Comparison of wavefront sensing and ablation imprinting for FEL focus diagnostics at FLASH2.

Extreme ultraviolet (EUV) photon beam characterization techniques, Hartmann wavefront sensing and single shot ablation imprinting, were compared along the caustic of a tightly focused free-electron laser (FEL) beam at beamline FL24 of FLASH2, the Free-electron LASer in Hamburg at DESY. The transverse coherence of the EUV FEL was determined by a Young's double pinhole experiment and used in a back-propagation algorithm which includes partial coherence to calculate the beam intensity profiles along the caustic from the wavefront measurements. A very good agreement of the profile structure and size is observed for different wavelengths between the back-propagated profiles, an indirect technique, and ablation imprints. As a result, the Hartmann wavefront sensor including its software MrBeam is a very useful, single shot pulse resolved and fast tool for non-invasive determination of focal spot size and shape and also for beam profiles along the caustic.

Transition from Paediatric to Adult Care in CAH: 20 Years of Experience at a Tertiary Referral Center.

Transition medicine aims at the coordinated transfer of young patients with a chronic disease from paediatric to adult care. The present study reflects 20 years of experience in transitioning patients with congenital adrenal hyperplasia (CAH) in a single center setting. Our endocrine transition-clinic was established in 2002 and offers joint paediatric and adult consultations. Data were evaluated retrospectively from 2002 to 2005 and 2008 to present. Fifty-nine patients (29 males) were transferred. Median age was 18.4 years (17.6-23.6). Ninety percent of the patients presented with 21-hydroxlase-deficiency (21-OHD), 38 patients (23 m) with salt-wasting (sw), 7 (1 m) with simple-virilising (sv) and 8 (3 m) with the non-classic (nc) form. Rarer enzyme deficiencies were found in 6 cases: 17α-OHD (2 sisters), P450-oxidoreductase-deficiency (2 siblings), 3ß-hydroxysteroid-dehydrogenase-deficiency (1 m) and 11ß-OHD (1 female). Thirty-four patients (57.6%, 20 m) are presently still attending the adult clinic, 1 patient (1.7%, m) moved away and 24 (40.7%, 8 m) were lost to follow-up (13 sw-21-OHD, 6 sv-21-OHD, 5 nc-21-OHD). Thirty-seven patients (62.7%) attended the adult clinic for >2 years after transfer, 17 (28.8%) for >10 years. In the lost to follow-up group, median time of attendance was 16.3 months (0-195.2). Defining a successful transfer as two or more visits in the adult department after initial consultation in the transition clinic, transfer was efficient in 84.7% of the cases. A seamless transfer to adult care is essential for adolescents with CAH. It requires a continuous joint support during the transition period, remains challenging, and necessitates adequate funding.

The beam transport system for the Small Quantum Systems instrument at the European XFEL: optical layout and first commissioning results.

The Small Quantum Systems instrument is one of the six operating instruments of the European XFEL, dedicated to the atomic, molecular and cluster physics communities. The instrument started its user operation at the end of 2018 after a commissioning phase. The design and characterization of the beam transport system are described here. The X-ray optical components of the beamline are detailed, and the beamline performances, transmission and focusing capabilities are reported. It is shown that the X-ray beam can be effectively focused as predicted by ray-tracing simulations. The impact of non-ideal X-ray source conditions on the focusing performances is discussed.

High-Resolution Table-Top NEXAFS Spectroscopy.

A table-top near-edge X-ray absorption fine structure (NEXAFS) spectroscopy system consisting of a soft X-ray source and an integrated spectrometer with a significantly improved resolution is presented. The soft X-ray source is based on a long-term stable and nearly debris-free picosecond laser-induced plasma generated in a pulsed krypton gas jet target. Photon energies ranging from 250 to 1000 eV can be used for the absorption spectroscopy of thin samples. The newly designed spectrometer accomplishes a spectral resolution of E/ΔE = 1535 at 430 eV, being close to typical synchrotron setups. Moreover, a simultaneous multi-edge analysis is possible. The performance of the new system is demonstrated by investigating the fine structure of the K- and L-absorption edges of various elements (carbon, calcium, oxygen, iron, nickel, and copper) for different types of samples. An excellent agreement with synchrotron spectra is achieved.

Evaluation of coercive measures in different psychiatric hospitals: the impact of institutional characteristics.

BACKGROUND: Epidemiological studies have demonstrated considerable differences in the use of coercive measures among psychiatric hospitals; however, the underlying reasons for these differences are largely unclear. We investigated to what extent these differences could be explained by institutional factors. METHODS: Four psychiatric hospitals with identical responsibilities within the mental health care system, but with different inpatient care organizations, participated in this prospective observational study. We included all patients admitted over a period of 24 months who were affected by mechanical restraint, seclusion, or compulsory medication. In addition to the patterns of coercive measures, we investigated the effect of each hospital on the frequency of compulsory medication and the cumulative duration of mechanical restraint and seclusion, using multivariate binary logistic regression. To compare the two outcomes between hospitals, odds ratios (OR) with corresponding 95% confidence intervals (CI) were calculated. RESULTS: Altogether, coercive measures were applied in 1542 cases, corresponding to an overall prevalence of 8%. The frequency and patterns of the modalities of coercive measures were different between hospitals, and the differences could be at least partially related to institutional characteristics. For the two hospitals that had no permanently locked wards, certain findings were particularly noticeable. In one of these hospitals, the probability of receiving compulsory medication was significantly higher compared with the other institutions (OR 1.9, CI 1.1-3.0 for patients < 65 years; OR 8.0, CI 3.1-20.7 for patients ≥65 years); in the other hospital, in patients younger than 65 years, the cumulative duration of restraint and seclusion was significantly longer compared with the other institutions (OR 2.6, CI 1.7-3.9). CONCLUSIONS: The findings are compatible with the hypothesis that more open settings are associated with a more extensive use of coercion. However, due to numerous influencing factors, these results should be interpreted with caution. In view of the relevance of this issue, further research is needed for a deeper understanding of the reasons underlying the differences among hospitals.

Improved gas-jet based extreme ultraviolet, soft X-ray laser plasma source.

We present a new nozzle design for an improved brilliance of laser-produced gas plasmas emitting in the soft X-ray and extreme ultraviolet spectral regime. A rotationally asymmetric gas jet is formed by employing two closely adjacent nozzles facing each other under the angle of 45°. The generated three-dimensional gas density distribution is tomographically analyzed using a Hartmann-Shack wavefront sensor. A comparison with numerical simulations accomplishes an optimization of the nozzle arrangement. The colliding gas jets create an optimized gas distribution with increased density, leading to a significant brilliance enhancement of the extreme ultraviolet, soft X-ray plasma.

[3-Countries-Manifest: Turning Point in Medicine - Patient Care on the Dangerous Path to Economization and Industrialization - 10 Demands for Humane Medical Care]. / 3-Länder-Manifest: Zeitenwende in der Medizin ­ Patientenversorgung auf dem gefährlichen Weg in die Ökonomisierung und Industrialisierung.

The 3-Country-Manifest extends beyond existing oaths, vows and codices. It is supposed to encourage discussion and close the gap in the conflict between medical-ethical principles and a dangerous development through economisation, commercialisation and industrialisation of the patient care.Ten demands are raised to clarify the medical profession's urgent concerns due to economic, technological and medical-ethical developments and as a result ensure that patient welfare will remain the pivotal measure of medicine in the future.The Physicians 3-Country-Manifest addresses concrete suggestions and topics as a starting point for a change in awareness and attitude in all interest groups in health care. It wants to accomplish the necessary turning point towards humanely designed medical care.

Adherence to long-term prophylactic treatment: microeconomic analysis of patients' behavior and the impact of financial incentives.

The effectiveness of medical therapies depends crucially on patients' adherence. To gain deeper insight into the behavioral mechanisms underlying adherence, we present a microeconomic model of the decision-making process of an individual who is initially in an asymptomatic clinical state and to whom a prophylactic therapy is offered with the aim of preventing damage to health in the future. The focus of modeling is the optimization of an intertemporal utility function, where time-inconsistent preferences are incorporated by a quasi-hyperbolic discount function. The predictions of the model concur with experience in clinical practice. Moreover, the introduction of time-inconsistency reveals a self-control problem of the individuals where resolutions made before may be given up at a later time. A more pronounced present bias leads to a decrease in adherence and, consequently, the gain in societal welfare resulting from the prophylactic therapy declines. Developing effective strategies to improve adherence is a major challenge in health care. As an example, the impact of financial incentives offered to the patients on adherence and welfare are investigated on the basis of the model. The results are consistent with empirical findings. The approach presented contributes to a better understanding of the complex interaction of the relevant determinants for adherence, particularly regarding the individuals' self-control problem.

[It can not be healthy not to be ill]. / Gar ned krank is a ned g'sund.

This article is written in remembrance of Karl Valentin's 70th anniversary of his death. He was a comedian and song writer suffering from vegetative dystonia and depression lifelong. This hypochondriac developed extreme self observation and had anxiety to get ill permanently. As one year old, his brother died of diphteria and he was close to death himself. After jumping in an ice cold river in Munich as a young man he caught a pneumonia. From that day he had a undefined long lasting lung disease. His performances and pieces of literature in Bavarian dialect are characterized by critical thoughts about the world in general and human vulnerability including his own in a philosophical way. His sarcastic view of the world, which was rarely pleasant for the counterpart still induced admiration of many audiences and was satisfying for Karl Valentin's egocentrism. He has been the most famous Bavarian comedian during world war II and during the early days of the Republic of Germany.

Papillary Thyroid Cancer and Coexisting Autoimmune Thyroiditis.

Histological findings often display an association between papillary thyroid carcinomas (PTC) and autoimmune thyroiditis (AIT) and so differ significantly from follicular thyroid carcinomas (FTC). The aim of this interdisciplinary, retrospective study was to evaluate the association of AIT in patients with PTC and FTC and a control group of benign nodular goiters. One hundred thyroidectomies with histologically confirmed differentiated thyroid carcinomas, 67 with PTC and 33 with FTC, were submitted for examination. The two control groups consisted of 60 patients with euthyroid nodular goiter, displaying no signs for malignancy (no surgery) and 100 patients (second control group) with surgery of a benign nodular goiter. Controls were collected to obtain data about the incidence of significantly increased TPOAbs in the first group and of lymphocytic infiltrates (LI) in the second group. High TPOAbs were found in 35% (23/67) of patients with PTC. LI were detected by histology in 48% (32/67) of PTC. Ten patients (10/32) of this group showed the clinical and histological manifestation of a classic AIT with diffuse dense LI as well as diffuse hypoechogeneity in ultrasonography. In 7/32 cases, the histological report described focal dense LI (fAIT) and in 15/32 cases scant scattered LI. AIT and fAIT, together 25% of all PTC (17/67), showed germinal centers and can therefore be characterized as chronic autoimmune thyroiditis. In this group, high TPOAb could be detected in 94% (16/17). Scan scattered LI without germinal centers (15/32) do not represent a fAIT, although TPOAb are high in 47% (7/15). The younger age group (<45 years) showed significantly more often high TPOAbs (p<0.023) in comparison with the age-group older than 60 years. In contrast to PTC, only 4/33 (12%) patients with FTC had high TPOAb levels. We conclude that in contrast to benign euthyroid goiters and to FTC, different degrees of LI are often associated with high TPOAb levels and seem to be significantly increased in PTC, particularly prominent in younger age. There is a high coincidence between LI and high TPOAb levels. In the presence of hypoechoic thyroid nodule, signs of thyroid autoimmunity such as the presence of high TPOAbs, lymphocytic infiltration in cytology, and/or characteristic ultrasonic features, are arguments that might favor the decision for surgery if a cytologically indeterminate thyroid nodule is found and focal autonomy is excluded by szintiscan.

Passive compensation of laser-induced higher-order aberrations in high-power NIR optics.

We report a method for passive compensation of thermally induced focal shifts and higher-order aberrations of NIR laser processing optics. Theoretical considerations are made on the elimination of aberrations including polarization effects using a multi-stage compensation element with optical flats of both positive and negative dn/dT. A compensation layout is designed and optimized utilizing numerical simulations of thermo-optic effects. Based on these findings, optical elements for compensation of an F-Theta objective are manufactured. By means of wavefront measurements and beam caustic measurements the feasibility of simultaneous passive compensation of focal shifts and higher-order aberrations is demonstrated.

[Endocrine problems during pregnancy]. / Wichtige endokrine Funktionsstörungen bei Schwangeren.

Endocrine disorders may have an important influence on fertility, the course of a pregnancy and fetal development. For example, fertility is decreased and the risk of miscarriage is increased in women with autoimmune disorders, such as Addison's disease or autoimmune thyroiditis. Treatment of endocrine diseases in many cases has to be adapted during the course of a pregnancy. In patients with Addison's disease the dosage of hydrocortisone necessarily has to be increased. This is also valid for the time of delivery. Disorders of the thyroid gland are of great importance during pregnancy. If hypothyroidism is diagnosed in early pregnancy, immediate treatment with levothyroxine should be initiated. Iodine supplementation is strongly recommended in all pregnant and breast-feeding women. Treatment of Graves's disease will be performed during the first trimenon with propylthiouracile, afterwards with methimazole (thiamazole). In contrast, thyrotoxicosis due to hCG should not be treated with methimazole. In this paper, we present an overview on the most important endocrine disorders during pregnancy.

The BH3 mimetic drug ABT-737 induces apoptosis and acts synergistically with chemotherapeutic drugs in thyroid carcinoma cells.

BACKGROUND: Patients with dedifferentiated and anaplastic thyroid carcinomas that do not take up radioiodine are resistant to chemotherapeutic treatment and external irradiation and thus are difficult to treat. Direct induction of apoptosis is a promising approach in these apoptosis-resistant tumor cells. The BH3 mimetic ABT-737 belongs to a new class of drugs that target anti-apoptotic proteins of the BCL-2 family and facilitate cell death. The purpose of this study was to investigate the effect of ABT-737 alone or in combination with chemotherapeutic drugs on thyroid carcinoma cell lines. METHODS: A total of 16 cell lines derived from follicular, papillary, and anaplastic thyroid carcinomas were treated with ABT-737. Cell viability was measured with MTT assay. Cell death was determined by cell cycle phase distribution and subG1 peak analyses, determination of caspase 3/7 activity and caspase cleavage products, lactate dehydrogenase (LDH) liberation assays and LC3 analysis by western blot. RESULTS: The number of viable cells was decreased in all cell lines examined after ABT-737 treatment, with IC50 values ranging from 0.73 to 15.6 µM. Biochemical markers of apoptosis like caspase activities, caspase cleavage products and DNA fragmentation determined as SubG1 peak were elevated after ABT-737 treatment, but no LC3 cleavage was induced by ABT-737 indicating no autophagic processes. In combination with doxorubicin and gemcitabine, ABT-737 showed synergistic effects on cell viability. CONCLUSIONS: With these experiments we demonstrated the efficacy of the BH3 mimetic drug ABT-737 against dedifferentiated thyroid carcinoma cells of various histological origins and showed synergistic effects with chemotherapeutic drugs. ABT-737-treated cells underwent an apoptotic cell death. ABT-737 and related BH3 mimetic drugs, alone or in combination, may thus be of value as a new therapeutic option for dedifferentiated thyroid carcinomas.

Resting heart rate is an independent predictor of all-cause mortality in the middle aged general population.

BACKGROUND: High resting heart rate (RHR) predicts cardiovascular outcomes in patients with vascular disease and heart failure. We evaluated the prognostic value of RHR in a large contemporary population-based, prospective cohort of individuals without known coronary artery disease. METHODS AND RESULTS: Resting heart rate (RHR) was determined in 4091 individuals (mean age 59.2 ± 7.7; 53 % women) from the Heinz Nixdorf RECALL study, of whom, 3348 were free of heart rate lowering medication. During 10.5 years of follow-up (median), 159 (3.9 %) individuals developed a coronary event and 398 (9.7 %) died of any cause. Persons without any event (n = 3603) had similar heart rates as persons with coronary events (69.5 ± 11 versus 69.9 ± 11 bpm, p = 0.51) but lower heart rates than persons who died (72.3 ± 13 bpm, p < 0.0001). In individuals without heart rate lowering medication, an increase in heart rate by 5 bpm was associated with an increased hazard ratio (HR) for all-cause mortality of 13 % in unadjusted analysis and also upon adjustment for traditional cardiovascular risk factors, including coronary artery calcification [full model: HR (95 % CI) 1.13 (1.07-1.20), p < 0.0001], but not for coronary events [HR 1.02 (0.94-1.11), p = 0.60]. In individuals without heart rate lowering medication, the HR (full model) for heart rate ≥70 versus <70 bpm with regard to all-cause mortality and coronary events was 1.68 (1.30-2.18), p < 0.0001, and 1.20 (0.82-1.77), p = 0.35. Analysis of the entire cohort revealed a continuous relationship of heart rate with all-cause mortality [HR for lowest to highest heart rate quartile 1.64 (1.22-2.22), p = 0.001, full model] but not with coronary events [HR 1.04 (0.65-1.66), p = 0.86]. CONCLUSIONS: In the general population without known coronary artery disease and heart rate lowering medication, elevated RHR is an independent risk marker for all-cause mortality but not for coronary events.

Hartmann wavefront sensors and their application at FLASH.

Different types of Hartmann wavefront sensors are presented which are usable for a variety of applications in the soft X-ray spectral region at FLASH, the free-electron laser (FEL) in Hamburg. As a typical application, online measurements of photon beam parameters during mirror alignment are reported on. A compact Hartmann sensor, operating in the wavelength range from 4 to 38 nm, was used to determine the wavefront quality as well as aberrations of individual FEL pulses during the alignment procedure. Beam characterization and alignment of the focusing optics of the FLASH beamline BL3 were performed with λ(13.5 nm)/116 accuracy for wavefront r.m.s. (w(rms)) repeatability, resulting in a reduction of w(rms) by 33% during alignment.

Induction of atypical cell death in thyroid carcinoma cells by the indirubin derivative 7-bromoindirubin-3'-oxime (7BIO).

BACKGROUND: The indirubin derivative 7-bromoindirubin-3'-oxime (7BIO) has already shown anticancer properties by causing cell death in some tumour cell lines and may be a new therapeutic option for treatment-resistant tumour cells. Since dedifferentiated and anaplastic thyroid carcinomas do not take up radioiodine and are insensitive to chemotherapeutic treatment and external radiation, direct cell death induction in these tumour cells may be a promising approach. We thus investigated the effect of 7BIO on thyroid carcinoma cell lines of different histological origins and characterized the type of cell death induction by 7BIO. METHODS: Cell viability was measured with MTT assay. Cell death was analysed by caspase 3/7 activity, lactate dehydrogenase liberation, caspase cleavage products, DNA fragmentation, cell cycle phase distribution and LC3B analysis. RESULTS: After 7BIO treatment, cell viability was reduced in all 14 thyroid carcinoma cell lines investigated. Treated cells showed DNA fragmentation, cell cycle arrest and lactate dehydrogenase liberation but no LC3B cleavage. Caspase activation following 7BIO treatment was found in five of six cell lines investigated. Interestingly, inhibition of caspases had no effect on viability of the cells after 7BIO incubation. CONCLUSIONS: Our results indicate that 7BIO efficiently killed dedifferentiated thyroid carcinoma cells. It induced a non-classical kind of cell death that was caspase-independent and includes DNA fragmentation. 7BIO and related indirubin components thus may have value as a new therapeutic option for dedifferentiated thyroid cancer irrespective of the exact target molecules and the kind of cell death they induce.

Cell death induction by the BH3 mimetic GX15-070 in thyroid carcinoma cells.

BACKGROUND: The evasion of cell death is one of the hallmarks of cancer, contributing to both tumor progression and resistance to therapy. Dedifferentiated and anaplastic thyroid carcinomas that do not take up radioiodine are resistant to conventional anticancer treatments and patients with these tumors are difficult to treat. BH3 mimetics are a new class of drugs that target anti-apoptotic proteins of the BCL-2 family and promote cell death. The purpose of this study was to analyze the molecular effects of the BH3 mimetic GX15-070 on thyroid carcinoma cell lines and to characterize cell death induced by GX15-070. METHODS: A total of 17 cell lines derived from follicular, papillary, and anaplastic thyroid carcinomas were treated with GX15-070. Cell viability was measured with MTT assay while cell cycle phase distribution and subG1 peaks were determined after propidium iodide staining. We assessed cell death via the caspase 3/7 activity, caspase cleavage products, lactate dehydrogenase (LDH) liberation assays, and a LC3 analysis by western blot. Ultrastructural changes were analysed by electron microscopy of GX15-070-treated cells. RESULTS: After GX15-070 treatment, the number of viable cells was decreased in all cell lines examined, with IC50 values ranging from 48nM to 3.25 µM. We observed biochemical markers of autophagic cell death and necrosis like LC3 conversion and LDH release after the GX15-070 treatment. Electron microscopy revealed several common characteristic ultrastructural changes like swelling of mitochondria, dilatation of rough endoplasmic reticulum, membrane blebbing and formation of vacuoles. GX15-070 treatment induced DNA fragmentation detected by subG1-peak induction and an arrest in G1 phase of the cell cycle. Caspase activation after GX15-070 incubation was detected but had no effect on viability of cells. CONCLUSIONS: With these experiments we demonstrated the efficacy of the BH3 mimetic drug GX15-070 acting against dedifferentiated thyroid carcinoma cells of various histological origins by the induction of cell death. GX15-070-treated cells underwent non-classical cell death with signs of apoptosis, autophagy and necrosis in parallel. GX15-07 and related compounds thus may be a new therapeutic option for dedifferentiated thyroid carcinoma of various histological subtypes.

Prediction of therapy response in acromegalic patients under pegvisomant therapy within the German ACROSTUDY cohort.

PURPOSE: This study aimed at investigating predicting factors for therapy response under growth hormone receptor antagonist therapy with a focus on subjective and patient-oriented measures. METHODS: Observational, multicenter nested-cohort study including 271 selected patients with the diagnosis of acromegaly and a minimum of one-year follow-up period within the German ACROSTUDY cohort (total cohort: n = 514). Outcome measures were the change of the biomarker IGF-1 (IGF-1 change and IGF-1 normalisation) between baseline and after 1 year of pegvisomant therapy (12 ± 6 months). Main predictors were patient-assessed subjective measures according to the Patient-Assessed Acromegaly Symptom Questionnaire (PASQ) in conjugation with age, gender, BMI, max. dosage of pegvisomant at follow-up and IGF-1 before the start of pegvisomant therapy. RESULTS: The mean age of the study population was 51.2 (13.9) years and the mean BMI was 29.5 (5.1) kg/m(2). In adjusted analyses, none of the individual perceived health (PASQ) scores, but age, BMI and IGF-1 at baseline were predictive for an IGF-1 decrease after 1 year of pegvisomant therapy and BMI and IGF-1, but equally none of the PASQ items, were predicting IGF-1 normalisation. CONCLUSIONS: Age, BMI and baseline IGF-1 but not subjective perceived health measures predict therapy response under second line medical therapy with pegvisomant.

Toroidal grating astigmatism of high-harmonics characterized by EUV Hartmann sensor.

The beam transport of single high-order harmonics in a monochromator arrangement is studied. A toroidal grating combines spectral filtering and focusing in order to produce a small individual spot for each harmonic. Here, the effect of small deviations from perfect alignment is investigated. Experimentally, a Hartmann sensor monitors the EUV wavefront while the grating is subjected to an online alignment procedure. The obtained results are confirmed by a simple theoretical description employing optical matrix methods.