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State-of-the-art fiber-laser systems can deliver femtosecond pulses at average powers beyond the kilowatt level and multi-mJ pulse energies by employing advanced large-mode-area fiber designs, chirped-pulse amplification, and the coherent combination of parallel fiber amplifiers. By using sophisticated coherent phase control, one or even several output ports can be modulated at virtually arbitrary power levels and switching speeds. In addition, an all-fiber setup for GHz-burst generation is described allowing to access an even wider range of laser parameters. The combination of all these approaches together with the robustness, efficiency, and excellent beam quality inherent to fiber-laser technology has the potential to strongly improve existing materials-processing applications.

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Observations of ocean surface waves at three sites along the northern coast of Alaska show a strong coupling with seasonal sea ice patterns. In the winter, ice cover is complete, and waves are abse...

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The 2011–2014 removal of two dams from the Elwha River, WA, delivered ~ 19 Mt of sediment to the marine environment, creating an opportunity to study the sensitivity of a coastal ecosystem to large-scale sediment input. Macroalgae, the primary habitat-forming species in the nearshore, disappeared from the region. It was hypothesized that this mortality event was caused by a reduction in benthic light availability due to increased turbidity. To investigate this connection, nearshore processes and benthic light availability were monitored at 7 locations along the 10-m isobath in 2016 and 2017. The primary driver of light attenuation was suspended sediment, with measured chlorophyll-a and CDOM concentrations contributing

[Image: see text] GSK2798745, a clinical candidate, was identified as an inhibitor of the transient receptor potential vanilloid 4 (TRPV4) ion channel for the treatment of pulmonary edema associated with congestive heart failure. We discuss the lead optimization of this novel spirocarbamate series and specifically focus on our strategies and solutions for achieving desirable potency, rat pharmacokinetics, and physicochemical properties. We highlight the use of conformational bias to deliver potency and optimization of volume of distribution and unbound clearance to enable desirable in vivo mean residence times.

Die Inzidenz vieler hamatologischer Neoplasien steigt im Alter. Besonders bei den hochproliferativen hamatologischen Neoplasien handelt es sich prinzipiell um kurativ behandelbare Erkrankungen, sofern eine teilweise erhebliche vorubergehende therapieassoziierte Toxizitat und damit verbundene Morbiditat und Mortalitat in Kauf genommen werden. Daher ist die Einschatzung der individuellen Reserven, objektiviert durch ein geriatrisches Assessment, mit Hinblick auf die Therapietolerabilitat von hoher Bedeutung. Es wurde eine Literaturrecherche in PubMed und von Kongressabstracts durchgefuhrt. Zur Einschatzung der individuellen Reserven sollte im Rahmen der Therapieplanung ein geriatrisches Screening erfolgen. Bei Auffalligkeit desselben wird ein geriatrisches Assessment (GA) nachgeschaltet. Dieses beinhaltet eine differenzierte Erfassung von Selbstversorgungskapazitat, Mobilitat, Kognition, Emotion, Ernahrungsstatus und des sozialen Umfelds. Zusatzlich erweist es sich in vielen Fallen als sinnvoll, die individuellen Komorbiditaten und die oftmals begleitende Polypharmazie sorgfaltig zu bewerten. Aus den Befunden des GA werden Interventionen abgeleitet, welche das Auftreten von Komplikationen vermindern konnen. Innerhalb der Hamatologie fehlen hierzu jedoch noch wesentliche Studienergebnisse, sodass die Resultate eines GA gegenwartig nur eine Pradiktion der Therapievertraglichkeit und des assoziierten Risikos fur eine Funktionalitatseinbuse erlauben. Fur die Anpassung der Therapieintensitat und die Integration geriatrischer Interventionen liegt in onkologischen Behandlungskonzepten bislang nur eine geringe Evidenz vor.

RIP1 kinase regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including inflammatory and neurological diseases. Currently, RIP1 kinase inhibitors have advanced into early clinical trials for evaluation in inflammatory diseases such as psoriasis, rheumatoid arthritis, and ulcerative colitis and neurological diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. In this paper, we report on the design of potent and highly selective dihydropyrazole (DHP) RIP1 kinase inhibitors starting from a high-throughput screen and the lead-optimization of this series from a lead with minimal rat oral exposure to the identification of dihydropyrazole 77 with good pharmacokinetic profiles in multiple species. Additionally, we identified a potent murine RIP1 kinase inhibitor 76 as a valuable in vivo tool molecule suitable for evaluating the role of RIP1 kinase in chronic models of disease. DHP 76 showed efficacy in mouse models of both multiple sclerosis and human retinitis pigmentosa.

When treating older adults, a main factor to consider is physical frailty. Because specific assessments in clinical trials are frequently lacking, critical appraisal of treatment evidence with respect to functional status is challenging. Our aim was to identify and categorize assessments for functional status given in clinical trials in older adults to allow for a retrospective characterization and indirect comparison of treatment evidence from these cohorts. We conducted 4 separate systematic reviews of randomized and nonrandomized controlled clinical trials in older people with hypertension, diabetes, depression, and dementia. All assessments identified that reflected functional status were analyzed. Assessments were categorized across 4 different functional status levels. These levels span from functionally not impaired, slightly impaired, significantly impaired, to severely impaired/disabled. If available from the literature, cut-offs for these 4 functioning levels were extracted. If not, or if the existing cut-offs did not match the predefined functional levels, cut-off points were defined by an expert group composed of geriatricians, pharmacists, pharmacologists, neurologists, psychiatrists, and epidemiologists using a patient-centered approach. We identified 51 instruments that included measures of functional status. Although some of the assessments had clearly defined cut-offs across our predefined categories, many others did not. In most cases, no cut-offs existed for slightly impaired or severely impaired older adults. Missing cut-offs or values to adjust were determined by the expert group and are presented as described. The functional status assessments that were identified and operationalized across 4 functional levels could now be used for a retrospective characterization of functional status in randomized controlled trials and observational studies. Allocated categories only serve as approximations and should be validated head-to-head in future studies. Moreover, as general standard, upcoming studies involving older adults should include and explicitly report functional impairment as a baseline characteristic of all participants enrolled.

Geotechnical data are increasingly utilized to aid investigations of coastal erosion and the development of coastal morphological models; however, measurement techniques are still challenged by environmental conditions and accessibility in coastal areas, and particularly, by nearshore conditions. These challenges are exacerbated for Arctic coastal environments. This article reviews existing and emerging data collection methods in the context of geotechnical investigations of Arctic coastal erosion and nearshore change. Specifically, the use of cone penetration testing (CPT), which can provide key data for the mapping of soil and ice layers as well as for the assessment of slope and block failures, and the use of free-fall penetrometers (FFPs) for rapid mapping of seabed surface conditions, are discussed. Because of limitations in the spatial coverage and number of available in situ point measurements by penetrometers, data fusion with geophysical and remotely sensed data is considered. Offshore and nearshore, the combination of acoustic surveying with geotechnical testing can optimize large-scale seabed characterization, while onshore most recent developments in satellite-based and unmanned-aerial-vehicle-based data collection offer new opportunities to enhance spatial coverage and collect information on bathymetry and topography, amongst others. Emphasis is given to easily deployable and rugged techniques and strategies that can offer near-term opportunities to fill current gaps in data availability. This review suggests that data fusion of geotechnical in situ testing, using CPT to provide soil information at deeper depths and even in the presence of ice and using FFPs to offer rapid and large-coverage geotechnical testing of surface sediments (i.e., in the upper tens of centimeters to meters of sediment depth), combined with acoustic seabed surveying and emerging remote sensing tools, has the potential to provide essential data to improve the prediction of Arctic coastal erosion, particularly where climate-driven changes in soil conditions may bias the use of historic observations of erosion for future prediction. Published version

Background Although antihyperglycemic pharmacotherapy in frail older adults with type 2 diabetes mellitus (T2DM) is challenging, recommendations from international guidelines are mainly based on indirect evidence from trials not including frail participants. Objective This systematic review investigated the effectiveness and safety of pharmacotherapy in frail older adults with T2DM. Material and methods Randomized (RCT) and non-randomized prospective clinical trials (non-RCT) were searched in three electronic databases (Medline, Embase, Central) up to October 2018. Trials in older adults with T2DM who were assessed as significantly or severely impaired by defined cut-off scores of assessment instruments on frailty, activities of daily living or physical functional impairment were included. Results Two reviewers independently screened 17,391 references for inclusion and assessed risk of bias with ROBINS‑I. Five non-RCTs and no RCT were identified. Treatment of T2DM without insulin compared to insulin could be associated with increased improvement in cardiac functions in patients with cardiac resynchronization therapy and with decreased falls in frail older women. While better glycemic control with low variability and low HbA1c (hemoglobin A1c) values ( Conclusion Well-designed, large-scale RCTs including this important group of patients are required to assess the effectiveness and safety of pharmacotherapy and HbA1c targets.

The \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^2{\mathrm{S}}_{1/2}{-}^2{\mathrm{P}}_{{1}/2}$$\end{document}2S1/2-2P1/2 and \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^2{\mathrm{S}}_{1/2}{-}^2{\mathrm{P}}_{{3}/2}$$\end{document}2S1/2-2P3/2 transitions in Li-like carbon ions stored and cooled at a velocity of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\beta \approx 0.47$$\end{document}β≈0.47 in the experimental storage ring (ESR) at the GSI Helmholtz Centre in Darmstadt have been investigated in a laser spectroscopy experiment. Resonance wavelengths were obtained using a new continuous-wave UV laser system and a novel extreme UV (XUV) detection system to detect forward emitted fluorescence photons. The results obtained for the two transitions are compared to existing experimental and theoretical data. A discrepancy found in an earlier laser spectroscopy measurement at the ESR with results from plasma spectroscopy and interferometry has been resolved and agreement between experiment and theory is confirmed.

Fiber-based laser sources for Coherent Anti-Stokes Raman scattering (CARS) microscopy and Stimulated Raman Spectroscopy (SRS) have been successfully used for label-free bio-imaging in the last few years. However, these systems were limited so far to a few experimental setups in university labs. We present the first extremely compact commercially available dual-wavelength source for CARS and SRS. With a foot-print of

We present a CEO-stable 1.1 kW CPA system that is designed to drive a few-cycle-generation stage ( 300W of average power at 100kHz repetition-rate providing

We present the first high-power coherently combined thulium-doped fiber-CPA. The laser system delivers >228 µJ pulse energy with 48 hours of operation even at an average-power >120 W. The simultaneous availability of 100 W class average power and 1 GW-class peak power in the 2 µm wavelength regime is not only unique in the world of science but also comes in a fully engineered and commercially available system design optimized for long-term operation..

Estuaries worldwide have experienced modifications including channel deepening and intertidal reclamation over several centuries, resulting in altered fine sediment routing. Estuaries respond differently based on preexisting geometries, freshwater and sediment supplies, and extents and types of modification. The Coos Bay Estuary in Oregon is a relatively small estuary with complex geometry that has been extensively modified since 1865. A sediment transport model calibrated to modern conditions is used to assess the corresponding changes in sediment dynamics. Over ∼150 years, channel deepening (from ∼6.7 to 11 m), a 12% increase in area, and a 21% increase in volume have led to greater tidal amplitudes, salinity intrusion, and estuarine exchange flow. These changes have reduced current magnitudes, reduced bed stresses, and increased stratification, especially during rainy periods. Historically, fluvially derived sediment was dispersed across broad, deltaic‐style flats and through small tidal channels. Now, river water and sediments are diverted into a dredged navigation channel where an estuarine turbidity maximum (ETM) forms, with modeled concentrations >50 mg/L and measured concentrations >100 mg/L during discharge events. This “new” ETM supplies sediment to proximal embayments in the middle estuary and the shallow flats. Overall, sediment trapping during winter (and high river discharges) has increased more than two‐fold, owing to increased accommodation space, altered pathways of supply, and altered bed stresses and tidal asymmetries. In contrast to funnel‐shaped estuaries with simpler geometries and river‐channel transitions, these results highlight the importance of channel routing together with dredging in enhancing sediment retention and shifting pathways of sediment delivery.

We present a sub-2 cycle laser system combining high average power, pulse energy and repetition rate with CEP-stable operation making this system an ideal driver for next-generation attosecond sources. The system is based on a fiber-chirped pulse amplification system incorporating coherent combination of 8 amplifier channels. The latter emits 300fs pulses, which are post-compressed down to the few-cycle regime in a two-stage multi-pass cell (MPC) nonlinear pulse compression. The first multi-pass cell is based on standard dielectric mirrors and achieves 1.7mJ

Scientific reports 11(1), 9370 (2021). doi:10.1038/s41598-021-88926-w, Published by Macmillan Publishers Limited, part of Springer Nature, [London]

We demonstrate a thulium-based fiber amplifier delivering pulses tunable between

In situ river discharge estimation is a critical component of studying rivers. A dominant method for establishing discharge monitoring in situ is a temporary gauge, which uses a rating curve to relate stage to discharge. However, this approach is constrained by cost and the time to develop the stage-discharge rating curve, as rating curves rely on numerous flow measurements at high and low stages. Here, we offer a novel alternative approach to traditional temporary gauges: estimating Discharge via Arrays of Pressure Transducers (DAPT). DAPT uses a Bayesian discharge algorithm developed for the upcoming Surface Water Ocean Topography satellite (SWOT) to estimate in situ discharge from automated water surface elevation measurements. We conducted sensitivity tests over 4,954 model runs on five gauged rivers and conclude that the DAPT method can robustly reproduce discharge with an average Nash-Sutcliffe Efficiency (NSE) of 0.79 and Kling-Gupta Efficiency of 0.78. Further, we find that the DAPT method estimates discharge similarly to an idealized temporary gauge created from the same input data (NSE differences of less than 0.1), and that results improve significantly with accurate priors. Finally, we test the DAPT method in nine poorly gauged rivers in a realistic and complex field setting in the Peace-Athabasca Delta, and show that the DAPT method largely outperforms a temporary gauge in this time and budget constrained setting. We therefore recommend DAPT as an effective tool for in situ discharge estimation in cases where there is not enough time or resources to develop a temporary gauge.