Prostate cancer treated with brachytherapy; an exploratory study of dose-dependent biomarkers and quality of life

BACKGROUND: Low-dose-rate permanent prostate brachytherapy (PPB) is an attractive treatment option for patients with localised prostate cancer with excellent outcomes. As standard CT-based post-implant dosimetry often correlates poorly with late treatment-related toxicity, this exploratory (proof of concept) study was conducted to investigate correlations between radiation − induced DNA damage biomarker levels, and acute and late bowel, urinary, and sexual toxicity. METHODS: Twelve patients treated with (125)I PPB monotherapy (145Gy) for prostate cancer were included in this prospective study. Post-implant CT based dosimetry assessed the minimum dose encompassing 90% (D(90%)) of the whole prostate volume (global), sub-regions of the prostate (12 sectors) and the near maximum doses (D(0.1cc), D(2cc)) for the rectum and bladder. Six blood samples were collected from each patient; pre-treatment, 1 h (h), 4 h, 24 h post-implant, at 4 weeks (w) and at 3 months (m). DNA double strand breaks were investigated by staining the blood samples with immunofluorescence antibodies to γH2AX and 53BP1 proteins (γH2AX/53BP1). Patient self-scored quality of life from the Expanded Prostate Cancer Index Composite (EPIC) were obtained at baseline, 1 m, 3 m, 6 m, 9 m, 1 year (y), 2y and 3y post-treatment. Spearman’s correlation coefficients were used to evaluate correlations between temporal changes in γH2AX/53BP1, dose and toxicity. RESULTS: The minimum follow up was 2 years. Population mean prostate D(90%) was 144.6 ± 12.1 Gy and rectal near maximum dose D(0.1cc) = 153.0 ± 30.8 Gy and D(2cc) = 62.7 ± 12.1 Gy and for the bladder D(0.1cc) = 123.1 ± 27.0 Gy and D(2cc) = 70.9 ± 11.9 Gy. Changes in EPIC scores from baseline showed high positive correlation between acute toxicity and late toxicity for both urinary and bowel symptoms. Increased production of γH2AX/53BP1 at 24 h relative to baseline positively correlated with late bowel symptoms. Overall, no correlations were observed between dose metrics (prostate global or sector doses) and γH2AX/53BP1 foci counts. CONCLUSIONS: Our results show that a prompt increase in γH2AX/53BP1foci at 24 h post-implant relative to baseline may be a useful measure to assess elevated risk of late RT − related toxicities for PPB patients. A subsequent investigation recruiting a larger cohort of patients is warranted to verify our findings. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13014-017-0792-1) contains supplementary material, which is available to authorized users

The Virtual-Spine Platform—Acquiring, visualizing, and analyzing individual sitting behavior

Back pain is a serious medical problem especially for those people sitting over long periods during their daily work. Here we present a system to help users monitoring and examining their sitting behavior. The Virtual-Spine Platform (VSP) is an integrated system consisting of a real-time body position monitoring module and a data visualization module to provide individualized, immediate, and accurate sitting behavior support. It provides a comprehensive spine movement analysis as well as accumulated data visualization to demonstrate behavior patterns within a certain period. The two modules are discussed in detail focusing on the design of the VSP system with adequate capacity for continuous monitoring and a web-based interactive data analysis method to visualize and compare the sitting behavior of different persons. The data was collected in an experiment with a small group of subjects. Using this method, the behavior of five subjects was evaluated over a working day, enabling inferences and suggestions for sitting improvements. The results from the accumulated data module were used to elucidate the basic function of body position recognition of the VSP. Finally, an expert user study was conducted to evaluate VSP and support future developments

Application of Diffusion Tensor Imaging Parameters to Detect Change in Longitudinal Studies in Cerebral Small Vessel Disease.

Cerebral small vessel disease (SVD) is the major cause of vascular cognitive impairment, resulting in significant disability and reduced quality of life. Cognitive tests have been shown to be insensitive to change in longitudinal studies and, therefore, sensitive surrogate markers are needed to monitor disease progression and assess treatment effects in clinical trials. Diffusion tensor imaging (DTI) is thought to offer great potential in this regard. Sensitivity of the various parameters that can be derived from DTI is however unknown. We aimed to evaluate the differential sensitivity of DTI markers to detect SVD progression, and to estimate sample sizes required to assess therapeutic interventions aimed at halting decline based on DTI data. We investigated 99 patients with symptomatic SVD, defined as clinical lacunar syndrome with MRI confirmation of a corresponding infarct as well as confluent white matter hyperintensities over a 3 year follow-up period. We evaluated change in DTI histogram parameters using linear mixed effect models and calculated sample size estimates. Over a three-year follow-up period we observed a decline in fractional anisotropy and increase in diffusivity in white matter tissue and most parameters changed significantly. Mean diffusivity peak height was the most sensitive marker for SVD progression as it had the smallest sample size estimate. This suggests disease progression can be monitored sensitively using DTI histogram analysis and confirms DTI's potential as surrogate marker for SVD

Assessing Model Predictions of Carbon Dynamics in Global Drylands

Drylands cover ca. 40% of the land surface and are hypothesised to play a major role in the global carbon cycle, controlling both long-term trends and interannual variation. These insights originate from land surface models (LSMs) that have not been extensively calibrated and evaluated for water-limited ecosystems. We need to learn more about dryland carbon dynamics, particularly as the transitory response and rapid turnover rates of semi-arid systems may limit their function as a carbon sink over multi-decadal scales. We quantified aboveground biomass carbon (AGC; inferred from SMOS L-band vegetation optical depth) and gross primary productivity (GPP; from PML-v2 inferred from MODIS observations) and tested their spatial and temporal correspondence with estimates from the TRENDY ensemble of LSMs. We found strong correspondence in GPP between LSMs and PML-v2 both in spatial patterns (Pearson’s r = 0.9 for TRENDY-mean) and in inter-annual variability, but not in trends. Conversely, for AGC we found lesser correspondence in space (Pearson’s r = 0.75 for TRENDY-mean, strong biases for individual models) and in the magnitude of inter-annual variability compared to satellite retrievals. These disagreements likely arise from limited representation of ecosystem responses to plant water availability, fire, and photodegradation that drive dryland carbon dynamics. We assessed inter-model agreement and drivers of long-term change in carbon stocks over centennial timescales. This analysis suggested that the simulated trend of increasing carbon stocks in drylands is in soils and primarily driven by increased productivity due to CO$_2$ enrichment. However, there is limited empirical evidence of this 50-year sink in dryland soils. Our findings highlight important uncertainties in simulations of dryland ecosystems by current LSMs, suggesting a need for continued model refinements and for greater caution when interpreting LSM estimates with regards to current and future carbon dynamics in drylands and by extension the global carbon cycle

Process-oriented analysis of dominant sources of uncertainty in the land carbon sink

The observed global net land carbon sink is captured by current land models. All models agree that atmospheric CO$_{2}$ and nitrogen deposition driven gains in carbon stocks are partially offset by climate and land-use and land-cover change (LULCC) losses. However, there is a lack of consensus in the partitioning of the sink between vegetation and soil, where models do not even agree on the direction of change in carbon stocks over the past 60 years. This uncertainty is driven by plant productivity, allocation, and turnover response to atmospheric CO$_{2}$ (and to a smaller extent to LULCC), and the response of soil to LULCC (and to a lesser extent climate). Overall, differences in turnover explain ~70% of model spread in both vegetation and soil carbon changes. Further analysis of internal plant and soil (individual pools) cycling is needed to reduce uncertainty in the controlling processes behind the global land carbon sink

Networked T Cell Death following Macrophage Infection by Mycobacterium tuberculosis

<div><h3>Background</h3><p>Depletion of T cells following infection by <em>Mycobacterium tuberculosis</em> (Mtb) impairs disease resolution, and interferes with clinical test performance that relies on cell-mediated immunity. A number of mechanisms contribute to this T cell suppression, such as activation-induced death and trafficking of T cells out of the peripheral circulation and into the diseased lungs. The extent to which Mtb infection of human macrophages affects T cell viability however, is not well characterised.</p> <h3>Methodology/Principal Findings</h3><p>We found that lymphopenia (<1.5×10⁹ cells/l) was prevalent among culture-positive tuberculosis patients, and lymphocyte counts significantly improved post-therapy. We previously reported that Mtb-infected human macrophages resulted in death of infected and uninfected bystander macrophages. In the current study, we sought to examine the influence of infected human alveolar macrophages on T cells. We infected primary human alveolar macrophages (the primary host cell for Mtb) or PMA-differentiated THP-1 cells with Mtb H37Ra, then prepared cell-free supernatants. The supernatants of Mtb-infected macrophages caused dose-dependent, caspase-dependent, T cell apoptosis. This toxic effect of infected macrophage secreted factors did not require TNF-α or Fas. The supernatant cytotoxic signal(s) were heat-labile and greater than 50 kDa in molecular size. Although ESAT-6 was toxic to T cells, other Mtb-secreted factors tested did not influence T cell viability; nor did macrophage-free Mtb bacilli or broth from Mtb cultures. Furthermore, supernatants from <em>Mycobacterium bovis</em> Bacille de Calmette et Guerin (BCG)- infected macrophages also elicited T cell death suggesting that ESAT-6 itself, although cytotoxic, was not the principal mediator of T cell death in our system.</p> <h3>Conclusions</h3><p>Mtb-Infected macrophages secrete heat-labile factors that are toxic to T cells, and may contribute to the immunosuppression seen in tuberculosis as well as interfere with microbial eradication in the granuloma.</p> </div

Implications of improved representations of plant respiration in a changing climate

Land-atmosphere exchanges influence atmospheric CO2. Emphasis has been on describing photosynthetic CO2 uptake, but less on respiration losses. New global datasets describe upper canopy dark respiration (R d) and temperature dependencies. This allows characterisation of baseline R d, instantaneous temperature responses and longer-term thermal acclimation effects. Here we show the global implications of these parameterisations with a global gridded land model. This model aggregates R d to whole-plant respiration R p, driven with meteorological forcings spanning uncertainty across climate change models. For pre-industrial estimates, new baseline R d increases R p and especially in the tropics. Compared to new baseline, revised instantaneous response decreases R p for mid-latitudes, while acclimation lowers this for the tropics with increases elsewhere. Under global warming, new R d estimates amplify modelled respiration increases, although partially lowered by acclimation. Future measurements will refine how R d aggregates to whole-plant respiration. Our analysis suggests R p could be around 30% higher than existing estimates.C.H. acknowledges the NERC CEH National Capability fund. We acknowledge the many climate research centres that contributed GCM outputs in to the Coupled Model Intercomparison Project (CMIP5) database. The support of the Australian Research Council to O.K.A. and P.M. (DP130101252, CE140100008, FT0991448, FT110100457) is acknowledged, as are awards DE-FG02-07ER64456 from the US Department of Energy, Office of Science, Office of Biological and Environmental Research and DEB-1234162 from the U.S. National Science Foundation (NSF) Long-Term Ecological Research Program (to P.B.R.); and National Science Foundation International Polar Year Grant (to K.L.G.). L.M.M. acknowledges the support of the Natural Environment Research Council (NERC) South American Biomass Burning Analysis (SAMBBA) project grant code NE/ J010057/1

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

Iliocaval venous obstruction, cardiac preload reserve, and exercise limitation

Cardiac output during exercise increases by as much as five-fold in the untrained man, and by as much as eight-fold in the elite athlete. Increasing venous return is a critical but much overlooked component of the physiological response to exercise. Cardiac disorders such as constrictive pericarditis, restrictive cardiomyopathy and pulmonary hypertension are recognised to impair preload and cause exercise limitation, however the effects of peripheral venous obstruction on cardiac function have not been well described. This manuscript will discuss how obstruction of the iliocaval venous outflow can lead to impairment in exercise tolerance; how such obstructions may be diagnosed, the potential implications of chronic obstructions on sympathetic nervous system activation, and relevance of venous compression syndromes in heart failure with preserved ejection fraction

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]