Somatic mutations in the Janus kinase 2 gene (JAK2) occur in many myeloproliferative neoplasms, but the molecular pathogenesis of myeloproliferative neoplasms with nonmutated JAK2 is obscure, and the ...diagnosis of these neoplasms remains a challenge.
We performed exome sequencing of samples obtained from 151 patients with myeloproliferative neoplasms. The mutation status of the gene encoding calreticulin (CALR) was assessed in an additional 1345 hematologic cancers, 1517 other cancers, and 550 controls. We established phylogenetic trees using hematopoietic colonies. We assessed calreticulin subcellular localization using immunofluorescence and flow cytometry.
Exome sequencing identified 1498 mutations in 151 patients, with medians of 6.5, 6.5, and 13.0 mutations per patient in samples of polycythemia vera, essential thrombocythemia, and myelofibrosis, respectively. Somatic CALR mutations were found in 70 to 84% of samples of myeloproliferative neoplasms with nonmutated JAK2, in 8% of myelodysplasia samples, in occasional samples of other myeloid cancers, and in none of the other cancers. A total of 148 CALR mutations were identified with 19 distinct variants. Mutations were located in exon 9 and generated a +1 base-pair frameshift, which would result in a mutant protein with a novel C-terminal. Mutant calreticulin was observed in the endoplasmic reticulum without increased cell-surface or Golgi accumulation. Patients with myeloproliferative neoplasms carrying CALR mutations presented with higher platelet counts and lower hemoglobin levels than patients with mutated JAK2. Mutation of CALR was detected in hematopoietic stem and progenitor cells. Clonal analyses showed CALR mutations in the earliest phylogenetic node, a finding consistent with its role as an initiating mutation in some patients.
Somatic mutations in the endoplasmic reticulum chaperone CALR were found in a majority of patients with myeloproliferative neoplasms with nonmutated JAK2. (Funded by the Kay Kendall Leukaemia Fund and others.).
The aim of this study was to develop two novel risk prediction scores for transfusion and bleeding that would be used to inform treatment decisions, quality assurance, and clinical trial design in ...cardiac surgery.
Clinical data prospectively collected from 26 UK cardiac surgical centres and a single European centre were used to develop two risk prediction models: one for any red blood cell (RBC) transfusion, and the other for large volume blood transfusion (≥4 RBC units; LVBT), an index of severe blood loss. ‘Complete case’ data were available for 24 749 patients. Multiple imputation was used for missing covariate data (typically <5% per variable), with the imputed data set containing 39 970 patients. Risk models were developed in the complete case data set, with internal validation using leave-one-centre-out cross-validation. The final selected models were fitted to the imputed data set. Final risk scores were then compared with the performance of three existing scores: the Transfusion Risk and Clinical Knowledge score (TRACK), the Transfusion Risk Understanding Scoring Tool (TRUST), and the Papworth Bleeding Risk Score (BRiSc).
The area under the receiver operating characteristic curve (AUC) was 0.77 (95% confidence interval 0.77–0.77) for the any RBC transfusion score and AUC 0.80 (0.79–0.80) for the LVBT score in the imputed data set. The LVBT model also showed excellent discrimination (Hosmer–Lemeshow P=0.32). In the imputed data set, the AUCs for the TRACK and TRUST scores for any RBC transfusion were 0.71 and 0.71, respectively, and for LVBT the AUC for the BRiSc score was 0.69.
Two new risk scores for any RBC transfusion or LVBT among cardiac surgery patients have excellent discrimination, and could inform clinical decision making.
Background The Great Australian Bight (GAB) comprises the majority of Australia’s southern coastline, but to date its deep water fauna has remained almost unknown. Recent issuing of oil and gas ...leases in the region has highlighted this lack of baseline biological data and established a pressing need to characterise benthic abyssal fauna. Methods From 2013 to 2017, six large-scale systematic surveys of the GAB were conducted from 200 to 5000 m depth, constituting the deepest systematic biological sampling in Australia. Sampling was conducted on soft sediment and hard substrates, both at pre-determined depth intervals along north-south transect lines and at sites of interest identified by multibeam sonar. Results A total of 66,721 invertebrate specimens were collected, comprising 1267 species, with 401 species (32%) new to science. In addition to the novelty of the fauna, there was a high degree of rarity, with 31% of species known only from single specimens. Conclusions In this paper, we provide an annotated checklist of the benthic invertebrate fauna of the deep GAB, supplemented with colour photos of live specimens and commentary on taxonomy, diversity and distributions. This work represents an important addition to knowledge of Australia’s deep sea fauna, and will provide the foundation for further ecological, biogeographical and systematic research.
The major driver of palaeoclimatic dynamics over the southeast Arabian region is the varying latitudinal interface between the Westerly driven shamaal winds and a northward branch of the ...southwesterly Indian Ocean Summer Monsoon (IOM). At present, this latter system is restricted in extent to the southern coastal regions of Yemen and Oman. Monsoonal winds are widely believed to have increased in strength and penetrated much further north across southeast Arabia at various intervals during the Quaternary, resulting in a series of humid phases, which early studies suggested focussed within MIS 3 and MIS 1. Recent speleothem studies from Oman and UAE have indicated humidity within MIS 5 which, with current debates surrounding early human dispersal and occupation, could be significant for affirming the regional potential for early occupation. We investigate two new geoproxy suites, from Al Ain and Tawi Asmar, northern UAE, in the presently hyper-arid. Rub' al-Khali Sand Sea, that preserve evidence of multiple episodes of aeolian deposition and humidity in the form of fluvial gravels, sands and silts, and dune sands. 35 OSL ages demonstrate humid episodes occurred in MIS 5e, 5a and the early Holocene, with a major dry dune building phase in late MIS 3, and the onset of dry conditions again from 6 ka. The fluvial sedimentary evidence from MIS 5e and 5a suggest that the present hyper-arid desert landscape of the northeastern Rub' al-Khali was at those times represented by an environment experiencing significant seasonal wadi flow. This provides an environmental context that supports recent studies indicating archaeological visibility in Arabia dating from MIS 5, and the presence of anatomically modern humans in Arabia at this time.
It has been hypothesised that in sand seas where multiple dune generations occur, each generation represents a distinct terrestrial response to contrasting palaeoatmospheric circulation conditions ...(Lancaster N, Kocurek G, Singhvi A, Pandey V, Deynoux M, Ghienne J-F et al. (2002) Late Pleistocene and Holocene dune activity and wind regimes in the western Sahara Desert of Mauritania. Geology 30: 991–994). However, reconstructing dunefield accumulation and preservation chronologies has often utilised a limited suite of samples because of the difficulties realised in accessing unconsolidated aeolian sands, which has limited the capacity to test this hypothesis. In the eastern United Arab Emirates, artificial excavation for quarrying and construction have generated a unique opportunity to examine and sample the internal structures of dune systems, and to generate data to test the hypothesis of dune generational development. This paper presents new data and chronologies from a multigenerational analysis of dune accumulation in the northeast dunefield of the Rub’ al-Khali. A complex developmental history during the Holocene is revealed, which does not fully conform to the notion of each dune generation forming in distinct palaeoclimatic phases, since the age ranges represented in the accumulation of secondary dunes is also found within a longer suite of accumulation ages from the underlying megaridges.
The Bodélé Depression, Chad is the planet's largest single source of dust. Deflation from the Bodélé could be seen as a simple coincidence of two key prerequisites: strong surface winds and a large ...source of suitable sediment. But here we hypothesise that long term links between topography, winds, deflation and dust ensure the maintenance of the dust source such that these two apparently coincidental key ingredients are connected by land‐atmosphere processes with topography acting as the overall controlling agent. We use a variety of observational and numerical techniques, including a regional climate model, to show that: 1) contemporary deflation from the Bodélé is delineated by topography and a surface wind stress maximum; 2) the Tibesti and Ennedi mountains play a key role in the generation of the erosive winds in the form of the Bodélé Low Level Jet (LLJ); 3) enhanced deflation from a stronger Bodélé LLJ during drier phases, for example, the Last Glacial Maximum, was probably sufficient to create the shallow lake in which diatoms lived during wetter phases, such as the Holocene pluvial. Winds may therefore have helped to create the depression in which erodible diatom material accumulated. Instead of a simple coincidence of nature, dust from the world's largest source may result from the operation of long term processes on paleo timescales which have led to ideal conditions for dust generation in the world's largest dust source. Similar processes plausibly operate in other dust hotspots in topographic depressions.
There is a growing trend to treat displaced midshaft clavicular fractures with primary open reduction and plate fixation; whether such treatment results in improved patient outcomes is debatable. The ...aim of this multicenter, single-blinded, randomized controlled trial was to compare union rates, functional outcomes, and economic costs for displaced midshaft clavicular fractures that were treated with either primary open reduction and plate fixation or nonoperative treatment.
In a prospective, multicenter, stratified, randomized controlled trial, 200 patients between sixteen and sixty years of age who had an acute displaced midshaft clavicular fracture were randomized to receive either primary open reduction and plate fixation or nonoperative treatment. Functional assessment was conducted at six weeks, three months, six months, and one year with use of the Disabilities of the Arm, Shoulder and Hand (DASH) and Constant scores. Union was evaluated with use of three-dimensional computed tomography. Complications were recorded, and an economic evaluation was performed.
The rate of nonunion was significantly reduced after open reduction and plate fixation (one nonunion) as compared with nonoperative treatment (sixteen nonunions) (relative risk = 0.07; p = 0.007). Group allocation to nonoperative treatment was independently predictive of the development of nonunion (p = 0.0001). Overall, DASH and Constant scores were significantly better after open reduction and plate fixation than after nonoperative treatment at the time of the one-year follow-up (DASH score, 3.4 versus 6.1 p = 0.04; Constant score, 92.0 versus 87.8 p = 0.01). However, when patients with nonunion were excluded from analysis, there were no significant differences in the Constant scores or DASH scores at any time point. Patients were less dissatisfied with symptoms of shoulder droop, local bump at the fracture site, and shoulder asymmetry in the open reduction and plate fixation group (p < 0.0001). The cost of treatment was significantly greater after open reduction and plate fixation (p < 0.0001).
Open reduction and plate fixation reduces the rate of nonunion after acute displaced midshaft clavicular fracture compared with nonoperative treatment and is associated with better functional outcomes. However, the improved outcomes appear to result from the prevention of nonunion by open reduction and plate fixation. Open reduction and plate fixation is more expensive and is associated with implant-related complications that are not seen in association with nonoperative treatment. The results of the present study do not support routine primary open reduction and plate fixation for the treatment of displaced midshaft clavicular fractures.
The ability of the anesthetics metomidate hydrochloride and tricaine methanesulfonate (MS-222) to mitigate the cortisol stress response of Channel Catfish Ictalurus punctatus was evaluated during a ...10-min confinement stress. The cortisol concentrations of Channel Catfish anesthetized in metomidate hydrochloride remained consistent throughout the 10-min exposure; however, for fish anesthetized with MS-222 and nonanesthetized fish, cortisol concentrations were approximately 7- and 22-fold higher, respectively, than the baseline concentrations. While both anesthetics reduced cortisol concentrations relative to those of nonanesthetized fish, these results suggest that MS-222 is an appropriate anesthetic to use during the initial 5 min of sedation and that metomidate hydrochloride is appropriate for longer periods of sedation.
Selamectin, 25-cyclohexyl-25-de(1-methylpropyl)-5-deoxy-22,23-dihydro-5-(hydroxyimino)-avermectin B1 monosaccharide, is a novel endectocide with a unique combination of efficacy and safety in dogs ...and cats following both oral and topical administration. The compound is active against fleas and ticks, intestinal hookworms and ascarids, and immature heartworms. Also it is well tolerated at higher dosages than 22,23-dihydroavermectin B1a (DHAVM) or milbemycin oxime in Collies, which is a breed known to exhibit idiosyncratic sensitivity to avermectins.
An early-to mid-Holocene humid phase has been identified in various Arabian geo-archives, although significant regional heterogeneity has been reported in the onset, duration and stability of this ...period. A multi-proxy lake and dune record from Wahalah in the United Arab Emirates (UAE) documents significant variations in hydrology, biological productivity and landscape stability during the first half of the Holocene. These data reveal that post-Last Glacial Maximum dune emplacement continued into the earliest part of the Holocene, with the onset of permanent lacustrine sedimentation at the site commencing ∼8.5kacal.BP. A long-term shift towards more arid conditions is inferred between ∼7.8 and 5.9kacal.BP, with intermittent flooding of the basin and distinct phases of instability throughout the catchment area. This transition is linked to the southwards migration of the Intertropical Convergence Zone (ITCZ) and associated weakening of monsoon rains. A peak in landscape instability is recorded between ∼5.9 and 5.3kacal.BP and is marked by a pronounced increase in regional dune emplacement. These variations are considered alongside the record of human settlement raising important questions about the interactions between population demographics, climate and environment in southeast Arabia during the Neolithic.
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