Increasing Navigation Speed at Endoluminal CT Colonography Reduces Colonic Visualization and Polyp Identification.

Purpose To investigate the effect of increasing navigation speed on the visual search and decision making during polyp identification for computed tomography (CT) colonography Materials and Methods Institutional review board permission was obtained to use deidentified CT colonography data for this prospective reader study. After obtaining informed consent from the readers, 12 CT colonography fly-through examinations that depicted eight polyps were presented at four different fixed navigation speeds to 23 radiologists. Speeds ranged from 1 cm/sec to 4.5 cm/sec. Gaze position was tracked by using an infrared eye tracker, and readers indicated that they saw a polyp by clicking a mouse. Patterns of searching and decision making by speed were investigated graphically and by multilevel modeling. Results Readers identified polyps correctly in 56 of 77 (72.7%) of viewings at the slowest speed but in only 137 of 225 (60.9%) of viewings at the fastest speed (P = .004). They also identified fewer false-positive features at faster speeds (42 of 115; 36.5%) of videos at slowest speed, 89 of 345 (25.8%) at fastest, P = .02). Gaze location was highly concentrated toward the central quarter of the screen area at faster speeds (mean gaze points at slowest speed vs fastest speed, 86% vs 97%, respectively). Conclusion Faster navigation speed at endoluminal CT colonography led to progressive restriction of visual search patterns. Greater speed also reduced both true-positive and false-positive colorectal polyp identification. © RSNA, 2017 Online supplemental material is available for this article.

A Bayesian approach to sequential meta-analysis.

As evidence accumulates within a meta-analysis, it is desirable to determine when the results could be considered conclusive to guide systematic review updates and future trial designs. Adapting sequential testing methodology from clinical trials for application to pooled meta-analytic effect size estimates appears well suited for this objective. In this paper, we describe a Bayesian sequential meta-analysis method, in which an informative heterogeneity prior is employed and stopping rule criteria are applied directly to the posterior distribution for the treatment effect parameter. Using simulation studies, we examine how well this approach performs under different parameter combinations by monitoring the proportion of sequential meta-analyses that reach incorrect conclusions (to yield error rates), the number of studies required to reach conclusion, and the resulting parameter estimates. By adjusting the stopping rule thresholds, the overall error rates can be controlled within the target levels and are no higher than those of alternative frequentist and semi-Bayes methods for the majority of the simulation scenarios. To illustrate the potential application of this method, we consider two contrasting meta-analyses using data from the Cochrane Library and compare the results of employing different sequential methods while examining the effect of the heterogeneity prior in the proposed Bayesian approach. Copyright © 2016 John Wiley & Sons, Ltd.

Rapid Macrocycle Threading by a Fluorescent Dye-Polymer Conjugate in Water with Nanomolar Affinity.

A macrocyclic tetralactam host is threaded by a highly fluorescent squaraine dye that is flanked by two polyethylene glycol (PEG) chains with nanomolar dissociation constants in water. Furthermore, the rates of bimolecular association are very fast with k(on) ≈ 10(6)-10(7) M(-1) s(-1). The association is effective under cell culture conditions and produces large changes in dye optical properties including turn-on near-infrared fluorescence that can be imaged using cell microscopy. Association constants in water are ∼1000 times higher than those in organic solvents and strongly enthalpically favored at 27 °C. The threading rate is hardly affected by the length of the PEG chains that flank the squaraine dye. For example, macrocycle threading by a dye conjugate with two appended PEG2000 chains is only three times slower than threading by a conjugate with triethylene glycol chains that are 20 times shorter. The results are a promising advance toward synthetic mimics of streptavidin/biotin.

Clean Photothermal Heating and Controlled Release from Near-Infrared Dye Doped Nanoparticles without Oxygen Photosensitization.

The photothermal heating and release properties of biocompatible organic nanoparticles, doped with a near-infrared croconaine (Croc) dye, were compared with analogous nanoparticles doped with the common near-infrared dyes ICG and IR780. Separate formulations of lipid-polymer hybrid nanoparticles and liposomes, each containing Croc dye, absorbed strongly at 808 nm and generated clean laser-induced heating (no production of (1)O2 and no photobleaching of the dye). In contrast, laser-induced heating of nanoparticles containing ICG or IR780 produced reactive (1)O2, leading to bleaching of the dye and also decomposition of coencapsulated payload such as the drug doxorubicin. Croc dye was especially useful as a photothermal agent for laser-controlled release of chemically sensitive payload from nanoparticles. Solution state experiments demonstrated repetitive fractional release of water-soluble fluorescent dye from the interior of thermosensitive liposomes. Additional experiments used a focused laser beam to control leakage from immobilized liposomes with very high spatial and temporal precision. The results indicate that fractional photothermal leakage from nanoparticles doped with Croc dye is a promising method for a range of controlled release applications.

Expanding the scope of the anion templated synthesis of interlocked structures.

Nature achieves impressively strong and selective complexation of small molecule anions through the elaborate binding sites of sophisticated proteins. Inspired by these examples, we have developed an anion templation strategy for the synthesis of mechanically interlocked host structures for anion recognition applications. Upon removal of the discrete anionic templating species, such host systems possess unique, three-dimensional, geometrically restrained cavities containing convergent hydrogen bond donor atoms. Such structures exhibit high affinity binding selectivity toward complementary anions. This Account describes recent advances in this anion templation meth odology, demonstrating the versatility and scope of this approach, and progressing to more diverse architectures. Specifically, we have prepared an expansive range of interlocked hosts with enhanced anion recognition properties, such as the ability to operate effectively in competitive aqueous media. We have produced these structures through the utilization of a new anion templated amide condensation synthetic method and through the incorporation of a range of different anion binding motifs, such as groups capable of effective solution-phase halogen bonding interactions. Importantly, direct comparisons between halogen bonding and hydrogen bonding systems reveal impressively magnified anion recognition properties for halogen bonding interlocked host systems. We have also employed the anion templation strategy successfully to construct selective electrochemical and luminescent anion sensors, as well as architectures of increasing complexity, such as a triply interlocked capsule and a handcuff catenane. The synthesis of these latter examples presents greater challenges; however, such molecules offer additional applications in higher order recognition and sensing and in switchable molecular devices. Having established anion templation as a viable synthetic route to interlocked architectures, we have used this strategy to fabricate a multitude of innovative structures. The key principles of this approach are the ability of anionic species to template the association of carefully designed components, and of the resulting molecular framework with its interlocked host cavity to display impressive anion recognition selectivity. Mechanically interlocked structures have numerous potential applications in nanotechnology. Therefore, the continuing development of effective synthetic methods, especially those which yield functional systems, is of great interest in the broad interdisciplinary field of supramolecular chemistry.

Near-infrared croconaine rotaxanes and doped nanoparticles for enhanced aqueous photothermal heating.

The photothermal effect is the generation of heat by molecules or particles upon high-energy laser irradiation, and near-infrared absorbers such as gold nanoparticles and organic dyes have a range of potential photothermal applications. The favourable photothermal properties of thiophene-functionalised croconaine dyes were recently discovered. The synthesis and properties of novel croconaine rotaxane and pseudorotaxane architectures capable of efficient photothermal performance in both organic and aqueous environments are reported. The versatility of this dye-encapsulation strategy was demonstrated by the preparation of two organic croconaine rotaxanes using different synthetic methods: the formation of an aqueous pseudorotaxane association complex, and the synthesis of water-soluble, croconaine-doped silicated micelle nanoparticles. All of these near-infrared-absorbing systems exhibit excellent photothermal behaviour, with pseudorotaxane and rotaxane formation vital for effective aqueous heat generation. Dye encapsulation provides steric protection to enhance the stability of a water-sensitive croconaine dye, while rotaxane-doped nanoparticles avoid detrimental band broadening caused by chromophore coupling.

Anion-induced shuttling of a naphthalimide triazolium rotaxane.

The anion-templated synthesis of a rotaxane structure, incorporating the new naphthalimide triazolium motif, is described and the interlocked host shown to exhibit selective, uni-directional, anion-induced shuttling. Initial pseudorotaxane investigations demonstrate the ability of a naphthalimide triazolium threading component to form interpenetrated assemblies with counter-anion-dependent co-conformations. (1)H NMR studies reveal that the shuttling behaviour of the analogous rotaxane host system is controlled by selective anion binding and by the nature of the solvent conditions. Complete macrocycle translocation only occurs upon the recognition of the smaller halide anions (chloride and bromide). The rotaxane solid-state crystal structure in the presence of chloride is in agreement with the solution-phase co-conformation. The sensitivity of the axle naphthalimide absorbance band to the position of the macrocycle component within the interlocked structure enabled the molecular motion to be observed by UV/Vis spectroscopy, and the chloride-induced shuttling of the rotaxane was reversed upon silver hexafluorophosphate addition.

Investigating the effect of macrocycle size in anion templated imidazolium-based interpenetrated and interlocked assemblies.

The effect of varying the size of the macrocycle component on the formation of anion templated imidazolium interpenetrated assemblies is investigated. Two different approaches to reducing the macrocycle size are undertaken and the stabilities of the resulting pseudorotaxanes incorporating substituted imidazolium threading components studied using (1)H NMR spectroscopy. Novel imidazolium axle containing interlocked rotaxane host structures are synthesised using chloride anion templated amide condensation and 'stoppering' methods, and the anion recognition properties of the 'stoppered' rotaxane investigated.

Investigating the imidazolium­anion interaction through the anion-templated construction of interpenetrated and interlocked assemblies.

The interaction between imidazolium cations and coordinating anions is investigated through the anion-templated assembly of interpenetrated and interlocked structures. The orientation of the imidazolium motif with respect to anion binding, and hence the hydrogen bond donor arrangement, was varied in acyclic receptors, interpenetrated assemblies, and the first mono-imidazolium interlocked systems. Their anion recognition properties and co-conformations were studied by solution-phase 1H NMR investigations, solid-state structures, molecular dynamics simulations, and density functional theory calculations. Our findings suggest that the imidazolium-anion binding interaction is dominated by electrostatics with hydrogen-bonding contributions having weak orientational dependence.

Effects of Lumbar Spine Abnormality and Serve Types on Lumbar Kinematics in Elite Adolescent Tennis Players.

BACKGROUND: Low back pain (LBP) is pervasive among elite junior tennis players. Previous research has explored the relationship between serving mechanics and LBP, though the participants in these studies had already experienced LBP. Therefore, it is unclear whether their serving mechanics caused the LBP or are a result of having LBP. Thus, the purpose of this study was to compare the flat and kick serve kinematics of asymptomatic elite adolescent male and female tennis players with and without lumbar spine abnormalities. Twenty-four players (nine of which had confirmed lumbar spine abnormalities) carried out a series of flat and kick serves, while marker trajectories were recorded by a 3D motion capture system. Pelvis and lumbar spine kinematics (anterior/posterior tilt, lateral tilt, axial rotation and flexion/extension, lateral flexion and axial rotation respectively) were compared between players with and without lumbar spine abnormalities, genders, and serve types using a mixed-effects model. Exploratory data pertaining to the order and timing of key serve events was also collected. RESULTS: Males had significantly greater posterior pelvis tilt than females during the drive phase of both flat (M, - 7.1 ± 5°; F, 4 ± 5.5°) and kick serves (M, - 8.6 ± 5.1°; F, 2.1 ± 5.8°). Independent of serve type, males also impacted the ball ~ 15 cm further into the court than females, while all players contacted flat serves significantly further forward (~ 17 cm). There were no effects for abnormality in the magnitude of pelvis and trunk kinematics. The order and timing of key serve events, however, did tend to differ between those with and without lumbar spine abnormalities. Players with abnormalities entered peak front knee flexion and initiated pelvis rotation earlier than players without abnormalities. Lastly, the timing of pelvis rotation was highly variable among females though not males. CONCLUSION: Pelvis and ball toss kinematics vary with gender and serve type but not necessarily abnormality in the elite adolescent serve. There is evidence to suggest that the order and timing of key serve events might help to identify those at risk of lumbar spine abnormalities; however, further research is needed to investigate the statistical significance of the timing of these events.

Essential components in natriuretic peptide-guided management of heart failure: an intervention synthesis.

Aim: To identify the key components of natriuretic peptide (NP)-guided treatment interventions which reduced hospitalisation in patients with heart failure (HF). Methods and results: We extracted detailed information on the components of interventions from studies of NP-guided treatment of HF identified in a previous systematic review. We used meta-regression techniques to assess univariate associations between components and the strength of the reduction in HF hospitalisations and all-cause mortality. A Bayesian meta-analysis approach was used to re-estimate study-level effects in order to identify the study with the most effective NP-guided monitoring intervention. Finally, we examined the intervention options common to the studies in which the 95% credible interval excluded no effect. We identified eight components of NP-guided treatment from ten studies. Univariate comparisons produced mainly equivocal results, but single trial choice and common components analysis led to similar conclusions. Using a predefined treatment protocol, setting a stringent NP target (N-terminal pro-B-type natriuretic peptide of 1000 pg/mL or B-type natriuretic peptide 100 pg/mL) and including a relative targetwere potential key components to reducing HF hospitalisations using NP-guided therapy. Conclusion: This analysis provides a description of the key components of NP-guided treatment which could help policy makers develop specific recommendations for HF management. Our research suggests that NP-guided interventions could be simplified, but more research in relevant health settings, such as primary care, is required.

A large-scale assessment of temporal trends in meta-analyses using systematic review reports from the Cochrane Library.

INTRODUCTION: Previous studies suggest that many systematic reviews contain meta-analyses that display temporal trends, such as the first study's result being more extreme than later studies' or a drift in the pooled estimate. We assessed the extent and characteristics of temporal trends using all Cochrane intervention reports published 2008-2012. METHODS: We selected the largest meta-analysis within each report and analysed trends using methods including a Z-test (first versus subsequent estimates); generalised least squares; and cumulative sum charts. Predictors considered include meta-analysis size and review group. RESULTS: Of 1288 meta-analyses containing at least 4 studies, the point estimate from the first study was more extreme and in the same direction as the pooled estimate in 738 (57%), with a statistically significant difference (first versus subsequent) in 165 (13%). Generalised least squares indicated trends in 717 (56%); 18% of fixed effects analyses had at least one violation of cumulative sum limits. For some methods, meta-analysis size was associated with temporal patterns and use of a random effects model, but there was no consistent association with review group. CONCLUSIONS: All results suggest that more meta-analyses demonstrate temporal patterns than would be expected by chance. Hence, assuming the standard meta-analysis model without temporal trend is sometimes inappropriate. Factors associated with trends are likely to be context specific.

Selective photothermal inactivation of cells labeled with near-infrared croconaine dye.

Photothermal inactivation of cells caused by laser heating of a near-infrared croconaine dye is more effective when the dye is located inside the cell. The cell inactivation is spatially confined - laser irradiation of a mixed population of two different cell lines produces selective inactivation of the cells labeled with croconaine dye and does not harm adjacent unlabeled cells.

Anion binding induced conformational changes exploited for recognition, sensing and pseudorotaxane disassembly.

Investigations to exploit the anion binding induced conformational changes displayed by a new class of acyclic receptor for anion recognition, fluorescence sensing and pseudorotaxane disassembly are described. A series of imidazolium-appended bis-amide-pyridine, pyridine N-oxide and pyridinium containing receptors are synthesised and their anion binding properties elucidated using (1)H NMR spectroscopy. Upon anion recognition, the receptors exhibit a substantial conformational change from an 'open' to a more 'closed' intramolecular geometry. The fluorescence anion sensing ability of a bis-pyrene-functionalised analogue is investigated, with anion-induced responses arising from excimer signalling mechanisms. A pseudorotaxane assembly formed between the pyridine N-oxide receptor acting as a threading component and an isophthalamide macrocycle is demonstrated to undergo disassembly resulting from the conformational behaviour exhibited by the thread upon chloride binding.