Abstract
Highly pathogenic avian influenza (HPAI) viruses of the A/Goose/Guangdong/1/1996 lineage (GsGd), which threaten the health of poultry, wildlife and humans, are spreading across Asia, Europe, ...Africa and North America but are currently absent from South America and Oceania. In December 2021, H5N1 HPAI viruses were detected in poultry and a free-living gull in St. John’s, Newfoundland and Labrador, Canada. Our phylogenetic analysis showed that these viruses were most closely related to HPAI GsGd viruses circulating in northwestern Europe in spring 2021. Our analysis of wild bird migration suggested that these viruses may have been carried across the Atlantic via Iceland, Greenland/Arctic or pelagic routes. The here documented incursion of HPAI GsGd viruses into North America raises concern for further virus spread across the Americas by wild bird migration.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Immune checkpoint inhibitor (ICI) monoclonal antibodies (mAbs) targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1) or its ligand (PD-L1) produce unique ...toxicity profiles. The objective of this review was to identify patterns and incidence of immune-related adverse events (irAE) based on tumour type and ICI class.
Medline, EMBASE and COCHRANE databases were searched to identify prospective monotherapy trials of ICIs from 2003 to November 2015. Paired reviewers selected studies for inclusion and extracted data. Odds ratio (OR),χ2 tests and multivariable regression models were used to analyse for effect size and associations.
We identified 48 trials (6938 patients), including 26 CTLA-4, 17 PD-1, 2 PD-L1 trials, and 3 studies tested both CTLA-4 and PD-1. Grade 3/4 irAE were more common with CTLA-4 mAbs compared with PD-1 (31% versus 10%). All grades colitis (OR 8.7, 95% CI 5.8–12.9), hypophysitis (OR 6.5, 95% CI 3.0–14.3) and rash (OR 2.0, 95% CI 1.8–2.3) were more frequent with CTLA-4 mAbs; whereas pneumonitis (OR 6.4, 95% CI 3.2–12.7), hypothyroidism (OR 4.3, 95% CI 2.9–6.3), arthralgia (OR 3.5, 95% CI 2.6–4.8) and vitiligo (OR 3.5, 95% CI 2.3–5.3) were more common with PD-1 mAbs. Comparison of irAE from the three most studied tumour types in PD-1 mAbs trials melanoma (n = 2048), non-small-cell lung cancer (n = 1030) and renal cell carcinoma (n = 573) showed melanoma patients had a higher frequency of gastrointestinal and skin irAE and lower frequency of pneumonitis.
CTLA-4 and PD-1 mAbs have distinct irAE profiles. Different immune microenvironments may drive histology-specific irAE patterns. Other tumour-dependent irAE profiles may be identified as data emerge from ICI trials.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is ...achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The net flux of carbon from land use and land-cover change (LULCC) accounted for 12.5% of anthropogenic carbon emissions from 1990 to 2010. This net flux is the most uncertain term in the global ...carbon budget, not only because of uncertainties in rates of deforestation and forestation, but also because of uncertainties in the carbon density of the lands actually undergoing change. Furthermore, there are differences in approaches used to determine the flux that introduce variability into estimates in ways that are difficult to evaluate, and not all analyses consider the same types of management activities. Thirteen recent estimates of net carbon emissions from LULCC are summarized here. In addition to deforestation, all analyses considered changes in the area of agricultural lands (croplands and pastures). Some considered, also, forest management (wood harvest, shifting cultivation). None included emissions from the degradation of tropical peatlands. Means and standard deviations across the thirteen model estimates of annual emissions for the 1980s and 1990s, respectively, are 1.14 ± 0.23 and 1.12 ± 0.25 Pg C yr−1 (1 Pg = 1015 g carbon). Four studies also considered the period 2000–2009, and the mean and standard deviations across these four for the three decades are 1.14 ± 0.39, 1.17 ± 0.32, and 1.10 ± 0.11 Pg C yr−1. For the period 1990–2009 the mean global emissions from LULCC are 1.14 ± 0.18 Pg C yr−1. The standard deviations across model means shown here are smaller than previous estimates of uncertainty as they do not account for the errors that result from data uncertainty and from an incomplete understanding of all the processes affecting the net flux of carbon from LULCC. Although these errors have not been systematically evaluated, based on partial analyses available in the literature and expert opinion, they are estimated to be on the order of ± 0.5 Pg C yr−1.
The Cassini Ultraviolet Imaging Spectrograph (UVIS) observed an occultation of the Sun by the water vapor plume at the south polar region of Saturn's moon Enceladus. The Extreme Ultraviolet (EUV) ...spectrum is dominated by the spectral signature of H2O gas, with a nominal line‐of‐sight column density of 0.90 ± 0.23 × 1016 cm−2 (upper limit of 1.0 × 1016 cm−2). The upper limit for N2 is 5 × 1013 cm−2, or <0.5% in the plume; the lack of N2 has significant implications for models of the geochemistry in Enceladus' interior. The inferred rate of water vapor injection into Saturn's magnetosphere is ∼200 kg/s. The calculated values of H2O flux from three occultations observed by UVIS have a standard deviation of 30 kg/s (15%), providing no evidence for substantial short‐term variability. Collimated gas jets are detected in the plume with Mach numbers of 5–8, implying vertical gas velocities that exceed 1000 m/sec. Observations at higher altitudes with the Cassini Ion Neutral Mass Spectrometer indicate correlated structure in the plume. Our results support the subsurface liquid model, with gas escaping and being accelerated through nozzle‐like channels to the surface, and are consistent with recent particle composition results from the Cassini Cosmic Dust Analyzer.
Key Points
N2 upper limit
Mach number of jets ranges from 5 to 8, more collimated than previous estimate
Flux of water vapor stable over last 6 years at 200 kg/sec
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
We present the first detailed elemental abundances in the ultra-faint Magellanic satellite galaxies Carina II (Car II) and Carina III (Car III). With high-resolution Magellan/MIKE spectroscopy, we ...determined the abundances of nine stars in Car II, including the first abundances of an RR Lyrae star in an ultra-faint dwarf galaxy (UFD), and two stars in Car III. The chemical abundances demonstrate that both systems are clearly galaxies and not globular clusters. The stars in these galaxies mostly display abundance trends matching those of other similarly faint dwarf galaxies: enhanced but declining /Fe ratios, iron-peak elements matching the stellar halo, and unusually low neutron-capture element abundances. One star displays a low outlying Sc/Fe = −1.0. We detect a large Ba scatter in Car II, likely due to inhomogeneous enrichment by low-mass asymptotic giant branch star winds. The most striking abundance trend is for Mg/Ca in Car II, which decreases from +0.4 to −0.4 and indicates clear variation in the initial progenitor masses of enriching core-collapse supernovae. So far, the only UFDs displaying a similar Mg/Ca trend are likely satellites of the Large Magellanic Cloud. We find two stars with Fe/H ≤ −3.5 whose abundances likely trace the first generation of metal-free Population III stars and are well fit by Population III core-collapse supernova yields. An appendix describes our new abundance uncertainty analysis that propagates line-by-line stellar parameter uncertainties.
There are limited data about the quality of immune-related adverse event (irAE) reporting in immune checkpoint inhibitor (ICI) clinical trial publications.
A systematic search of citations from ...Medline, EMBASE and Cochrane databases identified prospective clinical trials involving ICIs in advanced solid tumors from 2003 to 2013. A 21-point quality score (QS) was adapted from the CONSORT harms extension statement. Linear regression was used to identify factors associated with quality reporting.
After a review of 2628 articles, 50 trial reports were included, with ICIs as either monotherapy (54%) or part of a combination regimen (46%). The mean QS was 11.21 points (range 3.50-17.50 points). The median grade 3/4 AE rate reported was 21% (range 0%-66%) and 29/50 (58%) trials concluded that irAEs were tolerable. Multivariate regression analysis revealed that year of publication (within last 5 years, P = 0.01) and journal impact factor >15 (P = 0.004) were associated with higher QS. Complete reporting of specific characteristics of irAEs including onset, management and reversibility were reported by 14%, 8% and 6% of studies, respectively. The incidence of grade 3/4 adverse events was higher for inhibitors against CTLA-4 compared with other immune checkpoints (P < 0.001).
The reporting of irAEs is suboptimal. A standardized reporting method of irAEs that accounts for tolerability, management and reversibility is needed and would enable a more precise evaluation of the therapeutic risk benefit ratio of ICIs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Patients with castration-resistant prostate cancer derive only modest clinical benefit from available therapies. Blockade of the inhibitory programmed death 1 (PD-1) receptor by monoclonal antibodies ...has been effective in several malignancies. Results from the prostate adenocarcinoma cohort of the nonrandomized phase Ib KEYNOTE-028 trial of pembrolizumab in advanced solid tumors are presented.
Key eligibility criteria included advanced prostate adenocarcinoma, unsuccessful standard therapy, measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1), and PD-1 ligand (PD-L1) expression in ≥1% of tumor or stromal cells. Patients received pembrolizumab 10mg/kg every 2weeks until disease progression or intolerable toxicity for up to 24months. Primary end point was objective response rate (ORR) per RECIST v1.1 by investigator review.
Median patient age in this cohort (n=23) was 65years; 73.9% of patients received at least two prior therapies for metastatic disease. There were four confirmed partial responses, for an ORR of 17.4% 95% confidence interval (CI) 5.0%–38.8%; 8 of 23 (34.8%) patients had stable disease. Median duration of response was 13.5months. Median progression-free survival (PFS) and overall survival (OS) were 3.5 and 7.9months, respectively; 6-month PFS and OS rates were 34.8% and 73.4%, respectively. One patient remained on treatment at data cutoff. After a median follow-up of 7.9months, 14 (60.9%) patients experienced treatment-related adverse events (TRAEs), most commonly nausea (n=3, 13.0%). Four (17.3%) experienced grade 3/4 TRAEs: grade 3 peripheral neuropathy, grade 3 asthenia, grade 3 fatigue, and grade 4 lipase increase. No pembrolizumab-related deaths or discontinuations occurred.
Pembrolizumab resulted in durable objective response in a subset of patients with heavily pretreated, advanced PD-L1–positive prostate cancer, and its side effect profile was favorable.
NCT02054806
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The ability to measure gene expression on a genome-wide scale is one of the most promising accomplishments in molecular biology. Microarrays, the technology that first permitted this, were riddled ...with problems due to unwanted sources of variability. Many of these problems are now mitigated, after a decade's worth of statistical methodology development. The recently developed RNA sequencing (RNA-seq) technology has generated much excitement in part due to claims of reduced variability in comparison to microarrays. However, we show that RNA-seq data demonstrate unwanted and obscuring variability similar to what was first observed in microarrays. In particular, we find guanine-cytosine content (GC-content) has a strong sample-specific effect on gene expression measurements that, if left uncorrected, leads to false positives in downstream results. We also report on commonly observed data distortions that demonstrate the need for data normalization. Here, we describe a statistical methodology that improves precision by 42% without loss of accuracy. Our resulting conditional quantile normalization algorithm combines robust generalized regression to remove systematic bias introduced by deterministic features such as GC-content and quantile normalization to correct for global distortions.
Magnetizing the fuel in inertial confinement fusion relaxes ignition requirements by reducing thermal conductivity and changing the physics of burn product confinement. Diagnosing the level of fuel ...magnetization during burn is critical to understanding target performance in magneto-inertial fusion (MIF) implosions. In pure deuterium fusion plasma, 1.01 MeV tritons are emitted during deuterium-deuterium fusion and can undergo secondary deuterium-tritium reactions before exiting the fuel. Increasing the fuel magnetization elongates the path lengths through the fuel of some of the tritons, enhancing their probability of reaction. Based on this feature, a method to diagnose fuel magnetization using the ratio of overall deuterium-tritium to deuterium-deuterium neutron yields is developed. Analysis of anisotropies in the secondary neutron energy spectra further constrain the measurement. Secondary reactions also are shown to provide an upper bound for the volumetric fuel-pusher mix in MIF. The analysis is applied to recent MIF experiments M. R. Gomez et al., Phys. Rev. Lett. 113, 155003 (2014) on the Z Pulsed Power Facility, indicating that significant magnetic confinement of charged burn products was achieved and suggesting a relatively low-mix environment. Both of these are essential features of future ignition-scale MIF designs.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
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