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Background: The estimation of glomerular filtration rate (eGFR) is essential in the early detection of diabetic nephropathy. We herein compare the performance of common eGFR formulas against a gold standard measurement of GFR in patients with diabetes mellitus. Methods: GFR was measured in 93 patients with diabetes mellitus using iohexol clearance as the reference standard. The performance of the creatinine- and cystatin C-based EKFC formulas (2021, 2023) and the CKD-EPI formulas (2009, 2012) was compared against measured GFR. Results: Sixty patients with type 2 diabetes mellitus and 33 patients with type 1 diabetes mellitus were included. The creatinine-based EKFC formula showed lower bias and higher accuracy than the CKD-EPI formula. No significant difference was observed between the cystatin C-based formulas. The combined creatinine- and cystatin C-based formulas had the highest accuracy and lowest bias. Body fat or diabetes type did not significantly influence the accuracy of the cystatin C-based formulas. Conclusions: Our study demonstrated a slight advantage of the creatinine-based EKFC formula over the CKD-EPI formula in patients with diabetes. However, both for the CKD-EPI and the EKFC formula, the best performance was achieved by the combined creatinine- and cystatin C-based formulas. Graphical abstract:

Many metabolomic studies are interested in both polar and nonpolar analyses. However, the available sample volume often precludes multiple separate extractions. Therefore, there are major advantages in performing a biphasic extraction and retaining both phases for subsequent separate analyses. To be successful, such approaches require the method to be robust and repeatable for both phases. Hence, we determined the performance of three extraction protocols, plus two variant versions, using 25 μL of commercially available mouse plasma. The preferred option for nonpolar lipids was a modified diluted version of a method employing methyl tert-butyl ether (MTBE) suggested by Matyash and colleagues due to its high repeatability for nonpolar compounds. For polar compounds, the Bligh–Dyer method performs best for sensitivity but with consequentially poorer lipid performance. Overall, the scaled-down version of the MTBE method gave the best overall performance, with high sensitivity for both polar and nonpolar compounds and good repeatability for polar compounds in particular.

The paper describes the “Halle Institute for Economic Research (IWH) Forecasting Dashboard (ForDas)”. This tool aims at providing, on a non-commercial basis, historical and actual macroeconomic forecast data for the Germany economy to researchers and interested audiences. The database renders it possible to directly compare forecast quality across selected institutions and over time. It is partly based on data collected in the DFG-funded project “Macroeconomic forecasts in great crisis”.

Die Studie untersucht, welche Frames den medialen Diskurs zum Bundesamt für Verfassungsschutz bestimmen und wie sich diese Frames entwickelt haben. Zur Beantwortung dieser Fragen wird eine Frame-Analyse durchgeführt, wobei insgesamt 221 Artikel der Frankfurter Allgemeinen Zeitung und der Süddeutschen Zeitung analysiert werden, die zwischen dem 1. November 2011 und dem 31. Dezember 2019 veröffentlicht wurden. Die gewonnenen Erkenntnisse stützen bisherige Betrachtungen, wonach in der deutschen Gesellschaft eine skeptische Haltung gegenüber ihren Nachrichtendiensten vorherrscht.

The root system is an organ that indicates signs of stress when a plant is subjected to water‐deficit conditions. However, its assessment is challenging. An alternative has been to obtain variables through image processing. In this way, it allows the rapid evaluation of genetic diversity panels. It contributes to identifying genomic regions or genes associated with the expression of the root system under water‐deficit conditions. Hence, a public diversity panel of 360 inbred lines of maize was evaluated under well‐watered (WW) and water stress (WS) conditions. Roots were phenotyped through image‐based processing. Then, genome‐wide association studies were conducted in WW and WS for each trait, using the Fixed and random model Circulating Probability Unification method. We found 23 genes or genomic regions with significant associations, of which eleven are exclusive to the WW condition, seven to the WS condition, and four are simultaneously associated with both WW and WS. All genomic regions related to the root system in the WS condition are associated with physiological mechanisms and molecular responses related to tolerance to water‐deficit conditions that can be explored in subsequent studies and by breeding programs to obtain varieties that are more tolerant and water efficient to this condition. Is it possible to identify genes associated with plant performance under different water supply conditions through image processing?Are there genes that manifest themselves in different traits and contrasting water supply conditions?Can these genes be used in genomic studies to obtain tolerant or efficient varieties to water deficit conditions? Is it possible to identify genes associated with plant performance under different water supply conditions through image processing? Are there genes that manifest themselves in different traits and contrasting water supply conditions? Can these genes be used in genomic studies to obtain tolerant or efficient varieties to water deficit conditions?

Yield is a complex quantitative trait whose expression is sensitive to environmental stimuli. Therefore, soil‐related information can increase the predictive ability of genotype's performances across different locations. However, soil information is not always readily available worldwide or before the site or plot level growing season. Thus, in the current version, this tool has two functions. The first function retrieves soil samples and soil (from WoSIS Soil Profile Database) near your target location. Then it predicts 13 soil characteristics (physical and chemical). If the number of samples per location is greater than five, the function uses random forest to predict soil characteristics otherwise it averages the information. The output is a table with the target location and its latitude and longitude coordinates—the number of samples used, the root mean square error (RMSE), and the R‐square for each prediction. From a couple of instances in a trial (location), the second function predicts soil characteristics at the plot level via random forest. The output is a table with the plot IDs, coordinates, number of samples used to make predictions, the RMSE and R‐square for each prediction, the trait predicted, and the predicted value. As a proof‐of‐concept, we used the first function in the LSU Rice Breeding multi‐environmental trials (24 locations), identified the most important soil covariates to determine rice yield, and then clustered the locations. This tool can support breeders in better allocating trials in advance, borrow information from other regions, identify the best variety for each location, reduce costs, and increase accuracy. Soil characteristics are a valuable source of information to explain G × E.SoilType is a useful tool to receive and predict soil features for any geographical position.It will allow researchers to better model G × E at the plot level rather than using trial‐level measurements, as most studies do.

The first Stakeholder Network Meeting of the EU Horizon 2020-funded ONTOX project was held on 13–14 March 2023, in Brussels, Belgium. The discussion centred around identifying specific challenges, barriers and drivers in relation to the implementation of non-animal new approach methodologies (NAMs) and probabilistic risk assessment (PRA), in order to help address the issues and rank them according to their associated level of difficulty. ONTOX aims to advance the assessment of chemical risk to humans, without the use of animal testing, by developing non-animal NAMs and PRA in line with 21st century toxicity testing principles. Stakeholder groups (regulatory authorities, companies, academia, non-governmental organisations) were identified and invited to participate in a meeting and a survey, by which their current position in relation to the implementation of NAMs and PRA was ascertained, as well as specific challenges and drivers highlighted. The survey analysis revealed areas of agreement and disagreement among stakeholders on topics such as capacity building, sustainability, regulatory acceptance, validation of adverse outcome pathways, acceptance of artificial intelligence (AI) in risk assessment, and guaranteeing consumer safety. The stakeholder network meeting resulted in the identification of barriers, drivers and specific challenges that need to be addressed. Breakout groups discussed topics such as hazard versus risk assessment, future reliance on AI and machine learning, regulatory requirements for industry and sustainability of the ONTOX Hub platform. The outputs from these discussions provided insights for overcoming barriers and leveraging drivers for implementing NAMs and PRA. It was concluded that there is a continued need for stakeholder engagement, including the organisation of a ‘hackathon’ to tackle challenges, to ensure the successful implementation of NAMs and PRA in chemical risk assessment.

Remission of type 2 diabetes can occur as a result of weight loss and is characterised by liver fat and pancreas fat reduction and recovered insulin secretion. In this analysis, we aimed to investigate the mechanisms of weight loss- induced remission in people with prediabetes.

Zusammenfassung: Das plasmazytoide Urothelkarzinom (PUC) stellt eine seltene Variante des Urothelkarzinoms mit charakteristischen histopathologischen und klinischen Eigenschaften dar. Die Inzidenz beträgt zwischen 2,7 und 3,1% der muskelinvasiven Urothelkarzinome. Diese Form entspricht einem aggressiven, häufig lokal fortgeschrittenen „High-grade-Tumor“ mit schlechter Prognose. Eine negative E-Cadherin-Expression scheint für eine exakte Diagnose von Bedeutung zu sein. Eine systemische Chemotherapie könnte in der Behandlung des PUC zu einem verlängerten Überleben der Patienten führen.

Hintergrund: Typ-2-Diabetes wird seit neuestem in mehrere Subphänotypen eingeteilt, die in Zukunft eine spezifischere, pathophysiologisch orientierte Diabetestherapie ermöglichen können. Fragestellung: Es stellt sich die Frage, ob es oben erwähnte Subphänotypen auch bereits im Prädiabetesstadium gibt und ob diese eine effektivere Prävention ermöglichen. Material und Methoden: Es werden die bisher existierenden neueren Studien zu den Subphänotypen des Diabetes und Prädiabetes zusammengefasst. Ergebnisse: Die Definition von Subphänotypen des Typ-2-Diabetes könnte in Zukunft eine präzisere Therapie ermöglichen. Solche Untertypen scheinen auch schon im Prädiabetesbereich nachweisbar zu sein. Diskussion: Bereits im Stadium des Prädiabetes lassen sich Hoch- und Niedrigrisikogruppen identifizieren. Diese unterscheiden sich nicht nur bezüglich der Wahrscheinlichkeit der Entwicklung eines Diabetes, sondern auch hinsichtlich der Pathophysiologie, weswegen spezifische Präventionsmaßnahmen möglich und auch erforderlich sind.

Zinc (Zn) biofortification of rice can address Zn malnutrition in Asia. Identification and introgression of QTLs for grain Zn content and yield (YLD) can improve the efficiency of rice Zn biofortification. In four rice populations we detected 56 QTLs for seven traits by inclusive composite interval mapping (ICIM), and 16 QTLs for two traits (YLD and Zn) by association mapping. The phenotypic variance (PV) varied from 4.5% (qPN4.1) to 31.7% (qPH1.1). qDF1.1, qDF7.2, qDF8.1, qPH1.1, qPH7.1, qPL1.2, qPL9.1,qZn5.1, qZn5.2, qZn6.1and qZn7.1were identified in both dry and wet seasons; qZn5.1, qZn5.2, qZn5.3,qZn6.2,qZn7.1and qYLD1.2were detected by both ICIM and association mapping. qZn7.1had the highest PV (17.8%) and additive effect (2.5 ppm). Epistasis and QTL co-locations were also observed for different traits. The multi-trait genomic prediction values were 0.24 and 0.16 for YLD and Zn respectively. qZn6.2was co-located with a gene (OsHMA2) involved in Zn transport. These results are useful for Zn biofortificatiton of rice.

Sugar yield, which results from the combination of stalk biomass (SB) and sugar content (SC), stands as the critical trait for sugarcane breeding programs in Louisiana. Nevertheless, it remains uncertain how SB and SC have individually contributed to the recent increase in sugar yield and how the environment governs their relationship. We applied linear mixed models and the Finlay–Wilkinson model to analyze historical data from the Louisiana outfield variety trials, from plant cane to the third ratoon in multiple environments. The primary objectives were to determine (i) SC and SB genetic gain, (ii) the nature of the relationship between SB and SC, and (iii) whether genotypes are widely or specifically adapted to the environment. Our results showed that the breeding increased sugar yield by relying mostly on SB (0.600–0.652 Mg ha−1year−1and 0.893%–0.950% per year) and less on SC (0.371–0.384 kg year−1and 0.282%–0.292% per year). This was achieved by increasing genotypes SB sensitivity to environmental conditions (0.310% per year) on the plant cane rather than ratoon (nonsignificant). Additionally, the environment strongly controlled the relationship between SB and SC without a significant positive or negative trend on the population mean. From an environmental perspective, high‐yielding environments also provided conditions for high SC on plant cane. Our study highlights that environment characterization is fundamental to sugarcane breeding and emphasizes the opportunity to direct efforts on selecting genotypes that are responsive to the environmental quality by producing superior SB in the ratoon crop cycles. Stalk biomass increase ranged from 0.893% to 0.950% per year, while sugar content ranged from 0.282% to 0.292% per year.Breeding relied primarily on plant cane stalk biomass sensitivity to increase sugar yield over the years.Contrasting environmental conditions in the multi‐environment trials is essential to select high‐yield genotypes.Stalk biomass and sugar concentration relationship is uncertain with strong environmental control.High‐yielding environments also provided conditions for high sugar content only in plant cane.

Diabetesprävention kann durch Lebensstilintervention, Pharmakotherapie oder eine Kombination aus beiden erreicht werden. In einer Vielzahl von wegweisenden randomisierten, kontrollierten Studien wurde festgestellt, dass Präventionsprogramme das Typ-2-Diabetes-Risiko während der Interventionsphase effektiv senken und in den Jahren danach niedrig halten. Darüber hinaus wurde in diesen Untersuchungen auch eine Reduktion weiterer Morbiditätsrisiken, wie des Risikos kardiovaskulärer und maligner Erkrankungen, nachgewiesen. In vorliegender Übersichtsarbeit soll ein Überblick über die Langzeitergebnisse mehrere Jahre nach Abschluss von Diabetespräventionsprogrammen gegeben werden.

Refill friction stir spot welding is a solid-state spot-welding technique suited to lap joining of thin aluminium sheets, including difficult-to-weld 2xxx series alloys that are prone to hot cracking during fusion welding processes. Long welding time is an ongoing challenge that hinders industrial adoption of the process. To address this, the present study explores much shorter welding times than those previously reported in the literature and assesses the impact on joint quality. Joints of 1.8 mm thick AA2024-T3 sheet were produced with welding times from 3 s, down to 0.75 s and rotational speeds of 1000 rpm to 2500 rpm. Defect formations within the welds were studied with the aid of optical microscopy. The mechanical properties were evaluated using tensile lap shear testing and microhardness mapping, and failure modes were characterised using scanning electron microscopy. Various weld defects were found at all welding times and rotational speeds, and the defects enlarged with decreasing welding time and increasing RS. The highest lap shear strength of 9.21 kN was achieved with a welding time of 3 s and rotational speed of 2000 rpm; lap shear strengths of 7.02 kN and 6.37 kN were achieved for 1.5 s and 0.75 s welds, respectively.

The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P= 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.

Plant breeders widely use recurrent selection schemes to increase the frequency of favorable alleles for quantitative traits in a population. Although simultaneous selection is complex because it involves several traits combined with selection cycles, the use of selection indexes (SI) is applied to increase the chance of success of the breeding program. Despite many indices are available in the literature, simulations can help breeders to determine which selection index can be better adjusted considering the selection goals, the intensity, and the genetic correlation among traits over breeding cycles. In this context, we estimated the realized genetic gains in a tropical maize haploid inducer population after two cycles of recurrent selection, using external testers and optimizing the simultaneous selection for this breeding population in the long term via stochastic simulations. Furthermore, we proposed a new approach to optimize the initial weights by applying Smith‐Hazel method to maximize the genetic gains for all traits in a balanced way. Overall, the estimated gains in real induction rate were about 63% per cycle, improving the population performance from 0.8% to 2.8%. Moreover, our results confirm that the traditional Smith‐Hazel approach outperformed other methods for long‐term response to selection. Finally, recurrent selection with external testers may be a suitable method to improve the haploid induction rate in tropical maize populations. Recurrent selection with external testers may be a suitable method to improve the haploid induction rate.We proposed a new approach to optimize the initial weights for the Smith‐Hazel method.Stochastic simulations are useful for establishing specific selection indices according to the target traits.The traditional Smith‐Hazel method, when well defined, outperformed others.

ABSTRACTMost people are members of different groups. While the norms of these groups can align, they can also be contradicting, leading to dissonance within the social self. This is different from dissonance at the individual level because it is based solely on individuals’ membership in ingroups with conflicting norms. Building on the Social Identity Approach and Cognitive Dissonance Theory, we assume that norm conflict between ingroups increases psychological discomfort, particularly for people who are highly identified with both ingroups. Norm conflict was manipulated by showing participants the results of bogus surveys, indicating that their ingroups agree or disagree (in Experiment 1 on the topic of self-driving cars; in Experiment 2 on how to act in a moral dilemma). We tested several strategies to cope with norm conflict between ingroups, namely, lowering the credibility of the norm conflict information and/or norm prototypicality (Exp. 1 & 2), disidentification (Exp. 1), as well as compartmentalization and the restorative function of agentic groups (Exp. 2). In line with our assumptions, results indicated that norm conflict between ingroups led to increased psychological discomfort in Experiment 1 (N = 870) and Experiment 2 (N = 812). This was not moderated by the two ingroup identification levels. The results of Experiment 1 indicated that lowering perceived prototypicality of the norms was a coping strategy for high identifiers. No effects emerged for other coping strategies. Both experiments show evidence of dissonance within the social self and highlight the necessity for further examinations of its consequences and boundary conditions.

Otolaryngologic manifestations of infection with Blastomycesspecies are extremely rare and restricted geographically to recognized endemic regions. Here, we describe a case of laryngeal blastomycosis that presented as slowly progressive dysphonia. While a preliminary diagnosis was made using routine histopathology, a species identification of Blastomyces dermatitidiswas made using polymerase chain reaction amplification and rapid genotyping without the need for fungal culture. All symptoms resolved following 1 month of antifungal therapy. Rapid molecular differentiation of B dermatitidisfrom Blastomyces gilchristiiprovides important insights into pathogenesis given recent recognition of differences in clinical spectra.

Hintergrund: Diabetes mellitus ist eine komplexe Erkrankung, der unterschiedliche pathophysiologische Ursachen zugrunde liegen. Forschungen der letzten Jahre ergaben sowohl für den Prädiabetes als auch den Diabetes verschiedene phäno- und genotypisch definierte Untergruppen. Fragestellung: Für den klinischen Alltag ist es essenziell, die unterschiedlichen Subtypen zu erkennen. Es wird vorgeschlagen, diese mittels einer einfachen Messung der endogenen Insulinsekretion zu differenzieren. Material und Methoden: Mithilfe des im Nüchternzustand bestimmten C‑Peptid-Glukose-Verhältnisses (CGR) lässt sich die endogene Insulinsekretion abschätzen. Voraussetzung dafür ist eine erhaltene Nierenfunktion (GFR [glomeruläre Filtrationsrate] > 50 ml/min und 1,73 m2). Ergebnisse: Ein autoimmuner Diabetes (schwerer autoimmuner Diabetes, SAID) lässt sich durch ein niedriges C‑Peptid-Glukose-Verhältnis, also fehlende endogene Insulinsekretion, erkennen, ebenso der schwer insulindefiziente Diabetes (SIDD). Ein schwer insulinresistenter Diabetes (SIRD) zeichnet sich dagegen durch eine hohe CGR aus, gleichbedeutend mit einer Insulinhypersekretion. Diskussion: Das C‑Peptid-Glukose-Verhältnis lässt eine einfache Abschätzung unterschiedlicher pathophysiologischer Formen des Diabetes zu. Außerdem kann es einen wichtigen zusätzlichen Hinweis auf die Notwendigkeit einer Insulintherapie geben.

Vascular endothelial growth factor A (VEGF-A) has therapeutic cardiovascular effects, but delivery challenges have impeded clinical development. We report the first clinical study of naked mRNA encoding VEGF-A (AZD8601) injected into the human heart. EPICCURE (ClinicalTrials.gov: NCT03370887) was a randomized, double-blind study of AZD8601 in patients with left ventricular ejection fraction (LVEF) 30%–50% who were undergoing elective coronary artery bypass surgery. Thirty epicardial injections of AZD8601 (total 3 mg) or placebo in citrate-buffered saline were targeted to ischemic but viable myocardial regions mapped using quantitative [15O]-water positron emission tomography. Seven patients received AZD8601 and four received placebo and were followed for 6 months. There were no deaths or treatment-related serious adverse events and no AZD8601-associated infections, immune reactions, or arrhythmias. Exploratory outcomes indicated potential improvement in LVEF, Kansas City Cardiomyopathy Questionnaire scores, and N-terminal pro-B-type natriuretic peptide levels, but the study is limited in size, and significant efficacy conclusions are not possible from the dataset. Naked mRNA without lipid encapsulation may provide a safe delivery platform for introducing genetic material to cardiac muscle, but further studies are needed to confirm efficacy and safety in a larger patient pool.

The notion of quasi-particles is essential for understanding the behaviour of complex many-body systems. A prototypical example of a quasi-particle is a polaron, formed by an impurity strongly interacting with a surrounding medium. Fermi polarons, created in a Fermi sea, provide a paradigmatic realization of this concept. Importantly, such quasi-particles interact with each other via the modulation of the medium. However, although quantum simulation experiments with ultracold atoms have substantially improved our understanding of individual polarons, the detection of their interactions has so far remained elusive. Here we report the observation of mediated interactions between Fermi polarons consisting of K impurities embedded in a Fermi sea of Li atoms. Our results confirm two predictions of Landau’s Fermi-liquid theory: the shift in polaron energy due to mediated interactions, which is linear in the concentration of impurities; and its sign inversion with impurity quantum statistics. For weak-to-moderate interactions between the impurities and the medium, our results agree with the static predictions of Fermi-liquid theory. For stronger impurity–medium interactions, we show that the observed behaviour at negative energies can be explained by a more refined many-body treatment including retardation and dressed molecule formation.

Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P< 5 × 10−8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits.

In this paper, I propose the “squares-are-the-key method” as an update of the outdoor freehand-drawing class for architectural design. Let’s generate simplified 2D grids of site and floor plans, transform them to isometric grids, and insert essential height edges, taken from simplified elevations and sections, into it, on site.

In the treatment of type 2 diabetes, GLP-1 receptor agonists lower blood glucose concentrations, body weight, and have cardiovascular benefits. The efficacy and side effects of GLP-1 receptor agonists vary between people. Human pharmacogenomic studies of this inter-individual variation can provide both biological insight into drug action and provide biomarkers to inform clinical decision making. We therefore aimed to identify genetic variants associated with glycaemic response to GLP-1 receptor agonist treatment.

Recent technological advances in high‐throughput phenotyping have created new opportunities for the prediction of complex traits. In particular, phenomic prediction using hyperspectral reflectance could capture various signals that affect phenotypes genomic prediction might not explain. A total of 360 inbred maize (Zea maysL.) lines with or without plant growth‐promoting bacterial inoculation management under nitrogen stress were evaluated using 150 spectral wavelengths ranging from 386 to 1,021 nm and 13,826 single‐nucleotide polymorphisms. Six prediction models were explored to assess the predictive ability of hyperspectral and genomic data for inoculation status and plant growth‐related traits. The best models for hyperspectral prediction were partial least squares and automated machine learning. The Bayesian ridge regression and BayesB were the best performers for genomic prediction. Overall, hyperspectral prediction showed greater predictive ability for shoot dry mass and stalk diameter, whereas genomic prediction was better for plant height. The prediction models that simultaneously accommodated both hyperspectral and genomic data resulted in a predictive ability as high as that of phenomics or genomics alone. Our results highlight the usefulness of hyperspectral‐based phenotyping for management and phenomic prediction studies. Hyperspectral reflectance data can classify plant growth‐promoting bacteria inoculation status.Phenomic prediction performs better than genomic prediction depending on the target phenotype.Automated machine learning is a promising approach for automating hyperparameter tuning for classification and prediction.

The adoption of Directive 2010/63/EUon the protection of animals used for scientific purposes has given a major push to the formation of Three Rs initiatives in the form of centres and platforms. These centres and platforms are dedicated to the so-called Three Rs, which are the Replacement, Reduction and Refinement of animal use in experiments. ATLA’s 50th Anniversary year has seen the publication of two articles on European Three Rs centres and platforms. The first of these was about the progressive rise in their numbers and about their founding history; this second part focuses on their current status and activities. This article takes a closer look at their financial and organisational structures, describes their Three Rs focus and core activities (dissemination, education, implementation, scientific quality/translatability, ethics), and presents their areas of responsibility and projects in detail. This overview of the work and diverse structures of the Three Rs centres and platforms is not only intended to bring them closer to the reader, but also to provide role models and show examples of how such Three Rs centres and platforms could be made sustainable. The Three Rs centres and platforms are very important focal points and play an immense role as facilitators of Directive 2010/63/EU‘on the ground’ in their respective countries. They are also invaluable for the wide dissemination of information and for promoting the implementation of the Three Rs in general.

We report a new surgical technique for controlling flow with a PreserFlo MicroShunt, in patients with late postoperative hypotony, following a Baerveldt glaucoma drainage device implantation. We present 2 cases with late postoperative hypotony after Baerveldt-shunt implantations. In both cases, the outflow resistance of the Baerveldt tube was modulated by the insertion of a PreserFlo MicroShunt into the lumen of the Baerveldt tube. In the first case, the Microshunt was inserted through the distal opening of the tube in the anterior chamber. In the second case, an end plate, sided approach was chosen after opening the conjunctiva. In both cases, the hypotony was successfully treated. The intraocular pressure rose immediately after the procedure, and it remained well controlled within the targeted range during the first postoperative months without additional pressure-lowering medication. This novel surgical technique provided predictable flow reductions, according to the Hagen-Poiseuille equation. This approach offers a valuable alternative to permanent tube ligation.

The number of cases of European foulbrood (EFB) increased massively in Switzerland since 2000. According to Swiss legislation, the health status of all colonies within one kilometer from a case needs to be identified by a bee inspector. This results in a workload too high to be handled in due time in areas with a high prevalence and high colony density. Therefore, the primary goal of this study was testing the hypothesis that the number of visual inspections could be reduced if brood nest bees sampled by owners were tested by real-time PCR for the presence of Melissococcus plutonius,and results were assigned to one of the three categories “negative”, “positive,” or “strong positive” depending on the amount of bacterial DNA. Only apiaries with strong positive results were inspected visually. Furthermore, the development of the bacterial load over time was analyzed on an apiary level to determine whether this would allow predicting the outcome of an infection. For this purpose, bee samples of 88 apiaries were assayed by real-time PCR and visually inspected in parallel over several months. Comparison of the two methods revealed a sensitivity of the real-time PCR of 93.5% and a specificity of 58.6% relative to visual inspection. One month after first sampling the bacterial load was still on the same level in 54%, had increased in 17%, and decreased in 29% of 35 apiaries. Establishing predictions on the basis of real-time PCR results is therefore not possible. In conclusion, due to its poor specificity, preliminary real-time PCR would not allow reducing the number of visual inspections sufficiently to compensate the costs of additional laboratory diagnosis. However, real-time PCR may be a valuable tool for identifying infected colonies in the context of trade and migratory beekeeping.

Patients with relapsed/refractory acute myeloid leukemia (AML) have a dismal prognosis. Allogeneic stem cell transplantation (allo-SCT) provides a curative approach; however, the overall survival (OS) remains low (20% to 40%). In this setting, although some effective approaches have been evaluated in recent years, the management of such patients still remains challenging. In this study we evaluated the predictive role of post-transplant day 100 minimal residual disease (MRD) detection for post-transplantation outcomes for patients with refractory AML. Fifty-six adult patients with refractory AML (median age 58, range 20-76; male, 61%) who underwent allo-SCT were included in this retrospective monocentric study. Twenty-nine patients (52%) received fludarabine, amsacrine, and cytarabine (FLAMSA)–based conditioning. MRD was assessed using multicolored flow cytometry (MFC) according to European Leukemia Net guidelines (“different from normal” and leukemia-associated phenotype). The sensitivity of the method was 10−4to 10−5. The median marrow blast count at allo-SCT was 25% (range 6% to 91%). At day 100 after transplantation, 40 patients (71%) experienced MFC-MRD negativity, and 16 patients (29%) were MRD positive. All included patients survived at least 100 days after transplantation without relapse. Univariate and multivariate analysis based on Kaplan-Meier and Cox proportional hazards method were performed. The median follow-up was 16 months (range 3 to 66). The post-transplantation day 100 MRD-negative patients instead received 2 allografts (27% versus 6%, P = .08). In multivariate analysis, day 100 MRD status (negative versus positive) (OS: 0.23 [0.1 to 0.54], P=0.001; relapses: 0.20 [0.1 to 0.49], P = .0005) and FLAMSA versus other regimens (0.34 [0.1 to 0.83], P = .018; relapses: 0.43 [0.17 to 1.1], P = .07) independently impacted post-transplantation survival. We suggest that post-transplantation day 100 MFC-MRD detection plays predictive role in refractory AML patients and may help to define possible candidates for early post-transplantation interventions aiming to decrease the relapse risk and improve survival.

Heart regeneration is an unmet clinical need, hampered by limited renewal of adult cardiomyocytes and fibrotic scarring. Pluripotent stem cell-based strategies are emerging, but unravelling cellular dynamics of host–graft crosstalk remains elusive. Here, by combining lineage tracing and single-cell transcriptomics in injured non-human primate heart biomimics, we uncover the coordinated action modes of human progenitor-mediated muscle repair. Chemoattraction via CXCL12/CXCR4 directs cellular migration to injury sites. Activated fibroblast repulsion targets fibrosis by SLIT2/ROBO1 guidance in organizing cytoskeletal dynamics. Ultimately, differentiation and electromechanical integration lead to functional restoration of damaged heart muscle. In vivo transplantation into acutely and chronically injured porcine hearts illustrated CXCR4-dependent homing, de novo formation of heart muscle, scar-volume reduction and prevention of heart failure progression. Concurrent endothelial differentiation contributed to graft neovascularization. Our study demonstrates that inherent developmental programmes within cardiac progenitors are sequentially activated in disease, enabling the cells to sense and counteract acute and chronic injury.

Public awareness and discussion about animal experiments and replacement methods has greatly increased in recent years. The term ‘the Three Rs’, which stands for the Replacement, Reduction and Refinement of animal experiments, is inseparably linked in this context. A common goal within the Three Rs scientific community is to develop predictive non-animal models and to better integrate all available data from in vitro, in silicoand omics technologies into regulatory decision-making processes regarding, for example, the toxicity of chemicals, drugs or food ingredients. In addition, it is a general concern to implement (human) non-animal methods in basic research. Toward these efforts, there has been an ever-increasing number of Three Rs centres and platforms established over recent years — not only to develop novel methods, but also to disseminate knowledge and help to implement the Three Rs principles in policies and education. The adoption of Directive 2010/63/EUon the protection of animals used for scientific purposes gave a strong impetus to the creation of Three Rs initiatives, in the form of centres and platforms. As the first of a series of papers, this article gives an overview of the European Three Rs centres and platforms, and their historical development. The subsequent articles, to be published over the course of ATLA’s 50th Anniversary year, will summarise the current focus and tasks as well as the future and the plans of the Three Rs centres and platforms. The Three Rs centres and platforms are very important points of contact and play an immense role in their respective countries as ‘on the ground’ facilitators of Directive 2010/63/EU. They are also invaluable for the widespread dissemination of information and for promoting implementation of the Three Rs in general.

Erst 2017 wurde mit der Zulassung durch die US-amerikanische Aufsichtsbehörde FDA (U.S. Food and Drug Administration) ein Insulinpumpensystem behördlich genehmigt, das in Abhängigkeit vom Gewebezuckerwert automatisiert Insulin abgibt. In Deutschland sind seit 2021 Insulinpumpen mit Autokorrekturdosierung erhältlich. Nach Ansicht vieler Betroffener und Eltern von Kindern mit Typ-1-Diabetes wurde jedoch die Entwicklung von Technologien zur automatisierten Regulation des Blutzuckerspiegels von den Herstellern lange Zeit verschlafen. Daher begannen bereits Anfang der 2010er-Jahre Betroffene und ihre Angehörigen, selbst ein künstliches Bauchspeicheldrüsensystem, ein sog. „artificial pancreas system“ bzw. (Hybrid)-Closed-Loop-System, zu entwickeln, das mit allen notwendigen Informationen frei verfügbar ins Netz gestellt wurde. Bisher wurden dieses System und seine Wirksamkeit, wie z. B. die Auswirkungen der Nutzung auf eine verbesserte Lebensqualität, aber wenig systematisch evaluiert. Vor diesem Hintergrund untersuchte ein Team aus Bürgerwissenschaftler*innen mit Typ-1-Diabetes und akademisch Forschenden, ob sich durch die Nutzung dieser Technologien bessere Blutglukosewerte erzielen lassen und sich positive Effekte auf die Lebensqualität ergeben. Ziel dieses Beitrags ist es, den gemeinsamen Forschungsprozess und erste Ergebnisse aus diesem Projekt vorzustellen.

Fat accumulation outside subcutaneous adipose tissue often has unfavourable effects on systemic metabolism. In addition to non-alcoholic fatty liver disease, which has received considerable attention, pancreatic fat has become an important area of research throughout the past 10 years. While a number of diagnostic approaches are available to quantify pancreatic fat, multi-echo Dixon MRI is currently the most developed method. Initial studies have shown associations between pancreatic fat and the metabolic syndrome, impaired glucose metabolism and type 2 diabetes mellitus. Pancreatic fat is linked to reduced insulin secretion, at least under specific circumstances such as prediabetes, low BMI and increased genetic risk of type 2 diabetes mellitus. This Review summarizes the possible causes and metabolic consequences of pancreatic fat accumulation. In addition, potential therapeutic approaches for addressing pancreatic fat accumulation are discussed.

Aims: Age-related macular degeneration (AMD) is characterised by a progressive loss of central vision. Intermediate AMD is a risk factor for progression to advanced stages categorised as geographic atrophy (GA) and neovascular AMD. However, rates of progression to advanced stages vary between individuals. Recent advances in imaging and computing technologies have enabled deep phenotyping of intermediate AMD. The aim of this project is to utilise machine learning (ML) and advanced statistical modelling as an innovative approach to discover novel features and accurately quantify markers of pathological retinal ageing that can individualise progression to advanced AMD. Methods: The PINNACLE study consists of both retrospective and prospective parts. In the retrospective part, more than 400,000 optical coherent tomography (OCT) images collected from four University Teaching Hospitals and the UK Biobank Population Study are being pooled, centrally stored and pre-processed. With this large dataset featuring eyes with AMD at various stages and healthy controls, we aim to identify imaging biomarkers for disease progression for intermediate AMD via supervised and unsupervised ML. The prospective study part will firstly characterise the progression of intermediate AMD in patients followed between one and three years; secondly, it will validate the utility of biomarkers identified in the retrospective cohort as predictors of progression towards late AMD. Patients aged 55–90 years old with intermediate AMD in at least one eye will be recruited across multiple sites in UK, Austria and Switzerland for visual function tests, multimodal retinal imaging and genotyping. Imaging will be repeated every four months to identify early focal signs of deterioration on spectral-domain optical coherence tomography (OCT) by human graders. A focal event triggers more frequent follow-up with visual function and imaging tests. The primary outcome is the sensitivity and specificity of the OCT imaging biomarkers. Secondary outcomes include sensitivity and specificity of novel multimodal imaging characteristics at predicting disease progression, ROC curves, time from development of imaging change to development of these endpoints, structure-function correlations, structure-genotype correlation and predictive risk models. Conclusions: This is one of the first studies in intermediate AMD to combine both ML, retrospective and prospective AMD patient data with the goal of identifying biomarkers of progression and to report the natural history of progression of intermediate AMD with multimodal retinal imaging.