This thesis examines the role of reflection in Information, Advice and Guidance (IAG) practice, with particular reference to becoming aware of the role of taken-for-granted assumptions. It is ...grounded in the literature concerning taken-for-granted assumptions, personal knowledge and reflection in the context of professional practice. It is a qualitative study evolving through three iterative cycles, with an additional ‘pre-cycle’ exploring the origins of the research in the researcher’s own experience as an IAG professional working with ethnic minority women. The first main research cycle explored, in dialogue with a co-researcher, how we became aware of our own taken-for-granted assumptions. Subsequent cycles extend the data to responses from practitioners less close to me. Using the concept of researcher-as-bricoleur, a range of methodologies were employed. In the pre-cycle and first research cycle an auto-ethnograpahic approach captures the researcher’s voice and that of a co-researcher. In later cycles a heuristic approach enabled the researcher to focus on the self and engage with her own and other practitioners’ experiences of taken-for-granted assumptions. These cycles explored, through written capture sheets, conversational interviews and email exchanges, IAG practitioners’ understanding of and engagement with reflection and reflective practice. The research demonstrated different types and interpretations of reflection and reflective practice. Although practitioners described themselves as reflective and used self-reflection, this was insufficient to unearth taken-for-granted assumptions. The research ascertained that assumptions regarding whiteness were difficult to unearth, and were rarely acknowledged openly. Even less frequent was the sharing of unearthed assumptions with others. The research revealed that reflective practice has itself become taken-for-granted and does not achieve what it advocates. The need to coach and nurture the skill of reflective practice is emphasised, with one of the data analysis tools – the ‘I Poem’ – proposed as a reflective tool for enhancing self awareness and assisting practitioners to examine their reflective journals and reveal their taken-for-granted voice.
This thesis examines the role of reflection in Information, Advice and Guidance (IAG) practice, with particular reference to becoming aware of the role of taken-for-granted assumptions. It is ...grounded in the literature concerning taken-for-granted assumptions, personal knowledge and reflection in the context of professional practice. It is a qualitative study evolving through three iterative cycles, with an additional ‘precycle’ exploring the origins of the research in the researcher’s own experience as an IAG professional working with ethnic minority women. The first main research cycle explored, in dialogue with a co-researcher, how we became aware of our own taken-for-granted assumptions. Subsequent cycles extend the data to responses from practitioners less close to me. Using the concept of researcher-as-bricoleur, a range of methodologies were employed. In the pre-cycle and first research cycle an auto-ethnograpahic approach captures the researcher’s voice and that of a co-researcher. In later cycles a heuristic approach enabled the researcher to focus on the self and engage with her own and other practitioners’ experiences of taken-for-granted assumptions. These cycles explored, through written capture sheets, conversational interviews and email exchanges, IAG practitioners’ understanding of and engagement with reflection and reflective practice. The research demonstrated different types and interpretations of reflection and reflective practice. Although practitioners described themselves as reflective and used self-reflection, this was insufficient to unearth taken-for-granted assumptions. The research ascertained that assumptions regarding whiteness were difficult to unearth, and were rarely acknowledged openly. Even less frequent was the sharing of unearthed assumptions with others. The research revealed that reflective practice has itself become taken-for-granted and does not achieve what it advocates. The need to coach and nurture the skill of reflective practice is emphasised, with one of the data analysis tools – the ‘I Poem’ – proposed as a reflective tool for enhancing self awareness and assisting practitioners to examine their reflective journals and reveal their taken-for-granted voice.
We investigated the role of 3D genome architecture in instructing functional properties of glioblastoma stem cells (GSCs) by generating sub-5-kb resolution 3D genome maps by in situ Hi-C. Contact ...maps at sub-5-kb resolution allow identification of individual DNA loops, domain organization, and large-scale genome compartmentalization. We observed differences in looping architectures among GSCs from different patients, suggesting that 3D genome architecture is a further layer of inter-patient heterogeneity for glioblastoma. Integration of DNA contact maps with chromatin and transcriptional profiles identified specific mechanisms of gene regulation, including the convergence of multiple super enhancers to individual stemness genes within individual cells. We show that the number of loops contacting a gene correlates with elevated transcription. These results indicate that stemness genes are hubs of interaction between multiple regulatory regions, likely to ensure their sustained expression. Regions of open chromatin common among the GSCs tested were poised for expression of immune-related genes, including
We demonstrate that this gene is co-expressed with stemness genes in GSCs and that CD276 can be targeted with an antibody-drug conjugate to eliminate self-renewing cells. Our results demonstrate that integrated structural genomics data sets can be employed to rationally identify therapeutic vulnerabilities in self-renewing cells.
Community-onset urinary tract infections (UTIs) caused by extended-spectrum β-lactamase (ESBL)–producing Enterobacteriaceae, which are resistant to ceftriaxone and usually coresistant to ...fluoroquinolones, are increasing worldwide. We investigate and describe in detail UTIs caused by ESBL-producing Enterobacteriaceae in our emergency department (ED), and determine the proportion that occurred in patients without health care–associated risk factors and who received discordant initial antibiotic therapy.
At an urban public hospital in Northern California, microbiology staff prospectively reviewed ED urine culture results weekly for 1 year and presumptively identified ESBL-producing isolates by ceftriaxone plus ceftazidime resistance. For isolates associated with a clinical UTI, patient demographic and case clinical features were abstracted retrospectively. Health care–associated infections were defined by standard risk factors plus aged 65 years or older, bladder catheter, urologic procedure, functional dependence, or antibiotics in the previous 90 days. Community-associated infections were defined by absence of these. A subset of community-associated ESBL-producing Escherichia coli isolates underwent genotyping. Electronic health record query was used to determine the denominator of ED UTI patients who underwent urine culture during the study period.
Between August 2016 and July 2017, there were 1,045 unique ED patients diagnosed with a UTI, whose specimens underwent culture. There were 62 ESBL-producing isolates (5.9%; 95% confidence interval CI 4.6% to 7.5%). Selected characteristics of the entire ESBL UTI cohort were median age 50 years, 37 (60%) patients were women, 28 (44%) Hispanic, 11 (18%) had been hospitalized in the previous 3 months, 19 (31%) had pyelonephritis, 49 (79%) of isolates were E coli, 44 (71%) were levofloxacin-resistant, and 24 (23%) nitrofurantoin-resistant. Initial antibiotic choice was discordant with isolate susceptibility in 26 of 56 cases (46%; 95% CI 33% to 60%), and the initial oral antibiotic prescred was discordant in 19 of 41 cases (46%; 95% CI 31% to 63%). Twenty-seven infections (44%; 95% CI 31% to 57%) were categorized as community-associated. Eight patients with community-associated infection were women younger than 50 years, with no comorbidities and no more than 1 UTI in the previous year. Of 12 community-associated E coli isolates tested, all were confirmed to harbor ESBL genes; the CTX-M1 β-lactamase gene was found in 8 (67%); 4 belong to genotype ST131.
At this single Northern California ED, greater than 5% of culture-proven UTI were caused by ESBL-producing Enterobacteriaceae, and in nearly half of cases there was no identifiable health care–associated risk factor. Levofloxacin co-resistance and discordant antibiotic therapy were common.
Mitochondrial redox signals have a central role in neuronal physiology and disease. Here we describe a new optical approach to measure fast redox signals with single-organelle resolution in living ...mice that express genetically encoded redox biosensors in their neuronal mitochondria. Moreover, we demonstrate how parallel measurements with several biosensors can integrate these redox signals into a comprehensive characterization of mitochondrial function. This approach revealed that axonal mitochondria undergo spontaneous 'contractions' that are accompanied by reversible redox changes. These contractions are amplified by neuronal activity and acute or chronic neuronal insults. Multiparametric imaging reveals that contractions constitute respiratory chain-dependent episodes of depolarization coinciding with matrix alkalinization, followed by uncoupling. In contrast, permanent mitochondrial damage after spinal cord injury depends on calcium influx and mitochondrial permeability transition. Thus, our approach allows us to identify heterogeneity among physiological and pathological redox signals, correlate such signals to functional and structural organelle dynamics and dissect the underlying mechanisms.
Cardiac hypertrophy is a strong predictor of morbidity and mortality in patients with heart failure. Small molecule histone deacetylase (HDAC) inhibitors have been shown to suppress cardiac ...hypertrophy through mechanisms that remain poorly understood. We report that class I HDACs function as signal-dependent repressors of cardiac hypertrophy via inhibition of the gene encoding dual-specificity phosphatase 5 (DUSP5) DUSP5, a nuclear phosphatase that negatively regulates prohypertrophic signaling by ERK1/2. Inhibition of DUSP5 by class I HDACs requires activity of the ERK kinase, mitogenactivated protein kinase kinase (MEK), revealing a self-reinforcing mechanism for promotion of cardiac ERK signaling. In cardiac myocytes treated with highly selective class I HDAC inhibitors, nuclear ERK1/2 signaling is suppressed in a manner that is absolutely dependent on DUSP5. In contrast, cytosolic ERK1/2 activation is maintained under these same conditions. Ectopic expression of DUSP5 in cardiomyocytes results in potent inhibition of agonist-dependent hypertrophy through a mechanism involving suppression of the gene program for hypertrophie growth. These findings define unique roles for class I HDACs and DUSP5 as integral components of a regulatory signaling circuit that controls cardiac hypertrophy.
If and how neurons remodel their connections after CNS injury critically influences recovery of function. Here, we investigate the role of the growth‐initiating transcription factor STAT3 during ...remodelling of the injured corticospinal tract (CST). Endogenous STAT3 expression in lesioned cortical projection neurons is transient but can be sustained by viral gene transfer. Sustained activation of STAT3 enhances remodelling of lesioned CST fibres and induces de novo formation of collaterals from unlesioned CST fibres. In a unilateral pyramidotomy paradigm, this recruitment of unlesioned fibres leads to the formation of midline crossing circuits that establish ipsilateral forelimb activation and functional recovery.
Sustained STAT3 activation promotes the remodeling of damaged fibers in the injured spinal cord. It also recruits undamaged fibers from the contralateral site that cross the midline and restore ipsilateral forelimb function.
The remodeling of supraspinal axonal circuits mediates functional recovery after spinal cord injury. This process critically depends on the selection of appropriate synaptic connections between ...cortical projection and spinal relay neurons. To unravel the principles that guide this target selection, we used genetic and chemogenetic tools to modulate NMDA receptor (NMDAR) integrity and function, CREB-mediated transcription, and neuronal firing of relay neurons during injury-induced corticospinal remodeling. We show that NMDAR signaling and CREB-mediated transcription maintain nascent corticospinal tract (CST)-relay neuron contacts. These activity-dependent signals act during a defined period of circuit remodeling and do not affect mature or uninjured circuits. Furthermore, chemogenetic modulation of relay neuron activity reveals that the regrowing CST axons select their postsynaptic partners in a competitive manner and that preventing such activity-dependent shaping of corticospinal circuits limits motor recovery after spinal cord injury.
Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant frontotemporal dementia. The validation ...process retrospectively reviewed clinical records and compared the sensitivity of proposed and earlier criteria in a multi-site sample of patients with pathologically verified frontotemporal lobar degeneration. According to the revised criteria, 'possible' behavioural variant frontotemporal dementia requires three of six clinically discriminating features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviours, hyperorality and dysexecutive neuropsychological profile). 'Probable' behavioural variant frontotemporal dementia adds functional disability and characteristic neuroimaging, while behavioural variant frontotemporal dementia 'with definite frontotemporal lobar degeneration' requires histopathological confirmation or a pathogenic mutation. Sixteen brain banks contributed cases meeting histopathological criteria for frontotemporal lobar degeneration and a clinical diagnosis of behavioural variant frontotemporal dementia, Alzheimer's disease, dementia with Lewy bodies or vascular dementia at presentation. Cases with predominant primary progressive aphasia or extra-pyramidal syndromes were excluded. In these autopsy-confirmed cases, an experienced neurologist or psychiatrist ascertained clinical features necessary for making a diagnosis according to previous and proposed criteria at presentation. Of 137 cases where features were available for both proposed and previously established criteria, 118 (86%) met 'possible' criteria, and 104 (76%) met criteria for 'probable' behavioural variant frontotemporal dementia. In contrast, 72 cases (53%) met previously established criteria for the syndrome (P < 0.001 for comparison with 'possible' and 'probable' criteria). Patients who failed to meet revised criteria were significantly older and most had atypical presentations with marked memory impairment. In conclusion, the revised criteria for behavioural variant frontotemporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known frontotemporal lobar degeneration. Greater sensitivity of the proposed criteria may reflect the optimized diagnostic features, less restrictive exclusion features and a flexible structure that accommodates different initial clinical presentations. Future studies will be needed to establish the reliability and specificity of these revised diagnostic guidelines.
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