Therapy Insight: Parenteral Estrogen treatment for Prostate Cancer—a new dawn for an old therapy

Oral estrogens were the treatment of choice for carcinoma of the prostate for over four decades, but were abandoned because of an excess of cardiovascular and thromboembolic toxicity. It is now recognized that most of this toxicity is related to the first pass portal circulation, which upregulates the hepatic metabolism of hormones, lipids and coagulation proteins. Most of this toxicity can be avoided by parenteral (intramuscular or transdermal) estrogen administration, which avoids hepatic enzyme induction. It also seems that a short-term but modest increase in cardiovascular morbidity (but not mortality) is compensated for by a long-term cardioprotective benefit, which accrues progressively as vascular remodeling develops over time. Parenteral estrogen therapy has the advantage of giving protection against the effects of andropause (similar to the female menopause), which are induced by conventional androgen suppression and include osteoporotic fracture, hot flashes, asthenia and cognitive dysfunction. In addition, parenteral estrogen therapy is significantly cheaper than contemporary endocrine therapy, with substantive economic implications for health providers

Advances in hormone replacement therapy: making the menopause manageable

The importance of the results of some large, randomized controlled trials (RCTs) on Hormone Replacement Therapy (HRT) has modified the risk/benefit perception of HRT. Recent literature review supports a different management

Discerning Tumor Status from Unstructured MRI Reports—Completeness of Information in Existing Reports and Utility of Automated Natural Language Processing

Information in electronic medical records is often in an unstructured free-text format. This format presents challenges for expedient data retrieval and may fail to convey important findings. Natural language processing (NLP) is an emerging technique for rapid and efficient clinical data retrieval. While proven in disease detection, the utility of NLP in discerning disease progression from free-text reports is untested. We aimed to (1) assess whether unstructured radiology reports contained sufficient information for tumor status classification; (2) develop an NLP-based data extraction tool to determine tumor status from unstructured reports; and (3) compare NLP and human tumor status classification outcomes. Consecutive follow-up brain tumor magnetic resonance imaging reports (2000–­2007) from a tertiary center were manually annotated using consensus guidelines on tumor status. Reports were randomized to NLP training (70%) or testing (30%) groups. The NLP tool utilized a support vector machines model with statistical and rule-based outcomes. Most reports had sufficient information for tumor status classification, although 0.8% did not describe status despite reference to prior examinations. Tumor size was unreported in 68.7% of documents, while 50.3% lacked data on change magnitude when there was detectable progression or regression. Using retrospective human classification as the gold standard, NLP achieved 80.6% sensitivity and 91.6% specificity for tumor status determination (mean positive predictive value, 82.4%; negative predictive value, 92.0%). In conclusion, most reports contained sufficient information for tumor status determination, though variable features were used to describe status. NLP demonstrated good accuracy for tumor status classification and may have novel application for automated disease status classification from electronic databases

Massive Peatland Carbon Banks Vulnerable to Rising Temperatures

Peatlands contain one-third of the world’s soil carbon (C). If destabilized, decomposition of this vast C bank could accelerate climate warming; however, the likelihood of this outcome remains unknown. Here, we examine peatland C stability through five years of whole-ecosystem warming and two years of elevated atmospheric carbon dioxide concentrations (eCO2). Warming exponentially increased methane (CH4) emissions and enhanced CH4 production rates throughout the entire soil profile; although surface CH4 production rates remain much greater than those at depth. Additionally, older deeper C sources played a larger role in decomposition following prolonged warming. Most troubling, decreases in CO2:CH4 ratios in gas production, porewater concentrations, and emissions, indicate that the peatland is becoming more methanogenic with warming. We observed limited evidence of eCO2 effects. Our results suggest that ecosystem responses are largely driven by surface peat, but that the vast C bank at depth in peatlands is responsive to prolonged warming

Effectiveness of bisphosphonates on nonvertebral and hip fractures in the first year of therapy: The risedronate and alendronate (REAL) cohort study

INTRODUCTION: Randomized clinical trials have shown that risedronate and alendronate reduce fractures among women with osteoporosis. The aim of this observational study was to observe, in clinical practice, the incidence of hip and nonvertebral fractures among women in the year following initiation of once-a-week dosing of either risedronate or alendronate. METHODS: Using records of health service utilization from July 2002 through September 2004, we created two cohorts: women (ages 65 and over) receiving risedronate (n = 12,215) or alendronate (n = 21,615). Cox proportional hazard modeling was used to compare the annual incidence of nonvertebral fractures and of hip fractures between cohorts, adjusting for potential differences in risk factors for fractures. RESULTS: There were 507 nonvertebral fractures and 109 hip fractures. Through one year of therapy, the incidence of nonvertebral fractures in the risedronate cohort (2.0%) was 18% lower (95% CI 2% – 32%) than in the alendronate cohort (2.3%). The incidence of hip fractures in the risedronate cohort (0.4%) was 43% lower (95% CI 13% – 63%) than in the alendronate cohort (0.6%). These results were consistent across a number of sensitivity analyses. CONCLUSION: Patients receiving risedronate have lower rates of hip and nonvertebral fractures during their first year of therapy than patients receiving alendronate

The impact of incident vertebral and non-vertebral fractures on health related quality of life in postmenopausal women

BACKGROUND: Little empirical research has examined the multiple consequences of osteoporosis on quality of life. METHODS: Health related quality of life (HRQL) was examined in relationship to incident fractures in 2009 postmenopausal women 50 years and older who were seen in consultation at our tertiary care, university teaching hospital-affiliated office and who were registered in the Canadian Database of Osteoporosis and Osteopenia (CANDOO) patients. Patients were divided into three study groups according to incident fracture status: vertebral fractures, non-vertebral fractures and no fractures. Baseline assessments of anthropometric data, medical history, therapeutic drug use, and prevalent fracture status were obtained from all participants. The disease-targeted mini-Osteoporosis Quality of Life Questionnaire (mini-OQLQ) was used to measure HRQL. RESULTS: Multiple regression analyses revealed that subjects who had experienced an incident vertebral fracture had lower HRQL difference scores as compared with non-fractured participants in total score (-0.86; 95% confidence intervals (CI): -1.30, -0.43) and the symptoms (-0.76; 95% CI: -1.23, -0.30), physical functioning (-1.12; 95% CI: -1.57, -0.67), emotional functioning (-1.06; 95% CI: -1.44, -0.68), activities of daily living (-1.47; 95% CI: -1.97, -0.96), and leisure (-0.92; 95% CI: -1.37, -0.47) domains of the mini-OQLQ. Patients who experienced an incident non-vertebral fracture had lower HRQL difference scores as compared with non-fractured participants in total score (-0.47; 95% CI: -0.70, -0.25), and the symptoms (-0.25; 95% CI: -0.49, -0.01), physical functioning (-0.39; 95% CI: -0.65, -0.14), emotional functioning (-0.97; 95% CI: -1.20, -0.75) and the activities of daily living (-0.47; 95% CI: -0.73, -0.21) domains. CONCLUSION: Quality of life decreased in patients who sustained incident vertebral and non-vertebral fractures

Improving Efficiency and Quality of the Children’s ASD Diagnostic Pathway: Lessons Learned from Practice

The ‘autism diagnosis crisis’ and long waiting times for assessment are as yet unresolved, leading to undue stress and limiting\ud access to effective support. There is therefore a significant need for evidence to support practitioners in the development of\ud efficient services, delivering acceptable waiting times and effectively meeting guideline standards. This study reports statistically\ud significant reductions in waiting times for autism diagnostic assessment following a children’s health service improvement\ud programme. The average wait between referral and first appointment reduced from 14.2 to 10.4 weeks (t(21) = 4.3,\ud p < 0.05) and between referral and diagnosis shared, reduced from 270 to 122.5 days, (t(20) = 5.5, p < 0.05). The proportion\ud of girls identified increased from 5.6 to 2.7:1. Methods reported include: local improvement action planning; evidence based\ud pathways; systematic clinical data gathering and a training plan. This is a highly significant finding for many health services\ud wrestling with the challenges of demand and capacity for autism diagnosis and assessment

Programmed Cellular Necrosis Mediated by the Pore-Forming α-Toxin from Clostridium septicum

Programmed necrosis is a mechanism of cell death that has been described for neuronal excitotoxicity and ischemia/reperfusion injury, but has not been extensively studied in the context of exposure to bacterial exotoxins. The α-toxin of Clostridium septicum is a β-barrel pore-forming toxin and a potent cytotoxin; however, the mechanism by which it induces cell death has not been elucidated in detail. We report that α-toxin formed Ca2+-permeable pores in murine myoblast cells, leading to an increase in intracellular Ca2+ levels. This Ca2+ influx did not induce apoptosis, as has been described for other small pore-forming toxins, but a cascade of events consistent with programmed necrosis. Ca2+ influx was associated with calpain activation and release of cathepsins from lysosomes. We also observed deregulation of mitochondrial activity, leading to increased ROS levels, and dramatically reduced levels of ATP. Finally, the immunostimulatory histone binding protein HMGB1 was found to be released from the nuclei of α-toxin-treated cells. Collectively, these data show that α-toxin initiates a multifaceted necrotic cell death response that is consistent with its essential role in C. septicum-mediated myonecrosis and sepsis. We postulate that cellular intoxication with pore-forming toxins may be a major mechanism by which programmed necrosis is induced

Effect of vitamin D on bone mineral density of elderly patients with osteoporosis responding poorly to bisphosphonates

BACKGROUND: Bisphosphonates are indicated in the prevention and treatment of osteoporosis. However, bone mineral density (BMD) continues to decline in up to 15% of bisphosphonate users. While randomized trials have evaluated the efficacy of concurrent bisphosphonates and vitamin D, the incremental benefit of vitamin D remains uncertain. METHODS: Using data from the Canadian Database of Osteoporosis and Osteopenia (CANDOO), we performed a 2-year observational cohort study. At baseline, all patients were prescribed a bisphosphonate and counseled on vitamin D supplementation. After one year, patients were divided into two groups based on their response to bisphosphonate treatment. Non-responders were prescribed vitamin D 1000 IU daily. Responders continued to receive counseling on vitamin D. RESULTS: Of 449 patients identified, 159 were non-responders to bisphosphonates. 94% of patients were women. The mean age of the entire cohort was 74.6 years (standard deviation = 5.6 years). In the cohort of non-responders, BMD at the lumbar spine increased 2.19% (p < 0.001) the year after vitamin D was prescribed compared to a decrease of 0.55% (p = 0.36) the year before. In the cohort of responders, lumbar spine BMD improved 1.45% (p = 0.014) the first year and 1.11% (p = 0.60) the second year. The difference between the two groups was statistically significant the first year (p < 0.001) but not the second (p = 0.60). Similar results were observed at the femoral neck but were not statistically significant. CONCLUSION: In elderly patients with osteoporosis not responding to bisphosphonates, vitamin D 1000 IU daily may improve BMD at the lumbar spine

Vegetation Type Dominates the Spatial Variability in CH<inf>4</inf> Emissions Across Multiple Arctic Tundra Landscapes

Methane (CH4) emissions from Arctic tundra are an important feedback to global climate. Currently, modelling and predicting CH4 fluxes at broader scales are limited by the challenge of upscaling plot-scale measurements in spatially heterogeneous landscapes, and by uncertainties regarding key controls of CH4 emissions. In this study, CH4 and CO2 fluxes were measured together with a range of environmental variables and detailed vegetation analysis at four sites spanning 300 km latitude from Barrow to Ivotuk (Alaska). We used multiple regression modelling to identify drivers of CH4 flux, and to examine relationships between gross primary productivity (GPP), dissolved organic carbon (DOC) and CH4 fluxes. We found that a highly simplified vegetation classification consisting of just three vegetation types (wet sedge, tussock sedge and other) explained 54% of the variation in CH4 fluxes across the entire transect, performing almost as well as a more complex model including water table, sedge height and soil moisture (explaining 58% of the variation in CH4 fluxes). Substantial CH4 emissions were recorded from tussock sedges in locations even when the water table was lower than 40 cm below the surface, demonstrating the importance of plant-mediated transport. We also found no relationship between instantaneous GPP and CH4 fluxes, suggesting that models should be cautious in assuming a direct relationship between primary production and CH4 emissions. Our findings demonstrate the importance of vegetation as an integrator of processes controlling CH4 emissions in Arctic ecosystems, and provide a simplified framework for upscaling plot scale CH4 flux measurements from Arctic ecosystems