,Q32,Q400,Q430

Background: Calcific aortic valve disease (CAVD) is characterized by a phenotypic switch of valvular interstitial cells to bone-forming cells. Toll-like receptors (TLRs) are evolutionarily conserved pattern recognition receptors at the interface between innate immunity and tissue repair. Type I interferons (IFNs) are not only crucial for an adequate antiviral response but also implicated in bone formation. We hypothesized that the accumulation of endogenous TLR3 ligands in the valvular leaflets may promote the generation of osteoblast-like cells through enhanced type I IFN signaling. Methods: Human valvular interstitial cells isolated from aortic valves were challenged with mechanical strain or synthetic TLR3 agonists and analyzed for bone formation, gene expression profiles, and IFN signaling pathways. Different inhibitors were used to delineate the engaged signaling pathways. Moreover, we screened a variety of potential lipids and proteoglycans known to accumulate in CAVD lesions as potential TLR3 ligands. Ligand-receptor interactions were characterized by in silico modeling and verified through immunoprecipitation experiments. Biglycan ( Bgn ), Tlr3 , and IFN-α/β receptor alpha chain ( Ifnar1 )–deficient mice and a specific zebrafish model were used to study the implication of the biglycan (BGN)-TLR3-IFN axis in both CAVD and bone formation in vivo. Two large-scale cohorts (GERA [Genetic Epidemiology Research on Adult Health and Aging], n=55 192 with 3469 aortic stenosis cases; UK Biobank, n=257 231 with 2213 aortic stenosis cases) were examined for genetic variation at genes implicated in BGN-TLR3-IFN signaling associating with CAVD in humans. Results: Here, we identify TLR3 as a central molecular regulator of calcification in valvular interstitial cells and unravel BGN as a new endogenous agonist of TLR3. Posttranslational BGN maturation by xylosyltransferase 1 (XYLT1) is required for TLR3 activation. Moreover, BGN induces the transdifferentiation of valvular interstitial cells into bone-forming osteoblasts through the TLR3-dependent induction of type I IFNs. It is intriguing that Bgn −/− , Tlr3 −/− , and Ifnar1 −/− mice are protected against CAVD and display impaired bone formation. Meta-analysis of 2 large-scale cohorts with >300 000 individuals reveals that genetic variation at loci relevant to the XYLT1–BGN–TLR3–interferon-α/β receptor alpha chain (IFNAR) 1 pathway is associated with CAVD in humans. Conclusions: This study identifies the BGN-TLR3-IFNAR1 axis as an evolutionarily conserved pathway governing calcification of the aortic valve and reveals a potential therapeutic target to prevent CAVD.

The link between Financial inclusion (FIN ) and digital finance(DF) is the primary subject of this research. Digital finance and inclusive financial though have been adjudged to be related; there are quite a plethora of issues that are still unclear concerning the nature and type of their relationship. Why are they related and at what point are they related? Short or long-run relationship? To clarify these issues, the study applied the Auto regressive Distributed Lag (ARDL) long-run cointegrating technique to explicate our econometric models. Our data is time series in nature and is for Nigeria. The study established that, internet-powered electronic device users, a proxy for digital finance has a positive long-run relationship with FIN while Automated Teller machine (ATM) ownership and usage has a negative long-run relationship with FIN. The study recommended that internet service providers (ISPs) be integrated into the Nigerian FIN paradigm to enhance the accuracy and viability of financial service provision, leading to a decline in the unbanked population. Keywords: Digital finance, FIN, financial services, ARDL Bounds Test, Nigeria.

The link between e-payment system and financial inclusion (FI) is the fundamental interest of this paper. Series from the economy of Nigeria were adopted in testing the long-run equations of e-payment and FI. Furthermore, the normalized cointegration technique was applied to ascertain the definite relationship among our series. Our findings suggest that a long-run positive relationship existed between the surrogates of e-payments and financial inclusion in Nigeria. We recommended the widening and deepening of the e-payment mechanism in Nigeria to enhance sustainable financial inclusion. Keywords: E-payment, Financial Inclusion, Normalized Cointegration, Nigeria. JEL Classification:G20,G21,G28,C520.

The electricity-growth literature is replete with empirical evidences of studies that adopted the Gross Domestic Product (GDP) or its surrogates as measures of the quality of life. Hence, the fundamental focus of this study is to explore the link between electricity energy consumption and quality of life in Nigeria for the period 1990 to 2020.The Autoregressive Distributed Lag (ARDL) model was adapted as the econometric estimation technique for the examination of the link between electricity energy consumption (ELE) and the quality of life of electricity-dependent economic agents represented as HDI1 and HDI2. The resultant estimates and outcomes of the ARDL test indicated that there is no short and long-run connectivity between ELE and HDI (1). We concluded that, ELE has not been beneficial for the enhancement of the quality of life (when represented as HDI1) and / or its accumulation in the short- and long -run but has long run positive consequences for only HDI2. Therefore, the government of Nigeria, and the international bilateral and multilateral agencies for the development of quality of life should encourage electricity consumption as a complement of human well-being and quality of life especially HDI1 and HDI2 for short and long-run purposes. Keywords: Electricity Energy, Quality of life, Human Development, Cointegration, ARDL Bounds Test, Nigeria.

We derive generalizations of Dupire formula to the cases of general stochastic drift and/or stochastic local volatility. First, we handle a case in which the drift is given as difference of two stochastic short rates. Such a setting is natural in foreign exchange context where the short rates correspond to the short rates of the two currencies, equity single-currency context with stochastic dividend yield, or commodity context with stochastic convenience yield. We present the formula both in a call surface formulation as well as total implied variance formulation where the latter avoids calendar spread arbitrage by construction. We provide derivations for the case where both short rates are given as single factor processes and present the limits for a single stochastic rate or all deterministic short rates. The limits agree with published results. Then we derive a formulation that allows a more general stochastic drift and diffusion including one or more stochastic local volatility terms. In the general setting, our derivation allows the computation and calibration of the leverage function for stochastic local volatility models. Despite being implicit, the generalized Dupire formulae can be used numerically in a fixed-point iterative scheme.

Critical Action Learning (CAL) is a well-established approach to action learning. However, it has not necessarily been clear to action learning practitioners what makes CAL ‘critical’ and what are the implications in practice. In CAL, the facilitator has a key role in helping the set to engage with underlying emotions and power relations that are inevitably embedded in learning sets, and that both promote and prevent learning. The paper explains the main ideas of critical action learning, why facilitation is important, and how to facilitate CAL. Examples are provided from the authors’ practice and eight key components are presented as a guide to facilitating CAL. The aim of the paper is to improve the action learning community’s knowledge of how to facilitate critical action learning and when it is appropriate to utilize this approach.

En las páginas siguientes, voy a presentar un proyecto que he desarrollado para el casco antiguo de la ciudad de Málaga. Se debía integrar un edificio nuevo en un ambiente histórico.

Wine made or stored in clayware ceramic pots attracts the attention of consumers, but this practice is less studied than when classic stainless steel tanks or wood barrels are used. It is known that wine can be influenced by the container in which it is aged. To analyse the influence of ceramics on the chemical composition of wine, Armenian clay-based ceramic tablets were immersed in model wine and aged from 1 hour up to 16 months at 25 °C in darkness. The concentrations of 26 elements (namely: Al, B, Ba, Be, Ca, Cd, Co, Cr, Cu, Fe, Hg, K, Li, Mg, Mn, Mo, Na, Ni, P, Pb, S, Sr, Ti, V, W and Zn) in 19 samples were determined by ICP-AES analysis. Proton time domain NMR relaxometry was used to characterise the iron redox processes that occurred in the model wine in contact with a ceramic. A fast increase in the pH of the model wine in contact with the bare ceramic tablet (from 2.35 to 5) was recorded in 4 days. The coating of the ceramic tablets with beeswax showed a significant effect on the interaction between the model wine and the ceramic.

The κ-opioid receptor (KOR) represents a highly desirable therapeutic target for treating not only pain but also addiction and affective disorders1. However, the development of KOR analgesics has been hindered by the associated hallucinogenic side effects2. The initiation of KOR signalling requires the Gi/o-family proteins including the conventional (Gi1, Gi2, Gi3, GoA and GoB) and nonconventional (Gz and Gg) subtypes. How hallucinogens exert their actions through KOR and how KOR determines G-protein subtype selectivity are not well understood. Here we determined the active-state structures of KOR in a complex with multiple G-protein heterotrimers—Gi1, GoA, Gz and Gg—using cryo-electron microscopy. The KOR–G-protein complexes are bound to hallucinogenic salvinorins or highly selective KOR agonists. Comparisons of these structures reveal molecular determinants critical for KOR–G-protein interactions as well as key elements governing Gi/o-family subtype selectivity and KOR ligand selectivity. Furthermore, the four G-protein subtypes display an intrinsically different binding affinity and allosteric activity on agonist binding at KOR. These results provide insights into the actions of opioids and G-protein-coupling specificity at KOR and establish a foundation to examine the therapeutic potential of pathway-selective agonists of KOR.

Background: Bone or cartilage anomalies with affection of brain supplying arteries are a potential structural cause for ischemic stroke. In the following, we termed this entity bony stroke. Due to rarity of their description, there is no standardized workup and therapy for bony strokes. Methods: Retrospectively, we extracted diagnostic and therapeutic workup of all patients considered to have had a bony stroke between January 2017 to March 2022 at our comprehensive care center. Results: In total, 6 patients classified as a bony stroke were identified among 4200 acute patients with ischemic stroke treated during the study period. Each patient had recurrent ischemic strokes in the dependent vascular territory before diagnosis. Diagnosis was achieved by a combination of imaging devices, including sonography, computed tomography, and magnetic resonance imaging. In addition to conventional static imaging, the application of dynamic imaging modalities with the patients’ head in rotation or reclination confirmed a vessel affection following head movements in 3 patients (50%). Treatment options were interdisciplinary assessed and included the following: conservative treatment (n=1), endovascular stenting (n=2) or occlusion (n=2), surgical removal of bone/ cartilage (n=2), and surgical bypass treatment (n=1). In follow-up (mean 11.7 months), no patient experienced further ischemia. Conclusions: As a differential diagnosis, bony strokes may be considered in patients with recurrent ischemic stroke of unknown cause in one dependent vascular territory. Interdisciplinary evaluation and treatment may eliminate risk of stroke recurrence.

Summary: Background: The total endovascular repair of the aortic arch is becoming more and more an acceptable alternative to the open repair in selected patients. The aim of the present study is to perform a meta-analysis of the available data on the outcomes of the various endovascular techniques used to treat the pathologies in this challenging anatomical area. Patients and methods: An extensive electronic search in PubMed/MEDLINE, Science Direct Databases, and the Cochrane Library was conducted. All papers published up to January 2022 on the endovascular techniques in the aortic arch (chimney-thoracic endovascular aortic repair (ChTEVAR), fenestrated/branched grafts as custom made devices (CMD) and surgeon modified TEVAR (SM TEVAR) providing information about at least one of the essential outcomes defined in the inclusion criteria. Results: Out of the 5078 studies found through the search in the databases and registers, 26 studies with a total number of patients of 2327 with 3497 target vessels were included in the analysis. The studies reported a high technical success rate with an estimated proportion of 95.8% (95% CI, 93–97.6%). Moreover, the pooled estimation of the early type Ia/III endoleak was 8.1% (95% CI, 5.4–12.1%). The pooled mortality was 4.6% (95 CI, 3.2–6.6%) with a significant heterogeneity and the stroke had an estimated proportion (major and minor combined) of 4.8% (95% CI, 3.5–6.6%). A meta-regression analysis showed no significant variation between the groups in mortality (P=.324) showed however a significant difference between the therapeutic methods regarding stroke P

Comparison of radiation dose and image quality in routine abdominal and pelvic contrast-enhanced computed tomography (CECT) between a photon-counting detector CT (PCD-CT) and a dual energy dual source CT (DSCT).70 oncologic patients (mean age 66 ± 12 years, 29 females) were prospectively enrolled between November 2021 and February 2022. Abdominal CECT were clinically indicated and performed first on a 2Median time interval between the scans was 4 months (IQR: 3-6). CNRPCD-CT enables oncologic abdominal CT with a significantly reduced dose while keeping image quality similar to 2