A multicenter multinational study of abdominal candidiasis: epidemiology, outcomes and predictors of mortality

Abstract Purpose: Clinical data on patients with intra-abdominal candidiasis (IAC) is still scarce. Methods: We collected data from 13 hospitals in Italy, Spain, Brazil, and Greece over a 3-year period (2011\u20132013) including patients from ICU, medical, and surgical wards. Results: A total of 481 patients were included in the study. Of these, 27 % were hospitalized in ICU. Mean age was 63 years and 57 % of patients were male. IAC mainly consisted of secondary peritonitis (41 %) and abdominal abscesses (30 %); 68 (14 %) cases were also candidemic and 331 (69 %) hadconcomitant bacterial infections. The most commonly isolated Candida species were C. albicans (n = 308 isolates, 64 %) and C. glabrata (n = 76, 16 %). Antifungal treatment included echinocandins (64 %), azoles (32 %), and amphotericin B (4 %). Septic shock was documented in 40.5 % of patients. Overall 30-day hospital mortality was 27 % with 38.9 % mortality in ICU. Multivariate logistic regression showed that age (OR 1.05, 95 % CI 1.03\u20131.07, P\0.001), increments in 1-point APACHE II scores (OR 1.05, 95 % CI 1.01\u20131.08, P = 0.028), secondary peritonitis (OR 1.72, 95 % CI 1.02\u20132.89, P = 0.019), septic shock (OR 3.29, 95 % CI 1.88\u20135.86, P\0.001), and absence of adequate abdominal source control (OR 3.35, 95 % CI 2.01\u20135.63, P\0.001) wereassociated with mortality. In patients with septic shock, absence of source control correlated with mortality rates above 60 % irrespective of administration of an adequate antifungal therapy. Conclusions: Low percentages of concomitant candidemia and high mortality rates are documented in IAC. In patients presenting with septic shock, source control is fundamental

Synergistic Interactions between HDAC and Sirtuin Inhibitors in Human Leukemia Cells

Aberrant histone deacetylase (HDAC) activity is frequent in human leukemias. However, while classical, NAD+-independent HDACs are an established therapeutic target, the relevance of NAD+-dependent HDACs (sirtuins) in leukemia treatment remains unclear. Here, we assessed the antileukemic activity of sirtuin inhibitors and of the NAD+-lowering drug FK866, alone and in combination with traditional HDAC inhibitors. Primary leukemia cells, leukemia cell lines, healthy leukocytes and hematopoietic progenitors were treated with sirtuin inhibitors (sirtinol, cambinol, EX527) and with FK866, with or without addition of the HDAC inhibitors valproic acid, sodium butyrate, and vorinostat. Cell death was quantified by propidium iodide cell staining and subsequent flow-cytometry. Apoptosis induction was monitored by cell staining with FITC-Annexin-V/propidium iodide or with TMRE followed by flow-cytometric analysis, and by measuring caspase3/7 activity. Intracellular Bax was detected by flow-cytometry and western blotting. Cellular NAD+ levels were measured by enzymatic cycling assays. Bax was overexpressed by retroviral transduction. Bax and SIRT1 were silenced by RNA-interference. Sirtuin inhibitors and FK866 synergistically enhanced HDAC inhibitor activity in leukemia cells, but not in healthy leukocytes and hematopoietic progenitors. In leukemia cells, HDAC inhibitors were found to induce upregulation of Bax, a pro-apoptotic Bcl2 family-member whose translocation to mitochondria is normally prevented by SIRT1. As a result, leukemia cells become sensitized to sirtuin inhibitor-induced apoptosis. In conclusion, NAD+-independent HDACs and sirtuins cooperate in leukemia cells to avoid apoptosis. Combining sirtuin with HDAC inhibitors results in synergistic antileukemic activity that could be therapeutically exploited

Technical Design Report: Scientific Instrument MID

This technical design report (TDR) for the Materials Imaging and Dynamics (MID) scientific instrument at the European XFEL is based on the previous conceptual design report (CDR). The scope of the TDR is to present the current status of the technical design of the MID instrument. The report includes a description of the tunnel installations and the environment in the experiment hall, an outline of the MID X-ray hutches and optical laser installations, and the design of the beam transport system and X-ray optics, as well as specifications for the required instrumentation, detectors, X-ray diagnostics, and data acquisition systems. Our goal is to provide the user community from 2016 onwards with X-ray laser beams of unprecedented intensity and coherence in a scientific instrument optimized for materials science experiments. Due to the complex nature of the work, the picture presented in this TDR is necessarily incomplete and subject to changes. Nevertheless, the document indicates where we are heading by clearly defining functions and giving technical specifications of all components

Design and Throughput Simulations of a Hard X-Ray Split and Delay Line for the MID Station at the European XFEL

A hard X-ray Split and Delay Line (SDL) under development for the Materials Imaging and Dynamics (MID) station at the European X-Ray Free-Electron Laser (XFEL.EU) is presented. This device will provide pairs of X-ray pulses with a variable time delay ranging from-10 ps to 800 ps in a photon energy range from 5 to 10 keV. Throughput simulations in the SASE case indicate a total transmission of 1.1% or 3.5% depending on the operation mode. In the self-seeded case of XFEL.EU operation simulations indicate that the transmission can be improved to more than 11%

X-ray beam diagnostics at the MID instrument of the European X-ray Free-Electron Laser Facility

The Materials Imaging and Dynamics (MID) instrument at the European X-ray Free-Electron Laser Facility (EuXFEL) is equipped with a multipurpose diagnostic end-station (DES) at the end of the instrument. The imager unit in DES is a key tool for aligning the beam to a standard trajectory and for adjusting optical elements such as focusing lenses or the split-and-delay line. Furthermore, the DES features a bent-diamond-crystal spectrometer to disperse the spectrum of the direct beam to a line detector. This enables pulse-resolved characterization of the EuXFEL spectrum to provide X-ray energy calibration, and the spectrometer is particularly useful in commissioning special modes of the accelerator. Together with diamond-based intensity monitors, the imager and spectrometer form the DES unit which also contains a heavy-duty beamstop at the end of the MID instrument. Here, we describe the setup in detail and provide exemplary beam diagnostic results

Operational experience with Adaptive Gain Integrating Pixel Detectors at European XFEL

The European X-ray Free Electron Laser (European XFEL) is a cutting-edge user facility that generates per second up to 27,000 ultra-short, spatially coherent X-ray pulses within an energy range of 0.26 to more than 20 keV. Specialized instrumentation, including various 2D X-ray detectors capable of handling the unique time structure of the beam, is required. The one-megapixel AGIPD (AGIPD1M) detectors, developed for the European XFEL by the AGIPD Consortium, are the primary detectors used for user experiments at the SPB/SFX and MID instruments. The first AGIPD1M detector was installed at SPB/SFX when the facility began operation in 2017, and the second one was installed at MID in November 2018. The AGIPD detector systems require a dedicated infrastructure, well-defined safety systems, and high-level control procedures to ensure stable and safe operation. As of now, the AGIPD1M detectors installed at the SPB/SFX and MID experimental end stations are fully integrated into the European XFEL environment, including mechanical integration, vacuum, power, control, data acquisition, and data processing systems. Specific high-level procedures allow facilitated detector control, and dedicated interlock systems based on Programmable Logic Controllers ensure detector safety in case of power, vacuum, or cooling failure. The first 6 years of operation have clearly demonstrated that the AGIPD1M detectors provide high-quality scientific results. The collected data, along with additional dedicated studies, have also enabled the identification and quantification of issues related to detector performance, ensuring stable operation. Characterization and calibration of detectors are among the most critical and challenging aspects of operation due to their complex nature. A methodology has been developed to enable detector characterization and data correction, both in near real-time (online) and offline mode. The calibration process optimizes detector performance and ensures the highest quality of experimental results. Overall, the experience gained from integrating and operating the AGIPD detectors at the European XFEL, along with the developed methodology for detector characterization and calibration, provides valuable insights for the development of next-generation detectors for Free Electron Laser X-ray sources.

A multicenter multinational study of abdominal candidiasis: epidemiology, outcomes and predictors of mortality

Clinical data on patients with intra-abdominal candidiasis (IAC) is still scarce