OBJECTIVE:Studies from single centers have suggested that mortality from acute lung injury (ALI) has declined over time. However, recent trends in ALI mortality from centers across the United States ...are unknown. We sought to determine whether recent advances in the treatment of ALI and related critical illnesses have resulted in decreased mortality from ALI.
DESIGN:Retrospective cohort study of patients enrolled in the Acute Respiratory Distress Syndrome (ARDS) Network randomized controlled trials.
SETTING:Adult intensive care units participating in the ARDS Network trials.
PATIENTS:2,451 mechanically ventilated patients with ALI enrolled in the ARDS Network randomized controlled trials between 1996 and 2005.
MEASUREMENTS AND MAIN RESULTS:Crude mortality was 35% in 1996–1997 and declined during each subsequent time period to a low of 26% in 2004–2005 (test for trend p < 0.0005). After adjusting for demographic and clinical covariates, including receipt of lower tidal volume ventilation and severity of illness, the temporal trend persisted (test for trend p = 0.002). When analyzed by individual causes of lung injury, there were not any statistically significant temporal trends in 60-day mortality for the most common causes of lung injury (pneumonia, sepsis, aspiration, and trauma).
CONCLUSIONS:Over the past decade, there seems to be a clear temporal improvement in survival among patients with ALI treated at ARDS Network centers. Our findings strongly suggest that other advancements in critical care, aside from lower tidal volume ventilation, accounted for this improvement in mortality.
Natural source zone depletion (NSZD) of light non-aqueous phase liquids (LNAPLs) includes partitioning, transport and degradation of LNAPL components. NSZD is being considered as a site closure ...option during later stages of active remediation of LNAPL contaminated sites, and where LNAPL mass removal is limiting. To ensure NSZD meets compliance criteria and to design enhanced NSZD actions if required, residual risks posed by LNAPL and its long term behaviour require estimation. Prediction of long-term NSZD trends requires linking physicochemical partitioning and transport processes with bioprocesses at multiple scales within a modelling framework. Here we expand and build on the knowledge base of a recent review of NSZD, to establish the key processes and understanding required to model NSZD long term. We describe key challenges to our understanding, inclusive of the dominance of methanogenic or aerobic biodegradation processes, the potentially changeability of rates due to the weathering profile of LNAPL product types and ages, and linkages to underlying bioprocesses. We critically discuss different scales in subsurface simulation and modelling of NSZD. Focusing on processes at Darcy scale, 36 models addressing processes of importance to NSZD are investigated. We investigate the capabilities of models to accommodate more than 20 subsurface transport and transformation phenomena and present comparisons in several tables. We discuss the applicability of each group of models for specific site conditions.
•Key processes and understanding required to model NSZD are critically discussed.•Capabilities of 36 models to accommodate 21 important phenomena are compared.•Open questions explored upscaling, methanogenesis and chemical classes.•Discussions provided on emerging needs and tools for representative NSZD modelling.
The present guidelines are the most recent data on postoperative nausea and vomiting (PONV) and an update on the 2 previous sets of guidelines published in 2003 and 2007. These guidelines were ...compiled by a multidisciplinary international panel of individuals with interest and expertise in PONV under the auspices of the Society for Ambulatory Anesthesia. The panel members critically and systematically evaluated the current medical literature on PONV to provide an evidence-based reference tool for the management of adults and children who are undergoing surgery and are at increased risk for PONV. These guidelines identify patients at risk for PONV in adults and children; recommend approaches for reducing baseline risks for PONV; identify the most effective antiemetic single therapy and combination therapy regimens for PONV prophylaxis, including nonpharmacologic approaches; recommend strategies for treatment of PONV when it occurs; provide an algorithm for the management of individuals at increased risk for PONV as well as steps to ensure PONV prevention and treatment are implemented in the clinical setting.
A colony-level phenotype was used to map the major sex determination locus (designated X) in the honey bee (Apis mellifera). Individual queen bees (reproductive females) were mated to single drones ...(fertile males) by instrumental insemination. Haploid drone progeny of an F1 queen were each backcrossed to daughter queens from one of the parental lines. 98 of the resulting colonies containing backcross progeny were evaluated for the trait 'low brood-viability' resulting from the production of diploid drones that were homozygous at X. DNA samples from the haploid drone fathers of these colonies were used individually in polymerase chain reactions (PCR) with 10-base primers. These reactions generated random amplified polymorphic DNA (RAPD) markers that were analyzed for cosegregation with the colonylevel phenotype. One RAPD marker allele was shared by 22 of 25 drones that fathered low brood-viability colonies. The RAPD marker fragment was cloned and partially sequenced. Two primers were designed that define a sequence-tagged site (STS) for this locus. The primers amplified DNA marker fragments that cosegregated with the original RAPD marker. In order to more precisely estimate the linkage between X and the STS locus, another group of bees consisting of progeny from one of the low-brood viability colonies was used in segregation analysis. Four diploid drones and 181 of their diploid sisters (workers, nonfertile females) were tested for segregation of the RAPD and STS markers. The cosegregating RAPD and STS markers were codominant due to the occurrence of fragment-length alleles. The four diploid drones were homozygous for these markers but only three of the 181 workers were homozygotes (recombinants).
Abstract
The largest uncertainty in the historical radiative forcing of climate is caused by changes in aerosol particles due to anthropogenic activity. Sophisticated aerosol microphysics processes ...have been included in many climate models in an effort to reduce the uncertainty. However, the models are very challenging to evaluate and constrain because they require extensive in situ measurements of the particle size distribution, number concentration, and chemical composition that are not available from global satellite observations. The Global Aerosol Synthesis and Science Project (GASSP) aims to improve the robustness of global aerosol models by combining new methodologies for quantifying model uncertainty, to create an extensive global dataset of aerosol in situ microphysical and chemical measurements, and to develop new ways to assess the uncertainty associated with comparing sparse point measurements with low-resolution models. GASSP has assembled over 45,000 hours of measurements from ships and aircraft as well as data from over 350 ground stations. The measurements have been harmonized into a standardized format that is easily used by modelers and nonspecialist users. Available measurements are extensive, but they are biased to polluted regions of the Northern Hemisphere, leaving large pristine regions and many continental areas poorly sampled. The aerosol radiative forcing uncertainty can be reduced using a rigorous model–data synthesis approach. Nevertheless, our research highlights significant remaining challenges because of the difficulty of constraining many interwoven model uncertainties simultaneously. Although the physical realism of global aerosol models still needs to be improved, the uncertainty in aerosol radiative forcing will be reduced most effectively by systematically and rigorously constraining the models using extensive syntheses of measurements.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
For prostate cancer patients, the Gleason score is one of the most important prognostic factors, potentially determining treatment independent of the stage. However, Gleason scoring is based on ...subjective microscopic examination of tumor morphology and suffers from poor reproducibility. Here we present a deep learning system (DLS) for Gleason scoring whole-slide images of prostatectomies. Our system was developed using 112 million pathologist-annotated image patches from 1226 slides, and evaluated on an independent validation dataset of 331 slides. Compared to a reference standard provided by genitourinary pathology experts, the mean accuracy among 29 general pathologists was 0.61 on the validation set. The DLS achieved a significantly higher diagnostic accuracy of 0.70 (
= 0.002) and trended towards better patient risk stratification in correlations to clinical follow-up data. Our approach could improve the accuracy of Gleason scoring and subsequent therapy decisions, particularly where specialist expertise is unavailable. The DLS also goes beyond the current Gleason system to more finely characterize and quantitate tumor morphology, providing opportunities for refinement of the Gleason system itself.
The development of cancer is intimately associated with genetic abnormalities that target proteins with intrinsically disordered regions (IDRs). In human haematological malignancies, recurrent ...chromosomal translocation of nucleoporin (NUP98 or NUP214) generates an aberrant chimera that invariably retains the nucleoporin IDR-tandemly dispersed repeats of phenylalanine and glycine residues
. However, how unstructured IDRs contribute to oncogenesis remains unclear. Here we show that IDRs contained within NUP98-HOXA9, a homeodomain-containing transcription factor chimera recurrently detected in leukaemias
, are essential for establishing liquid-liquid phase separation (LLPS) puncta of chimera and for inducing leukaemic transformation. Notably, LLPS of NUP98-HOXA9 not only promotes chromatin occupancy of chimera transcription factors, but also is required for the formation of a broad 'super-enhancer'-like binding pattern typically seen at leukaemogenic genes, which potentiates transcriptional activation. An artificial HOX chimera, created by replacing the phenylalanine and glycine repeats of NUP98 with an unrelated LLPS-forming IDR of the FUS protein
, had similar enhancing effects on the genome-wide binding and target gene activation of the chimera. Deeply sequenced Hi-C revealed that phase-separated NUP98-HOXA9 induces CTCF-independent chromatin loops that are enriched at proto-oncogenes. Together, this report describes a proof-of-principle example in which cancer acquires mutation to establish oncogenic transcription factor condensates via phase separation, which simultaneously enhances their genomic targeting and induces organization of aberrant three-dimensional chromatin structure during tumourous transformation. As LLPS-competent molecules are frequently implicated in diseases
, this mechanism can potentially be generalized to many malignant and pathological settings.
The use of remote real-time continuous glucose monitoring (CGM) in the hospital has rapidly emerged to preserve personal protective equipment and reduce potential exposures during coronavirus disease ...2019 (COVID-19).
We linked a hybrid CGM and point-of-care (POC) glucose testing protocol to a computerized decision support system for continuous insulin infusion and integrated a validation system for sensor glucose values into the electronic health record. We report our proof-of-concept experience in a COVID-19 intensive care unit.
All nine patients required mechanical ventilation and corticosteroids. During the protocol, 75.7% of sensor values were within 20% of the reference POC glucose with an associated average reduction in POC of 63%. Mean time in range (70-180 mg/dL) was 71.4 ± 13.9%. Sensor accuracy was impacted by mechanical interferences in four patients.
A hybrid protocol integrating real-time CGM and POC is helpful for managing critically ill patients with COVID-19 requiring insulin infusion.
Select subsets of immune effector cells have the greatest propensity to mediate antitumor responses. However, procuring these subsets is challenging, and cell-based immunotherapy is hampered by ...limited effector-cell persistence and lack of on-demand availability. To address these limitations, we generated a triple-gene-edited induced pluripotent stem cell (iPSC). The clonal iPSC line was engineered to express a high affinity, non-cleavable version of the Fc receptor CD16a and a membrane-bound interleukin (IL)-15/IL-15R fusion protein. The third edit was a knockout of the ecto-enzyme CD38, which hydrolyzes NAD+. Natural killer (NK) cells derived from these uniformly engineered iPSCs, termed iADAPT, displayed metabolic features and gene expression profiles mirroring those of cytomegalovirus-induced adaptive NK cells. iADAPT NK cells persisted in vivo in the absence of exogenous cytokine and elicited superior antitumor activity. Our findings suggest that unique subsets of the immune system can be modeled through iPSC technology for effective treatment of patients with advanced cancer.
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•iADAPT NK cells and adaptive NK cells share metabolic and transcriptional features•iADAPT NK cells are cytokine autonomous•iADAPT NK cells display enhanced innate immune function
Optimized iPSC-derived NK (iNK) cells have been developed for on-demand cancer immunotherapy. Here, Cichocki and colleagues describe a triple-gene-edited iNK cell product, termed iADAPT NK, which persists and functions in vivo in the absence of exogenous cytokines and can be combined with therapeutic antibodies for enhanced tumor targeting.
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