50-W average power Ho:YAG SESAM-modelocked thin-disk oscillator at 2.1 um

Ultrafast laser systems operating with high-average power in the wavelength range from 1.9 um to 3 um are of interest for a wide range of applications for example in spectroscopy, material processing and as drivers for secondary sources in the XUV spectral region. In this area, laser systems based on holmium-doped gain materials directly emitting at 2.1 um have made significant progress over the past years, however so far only very few results were demonstrated in power-scalable high-power laser geometries. In particular, the thin-disk geometry is promising for directly modelocked oscillators with high average power levels that are comparable to amplifier systems at MHz repetition rate. In this paper, we demonstrate Semiconductor Saturable Absorber Mirror (SESAM) modelocked Ho:YAG thin-disk lasers (TDLs) emitting at 2.1 um wavelength with record-holding performance levels. In our highest average power configuration, we reach 50 W of average power, with 1.13 ps pulses, 2.11 uJ of pulse energy and ~1.9 MW of peak power. To the best of our knowledge, this represents the highest average power, as well as the highest output pulse energy so far demonstrated from a modelocked laser in the 2 um wavelength region. This record performance level was enabled by the recent development of high-power GaSb-based SESAMs with low loss, adapted for high intracavity power and pulse energy. We also explore the limitations in terms of reaching shorter pulse durations at high power with this gain material in the disk geometry and using SESAM modelocking, and present first steps in this direction, with the demonstration of 30 W of output power, with 692 fs pulses in another laser configuration.Comment: 12 pages, 10 figure

Ein neues bakterielles, von Adenosin abgeleitetes Nukleosid als Beispiel für RNA-Modifikationsschäden

Die Bereiche RNA-Modifikation und RNA-Schaden weisen beide eine Vielzahl nicht-kanonischer Nukleosidstrukturen auf. Während sich RNA-Modifikationen zur Verbesserung der RNA-Funktion entwickelt haben, impliziert die Bezeichnung RNA-Schaden negative Auswirkungen. Auf Grundlage der Markierung mit stabilen Isotopen und Massenspektrometrie berichten wir von der Identifizierung und Charakterisierung von 2-Methylthio-1,N6-ethenoadenosin (ms2ϵA), welches mit 1,N6-Ethenoadenin, einer Läsion, die durch Exposition von Nukleinsäuren gegenüber alkylierenden Chemikalien in vivo entsteht, verwandt ist. Im Gegensatz dazu zeigte ein ausgefeiltes Konzept zur Isopren-Markierung, dass die Biogenese von ms2ϵA die Spaltung eines Prenylrests in der bekannten transfer-RNA (tRNA)-Modifikation 2-Methylthio-N6-isopentenyladenosin (ms2i6A) beinhaltet. Die relative Häufigkeit von ms2ϵA in tRNAs von translatierenden Ribosomen lässt eine verminderte Funktionalität im Vergleich zur ursprünglichen RNA-Modifikation vermuten, wodurch die Natur der neuen Struktur in einer neu wahrgenommenen Überschneidung der beiden zuvor getrennten Bereiche, nämlich ein RNA-Modifikationsschaden, begründet wird

United European Gastroenterology evidence-based guidelines for the diagnosis and therapy of chronic pancreatitis (HaPanEU)

There have been substantial improvements in the management of chronic pancreatitis, leading to the publication of several national guidelines during recent years. In collaboration with United European Gastroenterology, the working group on 'Harmonizing diagnosis and treatment of chronic pancreatitis across Europe' (HaPanEU) developed these European guidelines using an evidence-based approach.Twelve multidisciplinary review groups performed systematic literature reviews to answer 101 predefined clinical questions. Recommendations were graded using the Grading of Recommendations Assessment, Development and Evaluation system and the answers were assessed by the entire group in a Delphi process online. The review groups presented their recommendations during the 2015 annual meeting of United European Gastroenterology. At this one-day, interactive conference, relevant remarks were voiced and overall agreement on each recommendation was quantified using plenary voting (Test and Evaluation Directorate). After a final round of adjustments based on these comments, a draft version was sent out to external reviewers.The 101 recommendations covered 12 topics related to the clinical management of chronic pancreatitis: aetiology (working party (WP)1), diagnosis of chronic pancreatitis with imaging (WP2 and WP3), diagnosis of pancreatic exocrine insufficiency (WP4), surgery in chronic pancreatitis (WP5), medical therapy (WP6), endoscopic therapy (WP7), treatment of pancreatic pseudocysts (WP8), pancreatic pain (WP9), nutrition and malnutrition (WP10), diabetes mellitus (WP11) and the natural course of the disease and quality of life (WP12). Using the Grading of Recommendations Assessment, Development and Evaluation system, 70 of the 101 (70%) recommendations were rated as 'strong' and plenary voting revealed 'strong agreement' for 99 (98%) recommendations.The 2016 HaPanEU/United European Gastroenterology guidelines provide evidence-based recommendations concerning key aspects of the medical and surgical management of chronic pancreatitis based on current available evidence. These recommendations should serve as a reference standard for existing management of the disease and as a guide for future clinical research

Reverted exhaustion phenotype of circulating lymphocytes as immune correlate of anti-PD1 first-line treatment in Hodgkin lymphoma

While classical Hodgkin lymphoma (HL) is highly susceptible to anti-programmed death protein 1 (PD1) antibodies, the exact modes of action remain controversial. To elucidate the circulating lymphocyte phenotype and systemic effects during anti-PD1 1st-line HL treatment we applied multicolor flow cytometry, FluoroSpot and NanoString to sequential samples of 81 HL patients from the NIVAHL trial (NCT03004833) compared to healthy controls. HL patients showed a decreased CD4 T-cell fraction, a higher percentage of effector-memory T cells and higher expression of activation markers at baseline. Strikingly, and in contrast to solid cancers, expression for 10 out of 16 analyzed co-inhibitory molecules on T cells (e.g., PD1, LAG3, Tim3) was higher in HL. Overall, we observed a sustained decrease of the exhausted T-cell phenotype during anti-PD1 treatment. FluoroSpot of 42.3% of patients revealed T-cell responses against ≥1 of five analyzed tumor-associated antigens. Importantly, these responses were more frequently observed in samples from patients with early excellent response to anti-PD1 therapy. In summary, an initially exhausted lymphocyte phenotype rapidly reverted during anti-PD1 1st-line treatment. The frequently observed IFN-y responses against shared tumor-associated antigens indicate T-cell-mediated cytotoxicity and could represent an important resource for immune monitoring and cellular therapy of HL

United European Gastroenterology evidence-based guidelines for the diagnosis and therapy of chronic pancreatitis (HaPanEU)

Background:There have been substantial improvements in the management of chronic pancreatitis, leading to the publication of several national guidelines during recent years. In collaboration with United European Gastroenterology, the working group on Harmonizing diagnosis and treatment of chronic pancreatitis across Europe' (HaPanEU) developed these European guidelines using an evidence-based approach. Methods: Twelve multidisciplinary review groups performed systematic literature reviews to answer 101 predefined clinical questions. Recommendations were graded using the Grading of Recommendations Assessment, Development and Evaluation system and the answers were assessed by the entire group in a Delphi process online. The review groups presented their recommendations during the 2015 annual meeting of United European Gastroenterology. At this one-day, interactive conference, relevant remarks were voiced and overall agreement on each recommendation was quantified using plenary voting (Test and Evaluation Directorate). After a final round of adjustments based on these comments, a draft version was sent out to external reviewers. Results: The 101 recommendations covered 12 topics related to the clinical management of chronic pancreatitis: aetiology (working party (WP)1), diagnosis of chronic pancreatitis with imaging (WP2 and WP3), diagnosis of pancreatic exocrine insufficiency (WP4), surgery in chronic pancreatitis (WP5), medical therapy (WP6), endoscopic therapy (WP7), treatment of pancreatic pseudocysts (WP8), pancreatic pain (WP9), nutrition and malnutrition (WP10), diabetes mellitus (WP11) and the natural course of the disease and quality of life (WP12). Using the Grading of Recommendations Assessment, Development and Evaluation system, 70 of the 101 (70%) recommendations were rated as strong' and plenary voting revealed strong agreement' for 99 (98%) recommendations. Conclusions:The 2016 HaPanEU/United European Gastroenterology guidelines provide evidence-based recommendations concerning key aspects of the medical and surgical management of chronic pancreatitis based on current available evidence. These recommendations should serve as a reference standard for existing management of the disease and as a guide for future clinical research

Cystatin C, a marker for successful aging and glomerular filtration rate, is not influenced by inflammation

Abstract Background. The plasma level of cystatin C is a better marker than plasma creatinine for successful aging. It has been assumed that the advantage of cystatin C is not only due to it being a better marker for glomerular filtration rate (GFR) than creatinine, but also because an inflammatory state of a patient induces a raised cystatin C level. However, the observations of an association between cystatin C level and inflammation stem from large cohort studies. The present work concerns the cystatin C levels and degree of inflammation in longitudinal studies of individual subjects without inflammation, who undergo elective surgery. Methods. Cystatin C, creatinine, and the inflammatory markers CRP, serum amyloid A (SAA), haptoglobin and orosomucoid were measured in plasma samples from 35 patients the day before elective surgery and subsequently during seven consecutive days. Results. Twenty patients had CRP-levels below 1 mg/L before surgery and low levels of the additional inflammatory markers. Surgery caused marked inflammation with high peak values of CRP and SAA on the second day after the operation. The cystatin C level did not change significantly during the observation period and did not correlate significantly with the level of any of the four inflammatory markers. The creatinine level was significantly reduced on the first postoperative day but reached the preoperative level towards the end of the observation period. Conclusion. The inflammatory status of a patient does not influence the role of cystatin C as a marker of successful aging, nor of GFR

International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations