U.K. HiGEM Shaffrey, L. C.; Stevens, I.; Norton, W. A. ...
Journal of climate,
04/2009, Letnik:
22, Številka:
8
Journal Article
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This article describes the development and evaluation of the U.K.’s new High-Resolution Global Environmental Model (HiGEM), which is based on the latest climate configuration of the Met Office ...Unified Model, known as the Hadley Centre Global Environmental Model, version 1 (HadGEM1). In HiGEM, the horizontal resolution has been increased to 0.83° latitude × 1.25° longitude for the atmosphere, and 1/3° × 1/3° globally for the ocean. Multidecadal integrations of HiGEM, and the lower-resolution HadGEM, are used to explore the impact of resolution on the fidelity of climate simulations.
Generally, SST errors are reduced in HiGEM. Cold SST errors associated with the path of the North Atlantic drift improve, and warm SST errors are reduced in upwelling stratocumulus regions where the simulation of low-level cloud is better at higher resolution. The ocean model in HiGEM allows ocean eddies to be partially resolved, which dramatically improves the representation of sea surface height variability. In the Southern Ocean, most of the heat transports in HiGEM is achieved by resolved eddy motions, which replaces the parameterized eddy heat transport in the lower-resolution model. HiGEM is also able to more realistically simulate small-scale features in the wind stress curl around islands and oceanic SST fronts, which may have implications for oceanic upwelling and ocean biology.
Higher resolution in both the atmosphere and the ocean allows coupling to occur on small spatial scales. In particular, the small-scale interaction recently seen in satellite imagery between the atmosphere and tropical instability waves in the tropical Pacific Ocean is realistically captured in HiGEM. Tropical instability waves play a role in improving the simulation of the mean state of the tropical Pacific, which has important implications for climate variability. In particular, all aspects of the simulation of ENSO (spatial patterns, the time scales at which ENSO occurs, and global teleconnections) are much improved in HiGEM.
Genomic instability arising from defective responses to DNA damage
or mitotic chromosomal imbalances
can lead to the sequestration of DNA in aberrant extranuclear structures called micronuclei (MN). ...Although MN are a hallmark of ageing and diseases associated with genomic instability, the catalogue of genetic players that regulate the generation of MN remains to be determined. Here we analyse 997 mouse mutant lines, revealing 145 genes whose loss significantly increases (n = 71) or decreases (n = 74) MN formation, including many genes whose orthologues are linked to human disease. We found that mice null for Dscc1, which showed the most significant increase in MN, also displayed a range of phenotypes characteristic of patients with cohesinopathy disorders. After validating the DSCC1-associated MN instability phenotype in human cells, we used genome-wide CRISPR-Cas9 screening to define synthetic lethal and synthetic rescue interactors. We found that the loss of SIRT1 can rescue phenotypes associated with DSCC1 loss in a manner paralleling restoration of protein acetylation of SMC3. Our study reveals factors involved in maintaining genomic stability and shows how this information can be used to identify mechanisms that are relevant to human disease biology
.
► A coupled physical-ecosystem model predicts future marine fisheries potential. ► A bioeconomic model evaluates fisheries sustainability against demand scenarios. ► Replacement of fishmeal in ...aquafeed will allow increasing fish consumption in 2050. ► Fisheries management will be critical.
Expansion in the world's human population and economic development will increase future demand for fish products. As global fisheries yield is constrained by ecosystems productivity and management effectiveness, per capita fish consumption can only be maintained or increased if aquaculture makes an increasing contribution to the volume and stability of global fish supplies. Here, we use predictions of changes in global and regional climate (according to IPCC emissions scenario A1B), marine ecosystem and fisheries production estimates from high resolution regional models, human population size estimates from United Nations prospects, fishmeal and oil price estimations, and projections of the technological development in aquaculture feed technology, to investigate the feasibility of sustaining current and increased per capita fish consumption rates in 2050. We conclude that meeting current and larger consumption rates is feasible, despite a growing population and the impacts of climate change on potential fisheries production, but only if fish resources are managed sustainably and the animal feeds industry reduces its reliance on wild fish. Ineffective fisheries management and rising fishmeal prices driven by greater demand could, however, compromise future aquaculture production and the availability of fish products.
The Engager aortic bioprosthesis consists of bovine pericardial leaflets mounted on a self-expandable frame with unique anatomic orientation capabilities to engage the aortic valve cusps. We report ...the initial North American transcatheter aortic valve implantation (TAVI) experience with the Engager device. Transapical TAVI was performed in 4 patients (mean age 80 ± 6 years, Society of Thoracic Surgeons score 5 ± 1%). The valve was anatomically oriented and successfully implanted in all patients. There were no conversions to open operation or major procedure-related adverse events. Pacemaker implantation was necessary in 1 patient. None of the patients showed paravalvular leak. The Engager device for TAVI provides anatomic orientation and anchoring that prevents coronary obstruction and paravalvular leak.
Transcatheter aortic valve implantation (TAVI) in the presence of a mechanical mitral valve (MMV) prosthesis is still challenging because of the rigid mitral frame within the aortomitral curtain. ...Moreover, low-lying coronary ostia represent a hazardous problem of coronary obstruction, especially in narrow or porcelain aortic roots. The present case demonstrates the successful management of 2 challenging anatomical issues, the rigid cage of the MMV and the low-lying left main coronary ostium (LMCO), with the implantation of the ACURATE-TA bioprosthesis (Symetis SA, Ecublens, Switzerland). It also highlights the importance of having multiple TAVI devices in order to choose the ideal transcatheter aortic bioprosthesis to fit the unique anatomical presentation of the patient.
After surgical resection of pancreatic ductal adenocarcinoma (PDAC), patients are predominantly treated with adjuvant chemotherapy, commonly consisting of gemcitabine (GEM)-based regimens or the ...modified FOLFIRINOX (mFFX) regimen. While mFFX regimen has been shown to be more effective than GEM-based regimens, it is also associated with higher toxicity. Current treatment decisions are based on patient performance status rather than on the molecular characteristics of the tumor. To address this gap, the goal of this study was to develop drug-specific transcriptomic signatures for personalized chemotherapy treatment.
We used PDAC datasets from preclinical models, encompassing chemotherapy response profiles for the mFFX regimen components. From them we identified specific gene transcripts associated with chemotherapy response. Three transcriptomic artificial intelligence signatures were obtained by combining independent component analysis and the least absolute shrinkage and selection operator-random forest approach. We integrated a previously developed GEM signature with three newly developed ones. The machine learning strategy employed to enhance these signatures incorporates transcriptomic features from the tumor microenvironment, leading to the development of the ‘Pancreas-View’ tool ultimately clinically validated in a cohort of 343 patients from the PRODIGE-24/CCTG PA6 trial.
Patients who were predicted to be sensitive to the administered drugs (n = 164; 47.8%) had longer disease-free survival (DFS) than the other patients. The median DFS in the mFFX-sensitive group treated with mFFX was 50.0 months stratified hazard ratio (HR) 0.31, 95% confidence interval (CI) 0.21-0.44, P < 0.001 and 33.7 months (stratified HR 0.40, 95% CI 0.17-0.59, P < 0.001) in the GEM-sensitive group when treated with GEM. Comparatively patients with signature predictions unmatched with the treatments (n = 86; 25.1%) or those resistant to all drugs (n = 93; 27.1%) had shorter DFS (10.6 and 10.8 months, respectively).
This study presents a transcriptome-based tool that was developed using preclinical models and machine learning to accurately predict sensitivity to mFFX and GEM.
•Transcriptomic signatures were developed for key pancreatic cancer drugs to enable personalized treatment.•The Pancreas-View tool integrates four drug signatures to assist informed therapeutic decisions.•Signatures accurately identify high responder patients, indicative of improved DFS and cancer-specific survival.•Clinical validation involving a cohort of 343 patients confirms the efficacy of this signature approach.•Transcriptomic signatures derived from preclinical models and machine learning offer a rationalized treatment strategy.
Cardiac surgery is frequently complicated by coagulopathic bleeding that is difficult to optimally manage using standard hemostatic testing. We hypothesized that point-of-care hemostatic testing ...within the context of an integrated transfusion algorithm would improve the management of coagulopathy in cardiac surgery and thereby reduce blood transfusions.
We conducted a pragmatic multicenter stepped-wedge cluster randomized controlled trial of a point-of-care-based transfusion algorithm in consecutive patients undergoing cardiac surgery with cardiopulmonary bypass at 12 hospitals from October 6, 2014, to May 1, 2015. Following a 1-month data collection at all participating hospitals, a transfusion algorithm incorporating point-of-care hemostatic testing was sequentially implemented at 2 hospitals at a time in 1-month intervals, with the implementation order randomly assigned. No other aspects of care were modified. The primary outcome was red blood cell transfusion from surgery to postoperative day 7. Other outcomes included transfusion of other blood products, major bleeding, and major complications. The analysis adjusted for secular time trends, within-hospital clustering, and patient-level risk factors. All outcomes and analyses were prespecified before study initiation.
Among the 7402 patients studied, 3555 underwent surgery during the control phase and 3847 during the intervention phase. Overall, 3329 (45.0%) received red blood cells, 1863 (25.2%) received platelets, 1645 (22.2%) received plasma, and 394 (5.3%) received cryoprecipitate. Major bleeding occurred in 1773 (24.1%) patients, and major complications occurred in 740 (10.2%) patients. The trial intervention reduced rates of red blood cell transfusion (adjusted relative risk, 0.91; 95% confidence interval, 0.85-0.98; P=0.02; number needed to treat, 24.7), platelet transfusion (relative risk, 0.77; 95% confidence interval, 0.68-0.87; P<0.001; number needed to treat, 16.7), and major bleeding (relative risk, 0.83; 95% confidence interval, 0.72-0.94; P=0.004; number needed to treat, 22.6), but had no effect on other blood product transfusions or major complications.
Implementation of point-of-care hemostatic testing within the context of an integrated transfusion algorithm reduces red blood cell transfusions, platelet transfusions, and major bleeding following cardiac surgery. Our findings support the broader adoption of point-of-care hemostatic testing into clinical practice.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT02200419.
Pain is a common problem among elite athletes and is frequently associated with sport injury. Both pain and injury interfere with the performance of elite athletes. There are currently no ...evidence-based or consensus-based guidelines for the management of pain in elite athletes. Typically, pain management consists of the provision of analgesics, rest and physical therapy. More appropriately, a treatment strategy should address all contributors to pain including underlying pathophysiology, biomechanical abnormalities and psychosocial issues, and should employ therapies providing optimal benefit and minimal harm. To advance the development of a more standardised, evidence-informed approach to pain management in elite athletes, an IOC Consensus Group critically evaluated the current state of the science and practice of pain management in sport and prepared recommendations for a more unified approach to this important topic.
CYP2D6 bioactivates codeine and tramadol, with intermediate and poor metabolizers (IMs and PMs) expected to have impaired analgesia. This pragmatic proof-of-concept trial tested the effects of ...CYP2D6-guided opioid prescribing on pain control.
Participants with chronic pain (94% on an opioid) from seven clinics were enrolled into CYP2D6-guided (n = 235) or usual care (n = 135) arms using a cluster design. CYP2D6 phenotypes were assigned based on genotype and CYP2D6 inhibitor use, with recommendations for opioid prescribing made in the CYP2D6-guided arm. Pain was assessed at baseline and 3 months using PROMIS
measures.
On stepwise multiple linear regression, the primary outcome of composite pain intensity (composite of current pain and worst and average pain in the past week) among IM/PMs initially prescribed tramadol/codeine (n = 45) had greater improvement in the CYP2D6-guided versus usual care arm (-1.01 ± 1.59 vs. -0.40 ± 1.20; adj P = 0.016); 24% of CYP2D6-guided versus 0% of usual care participants reported ≥30% (clinically meaningful) reduction in the composite outcome. In contrast, among normal metabolizers prescribed tramadol or codeine at baseline, there was no difference in the change in composite pain intensity at 3 months between CYP2D6-guided (-0.61 ± 1.39) and usual care (-0.54 ± 1.69) groups (adj P = 0.540).
These data support the potential benefits of CYP2D6-guided pain management.
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