The oceans are warming, but it is unclear how marine productivity will be affected under future c... more The oceans are warming, but it is unclear how marine productivity will be affected under future climate change. In this study we examined a wide range of paleo-productivity proxies along a latitudinal transect (36-58°S) in the SW Pacific during the early Holocene climatic optimum, to explore regional patterns of productivity in a slightly warmer-than present world. During the early Holocene there is a small increase in productivity in the subtropical waters, no change at the subtropical frontal zone, and conflicting evidence in records immediately south of the subtropical front, where an increase is inferred from one core site, but not at the other. Evidence for an increase in productivity in Antarctic Surface Waters south of the polar front, is also equivocal. We infer a small increase in productivity in subtropical waters and the ocean just south of the subtropical front was associated with changes in the ocean circulation of the SW Pacific, driven by changes in the Southern Hemisphere Westerly Winds split jet structure in this region. The relatively modest warming during the early Holocene climatic optimum in the SW Pacific indicates that this time period may provide an analogue for future productivity for the mid-century (2055) under IPCC Representative Concentration Pathway 8.5, or for the end of the century (2100) under Representative Concentration Pathway 4.5. However, higher resolution, down-scaled models, with realistic Southern Hemisphere Westerly Winds, will be necessary to forecast future productivity for this oceanographically complex region.
Fragile X Syndrome (FXS) is a learning disability seen in individuals who have >200 CGG †CCG repe... more Fragile X Syndrome (FXS) is a learning disability seen in individuals who have >200 CGG †CCG repeats in the 5 ′ untranslated region of the X-linked FMR1 gene. Such alleles are associated with a fragile site, FRAXA, a gap or constriction in the chromosome that is coincident with the repeat and is induced by folate stress or thymidylate synthase inhibitors like fluorodeoxyuridine (FdU). The molecular basis of the chromosome fragility is unknown. Previous work has suggested that the stable intrastrand structures formed by the repeat may be responsible, perhaps via their ability to block DNA synthesis. We have examined the replication dynamics of normal and FXS cells with and without FdU. We show here that an intrinsic problem with DNA replication exists in the FMR1 gene of individuals with FXS even in the absence of FdU. Our data suggest a model for chromosome fragility in FXS in which the repeat impairs replication from an origin of replication (ORI) immediately adjacent to the repeat. The fact that the replication problem occurs even in the absence of FdU suggests that this phenomenon may have in vivo consequences, including perhaps accounting for the loss of the X chromosome containing the fragile site that causes Turner syndrome (45, X0) in female carriers of such alleles. Our data on FRAXA may also be germane for the other FdU-inducible fragile sites in humans, that we show here share many common features with FRAXA.
1. 1. The green marine alga Enteromorpha intestinalis evolves dimethyl sulfide on removal from th... more 1. 1. The green marine alga Enteromorpha intestinalis evolves dimethyl sulfide on removal from the water. The precursor of the sulfide is dimethyl-β-propiothetin which has been isolated from the alga as the platinichloride, the picrate and the styphnate. 2. 2. The presence of a ...
A number of studies have begun to investigate the characteristics of cocaine abusers who are admi... more A number of studies have begun to investigate the characteristics of cocaine abusers who are admitted to outpatient cocaine treatment programs. One study has published success rates for such treatment. A review of this literature indicates that much of what is known is based on clinical experience with what may be nonrepresentative samples of upper-middle socioeconomic status Caucasians. More systematic study and more representative samples are needed; the current study attempts to address these issues by sampling 81 clients admitted to a comprehensive outpatient cocaine program in a public agency, assessing demographics and treatment success. The results indicate that this sample is indeed different from those in most recent studies in race, marital status, income, employment, and other demographic variables. For example, the sample in this study included higher percentages of clients who were non-Caucasians, single, blue-collar or unemployed, and had relatively lower annual incomes. Fewer demographic variables than expected correlated with treatment success. Among factors that did correlate with such measures of treatment outcome as continuing in treatment (vs dropping out), percent of sessions attended, and alcohol- and drug-free were educational level, length of abstinence from cocaine prior to beginning treatment, number of previous treatments, secondary substance currently used, and quality of current living situation. Retention in treatment is similar to other published data but indicates that cocaine abusers are indeed difficult to engage and keep in treatment long enough to make a significant impact on their drug use.
In clinical studies, treatment with subcutaneous interferon beta-1a (IFNβ-1a) has been shown to r... more In clinical studies, treatment with subcutaneous interferon beta-1a (IFNβ-1a) has been shown to reduce relapse rates and slow the progression of physical disability in patients with relapsing forms of multiple sclerosis (MS). A formulation of subcutaneous IFNβ-1a has been developed that is free of fetal bovine serum and human serum albumin. To evaluate (a) the impact on quality of life (QoL) and treatment satisfaction of transitioning from the original formulation of subcutaneous IFNβ-1a to the serum-free formulation in patients with relapsing forms of MS; and (b) the impact of dose titration versus non-titration during the transition on tolerability and patterns of analgesic use. QoL was measured by the Multiple Sclerosis Treatment Concerns Questionnaire Global Side Effects (GSE) score. Patients who had received the original formulation of IFNβ-1a subcutaneously for ≥24 weeks were randomized to receive the serum-free formulation of IFNβ-1a 44μg subcutaneously three times weekly for...
We contrast the pooling of multiple data sets with the compound HLOD (HLOD-C) and the posterior p... more We contrast the pooling of multiple data sets with the compound HLOD (HLOD-C) and the posterior probability of linkage (PPL), two approaches that have been shown to have more power in the presence of genetic heterogeneity. We also propose and evaluate several multipoint extensions.
For patients with multiple sclerosis (MS), electronic autoinjectors may improve convenience and r... more For patients with multiple sclerosis (MS), electronic autoinjectors may improve convenience and reduce discomfort associated with chronic injections. To assess ease of use, patient satisfaction, and functional reliability of an investigational electronic autoinjector for self-injection of subcutaneous interferon beta-1a (IFNβ-1a). This prospective, multicenter, open-label, single-arm, 12-week, Phase IIIb study enrolled patients aged 18-65 years with relapsing MS receiving IFNβ-1a 44μg subcutaneously 3 times weekly for ≥12 weeks before enrollment. Thereafter, patients continued their regimen using an electronic autoinjector. The primary endpoint was the proportion of patients rating the autoinjector 'easy to use' or 'very easy to use' on a User Trial Questionnaire at week 12. Secondary endpoints included patient responses to questions regarding device reliability, patient satisfaction, and convenience. Of 103 patients enrolled, 88 completed the study. The primary objective was met, with most patients (78%) indicating the device was 'easy to use' or 'very easy to use' at week 12 (worst-case imputation). In an analysis of secondary endpoints, over 60% of patients responded favorably to each of the User Trial questions regarding device ease-of-use and their satisfaction with the device. Overall convenience was judged the most important benefit of the device. Adverse events reported were consistent with the known safety profile of IFNβ-1a, with injection site reactions the most frequently reported. These data show that patients found the electronic autoinjector for delivery of subcutaneous IFNβ-1a reliable and easy to use, suggesting the device may help patients with relapsing MS to administer self-injections.
Background: LTC4 synthase is essential for the production of cysteinyl leukotrienes (Cys-LT), cri... more Background: LTC4 synthase is essential for the production of cysteinyl leukotrienes (Cys-LT), critical mediators in asthma. We have identified a novel promoter polymorphism at position -1072 (G/A) and a -444 (A/C) polymorphism has previously been reported. The role of these polymorphisms in the genetic susceptibility to asthma was examined. Methods: To test for genetic association with asthma phenotypes, 341 white families (two asthmatic siblings) and 184 non-asthmatic control subjects were genotyped. Genetic association was assessed using case control and transmission disequilibrium test (TDT) analyses. LTC4S promoter luciferase constructs and transiently transfected human HeLa and KU812F cells were generated to determine the functional role of these polymorphisms on basal transcription. Results: No associations were observed in case control analyses (-1072 A, q=0.09; -444 C, q=0.29); the TDT identified a borderline association between the -444 C allele and bronchial responsiveness to methacholine (p=0.065). Asthmatic children with the -444 C allele had a lower mean basal forced expiratory volume in 1 second (97.4 v 92.7% predicted, p=0.005). LTC4S promoter luciferase analyses provided no evidence for a functional role of either polymorphism in determining basal transcription. Conclusion: This study does not support a role for these polymorphisms in genetic susceptibility to asthma but provides evidence to suggest a role in determining lung function parameters.
The Journal of Strategic Information Systems, 1999
The Asian Economic Crisis presents perhaps a final opportunity for Australia's IT&T industry to m... more The Asian Economic Crisis presents perhaps a final opportunity for Australia's IT&T industry to make its presence felt on the world stage. As a centre of innovation and a desirable location for IT&T facilities, Australia has often been overlooked as its near neighbours to the north gain all the attention. This paper summarises the main obstacles Australia has to overcome in order to gain mind-share amongst the global IT&T supplier community. ᭧ Journal of Strategic Information Systems 8 (1999) 21-27 STRINF 1101 0963-8687/99/$ -see front matter ᭧
Patients with multiple sclerosis (MS) often receive long-term injectable therapy, and difficultie... more Patients with multiple sclerosis (MS) often receive long-term injectable therapy, and difficulties associated with self-injection can affect treatment adherence and efficacy. The objective of this study was to evaluate an investigational, ready-to-use, single-use autoinjector for self-injection of subcutaneous (sc) interferon beta-1a (IFNβ-1a). In this multicenter, open-label, single-arm study, patients with relapsing MS who were receiving IFNβ-1a sc 44 μg three times weekly for ≥ 12 weeks continued therapy using a single-use autoinjector and completed a user trial questionnaire at baseline and weeks 6 and 12. The primary endpoint was the proportion of patients rating the autoinjector as easy or very easy to use at week 12. At 12 weeks, 86% of 109 patients included in the intent-to-treat population rated the autoinjector easy or very easy to use (95% confidence interval, 80% - 93%), and the most important perceived benefit was its overall convenience. The majority (74%) of patients reported the device as somewhat or extremely convenient to use, and most (83%) agreed or strongly agreed that the device made injections simple. The single-use autoinjector was well received and supported by favorable ratings for simplified injections and convenience. The results suggest that the device may improve overall injection experience in patients with relapsing MS.
Random Forest is a prediction technique based on growing trees on bootstrap samples of data, in c... more Random Forest is a prediction technique based on growing trees on bootstrap samples of data, in conjunction with a random selection of explanatory variables to define the best split at each node. In the case of a quantitative outcome, the tree predictor takes on a numerical value. We applied Random Forest to the first replicate of the Genetic Analysis Workshop 13 simulated data set, with the sibling pairs as our units of analysis and identity by descent (IBD) at selected loci as our explanatory variables. With the knowledge of the true model, we performed two sets of analyses on three phenotypes: HDL, triglycerides, and glucose. The goal was to approach the mapping of complex traits from a multivariate perspective. The first set of analyses mimics a candidate gene approach with a high proportion of true genes among the predictors while the second set represents a genome scan analysis using microsatellite markers. Random Forest was able to identify a few of the major genes influencing the phenotypes, such as baseline HDL and triglycerides, but failed to identify the major genes regulating baseline glucose levels.
The oceans are warming, but it is unclear how marine productivity will be affected under future c... more The oceans are warming, but it is unclear how marine productivity will be affected under future climate change. In this study we examined a wide range of paleo-productivity proxies along a latitudinal transect (36-58°S) in the SW Pacific during the early Holocene climatic optimum, to explore regional patterns of productivity in a slightly warmer-than present world. During the early Holocene there is a small increase in productivity in the subtropical waters, no change at the subtropical frontal zone, and conflicting evidence in records immediately south of the subtropical front, where an increase is inferred from one core site, but not at the other. Evidence for an increase in productivity in Antarctic Surface Waters south of the polar front, is also equivocal. We infer a small increase in productivity in subtropical waters and the ocean just south of the subtropical front was associated with changes in the ocean circulation of the SW Pacific, driven by changes in the Southern Hemisphere Westerly Winds split jet structure in this region. The relatively modest warming during the early Holocene climatic optimum in the SW Pacific indicates that this time period may provide an analogue for future productivity for the mid-century (2055) under IPCC Representative Concentration Pathway 8.5, or for the end of the century (2100) under Representative Concentration Pathway 4.5. However, higher resolution, down-scaled models, with realistic Southern Hemisphere Westerly Winds, will be necessary to forecast future productivity for this oceanographically complex region.
Fragile X Syndrome (FXS) is a learning disability seen in individuals who have >200 CGG †CCG repe... more Fragile X Syndrome (FXS) is a learning disability seen in individuals who have >200 CGG †CCG repeats in the 5 ′ untranslated region of the X-linked FMR1 gene. Such alleles are associated with a fragile site, FRAXA, a gap or constriction in the chromosome that is coincident with the repeat and is induced by folate stress or thymidylate synthase inhibitors like fluorodeoxyuridine (FdU). The molecular basis of the chromosome fragility is unknown. Previous work has suggested that the stable intrastrand structures formed by the repeat may be responsible, perhaps via their ability to block DNA synthesis. We have examined the replication dynamics of normal and FXS cells with and without FdU. We show here that an intrinsic problem with DNA replication exists in the FMR1 gene of individuals with FXS even in the absence of FdU. Our data suggest a model for chromosome fragility in FXS in which the repeat impairs replication from an origin of replication (ORI) immediately adjacent to the repeat. The fact that the replication problem occurs even in the absence of FdU suggests that this phenomenon may have in vivo consequences, including perhaps accounting for the loss of the X chromosome containing the fragile site that causes Turner syndrome (45, X0) in female carriers of such alleles. Our data on FRAXA may also be germane for the other FdU-inducible fragile sites in humans, that we show here share many common features with FRAXA.
1. 1. The green marine alga Enteromorpha intestinalis evolves dimethyl sulfide on removal from th... more 1. 1. The green marine alga Enteromorpha intestinalis evolves dimethyl sulfide on removal from the water. The precursor of the sulfide is dimethyl-β-propiothetin which has been isolated from the alga as the platinichloride, the picrate and the styphnate. 2. 2. The presence of a ...
A number of studies have begun to investigate the characteristics of cocaine abusers who are admi... more A number of studies have begun to investigate the characteristics of cocaine abusers who are admitted to outpatient cocaine treatment programs. One study has published success rates for such treatment. A review of this literature indicates that much of what is known is based on clinical experience with what may be nonrepresentative samples of upper-middle socioeconomic status Caucasians. More systematic study and more representative samples are needed; the current study attempts to address these issues by sampling 81 clients admitted to a comprehensive outpatient cocaine program in a public agency, assessing demographics and treatment success. The results indicate that this sample is indeed different from those in most recent studies in race, marital status, income, employment, and other demographic variables. For example, the sample in this study included higher percentages of clients who were non-Caucasians, single, blue-collar or unemployed, and had relatively lower annual incomes. Fewer demographic variables than expected correlated with treatment success. Among factors that did correlate with such measures of treatment outcome as continuing in treatment (vs dropping out), percent of sessions attended, and alcohol- and drug-free were educational level, length of abstinence from cocaine prior to beginning treatment, number of previous treatments, secondary substance currently used, and quality of current living situation. Retention in treatment is similar to other published data but indicates that cocaine abusers are indeed difficult to engage and keep in treatment long enough to make a significant impact on their drug use.
In clinical studies, treatment with subcutaneous interferon beta-1a (IFNβ-1a) has been shown to r... more In clinical studies, treatment with subcutaneous interferon beta-1a (IFNβ-1a) has been shown to reduce relapse rates and slow the progression of physical disability in patients with relapsing forms of multiple sclerosis (MS). A formulation of subcutaneous IFNβ-1a has been developed that is free of fetal bovine serum and human serum albumin. To evaluate (a) the impact on quality of life (QoL) and treatment satisfaction of transitioning from the original formulation of subcutaneous IFNβ-1a to the serum-free formulation in patients with relapsing forms of MS; and (b) the impact of dose titration versus non-titration during the transition on tolerability and patterns of analgesic use. QoL was measured by the Multiple Sclerosis Treatment Concerns Questionnaire Global Side Effects (GSE) score. Patients who had received the original formulation of IFNβ-1a subcutaneously for ≥24 weeks were randomized to receive the serum-free formulation of IFNβ-1a 44μg subcutaneously three times weekly for...
We contrast the pooling of multiple data sets with the compound HLOD (HLOD-C) and the posterior p... more We contrast the pooling of multiple data sets with the compound HLOD (HLOD-C) and the posterior probability of linkage (PPL), two approaches that have been shown to have more power in the presence of genetic heterogeneity. We also propose and evaluate several multipoint extensions.
For patients with multiple sclerosis (MS), electronic autoinjectors may improve convenience and r... more For patients with multiple sclerosis (MS), electronic autoinjectors may improve convenience and reduce discomfort associated with chronic injections. To assess ease of use, patient satisfaction, and functional reliability of an investigational electronic autoinjector for self-injection of subcutaneous interferon beta-1a (IFNβ-1a). This prospective, multicenter, open-label, single-arm, 12-week, Phase IIIb study enrolled patients aged 18-65 years with relapsing MS receiving IFNβ-1a 44μg subcutaneously 3 times weekly for ≥12 weeks before enrollment. Thereafter, patients continued their regimen using an electronic autoinjector. The primary endpoint was the proportion of patients rating the autoinjector 'easy to use' or 'very easy to use' on a User Trial Questionnaire at week 12. Secondary endpoints included patient responses to questions regarding device reliability, patient satisfaction, and convenience. Of 103 patients enrolled, 88 completed the study. The primary objective was met, with most patients (78%) indicating the device was 'easy to use' or 'very easy to use' at week 12 (worst-case imputation). In an analysis of secondary endpoints, over 60% of patients responded favorably to each of the User Trial questions regarding device ease-of-use and their satisfaction with the device. Overall convenience was judged the most important benefit of the device. Adverse events reported were consistent with the known safety profile of IFNβ-1a, with injection site reactions the most frequently reported. These data show that patients found the electronic autoinjector for delivery of subcutaneous IFNβ-1a reliable and easy to use, suggesting the device may help patients with relapsing MS to administer self-injections.
Background: LTC4 synthase is essential for the production of cysteinyl leukotrienes (Cys-LT), cri... more Background: LTC4 synthase is essential for the production of cysteinyl leukotrienes (Cys-LT), critical mediators in asthma. We have identified a novel promoter polymorphism at position -1072 (G/A) and a -444 (A/C) polymorphism has previously been reported. The role of these polymorphisms in the genetic susceptibility to asthma was examined. Methods: To test for genetic association with asthma phenotypes, 341 white families (two asthmatic siblings) and 184 non-asthmatic control subjects were genotyped. Genetic association was assessed using case control and transmission disequilibrium test (TDT) analyses. LTC4S promoter luciferase constructs and transiently transfected human HeLa and KU812F cells were generated to determine the functional role of these polymorphisms on basal transcription. Results: No associations were observed in case control analyses (-1072 A, q=0.09; -444 C, q=0.29); the TDT identified a borderline association between the -444 C allele and bronchial responsiveness to methacholine (p=0.065). Asthmatic children with the -444 C allele had a lower mean basal forced expiratory volume in 1 second (97.4 v 92.7% predicted, p=0.005). LTC4S promoter luciferase analyses provided no evidence for a functional role of either polymorphism in determining basal transcription. Conclusion: This study does not support a role for these polymorphisms in genetic susceptibility to asthma but provides evidence to suggest a role in determining lung function parameters.
The Journal of Strategic Information Systems, 1999
The Asian Economic Crisis presents perhaps a final opportunity for Australia's IT&T industry to m... more The Asian Economic Crisis presents perhaps a final opportunity for Australia's IT&T industry to make its presence felt on the world stage. As a centre of innovation and a desirable location for IT&T facilities, Australia has often been overlooked as its near neighbours to the north gain all the attention. This paper summarises the main obstacles Australia has to overcome in order to gain mind-share amongst the global IT&T supplier community. ᭧ Journal of Strategic Information Systems 8 (1999) 21-27 STRINF 1101 0963-8687/99/$ -see front matter ᭧
Patients with multiple sclerosis (MS) often receive long-term injectable therapy, and difficultie... more Patients with multiple sclerosis (MS) often receive long-term injectable therapy, and difficulties associated with self-injection can affect treatment adherence and efficacy. The objective of this study was to evaluate an investigational, ready-to-use, single-use autoinjector for self-injection of subcutaneous (sc) interferon beta-1a (IFNβ-1a). In this multicenter, open-label, single-arm study, patients with relapsing MS who were receiving IFNβ-1a sc 44 μg three times weekly for ≥ 12 weeks continued therapy using a single-use autoinjector and completed a user trial questionnaire at baseline and weeks 6 and 12. The primary endpoint was the proportion of patients rating the autoinjector as easy or very easy to use at week 12. At 12 weeks, 86% of 109 patients included in the intent-to-treat population rated the autoinjector easy or very easy to use (95% confidence interval, 80% - 93%), and the most important perceived benefit was its overall convenience. The majority (74%) of patients reported the device as somewhat or extremely convenient to use, and most (83%) agreed or strongly agreed that the device made injections simple. The single-use autoinjector was well received and supported by favorable ratings for simplified injections and convenience. The results suggest that the device may improve overall injection experience in patients with relapsing MS.
Random Forest is a prediction technique based on growing trees on bootstrap samples of data, in c... more Random Forest is a prediction technique based on growing trees on bootstrap samples of data, in conjunction with a random selection of explanatory variables to define the best split at each node. In the case of a quantitative outcome, the tree predictor takes on a numerical value. We applied Random Forest to the first replicate of the Genetic Analysis Workshop 13 simulated data set, with the sibling pairs as our units of analysis and identity by descent (IBD) at selected loci as our explanatory variables. With the knowledge of the true model, we performed two sets of analyses on three phenotypes: HDL, triglycerides, and glucose. The goal was to approach the mapping of complex traits from a multivariate perspective. The first set of analyses mimics a candidate gene approach with a high proportion of true genes among the predictors while the second set represents a genome scan analysis using microsatellite markers. Random Forest was able to identify a few of the major genes influencing the phenotypes, such as baseline HDL and triglycerides, but failed to identify the major genes regulating baseline glucose levels.
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Papers by B. Hayward