Demographic change is advancing inexorably. The number of people in need of care is growing rapidly, while at the same time there is already a shortage of several thousand caregivers to provide adequate, needs-based nursing care. Intelligent assistance systems can make a contribution to solving this problem. In this article, diverse assistance systems from the areas of nursing care, health care, rehabilitation and training, and mobility are presented as examples. These different components, equipped with the appropriate sensors, data transmission units and interfaces, can all be integrated into a system platform and thus form a comprehensive intelligent, digital assistance system or a mobile diagnosis and therapy platform.

Conventional pathogenic bacteria-detection methods are lab-bound, time-consuming and need trained personnel. Microelectrodes can be used to recognize harmful microorganisms by dielectric impedance spectroscopy. However, crucial for this spectroscopy method are the spatial dimensions and layout of the electrodes, as the corresponding distribution of the electric field defines the sensor system parameters such as sensitivity, SNR, and dynamic range. Therefore, a variety of sensor models are created and evaluated. FEM simulations in 2D and 3D are conducted for this impedimetric sensor. The authors tested differently shaped structures, verified the linear influence of the excitation amplitude and developed a mathematical concept for a quality factor that practically allows us to distinguish arbitrary sensor designs and layouts. The effect of guard electrodes blocking outer influences on the electric field are investigated, and essential configurations are explored. The results lead to optimized electronic sensors in terms of geometrical dimensions. Possible material choices for real sensors as well as design and layout recommendations are presented.

Ion-Sensitive-Field-Effect-Transistors (ISFETs) are an alternative to the common glass electrode for pH sensing. They promise higher integration, easier manufacturing and are interesting for biological, medical and environmental applications. However, they require a different and slightly more complex readout circuit. We propose a new circuit based on a standard mixed-signal-processor with minimal required external components. The operating point of the ISFET is set with a servo loop in software using only the integrated DACs and opamps and an external resistor. With the internal ADC, feedback is provided for the software loop and the result is read. We compare this method with a fully analog ISFET readout circuit and show their equivalence. The new circuit provides some additional features, such as run time configurable operating point and channel type settings. The integrated MCU can also perform calibration and sensor diagnosis functionality and eases the integration in other systems and parallel operation of many units with its digital interfaces.

Background and Aims: The GUCY1A3 gene has been associated with coronary artery disease (CAD) by genome-wide association studies. The risk variant rs7692387 leads to reduced expression of GUCY1A3 and reduced inhibition of platelet aggregation. Transgenic animal models and analyses of large-scale clinical trials suggest that inhibition of platelet aggregation might be a therapeutic strategy to reduce CAD risk in carriers of the risk allele.

AIM:A common genetic variant at the GUCY1A3 coronary artery disease locus has been shown to influence platelet aggregation. The risk of ischaemic events including stent thrombosis varies with the efficacy of aspirin to inhibit platelet reactivity. This study sought to investigate whether homozygous GUCY1A3 (rs7692387) risk allele carriers display higher on-aspirin platelet reactivity and risk of ischaemic events early after coronary intervention. METHODS AND RESULTS:The association of GUCY1A3 genotype and on-aspirin platelet reactivity was analysed in the genetics substudy of the ISAR-ASPI registry (n = 1678) using impedance aggregometry. The clinical outcome cardiovascular death or stent thrombosis within 30 days after stenting was investigated in a meta-analysis of substudies of the ISAR-ASPI registry, the PLATO trial (n = 3236), and the Utrecht Coronary Biobank (n = 1003) comprising a total 5917 patients. Homozygous GUCY1A3 risk allele carriers (GG) displayed increased on-aspirin platelet reactivity compared with non-risk allele (AA/AG) carriers [150 (interquartile range 91-209) vs. 134 (85-194) AU⋅min, P < 0.01]. More homozygous risk allele carriers, compared with non-risk allele carriers, were assigned to the high-risk group for ischaemic events (>203 AU⋅min; 29.5 vs. 24.2%, P = 0.02). Homozygous risk allele carriers were also at higher risk for cardiovascular death or stent thrombosis (hazard ratio 1.70, 95% confidence interval 1.08-2.68; P = 0.02). Bleeding risk was not altered. CONCLUSION:We conclude that homozygous GUCY1A3 risk allele carriers are at increased risk of cardiovascular death or stent thrombosis within 30 days after coronary stenting, likely due to higher on-aspirin platelet reactivity. Whether GUCY1A3 genotype helps to tailor antiplatelet treatment remains to be investigated.

Zusammenfassung Die Atherosklerose mit ihren Folgeerkrankungen, der koronaren Herzkrankheit (KHK/MI) und der zerebralen arteriellen Verschlusskrankheit (cAVK/Schlaganfall), gilt weltweit als führende Todesursache. Schon lange sind sich die Forscher über die herausragende Rolle der Vererbung bei der Entstehung der Atherosklerose im Klaren, doch erst im vergangenen Jahrzehnt legten molekulargenetische und epidemiologische Methoden die Vererbungsstruktur der Erkrankung offen. Genomweite Assoziationsstudien konnten bisher über 160 Loci genomweit signifikant mit der KHK assoziieren. Funktionelle Analysen helfen bei der Entschlüsselung zugrunde liegender Mechanismen und sollen den Grundstein für die Entwicklung neuer Therapiestrategien legen. In der Zukunft könnten genetische Tests Patientengruppen mit erhöhtem Erkrankungsrisiko identifizieren sowie eine individualisierte und präzisere Medizin ermöglichen.

Atherosclerosis with its manifestations coronary artery disease and cerebral vascular disease is the leading cause of death worldwide. The importance of heritability in the pathogenesis has been known for a long time, but only in the past decade methodological progress and collaborative efforts started to unravel the genetic architecture propagating atherosclerosis. Genome-wide association studies significantly associated by now more than 160 chromosomal loci with coronary artery disease. Large-scale gene sequencing and functional analyses helped to reveal the causal link between genetic variants and functional mechanisms increasing the risk. Moving forward, knowledge on the biological background might help to identify patients at risk of coronary artery disease and lay the foundation of new therapeutic strategies for precision medicine.

Cell culture assays for therapeutic drug screening today are fully automated. Vitality of the cells is monitored by different sensors. For such a system, we propose a new reader unit, which is capable of reading two different fluorescent sensors and electrical impedance in 24-well-plates. Main goals are to reduce cost, complexity and size while achieving a similar performance as the existing reader unit. To achieve this, measurement electronics and signal paths for frequency domain fluorescence and bio-impedance measurement are combined. Central component is an integrated circuit for impedance spectroscopy. A new compact and economic optical setup is developed to read two different sensor spots on the bottom of the well. Measurement errors introduced by different components like DFT leakage, and frequency dependent signal delays are evaluated and compensated. A set of commercially available fluorescence sensor spots is used to verify the read out performance. The results are usable, with noise slightly higher than commercial readers. To verify the impedance measurement accuracy, measurements of known resistances are conducted. In the relevant impedance and frequency range for biological applications a suitable accuracy is achieved. Due to the higher sampling rate of the new reader, the higher noise can be reduced through averaging. The new system is significantly smaller and cheaper to manufacture than commercially available devices.

A paradigm shift seems to emerge, not only in industrial engineering ("Industry 4.0") but also in medicine: we are on the threshold to "Medicine 4.0". For many years, molecular biology had a leading position in life sciences, but today scientists start realizing that microelectronic systems, due to an increasing miniaturization, are reaching the scale of human cells and consequently can be used for therapeutic approaches. This article shows how microelectronics can play a major role in modern medicine, through the example of customized chemotherapy. This consists in determining, before the beginning of the treatment, what kind of chemotherapy or drug combination will be most effective for a given patient, and at which dose. This of course allows the lessening of a patient burden during treatment, but also to be more efficient and, in the long run, to save money. In order to do this, we have developed the Intelligent Microplate Reader (IMR), which allows us to accurately test different drugs on living cells by mimicking part of their usual environment.

The electronic advances of the last hundred years have made enormous contributions to medical research and the development of new therapeutic methods. In recent years in particular, it has been demonstrated that intelligent sensors, with appropriate radio interfaces, will soon allow diagnostic and therapeutic processes in medicine to be linked to one another - this will enable the development of completely new forms of therapy [1]. This new "Medicine 4.0" was the subject of a first article in the series, which presented the progress achieved through the merging of microsensor technology, microelectronics, information and communication technologies, with a particular focus on the case of personalized chemotherapy. The purpose of this new article is to present more practical applications of these new therapeutic methods.

Un changement de paradigme se dessine non seulement dans le monde de la technique (industrie 4.0), mais aussi en médecine : nous sommes aujourd’hui au seuil de la « médecine 4.0 ». Après de nombreuses années de primauté de la biologie moléculaire, il est aujourd’hui reconnu que les systèmes microélectroniques, grâce à leur miniaturisation croissante, progressent vers des dimensions équivalentes à celles des systèmes cellulaires et peuvent par conséquent être utilisés à des fins thérapeutiques. Cette revue montre, à travers l’exemple de la chimiothérapie personnalisée, comment la microélectronique sera amenée à jouer un rôle primordial dans la médecine moderne.

Les progrès électroniques des cent dernières années ont apporté d’énormes contributions à la recherche médicale et au développement de nouveaux procédés thérapeutiques. Au cours des dernières années notamment, il a été démontré que les capteurs intelligents, avec des interfaces radio appropriées, permettront bientôt de relier entre eux les processus diagnostiques et thérapeutiques en médecine - il sera ainsi possible de développer de toutes nouvelles formes de traitements [1]. Cette nouvelle « médecine 4.0 » a fait l’objet d’un premier article de la série, dans lequel étaient présentés les progrès acquis grâce à la fusion de la technologie des micro-capteurs, de la microélectronique et des technologies de l’information et de la communication, en détaillant particulièrement le cas de la chimiothérapie personnalisée. L’objet de ce nouvel article est de présenter davantage d’applications pratiques de ces nouvelles méthodes thérapeutiques.

Background: A chromosomal locus at 4q32.1 has been genome-wide significantly associated with coronary artery disease risk. The locus encompasses GUCY1A3, which encodes the &agr;1 subunit of the soluble guanylyl cyclase (sGC), a key enzyme in the nitric oxide/cGMP signaling pathway. The mechanism linking common variants in this region with coronary risk is not known. Methods: Gene expression and protein expression were analyzed with quantitative polymerase chain reaction and immunoblotting, respectively. Putative allele-specific transcription factors were identified with in silico analyses and validated via allele-specific quantification of antibody-precipitated chromatin fractions. Regulatory properties of the lead risk variant region were analyzed with reporter gene assays. To assess the effect of zinc finger E box-binding homeobox 1 transcription factor (ZEB1), siRNA-mediated knockdown and overexpression experiments were performed. Association of GUCY1A3 genotype and cellular phenotypes was analyzed with vascular smooth muscle cell migration assays and platelet aggregation analyses. Results: Whole-blood GUCY1A3 mRNA levels were significantly lower in individuals homozygous for the lead (rs7692387) risk variant. Likewise, reporter gene assays demonstrated significantly lower GUCY1A3 promoter activity for constructs carrying this allele. In silico analyses located a DNase I hypersensitivity site to rs7692387 and predicted binding of the transcription factor ZEB1 rather to the nonrisk allele, which was confirmed experimentally. Knockdown of ZEB1 resulted in more profound reduction of nonrisk allele promoter activity and a significant reduction of endogenous GUCY1A3 expression. Ex vivo–studied platelets from homozygous nonrisk allele carriers displayed enhanced inhibition of ADP-induced platelet aggregation by the nitric oxide donor sodium nitroprusside and the phosphodiesterase 5 inhibitor sildenafil compared with homozygous risk allele carriers. Moreover, pharmacological stimulation of sGC led to reduced migration only in vascular smooth muscle cells homozygous for the nonrisk allele. In the Hybrid Mouse Diversity Panel, higher levels of GUCY1A3 expression correlated with less atherosclerosis in the aorta. Conclusions: Rs7692387 is located in an intronic site that modulates GUCY1A3 promoter activity. The transcription factor ZEB1 binds preferentially to the nonrisk allele, leading to an increase in GUCY1A3 expression, higher sGC levels, and higher sGC activity after stimulation. Finally, human and mouse data link augmented sGC expression to lower risk of atherosclerosis.