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Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10−11), rs12454712 (BCL2; P = 2.7 × 10−8), and rs10506418 (FAM19A2; P = 1.9 × 10−8). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.

Background Circumpapillary retinal nerve fiber layer thickness (cpRNFLT) as assessed by spectral domain optical coherence tomography (SD-OCT) is a new technique used for the detection and evaluation of glaucoma and other optic neuropathies. Before translating cpRNFLT into clinics, it is crucially important to investigate anthropometric, biochemical, and clinical parameters potentially affecting cpRNFLT in a large population-based dataset. Methods The population-based LIFE-Adult Study randomly selected 10,000 participants from the population registry of Leipzig, Germany. All participants underwent standardized systemic assessment of various cardiometabolic risk markers and ocular imaging, including cpRNFLT measurement using SD-OCT (Spectralis, Heidelberg Engineering). After employing strict SD-OCT quality criteria, 8952 individuals were analyzed. Multivariable linear regression analyses were used to evaluate the independent associations of various cardiometabolic risk markers with sector-specific cpRNFLT. For significant markers, the relative strength of the observed associations was compared to each other to identify the most relevant factors influencing cpRNFLT. In all analyses, the false discovery rate method for multiple comparisons was applied. Results In the entire cohort, female subjects had significantly thicker global and also sectoral cpRNFLT compared to male subjects (p < 0.05). Multivariable linear regression analyses revealed a significant and independent association between global and sectoral cpRNFLT with biomarkers of renal function and lipid profile. Thus, thinner cpRNFLT was associated with worse renal function as assessed by cystatin C and estimated glomerular filtration rate. Furthermore, an adverse lipid profile (i.e., low high-density lipoprotein (HDL) cholesterol, as well as high total, high non-HDL, high low-density lipoprotein cholesterol, and high apolipoprotein B) was independently and statistically significantly related to thicker cpRNFLT. In contrast, we do not observe a significant association between cpRNFLT and markers of inflammation, glucose homeostasis, liver function, blood pressure, or obesity in our sector-specific analysis and globally. Conclusions Markers of renal function and lipid metabolism are predictors of sectoral cpRNFLT in a large and deeply phenotyped population-based study independently of previously established covariates. Future studies on cpRNFLT should include these biomarkers and need to investigate whether incorporation will improve the diagnosis of early eye diseases based on cpRNFLT.

This study investigates the differences and effects of transparency and explainability on trust, situation awareness, and satisfaction in the context of an automated car. Three groups were compared in a between-subjects design (n = 73). Participants in every group saw six graphically manipulated videos of an automated car from the driver’s perspective with either transparency, post-hoc explanations or both combined. Transparency resulted in higher trust, higher satisfaction and higher level 2 situational awareness (SA) than explainability. Transparency also resulted in higher level 2 SA than the combined condition, but did not differ in terms of trust or satisfaction. Moreover, explainability led to significantly worse satisfaction compared to combined feedback. Although our findings should be replicated in more ecologically valid driving situations, we tentatively conclude that transparency alone should be implemented in semi self-driving cars, and possibly automated systems in general, whenever possible to make them most satisfactory, trustworthy, and resulting in higher SA.

Background: Positron emission tomography (PET) has provided evidence that adult humans retain metabolically active brown adipose tissue (BAT) depots. Thyroid hormones (TH) stimulate BAT thermogenes...

Background: Patients with chronic kidney disease (CKD) have a high risk of premature cardiovascular diseases (CVD) and show increased mortality. Pro-neurotensin (Pro-NT) was associated with metabolic diseases and predicted incident CVD and mortality. However, Pro-NT regulation in CKD and its potential role linking CKD and mortality have not been investigated, so far. Methods: In a central lab, circulating Pro-NT was quantified in three independent cohorts comprising 4715 participants (cohort 1: patients with CKD; cohort 2: general population study; and cohort 3: non-diabetic population study). Urinary Pro-NT was assessed in part of the patients from cohort 1. In a 4th independent cohort, serum Pro-NT was further related to mortality in patients with advanced CKD. Tissue-specific Nts expression was further investigated in two mouse models of diabetic CKD and compared to non-diabetic control mice. Results: Pro-NT significantly increased with deteriorating renal function (P < 0.001). In meta-analysis of cohorts 1–3, Pro-NT was significantly and independently associated with estimated glomerular filtration rate (P ≤ 0.002). Patients in the middle/high Pro-NT tertiles at baseline had a higher all-cause mortality compared to the low Pro-NT tertile (Hazard ratio: 2.11, P = 0.046). Mice with severe diabetic CKD did not show increased Nts mRNA expression in different tissues compared to control animals. Conclusions: Circulating Pro-NT is associated with impaired renal function in independent cohorts comprising 4715 subjects and is related to all-cause mortality in patients with end-stage kidney disease. Our human and rodent data are in accordance with the hypotheses that Pro-NT is eliminated by the kidneys and could potentially contribute to increased mortality observed in patients with CKD.

Background If biochemical control of acromegaly is not achieved by operation and medication, radiotherapy may be indicated. Objective To describe fractionated radiotherapy (FRT) and stereotactic radiosurgery (SRS) regarding excess of IGF-1 and pituitary function. Design and methods A retrospective analysis of 352 patients (4126 patient-years) from the German Acromegaly Registry was performed. Follow-up was 1.0–45.1 years after radiotherapy. Therapeutic success was defined by low or normal IGF-1 according to center-specific reference ranges without (= remission) or on (= controlled disease) suppressive medication. Results Time between radiotherapy and last follow-up was 13.0 ± 8.2 years for FRT (n = 233) and 8.9 ± 5.0 years for SRS (n = 119, P P P = 0.021). The 10-year calculated remission rate was 48% for FRT and 52% for SRS (95% CI for the difference is −18 to 26% age points, P = 0.74) and the respective controlled disease rate was 23 and 26%. The odds ratio for adrenocorticotropic or thyreotropic insufficiency was 0.54 (95% CI: 0.30–1.00, P = 0.049) in SRS compared to FRT patients. Conclusion Both after FRT and SRS about 75% of patients with acromegaly are in remission or controlled after 10 years. A slightly faster achievement of target values was observed after SRS. The rate of pituitary insufficiency in FRT patients is significantly higher.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes., Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.

Compatibility and wide availability of WLAN make its integration with 3GPP-based networks (LTE, 5G), the most cost efficient solution to meet high service demands and ubiquitous radio coverage. In a heterogeneous network, seamless mobility, provisioning of quality of service (QoS) and proper distribution of load among interworking networks are the most challenging issues and need to be resolved accurately. In the literature, many theoretical algorithms (prediction based algorithms) and mathematical solutions (utility or cost function) have been proposed for load sharing in the heterogeneous networks. However, these algorithms are either based on assumptions like availability of certain parameters of neighbouring networks or possibility of exchanging the network conditions in real time. Such assumptions restrict the implementation of these solutions on real network infrastructures due to non-availability of protocols or interfaces to exchange the network parameters. Moreover, sustainability of the specified QoS for each traffic type is very important while assisting a 3GPP network with a non-3GPP network. This paper presents a QoS class identifier (QCI) aware load sharing technique based on the available information at the deciding entity of the anchor network. A network architecture is designed to efficiently provide radio coverage inside a building with single LTE small cell and an optimum number of WLAN APs (Access Points). The idea is to not only increase the overall network capacity but improve the user experience as well. Simulation results show that the proposed load sharing technique for the LTE-WLAN integrated network not only extends the mobile network services to the confined coverage of indoor environment but also maintains the QoS for high priority traffic.

The Industry 4.0 is offering novel opportunities for large enterprises or even small and medium enterprises (SME) to digitize and also simplify their existing production workflows. With the uprise of the Distributed Ledger Technology (DLT), the Industry 4.0 also receives new possibilities to set up a more secure, redundant and decentralized data infrastructure. Existing database systems can be exchanged with Blockchain systems, thus making use of its inherent immutability. Popular open-source Blockchain frameworks such as Hyperledger Fabric offer large customizability, which makes them attractive for dynamic Industry 4.0 applications. Though, the configuration of the required networks is not a trivial task. Due to its high flexibility and numerous configuration parameters, an interested developer needs to have a deep understanding or even some experience with the Hyperledger Fabric framework. Since most SMEs do not have a dedicated IT department, this paper aims to provide a design guideline for interested developers to optimally set up a Hyperledger Fabric v2.0 business network, which is suited for the desired use-case. With the special demands of Industry 4.0 in mind, this paper also provides three example use-cases, which can benefit from the use of DLT to enhance data security. The results are generalizable and comparable to previous works but differ in some version-specific aspects of Fabric.

The Near Field Communication (NFC) technology has experienced a steep rise in popularity due to new advances in contactless payment or virtual public transport tickets on mobile devices. Though, NFC can also be used to exchange arbitrary data between two devices within close distance. This aspect is inherently useful to prove physical access, e.g. during authentication. Modern wireless technologies such as Wi-Fi or Bluetooth 5.0 also use NFC for their pairing schemes. However, there does not exist any approach towards an NFC supported authentication scheme for digital signatures. This paper proposes a novel approach to authentically exchange public keys with the aid of NFC. Using said technique allows the key exchanging parties to prove their authenticity to each other, by exploiting the close and limited wireless communication distance of NFC. Using the proposed algorithm scalable, authentic and cost-effective sensor networks can be built, without compromising the security of the exchanged keys. With the proposed NFC challenge-response scheme, the public key of the sender can be transferred without any third party being able to smuggle in their own public key. Following the proposed scheme, any attempts to exchange unauthentic keys can be directly identified and consequently rejected. The proof-of-concept example shows, that the algorithm allows for dynamically adding of new sensors as well as an authentic communication between the gateway and the sensor devices.

ContextDespite the emerging evidence on the role of oxytocin (OXT) in metabolic diseases, there is a lack of well-powered studies addressing the relationship of circulating OXT with obesity and diabetes.Objectives and DesignHere, we measured OXT in a study cohort (n = 721; 396 women, 325 men; mean age ± SD, 47.7 ± 15.2 years) with subphenotypes related to obesity, including anthropometric traits such as body mass index [BMI (mean ± SD), 26.8 ± 4.6 kg/m2], waist-to-hip ratio (WHR; 0.88 ± 0.09), blood parameters (glucose, 5.32 ± 0.50 mmol/L; insulin, 5.3 ± 3.3 µU/mL), and oral glucose tolerance test to clarify the association with OXT. We also tested in a genome-wide association study (GWAS) whether the interindividual variation in OXT serum levels might be explained by genetic variation.ResultsThe OXT concentration was increased in subjects with elevated BMI and positively correlated with WHR, waist circumference, and triglyceride levels. The OXT concentration in subjects with BMI 30 kg/m2 (n = 137; 106.4 pg/mL, P = 8 × 10−6). OXT levels were also positively correlated with plasma glucose and insulin and were elevated in subjects with impaired glucose tolerance (P = 4.6 × 10−3). Heritability of OXT was estimated at 12.8%. In a GWAS, two hits in linkage disequilibrium close (19 kb) to the OXT reached genome-wide significant association (top-hit rs12625893, P = 3.1 × 10−8, explained variance 3%).ConclusionsOur data show that OXT is genetically affected by a variant near OXT and is associated with obesity and impaired glucose tolerance.

Background and aims Pro-Neurotensin (NT), a stable surrogate parameter of NT, has recently been introduced as a peptide predicting the development of obesity, diabetes mellitus, cardiovascular diseases, and cardiovascular mortality. However, regulation of Pro-NT in gestational diabetes mellitus (GDM) remains uninvestigated. Methods and results Pro-NT was quantified in 74 women with GDM, 74 healthy, gestational age-matched, pregnant controls, as well as in a second cohort comprising of 74 healthy, non-pregnant control women, using a chemiluminometric sandwich immunoassay. Pro-NT was correlated to measures of obesity, hypertension, glucose and lipid metabolism, renal function, and inflammation. Mean ± standard deviation of circulating Pro-NT levels were not significantly different in women with GDM (100.2 ± 75.7 pmol/l) as compared to healthy, pregnant controls (103.2 ± 37.4 pmol/l) and healthy, non-pregnant female controls (105.9 ± 38.9 pmol/l) (p = 0.661). Homeostasis model assessment of insulin resistance (HOMA-IR) and creatinine positively correlated with serum Pro-NT in multivariate regression analysis. In contrast, free fatty acids (FFA) were inversely correlated with circulating Pro-NT. Results sustained adjustment for pregnancy status. Conclusions Circulating Pro-NT is not independently associated with GDM, but is with HOMA-IR, creatinine, and FFA even after adjustment for pregnancy status.

Purpose Adipokines may play an important role in the complex etiology of human obesity and its metabolic complications. Here, we analyzed the relationship between 15 adipokines, eating behavior and body-mass index (BMI). Methods The study included 557 participants of the Sorbs (62.1% women, 37.9% men) and 3101 participants of the population-based LIFE-Adult cohorts (53.4% women, 46.4% men) who completed the German version of the Three-Factor-Eating Questionnaire to assess the eating behavior types cognitive restraint, disinhibition and hunger. Serum levels of 15 adipokines, including adiponectin, adipocyte fatty acid-binding protein (AFABP), angiopoietin-related growth factor (AGF), chemerin, fibroblast growth factor (FGF)-19, FGF-21, FGF-23, insulin-like growth factor (IGF)-1, interleukin (IL) 10, irisin, progranulin, vaspin, pro-neurotensin (pro-NT), pro-enkephalin (PENK) and leptin were measured. Based on significant correlations between several adipokines with different eating behavior items and BMI, we conducted mediation analyses, considering the eating behavior items as potential mediation variable towards BMI. Results Here, we found that the positive association between chemerin, AFABP or leptin and BMI in Sorbian women was mediated by higher restraint or disinhibited eating, respectively. Additionally, in Sorbian women, the negative relation between IGF-1 and BMI was mediated by higher disinhibition and the positive link between AGF and BMI by lower disinhibition. In Sorbian men, the negative relationship between PENK and BMI was mediated by lower disinhibition and hunger, whereas the negative relation between IGF-1 and BMI was mediated by higher hunger. In the LIFE-Adult women´s cohort, associations between chemerin and BMI were mediated by decreased hunger or disinhibition, respectively, whereas relations between PENK and BMI were fully mediated by decreased disinhibition. Conclusion Our study suggests that adipokines such as PENK, IGF-1, chemerin, AGF, AFABP and leptin might affect the development of obesity by directly modifying individual eating behavior. Given the observational nature of the study, future experimental or mechanistic work is warranted.

Fibroblast growth factor 21 (FGF21) is a regulator of addictive behavior. Increasing evidence suggests an impact of FGF21 on eating behavior, food and drug cravings and on other adipokines like insulin-like growth factor 1 (IGF-1) or adiponectin. We investigated the association of serum FGF21 and genetic variants with aspects of food and drug craving and obesity related metabolic parameters including serum adipokine levels. Standardized questionnaires, blood samples and anthropometric data of the Sorbs cohort (n = 1046) were analyzed using SPSS. For genetic analyses, the FGF21-locus ±10 kb was genotyped and analyzed using PLINK. Validation was conducted in a second independent cohort (n = 704). FGF21 was significantly associated with alcohol and coffee consumption, smoking and eating behavior (disinhibition). We confirmed correlations of FGF21 serum levels with IGF-1, adiponectin, pro-enkephalin, adipocyte fatty-acid-binding protein, chemerin and progranulin. FGF21 genetic variants were associated with anthropometric and metabolic parameters, adipokines, food and drug craving while strongest evidence was seen with low-density lipoprotein cholesterol (LDL-C). We highlight the potential role of FGF21 in food and drug cravings and provide new insights regarding the link of FGF21 with other adipokines as well as with metabolic traits, in particular those related to lipid metabolism (LDL-C).

Background/Objectives People with metabolically healthy obesity (MHO) may still have an increased risk for cardiovascular mortality compared to metabolically healthy lean (MHL) individuals. However, the mechanisms linking obesity to cardiovascular diseases are not entirely understood. We therefore tested the hypothesis that circulating cell adhesion molecules (CAMs) are higher in MHO compared to MHL individuals. Subjects/Methods Serum concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), E-selectin and P-selectin were measured in age- and sex-matched groups of MHL (n = 32), MHO categorized into BMI-matched insulin sensitive (IS, n = 32) or insulin resistant (IR) obesity (n = 32) and people with metabolically unhealthy obesity (MUO, n = 32). Results Indeed, individuals with MHO have significantly higher sICAM-1, E-selectin, and P-selectin serum concentrations compared to MHL people. However, these CAMs are still significantly lower in IS compared to IR MHO. There was no difference between the groups in sVCAM-1 serum concentrations. Compared to all other groups, circulating adhesion molecules were significantly higher in individuals with MUO. Conclusions These findings suggest that obesity-related increased cardiovascular risk is reflected and may be mediated by significantly higher CAMs. The mechanisms causing elevated adhesion molecules even in the absence of overt cardio-metabolic risk factors and whether circulating CAMs could predict cardiovascular events need to be explored.

Due to the rapid development of the Internet of Things (IoT) and consequently, the availability of more and more IoT data sources, mechanisms for searching and integrating IoT data sources become essential to leverage all relevant data for improving processes and services. This paper presents the IoT search framework IoTCrawler. The IoTCrawler framework is not only another IoT framework, it is a system of systems which connects existing solutions to offer interoperability and to overcome data fragmentation. In addition to its domain-independent design, IoTCrawler features a layered approach, offering solutions for crawling, indexing and searching IoT data sources, while ensuring privacy and security, adaptivity and reliability. The concept is proven by addressing a list of requirements defined for searching the IoT and an extensive evaluation. In addition, real world use cases showcase the applicability of the framework and provide examples of how it can be instantiated for new scenarios.

Process Modeling Languages (PMLs) help to define, structure and organize operational workflows. The Business Process Model and Notation 2.0 (BPMN), one of the most prominent PMLs, allows the definition and execution of process models including distributed participants and systems. An increasing number of BPMN use cases take place in unreliable communication environments, where connectivity may be intermittent or broken. Resilient processes need to avoid failures that may result in process interruptions or complete breakdowns.

Applying wireless communication technologies to agricultural vehicular networks often results in high end-to-end delays and loss of packets due to intermittent or broken connectivity. This paper analyses the methods for the successful delivery of the vehicular data within acceptable delay times. Different kinds of data that are generated and transmitted in agricultural networks are considered in this paper, followed by the data prioritization methods which allow critical data to be prioritized against other data. In this regard, Enhanced Distributed Channel Access, Differentiated Services, and application-based data rate variation are discussed in conjunction with the Simple Network Management Protocol. These techniques are simulated or tested separately and then together and the results show that even in poor network conditions, high-prioritized data is not lost or delayed.

Objective. Similar to obesity, lipodystrophy (LD) causes adipose tissue dysfunction and severe metabolic complications. Growth differentiation factor 15 (GDF15) belongs to the transforming growth factor &beta, superfamily and is dysregulated in metabolic disease including obesity and diabetes mellitus. Circulating levels in LD and the impact of leptin treatment have not been investigated so far. Material and Methods. GDF15 serum levels were quantified in 60 LD patients without human immunodeficiency virus infection and 60 controls matched for age, gender, and body mass index. The impact of metreleptin treatment on circulating GDF15 was assessed in a subgroup of patients. GDF15 mRNA expression was determined in metabolic tissues of leptin-deficient lipodystrophic aP2-nSREBP1c-Tg mice, obese ob/ob mice, and control C57Bl6 mice. Results. Median GDF15 serum concentrations were significantly higher in LD patients (819 ng/L) as compared to the control group (415 ng/L) (p &lt, 0.001). In multiple linear regression analysis, an independent and positive association remained between GDF15 on one hand and age, patient group, hemoglobin A1c, triglycerides, and C-reactive protein on the other hand. Moreover, there was an independent negative association between GFD15 and estimated glomerular filtration rate. Circulating GDF15 was not significantly affected by metreleptin treatment in LD patients. Gdf15 was upregulated in leptin-deficient lipodystrophic mice as compared to controls. Moreover, Gdf15 mRNA expression was downregulated by leptin treatment in lipodystrophic and obese animals. Conclusions. Serum concentrations of GDF15 are elevated in LD patients and independently associated with markers of metabolic dysfunction. Gdf15 expression is higher in lipodystrophic mice and downregulated by leptin treatment.

Glycaemic traits are used to diagnose and monitor type 2 diabetes, and cardiometabolic health. To date, most genetic studies of glycaemic traits have focused on individuals of European ancestry. Here, we aggregated genome-wide association studies in up to 281,416 individuals without diabetes (30% non-European ancestry) with fasting glucose, 2h-glucose post-challenge, glycated haemoglobin, and fasting insulin data. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P-8), 80% with no significant evidence of between-ancestry heterogeneity. Analyses restricted to European ancestry individuals with equivalent sample size would have led to 24 fewer new loci. Compared to single-ancestry, equivalent sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase understanding of diabetes pathophysiology by use of trans-ancestry studies for improved power and resolution.

Context Acromegaly is a rare disease caused by excessive growth hormone (GH) secretion from pituitary adenomas in most cases. If neurosurgical therapy is contraindicated or not sufficient, medical therapy is the second line therapy. Objective To describe current medical therapy in acromegaly. Design & Methods Retrospective data analysis from 2732 patients treated in 69 centers of the German Acromegaly Registry. 749 patients were seen within the recent 18 months, of which 420 were on medical therapy (56.1%). Results 73% of medically treated acromegalic patients had normal/low IGF-1 levels. 57% of patients with non-normalized IGF-1 levels had an IGF-1 value between 1- and 1.25-fold above the upper limit of normal. Most patients (55%) received somatostatin analogs as monotherapy, 12% GH receptor monotherapy, and 9% dopamine agonist therapy. Doses of each medical therapy varied widely, with 120 mg lanreotide LAR every 4 weeks, 30 mg octreotide LAR every 4 weeks, 140 mg pegvisomant per week and 1mg cabergoline per week being the most frequent used regimens. A combination of different medical regimens was used in almost 25% of the patients. Conclusion The majority of German acromegalic patients receiving medical therapy are controlled according to normal IGF-1 levels.

With the introduction of the Internet of Things (IoT) into every area of life, more and more applications are created that rely on information collected from IoT sensors. These applications are developed by third-party developers and depend on a continuous information flow but do not operate the sensor network themselves. However, in case of sensor failures, the flow of information will be interrupted which will pose a problem for the user/application as well as the data provider who might not be able to replace the sensor in time. Depending on the requirements of the application, estimators which are trained through machine learning algorithms, called Virtual Sensors, can ensure the uninterrupted operation of the application. However, for a solution that can be used in practice, the deployment of such a Virtual Sensor needs to be fast enough as well as fully automated, so that no human interaction and domain knowledge is required. This paper describes a framework that is capable of finding correlating IoT sensors in the surrounding environment, selecting a machine learning algorithm, and training a fitting model to run a Virtual Sensor.

Background The lack of human donors for allotransplantation forces the development of other strategies to circumvent the existing organ shortage documented on the waiting lists. Here, xenotransplantation offers a suitable option since the genetic modification of animals has become an established method that allows the generation of animals as donors of cells, tissues, and organs with reduced antigenicity. Methods Focus is given on the generation of decellularized matrix scaffolds, for example, for valve transplantation and/or repair, that have the potential being fully assimilated by the recipient as they are no longer a mechanical implant with risk of calcification and related failure. Results This new class of products is transplants that will be regulated either as medical devices or as cell-based medicinal products, that is, advanced therapy medicinal products, according to the regulations in the European Union. Conclusions In this review, we compile relevant regulatory aspects and point out the possibilities of how these products for human use may be regulated in the future.

Background The demand for donated human hearts far exceeds the number available. Xenotransplantation of genetically modified porcine organs provides an alternative. In 2000, an Advisory Board of the International Society for Heart and Lung Transplantation set the benchmark for commencing clinical cardiac xenotransplantation as consistent 60% survival of non-human primates after life-supporting porcine heart transplantations. Recently, we reported the stepwise optimization of pig-to-baboon orthotopic cardiac xenotransplantation finally resulting in consistent success, with 4 recipients surviving 90 (n = 2), 182, and 195 days. Here, we report on 4 additional recipients, supporting the efficacy of our procedure. Results The first 2 additional recipients succumbed to porcine cytomegalovirus (PCMV) infections on Days 15 and 27, respectively. In 2 further experiments, PCMV infections were successfully avoided, and 3-months survival was achieved. Throughout all the long-term experiments, heart, liver, and renal functions remained within normal ranges. Post-mortem cardiac diameters were slightly increased when compared with that at the time of transplantation but with no detrimental effect. There were no signs of thrombotic microangiopathy. The current regimen enabled the prolonged survival and function of orthotopic cardiac xenografts in altogether 6 of 8 baboons, of which 4 were now added. These results exceed the threshold set by the Advisory Board of the International Society for Heart and Lung Transplantation. Conclusions The results of our current and previous experimental cardiac xenotransplantations together fulfill for the first time the pre-clinical efficacy suggestions. PCMV-positive donor animals must be avoided.

Hyperledger Fabric is currently one of the most popular business Blockchain platforms. With its included functionality of executing custom smart contracts, Fabric has become one of the most widely used frameworks, e.g. for industry 4.0 applications. Though, most applications require a previously known data throughput. For a potentially interested developer, it is not trivial to decide, whether a given Fabric network configuration will meet the required expectations in regards to performance. Thus this work shows a performance analysis for Hyperledger Fabric v2.0 and focusses on the evaluation of throughput, latency and error rate, together with the overall scalability of the Fabric Blockchain platform. The results show, that Fabric v2.0 outperforms previous versions in almost any regard in addition to an improved smart contract lifecycle.

Aims Adipose tissue-secreted proteins, i.e. adipocytokines, have been identified as potential mediators linking fat mass and adipose tissue dysfunction with impaired glucose homeostasis, alterations in the inflammatory status, and risk of diabetes. The aim of this study was to determine whether seven circulating adipocytokines are associated with gestational diabetes mellitus (GDM) or are altered by metabolic and weight changes during pregnancy itself. Methods A panel of seven adipocytokines (i.e. adiponectin, adipocyte fatty acid-binding protein, chemerin, leptin, Pro-Enkephalin, progranulin, and Pro-Neurotensin) was quantified in serum in a cross-sectional cohort of 222 women with the following three groups matched for age and body mass index: (i) 74 pregnant women with GDM; (ii) 74 pregnant women without GDM; and (iii) 74 non-pregnant and healthy women. A stepwise statistical approach was used by performing pairwise comparisons, principal component analysis (PCA), and partial least square discriminant analysis (PLS-DA). Results Five out of seven adipocytokines were dysregulated between pregnant and non-pregnant women, i.e. adiponectin, chemerin, leptin, Pro-Enkephalin, and progranulin. None of the adipocytokines significantly differed between GDM and non-GDM status during pregnancy. The same five adipocytokines clustered in a principal component representing pregnancy-induced effects. Fasting insulin was the most relevant parameter in the discrimination of GDM as compared to pregnant women without GDM, whereas chemerin and adiponectin were most relevant factors to discriminate pregnancy status. Conclusions Pregnancy status but not presence of GDM can be distinguished by the seven investigated adipocytokines in discrimination analyses.

This paper deals with the use of Quality of Information (QoI) in the context of frameworks for data integration in the Internet of Things (IoT). It analyses existing approaches available to generate measures for information quality and proposes a concept to integrate real-time QoI calculation into an IoT framework. The approach shows several advantages when it comes to fault-detection, or the ranking of data streams when searching for IoT devices. However, the use of QoI often suffers from missing or incomplete metadata. This is addressed by a knowledge-based approach.

Objective Adipose tissue–derived signals potentially link obesity and adipose tissue dysfunction with metabolic and cardiovascular diseases. Although some adipocytokines have been closely related to metabolic and cardiovascular traits, it is unknown which adipocytokine or adipocytokine clusters serve as meaningful markers of metabolic syndrome (MS) components. Therefore, this study investigated the associations of 12 adipocytokines with components of the MS to identify the most relevant cytokines potentially related to specific metabolic profiles. Research Design and Methods Twelve cytokines [adiponectin, adipocyte fatty acid–binding protein (AFABP), angiopoietin-related growth factor, chemerin, fibroblast growth factor (FGF) 19, FGF21, FGF23, insulin-like growth factor-1, interleukin 10, irisin, progranulin, and vaspin] were quantified in a cross-sectional cohort of 1046 subjects. Hypothesis-free cluster analysis, multivariate regression analyses with parameters of the MS, and discriminant analysis were performed to assess associations and the relative importance of each cytokine for reflecting MS and its components. Results Among the studied adipocytokines, adiponectin, AFABP, chemerin, and FGF21 showed the strongest associations with MS and several MS components in discriminant analyses and multiple regression models. For certain metabolic components, these adipocytokines were better discriminators than routine metabolic markers. Other cytokines investigated in the present cohort are less able to distinguish between metabolically healthy and unhealthy subjects. Conclusions Adiponectin, AFABP, chemerin, and FGF21 showed the strongest associations with MS components in a general population, suggesting that adverse adipose tissue function is a major contributor to these metabolic abnormalities. Future prospective studies should address the question whether these adipocytokines can predict the development of metabolic disease states.

Item does not contain fulltext Rigorous organization and quality control (QC) are necessary to facilitate successful genome-wide association meta-analyses (GWAMAs) of statistics aggregated across multiple genome-wide association studies. This protocol provides guidelines for (i) organizational aspects of GWAMAs, and for (ii) QC at the study file level, the meta-level across studies and the meta-analysis output level. Real-world examples highlight issues experienced and solutions developed by the GIANT Consortium that has conducted meta-analyses including data from 125 studies comprising more than 330,000 individuals. We provide a general protocol for conducting GWAMAs and carrying out QC to minimize errors and to guarantee maximum use of the data. We also include details for the use of a powerful and flexible software package called EasyQC. Precise timings will be greatly influenced by consortium size. For consortia of comparable size to the GIANT Consortium, this protocol takes a minimum of about 10 months to complete.

Acromegaly is a rare disease generally brought about by a benign tumour in the pituitary and characterized by growth hormone (GH) and insulin-like growth factor 1 (IGF-1) excess. Increased mortality has been related to cardiovascular events that could be linked to these hormones and patients suffer from high rates of diabetes and hypertension. In this study, we examine if the incidence of myocardial infarction (MI) and stroke differ from that of the general population. Data from the German Acromegaly Registry in seven specialized endocrine centres were analysed (n = 479, 56% female, 46 years old at diagnosis, 5549 person-years from diagnosis). Standardized incidence ratios (SIR) were calculated as compared to the general population. MI and stroke incidences were very close to those of the general population with an SIR (95% CI) of 0.89 (0.47–1.52, p = 0.80) for MI and 1.17 (0.66–1.93, p = 0.61) for stroke. Acromegaly was uncontrolled in 16% of patients with MI or stroke versus 21% in those without (p = 0.56). Prevalence of hypertension at the initial visit was much higher in those with MI or stroke than those without (94 vs. 43%, p

Background The indirect water-deprivation test is the current reference standard for the diagnosis of diabetes insipidus. However, it is technically cumbersome to administer, and the resul...

The Internet of Things (IoT) is growing rapidly as more and more household appliances, sensors and actuators are connected to the internet and communicate with each other. Because these IoT devices usually have only limited processing and communication capabilities, an efficient communication protocol is required to reduce the protocol overhead. The Message Queue Telemetry Transport (MQTT) protocol provides such properties. MQTT is a publish/subscribe protocol, where each client can subscribe to a message topic in order to receive all messages published under that topic. The payload of a message (i.e., the content) can be encrypted to hide private information. However, to forward messages, the topic of a message needs to be read by the broker and thus cannot be encrypted and might reveal private information. This paper presents methods to avoid this problem. It features and evaluates a one-time password approach to provide a fully obfuscated communication method for MQTT topics. Thereby, the user tracking and the generation of profiles is prevented.

The Internet of Things (IoT) relies on sensor devices to measure real-world phenomena in order to provide IoT services. The sensor readings are shared with multiple entities, such as IoT services, other IoT devices or other third parties. The collected data may be sensitive and include personal information. To protect the privacy of the users, the data needs to be protected through an encryption algorithm. For sharing cryptographic cipher-texts with a group of users Attribute-Based Encryption (ABE) is well suited, as it does not require to create group keys. However, the creation of ABE cipher-texts is slow when executed on resource constraint devices, such as IoT sensors. In this paper, we present a modification of an ABE scheme, which not only allows to encrypt data efficiently using ABE but also reduces the size of the cipher-text, that must be transmitted by the sensor. We also show how our modification can be used to realise an instantaneous key revocation mechanism.

Islet xenotransplantation represents an attractive solution to overcome the shortage of human islets for use in type 1 diabetes. The wide-scale application of clinical islet xenotransplantation, however, requires that such a procedure takes place in a specifically and tightly regulated environment. With a view to promoting the safe application of clinical islet xenotransplantation, a few years ago the International Xenotransplantation Association (IXA) published a Consensus Statement that outlined the key ethical and regulatory requirements to be satisfied before the initiation of xenotransplantation studies in diabetic patients. This earlier IXA Statement also documented a disparate regulatory landscape among different geographical areas. This situation clearly fell short of the 2004 World Health Assembly Resolution WHA57.18 that urged Member States "to cooperate in the formulation of recommendations and guidelines to harmonize global practices" to ensure the highest ethical and regulatory standards on a global scale. In this new IXA report, IXA members who are active in xenotransplantation research in their respective geographic areas herewith briefly describe changes in the regulatory frameworks that have taken place in the intervening period in the various geographic areas or countries. The key reassuring take-home message of the present report is that many countries have embraced the encouragement of the WHO to harmonize the procedures in a more global scale. Indeed, important regulatory changes have taken place or are in progress in several geographic areas that include Europe, Korea, Japan, and China. Such significant regulatory changes encompass the most diverse facets of the clinical application of xenotransplantation and comprise ethical aspects, source animals and product specifications, study supervision, sample archiving, patient follow-up and even insurance coverage in some legislations. All these measures are expected to provide a better care and protection of recipients of xenotransplants but also a higher safety profile to xenotransplantation procedures with an ultimate net gain in terms of international public health.

Our world and our lives are changing in many ways. Communication, networking, and computing technologies are among the most influential enablers that shape our lives today. Digital data and connected worlds of physical objects, people, and devices are rapidly changing the way we work, travel, socialize, and interact with our surroundings, and they have a profound impact on different domains, such as healthcare, environmental monitoring, urban systems, and control and management applications, among several other areas. Cities currently face an increasing demand for providing services that can have an impact on people’s everyday lives. The CityPulse framework supports smart city service creation by means of a distributed system for semantic discovery, data analytics, and interpretation of large-scale (near-)real-time Internet of Things data and social media data streams. To goal is to break away from silo applications and enable cross-domain data integration. The CityPulse framework integrates multimodal, mixed quality, uncertain and incomplete data to create reliable, dependable information and continuously adapts data processing techniques to meet the quality of information requirements from end users. Different than existing solutions that mainly offer unified views of the data, the CityPulse framework is also equipped with powerful data analytics modules that perform intelligent data aggregation, event detection, quality assessment, contextual filtering, and decision support. This paper presents the framework, describes its components, and demonstrates how they interact to support easy development of custom-made applications for citizens. The benefits and the effectiveness of the framework are demonstrated in a use-case scenario implementation presented in this paper.

Voids in SiO2 films deposited on GaN were probed by using monoenergetic positron beams. The films were fabricated on GaN substrates by using plasma-enhanced chemical vapor deposition. The size and density of the voids in the films increased up to an annealing temperature of 800 °C and then decreased at 1000 °C. The observed annealing behaviors of the voids were attributed to the desorption of impurities incorporated during the deposition process and the shrinkage of the Si–O matrix by high-temperature annealing. Vacancy-type defects were introduced into the GaN substrate after 1000 °C annealing in O2 atmosphere due to the diffusion of Ga from the substrate to the SiO2 film. No out-diffusion of Ga into the SiO2 film was observed for the annealing in N2 atmosphere. Thus, the observed out-diffusion of Ga was attributed to the enhanced oxidation of GaN during the annealing in O2 atmosphere. The diffusion of positrons implanted into the GaN substrate toward the SiO2 film was suppressed by annealing, suggesting a decrease in the negative charges in the SiO2 film or near the SiO2/GaN interface.

The Internet of Things (IoT) offers an incredible innovation potential for developing smarter applications and services. However, today we see solutions in the development of vertical applications and services reflecting what used to be the early days of the Web, leading to fragmentation and intra-nets of Things. To achieve an open IoT ecosystem of systems and platforms, several key enablers are needed for effective, adaptive and scalable mechanisms for exploring and discovering IoT resources and their data/capabilities. This paper discusses our work in the EU H2020 IoTCrawler project. Its focus is on the integration and interoperability across different platforms, through dynamic and reconfigurable solutions for discovery and integration of data and services from legacy and new systems. This is complemented with adaptive, privacy-aware and secure solutions for crawling, indexing and searching in distributed IoT systems. IoTCrawler targets IoT development and demonstrations with a focus on Industry 4.0, Social IoT, Smart City and Smart Energy use cases.

Angesichts der bestehenden Knappheit an humanen Spenderorganen und -geweben kann die Entwicklung xenogener Zelltherapeutika (xZT) eine adaquate Behandlungsalternative sein. Insbesondere porcine Pankreasinseln und -inselzellen haben bereits zum jetzigen Zeitpunkt Eingang in die experimentelle Therapie von Typ 1 Diabetes mellitus (T1DM)-Patienten gefunden. Dabei stellen xZT sowohl aus medizinischer als auch aus ethischer und regulatorischer Sicht eine Herausforderung dar. So ist infolge der speziesubergreifenden Transplantation (Xenotransplantation) neben dem Risiko der immunologischen Abstosung auch das Infektionsrisiko durch Ubertragung von mikrobiellen und viralen Erregern zu berucksichtigen. Letzteres ist bidirektional und betrifft sowohl die Transmission vom Transplantat auf den Empfanger als auch die Transmission vom Empfanger auf das Transplantat. Die Uberschreitung der Speziesbarriere erfordert eine kritische Nutzen-Risiko-Bewertung und nach Abschluss der Behandlung eine sorgfaltige und langfristige Uberwachung der Patienten. Die internationalen rechtlichen und regulatorischen Anforderungen an xZT basieren u. a. auf den von der Weltgesundheitsorganisation (WHO) 2008 im Changsha Kommunique formulierten Kriterien, die in Europa nach Inkraftsetzen der EU-Verordnung uber Arzneimittel fur neuartige Therapien (ATMP) im Leitfaden fur xenogene Zelltherapeutika seitens der Europaischen Arzneimittelbehorde EMA mit abgebildet sind.

Irisin has been suggested as a novel myokine with beneficial effects in rodents. However, previous data in humans showed conflicting results regarding its association with metabolic phenotypes and regulation of secretion. Furthermore, although an association of rs726344 in FNDC5 (fibronectin type III domain containing 5) coding for irisin with insulin sensitivity was reported, the effects of genetic variation at this locus on irisin serum levels have not been investigated, so far. Therefore, we investigated circulating irisin and the associations with rs726344 in a cohort of1000 subjects.Irisin serum concentrations were measured with enzyme-linked immunosorbent assay. Associations with metabolic parameters including renal function, glucose and lipid metabolism, inflammation, as well as adipokine profiles, were assessed in regression models. Dynamic changes of serum irisin were investigated during oral glucose tolerance test (OGTT) in a subset of the cohort (n=136). rs726344 was genotyped in all subjects and analyzed for associations with serum irisin and traits of the metabolic syndrome.Irisin was negatively associated with fat mass, fasting glucose and dyslipidemia but not with other adipokines. Moreover, irisin decreased during an OGTT in a subcohort comprising subjects with normal glucose tolerance, impaired fasting glucose, impaired glucose tolerance and type 2 diabetes mellitus. rs726344 was not associated with serum irisin levels or with other anthropometric and biochemical parameters.Circulating irisin levels are associated with a beneficial metabolic profile but not with other adipokines and not with rs726344 in our cohort. Our data suggest a potential favorable role of irisin in the regulation of metabolism.

SummaryBrown adipose tissue (BAT) plays an important role in regulating core-body temperature in various species including man. [18F]FDGPET/ CT imaging first revealed the presence of metabolically active BAT depots and that decreased BAT function is associated with various metabolic conditions. Thyroid hormone (TH) in concert with sympathetic nervous system signalling (SNS) stimulates BAT thermogenesis and thyroid disorders result in dysfunctional BAT. Currently, research is focussing not only on BAT regulation but also on browning of white adipose tissue (WAT) to BAT beige adipose tissue (BeAT) in order to develop novel treatments for human obesity and related conditions. While [18F]FDG-PET/ CT imaging is continuing to provide valuable insights into BAT and BeAT function in health and disease, there is a pressing need to develop alternative radiotracers that reliably track their activity in vivo. As a result it is expected that preclinical micro PET/CT investigations of BAT and BeAT will gain in prominence.The aim of this short review is to i) describe fundamentals in BAT biology, ii) highlight some of the clinical and preclinical studies performed on humans and rodents with a focus on TH, BAT and PET/CT, and iii) bridge these data with our own studies within the DFG thyroid transact priority program.