Scanning Auger microscopy as applied to the analysis of highly textured YBaCu3Ox thin films

Scanning Auger electron spectroscopy and scanning electron microscopy have been used to investigate the local composition and structure of highly textured axis oriented YBaCuO films with thicknesses in the range 0.4–1 μm. The cuprate films were sputtered on MgO and sapphire (100)-oriented single-crystal substrates at room temperature followed by several anneal stages below or at 920°C in pure oxygen. The YBaCuO/sapphire sample was examined again after an additional 750°C air anneal for 24 h. By applying Auger line profiling on a freshly prepared cross-sectional surface of a thin cuprate film deposited on a sapphire substrate we have been able to show that barium aluminate segregation at grain boundaries is the main cause of the higher electrical resistance usually observed for cuprate films on Al2O3. The (drastic) reduction in Tc can be attributed to the substitution of aluminium in the cuprate at copper sites. Severe interdiffusion has been observed for the epitaxial c axis oriented YBaCu oxide films grown on an MgO substrate, which leads to a deterioration in the superconductivity. The main reason for reduced Tc and quality of cuprate films on MgO is the copper loss into the substrate, the depth of penetration of copper extending more than 400 nm below the YBaCuO---MgO interface. From our experimental results it is evident that Auger line profiling is an important tool in the analysis of high Tc superconducting thin films

Investigation of lyophilized antibody formulations to enable short freeze-drying cycles and storage at room temperature

Antibodies are dominating the biopharmaceutical market and are expected to grow further. Aiming to improve existing treatments, new antibody derivatives of improved efficacy and safety are being developed in a competitive market. Antibody derivatives include but are not limited to antibody-drug conjugates and Fc-fusion proteins. Due to their higher complexity, they are often less stable as liquids, increasing the demand for lyophilized formulations to ensure protein storage stability over the desired shelf life. In many cases, these antibody formats require lower doses, posing challenges to formulation and freeze-drying process development. Commercialized lyophilized antibodies typically contain disaccharides, most frequently sucrose, as a stabilizer and bulking agent. The low glass transition temperature of sucrose requires time- and energy-intensive, thus expensive freeze-drying cycles. At lower protein concentrations, this becomes even more relevant, raising the risk of product collapse during freeze-drying. Collapse occurs when primary drying is performed above the glass transition temperature or collapse temperature of the formulation. It is current dogma to design freeze-drying cycles that provide pharmaceutically elegant lyophilisates as collapse leads to batch inhomogeneity causing rejects, higher complaint rates, and most importantly may potentially be detrimental to protein storage stability. Thus, there is a need to look into alternative excipients for future freeze-dried antibody formulations. The presented work investigated amorphous excipients to be used as alternative excipients to sucrose for freeze-dried antibody formulations, increasing the formulation’s glass transition temperature. The main objectives were to investigate their ability to render pharmaceutically elegant lyophilisates upon short freeze-drying cycles, and to stabilize antibodies during freeze-drying and subsequent storage. Special focus was given to storage stability at elevated temperatures with the aim to study the potential for room temperature stable formulations. At first, an imaging technique was established to evaluate the impact of excipients and freeze-drying cycles on cake appearance and structure. Different imaging techniques were compared regarding qualitative and quantitative characterization of the entire lyophilisate, and their potential for non-invasive evaluation of structure and morphology in the glass vial (Chapter 1). The comparative analysis revealed limitations of scanning electron microscopy, the current state of the art technique to characterize cake morphology. Micro-computed tomography was introduced as a technique allowing for comprehensive and reproducible imaging of cake structure and morphology. Having established a method for evaluation of cake appearance, the next step of this work was focused on formulation development. Dextrans of different molecular weight from 1 to 500 kDa (Chapter 2) followed by HPBCD-based formulations in combination with other amorphous compounds (Chapter 3) were investigated. Their impact on thermal properties, cake appearance, other physico-chemical product quality attributes, and protein stability of two model antibodies was characterized. In particular, HPBCD was found to be a promising excipient, while dextran showed several limitations. Large dextrans of 40 kDa or higher were shown to increase the viscosity of the formulations leading to long reconstitution times, and did not sufficiently stabilize the antibodies during freeze-drying compared to smaller dextrans and HPBCD. The work highlighted limitations of dextrans with regards to protein stability, due to antibody glycation during storage at elevated temperatures. HPBCD rendered lyophilisates with good product quality attributes and ensured antibody stability during freeze-drying and even at elevated storage temperatures. Best antibody stability was obtained in combination with sucrose, highlighting the fact that disaccharides will remain a mandatory part of freeze-dried antibody formulations. To further maximize protein stability, a thorough characterization of the optimal ratio of HPBCD and sucrose will be essential. These formulations which provided good stability and product quality attributes were subsequently used for freeze-drying process optimization (Chapter 4). Primary drying parameters were optimized for a short freeze-drying cycle that renders pharmaceutically elegant lyophilisates. The presented work demonstrated that amorphous excipients with higher glass transition temperatures allow for shorter freeze-drying cycles while providing lyophilisates with improved cake appearance. Ultimately, the HPBCD-based formulation with addition of sucrose enabled the development of a short, single-step freeze-drying cycle while maintaining pharmaceutically elegant lyophilisates eventually reducing cycle time by 50%. Overall, the current work demonstrated the potential of alternative amorphous excipients, which in contrast to crystalline bulking agents contribute to protein stability while avoiding additional complexity in the freeze-drying cycle. The combined use of HPBCD with sucrose may provide a formulation for low concentrated protein formulations that enables the development of short freeze-drying cycles while maintaining pharmaceutically elegant lyophilisates. The presented work may encourage considerations to store freeze-dried formulations at (controlled) room temperature rather than refrigerated conditions in the future

Communion with Christ and Christian community in 1 Corinthians: a study of Paul's concept of Koinonia

Although the concept of χοιυωυια occurs only twice in 1 Corinthians (1:9 and 10:16), each of these two occurrences appears to be highly significant not only for the context in each case but also generally with reference to the character of the Apostle's argumentation in this epistle. In the first passage, which has almost entirely been neglected so far in the many scholarly contributions to the subject of χοιυωυια, the term occurs in the summarizing climax of the letter-opening (1 Cor 1:1-9) which is remarkably packed with theological and christological statements and which is structured by a laudatory description of God's wonderful works in the Corinthians' lives in past (vvA-6) present (v.7a) and future (vv.7b-8). The basic message which Paul wants his addressees to comprehend right from the beginning and which - according to the epistolary I P function of these nine verses - reveals his approach to their many serious problems, culminates in the concept of χοιυωυια, in the salvific communion with Christ crucified, God's Son, their risen Lord, a communion into which they had been called once-for-alI and where God's faithfulness continually preserved them until the end. The other instance in 1 Cor 10:16 is not a Pauline formulation but a presumably catechetical tradition on the Lord's Supper which the Apostle quoted and employed as an argument in the course of his lengthy discussion of the problem of idol-meat (1 Cor 8:1-11:1). Because of the communion (χοιυωυια) with the body and blood of Christ, i.e. the inclusive involvement into Christ's death and resurrection as it is tangibly expressed in the celebration of the Eucharist, any other competing relationships and meal fellowships with idols are necessarily excluded. So, in both cases of χοιυωυια in 1 Corinthians the concept is not an ecclesiological term but rather emphasizes the communion with Christ as the constant constitutive condition of the Christians' individual and community life

Validation of the Patient-Doctor-Relationship Questionnaire (PDRQ-9) in a Representative Cross- Sectional German Population Survey: Validation of the Patient-Doctor-RelationshipQuestionnaire (PDRQ-9) in a Representative Cross-Sectional German Population Survey

The patient-doctor relationship (PDR) as perceived by the patient is an important concept in primary care and psychotherapy. The PDR Questionnaire (PDRQ-9) provides a brief measure of the therapeutic aspects of the PDR in primary care. We assessed the internal and external validity of the German version of the PDRQ-9 in a representative crosssectional German population survey that included 2,275 persons aged$14 years who reported consulting with a primary care physician (PCP). The acceptance of the German version of this questionnaire was good. Confirmatory factor analysis demonstrated that the PRDQ-9 was unidimensional. The internal reliability (Cronbach’s a) of the total score was .95. The corrected item-total correlations were$.94. The mean satisfaction index of persons with a probable depressive disorder was lower than that of persons without a probable depressive disorder, indicating good discriminative concurrent criterion validity. The correlation coefficient between satisfaction with PDR and satisfaction with pain therapy was r = .51 in 489 persons who reported chronic pain, indicating good convergent validity. Despite the limitation of low variance in the PDRQ- 9 total scores, the results indicate that the German version of the PDRQ-9 is a brief questionnaire with good psychometric properties to assess German patients’ perceived therapeutic alliance with PCPs in public health research

Validation of the Fibromyalgia Survey Questionnaire within a Cross-Sectional Survey

The Fibromyalgia Survey Questionnaire (FSQ) assesses the key symptoms of fibromyalgia syndrome. The FSQ can be administrated in survey research and settings where the use of interviews to evaluate the number of pain sites and extent of somatic symptom intensity and tender point examination would be difficult. We validated the FSQ in a cross-sectional survey with FMS patients. In a cross-sectional survey, participants with physician diagnosis of FMS were recruited by FMS-self help organisations and nine clinical institutions of different levels of care. Participants answered the FSQ (composed by the Widespread Pain Index [WPI] and the Somatic Severity Score [SSS]) assessing the Fibromyalgia Survey Diagnostic Criteria (FSDC) and the Patient Health Questionnaire PHQ 4. American College of Rheumatology 1990 classification criteria were assessed in a subgroup of participants. 1,651 persons diagnosed with FMS were included into analysis. The acceptance of the FSQ-items ranged between 78.9 to 98.1% completed items. The internal consistency of the items of the SSS ranged between 0.75–0.82. 85.5% of the study participants met the FSDC. The concordance rate of the FSDC and ACR 1990 criteria was 72.7% in a subsample of 128 patients. The Pearson correlation of the SSS with the PHQ 4 depression score was 0.52 (p<0.0001) and with the PHQ anxiety score was 0.51 (p<0.0001) (convergent validity). 64/202 (31.7%) of the participants not meeting the FSDC criteria and 152/1283 (11.8%) of the participants meeting the FSDC criteria reported an improvement (slightly too very much better) in their health status since FMS-diagnosis (Chi2 = 55, p<0.0001) (discriminant validity). The study demonstrated the feasibility of the FSQ in a cross-sectional survey with FMS-patients. The reliability, convergent and discriminant validity of the FSQ were good. Further validation studies of the FSQ in clinical and general population settings are necessary

Spa Treatment (Balneotherapy) for Fibromyalgia—A Qualitative-Narrative Review and a Historical Perspective

Aim. To perform a narrative review of spa therapy for management of the fibromyalgia syndrome (FMS), evaluating this traditional time-honored form of therapy in a historical perspective. Methods. Medline was searched using the terms “Spa therapy,” “Balneotherapy,” and “Fibromyalgia” between 1990 (year of ACR fibromyalgia criteria publication) and April 2013. The Cochrane database was also searched. Publications relating to the implementation of spa therapy and related practices over the centuries were identified through references, searched, and reviewed. Results. Reports of balneotherapy were described from diverse locations throughout Europe and Asia, and various forms of water-related therapy have been incorporated for many musculoskeletal indications. In the management of FMS, spa therapy has generally been shown to be well accepted and moderately effective for symptom reduction. Conclusion. While achieving high-quality evidence-based conclusions is difficult for complex natural therapies such as spa therapy, the existing evidence indicates a positive effect in management of FMS. In view of the long history of this modality in the management of rheumatic pain as well as the inherent difficulties related to pharmacological treatment, the role of spa therapy should currently be recognized as part of a therapeutic program for FMS