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Sarcopenic dysphagia (SD) is swallowing difficulty associated with loss of generalized skeletal muscles and swallowing-related muscles. Diagnostic criteria for SD were suggested, yet there is a variability in instruments and cut-offs used. The aim of the current review is to critically evaluate tools used in diagnosis of sarcopenic dysphagia in the elderly. Comprehensive review of the literature was performed. Studies were qualitatively evaluated for the diagnostic tools used to make a diagnosis of "sarcopenic dysphagia" and compared to the known diagnostic criteria for SD and other accepted measures. Fourteen studies (N = 10,282) were selected from a search yield of 331 de-duplicated studies. Ninety-three percent of studies (13/14) were conducted in Japan. All subjects included were over the age of 65 years old (mean, 76.5 years). Various tools were used to assess sarcopenia including handgrip strength (14/14 of studies), followed by skeletal muscle mass/index (7/14), tongue pressure, gait speed, and calf circumference in 5/14 studies. The most commonly tool used for dysphagia and/or swallowing dysfunction was the food level intake scale (5/14 of studies) followed by the functional oral intake scale (3/14). The 100-mL water swallow test was used in 2 of the 14 included SD studies. Fiberoptic endoscopic evaluation of swallowing, videofluoroscopic swallowing study, EAT-10 questionnaire, and standardized swallow assessment were each used in only one SD study. Further research is required to validate SD diagnostic tools, establish cut-offs in different populations, and investigate their role in screening of dysphagia and swallowing dysfunction in the elderly.

Authorities regulate online transactions to protect consumers from unintended negative consequences. Regulatory cues (e.g. certifications) enable consumers to identify formally approved online gamb...

Background High infection rates among healthcare personnel in an uncontained pandemic can paralyze health systems due to staff shortages. Risk constellations and rates of seroconversion for healthcare workers (HCWs) during the first wave of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic are still largely unclear. Methods Healthcare personnel (n = 300) on different organizational units in the LMU Munich University Hospital were included and followed in this prospective longitudinal study from 24 March until 7 July 2020. Participants were monitored in intervals of 2 to 6 weeks using different antibody assays for serological testing and questionnaires to evaluate risk contacts. In a subgroup of infected participants, we obtained nasopharyngeal swabs to perform whole-genome sequencing for outbreak characterization. Results HCWs involved in patient care on dedicated coronavirus disease 2019 (COVID-19) wards or on regular non–COVID-19 wards showed a higher rate of SARS-CoV-2 seroconversion than staff in the emergency department and non-frontline personnel. The landscape of risk contacts in these units was dynamic, with a decrease in unprotected risk contacts in the emergency department and an increase on non–COVID-19 wards. Both intensity and number of risk contacts were associated with higher rates of seroconversion. On regular wards, staff infections tended to occur in clusters, while infections on COVID-19 wards were less frequent and apparently independent of each other. Conclusions Risk of SARS-CoV-2 infection for frontline HCWs was increased during the first pandemic wave in southern Germany. Stringent measures for infection control are essential to protect all patient-facing staff during the ongoing pandemic.

The fusion genes CBFB/MYH11 and RUNX1/RUNX1T1 block differentiation through disruption of the core binding factor (CBF) complex and are found in 10–15% of adult de novo acute myeloid leukemia (AML) cases. This AML subtype is associated with a favorable prognosis; however, nearly half of CBF-rearranged patients cannot be cured with chemotherapy. This divergent outcome might be due to additional mutations, whose spectrum and prognostic relevance remains hardly defined. Here, we identify nonsilent mutations, which may collaborate with CBF-rearrangements during leukemogenesis by targeted sequencing of 129 genes in 292 adult CBF leukemia patients, and thus provide a comprehensive overview of the mutational spectrum (‘mutatome’) in CBF leukemia. Thereby, we detected fundamental differences between CBFB/MYH11- and RUNX1/RUNX1T1-rearranged patients with ASXL2, JAK2, JAK3, RAD21, TET2, and ZBTB7A being strongly correlated with the latter subgroup. We found prognostic relevance of mutations in genes previously known to be AML-associated such as KIT, SMC1A, and DHX15 and identified novel, recurrent mutations in NFE2 (3%), MN1 (4%), HERC1 (3%), and ZFHX4 (5%). Furthermore, age >60 years, nonprimary AML and loss of the Y-chromosomes are important predictors of survival. These findings are important for refinement of treatment stratification and development of targeted therapy approaches in CBF leukemia.

Perceptions of threat from Russia’s military activities in Ukraine and President Trump’s critical attitude towards NATO have put the idea of a common European army on the agenda of European politic...

Objective To identify functional outcome and orbital complication rate of the preserved orbit and to identify predictors of orbital impairment in periorbital free flap reconstruction. Materials and methods A retrospective review was conducted on patients undergoing orbit-sparing surgery with periorbital free flap reconstruction at a tertiary institution from 2006 to 2017. Orbital complication rate and orbital functional outcomes were analyzed. A univariable and multivariable logistic regression analysis was used to assess predictors of functional outcome. Results Forty-nine patients met inclusion criteria. Ninety-eight percent of patients maintained a functional eye post-operatively. Most periorbital free flaps, 37 (75.5%), were performed following oncologic resection. Overall orbital function was graded as functional without impairment in 29 (59.2%) patients, functional with impairment in 19 (38.8%) patients, and nonfunctional in 1 (2.0%) patient. Postoperative orbital sequelae occurred in 32 (65.3%) patients. Twenty-one (42.9%) patients underwent 35 revision operations for late orbital sequelae. Extent of resection (OR, 5.93; CI 95%, 1.05–33.4; p = 0.044) and adjuvant RT (OR, 4.69; CI 95% 1.18–18.6; p = 0.028) significantly correlated with impairment in a functional orbit on multivariable analysis. Conclusion Orbit-sparing surgery with periorbital free flap reconstruction carries a significant risk of a variety of orbital sequelae, most commonly ectropion, requiring surgical intervention. However, most patients maintain a functional eye. The need for delayed exenteration/enucleation is low and is primarily limited to cancer recurrence. Significant predictors of complications include extent of resection and adjuvant radiation therapy.

Purpose: To evaluate interval between primary cancer diagnosis and uveal metastasis and assess survival outcomes based on whether the primary cancer was diagnosed before or after uveal metastasis. Methods: In this retrospective analysis, all patients with uveal metastasis evaluated on the Ocular Oncology Service, Wills Eye Hospital, Philadelphia, PA, USA between February 1, 1974 and June 1, 2017 were included. Features and outcomes based on timing of primary cancer diagnosis, whether before or after diagnosis of uveal metastasis, were assessed. Results: A total of 2214 uveal metastases were diagnosed in 1310 eyes of 1111 consecutive patients. Primary cancer was known prior to uveal metastasis in 742 patients (67%) and not known in 369 (33%). Of those not known, the primary cancer was later found in 192 patients (17%) and never found in 177 patients (16%). For those with known primary cancer, mean interval from primary cancer diagnosis to uveal metastasis was 5.2 years with differences in primary sites of gastrointestinal (2.1 years, p = 0.003), lung (2.2 years, p

​​Since its recent zoonotic spill-over severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is constantly adapting to the human host as illustrated by the emergence of variants of concern with increased transmissibility and immune evasion. Prolonged replication in immunosuppressed individuals and evasion from spike-specific antibodies is known to drive intra-host SARS-CoV-2 evolution. Here we show for the first time the major role of CD8 T cells in SARS-CoV-2 evolution. In a patient with chronic, ultimately fatal infection, we observed three spike mutations that prevented neutralisation by convalescent plasma therapy. Moreover, at least four mutations in non-spike proteins emerged that hampered CD8 T-cell recognition of mutant epitopes, two of these occurred before spike mutations. A comparison with worldwide sequencing data showed that several of these T-cell escape mutations had emerged independently as homoplasies in multiple circulating lineages. We propose that human leukocyte antigen class I contributes to shaping the evolutionary landscape of SARS-CoV-2.

Purpose We sought to review the clinical outcomes of conservative and operative treatment options for acute distal radioulnar joint (DRUJ) instability associated with distal radius fractures in adult patients. Methods A systematic search of PubMed, MEDLINE, and EMBASE for articles published between 1990 and 2020 involving DRUJ instability associated with distal radius fractures was performed. The primary outcomes analyzed included clinical grip strength; range of motion; the disability of the arm, shoulder and hand (DASH) score; and the modified Mayo wrist score (MMWS). Results Of the 531 articles identified in the literature search, 8 met our defined criteria and were included in the final analysis. The cumulative sample size was 258 patients at a mean follow-up of 11.1 months (range, 3–16.9 months). Treatment groups included cast immobilization in supination, K-wire stabilization, and triangular fibrocartilage complex (TFCC) repair. Statistical analysis revealed no difference across groups in active flexion-extension or DASH scores. A significant decrease in grip strength was found in patients who underwent TFCC repair compared with that in those who underwent both cast immobilization (P = .04) and K-wire stabilization (P = .02). Furthermore, we found a significant decrease in active pronation-supination between patients who underwent TFCC repair and those who underwent cast immobilization (P = .03). Patients who underwent TFCC repair were also found to exhibit decreased MMWS as compared with those who underwent K-wire stabilization (P = .05). Overall, persistent DRUJ instability was only found in 4 patients (1.5%), without a significant difference between treatment groups. Conclusions This study suggests functional advantages of certain treatment modalities over others, with the range of motion being highest in patients who underwent cast immobilization and grip strength being highest in patients who underwent K-wire stabilization. However, the mean DASH scores showed no difference across all groups, calling into question the clinical need to pursue operative treatment via K-wire stabilization or TFCC repair over conservative treatment via cast immobilization. This study will hopefully serve as a foundation for future prospective studies to help improve and standardize treatment algorithms in patients with DRUJ instability and distal radius fractures. Type of study/level of evidence: Therapeutic II.

This paper discusses different feature selection methods and CO2 flux data sets with a varying quality‐quantity balance for the application of a Random Forest model to predict daily CO2 fluxes at 250 m spatial resolution for the Rur catchment area in western Germany between 2010 and 2018. Measurements from eddy covariance stations of different ecosystem types, remotely sensed vegetation data from MODIS, and COSMO‐REA6 reanalysis data were used to train the model and predictions were validated by a spatial and temporal validation scheme. Results show the capabilities of a backwards feature elimination to remove irrelevant variables and an importance of high‐quality‐low‐quantity flux data set to improve predictions. However, results also show that spatial prediction is more difficult than temporal prediction by reflecting the mean value accurately though underestimating the variance of CO2 fluxes. Vegetated parts of the catchment acted as a CO2 sink during the investigation period, net capturing about 237 g C m−2 y−1. Croplands, coniferous forests, deciduous forests and grasslands were all sinks on average. The highest uptake was predicted to occur in late spring and early summer, while the catchment was a CO2 source in fall and winter. In conclusion, the Random Forest model predicted a narrower distribution of CO2 fluxes, though our methodological improvements look promising in order to achieve high‐resolution net ecosystem exchange data sets at the regional scale., Plain Language Summary: Whether ecosystems absorb or emit CO2 plays a major role in the global carbon cycle and impacts climate change. This exchange is already measured at scattered stations, but creating spatially resolved data sets remains a challenge. In this paper, we used satellite images of vegetation and meteorological data to predict the CO2 exchange of the Rur catchment area near the German‐Dutch‐Belgian border for every day from 2010 to 2018. In order to assess the prediction quality, we compared actual measurements from several stations within the catchment with the predictions at the locations of these stations. Results show that our method could increase prediction quality compared to previous process‐based models, though the error remains rather high. Vegetated parts of the catchment including coniferous forests, deciduous forests, grasslands, and croplands were all CO2 sinks on average. In late spring and early summer, they were the strongest sink, but in fall and winter a CO2 source., Key Points: CO2 flux upscaling with Random Forest can be improved with a backward feature elimination and strict quality control of flux data. Vegetated parts of the Rur catchment were predicted to be a CO2 sink on average, with the highest uptake in late spring and early summer. The Enhanced Vegetation Index and potential evapotranspiration are useful predictors for the regionalization of CO2 flux measurements., Deutsche Forschungsgemeinschaft, Institute of Environmental Meteorology of the University of Trier, Agrosphere Institute of the Forschungszentrum Jülich

Wastewater-based epidemiology (WBE) is a tool now increasingly proposed to monitor the SARS-CoV-2 burden in populations without the need for individual mass testing. It is especially interesting in metropolitan areas where spread can be very fast, and proper sewage systems are available for sampling with short flow times and thus little decay of the virus. We started in March 2020 to set up a once-a-week qualified spot sampling protocol in six different locations in Munich carefully chosen to contain primarily wastewater of permanent residential areas, rather than industry or hospitals. We used RT-PCR and sequencing to track the spread of SARS-CoV-2 in the Munich population with temporo-spatial resolution. The study became fully operational in mid-April 2020 and has been tracking SARS-CoV-2 RNA load weekly for one year. Sequencing of the isolated viral RNA was performed to obtain information about the presence and abundance of variants of concern in the Munich area over time. We demonstrate that the evolution of SARS-CoV-2 RNA loads (between, Graphical abstract Unlabelled Image

OBJECTIVES/HYPOTHESIS To describe multidimensional quality of life (QOL) outcomes in patients with sinonasal malignancies (SNM). To elucidate factors predicting worse QOL in this population. STUDY DESIGN Retrospective chart review at tertiary institution. METHODS A retrospective chart review on patients treated for SNM from 2006 to 2019 at a tertiary medical center was conducted. QOL outcomes were measured using the Hospital Anxiety and Depression Scale (HADS) and the Functional Assessment Cancer Therapy - Nasopharynx (FACT-NP) score. A stepwise multiple linear regression analysis was conducted to assess factors predicting worse QOL. RESULTS Eighty-one patients met inclusion criteria. Twelve (14.8%) patients had a subscale score >11 for anxiety (HADS-A) or depression (HADS-D) indicating significant anxiety or depression, at a median of 24 (8-68.5) months post treatment. The median FACT-NP total score was 136 (110-152). On multivariable analysis, advanced T classification, single status, and worse social support survey score were significant predictors of worse HADS score. Worse social support survey score was a significant predictor of worse total FACT-NP score. CONCLUSION After adjusting for confounders, at a median of 24 months after completion of definitive therapy for SNM, advanced T classification and single relationship status were found to be significant predictors of anxiety and depression (based on HADS). A worse social support survey score was associated with worse anxiety, depression, and QOL (based on HADS and FACT-NP). Identifying these factors early may help to guide treatment and psychiatric referral to at-risk individuals after the treatment of SNM. LEVEL OF EVIDENCE 3 Laryngoscope, 131:E2212-E2221, 2021.

A versatile portfolio of diagnostic tests is essential for the containment of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pandemic. Besides nucleic acid-based test systems and point-of-care (POCT) antigen (Ag) tests, quantitative, laboratory-based nucleocapsid Ag tests for SARS-CoV-2 have recently been launched. Here, we evaluated four commercial Ag tests on automated platforms and one POCT to detect SARS-CoV-2. We evaluated PCR-positive (n = 107) and PCR-negative (n = 303) respiratory swabs from asymptomatic and symptomatic patients at the end of the second pandemic wave in Germany (February–March 2021) as well as clinical isolates EU1 (B.1.117), variant of concern (VOC) Alpha (B.1.1.7) or Beta (B.1.351), which had been expanded in a biosafety level 3 laboratory. The specificities of automated SARS-CoV-2 Ag tests ranged between 97.0 and 99.7% (Lumipulse G SARS-CoV-2 Ag (Fujirebio): 97.03%, Elecsys SARS-CoV-2 Ag (Roche Diagnostics): 97.69%; LIAISON® SARS-CoV-2 Ag (Diasorin) and SARS-CoV-2 Ag ELISA (Euroimmun): 99.67%). In this study cohort of hospitalized patients, the clinical sensitivities of tests were low, ranging from 17.76 to 52.34%, and analytical sensitivities ranged from 420,000 to 25,000,000 Geq/ml. In comparison, the detection limit of the Roche Rapid Ag Test (RAT) was 9,300,000 Geq/ml, detecting 23.58% of respiratory samples. Receiver-operating-characteristics (ROCs) and Youden’s index analyses were performed to further characterize the assays’ overall performance and determine optimal assay cutoffs for sensitivity and specificity. VOCs carrying up to four amino acid mutations in nucleocapsid were detected by all five assays with characteristics comparable to non-VOCs. In summary, automated, quantitative SARS-CoV-2 Ag tests show variable performance and are not necessarily superior to a standard POCT. The efficacy of any alternative testing strategies to complement nucleic acid-based assays must be carefully evaluated by independent laboratories prior to widespread implementation.

Spectroscopy techniques are being implemented within the biopharmaceutical industry due to their non-destructive ability to measure multiple analytes simultaneously, however, minimal work has been applied focussing on their application at small scale. Miniature bioreactor systems are being applied across the industry for cell line development as they offer a high-throughput solution for screening and process optimization. The application of small volume, high-throughput, automated analyses to miniature bioreactors has the potential to significantly augment the type and quality of data from these systems and enhance alignment with large-scale bioreactors. Here, we present an evaluation of 1. a prototype that fully integrates spectroscopy to a miniature bioreactor system (ambr®15, Sartorius Stedim Biotech) enabling automated Raman spectra acquisition, 2. In 50 L single-use bioreactor bag (SUB) prototype with an integrated spectral window. OPLS models were developed demonstrating good accuracy for multiple analytes at both scales. Furthermore, the 50 L SUB prototype enabled on-line monitoring without the need for sterilization of the probe prior to use and minimal light interference was observed. We also demonstrate the ability to build robust models due to induced changes that are hard and costly to perform at large scale and the potential of transferring these models across the scales. The implementation of this technology enables integration of spectroscopy at the small scale for better process understanding and generation of robust models over a large design space while facilitating model transfer throughout the scales enabling continuity throughout process development and utilization and transfer of ever-increasing data generation from development to manufacturing.

Introduction: Hip fractures are one of the most common indications for hospitalization and orthopedic intervention. Fragility hip fractures are frequently associated with multiple comorbidities and thus may benefit from a structured multidisciplinary approach for treatment. The purpose of this article was to retrospectively analyze patient outcomes after the implementation of a multidisciplinary hip fracture pathway at a level I trauma center. Materials and Methods: A retrospective review of 263 patients over the age of 65 with fragility hip fracture was performed. Time to surgery, hospital length of stay, Charlson Comorbidity Index (CCI), American Society of Anesthesiologists, complication rates, and other clinical outcomes were compared between patients treated in the year before and after implementation of a multidisciplinary hip fracture pathway. Results: Timing to OR, hospital length of stay, and complication rates did not differ between pre- and postpathway groups. The postpathway group had a greater CCI score (pre: 3.10 ± 3.11 and post: 3.80 ± 3.18). Fewer total blood products were administered in the postpathway group (pre: 1.5 ± 1.8 and post: 0.8 ± 1.5). Discussion: The maintenance of clinical outcomes in the postpathway cohort, while having a greater CCI, indicates the same quality of care was provided for a more medically complex patient population. With a decrease in total blood products in the postpathway group, this highlights the economic importance of perioperative optimization that can be obtained in a multidisciplinary pathway. Conclusion: Implementation of a multidisciplinary hip fracture pathway is an effective strategy for maintaining care standards for fragility hip fracture management, particularly in the setting of complex medical comorbidities.

Purpose: To study mechanisms of therapy resistance and disease progression, we analyzed the evolution of cytogenetically normal acute myeloid leukemia (CN-AML) based on somatic alterations. Experimental Design: We performed exome sequencing of matched diagnosis, remission, and relapse samples from 50 CN-AML patients treated with intensive chemotherapy. Mutation patterns were correlated with clinical parameters. Results: Evolutionary patterns correlated with clinical outcome. Gain of mutations was associated with late relapse. Alterations of epigenetic regulators were frequently gained at relapse with recurring alterations of KDM6A constituting a mechanism of cytarabine resistance. Low KDM6A expression correlated with adverse clinical outcome, particularly in male patients. At complete remission, persistent mutations representing preleukemic lesions were observed in 48% of patients. The persistence of DNMT3A mutations correlated with shorter time to relapse. Conclusions: Chemotherapy resistance might be acquired through gain of mutations. Insights into the evolution during therapy and disease progression lay the foundation for tailored approaches to treat or prevent relapse of CN-AML. Clin Cancer Res; 24(7); 1716–26. ©2018 AACR.

Heterotopic ossification (HO) is widely recognized as a common occurrence among patients suffering from traumatic spinal cord injuries (SCI). The exact etiology of HO formation remains unknown. Published medical and surgical management strategies are often plagued with questionable effectiveness and frequent complications. There are minimal publications regarding the management strategies of HO in SCI patients as it pertains to plastic surgery. We present a case series of patients treated at our institution who underwent treatment for pressure ulcers with underlying HO to highlight the vast spectrum of clinical phenotypes present in this population. The pathophysiology, diagnostic tools, methods of prevention, and surgical management of HO are discussed here. We believe that there are two clinically relevant patterns of HO in SCI patients. A neurogenic process that occurs early after injury is usually bilateral and involves uninjured hip joints. Pressure sores that occur are related to poor joint mobility and subsequent development of pressure points. An infection-driven process in which HO development is associated with either pressure sores or septic hip joints is generally unilateral and not always associated with hip contractures. They present different challenges and reconstructive options to plastic surgeons. Although complications such as infection and HO recurrence are common, the functional and psychological benefits of restoring hip flexion are usually worthwhile.

The development and validation of hydroecological land-surface models to simulate agricultural areas require extensive data on weather, soil properties, agricultural management, and vegetation states and fluxes. However, these comprehensive data are rarely available since measurement, quality control, documentation, and compilation of the different data types are costly in terms of time and money. Here, we present a comprehensive dataset, which was collected at four agricultural sites within the Rur catchment in western Germany in the framework of the Transregional Collaborative Research Centre 32 (TR32) “Patterns in Soil–Vegetation–Atmosphere Systems: Monitoring, Modeling and Data Assimilation”. Vegetation-related data comprise fresh and dry biomass (green and brown, predominantly per organ), plant height, green and brown leaf area index, phenological development state, nitrogen and carbon content (overall > 17 000 entries), and masses of harvest residues and regrowth of vegetation after harvest or before planting of the main crop (> 250 entries). Vegetation data including LAI were collected in frequencies of 1 to 3 weeks in the years 2015 until 2017, mostly during overflights of the Sentinel 1 and Radarsat 2 satellites. In addition, fluxes of carbon, energy, and water (> 180 000 half-hourly records) measured using the eddy covariance technique are included. Three flux time series have simultaneous data from two different heights. Data on agricultural management include sowing and harvest dates as well as information on cultivation, fertilization, and agrochemicals (27 management periods). The dataset also includes gap-filled weather data (> 200 000 hourly records) and soil parameters (particle size distributions, carbon and nitrogen content; > 800 records). These data can also be useful for development and validation of remote-sensing products. The dataset is hosted at the TR32 database (https://www.tr32db.uni-koeln.de/data.php?dataID=1889, last access: 29 September 2020) and has the DOI https://doi.org/10.5880/TR32DB.39 (Reichenau et al., 2020).

Containment strategies and clinical management of coronavirus disease (COVID-19) patients during the current pandemic depend on reliable diagnostic PCR assays for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we compare 11 different RT-PCR test systems used in seven diagnostic laboratories in Germany in March 2020. While most assays performed well, we identified detection problems in a commonly used assay that may have resulted in false-negative test results during the first weeks of the pandemic.

Background There remains considerable variation in the extent of sinonasal preservation during the approach for endoscopic transsphenoidal hypophysectomy (TSH). We advocate for a minimally destructive approach utilizing turbinate lateralization, small posterior septectomy, no ethmoidectomy, and preservation of nasoseptal flap (NSF) pedicles bilaterally. Due to these factors, this approach may affect the rates of postoperative rhinosinusitis. The objective of this study is to define the rates of postoperative rhinosinusitis in patients undergoing this approach. Methods Single institution, retrospective chart review of patients undergoing TSH from 2005 to 2018. Results A total of 415 patients were identified and 14% developed an episode of postoperative rhinosinusitis within 3 months. These patients were significantly more likely to have had a history of recurrent acute or chronic rhinosinusitis. Most cases were sphenoethmoidal sinusitis managed with 1 to 2 courses of antibiotics. Of patients with postoperative rhinosinusitis, most did not undergo NSF. Average follow-up was 38 months. Six patients (1.4%) underwent post-TSH functional endoscopic sinus surgery (FESS). Average time from TSH to FESS was 26.3 months. Two of these patients had a history of prior chronic rhinosinusitis without polyposis. Two patients underwent revision TSH for recurrent tumor as the primary indication for surgery at time of FESS. Twenty-two-item Sino-Nasal Outcome Test (SNOT-22) scores generally increased immediately postoperatively, but frequently decreased below preoperative level by the time of last follow-up, regardless of whether patients developed rhinosinusitis. Conclusion Sinonasal preservation during TSH is associated with a low rate of postoperative rhinosinusitis requiring FESS and excellent long-term patient reported outcomes. We continue to advocate for sinonasal preservation during pituitary surgery.

Persistent sciatic arteries are a rare but clinically significant vascular etiology of lower extremity arterial aneurysms leading to distal embolization and limb ischemia. We present the case of a 60-year-old man with a symptomatic persistent left sciatic artery aneurysm with a hypoplastic superficial femoral artery who was successfully treated with a hybrid open and endovascular technique. This consisted of a surgical bypass from the common femoral artery to the above-knee popliteal artery with prosthetic graft combined with retrograde endovascular embolization of the sciatic artery aneurysm.

Introduction: The ulna is often resected to treat injuries resulting from trauma, congenital anomalies, as well as a result of procedures for tumors and arthritis in the wrist. However, there is no literature discussing the impact of ulnar shortening on force transmission. This study looks at how force is transmitted across the radiocapitellar joint (RCJ) after varying lengths of ulnar resection. Methods: 4 fresh-frozen cadaveric forearms (mean age 44.5 years) each with an intact elbow and distal humerus were secured onto a mounting plate, allowing for range of elbow motion to be tested: 45 degrees and 90 degrees in flexion, as well as supination, pronation, and neutral positioning of the forearm. Tests were done with varying ulnar conditions: normal intact, resected by 2 cm, resection of a quarter of the length, and resection of half of the length. Step loading was applied to a maximum of 150 N and resultant force across the RCJ was measured using a joint pressure sensor. Data from the four ulnar conditions were compared using repeated measure ANOVA with statistical significance set at p=0.05. Results: With the radioulnocarpal joint intact, the average force transmitted to the RCJ was 94.3±72.3 N with the elbow in 45-degree flexion and 123.6±69.3 N with 90-degree flexion and neutral pronation/supination. 45-degree supination caused a decrease in radiocapitellar force to 87.2±49.2 N and 81.7±56.2 N respectively, while 45-deree pronation increased the force to 123.2±67.5 N and 131.7±66.8 N respectively. In comparison to the control, an increase of statistical significance was found in supinated 90-degree flexion and supinated 45-degree flexion for both quarter- and half-length ulnar resections. In 45-degree flexion with neutral supination/pronation, the RCJ force was significantly higher than the intact after 2-cm ulna resection (pConclusion: This study demonstrates that with an intact ulna, 63% of applied axial force was transmitted to the RCJ when the elbow was flexed at 45, and 85% at 90 degrees. It also showed that the RCJ force transmission decreases with supination and increases with pronation. As the ulna is progressively shortened, increased force is transmitted across the RCJ, especially in elbow flexion and supination. A pronated position was observed to be protective of the RCJ.

Research infrastructures play a key role in launching a new generation of integrated long-term, geographically distributed observation programmes designed to monitor climate change, better understand its impacts on global ecosystems, and evaluate possible mitigation and adaptation strategies. The pan-European Integrated Carbon Observation System combines carbon and greenhouse gas (GHG; CO2, CH4, N2O, H2O) observations within the atmosphere, terrestrial ecosystems and oceans. High-precision measurements are obtained using standardised methodologies, are centrally processed and openly available in a traceable and verifiable fashion in combination with detailed metadata. The Integrated Carbon Observation System ecosystem station network aims to sample climate and land-cover variability across Europe. In addition to GHG flux measurements, a large set of complementary data (including management practices, vegetation and soil characteristics) is collected to support the interpretation, spatial upscaling and modelling of observed ecosystem carbon and GHG dynamics. The applied sampling design was developed and formulated in protocols by the scientific community, representing a trade-off between an ideal dataset and practical feasibility. The use of open-access, high-quality and multi-level data products by different user communities is crucial for the Integrated Carbon Observation System in order to achieve its scientific potential and societal value.

Chamber measurements of trace gas fluxes between the land surface and the atmosphere have been conducted for almost a century. Different chamber techniques, including static and dynamic, have been used with varying degrees of success in estimating greenhouse gases (CO2, CH4, N2O) fluxes. However, all of these have certain disadvantages which have either prevented them from providing an adequate estimate of greenhouse gas exchange or restricted them to be used under limited conditions. Generally, chamber methods are relatively low in cost and simple to operate. In combination with the appropriate sample allocations, chamber methods are adaptable for a wide variety of studies from local to global spatial scales, and they are particularly well suited for in situ and laboratory-based studies. Consequently, chamber measurements will play an important role in the portfolio of the Pan-European long-term research infrastructure Integrated Carbon Observation System. The respective working group of the Integrated Carbon Observation System Ecosystem Monitoring Station Assembly has decided to ascertain standards and quality checks for automated and manual chamber systems instead of defining one or several standard systems provided by commercial manufacturers in order to define minimum requirements for chamber measurements. The defined requirements and recommendations related to chamber measurements are described here.

Achieving lightweight construction through only material substitution does not realize the full potential of producing a lightweight material, hence, it is no longer sufficient. Weight-saving goals are best achieved through additional function integration. In order to implement this premise for mass production, a manufacturing process for joining and forming hybrid laminates using a new tool concept is presented. All materials used are widely producible and processable. The manufactured cover of an automotive center console serves to demonstrate a human interface device with impact detection and action execution. This is only possible through a machine learning system, which is implemented on a small&mdash, and thus space- and energy-saving&mdash, embedded system. The measurement results confirm the objective and show that localization was sufficiently accurate.

The silicon sample irradiated with femtosecond soft X-ray pulses at the Linac Coherent Light Source has been studied with several synchrotron X-ray diffraction topographic methods at HASYLAB. The irradiations were performed for two different wavelengths combined with various impact energy controlled by means of the gas attenuator. The topographic investigation revealed characteristic images of the created craters included the inner region reflecting the X-rays at lower angle, coming most probably from part of the silicon melted during the irradiation. The melted region was surrounded by strained outer region, similar to those observed in the case of rod-like inclusion but less regular in view of some irregularity of the beam used for generation of the craters. It was observed that the higher impact energy higher dose of the irradiating pulses resulted in increasing diameter of the melted area of the crater and the range of the strained region around it. Some features of the monochromatic and white beam back reflection section images of the craters were reproduced in numerically simulated images approximating the strain field in the crater by a droplet containing uniformly distributed point inclusions.

Heterozygous mutations in GATA2 underlie different syndromes, previously described as monocytopenia and mycobacterial avium complex infection (MonoMAC); dendritic cell, monocytes, B- and NK lymphocytes deficiency (DCML); lymphedema, deafness and myelodysplasia (Emberger syndrome) and familiar myelodysplastic syndrome/acute myeloid leukemia (MDS / AML). Onset and severity of clinical symptoms vary and preceding cytopenias are not always present. We describe a case of symptomatic DCML deficiency and rather discrete bone marrow findings due to GATA2 mutation. Exome sequencing revealed a somatic ASXL1 mutation and the patient underwent allogeneic stem cell transplantation successfully., Highlights • Allogeneic stem cell transplantation was performed for DCML caused by GATA2 mutation. • Genetic diagnostics were done by Sanger sequencing and whole exome sequencing. • We identified an ASXL1 mutation associated with high risk for leukemic transformation.

Background: Lipomas are common benign tumors. When they develop in proximity to peripheral nerves, they can cause neurologic symptoms secondary to mass effect. Previous reports have shown symptom resolution after removal of lipomas compressing various upper extremity peripheral nerves. However, brachial plexus lipomas are relatively rare. Our multidisciplinary experience with brachial plexus lipoma resection is reviewed in the largest case series to date. Methods: A retrospective chart review of all patients undergoing resection of brachial plexus lipomatous tumors between 2006 and 2016 was performed. Patient demographic data, diagnostic imaging, clinical presentation, operative details, surgical pathology, and clinical outcomes were reviewed. Results: Twelve brachial plexus lipomatous tumors were resected in 11 patients: 10 lipomas, 1 hibernoma, and 1 atypical lipomatous tumor. The most common tumor location was supraclavicular (50%), followed by axillary (42%), and proximal medial arm (8%). The most common brachial plexus segment involved was the upper trunk (50%), followed by posterior cord (25%), lateral pectoral nerve (8%), lower trunk (8%), and proximal median nerve (8%). Most patients presented with an enlarging painless mass (58%). Of the patients who presented with neurologic symptoms, symptoms resolved in the majority (80%). Conclusions: Brachial plexus lipomas are rare causes of compression neuropathy in the upper extremity. Careful resection and knowledge of brachial plexus anatomy, which may be distorted by the tumor, are critical to achieving a successful surgical outcome with predictable symptom resolution. Finally, surveillance magnetic resonance imaging may be warranted for atypical lesions.

The EnergyBus specification is the basis of an ongoing joint IEC/ISO standardisation effort focussing on public charging infrastructures for and interoperability of light electric vehicle components. This paper highlights how these efforts are supported by formal methods, starting at the design and specification level, up to establishing a certification framework for standards compliance of devices implementing the specification. The Modest Toolset supports the model-based analysis methods needed in this context.

Intracardiac microcavitations consist of airy microbubbles. They are typically found in patients with an intravascular line or device, mechanical heart valves or in decompression sickness. We report a case of a patient in mid-70s who was admitted due to weakness in both legs, left-thoracic pain and fever. Despite the lack of any of the risk factors mentioned above, spontaneous microcavitations were detected in the right sided cardiac cavities. After the detection of liver lesions suspicious for a metastatic disease, a colonoscopy was performed. An ulcerated colonic carcinoma at the ileocoecal valve was diagnosed and highly suspicious for being the entry port of the microcavitations. This unusual presentation of microcavitations together with a colonic neoplasia leads to hypotheses about the journey of the microbubbles from the ascending colon into the right heart. Gastrointestinal tumours are described as being the causes of microbubbles. Translocation of microbubbles through hepatopulmonary shunting are described in the context of locally applied particles of similar size during radioembolisation. A thorough aetiological workup is of importance since the underlying cause is potentially dangerous due to its own nature of disease and due the complications of the microcavitations such as paradoxical emboli or pulmonary sequelae.

Bragg diffraction achieved from two-dimensional protein crystals using femtosecond X-ray laser snapshots is presented., X-ray diffraction patterns from two-dimensional (2-D) protein crystals obtained using femtosecond X-ray pulses from an X-ray free-electron laser (XFEL) are presented. To date, it has not been possible to acquire transmission X-ray diffraction patterns from individual 2-D protein crystals due to radiation damage. However, the intense and ultrafast pulses generated by an XFEL permit a new method of collecting diffraction data before the sample is destroyed. Utilizing a diffract-before-destroy approach at the Linac Coherent Light Source, Bragg diffraction was acquired to better than 8.5 Å resolution for two different 2-D protein crystal samples each less than 10 nm thick and maintained at room temperature. These proof-of-principle results show promise for structural analysis of both soluble and membrane proteins arranged as 2-D crystals without requiring cryogenic conditions or the formation of three-dimensional crystals.

This paper presents a semi-active broadband vibrational-energy harvesting system. Based on a non-resonant rotational generator, electronic circuitry was used to overcome the physical start-up restrictions. Due to the functional design it remains an energy harvester suitable for battery-less devices. For the first time a vibrational energy harvester is presented that allows standardization and thus higher volume production. A system layout, simulation, and measurement data will be shown.

Frontal orbital advancement (FOA) for metopic synostosis results in cranial vault expansion, supporting underlying growth of the developing brain and improving head shape. Previous studies have shown that FOA in younger infants leads to a greater incidence of long-term growth restriction of intracranial volume; however, it is still unknown as to whether this is due to undercorrection at the time of surgery versus primary suture pathology. The purpose of our study is to provide a method for objective analyses of intracranial volumes in the early post-FOA period. A retrospective chart review was conducted on patients who underwent FOA over a 10-year period by a single surgeon. Data collected included patient characteristics and clinical outcomes. Radiological analysis of intracranial volumes pre- and post-FOA was determined using Amira volume-rendering software. Average increase in intracranial volume at 6 weeks post-FOA was 139.27 mL (80.01-225.25 mL) with average relative cranial vault expansion of 18.1% (3.3-48%). Patients who underwent FOA older than 12 months of age had an average increase in intracranial volume of 8.5% (3.3-13.1%). Patients younger than 12 months had a statistically higher average increase of 25% (12.8-48%). Frontal orbital advancement effectively increases intracranial volume in patients with metopic synostosis. When compared with older patients, patients younger than 1 year of age have a greater relative increase in intracranial volume in the immediate postoperative period. Quantifying cranial vault expansion after FOA can assist surgeons in surgical planning as well as in measuring and monitoring clinical outcomes within and across craniofacial centers regardless of technique.

We report a recent experiment where the first hard x-ray beam line, X-ray Pump Probe (XPP) instrument using the SLAC National Accelerator Laboratory's Linac Coherent Light Source (LCLS) free electron laser, was used to heat thin foils to high energy densities ∼ 107 J/cm 3. An intense 9 keV, 60 fs (FWHM) duration beam with energy of 2 - 4 mJ at the XPP beam line was focused using beryllium lenses to an irradiance approaching 1016 Wcm -2. Targets of 0.5 - 3.5 μm thick foils of Ag and Cu were studied using a suite of diagnostics including Fourier Domain Interferometry, energy calorimetry and grating and crystal spectrometers. The experimental details and spectroscopic results from the campaign will be described. Preliminary results indicate that the target is heated relatively uniformly to a temperature lower than 20 eV. © 2011 SPIE.

Research reveals a stereotypical media portrayal of Olympic athletes [Bissel and Holt, ‘Who's Got Game?’]. Using panel data from the 2004 and the 2008 Summer Olympic Games, this study aims at identifying potential trends in visual representation of athletes. The analysis of online visuals of three media powers, Brazil (Latin America), Germany (Europe) and the USA (North America) allows for the investigation of culture-specific vs. global trends and for the identification of convergence/divergence forces across time in media. Differences between male and female representation with respect to category of sport, dynamic, camera angle, number of people, emotion and level of body exposure are assessed with Mann–Whitney U-tests. The findings suggest that although the web media reinforces some of the gender stereotypes, across the investigated time, an improvement towards gender evenness as well as a cross cultural convergence of athletes' portrayal is present. While some gender disparities still exist, the Inte...

The leukemia-associated fusion gene CBFB/MYH11 results from a pericentric inversion of chromosome 16, inv(16)(p13.1q22), or less commonly from a t(16;16)(p13.1;q22). Although this cytogenetic aberration is associated with a rather favorable prognosis in acute myeloid leukemia (AML), nearly half of patients eventually relapse after standard chemotherapy. To systematically analyze the clonal evolution in this AML-subgroup, we performed whole exome sequencing (WES) of 13 adult CBFB/MYH11-rearranged AML patients using matched diagnostic, remission and relapse samples ('triplets'). Thereby, we found 2-12 (median: 8) somatic sequence variants per patient at diagnosis and 2-13 (median: 4) mutations at relapse. These included mutations in genes known to cooperate with CBFB/MYH11 (e.g. RAS, FLT3, KIT) as well as in genes, which had not been associated with AML previously (MYO15A, EVPL, ROS1, FTCD and ASL). Next, we designed a custom targeted sequencing assay (Haloplex, Agilent), including the candidate genes from exome sequencing, as well as genes known to be recurrently mutated in AML (455 genes, 1.86 Mbp total target sequence) and performed targeted sequencing of 32 CBFB/MYH11-rearranged AML triplet samples (including the 13 triplets initially analyzed by WES) with a median read depth of 500. The results are summarized in Figure 1. Fourteen genes were found mutated in at least two patients at diagnosis and 9 genes at the timepoint of relapse. In all CBFB/MYH11-rearranged patients, more than one additional mutation was identified, each of them at a distinct variant allele-frequency, indicating clonal heterogeneity. All but one FLT3 TKD (D835 or N676) mutation were lost at relapse, whereas FLT3 ITDs were stable in 3 out of 7 patients. One FLT3 ITD was gained at relapse. The majority of RAS,KIT and CBL mutations were lost and none was acquired at relapse. Particularly, the loss of 6 out of 7 KIT exon 8 frameshift mutations was surprising since KIT exon 8 frameshift mutations were negative prognostic markers in a cohort of 162 patients with CBFB/MYH11 rearranged leukemia (OS: HR= 3.12, p= 0.001; Opatz et al. submitted). In contrast, mutations in WT1 and DNMT3A were all stable during relapse evolution and four patients gained mutations in these two genes. Furthermore, aberrations in CSF3R, BCORL1 and ZBTB7A were acquired at relapse. Of note, WT1 mutations causing a frameshift in exon 6 were found in 9% of adult de novo AML with CBFB/MYH11-rearrangement and have recently been characterized by our research group as negative prognostic marker for overall survival (HR: 2.93, p= 0.011) (Opatz et al. submitted). These findings are in line with the observed gain of WT1 mutations in 10% of relapsed cytogenetically normal AML patients (Greif et al., 2018, Clin Cancer Res) suggesting a common mechanism of disease progress across cytogenetic subgroups. Surprisingly, a mutation in ZBTB7A, a gene frequently altered in RUNX1/RUNX1T1 positiv leukemia (23%) but rarely in CBFB/MYH11 positiv leukemia (2%), was gained at relapse in one patient. Mutations in epigenetic modifiers, cohesion complex components and janus kinases are known cooperating events in RUNX1/RUNX1T1 rearranged leukemia and were, except for DNMT3A, not found in our CBFB/MYH11-positive cohort. The new recurring mutations in MYO15A (n=3), ROS1 (n=2), FTCD (n=2) and ASL (n=2) were partially lost at relapse, whereas EVPL (n=2) mutations were stable during the course of disease. In addition, we identified mutations in APC2, TP53 and ZFHX4 (gained at relapse), PTPN11, MECOM, BCOR, NPM1 and IDH2 (stable) as well as in ABL1 (lost at relapse) in individual patients. Taken together, our findings suggest that mutations in signaling pathway genes seem to be unstable during disease progression and may thus not be required for the evolution of relapse. The frequent loss of signaling gene mutations indicates that relapse might evolve from an early ancestral clone carrying the CBFB/MYH11 rearrangement only. Figure 1: Mutation profile of 32 patients with CBFB/MYH11-rearranged AML. The stability of recurrently mutated genes during the evolution of relapse is shown. Diagonal lines indicate two mutations in the respective gene. Figure 1 Figure 1. Disclosures Thiede: AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding. Middeke:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Stoelzel:Neovii: Speakers Bureau. Metzeler:Novartis: Consultancy; Celgene: Consultancy, Research Funding.

During the last few years, thermopiles have come increasingly under the spotlight of commercial infrared sensing. This growing interest has motivated us to write an overview of micromachined thermopiles. The first part deals with the Seebeck effect and discusses the most important physical parameters with their interactions. We also describe the main noise sources and give a derivation of the figures of merit and their relevance for thermopile detectors. In the second part, a number of material systems, techniques and micromachined structures are discussed on the basis of different examples. We explain the motivation behind miniaturized thermopile detectors and give a functional explanation of physical interrelations. Finally, different applications are presented and discussed in terms of their future potential.

PURPOSE: The purpose of this study is to evaluate patients with uveal metastasis based on primary tumor site. METHODS: Retrospective analysis from Wills Eye Hospital, Philadelphia, PA, USA, for uveal metastasis clinical features and outcomes based on the primary tumor site. RESULTS: There were 2214 uveal metastases diagnosed in 1111 consecutive patients. The demographics included mean age of 60 years (median 61 years), Caucasian race (88%), and female gender (64%). The tumor was unilateral (82%) and primary site was established before uveal metastasis (67%). The primary tumor originated in the breast (37%), lung (26%), kidney (4%), gastrointestinal (GI) tract (4%), cutaneous melanoma (2%), lung carcinoid (2%), prostate (2%), thyroid (1%), pancreas (1%), other sites (3%), and unknown (16%). Comparative analysis of the 5 most common primary sites (breast, lung, kidney, GI tract, and cutaneous melanoma), revealed metastasis at mean age (57, 62, 66, 61, 59 years), as unilateral tumor (74%, 86%, 85%, 93%, 85%), with mean number of metastasis/eye (1.9, 1.7, 1.0, 1.1, 2.0), and in females (99%, 46%, 26%, 25%, 30%). Choroidal metastases measured mean base (9.3, 10.2, 9.1, 11.0, 7.3 mm), mean thickness (2.4, 3.6, 4.4, 4.0, 2.9 mm), and demonstrated predominant color yellow (94%, 91%, 56%, 97%, 36%). Of the 769 patients with documented follow-up, mean patient survival was poor (22.2, 11.5, 8.6, 12.4, 11.4 months) and Kaplan–Meier analysis revealed 3-year survival (33%, 19%, 0%, 14%, 21%) and 5-year survival (24%, 13%, 0%, 14%, 21%). The worst survival was found in patients with pancreatic metastasis (mean 4.2 months) and best survival with lung carcinoid (92% at 5 years). CONCLUSION: In a tertiary referral service, uveal metastasis originates from cancer in the breast, lung, kidney, GI tract, cutaneous melanoma, or others. Overall prognosis is poor with 5-year survival at 23% and worst survival with pancreatic metastasis whereas best survival with lung carcinoid metastasis.

We present results from experiments at the Linac Coherent Light Source (LCLS) demonstrating that serial femtosecond crystallography (SFX) can be performed to high resolution (~2.5 Å) using protein microcrystals deposited on an ultra-thin silicon nitride membrane and embedded in a preservation medium at room temperature. Data can be acquired at a high acquisition rate using x-ray free electron laser sources to overcome radiation damage, while sample consumption is dramatically reduced compared to flowing jet methods. We achieved a peak data acquisition rate of 10 Hz with a hit rate of ~38%, indicating that a complete data set could be acquired in about one 12-hour LCLS shift using the setup described here, or in even less time using hardware optimized for fixed target SFX. This demonstration opens the door to ultra low sample consumption SFX using the technique of diffraction-before-destruction on proteins that exist in only small quantities and/or do not produce the copious quantities of microcrystals required for flowing jet methods.

We present two novel micro scanning mirrors with large aperture and HR dielectric coatings suitable for high power laser applications in a miniaturized laser-surgical instrument for neurosurgery to cut skull tissue. An electrostatic driven 2D-raster scanning mirror with 5x7.1mm aperture is used for dynamic steering of a ps-laser beam of the laser cutting process. A second magnetic 2D-beam steering mirror enables a static beam correction of a hand guided laser instrument. Optimizations of a magnetic gimbal micro mirror with 6 mm x 8 mm mirror plate are presented; here static deflections of 3° were reached. Both MEMS devices were successfully tested with a high power ps-laser at 532nm up to 20W average laser power.

The cadherin gene FAT1, located on chromosome 4q34-35 (ref. 1) within a region frequently deleted in human cancers,2 encodes a large protein with 34 extracellular cadherin repeats.3 In solid tumors, aberrant expression of FAT1 was found to be associated with disease progression.4 Although the gene was originally cloned from a human T-cell acute lymphoblastic leukemia (T-ALL) cell line,4 FAT1 just recently gained interest owing to its altered gene expression levels and the detection of somatic mutations identified by next-generation sequencing (NGS) in acute leukemia.2, 5, 6, 7 FAT1 was shown to be aberrantly expressed in pediatric patients with acute leukemia, whereas hematopoietic progenitors from healthy donors lacked FAT1 expression.5, 8 In addition, a recent report correlated high FAT1 expression with a higher probability of relapse in a small cohort of pediatric patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) based on an in silico analysis comprising two BCP-ALL data sets including 32 and 27 patients.5

Atmospheric scintillations cause difficulties for applications where an undistorted propagation of electromagnetic radiation is essential. These scintillations are related to turbulent fluctuations of temperature and humidity that are in turn related to surface heat fluxes. We developed an approach that quantifies these scintillations by estimating C(n(2)) from surface fluxes that are derived from single-level routine weather data. In contrast to previous methods that are biased to dry and warm air, our method is directly applicable to several land surface types, environmental conditions, wavelengths, and measurement heights (lookup tables for a limited number of site-specific parameters are provided). The approach allows for an efficient evaluation of the performance of, e.g., infrared imaging systems, laser geodetic systems, and ground-to-satellite optical communication systems. We tested our approach for two grass fields in central and southern Europe, and for a wheat field in central Europe. Although there are uncertainties in the flux estimates, the impact on C(n(2)) is shown to be rather small. The C(n(2)) daytime estimates agree well with values determined from eddy covariance measurements for the application to the three fields. However, some adjustments were needed for the approach for the grass in southern Europe because of non-negligible boundary-layer processes that occur in addition to surface-layer processes.

We present results on the realization of an atomic inner-shell x-ray laser in neon at 1.46 nm wavelength, by photo-ionization pumping and, alternatively, stimulated resonant Raman scattering with an x-ray free-electron laser source.

Even though two-thirds of acute myeloid leukemia (AML) patients respond to induction chemotherapy and achieve complete remission (CR), the majority of these patients will eventually relapse. The time from CR to relapse is an important clinical indicator of disease aggressiveness, as patients relapsing within the first 6 months after initial diagnosis have a poorer prognosis in terms of response to salvage therapy and overall survival compared to patients with a later relapse. To learn about the evolution during the course of disease, we analyzed the somatic mutation patterns from initial diagnosis to relapse in 50 cytogenetically normal (CN) AML patients. Based on the ELN classification, 38% of the patients (n=19) were assigned as "favorable" at diagnosis, all other patients were classified as "intermediate-I". ELN classification was associated with time to relapse as "intermediate-I" patients relapsed earlier than "favorable" patients (median 9.3 months vs. 16.1 months, p=0.008, log-rank test). Somatic alterations were detected by exome sequencing and confirmed by targeted amplicon sequencing of matched diagnostic, remission and relapse samples. FLT3-ITD and NPM1 mutation status were obtained from routine diagnostic tests as the reliable detection of these markers by NGS remains challenging. The vast majority of somatic alterations were present both at diagnosis and at relapse, hereafter referred to as stable mutations (70%, Fig. 1A). All patients in our cohort had ≥1 stable mutation with DNMT3A being the most stably altered gene. In 47 out of 50 patients (94%), we observed mutations that were only found at diagnosis or only at relapse. Based on the mutation patterns, four distinct 'evolutionary' subgroups of patients were defined (Fig. 1B): (I) patients with an identical mutation profile at diagnosis and at relapse ("stable", n=3, 6%), (II) patients who gained mutations at relapse ("stable + gain", n=24, 48%), (III) patients that lost mutations at relapse ("stable + loss", n=8, 16%), and (IV) patients with both loss and gain of mutations at relapse ("mixed", n=15, 30%). Mutations that were lost during the course of the disease were detected in e.g. PTPN11 or NRAS. Relapse-specific mutations were identified in e.g. IDH1/2, WT1, KPNB1 or KDM6A. Evolutionary subgroups showed differences in time to relapse (Fig. 1C). Patients with "stable + loss" relapsed earlier (median 4.1 months) than patients with gain of mutation at relapse (groups "stable + gain" and "mixed", median 12.2 months). All patients in the category "stable + loss" developed relapse within the first year after complete remission. The "stable" group of 3 patients showed an intermediate time to relapse (median 9.6 months), but was too small for a statistically valid comparison. Ultimately, the genetic evolution of CN-AML patients without gain of new mutations at relapse (categories "stable" and "stable + loss") was associated with significantly earlier relapse compared to patients that gained mutations at relapse (categories "stable + gain" and "mixed", Fig. 1D, p=0.001, log-rank test). Distinct predominant patterns of clonal evolution were observed in the ELN genetic groups, as only one patient of the "stable + loss" group was initially classified as "favorable". Interestingly, applying the ELN classification on relapse samples revealed a switch from "favorable" to "intermediate-I" in six patients, all with gain of mutations at relapse. This points towards more aggressive genetic profiles at relapse in these patients. The acquisition of mutations and/or the outgrowth of a resistant clone during/after chemotherapy might require a longer time or is per se associated with a longer time to relapse and a more favorable prognosis. Loss of mutations at relapse suggest the presence of two clones at diagnosis, with a chemotherapy resistant clone expanding after the eradication of a chemotherapy sensitive clone. As both clones share mutations and only the sensitive clone contains specific alterations, the resistant clone might be an ancestor of the sensitive clone. Taken together, in some patients the AML cells may require additional genetic alterations to become chemotherapy resistant, whereas in other patients the selective eradication of a sensitive clone is a potential mechanism underlying disease progression. Understanding the evolution of AML under selective pressure of chemotherapy is essential to cure or prevent AML relapse. Disclosures Hiddemann: Roche: Other: Grants; Genentech: Other: Grants; Roche: Membership on an entity's Board of Directors or advisory committees.