Selbsttest und Fehlertoleranz mit zugelassener milder Degradation in integrierten CMOS-Sensorsystemen

In dieser Arbeit wird eine Erweiterung bisheriger intelligenter Sensorsysteme, basierend auf Anforderungen aus der Industrie nach steigender Leistung und erweiterten Systemfähigkeiten, vorgestellt. Die hier untersuchte Erweiterung stellt zusätzliche Funktionen zur Erhöhung der Betriebssicherheit im Fehlerfall zur Verfügung. Ein so erweitertes Sensorsystem beinhaltet eine Selbsttestfunktion mit Fehlererkennung, Fehleranalyse, Fehlerbeseitigung und Fehlersignalisierung. Ziel der Erweiterung ist es, Gefahren verursacht durch technische Systeme, die Messergebnisse von einem so erweiterten Sensorsystemen auswerten, durch nichterkannte fehlerhafte Messergebnisse zu minimieren. Aus Kostengründen kann die Fehlerbeseitigung häufig unter dem Aspekt einer unvollständigen Fehlerbeseitigung vorgenommen werden. Im Fehlerfall verringert sich somit die Leistungsfähigkeit des Sensorsystems (milde Degradation). Der Schwerpunkt dieser Arbeit liegt bei der Fehlererkennung von defekten Sensorelementen. Der Grund für die Wahl dieses Schwerpunktes ist, dass für Sensorelemente keine herkömmlichen Selbsttestverfahren existieren und dass gerade die Sensorelemente einer besonders hohen Gefahr der Zerstörung ausgesetzt sind, weil sie direkt mit der Umwelt in Kontakt kommen. In der Arbeit werden zuerst die Grundlagen zu Sensoren und Sensorsystemen beschrieben. Es werden unterschiedliche Fehlererkennungsmethoden vorgestellt und auf die Notwendigkeiten im Hinblick auf einen Einsatz in Sensorsystemen bewertet. Speziell für integrierte Sensoren weist die Methode der Selbstanregung des Sensorelementes mittels elektrischer Stimulation eine hohe Flexibilität auf. Allerdings sind der Selbstanregung durch die begrenzten elektrischen Stimulationsamplituden und den nur geringen Empfindlichkeiten der integrierten Sensorelemente Grenzen gesetzt. Diese Nachteile werden durch die im Rahmen der Arbeit entwickelten Methode der Korrelationsdetektion mit einer festen Stimulationssequenz verringert. Dazu wird das Sensorelement direkt oder indirekt elektrisch mit einer festgelegten Stimulationssequenz angeregt. Bei der direkten Stimulation wird das Sensorelement entsprechend dem eigentlichen Messprinzip angeregt. Bei der indirekten Stimulation erfolgt die Anregung über die Querempfindlichkeit des Sensorelementes. In einem fehlerfreien Sensorsystem wird die Stimulation des Sensorelementes in eine elektrische Größe konvertiert und gelangt über die gesamte Signalverarbeitungskette, wie die eigentliche Messgröße, zum Ausgang des Sensorsystems. In einem fehlerfreien Sensorsystem ist also die Stimulationssequenz im Ausgangssignal vorhanden. Aufgrund der begrenzten elektrischen Stimulationsamplituden, der meistens geringen Empfindlichkeit des Sensorelementes auf die Stimulation und dem Grund, dass die eigentliche Messwertaufnahme nur minimal gestört werden darf, ist die Amplitude der Stimulationssequenz im Ausgang des Sensorsystems nur sehr gering. Um ein solches kleines Signal zu detektieren, wird ein auf die Stimulationssequenz optimiertes Matched-Filter mit nachfolgendem Schwellwertentscheider eingesetzt. Der Vorteil dieser Fehlererkennungsmethode ist, dass neben dem Sensorelement auch die gesamte Signalverarbeitung auf einen Fehler untersucht und kein Eingriff in diese Kette notwendig wird. Die Funktionalität der entwickelten Fehlererkennungsmethode konnte an zwei Anwendungsbeispielen, einem Druck- und Temperatursensorelement, demonstriert werden. Am Beispiel des Drucksensorsystems wurden anschließend zwei Methoden zur Fehlerbeseitigung unter Anwendung der milden Degradation vorgestellt. An extension of smart sensor systems based on industrial requirements for increasing performance and system capability will be examined in this Ph.D. thesis. The extension towards a dependable sensor systems includes additional functions for increasing the reliability. A dependable sensor system contains error detection, error analysis, error removal, and error indication functions. The goal of this extension is to minimize the danger for humans or environment caused by technical systems, which evaluate non-recognized faulty measurement results generated by a non-dependable sensor system. Due to cost issues a full error removal is often impossible. In the case of a detected fault a mild or partial performance degradation may be the result. The error detection of defective sensor elements is the key part of this work. This key part has been chosen because no conventional self-testing strategy for sensor elements are available and defective sensor elements are highly probable because they usually exposed to rough environments. The Ph.D. thesis starts with a survey of integrated sensor systems. Some different error detection methods are presented and analyzed for implementation in integrated sensor systems. The electrical self-stimulation of the sensor element has some advantages special for integrated sensor systems. Due to limited electrical stimulation amplitudes and low sensitivities the self-stimulation of the sensor elements is limited. These disadvantages can be reduced using a new error detection method based on correlation detection of a fixed stimulation sequence. The sensor element is electrically stimulated directly or indirectly using a fixed stimulation sequence. Direct stimulation uses the measurement principle of the sensor element whereas indirect stimulation uses the cross-sensitivities of a sensor element. In a faulty-free sensor system the electrical stimulation is converted by the sensor element into an electrical signal and this is read out like the measurement result by the whole sensor signal processing. Therefore, in a faulty-free system the output of the sensor system contains the stimulation sequence. Due to the limited electrical stimulation amplitudes, the normally low sensitivity of the sensor element for the stimulation sequence, and the only small tolerable disturbance of the measurement process only a low amplitude of the stimulation sequence occurs at the output of the sensor system. To detect such a small signal a matched filter for the stimulation sequence followed by a threshold comparator is used. The advantage of this error detect method is that apart from the sensor element also the complete sensor signal processing is tested and no split of the sensor signal processing is necessary. The functionality of the proposed error detection method has been proven for two examples: 1st a temperature and 2nd a pressure sensor element. Using the example of an integrated capacitance pressure sensor system two methods for error removal with mild performance degradation is presented

A randomized controlled trial

Objective We report on the effect of hemoadsorption therapy to reduce cytokines in septic patients with respiratory failure. Methods This was a randomized, controlled, open-label, multicenter trial. Mechanically ventilated patients with severe sepsis or septic shock and acute lung injury or acute respiratory distress syndrome were eligible for study inclusion. Patients were randomly assigned to either therapy with CytoSorb hemoperfusion for 6 hours per day for up to 7 consecutive days (treatment), or no hemoperfusion (control). Primary outcome was change in normalized IL-6-serum concentrations during study day 1 and 7. Results 97 of the 100 randomized patients were analyzed. We were not able to detect differences in systemic plasma IL-6 levels between the two groups (n = 75; p = 0.15). Significant IL-6 elimination, averaging between 5 and 18% per blood pass throughout the entire treatment period was recorded. In the unadjusted analysis, 60-day-mortality was significantly higher in the treatment group (44.7%) compared to the control group (26.0%; p = 0.039). The proportion of patients receiving renal replacement therapy at the time of enrollment was higher in the treatment group (31.9%) when compared to the control group (16.3%). After adjustment for patient morbidity and baseline imbalances, no association of hemoperfusion with mortality was found (p = 0.19). Conclusions In this patient population with predominantly septic shock and multiple organ failure, hemoadsorption removed IL-6 but this did not lead to lower plasma IL-6-levels. We did not detect statistically significant differences in the secondary outcomes multiple organ dysfunction score, ventilation time and time course of oxygenation

Oxygenation effect of interventional lung assist in a lavage model of acute lung injury: a prospective experimental study

INTRODUCTION: The aim of the study was to test the hypothesis that a pumpless arteriovenous extracorporeal membrane oxygenator (interventional lung assist (ILA)) does not significantly improve oxygenation in a lavage model of acute lung injury. METHODS: The study was designed as a prospective experimental study. The experiments were performed on seven pigs (48–60 kg body weight). The pigs were anesthetized and mechanically ventilated. Both femoral arteries and one femoral vein were cannulated and connected with ILA. Acute lung injury was induced by repeated bronchoalveolar lavage until the arterial partial pressure of O(2 )was lower than 100 Torr for at least 30 minutes during ventilation with 100% O(2). RESULTS: ILA was applied with different blood flow rates through either one or both femoral arteries. Measurements were repeated at different degrees of pulmonary gas exchange impairment with the pulmonary venous admixture ranging from 35.0% to 70.6%. The mean (± standard deviation) blood flow through ILA was 15.5 (± 3.9)% and 21.7 (± 4.9)% of cardiac output with one and both arteries open, respectively. ILA significantly increased the arterial partial pressure of O(2 )from 64 (± 13) Torr to 71 (± 14) Torr and 74 (± 17) Torr with blood flow through one and both femoral arteries, respectively. O(2 )delivery through ILA increased with extracorporeal shunt flow (36 (± 14) ml O(2)/min versus 47 (± 17) ml O(2)/min) and reduced arterialization of the inlet blood. Pulmonary artery pressures were significantly reduced when ILA was in operation. CONCLUSION: Oxygenation is increased by ILA in severe lung injury. This effect is significant but small. The results indicate that the ILA use may not be justified if the improvement of oxygenation is the primary therapy goal

Resorbable screws versus pins for optimal transplant fixation (SPOT) in anterior cruciate ligament replacement with autologous hamstring grafts: rationale and design of a randomized, controlled, patient and investigator blinded trial [ISRCTN17384369]

BACKGROUND: Ruptures of the anterior cruciate ligament (ACL) are common injuries to the knee joint. Arthroscopic ACL replacement by autologous tendon grafts has established itself as a standard of care. Data from both experimental and observational studies suggest that surgical reconstruction does not fully restore knee stability. Persisting anterior laxity may lead to recurrent episodes of giving-way and cartilage damage. This might at least in part depend on the method of graft fixation in the bony tunnels. Whereas resorbable screws are easy to handle, pins may better preserve graft tension. The objective of this study is to determine whether pinning of ACL grafts reduces residual anterior laxity six months after surgery as compared to screw fixation. DESIGN/ METHODS: SPOT is a randomised, controlled, patient and investigator blinded trial conducted at a single academic institution. Eligible patients are scheduled to arthroscopic ACL repair with triple-stranded hamstring grafts, conducted by a single, experienced surgeon. Intraoperatively, subjects willing to engage in this study will be randomised to transplant tethering with either resorbable screws or resorbable pins. No other changes apply to locally established treatment protocols. Patients and clinical investigators will remain blinded to the assigned fixation method until the six-month follow-up examination. The primary outcome is the side-to-side (repaired to healthy knee) difference in anterior translation as measured by the KT-1000 arthrometer at a defined load (89 N) six months after surgery. A sample size of 54 patients will yield a power of 80% to detect a difference of 1.0 mm ± standard deviation 1.2 mm at a two-sided alpha of 5% with a t-test for independent samples. Secondary outcomes (generic and disease-specific measures of quality of life, magnetic resonance imaging morphology of transplants and devices) will be handled in an exploratory fashion. CONCLUSION: SPOT aims at showing a reduction in anterior knee laxity after fixing ACL grafts by pins compared to screws

CCL2 chemokine inhibition primes the tumor vasculature for improved nanomedicine delivery and efficacy

Blood vessel functionality is crucial for efficient tumor-targeted drug delivery. Heterogeneous distribution and perfusion of angiogenic blood vessels contribute to suboptimal accumulation of (nano-) therapeutics in tumors and metastases. To attenuate pathological angiogenesis, an L-RNA aptamer inhibiting the C–C motif chemokine ligand 2 (CCL2) was administered to mice bearing orthotopic 4T1 triple-negative breast cancer tumors. The effect of CCL2 inhibition on tumor blood vessel functionality and tumor-targeted drug delivery was evaluated via multimodal and multiscale optical imaging, employing fluorophore-labeled polymeric (10 nm) and liposomal (100 nm) nanocarriers. Anti-CCL2 treatment induced a dose-dependent anti-angiogenic effect, reflected by a decreased relative blood volume, increased blood vessel maturity and functionality, and reduced macrophage infiltration, accompanied by a shift in the polarization of tumor-associated macrophages (TAM) towards a less M2-like and more M1-like phenotype. In line with this, CCL2 inhibitor treatment improved the delivery of polymers and liposomes to tumors, and enhanced the antitumor efficacy of free and liposomal doxorubicin. Together, these findings demonstrate that blocking the CCL2-CCR2 axis modulates TAM infiltration and polarization, resulting in vascular normalization and improved tumor-targeted drug delivery

Downregulation of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) in human hepatocellular carcinoma and their prognostic significance

<p>Abstract</p> <p>Background</p> <p>Organic cation transporters (OCT) are responsible for the uptake and intracellular inactivation of a broad spectrum of endogenous substrates and detoxification of xenobiotics and chemotherapeutics. The transporters became pharmaceutically interesting, because OCTs are determinants of the cytotoxicity of platin derivates and the transport activity has been shown to correlate with the sensitivity of tumors towards tyrosine kinase inhibitors. No data exist about the relevance of OCTs in hepatocellular carcinoma (HCC).</p> <p>Methods</p> <p>OCT1 (<it>SLC22A1</it>) and OCT3 (<it>SLC22A3</it>) mRNA expression was measured in primary human HCC and corresponding non neoplastic tumor surrounding tissue (TST) by real time PCR (n = 53). Protein expression was determined by western blot analysis and immunofluorescence. Data were correlated with the clinicopathological parameters of HCCs.</p> <p>Results</p> <p>Real time PCR showed a downregulation of <it>SLC22A1 </it>and <it>SLC22A3 </it>in HCC compared to TST (p ≤ 0.001). A low <it>SLC22A1 </it>expression was associated with a worse patient survival (p < 0.05). Downregulation was significantly associated with advanced HCC stages, indicated by a higher number of T3 tumors (p = 0.025) with a larger tumor diameter (p = 0.035), a worse differentiation (p = 0.001) and higher AFP-levels (p = 0.019). In accordance, <it>SLC22A1 </it>was less frequently downregulated in tumors with lower stages who underwent transarterial chemoembolization (p < 0.001) and liver transplantation (p = 0.001). Tumors with a low <it>SLC22A1 </it>expression (< median) showed a higher <it>SLC22A3 </it>expression compared to HCC with high <it>SLC22A1 </it>expression (p < 0.001). However, there was no significant difference in tumor characteristics according to the level of the <it>SLC22A3 </it>expression.</p> <p>In the western blot analysis we found a different protein expression pattern in tumor samples with a more diffuse staining in the immunofluorescence suggesting that especially OCT1 is not functional in advanced HCC.</p> <p>Conclusion</p> <p>The downregulation of OCT1 is associated with tumor progression and a worse patient survival.</p

Sigh in patients with acute hypoxemic respiratory failure and acute respiratory distress syndrome: the PROTECTION pilot randomized clinical trial

Background: Sigh is a cyclic brief recruitment manoeuvre: previous physiological studies showed that its use could be an interesting addition to pressure support ventilation to improve lung elastance, decrease regional heterogeneity and increase release of surfactant. Research question: Is the clinical application of sigh during pressure support ventilation (PSV) feasible? Study design and methods: We conducted a multi-center non-inferiority randomized clinical trial on adult intubated patients with acute hypoxemic respiratory failure or acute respiratory distress syndrome undergoing PSV. Patients were randomized to the No Sigh group and treated by PSV alone, or to the Sigh group, treated by PSV plus sigh (increase of airway pressure to 30 cmH2Ofor 3 seconds once per minute) until day 28 or death or successful spontaneous breathing trial. The primary endpoint of the study was feasibility, assessed as non-inferiority (5% tolerance) in the proportion of patients failing assisted ventilation. Secondary outcomes included safety, physiological parameters in the first week from randomization, 28-day mortality and ventilator-free days. Results: Two-hundred fifty-eight patients (31% women; median age 65 [54-75] years) were enrolled. In the Sigh group, 23% of patients failed to remain on assisted ventilation vs. 30% in the No Sigh group (absolute difference -7%, 95%CI -18% to 4%; p=0.015 for non-inferiority). Adverse events occurred in 12% vs. 13% in Sigh vs. No Sigh (p=0.852). Oxygenation was improved while tidal volume, respiratory rate and corrected minute ventilation were lower over the first 7 days from randomization in Sigh vs. No Sigh. There was no significant difference in terms of mortality (16% vs. 21%, p=0.342) and ventilator-free days (22 [7-26] vs. 22 [3-25] days, p=0.300) for Sigh vs. No Sigh. Interpretation: Among hypoxemic intubated ICU patients, application of sigh was feasible and without increased risk