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Search Results: 1 - 10 of 339890 matches for " David J. Templeton "
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Trends in detectable viral load by calendar year in the Australian HIV observational database
Law Matthew G,Woolley Ian,Templeton David J,Roth Norm
Journal of the International AIDS Society , 2011, DOI: 10.1186/1758-2652-14-10
Abstract: Background Recent papers have suggested that expanded combination antiretroviral treatment (cART) through lower viral load may be a strategy to reduce HIV transmission at a population level. We assessed calendar trends in detectable viral load in patients recruited to the Australian HIV Observational Database who were receiving cART. Methods Patients were included in analyses if they had started cART (defined as three or more antiretrovirals) and had at least one viral load assessment after 1 January 1997. We analyzed detectable viral load (>400 copies/ml) in the first and second six months of each calendar year while receiving cART. Repeated measures logistic regression methods were used to account for within and between patient variability. Rates of detectable viral load were predicted allowing for patients lost to follow up. Results Analyses were based on 2439 patients and 31,339 viral load assessments between 1 January 1997 and 31 March 2009. Observed detectable viral load in patients receiving cART declined to 5.3% in the first half of 2009. Predicted detectable viral load based on multivariate models, allowing for patient loss to follow up, also declined over time, but at higher levels, to 13.8% in 2009. Conclusions Predicted detectable viral load in Australian HIV Observational Database patients receiving cART declined over calendar time, albeit at higher levels than observed. However, over this period, HIV diagnoses and estimated HIV incidence increased in Australia.
The Significance of HIV ‘Blips’ in Resource-Limited Settings: Is It the Same? Analysis of the Treat Asia HIV Observational Database (TAHOD) and the Australian HIV Observational Database (AHOD)
Rupa Kanapathipillai, Hamish McManus, Adeeba Kamarulzaman, Poh Lian Lim, David J. Templeton, Matthew Law, Ian Woolley
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0086122
Abstract: Introduction Magnitude and frequency of HIV viral load blips in resource-limited settings, has not previously been assessed. This study was undertaken in a cohort from a high income country (Australia) known as AHOD (Australian HIV Observational Database) and another cohort from a mixture of Asian countries of varying national income per capita, TAHOD (TREAT Asia HIV Observational Database). Methods Blips were defined as detectable VL (≥ 50 copies/mL) preceded and followed by undetectable VL (<50 copies/mL). Virological failure (VF) was defined as two consecutive VL ≥50 copies/ml. Cox proportional hazard models of time to first VF after entry, were developed. Results 5040 patients (AHOD n = 2597 and TAHOD n = 2521) were included; 910 (18%) of patients experienced blips. 744 (21%) and 166 (11%) of high- and middle/low-income participants, respectively, experienced blips ever. 711 (14%) experienced blips prior to virological failure. 559 (16%) and 152 (10%) of high- and middle/low-income participants, respectively, experienced blips prior to virological failure. VL testing occurred at a median frequency of 175 and 91 days in middle/low- and high-income sites, respectively. Longer time to VF occurred in middle/low income sites, compared with high-income sites (adjusted hazards ratio (AHR) 0.41; p<0.001), adjusted for year of first cART, Hepatitis C co-infection, cART regimen, and prior blips. Prior blips were not a significant predictor of VF in univariate analysis (AHR 0.97, p = 0.82). Differing magnitudes of blips were not significant in univariate analyses as predictors of virological failure (p = 0.360 for blip 50–≤1000, p = 0.309 for blip 50–≤400 and p = 0.300 for blip 50–≤200). 209 of 866 (24%) patients were switched to an alternate regimen in the setting of a blip. Conclusion Despite a lower proportion of blips occurring in low/middle-income settings, no significant difference was found between settings. Nonetheless, a substantial number of participants were switched to alternative regimens in the setting of blips.
Extended Adjuvant Tamoxifen for Early Breast Cancer: A Meta-Analysis
Mustafa Al-Mubarak, Ariadna Tibau, Arnoud J. Templeton, David W. Cescon, Alberto Ocana, Bostjan Seruga, Eitan Amir
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0088238
Abstract: Background Hormone receptor positive breast cancer is characterized by the potential for disease recurrence many years after initial diagnosis. Endocrine therapy has been shown to reduce the risk of such recurrence, but the optimal duration of endocrine therapy remains unclear. Methods We conducted a systematic review and meta-analysis to quantify the benefits and harms of extended adjuvant tamoxifen (>5 years of therapy) compared with adjuvant tamoxifen (5 years of therapy). Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for disease recurrence, death and adverse events. Subgroup analyses by timing of recurrence and baseline lymph node and menopause status were carried. Results Five trials comprising 21,554 patients were included. Extended adjuvant tamoxifen was not associated with a significant reduction in the risk of recurrence (OR:0.89, 95% CI 0.76–1.05, p = 0.17). There was no association between extended adjuvant tamoxifen and all-cause death (OR:0.99, 95% CI 0.84–1.16, p = 0.88). There was an apparent reduction in risk of recurrence occurring after completion of extended adjuvant tamoxifen with little evidence of effect during therapy, however, this difference was not significant (p for difference 0.10). Subgroup analysis suggested that a greater effect size among lymph node positive patients compared with those who are lymph node negative (NNT: 25 vs. 49). There was no apparent difference in the effect between pre- and post-menopausal patients. Endometrial carcinoma was substantially more frequent with extended adjuvant tamoxifen (OR:2.06, 95% CI 1.65–2.58, p<0.001, number needed to harm:89). Conclusion In unselected patients, extended adjuvant tamoxifen is not associated with a significant reduction in recurrence, or a reduction in all-cause death. Patients with lymph node positive breast cancer may derive some benefit. Reduction in the risk of recurrence appears to occur only after completion of extended adjuvant therapy.
The Relationship between Water, Sanitation and Schistosomiasis: A Systematic Review and Meta-analysis
Jack E. T. Grimes ,David Croll,Wendy E. Harrison,Jürg Utzinger,Matthew C. Freeman,Michael R. Templeton
PLOS Neglected Tropical Diseases , 2014, DOI: 10.1371/journal.pntd.0003296
Abstract: Background Access to “safe” water and “adequate” sanitation are emphasized as important measures for schistosomiasis control. Indeed, the schistosomes' lifecycles suggest that their transmission may be reduced through safe water and adequate sanitation. However, the evidence has not previously been compiled in a systematic review. Methodology We carried out a systematic review and meta-analysis of studies reporting schistosome infection rates in people who do or do not have access to safe water and adequate sanitation. PubMed, Web of Science, Embase, and the Cochrane Library were searched from inception to 31 December 2013, without restrictions on year of publication or language. Studies' titles and abstracts were screened by two independent assessors. Papers deemed of interest were read in full and appropriate studies included in the meta-analysis. Publication bias was assessed through the visual inspection of funnel plots and through Egger's test. Heterogeneity of datasets within the meta-analysis was quantified using Higgins' I2. Principal Findings Safe water supplies were associated with significantly lower odds of schistosomiasis (odds ratio (OR) = 0.53, 95% confidence interval (CI): 0.47–0.61). Adequate sanitation was associated with lower odds of Schistosoma mansoni, (OR = 0.59, 95% CI: 0.47–0.73) and Schistosoma haematobium (OR = 0.69, 95% CI: 0.57–0.84). Included studies were mainly cross-sectional and quality was largely poor. Conclusions/Significance Our systematic review and meta-analysis suggests that increasing access to safe water and adequate sanitation are important measures to reduce the odds of schistosome infection. However, most of the studies were observational and quality was poor. Hence, there is a pressing need for adequately powered cluster randomized trials comparing schistosome infection risk with access to safe water and adequate sanitation, more studies which rigorously define water and sanitation, and new research on the relationships between water, sanitation, hygiene, human behavior, and schistosome transmission.
Using population attributable risk to choose HIV prevention strategies in men who have sex with men
Rebecca J Guy, Handan Wand, David P Wilson, Garrett Prestage, Fengyi Jin, David J Templeton, Basil Donovan, Andrew E Grulich, John M Kaldor
BMC Public Health , 2011, DOI: 10.1186/1471-2458-11-247
Abstract: Proportional hazard analyses were used to examine the association between sexual behaviours in the last six months and sexually transmissible infections on HIV incidence in a cohort of 1426 HIV-negative MSM who were recruited primarily from community-based sources between 2001 and 2004 and followed to mid-2007. We then estimated the proportion of HIV infections that would be prevented if specific factors were no longer present in the population, using a population attributable risk (PAR) method which controls for confounding among factors. We also calculated the average lifetime healthcare costs incurred by the HIV infections associated with specific factors by estimating costs associated with clinical care and treatment following infection and discounting at 3% (1% and 5% sensitivity) to present value.Unprotected anal intercourse (UAI) with a known HIV-positive partner was reported by 5% of men, the hazard ratio (HR) was 16.1 (95%CI:6.4-40.5), the PAR was 34% (95%CI:24-44%) and the average lifetime HIV-related healthcare costs attributable to UAI with HIV-positive partners were $AUD102 million (uncertainty range: $93-114 m). UAI with unknown HIV status partners was reported by 25% of men, the HR was 4.4 (95%CI:1.8-11.2), the PAR was 33% (95%CI:26-42%) and the lifetime incurred costs were $AUD99 million. Anal warts prevalence was 4%, the HR was 5.2 (95%CI:2.4-11.2), the PAR was 13% (95%CI:9-19%) and the lifetime incurred costs were $AUD39 million.Our analysis has found that although UAI with an HIV-positive sexual partner is a relatively low-prevalence behaviour (reported by 5% of men), if this behaviour was not present in the population, the number of infections would be reduced by one third. No other single behaviour or sexually transmissible infections contributes to a greater proportion of infections and HIV-related healthcare costs.In Australia, there were 1050 new cases of HIV diagnosed in 2009, bringing the estimated number of people living with HIV infection
Model Reduction with MapReduce-enabled Tall-and-Skinny Singular Value Decomposition
Paul G. Constantine,David F. Gleich,Yangyang Hou,Jeremy Templeton
Mathematics , 2013, DOI: 10.1137/130925219
Abstract: We present a method for computing reduced-order models of parameterized partial differential equation solutions. The key analytical tool is the singular value expansion of the parameterized solution, which we approximate with a singular value decomposition of a parameter snapshot matrix. To evaluate the reduced-order model at a new parameter, we interpolate a subset of the right singular vectors to generate the reduced-order model's coefficients. We employ a novel method to select this subset that uses the parameter gradient of the right singular vectors to split the terms in the expansion yielding a mean prediction and a prediction covariance---similar to a Gaussian process approximation. The covariance serves as a confidence measure for the reduce order model. We demonstrate the efficacy of the reduced-order model using a parameter study of heat transfer in random media. The high-fidelity simulations produce more than 4TB of data; we compute the singular value decomposition and evaluate the reduced-order model using scalable MapReduce/Hadoop implementations. We compare the accuracy of our method with a scalar response surface on a set of temperature profile measurements and find that our model better captures sharp, local features in the parameter space.
Compressed Sensing and Reconstruction of Unstructured Mesh Datasets
Maher Salloum,Nathan Fabian,David M. Hensinger,Jeremy A. Templeton
Mathematics , 2015,
Abstract: Exascale computing promises quantities of data too large to efficiently store and transfer across networks in order to be able to analyze and visualize the results. We investigate Compressive Sensing (CS) as a way to reduce the size of the data as it is being stored. CS works by sampling the data on the computational cluster within an alternative function space such as wavelet bases, and then reconstructing back to the original space on visualization platforms. While much work has gone into exploring CS on structured data sets, such as image data, we investigate its usefulness for point clouds such as unstructured mesh datasets found in many finite element simulations. We sample using second generation wavelets (SGW) and reconstruct using the Stagewise Orthogonal Matching Pursuit (StOMP) algorithm. We analyze the compression ratios achievable and quality of reconstructed results at each compression rate. We are able to achieve compression ratios between 10 and 30 on moderate size datasets with minimal visual deterioration as a result of the lossy compression.
The Use of the S-MART Tourniquet in Hand Surgery: A Safe and Effective Way to Provide a Bloodless Field
O. Templeton-Ward,J. Feher,P. Davey
Surgery Research and Practice , 2014, DOI: 10.1155/2014/402184
Abstract: We have retrospectively reviewed our use of the S-MART sterile silicon ring self-exsanguinating tourniquet in 300 consecutive minor hand surgical procedures. A total of 3 postoperative complications were identified, only 1 of which was directly related to the tourniquet’s use. We outline the reasons of why we feel that this device provides a safe and effective bloodless field and the benefits of its use. 1. Introduction The S-MART tourniquet (OHK Medical Devices, Newark, NJ) is a novel single-use tourniquet, which provides exsanguination of the limb, arterial occlusion, and application of sterile stockinet in one device. Its use in extremity surgery has been documented, but the largest series to date has been 51 patients [1, 2]. The S-MART tourniquet works by virtue of a core silicon ring which provides the pressure required to expel luminal blood during application and maintain arterial occlusion throughout the procedure once in situ. This ring is wrapped in sterile stockinet with pull handles attached to facilitate application. Figure 1 shows a cross section of the S-MART and Figure 2 shows its application. Figure 1: Cross section of the S-MART tourniquet. Figure 2: S-MART after application. In a recent article, Noordin et al. [3] criticized the use of nonpneumatic ring type tourniquets such as the S-MART in nonbattlefield settings claiming that their use may increase the occurrence of tourniquet-related adverse events. The article discussed two particular adverse events: tourniquet-related nerve injury and skin blistering. We have been using the S-MART tourniquet for all appropriate hand and wrist procedures in our day surgery department for a number of years; anecdotally we have not noticed any increase in the complications suggested by Noordin et al. and thus felt it would be worthwhile to review a cohort of patients to ensure this was the case; we report our experience. 2. Methods Our cohort included the last 300 patients undergoing one of the 4 most common procedures in our department: carpal tunnel decompression, De Quervain’s decompression, trigger finger release, and ganglion excision with a minimum of 6-month follow-up (prior to January 2010). Exclusion criteria were incomplete notes, no documented postoperative follow-up, inability to use S-MART tourniquet (limb circumference too great), and preexisting soft tissue damage or neurological lesion (other than carpal tunnel syndrome) affecting the limb concerned. All procedures were carried out under the supervision of the senior author (P. Davey); 50 patients were excluded (47 missing or
Phase I Clinical Trial of Systemically Administered TUSC2(FUS1)-Nanoparticles Mediating Functional Gene Transfer in Humans
Charles Lu, David J. Stewart, J. Jack Lee, Lin Ji, Rajagopal Ramesh, Gitanjali Jayachandran, Maria I. Nunez, Ignacio I. Wistuba, Jeremy J. Erasmus, Marshall E. Hicks, Elizabeth A. Grimm, James M. Reuben, Veerabhadran Baladandayuthapani, Nancy S. Templeton, John D. McMannis, Jack A. Roth
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034833
Abstract: Background Tumor suppressor gene TUSC2/FUS1 (TUSC2) is frequently inactivated early in lung cancer development. TUSC2 mediates apoptosis in cancer cells but not normal cells by upregulation of the intrinsic apoptotic pathway. No drug strategies currently exist targeting loss-of–function genetic abnormalities. We report the first in-human systemic gene therapy clinical trial of tumor suppressor gene TUSC2. Methods Patients with recurrent and/or metastatic lung cancer previously treated with platinum-based chemotherapy were treated with escalating doses of intravenous N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTAP):cholesterol nanoparticles encapsulating a TUSC2 expression plasmid (DOTAP:chol-TUSC2) every 3 weeks. Results Thirty-one patients were treated at 6 dose levels (range 0.01 to 0.09 milligrams per kilogram). The MTD was determined to be 0.06 mg/kg. Five patients achieved stable disease (2.6–10.8 months, including 2 minor responses). One patient had a metabolic response on positron emission tomography (PET) imaging. RT-PCR analysis detected TUSC2 plasmid expression in 7 of 8 post-treatment tumor specimens but not in pretreatment specimens and peripheral blood lymphocyte controls. Proximity ligation assay, performed on paired biopsies from 3 patients, demonstrated low background TUSC2 protein staining in pretreatment tissues compared with intense (10–25 fold increase) TUSC2 protein staining in post-treatment tissues. RT-PCR gene expression profiling analysis of apoptotic pathway genes in two patients with high post-treatment levels of TUSC2 mRNA and protein showed significant post-treatment changes in the intrinsic apoptotic pathway. Twenty-nine genes of the 82 tested in the apoptosis array were identified by Igenuity Pathway Analysis to be significantly altered post-treatment in both patients (Pearson correlation coefficient 0.519; p<0.01). Conclusions DOTAP:chol-TUSC2 can be safely administered intravenously in lung cancer patients and results in uptake of the gene by human primary and metastatic tumors, transgene and gene product expression, specific alterations in TUSC2-regulated pathways, and anti-tumor effects (to our knowledge for the first time for systemic DOTAP:cholesterol nanoparticle gene therapy). Trial Registration ClinicalTrials.gov NCT00059605
PDX-1 Is a Therapeutic Target for Pancreatic Cancer, Insulinoma and Islet Neoplasia Using a Novel RNA Interference Platform
Shi-He Liu, Donald D. Rao, John Nemunaitis, Neil Senzer, Guisheng Zhou, David Dawson, Marie-Claude Gingras, Zhaohui Wang, Richard Gibbs, Michael Norman, Nancy S. Templeton, Francesco J. DeMayo, Bert O'Malley, Robbi Sanchez, William E. Fisher, F. Charles Brunicardi
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0040452
Abstract: Pancreatic and duodenal homeobox-1 (PDX-1) is a transcription factor that regulates insulin expression and islet maintenance in the adult pancreas. Our recent studies demonstrate that PDX-1 is an oncogene for pancreatic cancer and is overexpressed in pancreatic cancer. The purpose of this study was to demonstrate that PDX-1 is a therapeutic target for both hormonal symptoms and tumor volume in mouse models of pancreatic cancer, insulinoma and islet neoplasia. Immunohistochemistry of human pancreatic and islet neoplasia specimens revealed marked PDX-1 overexpression, suggesting PDX-1 as a “drugable” target within these diseases. To do so, a novel RNA interference effector platform, bifunctional shRNAPDX-1, was developed and studied in mouse and human cell lines as well as in mouse models of pancreatic cancer, insulinoma and islet neoplasia. Systemic delivery of bi-shRNAhumanPDX-1 lipoplexes resulted in marked reduction of tumor volume and improved survival in a human pancreatic cancer xenograft mouse model. bi-shRNAmousePDX-1 lipoplexes prevented death from hyperinsulinemia and hypoglycemia in an insulinoma mouse model. shRNAmousePDX-1 lipoplexes reversed hyperinsulinemia and hypoglycemia in an immune-competent mouse model of islet neoplasia. PDX-1 was overexpressed in pancreatic neuroendocrine tumors and nesidioblastosis. These data demonstrate that PDX-1 RNAi therapy controls hormonal symptoms and tumor volume in mouse models of pancreatic cancer, insulinoma and islet neoplasia, therefore, PDX-1 is a potential therapeutic target for these pancreatic diseases.
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