Efficacy of the positioning system when measuring canine intraocular pressures with the Reichert® Tono-Vera® Vet rebound tonometer.

OBJECTIVE: To compare intraocular pressure (IOP) measurements in dogs taken with the Reichert® Tono-Vera® Vet rebound tonometer with and without the automatic positioning system. ANIMALS STUDIED: Measurements were taken on 49 eyes from 26 Beagle-derived dogs with variable genetics-four non-glaucomatous and 22 ADAMTS10-mutant dogs affected with different stages of open-angle glaucoma. Seventeen of the 26 dogs were measured 2-4 times on different days with variable intervals since IOP-lowering medications were administered. PROCEDURES: In each dog, tonometry was performed with the Tono-Vera® Vet using three different methods in a randomized order: (Method 1) Average of three readings with an automatic positioning system; (Method 2) one reading with an automatic positioning system; and (Method 3) average of three readings obtained without the automatic positioning system. Statistical analyses included one-way ANOVA, Tukey pairwise comparisons, and Bland-Altman plots (MiniTab®). RESULTS: With each of the three tonometry methods, 116 measurements were taken, resulting in 348 total IOP measurements with a range of 12.8-49.9 mmHg. The means and standard deviations for each method were 25.4 ± 6.9 mmHg (Method 1), 26.0 ± 7.2 mmHg (Method 2), and 26.9 ± 7.7 mmHg (Method 3), with no significant differences (p = .27). Mean IOP variances were also not significantly different between tonometry methods (p = .24 to .78). CONCLUSIONS: Because mean IOPs and their standard deviations were not statistically different between the three tonometry methods, we conclude that Tono-Vera® Vet measurements conducted without the aid of the positioning system still provide reliable results.

Comparison of three rebound tonometers in normal and glaucomatous dogs.

OBJECTIVE: The objectives of the study were to compare intraocular pressure (IOP) readings across a wide range and obtained via three rebound tonometers in ADAMTS10-mutant Beagle-derived dogs with different stages of open-angle glaucoma (OAG) and normal control dogs and to investigate the effect of central corneal thickness (CCT). ANIMALS STUDIED: Measurements were performed on 99 eyes from 50 Beagle-derived dogs with variable genetics-16 non-glaucomatous and 34 with ADAMTS10-OAG. Seventeen OAG eyes were measured twice-with and without the use of IOP-lowering medications. PROCEDURES: IOP was measured in each eye using three tonometers with their "dog" setting-ICare® Tonovet (TV), ICare® Tonovet Plus® (TVP), and the novel Reichert® Tono-Vera® Vet (TVA)-in randomized order. CCT was measured with the Accutome® PachPen. Statistical analyses included one-way ANOVA, Tukey pairwise comparisons, and regression analyses of tonometer readings and pairwise IOP-CCT Pearson correlations (MiniTab®). RESULTS: A total of 116 IOP measurements were taken with each of the three tonometers. When comparing readings over a range of ~7-77 mmHg, mean IOPs from the TV were significantly lower compared with TVP (-4.6 mmHg, p < .001) and TVA (-3.7 mmHg, p = .001). We found no significant differences between TVA and TVP measurements (p = .695). There was a moderate positive correlation between CCT and IOP for TVA (r = 0.53, p < .001), TVP (r = 0.48, p < .001), and TV (r = 0.47, p < .001). CONCLUSIONS: Our data demonstrate strong agreement between TVP and TVA, suggesting that the TVA may similarly reflect true IOP values in canines. CCT influenced IOP measurements of all three tonometers.

Late Outcomes of Patients With Prehospital ST-Segment Elevation and Appropriate Cardiac Catheterization Laboratory Nonactivation.

Background Patients with suspected ST-segment-elevation myocardial infarction (STEMI) and cardiac catheterization laboratory nonactivation (CCL-NA) or cancellation have reportedly similar crude and higher adjusted risks of death compared with those with CCL activation, though reasons for these poor outcomes are not clear. We determined late clinical outcomes among patients with prehospital ECG STEMI criteria who had CCL-NA compared with those who had CCL activation. Methods and Results We identified consecutive prehospital ECG transmissions between June 2, 2010 to October 6, 2016. Diagnoses according to the Fourth Universal Definition of myocardial infarction (MI), particularly rates of myocardial injury, were adjudicated. The primary outcome was all-cause death. Secondary outcomes included cardiovascular death/MI/stroke and noncardiovascular death. To explore competing risks, cause-specific hazard ratios (HRs) were obtained. Among 1033 included ECG transmissions, there were 569 (55%) CCL activations and 464 (45%) CCL-NAs (1.8% were inappropriate CCL-NAs). In the CCL activation group, adjudicated index diagnoses included MI (n=534, 94%, of which 99.6% were STEMI and 0.4% non-STEMI), acute myocardial injury (n=15, 2.6%), and chronic myocardial injury (n=6, 1.1%). In the CCL-NA group, diagnoses included MI (n=173, 37%, of which 61% were non-STEMI and 39% STEMI), chronic myocardial injury (n=107, 23%), and acute myocardial injury (n=47, 10%). At 2 years, the risk of all-cause death was higher in patients who had CCL-NA compared with CCL activation (23% versus 7.9%, adjusted risk ratio, 1.58, 95% CI, 1.24-2.00), primarily because of an excess in noncardiovascular deaths (adjusted HR, 3.56, 95% CI, 2.07-6.13). There was no significant difference in the adjusted risk for cardiovascular death/MI/stroke between the 2 groups (HR, 1.23, 95% CI, 0.87-1.73). Conclusions CCL-NA was not primarily attributable to missed STEMI, but attributable to "masquerading" with high rates of non-STEMI and myocardial injury. These patients had worse late outcomes than patients who had CCL activation, mainly because of higher rates of noncardiovascular deaths.

Utility of prehospital electrocardiogram interpretation in ST-segment elevation myocardial infarction utilizing computer interpretation and transmission for interventional cardiologist consultation.

OBJECTIVES: We examined the appropriateness of prehospital cardiac catheter laboratory activation (CCL-A) in ST-segment elevation myocardial infarction (STEMI) utilizing the University of Glasgow algorithm (UGA) and remote interventional cardiologist consultation. BACKGROUND: The incremental benefit of prehospital electrocardiogram (PH-ECG) transmission on the diagnostic accuracy and appropriateness of CCL-A has been examined in a small number of studies with conflicting results. METHODS: We identified consecutive PH-ECG transmissions between June 2, 2010 and October 6, 2016. Blinded adjudication of ECGs, appropriateness of CCL-A, and index diagnoses were performed using the fourth universal definition of MI. The primary outcome was the appropriate CCL-A rate. Secondary outcomes included rates of false-positive CCL-A, inappropriate CCL-A, and inappropriate CCL nonactivation. RESULTS: Among 1088 PH-ECG transmissions, there were 565 (52%) CCL-As and 523 (48%) CCL nonactivations. The appropriate CCL-A rate was 97% (550 of 565 CCL-As), of which 4.9% (n = 27) were false-positive. The inappropriate CCL-A rate was 2.7% (15 of 565 CCL-As) and the inappropriate CCL nonactivation rate was 3.6% (19 of 523 CCL nonactivations). Reasons for appropriate CCL nonactivation (n = 504) included nondiagnostic ST-segment elevation (n = 128, 25%), bundle branch block (n = 132, 26%), repolarization abnormality (n = 61, 12%), artefact (n = 72, 14%), no ischemic symptoms (n = 32, 6.3%), severe comorbidities (n = 26, 5.2%), transient ST-segment elevation (n = 20, 4.0%), and others. CONCLUSIONS: PH-ECG interpretation utilizing UGA with interventional cardiologist consultation accurately identified STEMI with low rates of inappropriate and false-positive CCL-As, whereas using UGA alone would have almost doubled CCL-As. The benefits of cardiologist consultation were identifying "masquerading" STEMI and avoiding unnecessary CCL-As.

Protocol for a randomised controlled trial evaluating the impact of a community pharmacy discharge medication reconciliation service on unplanned hospital readmissions - The DCMedsRec trial.

INTRODUCTION: A substantial proportion of hospital admissions and readmissions are directly attributable to preventable medication-related harm. Interventions that reduce these harms could avert significant suffering and healthcare costs. OBJECTIVES: The Discharge Medications Reconciliation (DCMedsRec) trial will evaluate a structured medication reconciliation service by community pharmacists post hospital discharge on the risk of 30-day unplanned readmission. Electronic access to the Hospital Discharge Summary via My Health Record will underpin this service. METHODS: DCMedsRec is a non-blinded randomised controlled trial of an intervention by community pharmacists within 30 days of hospital discharge in Melbourne, Australia. Patients discharged from hospital will be assessed by a hospital pharmacist for trial eligibility. If eligible, patients will be randomised to either a control or intervention group by sequentially marked sealed envelopes. Intervention patients receive an invitation to the DCMedsRec service at a participating community pharmacy, who will be reimbursed. Control patients will receive usual care. A Number Needed to Treat of 20 will require 293 DCMedsRec interventions to achieve 80% power. With a predicted 30% uptake, a minimum sample of 977 in the intervention arm is required. OUTCOMES: The primary outcome will be the rate of 30-day unplanned hospital readmission in intervention (DCMedsRec) versus usual care groups. Secondary analyses will evaluate the economic impact of the intervention and a qualitative thematic analysis of the experience and value of the service for both patients and service providers (community pharmacists). ANALYSIS: An intention-to-treat analysis will be used to assess intervention efficacy and results will be reported using risk ratios with 95% confidence intervals. Cost-effectiveness analysis will compare within-trial costs and outcomes of the DCMedsRec versus usual care from a health-system perspective. TRIAL REGISTRATION AND FUNDING: This trial is registered with the Australian and New Zealand Clinical Trials Register and funded by the Australian Digital Health Agency.

The impact of legislation on acute synthetic cannabinoid harms resulting in ambulance attendance.

BACKGROUND: Synthetic cannabinoid receptor agonists (SCRAs) have been challenging current drug policy due to the rapid emergence of new variants, and their propensity for acute harm. In Australia, as in other parts of the world, multiple regulatory changes have occurred in response to these new psychoactive compounds, and population surveys indicate use is declining. This suggests that related harms would also be declining. We examined the impact of drug legislative changes on acute SCRA-related harms resulting in ambulance attendance. Secondary aims were to describe patient and attendance characteristics. METHODS: A retrospective analysis of coded ambulance attendance data from Victoria, Australia (January 2014-December 2018). Interrupted time-series was used to analyse the trajectories of SCRA-related attendances relative to legislative changes. RESULTS: During the study period, 3727 SCRA-related ambulance attendances were identified. There was an upward trend in attendances following legislation scheduling specific SCRAs in Victoria in October 2016 (slope = 1.31, 95% CI 1.17, 1.45). A downward trend in attendances followed 'blanket' legislation targeting all new psychoactive substances, implemented in Victoria in November 2017 (slope = -1.87, 95% CI -2.27, -1.46). Patient median age was 33 years, 80.5% were male, co-occurring substance use was identified in 30.4% cases, and 15.2% had >1 SCRA-related attendance. Overall, 69.4% cases were transported to hospital, with the odds of transport to hospital increasing each year from 2016. CONCLUSION: This study represents a population-level examination of the impact of drug policy on acute SCRA-related harms resulting in ambulance attendance. Scheduling of specific SCRAs was associated with a spike in attendances, likely due to the introduction of more harmful variants in the drug market. Blanket legislation was associated with a reduction in SCRA-related attendances, however, a corresponding increase in cases transported to hospital indicates a greater severity of harm that may have been inadvertently promoted by this policy.

The use of biologics in the management of cardiovascular diseases.

The use of biologic agents including monoclonal antibodies, recombinant proteins, non-coding RNAs (miRNAs), gene therapy and, especially, stem cell therapy have revolutionized the treatment of a variety of diseases. Most notably, success in treating cancers have been achieved using hematopoietic stem cell therapy. Use of these agents in the treatment of cardiovascular disease is still in its infancy but recent advances have identified several new biologic agents. Current clinical trials are evaluating the success of stem cell therapy and fibroblast therapy as well as agents that either mimic or inhibit non-coding RNAs (miRNAs) as possible treatments for a several cardiac pathologies including heart failure, myocardial infarction, arrhythmias, coronary artery disease and ischemic heart disease. This review will focus on the use of stem cells and miRNA agents to characterize the current status of these agents and describe some of the nuances that have led to the extraordinary interest in them as therapeutic agents.

Corneal hysteresis and its relevance to glaucoma.

PURPOSE OF REVIEW: Glaucoma is a leading cause of irreversible blindness worldwide. It is estimated that roughly 60.5 million people had glaucoma in 2010 and that this number is increasing. Many patients continue to lose vision despite apparent disease control according to traditional risk factors. The purpose of this review is to discuss the recent findings with regard to corneal hysteresis, a variable that is thought to be associated with the risk and progression of glaucoma. RECENT FINDINGS: Low corneal hysteresis is associated with optic nerve and visual field damage in glaucoma and the risk of structural and functional glaucoma progression. In addition, hysteresis may enhance intraocular pressure (IOP) interpretation: low corneal hysteresis is associated with a larger magnitude of IOP reduction following various glaucoma therapies. Corneal hysteresis is dynamic and may increase in eyes after IOP-lowering interventions are implemented. SUMMARY: It is widely accepted that central corneal thickness is a predictive factor for the risk of glaucoma progression. Recent evidence shows that corneal hysteresis also provides valuable information for several aspects of glaucoma management. In fact, corneal hysteresis may be more strongly associated with glaucoma presence, risk of progression, and effectiveness of glaucoma treatments than central corneal thickness.

Stressing the heart of the matter: re-thinking the mechanisms underlying therapeutic effects of n-3 polyunsaturated fatty acids.

Despite their clear therapeutic effects in coronary heart disease, use of n-3 polyunsaturated fatty acids (PUFAs) to treat other types of cardiovascular disease remains controversial, and serious obstacles exist in implementing them as a reliable and consistent drug therapy. The foremost of these is that a molecular mechanism and relevant dosages have not been firmly established in other forms of cardiovascular disease. In this brief review, we highlight the current state of knowledge regarding the mechanisms behind n-3 PUFA action in the cardiovascular system. We also propose the novel hypothesis that lipid peroxidation products derived from n-3 PUFAs may be driving much of their beneficial cardiovascular effects, particularly in the myocardium. We conclude by discussing evidence to support this hypothesis, and its possible clinical ramifications.

Cannabidiol and clozapine reverse MK-801-induced deficits in social interaction and hyperactivity in Sprague-Dawley rats.

Recently, a novel paradigm has been designed to assess social investigative behaviour in pairs of Sprague-Dawley rats, which involves physical separation whilst ensuring they are able to maintain contact through other social cues. We have modified this set-up in order to assess not just social behaviour but also locomotor activity of the rats. Results showed that the MK-801- (0.3 mg/kg) treated rats displayed reduced social investigative behaviour, hyperactivity as well as reduced attention span. Pretreatment with the phytocannabinoid cannabidiol (3 mg/kg) not only normalised social investigative behaviour but increased it beyond control levels. Pretreatment with clozapine (1, 3 mg/kg) also normalised social investigative behaviour. Both cannabidiol and clozapine inhibited MK-801-induced hyperactivity. However, there were no effects of pretreatment on impairments to attention span. Our findings reinforce several aspects of the validity of the MK-801-induced model of social withdrawal and hyperactivity and also support the use of this novel set-up for further investigations to assess the antipsychotic potential of novel compounds.

In vitro opioid receptor assays.

Although opioid analgesics have been used for centuries, identification of opioid receptors and the ability of an opioid receptor antagonist to block natural pain processes prompted a search for endogenous opioid peptides. In vitro models were needed to characterize opioid activity in biological samples. The longitudinal muscle/myenteric plexus (LM/MP) of the guinea pig ileum was the classical in vitro assay system, but the development of the mouse vas deferens (MVD) assay provided another important model that could be employed. Both assays entail electrical stimulation of intramural nerves to produce muscle contractions of the target organ. The robust contractions of the LM/MP are inhibited by µ and κ opioid receptor agonists, while the more labile contractions of the MVD are inhibited by µ, κ, and δ opioid receptor agonists. These in vitro assay systems are useful for evaluating biological activity of unknown substances and studying the properties of drug tolerance and both are described in this unit.

Spin effects in InAs self-assembled quantum dots.

We have studied the polarized resolved photoluminescence in an n-type resonant tunneling diode (RTD) of GaAs/AlGaAs which incorporates a layer of InAs self-assembled quantum dots (QDs) in the center of a GaAs quantum well (QW). We have observed that the QD circular polarization degree depends on applied voltage and light intensity. Our results are explained in terms of the tunneling of minority carriers into the QW, carrier capture by InAs QDs and bias-controlled density of holes in the QW.

The effect of chronic opioid vs. cannabinoid exposure on the expression of tolerance to morphine- or WIN-55,212-2-induced analgesia and hypothermia in the guinea pig.

Earlier studies using the guinea pig longitudinal muscle/myenteric plexus (LM/MP) demonstrated that chronic morphine treatment in vivo leads to the development of heterologous tolerance while chronic treatment with WIN 55,212-2 induces homologous tolerance. Few studies have evaluated whether a similar difference in tolerance development exists to the analgesic or hypothermic effects of these agents. Tolerance produced following chronic morphine (7 days) or WIN-55,212-2 (5 days) injection was assessed by determining the alteration in hypothermic response (using a rectal thermometer) or mechanical (paw pressure) or thermal (hot plate) analgesic threshold to challenge doses of WIN-55,212-2 and morphine. The tolerance observed in the hot plate test corresponded closely to that observed in the LM/MP studies where morphine pretreatment produced heterologous tolerance and WIN-55,212-2 pretreatment induced homologous tolerance. In contrast, chronic WIN-55,212-2 pretreatment precipitated tolerance to the analgesic effect of morphine in the paw pressure model despite the absence of an analgesic effect to this agent. Unlike chronic treatment with WIN-55,212-2, no tolerance to the hypothermic effect of WIN-55,212-2 was observed following morphine treatment. However, the hypothermic response observed to morphine challenge was modest suggesting that tolerance to this effect may be difficult to assess or not biologically relevant. The non-uniform character of tolerance observed in different models further suggests that the analysis of tolerance using in vivo test systems involves complex neuronal interactions in which altered responsiveness at one site may produce cascading cellular effects within a neuronal circuit that may differentially impact on tolerance expression.

Time course of altered sensitivity to inhibitory and excitatory agonist responses in the longitudinal muscle-myenteric plexus and analgesia in the Guinea pig after chronic morphine treatment.

Tolerance that develops after chronic morphine exposure has been proposed to be an adaptive response that develops and decays over a defined time course. The present study examined the development of tolerance to the acute hypothermic and analgesic effects of morphine and correlated the time course for the desensitization in vivo with the reduced responsiveness to DAMGO and 2-CADO and increased responsiveness to nicotine of the longitudinal muscle/myenteric plexus (LM/MP) preparation in vitro. Assessment was performed at various times after morphine or placebo pellet implantation. Morphine produced a modest hypothermic response to which no tolerance developed. However, the development of tolerance to the analgesic effect of morphine, the inhibitory effect of DAMGO and CADO on neurogenic twitches of the LM/MP and hypersensitivity to the contractile response to nicotine was observed to occur in a time-dependent manner. The alterations in sensitivity to DAMGO, nicotine, and responsiveness to morphine analgesia occurred between days 4 and 10 and returned to normal by day 14 post-implantation. In contrast, sensitivity of LM/MP preparations to 2-CADO displayed a similar time-dependent onset but the tolerance persisted beyond 14 days after implantation. These data suggest that the heterologous tolerance that develops after chronic morphine treatment is time-dependent and persistent but, ultimately returns to normal in the absence of any intervention. Furthermore, the data suggest that the basis of the adaptive phenomenon may involve multiple cellular mechanisms including the modulation of cell excitability and normal physiology but the consequences of the adaptation extend to all effects of the agonist.