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Renal cell carcinoma (RCC), is the most common kidney cancer of adults, originating in the lining of the proximal convoluted tubule. Prognosis is poor in patients with advanced or metastasized RCC. Drug resistance towards Standard of Care (SoC, incl. everolimus, sorafenib, or sunitinib) drugs develops frequently within months. Therefore, development of novel options to target acquired TKI resistance mechanisms in advanced and metastatic RCC is still an urgent medical need. Preclinical models with high translational relevance can promote the implementation of novel personalized therapies. To evaluate novel targeted therapies and their combinations in preclinical settings, patient-derived xenograft (PDX) models represent valuable tools. Responsible local ethics committees approved usage of patient tissue and all animal procedures. In this study, RCC tissue from 167 patients was collected and xenotransplanted in mice. Partially, a multi-region approach, xenografting tissue from different regions of one tumor, was used. PDX models were characterized by immunohistochemistry (Ki-67, CD31, Pax2 and Pax8 antibodies), gene expression, copy number variations and mutational analyses. To evaluate in vivo drug response of RCC PDX models, mice transplanted with PDX tumors were treated with bevacizumab (i.p.), with everolimus, sorafenib, or sunitinib (p.o.). Adopted clinical response criteria for solid tumors (RECIST) were applied to classify the anti-tumor activity of the tested compounds in RCC PDX models. Next generation sequencing (NGS, panel) and transcriptome data were used to compare primary tumors and metastases. A comprehensive panel of subcutaneous RCC PDX models with well-conserved molecular and pathological features over multiple passages was established. The overall take for the RCC PDX in this study was 21%. Tumor growth characteristics were heterogeneous throughout the different models but were stable during in vivo passaging. Drug screening towards four SoC drugs, targeting the VEGF and PI3K/mTOR pathway, revealed individual and heterogeneous response profiles in the PDX, resembling the clinical situation. Intra-tumor heterogeneity can be assessed via PDX models from multi-tumor regions from one patient in our platform. Development of corresponding in vitro cell culture models from the PDX enables advanced high throughput drug screening in a personalized context. Analyzing novel targeted molecules is possible due to the pre-established molecular characterization of the PDX at the genomic and expression level. In conclusion, we established a new and molecularly characterized panel of RCC PDX models with high relevance for translational preclinical research. Citation Format: Dennis Kobelt, Dennis Gürgen, Michael Becker, Mathias Dahlmann, Susanne Flechsig, Elke Schaeffeler, Florian A. Büttner, Christian Schmees, Regina Bohnert, Jens Bedke, Matthias Schwab, Johann J. Wendler, Martin Schostak, Burkhard Jandrig, Wolfgang Walther, Jens Hoffmann. An in vivo platform of pre-characterized renal cell carcinoma (RCC) patient-derived xenograft models allows the preclinical evaluation of patient-tailored intervention strategies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 44.

Zusammenfassung Für die Etablierung von Carbonbeton in der industriellen Praxis sind Prüfverfahren zur reproduzierbaren Bestimmung der mechanischen Kennwerte textiler Bewehrungsstrukturen essentiell, insbesondere der Zugfestigkeit. Zu diesem Zweck wurde im Rahmen des Forschungsvorhabens C³-V1.2 ein neuartiges Prüfverfahren entwickelt und qualifiziert. Mit diesem Verfahren können Carbonfaserstränge aus flexiblen, steifen und bedingt biegbaren Bewehrungsgelegen hinsichtlich ihrer Zugfestigkeit mit geringem Präparationsaufwand und reproduzierbar charakterisiert werden.

Modern health care demands knowledge, swift action, and critical thinking from nurses. New and experienced registered nurses are better able to provide excellent care when they are supported by documents that drive consistent nursing action. The process of developing these documents is critically important. Technical writers can improve the adoption of carefully designed forms that help newly licensed registered nurses develop a foundation in critical thinking as they move through orientation.

Rheumatoid arthritis (RA) is one of the most frequent chronic inflammatory rheumatic diseases and when untreated leads to chronic tissue destruction and increased mortality. Due to innovative systemic treatment strategies established over the last 20-25 years, the prognosis has considerably improved in terms of disease and socioeconomic burdens, symptoms, long-term prognosis, ability to work and mortality; however, as a rule a prerequisite is long-term and continuous treatment. A medicinal cure of RA is still not in view. For many patients this means the long-term use of very expensive medications. In addition to hemato-oncology, rheumatology has become the second most expensive discipline in Germany in terms of cost per patient. Convincing data from many studies imply that an early start of treatment within the first few weeks after clinical onset of symptoms improves the prognosis, reduces the necessity for expensive drugs and thereby considerably decreases medical costs. This results in the requirement that every patient with symptoms of arthritis must be seen by a rheumatologist within the first 6 weeks following initial manifestation of the disease. Such an improvement in treatment can only be achieved in Germany if the numbers of rheumatologists and trained healthcare professionals in practices such as clinics are considerably increased. This is not only in the interests of patients but also in the interests of the health insurance companies because the investment in the healthcare infrastructure with internistic rheumatologists will result in substantial economic benefits for the cost bearer. It must be the common task of all players in healthcare policy, cost bearers and internistic rheumatologists to provide optimal conditions in medical as well as economical terms.

Systemic disease demands systemic thinkers. In this mission statement we define rheumatology, describe the role of the German Society of Rheumatology and the rheumatologist's spirit to their discipline. Rheumatologists are dedicated to improving the quality of life of their acute, chronic, and rehabilitative patients on the basis of up to date evidence and strong physician-patient relations. We think, act and interact systemically, scientifically, consistently, transparently, reliably, inclusively, innovatively and enthusiastically.

Short-wave infrared (SWIR) HgCdTe electron avalanche photodiodes (eAPDs) with different doping profiles have been characterized for use in SWIR gated viewing systems. Gated viewing offers enhanced image contrast in scenes with clutter from the foreground or background. HgCdTe-based eAPDs show exponential gain–voltage characteristics and low excess noise and are, therefore, well suited for active imaging applications. The gain achievable at a fixed reverse voltage varies with the bandgap of the Hg1−xCdxTe detector material. We analyze current–voltage and gain–voltage plots measured on SWIR Hg1−xCdxTe eAPDs with x = 0.45, corresponding to a cutoff wavelength of 2.55 μm at 150 K. The cutoff has been chosen as a trade-off between achievable APD gain and operating temperature for SWIR gated-viewing systems with target distances of about 1000 m. Focal plane arrays with a readout-integrated circuit featuring a fast internal clock have been built and their performance with respect to gated viewing applications has been evaluated on a laboratory demonstrator for short distances. Future plans for a field demonstrator for distances up to 1000 m are described briefly at the end.

AIM has developed IR modules including the FPAs for a wide range of applications. For SWIR applications FPAs based on liquid phase epitaxy (LPE) are available. These devices having different array sizes and are usable in a wide range of hyperspectral imaging applications. Silicon readout circuits provide various integration and readout modes including specific functions for spectral imaging applications. An important advantage of MCT based detectors is the tunable band gap. The spectral sensitivity of MCT detectors can be engineered to cover the extended SWIR spectral region up to 2.5μm without compromising in performance. AIM developed and released the technology option to extend the spectral sensitivity of its SWIR modules also into the VIS. This has been successfully demonstrated for different FPA designs. A short overview is given in tis paper. AIM has qualified this VIS technology option based on a 1024x256 FPA capable for extended hyperspectral applications. Within this paper the test approach and the results will be presented.

Rheumatoid arthritis (RA) is one of the most frequent chronic inflammatory rheumatic diseases and when untreated leads to chronic tissue destruction and increased mortality. Due to innovative systemic treatment strategies established over the last 20-25 years, the prognosis has considerably improved in terms of disease and socioeconomic burdens, symptoms, long-term prognosis, ability to work and mortality; however, as a rule a prerequisite is long-term and continuous treatment. A medicinal cure of RA is still not in view. For many patients this means the long-term use of very expensive medications. In addition to hemato-oncology, rheumatology has become the second most expensive discipline in Germany in terms of cost per patient. Convincing data from many studies imply that an early start of treatment within the first few weeks after clinical onset of symptoms improves the prognosis, reduces the necessity for expensive drugs and thereby considerably decreases medical costs. This results in the requirement that every patient with symptoms of arthritis must be seen by a rheumatologist within the first 6 weeks following initial manifestation of the disease. Such an improvement in treatment can only be achieved in Germany if the numbers of rheumatologists and trained healthcare professionals in practices such as clinics are considerably increased. This is not only in the interests of patients but also in the interests of the health insurance companies because the investment in the healthcare infrastructure with internistic rheumatologists will result in substantial economic benefits for the cost bearer. It must be the common task of all players in healthcare policy, cost bearers and internistic rheumatologists to provide optimal conditions in medical as well as economical terms.

Microbial transglutaminase (MTG, EC 2.3.2.13) of Streptomyces mobaraensis is widely used in industry for its ability to synthesize isopeptide bonds between the proteinogenic side chains of glutamine and lysine. The activated wild-type enzyme irreversibly denatures at 60 °C with a pseudo-first-order kinetics and a half-life time (t1/2) of 2 min. To increase the thermoresistance of MTG for higher temperature applications, we generated 31 variants based on previous results obtained by random mutagenesis, DNA shuffling and saturation mutagenesis. The best variant TG16 with a specific combination of five of seven substitutions (S2P, S23Y, S24 N, H289Y, K294L) shows a 19-fold increased half-life at 60 °C (t1/2 = 38 min). As measured by differential scanning fluorimetry, the transition point of thermal unfolding was increased by 7.9 °C. Also for the thermoresistant variants, it was shown that inactivation process follows a pseudo-first-order reaction which is accompanied by irreversible aggregation and intramolecular self-crosslinking of the enzyme. Although the mutations are mostly located on the surface of the enzyme, kinetic constants determined with the standard substrate CBZ-Gln-Gly-OH revealed a decrease in KM from 8.6 mM (± 0.1) to 3.5 mM (± 0.1) for the recombinant wild-type MTG and TG16, respectively. The improved performance of TG16 at higher temperatures is exemplary demonstrated with the crosslinking of the substrate protein β-casein at 60 °C. Using molecular dynamics simulations, it was shown that the increased thermoresistance is caused by a higher backbone rigidity as well as increased hydrophobic interactions and newly formed hydrogen bridges.

We present our latest results on n-on-p as well as on p-on-n low dark current planar mercury cadmium telluride (MCT) photodiode technology long wavelength infrared (LWIR) and very long wavelength infrared (VLWIR) two-dimensional focal plane arrays (FPAs) with quantum efficiency (QE) cut-off wavelength >11 μm at 80 K and a 512 × 640 pixel format FPA at 20 μm pitch stitched from two 512 × 320 pixel photodiode arrays. Significantly reduced dark currents as compared with Tennant’s “Rule 07” are demonstrated in both polarities while retaining good detection efficiency ≥60% for operating temperatures between 30 K and 100 K. This allows for the same dark current performance at 20 K higher operating temperature than with previous AIM INFRAROT-MODULE GmbH (AIM) technology. For p-on-n LWIR MCT FPAs, broadband photoresponse nonuniformity of only about 1.2% is achieved at 55 K with low defective pixel numbers. For an n-on-p VLWIR MCT FPA with 13.6 μm cut-off at 55 K, excellent photoresponse nonuniformity of about 3.1% is achieved at moderate defective pixel numbers. This advancement in detector technology paves the way for outstanding signal-to-noise ratio performance infrared detection, enabling cutting-edge next-generation LWIR/VLWIR detectors for space instruments and devices with higher operating temperature and low size, weight, and power for field applications.

To assess safety, effectiveness and onset of effect of rituximab (RTX) in routine clinical treatment of severe, active rheumatoid arthritis (RA). Prospective, multi-centre, non-interventional study in rheumatological outpatient clinics or private practices in Germany. RTX-naive adult patients were to receive RTX according to marketing authorisation and at their physician’s discretion. Also according to their physician’s discretion, patients could receive a second cycle of RTX (re-treatment = treatment continuation). Major outcome was the change in Disease Activity Score based on 28-joints count and erythrocyte sedimentation rate (DAS28-ESR) over 24 weeks and during 6 months of re-treatment. Overall, 1653 patients received at least one cycle RTX; 99.2% of these had received disease-modifying antirheumatic drugs (DMARD) pre-treatment and 75.5% anti-tumor necrosis factor(TNF)‑α pre-treatment. After a mean interval of 8.0 months, 820 patients received RTX re-treatment. Mean DAS28-ESR decreased from 5.3 at baseline to 3.8 after 24 weeks (−1.5 [95% confidence interval, CI: −1.6; −1.4]), and from 4.1 at start of cycle 2 to 3.5 at study end (change from baseline: −1.8 [95% CI: −2.0; −1.7]). Improvements in DAS28-ESR and Health Assessment Questionnaire (HAQ) score occurred mainly during the first 12 weeks of RTX treatment, with further DAS28-ESR improvement until week 24 or month 6 of re-treatment. Improvements in DAS28-ESR and EULAR responses were more pronounced in seropositive patients. RF was a predictor of DAS28-ESR change to study end. Safety analysis showed the established profile of RTX. RTX was safe and effective in a real-life setting with rapid and sustained improvement in RA signs and symptoms.

The incidence of renal cell carcinoma has been rising for years. At the same time there is an increasing prevalence of chronic renal failure with subsequent higher morbidity and shorter life expectancy in those affected. In the last decades the gold standard has thus shifted from radical to partial nephrectomy or tumor enucleation. A treatment alternative can be advantageous for selected patients with high morbidity and an increased risk of complications in anesthesia or surgery. Active surveillance represents a controlled delay in the initiation of treatment with a curative intention. Percutaneous radiofrequency ablation and laparoscopic cryoablation are currently the most commonly used treatment alternatives. Newer ablation procedures, such as high-intensity focused ultrasound, irreversible electroporation, microwave ablation, stereotactic ablative radiotherapy and high-dose brachytherapy have a high potential in some cases but are still considered experimental for the treatment.

In the recent years AIM has developed IR modules for imaging applications sensitive in the extended SWIR (eSWIR) spectral range with a cut-off wavelength of 2.5μm. The modules are based on AIM’s state-of-the-art MCT FPA technology with a dedicated ROIC integrated in a low size, weight and power (SWaP) Dewar/Cooler configuration. The different modules are either designated to combine emissive and reflective imaging in one sensor by already detecting thermal radiation in the eSWIR band or to make use of laser illumination including gating capability. Further integration including a lens, image processing electronics and power supply was done resulting in sights for targeting and reconnaissance applications. For targeting under low-light conditions a low SWaP MCT eSWIR module in a 640x512 format with 10μm pitch was developed. The module was integrated to a compact clip-on weapon sight for small arms providing medium range performance up to 1000m. For reconnaissance applications a MCT based SWIR 2D APD array in a 640x512 15μm pitch format was developed providing gated viewing capability. The device was optimized to provide a higher gain for improvement of the signal to noise ratio (SNR). The module was integrated in a camera demonstrator including a 1.5μm laser illuminator for field trials to demonstrate long range identification. The paper will present the latest performance results including field trials of MCT based eSWIR modules and sights for imaging applications.

To push HOT-performance, AIMs existing n-on-p technology has been improved by introducing Gold as an acceptor and reducing its concentration to the lower 10 15 /cm 3 range as well as by optimizing the passivation process. This results in a substantial reduction in dark current density, a prerequisite for HOT operation. Recent dark current data are compared to ones previously obtained as well as to Tennant`s Rule07 [1], a generally accepted bench mark in this context. Furthermore, we present electro-optical parameters obtained in the temperature range from 120 K to 170 K on resulting FPAs with 640x512 pixels, a pitch of 15 μm and a typical (80 K) cutoff wavelength of 5.1 μm.

The target of focal therapy (FT) in prostate cancer (PC) is partial treatment of the prostate aiming at preserving surrounding anatomical structures. The intention is to minimize typical side effects of radical treatment options combined with local tumor control. Numerous established and new technologies are used. Results of published studies showed a good safety profile, few side effects and good preservation of functional results. Oncologic long-term data are lacking so far. Photodynamic therapy (PDT) is the only technology that has been studied in a published prospective randomized trial. The FT is challenged by the multifocality of PC; therefore, the quality of prostate biopsy, histopathological assessment as well as imaging are of paramount importance. Multiparametric magnetic resonance imaging (MRI) has gained increasing importance. The FT is experimental and should only be offered within clinical trials.

A more than 100-year period, where the prostate was only seen and treated as a whole is coming to an end right now. Finally, high resolution imaging is providing deep insights and detailed information so that new therapeutic procedures can aim for the smallest targets within the gland. The long-standing wish of patients for individual noninvasive diagnostics and treatment of prostate diseases can now be fulfilled by providing new tailored concepts; however, in order to transfer the enormous amount of new information into the specific clinical patient situation, a closely knit interdisciplinary approach is required. In this setting, the traditional outpatient consultation service is overstretched in every aspect. It is now the time for new innovative constructs. The current one-sided service concept for urologists, radiologists and radiation therapists is therefore behind the times and the development of a "prostate management team" with equally cooperating partners from each specialty is the task for the future.

Objectives SUSTAIN is a prospective, multi-center non-interventional study in Germany to observe long term efficacy and safety, quality of life and further patient reported outcomes in patients with active psoriatic arthritis under treatment with Ustekinumab in routine clinical care. Methods In this study treatment with Ustekinumab is according to the label (Stelara®). It is planned to observe 400 patients at 75 centers for 160 weeks with documentation intervals at week 0 and 4 and then every 12 weeks. Besides demographic data, the following data will be documented: Amount of swollen and tender joints, tender entheses, skin symptoms (BSA and PASI), patient reported outcome concerning disease activity and pain, Health Assessment Questionnaire (HAQ), quality of life (SF-12), sleep quality (VAS), satisfaction with therapy of patient and physician, safety (adverse events [AE]/serious adverse events [SAE]), pharmacoeconomic aspects, number of patients with “Minimal Disease Activity” (MDA), number of patients with MDA at week 28 und 52. Results Overall, there have been 189 patients (56% women) at 59 centers documented after 11 months. At week 4 154 patients and at week 16 112 patients. At baseline, the patients had a mean age of 56 years (29–85), body weight 87 kg (50–147), BMI 30 (19–47), showed arthritis at small (68.8%) and/or big (51.3%) joints, skeletal involvement (19%), enthesitis (13.2%). The number of tender joints improved from a mean of 8,6 (CI 95% 7.1/10.2) to 4.7 (3.1/6.3) at week 16, number of swollen joints from 3,4 (2,6/4,2) to 1,4 (0.9/1.9). The patient reported global disease activity (0–100) decreased from 55.1 to 38.6 at week 16. Further improvements were documented for enthesitis, PSA, BSA, PASI, and pain. Efficacy of the therapy with Ustekinumab after 16 weeks was assessed as “very good” by 32.3% and as “good” by 44.8% of the treating physicians and by 34% and 40.2%, respectively, of the patients. In total, 60 adverse events were reported, of which four were serious. All in all safety of therapy with Ustekinumab after 16 weeks was assessed as “very good” by 51% and as “good” by 43.8% of the treating physicians, and by 55% and 37%, respectively, of the patients. Conclusions The non-interventional study SUSTAIN showed relevant improvements with elevated therapy satisfaction and good safety in patients with active psoriatic arthritis after 16 weeks under real world condition. Disclosure of Interest J. Wendler Consultant for: Janssen-Cilag GmbH, Speakers bureau: Janssen-Cilag GmbH, I. Schwarze: None declared, H. Schwenke: None declared, J. Behrens Employee of: Janssen-Cilag GmbH, T. Gruppe Employee of: Janssen-Cilag GmbH, F. Behrens Consultant for: Janssen-Cilag GmbH, Speakers bureau: Janssen-Cilag GmbH

Size, weight and power (SWaP) reduction is highly desired by applications such as sights for the dismounted soldier or small gimbals for UAVs. But why have high performance and small size of IR systems inevitably exclude each other? Namely, recent development progress in the fields of miniature cryocoolers, short dewars and high operating temperature (HOT) FPAs combined with pitch size reduction opens the door for very compact MWIR-modules while keeping high electro-optical performance. Now, AIM has realized first prototypes of an ultra-compact high-performance MWIR engine in a total volume of only 18cl (60mm length x 60mm height x 50mm width). Impressive SWaP characteristics are completed by a total weight below 400g and a power consumption < 4W in basic imaging mode. The engine consists of a XGA-format (1024x768) MCT detector array with 10μm pitch and a low power consuming ROIC. It is cooled down to a typical operating temperature of ~160K by the miniature linear cryocooler SX020. The dewar uses a short coldfinger and is designed to reduce the heat load as much as possible. The cooler drive electronics is implemented in the CCE layout in order to reduce the required space of the printed boards and to save power. Uncorrected 14bit video data is provided via Camera Link. Optionally, a small image processing board can be stacked on top of the CCE to gain access to basic functions such as BPR, 2- point NUC and dynamic reduction. This paper will present the design, functionalities and performance data of the ultra-compact MCT MWIR engine operated at HOT.

For SWIR imaging applications, based on AIM’s state-of-the-art MCT IR technology specific detector designs for either low light level imaging or laser illuminated active imaging are under development. For imaging under low-light conditions a low-noise 640x512 15μm pitch ROIC with CTIA input stages and correlated double sampling was designed. The ROIC provides rolling shutter and snapshot integration. To reduce size, weight, power and cost (SWaP-C) a 640x512 format detector in a 10μm pitch is been realized. While LPE grown MCT FPAs with extended 2.5μm cut-off have been fabricated and integrated also MBE grown MCT on GaAs is considered for future production. The module makes use of the extended SWIR (eSWIR) spectral cut-off up to 2.5μm to allow combination of emissive and reflective imaging by already detecting thermal radiation in the eSWIR band. A demonstrator imager was built to allow field testing of this concept. A resulting product will be a small, compact clip-on weapon sight. For active imaging a detector module was designed providing gating capability. SWIR MCT avalanche photodiodes have been implemented and characterized on FPA level in a 640x512 15μm pitch format. The specific ROIC provides also the necessary functions for range gate control and triggering by the laser illumination. The FPAs are integrated in a compact dewar cooler configuration using AIM’s split linear cooler. A command and control electronics (CCE) provides supply voltages, biasing, clocks, control and video digitization for easy system interfacing. First lab and field tests of a gated viewing demonstrator have been carried out and the module has been further improved.

Few tools exist to visualize and manipulate neurons that are targets of neuromodulators. We present iTango, a light- and ligand-gated gene expression system based on a light-inducible split tobacco etch virus protease. Cells expressing the iTango system exhibit increased expression of a marker gene in the presence of dopamine and blue-light exposure, both in vitro and in vivo. We demonstrated the iTango system in a behaviorally relevant context, by inducing expression of optogenetic tools in neurons under dopaminergic control during a behavior of interest. We thereby gained optogenetic control of these behaviorally relevant neurons. We applied the iTango system to decipher the roles of two classes of dopaminergic neurons in the mouse nucleus accumbens in a sensitized locomotor response to cocaine. Thus, the iTango platform allows for control of neuromodulatory circuits in a genetically and functionally defined manner with spatial and temporal precision.

Recent findings suggest that autoimmune disorders predispose to a diminished capacity to taste and smell. This has been shown for patients with systemic lupus erythematosus as well as for patients with rheumatoid arthritis (RA). Granulomatosis with polyangiitis (GPA), with its particular manifestations in the upper respiratory tract, may therefore have an even higher impact on these senses. The aims of this study were to evaluate the gustatory and olfactory function in patients with GPA, to compare them to sex- and age-matched healthy controls, and to correlate these findings with their GPA disease severity.Patients with established GPA were analysed by standardized assessments for gustatory and olfactory functions and examined for disease activity, stage of disease, and treatment.Forty-four GPA patients were tested for their chemosensory functions. Compared to age- and sex-matched healthy controls, GPA patients showed significantly decreased olfactory scores along with diminished scores for their gustatory functions. The diminished sense of smell in GPA patients correlated significantly with elevated C-reactive protein (CRP) values whereas the gustatory impairment correlated with the duration and extent of the disease.Our results indicate that olfactory and gustatory functions are significantly decreased in GPA. As the olfactory function of these patients was comparable to patients with RA, chemosensory impairment may not simply be a consequence of the involvement of the upper respiratory tract, but rather a common complication of systemic autoimmune diseases.

Significant improvements of HgCdTe (MCT) detectors for the midwave infrared (MWIR) region with cutoff wavelength of about 5.2 μm at 77 K have been achieved. Optimizing the CdTe passivation proved to be a decisive step towards higher operating temperatures. The optimization was done by refining the interdiffusion process of the CdTe passivation layer with the liquid phase epitaxy-grown layer. The dark current density was reduced almost to the level of Rule 07, a common infrared detector benchmark. Additionally, improving the passivation process also decreased tunneling. These advancements also showed up in the focal-plane array (FPA) performance. A considerable reduction of the noise-equivalent temperature difference at temperatures above 130 K was attained. Based on these preliminary results, an operating temperature for these devices of more than 160 K is expected. Additionally, infrared (IR) pictures taken with a MWIR MCT-based FPA processed with the previous, slightly improved technology are presented. It is shown that good picture quality is attained at operating temperature of 140 K while retaining operability of 99.61%.

Due to continuous improvement of traditional liquid-phase epitaxy n-on-p technology, excellent mid-wavelength infrared HgCdTe (MCT) detectors with 1280 × 1024 pixels and 15 μm pitch size have been produced at AIM. At an operating temperature (TOP) of 80 K, a noise equivalent temperature difference (NETD) of 17.8 mK and an operability of 99.96% have been obtained. At TOP = 130 K, the operability remains high at 99.58%. On the basis of these results, the sensitivity of this detector design has been extended into the long-wavelength infrared (LWIR) region, obtaining a detector with an NETD of 30.4 mK and an operability of 99.81% at TOP = 80 K. In parallel, the growing maturity of molecular-beam epitaxy (MBE) growth of MCT on GaAs substrates has led to an improvement of the performance of the MWIR 640 × 512, 15-μm-pitch detector from an operability of 99.30% in 2011 to 99.83% recently.

Over-stimulation of G-protein coupled receptors (GPCRs) such as α1-adrenergic, muscarinic, endothelin, and AT1 receptors is considered to drive benign prostatic hyperplasia (BHP) which is often associated with lower urinary tract syndrome (LUTS). However, in addition to physiologic GPCR ligands, there is a new class of autoantibodies called functional autoantibodies that target the same GPCRs (GPCR-AABs) for over-stimulation, thus, presenting pathogenic potency. We hypothesize that patients with BPH/LUTS could carry GPCR-AABs representing potential targets for treatment.GPCR-AABs were identified, quantified, and characterized in the serum from 20 patients (aged 55-82 years, median 71 years) with BPH using the bioassay of spontaneously beating cultured neonatal rat cardiomyocytes.A sum of 60% of the patients were positive for agonistic autoantibodies directed against the endothelin A receptor (ETA-AABs). ETA-AABs were associated with the IgG 1 subclass, targeted an epitope located on the second extracellular receptor loop and their agonistic activity could be neutralized by the aptamer BC007.Agonistic ETA-AABs could-via uncontrolled over-boarding endothelin A receptor stimulation-contribute to the pathogenesis of BPH/LUTS. The in vitro demonstrated ETA-AAB neutralization by the aptamer BC007 could open the door for a new treatment strategy in patients with BPH/LUTS. Prostate 77:458-465, 2017. © 2016 Wiley Periodicals, Inc.

AIM has developed SWIR modules including FPAs based on liquid phase epitaxy (LPE) grown MCT usable in a wide range of hyperspectral imaging applications. Silicon read-out integrated circuits (ROIC) provide various integration and readout modes including specific functions for spectral imaging applications. An important advantage of MCT based detectors is the tunable band gap. The spectral sensitivity of MCT detectors can be engineered to cover the extended SWIR spectral region up to 2.5μm without compromising in performance. AIM developed the technology to extend the spectral sensitivity of its SWIR modules also into the VIS. This has been successfully demonstrated for 384x288 and 1024x256 FPAs with 24μm pitch. Results are presented in this paper. The FPAs are integrated into compact dewar cooler configurations using different types of coolers, like rotary coolers, AIM’s long life split linear cooler MCC030 or extreme long life SF100 Pulse Tube cooler. The SWIR modules include command and control electronics (CCE) which allow easy interfacing using a digital standard interface. The development status and performance results of AIM’s latest MCT SWIR modules suitable for hyperspectral systems and applications will be presented.

Based on AIM’s state-of-the-art MCT IR technology, detector modules for the SWIR spectral range have been developed, fabricated and characterized. While LPE grown MCT FPAs with extended 2.5μm cut-off have been fabricated and integrated also MBE grown MCT on GaAs is considered for future production. Two imaging applications have been in focus operating either in passive mode by making use of e.g. the night glow, or in active mode by laser illumination for gated viewing. Dedicated readout integrated circuits (ROIC), realized in 0.18μm Si-CMOS technology providing the required functionality for passive imaging and gated imaging, have been designed and implemented. For both designs a 640x512 15μm pitch format was chosen. The FPAs are integrated in compact dewar cooler configurations using AIM’s split linear coolers. A command and control electronics (CCE) provides supply voltages, biasing, clocks, control and video digitization for easy system interfacing. For imaging under low-light conditions a low-noise 640x512 15μm pitch ROIC with CTIA input stages and correlated double sampling was designed. The ROIC provides rolling shutter and snapshot integration. To reduce size, weight, power and cost (SWaP-C) a 640x512 format detector in a 10μm pitch is under development. The module makes use of the extended SWIR spectral cut-off up to 2.5μm. To be used for active gated-viewing operation SWIR MCT avalanche photodiodes have been implemented and characterized on FPA level in a 640x512 15μm pitch format. The specific ROIC provides also the necessary functions for range gate control and triggering by the laser illumination. First lab and field tests of a gated viewing demonstrator have been carried out. The paper will present the development status and performance results of AIM’s MCT based SWIR Modules for imaging applications.

It is only some years ago, since VGA format detectors in 15μm pitch, manufactured with AIM’s MCT n-on-p LPE standard technology, have been introduced to replace TV/4 format detector arrays as a system upgrade. In recent years a rapid increase in the demand for higher resolution, while preserving high thermal resolution, compactness and low power budget is observed. To satisfy these needs AIM has realized first prototypes of MWIR XGA format (1024x768) detector arrays in 10μm pitch. They fit in the same compact dewar as 640x512, 15μm pitch detector arrays. Therefore, they are best suited for system upgrade purposes to benefit from higher spatial resolution and keep cost on system level low. By combining pitch size reduction with recent development progress in the fields of miniature cryocoolers, short dewars and high operating temperatures the way ahead to ultra-compact high performance MWIR-modules is prepared. For cost reduction MBE grown MCT on commercially available GaAs substrates is introduced at AIM. Recently, 640x512, 15μm pitch FPAs, grown with MBE have successfully passed long-term high temperature storage tests as a crucial step towards serial production readiness level for use in future products. Pitch size reduction is not limited to arrays sensitive in the MWIR, but is of great interest for high performance LWIR or 3rd Gen solutions. Some applications such as rotorcraft pilotage require superior spatial resolution in a compact design to master severe weather conditions or degraded visual environment such as brown-out. For these applications AIM is developing both LWIR as well as dual band detector arrays in HD-format (1280x720) with 12μm pitch. This paper will present latest results in the development of detector arrays with small pitch sizes of 10μm and 12μm at AIM, together with their usage to realize compact cooled IR-modules.

The rising incidence of renal cell carcinoma, its more frequent early detection (stage T1a) and the increasing prevalence of chronic renal failure with higher morbidity and shorter life expectancy underscore the need for multimodal focal nephron-sparing therapy.During the past decade, the gold standard shifted from radical to partial nephrectomy. Depending on the surgeon's experience, the patient's constitution and the tumor's location, the intervention can be performed laparoscopically with the corresponding advantages of lower invasiveness. A treatment alternative can be advantageous for selected patients with high morbidity and/or an increased risk of complications associated with anesthesia or surgery. Corresponding risk stratification necessitates previous confirmation of the small renal mass (cT1a) by histological examination of biopsy samples. Active surveillance represents a controlled delay in the initiation of treatment.Percutaneous radiofrequency ablation (RFA) and laparoscopic cryoablation are currently the most common treatment alternatives, although there are limitations particularly for renal tumors located centrally near the hilum. More recent ablation procedures such as high intensity focused ultrasound (HIFU), irreversible electroporation, microwave ablation, percutaneous stereotactic ablative radiotherapy and high-dose brachytherapy have high potential in some cases but are currently regarded as experimental for the treatment of renal cell carcinoma.

Cells of the adaptive immune system are relevant for the anti-tumor immune response; therefore, the basal therapy with disease-modifying antirheumatic drugs (DMARD) in rheumatoid arthritis patients with a history of gastrointestinal cancer must be carefully considered.This article presents the evidence regarding colorectal cancer (CRC) and rheumatoid arthritis.The article is based on a PubMed search as well as a search in congress abstracts of the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). Current recommendations regarding screening and follow-up of CRC are summarized for clinically active rheumatologists. The current status of therapy and future therapeutic options are presented. The lower incidence of CRC in rheumatoid arthritis (RA) patients and the incidence under treatment with various DMARDs are described. The treatment options for RA patients in different tumor situations, e.g. during cytostatic therapy, palliative and curative situations are discussed, as well as the available evidence. In spite of the unsatisfactory level of evidence, conclusions and practical considerations for use by rheumatologists in clinical practice are discussed.

Durch die fast flachendeckende Anwendung bildgebender Diagnostik wie Ultraschall, Magnetresonanz- oder Computertomographie wird eine zunehmende Anzahl von Nierentumoren in einem fruhen, lokal begrenzten, oft symptomlosen Stadium diagnostiziert. Aus bisherigen Beobachtungsstudien weis man, dass diese kleinen, inzidenten Nierentumoren einerseits zwar in bis zu 87 % der Falle maligne sind, andererseits jedoch meist nur sehr langsam wachsen und sehr selten metastasieren, weswegen auch diese Tumoren zunehmend nierenerhaltend operiert werden. Als Alternative stehen die folgenden bildgestutzten, lokalablativen Verfahren zur Verfugung: Radiofrequenzablation, Kryoablation, bildgefuhrte interstitielle Hochdosisratenbrachytherapie sowie die Mikrowellenablation, die Laserablation und die Ablation durch hochintensiven, fokussierten Ultraschall. Alle Techniken sind entweder minimalinvasiv perkutan oder laparoskopisch anwendbar und weisen niedrigere Komplikationsraten als die Nierenteilresektion auf.

Purpose To establish consensus on follow-up (FU) after focal therapy (FT) in renal masses. To formulate recommendations to aid in clinical practice and research. Methods Key topics and questions for consensus were identified from a systematic literature research. A Web-based questionnaire was distributed among participants selected based on their contribution to the literature and/or known expertise. Three rounds according to the Delphi method were performed online. Final discussion was conducted during the “8th International Symposium on Focal Therapy and Imaging in Prostate and Kidney Cancer” among an international multidisciplinary expert panel. Results Sixty-two participants completed all three rounds of the online questionnaire. The panel recommended a minimum follow-up of 5 years, preferably extended to 10 years. The first FU was recommended at 3 months, with at least two imaging studies in the first year. Imaging was recommended biannually during the second year and annually thereafter. The panel recommended FU by means of CT scan with slice thickness ≤3 mm (at least three phases with excretory phase if suspicion of collecting system involvement) or mpMRI. Annual checkup for pulmonary metastasis by CT thorax was advised. Outside study protocols, biopsy during follow-up should only be performed in case of suspicion of residual/persistent disease or radiological recurrence. Conclusions The consensus led to clear FU recommendations after FT of renal masses supported by a multidisciplinary expert panel. In spite of the low level of evidence, these recommendations can guide clinicians and create uniformity in the follow-up practice and for clinical research purposes. Electronic supplementary material The online version of this article (doi:10.1007/s00345-016-1828-0) contains supplementary material, which is available to authorized users.

Sind die Treat to Target (T2T)-evidenzbasierten Empfehlungen der internationalen Treat to Target (T2T)-Initiative im ambulanten Versorgungsalltag in Deutschland umsetzbar? Mit einzelnen Krankenkassen wurden regionale Selektivvertrage abgeschlossen, die u. a. strukturiertes Assessment, zielorientierte Basistherapie und „tight control“ enthalten. Eine bundesweit flachendeckende Umsetzbarkeit scheint jedoch in weiter Ferne: Wesentliches Defizit ist die Unterversorgung in der Rheumatologie. In der aktuellen von KV und den Krankenkassen umgesetzten Regelversorgung wird eine Realisierung der T2T-Empfehlungen nicht nur nicht moglich, sondern sogar behindert. Selektivvertrage und die „Ambulante Spezialfacharztliche Versorgung“ des neuen Versorgungsstrukturgesetzes kommen der rheumatologischen Versorgung entgegen. Erst die praktische Umsetzung wird die wirklichen Moglichkeiten aufzeigen. Die aktuelle Situation verlangt nach einem „Nationalen Aktionsplan rheumatologische Versorgung“, uber den auch Inhalte von T2T implementiert werden konnen.

The social recognition of depression in general and as a comorbidity in illnesses such as rheumatoid arthritis (RA) has essentially changed in recent years. Previous studies have shown that the occurrence of depression in RA patients is closely related to the individual ways of coping with disease and the corresponding impact of disease on daily life. Patients who are experiencing feelings of helplessness while facing the illness are prone to depressive disorders, especially if effective strategies for managing the impact of disease are lacking. Tools for early recognition of depression include instruments such as patient questionnaires or interview protocols which should be interpreted with caution due to the overlap of symptoms arising from RA and depression. A supplemental cognitive behavioral intervention in addition to medication with antidepressive drugs provides an opportunity to identify the underlying cause of depression and learn about effective coping strategies to at least partially maintain self-control of RA.

A removal, as far as possible, of the GaSb substrate is needed to optimize the quantum efficiency and the longevity, i.e., the maximum number of cool down cycles, of dual-colour InAs/GaSb superlattice focal plane array detectors for the mid-wavelength infrared atmospheric transmission window at 3-5 µm. For this purpose, three different vertical detector structures have been investigated and are compared in the present paper. A basic structure, comprising only the essential layers is evaluated against two more advanced structures, which include a lattice-matched InAsSb etch stop layer. For the basic structure the remaining substrate thickness amounts to roughly 20 µm. With a second structure, which employs an etch stop separated from the active diode structure by a sufficiently thick GaSb spacer layer, the substrate and the etch stop layer can be completely removed by combining mechanical lapping and polishing as well as different wet chemical etchants. Here, only epitaxially grown layers remain, but the spacer is still common to all pixels. A third structure combined with further optimized front- and backside processes is suited for the complete mechanical separation of dual-colour detector pixels in the focal plane array arrangement (© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Neue Therapieprinzipien und Fortschritte in der Diagnostik haben es ermoglicht, bei Erkrankungen des rheumatischen Formenkreises und hier besonders bei der rheumatoiden Arthritis (RA) ein Krankheitsbild fruh zu definieren und durch eine fruhzeitig begonnene Medikation bei einem betrachtlichem Anteil der Patienten eine niedrige Krankheitsaktivitat oder Remission zu erzielen. Mit der zusatzlichen Entwicklung neuer Parameter zur Analyse der Krankheitsaktivitat stellte sich eine internationale Arbeitsgruppe von Rheumatologen und Rheumapatienten – in Anlehnung an die Optimierung der Therapie von Patienten mit einem Hypertonus oder Diabetes – die Aufgabe, einen Behandlungsplan fur die RA zu entwickeln mit dem Ziel, so haufig wie moglich eine Remission zu erzielen. Diese Treat-To-Target-Empfehlungen wurden von nationalen Arbeitsgruppen, so auch in Deutschland, hinsichtlich ihrer Umsetzbarkeit in die Infrastruktur des deutschen Gesundheitswesens diskutiert und Moglichkeiten zur Implementierung erortert. Am Modell der RA wurden wichtige Aktionselemente und Postulate fur eine verbesserte Versorgung von Menschen mit der Volkskrankheit Rheuma aufgestellt, die in dem vorliegenden Manuskript im Einzelnen diskutiert werden.

Die rheumatologische Versorgung in Deutschland ist beeinflusst von limitierten Ressourcen. Die Professionalisierung von medizinischen Assistenzberufen ist ein Weg, Ressourcen besser zu nutzen. Das Curriculum „Rheumatologische Fachassistenz DGRh-BDRh“ der Deutschen Gesellschaft fur Rheumatologie (DGRh) und des Berufsverbands der deutschen Rheumatologen (BDRh) wurde entwickelt, um systematisch Fachassistenten aus Ambulanz und Klinik zu qualifizieren. Seit 2006 wurden insgesamt 499 Teilnehmer an jeweils 4 Wochenenden geschult und der Erwerb der Qualifikation durch Examen uberpruft. Das Themengebiet umspannt Grundlagen der Anatomie und der Krankheitslehre bis hin zu modernen Methoden der Diagnostik und Therapie, inklusive praktischer Fahigkeiten. Aufbauend auf diesem Grundkurs wurden ein Kurs „Stationare Pflege“ und ein „Refresher-Kurs“ entwickelt. Nach 8 Grundkursen wurde eine Evaluation vorgenommen. Der Rucklauf lag bei 51,6%. 95% gaben an, dass sich ihr Wissen zum Verstandnis rheumatologischer Erkrankungen „sehr deutlich“ bzw. „deutlich“ verbessert hat; 90% antworteten, dass sie „Akuttermine“ besser abschatzen konnten, und 86% gaben an, bei der Einschatzung einer Notfallsituation sicherer zu sein. 50% der Befragten bestatigten, dass sich ihr Arbeits- und Aufgabenfeld geandert habe. So wurden u. a. selbststandigeres Arbeiten, Erheben einer orientierenden Anamnese, Betreuung von Studien, Information und Anlegen von Infusionen als neue Bereiche genannt. Zusammenfassend zeigen die Ergebnisse, dass das Curriculum ein wirksamer Schritt in Richtung der Professionalisierung medizinischer Assistenzberufe ist.

Within a very few years, InAs/GaSb superlattice technology has proven its suitability for high-performance infrared imaging detector arrays. At the Fraunhofer Institute for Applied Solid State Physics (IAF) and AIM Infrarot-Module GmbH, efforts have been focused on developing mature fabrication technology for dual-color InAs/GaSb superlattice focal-plane arrays for simultaneous, colocated detection at 3 µm to 4 µm and 4 µm to 5 µm in the mid-wavelength infrared atmospheric transmission window. Integrated into a wide-field-of-view missile approach warning system for an airborne platform, a very low number of pixel outages and cluster defects is mandatory for bispectral detector arrays. Process refinements, intense root-cause analysis, and specific test methodologies employed at various stages during the process have proven to be the key for yield enhancements.

Pain is the leading symptom and as well the main complaint of most patients with rheumatic diseases. Thus, assessment of pain is essential for monitoring disease activity and therapy response. Pain can be assessed with one-dimensional tools such as numeric rating scales or visual analogue scales. Both are more powerful in detecting changes in pain intensity than a verbal categorical rating scale and are widely used in clinical trials as well as in daily routine care. Any assessment of pain must take into account other factors, such as cognitive impairment or dementia, and assessment tools validated in the specific disease and patient groups being studied. Chronic rheumatic pain assessment and its impact on physical, emotional, and social functions requires more sophisticated multidimensional qualitative tools. Due to various reasons their use is not established in daily clinical rheumatology although they demonstrate therapeutic impact if used appropriately.

The optimization, based on computational, thermodynamic, and crystallographic data, of a series of small-molecule ligands of the Phe43 cavity of the envelope glycoprotein gp120 of human immunodeficiency virus (HIV) has been achieved. Importantly, biological evaluation revealed that the small-molecule CD4 mimics (4–7) inhibit HIV-1 entry into target cells with both significantly higher potency and neutralization breadth than previous congeners, while maintaining high selectivity for the target virus. Their binding mode was characterized via thermodynamic and crystallographic studies.

Thermal imagers based on cooled LWIR Modules are the choice for many Army applications in battlefield conditions like e.g. Gunner and Commander Sights in armored vehicles or Pilotage and Targeting Sights for helicopters. AIM has developed and produces LWIR FPAs based on liquid phase epitaxy (LPE) grown MCT on in-house grown CdZnTe substrates with different formats up to detector arrays with 1280x1024 elements in a 15μm pitch. LWIR detector arrays with different spectral cut-off wavelengths in the range of 9μm up to >12μm have been produced and characterized. For cost reduction a fabrication of molecular beam epitaxy (MBE) grown MCT on GaAs substrates is developed. Critical performance parameters of the detector arrays are temporal noise at low frequencies and the residual fixed pattern noise after non-uniformity correction. A performance-limiting factor of a LWIR FPA is also the available full well capacity (FWC) of the readout integrated circuit (ROIC) for signal integration. AIM has done a redesign of the standard 640x512, 15μm pitch ROIC using now 0.18μm Si-CMOS technology. The available FWC for signal integration could be significantly increased resulting in better NETD performance. Further developments are done for pitch reduction to realize LWIR modules also with 12μm and 10μm pixel pitch. The FPAs are integrated in compact dewar cooler configurations using different kinds of cooler types, like AIM’s split linear coolers SX095 or SX040 or rotary integral types depending whatever fits best to the application. The paper will present the development status and performance results of AIM’s latest improved MCT LWIR Modules.

For the Abrasive Flow Machining (AFM) process, a highly viscous polymeric carrier mixed with abrasive grain is used for deburring, edge rounding and the general improvement of surface quality of workpieces with complex geometries. At present, time-consuming and expensive feasibility studies and parameter analyses are required for each new application. According to a market study of 2012, more than 50% of AFM users request the availability of a process simulation to model and optimize the flow and predict the results by use of numerical methods. The key challenge is the accurate description of the complex behavior of the viscoelastic abrasive medium. This paper examines a CFD approach to the flow simulation by integrating the non-Newtonian, shear-thinning characteristics of a Maxwell fluid into the inelastic Navier-Stokes equations. With the implementation of the viscoelastic material model in ANSYS CFX, physically reasonable results can be achieved and validated by experimental machining results of additively manufacturedSLM workpieces. The results for flat, reference workpieces as well as for turbine bladesare discussed and compared to experimental results.