Plasma pTau217 predicts continuous brain amyloid levels in preclinical and early Alzheimer's disease.

BACKGROUND: This study investigated the potential of phosphorylated plasma Tau217 ratio (pTau217R) and plasma amyloid beta (Aß) 42/Aß40 in predicting brain amyloid levels measured by positron emission tomography (PET) Centiloid (CL) for Alzheimer's disease (AD) staging and screening. METHODS: Quantification of plasma pTau217R and Aß42/Aß40 employed immunoprecipitation-mass spectrometry. CL prediction models were developed on a cohort of 904 cognitively unimpaired, preclinical and early AD subjects and validated on two independent cohorts. RESULTS: Models integrating pTau217R outperformed Aß42/Aß40 alone, predicting amyloid levels up to 89.1 CL. High area under the receiver operating characteristic curve (AUROC) values (89.3% to 94.7%) were observed across a broad CL range (15 to 90). Utilizing pTau217R-based models for low amyloid levels reduced PET scans by 70.5% to 78.6%. DISCUSSION: pTau217R effectively predicts brain amyloid levels, surpassing cerebrospinal fluid Aß42/Aß40's range. Combining it with plasma Aß42/Aß40 enhances sensitivity for low amyloid detection, reducing unnecessary PET scans and expanding clinical utility. GOV IDENTIFIERS: NCT02956486 (MissionAD1), NCT03036280 (MissionAD2), NCT04468659 (AHEAD3-45), NCT03887455 (ClarityAD) HIGHLIGHTS: Phosphorylated plasma Tau217 ratio (pTau217R) effectively predicts amyloid-PET Centiloid (CL) across a broad spectrum. Integrating pTau217R with Aß42/Aß40 extends the CL prediction upper limit to 89.1 CL. Combined model predicts amyloid status with high accuracy, especially in cognitively unimpaired individuals. This model identifies subjects above or below various CL thresholds with high accuracy. pTau217R-based models significantly reduce PET scans by up to 78.6% for screening out individuals with no/low amyloid.

Artificial intelligence for dementia drug discovery and trials optimization.

Drug discovery and clinical trial design for dementia have historically been challenging. In part these challenges have arisen from patient heterogeneity, length of disease course, and the tractability of a target for the brain. Applying big data analytics and machine learning tools for drug discovery and utilizing them to inform successful clinical trial design has the potential to accelerate progress. Opportunities arise at multiple stages in the therapy pipeline and the growing availability of large medical data sets opens possibilities for big data analyses to answer key questions in clinical and therapeutic challenges. However, before this goal is reached, several challenges need to be overcome and only a multi-disciplinary approach can promote data-driven decision-making to its full potential. Herein we review the current state of machine learning applications to clinical trial design and drug discovery, while presenting opportunities and recommendations that can break down the barriers to implementation.

Multi-resonant open-access microcavity arrays for light matter interaction.

We report the realisation of a high-finesse open-access cavity array, tailored towards the creation of multiple coherent light-matter interfaces within a compact environment. We describe the key technical developments put in place to fabricate such a system, comprising the creation of tapered pyramidal substrates and an in-house laser machining setup. Cavities made from these mirrors are characterised, by laser spectroscopy, to possess similar optical properties to state-of-the-art fibre-tip cavities, but offer a compelling route towards improved performance, even when used to support only a single mode. The implementation of a 2×2 cavity array and the independent frequency tuning between three neighbouring sites are demonstrated.

SCoVMod - a spatially explicit mobility and deprivation adjusted model of first wave COVID-19 transmission dynamics.

Background: Mobility restrictions prevent the spread of infections to disease-free areas, and early in the coronavirus disease 2019 (COVID-19) pandemic, most countries imposed severe restrictions on mobility as soon as it was clear that containment of local outbreaks was insufficient to control spread. These restrictions have adverse impacts on the economy and other aspects of human health, and it is important to quantify their impact for evaluating their future value. Methods: Here we develop Scotland Coronavirus transmission Model (SCoVMod), a model for COVID-19 in Scotland, which presents unusual challenges because of its diverse geography and population conditions. Our fitted model captures spatio-temporal patterns of mortality in the first phase of the epidemic to a fine geographical scale. Results: We find that lockdown restrictions reduced transmission rates down to an estimated 12\% of its pre-lockdown rate. We show that, while the timing of COVID-19 restrictions influences the role of the transmission rate on the number of COVID-related deaths, early reduction in long distance movements does not. However, poor health associated with deprivation has a considerable association with mortality; the Council Area (CA) with the greatest health-related deprivation was found to have a mortality rate 2.45 times greater than the CA with the lowest health-related deprivation considering all deaths occurring outside of carehomes. Conclusions: We find that in even an early epidemic with poor case ascertainment, a useful spatially explicit model can be fit with meaningful parameters based on the spatio-temporal distribution of death counts. Our simple approach is useful to strategically examine trade-offs between travel related restrictions and physical distancing, and the effect of deprivation-related factors on outcomes.

Increasing the Cognitive Screening Efficiency of Global Phase III Trials in Early Alzheimer Disease: The Cognitive Task Force.

PURPOSE: A Cognitive Task Force (CTF) was established for the MissionAD program with the aim of reducing the screen failure (SF) rate to ∼30% and thereby reduce unnecessary subject burden, site burden, and excess trial costs. METHODS/SUBJECTS: The MissionAD program consisted of 2 global phase 3 studies evaluating the BACE inhibitor elenbecestat in subjects with early Alzheimer disease. The CTF monitored and engaged with MissionAD clinical sites to provide support through collegial discussions to maximize the efficiency of the preconsent recruitment phase. RESULTS: The CTF significantly improved cognitive screening efficiency in the MissionAD program, with a 24% decline in cognitive SF rate for the sites that the CTF contacted. The study-wide 11.5% reduction in cognitive SF rates were likely further driven by wider country-level initiatives in which CTF members held CTF-specific Investigator meetings with the recruitment staff, speaking to all sites on a country level regardless of their recruitment performance. CONCLUSIONS: The establishment of a CTF to support efficient cognitive screening is highly recommended for future Alzheimer disease studies. Additional benefits included improved site relationships, increased engagement in MissionAD and access to a group of cognitive experts for consulting, with a focus on achieving more efficient trial recruitment.

Dexmedetomidine prolongs the duration of action of mepivacaine on anesthesia of the palmar digital nerves of horses.

OBJECTIVE: To determine whether palmar digital nerve (PDN) blockade in horses with a combination of dexmedetomidine and mepivacaine would block the response to mechanical force applied to the digit longer than would anesthetizing these nerves with mepivacaine alone or dexmedetomidine alone. ANIMALS: 8 mares with no signs of lameness. PROCEDURES: In a randomized, crossover, blinded, experimental study, both PDNs of the same forelimb of each horse were anesthetized by perineural injection with either 30 mg mepivacaine alone, 250 µg of dexmedetomidine alone, or 30 mg mepivacaine combined with 250 µg of dexmedetomidine. Each horse received each treatment, and treatments were administered ≥ 2 weeks apart. The mechanical nociceptive threshold was measured at a region between the heel bulbs with the use of a digital force gauge before (baseline) and at 15-minute intervals after treatment. RESULTS: The mean duration of sensory blockade of the digit was 2-fold longer when a combination of mepivacaine and dexmedetomidine was administered (371 minutes), compared with when mepivacaine alone was administered (186 minutes). Treatment with dexmedetomidine alone did not change the mechanical nociceptive threshold substantially from baseline and resulted in no clinical signs of sedation. CLINICAL RELEVANCE: Results indicated that relief from digital pain provided by perineural treatment with mepivacaine for PDN blockade can be extended by adding dexmedetomidine to the injectate.

Influence of a novel scaffold composed of polyurethane, hydroxyapatite, and decellularized bone particles on the healing of fourth metacarpal defects in mares.

OBJECTIVE: To determine the effect of a novel scaffold, designed for use in bone regeneration, on healing of splint bone segmental defects in mares. STUDY DESIGN: In vivo experimental study. SAMPLE POPULATION: Five adult mares (4-10 years old; mean weight, 437.7 kg ± 29 kg). METHODS: Bilateral 2-cm full-thickness defects were created in the fourth metacarpal bones (MCIV) of each horse. Each defect was randomly assigned to either a novel scaffold treatment (n = 5) or an untreated control (n = 5). The scaffold was composed of polyurethane, hydroxyapatite, and decellularized bone particles. Bone healing was assessed for a period of 60 days by thermography, ultrasonography, radiography, and computed tomography (CT). Biopsies of each defect were performed 60 days after surgery for histological evaluation. RESULTS: On the basis of radiographic analysis, scaffold-treated defects had greater filling (67.42% ± 26.7%) compared with untreated defects (35.88% ± 32.7%; P = .006). After 60 days, CT revealed that the density of the defects treated with the scaffolds (807.80 ± 129.6 Hounsfield units [HU]) was greater than density of the untreated defects (464.80 ± 81.3 HU; P = .004). Evaluation of histology slides provided evidence of bone formation within an average of 9.43% ± 3.7% of the cross-sectional area of scaffolds in contrast to unfilled defects in which connective tissue was predominant throughout the biopsy specimens. CONCLUSION: The novel scaffold was biocompatible and supported bone formation within the MCIV segmental defects. CLINICAL SIGNIFICANCE: This novel scaffold offers an effective option for filling bone voids in horses when support of bone healing is indicated.

Sedative effects and pharmacokinetics of detomidine when administered intravenously and intravaginally as a gel in alpacas.

OBJECTIVES: To evaluate the sedative effects and pharmacokinetics of detomidine gel administered intravaginally to alpacas in comparison with intravenously (IV) administered detomidine. STUDY DESIGN: Randomized, crossover, blinded experiment. ANIMALS: A group of six healthy adult female Huacaya alpacas (70.3 ± 7.9 kg). METHODS: Alpacas were studied on two occasions separated by ≥5 days. Treatments were IV detomidine hydrochloride (70 µg kg-1; treatment DET-IV) or detomidine gel (200 µg kg-1; treatment DET-VAG) administered intravaginally. Sedation and heart rate (HR) were evaluated at intervals for 240 minutes. Venous blood was collected at intervals for 360 minutes after treatment for analysis of detomidine, carboxydetomidine and hydroxydetomidine using liquid chromatography-tandem mass spectrometry. Measured variables were compared between treatments and over time using mixed model analysis. Data are presented as the mean ± standard error of the mean, and a p value of <0.05 was considered significant. RESULTS: Onset of sedation was faster in treatment DET-IV (1.6 ± 0.2 minutes) than in treatment DET-VAG (13.0 ± 2.5 minutes). Time to maximum sedation was shorter in treatment DET-IV (8.3 ± 1.3 minutes) than in treatment DET-VAG (25 ± 4 minutes). Duration of sedation was not different between treatments. There was a significant linear relationship between sedation score and plasma detomidine concentration. HR was less than baseline for 60 and 125 minutes for treatments DET-IV and DET-VAG, respectively. The maximal decrease in HR occurred at 15 minutes for both treatments. The mean maximum plasma concentration of detomidine, time to maximum concentration and bioavailability for treatment DET-VAG were 39.6 ng mL-1, 19.9 minutes and 20%, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Detomidine administration at the doses studied resulted in moderate sedation when administered IV or intravaginally to alpacas.

Efficacy and duration of effect for liposomal bupivacaine when administered perineurally to the palmar digital nerves of horses.

OBJECTIVE: To determine the efficacy and duration of effect for liposomal bupivacaine following perineural administration to the medial and lateral palmar digital nerves of horses. ANIMALS: 9 nonlame mares. PROCEDURES: For each horse, 2 mL of liposomal bupivacaine (13.3 mg/mL; total dose, 53.2 mg or approx 0.11 mg/kg) or sterile saline (0.9% NaCl) solution was injected adjacent to the medial and lateral palmar digital nerves at the level of the distal aspect of the proximal sesamoid bones of a randomly selected forelimb. Twenty-one days later, the opposite treatment was administered in the contralateral forelimb. A digital algometer was used to measure the mechanical nociceptive threshold (MNT) immediately before and at predetermined times for 48 hours after injection of each treatment. The mean MNT was compared between the 2 treatments at each measurement time. RESULTS: The mean MNT for the liposomal bupivacaine-treated limbs was significantly greater (ie, the limb was less sensitive) than that for the saline-treated limbs between 30 minutes and 4 hours after treatment injection. Following liposomal bupivacaine administration, 1 horse developed mild swelling at the injection sites that resolved without treatment within 24 hours. No other adverse effects were observed. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that liposomal bupivacaine is another option for perineural anesthesia in horses. Further research is necessary to determine the optimal dose and better elucidate the duration of effect for the drug when used for palmar digital nerve blocks in horses.

Evaluation of the sedative effects and pharmacokinetics of detomidine gel administered intravaginally to horses.

OBJECTIVES: To determine the sedative effects and pharmacokinetic profile of detomidine when administered intravaginally as a gel formulation to horses. STUDY DESIGN: Randomized, crossover, masked experimental design. ANIMALS: A group of six healthy adult mares (494 ± 56 kg). METHODS: Mares were studied on two occasions and were administered either detomidine hydrochloride (10 µg kg-1) intravenously (treatment IV) or detomidine gel (40 µg kg-1) intravaginally (treatment IVG), separated by 1 week. Sedation, ataxia, muzzle-floor distance and heart rate (HR) were evaluated every 15 minutes for 240 minutes. Venous blood samples were collected at 15, 30, 45, 60, 90, 120, 150, 180, 240, 300 and 360 minutes postadministration and were analyzed for detomidine and metabolites using liquid chromatography-tandem mass spectrometry. Measured variables were compared over time and between treatments using mixed model analysis. Correlation between drug plasma concentrations and muzzle-floor distance, and sedation and ataxia scores was determined using the Spearman correlation coefficient. Data are presented as mean ± standard error of the mean and p value was set at <0.05. RESULTS: Sedation was shorter with IV (119 ± 16 minutes) than with IVG (188 ± 22 minutes). Ataxia scores remained greater than baseline for 90 and 135 minutes for treatments IV and IVG, respectively. HR was lower than baseline for 45 and 30 minutes for IV and IVG, respectively, but did not differ between treatments. The mean maximum plasma concentration of detomidine, time to maximum concentration and bioavailability for treatment IVG was 8.57 ng mL-1, 0.37 hour and 25%, respectively. There was a significant correlation (r = 0.68) between plasma detomidine concentrations and sedation score. CONCLUSIONS AND CLINICAL RELEVANCE: Detomidine gel administered intravaginally resulted in clinically important sedation and is a viable method for detomidine gel delivery in mares.

Effect of fentanyl on the induction dose and minimum infusion rate of alfaxalone preventing movement in dogs.

OBJECTIVE: To determine the effect of fentanyl on the induction dose and minimum infusion rate of alfaxalone required to prevent movement in response to a noxious stimulus (MIRNM) in dogs. STUDY DESIGN: Experimental crossover design. ANIMALS: A group of six healthy, adult, intact female mixed-breed dogs, weighing 19.7 ± 1.3 kg. METHODS: Dogs were randomly administered one of three treatments at weekly intervals: premedication with 0.9% saline (treatment A), fentanyl 5 µg kg-1 (treatment ALF) or fentanyl 10 µg kg-1 (treatment AHF), administered intravenously over 5 minutes. Anesthesia was induced 5 minutes later with incremental doses of alfaxalone to achieve intubation and was maintained for 90 minutes in A with alfaxalone (0.12 mg kg-1 minute-1), in ALF with alfaxalone (0.09 mg kg-1 minute-1) and fentanyl (0.1 µg kg-1 minute-1) and in AHF with alfaxalone (0.06 mg kg-1 minute-1) and fentanyl (0.2 µg kg-1 minute-1). The alfaxalone infusion was increased or decreased by 0.006 mg kg-1 minute-1 based on positive or negative response to antebrachium stimulation (50 V, 50 Hz, 10 ms). Data were analyzed using a mixed-model anova and presented as least squares means ± standard error. RESULTS: Alfaxalone induction doses were 3.50 ± 0.13 (A), 2.17 ± 0.10 (ALF) and 1.67 ± 0.10 mg kg-1 (AHF) and differed among treatments (p < 0.05). Alfaxalone MIRNM was 0.17 ± 0.01 (A), 0.10 ± 0.01 (ALF) and 0.07 ± 0.01 mg kg-1 minute-1 (AHF) and differed among treatments. ALF and AHF decreased the MIRNM by 44 ± 8% and 62 ± 5%, respectively (p < 0.05). Plasma alfaxalone concentrations at MIRNM were 5.82 ± 0.48 (A), 4.40 ± 0.34 (ALF) and 2.28 ± 0.09 µg mL-1 (AHF). CONCLUSIONS AND CLINICAL RELEVANCE: Fentanyl, at the doses studied, significantly decreased the alfaxalone induction dose and MIRNM.

Manipulation of contact network structure and the impact on foot-and-mouth disease transmission.

The movements of livestock between premises and markets can be characterised as a dynamic network where the structure of the network itself can critically impact the transmission dynamics of many infectious diseases. As evidenced by the 2001 foot-and-mouth disease (FMD) epidemic in the UK, this can involve transmission over large geographical distances and can result in major economic loss. One consequence of the FMD epidemic was the introduction of mandatory livestock movement restrictions: a 13-day standstill in Scotland for cattle and sheep after moving livestock onto a farm (allowing many exemptions) and a 6-day standstill for cattle and sheep in England and Wales (with minor exemptions, e.g. direct movements to slaughter). Such standstills are known to be effective but commercial considerations result in pressures to relax them. When contemplating legislative changes such as a change in length of movement restrictions we need to consider the consequent effect these could have on the emergent properties of the system, i.e. the network structure itself. In this study, we investigate how disease dynamics change when the local contact structure of the recorded livestock movement network in Scotland is altered through rewiring movements between premises. The network rewiring used here changes the structure of the recorded trade network through a combination of altered movement restrictions and redirection of movements between holdings and markets to avoid nonsensical activity (e.g. movements to markets on days when they are inactive) while conserving other characteristics (e.g. movement date as closely as possible and market sales of the correct animal production type). Rewiring results in networks with higher clustering coefficients and lower network density. The impact of rewiring on a hypothetical foot-and-mouth disease outbreak in Scotland was assessed by stochastic simulation, considering scenarios with and without exemptions to the standstill rules. As expected, rewiring leads to a decrease in outbreak size and - if standstill exemptions are prohibited - higher probability of smaller outbreaks. Without exemptions, a shorter movement standstill is almost as effective as a longer standstill period, indicating that a simpler biosecurity system would offer minimal additional risk for FMD. These results suggest that explicitly manipulating the contact network structure in a sensible way has the potential to significantly impact disease control.

Minimum alveolar concentration: Key concepts and a review of its pharmacological reduction in dogs. Part 2.

OBJECTIVE: To outline the major components of the minimum alveolar concentration (MAC) and review the literature regarding pharmacological manipulation of the MAC of halothane, isoflurane, sevoflurane, enflurane, and desflurane in dogs. The pharmacological agents included are alpha-2 agonists, benzodiazepines, propofol, opioids, lidocaine, acepromazine, non-steroidal anti-inflammatory agents (NSAIDs), maropitant, and NMDA antagonists. Part 2 of this review will focus on the effect of opioids, lidocaine, NSAIDs, maropitant, acepromazine, and NMDA antagonists on MAC. DATABASES USED: PubMed, Google Scholar, CAB Abstracts. Search terms used: minimum alveolar concentration, MAC, dog, canine, inhaled anesthetic potency, isoflurane, sevoflurane, desflurane, enflurane, and halothane. CONCLUSIONS: Opioids, lidocaine, NSAIDs, maropitant, acepromazine, and NMDA antagonists have been shown to reduce the MAC of inhaled anesthetics in dogs and allow for clinically important decreases in inhalant anesthetic use. Thus, the use of these agents potentially decrease the adverse cardiovascular and pulmonary effects associated with the use of high concentrations of inhaled anesthetics.

Minimum alveolar concentration: Key concepts and a review of its pharmacological reduction in dogs. Part 1.

OBJECTIVE: To outline the major components of the minimum alveolar concentration (MAC) and review the literature in regard to pharmacological manipulation of the MAC of halothane, isoflurane, sevoflurane, enflurane, and desflurane in dogs. The pharmacologic agents included are alpha-2 agonists, benzodiazepines, propofol, maropitant, opioids, lidocaine, acepromazine, non-steroidal anti-inflammatory agents, and NMDA antagonists. Part 1 will focus on summarizing the relevance, measurement, and mechanisms of MAC and review the effects of alpha-2 agonists, benzodiazepines, and propofol on MAC. DATABASES USED: PubMed, Google Scholar, CAB Abstracts. Search terms used: minimum alveolar concentration, MAC, dog, canine, inhaled anesthetic potency, isoflurane, sevoflurane, desflurane, enflurane, and halothane. CONCLUSIONS: Many drugs reduce the MAC of inhaled anesthetics in dogs, and allow for a clinically important decrease in inhalant anesthetic use. A decrease in MAC may decrease the adverse cardiovascular and pulmonary effects associated with the use of high concentrations of inhaled anesthetics.

Effects of stacked wedge pads and chains applied to the forefeet of Tennessee Walking Horses for a five-day period on behavioral and biochemical indicators of pain, stress, and inflammation.

OBJECTIVE To determine the effects of stacked wedge pads and chains applied to the forefeet of Tennessee Walking Horses on behavioral and biochemical indicators of pain, stress, and inflamation. ANIMALS 20 Tennessee Walking Horses. PROCEDURES Horses were randomly assigned to 2 treatment groups: keg shoes (control; n = 10) or stacked wedge pads and exercise with chains (10). Ten days before treatment application, an accelerometer was attached at the left metatarsus of each horse to record daily activity. Horses were exercised for 20 minutes daily, beginning on day -7. On day 0, exercise ceased, the forefeet were trimmed, and the assigned treatment was applied. From days 1 through 5, horses were exercised as before. Blood samples for measurement of plasma cortisol, substance P, and fibrinogen concentrations were collected on days -5, 1, and 5 before and after exercise and every 30 minutes thereafter for 6 hours. RESULTS No significant differences in plasma concentrations of cortisol, substance P, and fibrinogen were detected between groups. Although lying behaviors changed after shoes were applied, these behaviors did not differ significantly between groups. Shoeing appeared to have altered behavior to a greater extent than did the type of treatment applied. CONCLUSIONS AND CLINICAL RELEVANCE Application of stacked wedge pads and chains to the forefeet of horses for a 5-day period as performed in this study evoked no acute or subacute stress or nociceptive response as measured. Although these findings should not be extrapolated to the long-term use of such devices in Tennessee Walking Horses performing the running walk, the data should be considered when making evidence-based decisions relating to animal welfare and the use of stacked wedge pads and chains.

Dissipatively coupled waveguide networks for coherent diffusive photonics.

A photonic circuit is generally described as a structure in which light propagates by unitary exchange and transfers reversibly between channels. In contrast, the term 'diffusive' is more akin to a chaotic propagation in scattering media, where light is driven out of coherence towards a thermal mixture. Based on the dynamics of open quantum systems, the combination of these two opposites can result in novel techniques for coherent light control. The crucial feature of these photonic structures is dissipative coupling between modes, via an interaction with a common reservoir. Here, we demonstrate experimentally that such systems can perform optical equalisation to smooth multimode light, or act as a distributor, guiding it into selected channels. Quantum thermodynamically, these systems can act as catalytic coherent reservoirs by performing perfect non-Landauer erasure. For lattice structures, localised stationary states can be supported in the continuum, similar to compacton-like states in conventional flat-band lattices.

Effect of dexmedetomidine on the minimum infusion rate of propofol preventing movement in dogs.

OBJECTIVE: To determine the effect of dexmedetomidine on induction dose and minimum infusion rate of propofol preventing movement (MIRNM). STUDY DESIGN: Randomized crossover, unmasked, experimental design. ANIMALS: Three male and three female healthy Beagle dogs weighing 10.2 ± 2.8 kg. METHODS: Dogs were studied on three occasions at weekly intervals. Premedications were 0.9% saline (treatment P) or dexmedetomidine (1 µg kg-1, treatment PLD; 2 µg kg-1, treatment PHD) intravenously. Anesthesia was induced with propofol (2 mg kg-1 and then 1 mg kg-1 every 15 seconds) until intubation. Anesthesia was maintained for 90 minutes in P with propofol (0.5 mg kg-1 minute-1) and saline, in PLD with propofol (0.35 mg kg-1 minute-1) and dexmedetomidine (1 µg kg-1 hour-1), and in PHD with propofol (0.3 mg kg-1 minute-1) and dexmedetomidine (2 µg kg-1 hour-1). The stimulus (50 V, 50 Hz, 10 ms) was applied to the antebrachium, and propofol infusion was increased or decreased by 0.025 mg kg-1 minute-1 based on a positive or negative response, respectively. Data were analyzed using a mixed-model anova and presented as mean ± standard error. RESULTS: Propofol induction doses were 8.68 ± 0.57 (P), 6.13 ± 0.67 (PLD) and 4.78 ± 0.39 (PHD) mg kg-1 and differed among treatments (p < 0.05). Propofol MIRNM values were 0.68 ± 0.13, 0.49 ± 0.16 and 0.26 ± 0.05 mg kg-1 minute-1 for P, PLD and PHD, respectively. Propofol MIRNM decreased 59% in PHD (p < 0.05). Plasma propofol concentrations were 14.04 ± 2.30 (P), 11.30 ± 4.30 (PLD) and 7.96 ± 0.72 (PHD) µg mL-1 and dexmedetomidine concentrations were 0.68 ± 0.12 (PLD) and 0.89 ± 0.08 (PHD) ng mL-1 at MIRNM determination. CONCLUSIONS AND CLINICAL RELEVANCE: Dexmedetomidine (1 and 2 µg kg-1) decreased propofol induction dose. Dexmedetomidine (2 µg kg-1 hour-1) resulted in a significant decrease in propofol MIRNM.

Effect of fentanyl on the induction dose and minimum infusion rate of propofol preventing movement in dogs.

OBJECTIVE: To determine the effect of fentanyl on the induction dose of propofol and minimum infusion rate required to prevent movement in response to noxious stimulation (MIRNM) in dogs. STUDY DESIGN: Crossover experimental design. ANIMALS: Six healthy, adult intact male Beagle dogs, mean±standard deviation 12.6±0.4 kg. METHODS: Dogs were administered 0.9% saline (treatment P), fentanyl (5 µg kg-1) (treatment PLDF) or fentanyl (10 µg kg-1) (treatment PHDF) intravenously over 5 minutes. Five minutes later, anesthesia was induced with propofol (2 mg kg-1, followed by 1 mg kg-1 every 15 seconds to achieve intubation) and maintained for 90 minutes by constant rate infusions (CRIs) of propofol alone or with fentanyl: P, propofol (0.5 mg kg-1 minute-1); PLDF, propofol (0.35 mg kg-1 minute-1) and fentanyl (0.1 µg kg-1 minute-1); PHDF, propofol (0.3 mg kg-1 minute-1) and fentanyl (0.2 µg kg-1 minute-1). Propofol CRI was increased or decreased based on the response to stimulation (50 V, 50 Hz, 10 mA), with 20 minutes between adjustments. Data were analyzed using a mixed-model anova and presented as mean±standard error. RESULTS: ropofol induction doses were 6.16±0.31, 3.67±0.21 and 3.33±0.42 mg kg-1 for P, PLDF and PHDF, respectively. Doses for PLDF and PHDF were significantly decreased from P (p<0.05) but not different between treatments. Propofol MIRNM was 0.60±0.04, 0.29±0.02 and 0.22±0.02 mg kg-1 minute-1 for P, PLDF and PHDF, respectively. MIRNM in PLDF and PHDF was significantly decreased from P. MIRNM in PLDF and PHDF were not different, but their respective percent decreases of 51±3 and 63±2% differed (p=0.035). CONCLUSIONS AND CLINICAL RELEVANCE: Fentanyl, at the doses studied, caused statistically significant and clinically important decreases in the propofol induction dose and MIRNM.

Assessment of agreement among diplomates of the American College of Veterinary Anesthesia and Analgesia for scoring the recovery of horses from anesthesia by use of subjective grading scales and development of a system for evaluation of the recovery of horses from anesthesia by use of accelerometry.

OBJECTIVE To evaluate agreement among diplomates of the American College of Veterinary Anesthesia and Analgesia for scores determined by use of a simple descriptive scale (SDS) or a composite grading scale (CGS) for quality of recovery of horses from anesthesia and to investigate use of 3-axis accelerometry (3AA) for objective evaluation of recovery. ANIMALS 12 healthy adult horses. PROCEDURES Horses were fitted with a 3AA device and then were anesthetized. Eight diplomates evaluated recovery by use of an SDS, and 7 other diplomates evaluated recovery by use of a CGS. Agreement was tested with κ and AC1 statistics for the SDS and an ANOVA for the CGS. A library of mathematical models was used to map 3AA data against CGS scores. RESULTS Agreement among diplomates using the SDS was slight (κ = 0.19; AC1 = 0.22). The CGS scores differed significantly among diplomates. Best fit of 3AA data against CGS scores yielded the following equation: RS = 9.998 × SG0.633 × ∑UG0.174, where RS is a horse's recovery score determined with 3AA, SG is acceleration of the successful attempt to stand, and ∑UG is the sum of accelerations of unsuccessful attempts to stand. CONCLUSIONS AND CLINICAL RELEVANCE Subjective scoring of recovery of horses from anesthesia resulted in poor agreement among diplomates. Subjective scoring may lead to differences in conclusions about recovery quality; thus, there is a need for an objective scoring method. The 3AA system removed subjective bias in evaluations of recovery of horses and warrants further study.

Pharmacokinetics and pharmacodynamics of midazolam following intravenous and intramuscular administration to sheep.

OBJECTIVE To determine the pharmacokinetic and pharmacodynamic effects of midazolam following IV and IM administration in sheep. ANIMALS 8 healthy adult rams. PROCEDURES Sheep were administered midazolam (0.5 mg/kg) by the IV route and then by the IM route 7 days later in a crossover study. Physiologic and behavioral variables were assessed and blood samples collected for determination of plasma midazolam and 1-hydroxymidazolam (primary midazolam metabolite) concentrations immediately before (baseline) and at predetermined times for 1,440 minutes after midazolam administration. Pharmacokinetic parameters were calculated by compartmental and noncompartmental methods. RESULTS Following IV administration, midazolam was rapidly and extensively distributed and rapidly eliminated; mean ± SD apparent volume of distribution, elimination half-life, clearance, and area under the concentration-time curve were 838 ± 330 mL/kg, 0.79 ± 0.44 hours, 1,272 ± 310 mL/h/kg, and 423 ± 143 h·ng/mL, respectively. Following IM administration, midazolam was rapidly absorbed and bioavailability was high; mean ± SD maximum plasma concentration, time to maximum plasma concentration, area under the concentration-time curve, and bioavailability were 820 ± 268 ng/mL, 0.46 ± 0.26 hours, 1,396 ± 463 h·ng/mL, and 352 ± 148%, respectively. Respiratory rate was transiently decreased from baseline for 15 minutes after IV administration. Times to peak sedation and ataxia after IV administration were less than those after IM administration. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated midazolam was a suitable short-duration sedative for sheep, and IM administration may be a viable alternative when IV administration is not possible.