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Background C-reactive protein (CRP) point-of-care testing can reduce antibiotic use in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in primary care, without compromising patient care. Further safe reductions may be possible.Aim To investigate the associations between presenting features and antibiotic prescribing in patients with AECOPD in primary care.Design and setting Secondary analysis of a randomised controlled trial of participants presenting with AECOPD in primary care (the PACE trial).Method Clinicians collected participants’ demographic features, comorbid illnesses, clinical signs, and symptoms. Antibiotic prescribing decisions were made after participants were randomised to receive a point-of-care CRP measurement or usual care. Multivariable regression models were fitted to explore the association between patient and clinical features and antibiotic prescribing, and extended to further explore any interactions with CRP measurement category (CRP not measured, CRP Results A total of 649 participants from 86 general practices across England and Wales were included. Odds of antibiotic prescribing were higher in the presence of clinician-recorded crackles (adjusted odds ratio [AOR] = 5.22, 95% confidence interval [CI] = 3.24 to 8.41), wheeze (AOR = 1.64, 95% CI = 1.07 to 2.52), diminished vesicular breathing (AOR = 2.95, 95% CI = 1.70 to 5.10), or clinician-reported evidence of consolidation (AOR = 34.40, 95% CI = 2.84 to 417.27). Increased age was associated with lower odds of antibiotic prescribing (AOR per additional year increase = 0.98, 95% CI = 0.95 to 1.00), as was the presence of heart failure (AOR = 0.32, 95% CI = 0.12 to 0.85).Conclusion Several demographic features and clinical signs and symptoms are associated with antibiotic prescribing in AECOPD. Diagnostic and prognostic value of these features may help identify further safe reductions.

Katie H Sizeland,1 Hannah C Wells,2 Nigel M Kirby,3 Adrian Hawley,3 Stephen T Mudie,3 Tim M Ryan,3 Richard G Haverkamp2 1Human Health, ANSTO, Lucas Heights, Sydney, NSW 2234, Australia; 2School of Food and Advanced Technology, Massey University, Palmerston North 4472, New Zealand; 3SAXS/WAXS Beamline, Australian Synchrotron, ANSTO, Clayton, Melbourne, VIC 3168, AustraliaCorrespondence: Richard G HaverkampSchool of Food and Advanced Technology, Massey University, Private Bag 1112, Palmerston North 4472, New ZealandTel +64 6 356 9099Email r.haverkamp@massey.ac.nzBackground: Type I collagen is the major component of the extracellular matrix of the knee’s meniscus and plays a central role in that joint’s biomechanical properties. Repair and reconstruction of tissue damage often requires a scaffold to assist the body to rebuild. The middle zone of bovine meniscus is a material that may be useful for the preparation of extracellular matrix scaffolds.Methods: Here, synchrotron-based small-angle X-ray scattering (SAXS) patterns of bovine meniscus were collected during unconfined compression. Collagen fibril orientation, D-spacing, compression distance and force were measured.Results: The collagen fibrils in middle zone meniscal fibrocartilage become more highly oriented perpendicular to the direction of compression. The D-spacing also increases, from 65.0 to 66.3 nm with compression up to 0.43 MPa, representing a 1.8% elongation of collagen fibrils perpendicular to the compression.Conclusion: The elasticity of the collagen fibrils under tension along their length when the meniscus is compressed, therefore, contributes to the overall elastic response of the meniscus only under loads that exceed those likely to be experienced physiologically.Keywords: collagen, meniscus, compression, SAXS, scaffold

Additional file 1.

Background Little is known about clinicians’ experiences of using a point-of-care test (POCT) to inform management of urinary tract infection (UTI) in general practice.\ud \ud \ud Aim To explore experiences of using the Flexicult test to inform management of UTI and views on requirements for an optimal POCT to inform successful implementation.\ud \ud \ud Design & setting Telephone interviews with 35 primary care clinicians and healthcare professionals in Wales, England, Spain, and the Netherlands, who had participated in a trial of the Flexicult POCT for UTI based on urine culture.\ud \ud \ud Method Thematic analysis of semi-structured interviews.\ud \ud \ud Results Most primary care clinicians interviewed agreed on the need for a POCT in UTI management, and that the Flexicult POCT delivered quicker results than laboratory results used in usual care, reassured patients, boosted their confidence in decision-making, and reminded them about antibiotic stewardship. However, clinicians also reported difficulties in interpreting results, limitations on when the Flexicult could be used, and concerns that testing all patients would strain care delivery and prolong patient discomfort when delaying decisions until a non-rapid POCT result was available. An optimal POCT would produce more rapid results, and be reliable and easy to use. Uptake into routine care would be enhanced by: clear guidance on which patients should be tested; training for interpreting ‘grey area’ results; reiterating that even ‘straightforward’ cases might be better managed with a test; clear messages about stopping unnecessary antibiotics versus completing a course; and better self-management strategies to accompany implementation of delayed, or non-prescription of, antibiotics.\ud Conclusion Primary care clinicians believe that POCT tests could play a useful role in the management of UTI and gave clear recommendations for successful implementation.

Amphiphilic block copolymers with synthetic nucleobase-containing blocks as the hydrophobic segments were successfully synthesized using RAFT polymerisation and then self-assembled via solvent switch in aqueous solutions., Amphiphilic nucleobase-containing block copolymers with poly(oligo(ethylene glycol) methyl ether methacrylate) as the hydrophilic block and nucleobase-containing blocks as the hydrophobic segments were successfully synthesized using RAFT polymerization and then self-assembled via solvent switch in aqueous solutions. Effects of the common solvent on the resultant morphologies of the adenine (A) and thymine (T) homopolymers, and A/T copolymer blocks and blends were investigated. These studies highlighted that depending on the identity of the common solvent, DMF or DMSO, spherical micelles or bicontinuous micelles were obtained. We propose that this is due to the presence of A–T interactions playing a key role in the morphology and stability of the resultant nanoparticles, which resulted in a distinct system compared to individual adenine or thymine polymers. Finally, the effects of annealing on the self-assemblies were explored. It was found that annealing could lead to better-defined spherical micelles and induce a morphology transition from bicontinuous micelles to onion-like vesicles, which was considered to occur due to a structural rearrangement of complementary nucleobase interactions resulting from the annealing process.

We report the effect of low-energy thermal neutron irradiation on the antiproliferative activities of a highly hydrophobic organometallic arene ruthenium dithiolato–carborane complex [Ru(p-cymene) (1,2-dicarba-closo-dodecarborane-1,2-dithiolato)] (1), and of its formulation in Pluronic® triblock copolymer P123 core–shell micelles (RuMs). Complex 1 was highly active, with and without neutron irradiation, towards human ovarian cancer cells (A2780; IC50 0.14 μM and 0.17 μM, respectively) and cisplatin-resistant human ovarian cancer cells (A2780cisR; IC50 0.05 and 0.13 μM, respectively). Complex 1 was particularly sensitive to neutron irradiation in A2780cisR cells (2.6 × more potent after irradiation compared to non-irradiation). Although less potent, the encapsulated complex 1 as RuMs nanoparticles resulted in higher cellular accumulation (2.5×), and was sensitive to neutron irradiation in A2780 cells (1.4× more potent upon irradiation compared to non-irradiation).

Table S1. Review quality according to selected AMSTAR criteria. (DOCX 21 kb)

SPIRIT 2013 Checklist: recommended items to address in a clinical trial protocol and related documents. (DOC 123 kb)

A series of poly(L lactide) b poly(acrylic acid) (PLLA b PAA) diblock copolymers with a range of hydrophobic or hydrophilic block lengths were designed in order to tune the size of the resultant cylindrical micelles using a crystallization driven self assembly (CDSA) approach. The precursor poly(L lactide) b poly(tetrahydropyran acrylate) (PLLA b PTHPA) was synthesized by a combination of ring opening polymerization (ROP) and reversible addition fragmentation chain transfer (RAFT) polymerization. The CDSA process was carried out in tetrahydrofuran/water (THF/H2O) mixture during the hydrolysis of PTHPA block at 65 °C using an evaporation method. A majority of PLLA b PAA diblock copolymers resulted in the formation of cylindrical micelles with narrow size distribution (Lw/Ln < 1.30) as determined by transmission electron microscopy (TEM) and dynamic light scattering (DLS). Furthermore the length of PLLA block was found to control the length of the resultant cylindrical micelles while the length of PAA block governed their widths. Synchrotron small angle X ray scattering (SAXS) further proved that the length increase of these cylinders was a consequence of the decreasing PLLA block lengths. The crystalline core nature of these cylinders was characterized by wide angle X ray diffraction (WAXD) and the relative core crystallinity was calculated to compare different samples. Both the hydrophobic weight fraction and the relative core crystallinity were found to determine the geometry of the formed PLLA b PAA cylindrical micelles. Finally changing the pH conditions of the CDSA process was found to have no significant effect on tuning the resultant dimensions of the cylinders.

The recommended treatment of side effects that may occur when receiving everolimus. (PDF 41 kb)

Frequency categories of adverse reactions reported in the pooled analysis considered for the safety pooling. (PDF 76 kb)

SPIRIT checklist of key issues addressed in the trial protocol. (PDF 59 kb)

Neuropsychological assessment schedule of all neuropsychological assessments to be carried out as part of the trial. (PDF 53 kb)

Study assessment schedule of all assessments to be carried out as part of the trial. (PDF 46 kb)

Polymer self-assembly in solution is a simple strategy for the preparation of elegant yet complex nanomaterials. However, exhaustive synthesis of the copolymer synthons is often required to access specific assemblies. In this work we show that the blending of just two diblock copolymers with identical block lengths but varying hydrophobic monomer incorporations can be used to access a range of assemblies of intermediate hydrophobic composition. Indeed, the nanostructures produced from blending are identical to those formed with the directly synthesized copolymer of the same composition. This new approach presents researchers with a more efficient and accessible methodology to access precision self-assembled nanostructures, and we highlight its potential by applying it to a demonstrator catalytically active system.\ud

AB and ABA di- and triblock copolymers where A is the hydrophilic poly(oligoethylene glycol methacrylate) (POEGMA) block and B is a thermo-responsive sulfobetaine block [2-(methacryloyloxy) ethyl] dimethyl-(3-sulfopropyl) ammonium hydroxide (PDMAPS) were synthesised by aqueous RAFT polymerisation with narrow dispersity (ĐM ≤ 1.22), as judged by aqueous SEC analysis. The di- and triblock copolymers self-assembled in salt-free water to form micelles with a PDMAPS core and the self-assembly of these polymers was explored by SLS and TEM analysis. The micelles were shown, by DLS analysis, to undergo a micelle-to-unimer transition at a critical temperature, which was dependent upon the length of the POEGMA block. Increasing the length of the third, POEGMA, block decreased the temperature at which the micelle-to-unimer transition occurred as a result of the increased hydrophilicity of the polymer. The dissociation of the micelles was further studied by SLS and synchrotron SAXS. SAXS analysis revealed that the micelle dissociation began at temperatures below that indicated by DLS analysis and that both micelles and unimers coexist. This highlights the importance of using multiple complementary techniques in the analysis of self-assembled structures. In addition the micelle-to-unimer morphology transition was employed to encapsulate and release a hydrophobic dye, Nile Red, as shown by fluorescence spectroscopy.\ud

Co-crystallization of polymers with different configurations/tacticities provides access to materials with enhanced performance. The stereocomplexation of isotactic poly(L-lactide) and poly(D-lactide) has led to improved properties compared with each homochiral material. Herein, we report the preparation of stereocomplex micelles from a mixture of poly(L-lactide)-b-poly(acrylic acid) and poly(D-lactide)-b-poly(acrylic acid) diblock copolymers in water via crystallization-driven self-assembly. During the formation of these stereocomplex micelles, an unexpected morphological transition results in the formation of dense crystalline spherical micelles rather than cylinders. Furthermore, mixture of cylinders with opposite homochirality in either THF/H2O mixtures or in pure water at 65 °C leads to disassembly into stereocomplexed spherical micelles. Similarly, a transition is also observed in a related PEO-b-PLLA/PEO-b-PDLA system, demonstrating wider applicability. This new mechanism for morphological reorganization, through competitive crystallization and stereocomplexation and without the requirement for an external stimulus, allows for new opportunities in controlled release and delivery applications., A polymer stereocomplex can possess quite different properties to its constituent homopolymers. Here, the authors prepare stereocomplex micelles of amphiphilic block-copolymers via crystallization-driven self-assembly, and observe a change from cylindrical to mixed spherical micelle morphology.

We report the encapsulation of highly hydrophobic 16-electron organometallic ruthenium and osmium carborane complexes [Ru/Os(p-cymene)(1,2-dicarba-closo-dodecarborane-1,2-dithiolate)] (1 and 2) in Pluronic® triblock copolymer P123 core–shell micelles. The spherical nanoparticles RuMs and OsMs, dispersed in water, were characterized by dynamic light scattering (DLS), cryogenic transmission electron microscopy (cryo-TEM), and synchrotron small-angle X-ray scattering (SAXS; diameter ca. 15 and 19 nm, respectively). Complexes 1 and 2 were highly active towards A2780 human ovarian cancer cells (IC50 0.17 and 2.50 μM, respectively) and the encapsulated complexes, as RuMs and OsMs nanoparticles, were less potent (IC50 6.69 μM and 117.5 μM, respectively), but more selective towards cancer cells compared to normal cells.\ud

The synthesis of nucleobase-containing polymers was successfully performed by RAFT dispersion polymerization in both chloroform and 1,4-dioxane and self-assembly was induced by the polymerizations. A combination of scattering and microscopy techniques were used to characterize the morphologies. It is found that the morphologies of self-assembled nucleobase-containing polymers are solvent dependent. By varying the DP of the core-forming block, only spherical micelles with internal structures were obtained in chloroform when using only adenine-containing methacrylate or a mixture of adenine-containing methacrylate and thymine-containing methacrylate as monomers. However, higher order structures and morphology transitions were observed in 1,4-dioxane. A sphere-rod-lamella-twisted bilayer transition was observed in this study. Moreover, the kinetics of the dispersion polymerizations were studied in both solvents, suggesting a different formation mechanism in these systems.\ud

Metal nanocrystals offer new concepts for the design of nanodevices with a range of potential applications. Currently the formation of metal nanocrystals cannot be controlled at the level of individual atoms. Here we describe a new general method for the fabrication of multi-heteroatom-doped graphitic matrices decorated with very small, ångström-sized, three-dimensional (3D)-metal crystals of defined size. We irradiate boron-rich precious-metal-encapsulated self-spreading polymer micelles with electrons and produce, in real time, a doped graphitic support on which individual osmium atoms hop and migrate to form 3D-nanocrystals, as small as 15 Å in diameter, within 1 h. Crystal growth can be observed, quantified and controlled in real time. We also synthesize the first examples of mixed ruthenium–osmium 3D-nanocrystals. This technology not only allows the production of ångström-sized homo- and hetero-crystals, but also provides new experimental insight into the dynamics of nanocrystals and pathways for their assembly from single atoms.

Refereed/Peer-reviewed Hypothesis: Dairy proteins and mono- and diglycerides (MDG) are often used in unison to tailor the properties of dairy-based emulsions. However, there are significant gaps in our understanding of how proteins affect lipid crystallisation at the oil–water interface. We have used a unique combination of interfacially-sensitive techniques to elucidate the impact of dairy proteins on interfacial MDG crystal formation. Experiments: The formation temperature of interfacial MDG crystals was assessed through interfacial tension studies via drop shape analysis. Small and Wide-Angle X-ray Scattering measurements were performed on isolated oil–water interfaces, allowing for in-situ interrogation of MDG crystal structure and concentration at and near the interface. Findings: Dairy proteins are seen to reduce the temperature at which MDG crystals form at the oil–water interface. The displacement of proteins upon interfacial crystal formation was also clearly observed in interfacial tension measurements. For the first time, lipid crystals formed at the oil–water interface have been characterised using X-ray scattering. All scattering studies showed no change to the MDG crystal structures at the oil–water interface in the presence of adsorbed proteins. The results demonstrate that informed selection of emulsifier components is critical to controlling interfacial crystallisation with concomitant impact on emulsion stability.

Plant growth and survival depend upon the activity of membrane transporters that control the movement and distribution of solutes into, around, and out of plants. Although many plant transporters are known, their intrinsic properties make them difficult to study. In barley (Hordeum vulgare), the root anion-permeable transporter Bot1 plays a key role in tolerance to high soil boron, facilitating the efflux of borate from cells. However, its three-dimensional structure is unavailable and the molecular basis of its permeation function is unknown. Using an integrative platform of computational, biophysical, and biochemical tools as well as molecular biology, electrophysiology, and bioinformatics, we provide insight into the origin of transport function of Bot1. An atomistic model, supported by atomic force microscopy measurements, reveals that the protein folds into 13 transmembrane-spanning and five cytoplasmic a-helices. We predict a trimeric assembly of Bot1 and the presence of a Na+ ion binding site, located in the proximity of a pore that conducts anions. Patch-clamp electrophysiology of Bot1 detects Na+-dependent polyvalent anion transport in a Nernstian manner with channel-like characteristics. Using alanine scanning, molecular dynamics simulations, and transport measurements, we show that conductance by Bot1 is abolished by removal of the Na+ ion binding site. Our data enhance the understanding of the permeation functions of Bot1. Refereed/Peer-reviewed

Lipid-based liquid crystalline systems are showing potential as stimuli-responsive nanomaterials, and NIR-responsive gold nanoparticles have been demonstrated to provide control of transitions in nonlamellar phases. In this study, we focus on a deeper understanding of the photothermal response of both lamellar and non-lamellar phases, and new systems formed by alternative lipid systems not previously reported, by linking the photothermal heating to the bulk thermal properties of the materials. Dynamic photothermal studies were performed using NIR laser irradiation and monitoring the structural response using time resolved small angle X-ray scattering for the bulk phases and hexosomes. In addition, cryoFESEM and cryoTEM were used to visualise and assess the effect of GNR incorporation into hexagonal phase nanostructures. The ability of the systems to respond to photothermal heating was correlated with the thermal phase behaviour and heat capacities of the different structures. Access to alternative phase transitions in these systems and understanding the likely photothermal response will facilitate different modes of application of these hybrid nanomaterials for on-demand drug delivery applications. Refereed/Peer-reviewed

Lipid-based liquid-crystalline matrixes provide a unique prospect for stimuli-responsive nanomaterials, attributed to the ability to effect self-assembly of the lipids at the molecular level. Differences in liquid crystal nanostructure have previously been shown to change drug diffusion and hence release, with research progressing toward the use of in situ changes to nanostructure to control drug release. Toward this goal, we have previously communicated the ability to switch between nonlamellar structures using gold nanorod (GNR)−phytantriol-based liquid-crystalline hybrid nanomaterials as near-infrared light responsive systems (Fong et al. Langmuir 2010, 26, 6136− 6139). In this study, the effect of laser activation on matrix nanostructure with changes in a number of system variables including lipid composition, GNR aspect ratio, GNR concentration, and laser pulse time were investigated. The nanostructure of the matrix was followed using small-angle X-ray scattering, while both cryoFESEM and cryoTEM were used to visualize the effect of GNR incorporation into the liquid crystal nanostructure. The system response was found to be dependent on all variables, thus demonstrating the potential of these nanocomposite materials as reversible "on-demand" drug delivery applications. Refereed/Peer-reviewed

The nanostructure of mesophase liquid crystals prepared from amphiphilic lipids controls the rate of release of incorporated agents from the material, such as drug molecules, and reversible transition between different nanostructures essentially provides an "on-off" switch for release (Fong, W.-K.; Hanley, T.; Boyd, B. J. J. Controlled Release 2009, 135, 218-226). In this study, the incorporation of plasmonic hydrophobized gold nanorods (GNRs) permits reversible manipulation of nanostructure on-demand, by irradiation of the matrix using a near-infrared laser. Synchrotron small-angle X-ray scattering was used to probe the kinetics of the response of nanostructure to laser irradiation, and the specificity of the approach is shown by the lack of response in the absence of nanorods, or for GNR whose dimensions are not matched to the specific wavelength of the incident light.