Federal Ministry Of Education Research Articles

Healthcare 3.0: How to Transform Machine Learning Prototypes into Functional Healthcare Applications for Diagnostic Assistance?

AbstractBackgroundAs the number of elderly people is rapidly increasing, we are faced with the challenge that diagnostic services are demanded more frequently. At the same time, the number of medical centers and available experts remains almost constant. Tools for diagnostic assistance are urgently needed to improve the effectiveness of healthcare. In four externally funded projects, we will investigate aspects and strategies of how machine learning prototype systems can be translated into functional healthcare applications.MethodIn the ongoing project “ExplAInation” funded by the German research foundation (DFG), we are developing an artificial neural network framework to generate visual and textual explanations to improve the comprehensibility and interpretability of deep learning models. This effort includes participatory research with clinical users. In the complementary project “TESIComp” funded by the Federal Ministry of Education and Research (BMBF), we will investigate ethical and social aspects of the emerging field of computational psychiatry. Patients, caregivers, and medical doctors will be interviewed, which will be qualitatively analyzed. Within the German Medical Informatics Initiative, we will contribute to the project “Open Medical Inference” (OMI), which will develop a network of distributed machine learning evaluation services. We also participate in the international “Clinical AI‐based Diagnostics” (CAIDX) consortium, which receives funding from the European Interreg Baltic Sea Region program.ResultWe developed a deep learning application for the detection of dementia atrophy patterns in brain MRI scans. Derived relevance maps highlight diagnostically important brain areas for further evaluation by the radiologists. Interviews with clinicians will provide information on expectations, key requirements and the functional utility of machine learning‐based assistance. Interviews with patients and caregivers will elucidate future changes and challenges in the doctor’s role and responsibilities. The OMI network will allow hospitals to use distributed machine learning evaluation services remotely, without the need of operating all the tools locally. In CAIDX, we will develop best‐practice guidelines for the overarching process of integrating machine learning prototypes and commercial tools into the hospital.ConclusionIn “Healthcare 3.0”, the digital transformation will change current diagnostic procedures and roles. Our activities focus on the involved stakeholders, regulatory aspects and implementation strategies to better steer this process.

Healthcare 3.0: How to Transform Machine Learning Prototypes into Functional Healthcare Applications for Diagnostic Assistance?

AbstractBackgroundAs the number of elderly people is rapidly increasing, we are faced with the challenge that diagnostic services are demanded more frequently. At the same time, the number of medical centers and available experts remains almost constant. Tools for diagnostic assistance are urgently needed to improve the effectiveness of healthcare. In four externally funded projects, we will investigate aspects and strategies of how machine learning prototype systems can be translated into functional healthcare applications.MethodIn the ongoing project “ExplAInation” funded by the German research foundation (DFG), we are developing an artificial neural network framework to generate visual and textual explanations to improve the comprehensibility and interpretability of deep learning models. This effort includes participatory research with clinical users. In the complementary project “TESIComp” funded by the Federal Ministry of Education and Research (BMBF), we will investigate ethical and social aspects of the emerging field of computational psychiatry. Patients, caregivers, and medical doctors will be interviewed, which will be qualitatively analyzed. Within the German Medical Informatics Initiative, we will contribute to the project “Open Medical Inference” (OMI), which will develop a network of distributed machine learning evaluation services. We also participate in the international “Clinical AI‐based Diagnostics” (CAIDX) consortium, which receives funding from the European Interreg Baltic Sea Region program.ResultWe developed a deep learning application for the detection of dementia atrophy patterns in brain MRI scans. Derived relevance maps highlight diagnostically important brain areas for further evaluation by the radiologists. Interviews with clinicians will provide information on expectations, key requirements and the functional utility of machine learning‐based assistance. Interviews with patients and caregivers will elucidate future changes and challenges in the doctor’s role and responsibilities. The OMI network will allow hospitals to use distributed machine learning evaluation services remotely, without the need of operating all the tools locally. In CAIDX, we will develop best‐practice guidelines for the overarching process of integrating machine learning prototypes and commercial tools into the hospital.ConclusionIn “Healthcare 3.0”, the digital transformation will change current diagnostic procedures and roles. Our activities focus on the involved stakeholders, regulatory aspects and implementation strategies to better steer this process.

Business model innovation of German VET service providers in international contexts – a longitudinal survey

ABSTRACT To support German VET providers in their internationalisation, the Federal Ministry of Education and Research (BMBF) has created two funding programs ‘Vocational Training Export’ (BEX; 2010–2017) and ‘Internationalisation of Vocational Education’ (IBB; 2017–2022) for the development of international business models in VET. In this paper, innovations of the business models of the projects are analysed in order to find out the extent to which the innovations have occurred. The sample includes all funded projects (18), in which a minimum of one organisation was funded subsequently in both funding programs. The data includes project documents and qualitative interviews with project actors. In order to identify the business model innovativeness of the projects, a model by Taran, Boer, and Lindgren is used and extended by a further dimension (system) according to Bronfenbrenner and Kell. The data shows that nearly all projects innovate in several areas of the business model. While these are mainly incremental in nature in BEX, radical innovations dominate among the IBB projects. Among other things, it is also evident that the BEX projects with their innovations relate primarily to the meso level (institutions), while the IBB projects address more strongly the exo level (societal subsystems) with their novelties.

Clinical implications of incorporating genetic and non-genetic risk factors in CanRisk-based breast cancer risk prediction

BackgroundBreast cancer (BC) risk prediction models consider cancer family history (FH) and germline pathogenic variants (PVs) in risk genes. It remains elusive to what extent complementation with polygenic risk score (PRS) and non-genetic risk factor (NGRFs) data affects individual intensified breast surveillance (IBS) recommendations according to European guidelines. MethodsFor 425 cancer-free women with cancer FH (mean age 40·6 years, range 21–74), recruited in France, Germany and the Netherlands, germline PV status, NGRFs, and a 306 variant-based PRS (PRS306) were assessed to calculate estimated lifetime risks (eLTR) and estimated 10-year risks (e10YR) using CanRisk. The proportions of women changing country-specific European risk categories for IBS recommendations, i.e. ≥20 % and ≥30 % eLTR, or ≥5 % e10YR were determined. FindingsOf the women with non-informative PV status, including PRS306 and NGRFs changed clinical recommendations for 31·0 %, (57/184, 20 % eLTR), 15·8 % (29/184, 30 % eLTR) and 22·4 % (41/183, 5 % e10YR), respectively whereas of the women tested negative for a PV observed in their family, clinical recommendations changed for 16·7 % (25/150), 1·3 % (2/150) and 9·5 % (14/147). No change was observed for 82 women with PVs in high-risk genes (BRCA1/2, PALB2). Combined consideration of eLTRs and e10YRs identified BRCA1/2 PV carriers benefitting from IBS <30 years, and women tested non-informative/negative for whom IBS may be postponed. InterpretationFor women who tested non-informative/negative, PRS and NGRFs have a considerable impact on IBS recommendations. Combined consideration of eLTRs and e10YRs allows personalizing IBS starting age. FundingHorizon 2020, German Cancer Aid, Federal Ministry of Education and Research, Köln Fortune.

Data Stewardship – Austrian National Strategy and Alignment

Within the FAIR Data Austria project, supported by the Federal Ministry for Education, Science, and Research (BMBWF), a national strategy has been established to advance the creation of tailored Data Stewardship solutions for the Austrian context. The strategy, formalized as a toolbox, delineates various Data Steward models, corresponding competencies, and accessible training resources. Despite the crucial role of Data Stewardship in supporting data-driven scientific research, Austrian universities encounter challenges in its implementation. Issues include lack of consensus on the skills, roles, and responsibilities of Data Stewards, coupled with insufficient funding for these positions. This article explores these challenges and emphasizes the importance of addressing them to promote effective Data Stewardship within the Austrian academic landscape.

Integrate-and-fire circuit for converting analog signals to spikes using phase encoding * *The authors would like to thank Alexander Lenz and Susanne Junghans for their expertise and input, which was very valuable for implementing and testing the designed circuit. The authors would also like to thank the Technical University of Dresden for granting them access to the SpiNNaker 2 chip

Processing sensor data with spiking neural networks on digital neuromorphic chips requires converting continuous analog signals into spike pulses. Two strategies are promising for achieving low energy consumption and fast processing speeds in end-to-end neuromorphic applications. First, to directly encode analog signals to spikes to bypass the need for an analog-to-digital converter. Second, to use temporal encoding techniques to maximize the spike sparsity, which is a crucial parameter for fast and efficient neuromorphic processing. In this work, we propose an adaptive control of the refractory period of the leaky integrate-and-fire (LIF) neuron model for encoding continuous analog signals into a train of time-coded spikes. The LIF-based encoder generates phase-encoded spikes that are compatible with digital hardware. We implemented the neuron model on a physical circuit and tested it with different electric signals. A digital neuromorphic chip processed the generated spike trains and computed the signal’s frequency spectrum using a spiking version of the Fourier transform. We tested the prototype circuit on electric signals up to 1 kHz. Thus, we provide an end-to-end neuromorphic application that generates the frequency spectrum of an electric signal without the need for an ADC or a digital signal processing algorithm.

Efficacy and safety of zapnometinib in hospitalised adult patients with COVID-19 (RESPIRE): a randomised, double-blind, placebo-controlled, multicentre, proof-of-concept, phase 2 trial

Zapnometinib is an oral, non-ATP-competitive, small-molecule inhibitor of MEK1/MEK2 with immunomodulatory and antiviral properties. We aimed to investigate the safety and efficacy of zapnometinib in patients with COVID-19. In this randomised, double-blind, placebo-controlled, multicentre, proof-of-concept, phase 2 trial, we recruited hospitalised adults with moderate or severe COVID-19 from 18 hospitals in Germany, India, Romania, South Africa, and Spain. Those requiring ICU admission or ventilator support at screening or randomisation were excluded. Patients were randomly assigned (1:1) to receive oral zapnometinib (900mg on Day 1; 600mg on Days 2-6) or matching placebo, on top of standard of care. Randomisation, stratified by baseline clinical severity status (CSS 3 or 4, measured on a 7-point ordinal scale), was done using Interactive Response Technology. Patients, investigators, and the sponsor were masked to treatment allocation. The primary endpoint was CSS at Day 15 and was conducted on the full analysis set (FAS: all patients who were randomised to the study, received at least one dose of study medication and had at least one post-dose assessment of CSS, as randomised). Safety analyses were conducted on the safety analysis set (all study participants who received at least one dose of study medication, as treated). This study is registered at ClinicalTrials.gov (NCT04776044) and EudraCT (2020-004206-59). The trial was terminated early as the emergence of the Omicron variant impacted recruitment. Between 12th April 2021 and 9th August 2022, 104 of the planned 220 patients were enrolled and randomly assigned, 103 were treated, and 101 were included in the FAS (zapnometinib: n=50; placebo: n=51). The primary outcome was not significantly different between the two groups, but patients on zapnometinib had higher odds of improved CSS versus placebo (odds ratio [OR] 1.54 [95% CI 0.72-3.33]; p=0.26). Predefined subgroup analyses identified trends for improved CSS in patients with severe disease at baseline (OR 2.57 [0.76-8.88]; p=0.13) and non-Omicron variants (OR 2.36 [0.85-6.71]; p=0.10); the p value of the CSS subgroup by Treatment interaction term in the model was p=0.28. The frequency and intensity of adverse events was low and similar between arms. Twenty (39.2%) patients treated with zapnometinib experienced adverse events compared with eighteen (34.6%) patients treated with placebo. One patient receiving zapnometinib and two patients receiving placebo died during the study. None of the deaths were considered related to study medication. These results provide proof-of-concept for the innovative approach of targeting the Raf/MEK/ERK pathway in patients with hospitalised moderate/severe COVID-19. Further clinical studies will be required to evaluate the clinical benefit of zapnometinib in this and other indications. Atriva Therapeutics GmbH and the Federal Ministry of Education and Research, Germany.

Home-based family caregiver-delivered music and reading interventions for people living with dementia (HOMESIDE trial): an international randomised controlled trial

Music interventions provided by qualified therapists within residential aged care are effective at attenuating behavioural and psychological symptoms (BPSD) of people with dementia (PwD). The impact of music interventions on dementia symptom management when provided by family caregivers is unclear. We implemented a community-based, large, pragmatic, international, superiority, single-masked randomised controlled trial to evaluate if caregiver-delivered music was superior to usual care alone (UC) on reducing BPSD of PwD measured by the Neuropsychiatric Inventory-Questionnaire (NPI-Q). The study included an active control (reading). People with dementia (NPI-Q score ≥6) and their caregiver (dyads) from one of five countries were randomly allocated to caregiver-delivered music, reading, or UC with a 1:1:1 allocation stratified by site. Caregivers received three online protocolised music or reading training sessions delivered by therapists and were recommended to provide five 30-min reading or music activities per week (minimum twice weekly) over 90-days. The NPI-Q severity assessment of PwD was completed online by masked assessors at baseline, 90- (primary) and 180-days post-randomisation and analysed on an intention-to-treat basis using a likelihood-based longitudinal data analysis model. ACTRN12618001799246; ClinicalTrials.govNCT03907748. Between 27th November 2019 and 7th July 2022, we randomised 432 eligible of 805 screened dyads (music n=143, reading n=144, UC n=145). There was no statistical or clinically important difference in the change from baseline BPSD between caregiver-delivered music (-0.15, 95% CI-1.41 to 1.10, p=0.81) or reading (-1.12, 95% CI-2.38 to 0.14, p=0.082) and UC alone at 90-days. No related adverse events occurred. Our findings suggested that music interventions and reading interventions delivered by trained caregivers in community contexts do not decrease enduring BPSD symptoms. Our funding was provided by National Health and Medical Research Council, Australia; The Research Council of Norway; Federal Ministry of Education and Research, Germany; National Centre for Research and Development, Poland; Alzheimer's Society, UK, as part of the Joint Programme for Neurodegenerative Diseases consortia scheme.

The Jurisprudence of University Lecturers’ and Students’ Knowledge of Nigerian Education Laws

This study investigates the university lecturers’ and students’ knowledge of Nigerian Education Laws which brings peace, progress, tranquility, and development to an academic environment with a view to find out how lecturers and students are knowledgeable about Nigerian Education Laws. It juxtaposes knowledge of education laws by lecturers and that of the students. It will be of benefit to students, lecturers, the education communities where education law is useful and applicable. It will be of benefit to the law community - the lawyers, judges, lecturers, students among others. Curriculum developers, education administrators, the National Universities Commission, the Federal Ministry of Education and its parastatal/agencies and the public will benefit from this work. Historical and case study designs were adopted. The doctrinal method was used in data collection. The primary sources of data were the Education Ordinance 1887, Education Code 1903, Education Ordinance 1928, Education Ordinance 1916, Education Code 1926, Education Ordinance 1948, Education Act 1952, Education Edicts 1966-1979, the Constitution of the Federal Republic of Nigeria 1979 and 1999, Education Law 1999 and the Universal Basic Education Act 2004; sources of secondary data were published textbooks, scholarly peer-reviewed journals, and articles. Data were content-analysed, compared, contrasted and presented thematically which brought about the relevance of the study. The research findings are that lecturers and students have knowledge of Nigerian Education Laws and that knowledge of Nigerian Education Laws makes lecturers and students conduct themselves within the purview of the rules and regulations of the institutions. It is recommended that knowledge of Nigerian Education Laws should be a continuous exercise in an academic environment. Lecturers and students should be trained and retrained in respect of the education laws to avoid any gap in the level of knowledge of Nigerian Education Laws.

O.4.5-5 Are more active children healthier in the long run? – Results from the MoMo study

Abstract Purpose Various recommendations emphasize the importance of regular physical activity (PA) for building and maintaining health in adults as well as in children and adolescents. Using longitudinal data from the German MoMo study, this analysis aimed at investigating whether children who were more active over time were healthier eleven years later compared to those that were less active over the time. Methods 1407 participants (55.5 % female; mean age at Baseline = 8.2 ± 3.8 y.) completed three times of measurement within three survey waves of the MoMo study (Baseline: 2003 – 2006; Wave 1: 2009 – 2012; Wave 2: 2015 - 2017). The study included a self-report questionnaire among others. Participants who reported active participation at all times of measurement were compared to those who reported no participation at all. The groups were compared regarding their self-reported health status, and whether they reported recurrent headache in the past three months. 95%-Confidence Intervals (95%CI) were used, and odds ratios were calculated to determine differences between the groups. Results The active group was more likely to rate their health as “very good” (46.9%, 95%CI = [30.9,63.6]) compared to their fewer active peers (18.4%, 95%CI = [11.3,28.6]) (OR(95%CI) = 3.9 [1.6,9.7]). Additionally, the active group reported less recurrent headache (35.7%; 95%CI = [31.3,40.4]) at the last measurement point compared to the least active counterparts (55.5 %; 95%CI = [48.9,62.0]) (OR(95%CI) = .5[.3,.6]). Conclusions Continuous physical activity during childhood and adolescence, e.g. in a sports club, not only increases the chance of a better self-perceived health, but also seems to reduce the risk of health impairments, such as recurrent headaches. Therefore, promoting physical activity as proposed by the World Health Organization and others is an important part of a healthy lifestyle. Support/Funding Source This work has been developed within the MoMo-Study (MoMo) (2003 – 2021). MoMo is funded by the Federal Ministry of Education and Research (funding reference number: 01ER1503) within the research program ‘long-term studies’ in public health research.

EKONT-2: advancement of a demonstrator for dry–mechanical decontamination of corners and inner edges in nuclear facilities

Abstract. In order to be able to dismantle nuclear power plants after decommissioning, all surfaces must be decontaminated before conventional demolition. Difficulties in decontamination are not caused by large and easily accessible areas but rather by the corners and inner edges that are difficult to access and cannot be reached with existing machines. In order to be able to decontaminate these areas, however, hand-held tools are currently being used that were developed for conventional dismantling and building renovation. In order to ensure occupational safety and to prevent the spread of contamination, these devices must be used with an external suction system. The area coverage that is already low is thus further reduced, and hard-to-reach areas are even more difficult to reach. These factors and working in protective suits make these decontamination tasks a great challenge for the workers carrying out the work. The EKONT-2 research project was launched to make this work easier and more efficient. This project, which is funded by the Federal Ministry of Education and Research (BMBF), has set itself the goal of developing an innovative, partially automated demonstrator for dry-mechanical decontamination of corners, edges and imperfections in nuclear facilities. For this purpose, different active principles have already been examined, evaluated according to scientific methods and implemented in the form of four test models. One of the test models enables material removal with high-frequency vibrations and a diamond-coated tool. The other three demonstrators remove the material with rotating diamond discs and rotate in different directions depending on the design. To realise the different directions of rotation, one of the demonstrators is equipped with a newly developed gear, for which a patent application has already been submitted. Before the devices could go into practical testing, various performance parameters were recorded and evaluated in a test stand specially developed for this purpose. In addition, the reliability of the devices could already be tested, and any problems that arose could be rectified. After this detailed test of the devices in the test stand, the test samples could be checked for their practical suitability in the Obrigheim nuclear power plant. Here, workers at SAT Kerntechnik GmbH tested the devices in a real environment and were able to give mostly positive feedback on the developed demonstrators. In addition, the feedback has revealed potential for improvement that is to be pursued and implemented in a subsequent project.

Comparing the Lithiation and Sodiation of Hard-Carbon Using Online Electrochemical Mass Spectrometry

Sodium-ion batteries (SIBs) are a promising alternative to lithium-ion batteries (LIBs), especially for applications in which weight and size play a subordinate role.1 In contrast to LIBs, graphite is not a viable anode active material for SIBs since sodium cannot be inserted into graphite. So-called hard-carbons are promising anode active materials for SIBs because of their easy synthesis, high capacity, and high cycling stability.2 Major challenges are the high irreversible capacity in the first cycle and the stability of the solid electrolyte interphase (SEI).3 - 4 Online electrochemical mass spectrometry (OEMS) is a powerful tool for identifying and quantifying evolved gasses during SEI formation, giving insight into the mechanism of SEI formation. For LIB research, our group had developed a two-compartment OEMS cell design that enables the investigation of evolved gases from one of the electrodes of a battery cell without interference from the gases evolved from the other electrode, which is particularly useful for the mechanistic study of electrolyte additives or impurities without influences of the counter electrode.5–8 In this study, we investigate the gas evolution during the first lithiation/delithiation cycles of a hard-carbon anode active material using our existing two-compartment cell design. This will then be compared to the gas evolution during the first sodiation/desodiation cycles of the same hard-carbon material using a newly developed two-compartment OEMS-cell design for the study of sodium-ion batteries, which is based on a gas impermeable solid electrolyte separator composed of sodium ion conducting β-alumina. We compare the quantities of evolved gasses and look at the onset potentials of gas evolution during the first alkaline metal insertion. On the basis of gassing and impedance data,9,10 the differences in SEI formation and its properties will be discussed.Acknowledgments: We gratefully acknowledge funding by the BMBF (Federal Ministry of Education and Research, Germany) for its financial support under the auspices of the ExZellTUM III project, grant number 03XP0255

Deconvolution of an Soc-Dependent Contact Resistance in a Multilayer Pouch Cell Using Impedance Spectroscopy

Electrochemical impedance spectroscopy (EIS) can be used as an effective non-destructive and easy-to-implement measurement method to determine the electrochemical response and state-of-health of battery cells. However, the analysis of the individual impedance contributions of the anode and cathode in a conventional two-electrode setup is quite complex due to several overlapping processes and the dominating inductive contributions at high frequencies (f ≥ 1 kHz) [1]. Therefore, in the absence of prior knowledge at the electrode level, statements about specific SoC-dependent characteristics may lead to an erroneous analysis of the impedance data. As an example, in a study by Kollmeyer et al. [2], a SoC-dependent change of the high-frequency x-axis intercept - in the literature also often defined as the high-frequency ohmic resistance Rhf [3] - is observed, which in this case, however, rather indicates superimposed impedance contributions of an interfacial contact impedance Rcont/Qcont due to dominating inductances.To address the latter point, we simulate impedance spectra of a model electrode in blocking conditions with a contact impedance Rcont/Qcont and series-connected inductance, scaling the parameter for different geometric electrode areas Ageo. We show how, for larger electrodes, the decreasing high-frequency impedance contributions of Rcont/Qcont are increasingly superimposed by the inductance. To validate our theoretical finding, we compare laboratory-scale impedance spectra (Ageom= 0.94 cm²) acquired with a gold wire microreference (GWRE) T-cell setup with those of a large-scale cell (Ageom= 1475 cm², Fig. 1), both built with the same anode and cathode electrodes. For this, we measure SoC-dependent EIS of the NCA cathode in a 3.6 mAh NCA/Si T-cell via the GWRE, which shows an SoC-dependent contact resistance at high frequencies that is clearly visible as a high-frequency feature in the 50% SoC full-cell spectrum (f ≥ 1 kHz, Fig. 1b). In contrast, for the 5.6 Ah multilayer pouch cell with the same electrodes we see an SoC-dependent apparent high-frequency resistance Rhf app, as observed by Kollmeyer et al. [2], but, as shown in the 50% SoC impedance spectrum depicted in Fig. 1a, we do not observe the high-frequency semicircle (f ≥ 1 kHz) that was observed for the 3.6 mAh T-cell (Fig. 1b). Based on the simulation results and T-cell analysis, we can attribute the SoC dependence of the Rhf app of the multilayer pouch cell spectra to the SoC-dependent cathode contact resistance superimposed by inductances.Acknowledgments:S.H. gratefully acknowledges the financial support from the BMBF (Federal Ministry of Education and Research, Germany), under the auspices of the ExZellTUM III project (grant number 03XP0255). The authors want to thank the research battery production team at the iwb (TUM) for manufacturing the large-format pouch cells.

Fasting indices of glucose-insulin-metabolism across life span and prediction of glycemic deterioration in children with obesity from new diagnostic cut-offs.

Fasting indices of glucose-insulin-metabolism are an easy and affordable tool to assess insulin resistance. We aimed to establish reference ranges for fasting insulin indices that reflect age-dependent variation over the entire life span and subsequently test their clinical application regarding the prediction of glycemic deterioration in children. We calculated age- and puberty-dependent reference values for HOMA-IR, HOMA2-IR, HOMA-β, McAuley index, fasting insulin, and fasting glucose from 6994 observations of 5512 non-obese healthy subjects aged 5-80 years. Applying those references, we determined the prevalence of insulin resistance among 2538 subjects with obesity. Furthermore, we investigated the intraindividual stability and the predictive values for future dysglycemia of these fasting indices in 516 children and adolescents with obesity up to 19 years of follow-up. We validated the results in three independent cohorts. There was a strong age-dependent variation of all indices throughout the life span, including prolonged recovery of pubertal insulin resistance and a subsequent continuous increase throughout adulthood. Already from age 5 years onwards, >40% of children with obesity presented with elevated parameters of insulin resistance. Applying newly developed reference ranges, insulin resistance among children with obesity doubled the risk for future glycemic deterioration (HOMA-IR HR 1.88 (95% CI 1.1-3.21)), fasting insulin HR 1.89 (95% CI 1.11-3.23). In contrast, fasting glucose alone was not predictive for emerging dysglycemia in children with obesity (HR 1.03 (95% CI 0.62-1.71)). The new insulin-based thresholds were superior to fasting glucose and HbA1c in detecting children eventually manifesting with dysglycemia in prospective analyses. The variation of fasting glucose-insulin-metabolism across the life span necessitates age-specific reference ranges. The improved prediction of future glycemic deterioration by indices based on fasting insulin beyond simple glucose measures alone could help to stratify risk characteristics of children with obesity in order to guide patient-tailored prevention and intervention approaches. German Research Foundation (DFG)-through SFB 1052, project number 209933838, subproject C5; Federal Ministry of Education and Research, Germany; European Union-European Regional Development Fund; Free State of Saxony. The German Diabetes Association, the CarbHealth consortium (01EA1908B). EU-IMI2-Consortium SOPHIA (grant agreement No 875534), German Center for Diabetes Research (DZD), grant number 82DZD14E03.

Coexistence or cooperation? The perspective of people affected by dementia on participation and research‐ a TaNDem study –

AbstractBackgroundSo far, health services research in dementia has yet led to insufficient transfer of research evidence into healthcare practice or implementation of patient and caregiver perspective into the design of research studies. A strong transdisciplinary network of people with dementia, relatives, researchers, and healthcare service providers is needed to improve research and practice and to speed up the interaction between these stakeholders. Here, we aimed to integrate the perspective of people with dementia and caregivers on health services research into the establishment of a translational network for health services research in dementia (TaNDem, funded by the Federal Ministry of Education and Research).MethodsWe interviewed four people with dementia (mean age: 76.0 years; mean MMSE: 25.5) and 16 family caregivers (15 single interviews, one pair; mean age: 62.6 years). We asked participants about their priorities and expectations in dementia research and their motivation to participate in research projects and networks. The interviews were transcribed and analyzed using qualitative content analysis, according to Mayring.ResultsMost interviewees lacked an idea of how research or researchers work. They could only imagine participating in research projects as consultant, but not as co‐researchers with decision‐making power. Participants were afraid of knowledge gaps and embarrassment in the presence of researchers. However, participating in research projects was perceived as essential to prevent and treat dementia for future affected ones. The interviews elicit five areas of interest that should be addressed by the network: pathogenic themes (e.g., early disease detection; prevention), communication &amp; arrangement (e.g., finding support and supply), disease specific care (specialized staff and facilities), support offers (self‐help; case management) and tasks for policy (plan supply capacities; solve the shortage of staff).ConclusionThe interviewees identified research gaps that contrasted with the self‐perceived focus of researchers on the research topics. Research must evolve to become more tangible, visible, and understandable for people with dementia and relatives so they can participate actively and on a long‐term basis in research projects. We need case management and a culture of participation to reach people with dementia and their relatives with offers of supply, support, and participation in research.

In mouse kidney endogenous transmembrane serine protease 2 (TMPRSS2) contributes to proteolytic processing and activation of the epithelial sodium channel (ENaC)

Regulation of ENaC in the distal nephron is essential for sodium homeostasis and blood pressure control. A unique feature of ENaC is its complex proteolytic processing leading to channel activation due to release of inhibitory tracts from its α- and γ-subunits. In particular, fully cleaved γ-ENaC is critical for high channel activity. However, the physiologically relevant proteases involved remain elusive. Using Xenopus laevis oocytes and H441 airway epithelial cells, we recently demonstrated that TMPRSS2 proteolytically activates ENaC by cleaving the channel’s γ-subunit ( J Biol Chem 2022 Jun;298(6):102004). Here we investigate whether TMPRSS2 also contributes to proteolytic ENaC regulation in the kidney. Using mRNA sequencing, we demonstrated that mouse cortical collecting duct (mCCD cl1 ) cells express TMPRSS2 at a high level unaffected by aldosterone, an important ENaC stimulating hormone. TMPRSS2 knockdown by CRISPR/Cas9 technology significantly reduced fully cleaved γ-ENaC in membrane-enriched fractions of mCCD cl1 cell lysates (n=5). Apical application of chymotrypsin significantly stimulated ENaC-mediated short circuit current ( I SC ) in TMPRSS2-knockdown cells, but not in control cells (2.0 ± 1.1 μA/cm² vs. 0.2 ± 0.6 μA/cm²; n=13-14; p&lt;0.001; mean ± SD). Moreover, the stimulatory effect of aldosterone on I SC was impaired in TMPRSS2-knockdown cells compared to control cells (9.1 ± 4.0 μA/cm² vs. 18.3 ± 4.0 μA/cm²; n=7-8; p&lt;0.01). After aldosterone treatment I SC stimulation by chymotrypsin was enhanced in TMPRSS2-knockdown cells (5.3 ± 1.9 μA/cm²; n=7) but undetectable in control cells (−0.8 ± 1.6 μA/cm²; n=8). These findings indicate that TMPRSS2 deficiency impairs proteolytic ENaC activation in mCCD cl1 cells. To confirm this in an in vivo model, we used constitutive TMPRSS2 knockout mice ( Tmprss2 -/- ). Using a combination of RNAscope technology and immunofluorescence, we demonstrated high expression of Tmprss2 mRNA in renal tubular cells, including cells with β-ENaC protein staining. Importantly, the ratio of fully to partially cleaved γ-ENaC was significantly reduced in membrane-enriched fractions of whole-kidney lysates from Tmprss2 -/- mice (n=10). Maintained on a standard diet, Tmprss2 -/- mice had no apparent renal phenotype with plasma aldosterone levels similar to those of Tmprss2 +/+ mice (120 ± 43 pg/ml in Tmprss2 -/- vs. 92 ± 17 pg/mL in Tmprss2 +/+ ; n=7-10). Moreover, the ability of Tmprss2 -/- mice to reduce urinary sodium excretion in response to four days of low sodium diet was fully preserved. However, under low sodium diet plasma aldosterone increased to significantly higher levels in Tmprss2 -/- mice compared to controls (752 ± 146 pg/ml in Tmprss2 -/- vs. 268 ± 55 pg/ml in Tmprss2 +/+ ; n=7-11; p&lt;0.01). This is most likely a compensatory response to compromised proteolytic ENaC activation due to TMPRSS2 deficiency. We conclude that TMPRSS2 plays a physiological role in proteolytic ENaC processing and activation in the kidney. This study was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - Project-ID 509149993, TRR 374 (subproject A4 to A.I. and C.K.) and the Bayerisches Staatsministerium für Wissenschaft und Kunst (Bavarian Ministry of Art and Science), project VI-Corona-Forschung (subproject 07 to M.B. and T.G). A.K. was supported by the Interdisziplinäres Zentrum für klinische Forschung (IZKF) Erlangen. S.W. was supported by the Bundesministerium für Bildung und Forschung (BMBF, Federal Ministry of Education and Research, Germany), project SENSE-CoV2, 01KI20172A. P.S. and F.A. were funded by the IZKF Tübingen. The authors declare no conflicts of interest. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Policy reforms in Technical Vocational Education and Training (TVET) for sustainable development in Abia State, Nigeria

The study determined the relevance of policy reforms in Technical Vocational Education and Training for sustainable development in Abia State, Nigeria. The survey research design was used. The population of the study consisted of 4,302 persons made up of 300 officers of Vocational Technical Education Boards and 4,002 teachers of vocational subjects in all the Vocational Technical schools in Abia State in the 2020/2021 academic year. The sample comprised 356 respondents made up of 32 Vocational Technical Education Boards staff and 324 vocational teachers. The sample was selected using stratified random sampling technique. A questionnaire titled “TVET Policy Reforms for Sustainable Development in Abia State Questionnaire” was used for data collection. The questionnaire which contained 31 items structured on a four-point scale was validated by three experts and its internal consistency reliability index was 0.88 determined using Cronbach alpha statistics. The mean with standard deviation was used to answer the research questions while independent t-test was used to test the null hypotheses at 0.05 level of significance. The findings showed that reforms are needed in 10 areas of the TVET policy; and that TVET policy reforms are useful for sustainable development in 10 ways. Also, 10 challenges against achievement of TVET policy objectives were found. The researchers concluded that there is dire need for reforms in Nigeria’s TVET policy in the ten areas identified in this study in order to facilitate sustainable development in Abia State and the entire country. It was recommended among others, that the Federal Ministry of Education should initiate moves for significant reforms in Technical Vocational Education and Training policy in Nigeria as soon as is practicable.

Incidence of syndromes associated with Frontotemporal Lobar Degeneration (S19.004)

Incidence of syndromes associated with Frontotemporal Lobar Degeneration (S19.004)

Artificial intelligence for tumour tissue detection and histological regression grading in oesophageal adenocarcinomas: a retrospective algorithm development and validation study

Oesophageal adenocarcinoma and adenocarcinoma of the oesophagogastric junction are among the most common malignant epithelial tumours. Most patients receive neoadjuvant therapy before complete tumour resection. Histological assessment after resection includes identification of residual tumour tissue and areas of regressive tumour, data which are used to calculate a clinically relevant regression score. We developed an artificial intelligence (AI) algorithm for tumour tissue detection and tumour regression grading in surgical specimens from patients with oesophageal adenocarcinoma or adenocarcinoma of the oesophagogastric junction. We used one training cohort and four independent test cohorts to develop, train, and validate a deep learning tool. The material consisted of histological slides from surgically resected specimens from patients with oesophageal adenocarcinoma and adenocarcinoma of the oesophagogastric junction from three pathology institutes (two in Germany, one in Austria) and oesophageal cancer cohort of The Cancer Genome Atlas (TCGA). All slides were from neoadjuvantly treated patients except for those from the TCGA cohort, who were neoadjuvant-therapy naive. Data from training cohort and test cohort cases were extensively manually annotated for 11 tissue classes. A convolutional neural network was trained on the data using a supervised principle. First, the tool was formally validated using manually annotated test datasets. Next, tumour regression grading was assessed in a retrospective cohort of post-neoadjuvant therapy surgical specimens. The grading of the algorithm was compared with that of a group of 12 board-certified pathologists from one department. To further validate the tool, three pathologists processed whole resection cases with and without AI assistance. Of the four test cohorts, one included 22 manually annotated histological slides (n=20 patients), one included 62 sides (n=15), one included 214 slides (n=69), and the final one included 22 manually annotated histological slides (n=22). In the independent test cohorts the AI tool had high patch-level accuracy for identifying both tumour and regression tissue. When we validated the concordance of the AI tool against analyses by a group of pathologists (n=12), agreement was 63·6% (quadratic kappa 0·749; p<0·0001) at case level. The AI-based regression grading triggered true reclassification of resected tumour slides in seven cases (including six cases who had small tumour regions that were initially missed by pathologists). Use of the AI tool by three pathologists increased interobserver agreement and substantially reduced diagnostic time per case compared with working without AI assistance. Use of our AI tool in the diagnostics of oesophageal adenocarcinoma resection specimens by pathologists increased diagnostic accuracy, interobserver concordance, and significantly reduced assessment time. Prospective validation of the tool is required. North Rhine-Westphalia state, Federal Ministry of Education and Research of Germany, and the Wilhelm Sander Foundation.

Predictive performance of multi-model ensemble forecasts of COVID-19 across European nations.

Background: Short-term forecasts of infectious disease contribute to situational awareness and capacity planning. Based on best practice in other fields and recent insights in infectious disease epidemiology, one can maximise forecasts’ predictive performance by combining independent models into an ensemble. Here we report the performance of ensemble predictions of COVID-19 cases and deaths across Europe from March 2021 to March 2022. Methods: We created the European COVID-19 Forecast Hub, an online open-access platform where modellers upload weekly forecasts for 32 countries with results publicly visualised and evaluated. We created a weekly ensemble forecast from the equally-weighted average across individual models' predictive quantiles. We measured forecast accuracy using a baseline and relative Weighted Interval Score (rWIS). We retrospectively explored ensemble methods, including weighting by past performance. Results: We collected weekly forecasts from 48 models, of which we evaluated 29 models alongside the ensemble model. The ensemble had a consistently strong performance across countries over time, performing better on rWIS than 91% of forecasts for deaths (N=763 predictions from 20 models), and 83% forecasts for cases (N=886 predictions from 23 models). Performance remained stable over a 4-week horizon for death forecasts but declined with longer horizons for cases. Among ensemble methods, the most influential choice came from using a median average instead of the mean, regardless of weighting component models. Conclusions: Our results support combining independent models into an ensemble forecast to improve epidemiological predictions, and suggest that median averages yield better performance than methods based on means. We highlight that forecast consumers should place more weight on incident death forecasts than case forecasts at horizons greater than two weeks. Funding: European Commission, Ministerio de Ciencia, Innovación y Universidades, FEDER; Agència de Qualitat i Avaluació Sanitàries de Catalunya; Netzwerk Universitätsmedizin; Health Protection Research Unit; Wellcome Trust; European Centre for Disease Prevention and Control; Ministry of Science and Higher Education of Poland; Federal Ministry of Education and Research; Los Alamos National Laboratory; German Free State of Saxony; NCBiR; FISR 2020 Covid-19 I Fase; Spanish Ministry of Health / REACT-UE (FEDER); National Institutes of General Medical Sciences; Ministerio de Sanidad/ISCIII; PERISCOPE European H2020; PERISCOPE European H2021; InPresa; National Institutes of Health, NSF, US Centers for Disease Control and Prevention, Google, University of Virginia, Defense Threat Reduction Agency.