1,393 research outputs found

    Acquired and intrinsic resistance to vemurafenib in BRAFV600E‐driven melanoma brain metastases

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    BRAFV600‐mutated melanoma brain metastases (MBMs) are responsive to BRAF inhibitors, but responses are generally less durable than those of extracranial metastases. We tested the hypothesis that the drug efflux transporters P‐glycoprotein (P‐gp; ABCB1) and breast cancer resistance protein (BCRP; ABCG2) expressed at the blood–brain barrier (BBB) offer MBMs protection from therapy. We intracranially implanted A375 melanoma cells in wild‐type (WT) and Abcb1a/b;Abcg2−/− mice, characterized the tumor BBB, analyzed drug levels in plasma and brain lesions after oral vemurafenib administration, and determined the efficacy against brain metastases and subcutaneous lesions. Although contrast‐enhanced MRI demonstrated that the integrity of the BBB is disrupted in A375 MBMs, vemurafenib achieved greater antitumor efficacy against MBMs in Abcb1a/b;Abcg2−/− mice compared with WT mice. Concordantly, P‐gp and BCRP are expressed in MBM‐associated brain endothelium both in patients and in A375 xenografts and expression of these transporters limited vemurafenib penetration into A375 MBMs. Although initially responsive, A375 MBMs rapidly developed therapy resistance, even in Abcb1a/b;Abcg2−/− mice, and this was unrelated to pharmacokinetic or target inhibition issues. Taken together, we demonstrate that both intrinsic and acquired resistance can play a role in MBMs

    Global phylogeography and ancient evolution of the widespread human gut virus crAssphage

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    Microbiomes are vast communities of microorganisms and viruses that populate all natural ecosystems. Viruses have been considered to be the most variable component of microbiomes, as supported by virome surveys and examples of high genomic mosaicism. However, recent evidence suggests that the human gut virome is remarkably stable compared with that of other environments. Here, we investigate the origin, evolution and epidemiology of crAssphage, a widespread human gut virus. Through a global collaboration, we obtained DNA sequences of crAssphage from more than one-third of the world's countries and showed that the phylogeography of crAssphage is locally clustered within countries, cities and individuals. We also found fully colinear crAssphage-like genomes in both Old-World and New-World primates, suggesting that the association of crAssphage with primates may be millions of years old. Finally, by exploiting a large cohort of more than 1,000 individuals, we tested whether crAssphage is associated with bacterial taxonomic groups of the gut microbiome, diverse human health parameters and a wide range of dietary factors. We identified strong correlations with different clades of bacteria that are related to Bacteroidetes and weak associations with several diet categories, but no significant association with health or disease. We conclude that crAssphage is a benign cosmopolitan virus that may have coevolved with the human lineage and is an integral part of the normal human gut virome

    Examining the Threat of ChatGPT to the Validity of Short Answer Assessments in an Undergraduate Medical Program

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    OBJECTIVES ChatGPT is an artificial intelligence model that can interpret free-text prompts and return detailed, human-like responses across a wide domain of subjects. This study evaluated the extent of the threat posed by ChatGPT to the validity of short-answer assessment problems used to examine pre-clerkship medical students in our undergraduate medical education program. METHODS Forty problems used in prior student assessments were retrieved and stratified by levels of Bloom's Taxonomy. Thirty of these problems were submitted to ChatGPT-3.5. For the remaining 10 problems, we retrieved past minimally passing student responses. Six tutors graded each of the 40 responses. Comparison of performance between student-generated and ChatGPT-generated answers aggregated as a whole and grouped by Bloom's levels of cognitive reasoning, was done using t-tests, ANOVA, Cronbach's alpha, and Cohen's d. Scores for ChatGPT-generated responses were also compared to historical class average performance. RESULTS ChatGPT-generated responses received a mean score of 3.29 out of 5 (n = 30, 95% CI 2.93-3.65) compared to 2.38 for a group of students meeting minimum passing marks (n = 10, 95% CI 1.94-2.82), representing higher performance ( P  = .008, η 2  = 0.169), but was outperformed by historical class average scores on the same 30 problems (mean 3.67, P  = .018) when including all past responses regardless of student performance level. There was no statistically significant trend in performance across domains of Bloom's Taxonomy. CONCLUSION While ChatGPT was able to pass short answer assessment problems spanning the pre-clerkship curriculum, it outperformed only underperforming students. We remark that tutors in several cases were convinced that ChatGPT-produced responses were produced by students. Risks to assessment validity include uncertainty in identifying struggling students and inability to intervene in a timely manner. The performance of ChatGPT on problems requiring increasing demands of cognitive reasoning warrants further research

    S1 Data -

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    Endovascular thrombectomy (EVT) is the standard of care for large vessel occlusion stroke. Use of Computed Tomographic Perfusion (CTP) to select EVT candidates is variable. The frequency of treatment and outcome in patients with unfavourable CTP patterns is unknown. A retrospective analysis of CTP utilisation prior to EVT was conducted. All CTP data were analysed centrally and a Target Mismatch was defined as an infarct core ≀70 ml, penumbral volume ≄15ml, and a total hypoperfused volume:core volume ratio >1.8. The primary outcome was good functional outcome at 90 days, defined as a modified Rankin Scale (mRS) score 0–2. follow-up infarct volume, core expansion and penumbral salvage volumes were secondary outcomes. Of 572 anterior circulation EVT patients, CTP source image data required to generate objective maps were available in 170, and a Target Mismatch was present in 151 (89%). The rate of 90-day good functional outcome was similar between Target Mismatch (53%) and Large Core Non-Mismatch groups (46%, p = 0.629). Median follow-up infarct volume in the Large Core Non-Mismatch group (104ml [IQR 25ml-189ml]) was larger than that in the Target Mismatch patients (16ml [8ml-47ml], p</div

    The Robotic Multi-Object Focal Plane System of the Dark Energy Spectroscopic Instrument (DESI)

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    International audienceA system of 5,020 robotic fiber positioners was installed in 2019 on the Mayall Telescope, at Kitt Peak National Observatory. The robots automatically re-target their optical fibers every 10 - 20 minutes, each to a precision of several microns, with a reconfiguration time less than 2 minutes. Over the next five years, they will enable the newly-constructed Dark Energy Spectroscopic Instrument (DESI) to measure the spectra of 35 million galaxies and quasars. DESI will produce the largest 3D map of the universe to date and measure the expansion history of the cosmos. In addition to the 5,020 robotic positioners and optical fibers, DESI's Focal Plane System includes 6 guide cameras, 4 wavefront cameras, 123 fiducial point sources, and a metrology camera mounted at the primary mirror. The system also includes associated structural, thermal, and electrical systems. In all, it contains over 675,000 individual parts. We discuss the design, construction, quality control, and integration of all these components. We include a summary of the key requirements, the review and acceptance process, on-sky validations of requirements, and lessons learned for future multi-object, fiber-fed spectrographs

    Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel

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    International audienceTo date, most BC GWASs have been performed Background Polygenic risk score (PRS), calculated in individuals of European (EUR) ancestry, and based on genome-wide association studies (GWASs), the generalisation of EUR-based PRS to other can improve breast cancer (BC) risk assessment. populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. Methods We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. Results In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). Conclusions Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women

    Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

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    BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in similar to 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1x10(-4)) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1x10(-4)). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4x10(-3)), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7x10(-8)). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10(-5)).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old

    Compound Brands and the Multi-Creation of Brand Associations: Evidence from Airports and Shopping Malls

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    The authors identify a new type of brand concept, which they term as a compound brand. Compound brands have their brand associations multi-created such that the focal brand entity, their tenants, and ancillary entities all act as sources of primary brand associations. To test the possibility of compound brands, two potential compound brands are studied, airports and shopping malls. This was completed by undertaking 480 semi-structured interviews (240 for each entity) to identify the underlying brand association structure and which associations are important for consumer brand choice. Thematic analysis was used to analyse the qualitative data. Participant responses support that compound brand association structures are created by the focal branded entity (e.g., an airport), its tenants (e.g., shops and restaurants), as well as ancillary entities (e.g., location and customers). The contributions of tenants and ancillary entities towards the brand association structures of airports and shopping malls were also statistically significant with large effect sizes. A continuum exists as to how much of the compound brand’s association structure is created by its tenants, with statistically significant differences between airports and shopping malls in terms of how much tenants contribute to overall brand association structures for the compound brand