The role of follicular anti-Mullerian hormone in women undergoing IVF/ICSI with regard to size, oocyte presence, sociodemographic parameters, treatment variables, and other hormones and vitamins.

AIMS: The aim of this study was to evaluate the relationship between follicular anti-Mullerian hormone (fAMH) regarding follicle size, the presence of an oocyte, sociodemographic parameters, and other hormones and vitamins in follicular fluid. MATERIALS AND METHODS: This prospective exploratory cohort study included 376 follicles from 61 women undergoing IVF/ICSI cycles. The size of each follicle was measured individually, and they were divided into a large and a small group according to their size. The presence of oocytes was detected on the day of oocyte retrieval. Sociodemographic factors were documented during the course of preliminary testing. Then, other parameters of patients' serum and follicular fluid were measured. RESULTS: Small follicles contained a significantly higher concentration of fAMH than large ones did. We showed that the presence of an oocyte in a follicle is associated with a significantly higher fAMH level than in those without one (p < .001). There exists a significant but weak correlation between fAMH and the sociodemographic parameter of patients' age (r = -0.11, p < .001). We did not find a correlation with the patients' BMI (r = 0.03, p < .006). We also investigated the connections between fAMH and other parameters, such as vitamin D (r = -0.13, p < .001), LH (r = 0.35, p < .001)), and progesterone (r = -0.21, p < .001) in follicular fluid. CONCLUSIONS: This knowledge can be useful for the future development of reproductive medicine. Our results can provide an important building block for this matter.

Mission statement from rheumatologists in the German Society of Rheumatology (DGRh e. V.) : We live rheumatology.

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.

Cost-effectiveness of social oocyte freezing in Germany: estimates based on a Markov model.

PURPOSE: Is oocyte freezing for non-medical reasons-the so-called "social freezing" (SF)-cost-effective compared to standard in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) in Germany today? METHODS: We developed a model based on three strategies for women planning to postpone pregnancy. In each strategy, women actively practiced contraception until 40 then tried to conceive naturally for 1 year. If unsuccessful, women using strategy I (oocyte cryopreservation) attempted ICSI with frozen oocytes in the 2nd year, while women using strategy II (no action) further attempted natural conception. In strategy III (IVF/ICSI), women underwent 1 year of IVF/ICSI. If still unsuccessful, each strategy was followed by attempting natural conception again until 45. We used an adaptive Markov model to estimate and compare live birth rates and cost-effectiveness measures. RESULTS: For strategy I, cumulative live birth rates at age 45 generally declined with the woman's age at freezing and were between 71.4% (25 years) and 67.6% (38 years), while the cumulative success rate was 51.5% for strategy II and 60.8% for strategy III. The costs per live birth of egg freezing were age-dependent ranging between 22,418 € (30 years) and 25,590 € (38 years). The costs for strategy III were lower at 20,293 € per live birth. CONCLUSION: Based on our results, social freezing in Germany may lead to additional pregnancies among women over 40 but also to significantly higher costs, since given the current live birth success rates and pricing, social freezing does not appear to be cost-effective.

[Mission statement from rheumatologists in the German Society of Rheumatology (DGRh e. V.) : We live rheumatology. German version]. / Leitbild der Rheumatologinnen und Rheumatologen in der Deutschen Gesellschaft für Rheumatologie e. V. (DGRh e. V.) : Wir sind die Rheumatologie.

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.

Towards X-ray transient grating spectroscopy.

The extension of transient grating spectroscopy to the x-ray regime will create numerous opportunities, ranging from the study of thermal transport in the ballistic regime to charge, spin, and energy transfer processes with atomic spatial and femtosecond temporal resolution. Studies involving complicated split-and-delay lines have not yet been successful in achieving this goal. Here we propose a novel, simple method based on the Talbot effect for converging beams, which can easily be implemented at current x-ray free electron lasers. We validate our proposal by analyzing printed interference patterns on polymethyl methacrylate and gold samples using ∼3 keV X-ray pulses.

[Biologics in rheumatology]. / Biologika in der Rheumatologie.

BACKGROUND: Monoclonal antibodies and fusion proteins were introduced into clinical rheumatology 20 years ago. Nowadays they are an established component of modern internal medical practice. OBJECTIVE: This article gives an overview of the breadth of biologics currently in clinical use. MATERIAL AND METHODS: Evaluation of published approval studies and guideline recommendations, discussion of the immunological principles and targets in the treatment with biologics. RESULTS: Monoclonal antibodies and fusion proteins for influencing cytokine signals, T­cell costimulation and B­cell function are the most important innovations in the treatment of rheumatological diseases. Nowadays they are indispensible for the treatment of moderate and severe disease courses of rheumatoid arthritis, spondylarthropathies and vasculitides. CONCLUSION: Although a cure or permanent freedom from symptoms in rheumatological autoimmune diseases is still not possible, much more favorable disease courses with less long-term limitations can be achieved by the early administration of biologics.

[Revised version of the statement by the DGRh on biosimilars-update 2017]. / Neufassung der Stellungnahme der DGRh zu Biosimilars ­ Update 2017.

The treatment of rheumatic diseases with bioloics has significantly improved the prognosis of patients. Currently, there are 13 preparations available in Germany for the treatment of patients with inflammatory rheumatic diseases. These original preparations generally have-depending on the individual country-15 years of patent protection. As soon as the patent has expired, approved biosimilars can be brought into use. For the approval of a biosimilar, authorities such as the European Medical Agency or the American Food and Drug Administration require proof of the best possible comparability with respect to efficacy and safety in comparison to the original or reference product. Since 2015, biosimilars of inifliximab, adalimumab, etanercept and rituximab have been granted approval in the European Union, the USA, Japan and in other countries. Further biosimilar products for these reference products are in development for treatment in rheumatology. From a societal and medical point of view, this opens up the possibility to increase the availability of biopharmaceutical products for patients through lower prices. In Germany, this possibility has already occurred-statutory health insurance physicians have introduced quotas for biosimilars, which will ultimately decrease spending and healthcare costs. This can lead to price reductions of the original products, which has already happened in Germany. Biosimilars can be prescribed for new patients or as a change from the original to the generic drug. When switching, a distinction is made between individual switching (interchangeability), which is made in individual consultation between the physician and the patient, and nonmedical switching (substitution) made at the societal or governmental level, which is made in the context of health care cost containment, and then, for example, implemented at the pharmacy level. Preliminary data from Norway and Denmark are available for substitution on the basis of results from large studies or registries in which systematic changes were made. The previous conclusion was that this does not lead to new problems for the patients. The German Society for Rheumatology recognizes the advantages of introducing biosimilars in Germany, but recommends that their use be based primarily on a joint decision by the treating physician and patient.

[Differential diagnostic spectrum of psoriasis vs. psoriatic arthritis in skin and joints]. / Differenzialdiagnostisches Spektrum der Psoriasis versus Psoriasisarthritis an Haut und Gelenken.

Psoriasis and psoriatic arthritis are common disease entities in the daily routine of dermatologists and rheumatologists. The clinical management of the diseases profits tremendously from interdisciplinary contacts and shared decision-making processes. For dermatologists, recognition of early clinical symptoms of inflammatory arthropathies is pivotal. Rheumatologists, on the other hand, are required to make an early assessment of skin and nail changes in patients, since they are important parameters in the clinical classification of inflammatory joint diseases, in particular for the diagnosis of psoriatic arthritis. In patients with psoriasis, lesions on the scalp, in the anal cleft, and nail changes as well as severe generalized skin disease are all regarded as risk factors for psoriatic arthritis. The symptoms of the associated joint and spinal afflictions can vary considerably and confirmation of the diagnosis, in particular in early stages of the disease often represents a considerable challenge. The most common clinical manifestations of psoriasis and psoriatic arthritis and their differential diagnostics are discussed.

Patient preferences for palliative treatment of locally advanced or metastatic gastric cancer and adenocarcinoma of the gastroesophageal junction: a choice-based conjoint analysis study from Germany.

BACKGROUND: Decisions on palliative chemotherapy (CT) for locally advanced or metastatic gastric cancer (mGC) require trade-offs between potential benefits and risks for patients. Healthcare providers and payers agree that patient-preferences should be considered. We conducted a choice-based conjoint (CBC) analysis study in pre-treated patients from Germany with mGC or locally advanced or metastatic adenocarcinoma of the gastroesophageal junction (mGEJ-Ca), to evaluate their preferences when hypothetically selecting a CT regimen. METHODS: German oncologists and gastroenterologists were contacted to identify patients with mGC or mGEJ-Ca who had completed ≥2 cycles of palliative CT in first or later lines of therapy (CT ongoing or complete). The primary objective was to quantify patient preferences for palliative CT by CBC analysis. Six in-depth qualitative interviews identified 3 attributes: treatment tolerability, quality of life in terms of ability of self-care, and additional survival benefit. The CBC matrix was constructed with 4 factor levels per attribute and each participant was presented with 15 different iterations of these levels. A minimum of 50 participants was needed. Consenting patients completed the CBC survey, choosing systematically among profiles. CBC models were estimated by multinomial logistic regression (MLR) and hierarchical Bayesian (HB) analysis. Estimates of importance for each attribute and factor-level were calculated. RESULTS: Fifty-five patients participated in the CBC survey (78.2% male, median age 63 years, 81.8% currently receiving CT). Across this sample, low treatment toxicity was ranked highest (44.6% relative importance, MLR analysis), followed by ability to self-care (32.3%), and an additional survival benefit of up to 3 months (3 months 23.1%, 2 months 18.3%, 1 month 11.2%). The MLR analysis showed high validity (certainty 37.9%, chi square p < 0.01, root-likelihood 0.505). The HB analysis yielded similar results. CONCLUSIONS: Patients' preferences related to a new hypothetical palliative CT of mGC or mGEJ-Ca can be assessed by CBCanalysis. Although in real-life, patients initially need to decide on CT before they have any experience, and patients' varied experiences with CT will have impacted specific responses, low toxicity and self-care ability were considered as most important by this group of patients with mGC or mGEJ-Ca.

Pushing the limits: an instrument for hard X-ray imaging below 20 nm.

Hard X-ray microscopy is a prominent tool suitable for nanoscale-resolution non-destructive imaging of various materials used in different areas of science and technology. With an ongoing effort to push the 2D/3D imaging resolution down to 10 nm in the hard X-ray regime, both the fabrication of nano-focusing optics and the stability of the microscope using those optics become extremely challenging. In this work a microscopy system designed and constructed to accommodate multilayer Laue lenses as nanofocusing optics is presented. The developed apparatus has been thoroughly characterized in terms of resolution and stability followed by imaging experiments at a synchrotron facility. Drift rates of ∼2 nm h(-1) accompanied by 13 nm × 33 nm imaging resolution at 11.8 keV are reported.

[Fatal incidents by crowd crush during mass events. (Un)preventable phenomenon?]. / Tödliche zwischenfälle durch menschengedränge bei grossveranstaltungen. (Un-)vermeidbares phänomen?

BACKGROUND: Crowd crushes with dozens or even hundreds of casualties have occurred several times at the Hajj in Saudi Arabia and also in soccer stadiums in Western Europe. As fatal accidents after human stampedes during mass events occur very rarely and are usually accompanied by many years of criminal court proceedings in order to identify underlying responsible mechanisms and culprits, it is very difficult to draw conclusions and formulate precautions from an emergency medical point of view. METHODS: This study analyzed a fatal crowd crush which occurred on 4 December 1999 following the "Air & Style" snowboard contest with approximately 22,000 people attending in the Bergisel stadium in Innsbruck, Austria. Firstly, focused interviews were conducted with professional rescuers, police and physicians and secondly publicly available court records dealing with this incident in the district court of Innsbruck, Austria were analyzed. RESULTS: During the snowboard contest 87 emergency medical technicians, 6 emergency physicians, 1 leading emergency physician, 21 policemen and 140 security personnel were present. Following the accident additionally some 100 emergency medical technicians, 36 emergency medical service vehicles and 4 physician-staffed emergency medical service vehicles responded to the scene. The deadly crowd crush resulting in 6 fatalities, 4 patients still in a vegetative state and 38 injured, was due to a severe crowd accumulation at one stadium exit, which was not recognized and dispersed in time. Construction of the exit in line with darkness, steep slope and slippery surface contributed adversely to this dangerous situation, although panic did not occur at any time. CONCLUSIONS: Unfortunately, there is no patent remedy to completely prevent fatal accidents by a crowd crush at mass events. If planning is initiated early, sufficient material and personnel reserves are kept in reserve and despite conflicting interests of the organizers, the host community, security, police and emergency medical services, a joint concept is designed and followed, the risk of a severe incident can be kept to a minimum. Each involved party including the spectators have to be aware of their responsibility in order to contribute to the success and safety of the mass event. A comprehensive and critical review of all facts and implementation of conclusions implies a time and financial burden but has a positive impact on the success and safety of mass events.

Quality assurance and improvement in oncology using guideline-derived quality indicators - results of gynaecological cancer centres certified by the German cancer society (DKG).

PURPOSE: Based on the example of Gynaecological Cancer Centres (GCCs) certified by the German Cancer Society, this study evaluates the results of medical-guideline-derived quality indicators (QIs) for cervical cancer (CC) and ovarian cancer (OC), examines the development of indicator implementation over time as well as the status of guideline-compliant care and identifies improvement measures. METHODS: QI results for patients with CC and OC treated in GCCs between 2015 and 2019 are analysed. The median, overall proportion and standard deviation of each QI were calculated. Two-sided Cochran-Armitage tests were applied. RESULTS: QIs are divided into two categories: process-organization (PO-QIs) and treatment-procedures (TP-QIs), to allow a differentiated analysis for identifying improvement measures. PO-QIs that reflect the implementation of processes and structures show a high degree of application. PO-QIs have a tremendous influence on the quality of care and are easy to implement through SOPs. TP-QIs report on treatments that are performed in the GCC. TP-QIs that report on systemic therapies reach a plateau where the guideline is known, but patient-related-factors meaningfully prevent further increase. TP-QIs that report on surgical interventions fluctuate. The most relevant factors are practitioners' personal skills. Besides the discussion of results amongst peers during the audit, improvement measures could include surgical courses or coaching. CONCLUSION: The analysis shows that a combination of different measures is necessary to anchor quality sustainably in health care and thus improve it.

Final overall survival results of phase III GCIG CALYPSO trial of pegylated liposomal doxorubicin and carboplatin vs paclitaxel and carboplatin in platinum-sensitive ovarian cancer patients.

BACKGROUND: The CALYPSO phase III trial compared CD (carboplatin-pegylated liposomal doxorubicin (PLD)) with CP (carboplatin-paclitaxel) in patients with platinum-sensitive recurrent ovarian cancer (ROC). Overall survival (OS) data are now mature. METHODS: Women with ROC relapsing > 6 months after first- or second-line therapy were randomised to CD or CP for six cycles in this international, open-label, non-inferiority trial. The primary endpoint was progression-free survival. The OS analysis is presented here. RESULTS: A total of 976 patients were randomised (467 to CD and 509 to CP). With a median follow-up of 49 months, no statistically significant difference was observed between arms in OS (hazard ratio = 0.99 (95% confidence interval 0.85, 1.16); log-rank P = 0.94). Median survival times were 30.7 months (CD) and 33.0 months (CP). No statistically significant difference in OS was observed between arms in predetermined subgroups according to age, body mass index, treatment-free interval, measurable disease, number of lines of prior chemotherapy, or performance status. Post-study cross-over was imbalanced between arms, with a greater proportion of patients randomised to CP receiving post-study PLD (68%) than patients randomised to CD receiving post-study paclitaxel (43%; P < 0.001). CONCLUSION: Carboplatin-PLD led to delayed progression and similar OS compared with carboplatin-paclitaxel in platinum-sensitive ROC.

A phase II trial (AGO 2.11) in platinum-resistant ovarian cancer: a randomized multicenter trial with sunitinib (SU11248) to evaluate dosage, schedule, tolerability, toxicity and effectiveness of a multitargeted receptor tyrosine kinase inhibitor monotherapy.

BACKGROUND: Recurrent platinum-resistant ovarian cancer usually has a poor outcome with conventional chemotherapeutic therapy and new treatment modalities are warranted. This phase II study was conducted to evaluate sunitinib, an oral antiangiogenic multitargeted tyrosin kinase inhibitor, in this setting. MATERIAL AND METHODS: The primary end point of this randomized phase II trial was the objective response rate according to RECIST criteria and/or Gynecologic Cancer InterGroup CA125 response criteria to sunitinib in patients with recurrent platinum-resistant ovarian cancer who were pretreated with up to three chemotherapies. A selection design was employed to compare two schedules of sunitinib (arm 1: 50 mg sunitinib daily orally for 28 days followed by 14 days off drug; and arm 2: 37.5 mg sunitinib administered daily continuously). RESULTS: Of 73 patients enrolled, 36 patients were randomly allocated to the noncontinuous treatment arm (arm 1) and 37 patients were randomly allocated to the continuous treatment arm (arm 2). The mean age was 58.8 and 58.5 years, respectively. We observed six responders (complete response + partial response) in arm 1 (16.7%) and 2 responders in arm 2 (5.4%). The median progression-free survival (arm 1: 4.8 [2.9-8.1] months; arm 2: 2.9 [2.9-5.1] months) and the median overall survival (arm 1: 13.6 [7.0-23.2] months; arm 2: 13.7 [8.4-25.6] months) revealed no significant difference. Adverse events included fatigue as well as cardiovascular, gastrointestinal and abdominal symptoms, hematologic and hepatic laboratory abnormalities. Pattern and frequency of adverse events revealed no substantial differences between both treatment groups. CONCLUSIONS: Sunitinib treatment is feasible and moderately active in relapsed platinum-resistant ovarian cancer. The noncontinuous treatment schedule should be chosen for further studies in ovarian cancer.

Corticotropin releasing hormone (CRH) response in patients with early rheumatoid arthritis due to polymorphisms in the CRH gene.

OBJECTIVES: To further evaluate the impact of corticotropin releasing hormone (CRH) promoter polymorphisms on the stress response in rheumatoid arthritis (RA) patients an insulin hypoglycaemia test (IHT) was performed studying the dynamics of CRH production. METHODS: Polymorphisms of the human CRH promoter were determined in controls and cortisol naive patients with early RA. Serum glucose and plasma CRH were measured at baseline and up to 120 min following induction of hypoglycemia. RESULTS: During IHT RA patients bearing the A2B2 allele exhibited an earlier CRH response compared to A1B1 positive patients. CONCLUSIONS: Stress-induced response of CRH is differentially modulated by CRH promoter polymorphisms in RA patients.

[Systematic assessment and improvement of medical data quality]. / Systematische Bewertung und Steigerung der Qualität medizinischer Daten.

Public health research depends on empirical information that is based on data of high quality. The aim of this study was to apply the current guidelines developed by the Technology and Methodology Platform for Networked Medical Research (TMF) for the independent assessment and enhancement of data quality. A clinical register of female breast cancer patients from two periods (N = 389 of 1996-1997 and N = 488 of 2003-2004) was used. To check the plausibility, organization, and correctness of the data quality levels, data quality indicators (DQI) were chosen, operationalized, and the variance ratios of normative-analytic-defined thresholds were calculated. Significant deviations led to data improvement, which included the commonly known source data verification (SDV). A summary data quality score was calculated before and after application of the guidelines. Eleven out of 24 DQIs were tested. Data quality systematically increased from 51.6 to 67.7%. The guidelines facilitate a systematic assessment and improvement of data quality with a reasonable use of resources. This target-oriented procedure allows for a high transparency of the available data quality, which is essential for health research.

Prognostic nomogram to predict progression-free survival in patients with platinum-sensitive recurrent ovarian cancer.

BACKGROUND: Patients with platinum-sensitive recurrent ovarian cancer are a heterogeneous group, and it is not possible to accurately predict the progression-free survival (PFS) in these patients. We developed and validated a nomogram to help improve prediction of PFS in patients treated with platinum-based chemotherapy. METHODS: The nomogram was developed in a training cohort (n=955) from the CALYPSO trial and validated in the AGO-OVAR 2.5 Study (n=340). The proportional-hazards model (nomogram) was based on pre-treatment characteristics. RESULTS: The nomogram had a concordance index (C-index) of 0.645. Significant predictors were tumour size platinum-chemotherapy-free interval, CA-125, number of organ metastatic sites and white blood count. When the nomogram was applied without CA-125 (CA-125 was not available in validation cohort), the C-indices were 0.624 (training) and 0.594 (validation). When classification was based only on the platinum-chemotherapy-free interval, the indices were 0.571 (training) and 0.560 (validation). The calibration plot in the validation cohort based on four predictors (without CA-125) suggested good agreement between actual and nomogram-predicted 12-month PFS probabilities. CONCLUSION: This nomogram, using five pre-treatment characteristics, improves prediction of PFS in patients with platinum-sensitive ovarian cancer having platinum-based chemotherapy. It will be useful for the design and stratification of patients in clinical trials and also for counselling patients.

Intraperitoneal treatment with the trifunctional bispecific antibody Catumaxomab in patients with platinum-resistant epithelial ovarian cancer: a phase IIa study of the AGO Study Group.

OBJECTIVE: The aim of this study was to select the best catumaxomab regimen for further investigation in ovarian cancer based on confirmed tumour response. METHODS: Randomised open-label phase IIa study in women with platinum-resistant or -refractory epithelial ovarian cancer. Catumaxomab (6-hour intraperitoneal infusion on days 0, 3, 7 and 10) was administered at a low (10, 10, 10 and 10 µg) or high dose (10, 20, 50 and 100 µg). Responders were patients with either a complete (CR) or partial (PR) response. RESULTS: Forty-five patients were randomised to receive either low dose (23) or high dose (22). There were no responders in the low-dose versus one patient (5%) in the high-dose group with a PR. In the low-dose group, two patients (9%) had stable disease compared with five patients (23%) in the high-dose group. Catumaxomab was well tolerated and there was no difference between the dose groups in the incidence of treatment-induced adverse events, the most common of which were gastrointestinal and injection-site reactions. CONCLUSION: Catumaxomab had modest activity in platinum-resistant ovarian cancer. The high-dose regimen was associated with a slightly better therapeutic index than the low dose regimen.

[Immune senescence and autoimmunity. Does the immune system really age, or just the organs which supply it?]. / Immunseneszenz und Autoimmunität. Altert das Immunsystem wirklich, oder nur die Organe, die es versorgen?

Degenerative ageing processes are to a great extent responsible for organ-specific morbidity and mortality among our population. The incidence of many autoimmune diseases also increases significantly with age, as is evident with rheumatoid arthritis (RA) for example. From an immunological and pathogenetic perspective, that the changes in the immune system of RA patients is comparable to the physiological ageing process seen in healthy individuals approximately 20 years later is of great interest. Despite the manifold functional changes seen in the immune system of older people, the incidence of infection in very elderly patients with RA is only marginally increased, such that immune suppression in older RA patients should be carried out just as consequently as in younger patients. Age-related changes and diseases in other organ systems should receive particular attention, since such complications can have a negative effect on the course of the autoimmune disease as well as the rate of side effects.