Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency.

Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs)1,2, conferring a predisposition to life-threatening COVID-19 pneumonia3. Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52LOF/IκBδGOF). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for NFKB2 variants causing haploinsufficiency of p100 and p52 (hereafter, p52LOF/IκBδLOF) or gain-of-function of p52 (hereafter, p52GOF/IκBδLOF). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-κB2 have very few tissue-specific autoantibodies. However, their thymuses have an abnormal structure, with few AIRE-expressing medullary thymic epithelial cells. Human inborn errors of the alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases.

Evaluation of the telemedical health care network "SAFE BIRTH" for pregnant women at risk, premature and sick newborns and their families: study protocol of a cluster-randomized controlled stepped-wedge trial.

BACKGROUND: The Perinatal Center of the University Hospital Carl Gustav Carus Dresden has initiated the telemedical healthcare network "SAFE BIRTH" to coordinate and improve specialized care in non-metropolitan regions for pregnant women and newborns. The network incorporates five intervention bundles (IB): (1) Multi-professional, inter-disciplinary prenatal care plan; (2) Neonatal resuscitation; (3) Neonatal antibiotic stewardship; (4) Inter-facility transfer of premature and sick newborns; (5) Psycho-social support for parents. We evaluate if the network improves care close to home for pregnant women, premature and sick newborns. METHODS: To evaluate the complex healthcare intervention "SAFE BIRTH" we will conduct a cluster-randomized controlled stepped-wedge trial in five prenatal medical outpatient offices and eight non-metropolitan hospitals in Saxony, Germany. The offices and hospitals will be randomly allocated to five respectively eight sequential steps over a 30-month period to implement the telemedical IB. We define one specific primary process outcome for each IB (for instance IB#1: "Proportion of patients with inclusion criterion IB#1 who have a prenatal care plan and psychosocial counseling within one week"). We estimated a separate multilevel logistic regression model for each primary process outcome using the intervention status as a regressor (control or intervention group). Across all IB, a total of 1,541 and 1,417 pregnant women or newborns need to be included in the intervention and control group, respectively, for a power above 80% for small to medium intervention effects for all five hypothesis tests. Additionally, we will assess job satisfaction and sense of safety of health professionals caring for newborns (questionnaire survey) and we will assess families' satisfaction, resilience, quality of life and depressive, anxiety and stress symptoms (questionnaire surveys). We will also evaluate the cost-effectiveness of "SAFE BIRTH" (statutory health insurance routine data, process data) and barriers to its implementation (semi-structured interviews). We use multilevel regression models adjusting for relevant confounders (e.g. socioeconomic status, age, place of residence), as well as descriptive analyses and qualitative content analyses. DISCUSSION: If the telemedical healthcare network "SAFE BIRTH" proves to be effective and cost-efficient, strategies for its translation into routine care should be developed. TRIAL REGISTRATION: German clinical trials register. DRKS-ID: DRKS00031482.

[Nationally standardized broad consent in practice: initial experiences, current developments, and critical assessment]. / National standardisierter Broad Consent in der Praxis: erste Erfahrungen, aktuelle Entwicklungen und kritische Betrachtungen.

BACKGROUND: The digitalization in the healthcare sector promises a secondary use of patient data in the sense of a learning healthcare system. For this, the Medical Informatics Initiative's (MII) Consent Working Group has created an ethical and legal basis with standardized consent documents. This paper describes the systematically monitored introduction of these documents at the MII sites. METHODS: The monitoring of the introduction included regular online surveys, an in-depth analysis of the introduction processes at selected sites, and an assessment of the documents in use. In addition, inquiries and feedback from a large number of stakeholders were evaluated. RESULTS: The online surveys showed that 27 of the 32 sites have gradually introduced the consent documents productively, with a current total of 173,289 consents. The analysis of the implementation procedures revealed heterogeneous organizational conditions at the sites. The requirements of various stakeholders were met by developing and providing supplementary versions of the consent documents and additional information materials. DISCUSSION: The introduction of the MII consent documents at the university hospitals creates a uniform legal basis for the secondary use of patient data. However, the comprehensive implementation within the sites remains challenging. Therefore, minimum requirements for patient information and supplementary recommendations for best practice must be developed. The further development of the national legal framework for research will not render the participation and transparency mechanisms developed here obsolete.

Sequencing the B Cell Receptor Repertoires of Antibody-Deficient Individuals With and Without Infection Susceptibility.

PURPOSE: Most individuals with antibody deficiency (hypogammaglobulinemia) need immunoglobulin replacement therapy (IgG-RT) from healthy plasma donors to stay clear of infections. However, a small subset of hypogammaglobulinemic patients do not require this substitution therapy. We set out to investigate this clinical conundrum by asking whether the peripheral B cell receptor repertoires differ between antibody-deficient patients who do and do not need IgG-RT. METHODS: We sequenced and analyzed IgG and IgM heavy chain B cell receptor repertoires from peripheral blood mononuclear cells (PBMCs) isolated from patients with low serum IgG concentrations who did or did not require IgG-RT. RESULTS: Compared to the patients who did not need IgG-RT, those who needed IgG-RT had higher numbers of IgG antibody clones, higher IgM diversity, and less oligoclonal IgG and IgM repertoires. The patient cohorts had different heavy chain variable gene usage, and the patients who needed IgG-RT had elevated frequencies of IgG clones with higher germline identity (i.e., fewer somatic hypermutations). CONCLUSION: Antibody-deficient patients with infection susceptibility who needed IgG-RT had more diverse peripheral antibody repertoires that were less diverged from germline and thus may not be as optimal for targeting pathogens, possibly contributing to infection susceptibility.

The GAIN Registry - a New Prospective Study for Patients with Multi-organ Autoimmunity and Autoinflammation.

Patient registries are a very important and essential tool for investigating rare diseases, as most physicians only see a limited number of cases during their career. Diseases of multi-organ autoimmunity and autoinflammation are especially challenging, as they are characterized by diverse clinical phenotypes and highly variable expressivity. The GAIN consortium (German multi-organ Auto Immunity Network) developed a dataset addressing these challenges. ICD-11, HPO, and ATC codes were incorporated to document various clinical manifestations and medications with a defined terminology. The GAIN dataset comprises detailed information on genetics, phenotypes, medication, and laboratory values. Between November 2019 and July 2022, twelve centers from Europe have registered 419 patients with multi-organ autoimmunity or autoinflammation. The median age at onset of symptoms was 13 years (IQR 3-28) and the median delay from onset to diagnosis was 5 years (IQR 1-14). Of 354 (84.5%) patients who were genetically tested, 248 (59.2%) had a defined monogenetic cause. For 87 (20.8%) patients, no mutation was found and for 19 (4.5%), the result was pending. The most common gene affected was NFkB1 (48, 11.5%), and the second common was CTLA4 (40, 9.5%), both genetic patient groups being fostered by specific research projects within GAIN. The GAIN registry may serve as a valuable resource for research in the inborn error of immunity community by providing a platform for etiological and diagnostic research projects, as well as observational trials on treatment options.

Data protection-compliant broad consent for secondary use of health care data and human biosamples for (bio)medical research: Towards a new German national standard.

BACKGROUND: The secondary use of deidentified but not anonymized patient data is a promising approach for enabling precision medicine and learning health care systems. In most national jurisdictions (e.g., in Europe), this type of secondary use requires patient consent. While various ethical, legal, and technical analyses have stressed the opportunities and challenges for different types of consent over the past decade, no country has yet established a national consent standard accepted by the relevant authorities. METHODS: A working group of the national Medical Informatics Initiative in Germany conducted a requirements analysis and developed a GDPR-compliant broad consent standard. The development included consensus procedures within the Medical Informatics Initiative, a documented consultation process with all relevant stakeholder groups and authorities, and the ultimate submission for approval via the national data protection authorities. RESULTS: This paper presents the broad consent text together with a guidance document on mandatory safeguards for broad consent implementation. The mandatory safeguards comprise i) independent review of individual research projects, ii) organizational measures to protect patients from involuntary disclosure of protected information, and iii) comprehensive information for patients and public transparency. This paper further describes the key issues discussed with the relevant authorities, especially the position on additional or alternative consent approaches such as dynamic consent. DISCUSSION: Both the resulting broad consent text and the national consensus process are relevant for similar activities internationally. A key challenge of aligning consent documents with the various stakeholders was explaining and justifying the decision to use broad consent and the decision against using alternative models such as dynamic consent. Public transparency for all secondary use projects and their results emerged as a key factor in this justification. While currently largely limited to academic medicine in Germany, the first steps for extending this broad consent approach to wider areas of application, including smaller institutions and medical practices, are currently under consideration.

IL-2 receptors preassemble and signal in the ER/Golgi causing resistance to antiproliferative anti-IL-2Rα therapies.

Interleukin-2 (IL-2) and IL-15 play pivotal roles in T cell activation, apoptosis, and survival, and are implicated in leukemias and autoimmune diseases. Their heterotrimeric receptors share their ß- and γc-chains, but have distinct α-chains. Anti-IL-2Rα (daclizumab) therapy targeting cell surface-expressed receptor subunits to inhibit T cell proliferation has only brought limited success in adult T cell leukemia/lymphoma (ATL) and in multiple sclerosis. We asked whether IL-2R subunits could already preassemble and signal efficiently in the endoplasmic reticulum (ER) and the Golgi. A combination of daclizumab and anti-IL-2 efficiently blocked IL-2-induced proliferation of IL-2-dependent wild-type (WT) ATL cells but not cells transfected with IL-2, suggesting that in IL-2-producing cells signaling may already take place before receptors reach the cell surface. In the Golgi fraction isolated from IL-2-producing ATL cells, we detected by Western blot phosphorylated Jak1, Jak3, and a phosphotyrosine signal attributed to the γc-chain, which occurred at much lower levels in the Golgi of WT ATL cells. We expressed EGFP- and mCherry-tagged receptor chains in HeLa cells to study their assembly along the secretory pathway. Confocal microscopy, Förster resonance energy transfer, and imaging fluorescence cross-correlation spectroscopy analysis revealed partial colocalization and molecular association of IL-2 (and IL-15) receptor chains in the ER/Golgi, which became more complete in the plasma membrane, further confirming our hypothesis. Our results define a paradigm of intracellular autocrine signaling and may explain resistance to antagonistic antibody therapies targeting receptors at the cell surface.

[Treatment practice of patients with Parkinson's disease in Saxony : A secondary data-based analysis of utilization in the observation period 2011-2019]. / Versorgungssituation von Parkinson-Patienten in Sachsen : Eine sekundärdatenbasierte Analyse der Inanspruchnahme im Beobachtungszeitraum 2011 bis 2019.

BACKGROUND: The consequences of demographic change are already noticeable in Saxony, the federal state with the highest average age in Germany and predominantly rural areas. In order to improve medical care for patients with Parkinson's disease (PwP), a status quo analysis of current care practice is required. OBJECTIVE: To what extent does the utilization of medical services by PwP differ a) between urban and rural areas in Saxony and b) between PwP with and without neurologist contact in the observation period from 2011 to 2019? MATERIAL AND METHODS: The cohort study was based on extensive routine data for Saxony from the health insurance company AOK PLUS from 2010 to 2019. A cohort of 15,744 PwP (n = 67,448 patient-years) was compared to a matched cohort (n = 674,480 patient-years; criteria: year of birth, gender, year of insurance, place of residence: urban/rural) without an ICD-10 coding of a movement disorder. RESULTS: Overall, there was a steady increase in the number of PwP in the dynamic cohort from 2011 (n = 6829) to 2019 (n = 8254). Urban-rural differences included a smaller proportion of patients being seen by a neurologist in rural areas. The PwP had a 3.5 to 4­fold higher risk of dying compared to those in the comparison cohort. Changes in drug therapy for Parkinson's disease (i.e., increases in COMT and MAO inhibitors) and in remedy delivery (i.e., increases in occupational therapy and speech therapy) over the observation period were primarily seen in PwP who were seen by a neurologist. DISCUSSION: The study identified increased morbidity and mortality in PwP who are suitable targets for innovative care concepts. The increasing number of patients and the described differences document the need for this. At the same time, changes in prescription practice show that innovative forms of treatment are being used by neurologists in outpatient care.

Agonist binding directs dynamic competition among nuclear receptors for heterodimerization with retinoid X receptor.

Retinoid X receptor (RXR) plays a pivotal role as a transcriptional regulator and serves as an obligatory heterodimerization partner for at least 20 other nuclear receptors (NRs). Given a potentially limiting/sequestered pool of RXR and simultaneous expression of several RXR partners, we hypothesized that NRs compete for binding to RXR and that this competition is directed by specific agonist treatment. Here, we tested this hypothesis on three NRs: peroxisome proliferator-activated receptor gamma (PPARγ), vitamin D receptor (VDR), and retinoic acid receptor alpha (RARα). The evaluation of competition relied on a nuclear translocation assay applied in a three-color imaging model system by detecting changes in heterodimerization between RXRα and one of its partners (NR1) in the presence of another competing partner (NR2). Our results indicated dynamic competition between the NRs governed by two mechanisms. First, in the absence of agonist treatment, there is a hierarchy of affinities between RXRα and its partners in the following order: RARα > PPARγ > VDR. Second, upon agonist treatment, RXRα favors the liganded partner. We conclude that recruiting RXRα by the liganded NR not only facilitates a stimulus-specific cellular response but also might impede other NR pathways involving RXRα.

Simultaneous Mapping of Molecular Proximity and Comobility Reveals Agonist-Enhanced Dimerization and DNA Binding of Nuclear Receptors.

Single Plane Illumination Microscopy (SPIM) revolutionized time lapse imaging of live cells and organisms due to its high speed and reduced photodamage. Quantitative mapping of molecular (co)mobility by fluorescence (cross-)correlation spectroscopy (F(C)CS) in a SPIM has been introduced to reveal molecular diffusion and binding. A complementary aspect of interactions is proximity, which can be studied by Förster resonance energy transfer (FRET). Here, we extend SPIM-FCCS by alternating laser excitation, which reduces false positive cross-correlation and facilitates comapping of FRET. Thus, different aspects of interacting systems can be studied simultaneously, and molecular subpopulations can be discriminated by multiparameter analysis. After demonstrating the benefits of the method on the AP-1 transcription factor, the dimerization and DNA binding behavior of retinoic acid receptor (RAR) and retinoid X receptor (RXR) is revealed, and an extension of the molecular switch model of the nuclear receptor action is proposed. Our data imply that RAR agonist enhances RAR-RXR heterodimerization, and chromatin binding/dimerization are positively correlated. We also propose a ligand induced conformational change bringing the N-termini of RAR and RXR closer together. The RXR agonist increased homodimerization of RXR suggesting that RXR may act as an autonomous transcription factor.

[Intrauterine Growth Restriction: Transsectoral, Interdisciplinary and Multiprofessional Care for Pregnant Women and Newborns in a Feto-neonatal Pathway: A Project of the Innovationsfonds]. / Intrauterine Wachstumsrestriktion: Transsektorale, interdisziplinäre und multiprofessionelle Betreuung von Schwangeren und Neugeborenen im Feto-Neonat-Pfad: Ein Projekt des Innovationsfonds.

Intrauterine growth restriction (IUGR) is present in fetuses that do not achieve their full in-utero growth potential. IUGR needs to be discriminated from small for gestational age (SGA) because IUGR newborns in particular experience long-term side effects from their small growth. IUGR fetuses have a significantly increased risk of prematurity and a distinct risk profile compared to adequate-for-gestational-age preterm newborns. Complications of prematurity are more frequent, including bronchopulmonary dysplasia, intraventricular hemorrhage, and meconium ileus. IUGR newborns are at risk of long-term health issues like cerebral palsy, impaired lung function, and delayed speech development. Interdisciplinary and interprofessional care of IUGR pregnancies in the context of a standardized health care research project is feasible: Pregnant women at risk are identified, early therapy with acetylsalicylic acid is started as indicated, risk-adapted care at level III centers is organized including psychosocial interventions and neonatal consultations. Postnatally, integrated neonatal care focusing on parent-child interaction and optimized nutrition is a hallmark. Afterwards, in-depth pediatric follow-up visits with local pediatricians help to identify growth and neurodevelopment problems early. The effects, acceptance. and cost efficiency of this approach are evaluated prospectively as part of an Innovationsfonds project.

[Good Practice Data Linkage]. / Gute Praxis Datenlinkage (GPD).

Individual data linkage of different data sources for research purposes is being increasingly used in Germany in recent years. However, generally accepted methodological guidance is missing. The aim of this article is to define such methodological standards for research projects. Another aim is to provide readers with a checklist for critical appraisal of research proposals and articles. Since 2016, an expert panel of members of different German scientific societies have worked together and developed 7 guidelines with a total of 27 practical recommendations. These recommendations include (1) research aims, questions, data sources and resources, (2) infrastructure and data flow, (3) data privacy, (4) ethics, (5) key variables and type of linkage, (6) data validation/quality assurance and (7) long-term use for future research questions. The authors provide a rationale for each recommendation. Future revisions will include any new developments in science and data privacy.

Random Motion of Chromatin Is Influenced by Lamin A Interconnections.

Using fluorescence correlation spectroscopy in single-plane illumination microscopy, we investigated the dynamics of chromatin in interphase mouse adult fibroblast cell nuclei under the influence of the intermediate filament protein lamin A. We find that 1) lamin A-eGFP and histone H2A-mRFP show significant comobility, indicating that their motions are clearly interconnected in the nucleus, and 2) that the random motion of histones H2A within the chromatin network is subdiffusive, i.e., the effective diffusion coefficient decreases for slow timescales. Knocking out lamin A changes the diffusion back to normal. Thus, lamin A influences the dynamics of the entire chromatin network. Our conclusion is that lamin A plays a central role in determining the viscoelasticity of the chromatin network and helping to maintain local ordering of interphase chromosomes.

[Quo Vadis Data Linkage in Germany? An Initial Inventory]. / Quo vadis Datenlinkage in Deutschland? Eine erste Bestandsaufnahme.

In recent years, linking different data sources, also called data linkage or record linkage, to address scientific questions, is being increasingly used in Germany. However, there are very few published reports and new projects develop the necessary tools independently of each other. Therefore, a team of researchers joined together to exchange their experiences on data linkage and to give suggestions on how linkage could be done for scientists, reviewers as well as members of data privacy boards and ethics committees. It is the aim of this article to assist future projects that want to link German data on an individual level. In addition to the legal framework conditions (data privacy), also examples of types of data linkage, their fields of application und potential pitfalls as well as the methods of preventing them will be described in an application-oriented fashion.

Impact of the Triglyceride/High-Density Lipoprotein Cholesterol Ratio and the Hypertriglyceremic-Waist Phenotype to Predict the Metabolic Syndrome and Insulin Resistance.

Insulin resistance is the underlying mechanism for the metabolic syndrome and associated dyslipidaemia that theoretically implies a practical tool for identifying individuals at risk for cardiovascular disease and type-2-diabetes. Another screening tool is the hypertriglyceremic-waist phenotype (HTW). There is important impact of the ethnic background but a lack of studied European populations for the association of the triglyceride/high-density lipoprotein cholesterol (HDL-C) ratio and insulin resistance. This observational, retrospective study evaluated lipid ratios and the HTW for predicting the metabolic syndrome/insulin resistance in 1932 non-diabetic individuals from Germany in the fasting state and during a glucose tolerance test. The relations of triglyceride/HDL-C, total-cholesterol/HDL-C, and low-density lipoprotein cholesterol/HDL-C with 5 surrogate estimates of insulin resistance/sensitivity and metabolic syndrome were analysed by linear regression analysis and receiver operating characteristics (ROC) in participants with normal (n=1 333) or impaired fasting glucose (n=599), also for the impact of gender. Within the lipid ratios, triglyceride/HDL-C had the strongest associations with insulin resistance/sensitivity markers. In the prediction of metabolic syndrome, diagnostic accuracy was good for triglyceride/HDL-C (area under the ROC curve 0.817) with optimal cut-off points (in mg/dl units) of 2.8 for men (80% sensitivity, 71% specificity) and 1.9 for women (80% sensitivity, 75% specificity) and fair for HTW and HOMA-IR (area under the curve 0.773 and 0.761). These data suggest the triglyceride/HDL-C ratio as a physiologically relevant and practical index for predicting the concomitant presence of metabolic syndrome, insulin resistance and dyslipidaemia for therapeutic and preventive care in apparently healthy European populations.

Effects on Engagement and Health Literacy Outcomes of Web-Based Materials Promoting Physical Activity in People With Diabetes: An International Randomized Trial.

BACKGROUND: Developing accessible Web-based materials to support diabetes self-management in people with lower levels of health literacy is a continuing challenge. OBJECTIVE: The objective of this international study was to develop a Web-based intervention promoting physical activity among people with type 2 diabetes to determine whether audiovisual presentation and interactivity (quizzes, planners, tailoring) could help to overcome the digital divide by making digital interventions accessible and effective for people with all levels of health literacy. This study also aimed to determine whether these materials can improve health literacy outcomes for people with lower levels of health literacy and also be effective for people with higher levels of health literacy. METHODS: To assess the impact of interactivity and audiovisual features on usage, engagement, and health literacy outcomes, we designed two versions of a Web-based intervention (one interactive and one plain-text version of the same content) to promote physical activity in people with type 2 diabetes. We randomly assigned participants from the United Kingdom, Austria, Germany, Ireland, and Taiwan to either an interactive or plain-text version of the intervention in English, German, or Mandarin. Intervention usage was objectively recorded by the intervention software. Self-report measures were taken at baseline and follow-up (immediately after participants viewed the intervention) and included measures of health literacy, engagement (website satisfaction and willingness to recommend the intervention to others), and health literacy outcomes (diabetes knowledge, enablement, attitude, perceived behavioral control, and intention to undertake physical activity). RESULTS: In total, 1041 people took part in this study. Of the 1005 who completed health literacy information, 268 (26.67%) had intermediate or low levels of health literacy. The interactive intervention overall did not produce better outcomes than did the plain-text version. Participants in the plain-text intervention group looked at significantly more sections of the intervention (mean difference -0.47, 95% CI -0.64 to -0.30, P<.001), but this did not lead to better outcomes. Health literacy outcomes, including attitudes and intentions to engage in physical activity, significantly improved following the intervention for participants in both intervention groups. These improvements were similar across higher and lower health literacy levels and in all countries. Participants in the interactive intervention group had acquired more diabetes knowledge (mean difference 0.80, 95% CI 0.65-0.94, P<.001). Participants from both groups reported high levels of website satisfaction and would recommend the website to others. CONCLUSIONS: Following established practice for simple, clear design and presentation and using a person-based approach to intervention development, with in-depth iterative feedback from users, may be more important than interactivity and audiovisual presentations when developing accessible digital health interventions to improve health literacy outcomes. CLINICALTRIAL: International Standard Randomized Controlled Trial Number (ISRCTN): 43587048; http://www.isrctn.com/ISRCTN43587048. (Archived by WebCite at http://www.webcitation.org/6nGhaP9bv).

Remotely sensing the German Wadden Sea-a new approach to address national and international environmental legislation.

The Wadden Sea along the North Sea coasts of Denmark, Germany, and the Netherlands is the largest unbroken system of intertidal sand and mud flats in the world. Its habitats are highly productive and harbour high standing stocks and densities of benthic species, well adapted to the demanding environmental conditions. Therefore, the Wadden Sea is one of the most important areas for migratory birds in the world and thus protected by national and international legislation, which amongst others requires extensive monitoring. Due to the inaccessibility of major areas of the Wadden Sea, a classification approach based on optical and radar remote sensing has been developed to support environmental monitoring programmes. In this study, the general classification framework as well as two specific monitoring cases, mussel beds and seagrass meadows, are presented. The classification of mussel beds profits highly from inclusion of radar data due to their rough surface and achieves agreements of up to 79 % with areal data from the regular monitoring programme. Classification of seagrass meadows reaches even higher agreements with monitoring data (up to 100 %) and furthermore captures seagrass densities as low as 10 %. The main classification results are information on area and location of individual habitats. These are needed to fulfil environmental legislation requirements. One of the major advantages of this approach is the large areal coverage with individual satellite images, allowing simultaneous assessment of both accessible and inaccessible areas and thus providing a more complete overall picture.

Views of People With High and Low Levels of Health Literacy About a Digital Intervention to Promote Physical Activity for Diabetes: A Qualitative Study in Five Countries.

BACKGROUND: Low health literacy is associated with poor health-related knowledge, illness self-management, health service use, health, and survival, and thus addressing issues related to low health literacy has been highlighted as a pressing international priority. OBJECTIVE: To explore views of a digital health promotion intervention designed to be accessible to people with lower levels of health literacy, in particular examining reactions to the interactive and audiovisual elements of the intervention. METHODS: Qualitative think-aloud interviews were carried out with 65 adults with type 2 diabetes in the UK, Ireland, USA, Germany, and Austria, with purposive sampling to ensure representation of people with lower levels of health literacy. Inductive thematic analysis was used to identify common themes. We then systematically compared views in subgroups based on country, health literacy level, age, gender, and time since diagnosis. RESULTS: Most participants from the chosen countries expressed positive views of most elements and features of the intervention. Some interactive and audiovisual elements required modification to increase their usability and perceived credibility and relevance. There were some differences in views based on age and gender, but very few differences relating to health literacy level or time since diagnosis. CONCLUSIONS: In general, participants found the intervention content and format accessible, appropriate, engaging, and motivating. Digital interventions can and should be designed to be accessible and engaging for people with a wide range of health literacy levels.

Proteomic, Metabolomic, and Fatty Acid Profiling of Small Extracellular Vesicles from Glioblastoma Stem-Like Cells and Their Role in Tumor Heterogeneity.

Glioblastoma is a deadly brain tumor for which there is no cure. The presence of glioblastoma stem-like cells (GSCs) contributes to the heterogeneous nature of the disease and makes developing effective therapies challenging. Glioblastoma cells have been shown to influence their environment by releasing biological nanostructures known as extracellular vesicles (EVs). Here, we investigated the role of GSC-derived nanosized EVs (<200 nm) in glioblastoma heterogeneity, plasticity, and aggressiveness, with a particular focus on their protein, metabolite, and fatty acid content. We showed that conditioned medium and small extracellular vesicles (sEVs) derived from cells of one glioblastoma subtype induced transcriptomic and proteomic changes in cells of another subtype. We found that GSC-derived sEVs are enriched in proteins playing a role in the transmembrane transport of amino acids, carboxylic acids, and organic acids, growth factor binding, and metabolites associated with amino acid, carboxylic acid, and sugar metabolism. This suggests a dual role of GSC-derived sEVs in supplying neighboring GSCs with valuable metabolites and proteins responsible for their transport. Moreover, GSC-derived sEVs were enriched in saturated fatty acids, while their respective cells were high in unsaturated fatty acids, supporting that the loading of biological cargos into sEVs is a highly regulated process and that GSC-derived sEVs could be sources of saturated fatty acids for the maintenance of glioblastoma cell metabolism. Interestingly, sEVs isolated from GSCs of the proneural and mesenchymal subtypes are enriched in specific sets of proteins, metabolites, and fatty acids, suggesting a molecular collaboration between transcriptionally different glioblastoma cells. In summary, this study revealed the complexity of GSC-derived sEVs and unveiled their potential contribution to tumor heterogeneity and critical cellular processes commonly deregulated in glioblastoma.

Family history of diabetes is associated with higher risk for prediabetes: a multicentre analysis from the German Center for Diabetes Research.

AIMS/HYPOTHESIS: Prediabetes is a collective term for different subphenotypes (impaired glucose tolerance [IGT] and/or impaired fasting glucose [IFG]) with different pathophysiologies. A positive family history for type 2 diabetes (FHD) is associated with increased risk for type 2 diabetes. We assumed that it would also associate with prediabetes, but wondered whether all subphenotypes are related to a positive family history. METHODS: In a study population of 8,106 non-diabetic individuals of European origin collected from four study centres (normal glucose tolerance, NGT n = 5,482, IFG and/or IGT n = 2,624), we analysed whether having at least one first degree relative with diabetes is associated with prediabetes. The analyses were performed using the same models in each population separately. Afterwards, a meta-analysis was performed. RESULTS: FHD was significantly associated with the risk for prediabetes (IFG and/or IGT, OR 1.40; 95% CI 1.27, 1.54). This association remained significant in multivariable logistic regression models including sex, age and BMI (OR 1.26; 95% CI 1.14, 1.40). When different prediabetic outcomes were considered separately, the association was found for isolated IFG (OR 1.37; 95% CI 1.20, 1.57), isolated IGT (OR 1.25; 95% CI 1.07, 1.46) as well as for the combination IFG+IGT (OR 1.64; 95% CI 1.40, 1.93). After stratification on BMI, association between FHD and prediabetes was seen only in non-obese individuals (BMI < 30 kg/m(2)). CONCLUSIONS/INTERPRETATION: We found that FHD is an important risk factor for prediabetes, especially for combined IGT and IFG. Its relevance seems to be more evident in the non-obese.