Medicine Research
https://hdl.handle.net/10023/49
2024-03-29T13:36:19Z
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Exploring the training and scope of practice of GPs in England, Germany and Spain
https://hdl.handle.net/10023/17314
Objective: To explore general practitioner (GP) training, continuing professional development, scope of practice, ethical issues and challenges in the working environment in three European countries. Method: Qualitative study of 35 GPs from England, Germany and Spain working in urban primary care practices. Participants were recruited using convenience and snowball sampling techniques. Semi-structured interviews were recorded, transcribed and analysed by four independent researchers adopting a thematic approach. Results: Entrance to and length of GP training differ between the three countries, while continuing professional development is required in all three, although with different characteristics. Key variations in the scope of practice include whether there is a gatekeeping role, whether GPs work in multidisciplinary teams or singlehandedly, the existence of appraisal processes, and the balance between administrative and clinical tasks. However, similar challenges, including the need to adapt to an ageing population, end-of-life care, ethical dilemmas, the impact of austerity measures, limited time for patients and gaps in coordination between primary and secondary care are experienced by GPs in all three countries. Conclusion: Primary health care variations have strong historical roots, derived from the different national experiences and the range of clinical services delivered by GPs. There is a need for an accessible source of information for GPs themselves and those responsible for safety and quality standards of the healthcare workforce. This paper maps out the current situation before Brexit is being implemented in the UK which could see many of the current EU arrangements and legislation to assure professional mobility between the UK and the rest of Europe dismantled.
This work was supported by the European Union 7th Framework Programme EU Cross Border Care Collaboration (EUCBCC). Contract no: 242058.
2019-03-01T00:00:00Z
Glonti, Ketevan
Struckmann, Verena
Alconada, Alvaro
Pettigrew, Luisa M.
Hernandez-Santiago, Virginia
Minue, Sergio
Risso-Gill, Isabelle
McKee, Martin
Legido-Quigley, Helena
Objective: To explore general practitioner (GP) training, continuing professional development, scope of practice, ethical issues and challenges in the working environment in three European countries. Method: Qualitative study of 35 GPs from England, Germany and Spain working in urban primary care practices. Participants were recruited using convenience and snowball sampling techniques. Semi-structured interviews were recorded, transcribed and analysed by four independent researchers adopting a thematic approach. Results: Entrance to and length of GP training differ between the three countries, while continuing professional development is required in all three, although with different characteristics. Key variations in the scope of practice include whether there is a gatekeeping role, whether GPs work in multidisciplinary teams or singlehandedly, the existence of appraisal processes, and the balance between administrative and clinical tasks. However, similar challenges, including the need to adapt to an ageing population, end-of-life care, ethical dilemmas, the impact of austerity measures, limited time for patients and gaps in coordination between primary and secondary care are experienced by GPs in all three countries. Conclusion: Primary health care variations have strong historical roots, derived from the different national experiences and the range of clinical services delivered by GPs. There is a need for an accessible source of information for GPs themselves and those responsible for safety and quality standards of the healthcare workforce. This paper maps out the current situation before Brexit is being implemented in the UK which could see many of the current EU arrangements and legislation to assure professional mobility between the UK and the rest of Europe dismantled.
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The utility of liver function tests for mortality prediction within one year in primary care using the algorithm for liver function investigations (ALFI)
https://hdl.handle.net/10023/16259
Background: Although liver function tests (LFTs) are routinely measured in primary care, raised levels in patients with no obvious liver disease may trigger a range of subsequent expensive and unnecessary management plans. The aim of this study was to develop and validate a prediction model to guide decision-making by general practitioners, which estimates risk of one year all-cause mortality in patients with no obvious liver disease. Methods: In this population-based historical cohort study, biochemistry data from patients in Tayside, Scotland, with LFTs performed in primary care were record-linked to secondary care and prescription databases to ascertain baseline characteristics, and to mortality data. Using this derivation cohort a survival model was developed to predict mortality. The model was assessed for calibration, discrimination (using the C-statistic) and performance, and validated using a separate cohort of Scottish primary care practices. Results: From the derivation cohort (n = 95 977), 2.7% died within one year. Predictors of mortality included: age; male gender; social deprivation; history of cancer, renal disease, stroke, ischaemic heart disease or respiratory disease; statin use; and LFTs (albumin, transaminase, alkaline phosphatase, bilirubin, and gamma-glutamyltransferase). The C-statistic for the final model was 0.82 (95% CI 0.80-0.84), and was similar in the validation cohort (n = 11 653) 0.86 (0.79-0.90). As an example of performance, for a 10% predicted probability cut-off, sensitivity = 52.8%, specificity = 94.0%, PPV = 21.0%, NPV = 98.5%. For the model without LFTs the respective values were 43.8%, 92.8%, 15.6%, 98.1%. Conclusions: The Algorithm for Liver Function Investigations (ALFI) is the first model to successfully estimate the probability of all-cause mortality in patients with no apparent liver disease having LFTs in primary care. While LFTs added to the model's discrimination and sensitivity, the clinical utility of ALFI remains to be established since LFTs did not improve an already high NPV for short term mortality and only modestly improved a very low PPV.
This work was supported by the National Health Service Research & Development Programme Health Technology Assessment Programme (project number 03/38/02) and the Backett Weir Russell Career Development Fellowship.
2012-12-14T00:00:00Z
McLernon, David J.
Dillon, John F.
Sullivan, Frank M.
Roderick, Paul
Rosenberg, William M.
Ryder, Stephen D.
Donnan, Peter T.
Background: Although liver function tests (LFTs) are routinely measured in primary care, raised levels in patients with no obvious liver disease may trigger a range of subsequent expensive and unnecessary management plans. The aim of this study was to develop and validate a prediction model to guide decision-making by general practitioners, which estimates risk of one year all-cause mortality in patients with no obvious liver disease. Methods: In this population-based historical cohort study, biochemistry data from patients in Tayside, Scotland, with LFTs performed in primary care were record-linked to secondary care and prescription databases to ascertain baseline characteristics, and to mortality data. Using this derivation cohort a survival model was developed to predict mortality. The model was assessed for calibration, discrimination (using the C-statistic) and performance, and validated using a separate cohort of Scottish primary care practices. Results: From the derivation cohort (n = 95 977), 2.7% died within one year. Predictors of mortality included: age; male gender; social deprivation; history of cancer, renal disease, stroke, ischaemic heart disease or respiratory disease; statin use; and LFTs (albumin, transaminase, alkaline phosphatase, bilirubin, and gamma-glutamyltransferase). The C-statistic for the final model was 0.82 (95% CI 0.80-0.84), and was similar in the validation cohort (n = 11 653) 0.86 (0.79-0.90). As an example of performance, for a 10% predicted probability cut-off, sensitivity = 52.8%, specificity = 94.0%, PPV = 21.0%, NPV = 98.5%. For the model without LFTs the respective values were 43.8%, 92.8%, 15.6%, 98.1%. Conclusions: The Algorithm for Liver Function Investigations (ALFI) is the first model to successfully estimate the probability of all-cause mortality in patients with no apparent liver disease having LFTs in primary care. While LFTs added to the model's discrimination and sensitivity, the clinical utility of ALFI remains to be established since LFTs did not improve an already high NPV for short term mortality and only modestly improved a very low PPV.
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An ethnographic exploration of influences on prescribing in general practice : Why is there variation in prescribing practices?
https://hdl.handle.net/10023/16257
Background: Prescribing is a core activity for general practitioners, yet significant variation in the quality of prescribing has been reported. This suggests there may be room for improvement in the application of the current best research evidence. There has been substantial investment in technologies and interventions to address this issue, but effect sizes so far have been small to moderate. This suggests that prescribing is a decision-making process that is not sufficiently understood. By understanding more about prescribing processes and the implementation of research evidence, variation may more easily be understood and more effective interventions proposed.Methods: An ethnographic study in three Scottish general practices with diverse organizational characteristics. Practices were ranked by their performance against Audit Scotland prescribing quality indicators, incorporating established best research evidence. Two practices of high prescribing quality and one practice of low prescribing quality were recruited. Participant observation, formal and informal interviews, and a review of practice documentation were employed.Results: Practices ranked as high prescribing quality consistently made and applied macro and micro prescribing decisions, whereas the low-ranking practice only made micro prescribing decisions. Macro prescribing decisions were collective, policy decisions made considering research evidence in light of the average patient, one disease, condition, or drug. Micro prescribing decisions were made in consultation with the patient considering their views, preferences, circumstances and other conditions (if necessary).Although micro prescribing can operate independently, the implementation of evidence-based, quality prescribing was attributable to an interdependent relationship. Macro prescribing policy enabled prescribing decisions to be based on scientific evidence and applied consistently where possible. Ultimately, this influenced prescribing decisions that occur at the micro level in consultation with patients.Conclusion: General practitioners in the higher prescribing quality practices made two different 'types' of prescribing decision; macro and micro. Macro prescribing informs micro prescribing and without a macro basis to draw upon the low-ranked practice had no effective mechanism to engage with, reflect on and implement relevant evidence. Practices that recognize these two levels of decision making about prescribing are more likely to be able to implement higher quality evidence.
2013-06-21T00:00:00Z
Grant, Aileen
Sullivan, Frank
Dowell, Jon
Background: Prescribing is a core activity for general practitioners, yet significant variation in the quality of prescribing has been reported. This suggests there may be room for improvement in the application of the current best research evidence. There has been substantial investment in technologies and interventions to address this issue, but effect sizes so far have been small to moderate. This suggests that prescribing is a decision-making process that is not sufficiently understood. By understanding more about prescribing processes and the implementation of research evidence, variation may more easily be understood and more effective interventions proposed.Methods: An ethnographic study in three Scottish general practices with diverse organizational characteristics. Practices were ranked by their performance against Audit Scotland prescribing quality indicators, incorporating established best research evidence. Two practices of high prescribing quality and one practice of low prescribing quality were recruited. Participant observation, formal and informal interviews, and a review of practice documentation were employed.Results: Practices ranked as high prescribing quality consistently made and applied macro and micro prescribing decisions, whereas the low-ranking practice only made micro prescribing decisions. Macro prescribing decisions were collective, policy decisions made considering research evidence in light of the average patient, one disease, condition, or drug. Micro prescribing decisions were made in consultation with the patient considering their views, preferences, circumstances and other conditions (if necessary).Although micro prescribing can operate independently, the implementation of evidence-based, quality prescribing was attributable to an interdependent relationship. Macro prescribing policy enabled prescribing decisions to be based on scientific evidence and applied consistently where possible. Ultimately, this influenced prescribing decisions that occur at the micro level in consultation with patients.Conclusion: General practitioners in the higher prescribing quality practices made two different 'types' of prescribing decision; macro and micro. Macro prescribing informs micro prescribing and without a macro basis to draw upon the low-ranked practice had no effective mechanism to engage with, reflect on and implement relevant evidence. Practices that recognize these two levels of decision making about prescribing are more likely to be able to implement higher quality evidence.
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Crambled : a Shiny application to enable intuitive resolution of conflicting cellularity estimates
https://hdl.handle.net/10023/16248
It is now commonplace to investigate tumour samples using whole-genome sequencing, and some commonly performed tasks are the estimation of cellularity (or sample purity), the genome-wide profiling of copy numbers, and the assessment of sub-clonal behaviours. Several tools are available to undertake these tasks, but often give conflicting results - not least because there is often genuine uncertainty due to a lack of model identifiability. Presented here is a tool, "Crambled", that allows for an intuitive visual comparison of the conflicting solutions. Crambled is implemented as a Shiny application within R, and is accompanied by example images from two use cases (one tumour sample with matched normal sequencing, and one standalone cell line example) as well as functions to generate the necessary images from any sequencing data set. Through the use of Crambled, a user may gain insight into why each tool has offered its given solution and combined with a knowledge of the disease being studied can choose between the competing solutions in an informed manner.
2015-12-07T00:00:00Z
Lynch, Andy
It is now commonplace to investigate tumour samples using whole-genome sequencing, and some commonly performed tasks are the estimation of cellularity (or sample purity), the genome-wide profiling of copy numbers, and the assessment of sub-clonal behaviours. Several tools are available to undertake these tasks, but often give conflicting results - not least because there is often genuine uncertainty due to a lack of model identifiability. Presented here is a tool, "Crambled", that allows for an intuitive visual comparison of the conflicting solutions. Crambled is implemented as a Shiny application within R, and is accompanied by example images from two use cases (one tumour sample with matched normal sequencing, and one standalone cell line example) as well as functions to generate the necessary images from any sequencing data set. Through the use of Crambled, a user may gain insight into why each tool has offered its given solution and combined with a knowledge of the disease being studied can choose between the competing solutions in an informed manner.
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Experimental models of cryptococcosis
https://hdl.handle.net/10023/16247
Cryptococcosis is a life-threatening fungal disease that infects around one million people each year. Establishment and progression of disease involves a complex interplay between the fungus and a diverse range of host cell types. Over recent years, numerous cellular, tissue, and animal models have been exploited to probe this host-pathogen interaction. Here we review the range of experimental models that are available for cryptococcosis research and compare the relative advantages and limitations of the different systems.
2012-01-01T00:00:00Z
Sabiiti, Wilber
May, Robin C
Pursall, E Rhiannon
Cryptococcosis is a life-threatening fungal disease that infects around one million people each year. Establishment and progression of disease involves a complex interplay between the fungus and a diverse range of host cell types. Over recent years, numerous cellular, tissue, and animal models have been exploited to probe this host-pathogen interaction. Here we review the range of experimental models that are available for cryptococcosis research and compare the relative advantages and limitations of the different systems.
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Somatic cancer genetics in the UK : real-world data from phase I of the Cancer Research UK Stratified Medicine Programme
https://hdl.handle.net/10023/16134
Introduction: Phase I of the Cancer Research UK Stratified Medicine Programme (SMP1) was designed to roll out molecular pathology testing nationwide at the point of cancer diagnosis, as well as facilitate an infrastructure where surplus cancer tissue could be used for research. It offered a non-trial setting to examine common UK cancer genetics in a real-world context. Methods: A total of 26 sites in England, Wales and Scotland, recruited samples from 7814 patients for genetic examination between 2011 and 2013. Tumour types involved were breast, colorectal, lung, prostate, ovarian cancer and malignant melanoma. Centralised molecular testing of surplus material from resections or biopsies of primary/metastatic tissue was performed, with samples examined for 3-5 genetic alterations deemed to be of key interest in site-specific cancers by the National Cancer Research Institute Clinical Study groups. Results: 10 754 patients (98% of those approached) consented to participate, from which 7814 tumour samples were genetically analysed. In total, 53% had at least one genetic aberration detected. From 1885 patients with lung cancer, KRAS mutation was noted to be highly prevalent in adenocarcinoma (37%). In breast cancer (1873 patients), there was a striking contrast in TP53 mutation incidence between patients with ductal cancer (27.3%) and lobular cancer (3.4%). Vast inter-tumour heterogeneity of colorectal cancer (1550 patients) was observed, including myriad double and triple combinations of genetic aberrations. Significant losses of important clinical information included smoking status in lung cancer and loss of distinction between low-grade and high-grade serous ovarian cancers. Conclusion: Nationwide molecular pathology testing in a non-trial setting is feasible. The experience with SMP1 has been used to inform ongoing CRUK flagship programmes such as the CRUK National Lung MATRIX trial and TRACERx.
This study was supported by Cancer Research UK, AstraZeneca and Pfizer UK.
2018-09-05T00:00:00Z
Lindsay, Colin R
Shaw, Emily C
Blackhall, Fiona
Blyth, Kevin G
Brenton, James D
Chaturvedi, Anshuman
Clarke, Noel
Dick, Craig
Evans, Thomas R J
Hall, Geoff
Hanby, Andrew M
Harrison, David J
Johnston, Stephen R D
Mason, Malcolm D
Morton, Dion
Newton-Bishop, Julia
Nicholson, Andrew G
Oien, Karin A
Popat, Sanjay
Rassl, Doris
Sharpe, Rowena
Taniere, Phillipe
Walker, Ian
Wallace, William A
West, Nicholas P
Butler, Rachel
Gonzalez de Castro, David
Griffiths, Mike
Johnson, Peter W M
Introduction: Phase I of the Cancer Research UK Stratified Medicine Programme (SMP1) was designed to roll out molecular pathology testing nationwide at the point of cancer diagnosis, as well as facilitate an infrastructure where surplus cancer tissue could be used for research. It offered a non-trial setting to examine common UK cancer genetics in a real-world context. Methods: A total of 26 sites in England, Wales and Scotland, recruited samples from 7814 patients for genetic examination between 2011 and 2013. Tumour types involved were breast, colorectal, lung, prostate, ovarian cancer and malignant melanoma. Centralised molecular testing of surplus material from resections or biopsies of primary/metastatic tissue was performed, with samples examined for 3-5 genetic alterations deemed to be of key interest in site-specific cancers by the National Cancer Research Institute Clinical Study groups. Results: 10 754 patients (98% of those approached) consented to participate, from which 7814 tumour samples were genetically analysed. In total, 53% had at least one genetic aberration detected. From 1885 patients with lung cancer, KRAS mutation was noted to be highly prevalent in adenocarcinoma (37%). In breast cancer (1873 patients), there was a striking contrast in TP53 mutation incidence between patients with ductal cancer (27.3%) and lobular cancer (3.4%). Vast inter-tumour heterogeneity of colorectal cancer (1550 patients) was observed, including myriad double and triple combinations of genetic aberrations. Significant losses of important clinical information included smoking status in lung cancer and loss of distinction between low-grade and high-grade serous ovarian cancers. Conclusion: Nationwide molecular pathology testing in a non-trial setting is feasible. The experience with SMP1 has been used to inform ongoing CRUK flagship programmes such as the CRUK National Lung MATRIX trial and TRACERx.
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Has primary care antimicrobial use really been increasing? Comparison of changes in different prescribing measures for a complete geographic population 1995–2014
https://hdl.handle.net/10023/16115
Objectives To elucidate how population trends in total antimicrobials dispensed in the community translate into individual exposure. Methods Retrospective, population-based observational study of all antimicrobial prescribing in a Scottish region in financial years 1995, 2000 and 2005–14. Analysis of temporal changes in all antimicrobials and specific antimicrobials measured in: WHO DDD per 1000 population; prescriptions per 1000 population; proportion of population with ≥1 prescription; mean number of prescriptions per person receiving any; mean DDD per prescription. Results Antimicrobial DDD increased between 1995 and 2014, from 5651 to 6987 per 1000 population [difference 1336 (95% CI 1309–1363)]. Prescriptions per 1000 fell (from 821 to 667, difference –154, –151 to –157), as did the proportion prescribed any antimicrobial [from 39.3% to 30.8% (–8.5, –8.4 to –8.6)]. Rising mean DDD per prescription, from 6.88 in 1995 to 10.47 in 2014 (3.59, 3.55–3.63), drove rising total DDD. In the under-5s, every measure fell over time (68.2% fall in DDD per 1000; 60.7% fall in prescriptions per 1000). Among 5–64 year olds, prescriptions per 1000 were lowest in 2014 but among older people, despite a reduction since 2010, the 2014 rate was still higher than in 2000. Trends in individual antimicrobials provide some explanation for overall trends. Conclusions Rising antimicrobial volumes up to 2011 were mainly due to rising DDD per prescription. Trends in dispensed drug volumes do not readily translate into information on individual exposure, which is more relevant for adverse consequences including emergence of resistance.
2017-10-01T00:00:00Z
Neilly, Mark D. J.
Guthrie, Bruce
Hernandez Santiago, Virginia
Vadiveloo, Thenmalar
Donnan, Peter T.
Marwick, Charis A.
Objectives To elucidate how population trends in total antimicrobials dispensed in the community translate into individual exposure. Methods Retrospective, population-based observational study of all antimicrobial prescribing in a Scottish region in financial years 1995, 2000 and 2005–14. Analysis of temporal changes in all antimicrobials and specific antimicrobials measured in: WHO DDD per 1000 population; prescriptions per 1000 population; proportion of population with ≥1 prescription; mean number of prescriptions per person receiving any; mean DDD per prescription. Results Antimicrobial DDD increased between 1995 and 2014, from 5651 to 6987 per 1000 population [difference 1336 (95% CI 1309–1363)]. Prescriptions per 1000 fell (from 821 to 667, difference –154, –151 to –157), as did the proportion prescribed any antimicrobial [from 39.3% to 30.8% (–8.5, –8.4 to –8.6)]. Rising mean DDD per prescription, from 6.88 in 1995 to 10.47 in 2014 (3.59, 3.55–3.63), drove rising total DDD. In the under-5s, every measure fell over time (68.2% fall in DDD per 1000; 60.7% fall in prescriptions per 1000). Among 5–64 year olds, prescriptions per 1000 were lowest in 2014 but among older people, despite a reduction since 2010, the 2014 rate was still higher than in 2000. Trends in individual antimicrobials provide some explanation for overall trends. Conclusions Rising antimicrobial volumes up to 2011 were mainly due to rising DDD per prescription. Trends in dispensed drug volumes do not readily translate into information on individual exposure, which is more relevant for adverse consequences including emergence of resistance.
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How important are the influencing factors to the decision on whether to provide seafood in infant and young child feeding?
https://hdl.handle.net/10023/15080
Seafood is recommended as part of a healthy, balanced introductory diet however, consumption rates are low in young children. Research has previously investigated the influences to seafood consumption in consumers and non-consumers however the importance of these factors in mothers' decisions on whether to provide seafood for their child during the early years is unknown. This study aimed to measure the importance of factors that influence mothers' decisions on providing seafood for their child during infant and young child feeding (six months to four years). A mixed method Q methodology and cognitive interview approach was used with 32 mothers in Scotland. Despite a large consensus of opinion between mothers (n = 20) on the importance of factors on their decision-making, two viewpoints emerged highlighting an importance placed on food attributes and the infant, and convenience and family-centred. This study is the first to quantify the influences on the decision to provide seafood during early years’ feeding and could be used to inform and tailor seafood-based dietary promotions and interventions for parents.
This study was funded by the Seafish Authority and Interface Food and Drink Scotland as part of a PhD scholarship for SC.
2017-10-01T00:00:00Z
Carstairs, Sharon A.
Marais, Debbi
Craig, Leone C. A.
Kiezebrink, Kirsty
Seafood is recommended as part of a healthy, balanced introductory diet however, consumption rates are low in young children. Research has previously investigated the influences to seafood consumption in consumers and non-consumers however the importance of these factors in mothers' decisions on whether to provide seafood for their child during the early years is unknown. This study aimed to measure the importance of factors that influence mothers' decisions on providing seafood for their child during infant and young child feeding (six months to four years). A mixed method Q methodology and cognitive interview approach was used with 32 mothers in Scotland. Despite a large consensus of opinion between mothers (n = 20) on the importance of factors on their decision-making, two viewpoints emerged highlighting an importance placed on food attributes and the infant, and convenience and family-centred. This study is the first to quantify the influences on the decision to provide seafood during early years’ feeding and could be used to inform and tailor seafood-based dietary promotions and interventions for parents.
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Human immunodeficiency virus seroconversion presenting with acute inflammatory demyelinating polyneuropathy : a case report
https://hdl.handle.net/10023/13038
Introduction: Acute Human Immunodeficiency Virus infection is associated with a range of neurological conditions. Guillain-Barré syndrome is a rare presentation; acute inflammatory demyelinating polyneuropathy is the commonest form of Guillain-Barré syndrome. Acute inflammatory demyelinating polyneuropathy has occasionally been reported in acute Immunodeficiency Virus infection but little data exists on frequency, management and outcome. Case presentation: We describe an episode of Guillain-Barré syndrome presenting as acute inflammatory demyelinating polyneuropathy in a 30-year-old man testing positive for Immunodeficiency Virus, probably during acute seroconversion. Clinical suspicion was confirmed by cerebrospinal fluid analysis and nerve conduction studies. Rapid clinical deterioration prompted intravenous immunoglobulin therapy and early commencement of highly active anti-retroviral therapy. All symptoms resolved within nine weeks. Conclusion: Unusual neurological presentations in previously fit patients are an appropriate indication for Immunodeficiency-Virus testing. Highly active anti-retroviral therapy with adequate penetration of the central nervous system should be considered as an early intervention, alongside conventional therapies such as intravenous immunoglobulin.
2008-12-04T00:00:00Z
Sloan, Derek J
Nicolson, Andrew
Miller, Alastair RO
Beeching, Nick J
Beadsworth, Mike BJ
Introduction: Acute Human Immunodeficiency Virus infection is associated with a range of neurological conditions. Guillain-Barré syndrome is a rare presentation; acute inflammatory demyelinating polyneuropathy is the commonest form of Guillain-Barré syndrome. Acute inflammatory demyelinating polyneuropathy has occasionally been reported in acute Immunodeficiency Virus infection but little data exists on frequency, management and outcome. Case presentation: We describe an episode of Guillain-Barré syndrome presenting as acute inflammatory demyelinating polyneuropathy in a 30-year-old man testing positive for Immunodeficiency Virus, probably during acute seroconversion. Clinical suspicion was confirmed by cerebrospinal fluid analysis and nerve conduction studies. Rapid clinical deterioration prompted intravenous immunoglobulin therapy and early commencement of highly active anti-retroviral therapy. All symptoms resolved within nine weeks. Conclusion: Unusual neurological presentations in previously fit patients are an appropriate indication for Immunodeficiency-Virus testing. Highly active anti-retroviral therapy with adequate penetration of the central nervous system should be considered as an early intervention, alongside conventional therapies such as intravenous immunoglobulin.
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The John Bryden memorial lecture : improving health with the community health index and developments in record linkage
https://hdl.handle.net/10023/12803
Dr. John Bryden was the executive officer of European Federation for Medical Informatics for a decade between 1998 and 2008. When he retired from active work within the federation, he was awarded an honorary fellowship. In one of his early papers from the 1960s, he described how some relatively novel machines called computers might replace the punched cards that were being used at the time. He saw, before many others, that computers could be used for the care of individual patients and even more so for groups of patients. He implemented a unique patient identifier (community health index) which has enabled Scotland to link electronic medical record data for clinical management of chronic disease deterministically. An example was the development of the Glasgow Coma Scale. One benefit of demonstrating significant value in projects such as this at an early stage of record linkage was that the governance framework for the use of data became relatively permissive. Another major success was diabetes care; it became possible to apply insights from the aggregate data to improve services and make them more efficient. Scotland has developed safe havens for data where not only the physical environment but also the people, mechanisms and projects are all subject to control to ensure safety and confidentiality. Similar moves are under way in Europe. TRANSFoRm (www.transformproject.eu) led by King's college in London is mainly focused on primary care data. Excellence in medical informatics is possible as a result of the work of its pioneers, including John Bryden's first paper suggesting that computers might be useful.
2014-01-01T00:00:00Z
Sullivan, Frank
Dr. John Bryden was the executive officer of European Federation for Medical Informatics for a decade between 1998 and 2008. When he retired from active work within the federation, he was awarded an honorary fellowship. In one of his early papers from the 1960s, he described how some relatively novel machines called computers might replace the punched cards that were being used at the time. He saw, before many others, that computers could be used for the care of individual patients and even more so for groups of patients. He implemented a unique patient identifier (community health index) which has enabled Scotland to link electronic medical record data for clinical management of chronic disease deterministically. An example was the development of the Glasgow Coma Scale. One benefit of demonstrating significant value in projects such as this at an early stage of record linkage was that the governance framework for the use of data became relatively permissive. Another major success was diabetes care; it became possible to apply insights from the aggregate data to improve services and make them more efficient. Scotland has developed safe havens for data where not only the physical environment but also the people, mechanisms and projects are all subject to control to ensure safety and confidentiality. Similar moves are under way in Europe. TRANSFoRm (www.transformproject.eu) led by King's college in London is mainly focused on primary care data. Excellence in medical informatics is possible as a result of the work of its pioneers, including John Bryden's first paper suggesting that computers might be useful.
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Toward onset prevention of cognitive decline in adults with Down syndrome (the TOP-COG study) : study protocol for a randomized controlled trial
https://hdl.handle.net/10023/12799
BACKGROUND: Early-onset dementia is common in Down syndrome adults, who have trisomy 21. The amyloid precursor protein gene is on chromosome 21, and so is over-expressed in Down syndrome, leading to amyloid β (Aβ) over-production, a major upstream pathway leading to Alzheimer disease (AD). Statins (microsomal 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors), have pleiotropic effects including potentially increasing brain amyloid clearance, making them plausible agents to reduce AD risk. Animal models, human observational studies, and small scale trials support this rationale, however, there are no AD primary prevention trials in Down syndrome adults. In this study we study aim to inform the design of a full-scale primary prevention trial. METHODS/DESIGN: TOP-COG is a feasibility and pilot double-blind randomized controlled trial (RCT), with a nested qualitative study, conducted in the general community. About 60 Down syndrome adults, aged ≥50 will be included. The intervention is oral simvastatin 40 mg at night for 12 months, versus placebo. The primary endpoint is recruitment and retention rates. Secondary endpoints are (1) tolerability and safety; (2) detection of the most sensitive neurocognitive instruments; (3) perceptions of Down syndrome adults and caregivers on whether to participate, and assessment experiences; (4) distributions of cognitive decline, adaptive behavior, general health/quality of life, service use, caregiver strain, and sample size implications; (5) whether Aβ42/Aβ40 is a cognitive decline biomarker. We will describe percentages recruited from each source, the number of contacts to achieve this, plus recruitment rate by general population size. We will calculate summary statistics with 90% confidence limits where appropriate, for each study outcome as a whole, by treatment group and in relation to baseline age, cognitive function, cholesterol and other characteristics. Changes over time will be summarized graphically. The sample size for a definitive RCT will be estimated under alternative assumptions. DISCUSSION: This study is important, as AD is a major problem for Down syndrome adults, for whom there are currently no effective preventions or treatments. It will also delineate the most suitable assessment instruments for this population. Recruitment of intellectually disabled adults is notoriously difficult, and we shall provide valuable information on this, informing future studies. TRIAL REGISTRATION: Current Controlled Trials ISRCTN Register ID: ISRCTN67338640 (17 November 2011).
This study is funded by the Chief Scientist Office, Scottish Government Health Department (reference: CZH/4/626). JS is funded by the NHS Lothian R&D Directorate.
2014-06-03T00:00:00Z
Cooper, Sally-Ann
Caslake, Muriel
Evans, Jonathan
Hassiotis, Angela
Jahoda, Andrew
McConnachie, Alex
Morrison, Jill
Ring, Howard
Starr, John
Stiles, Ciara
Sullivan, Frank
BACKGROUND: Early-onset dementia is common in Down syndrome adults, who have trisomy 21. The amyloid precursor protein gene is on chromosome 21, and so is over-expressed in Down syndrome, leading to amyloid β (Aβ) over-production, a major upstream pathway leading to Alzheimer disease (AD). Statins (microsomal 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors), have pleiotropic effects including potentially increasing brain amyloid clearance, making them plausible agents to reduce AD risk. Animal models, human observational studies, and small scale trials support this rationale, however, there are no AD primary prevention trials in Down syndrome adults. In this study we study aim to inform the design of a full-scale primary prevention trial. METHODS/DESIGN: TOP-COG is a feasibility and pilot double-blind randomized controlled trial (RCT), with a nested qualitative study, conducted in the general community. About 60 Down syndrome adults, aged ≥50 will be included. The intervention is oral simvastatin 40 mg at night for 12 months, versus placebo. The primary endpoint is recruitment and retention rates. Secondary endpoints are (1) tolerability and safety; (2) detection of the most sensitive neurocognitive instruments; (3) perceptions of Down syndrome adults and caregivers on whether to participate, and assessment experiences; (4) distributions of cognitive decline, adaptive behavior, general health/quality of life, service use, caregiver strain, and sample size implications; (5) whether Aβ42/Aβ40 is a cognitive decline biomarker. We will describe percentages recruited from each source, the number of contacts to achieve this, plus recruitment rate by general population size. We will calculate summary statistics with 90% confidence limits where appropriate, for each study outcome as a whole, by treatment group and in relation to baseline age, cognitive function, cholesterol and other characteristics. Changes over time will be summarized graphically. The sample size for a definitive RCT will be estimated under alternative assumptions. DISCUSSION: This study is important, as AD is a major problem for Down syndrome adults, for whom there are currently no effective preventions or treatments. It will also delineate the most suitable assessment instruments for this population. Recruitment of intellectually disabled adults is notoriously difficult, and we shall provide valuable information on this, informing future studies. TRIAL REGISTRATION: Current Controlled Trials ISRCTN Register ID: ISRCTN67338640 (17 November 2011).
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Using electronic health records to support clinical trials : a report on stakeholder engagement for EHR4CR
https://hdl.handle.net/10023/12797
BACKGROUND: The conduct of clinical trials is increasingly challenging due to greater complexity and governance requirements as well as difficulties with recruitment and retention. Electronic Health Records for Clinical Research (EHR4CR) aims at improving the conduct of trials by using existing routinely collected data, but little is known about stakeholder views on data availability, information governance, and acceptable working practices. METHODS: Senior figures in healthcare organisations across Europe were provided with a description of the project and structured interviews were subsequently conducted to elicit their views. RESULTS: 37 structured interviewees in Germany, UK, Switzerland, and France indicated strong support for the proposed EHR4CR platform. All interviewees reported that using the platform for assessing feasibility would enhance the conduct of clinical trials and the majority also felt it would reduce workloads. Interviewees felt the platform could enhance trial recruitment and adverse event reporting but also felt it could raise either ethical or information governance concerns in their country. CONCLUSIONS: There was clear support for EHR4CR and a belief that it could reduce workloads and improve the conduct and quality of trials. However data security, privacy, and information governance issues would need to be carefully managed in the development of the platform.
The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement number 115189, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ in kind contribution.
2015-01-01T00:00:00Z
McCowan, Colin
Thomson, Elizabeth
Szmigielski, Cezary A
Kalra, Dipak
Sullivan, Frank M.
Prokosch, Hans-Ulrich
Dugas, Martin
Ford, Ian
BACKGROUND: The conduct of clinical trials is increasingly challenging due to greater complexity and governance requirements as well as difficulties with recruitment and retention. Electronic Health Records for Clinical Research (EHR4CR) aims at improving the conduct of trials by using existing routinely collected data, but little is known about stakeholder views on data availability, information governance, and acceptable working practices. METHODS: Senior figures in healthcare organisations across Europe were provided with a description of the project and structured interviews were subsequently conducted to elicit their views. RESULTS: 37 structured interviewees in Germany, UK, Switzerland, and France indicated strong support for the proposed EHR4CR platform. All interviewees reported that using the platform for assessing feasibility would enhance the conduct of clinical trials and the majority also felt it would reduce workloads. Interviewees felt the platform could enhance trial recruitment and adverse event reporting but also felt it could raise either ethical or information governance concerns in their country. CONCLUSIONS: There was clear support for EHR4CR and a belief that it could reduce workloads and improve the conduct and quality of trials. However data security, privacy, and information governance issues would need to be carefully managed in the development of the platform.
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Prediction of liver disease in patients whose liver function tests have been checked in primary care : model development and validation using population-based observational cohorts
https://hdl.handle.net/10023/12798
OBJECTIVE: To derive and validate a clinical prediction model to estimate the risk of liver disease diagnosis following liver function tests (LFTs) and to convert the model to a simplified scoring tool for use in primary care. DESIGN: Population-based observational cohort study of patients in Tayside Scotland identified as having their LFTs performed in primary care and followed for 2 years. Biochemistry data were linked to secondary care, prescriptions and mortality data to ascertain baseline characteristics of the derivation cohort. A separate validation cohort was obtained from 19 general practices across the rest of Scotland to externally validate the final model. SETTING: Primary care, Tayside, Scotland. PARTICIPANTS: Derivation cohort: LFT results from 310 511 patients. After exclusions (including: patients under 16 years, patients having initial LFTs measured in secondary care, bilirubin >35 μmol/L, liver complications within 6 weeks and history of a liver condition), the derivation cohort contained 95 977 patients with no clinically apparent liver condition. Validation cohort: after exclusions, this cohort contained 11 653 patients. PRIMARY AND SECONDARY OUTCOME MEASURES: Diagnosis of a liver condition within 2 years. RESULTS: From the derivation cohort (n=95 977), 481 (0.5%) were diagnosed with a liver disease. The model showed good discrimination (C-statistic=0.78). Given the low prevalence of liver disease, the negative predictive values were high. Positive predictive values were low but rose to 20-30% for high-risk patients. CONCLUSIONS: This study successfully developed and validated a clinical prediction model and subsequent scoring tool, the Algorithm for Liver Function Investigations (ALFI), which can predict liver disease risk in patients with no clinically obvious liver disease who had their initial LFTs taken in primary care. ALFI can help general practitioners focus referral on a small subset of patients with higher predicted risk while continuing to address modifiable liver disease risk factors in those at lower risk.
This work was supported by the UK National Health Service Research & Development Programme Health Technology Assessment Programme (project number 03/38/02) and also by the Backett Weir Russell Career Development Fellowship, University of Aberdeen.
2014-06-02T00:00:00Z
McLernon, David J
Donnan, Peter T
Sullivan, Frank M
Roderick, Paul
Rosenberg, William M
Ryder, Steve D
Dillon, John F
OBJECTIVE: To derive and validate a clinical prediction model to estimate the risk of liver disease diagnosis following liver function tests (LFTs) and to convert the model to a simplified scoring tool for use in primary care. DESIGN: Population-based observational cohort study of patients in Tayside Scotland identified as having their LFTs performed in primary care and followed for 2 years. Biochemistry data were linked to secondary care, prescriptions and mortality data to ascertain baseline characteristics of the derivation cohort. A separate validation cohort was obtained from 19 general practices across the rest of Scotland to externally validate the final model. SETTING: Primary care, Tayside, Scotland. PARTICIPANTS: Derivation cohort: LFT results from 310 511 patients. After exclusions (including: patients under 16 years, patients having initial LFTs measured in secondary care, bilirubin >35 μmol/L, liver complications within 6 weeks and history of a liver condition), the derivation cohort contained 95 977 patients with no clinically apparent liver condition. Validation cohort: after exclusions, this cohort contained 11 653 patients. PRIMARY AND SECONDARY OUTCOME MEASURES: Diagnosis of a liver condition within 2 years. RESULTS: From the derivation cohort (n=95 977), 481 (0.5%) were diagnosed with a liver disease. The model showed good discrimination (C-statistic=0.78). Given the low prevalence of liver disease, the negative predictive values were high. Positive predictive values were low but rose to 20-30% for high-risk patients. CONCLUSIONS: This study successfully developed and validated a clinical prediction model and subsequent scoring tool, the Algorithm for Liver Function Investigations (ALFI), which can predict liver disease risk in patients with no clinically obvious liver disease who had their initial LFTs taken in primary care. ALFI can help general practitioners focus referral on a small subset of patients with higher predicted risk while continuing to address modifiable liver disease risk factors in those at lower risk.
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Improving the quality of cognitive screening assessments : ACEmobile, an iPad-based version of the Addenbrooke's Cognitive Examination-III
https://hdl.handle.net/10023/12759
Introduction: Ensuring reliable administration and reporting of cognitive screening tests are fundamental in establishing good clinical practice and research. This study captured the rate and type of errors in clinical practice, using the Addenbrooke's Cognitive Examination-III (ACE-III), and then the reduction in error rate using a computerized alternative, the ACEmobile app. Methods: In study 1, we evaluated ACE-III assessments completed in National Health Service (NHS) clinics (n = 87) for administrator error. In study 2, ACEmobile and ACE-III were then evaluated for their ability to capture accurate measurement. Results: In study 1, 78% of clinically administered ACE-IIIs were either scored incorrectly or had arithmetical errors. In study 2, error rates seen in the ACE-III were reduced by 85%–93% using ACEmobile. Discussion: Error rates are ubiquitous in routine clinical use of cognitive screening tests and the ACE-III. ACEmobile provides a framework for supporting reduced administration, scoring, and arithmetical error during cognitive screening.
The authors would like to acknowledge the National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care in the South West Peninsula (PenCLAHRC) and Clinical Trials Methods in Neurodegenerative Diseases (Programme Grant RP-PG-0707-10124).
2018-01-01T00:00:00Z
Newman, Craig G. J.
Bevins, Adam D.
Zajicek, John P.
Hodges, John R.
Vuillermoz, Emil
Dickenson, Jennifer M.
Kelly, Denise S.
Brown, Simona
Noad, Rupert F.
Introduction: Ensuring reliable administration and reporting of cognitive screening tests are fundamental in establishing good clinical practice and research. This study captured the rate and type of errors in clinical practice, using the Addenbrooke's Cognitive Examination-III (ACE-III), and then the reduction in error rate using a computerized alternative, the ACEmobile app. Methods: In study 1, we evaluated ACE-III assessments completed in National Health Service (NHS) clinics (n = 87) for administrator error. In study 2, ACEmobile and ACE-III were then evaluated for their ability to capture accurate measurement. Results: In study 1, 78% of clinically administered ACE-IIIs were either scored incorrectly or had arithmetical errors. In study 2, error rates seen in the ACE-III were reduced by 85%–93% using ACEmobile. Discussion: Error rates are ubiquitous in routine clinical use of cognitive screening tests and the ACE-III. ACEmobile provides a framework for supporting reduced administration, scoring, and arithmetical error during cognitive screening.
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Insightful Practice : a robust measure of medical students' professional response to feedback on their performance
https://hdl.handle.net/10023/12022
Background: Healthcare professionals need to show accountability, responsibility and appropriate response to audit feedback. Assessment of Insightful Practice (engagement, insight and appropriate action for improvement) has been shown to offer a robust system, in general practice, to identify concerns in doctors' response to independent feedback. This study researched the system's utility in medical undergraduates. Methods: Setting and participants: 28 fourth year medical students reflected on their performance feedback. Reflection was supported by a staff coach. Students' portfolios were divided into two groups (n∈=∈14). Group 1 students were assessed by three staff assessors (calibrated using group training) and Group 2 students' portfolios were assessed by three staff assessors (un-calibrated by one-to-one training). Assessments were by blinded web-based exercise and assessors were senior Medical School staff. Design: Case series with mixed qualitative and quantitative methods. A feedback dataset was specified as (1) student-specific End-of-Block Clinical Feedback, (2) other available Medical School assessment data and, (3) an assessment of students' identification of prescribing errors. Analysis and statistical tests: Generalisability G-theory and associated Decision D- studies were used to assess the reliability of the system and a subsequent recommendation on students' suitability to progress training. One-to-one interviews explored participants' experiences. Main outcome measures: The primary outcome measure was inter-rater reliability of assessment of students' Insightful Practice. Secondary outcome measures were the reaction of participants and their self-reported behavioural change. Results: The method offered a feasible and highly reliable global assessment for calibrated assessors, G (inter-rater reliability)∈>∈0.8 (two assessors), but not un-calibrated assessors G∈<∈0.31. Calibrated assessment proved an acceptable basis to enhance feedback and identify concern in professionalism. Students reported increased awareness in teamwork and in the importance of heeding advice. Coaches reported improvement in their feedback skills and commitment to improving the quality of student feedback. Conclusions: Insightful practice offers a reliable and feasible method to evaluate medical undergraduates' professional response to their training feedback. The piloted system offers a method to assist the early identification of students at risk and monitor, where required, the remediation of students to get their level(s) of professional response to feedback back 'on track'.
2015-08-01T00:00:00Z
Murphy, Douglas
Aitchison, Patricia
Hernandez Santiago, Virginia
Davey, Peter
Mires, Gary
Nathwani, Dilip
Background: Healthcare professionals need to show accountability, responsibility and appropriate response to audit feedback. Assessment of Insightful Practice (engagement, insight and appropriate action for improvement) has been shown to offer a robust system, in general practice, to identify concerns in doctors' response to independent feedback. This study researched the system's utility in medical undergraduates. Methods: Setting and participants: 28 fourth year medical students reflected on their performance feedback. Reflection was supported by a staff coach. Students' portfolios were divided into two groups (n∈=∈14). Group 1 students were assessed by three staff assessors (calibrated using group training) and Group 2 students' portfolios were assessed by three staff assessors (un-calibrated by one-to-one training). Assessments were by blinded web-based exercise and assessors were senior Medical School staff. Design: Case series with mixed qualitative and quantitative methods. A feedback dataset was specified as (1) student-specific End-of-Block Clinical Feedback, (2) other available Medical School assessment data and, (3) an assessment of students' identification of prescribing errors. Analysis and statistical tests: Generalisability G-theory and associated Decision D- studies were used to assess the reliability of the system and a subsequent recommendation on students' suitability to progress training. One-to-one interviews explored participants' experiences. Main outcome measures: The primary outcome measure was inter-rater reliability of assessment of students' Insightful Practice. Secondary outcome measures were the reaction of participants and their self-reported behavioural change. Results: The method offered a feasible and highly reliable global assessment for calibrated assessors, G (inter-rater reliability)∈>∈0.8 (two assessors), but not un-calibrated assessors G∈<∈0.31. Calibrated assessment proved an acceptable basis to enhance feedback and identify concern in professionalism. Students reported increased awareness in teamwork and in the importance of heeding advice. Coaches reported improvement in their feedback skills and commitment to improving the quality of student feedback. Conclusions: Insightful practice offers a reliable and feasible method to evaluate medical undergraduates' professional response to their training feedback. The piloted system offers a method to assist the early identification of students at risk and monitor, where required, the remediation of students to get their level(s) of professional response to feedback back 'on track'.
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Factors influencing mothers' decisions on whether to provide seafood during early years’ feeding : a qualitative study
https://hdl.handle.net/10023/11833
The first year of a child's life is a key period of transition from an exclusive milk diet to solid foods to meet growing nutritional demands. An increased requirement for nutrients includes the introduction of protein-rich solid foods, such as seafood, which additionally provides valuable omega-3 fatty acids. However, consumption of seafood is low in the British child population. The aim of this study was to identify maternal perceptions of the factors that can influence the decision on whether to provide seafood during early years' feeding using a multi-method qualitative study design. A total of 26 discussions posted by mothers on parenting websites; Mumknowsbest, Mumsnet and Netmums, accessed July 2013, together with discussions from six focus groups (February–July 2014) in the North East of Scotland were included for thematic qualitative analysis. Discussions on the inclusion of seafood during the early years were centred across four interrelating themes; - food-related attributes, mother-centred aspects, family-centred aspects, and external information sources. Concerns regarding safety and mothers' limited knowledge and skills on seafood were apparent from discussions; however, the practicalities of providing a cost effective family meal were also issues raised by mothers. An understanding of the numerous and sometimes contradictory influences on mothers' decisions to include seafood during early years' period could be used to develop strategies to help increase regular seafood consumption. In particular, ensuring formal information and guidance clearly addresses the safety concerns of mothers and the development of practical education schemes to encourage and teach cooking skills should be considered.
This study was funded by the Seafish Authority and Interface Food and Drink Scotland as part of a PhD scholarship for SC.
2017-01-01T00:00:00Z
Carstairs, Sharon A.
Craig, Leone C. A.
Marais, Debbi
Kiezebrink, Kirsty
The first year of a child's life is a key period of transition from an exclusive milk diet to solid foods to meet growing nutritional demands. An increased requirement for nutrients includes the introduction of protein-rich solid foods, such as seafood, which additionally provides valuable omega-3 fatty acids. However, consumption of seafood is low in the British child population. The aim of this study was to identify maternal perceptions of the factors that can influence the decision on whether to provide seafood during early years' feeding using a multi-method qualitative study design. A total of 26 discussions posted by mothers on parenting websites; Mumknowsbest, Mumsnet and Netmums, accessed July 2013, together with discussions from six focus groups (February–July 2014) in the North East of Scotland were included for thematic qualitative analysis. Discussions on the inclusion of seafood during the early years were centred across four interrelating themes; - food-related attributes, mother-centred aspects, family-centred aspects, and external information sources. Concerns regarding safety and mothers' limited knowledge and skills on seafood were apparent from discussions; however, the practicalities of providing a cost effective family meal were also issues raised by mothers. An understanding of the numerous and sometimes contradictory influences on mothers' decisions to include seafood during early years' period could be used to develop strategies to help increase regular seafood consumption. In particular, ensuring formal information and guidance clearly addresses the safety concerns of mothers and the development of practical education schemes to encourage and teach cooking skills should be considered.
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Respectful care in labour
https://hdl.handle.net/10023/11621
Provision of respectful care in labour requires awareness of the special circumstances of childbirth as a natural process. The need for woman centred humanistic care runs alongside the duty to provide access to clinical interventions as required, recognising the limitations of risk assessment. Avoidance of over medicalisation and inappropriate interventions contributes to respectful care, as does leadership to develop and sustain good working relationships among staff, so that women experience care provided by staff who are functioning at their best. Institutionalising respectful care provision alongside evidence based clinical practice represents the goal of ‘mother-baby friendly birthing facilities’ as advocated by FIGO.
2016-11-01T00:00:00Z
Stones, William
Provision of respectful care in labour requires awareness of the special circumstances of childbirth as a natural process. The need for woman centred humanistic care runs alongside the duty to provide access to clinical interventions as required, recognising the limitations of risk assessment. Avoidance of over medicalisation and inappropriate interventions contributes to respectful care, as does leadership to develop and sustain good working relationships among staff, so that women experience care provided by staff who are functioning at their best. Institutionalising respectful care provision alongside evidence based clinical practice represents the goal of ‘mother-baby friendly birthing facilities’ as advocated by FIGO.
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Epigenetic and oncogenic regulation of SLC16A7 (MCT2) results in protein over-expression, impacting on signalling and cellular phenotypes in prostate cancer
https://hdl.handle.net/10023/11445
Monocarboxylate Transporter 2 (MCT2) is a major pyruvate transporter encoded by the SLC16A7 gene. Recent studies pointed to a consistent overexpression of MCT2 in prostate cancer (PCa) suggesting MCT2 as a putative biomarker and molecular target. Despite the importance of this observation the mechanisms involved in MCT2 regulation are unknown. Through an integrative analysis we have discovered that selective demethylation of an internal SLC16A7/MCT2 promoter is a recurrent event in independent PCa cohorts. This demethylation is associated with expression of isoforms differing only in 5'-UTR translational control motifs, providing one contributing mechanism for MCT2 protein overexpression in PCa. Genes co-expressed with SLC16A7/MCT2 also clustered in oncogenic-related pathways and effectors of these signalling pathways were found to bind at the SLC16A7/MCT2 gene locus. Finally, MCT2 knock-down attenuated the growth of PCa cells. The present study unveils an unexpected epigenetic regulation of SLC16A7/MCT2 isoforms and identifies a link between SLC16A7/MCT2, Androgen Receptor (AR), ETS-related gene (ERG) and other oncogenic pathways in PCa. These results underscore the importance of combining data from epigenetic, transcriptomic and protein level changes to allow more comprehensive insights into the mechanisms underlying protein expression, that in our case provide additional weight to MCT2 as a candidate biomarker and molecular target in PCa.
Felisbino S. received a fellowship from the Sao Paulo Research Foundation (FAPESP) ref. 2013/08830-2 and 2013/06802-1. Anne Y Warren research time funded by: Cambridge Biomedical Research Centre.
2015-06-02T00:00:00Z
Pértega-Gomes, Nelma
Vizcaino, Jose R.
Felisbino, Sergio
Warren, Anne Y.
Shaw, Greg
Kay, Jonathan
Whitaker, Hayley
Lynch, Andy G.
Fryer, Lee
Neal, David E.
Massie, Charles E.
Monocarboxylate Transporter 2 (MCT2) is a major pyruvate transporter encoded by the SLC16A7 gene. Recent studies pointed to a consistent overexpression of MCT2 in prostate cancer (PCa) suggesting MCT2 as a putative biomarker and molecular target. Despite the importance of this observation the mechanisms involved in MCT2 regulation are unknown. Through an integrative analysis we have discovered that selective demethylation of an internal SLC16A7/MCT2 promoter is a recurrent event in independent PCa cohorts. This demethylation is associated with expression of isoforms differing only in 5'-UTR translational control motifs, providing one contributing mechanism for MCT2 protein overexpression in PCa. Genes co-expressed with SLC16A7/MCT2 also clustered in oncogenic-related pathways and effectors of these signalling pathways were found to bind at the SLC16A7/MCT2 gene locus. Finally, MCT2 knock-down attenuated the growth of PCa cells. The present study unveils an unexpected epigenetic regulation of SLC16A7/MCT2 isoforms and identifies a link between SLC16A7/MCT2, Androgen Receptor (AR), ETS-related gene (ERG) and other oncogenic pathways in PCa. These results underscore the importance of combining data from epigenetic, transcriptomic and protein level changes to allow more comprehensive insights into the mechanisms underlying protein expression, that in our case provide additional weight to MCT2 as a candidate biomarker and molecular target in PCa.
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A primary care Web-based Intervention Modeling Experiment replicated behavior changes seen in earlier paper-based experiment
https://hdl.handle.net/10023/11314
Objectives: Intervention Modeling Experiments (IMEs) are a way of developing and testing behavior change interventions before a trial. We aimed to test this methodology in a Web-based IME that replicated the trial component of an earlier, paper-based IME. Study Design and Setting: Three-arm, Web-based randomized evaluation of two interventions (persuasive communication and action plan) and a "no intervention" comparator. The interventions were designed to reduce the number of antibiotic prescriptions in the management of uncomplicated upper respiratory tract infection. General practitioners (GPs) were invited to complete an online questionnaire and eight clinical scenarios where an antibiotic might be considered. Results: One hundred twenty-nine GPs completed the questionnaire. GPs receiving the persuasive communication did not prescribe an antibiotic in 0.70 more scenarios (95% confidence interval [CI] = 0.17-1.24) than those in the control arm. For the action plan, GPs did not prescribe an antibiotic in 0.63 (95% CI = 0.11-1.15) more scenarios than those in the control arm. Unlike the earlier IME, behavioral intention was unaffected by the interventions; this may be due to a smaller sample size than intended. Conclusions: A Web-based IME largely replicated the findings of an earlier paper-based study, providing some grounds for confidence in the IME methodology.
Copyright © 2016 Elsevier Inc. All rights reserved.
2016-12-01T00:00:00Z
Treweek, Shaun
Francis, Jill J.
Bonetti, Debbie
Barnett, Karen
Eccles, Martin P.
Hudson, Jemma
Jones, Claire
Pitts, Nigel B.
Ricketts, Ian W.
Sullivan, Frank
Weal, Mark
MacLennan, Graeme
Objectives: Intervention Modeling Experiments (IMEs) are a way of developing and testing behavior change interventions before a trial. We aimed to test this methodology in a Web-based IME that replicated the trial component of an earlier, paper-based IME. Study Design and Setting: Three-arm, Web-based randomized evaluation of two interventions (persuasive communication and action plan) and a "no intervention" comparator. The interventions were designed to reduce the number of antibiotic prescriptions in the management of uncomplicated upper respiratory tract infection. General practitioners (GPs) were invited to complete an online questionnaire and eight clinical scenarios where an antibiotic might be considered. Results: One hundred twenty-nine GPs completed the questionnaire. GPs receiving the persuasive communication did not prescribe an antibiotic in 0.70 more scenarios (95% confidence interval [CI] = 0.17-1.24) than those in the control arm. For the action plan, GPs did not prescribe an antibiotic in 0.63 (95% CI = 0.11-1.15) more scenarios than those in the control arm. Unlike the earlier IME, behavioral intention was unaffected by the interventions; this may be due to a smaller sample size than intended. Conclusions: A Web-based IME largely replicated the findings of an earlier paper-based study, providing some grounds for confidence in the IME methodology.
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Protocol for a randomised controlled trial evaluating the effects of providing essential medicines at no charge : the Carefully seLected and Easily Accessible at No Charge Medicines (CLEAN Meds) trial
https://hdl.handle.net/10023/11052
Introduction : Cost-related non-adherence to medicines is common in low-income, middle-income and high-income countries such as Canada. Medicine non-adherence is associated with poor health outcomes and increased mortality. This randomised trial will test the impact of a carefully selected list of essential medicines at no charge (compared with usual medicine access) in primary care patients reporting cost-related non-adherence. Methods and analysis : This is an open-label, parallel two-arm, superiority, individually randomised controlled trial conducted in three primary care sites (one urban, two rural) in Ontario, Canada, that was codesigned by a community guidance panel. Adult patients (≥18 years) who report cost-related non-adherence to medicines are eligible to participate in the study. Participants will be randomised to receive free and convenient access to a carefully selected list of 125 essential medicines (based on the WHO's Model List of Essential Medicines) or usual means of medicine access. Care for patients in both groups will otherwise be unchanged. The primary outcome of this trial is adherence to appropriately prescribed medicines. Secondary outcomes include medicine adherence, appropriate prescribing, blood pressure, haemoglobin A1c, low-density lipoprotein cholesterol, patient-oriented outcomes and healthcare costs. All participants will be followed for at least 12 months. Ethics and dissemination : Ethics approval was obtained in all three participating sites. Results of the main trial and secondary outcomes will be submitted for publication in a peer-reviewed journal and discussed with members of the public and decision makers. Trial registration number : NCT02744963.
NP, RHG and ADP were supported as Clinician Scientists by the Department of Family and Community Medicine at the University of Toronto and at St Michael's Hospital. NP is supported by a fellowship from Physicians Services Incorporated Foundation. KT was supported as a Clinician Scientist by the Department of Family and Community Medicine at the University of Toronto and at Toronto Western Hospital. ML received salary support through a Canada Research Chair and a Michael Smith Foundation for Health Research Scholar Award.
2017-06-12T00:00:00Z
Persaud, Nav
Lee, Taehoon
Ahmad, Haroon
Li, Winny
Taglione, Michael Sergio
Rajakulasingam, Yathavan
Umali, Norman
Boozary, Andrew
Glazier, Richard H
Gomes, Tara
Hwang, Stephen W
Jüni, Peter
Law, Michael
Mamdani, Muhammad M
Manns, Braden
Martin, Danielle
Morgan, Steve
Oh, Paul
Pinto, Andrew David
Shah, Baiju R
Sullivan, Frank M.
Thorpe, Kevin E
Tu, Karen
Laupacis, Andreas
Introduction : Cost-related non-adherence to medicines is common in low-income, middle-income and high-income countries such as Canada. Medicine non-adherence is associated with poor health outcomes and increased mortality. This randomised trial will test the impact of a carefully selected list of essential medicines at no charge (compared with usual medicine access) in primary care patients reporting cost-related non-adherence. Methods and analysis : This is an open-label, parallel two-arm, superiority, individually randomised controlled trial conducted in three primary care sites (one urban, two rural) in Ontario, Canada, that was codesigned by a community guidance panel. Adult patients (≥18 years) who report cost-related non-adherence to medicines are eligible to participate in the study. Participants will be randomised to receive free and convenient access to a carefully selected list of 125 essential medicines (based on the WHO's Model List of Essential Medicines) or usual means of medicine access. Care for patients in both groups will otherwise be unchanged. The primary outcome of this trial is adherence to appropriately prescribed medicines. Secondary outcomes include medicine adherence, appropriate prescribing, blood pressure, haemoglobin A1c, low-density lipoprotein cholesterol, patient-oriented outcomes and healthcare costs. All participants will be followed for at least 12 months. Ethics and dissemination : Ethics approval was obtained in all three participating sites. Results of the main trial and secondary outcomes will be submitted for publication in a peer-reviewed journal and discussed with members of the public and decision makers. Trial registration number : NCT02744963.
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3T MRI investigation of cardiac left ventricular structure and function in a UK population : he Tayside screening for the prevention of cardiac events (TASCFORCE) study
https://hdl.handle.net/10023/10759
Purpose: To scan a volunteer population using 3.0T magnetic resonance imaging (MRI). MRI of the left ventricular (LV) structure and function in healthy volunteers has been reported extensively at 1.5T. Materials and Methods: A population of 1528 volunteers was scanned. A standardized approach was taken to acquire steady-state free precession (SSFP) LV data in the short-axis plane, and images were quantified using commercial software. Six observers undertook the segmentation analysis. Results: Mean values (±standard deviation, SD) were: ejection fraction (EF) = 69 ± 6%, end diastolic volume index (EDVI) = 71 ± 13 ml/m2 , end systolic volume index (ESVI) = 22 ± 7 ml/m2 , stroke volume index (SVI) = 49 ± 8 ml/m2 , and LV mass index (LVMI) = 55 ± 12 g/m2 . The mean EF was slightly larger for females (69%) than for males (68%), but all other variables were smaller for females (EDVI 68v77 ml/m2 , ESVI 21v25 ml/m2 , SVI 46v52 ml/m2 , LVMI 49v64 g/m2, all P < 0.05). The mean LV volume data mostly decreased with each age decade (EDVI males: -2.9 ± 1.3 ml/m2 , females: -3.1 ± 0.8 ml/m2 ; ESVI males: -1.3 ± 0.7 ml/m2 , females: -1.7 ± 0.5 ml/m2 ; SVI males: -1.7 ± 0.9 ml/m2 , females: -1.4 ± 0.6 ml/m2 ; LVMI males: -1.6 ± 1.1 g/m2 , females: -0.2 ± 0.6 g/m2 but the mean EF was virtually stable in males (0.6 ± 0.6%) and rose slightly in females (1.2 ± 0.5%) with age. Conclusion: LV reference ranges are provided in this population-based MR study at 3.0T. The variables are similar to those described at 1.5T, including variations with age and gender. These data may help to support future population-based MR research studies that involve the use of 3.0T MRI scanners.
Contract grant sponsor: Souter Charitable Trust, and Chest, Heart and Stroke Scotland; Contract grant sponsor: Wellcome Trust; contract grant number: WT 085664 (Clinical Research Fellowship to J.W-McC.)
2016-11-01T00:00:00Z
Gandy, Stephen J.
Lambert, Matthew
Belch, Jill
Cavin, Ian
Crowe, Elena
Littleford, Roberta
MacFarlane, Jennifer A
Matthew, Shona Z
Martin, Patricia
Nicholas, R. Stephen
Struthers, Allan
Sullivan, Frank
Waugh, Shelley A.
White, Richard D.
Weir-McCall, Jonathan R.
Houston, J. Graeme
Purpose: To scan a volunteer population using 3.0T magnetic resonance imaging (MRI). MRI of the left ventricular (LV) structure and function in healthy volunteers has been reported extensively at 1.5T. Materials and Methods: A population of 1528 volunteers was scanned. A standardized approach was taken to acquire steady-state free precession (SSFP) LV data in the short-axis plane, and images were quantified using commercial software. Six observers undertook the segmentation analysis. Results: Mean values (±standard deviation, SD) were: ejection fraction (EF) = 69 ± 6%, end diastolic volume index (EDVI) = 71 ± 13 ml/m2 , end systolic volume index (ESVI) = 22 ± 7 ml/m2 , stroke volume index (SVI) = 49 ± 8 ml/m2 , and LV mass index (LVMI) = 55 ± 12 g/m2 . The mean EF was slightly larger for females (69%) than for males (68%), but all other variables were smaller for females (EDVI 68v77 ml/m2 , ESVI 21v25 ml/m2 , SVI 46v52 ml/m2 , LVMI 49v64 g/m2, all P < 0.05). The mean LV volume data mostly decreased with each age decade (EDVI males: -2.9 ± 1.3 ml/m2 , females: -3.1 ± 0.8 ml/m2 ; ESVI males: -1.3 ± 0.7 ml/m2 , females: -1.7 ± 0.5 ml/m2 ; SVI males: -1.7 ± 0.9 ml/m2 , females: -1.4 ± 0.6 ml/m2 ; LVMI males: -1.6 ± 1.1 g/m2 , females: -0.2 ± 0.6 g/m2 but the mean EF was virtually stable in males (0.6 ± 0.6%) and rose slightly in females (1.2 ± 0.5%) with age. Conclusion: LV reference ranges are provided in this population-based MR study at 3.0T. The variables are similar to those described at 1.5T, including variations with age and gender. These data may help to support future population-based MR research studies that involve the use of 3.0T MRI scanners.
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Bell's Palsy in Children (BellPIC) : protocol for a multicentre, placebo-controlled randomized trial
https://hdl.handle.net/10023/10602
Background: Bell's palsy or acute idiopathic lower motor neurone facial paralysis is characterized by sudden onset paralysis or weakness of the muscles to one side of the face controlled by the facial nerve. While there is high level evidence in adults demonstrating an improvement in the rate of complete recovery of facial nerve function when treated with steroids compared with placebo, similar high level studies on the use of steroids in Bell's palsy in children are not available. The aim of this study is to assess the utility of steroids in Bell's palsy in children in a randomised placebo-controlled trial. Methods/Design: We are conducting a randomised, triple-blinded, placebo controlled trial of the use of prednisolone to improve recovery from Bell's palsy at 1 month. Study sites are 10 hospitals within the Australian and New Zealand PREDICT (Paediatric Research in Emergency Departments International Collaborative) research network. 540 participants will be enrolled. To be eligible patients need to be aged 6 months to < 18 years and present within 72 hours of onset of clinician diagnosed Bell's palsy to one of the participating hospital emergency departments. Patients will be excluded in case of current use of or contraindications to steroids or if there is an alternative diagnosis. Participants will receive either prednisolone 1 mg/kg/day to a maximum of 50 mg/day or taste matched placebo for 10 days. The primary outcome is complete recovery by House-Brackmann scale at 1 month. Secondary outcomes include assessment of recovery using the Sunnybrook scale, the emotional and functional wellbeing of the participants using the Pediatric Quality of Life Inventory and Child Health Utility 9D Scale, pain using Faces Pain Scale Revised or visual analogue scales, synkinesis using a synkinesis assessment questionnaire and health utilisation costs at 1, 3 and 6 months. Participants will be tracked to 12 months if not recovered earlier. Data analysis will be by intention to treat with primary outcome presented as differences in proportions and an odds ratio adjusted for site and age. Discussion: This large multicenter randomised trial will allow the definitive assessment of the efficacy of prednisolone compared with placebo in the treatment of Bell's palsy in children.
2017-02-13T00:00:00Z
Babl, Franz E.
Mackay, Mark T.
Borland, Meredith L.
Herd, David W.
Kochar, Amit
Hort, Jason
Rao, Arjun
Cheek, John A.
Furyk, Jeremy
Barrow, Lisa
George, Shane
Zhang, Michael
Gardiner, Kaya
Lee, Katherine J.
Davidson, Andrew
Berkowitz, Robert
Sullivan, Frank
Porrello, Emily
Dalziel, Kim Marie
Anderson, Vicki
Oakley, Ed
Hopper, Sandy
Williams, Fiona
Wilson, Catherine
Williams, Amanda
Dalziel, Stuart R.
PREDICT (Paediatric Research In Emergency Departments International Collaborative) research network
Background: Bell's palsy or acute idiopathic lower motor neurone facial paralysis is characterized by sudden onset paralysis or weakness of the muscles to one side of the face controlled by the facial nerve. While there is high level evidence in adults demonstrating an improvement in the rate of complete recovery of facial nerve function when treated with steroids compared with placebo, similar high level studies on the use of steroids in Bell's palsy in children are not available. The aim of this study is to assess the utility of steroids in Bell's palsy in children in a randomised placebo-controlled trial. Methods/Design: We are conducting a randomised, triple-blinded, placebo controlled trial of the use of prednisolone to improve recovery from Bell's palsy at 1 month. Study sites are 10 hospitals within the Australian and New Zealand PREDICT (Paediatric Research in Emergency Departments International Collaborative) research network. 540 participants will be enrolled. To be eligible patients need to be aged 6 months to < 18 years and present within 72 hours of onset of clinician diagnosed Bell's palsy to one of the participating hospital emergency departments. Patients will be excluded in case of current use of or contraindications to steroids or if there is an alternative diagnosis. Participants will receive either prednisolone 1 mg/kg/day to a maximum of 50 mg/day or taste matched placebo for 10 days. The primary outcome is complete recovery by House-Brackmann scale at 1 month. Secondary outcomes include assessment of recovery using the Sunnybrook scale, the emotional and functional wellbeing of the participants using the Pediatric Quality of Life Inventory and Child Health Utility 9D Scale, pain using Faces Pain Scale Revised or visual analogue scales, synkinesis using a synkinesis assessment questionnaire and health utilisation costs at 1, 3 and 6 months. Participants will be tracked to 12 months if not recovered earlier. Data analysis will be by intention to treat with primary outcome presented as differences in proportions and an odds ratio adjusted for site and age. Discussion: This large multicenter randomised trial will allow the definitive assessment of the efficacy of prednisolone compared with placebo in the treatment of Bell's palsy in children.
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Prevalence of genital chlamydia infection in urban women of reproductive age, Nairobi, Kenya
https://hdl.handle.net/10023/9563
Background: Chlamydia trachomatis is one of the major causes of sexually transmitted infections throughout the world. Most infections are asymptomatic and remain undetected. Burden of disease in the Kenyan population is not well characterised. This study was done to define the prevalence of genital Chlamydia infection in a representative female population. Findings: A cross-sectional study design was employed. All women attending out-patient clinics (antenatal, gynaecology, family planning) and accident and emergency departments at two study sites over a five month period were invited to consent to completion of a questionnaire and vaginal swab collection. A rapid point-of-care immunoassay based test was performed on the swabs. Women who tested positive for Chlamydia were offered treatment, together with their partner(s), and advised to come for a follow-up test. A total of 300 women were tested. The prevalence of genital Chlamydia trachomatis was found to be 6% (95% CI 3.31% - 8.69%). The prevalence was higher in women who represented a higher socioeconomic level, but this difference was not significant (p=0.061). Use of vaginal swabs was observed to be a more acceptable form of sample collection. Conclusion: The prevalence of genital Chlamydia is significant in our female population. There is a justifiable need to institute opportunistic screening programs to reduce the burden of this disease. Rapid and low cost point-of-care testing as a potential component of sexually transmitted infection (STI) screening can be utilised.
2013-02-04T00:00:00Z
Kohli, Ruchika
Konya, Walter P.
Obura, Timona
Stones, William
Revathi, Gunturu
Background: Chlamydia trachomatis is one of the major causes of sexually transmitted infections throughout the world. Most infections are asymptomatic and remain undetected. Burden of disease in the Kenyan population is not well characterised. This study was done to define the prevalence of genital Chlamydia infection in a representative female population. Findings: A cross-sectional study design was employed. All women attending out-patient clinics (antenatal, gynaecology, family planning) and accident and emergency departments at two study sites over a five month period were invited to consent to completion of a questionnaire and vaginal swab collection. A rapid point-of-care immunoassay based test was performed on the swabs. Women who tested positive for Chlamydia were offered treatment, together with their partner(s), and advised to come for a follow-up test. A total of 300 women were tested. The prevalence of genital Chlamydia trachomatis was found to be 6% (95% CI 3.31% - 8.69%). The prevalence was higher in women who represented a higher socioeconomic level, but this difference was not significant (p=0.061). Use of vaginal swabs was observed to be a more acceptable form of sample collection. Conclusion: The prevalence of genital Chlamydia is significant in our female population. There is a justifiable need to institute opportunistic screening programs to reduce the burden of this disease. Rapid and low cost point-of-care testing as a potential component of sexually transmitted infection (STI) screening can be utilised.
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Seafood inclusion in commercial main meal early years' food products
https://hdl.handle.net/10023/9368
Seafood consumption is recommended as part of a healthy, balanced diet. Under-exposure to seafood during early years feeding, when taste and food acceptance is developed, may impact on the future development of a varied diet. This study aimed to investigate the availability and nutritional content of seafood in commercial infant meals compared to the other food types. A survey was conducted of all commercial infant main meal products available for purchase in supermarkets, high street retailers and online stores within the United Kingdom. The primary food type (seafood, poultry, meat and vegetables) within each product, nutritional composition per 100 g, and ingredient contribution were assessed. Of the original 341 main meal products seafood (n = 13; 3.8%) was underrepresented compared to poultry (103; 30.2%), meat (121; 35.5%) and vegetables (104; 30.5%). The number of the seafood meals increased three years later (n = 20; 6.3%) vegetable meals remained the largest contributor to the market (115; 36.4%) with meat (99; 31.3%) and poultry (82; 26.0%) both contributing slightly less than previously. Seafood-based meals provided significantly higher energy (83.0 kcal), protein (4.6 g), and total fat (3.2 g) than vegetable (68 kcal, 2.7 g, 1.9 g), meat (66 kcal, 3.0 g, 2.1 g) and poultry-based meals (66 kcal, 3.0 g, 2.1 g) and higher saturated fat (1.3 g) than poultry (0.4 g) and vegetable-based (0.6 g) meals (all per 100 g) which may be attributed to additional dairy ingredients. Parents who predominantly use commercial products to wean their infant may face challenges in sourcing a range of seafood products to enable the introduction of this food into the diet of their infant.
The study was funded by the Seafish and Interface Food and Drink as part of a Doctorate Scholarship undertaken at the University of Aberdeen.
2016-10-01T00:00:00Z
Carstairs, Sharon Ann
Marais, Debbi
Craig, Leone
Kiezebrink, Kirsty
Seafood consumption is recommended as part of a healthy, balanced diet. Under-exposure to seafood during early years feeding, when taste and food acceptance is developed, may impact on the future development of a varied diet. This study aimed to investigate the availability and nutritional content of seafood in commercial infant meals compared to the other food types. A survey was conducted of all commercial infant main meal products available for purchase in supermarkets, high street retailers and online stores within the United Kingdom. The primary food type (seafood, poultry, meat and vegetables) within each product, nutritional composition per 100 g, and ingredient contribution were assessed. Of the original 341 main meal products seafood (n = 13; 3.8%) was underrepresented compared to poultry (103; 30.2%), meat (121; 35.5%) and vegetables (104; 30.5%). The number of the seafood meals increased three years later (n = 20; 6.3%) vegetable meals remained the largest contributor to the market (115; 36.4%) with meat (99; 31.3%) and poultry (82; 26.0%) both contributing slightly less than previously. Seafood-based meals provided significantly higher energy (83.0 kcal), protein (4.6 g), and total fat (3.2 g) than vegetable (68 kcal, 2.7 g, 1.9 g), meat (66 kcal, 3.0 g, 2.1 g) and poultry-based meals (66 kcal, 3.0 g, 2.1 g) and higher saturated fat (1.3 g) than poultry (0.4 g) and vegetable-based (0.6 g) meals (all per 100 g) which may be attributed to additional dairy ingredients. Parents who predominantly use commercial products to wean their infant may face challenges in sourcing a range of seafood products to enable the introduction of this food into the diet of their infant.
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Adult dental anxiety : recent assessment approaches and psychological management in a dental practice setting
https://hdl.handle.net/10023/8821
Dental Anxiety of patients is a common feature of the everyday experience of dental practice. This article advocates the use of regular assessment of this psychological construct to assist in patient management. Various tools, such as the Modified Dental Anxiety Scale (MDAS), are available to monitor dental anxiety that are quick to complete and easy to interpret. Patient burden is low. A new mobile phone assessment system (DENTANX) is being developed for distribution. This application and other psychological interventions are being investigated to assist patients to receive dental care routinely.
2016-05-01T00:00:00Z
Humphris, Gerald Michael
Spyt, James
Herbison, Alice
Kelsey, Tom
Dental Anxiety of patients is a common feature of the everyday experience of dental practice. This article advocates the use of regular assessment of this psychological construct to assist in patient management. Various tools, such as the Modified Dental Anxiety Scale (MDAS), are available to monitor dental anxiety that are quick to complete and easy to interpret. Patient burden is low. A new mobile phone assessment system (DENTANX) is being developed for distribution. This application and other psychological interventions are being investigated to assist patients to receive dental care routinely.
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Using 'dead or dependent' as an outcome measure in clinical trials in Parkinson's disease
https://hdl.handle.net/10023/8804
BACKGROUND: Simple, robust, sensitive and clinically meaningful outcome measures are required for neuroprotective trials in Parkinson's disease (PD). We explored the feasibility of a composite binary outcome measure, 'dead or dependent', in such trials using data from a prospective follow-up study of an incident cohort of PD patients. METHODS: Two hundred incident patients had an annual follow-up, including assessment of the Hoehn-Yahr stage (H-Y) and Schwab and England Activities of Daily Living Scale (S&E). Annual scores were converted into binary variables (H-Y <3 vs H-Y ≥3, and S&E ≥80% vs S&E <80%). A new outcome of 'dead or dependent' was also created, with dependence in activities of daily living defined as S&E <80%. Using these data, sample sizes were calculated for a hypothetical three-year randomised trial in which the trial outcome was defined by a binary clinical variable, all-cause mortality, or PD-related mortality. RESULTS: At 3 years, 18.0% of patients were dead and 38.4% were dead or dependent. At 80% power, large sample sizes were required if PD-related mortality (n=1938 per study arm) or all-cause mortality (n=734) were used as the outcome, even for large treatment effects (30% reduction in relative risk). The new outcome of 'death or dependency' required the smallest sample sizes of all the outcome measures (n=277 for 30% reduction in relative risk, 627 for a 20% reduction). CONCLUSIONS: 'Death or dependency' is a feasible and potentially useful outcome measure in PD trials of neuroprotective agents, but further work is required to validate its use and define dependency.
DM was funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research Programme (Grant Reference Number RP-PG-0707-10124). The PINE study was funded by Parkinson’s UK (grant numbers G0502 and G0914), the BMA Doris Hillier Award, NHS Grampian Endowments, RS MacDonald Trust and SPRING (Special Parkinson’s Research Interest Group).
2015-02-01T00:00:00Z
McGhee, David
Parker, Alexander
Fielding, Shona
Zajicek, John
Counsell, Carl
BACKGROUND: Simple, robust, sensitive and clinically meaningful outcome measures are required for neuroprotective trials in Parkinson's disease (PD). We explored the feasibility of a composite binary outcome measure, 'dead or dependent', in such trials using data from a prospective follow-up study of an incident cohort of PD patients. METHODS: Two hundred incident patients had an annual follow-up, including assessment of the Hoehn-Yahr stage (H-Y) and Schwab and England Activities of Daily Living Scale (S&E). Annual scores were converted into binary variables (H-Y <3 vs H-Y ≥3, and S&E ≥80% vs S&E <80%). A new outcome of 'dead or dependent' was also created, with dependence in activities of daily living defined as S&E <80%. Using these data, sample sizes were calculated for a hypothetical three-year randomised trial in which the trial outcome was defined by a binary clinical variable, all-cause mortality, or PD-related mortality. RESULTS: At 3 years, 18.0% of patients were dead and 38.4% were dead or dependent. At 80% power, large sample sizes were required if PD-related mortality (n=1938 per study arm) or all-cause mortality (n=734) were used as the outcome, even for large treatment effects (30% reduction in relative risk). The new outcome of 'death or dependency' required the smallest sample sizes of all the outcome measures (n=277 for 30% reduction in relative risk, 627 for a 20% reduction). CONCLUSIONS: 'Death or dependency' is a feasible and potentially useful outcome measure in PD trials of neuroprotective agents, but further work is required to validate its use and define dependency.
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Equitable tuberculosis care in the North West of England : analysis of tuberculosis cohort review data
https://hdl.handle.net/10023/8789
BACKGROUND: In the United Kingdom, tuberculosis (TB) predominantly affects the most deprived populations, yet the extent to which deprivation affects TB care outcomes is unknown. METHODS: Since 2011, the North West TB Cohort Audit collaboration has undertaken quarterly reviews of outcomes against consensus-defined care standard indicators for all individuals notified with TB. We investigated associations between adverse TB care outcomes and Index of Multiple Deprivation (IMD) 2010 scores measured at lower super output area of residence using logistic regression models. RESULTS: Of 1831 individuals notified with TB between 2011 and 2014, 62% (1131/1831) came from the most deprived national quintile areas. In single variable analysis, greater deprivation was significantly associated with increased likelihood of the completion of a standardised risk assessment (OR 2.99, 95%CI 5.27–19.65) and offer of a human immunodeficiency virus test (OR 1.72, 95%CI 1.10–2.62). In multivariable analysis, there were no significant associations. CONCLUSIONS: TB patients in the most deprived areas had similar care indicators across a range of standards to those of individuals living in the more affluent areas, suggesting that the delivery of TB care in the North West of England is equitable. The extent to which the cohort review process contributes to, and sustains, this standard of care deserves further study.
2016-06-01T00:00:00Z
MacPherson, P.
Squire, S. B.
Cleary , P.
Davies, S.
Wake, C.
Dee, K.
Walker, J.
Farrow, S.
McMaster, P.
Woodhead, M.
Sloan, Derek James
North West TB Audit Steering Committee
BACKGROUND: In the United Kingdom, tuberculosis (TB) predominantly affects the most deprived populations, yet the extent to which deprivation affects TB care outcomes is unknown. METHODS: Since 2011, the North West TB Cohort Audit collaboration has undertaken quarterly reviews of outcomes against consensus-defined care standard indicators for all individuals notified with TB. We investigated associations between adverse TB care outcomes and Index of Multiple Deprivation (IMD) 2010 scores measured at lower super output area of residence using logistic regression models. RESULTS: Of 1831 individuals notified with TB between 2011 and 2014, 62% (1131/1831) came from the most deprived national quintile areas. In single variable analysis, greater deprivation was significantly associated with increased likelihood of the completion of a standardised risk assessment (OR 2.99, 95%CI 5.27–19.65) and offer of a human immunodeficiency virus test (OR 1.72, 95%CI 1.10–2.62). In multivariable analysis, there were no significant associations. CONCLUSIONS: TB patients in the most deprived areas had similar care indicators across a range of standards to those of individuals living in the more affluent areas, suggesting that the delivery of TB care in the North West of England is equitable. The extent to which the cohort review process contributes to, and sustains, this standard of care deserves further study.
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Kinetics of Mycobacterium tuberculosis-specific IFN-γ responses and sputum bacillary clearance in HIV-infected adults during treatment of pulmonary tuberculosis
https://hdl.handle.net/10023/8653
In HIV-uninfected adults with pulmonary tuberculosis (TB), anti-TB treatment is associated with changes in Mycobacterium tuberculosis (Mtb)-specific immune responses, which correlate with sputum bacillary load. It is unclear if this occurs in HIV-infected TB patients. We investigated changes in Mtb-specific immune responses and sputum bacillary clearance during anti-TB treatment in HIV-infected and HIV-uninfected adults with pulmonary TB. Sputum bacillary load was assessed by smear microscopy and culture. Mtb-specific IFN-γ secreting peripheral blood mononuclear cells were enumerated using an ELISPOT assay following stimulation with PPD, ESAT-6 and CFP-10. The baseline frequency of Mtb-specific IFN-γ secreting cells was lower in HIV-infected than HIV-uninfected patients (median PPD 32 vs. 104 Spot Forming Units (SFU), p = 0.05; CFP-10 19 vs. 74 SFU, p = 0.01). ESAT-6-specific IFN-γ secreting cells and sputum bacillary load declined progressively during treatment in both HIV-infected and HIV-uninfected patients. HIV infection did not influence the 2-month sputum culture conversion rate (Odds Ratio 0.89, p = 0.95). These findings suggest that changes in ESAT-6-specific immune responses during anti-TB treatment correspond with changes in sputum bacillary load irrespective of host HIV infection status. The utility of Mtb-specific IFN-γ responses as a proxy measure of treatment response in HIV-infected TB patients warrants further evaluation in other settings.
This work was supported by funding from the Wellcome Trust (UK) through Fellowships 092773/Z/10/Z (to D.T.M), 086757/Z/08/Z (to D.J.S) and 088696/Z/09/Z (to H.C.M). Core funding from the Wellcome Trust supports the laboratory and office facilities at the Malawi-Liverpool-Wellcome Trust Clinical Research Programme.
2015-07-01T00:00:00Z
Mzinza, David T.
Sloan, Derek James
Jambo, Kondwani C.
Shani, Doris
Kamdolozi, Mercy
Wilkinson, Katalin A.
Wilkinson, Robert J.
Davies, Geraint R.
Heyderman, Robert S.
Mwandumba, Henry C.
In HIV-uninfected adults with pulmonary tuberculosis (TB), anti-TB treatment is associated with changes in Mycobacterium tuberculosis (Mtb)-specific immune responses, which correlate with sputum bacillary load. It is unclear if this occurs in HIV-infected TB patients. We investigated changes in Mtb-specific immune responses and sputum bacillary clearance during anti-TB treatment in HIV-infected and HIV-uninfected adults with pulmonary TB. Sputum bacillary load was assessed by smear microscopy and culture. Mtb-specific IFN-γ secreting peripheral blood mononuclear cells were enumerated using an ELISPOT assay following stimulation with PPD, ESAT-6 and CFP-10. The baseline frequency of Mtb-specific IFN-γ secreting cells was lower in HIV-infected than HIV-uninfected patients (median PPD 32 vs. 104 Spot Forming Units (SFU), p = 0.05; CFP-10 19 vs. 74 SFU, p = 0.01). ESAT-6-specific IFN-γ secreting cells and sputum bacillary load declined progressively during treatment in both HIV-infected and HIV-uninfected patients. HIV infection did not influence the 2-month sputum culture conversion rate (Odds Ratio 0.89, p = 0.95). These findings suggest that changes in ESAT-6-specific immune responses during anti-TB treatment correspond with changes in sputum bacillary load irrespective of host HIV infection status. The utility of Mtb-specific IFN-γ responses as a proxy measure of treatment response in HIV-infected TB patients warrants further evaluation in other settings.
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Vitamin D deficiency in Malawian adults with pulmonary tuberculosis : risk factors and treatment outcomes
https://hdl.handle.net/10023/8651
SETTING: Vitamin D deficiency is common in African adults with tuberculosis (TB), and may be exacerbated by the metabolic effects of anti-tuberculosis drugs and antiretroviral therapy (ART). It is unclear whether vitamin D deficiency influences response to antituberculosis treatment. OBJECTIVES : To describe risk factors for baseline vitamin D deficiency in Malawian adults with pulmonary TB, assess the relationship between serum 25-hydroxy vitamin D (25[OH]D) concentration and treatment response, and evaluate whether the administration of anti-tuberculosis drugs and ART is deleterious to vitamin D status during treatment. DESIGN: A prospective longitudinal cohort study. RESULTS : The median baseline 25(OH)D concentration of the 169 patients (58% human immunodeficiency virus [HIV] infected) recruited was 57 nmol/l; 47 (28%) had vitamin D deficiency (<50 nmol/l). Baseline 25(OH)D concentrations were lower during the cold season (P < 0.001), with food insecurity (P = 0.034) or in patients who consumed alcohol (P = 0.019). No relationship between vitamin D status and anti-tuberculosis treatment response was found. 25(OH)D concentrations increased during anti-tuberculosis treatment, irrespective of HIV status or use of ART. CONCLUSIONS : Vitamin D deficiency is common among TB patients in Malawi, but this does not influence treatment response. Adverse metabolic effects of drug treatment may be compensated by the positive impact of clinical recovery preventing exacerbation of vitamin D deficiency during anti-tuberculosis treatment.
The study was supported by a Wellcome Trust (London, UK) Clinical PhD Fellowship awarded to DS (086757/Z/08/A) and the Malawi Liverpool Wellcome Trust (MLW) Core grant from the Wellcome Trust.
2015-08-01T00:00:00Z
Sloan, Derek James
Mwandumba, H. C.
Kamdolozi, M.
Shani, D.
Chisale, B.
Dutton, J.
Khoo, S. H.
Allain, T. J.
Davies, G. R.
SETTING: Vitamin D deficiency is common in African adults with tuberculosis (TB), and may be exacerbated by the metabolic effects of anti-tuberculosis drugs and antiretroviral therapy (ART). It is unclear whether vitamin D deficiency influences response to antituberculosis treatment. OBJECTIVES : To describe risk factors for baseline vitamin D deficiency in Malawian adults with pulmonary TB, assess the relationship between serum 25-hydroxy vitamin D (25[OH]D) concentration and treatment response, and evaluate whether the administration of anti-tuberculosis drugs and ART is deleterious to vitamin D status during treatment. DESIGN: A prospective longitudinal cohort study. RESULTS : The median baseline 25(OH)D concentration of the 169 patients (58% human immunodeficiency virus [HIV] infected) recruited was 57 nmol/l; 47 (28%) had vitamin D deficiency (<50 nmol/l). Baseline 25(OH)D concentrations were lower during the cold season (P < 0.001), with food insecurity (P = 0.034) or in patients who consumed alcohol (P = 0.019). No relationship between vitamin D status and anti-tuberculosis treatment response was found. 25(OH)D concentrations increased during anti-tuberculosis treatment, irrespective of HIV status or use of ART. CONCLUSIONS : Vitamin D deficiency is common among TB patients in Malawi, but this does not influence treatment response. Adverse metabolic effects of drug treatment may be compensated by the positive impact of clinical recovery preventing exacerbation of vitamin D deficiency during anti-tuberculosis treatment.
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Discordance between clinical and immunological ART eligibility criteria for children in Malawi
https://hdl.handle.net/10023/7002
Background Since May 2014, all HIV positive children aged less than five years in Malawi are eligible for ART. For children older than five years they are eligible if they are in WHO stage III/IV, if stage I/II, if their CD4 < 500 cells/mm3. Our goal was to compare the WHO clinical classification criteria (WHO stage + CD4/age) to CD4 count (CD4/age) on all children. Prior to 2014, children aged 2-5 years in stage I and II were eligible for ART if their CD4 was < 750 cells/mm3. We were interested in the increase in children in this age group who now met the eligibility criteria and their average CD4 count. Methods Data including age, stage and CD4 count were used. We examined the effect of using two different criteria; WHO staging and checking CD4 count if stage I or II versus CD4 count on all, on the numbers of children eligibility for ART in a cohort of 969 children aged 0 to 14 years in Blantyre, Malawi. Results Using WHO stage + CD4/age, 786 patients out of 969 would have been treated and 183 would not. Using CD4/age, 745 patients out of 969 would have been treated and 224 would not. Within the 224 patients not treated by CD4 classification, 41 were clinical stage III or IV. The most common staging condition in these 41 children was low weight for age (i.e. underweight). 41% of children age2-5 years have a CD4 count >750. Conclusion Most children are correctly started on treatment using recent guidelines. 41% more children <5 years will be started on ART.
2014-09-22T00:00:00Z
O'Hare, Bernadette Ann-Marie
Milner, Jr, Danny A.
Newberry, Laura
Pelani, Isaac
Malista, Ken
Background Since May 2014, all HIV positive children aged less than five years in Malawi are eligible for ART. For children older than five years they are eligible if they are in WHO stage III/IV, if stage I/II, if their CD4 < 500 cells/mm3. Our goal was to compare the WHO clinical classification criteria (WHO stage + CD4/age) to CD4 count (CD4/age) on all children. Prior to 2014, children aged 2-5 years in stage I and II were eligible for ART if their CD4 was < 750 cells/mm3. We were interested in the increase in children in this age group who now met the eligibility criteria and their average CD4 count. Methods Data including age, stage and CD4 count were used. We examined the effect of using two different criteria; WHO staging and checking CD4 count if stage I or II versus CD4 count on all, on the numbers of children eligibility for ART in a cohort of 969 children aged 0 to 14 years in Blantyre, Malawi. Results Using WHO stage + CD4/age, 786 patients out of 969 would have been treated and 183 would not. Using CD4/age, 745 patients out of 969 would have been treated and 224 would not. Within the 224 patients not treated by CD4 classification, 41 were clinical stage III or IV. The most common staging condition in these 41 children was low weight for age (i.e. underweight). 41% of children age2-5 years have a CD4 count >750. Conclusion Most children are correctly started on treatment using recent guidelines. 41% more children <5 years will be started on ART.
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Uterine Fibroid Embolization for symptomatic fibroids : study at a teaching hospital in Kenya
https://hdl.handle.net/10023/6979
Objective: Characterization of magnetic (MRI) features in women undergoing uterine fibroid embolization (UFE) and identification of clinical correlates in an African population. Materials and Methods: Patients with symptomatic fibroids who are selected to undergo UFE at the hospital formed the study population. The baseline MRI features, baseline symptom score, short-term imaging outcome, and mid-term symptom scores were analyzed for interval changes. Assessment of potential associations between short-term imaging features and mid-term symptom scores was also done. Results: UFE resulted in statistically significant reduction (P < 0.001) of dominant fibroid, uterine volumes, and reduction of symptom severity scores, which were 43.7%, 40.1%, and 37.8%, respectively. Also, 59% of respondents had more than 10 fibroids. The predominant location of the dominant fibroid was intramural. No statistically significant association was found between clinical and radiological outcome. Conclusion: The response of uterine fibroids to embolization in the African population is not different from the findings reported in other studies from the west. The presence of multiple and large fibroids in this study is consistent with the case mix described in other studies of African-American populations. Patient counseling should emphasize the independence of volume reduction and symptom improvement. Though volume changes are of relevance for the radiologist in understanding the evolution of the condition and identifying potential technical treatment failures, it should not be the main basis of evaluation of treatment success.
This study was funded by the Aga Khan University Date of Acceptance: 24/02/2015
2015-03-31T00:00:00Z
Mutai, John
Vinayak, Sudhir
Stones, William
Hacking, Nigel
Mariara, Charles
Objective: Characterization of magnetic (MRI) features in women undergoing uterine fibroid embolization (UFE) and identification of clinical correlates in an African population. Materials and Methods: Patients with symptomatic fibroids who are selected to undergo UFE at the hospital formed the study population. The baseline MRI features, baseline symptom score, short-term imaging outcome, and mid-term symptom scores were analyzed for interval changes. Assessment of potential associations between short-term imaging features and mid-term symptom scores was also done. Results: UFE resulted in statistically significant reduction (P < 0.001) of dominant fibroid, uterine volumes, and reduction of symptom severity scores, which were 43.7%, 40.1%, and 37.8%, respectively. Also, 59% of respondents had more than 10 fibroids. The predominant location of the dominant fibroid was intramural. No statistically significant association was found between clinical and radiological outcome. Conclusion: The response of uterine fibroids to embolization in the African population is not different from the findings reported in other studies from the west. The presence of multiple and large fibroids in this study is consistent with the case mix described in other studies of African-American populations. Patient counseling should emphasize the independence of volume reduction and symptom improvement. Though volume changes are of relevance for the radiologist in understanding the evolution of the condition and identifying potential technical treatment failures, it should not be the main basis of evaluation of treatment success.
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Evaluation of glutathione S-transferase Pi in non-invasive ductal carcinoma of breast
https://hdl.handle.net/10023/6247
Glutathione S-transferase Pi (GST P) has been reported to be a marker of dysplastic lesions. For this reason expression of GST P by intraduct breast carcinoma was evaluated by immunohistochemistry. Thirty-seven of 92 carcinomas (40%) were GST P positive. GST P staining did not correlate with histological variables, c-erbB-2 overexpression or with clinical outcome. The GST P status of recurrences did not correlate with that of the index lesion. There is little evidence that GST P is a useful marker of the potential of intraduct breast carcinoma to become invasive.
1994-01-01T00:00:00Z
Bellamy, C O
Harrison, D J
Glutathione S-transferase Pi (GST P) has been reported to be a marker of dysplastic lesions. For this reason expression of GST P by intraduct breast carcinoma was evaluated by immunohistochemistry. Thirty-seven of 92 carcinomas (40%) were GST P positive. GST P staining did not correlate with histological variables, c-erbB-2 overexpression or with clinical outcome. The GST P status of recurrences did not correlate with that of the index lesion. There is little evidence that GST P is a useful marker of the potential of intraduct breast carcinoma to become invasive.
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Adenovirus-mediated Cre deletion of floxed sequences in primary mouse cells is an efficient alternative for studies of gene deletion
https://hdl.handle.net/10023/6245
This study evaluates the utility of Cre-expressing adenovirus for deletion of floxed genes in primary cells using primary murine hepatocytes. Adenovirus infection was very efficient, even at very low MOI (>95% infection at a MOI of 6) and did not reduce viability. High level LacZ expression was cytotoxic to hepatocytes but Cre expression had no effect on viability. Cre-mediated recombination was completed within a timespan that permits experimentation during primary culture (>95% recombination after 24 h), independently of the number of floxed alleles per cell. Recombination did not induce p53 or produce cytological nuclear abnormalities (even in polyploid cells). Contrary to expectation, deletion of DNA ligase 1 did not alter cell cycle progression, although Cre expression hastens entry to S phase from G(1), independently of the presence of floxed sequences. We conclude that adenovirus-mediated deletion of floxed alleles in primary cells is a straightforward and highly efficient tool for conducting preliminary studies of conditional gene targeting. Primary cells have advantages of differentiation, relative purity and ease of experimentation within controlled conditions, while avoiding confounding problems encountered in vivo (i.e. target cell specificity, kinetics and level of recombination, and elicitation of inflammatory and immune responses). This system could help Identify important phenotypic effects and design and interpret in vivo studies.
2001-08-15T00:00:00Z
Prost, Sandrine
Sheahan, Sheahan
Rannie, Dominic
Harrison, David
This study evaluates the utility of Cre-expressing adenovirus for deletion of floxed genes in primary cells using primary murine hepatocytes. Adenovirus infection was very efficient, even at very low MOI (>95% infection at a MOI of 6) and did not reduce viability. High level LacZ expression was cytotoxic to hepatocytes but Cre expression had no effect on viability. Cre-mediated recombination was completed within a timespan that permits experimentation during primary culture (>95% recombination after 24 h), independently of the number of floxed alleles per cell. Recombination did not induce p53 or produce cytological nuclear abnormalities (even in polyploid cells). Contrary to expectation, deletion of DNA ligase 1 did not alter cell cycle progression, although Cre expression hastens entry to S phase from G(1), independently of the presence of floxed sequences. We conclude that adenovirus-mediated deletion of floxed alleles in primary cells is a straightforward and highly efficient tool for conducting preliminary studies of conditional gene targeting. Primary cells have advantages of differentiation, relative purity and ease of experimentation within controlled conditions, while avoiding confounding problems encountered in vivo (i.e. target cell specificity, kinetics and level of recombination, and elicitation of inflammatory and immune responses). This system could help Identify important phenotypic effects and design and interpret in vivo studies.
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While K-ras is essential for mouse development, expression of the K-ras 4A splice variant is dispensable
https://hdl.handle.net/10023/6244
In mammals, the three classical ras genes encode four highly homologous proteins, N-Ras, H-Ras, and the isoforms K-Ras 4A and 4B. Previous studies have shown that K-ras is essential for mouse development and that while K-ras 4A and 4B are expressed during development, K-ras 4A expression is regulated temporally and spatially and occurs in adult kidney, intestine, stomach, and liver. In the present study, the pattern of K-ras 4A expression was examined in a wide range of wild-type adult mouse tissues, and gene targeting was used to generate K-ras 4A-deficient mice to examine its role in development. It was found that K-ras 4A is also expressed in uterus, lung, pancreas, salivary glands, seminal vesicles, bone marrow cells, and cecum, where it was the major K-Ras isoform expressed. Mating between K-ras(tmDelta4A/+) mice produced viable K-ras(tmDelta4A/tmDelta4A) offspring with the expected Mendelian ratios of inheritance, and these mice expressed the K-ras 4B splice variant only. K-ras(tmDelta4A/tmDelta4A) mice were fertile and showed no histopathological abnormalities on inbred (129/Ola) or crossbred (129/Ola x C57BL/6) genetic backgrounds. The results demonstrate that K-Ras 4A, like H- and N-Ras, is dispensable for normal mouse development, at least in the presence of functional K-Ras 4B.
2003-12-01T00:00:00Z
Plowman, Sarah J
Williamson, D James
O'Sullivan, Maureen J
Doig, Jennifer
Ritchie, Ann-Marie
Harrison, David J
Melton, David W
Arends, Mark J
Hooper, Martin L
Patek, Charles E
In mammals, the three classical ras genes encode four highly homologous proteins, N-Ras, H-Ras, and the isoforms K-Ras 4A and 4B. Previous studies have shown that K-ras is essential for mouse development and that while K-ras 4A and 4B are expressed during development, K-ras 4A expression is regulated temporally and spatially and occurs in adult kidney, intestine, stomach, and liver. In the present study, the pattern of K-ras 4A expression was examined in a wide range of wild-type adult mouse tissues, and gene targeting was used to generate K-ras 4A-deficient mice to examine its role in development. It was found that K-ras 4A is also expressed in uterus, lung, pancreas, salivary glands, seminal vesicles, bone marrow cells, and cecum, where it was the major K-Ras isoform expressed. Mating between K-ras(tmDelta4A/+) mice produced viable K-ras(tmDelta4A/tmDelta4A) offspring with the expected Mendelian ratios of inheritance, and these mice expressed the K-ras 4B splice variant only. K-ras(tmDelta4A/tmDelta4A) mice were fertile and showed no histopathological abnormalities on inbred (129/Ola) or crossbred (129/Ola x C57BL/6) genetic backgrounds. The results demonstrate that K-Ras 4A, like H- and N-Ras, is dispensable for normal mouse development, at least in the presence of functional K-Ras 4B.
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Genetic and epigenetic analyses of MBD3 in colon and lung cancer
https://hdl.handle.net/10023/6243
MBD3: is a member of the methyl-CpG-binding domain family and is located on chromosome 19p13.3, a region of loss of heterozygosity in colon and lung cancers. We therefore screened samples for abnormalities in MBD3. Our results indicate that MBD3 is not a major target of genetic and epigenetic alteration in these cancers.
2004-05-17T00:00:00Z
Zhu, Y
Harrison, D J
Bader, S A
MBD3: is a member of the methyl-CpG-binding domain family and is located on chromosome 19p13.3, a region of loss of heterozygosity in colon and lung cancers. We therefore screened samples for abnormalities in MBD3. Our results indicate that MBD3 is not a major target of genetic and epigenetic alteration in these cancers.
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Deficiency of G1 regulators P53, P21Cip1 and/or pRb decreases hepatocyte sensitivity to TGFbeta cell cycle arrest
https://hdl.handle.net/10023/6238
TGFbeta is critical to control hepatocyte proliferation by inducing G1-growth arrest through multiple pathways leading to inhibition of E2F transcription activity. The retinoblastoma protein pRb is a key controller of E2F activity and G1/S transition which can be inhibited in viral hepatitis. It is not known whether the impairment of pRb would alter the growth inhibitory potential of TGFbeta in disease. We asked how Rb-deficiency would affect responses to TGFbeta-induced cell cycle arrest.
2007-11-19T00:00:00Z
Sheahan, Sharon
Bellamy, Christopher O
Dunbar, Donald R
Harrison, David J
Prost, Sandrine
TGFbeta is critical to control hepatocyte proliferation by inducing G1-growth arrest through multiple pathways leading to inhibition of E2F transcription activity. The retinoblastoma protein pRb is a key controller of E2F activity and G1/S transition which can be inhibited in viral hepatitis. It is not known whether the impairment of pRb would alter the growth inhibitory potential of TGFbeta in disease. We asked how Rb-deficiency would affect responses to TGFbeta-induced cell cycle arrest.
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Heterogeneity mapping of protein expression in tumors using quantitative immunofluorescence
https://hdl.handle.net/10023/6233
Morphologic heterogeneity within an individual tumor is well-recognized by histopathologists in surgical practice. While this often takes the form of areas of distinct differentiation into recognized histological subtypes, or different pathological grade, often there are more subtle differences in phenotype which defy accurate classification (Figure 1). Ultimately, since morphology is dictated by the underlying molecular phenotype, areas with visible differences are likely to be accompanied by differences in the expression of proteins which orchestrate cellular function and behavior, and therefore, appearance. The significance of visible and invisible (molecular) heterogeneity for prognosis is unknown, but recent evidence suggests that, at least at the genetic level, heterogeneity exists in the primary tumor(1,2), and some of these sub-clones give rise to metastatic (and therefore lethal) disease. Moreover, some proteins are measured as biomarkers because they are the targets of therapy (for instance ER and HER2 for tamoxifen and trastuzumab (Herceptin), respectively). If these proteins show variable expression within a tumor then therapeutic responses may also be variable. The widely used histopathologic scoring schemes for immunohistochemistry either ignore, or numerically homogenize the quantification of protein expression. Similarly, in destructive techniques, where the tumor samples are homogenized (such as gene expression profiling), quantitative information can be elucidated, but spatial information is lost. Genetic heterogeneity mapping approaches in pancreatic cancer have relied either on generation of a single cell suspension(3), or on macrodissection(4). A recent study has used quantum dots in order to map morphologic and molecular heterogeneity in prostate cancer tissue(5), providing proof of principle that morphology and molecular mapping is feasible, but falling short of quantifying the heterogeneity. Since immunohistochemistry is, at best, only semi-quantitative and subject to intra- and inter-observer bias, more sensitive and quantitative methodologies are required in order to accurately map and quantify tissue heterogeneity in situ. We have developed and applied an experimental and statistical methodology in order to systematically quantify the heterogeneity of protein expression in whole tissue sections of tumors, based on the Automated QUantitative Analysis (AQUA) system(6). Tissue sections are labeled with specific antibodies directed against cytokeratins and targets of interest, coupled to fluorophore-labeled secondary antibodies. Slides are imaged using a whole-slide fluorescence scanner. Images are subdivided into hundreds to thousands of tiles, and each tile is then assigned an AQUA score which is a measure of protein concentration within the epithelial (tumor) component of the tissue. Heatmaps are generated to represent tissue expression of the proteins and a heterogeneity score assigned, using a statistical measure of heterogeneity originally used in ecology, based on the Simpson's biodiversity index(7). To date there have been no attempts to systematically map and quantify this variability in tandem with protein expression, in histological preparations. Here, we illustrate the first use of the method applied to ER and HER2 biomarker expression in ovarian cancer. Using this method paves the way for analyzing heterogeneity as an independent variable in studies of biomarker expression in translational studies, in order to establish the significance of heterogeneity in prognosis and prediction of responses to therapy.
2011-10-25T00:00:00Z
Faratian, Dana
Christiansen, Jason
Gustavson, Mark
Jones, Christine
Scott, Christopher
Um, InHwa
Harrison, David J
Morphologic heterogeneity within an individual tumor is well-recognized by histopathologists in surgical practice. While this often takes the form of areas of distinct differentiation into recognized histological subtypes, or different pathological grade, often there are more subtle differences in phenotype which defy accurate classification (Figure 1). Ultimately, since morphology is dictated by the underlying molecular phenotype, areas with visible differences are likely to be accompanied by differences in the expression of proteins which orchestrate cellular function and behavior, and therefore, appearance. The significance of visible and invisible (molecular) heterogeneity for prognosis is unknown, but recent evidence suggests that, at least at the genetic level, heterogeneity exists in the primary tumor(1,2), and some of these sub-clones give rise to metastatic (and therefore lethal) disease. Moreover, some proteins are measured as biomarkers because they are the targets of therapy (for instance ER and HER2 for tamoxifen and trastuzumab (Herceptin), respectively). If these proteins show variable expression within a tumor then therapeutic responses may also be variable. The widely used histopathologic scoring schemes for immunohistochemistry either ignore, or numerically homogenize the quantification of protein expression. Similarly, in destructive techniques, where the tumor samples are homogenized (such as gene expression profiling), quantitative information can be elucidated, but spatial information is lost. Genetic heterogeneity mapping approaches in pancreatic cancer have relied either on generation of a single cell suspension(3), or on macrodissection(4). A recent study has used quantum dots in order to map morphologic and molecular heterogeneity in prostate cancer tissue(5), providing proof of principle that morphology and molecular mapping is feasible, but falling short of quantifying the heterogeneity. Since immunohistochemistry is, at best, only semi-quantitative and subject to intra- and inter-observer bias, more sensitive and quantitative methodologies are required in order to accurately map and quantify tissue heterogeneity in situ. We have developed and applied an experimental and statistical methodology in order to systematically quantify the heterogeneity of protein expression in whole tissue sections of tumors, based on the Automated QUantitative Analysis (AQUA) system(6). Tissue sections are labeled with specific antibodies directed against cytokeratins and targets of interest, coupled to fluorophore-labeled secondary antibodies. Slides are imaged using a whole-slide fluorescence scanner. Images are subdivided into hundreds to thousands of tiles, and each tile is then assigned an AQUA score which is a measure of protein concentration within the epithelial (tumor) component of the tissue. Heatmaps are generated to represent tissue expression of the proteins and a heterogeneity score assigned, using a statistical measure of heterogeneity originally used in ecology, based on the Simpson's biodiversity index(7). To date there have been no attempts to systematically map and quantify this variability in tandem with protein expression, in histological preparations. Here, we illustrate the first use of the method applied to ER and HER2 biomarker expression in ovarian cancer. Using this method paves the way for analyzing heterogeneity as an independent variable in studies of biomarker expression in translational studies, in order to establish the significance of heterogeneity in prognosis and prediction of responses to therapy.
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Long-term culture of human breast cancer specimens and their analysis using optical projection tomography
https://hdl.handle.net/10023/6232
Breast cancer is a leading cause of mortality in the Western world. It is well established that the spread of breast cancer, first locally and later distally, is a major factor in patient prognosis. Experimental systems of breast cancer rely on cell lines usually derived from primary tumours or pleural effusions. Two major obstacles hinder this research: (i) some known sub-types of breast cancers (notably poor prognosis luminal B tumours) are not represented within current line collections; (ii) the influence of the tumour microenvironment is not usually taken into account. We demonstrate a technique to culture primary breast cancer specimens of all sub-types. This is achieved by using three-dimensional (3D) culture system in which small pieces of tumour are embedded in soft rat collagen I cushions. Within 2-3 weeks, the tumour cells spread into the collagen and form various structures similar to those observed in human tumours1. Viable adipocytes, epithelial cells and fibroblasts within the original core were evident on histology. Malignant epithelial cells with squamoid morphology were demonstrated invading into the surrounding collagen. Nuclear pleomorphism was evident within these cells, along with mitotic figures and apoptotic bodies. We have employed Optical Projection Tomography (OPT), a 3D imaging technology, in order to quantify the extent of tumour spread in culture. We have used OPT to measure the bulk volume of the tumour culture, a parameter routinely measured during the neo-adjuvant treatment of breast cancer patients to assess response to drug therapy. Here, we present an opportunity to culture human breast tumours without sub-type bias and quantify the spread of those ex vivo. This method could be used in the future to quantify drug sensitivity in original tumour. This may provide a more predictive model than currently used cell lines.
2011-07-29T00:00:00Z
Leeper, Alexander D
Farrell, Joanne
Dixon, J Michael
Wedden, Sarah E
Harrison, David J
Katz, Elad
Breast cancer is a leading cause of mortality in the Western world. It is well established that the spread of breast cancer, first locally and later distally, is a major factor in patient prognosis. Experimental systems of breast cancer rely on cell lines usually derived from primary tumours or pleural effusions. Two major obstacles hinder this research: (i) some known sub-types of breast cancers (notably poor prognosis luminal B tumours) are not represented within current line collections; (ii) the influence of the tumour microenvironment is not usually taken into account. We demonstrate a technique to culture primary breast cancer specimens of all sub-types. This is achieved by using three-dimensional (3D) culture system in which small pieces of tumour are embedded in soft rat collagen I cushions. Within 2-3 weeks, the tumour cells spread into the collagen and form various structures similar to those observed in human tumours1. Viable adipocytes, epithelial cells and fibroblasts within the original core were evident on histology. Malignant epithelial cells with squamoid morphology were demonstrated invading into the surrounding collagen. Nuclear pleomorphism was evident within these cells, along with mitotic figures and apoptotic bodies. We have employed Optical Projection Tomography (OPT), a 3D imaging technology, in order to quantify the extent of tumour spread in culture. We have used OPT to measure the bulk volume of the tumour culture, a parameter routinely measured during the neo-adjuvant treatment of breast cancer patients to assess response to drug therapy. Here, we present an opportunity to culture human breast tumours without sub-type bias and quantify the spread of those ex vivo. This method could be used in the future to quantify drug sensitivity in original tumour. This may provide a more predictive model than currently used cell lines.
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Apoptosis and DNA methylation
https://hdl.handle.net/10023/6229
Epigenetic mechanisms assist in maintaining gene expression patterns and cellular properties in developing and adult tissues. The molecular pathology of disease states frequently includes perturbation of DNA and histone methylation patterns, which can activate apoptotic pathways associated with maintenance of genome integrity. This perspective focuses on the pathways linking DNA methyltransferases and methyl-CpG binding proteins to apoptosis, and includes new bioinformatic analyses to characterize the evolutionary origin of two G/T mismatch-specific thymine DNA glycosylases, MBD4 and TDG.
2011-04-01T00:00:00Z
Meng, Huan X
Hackett, James A
Nestor, Colm
Dunican, Donncha S
Madej, Monika
Reddington, James P
Pennings, Sari
Harrison, David J
Meehan, Richard R
Epigenetic mechanisms assist in maintaining gene expression patterns and cellular properties in developing and adult tissues. The molecular pathology of disease states frequently includes perturbation of DNA and histone methylation patterns, which can activate apoptotic pathways associated with maintenance of genome integrity. This perspective focuses on the pathways linking DNA methyltransferases and methyl-CpG binding proteins to apoptosis, and includes new bioinformatic analyses to characterize the evolutionary origin of two G/T mismatch-specific thymine DNA glycosylases, MBD4 and TDG.
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Targeting of Rac GTPases blocks the spread of intact human breast cancer
https://hdl.handle.net/10023/6227
High expression of Rac small GTPases in invasive breast ductal carcinoma is associated with poor prognosis, but its therapeutic value in human cancers is not clear. The aim of the current study was to determine the response of human primary breast cancers to Rac-based drug treatments ex vivo. Three-dimensional organotypic cultures were used to assess candidate therapeutic avenues in invasive breast cancers. Uniquely, in these primary cultures, the tumour is not disaggregated, with both epithelial and mesenchymal components maintained within a 3-dimensional matrix of type I collagen. EHT 1864, a small molecule inhibitor of Rac GTPases, prevents spread of breast cancers in this setting, and also reduces proliferation at the invading edge. Rac1+ epithelial cells in breast tumours also contain high levels of the phosphorylated form of the transcription factor STAT3. The small molecule Stattic inhibits activation of STAT3 and induces effects similar to those seen with EHT 1864. Pan-Rac inhibition of proliferation precedes down-regulation of STAT3 activity, defining it as the last step in Rac activation during human breast cancer invasion. Our data highlights the potential use of Rac and STAT3 inhibition in treatment of invasive human breast cancer and the benefit of studying novel cancer treatments using 3-dimensional primary tumour tissue explant cultures.
2012-06-01T00:00:00Z
Katz, Elad
Sims, Andrew H
Sproul, Duncan
Caldwell, Helen
Dixon, Mike
Meehan, Richard R
Harrison, David J
High expression of Rac small GTPases in invasive breast ductal carcinoma is associated with poor prognosis, but its therapeutic value in human cancers is not clear. The aim of the current study was to determine the response of human primary breast cancers to Rac-based drug treatments ex vivo. Three-dimensional organotypic cultures were used to assess candidate therapeutic avenues in invasive breast cancers. Uniquely, in these primary cultures, the tumour is not disaggregated, with both epithelial and mesenchymal components maintained within a 3-dimensional matrix of type I collagen. EHT 1864, a small molecule inhibitor of Rac GTPases, prevents spread of breast cancers in this setting, and also reduces proliferation at the invading edge. Rac1+ epithelial cells in breast tumours also contain high levels of the phosphorylated form of the transcription factor STAT3. The small molecule Stattic inhibits activation of STAT3 and induces effects similar to those seen with EHT 1864. Pan-Rac inhibition of proliferation precedes down-regulation of STAT3 activity, defining it as the last step in Rac activation during human breast cancer invasion. Our data highlights the potential use of Rac and STAT3 inhibition in treatment of invasive human breast cancer and the benefit of studying novel cancer treatments using 3-dimensional primary tumour tissue explant cultures.
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Allosteric modulation of Beta1 Integrin function induces lung tissue repair
https://hdl.handle.net/10023/6226
The cellular cytoskeleton, adhesion receptors, extracellular matrix composition, and their spatial distribution are together fundamental in a cell's balanced mechanical sensing of its environment. We show that, in lung injury, extracellular matrix-integrin interactions are altered and this leads to signalling alteration and mechanical missensing. The missensing, secondary to matrix alteration and cell surface receptor alterations, leads to increased cellular stiffness, injury, and death. We have identified a monoclonal antibody against ?1 integrin which caused matrix remodelling and enhancement of cell survival. The antibody acts as an allosteric dual agonist/antagonist modulator of ?1 integrin. Intriguingly, this antibody reversed both functional and structural tissue injury in an animal model of degenerative disease in lung.
2012-01-01T00:00:00Z
Aljamal-naylor, Rehab
Wilson, Linda
Mcintyre, Susan
Rossi, Fiona
Harrison, Beth
Marsden, Mark
Harrison, David J.
The cellular cytoskeleton, adhesion receptors, extracellular matrix composition, and their spatial distribution are together fundamental in a cell's balanced mechanical sensing of its environment. We show that, in lung injury, extracellular matrix-integrin interactions are altered and this leads to signalling alteration and mechanical missensing. The missensing, secondary to matrix alteration and cell surface receptor alterations, leads to increased cellular stiffness, injury, and death. We have identified a monoclonal antibody against ?1 integrin which caused matrix remodelling and enhancement of cell survival. The antibody acts as an allosteric dual agonist/antagonist modulator of ?1 integrin. Intriguingly, this antibody reversed both functional and structural tissue injury in an animal model of degenerative disease in lung.
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Aquaporin 4 is a ubiquitously expressed isoform in the dogfish (Squalus acanthias) shark
https://hdl.handle.net/10023/4985
The dogfish ortholog of aquaporin 4 (AQP4) was amplified from cDNA using degenerate PCR followed by cloning and sequencing. The complete coding region was then obtained using 5′ and 3′ RACE techniques. Alignment of the sequence with AQP4 amino acid sequences from other species showed that dogfish AQP4 has high levels (up to 65.3%) of homology with higher vertebrate sequences but lower levels of homology to Agnathan (38.2%) or teleost (57.5%) fish sequences. Northern blotting indicated that the dogfish mRNA was approximately 3.2 kb and was highly expressed in the rectal gland (a shark fluid secretory organ). Semi-quantitative PCR further indicates that AQP4 is ubiquitous, being expressed in all tissues measured but at low levels in certain tissues, where the level in liver > gill > intestine. Manipulation of the external environmental salinity of groups of dogfish showed that when fish were acclimated in stages to 120% seawater (SW) or 75% SW, there was no change in AQP4 mRNA expression in either rectal gland, kidney, or esophagus/cardiac stomach. Whereas quantitative PCR experiments using the RNA samples from the same experiment, showed a significant 63.1% lower abundance of gill AQP4 mRNA expression in 120% SW-acclimated dogfish. The function of dogfish AQP4 was also determined by measuring the effect of the AQP4 expression in Xenopus laevis oocytes. Dogfish AQP4 expressing-oocytes, exhibited significantly increased osmotic water permeability (Pf) compared to controls, and this was invariant with pH. Permeability was not significantly reduced by treatment of oocytes with mercury chloride, as is also the case with AQP4 in other species. Similarly AQP4 expressing-oocytes did not exhibit enhanced urea or glycerol permeability, which is also consistent with the water-selective property of AQP4 in other species.
Christopher P.Cutler is in receipt of a grant from the National Science Foundation, NSFIOS0844818.
2012-01-10T00:00:00Z
Cutler, Christopher Paul
McIver, Bryce
Cramb, Gordon
Zeidel, Mark
The dogfish ortholog of aquaporin 4 (AQP4) was amplified from cDNA using degenerate PCR followed by cloning and sequencing. The complete coding region was then obtained using 5′ and 3′ RACE techniques. Alignment of the sequence with AQP4 amino acid sequences from other species showed that dogfish AQP4 has high levels (up to 65.3%) of homology with higher vertebrate sequences but lower levels of homology to Agnathan (38.2%) or teleost (57.5%) fish sequences. Northern blotting indicated that the dogfish mRNA was approximately 3.2 kb and was highly expressed in the rectal gland (a shark fluid secretory organ). Semi-quantitative PCR further indicates that AQP4 is ubiquitous, being expressed in all tissues measured but at low levels in certain tissues, where the level in liver > gill > intestine. Manipulation of the external environmental salinity of groups of dogfish showed that when fish were acclimated in stages to 120% seawater (SW) or 75% SW, there was no change in AQP4 mRNA expression in either rectal gland, kidney, or esophagus/cardiac stomach. Whereas quantitative PCR experiments using the RNA samples from the same experiment, showed a significant 63.1% lower abundance of gill AQP4 mRNA expression in 120% SW-acclimated dogfish. The function of dogfish AQP4 was also determined by measuring the effect of the AQP4 expression in Xenopus laevis oocytes. Dogfish AQP4 expressing-oocytes, exhibited significantly increased osmotic water permeability (Pf) compared to controls, and this was invariant with pH. Permeability was not significantly reduced by treatment of oocytes with mercury chloride, as is also the case with AQP4 in other species. Similarly AQP4 expressing-oocytes did not exhibit enhanced urea or glycerol permeability, which is also consistent with the water-selective property of AQP4 in other species.
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Expression and localization of Aquaporin 1a in the sea-bass (Dicentrarchus labrax) during ontogeny
https://hdl.handle.net/10023/4969
The successful establishment of a species in a given habitat depends on the ability of each of its developing stages to adapt to the environment. In order to understand this process we have studied the adaptation of a euryhaline fish, the sea-bass Dicentrarchus labrax, to various salinities during its ontogeny. The expression and localization of Aquaporin 1a (AQP1a) mRNA and protein were determined in different osmoregulatory tissues. In larvae, the sites of AQP1a expression are variable and they shift according to age, implying functional changes. In juveniles after metamorphosis (D32–D48 post-hatch, 15–25mm) and in pre-adults, an increase in AQP1a transcript abundance was noted in the digestive tract, and the AQP1a location was observed in the intestine. In juveniles (D87–D100 post-hatch, 38–48 mm), the transcript levels of AQP1a in the digestive tract and in the kidney were higher in sea water (SW) than at lower salinity. These observations, in agreement with existing models, suggest that in SW-acclimated fish, the imbibed water is absorbed via AQP1a through the digestive tract, particularly the intestine and the rectum. In addition, AQP1a may play a role in water reabsorption in the kidney. These mechanisms compensate dehydration in SW, and they contribute to the adaptation of juveniles to salinity changes during sea-lagoon migrations. These results contribute to the interpretation of the adaptation of populations to habitats where salinity varies.
2011-07-12T00:00:00Z
Giffard-Mena, Ivone
Boulo, Viviane
Abed, Charline
Cramb, Gordon
Charmantier, Guy
The successful establishment of a species in a given habitat depends on the ability of each of its developing stages to adapt to the environment. In order to understand this process we have studied the adaptation of a euryhaline fish, the sea-bass Dicentrarchus labrax, to various salinities during its ontogeny. The expression and localization of Aquaporin 1a (AQP1a) mRNA and protein were determined in different osmoregulatory tissues. In larvae, the sites of AQP1a expression are variable and they shift according to age, implying functional changes. In juveniles after metamorphosis (D32–D48 post-hatch, 15–25mm) and in pre-adults, an increase in AQP1a transcript abundance was noted in the digestive tract, and the AQP1a location was observed in the intestine. In juveniles (D87–D100 post-hatch, 38–48 mm), the transcript levels of AQP1a in the digestive tract and in the kidney were higher in sea water (SW) than at lower salinity. These observations, in agreement with existing models, suggest that in SW-acclimated fish, the imbibed water is absorbed via AQP1a through the digestive tract, particularly the intestine and the rectum. In addition, AQP1a may play a role in water reabsorption in the kidney. These mechanisms compensate dehydration in SW, and they contribute to the adaptation of juveniles to salinity changes during sea-lagoon migrations. These results contribute to the interpretation of the adaptation of populations to habitats where salinity varies.
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Numerical investigation of passive optical sorting of plasmon nanoparticles
https://hdl.handle.net/10023/4736
We explore the passive optical sorting of plasmon nanoparticles and investigate the optimal wavelength and optimal beam shape of incident field. The condition for optimal wavelength is found by maximising the nanoparticle separation whilst minimising the temperature increase in the system. We then use the force optical eigenmode (FOEi) method to find the beam shape of incident electromagnetic field, maximising the force difference between plasmon nanoparticles. The maximum force difference is found with respect to the whole sorting region. The combination of wavelength and beam shape study is demonstrated for a specific case of gold nanoparticles of radius 40 nm and 50 nm respectively. The optimum wavelength for this particular situation is found to be above 700 nm. The optimum beam shape depends upon the size of sorting region and ranges from plane-wave illumination for infinite sorting region to a field maximising gradient force difference in a single point. (C) 2011 Optical Society of America
Funding: UK Engineering and Physical Sciences Research Council for funding, KD is a Royal Society-Wolfson Merit Award Holder.
2011-07-06T00:00:00Z
Ploschner, Martin
Mazilu, Michael
Cizmar, Tomas
Dholakia, Kishan
We explore the passive optical sorting of plasmon nanoparticles and investigate the optimal wavelength and optimal beam shape of incident field. The condition for optimal wavelength is found by maximising the nanoparticle separation whilst minimising the temperature increase in the system. We then use the force optical eigenmode (FOEi) method to find the beam shape of incident electromagnetic field, maximising the force difference between plasmon nanoparticles. The maximum force difference is found with respect to the whole sorting region. The combination of wavelength and beam shape study is demonstrated for a specific case of gold nanoparticles of radius 40 nm and 50 nm respectively. The optimum wavelength for this particular situation is found to be above 700 nm. The optimum beam shape depends upon the size of sorting region and ranges from plane-wave illumination for infinite sorting region to a field maximising gradient force difference in a single point. (C) 2011 Optical Society of America
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MOSAL : software tools for multiobjective sequence alignment
https://hdl.handle.net/10023/4437
Multiobjective sequence alignment brings the advantage of providing a set of alignments that represent the trade-off between performing insertion/deletions and matching symbols from both sequences. Each of these alignments provide a potential explanation of the relationship between the sequences. We introduce MOSAL, a software tool that provides an open-source implementation and an on-line application for multiobjective pairwise sequence alignment.
2014-01-08T00:00:00Z
Paquete, Luís
Matias, Pedro
Abbasi, Maryam
Monsanto Pinheiro, Miguel
Multiobjective sequence alignment brings the advantage of providing a set of alignments that represent the trade-off between performing insertion/deletions and matching symbols from both sequences. Each of these alignments provide a potential explanation of the relationship between the sequences. We introduce MOSAL, a software tool that provides an open-source implementation and an on-line application for multiobjective pairwise sequence alignment.
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Dynamic size tuning of multidimensional optically bound matter
https://hdl.handle.net/10023/4341
We generate and dynamically control one-, two- and three-dimensional optically bound structures of soft matter in the geometry of counter-propagating incoherent laser beams. We report results for the Bessel, Gaussian, and Laguerre-Gaussian laser modes and particularly focus on the influence of the lateral dimensions of the beam profile on the resulting self-arranged optically bound structures. Employing the transfer of the orbital angular momentum of light in the Laguerre-Gaussian beams, we show that optically bound structures can conserve their spatial arrangements even while orbiting along the beam circumference.
2011-09-01T00:00:00Z
Brzobohaty, Oto
Karasek, Vitezslav
Cizmar, Tomas
Zemanek, Pavel
We generate and dynamically control one-, two- and three-dimensional optically bound structures of soft matter in the geometry of counter-propagating incoherent laser beams. We report results for the Bessel, Gaussian, and Laguerre-Gaussian laser modes and particularly focus on the influence of the lateral dimensions of the beam profile on the resulting self-arranged optically bound structures. Employing the transfer of the orbital angular momentum of light in the Laguerre-Gaussian beams, we show that optically bound structures can conserve their spatial arrangements even while orbiting along the beam circumference.
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Human tissue in systems medicine
https://hdl.handle.net/10023/4311
Histopathology, the examination of an architecturally artefactual, two dimensional, static image remains a potent tool allowing diagnosis and empirical expectation of prognosis. Considerable optimism exists that the advent of molecular genetic testing and other biomarker strategies will improve or even replace this ancient technology. A number of biomarkers add considerable value for prediction of whether a treatment will work. This short review argues that a systems medicine approach to pathology will not seek to replace traditional pathology, but rather augment it. Systems approaches need to incorporate quantitative morphological, protein, mRNA and DNA. A significant challenge for clinical implementation of systems pathology is how to optimise information available from tissue, which is frequently sub-optimal in quality and amount, and yet generate useful predictive models which work. The transition of histopathology to systems pathophysiology and the use of multiscale datasets ushers in a new era in diagnosis, prognosis and prediction based on analysis of human tissue.
2013-12-01T00:00:00Z
Caie, Peter David
Schuur, Klaas
Oniscu, Anca
Mullen, Peter
Reynolds, Paul Andrew
Harrison, David James
Histopathology, the examination of an architecturally artefactual, two dimensional, static image remains a potent tool allowing diagnosis and empirical expectation of prognosis. Considerable optimism exists that the advent of molecular genetic testing and other biomarker strategies will improve or even replace this ancient technology. A number of biomarkers add considerable value for prediction of whether a treatment will work. This short review argues that a systems medicine approach to pathology will not seek to replace traditional pathology, but rather augment it. Systems approaches need to incorporate quantitative morphological, protein, mRNA and DNA. A significant challenge for clinical implementation of systems pathology is how to optimise information available from tissue, which is frequently sub-optimal in quality and amount, and yet generate useful predictive models which work. The transition of histopathology to systems pathophysiology and the use of multiscale datasets ushers in a new era in diagnosis, prognosis and prediction based on analysis of human tissue.
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Femtosecond optoinjection of intact tobacco BY-2 cells using a reconfigurable photoporation platform
https://hdl.handle.net/10023/4234
A tightly-focused ultrashort pulsed laser beam incident upon a cell membrane has previously been shown to transiently increase cell membrane permeability while maintaining the viability of the cell, a technique known as photoporation. This permeability can be used to aid the passage of membrane-impermeable biologically-relevant substances such as dyes, proteins and nucleic acids into the cell. Ultrashort-pulsed lasers have proven to be indispensable for photoporating mammalian cells but they have rarely been applied to plant cells due to their larger sizes and rigid and thick cell walls, which significantly hinders the intracellular delivery of exogenous substances. Here we demonstrate and quantify femtosecond optical injection of membrane impermeable dyes into intact BY-2 tobacco plant cells growing in culture, investigating both optical and biological parameters. Specifically, we show that the long axial extent of a propagation invariant (“diffraction-free”) Bessel beam, which relaxes the requirements for tight focusing on the cell membrane, outperforms a standard Gaussian photoporation beam, achieving up to 70% optoinjection efficiency. Studies on the osmotic effects of culture media show that a hypertonic extracellular medium was found to be necessary to reduce turgor pressure and facilitate molecular entry into the cells.
2013-11-14T00:00:00Z
Mitchell, C.A.
Kalies, S.
Cizmár, T.
Heisterkamp, A.
Torrance, L.
Roberts, A.G.
Gunn-Moore, F.J.
Dholakia, K.
A tightly-focused ultrashort pulsed laser beam incident upon a cell membrane has previously been shown to transiently increase cell membrane permeability while maintaining the viability of the cell, a technique known as photoporation. This permeability can be used to aid the passage of membrane-impermeable biologically-relevant substances such as dyes, proteins and nucleic acids into the cell. Ultrashort-pulsed lasers have proven to be indispensable for photoporating mammalian cells but they have rarely been applied to plant cells due to their larger sizes and rigid and thick cell walls, which significantly hinders the intracellular delivery of exogenous substances. Here we demonstrate and quantify femtosecond optical injection of membrane impermeable dyes into intact BY-2 tobacco plant cells growing in culture, investigating both optical and biological parameters. Specifically, we show that the long axial extent of a propagation invariant (“diffraction-free”) Bessel beam, which relaxes the requirements for tight focusing on the cell membrane, outperforms a standard Gaussian photoporation beam, achieving up to 70% optoinjection efficiency. Studies on the osmotic effects of culture media show that a hypertonic extracellular medium was found to be necessary to reduce turgor pressure and facilitate molecular entry into the cells.
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Differential timing of gene expression regulation between leptocephali of the two Anguilla eel species in the Sargasso Sea
https://hdl.handle.net/10023/3460
The unique life-history characteristics of North Atlantic catadromous eels have long intrigued evolutionary biologists, especially with respect to mechanisms that could explain their persistence as two ecologically very similar but reproductively and geographically distinct species. Differential developmental schedules during young larval stages have commonly been hypothesized to represent such a key mechanism. We performed a comparative analysis of gene expression by means of microarray experiments with American and European eel leptocephali collected in the Sargasso Sea in order to test the alternative hypotheses of (1) differential timing of gene expression regulation during early development versus (2) species-specific differences in expression of particular genes. Our results provide much stronger support for the former hypothesis since no gene showed consistent significant differences in expression levels between the two species. In contrast, 146 genes showed differential timings of expression between species, although the observed expression level differences between the species were generally small. Consequently, species-specific gene expression regulation seems to play a minor role in species differentiation. Overall, these results show that the basis of the early developmental divergence between the American and European eel is probably influenced by differences in the timing of gene expression regulation for genes involved in a large array of biological functions.
2011-12-01T00:00:00Z
Bernatchez, Louis
St-Cyr, Jerome
Normandeau, Eric
Maes, Gregory
Als, Thomas
Kalujnaia, Svetlana
Cramb, Gordon
Castonguay, Martin
Hansen, Michael
The unique life-history characteristics of North Atlantic catadromous eels have long intrigued evolutionary biologists, especially with respect to mechanisms that could explain their persistence as two ecologically very similar but reproductively and geographically distinct species. Differential developmental schedules during young larval stages have commonly been hypothesized to represent such a key mechanism. We performed a comparative analysis of gene expression by means of microarray experiments with American and European eel leptocephali collected in the Sargasso Sea in order to test the alternative hypotheses of (1) differential timing of gene expression regulation during early development versus (2) species-specific differences in expression of particular genes. Our results provide much stronger support for the former hypothesis since no gene showed consistent significant differences in expression levels between the two species. In contrast, 146 genes showed differential timings of expression between species, although the observed expression level differences between the species were generally small. Consequently, species-specific gene expression regulation seems to play a minor role in species differentiation. Overall, these results show that the basis of the early developmental divergence between the American and European eel is probably influenced by differences in the timing of gene expression regulation for genes involved in a large array of biological functions.
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Fluorescence suppression using wavelength modulated Raman spectroscopy in fiber-probe-based tissue analysis
https://hdl.handle.net/10023/3303
In the field of biomedical optics, Raman spectroscopy is a powerful tool for probing the chemical composition of biological samples. In particular, fiber Raman probes play a crucial role for in vivo and ex vivo tissue analysis. However, the high-fluorescence background typically contributed by the auto fluorescence from both a tissue sample and the fiber-probe interferes strongly with the relatively weak Raman signal. Here we demonstrate the implementation of wavelength-modulated Raman spectroscopy (WMRS) to suppress the fluorescence background while analyzing tissues using fiber Raman probes. We have observed a significant signal-to-noise ratio enhancement in the Raman bands of bone tissue, which have a relatively high fluorescence background. Implementation of WMRS in fiber-probe-based bone tissue study yielded usable Raman spectra in a relatively short acquisition time (∼30 s), notably without any special sample preparation stage. Finally, we have validated its capability to suppress fluorescence on other tissue samples such as adipose tissue derived from four different species.
The work was funded by CR-UK/EPSRC/MRC/DoH (England) imaging programme.
2012-07-09T00:00:00Z
Balagopal, Bavishna
Ashok, Praveen Cheriyan
Mazilu, Michael
Riches, Andrew Clive
Herrington, C Simon
Dholakia, Kishan
In the field of biomedical optics, Raman spectroscopy is a powerful tool for probing the chemical composition of biological samples. In particular, fiber Raman probes play a crucial role for in vivo and ex vivo tissue analysis. However, the high-fluorescence background typically contributed by the auto fluorescence from both a tissue sample and the fiber-probe interferes strongly with the relatively weak Raman signal. Here we demonstrate the implementation of wavelength-modulated Raman spectroscopy (WMRS) to suppress the fluorescence background while analyzing tissues using fiber Raman probes. We have observed a significant signal-to-noise ratio enhancement in the Raman bands of bone tissue, which have a relatively high fluorescence background. Implementation of WMRS in fiber-probe-based bone tissue study yielded usable Raman spectra in a relatively short acquisition time (∼30 s), notably without any special sample preparation stage. Finally, we have validated its capability to suppress fluorescence on other tissue samples such as adipose tissue derived from four different species.
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Camera-related behaviours of female dental nurses and nursery school children during fluoride varnish application interactions in nursery school settings
https://hdl.handle.net/10023/1851
Objective. To investigate camera awareness of female dental nurses and nursery school children as the frequency of camera-related behaviours observed during fluoride varnish applications in a community based health programme. Methods. Fifty-one nurse–child interactions (three nurse pairs and 51 children) were video recorded when Childsmile nurses were applying fluoride varnish onto the teeth of children in nursery school settings. Using a pre-developed coding scheme, nurse and child verbal and nonverbal behaviours were coded for camera-related behaviours. Results. On 15 of 51 interactions (29.4%), a total of 31 camera-related behaviours were observed for dental nurses (14 instances over nine interactions) and children (17 instances over six interactions). Camera-related behaviours occurred infrequently, occupied 0.3% of the total interaction time and displayed at all stages of the dental procedure, though tended to peak at initial stages. Conclusions. Certain camera-related behaviours of female dental nurses and nursery school children were observed in their interactions when introducing a dental health preventive intervention. Since the frequency of camera-related behaviours are so few they are of little consequence when video-recording adults and children undertaking dental procedures.
2010-09-01T00:00:00Z
Zhou, Yuefang
Forbes, Gillian Mackenzie
Humphris, Gerald Michael
Objective. To investigate camera awareness of female dental nurses and nursery school children as the frequency of camera-related behaviours observed during fluoride varnish applications in a community based health programme. Methods. Fifty-one nurse–child interactions (three nurse pairs and 51 children) were video recorded when Childsmile nurses were applying fluoride varnish onto the teeth of children in nursery school settings. Using a pre-developed coding scheme, nurse and child verbal and nonverbal behaviours were coded for camera-related behaviours. Results. On 15 of 51 interactions (29.4%), a total of 31 camera-related behaviours were observed for dental nurses (14 instances over nine interactions) and children (17 instances over six interactions). Camera-related behaviours occurred infrequently, occupied 0.3% of the total interaction time and displayed at all stages of the dental procedure, though tended to peak at initial stages. Conclusions. Certain camera-related behaviours of female dental nurses and nursery school children were observed in their interactions when introducing a dental health preventive intervention. Since the frequency of camera-related behaviours are so few they are of little consequence when video-recording adults and children undertaking dental procedures.
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Hypotension in obstetric spinal anaesthesia: a lesson from pre-eclampsia
https://hdl.handle.net/10023/1823
Editorial; Part of the Portfolio Thesis by Geoffrey H. Sharwood-Smith: The inferior vena caval compression theory of hypotension in obstetric spinal anaesthesia: studies in normal and preeclamptic pregnancy, a literature review and revision of fundamental concepts, available at http://hdl.handle.net/10023/1815
2009-03-01T00:00:00Z
Sharwood-Smith, Geoffrey H.
Drummond, G. B.
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Assessment of pulse transit time to indicate cardiovascular changes during obstetric spinal anaesthesia
https://hdl.handle.net/10023/1822
Background. Pulse transit time (PTT) measurement may provide rapidly available beat-to-beat cardiovascular information when conditions change quickly and routine invasive arterial pressure measurement is not justified, for example during obstetric spinal anaesthesia.
Method. We obtained ethics approval for an observational study of PTT during the onset of spinal anaesthesia in patients having elective or urgent Caesarean section. PTT was measured as the difference in time between the peak of the ECG R wave and the upstroke of the toe plethysmograph. Arterial pressure was measured by non-invasive sphygmomanometry.
Results. We analysed data from 58 normotensive patients and 15 patients with pregnancy-induced hypertension (PIH). PTT increased with the onset of spinal anaesthesia as arterial pressure decreased. An increase of 20% in PTT was 74% sensitive and 70% specific in indicating a decrease in mean arterial pressure of more than 10%. Changes in PTT were related to changes in mean arterial pressure (r2=0.55, P<0.0001). Arterial pressure changes were greater and PTT increased significantly more quickly in the normotensive patients than in the patients with hypertension [median, quartiles: 32 (14, 56) ms min−1 compared with 7 (6, 18) ms min−1; P<0.01, Mann–Whitney U-test]. However, the relationship between PTT and arterial pressure was similar for the normotensive patients and the patients with PIH.
Conclusion. PTT measurement gave a beat-to-beat indication of arterial pressure during spinal anaesthesia, and could be developed to allow prediction of the onset of hypotension.
Part of the Portfolio Thesis by Geoffrey H. Sharwood-Smith: The inferior vena caval compression theory of hypotension in obstetric spinal anaesthesia: studies in normal and preeclamptic pregnancy, a literature review and revision of fundamental concepts, available at http://hdl.handle.net/10023/1815
2006-01-01T00:00:00Z
Sharwood-Smith, Geoffrey H.
Bruce, J.
Drummond, G.
Background. Pulse transit time (PTT) measurement may provide rapidly available beat-to-beat cardiovascular information when conditions change quickly and routine invasive arterial pressure measurement is not justified, for example during obstetric spinal anaesthesia.
Method. We obtained ethics approval for an observational study of PTT during the onset of spinal anaesthesia in patients having elective or urgent Caesarean section. PTT was measured as the difference in time between the peak of the ECG R wave and the upstroke of the toe plethysmograph. Arterial pressure was measured by non-invasive sphygmomanometry.
Results. We analysed data from 58 normotensive patients and 15 patients with pregnancy-induced hypertension (PIH). PTT increased with the onset of spinal anaesthesia as arterial pressure decreased. An increase of 20% in PTT was 74% sensitive and 70% specific in indicating a decrease in mean arterial pressure of more than 10%. Changes in PTT were related to changes in mean arterial pressure (r2=0.55, P<0.0001). Arterial pressure changes were greater and PTT increased significantly more quickly in the normotensive patients than in the patients with hypertension [median, quartiles: 32 (14, 56) ms min−1 compared with 7 (6, 18) ms min−1; P<0.01, Mann–Whitney U-test]. However, the relationship between PTT and arterial pressure was similar for the normotensive patients and the patients with PIH.
Conclusion. PTT measurement gave a beat-to-beat indication of arterial pressure during spinal anaesthesia, and could be developed to allow prediction of the onset of hypotension.
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Pulse transit time confirms altered response to spinal anaesthesia in pregnancy induced hypertension
https://hdl.handle.net/10023/1821
Poster presented at the International Society for the Study of Hypertension in Pregnancy (ISSHP)Congress, Toronto 2002.; Part of the Portfolio Thesis by Geoffrey H. Sharwood-Smith: The inferior vena caval compression theory of hypotension in obstetric spinal anaesthesia: studies in normal and preeclamptic pregnancy, a literature review and revision of fundamental concepts, available at http://hdl.handle.net/10023/1815
2002-01-01T00:00:00Z
Sharwood-Smith, Geoffrey H.
Drummond, G.
Bruce, J.
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Pulse transit time confirms altered haemodynamic response to spinal anaesthesia in pregnancy induced hypertension
https://hdl.handle.net/10023/1820
Original abstract presented at the International Society for the Study of Hypertension in Pregnancy (ISSHP)Congress, Toronto 2002 and published in the affiliated Journal 'Hypertension in Pregnancy'.; Part of the Portfolio Thesis by Geoffrey H. Sharwood-Smith: The inferior vena caval compression theory of hypotension in obstetric spinal anaesthesia: studies in normal and preeclamptic pregnancy, a literature review and revision of fundamental concepts, available at http://hdl.handle.net/10023/1815
2002-01-01T00:00:00Z
Sharwood-Smith, Geoffrey H.
Drummond, G.
Bruce, J.
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Pulse transit time: a new approach to haemodynamic monitoring in obstetric spinal anaesthesia
https://hdl.handle.net/10023/1819
Part of the Portfolio Thesis by Geoffrey H. Sharwood-Smith: The inferior vena caval compression theory of hypotension in obstetric spinal anaesthesia: studies in normal and preeclamptic pregnancy, a literature review and revision of fundamental concepts, available at http://hdl.handle.net/10023/1815; Original abstract presented at the Obstetric Anaesthetisits' Association congress 2002, Nottingham, 9-10 May.
2002-05-01T00:00:00Z
Bruce, J.
Sharwood-Smith, Geoffrey H.
Drummond, G.
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Ephedrine requirements are reduced during spinal anaesthesia for caesarean section in preeclampsia
https://hdl.handle.net/10023/1818
Background:
Despite controversy over the haemodynamically safest blockade for caesarean section in women with severe preeclampsia, an increasing number of anaesthetists now opt for spinal anaesthesia. In a previous study we found that spinal compared to epidural anaesthesia offered an equally safe but more effective option for these patients. The current study was designed to compare the hypotension induced by spinal anaesthesia, as measured by ephedrine requirement, between 20 normotensive and 20 severely preeclamptic but haemodynamically stabilised women.
Method:
Standardised spinal anaesthesia was instituted and ephedrine was given in boluses of 6 mg if the systolic pressure fell >20% from the baseline, or if the patient exhibited symptoms of hypotension.
Results:
The mean ephedrine requirement of the normotensive group (27.9 ± 11.6 mg) was significantly greater (P < 0.01) than that of the preeclamptic group (16.4 ± 15.0 mg).
Conclusion:
This suggests that the hypotension induced by spinal anaesthesia in women with severe but haemodynamically stabilised preeclampsia, is less than that of normotensive patients.
Part of the Portfolio Thesis by Geoffrey H. Sharwood-Smith: The inferior vena caval compression theory of hypotension in obstetric spinal anaesthesia: studies in normal and preeclamptic pregnancy, a literature review and revision of fundamental concepts, available at http://hdl.handle.net/10023/1815
2005-01-01T00:00:00Z
Clark, V. A.
Sharwood-Smith, Geoffrey H.
Stewart, A. V. G.
Background:
Despite controversy over the haemodynamically safest blockade for caesarean section in women with severe preeclampsia, an increasing number of anaesthetists now opt for spinal anaesthesia. In a previous study we found that spinal compared to epidural anaesthesia offered an equally safe but more effective option for these patients. The current study was designed to compare the hypotension induced by spinal anaesthesia, as measured by ephedrine requirement, between 20 normotensive and 20 severely preeclamptic but haemodynamically stabilised women.
Method:
Standardised spinal anaesthesia was instituted and ephedrine was given in boluses of 6 mg if the systolic pressure fell >20% from the baseline, or if the patient exhibited symptoms of hypotension.
Results:
The mean ephedrine requirement of the normotensive group (27.9 ± 11.6 mg) was significantly greater (P < 0.01) than that of the preeclamptic group (16.4 ± 15.0 mg).
Conclusion:
This suggests that the hypotension induced by spinal anaesthesia in women with severe but haemodynamically stabilised preeclampsia, is less than that of normotensive patients.
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Regional anaesthesia for caesarean section in severe preeclampsia: spinal anaesthesia is the preferred choice
https://hdl.handle.net/10023/1817
Standard textbooks advocate epidural rather than spinal anaesthesia for caesarean section in severe preeclampsia. The basis for this recommendation is the theoretical risk of severe hypotension but no published scientific studies have been identified to support this assertion. We therefore designed a prospective study to compare spinal versus epidural anaesthesia in severely pre-eclamptic patients requiring hypotensive therapy. Following ethics committee approval, 28 women with preeclampsia requiring hypotensive medication who were scheduled for urgent (not emergency) or elective caesarean section consented to receive epidural or spinal anaesthesia by random assignment. Seven patients were excluded due to protocol violations. Four of these were in the epidural group of which two were excluded due to inadequate analgesia. No spinal patient was excluded because of inadequate analgesia. Mean ephedrine dosage was 5.2 mg (range 0–24 mg) in the spinal group and 6.3 mg (range 0–27 mg) in the epidural group. Six of the 11 patients in the spinal group required no ephedrine as did five of 10 in the epidural group. One patient in the spinal group suffered from mild intraoperative pain. By contrast in the epidural group three patients had mild pain and four others had pain severe enough to warrant intraoperative analgesia. There were no differences in neonatal outcomes. These findings support recent studies suggesting the safety and efficacy of spinal anaesthesia in this group of patients.
Part of the Portfolio Thesis by Geoffrey H. Sharwood-Smith: The inferior vena caval compression theory of hypotension in obstetric spinal anaesthesia: studies in normal and preeclamptic pregnancy, a literature review and revision of fundamental concepts, available at http://hdl.handle.net/10023/1815
1999-04-01T00:00:00Z
Sharwood-Smith, Geoffrey H.
Clark, V.
Watson, E.
Standard textbooks advocate epidural rather than spinal anaesthesia for caesarean section in severe preeclampsia. The basis for this recommendation is the theoretical risk of severe hypotension but no published scientific studies have been identified to support this assertion. We therefore designed a prospective study to compare spinal versus epidural anaesthesia in severely pre-eclamptic patients requiring hypotensive therapy. Following ethics committee approval, 28 women with preeclampsia requiring hypotensive medication who were scheduled for urgent (not emergency) or elective caesarean section consented to receive epidural or spinal anaesthesia by random assignment. Seven patients were excluded due to protocol violations. Four of these were in the epidural group of which two were excluded due to inadequate analgesia. No spinal patient was excluded because of inadequate analgesia. Mean ephedrine dosage was 5.2 mg (range 0–24 mg) in the spinal group and 6.3 mg (range 0–27 mg) in the epidural group. Six of the 11 patients in the spinal group required no ephedrine as did five of 10 in the epidural group. One patient in the spinal group suffered from mild intraoperative pain. By contrast in the epidural group three patients had mild pain and four others had pain severe enough to warrant intraoperative analgesia. There were no differences in neonatal outcomes. These findings support recent studies suggesting the safety and efficacy of spinal anaesthesia in this group of patients.
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Identification of a novel class of mammalian phosphoinositol-specific phospholipase C enzymes.
https://hdl.handle.net/10023/956
Phosphoinositol (PhoIns)-specific phospholipase C enzymes (PLCs) are central to the inositol lipid signaling pathways and contribute to intracellular Ca2+ release and protein kinase C activation. Five distinct classes of PhoIns-specific PLCs are known to exist in mammals, which are activated by membrane receptor-mediated events. Here we have identified a sixth class of PhoIns-specific PLC with a novel domain structure, which we have termed PLC-eta. Two putative PLC-eta enzymes were identified in humans and in mice. Sequence analysis revealed that residues implicated in substrate binding and catalysis from other PhoIns-specific PLCs are conserved in the novel enzymes. PLC-eta enzymes are most closely related to the PLC-delta class and share a close evolutionary relationship with other PLC isozymes. EST analysis and RT-PCR data suggest that PLC-eta enzymes are expressed in several cell types and, by analogy with other mammalian PhoIns-specific PLCs, are likely to be involved in signal transduction pathways.
2005-01-01T00:00:00Z
Stewart, AJ
Mukherjee, J
Roberts, SJ
Lester, D
Farquharson, C
Phosphoinositol (PhoIns)-specific phospholipase C enzymes (PLCs) are central to the inositol lipid signaling pathways and contribute to intracellular Ca2+ release and protein kinase C activation. Five distinct classes of PhoIns-specific PLCs are known to exist in mammals, which are activated by membrane receptor-mediated events. Here we have identified a sixth class of PhoIns-specific PLC with a novel domain structure, which we have termed PLC-eta. Two putative PLC-eta enzymes were identified in humans and in mice. Sequence analysis revealed that residues implicated in substrate binding and catalysis from other PhoIns-specific PLCs are conserved in the novel enzymes. PLC-eta enzymes are most closely related to the PLC-delta class and share a close evolutionary relationship with other PLC isozymes. EST analysis and RT-PCR data suggest that PLC-eta enzymes are expressed in several cell types and, by analogy with other mammalian PhoIns-specific PLCs, are likely to be involved in signal transduction pathways.