Search

ABSTRACT:Background and purpose:To assess cost-effectiveness of late time-window endovascular treatment (EVT) in a clinical trial setting and a “real-world” setting.Methods:Data are from the randomized ESCAPE trial and a prospective cohort study (ESCAPE-LATE). Anterior circulation large vessel occlusion patients presenting > 6 hours from last-known-well were included, whereby collateral status was an inclusion criterion for ESCAPE but not ESCAPE-LATE. A Markov state transition model was built to estimate lifetime costs and quality-adjusted life-years (QALYs) for EVT in addition to best medical care vs. best medical care only in a clinical trial setting (comparing ESCAPE-EVT to ESCAPE control arm patients) and a “real-world” setting (comparing ESCAPE-LATE to ESCAPE control arm patients). We performed an unadjusted analysis, using 90-day modified Rankin Scale(mRS) scores as model input and analysis adjusted for baseline factors. Acceptability of EVT was calculated using upper/lower willingness-to-pay thresholds of 100,000 USD/50,000 USD/QALY.Results:Two-hundred and forty-nine patients were included (ESCAPE-LATE:n= 200, ESCAPE EVT-arm:n= 29, ESCAPE control-arm:n= 20). Late EVT in addition to best medical care was cost effective in the unadjusted analysis both in the clinical trial and real-world setting, with acceptability 96.6%–99.0%. After adjusting for differences in baseline variables between the groups, late EVT was marginally cost effective in the clinical trial setting (acceptability:49.9%–61.6%), but not the “real-world” setting (acceptability:32.9%–42.6%).Conclusion:EVT for LVO-patients presenting beyond 6 hours was cost effective in the clinical trial setting and “real-world” setting, although this was largely related to baseline patient differences favoring the “real-world” EVT group. After adjusting for these, EVT benefit was reduced in the trial setting, and absent in the real-world setting.

The distribution and state of subsea permafrost is largely unknown. Present maps, which rely heavily on model results, suggest that subsea permafrost is confined to the Beaufort, Siberian and Laptev seas. Here we show that discontinuous subsea permafrost exists along the Labrador coast (56 °N) under the influence of the Labrador Coastal Current. High-resolution bathymetric data reveal the presence of subsea thermokarst environments on the coastal seabed of Nain, Nunatsiavut, where an ice-rich sediment sample was recovered in July 2022 at a water depth of 27 m. Porewater analysis indicates that ground ice can persist in the sediments due to freshened submarine groundwater seepage that freezes at higher temperatures (0 °C) than seawater (−1.8 °C). The formation and preservation of subsea permafrost landforms is due to cold waters of the Labrador Coastal Current entering the coastal areas and remaining less than 0 °C for most of the year. Therefore, evidence of subsea permafrost landforms in coastal Labrador and the distribution of cold bottom water in the Northern Hemisphere suggests that subsea permafrost is likely to be preserved elsewhere in subarctic regions, especially where freshened submarine groundwater seepage elevates the freezing temperature. This highlights the potential underestimation of subsea permafrost in the world’s coastal oceans.

A leading explanation for translational failure in neurodegenerative disease is that new drugs are evaluated late in the disease course when clinical features have become irreversible. Here, to address this gap, we cognitively profiled 21,051 people aged 17–85 years as part of the Genes and Cognition cohort within the National Institute for Health and Care Research BioResource across England. We describe the cohort, present cognitive trajectories and show the potential utility. Surprisingly, when studied at scale, the APOEgenotype had negligible impact on cognitive performance. Different cognitive domains had distinct genetic architectures, with one indicating brain region-specific activation of microglia and another with glycogen metabolism. Thus, the molecular and cellular mechanisms underpinning cognition are distinct from dementia risk loci, presenting different targets to slow down age-related cognitive decline. Participants can now be recalled stratified by genotype and cognitive phenotype for natural history and interventional studies of neurodegenerative and other disorders.

Abstract:This article extends upon research about the politics of work and the digital mundane. It does this via an ethnographic study I undertook at a digital detox retreat located in North America. At this particular digital detox retreat, participants were invited to relinquish use of their digital devices, discussion of their professions and use of their ‘real names’ for a four-day period. I consider the pertinence of why a detox from the ‘digital’ and from ‘work’ were bound with one another and how the centrality that was accorded to ‘work’ at this retreat was tied in with a cultural framework of the digital mundane. I tie themes iterated in ‘digital detox’ literature with epistemological concerns, highlighting how the signifier of the ‘digital’ allows for an obscuring of high-tech politics and agendas.

Intravenous thrombolysis with alteplase bolus followed by infusion is a global standard of care for patients with acute ischaemic stroke. We aimed to determine whether tenecteplase given as a single bolus might increase reperfusion compared with this standard of care.

Clinical sequencing efforts are rapidly identifying sarcoma gene fusions that lack functional validation. An example is the fusion of transcriptional coactivators, VGLL2-NCOA2, found in infantile rhabdomyosarcoma. To delineate VGLL2-NCOA2 tumorigenic mechanisms and identify therapeutic vulnerabilities, we implement a cross-species comparative oncology approach with zebrafish, mouse allograft, and patient samples. We find that VGLL2-NCOA2 is sufficient to generate mesenchymal tumors that display features of immature skeletal muscle and recapitulate the human disease. A subset of VGLL2-NCOA2 zebrafish tumors transcriptionally cluster with embryonic somitogenesis and identify VGLL2-NCOA2 developmental programs, including a RAS family GTPase, ARF6. In VGLL2-NCOA2 zebrafish, mouse, and patient tumors, ARF6 is highly expressed. ARF6 knockout suppresses VGLL2-NCOA2 oncogenic activity in cell culture, and, more broadly, ARF6 is overexpressed in adult and pediatric sarcomas. Our data indicate that VGLL2-NCOA2 is an oncogene that leverages developmental programs for tumorigenesis and that reactivation or persistence of ARF6 could represent a therapeutic opportunity.

The Sonoran Desert portion of the Basin and Range physiographic province contains a number of streams that now flow across once-closed basins. We explore here the research questions of if and how granitic rock pediments respond to the transition from rimming endorheic basins to bordering through-flowing streams. Granitic rock pediments of the northern Usery and eastern McDowell Mountains once graded to the closed Miocene–Pliocene Pemberton basin that occupied the present-day location of the confluence of the Salt and Verde Rivers. The process of lake overflow, which integrated these rivers, first aggraded fill terraces that, in turn, caused aggradation of a mantle of transported grus on bedrock pediments. Subsequent episodic incision of the Salt and Verde rivers lowered the base level; this led to the development of erosional features such as rolling topography of a degrading pediment mantle; exposure of the former piedmont angle and its associated zones of enhanced bedrock decay and regolith carbonate; and exposure of spheroidally weathered bedrock and emerging tors, some of which experienced 20thcentury erosion. The granitic pediments of the former Pemberton Basin, which now transport grus to the Salt and Verde rivers, have actively adjusted to aggradational and degradational events associated with drainage integration and do not appear to be inherited from an ancient wet climatic interval.

Measuring rates of valley head migration and determining the timing of canyon‐opening are insightful for the evolution of planetary surfaces. Spatial gradients of in situ‐produced cosmogenic nuclide concentrations along horizontal transects provide a framework for assessing the migration of valley networks and similar topographic features. We developed a new derivation for valley head retreat rates from the concentrations of in situ‐produced cosmogenic radionuclides in valley walls. The retreat rate is inversely proportional to the magnitude of the spatial concentration gradient and proportional to local nuclide production rates. By solving for a spatial gradient in concentration along a valley parallel transect, we created an expression for the explicit determination of valley head retreat, which we refer to herein as unzipping. We applied this expression to a seepage‐derived drainage network developing along the Apalachicola River, Florida, USA. Sample concentrations along a valley margin transect varied systematically from 2.9 × 105to 3.5 × 105atoms/g resulting in a gradient of 160 atoms/g/m, and from this value a valley head retreat rate of 0.025 m/y was found. The discrepancy between overall network age and current rates of valley head migration suggests intermittent network growth which is consistent with glacial‐interglacial precipitation variations during the Pleistocene. This method can be applied to a wide range of Earth‐surface environments. For the 10Be system, this method should be sensitive to unzipping rates bounded between 10−6and 100m/y. The pace at which landforms develop is an important control on many biological, chemical, and physical processes operating at Earth's surface. Rates of landscape change are often quantified by measuring the accumulation of cosmogenic radionuclides in near‐surface Earth materials, as an indicator of the erosion rate and age of landforms. In this study, we advance a method for querying the rate of horizontal topographic changes, such as valley growth or ice margin retreat, by sampling material in a horizontal transect and observing patterns in the nuclide concentrations in a spatial gradient. We present the results of numerical modeling that describe the limits of this approach due to the rate and consistency of ongoing landscape evolution processes. We present the first empirical data on the growth rate of a well‐studied seepage channel network in Florida, which suggests that the time‐averaged channel advance rate is 0.025 m/y. Furthermore, our measurements indicate that the age of the incising plateau surface is between 2 and 2.5 My and that the regional uplift rate is between 27 and 38 m/My. Propagation rates of morphologic features determined by nuclide concentration gradients along a horizontal transectUplift rate of the Florida panhandle estimated between 0.027 and 0.038 mm/y from a nuclide depth profileChanges in climate over the Quaternary likely drove variable growth rates of seepage valleys along the Apalachicola River Propagation rates of morphologic features determined by nuclide concentration gradients along a horizontal transect Uplift rate of the Florida panhandle estimated between 0.027 and 0.038 mm/y from a nuclide depth profile Changes in climate over the Quaternary likely drove variable growth rates of seepage valleys along the Apalachicola River

Grainyhead belongs to a recently identified group of transcription factors which share a 250-amino-acid domain required for binding to DNA and a carboxy-terminal dimerization domain. The activities of Grainyhead and other members of the family appear to be modulated so that they can participate in different developmental processes. We have examined the structure and function of mRNAs from the Drosophila grainyheadgene and demonstrated that alternate splicing is responsible for generating a neuroblast-specific isoform of the protein. A mutation which abolishes this isoform results in pupal and adult lethality. Reporter genes containing different Grainyhead binding sites exhibit tissue-specific patterns of expression that correlate with the Grainyhead isoforms, suggesting that the alternate splicing serves to alter the repertoire of target genes controlled in the neuroblasts.

IntroductionInitially described in Japan in 1957, moyamoya angiopathy is recognised in other populations, particularly within Europe and North America. Moyamoya disease (MMD) is a rare chronic progressive cerebrovascular disorder of unknown aetiology characterised by concentric stenosis of large intracranial vessels with collateralisation from moyamoya vessels and the leptomeningeal vessels. Affected individuals may present with transient ischaemic attacks or ischaemic stroke, however presentations with intracerebral haemorrhage, epilepsy or cognitive impairment in both children and adults also occur. Those with moyamoya syndrome (MMS), MMD in the setting of an associated disease such as neurofibromatosis, type one diabetes mellitus and trisomy 21, appear to follow a similar clinical course.MethodsWe conducted a retrospective review of patients with Moyamoya angiopathy who presented to the Townsville or Mackay Hospital Health Service between January 2012 and January 2018.ResultsWe identified eleven cases of moyamoya angiopathy between 2012 and 2018. The cumulative incidence in our study population was 0.436 per 1 00 000 persons per year. The most common presentation was ischaemic stroke. We will present additional morphologic data, functional cerebral blood flow studies and outcomes following revascularisation (including ECIC bypass).ConclusionThe findings from our small case series suggests the incidence of moyamoya angiopathy within Northern Queensland is higher than anticipated in European and Northern American populations. Additional research is required to ascertain whether this is primarily due to an increased awareness of the condition and extended diagnostic workup within our centre, specific patient characteristics which predispose to the disease or due to increasing prevalence of moyamoya angiopathy in the general population.

Mission Rabies have developed an app both assisting the monitoring and direction of field vaccination teams, and recording project findings to enable research. WVS is building on this for use in varied projects from emergency disaster response to wildlife poaching and reducing traffic accidents involving donkeys.

WVS is a UK charity that provides sustainable veterinary resources to assist animal charities, and works to help animals in need throughout the world.

A letter to the editor is presented which talks about pay increase in exchange for ratios.