Radiographic calibration for pubic diastasis assessment in bladder exstrophy-epispadias complex: a phantom study.

BACKGROUND: The assessment of pubic diastasis is important for the surgical planning of patients with bladder exstrophy-epispadias complex. Understanding how the diastasis changes during surgical follow-up may help predict patient morbidity. Radiography can follow diastasis but may be affected by patient and technical imaging factors including body size, imaging protocol, and equipment. Using imaging calibration and anatomic ratios may mitigate differences due to these aspects. OBJECTIVE: Use imaging phantoms to assess the effect of radiographic calibration on measurements of pubic diastasis and an internal anatomic ratio as a child grows. MATERIALS AND METHODS: Radiographic images were obtained of three different sizes of computed tomography phantoms (older child, child, and infant) using three imaging techniques that include the osseous pelvis in children. All phantoms were imaged with abdomen and pelvis techniques. The infant phantom was additionally imaged using a thoracoabdominal technique. These exposures were all repeated with systems from three manufacturers. Linear measurements were made between radiographic markers placed to simulate pubic diastasis and sacral width. A ratio was also created between these distances. Measurements with and without image calibration were made by two pediatric radiologists using rulers placed at the time of image acquisition. RESULTS: There was excellent interrater agreement for measurements, ICC >0.99. Anterior distances were more affected by magnification than posterior ones with a significant difference between uncalibrated versus calibrated anterior distances (p=0.04) and not for posterior ones (p=0.65). There was no difference between radiographic equipment manufacturers without or with calibration (p values 0.66 to 0.99). There was a significant difference in simulated pubic distance between thoracoabdominal and abdomen (p=0.04) as well as pelvic (p=0.04) techniques which resolved with calibration, each p=0.6. The ratio between the simulated pubic diastasis and sacral width differed by phantom size (all p<0.01) and imaging technique (p values 0.01 to 0.03) with or without calibration. However, the numerical differences may not be clinically significant. CONCLUSION: Image calibration results in more uniform measurements that are more accurate than uncalibrated ones across patient size, imaging techniques, and equipment. Image calibration is necessary for accurate measurement of inter-pubic distances on all projection imaging. Small differences in the pelvic ratio likely are not clinically significant, but until there is a better understanding, image calibration may be prudent.

Comparing abundance distributions and range maps in spatial conservation planning for migratory species.

Most spatial conservation planning for wide-ranging or migratory species is constrained by poor knowledge of species' spatiotemporal dynamics and is only based on static species' ranges. However, species have substantial variation in abundance across their range and migratory species have important spatiotemporal population dynamics. With growing ecological data and advancing analytics, both of these can be estimated and incorporated into spatial conservation planning. However, there is limited information on the degree to which including this information affects conservation planning. We compared the performance of systematic conservation prioritizations for different scenarios based on varying the input species' distributions by ecological metric (abundance distributions versus range maps) and temporal sampling resolution (weekly, monthly, or quarterly). We used the example of a community of 41 species of migratory shorebirds that breed in North America, and we used eBird data to produce weekly estimates of species' abundances and ranges. Abundance distributions at a monthly or weekly resolution led to prioritizations that most efficiently protected species throughout the full annual cycle. Conversely, spatial prioritizations based on species' ranges required more sites and left most species insufficiently protected for at least part of their annual cycle. Prioritizations with only quarterly species ranges were very inefficient as they needed to target 40% of species' ranges to include 10% of populations. We highlight the high value of abundance information for spatial conservation planning, which leads to more efficient and effective spatial prioritization for conservation. Overall, we provide evidence that spatial conservation planning for wide-ranging migratory species is most robust and efficient when informed by species' abundance information from the full annual cycle.

A Mathematical Model of Granulopoiesis Incorporating the Negative Feedback Dynamics and Kinetics of G-CSF/Neutrophil Binding and Internalization.

We develop a physiological model of granulopoiesis which includes explicit modelling of the kinetics of the cytokine granulocyte colony-stimulating factor (G-CSF) incorporating both the freely circulating concentration and the concentration of the cytokine bound to mature neutrophils. G-CSF concentrations are used to directly regulate neutrophil production, with the rate of differentiation of stem cells to neutrophil precursors, the effective proliferation rate in mitosis, the maturation time, and the release rate from the mature marrow reservoir into circulation all dependent on the level of G-CSF in the system. The dependence of the maturation time on the cytokine concentration introduces a state-dependent delay into our differential equation model, and we show how this is derived from an age-structured partial differential equation model of the mitosis and maturation and also detail the derivation of the rest of our model. The model and its estimated parameters are shown to successfully predict the neutrophil and G-CSF responses to a variety of treatment scenarios, including the combined administration of chemotherapy and exogenous G-CSF. This concomitant treatment was reproduced without any additional fitting to characterize drug-drug interactions.

Reflex testing for Lynch syndrome: if we build it, will they come? Lessons learned from the uptake of clinical genetics services by individuals with newly diagnosed colorectal cancer (CRC).

The aim of this qualitative study was to examine the experience of individuals facing a choice about genetic counselling/testing in the context of newly diagnosed colorectal cancer (CRC). Nineteen individuals with newly diagnosed CRC, including 12 individuals who accepted genetic counselling ("acceptors") and 7 individuals who declined genetic counselling ("refusers"), were interviewed using a standardized questionnaire guide which focused on motivations and barriers experienced in the decision process. Data were analyzed using Karlsson's Empirical Phenomenological method of data analysis (Karlsson in Psychological qualitative research from a phenomenological perspective. Almgvist and Wiksell International, Stockholm, 1993). Three major themes were identified: facing challenges in health literacy; mapping an unknown territory; and adjusting to cancer. The study participants' testimonies provided novel insights into potential reasons for patient non-engagement in pilot studies of reflex testing for Lynch syndrome, and allowed us to formulate several recommendations for enhancing patient engagement. Our study findings suggest that patient engagement in clinical cancer genetics services, including reflex testing for Lynch syndrome, can only be achieved by addressing current health literacy issues, by deconstructing current misconceptions related to potential abuses of genetic information, by emphasizing the clinical utility of genetic assessment, and by adapting genetics practices to the specific context of cancer care.

Risk factors associated with reduced work productivity among people with chronic knee pain.

OBJECTIVE: To determine the burden and risk factors associated with reduced work productivity among people with chronic knee pain. METHOD: A longitudinal study, nested within a randomised controlled trial (RCT) evaluating the long-term effects of dietary supplements, was conducted among people with chronic knee pain in paid employment (n = 360). Participants recorded days off work (absenteeism) and reduced productivity while at work (presenteeism) for seven days every two months over a 12-month period in a study specific diary. Examined risk factors included knee pain severity, occupational group, radiographic disease severity, physical activity, body mass index (BMI), health-related quality of life (SF-12) and co-morbidity. RESULTS: Over the 12-month follow up period, 50 (14%) participants reported one or more days off work due to knee problems, while 283 (79%) reported reduced productivity while at work (presenteeism <100%). In multivariate analysis, the only significant risk factor for absenteeism was having an SF-12 Mental Component Summary (MCS) score <40 (OR: 2.49 [95% CI: 1.03-5.98]). Significant risk factors for presenteeism included; reporting an; SF-12 Physical Component Summary (PCS) score <50 (OR: 1.99 [95% CI: 1.05-3.76]), semi-manual labour (OR: 2.23 [1.09-4.59]) or manual labour (OR: 6.40 [1.44-28.35]) or a high maximum knee pain (4-6 out of 10) (OR: 2.29 [1.17-4.46]). CONCLUSIONS: This longitudinal study found that among this cohort of people with chronic knee pain, the burden of reduced work productivity is mainly attributable to presenteeism rather absenteeism. This study demonstrated that effective strategies to increase work productivity should focus on reducing knee pain or physical disability especially among workers in manual or semi-manual labour.

Estimating peak work rate during incremental cycle ergometry from the 6-minute walk distance: differences between reference equations.

BACKGROUND: Prescription of an appropriate exercise training intensity is critical to optimise the outcomes of pulmonary rehabilitation; however, prescribing cycle ergometry training is challenging if peak work is unknown. Recently two studies reported regression equations which allow estimation of peak cycle work rate from the 6-minute walk distance (6MWD) in chronic obstructive pulmonary disease (COPD). OBJECTIVES: To compare estimates of peak work and target training work rate (60% peak) obtained from these equations. METHODS: Sixty-four (38 male) subjects, mean ± SD age 70 ± 8 years and FEV(1) 49 ± 18% predicted with COPD performed the 6-minute walk test according to a standardised protocol. Estimates of peak work were obtained using the published equations and agreement was examined using Bland and Altman plots. RESULTS: Mean 6MWD was 376 ± 86 m compared to 464 ± 110 m and 501 ± 83 m in samples used to derive the equations. There was substantial variation in estimates of peak work between equations (range 1-75 Watts difference) with a coefficient of variation of 35%. Differences were greater in men than in women (p < 0.001). The Luxton equation predicted higher peak work than the Hill equation in younger subjects and at work rates over 50 Watts. Estimated training work rate differed by more than 20 Watts in 18 subjects (28%). CONCLUSIONS: This comparison of reference equations for predicting peak cycle work rate from 6MWD indicates substantial variation between methods that differs systematically across the range of work rates. Further research is required to validate the equations and assess their utility for exercise prescription in pulmonary rehabilitation.

A novel antagonist of the prostaglandin E(2) EP(4) receptor inhibits Th1 differentiation and Th17 expansion and is orally active in arthritis models.

BACKGROUND AND PURPOSE: Rheumatoid arthritis (RA) is an autoimmune disorder involving subsets of activated T cells, in particular T helper (Th) 1 and Th17 cells, which infiltrate and damage tissues and induce inflammation. Prostaglandin E(2) (PGE(2)) enhances the Th17 response, exacerbates collagen-induced arthritis (CIA) and promotes inflammatory pain. The current study investigated whether selective antagonism of the PGE(2) EP(4) receptor would suppress Th1/Th17 cell development and inflammatory arthritis in animal models of RA. EXPERIMENTAL APPROACH: Effects of PGE(2) and a novel EP(4) receptor antagonist ER-819762 on Th1 differentiation, interleukin-23 (IL-23) production by dendritic cells (DCs), and Th17 development were assessed in vitro. The effect of ER-819762 was evaluated in CIA and glucose-6-phosphate isomerase (GPI)-induced arthritis models. In addition, the effects of ER-819762 on pain were evaluated in a model of chronic inflammatory pain induced by complete Freund's adjuvant (CFA) in the rat. KEY RESULTS: Stimulation of the EP(4) receptor enhanced Th1 differentiation via phosphatidylinositol 3 kinase signalling, selectively promoted Th17 cell expansion, and induced IL-23 secretion by activated DCs, effects suppressed by ER-819762 or anti-PGE(2) antibody. Oral administration of ER-19762 suppressed Th1 and Th17 cytokine production, suppressed disease in collagen- and GPI-induced arthritis in mice, and suppressed CFA-induced inflammatory pain in rats. CONCLUSION AND IMPLICATIONS: PGE(2) stimulates EP(4) receptors to promote Th1 differentiation and Th17 expansion and is critically involved in development of arthritis in two animal models. Selective suppression of EP(4) receptor signalling may have therapeutic value in RA both by modifying inflammatory arthritis and by relieving pain.

An open-source deconvolution software package for 3-D quantitative fluorescence microscopy imaging.

Deconvolution techniques have been widely used for restoring the 3-D quantitative information of an unknown specimen observed using a wide-field fluorescence microscope. Deconv, an open-source deconvolution software package, was developed for 3-D quantitative fluorescence microscopy imaging and was released under the GNU Public License. Deconv provides numerical routines for simulation of a 3-D point spread function and deconvolution routines implemented three constrained iterative deconvolution algorithms: one based on a Poisson noise model and two others based on a Gaussian noise model. These algorithms are presented and evaluated using synthetic images and experimentally obtained microscope images, and the use of the library is explained. Deconv allows users to assess the utility of these deconvolution algorithms and to determine which are suited for a particular imaging application. The design of Deconv makes it easy for deconvolution capabilities to be incorporated into existing imaging applications.

CELL SEGMENTATION USING HESSIAN-BASED DETECTION AND CONTOUR EVOLUTION WITH DIRECTIONAL DERIVATIVES.

The large amount of data produced by biological live cell imaging studies of cell behavior requires accurate automated cell segmentation algorithms for rapid, unbiased and reproducible scientific analysis. This paper presents a new approach to obtain precise boundaries of cells with complex shapes using ridge measures for initial detection and a modified geodesic active contour for curve evolution that exploits the halo effect present in phase-contrast microscopy. The level set contour evolution is controlled by a novel spatially adaptive stopping function based on the intensity profile perpendicular to the evolving front. The proposed approach is tested on human cancer cell images from LSDCAS and achieves high accuracy even in complex environments.

Validity of the modified 20-metre shuttle test: assessment of cardiorespiratory fitness in people who have sustained a traumatic brain injury.

PRIMARY OBJECTIVE: To validate the modified 20-metre shuttle test in adults who have sustained a traumatic brain injury (TBI). DESIGN: Single-sample validity study. SETTING: Brain injury rehabilitation unit. PARTICIPANTS: Twenty-four adults with severe TBI, discharged from hospital for at least 6-months. PROTOCOL: Participants attended the facility for a familiarization session, followed by a symptom-limited treadmill test and a modified shuttle test on two separate days. The treadmill test was based on an individualised protocol which used a physiotherapist-selected speed and increments in gradient every minute until volitional fatigue. The modified shuttle test was externally-paced and commenced with a speed of 2.4 km h(-1) which increased every minute until volitional fatigue. MAIN MEASURES: Four primary measures were taken from both tests: peak oxygen uptake, peak heart rate, maximal velocity and rating of perceived exertion. RESULTS: All participants completed the study. There were no adverse events. A high correlation was observed between the modified shuttle test and the treadmill test for peak oxygen uptake, peak heart rate and maximal velocity (r = 0.96, r = 0.80, r = 0.82, respectively; p < 0.001), but not for rating of perceived exertion (r = 0.013, p = 0.952). CONCLUSION: The modified shuttle test is a valid measure of cardiorespiratory fitness in people who have sustained a TBI.

Origin of bistability in the lac Operon.

Multistability is an emergent dynamic property that has been invoked to explain multiple coexisting biological states. In this work, we investigate the origin of bistability in the lac operon. To do this, we develop a mathematical model for the regulatory pathway in this system and compare the model predictions with other experimental results in which a nonmetabolizable inducer was employed. We investigate the effect of lactose metabolism using this model, and show that it greatly modifies the bistable region in the external lactose (Le) versus external glucose (Ge) parameter space. The model also predicts that lactose metabolism can cause bistability to disappear for very low Ge. We have also carried out stochastic numerical simulations of the model for several values of Ge and Le. Our results indicate that bistability can help guarantee that Escherichia coli consumes glucose and lactose in the most efficient possible way. Namely, the lac operon is induced only when there is almost no glucose in the growing medium, but if Le is high, the operon induction level increases abruptly when the levels of glucose in the environment decrease to very low values. We demonstrate that this behavior could not be obtained without bistability if the stability of the induced and uninduced states is to be preserved. Finally, we point out that the present methods and results may be useful to study the emergence of multistability in biological systems other than the lac operon.

A 4-day sodium-controlled diet reduces variability of overnight sodium excretion in free-living normotensive adolescents.

The present analysis examined changes in the variability of overnight sodium excretion in 84 free-living adolescents (ages 15 to 19 years) on a 4-day sodium-controlled diet in which foods provided were selected by adolescents from an extensive list of menu items. The only selection criterion imposed was that foods selected for each day contain 4,000+/-200 mg sodium. Adolescents collected overnight urine samples. Repeated measures analysis of variance tested the effect of diet day on overnight sodium excretion, overnight urinary sodium concentration, and overnight urinary volume. Variance ratio test evaluated changes in overnight sodium excretion variance across days. Day 4 overnight sodium excretion was statistically lower than days 1 to 3 (1.84 vs 6.54, 5.94, and 5.52 mEq/h [1.84 vs 6.54, 5.94, and 5.52 mmol/h]). Day 4 overnight urinary sodium concentration was lower than days 1 to 3 (32.16 vs 119.64, 109.61, and 111.32 mEq/L [32.16 vs 119.64, 109.61, and 111.32 mmol/L]). The variance of overnight sodium excretion from day 1 to day 4 was reduced 10-fold from 20.1 mEq/h (20.1 mmol/h) to 1.90 mEq/h (1.90 mmol/h). Daily overnight urine volumes remained constant, averaging 451.7 mL/day. The dietary protocol successfully reduced the variability of sodium intake as estimated by overnight sodium excretion in free-living adolescents. The protocol could be expanded to include baseline values, additional days of sodium control, and varying levels of dietary sodium intake.

Segregation of genomes in polyploid tumour cells following mitotic catastrophe.

Following irradiation p53-function-deficient tumour cells undergo mitotic catastrophe and form endopolyploid cells. A small proportion of these segregates nuclei, and give rise to viable descendants. Here we studied this process in five tumour cell lines. After mitotic failure, tumour cells enter the endocycle and form mono-nucleated or multi-nucleated giant cells (MOGC and MNGC). MNGC arise from arrested anaphases, MOGC, from arrested metaphases. In both cases the individual genomes establish a radial pattern by links to a single microtubule organizing centre. Segregation of genomes is also ordered. MNGC present features of mitosis being resumed from late anaphase. In MOGC the sub-nuclei retain arrangement of stacked metaphase plates and are separated by folds of the nuclear envelope. Mitosis then resumes in sub-nuclei directly from metaphase. The data presented indicate that endopolyploid tumour cells preserve the integrity of individual genomes and can potentially re-initiate mitosis from the point at which it was interrupted.

Association of ambulatory blood pressure and dietary caffeine in adolescents.

BACKGROUND: Although relatively little is known about the responsible factors, there is an increased prevalence of essential hypertension in youth. Our previous research using casual blood pressure (BP) suggests a role for caffeine intake. The objective of this study was to assess the association between caffeine intake and ambulatory BP patterns among adolescents and to replicate our previous findings that compared caffeine intake to BP values obtained at a single time point. METHODS: Eighty-two African-American and non-Hispanic white adolescents (15 to 19 years old) with normal systolic BP selected foods and beverages for a 4-day sodium-controlled diet. Subjects were stratified into three groups based on the amount of caffeine in these foods. Ambulatory BP measures (24-h) were recorded during 1 day of the 4-day diet. The effects of ethnicity, caffeine, and the interaction of ethnicity and caffeine on BP were assessed for daytime and nighttime hours controlling for gender and body mass index. RESULTS: The level of dietary caffeine was positively associated with daytime systolic BP (F(2,76) = 3.1, P = .05, partial R(2) = 0.07) and daytime diastolic BP (F = 3.53(2,76), P = .03, partial R(2) = 0.07). Caffeine's effect on systolic BP was most pronounced for African-American subjects. These results replicated our earlier findings. There was no association between caffeine intake and nighttime BP. CONCLUSIONS: This investigation replicates and extends our previous findings that caffeine consumption impacts the BP of adolescents, during the daytime when sympathetic nervous system responses dominate BP control. Controlled studies that examine the pressor effects of caffeine intake at levels typical of the dietary patterns of today's adolescents are needed.

Stimulus-dependent onset latency of inhibitory recurrent activity.

This paper gives an explanation for the experimentally observed onset latencies of the inhibitory responses that vary from a few milliseconds to hundreds of milliseconds in systems where the conduction delays are only several milliseconds in the feedback pathways. To do this we use a simple mathematical model. The model consists of two delay differential equations (DDE) where the nonlinear relation between the postsynaptic potential and the firing frequency of the neuron population arises from the stoichiometry of the transmitter-receptor kinetics. The parameters of the model refer to the hippocampal feedback system, and the modeling results are compared with corresponding experiments.

Information capacity and pattern formation in a tent map network featuring statistical periodicity.

We provide quantitative support to the observation that lattices of coupled maps are "efficient" information coding devices. It has been suggested recently that lattices of coupled maps may provide a model of information coding in the nervous system because of their ability to create structured and stimulus-dependent activity patterns which have the potential to be used for storing information. In this paper, we give an upper bound to the effective number of patterns that can be used to store information in the lattice by evaluating numerically its information capacity or information rate as a function of the coupling strength between the maps. We also estimate the time taken by the lattice to establish a limiting activity pattern.

The rate of apoptosis in post mitotic neutrophil precursors of normal and neutropenic humans.

Using data on the fraction of post-mitotic neutrophil precursors (CD15+ cells) displaying positive markers for apoptosis in 12 normal humans, and a simple mathematical model, we have estimated the apoptotic rate to be about 0.28/day in this compartment. This implies that the influx of myelocytes into the post-mitotic compartment exceeds twice the granulocyte turnover rate (GTR), and that about 55% of the cells entering this compartment die before being released into the blood. The normal half life of apoptotic post-mitotic neutrophil precursors is calculated to be 10.4 h. Comparable calculations for patients indicate apoptosis rates in the post-mitotic compartment of about 17 times normal for one myelokathexis patient and rates of about 13 times normal for the one cyclical neutropenic patient and two severe congenital neutropenic patients. The estimated half life for apoptotic post-mitotic neutrophil precursors in the myelokathexis patient was about 0.4 h, 1.4 h in the cyclical neutropenia patient, and about 0.6 h in the severe congenital neutropenic patients.

Development of the large scale digital cell analysis system.

Quantitative analysis of large numbers of cells exposed to various stresses would be facilitated by an automated microscope system designed to monitor up to 1000 microscope fields over time intervals of up to one month. The Large Scale Digital Cell Analysis System (LSDCAS) was designed by the authors to provide such analysis capabilities. This report presents a description of the development of the LSDCAS and its application to the study of cells undergoing radiation-induced mitotic catastrophe. A detailed description of the data acquisition algorithms used and the hardware configuration underlying the system is presented. Quantitative analysis of colony formation of cells exposed to 5 Gy X irradiation is presented. Upon analysis, it was found that the plating efficiency in irradiated populations agreed with that obtained using conventional colony-formation assays, indicating the accuracy of LSDCAS in the determination of cell clonogenicity. An unexpected finding was that fully 50% of the surviving colonies exhibited mitotic catastrophe that persisted throughout colony formation. Ongoing extension of the capabilities of the LSDCAS using image segmentation techniques applied to a variety of cellular endpoints is then briefly described.

Meta-analyses in systematic reviews of randomized controlled trials in perinatal medicine: comparison of fixed and random effects models.

There is a need for empirical work comparing the random effects model with the fixed effects model in the calculation of a pooled relative risk in the meta-analysis in systematic reviews of randomized controlled trials. Such comparisons are particularly important when trial results are heterogeneous. We considered 84 independent meta-analyses in which each trial included a set of different women/newborns. These meta-analyses were included in systematic reviews published in the Cochrane Library's pregnancy and childbirth module. Twenty-one of these 84 meta-analyses demonstrated statistical heterogeneity at p<0.10. The random effects model estimates showed wider confidence intervals, particularly in those meta-analyses showing heterogeneity in the trial results. The summary relative risk for the random effects model tended to show a larger protective treatment effect than the fixed effects model in the heterogeneous meta-analyses. In this set of meta-analyses, statistical evaluation of publication bias cannot be shown to account for heterogeneity. Our empirical conclusion is that there may be opposing effects if the random effects model is used in the meta-analysis of clinical trials showing heterogeneity in the results: stronger treatment effects reflected in the summary relative risk, but wider confidence intervals about this summary measure.