Tetrahydrocannabinol and Cannabidiol in Tourette Syndrome.

BACKGROUND: Tourette syndrome is characterized by chronic motor and vocal tics. There is preliminary evidence of benefit from cannabis products containing Δ9-tetrahydrocannabinol (THC) and that coadministration of cannabidiol (CBD) improves the side-effect profile and safety. METHODS: In this double-blind, crossover trial, participants with severe Tourette syndrome were randomly assigned to a 6-week treatment period with escalating doses of an oral oil containing 5 mg/ml of THC and 5 mg/ml of CBD, followed by a 6-week course of placebo, or vice versa, separated by a 4-week washout period. The primary outcome was the total tic score on the Yale Global Tic Severity Scale (YGTSS; range, 0 to 50 [higher scores indicate greater severity of symptoms]). Secondary outcomes included video-based assessment of tics, global impairment, anxiety, depression, and obsessive-compulsive symptoms. Outcomes were correlated with plasma levels of cannabinoid metabolites. A computerized cognitive battery was administered at the beginning and the end of each treatment period. RESULTS: Overall, 22 participants (eight female participants) were enrolled. Reduction in total tic score (at week 6 relative to baseline) as measured by the YGTSS was 8.9 (±7.6) in the active group and 2.5 (±8.5) in the placebo group. In a linear mixed-effects model, there was a significant interaction of treatment (active/placebo) and visit number on tic score (coefficient = −2.28; 95% confidence interval, −3.96 to −0.60; P=0.008), indicating a greater decrease (improvement) in tics under active treatment. There was a correlation between plasma 11-carboxy-tetrahydrocannabinol levels and the primary outcome, which was attenuated after exclusion of an outlier. The most common adverse effect in the placebo period was headache (n=7); in the active treatment period, it was cognitive difficulties, including slowed mentation, memory lapses, and poor concentration (n=8). CONCLUSIONS: In severe Tourette syndrome, treatment with THC and CBD reduced tics and may reduce impairment due to tics, anxiety, and obsessive-compulsive disorder; although in some participants this was associated with slowed mentation, memory lapses, and poor concentration. (Funded by the Wesley Medical Research Institute, Brisbane, and the Lambert Initiative for Cannabinoid Therapeutics, a philanthropically-funded research organization at the University of Sydney, Australia; Australian and New Zealand Clinical Trials Registry number, ACTRN12618000545268.)

Performance monitoring in cardiac surgery: application of statistical process control to a single-site database.

BACKGROUND: Graphical Statistical Process Control (SPC) tools have been shown to promptly identify significant variations in clinical outcomes in a range of health care settings. We explored the application of these techniques to quantitatively inform the routine cardiac surgical (CAS) morbidity and mortality (M&M) review processes at a single site. METHODS: Baseline clinical and procedural data relating to 5265 consecutive cardiac surgical procedures, performed at St Andrew's War Memorial Hospital (SAWMH) between the 1st January 2003 and the 30th April 2012, were retrospectively evaluated. A range of appropriate clinical outcome indicators (COIs) were developed and evaluated using a combination of Cumulative Sum charts, Exponentially Weighted Moving Average charts and Funnel Plots. Charts were updated regularly and discussed at the cardiac surgery unit's bi-monthly M&M meetings. Risk adjustment (RA) for the COIs was developed and validated for incorporation into the charts to improve monitoring performance. RESULTS: Discrete and aggregated measures, including blood product/reoperation, major acute post-procedural complications, cardiopulmonary bypass duration and Length of Stay/Readmission < 28 days have proved to be valuable measures for monitoring outcomes. Instances of variation in performance identified using the charts were examined thoroughly and could be related to changes in clinical practice (e.g. antifibrinolytic use) as well as differences in individual operator performance (in some instances, driven by case mix). CONCLUSIONS: SPC tools can promptly detect meaningful changes in clinical outcome thereby allowing early intervention to address altered performance. Careful interpretation of charts for group and individual operators has proven helpful in detecting and differentiating systemic versus individual variation.

Use of graphical statistical process control tools to monitor and improve outcomes in cardiac surgery.

BACKGROUND: Graphical Statistical Process Control (SPC) tools have been shown to promptly identify significant variations in clinical outcomes in a range of health care settings. We explored the application of these techniques to qualitatively inform the routine cardiac surgical morbidity and mortality (M&M) review process at a single site. METHODS: Baseline clinical and procedural data relating to 4774 consecutive cardiac surgical procedures, performed between the 1st January 2003 and the 30th April 2011, were retrospectively evaluated. A range of appropriate performance measures and benchmarks were developed and evaluated using a combination of CUmulative SUM (CUSUM) charts, Exponentially Weighted Moving Average (EWMA) charts and Funnel Plots. Charts have been discussed at the unit's routine M&M meetings. Risk adjustment (RA) based on EuroSCORE has been incorporated into the charts to improve performance. RESULTS: Discrete and aggregated measures, including Blood Product/Reoperation, major acute post-procedural complications and Length of Stay/Readmission<28 days have proved to be usable measures for monitoring outcomes. Monitoring trends in minor morbidities provides a valuable warning of impending changes in significant events. Instances of variation in performance have been examined and could be related to differences in individual operator performance via individual operator curves. CONCLUSION: SPC tools facilitate near "real-time" performance monitoring allowing early detection and intervention in altered performance. Careful interpretation of charts for group and individual operators has proven helpful in detecting and differentiating systemic vs. individual variation.

Impact of quantitative feedback and benchmark selection on radiation use by cardiologists performing cardiac angiography.

Audit of and feedback on both group and individual data provided immediately after the point of care and compared with realistic benchmarks of excellence have been demonstrated to drive change. This study sought to evaluate the impact of immediate benchmarked quantitative case-based performance feedback on the clinical practice of cardiologists practicing at a private hospital in Brisbane, Australia. The participating cardiologists were assigned to one of two groups: Group 1 received patient and procedural details for review and Group 2 received Group 1 data plus detailed radiation data relating to the procedures and comparative benchmarks. In Group 2, Linear-by-Linear Association analysis suggests a link between change in radiation use and initial radiation dose category (p=0.014) with only those initially 'challenged' by the benchmarks showing improvement. Those not 'challenged' by the benchmarks deteriorated in performance compared with those starting well below the benchmarks showing greatest increase in radiation use. Conversely, those blinded to their radiation use (Group 1) showed general improvement in radiation use throughout the study compared with those performing initially close to the benchmarks showing greatest improvement. This study shows that use of non-challenging benchmarks in case-based radiation risk feedback does not promote a reduction in radiation use; indeed, it may contribute to increased doses. Paradoxically, cardiologists who are aware of performance monitoring but blinded to individual case data appear to maintain, if not reduce, their radiation use.

Risk modelling in quality clinical registries: monitoring lesion treatment failure rate in percutaneous coronary interventions.

AIMS: This paper describes the development of a risk adjustment (RA) model predictive of individual lesion treatment failure in percutaneous coronary interventions (PCI) for use in a quality monitoring and improvement program. METHODS AND RESULTS: Prospectively collected data for 3972 consecutive revascularisation procedures (5601 lesions) performed between January 2003 and September 2011 were studied. Data on procedures to September 2009 (n=3100) were used to identify factors predictive of lesion treatment failure. Factors identified included lesion risk class (p<0.001), occlusion type (p<0.001), patient age (p=0.001), vessel system (p<0.04), vessel diameter (p<0.001), unstable angina (p=0.003) and presence of major cardiac risk factors (p=0.01). A Bayesian RA model was built using these factors with predictive performance of the model tested on the remaining procedures (area under the receiver operating curve: 0.765, Hosmer-Lemeshow p value: 0.11). Cumulative sum, exponentially weighted moving average and funnel plots were constructed using the RA model and subjectively evaluated. CONCLUSION: A RA model was developed and applied to SPC monitoring for lesion failure in a PCI database. If linked to appropriate quality improvement governance response protocols, SPC using this RA tool might improve quality control and risk management by identifying variation in performance based on a comparison of observed and expected outcomes.

Data Quality Improvement in Clinical Databases Using Statistical Quality Control: Review and Case Study.

Ensuring the quality of data being collected in clinical and medical contexts is a concern for data managers and users. Quality assurance frameworks, systematic audits, and correction procedures have been proposed to enhance the accuracy and completeness of databases. Following an overview of the undertaken approaches, particularly statistical methods, the authors promote acceptance sampling plans (ASPs) and statistical process control (SPC) tools, including control charts and root cause analysis, as the technical core of the data quality improvement mechanism. They review ASP and SPC techniques and discuss their implementation in data quality evaluation and improvement. Two case studies are presented in which the authors apply some of the techniques to databases maintained by a local hospital. Finally, guidelines are proposed for which techniques are appropriate with regard to dataflow and database specifications.

The role of quantitative feedback in coronary angiography radiation reduction.

OBJECTIVE: To evaluate the benefits of radiation education with and without feedback reporting in altering clinician radiation use behaviour in performing coronary angiography (CA). DESIGN: A retrospective review of radiation use (fluoroscopy time) in coronary angiograms performed between July 1996 and December 2005 by 10 cardiologists to assess the impact of various interventions aimed at minimizing radiation risk. The impact of interventions such as education and audit/feedback was correlated against radiation use using cumulative sum and cumulative expected minus observed charts. SETTING: Private Hospital in Brisbane, Australia. PARTICIPANTS: Ten cardiologists. INTERVENTION: Education and audit/feedback. RESULTS: Baseline radiation use subject to standard guidelines was stable. Group performance charts show a modest transient improvement in radiation use associated with an education intervention alone. However, regular detailed personalized feedback comparing an individual's radiation use to group and external benchmarks was successful in achieving sustained reduction in overall radiation use. For individual participants, significant improvement was noted in 7 of 10 cardiologists. CONCLUSION: Although an improved theoretical understanding of effective radiation hygiene strategies might contribute to reduced radiation use, this study suggests that regular detailed quantitative feedback supporting education is an effective tool in altering radiation use in CA. Understanding triggers that stimulate change in clinician behaviour is critical to the design of systems to optimize clinical performance. Confidentially reported benchmarking systems may be a useful tool to alter clinician behaviour.

Simultaneous monitoring of tissue PO2 and NADH fluorescence during synaptic stimulation and spreading depression reveals a transient dissociation between oxygen utilization and mitochondrial redox state in rat hippocampal slices.

Nicotinamide adenine dinucleotide (NADH) imaging can be used to monitor neuronal activation and ascertain mitochondrial dysfunction, for example during hypoxia. During neuronal stimulation in vitro, NADH normally becomes more oxidized, indicating enhanced oxygen utilization. A subsequent NADH overshoot during activation or on recovery remains controversial and reflects either increased metabolic activity or limited oxygen availability. Tissue P(2) measurements, obtained simultaneously with NADH imaging in area CA1 in hippocampal slices, reveal that during prolonged train stimulation (ST) in 95% O(2), a persistent NADH oxidation is coupled with increased metabolic demand and oxygen utilization, for the duration of the stimulation. However, under conditions of either decreased oxygen supply (ST-50% O(2)) or enhanced metabolic demand (K(+)-induced spreading depression (K(+)-SD) 95% O(2)) the NADH oxidation is brief and the redox balance shifts early toward reduction, leading to a prolonged NADH overshoot. Yet, oxygen utilization remains elevated and is correlated with metabolic demand. Under these conditions, it appears that the rate of NAD(+) reduction may transiently exceed oxidation, to maintain an adequate oxygen flux and ATP production. In contrast, during SD in 50% O(2), the oxygen levels dropped to a point at which oxidative metabolism in the electron transport chain is limited and the rate of utilization declined.

Attenuation of edema and infarct volume following focal cerebral ischemia by early but not delayed administration of a novel small molecule KDR kinase inhibitor.

Vascular endothelial growth factor (VEGF) may mediate increases in vascular permeability and hence plasma extravasation and edema following cerebral ischemia. To better define the role of VEGF in edema, we examined the effectiveness of a novel small molecule KDR kinase inhibitor Compound-1 in reducing edema and infarct volume following focal cerebral ischemia in studies utilizing treatment regimens initiated both pre- and post-ischemia, and with study durations of 24-72 h. Rats were subjected to 90 min of middle cerebral artery occlusion (MCAO) followed by reperfusion. Pretreatment with Compound-1 (40 mg/kg p.o.) starting 0.5h before occlusion significantly reduced infarct volume at 72 h post-MCAO (vehicle, 194.1+/-22.9 mm(3) vs. Compound-1, 127.6+/-22.8mm(3) and positive control MK-801, 104.4+/-22.6mm(3), both p<0.05 compared to vehicle control), whereas Compound-1 treatment initiated at 2h after occlusion did not affect infarct volume. Compound-1 pretreatment also significantly reduced brain water content at 24h (vehicle, 80.3+/-0.2% vs. Compound-1, 79.7+/-0.2%, p<0.05) but not at 72 h after MCAO. These results demonstrate that early pretreatment administration of a KDR kinase inhibitor elicited an early, transient decrease in edema and subsequent reduction in infarct volume, implicating VEGF as a mediator of stroke-related vascular permeability and ischemic injury.

NADH hyperoxidation correlates with enhanced susceptibility of aged rats to hypoxia.

Aging increases mitochondrial dysfunction and susceptibility to hypoxia. Previous reports have indicated an association between post-hypoxic hyperoxidation of intra-mitochondrial enzymes and delayed neuronal injury. Therefore we investigated the relationship between NADH fluorescence and neuronal function during and after hypoxia across the lifespan. Hippocampal slices were prepared from adult (1 to >22 months) F344 rats. NADH fluorescence, extracellular voltage and tissue PO(2) were recorded from the CA1 region during hypoxia (95% N(2)) of various lengths following onset of hypoxic spreading depression (hsd). Slices from younger rats recovered evoked neuronal responses to a greater degree and exhibited less hyperoxidation after a hypoxic episode, than slices from older rats. However, the use of Ca(2+) free-media in slices from >22 month old rats improved recovery and delayed NADH hyperoxidation (2.5 min hypoxia after hsd). Post-hypoxic decrease of NADH fluorescence (hyperoxidation) was age dependent and correlated with decreased neuronal recovery. Slices exposed to repeated hypoxic episodes yielded data suggesting depletion of the NAD(+) pool, which may have contributed to the deterioration of neuronal function.

Lactate uptake contributes to the NAD(P)H biphasic response and tissue oxygen response during synaptic stimulation in area CA1 of rat hippocampal slices.

Synaptic train stimulation (10 Hz x 25 s) in hippocampal slices results in a biphasic response of NAD(P)H fluorescence indicating a transient oxidation followed by a prolonged reduction. The response is accompanied by a transient tissue PO(2) decrease indicating enhanced oxygen utilization. The activation of mitochondrial metabolism and/or glycolysis may contribute to the secondary NAD(P)H peak. We investigated whether extracellular lactate uptake via monocarboxylate transporters (MCTs) contributes to the generation of the NAD(P)H response during neuronal activation. We measured the effect of lactate uptake inhibition [using the MCT inhibitor alpha-cyano-4-hydroxycinnamate (4-CIN)] on the NAD(P)H biphasic response, tissue PO(2) response, and field excitatory post-synaptic potential in hippocampal slices during synaptic stimulation in area CA1 (stratum radiatum). The application of 4-CIN (150-250 micromol/L) significantly decreased the reduction phase of the NAD(P)H response. When slices were supplemented with 20 mmol/L lactate in 150-250 micromol/L 4-CIN, the secondary NAD(P)H peak was restored; whereas 20 mmol/L pyruvate supplementation did not produce a recovery. Similarly, the tissue PO(2) response was decreased by MCT inhibition; 20 mmol/L lactate restored this response to control levels at all 4-CIN concentrations. These results indicate that lactate uptake via MCTs contributes significantly to energy metabolism in brain tissue and to the generation of the delayed NAD(P)H peak after synaptic stimulation.

Differences in O2 availability resolve the apparent discrepancies in metabolic intrinsic optical signals in vivo and in vitro.

Monitoring changes in the fluorescence of metabolic chromophores, reduced nicotinamide adenine dinucleotide and flavin adenine dinucleotide, and the absorption of cytochromes, is useful to study neuronal activation and mitochondrial metabolism in the brain. However, these optical signals evoked by stimulation, seizures and spreading depression in intact brain differ from those observed in vitro. The responses in vivo consist of a persistent oxidized state during neuronal activity followed by mild reduction during recovery. In vitro, however, brief oxidation is followed by prolonged and heightened reduction, even during persistent neuronal activation. In normally perfused, oxygenated and activated brain tissue in vivo, partial pressure of oxygen (P(O2)) levels often undergo a brief 'dip' that is always followed by an overshoot above baseline, due to increased blood flow (neuronal-vascular coupling). By contrast, in the absence of blood circulation, tissue P(O2)in vitro decreases more markedly and recovers slowly to baseline without overshooting. Although oxygen is abundant in vivo, it is diffusion-limited in vitro. The disparities in mitochondrial and tissue oxygen availability account for the different redox responses.

Optical and pharmacological tools to investigate the role of mitochondria during oxidative stress and neurodegeneration.

Mitochondria are critical for cellular adenosine triphosphate (ATP) production; however, recent studies suggest that these organelles fulfill a much broader range of tasks. For example, they are involved in the regulation of cytosolic Ca(2+) levels, intracellular pH and apoptosis, and are the major source of reactive oxygen species (ROS). Various reactive molecules that originate from mitochondria, such as ROS, are critical in pathological events, such as ischemia, as well as in physiological events such as long-term potentiation, neuronal-vascular coupling and neuronal-glial interactions. Due to their key roles in the regulation of several cellular functions, the dysfunction of mitochondria may be critical in various brain disorders. There has been increasing interest in the development of tools that modulate mitochondrial function, and the refinement of techniques that allow for real time monitoring of mitochondria, particularly within their intact cellular environment. Innovative imaging techniques are especially powerful since they allow for mitochondrial visualization at high resolution, tracking of mitochondrial structures and optical real time monitoring of parameters of mitochondrial function. The techniques discussed include classic imaging techniques, such as rhodamine-123, the highly advanced semi-conductor nanoparticles (quantum dots), and wide field microscopy as well as high-resolution multiphoton imaging. We have highlighted the use of these techniques to study mitochondrial function in brain tissue and have included studies from our laboratories in which these techniques have been successfully applied.

Hypoxic/Ischemic models in newborn piglet: comparison of constant FiO2 versus variable FiO2 delivery.

A comparison of a constant (continuous delivery of 4% FiO2) and a variable (initial 5% FiO2 with adjustments to induce low amplitude EEG (LAEEG) and hypotension) hypoxic/ischemic insult was performed to determine which insult was more effective in producing a consistent degree of survivable neuropathological damage in a newborn piglet model of perinatal asphyxia. We also examined which physiological responses contributed to this outcome. Thirty-nine 1-day-old piglets were subjected to either a constant hypoxic/ischemic insult of 30- to 37-min duration or a variable hypoxic/ischemic insult of 30-min low peak amplitude EEG (LAEEG <5 microV) including 10 min of low mean arterial blood pressure (MABP <70% of baseline). Control animals (n = 6) received 21% FiO2 for the duration of the experiment. At 72 h, the piglets were euthanased, their brains removed and fixed in 4% paraformaldehyde and assessed for hypoxic/ischemic injury by histological analysis. Based on neuropathology scores, piglets were grouped as undamaged or damaged; piglets that did not survive to 72 h were grouped separately as dead. The variable insult resulted in a greater number of piglets with neuropathological damage (undamaged = 12.5%, damaged = 68.75%, dead = 18.75%) while the constant insult resulted in a large proportion of undamaged piglets (undamaged = 50%, damaged = 22.2%, dead = 27.8%). A hypoxic insult varied to maintain peak amplitude EEG <5 microV results in a greater number of survivors with a consistent degree of neuropathological damage than a constant hypoxic insult. Physiological variables MABP, LAEEG, pH and arterial base excess were found to be significantly associated with neuropathological outcome.