Single-nanometer iron oxide nanoparticles as tissue-permeable MRI contrast agents.

Magnetic nanoparticles are robust contrast agents for MRI and often produce particularly strong signal changes per particle. Leveraging these effects to probe cellular- and molecular-level phenomena in tissue can, however, be hindered by the large sizes of typical nanoparticle contrast agents. To address this limitation, we introduce single-nanometer iron oxide (SNIO) particles that exhibit superparamagnetic properties in conjunction with hydrodynamic diameters comparable to small, highly diffusible imaging agents. These particles efficiently brighten the signal in T1-weighted MRI, producing per-molecule longitudinal relaxation enhancements over 10 times greater than conventional gadolinium-based contrast agents. We show that SNIOs permeate biological tissue effectively following injection into brain parenchyma or cerebrospinal fluid. We also demonstrate that SNIOs readily enter the brain following ultrasound-induced blood-brain barrier disruption, emulating the performance of a gadolinium agent and providing a basis for future biomedical applications. These results thus demonstrate a platform for MRI probe development that combines advantages of small-molecule imaging agents with the potency of nanoscale materials.

Clinically Translatable Transcrocetin Delivery Platform for Correction of Tumor Hypoxia and Enhancement of Radiation Therapy Effects.

Improving the tumor reoxygenation to sensitize the tumor to radiation therapy is a cornerstone in radiation oncology. Here, the pre-clinical development of a clinically transferable liposomal formulation encapsulating trans sodium crocetinate (NP TSC) is reported to improve oxygen diffusion through the tumor environment. Early pharmacokinetic analysis of the clinical trial of this molecule performed on 37 patients orient to define the optimal fixed dosage to use in a triple-negative breast cancer model to validate the therapeutic combination of radiation therapy and NP TSC. Notably, it is reported that this formulation is non-toxic in both humans and mice at the defined fixed concentration, provides a normalization of the tumor vasculature within 72 h window after systemic injection, leads to a transient increase (50% improvement) in the tumor oxygenation, and significantly improves the efficacy of both mono-fractionated and fractionated radiation therapy treatment. Together, these findings support the introduction of a first-in-class therapeutic construct capable of tumor-specific reoxygenation without associated toxicities.

Metal-based imaging agents: progress towards interrogating neurodegenerative disease.

Central nervous system (CNS) neurodegeneration is defined by a complex series of pathological processes that ultimately lead to death. The precise etiology of these disorders remains unknown. Recent efforts show that a mechanistic understanding of the malfunctions underpinning disease progression will prove requisite in developing new treatments and cures. Transition metals and lanthanide ions display unique characteristics (i.e., magnetism, radioactivity, and luminescence), often with biological relevance, allowing for direct application in CNS focused imaging modalities. These techniques include positron emission tomography (PET), single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), and luminescent-based imaging (LumI). In this Tutorial Review, we have aimed to highlight the various metal-based imaging techniques developed in the effort to understand the pathophysiological processes associated with neurodegeneration. Each section has been divided so as to include an introduction to the particular imaging technique in question. This is then followed by a summary of key demonstrations that have enabled visualization of a specific neuropathological biomarker. These strategies have either exploited the high binding affinity of a receptor for its corresponding biomarker or a specific molecular transformation caused by a target species, all of which produce a concomitant change in diagnostic signal. Advantages and disadvantages of each method with perspectives on the utility of molecular imaging agents for understanding the complexities of neurodegenerative disease are discussed.

Constraining Ion-Scale Heating and Spectral Energy Transfer in Observations of Plasma Turbulence.

We perform a statistical study of the turbulent power spectrum at inertial and kinetic scales observed during the first perihelion encounter of the Parker Solar Probe. We find that often there is an extremely steep scaling range of the power spectrum just above the ion-kinetic scales, similar to prior observations at 1 A.U., with a power-law index of around -4. Based on our measurements, we demonstrate that either a significant (>50%) fraction of the total turbulent energy flux is dissipated in this range of scales, or the characteristic nonlinear interaction time of the turbulence decreases dramatically from the expectation based solely on the dispersive nature of nonlinearly interacting kinetic Alfvén waves.

Covalent Attachment of Active Enzymes to Upconversion Phosphors Allows Ratiometric Detection of Substrates.

Upconverting phosphors (UCPs) convert multiple low energy photons into higher energy emission via the process of photon upconversion and offer an attractive alternative to organic fluorophores for use as luminescent probes. Here, UCPs were capped with functionalized silica in order to provide a surface to covalently conjugate proteins with surface-accessible cysteines. Variants of green fluorescent protein (GFP) and the flavoenzyme pentaerythritol tetranitrate reductase (PETNR) were then attached via maleimide-thiol coupling in order to allow energy transfer from the UCP to the GFP or flavin cofactor of PETNR, respectively. PETNR retains its activity when coupled to the UCPs, which allows reversible detection of enzyme substrates via ratiometric sensing of the enzyme redox state.

Does the Partners in Health scale allow meaningful comparisons of chronic condition self-management between men and women? Testing measurement invariance.

AIMS: To determine if the Partners in Health scale, pertinent to assessing patient chronic condition self-management, operates equivalently for men and women. BACKGROUND: There are distinct gender-based differences in self-management behaviours and health perceptions. This may introduce non-invariance in self-report measures. Testing of measurement invariance is a recommended practice in nursing science to ensure robust metrics. DESIGN: A representative cross-sectional population survey in South Australian. METHOD: In 2014, 940 people responded to the South Australian Health Omnibus Survey, a battery of health-related questions. MI and estimation of heterogeneity was tested using Bayesian confirmatory factor analysis. RESULTS: Findings showed self-management constructs were interpreted equivalently between men and women. Observed population heterogeneity associated lower education levels with poorer illness and treatment knowledge, smokers with poorer treatment partnerships and mental health problems with lower coping capacity. CONCLUSION: Approximate measurement invariance was achieved between men and women for Partners in Health scale. IMPACT: There is a lack of well-validated generic instruments, including investigation into gender variability, for measuring chronic condition self-management behaviours. Lower education levels were found to connect with poorer knowledge of health condition and treatment. Mental health problems attenuated ability to cope with the effect of the condition. Findings can facilitate the development of better tailored interventions for self-management of patients' chronic condition/s.

How does routinely delivered cognitive-behavioural therapy for gambling disorder compare to "gold standard" clinical trial?

Currently, it is unknown whether treatment outcomes derived from randomized controlled trials (RCTs) of cognitive-behavioural therapy (CBT) for problem gamblers still hold when applied to patients seen in routine practice. Thus, data from an RCT of cognitive therapy versus exposure therapy for problem gambling versus patients of a gambling help service were compared. Assessments of problem gambling severity, psychosocial impairment, and alcohol use were undertaken at baseline and post-treatment and evaluated within a counterfactual framework. Findings showed that the contrast between routine CBT for pokies and horse betting had a significant effect, indicative of a 62% lower gambling urge score if routine CBT recipients had all been horse/track betters opposed to gambling with "pokies." However, the majority of contrasts indicated therapeutic outcomes achieved in routine CBT treatments were of equivalent robustness relative to RCT conditions. The present findings infer routine practice treatment outcomes are as efficacious as those generated in RCT contexts.

Sensing Uranyl(VI) Ions by Coordination and Energy Transfer to a Luminescent Europium(III) Complex.

The release of uranyl(VI) is a hazardous environmental issue, with limited ways to monitor accumulation in situ. Here, we present a method for the detection of uranyl(VI) ions through the utilization of a unique fluorescence energy transfer process to europium(III). Our system displays the first example of a "turn-on" europium(III) emission process with a small, water-soluble lanthanide complex triggered by uranyl(VI) ions.

A new paramagnetically shifted imaging probe for MRI.

PURPOSE: To develop and characterize a new paramagnetic contrast agent for molecular imaging by MRI. METHODS: A contrast agent was developed for direct MRI detection through the paramagnetically shifted proton magnetic resonances of two chemically equivalent tert-butyl reporter groups within a dysprosium(III) complex. The complex was characterized in phantoms and imaged in physiologically intact mice at 7 Tesla (T) using three-dimensional (3D) gradient echo and spectroscopic imaging (MRSI) sequences to measure spatial distribution and signal frequency. RESULTS: The reporter protons reside ∼6.5 Å from the paramagnetic center, resulting in fast T1 relaxation (T1 = 8 ms) and a large paramagnetic frequency shift exceeding 60 ppm. Fast relaxation allowed short scan repetition times with high excitation flip angle, resulting in high sensitivity. The large dipolar shift allowed direct frequency selective excitation and acquisition of the dysprosium(III) complex, independent of the tissue water signal. The biokinetics of the complex were followed in vivo with a temporal resolution of 62 s following a single, low-dose intravenous injection. The lower concentration limit for detection was ∼23 µM. Through MRSI, the temperature dependence of the paramagnetic shift (0.28 ppm.K-1 ) was exploited to examine tissue temperature variation. CONCLUSIONS: These data demonstrate a new MRI agent with the potential for physiological monitoring by MRI. Magn Reson Med 77:1307-1317, 2017. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Measuring chronic condition self-management in an Australian community: factor structure of the revised Partners in Health (PIH) scale.

PURPOSE: To evaluate the factor structure of the revised Partners in Health (PIH) scale for measuring chronic condition self-management in a representative sample from the Australian community. METHODS: A series of consultations between clinical groups underpinned the revision of the PIH. The factors in the revised instrument were proposed to be: knowledge of illness and treatment, patient-health professional partnership, recognition and management of symptoms and coping with chronic illness. Participants (N = 904) reporting having a chronic illness completed the revised 12-item scale. Two a priori models, the 4-factor and bi-factor models were then evaluated using Bayesian confirmatory factor analysis (BCFA). Final model selection was established on model complexity, posterior predictive p values and deviance information criterion. RESULTS: Both 4-factor and bi-factor BCFA models with small informative priors for cross-loadings provided an acceptable fit with the data. The 4-factor model was shown to provide a better and more parsimonious fit with the observed data in terms of substantive theory. McDonald's omega coefficients indicated that the reliability of subscale raw scores was mostly in the acceptable range. CONCLUSION: The findings showed that the PIH scale is a relevant and structurally valid instrument for measuring chronic condition self-management in an Australian community. The PIH scale may help health professionals to introduce the concept of self-management to their patients and provide assessment of areas of self-management. A limitation is the narrow range of validated PIH measurement properties to date. Further research is needed to evaluate other important properties such as test-retest reliability, responsiveness over time and content validity.

Self-Perceived Distress and Impairment in Problem Gamblers: A Study of Pre- to Post-treatment Measurement Invariance.

Gambling help services typically evaluate treatment outcomes using self-reported responses and measurements. However, gamblers' conceptualisations and prioritisations with respect to these measurements may shift over time. Thus, changes in the self-reported responses may not always reflect true change in the individuals. This study investigated for response shift in self-report measures of psychological distress and impairment in 293 help-seeking problem gamblers. We used confirmatory factor analysis to model data structures from pre-treatment to post-treatment. The findings indicated that a response shift had occurred. Two items became less important and one item became more important in measuring psychological distress. Measurement invariance was achieved for the complete set of items for impairment. These findings provide a more in-depth understanding of the nature of self-report outcomes in otherwise routinely collected data.

Experiences and Perceptions of Problem Gamblers on Cognitive and Exposure Therapies When Taking Part in a Randomised Controlled Trial: A Qualitative Study.

In South Australia (SA) problem gambling is mainly a result of the widespread availability of electronic gaming machines. A key treatment provider in SA offers free cognitive and behavioural therapy (CBT) to help-seeking problem gamblers. The CBT program focuses on the treatment of clients' urge to gamble using exposure therapy (ET) and cognitive therapy (CT) to restructure erroneous gambling beliefs. The aim of this study was to explore treatment specific and non-specific effects for CT alone and ET alone using qualitative interviews. Interviewees were a sub-sample of participants from a randomised trial that investigated the relative efficacy of CT versus ET. Findings revealed that all interviewees gained benefit from their respective therapies and their comments did not appear to favour one therapy over another. Both treatment specific and treatment non-specific effects were well supported as playing a therapeutic role to recovery. Participants' comments in both therapy groups suggested that symptom reduction was experienced on a gambling related urge-cognition continuum. In addition to symptom improvement from therapy-specific mechanisms, ET participants described a general acquisition of "rational thought" from their program of therapy and CT participants had "taken-over" their gambling urges. The findings also highlighted areas for further improvement including therapy drop-out.

'Imagine if I gave up smoking ...': a qualitative exploration of Aboriginal participants' perspectives of a self-management pilot training intervention.

This paper reports on a pilot qualitative study investigating Aboriginal participants' perspectives of the Flinders Living Well Smoke Free (LWSF) 'training intervention'. Health workers nationally have been trained in this program, which offers a self-management approach to reducing smoking among Aboriginal clients. A component of the training involves Aboriginal clients volunteering their time in a mock care-planning session providing the health workers with an opportunity to practise their newly acquired skills. During this simulation, the volunteer clients receive one condensed session of the LWSF intervention imitating how the training will be implemented when the health workers have completed the training. For the purpose of this study, 10 Aboriginal clients who had been volunteers in the mock care-planning process, underwent a semi-structured interview at seven sites in Australia, including mainstream health services, Aboriginal community controlled health services and remote Aboriginal communities. The study aimed to gauge their perspectives of the training intervention they experienced. Early indications suggest that Aboriginal volunteer clients responded positively to the process, with many reporting substantial health behaviour change or plans to make changes since taking part in this mock care-planning exercise. Enablers of the intervention are discussed along with factors to be considered in the training program.

Challenging lanthanide relaxation theory: erbium and thulium complexes that show NMR relaxation rates faster than dysprosium and terbium analogues.

Measurements of the proton NMR paramagnetic relaxation rates for several series of isostructural lanthanide(III) complexes have been performed in aqueous solution over the field range 1.0 to 16.5 Tesla. The field dependence has been modeled using Bloch-Redfield-Wangsness theory, allowing values for the electronic relaxation time, Tle and the magnetic susceptibility, µeff, to be estimated. Anomalous relaxation rate profiles were obtained, notably for erbium and thulium complexes of low symmetry 8-coordinate aza-phosphinate complexes. Such behaviour challenges accepted theory and can be interpreted in terms of changes in Tle values that are a function of the transient ligand field induced by solvent collision and vary considerably between Ln(3+) ions, along with magnetic susceptibilities that deviate significantly from free-ion values.

Effects of Affective and Anxiety Disorders on Outcome in Problem Gamblers Attending Routine Cognitive-Behavioural Treatment in South Australia.

This study evaluated the influence of 12-month affective and anxiety disorders on treatment outcomes for adult problem gamblers in routine cognitive-behavioural therapy. A cohort study at a state-wide gambling therapy service in South Australia. Primary outcome measure was rated by participants using victorian gambling screen (VGS) 'harm to self' sub-scale with validated cut score 21+ (score range 0-60) indicative of problem gambling behaviour. Secondary outcome measure was Work and Social Adjustment Scale (WSAS). Independent variable was severity of affective and anxiety disorders based on Kessler 10 scale. We used propensity score adjusted random-effects models to estimate treatment outcomes for sub-populations of individuals from baseline to 12 month follow-up. Between July, 2010 and December, 2012, 380 participants were eligible for inclusion in the final analysis. Mean age was 44.1 (SD = 13.6) years and 211 (56%) were males. At baseline, 353 (92.9%) were diagnosed with a gambling disorder using VGS. For exposure, 175 (46%) had a very high probability of a 12-month affective or anxiety disorder, 103 (27%) in the high range and 102 (27%) in the low to moderate range. For the main analysis, individuals experienced similar clinically significant reductions (improvement) in gambling related outcomes across time (p < 0.001). Individuals with co-varying patterns of problem gambling and 12 month affective and anxiety disorders who present to a gambling help service for treatment in metropolitan South Australia gain similar significant reductions in gambling behaviours from routine cognitive-behavioural therapy in the mid-term.

Predictors of relapse in problem gambling: a prospective cohort study.

To explore the variation of predictors of relapse in treatment and support seeking gamblers. A prospective cohort study with 158 treatment and support seeking problem gamblers in South Australia. Key measures were selected using a consensus process with international experts in problem gambling and related addictions. The outcome measures were Victorian Gambling Screen (VGS) and behaviours related to gambling. Potential predictors were gambling related cognitions and urge, emotional disturbance, social support, sensation seeking traits, and levels of work and social functioning. Mean age of participants was 44 years (SD = 12.92 years) and 85 (54 %) were male. Median time for participants enrollment in the study was 8.38 months (IQR = 2.57 months). Patterns of completed measures for points in time included 116 (73.4 %) with at least a 3 month follow-up. Using generalised mixed-effects regression models we found gambling related urge was significantly associated with relapse in problem gambling as measured by VGS (OR 1.29; 95 % CI 1.12-1.49) and gambling behaviours (OR 1.16; 95 % CI 1.06-1.27). Gambling related cognitions were also significantly associated with VGS (OR 1.06; 95 % CI 1.01-1.12). There is consistent association between urge to gamble and relapse in problem gambling but estimates for other potential predictors may have been attenuated because of methodological limitations. This study also highlighted the challenges presented from a cohort study of treatment and support seeking problem gamblers.

Characterisation and evaluation of paramagnetic fluorine labelled glycol chitosan conjugates for (19)F and (1)H magnetic resonance imaging.

Medium molecular weight glycol chitosan conjugates have been prepared, linked by an amide bond to paramagnetic Gd(III), Ho(III) and Dy(III) macrocyclic complexes in which a trifluoromethyl reporter group is located 6.5 Å from the paramagnetic centre. The faster relaxation of the observed nucleus allows modified pulse sequences to be used with shorter acquisition times. The polydisperse materials have been characterised by gel permeation chromatography, revealing an average molecular weight on the order of 13,800 (Gd), 14,600 (Dy) and 16,200 (Ho), consistent with the presence of 8.5, 9.5 and 13 complexes, respectively. The gadolinium conjugate was prepared for both a q = 1 monoamide tricarboxylate conjugate (r1p 11.2 mM(-1) s(-1), 310 K, 1.4 T) and a q = 0 triphosphinate system, and conventional contrast-enhanced proton MRI studies at 7 T were undertaken in mice bearing an HT-29 or an HCT-116 colorectal tumour xenograft (17 µmol/kg). Enhanced contrast was observed following injection in the tail vein in tumour tissue, with uptake also evident in the liver and kidney with a tumour-to-liver ratio of 2:1 at 13 min, and large amounts in the kidney and bladder consistent with predominant renal clearance. Parallel experiments observing the (19)F resonance in the holmium conjugate complex using a surface coil did not succeed owing to its high R2 value (750 Hz, 7 T). However, the fluorine signal in the dysprosium triphosphinate chitosan conjugate [R1/R2 = 0.6 and R1 = 145 Hz (7 T)] was sharper and could be observed in vivo at -65.7 ppm, following intravenous tail vein injection of a dose of 34 µmol/kg.

Experimental measurement and theoretical assessment of fast lanthanide electronic relaxation in solution with four series of isostructural complexes.

The rates of longitudinal relaxation for ligand nuclei in four isostructural series of lanthanide(III) complexes have been measured by solution state NMR at 295 K at five magnetic fields in the range 4.7-16.5 T. The electronic relaxation time T(le) is a function of both the lanthanide ion and the local ligand field. It needs to be considered when relaxation probes for magnetic resonance applications are devised because it affects the nuclear relaxation, especially over the field range 0.5 to 4.7 T. Analysis of the data, based on Bloch-Redfield-Wangsness theory describing the paramagnetic enhancement of the nuclear relaxation rate has allowed reliable estimates of electronic relaxation times, T(1e), to be obtained using global minimization methods. Values were found in the range 0.10-0.63 ps, consistent with fluctuations in the transient ligand field induced by solvent collision. A refined theoretical model for lanthanide electronic relaxation beyond the Redfield approximation is introduced, which accounts for the magnitude of the ligand field coefficients of order 2, 4, and 6 and their relative contributions to the rate 1/T(le). Despite the considerable variation of these contributions with the nature of the lanthanide ion and its fluctuating ligand field, the theory explains the modest change of measured T(le) values and their remarkable statistical ordering across the lanthanide series. Both experiment and theory indicate that complexes of terbium and dysprosium should most efficiently promote paramagnetic enhancement of the rate of nuclear relaxation.

Chronic condition management and self-management in Aboriginal communities in South Australia: outcomes of a longitudinal study.

OBJECTIVES: This paper describes the longitudinal component of a larger mixed methods study into the processes and outcomes of chronic condition management and self-management strategies implemented in three Aboriginal communities in South Australia. The study was designed to document the connection between the application of structured systems of care for Aboriginal people and their longer-term health status. METHODS: The study concentrated on three diverse Aboriginal communities in South Australia; the Port Lincoln Aboriginal Health Service, the Riverland community, and Nunkuwarrin Yunti Aboriginal Health Service in the Adelaide metropolitan area. Repeated-measure clinical data were collected for individual participants using a range of clinical indicators for diabetes (type 1 and 2) and related chronic conditions. Clinical data were analysed using random effects modelling techniques with changes in key clinical indicators being modelled at both the individual and group levels. RESULTS: Where care planning has been in place longer than in other sites overall improvements were noted in BMI, cholesterol (high density and low density lipids) and HbA1c. These results indicate that for Aboriginal patients with complex chronic conditions, participation in and adherence to structured care planning and self-management strategies can contribute to improved overall health status and health outcomes. CONCLUSIONS: The outcomes reported here represent an initial and important step in quantifying the health benefits that can accrue for Aboriginal people living with complex chronic conditions such as diabetes, heart disease and respiratory disease. The study highlights the benefits of developing long-term working relationships with Aboriginal communities as a basis for conducting effective collaborative health research programs. WHAT IS KNOWN ABOUT THE TOPIC? Chronic condition management and self-management programs have been available to Aboriginal people in a range of forms for some time. We know that some groups of patients are keen to engage with care planning and self-management protocols and we have anecdotal evidence of this engagement leading to improved quality of life and health outcomes for Aboriginal people. WHAT DOES THIS PAPER ADD? This paper provides early evidence of sustained improvement over time for a cohort of Aboriginal people who are learning to deal with a range of chronic illnesses through accessing structured systems of support and care. WHAT ARE THE IMPLICATIONS FOR PRACTITIONERS? This longitudinal evidence of improved outcomes for Aboriginal people is encouraging and should lead on to more definitive studies of outcomes accruing for people engaged in structured systems of care. Not only does this finding have implications for the overall management of chronic illness in Aboriginal communities, but it points the way to how health services might best invest their resources and efforts to improve the health status of people with chronic conditions and, in the process, close the gap between the life expectancy of Aboriginal people and that of other community groups in Australia.

Texaphyrin-Based Calcium Sensor for Multimodal Imaging.

The ability to monitor intracellular calcium concentrations using fluorescent probes has led to important insights into biological signaling processes at the cellular level. An important challenge is to relate such measurements to broader patterns of signaling across fields of view that are inaccessible to optical techniques. To meet this need, we synthesized molecular probes that couple calcium-binding moieties to lanthanide texaphyrins, resulting in complexes endowed with a diverse complement of magnetic and photophysical properties. We show that the probes permit intracellular calcium levels to be assessed by fluorescence, photoacoustic, and magnetic resonance imaging modalities and that they are detectable by multimodal imaging in brain tissue. This work thus establishes a route for monitoring signaling processes over a range of spatial and temporal scales.