Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Highly-parallelized simulation of a pixelated LArTPC on a GPU

The rapid development of general-purpose computing on graphics processing units (GPGPU) is allowing the implementation of highly-parallelized Monte Carlo simulation chains for particle physics experiments. This technique is particularly suitable for the simulation of a pixelated charge readout for time projection chambers, given the large number of channels that this technology employs. Here we present the first implementation of a full microphysical simulator of a liquid argon time projection chamber (LArTPC) equipped with light readout and pixelated charge readout, developed for the DUNE Near Detector. The software is implemented with an end-to-end set of GPU-optimized algorithms. The algorithms have been written in Python and translated into CUDA kernels using Numba, a just-in-time compiler for a subset of Python and NumPy instructions. The GPU implementation achieves a speed up of four orders of magnitude compared with the equivalent CPU version. The simulation of the current induced on 10^3 pixels takes around 1 ms on the GPU, compared with approximately 10 s on the CPU. The results of the simulation are compared against data from a pixel-readout LArTPC prototype

The DUNE far detector vertical drift technology. Technical design report

DUNE is an international experiment dedicated to addressing some of the questions at the forefront of particle physics and astrophysics, including the mystifying preponderance of matter over antimatter in the early universe. The dual-site experiment will employ an intense neutrino beam focused on a near and a far detector as it aims to determine the neutrino mass hierarchy and to make high-precision measurements of the PMNS matrix parameters, including the CP-violating phase. It will also stand ready to observe supernova neutrino bursts, and seeks to observe nucleon decay as a signature of a grand unified theory underlying the standard model. The DUNE far detector implements liquid argon time-projection chamber (LArTPC) technology, and combines the many tens-of-kiloton fiducial mass necessary for rare event searches with the sub-centimeter spatial resolution required to image those events with high precision. The addition of a photon detection system enhances physics capabilities for all DUNE physics drivers and opens prospects for further physics explorations. Given its size, the far detector will be implemented as a set of modules, with LArTPC designs that differ from one another as newer technologies arise. In the vertical drift LArTPC design, a horizontal cathode bisects the detector, creating two stacked drift volumes in which ionization charges drift towards anodes at either the top or bottom. The anodes are composed of perforated PCB layers with conductive strips, enabling reconstruction in 3D. Light-trap-style photon detection modules are placed both on the cryostat's side walls and on the central cathode where they are optically powered. This Technical Design Report describes in detail the technical implementations of each subsystem of this LArTPC that, together with the other far detector modules and the near detector, will enable DUNE to achieve its physics goals

The Janus-faced Nature of miR-22 in Hematopoiesis: Is It an Oncogenic Tumor Suppressor or Rather a Tumor-Suppressive Oncogene?

10.1371/journal.pgen.1006505PLoS Genetics131e100650

An assessment of the future of closed-cycle gas turbines

The closed-cycle gas turbine (CCGT) has not reached the worldwide level of success that was expected inspite of the strongly desirable features of this concept and the success of several large closed-cycle power plants operating in Western Europe today. However, an assessment of the CCGT's future has recently been made at the Institute of Gas Technology (IGT), and IGT has shown that due to innovative developments in technologies relevant to the development of CCGT's, coupled with worldwide changes in some economic factors, the CCGT could become a successful competitor of other externally fired power plants and also of internal combustion engines, especially in sizes ranging from 200 to 5000 kW. Documentation of data recently published in the technical literature and some recent relevant developments at IGT in the area of combustion, show a promising future for the cost. 13 refs., 4 figs., 1 tab

PML/RAR alpha-regulated miR-181a/b cluster targets the tumor suppressor RASSF1A in acute promyelocytic leukemia

In acute promyelocytic leukemia (APL), all-trans retinoic acid (ATRA) treatment induces granulocytic maturation and complete remission of leukemia. microRNAs are known to be critical players in the formation of the leukemic phenotype. In this study, we report downregulation of the miR-181a/b gene cluster in APL blasts and NB4 leukemia cells upon ATRA treatment as a key event in the drug response. We found that miR-181a/b expression was activated by the PML/RAR\u3b1 oncogene in cells and transgenic knock-in mice, an observation confirmed and extended by evidence of enhanced expression of miR-181a/b in APL patient specimens. RNA interference (RNAi)-mediated attenuation of miR-181a/b expression in NB4 cells was sufficient to reduce colony-forming capacity, proliferation, and survival. Mechanistic investigations revealed that miR-181a/b targets the ATRA-regulated tumor suppressor gene RASSF1A by direct binding to its 3'-untranslated region. Enforced expression of miR-181a/b or RNAi-mediated attenuation of RASSF1A inhibited ATRA-induced granulocytic differentiation via regulation of the cell-cycle regulator cyclin D1. Conversely, RASSF1A overexpression enhanced apoptosis. Finally, RASSF1A levels were reduced in PML/RAR\u3b1 knock-in mice and APL patient samples. Taken together, our results define miR-181a and miR-181b as oncomiRs in PML/RAR\u3b1-associated APL, and they reveal RASSF1A as a pivotal element in the granulocytic differentiation program induced by ATRA in APL

NF-?B/STAT5/miR-155 network targets PU.1 in FLT3-ITD-driven acute myeloid leukemia

Leukemia293535-54

ABR, a novel inducer of transcription factor C/EBPα, is necessary for myeloid differentiation and a favorable prognostic factor in acute myeloid leukemia

Introduction: Active BCR related (ABR) protein is closely homologous to BCR, which acts as a tumor suppressor in leukemia. Repression of ABR expression has been reported in t(8;21) acute myeloid leukemia (AML). However, the specific function of ABR in myeloid differentiation or AML has not been studied yet. Methods: We utilized acute myeloid leukemia U937 cell line, mouse bone marrow cells and human bone marrow cells from patients with acute myeloid leukemia. Cell differentiation was assessed by flow cytometry. Cell-cycle analysis was performed with propidium iodide and analyzed by flow cytometry. RNA detection was performed by quantitative real-time PCR. Protein detection was performed by immunoblot analyses. Trans¬fections of constructs pEYFP-ABR, pcDNA3.1-E2F1, ABR siRNA or CE¬BPA siRNA in U937 cells were performed via electroporation. Results: We observed highly reduced ABR mRNA in AML patients from different karyotypes. Moreover, AML patients with high ABR expression survive significantly longer after hematopoietic stem cell transplantation. Here we found for the first time that older patients with AML that have high ABR expression benefited from azacytidine treatment, presenting an early response. Furthermore, treatment of leukemic cells with azacytidine induces ABR expression. ABR expression is increased while M-CSF and G-CSF stimulated myeloid differentiation of mouse bone marrow cells. In contrast to this, siRNA mediated block of ABR prevents myeloid differen¬tiation. We identified ABR as a novel player in myelopoiesis via increasing the expression of the myeloid transcription factor C/EBPα, a major regu¬lator of myeloid differentiation and functionally impaired in leukemia. Fi¬nally, ABR blocks cell-cycle progression and downregulates the cell-cycle activator E2F1, indicating the functional role of ABR as tumor suppressor in leukemic cells. Conclusions: Taken together, our data demonstrate that ABR plays a crit¬ical role in myelopoiesis via inducing C/EBPα and indicate the strong tu¬mor suppressor potential of ABR expression in AML. Targeted treatments that increase endogenous levels of ABR might represent novel therapeutic strategies

Disruption of the C/EBP? - MiR-182 balance impairs granulocytic differentiation

10.1038/s41467-017-00032-6Nature Communications813

Disturbance of the C/EBP alpha-miR-182 balance impairs granulocytic differentiation and promotes development of acute myeloid leukemia

Introduction: Silencing of major myeloid transcription factor C/EBPa by gene mutation, promoter hypermethylation or posttranslational modifications is well described and occurs in ~50% of acute myeloid leukemia (AML) cases. Deregulation of C/EBPa by microRNAs, a class of small non-coding RNAs, as a substantial event during AML development or during myeloid differentiation has not been studied yet. Methods: We screened for C/EBPa dependent miRNAs in inducible K562-C/EBPa-ER cells using Illumina’s Next Generation Sequencing. For in vitro functional studies including gain-of-function and loss-of-function experiments, we utilized common acute myeloid leukemia cell lines, human hematopoietic stem cells from umbilical cord blood, murine hematopoietic stem cells from mouse bone marrow and primary human cells from patients with acute myeloid leukemia. For in vivo investigations, we manipulated Lin-Sca-1+c-Kit+ (LSK) murine hematopoietic progenitor cells by lentiviral infection and transplanted them into lethally irradiated littermates. The resulting phenotype was analyzed by flow cytometry and morphological staining of blood and bone marrow. Results: We identified oncogenic miR-182 as strong regulator of C/EBPa during myeloid differentiation and in AML. Moreover, we uncovered a novel regulatory loop between C/EBPa and miR-182. While C/EBPa blocks miR-182 expression by direct promoter binding during myeloid differentiation, enforced expression of miR-182 leads to reduced C/EBPa protein levels and impairs granulopoiesis in vitro and in a transplantation based mouse model in vivo. In contrast to this, a knockdown of miR-182 expression enhances C/EBPa protein levels in human AML. Furthermore, we observed highly elevated miR-182 expression levels particularly in AML patients with C-terminal CEBPA mutations and thereby uncovered a mechanism how C/EBPa blocks miR-182 expression. Finally by evaluation of TCGA database, we identified miR-182 expression as a strong adverse prognostic factor in cytogenetically high risk AML patients. Conclusions: Taken together, our data demonstrate the importance of a controlled balance between C/EBPa and miR-182 for the maintenance of healthy granulopoiesis and might uncover a novel mechanism for potential treatment strategies in AML. Disclosure: No conflict of interest disclosed