IRE1 and PERK signaling regulates inflammatory responses in a murine model of contact hypersensitivity.

BACKGROUND: Contact sensitizers may interfere with correct protein folding. Generation of un-/misfolded proteins can activate the IRE-1 or PERK signaling pathways initiating the unfolded protein response (UPR) and thereby determine inflammatory immune responses. We have analyzed the effect of sensitizers with different potencies on the induction of UPR activation/inhibition and the subsequent generation of a pro-inflammatory micromilieu in vitro as well as the effect of UPR modulation on the inflammatory response in the murine contact hypersensitivity (CHS) in vivo. METHODS: Semi-quantitative and quantitative PCR, fluorescence microscopy, ELISA, NF-κB activation and translocation assays, DC/keratinocyte co-culture assay, FACS, and in vivo CHS experiments were performed. RESULTS: Sensitizers and irritants activate IRE-1 and PERK in murine and human keratinocytes. Synergistic effects occur after combination of different weak sensitizers / addition of irritants. Moreover, tolerogenic dinitrothiocyanobenzene can be converted into a strong sensitizer by pre-activation of the UPR. Blocking UPR signaling results in decreased NF-κB activation and cytokine production in keratinocytes and in activation marker downregulation in a HaCaT/THP-1 co-culture. Interestingly, not only systemic but also topical application of UPR inhibitors abrogates CHS responses in vivo. CONCLUSION: These observations highlight an important role of the UPR in determination of the inflammatory response in vitro and in vivo further underlining the importance of tissue stress and damage responses in the development of ACD and provide mechanistically based concepts as a basis for the development of new therapeutic approaches to treat allergic contact dermatitis.

Health economic benefits through the use of diagnostic support systems and expert knowledge.

BACKGROUND: Rare diseases are difficult to diagnose. Due to their rarity, heterogeneity, and variability, rare diseases often result not only in extensive diagnostic tests and imaging studies, but also in unnecessary repetitions of examinations, which places a greater overall burden on the healthcare system. Diagnostic decision support systems (DDSS) optimized by rare disease experts and used early by primary care physicians and specialists are able to significantly shorten diagnostic processes. The objective of this study was to evaluate reductions in diagnostic costs incurred in rare disease cases brought about by rapid referral to an expert and diagnostic decision support systems. METHODS: Retrospectively, diagnostic costs from disease onset to diagnosis were analyzed in 78 patient cases from the outpatient clinic for rare inflammatory systemic diseases at Hannover Medical School. From the onset of the first symptoms, all diagnostic measures related to the disease were taken from the patient files and documented for each day. The basis for the health economic calculations was the Einheitlicher Bewertungsmaßstab (EBM) used in Germany for statutory health insurance, which assigns a fixed flat rate to the various medical services. For 76 cases we also calculated the cost savings that would have been achieved by the diagnosis support system Ada DX applied by an expert. RESULTS: The expert was able to achieve significant savings for patients with long courses of disease. On average, the expert needed only 27 % of the total costs incurred in the individual treatment odysseys to make the correct diagnosis. The expert also needed significantly less time and avoided unnecessary examination repetitions. If a DDSS had been applied early in the 76 cases studied, only 51-68 % of the total costs would have incurred and the diagnosis would have been made earlier. Earlier diagnosis would have significantly reduced costs. CONCLUSION: The study showed that significant savings in the diagnostic process of rare diseases can be achieved through rapid referral to an expert and the use of DDSS. Faster diagnosis not only achieves savings, but also enables the right therapy and thus an increase in the quality of life for patients.

Impact of wound duration on diabetic foot ulcer healing: evaluation of a new sucrose octasulfate wound dressing.

OBJECTIVE: A common and frequent complication of diabetes is diabetic foot ulcers (DFU), which can have high treatment costs and severe adverse events. This study aims to evaluate the effects of wound duration on wound healing and the impact on costs, including treatment with a new sucrose octasulfate dressing compared with a control dressing. METHOD: Based on the Explorer study (a two-armed randomised double-blind clinical trial), a cost-effectiveness analysis compared four different patient groups distinguished by their wound duration and additionally two DFU treatment options: a sucrose octasulfate dressing and a neutral dressing (as control). Clinical outcomes and total direct costs of wound dressings were evaluated over 20 weeks from the perspective of the Social Health Insurance in Germany. Simulation of long-term outcomes and costs were demonstrated by a five cycle Markov model. RESULTS: The results show total wound healing rates between 71% and 14.8%, and direct treatment costs for DFU in the range of €2482-3278 (sucrose octasulfate dressing) and €2768-3194 (control dressing). Patients with a wound duration of ≤2 months revealed the highest wound healing rates for both the sucrose octasulfate dressing and control dressing (71% and 41%, respectively) and had the lowest direct treatment costs of €2482 and €2768, respectively. The 100-week Markov model amplified the results. Patients with ≤2 months' wound duration achieved wound healing rates of 98% and 88%, respectively and costs of €3450 and €6054, respectively (CE=€3520, €6864). Sensitivity analysis revealed that the dressing changes per week were the most significant uncertainty factor. CONCLUSION: Based on the findings of this study, early treatment of DFU with a sucrose octasulfate dressing is recommended from a health economic view due to lower treatment costs, greater cost-effectiveness and higher wound healing rates.

[Faster diagnosis of rare diseases with artificial intelligence-A precept of ethics, economy and quality of life]. / Mit künstlicher Intelligenz schneller zur Diagnose seltener Erkrankungen ­ ein Gebot der Ethik, Ökonomie und Lebensqualität.

BACKGROUND: Approximately 300 million people worldwide suffer from a rare disease. An optimal treatment requires a successful diagnosis. This takes a particularly long time, especially for rare diseases. Digital diagnosis support systems could be important aids in accelerating a successful diagnosis in the future. OBJECTIVE: The current possibilities of digital diagnostic support systems in the diagnosis of rare diseases and questions that still need to be clarified are presented in relation to the parameters of ethics, economy and quality of life. MATERIAL AND METHODS: Current research results of the authors were compiled and discussed in the context of the current literature. A case study is used to illustrate the potential of digital diagnostic support systems. RESULTS: Digital diagnostic support systems and experts together can accelerate the successful diagnosis in patients with rare diseases. This could have a positive impact on patients' quality of life and lead to potential savings in direct and indirect costs in the healthcare system. CONCLUSION: Ensuring data security, legal certainty and functionality in the use of digital diagnostic support systems is of great importance in order to create trust among experts and patients. Continuous further development of the systems by means of artificial intelligence (AI) could also enable patients to accelerate diagnosis in the future.

Infrared Resonance Tuning of Nanoslit Antennas with Phase-Change Materials.

Phase-change materials (PCMs) have been established as prime candidates for nonvolatile resonance tuning of nanophotonic components based on a large optical contrast between their amorphous and crystalline states. Recently, the plasmonic PCM In3SbTe2 was introduced, which can be switched from an amorphous dielectric state to a crystalline metallic one over the entire infrared spectral range. While locally switching the PCM around metallic nanorod antennas has already been demonstrated, similar tuning of inverse antenna structures (nanoslits) has not yet been investigated. Here, we demonstrate optical resonance tuning of nanoslit antennas with dielectric and plasmonic PCMs. We compare two geometries with fundamentally different resonance tuning mechanisms: tuning the resonance of aluminum slit antennas by change of the refractive index (dielectric PCM Ge3Sb2Te6), and creating slit-like volumes of amorphous In3SbTe2 and modifying the slit geometry directly (plasmonic PCM In3SbTe2). While the tuning range with the plasmonic PCM is about 3.4 µm and only limited by fabrication, the resonances with the dielectric PCM feature a three times larger quality factor compared to resonances obtained with the plasmonic PCM.