83 research outputs found
The Objective Structured Clinical Examination and student collusion: marks do not tell the whole truth.
No full textObjective: To determine whether the marks in the third year Objective Structured
Clinical Examination (OSCE) were affected by the collusion reported by the
students themselves on an electronic discussion board.reported by the students
themselves on an electronic discussion board
Deciphering the non-small cell lung cancer tumour microenvironment using imaging mass cytometry
No full textThe tumour microenvironment (TME) is a clinically actionable target in tumour biology. Deciphering the microenvironmental context of cancer genome evolution will shed light on the selective pressures which shape the expansion of immune-evading subclones. Imaging mass cytometry (IMC) is a multiplexed imaging technique which permits interrogation of multiple TME cell phenotypes simultaneously while retaining information about tissue architecture. Since the relative positioning of cell subtypes dictates their function, imaging can reveal novel immune evasion mechanisms, therapeutic targets and biomarkers of treatment response associated with cellular organisation. In this thesis, paired IMC, whole exome sequencing and RNA-sequencing data were used to interrogate the lung cancer TME and associations with tumour genetics in 81 patients with early-stage treatment-naïve non-small cell lung cancer (n=198 regions, 2.3million cells) from the TRACERx study. A novel hybrid deep learning-classical cell segmentation method was developed to extract single-cell information from IMC images and describe microenvironmental composition in tumour and normal lung tissue, while tools Refphase and CONIPHER were developed to improve resolution of subclonal structure. Integrating IMC-derived single-cell data with paired genetics, plasma cells were found to be enriched in high TMB tumour regions. Tregs and dysfunctional T cells were enriched in KRASmut adenocarcinomas, and neutrophils in PIK3CAmut squamous cell carcinomas (LUSC). TME associations with neoantigen burden, calculated considering lost HLA genes, differed between histologies. Cancer antigen presentation dysfunction was most frequent in TMEs characterised by TIL and macrophage infiltration into tumour nests whereas immune low TMEs were characterised by increased spatial inter-positioning of ɑSMA fibroblasts between CD8 T cells and tumour cells. Finally, neutrophil-rich TMEs were associated with expanded tumour subclones and in LUSC reduced vasculature and tumour MCT4 expression. Together, this is the first lung cancer study to integrate highly multiplexed imaging and genetics data, providing new insights into the microenvironmental context of cancer evolution
Clustering_input
No full textThis data that has been normalised and scaled and has been input for the Rphenograph script for clustering
Is collaboration a necessary component of problem-based learning?
No full textThe instructional method of problem-based learning (PBL) has continued to grow in popularity among educators at all levels despite a lack of definitive empirical support for its use. To date, research findings documenting positive outcomes associated with PBL have been largely insufficient in addressing many of the concerns raised by critics of the method. Specifically, many of the studies in problem-based learning to this point have involved an absence of experimental control and/or the presence of significant methodological flaws, both of which have drawn the criticism that the collective body of research related to the efficacy of PBL suffers from a general lack of validity (Colliver, 2000; Savery, 2006). The current study involved a component analysis of problem-based learning conducted in an authentic learning environment. This research sought to answer the following questions: What is the influence of positive interdependence within groups on student performance in PBL? What is the influence of the social aspect of group work on student performance in PBL? What is the influence of PBL instructional designs on the development of skills needed for successful collaboration? A crossed, within-subjects design was used to compare the academic performance of students across three experimental conditions within the context of three sections of an undergraduate Educational Psychology course. The three conditions included PBL-Positive Interdependence, PBL-High Positive Interdependence, and PBL-Independent. The instructor, course content, instructional time, and course materials were controlled to ensure consistency across the three sections. The results of the current study suggest that the collaborative aspect of PBL is essential to the success of students engaged in this form of instruction. Additionally, the findings of the current study suggest that student success in collaborative learning environments may rely on the existence of adequate structure to scaffold the students’ development of skills related to the collaborative process. The findings of the current study confirm that PBL is most effective when implemented in its purest form, and that problem-based instructional designs without a collaborative component cannot be considered as a pedagogically equivalent alternative to problem-based learning as it is commonly defined.Ph. D.Includes bibliographical referencesby Christopher James Manent
Using DNA sequencing data to quantify T cell fraction and therapy response
No full textThe immune microenvironment influences tumour evolution and can be both prognostic and predict response to immunotherapy1,2. However, measurements of tumour infiltrating lymphocytes (TILs) are limited by a shortage of appropriate data. Whole-exome sequencing (WES) of DNA is frequently performed to calculate tumour mutational burden and identify actionable mutations. Here we develop T cell exome TREC tool (T cell ExTRECT), a method for estimation of T cell fraction from WES samples using a signal from T cell receptor excision circle (TREC) loss during V(D)J recombination of the T cell receptor-α gene (TCRA (also known as TRA)). TCRA T cell fraction correlates with orthogonal TIL estimates and is agnostic to sample type. Blood TCRA T cell fraction is higher in females than in males and correlates with both tumour immune infiltrate and presence of bacterial sequencing reads. Tumour TCRA T cell fraction is prognostic in lung adenocarcinoma. Using a meta-analysis of tumours treated with immunotherapy, we show that tumour TCRA T cell fraction predicts immunotherapy response, providing value beyond measuring tumour mutational burden. Applying T cell ExTRECT to a multi-sample pan-cancer cohort reveals a high diversity of the degree of immune infiltration within tumours. Subclonal loss of 12q24.31–32, encompassing SPPL3, is associated with reduced TCRA T cell fraction. T cell ExTRECT provides a cost-effective technique to characterize immune infiltrate alongside somatic changes.</p
Age, provenance, and geochemical relationships amongst the Great Valley Group, Coast Range Ophiolite, and Franciscan subduction complex at Del Puerto Canyon, central California
No full textThe Great Valley Forearc (GVF) basin of California, USA, preserves an extensive rock record of the Jurassic–Paleogene tectonic development of the California segment of the North American Cordillera. We present new U-Pb geochronology, zircon and whole-rock geochemistry, and petrographic analyses from the Great Valley Group (GVG), Franciscan subduction complex, and Coast Range Ophiolite (CRO) in the northern San Joaquin Valley to better understand the timing and location of initial forearc sedimentation, and how sediment routing systems may have evolved during Cretaceous time. Basal GVG strata of the Knoxville Formation were deposited ca. 145–140 Ma and are separated by an ~40 m.y. unconformity with overlying strata of the Upper Cretaceous Panoche Formation. Pre-Mesozoic zircon grains are present in both the Knoxville and Panoche formations, but are sparse (0%–7%) compared to other GVG sandstones. Zircon geochemistry records felsic igneous sources (Th/U 0.9–0.2) during both periods of deposition, and epsilon Hf signatures reveal a shift from juvenile to more evolved sources between Knoxville and Panoche deposition. Whole-rock geochemistry shows increasing compositional maturity from latest Jurassic crystallization of the CRO to Early and Late Cretaceous deposition of the GVG. Integrating these data, we present a tectonic model for the northern San Joaquin portion of the GVF basin from ca. 145 Ma to 80 Ma that documents the onset of basin deposition and details sediment pathways during the Early to earliest Late Cretaceous. In addition, we discuss potential drivers for the ~40 m.y. unconformity within the San Joaquin Valley and implications of this work for global forearc basin processes
MEDICC2: whole-genome doubling aware copy-number phylogenies for cancer evolution
No full textAneuploidy, chromosomal instability, somatic copy-number alterations, and whole-genome doubling (WGD) play key roles in cancer evolution and provide information for the complex task of phylogenetic inference. We present MEDICC2, a method for inferring evolutionary trees and WGD using haplotype-specific somatic copy-number alterations from single-cell or bulk data. MEDICC2 eschews simplifications such as the infinite sites assumption, allowing multiple mutations and parallel evolution, and does not treat adjacent loci as independent, allowing overlapping copy-number events. Using simulations and multiple data types from 2780 tumors, we use MEDICC2 to demonstrate accurate inference of phylogenies, clonal and subclonal WGD, and ancestral copy-number states
CONIPHER: a computational framework for scalable phylogenetic reconstruction with error correction
No full textIntratumor heterogeneity provides the fuel for the evolution and selection of subclonal tumor cell populations. However, accurate inference of tumor subclonal architecture and reconstruction of tumor evolutionary histories from bulk DNA sequencing data remains challenging. Frequently, sequencing and alignment artifacts are not fully filtered out from cancer somatic mutations, and errors in the identification of copy number alterations or complex evolutionary events (e.g., mutation losses) affect the estimated cellular prevalence of mutations. Together, such errors propagate into the analysis of mutation clustering and phylogenetic reconstruction. In this Protocol, we present a new computational framework, CONIPHER (COrrecting Noise In PHylogenetic Evaluation and Reconstruction), that accurately infers subclonal structure and phylogenetic relationships from multisample tumor sequencing, accounting for both copy number alterations and mutation errors. CONIPHER has been used to reconstruct subclonal architecture and tumor phylogeny from multisample tumors with high-depth whole-exome sequencing from the TRACERx421 dataset, as well as matched primary-metastatic cases. CONIPHER outperforms similar methods on simulated datasets, and in particular scales to a large number of tumor samples and clones, while completing in under 1.5 h on average. CONIPHER enables automated phylogenetic analysis that can be effectively applied to large sequencing datasets generated with different technologies. CONIPHER can be run with a basic knowledge of bioinformatics and R and bash scripting languages
Labor and women's nutrition : a study of energy expenditure, fertility, and nutritional status in Ghana
No full textEconomic approaches to health and nutrition have focused largely on measures of child nutrition and related variables (such as birth weight) as indicators of household production of nutritional outcomes. But when dealing with adult nutrition, economists have to address an issue that has generated tremendous controversy in the clinical nutrition literature. That issue is heterogeneity in an individual's energy expenditures. Preschoolers'energy expenditure also differs, but the differences are small enough to be ignored. Not so for adults, whose waking hours are devoted mostly to labor activities of which the energy costs vary enormously. Variables measuring time allocation to various types of labor tasks were used to proxy differences in energy expenditure. Parity has also been hypothesized to be an important determinant of female nutritional health in high fertility countries - with rapid reproductive cycling contributing to a cumulative nutritional decline. But the"maternal depletion syndrome"remains controversial. Much of the evidence to date has been impressionistic - or the results of studies based on small, nonrandom cohorts. Higgins and Alderman used a two-step instrumental variables technique to get consistent estimates of the structural parameters. Energy expenditure, as embodied in individual time allocations over the previous seven days, was found to be an important determinant of women's nutritional status. Time devoted to agricultural tasks, in particular, had a strong negative effect. The results also appear to confirm the existence of a maternal depletion syndrome. Perhaps more important, evidence was found of a substantial downward bias of the calorie-elasticity estimate when the energy expenditure proxies were excluded.Health Monitoring&Evaluation,Health Economics&Finance,Agricultural Knowledge&Information Systems,Environmental Economics&Policies,Economic Theory&Research
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