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The photoinjector test facility at DESY, Zeuthen site (PITZ), was built to develop and optimize photoelectron sources for superconducting linacs for high-brilliance, short-wavelength free-electron laser (FEL) applications like the free-electron laser in Hamburg (FLASH) and the European x-ray free-electron laser (XFEL). In this paper, the detailed characterization of two laser-driven rf guns with different operating conditions is described. One experimental optimization of the beam parameters was performed at an accelerating gradient of about 43 MV/m at the photocathode and the other at about 60 MV/m. In both cases, electron beams with very high phase-space density have been demonstrated at a bunch charge of 1 nC and are compared with corresponding simulations. The rf gun optimized for the lower gradient has surpassed all the FLASH requirements on beam quality and rf parameters (gradient, rf pulse length, repetition rate) and serves as a spare gun for this facility. The rf gun studied with increased accelerating gradient at the cathode produced beams with even higher brightness, yielding the first demonstration of the beam quality required for driving the European XFEL: The geometric mean of the normalized projected rms emittance in the two transverse directions was measured to be 1.26±0.13 mm mrad for a 1-nC electron bunch. When a 10% charge cut is applied excluding electrons from those phase-space regions where the measured phase-space density is below a certain level and which are not expected to contribute to the lasing process, the normalized projected rms emittance is about 0.9 mm mrad.

Objective: We aimed to determine how 2 definitions of end-stage knee osteoarthritis (esKOA) and each component (knee symptoms, persistent knee pain, radiographic severity, and presence of limited mobility or instability) related to future knee replacement (KR)., Methods: We performed knee-based analyses of Osteoarthritis Initiative data from baseline to the first 4 annual follow-up visits, and data on KR from baseline until the fifth yearly contact. We calculated a base model using common risk factors for KR in logistic regression models with generalized estimating equations. We assessed model performance with area under the receiver-operating characteristic curve (AUC) and Hosmer-Lemeshow test. We then added esKOA or each component from the visit (< 12 months) before a KR and change in the year before a KR. We calculated the net reclassification improvement (NRI) index and the integrated discrimination improvement (IDI) index., Results: Our sample was mostly female (58%), ≥ 65 years old, White (82%), and without radiographic knee osteoarthritis (50%). At the visit before a KR, Kellgren-Lawrence (KL) grades (ordinal scale; AUC 0.88, NRI 1.12, IDI 0.11), the alternate definition of esKOA (AUC 0.84, NRI 1.16, IDI 0.12), and a model with every component of esKOA (AUC 0.91, NRI 1.30, IDI 0.17) had the best performances. During the year before a KR, change in esKOA status (alternate definition) had the best performance (AUC 0.86, NRI 1.24, IDI 0.12)., Conclusion: Radiographic severity may be a screening tool to find a knee that will likely receive a KR. However, esKOA may be an ideal outcome in clinical trials because a change in esKOA state predicts future KR., (Copyright © 2023 by the Journal of Rheumatology.)

Objective: We aimed to describe the natural history leading to end-stage knee osteoarthritis (esKOA), focusing on knee symptoms, radiographic severity, and the presence of limited mobility or instability., Methods: We performed knee-based analyses of Osteoarthritis Initiative data from 7691 knees (4165 participants). We used a validated definition of esKOA that relied on meeting one of two criteria: (1) severe radiographic knee osteoarthritis (Kellgren-Lawrence [KL] grade=4) with moderate-to-intense pain (Likert WOMAC pain+function>11/88) or (2) KL grade<4 with intense or severe pain (WOMAC pain+function>22) and limited mobility (flexion contracture≥5°) or instability (based on a varus and valgus stress test). We also introduced an alternate definition of esKOA that relied on meeting one of two criteria that omitted physical exam findings:(1) severe radiographic knee osteoarthritis (KL grade=4) with at least moderate symptoms or (2) KL grade=2 or 3 with intense or severe symptoms and persistent knee pain (frequent knee pain during three or more months in the past year). We used descriptive statistics to explore the frequency of components of esKOA at the index visit when they had incident esKOA, at the annual visit before developing esKOA, and the interval change between those visits., Results: Our analytic sample was mostly female (58%), without radiographic knee osteoarthritis (KL grade=0 or 1; 60%), without stability or mobility concerns (91%), and without persistent knee pain (77%). At the visit before incident esKOA, most knees already had moderate-to-severe radiographic osteoarthritis using the original (62%) or alternate (50%) definition (versus <15% for either definition of no esKOA). Over 80% of knees that reached the criteria for esKOA achieved this based on increased knee symptom severity - typically without worsening radiographic severity (80%)., Conclusion: Radiographic severity predisposed a knee to esKOA. However, worsening knee symptoms led to the development of incident esKOA. If investigators want to increase the chance of identifying incident esKOA as an outcome, they should enrich their study samples with people with moderate-to-severe radiographic osteoarthritis. Our findings also highlight the potential reversibility of esKOA (a knee that is classified with esKOA but later is not classified with esKOA). Reversibility is not a flaw of an outcome defining esKOA but rather a desirable clinical outcome to demonstrate a therapeutic intervention can help people with esKOA improve their knee symptoms and delay a knee replacement., Competing Interests: Declaration of Competing Interest JBD and TEM served on an advisory board for Novartis. The authors have no other conflicts of interest with regard to this work., (Copyright © 2022. Published by Elsevier Inc.)

Objective: We previously published data representing calculations for sample sizes assuming that the reduction of the incidence of knee joint replacement (KJR) would be an endpoint to prove efficacy of a disease-modifying drug in osteoarthritis (DMOAD). The sample sizes required for such hypothetical studies appeared to be high, rendering those studies unrealistic in the clinical research setting for practical reasons. The purpose of this work is to calculate sample sizes for hypothetical trials for DMOAD efficacy using a proxy for reaching end-stage knee osteoarthritis (esKOA) as an endpoint., Methods: Based on a sub-population of the Osteoarthritis Initiative, the cumulative incidence for both esKOA and KJR were calculated for a period of four years. The sample sizes of hypothetical DMOAD trials were then calculated for particular sub-cohorts of the OAI subpopulation, subdividing the groups according to age, Kellgren-Lawrence (KL) grades and gender., Results: Both the incidence for esKOA and for KJR over the four year period increase along with rising age, severity of OA and being female. The sample sizes to detect DMOAD efficacy are considerably smaller if reduction of the incidence of esKOA is chosen as an endpoint instead of reduction of the incidence of KJR., Conclusion: In the future, generating health-economic data may become increasingly important to gain reimbursement. By choosing esKOA as an endpoint in DMOAD trials, we are able to show in our work that clinical trials in the field of OA are feasible, merely including a few hundred study participants per study arm., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: This publication summarizes the clinical development of the compound SAR113945, an IκB kinase inhibitor injected intra-articularly in a slow-release formulation to treat patients with symptomatic osteoarthritis (OA) of the knee., Results: In vitro experiments demonstrated a specific inhibition of the IκB kinase complex. Profiling of SAR113945 on kinases, enzymes and ion channels supported the initiation of a clinical development. Cellular assay systems also revealed an inhibition in the synthesis of interleukin 1β, tumor necrosis factor α (TNFα) and the prostaglandin E2 (PGE 2 ). In vivo studies demonstrated positive effects of SAR113945 on thermal and mechanical hyperalgesia and even showed superiority in comparison with triamcinolone. Pharmacokinetic measurements showed a sustained release of dissolved SAR113945 locally supporting a comparably high exposure in the knee joint combined with a low systemic exposure. Three phase 1 studies with a dose-escalating design confirmed safety and tolerability of SAR113945. In those studies SAR113945 showed a positive trend on the WOMAC scores. The proof-of-concept or phase 2a study failed to show any effect in the overall group of recruited study participants for the primary endpoint, the WOMAC pain subscore at day 56, but showed a statistically significant difference in a subgroup of patients who had presented with effusion at baseline., Conclusion: Inhibiting the NFκB signaling pathway is an attractive method to treat patients with signs and symptoms of OA. The preclinical work and the results of the phase 1 studies appeared promising for a full clinical development, however, the proof-of-concept study failed to show efficacy in a larger patient sample size., (Copyright © 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

To evaluate in an interventional trial on knee osteoarthritis (OA) the level and change of two serum biomarkers and their correlation with imaging parameters. The previously reported interventional OA study (ClinicalTrials.gov: NCT00536302) identified a positive effect of collagen hydrolysate (CH) on cartilage morphology in patients with knee OA using delayed gadolinium enhanced magnetic resonance imaging (dGEMRIC). It was the objective in this research project to evaluate in an interventional clinical trial on knee OA the level and change of two serum biomarkers and their correlation with imaging parameters. In blood samples of study participants, we determined the concentration of procollagen type II N-terminal propeptide (PIIANP) and aggrecan chondroitin sulfate 846 epitope (CS846) at baseline (BL) and at the follow-up (FU) visits at 24 and 48 weeks. We measured the level and change of biomarker concentrations in both study groups, and the correlation of those changes with changes in dGEMRIC. For the biomarker PIIANP, we observed a significantly greater increase in the CH group (29.9% vs. 1.2% at week 24, P= 0.001). For CS846, the mean concentration was lower among the CH treated participants at 24 weeks (78% vs. 96%, P= 0.045). Consistent correlations of changes in biomarkers PIIANP and CS846 with changes of the dGEMRIC score could not be observed. In this study, different changes per treatment group, CH and placebo were seen for dGEMRIC and PIIANP BL to 24 weeks FU, but only weak correlations between changes in dGEMRIC and biochemical markers.

Objective: To evaluate the extent to which the current designs of clinical trials in knee osteoarthritis (OA) permit detection of a therapeutic effect of disease-modifying OA drugs (DMOADs) on the incidence of knee replacement, and to provide estimates of the required sample sizes., Methods: We selected distinct subcohorts of the Osteoarthritis Initiative (OAI), based on available information on eligibility criteria for clinical knee OA trials (ClinicalTrials.gov) and additional subcohorts stratified for age, sex, and the severity of radiographic OA. The observed incidence of knee replacement in these OAI subcohorts was used to estimate the expected incidence of knee replacement in the control group of a clinical trial. Based on this estimate, the sample sizes required to detect hypothetical treatment effects on the incidence of knee replacement were calculated, assuming observation periods of 2, 5, or 7 years., Results: The cumulative knee replacement incidence rates in the OAI subcohorts ranged from 0.9% to 12.9%. The corresponding sample sizes required to detect 50% improvement by the DMOAD, with a power of 80% and 95% confidence, were 5,459 and 362, respectively. Including only women with advanced age and radiographic OA increased the incidence of knee replacement and decreased the required sample size., Conclusion: The sample sizes that are commonly used in clinical trials do not enable the effects of a DMOAD on incident knee replacement to be detected with sufficient power and confidence. The estimated incidence rates of knee replacement and the corresponding sample sizes are important for informing the design of trials for disease course-modifying effects as well as for socioeconomic evaluation of a DMOAD in terms of preventing knee replacement., (© 2015, American College of Rheumatology.)

Objective: To determine whether either of two magnetic resonance imaging approaches - delayed gadolinium enhanced magnetic resonance imaging of cartilage (dGEMRIC), or T2 mapping - can detect short-term changes in knee hyaline cartilage among individuals taking a formulation of collagen hydrolysate., Design: Single center, prospective, randomized, placebo-controlled, double-blind, pilot trial of collagen hydrolysate for mild knee osteoarthritis (OA). Participants were allowed to continue the prior analgesic use. The primary outcome was change in dGEMRIC T1 relaxation time in the cartilage regions of interest at the 24-week timepoint. Secondary endpoints included the change in dGEMRIC T1 relaxation time between baseline and 48 weeks, the change in T2 relaxation time at 0, 24 and 48 weeks, the symptom and functional measures obtained at each of the visits, and overall analgesic use., Results: Among a sample of 30 randomized subjects the dGEMRIC score increased in the medial and lateral tibial regions of interest (median increase of 29 and 41 ms respectively) in participants assigned to collagen hydrolysate but decreased (median decline 37 and 36 ms respectively) in the placebo arm with the changes between the two groups at 24 weeks reaching significance. No other significant changes between the two groups were seen in the other four regions, or in any of the T2 values or in the clinical outcomes., Conclusions: These preliminary results suggest that the dGEMRIC technique may be able to detect change in proteoglycan content in knee cartilage among individuals taking collagen hydrolysate after 24 weeks., (Copyright © 2011 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

To more effectively manage the substantial bleeding encountered during surgical procedures in oto-rhino-laryngology, we developed a novel hemostatic sponge made of pharmaceutical grade, chemically cross-linked gelatin. The sponge is characterized by a high pore density, reduced ligaments, and a high nanoscale roughness of lamella surfaces in the matrix. In vitro blood uptake assays revealed a very rapid absorption of human blood, which was two to three times faster than that measured with comparative hemostyptic devices. In an in vitro hemorrhage model using human veins, the novel gelatin sponge matrix induced hemostasis less than a minute after bleeding was induced. The sponge was shown to bring about rapid hemostasis when it was administered in a young patient suffering from acute bleeding of a pharyngeal angiofibroma, even though the patient had been treated with an anticoagulant because of a transient ischemic attack. As the gelatin matrix of the sponge is biocompatible and resorbable, the hemostyptic device could be left in place and was shown to be resorbed within 2 weeks. We hypothesize that the excellent hemostatic performance of the sponge might be linked to enhanced capillary effects in conjunction with optimized anchoring of fibrinogen on the nano-rough material surface, as suggested by scanning electron microscopy. The novel gelatin sponge appears to be a promising hemostatic matrix, which could be of great benefit for patients suffering from epistaxis and other acute injuries resulting in severe bleeding.

The primitive neuroectodermal tumor (PNET) is an extremely aggressive soft tissue neoplasm that occurs in children and adolescents. We retrospectively reviewed our therapeutic experience with a multidisciplinary approach, combining surgery, chemotherapy, and radiation therapy. Treatment of PNET was carried out in compliance with the soft tissue protocol (CWS) from the German Society of Pediatric Oncology. Biopsy-proven diagnosis was followed by chemotherapy, which in all cases led to partial remission, allowing excision of the remainder of the tumor without mutilation. After excision, irradiation of the tumor site and two further sequences of chemotherapy were performed. When PNET of the paravertebral region caused symptoms of paralysis and immediate surgery was required, postoperative chemotherapy, a second-look operation, and irradiation were undertaken. Between 1986 and 1998 we treated 13 patients (median age 15 years). In five patients the PNET originated from the chest wall and in eight patients from the paravertebral and retroperitoneal region. Five patients died after 20 months on average, and the remaining eight patients are in full remission after 7, 16, 46, 55, 70, 74, 75, and 115 months, respectively. Close cooperation between surgeons and their pediatric and radiotherapy colleagues is obligatory when treating PNET. Chemotherapy as the first stage is mandatory to avoid a mutilating surgical procedure and intraoperative tumor cell dissemination.

Between 1985 and 1997, we performed a locoregional chemotherapy in 59 patients suffering from non-resectable liver metastases of breast cancer. 36 of them only had liver metastases, in 23 patients liver metastases were combined with extrahepatic tumor spread. Furthermore, in 7 patients locoregional chemotherapy was used as a adjuvant regimen after metastasectomy. The average age of our patients was 52 (32-81) years. In most of our patients, a cytostatic scheme of mitoxantron, 5-fluorouracil and doxorubicin or a scheme of vincristin, mitomycin and mitoxantron was administered. The median survival of all patients was 11 months, in the patients with no additional extrahepatic tumor spread it was 16, in the patients with extrahepatic metastases 3 months, respectively.

The three osseous parts of the human pelvis form a continuous structure because of the symphysis and both iliosacral joints that-owing to their mobility-make possible a shock-absorption of vertical forces. The goal in the treatment of ruptures of the symphysis and/or of the sacroiliac joints is the restoration of functioning joints. Especially in the adolescent, a stiffening of these joints has to be avoided. Therefore, we treat ruptures of the pelvic joints with an overbridging banding that preserves the function of shock absorption. Due to utilisation of a banding, made up of polydioxanone, another operation to remove internal fixation material is not necessary. Rupture of the symphysis or iliosacral joint in the pediatric patient is very rare. Only three among the 67 patients whom we operated on because of a rupture of the symphysis or iliosacral joints between 1984 and 1990 were children. These were an eleven-year-old girl and a nine-year-old boy, who had suffered a rupture of the symphysis, and an eight-year-old boy with a disrupted iliosacral joint. In these children a banding with PDS suture was performed. At a follow-up examination, the children were free from pain and did not feel restricted in their daily routine or their physical activities.