Taking the first step: protocol for a cluster randomised implementation trial comparing strategies on access to exercise programmes for people with knee osteoarthritis.

INTRODUCTION: This cluster randomised implementation trial will assess the effect of two behavioural change interventions on the proportion of people with structural knee osteoarthritis (OA) referred and attending exercise-based professionals (physiotherapists and exercise physiologists). The interventions are designed to increase awareness of guidelines, benefits and access pathways for exercise therapy. We hypothesise either strategy will result in more people with knee OA being referred and attending physiotherapy/exercise physiology than current standard of care. METHODS AND ANALYSIS: We will recruit 30 radiology clinics. 10 clinics will be randomly assigned to each trial arm with 1020 people with knee OA consecutively recruited (102 people per practice) into each arm. Intervention arm 1 is an educational reminder message targeted at primary care practitioners with a hyperlink to national guidelines regarding knee OA clinical management. It will be included in the reporting template of a plain knee X-ray. Intervention arm 2 is the reminder message and a patient-facing infographic explaining the benefits and access pathways for exercise. Both interventions will be delivered once, by the radiology clinics, when a person undergoes plain X-ray for non-traumatic knee pain/dysfunction. The primary outcome is referral to physiotherapist/exercise physiology. The secondary outcome is attendance to that appointment. Both outcomes are self-reported via an online survey administered 4 weeks after the X-ray. Additional survey questions explore facilitators and barriers to appointment attendance and acceptability of the interventions. A subsample of the intervention groups will be recruited for semistructured telephone-based interviews to further explore these latter outcomes. ETHICS AND DISSEMINATION: The study protocol was approved by Macquarie University Human Research Ethics Committee (#520221190343842) and prospectively registered with the Australian New Zealand Clinical Trials Registry. The findings of the trial will be disseminated through peer-reviewed scientific journals and conferences. We will engage with Australian physician colleges and main-stream media to distribute findings. TRIAL REGISTRATION NUMBER: ACTRN12622001414707p.

Reliability and validity of subjective radiologist reporting of temporal changes in lumbar spine MRI findings.

BACKGROUND: The importance of lumbar findings on magnetic resonance imaging (MRI) remains controversial. Changes in lumbar MRI findings over time may provide important insights into the causes of low back pain. However, the reliability and validity of temporal changes are unknown. OBJECTIVE: To (1) investigate the interrater reliability of subjective radiologist reporting of temporal changes in lumbar spine MRI findings and (2) determine how commonly temporal changes are reported when two scans are conducted 30 minutes apart (considered false positives). DESIGN: Cross-sectional study. SETTING: Radiology clinic. PARTICIPANTS: Forty volunteers (mean age 40; 53% female) with current (n = 31) or previous (n = 9) low back pain underwent initial lumbar MRI on a single 3T scanner. Participants then lay on a bed for 30 minutes before undergoing an identical MRI. In addition, we purposely selected five participants from a previous study with repeat lumbar MRI scans where temporal changes were reported in at least one MRI finding (1-12 weeks after initial scan) and another five participants where no temporal change was reported. The 10 participants were included in analyses for aim 1 only. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Two blinded radiologists reported on temporal changes between the baseline and repeat scan for 12 different MRI findings (eg, disk herniation, annular fissure) at five levels. RESULTS: The interrater reliability of subjective reporting of temporal changes was poor for all MRI findings based on Kappa values (≤ 0.24), but agreement was relatively high (≥ 90.8%). This is explained by the low prevalence of temporal changes as demonstrated by high values for Prevalence and Bias Adjusted Kappa (≥ 0.82). "False positive" temporal changes were reported by at least one radiologist for most MRI findings, but the rate was generally low. CONCLUSIONS: Caution is required when interpreting temporal changes in lumbar MRI findings owing to low reliability and some false positive reporting.

Magnetic Resonance Spectroscopic Assessment of Isocitrate Dehydrogenase Status in Gliomas: The New Frontiers of Spectrobiopsy in Neurodiagnostics.

BACKGROUND: In the era of integrated genomic-histologic analysis of brain tumors, new biomarkers have been introduced as diagnostic, prognostic, and therapeutic indicators. The analysis of the mutation in the isocitrate dehydrogenase (IDH) genes IDH1 and IDH2 has provided important diagnostic and prognostic information for patients affected by diffuse glioma (i.e., the presence of the mutation has been related to an increased survival rate). The reference standard of IDH mutation detection has been its assessment in surgical specimens, immunohistochemistry, and/or genetic sequencing. Knowing the IDH status information preoperatively would be of great importance, because it has been related to tumor progression and the response to treatment. The oncometabolite 2-hydroxyglutarate (2HG), accumulated in gliomas with IDH mutation status, can be detected in vivo using magnetic resonance spectroscopy (MRS). METHODS: The 2HG-MRS technique remains technically challenging. We have summarized the results of the first pilot study in Australia, which included 10 patients affected by glioma. The data recorded from May 2017 to November 2018 were analyzed. RESULTS: In our exploratory study, we reached a sensitivity and specificity of 100%, confirming the strong predictive role of 2HG, as detected using MRS, in the diagnosis of glioma. CONCLUSION: In the present study, we have focused on methodological tips and future perspectives of the technique in the neuroimaging and neuro-oncological scenario. We would advocate the integration of 2HG-MRS into standard clinical practice.

Proteomic analysis of the dorsal and ventral hippocampus of rats maintained on a high fat and refined sugar diet.

The typical Western diet, rich in high saturated fat and refined sugar (HFS), has been shown to increase cognitive decline with aging and Alzheimer's disease, and to affect cognitive functions that are dependent on the hippocampus, including memory processes and reversal learning. To investigate neurophysiological changes underlying these impairments, we employed a proteomic approach to identify differentially expressed proteins in the rat dorsal and ventral hippocampus following maintenance on an HFS diet. Rats maintained on the HFS diet for 8 weeks were impaired on a novel object recognition task that assesses memory and on a Morris Water Maze task assessing reversal learning. Quantitative label-free shotgun proteomic analysis was conducted on biological triplicates for each group. For the dorsal hippocampus, 59 proteins were upregulated and 36 downregulated in the HFS group compared to controls. Pathway ana-lysis revealed changes to proteins involved in molecular transport and cellular and molecular signaling, and changes to signaling pathways including calcium signaling, citrate cycle, and oxidative phosphorylation. For the ventral hippocampus, 25 proteins were upregulated and 27 downregulated in HFS fed rats. Differentially expressed proteins were involved in cell-to-cell signaling and interaction, and cellular and molecular function. Changes to signaling pathways included protein ubiquitination, ubiquinone biosynthesis, oxidative phosphorylation, and mitochondrial dysfunction. This is the first shotgun proteomics study to examine protein changes in the hippocampus following long-term consumption of a HFS diet, identifying changes to a large number of proteins including those involved in synaptic plasticity and energy metabolism. All MS data have been deposited in the ProteomeXchange with identifier PXD000028.

Catecholamine receptors differentially mediate impulsive choice in the medial prefrontal and orbitofrontal cortex.

Impulsivity is characteristic of several mental health disorders and is largely mediated by the prefrontal cortex subregions: the medial prefrontal cortex (mPFC) and the orbitofrontal cortex (OFC). Dopamine (DA) and norepinephrine (NE) are known to modulate activity of the prefrontal cortex, however their direct role in impulsive choice is not known. The aim of the present study was to investigate the effect of microinjecting DA or NE compounds in the mPFC or OFC on impulsive choice as measured by a delayed reinforcement (DR) task in male Wistar Kyoto rats. Following training in the DR task, rats were pretreated with DA D(1) and D(2) receptor antagonists (SCH23390 3 µg/side, raclopride 3 or 6 µg/side) or NE α(1) and α(2) receptor agonists (phenylephrine 0.1 or 0.3 µg/side, guanfacine 1 or 3 µg/side, respectively) into the mPFC or OFC and the effect on impulsive behavior was assessed. Pretreatment with raclopride into the mPFC or OFC significantly increased impulsive choice, however only pretreatment with SCH23390 into the mPFC, and not the OFC, significantly increased impulsive choice. Pretreatment with the NE receptor agonists had no effect on impulsive choice. This study suggests that DA receptors, but not NE receptors, differentially mediate impulsive choice in sub-regions of the prefrontal cortex.

Long-term effects of chronic oral Ritalin administration on cognitive and neural development in adolescent wistar kyoto rats.

The diagnosis of Attention Deficit Hyperactivity Disorder (ADHD) often results in chronic treatment with psychostimulants such as methylphenidate (MPH, Ritalin®). With increases in misdiagnosis of ADHD, children may be inappropriately exposed to chronic psychostimulant treatment during development. The aim of this study was to assess the effect of chronic Ritalin treatment on cognitive and neural development in misdiagnosed "normal" (Wistar Kyoto, WKY) rats and in Spontaneously Hypertensive Rats (SHR), a model of ADHD. Adolescent male animals were treated for four weeks with oral Ritalin® (2 × 2 mg/kg/day) or distilled water (dH2O). The effect of chronic treatment on delayed reinforcement tasks (DRT) and tyrosine hydroxylase immunoreactivity (TH-ir) in the prefrontal cortex was assessed. Two weeks following chronic treatment, WKY rats previously exposed to MPH chose the delayed reinforcer significantly less than the dH2O treated controls in both the DRT and extinction task. MPH treatment did not significantly alter cognitive performance in the SHR. TH-ir in the infralimbic cortex was significantly altered by age and behavioural experience in WKY and SHR, however this effect was not evident in WKY rats treated with MPH. These results suggest that chronic treatment with MPH throughout adolescence in "normal" WKY rats increased impulsive choice and altered catecholamine development when compared to vehicle controls.

Oxytocin directly administered into the nucleus accumbens core or subthalamic nucleus attenuates methamphetamine-induced conditioned place preference.

Accumulating evidence indicates that the neuropeptide oxytocin (OXY) may modulate reward-related behavioural responses to methamphetamine (METH) administration. Limited research has examined the effect of OXY on METH-induced conditioned place preference (CPP) and little is known about the neural mechanisms involved. A Fos immunohistochemistry study recently demonstrated that peripheral OXY administration reduced METH-induced Fos expression within the nucleus accumbens (NAc) core and subthalamic nucleus (STh) in rats. The current study aimed to (i) investigate the effect of systemically administered OXY on METH-induced CPP, (ii) determine the effectiveness of a single-trial CPP procedure with METH, in order to (iii) evaluate whether pretreatment with OXY injected directly into the NAc core or the STh attenuates METH-induced CPP. Results showed that male Sprague Dawley rats learned to associate unique compartmental cues with METH (1 mg/kg, i.p.) such that they spent more time in the METH-paired compartment and less time in the saline-paired compartment. Pretreatment with systemic OXY (0.6 mg, i.p.), or OXY (0.6 ng, i.c.) microinjected into the NAc core or the STh prior to METH administration attenuated the formation of a CPP to METH. This provides further evidence that OXY acts within either the NAc core or the STh to reduce the rewarding effects of METH administration.

Re-evaluation of an animal model for ADHD using a free-operant choice task.

Previous research using free-operant procedures have reported that the Spontaneously Hypertensive Rat (SHR) is more impulsive and inattentive than the Wistar-Kyoto (WKY) rat. Recently these behavioural differences have been suggested to be a consequence of differences in the overall activity of these strains. This study compared SHRs to WKYs on locomotor activity and delay sensitivity using a delayed reinforcement (DR) and extinction (EXT) task. SHRs maintained higher locomotor activity than WKYs, however no significant group differences were found on the total lever presses in the DR or EXT tasks. During the DR task, SHRs shifted to selecting the immediate small reinforcer significantly faster than WKYs as the delay increased. WKYs predominantly selected the lever previously associated with the delayed large reinforcer throughout the EXT task, while the SHRs showed no such preference. The significant group differences found on lever selection during the DR and EXT tasks suggests that SHRs are more sensitive to delays, therefore providing further support for the face validity of the SHR as an animal model of ADHD.