ORCID Profile
0000-0002-9143-3156
Current Organisations
University of Cambridge
,
Cambridge University Hospitals
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Publisher: Springer Science and Business Media LLC
Date: 23-09-2021
Publisher: Springer Science and Business Media LLC
Date: 09-2015
DOI: 10.1038/NATURE14888
Publisher: CSIRO Publishing
Date: 2015
DOI: 10.1071/AH14102
Abstract: Objectives The aim of the present study was to provide descriptive planning data for a hospital-based Aboriginal Health Liaison Officer (AHLO) program, specifically quantifying episodes of care and outcomes within 28 days after discharge. Methods A follow-up study of Aboriginal in-patient hospital episodes was undertaken using person-based linked administrative data from four South Metropolitan hospitals in Perth, Western Australia (2006–11). Outcomes included 28-day deaths, emergency department (ED) presentations and in-patient re-admissions. Results There were 8041 eligible index admissions among 5113 in iduals, with episode volumes increasing by 31% over the study period. Among patients 25 years and older, the highest ranking comorbidities included injury (47%), drug and alcohol disorders (41%), heart disease (40%), infection (40%), mental illness (31%) and diabetes (31%). Most events (96%) ended in a regular discharge. Within 28 days, 24% of events resulted in ED presentations and 20% resulted in hospital re-admissions. Emergency readmissions (13%) were twice as likely as booked re-admissions (7%). Stratified analyses showed poorer outcomes for older people, and for emergency and tertiary hospital admissions. Conclusions Future planning must address the greater service volumes anticipated. The high prevalence of comorbidities requires intensive case management to address case complexity. These data will inform the refinement of the AHLO program to improve in-patient experiences and outcomes. What is known about the topic? The health gap between Aboriginal and non-Aboriginal Australians is well documented. Aboriginal people have significantly higher hospital utilisation rates, as well as higher rates of complications, comorbidities and discharges against medical advice (DAMA). Aboriginal patients receive most of their specialist services in hospital however, detailed person-based analyses are limited and planning is often based on crude data. What does this paper add? This is the first analysis of linked data focusing on Aboriginal patient flows and volume and 28-day health system outcomes following hospital admission for all causes in a large metropolitan setting. Because the data were linked, admissions belonging to a single episode of care were combined, ensuring that transfers were not counted as re-admissions. Linkage also allowed follow up across time. The results highlight the main disease groups for which Aboriginal patients are admitted, how this varies by age and the high proportion of patients returning to (any) hospital within 28 days, either through EDs or as booked (pre-arranged) admissions. These data aid in the planning of hospital-based Aboriginal health liaison services. What are the implications for practitioners? The paper outlines the complexity with which many Aboriginal patients present to hospital and the risk of DAMA and re-admission. Clinical and organisational strategies can be put in place in hospitals to address these risks and ensure improved continuity of care with community-based primary health services. The Western Australian South Metropolitan Health Service is reviewing these data and will monitor the impact of the hospital-based AHLO program.
Publisher: American Society of Hematology
Date: 02-09-2010
DOI: 10.1182/BLOOD-2009-12-259747
Abstract: The JAK2 V617F mutation is found in most patients with a myeloproliferative neoplasm and is sufficient to produce a myeloproliferative phenotype in murine retroviral transplantation or transgenic models. However, several lines of evidence suggest that disease phenotype is influenced by the level of mutant JAK2 signaling, and we have therefore generated a conditional knock-in mouse in which a human JAK2 V617F is expressed under the control of the mouse Jak2 locus. Human and murine Jak2 transcripts are expressed at similar levels, and mice develop modest increases in hemoglobin and platelet levels reminiscent of human JAK2 V617F–positive essential thrombocythemia. The phenotype is transplantable and accompanied by increased terminal erythroid and megakaryocyte differentiation together with increased numbers of clonogenic progenitors, including erythropoietin-independent erythroid colonies. Unexpectedly, JAK2V617F mice develop reduced numbers of lineage−Sca-1+c-Kit+ cells, which exhibit increased DNA damage, reduced apoptosis, and reduced cell cycling. Moreover, competitive bone marrow transplantation studies demonstrated impaired hematopoietic stem cell function in JAK2V617F mice. These results suggest that the chronicity of human myeloproliferative neoplasms may reflect a balance between impaired hematopoietic stem cell function and the accumulation of additional mutations.
Publisher: American Society of Hematology
Date: 21-04-2022
Abstract: The accessibility of cell surface proteins makes them tractable for targeting by cancer immunotherapy, but identifying suitable targets remains challenging. Here we describe plasma membrane profiling of primary human myeloma cells to identify an unprecedented number of cell surface proteins of a primary cancer. We used a novel approach to prioritize immunotherapy targets and identified a cell surface protein not previously implicated in myeloma, semaphorin-4A (SEMA4A). Using knock-down by short-hairpin RNA and CRISPR/nuclease-dead Cas9 (dCas9), we show that expression of SEMA4A is essential for normal myeloma cell growth in vitro, indicating that myeloma cells cannot downregulate the protein to avoid detection. We further show that SEMA4A would not be identified as a myeloma therapeutic target by standard CRISPR/Cas9 knockout screens because of exon skipping. Finally, we potently and selectively targeted SEMA4A with a novel antibody-drug conjugate in vitro and in vivo.
Publisher: Elsevier BV
Date: 07-2014
DOI: 10.1016/J.HEALTHPLACE.2014.05.004
Abstract: This study analysed spatial and temporal variation in childhood incidence of type 1 diabetes mellitus (T1DM) among Western Australia׳s 36 Health Districts from 1991 to 2010. There was a strong latitudinal gradient of 3.5% (95% CI, 0.2-7.2) increased risk of T1DM per degree south of the Equator, as averaged across the range 15-35° south. This pattern is consistent with the hypothesis of vitamin D deficiency at higher latitudes. In addition there was a 2.4% (95% CI, 1.3-3.6) average increase in T1DM incidence per year. These effects could not be explained by population density, socioeconomic status, remoteness or ethnicity.
Publisher: American Society of Hematology
Date: 12-12-2019
Abstract: Cohesin mutations are common in myeloid malignancy. Sasca et al elucidate the potential role of cohesin loss in myelodysplastic syndrome and acute myeloid leukemia (MDS/AML). They demonstrate that cohesin binding is critical for erythroid-specific gene expression and that reduction in cohesin impairs terminal erythroid maturation and promotes myeloid malignancy.
Publisher: Springer Science and Business Media LLC
Date: 02-08-2010
DOI: 10.1038/ONC.2010.320
Abstract: The T-cell oncogene Lim-only 2 (LMO2) critically influences both normal and malignant haematopoiesis. LMO2 is not normally expressed in T cells, yet ectopic expression is seen in the majority of T-acute lymphoblastic leukaemia (T-ALL) patients with specific translocations involving LMO2 in only a subset of these patients. Ectopic lmo2 expression in thymocytes of transgenic mice causes T-ALL, and retroviral vector integration into the LMO2 locus was implicated in the development of clonal T-cell disease in patients undergoing gene therapy. Using array-based chromatin immunoprecipitation, we now demonstrate that in contrast to B-acute lymphoblastic leukaemia, human T-ALL s les largely use promoter elements with little influence from distal enhancers. Active LMO2 promoter elements in T-ALL included a previously unrecognized third promoter, which we demonstrate to be active in cell lines, primary T-ALL patients and transgenic mice. The ETS factors ERG and FLI1 previously implicated in lmo2-dependent mouse models of T-ALL bind to the novel LMO2 promoter in human T-ALL s les, while in return LMO2 binds to blood stem rogenitor enhancers in the FLI1 and ERG gene loci. Moreover, LMO2, ERG and FLI1 all regulate the +1 enhancer of HHEX/PRH, which was recently implicated as a key mediator of early progenitor expansion in LMO2-driven T-ALL. Our data therefore suggest that a self-sustaining triad of LMO2/ERG/FLI1 stabilizes the expression of important mediators of the leukaemic phenotype such as HHEX/PRH.
Publisher: Springer Science and Business Media LLC
Date: 04-07-2018
DOI: 10.1038/LEU.2017.210
Abstract: Prognostic gene expression signatures have been proposed as clinical tools to clarify therapeutic options in acute myeloid leukemia (AML). However, these signatures rely on measuring large numbers of genes and often perform poorly when applied to independent cohorts or those with older patients. Long intergenic non-coding RNAs (lincRNAs) are emerging as important regulators of cell identity and oncogenesis, but knowledge of their utility as prognostic markers in AML is limited. Here we analyze transcriptomic data from multiple cohorts of clinically annotated AML patients and report that (i) microarrays designed for coding gene expression can be repurposed to yield robust lincRNA expression data, (ii) some lincRNA genes are located in close proximity to hematopoietic coding genes and show strong expression correlations in AML, (iii) lincRNA gene expression patterns distinguish cytogenetic and molecular subtypes of AML, (iv) lincRNA signatures composed of three or four genes are independent predictors of clinical outcome and further dichotomize survival in European Leukemia Net (ELN) risk groups and (v) an analytical tool based on logistic regression analysis of quantitative PCR measurement of four lincRNA genes (LINC4) can be used to determine risk in AML.
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1038/GIM.2016.143
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Laura Kirkland.