Diazepam-ketamine and propofol are associated with acceptable induction and recovery from anaesthesia. Propofol had inferior anaesthetic induction characteristics, but superior and quicker recovery from anaesthesia compared with diazepam-ketamine.Induction of anaesthesia occasionally has been associated with undesirable behaviour in dogs. High quality of induction of anaesthesia with propofol has been well described while in contrast variable induction and recovery quality has been associated with diazepam-ketamine. In this study, anaesthetic induction and recovery characteristics of diazepam-ketamine combination with propofol alone were compared in dogs undergoing elective orchidectomy. Thirty-six healthy adult male dogs were used. After habitus scoring , the dogs were sedated with morphine and acepromazine. Forty minutes later a premedication score (SDS) was allocated and general anaesthesia was induced using a combination of diazepam-ketamine (Group D/K) or propofol (Group P) and maintained with isoflurane. Scores for the quality of induction, intubation and degree of myoclonus were allocated (SDS). Orchidectomy was performed after which recovery from anaesthesia was scored (SDS) and times to extubation and standing were recorded. Data were analysed using descriptive statistics and Kappa Reliability and Kendall Tau B tests. Both groups were associated with acceptable quality of induction and recovery from anaesthesia. Group P, however, was associated with a poorer quality of induction ( It may also be indicated in certain cases with cardiovascular compromise  has a wide initial dose range (2 mg/kg – 8 mg/kg) in dogs and induces rapid central nervous system depression facilitating anaesthetic induction within 20–30 seconds after commencement of intravenous administration  of 5.5 kg ± 2.3 kg and with a mean age of 26 ± 13 months were randomly assigned to an induction regimen of either diazepam-ketamine (Group D/K) or propofol (Group P). Dogs were declared healthy based on physiologically normal haematological  and serum chemistry  profiles and clinical examination performed upon admission to the hospital.Prior to anaesthesia, each dog was starved of food for 8–12 hours, then placed in a quiet, warm cage and left undisturbed for 30 minutes prior to being allocated a cage habitus score . Sixty seconds after initiation of bolus administration, depth of anaesthesia was assessed by a co-investigator by orderly testing of the lateral and medial palpebral reflex, menace reflex and jaw tone. If depth of anaesthesia was deemed insufficient for endotracheal intubation, a follow-up intravenous bolus was administered, which in Group-D/K dogs was 0.175 mg/kg and 2.5 mg/kg of diazepam and ketamine, respectively and in Group-P dogs was 1 mg/kg of propofol over 30 seconds. Follow-up boli were administered until endotracheal intubation could be achieved.Immediately after sedation scoring, a 22-gauge indwelling cannula  was inserted into the right cephalic vein to facilitate intravenous administration of anaesthetic induction drugs. General anaesthesia was induced in Group-D/K dogs with an initial combination dose of diazepam  and ketamine  of 0.375 mg/kg and 5 mg/kg, respectively and in Group-P dogs with an initial propofol  dose of 2 mg/kg. Induction boli were administered over a 30-second period using a volumetric infusion pump . The system delivered isoflurane  in oxygen via a Tec5 out-of-circuit precision vaporiser  initially set to 2% with a fresh gas flow rate set to 600 mL/kg/min. Spontaneous ventilation was permitted.pO2) measured and recorded every 5 minutes. A balanced crystalloid  was administered intra-operatively at a rate of 10 mL/kg/h for the duration of the anaesthesia.The overall quality of anaesthetic induction was then scored according to three separate induction criteria as described in Surgery time was recorded on completion of the orchidectomy, isoflurane and oxygen administration stopped and the dogs moved to a designated recovery area to recover from general anaesthesia. A quality of recovery score was then allocated by the primary and co-investigator .Video recording of the entire induction protocol was performed for retrospective analysis by a specialist anaesthetist blinded to the induction agents used. The same induction scoring system  was usedt-test, while non-parametric data  were analysed using the Wilcoxon-Mann-Whitney test. A significant level of p < 0.05 was set. Comparison of agreement between the observers was tested using the Kappa Reliability or Kendall Tau B tests  were analysed for statistical significance using the p > 0.05) between Group D/K and Group P were observed with regard to age and weight. Additionally, there were no statistically significant differences with regard to cage habitus score, sedation score and duration of anaesthetic maintenance , as Group D/K had better induction scores depicted by shorter induction times (p = 0.018) and fewer follow-up boli required to achieve endotracheal intubation , with nine dogs in Group P (n = 18) observed to have myoclonus. Group D/K had a very low incidence of myoclonus, with only one dog having muscle tremors.Group P had a greater incidence of myoclonus than Group D/K (p = 0.00002) and Group P had significantly superior recoveries when compared with Group D/K  in all categories of induction and recovery scoring, barring the intubation score, where Kendall's Tau B test indicated fair agreement (0.32).All dogs were client owned and consent was required in writing prior to being enrolled in the study. The dogs enrolled in the study were exposed to a moderate degree of discomfort as a result of the orchidectomy performed. The surgical procedure was performed by a specialist surgeon and all venepunctures as well as intravenous cannula placement for blood collection and drug administration, respectively, were performed by experienced veterinarians to limit the level of discomfort experienced. Appropriate analgesia including morphine and carprofen were provided during the peri-anaesthetic period. The present study was pre-approved by both the Animal Ethics Committee and the Research Committee of the Faculty of Veterinary Science, University of Pretoria (V017-33).This study demonstrated that Group D/K was associated with better quality of induction and myoclonus scores when compared with Group P. Recovery from anaesthesia was observed to be inferior and of longer duration for Group D/K than for Group P.et al.et al.et al.et al.et al.et al.The high quality of induction score associated with Group D/K in the present study supports current literature, which describes excitement-free dissociative anaesthesia with sufficient muscle relaxation to permit endotracheal intubation in dogs degree of pre-anaesthetic sedation achievedclinician experiencescoring system usedsignalment of the dogs that were used in the trial.et al.et al. (et al. (et al. (et al.The propofol dose range described for anaesthetic induction in dogs is wide (Jiménez .et al. . The rat.et al. . This wa (et al.  and Robi (et al. . The slo. et al.. As a reet al.et al.et al.et al.et al. (et al.Adequate premedication provides anxiolysis, muscle relaxation and analgesia as well as decreasing induction agent dose requirements (Grint, Alderson & Dugdale .et al. . In addi. et al..Timeous endotracheal intubation after induction of anaesthesia with a short-acting induction agent may be challenging, as previously reported in dogs anaesthetised with propofol (Clarke & Hall Signalment plays a role in the induction dose requirements in dogs. A study performed by Boveri, Brearley and Dugdale  highlighet al. (One dog in Group D/K that scored poorly on induction and, similar to an outlier in the study by White et al. , may havet al.et al.et al.et al.Recovery was statistically superior and shorter in Group P when compared with Group D/K. Historically propofol generally has been associated with acceptable recoveries and the results of the present study further support published literature (Bufalari et al. (et al.Dogs induced with diazepam-ketamine were associated with statistically inferior and prolonged recoveries when compared with propofol. Clinically, however, the quality of anaesthesia was acceptable. Recovery from diazepam-ketamine demonstrated an unremarkable return to consciousness, routine extubation, occasional paddling and vocalisation. Such a recovery, in a clinical setting, is considered acceptable as dogs were not at risk of self-inflicted injury as a result of trauma and most dogs would be able to stand after a relatively short period. Subjectively superior recoveries when compared with the present study's results were described by White et al.  in dogs . et al..et al.et al.et al. was recently questioned by Ferchichi et al. (The subjective scoring systems incorporated in the present study successfully differentiated the quality of induction and recovery between two groups of healthy dogs. A moderate to good level of agreement between observers was achieved but only after sufficient training on the correct use of the scales. The SDS scoring systems used to score induction and recovery from anaesthesia have been described previously in literature but have not been fully validated (Amengual i et al.  in termsthe methodology of associating induction and recovery characteristics to a single agent without confirming adequate plasma concentrations of the induction agent/sthe strength of comparing induction scores from two induction agents where administrations of the agents were not at equipotent dosesremarking on the quality of anaesthetic recovery from a specific induction agent without demonstrating the presence of the drug in adequate concentrations in plasma.et al. (These arguments raised valid concerns and demonstrate limitations in the present study as well as the study performed by Jiménez et al. . The resThe present study performed anaesthesia exclusively in healthy, adult male dogs weighing less than 10 kg. Future studies performed in female dogs, juvenile dogs or dogs weighing in excess of 10 kg may yield different results and outcomes.The use of propofol alone and a diazepam-ketamine combination both produced clinically acceptable induction of anaesthesia in the dogs in this study; however, propofol administered at a low dose rate produced measurably inferior induction characteristics. Recovery from anaesthesia induced with both of these protocols was satisfactory; however, recovery from propofol was more rapid and associated with less excitement and ataxia.


A mechanics-based brain damage framework is used to model the abnormal accumulation of hyperphosphorylated p-tau associated with chronic traumatic encephalopathy within the brains of deceased National Football League (NFL) players studied at Boston University and to provide a framework for understanding the damage mechanisms. p-tau damage is formulated as the multiplicative decomposition of three independently evolving damage internal state variables (ISVs): nucleation related to number density, growth related to the average area, and coalescence related to the nearest neighbor distance. The ISVs evolve under different rates for three well known mechanical boundary conditions, which in themselves introduce three different rates making a total of nine scenarios, that we postulate are related to brain damage progression: (1) monotonic overloads, (2) cyclic fatigue which corresponds to repetitive impacts, and (3) creep which is correlated to damage accumulation over time. Different NFL player positions are described to capture the different types of damage progression. Skill position players, such as quarterbacks, are expected to exhibit a greater p-tau protein accumulation during low cycle fatigue (higher amplitude impacts with a lesser number), and linemen who exhibit a greater p-tau protein accumulation during high cycle fatigue (lower amplitude impacts with a greater number of impacts). This mechanics-based damage framework presents a foundation for developing a multiscale model for traumatic brain injury that combines mechanics with biology. Note that mechanical “fatigue” is not medical fatigue; mechanical fatigue includes an external force of a particular amplitude that is cycled at a certain frequency.Regarding applied mechanics, Garrison and MoodyN) or reversals (2N) occur over time at a particular frequency; hence, the repetitive impact  frequency is important when considering the onset of CTE as high-amplitude impacts are associated with low-cycle fatigue (LCF) and low-amplitude impacts are associated with high-cycle fatigue (HCF). When a body is subjected to an applied stress over time, “creep” arises from straining and damage. Hence, the time duration of a material under stress is important.Five possible creep stress fields in the brain can be acknowledged: (1) intracranial pressure (ICP), (2) gravity inducing a body force, (3) a local stress field arising from an adjacent damaged local brain region (p-tau) due to local expansions and contractions thus inducing stress gradients on the adjacent material  exhibited the least amount of damage and was associated with an age of 28 years old with data scatter of 13 years; Level 2 incurred more damage and was associated with an age of 44 years old with data scatter of 16 years; Level 3 incurred even more damage and was associated with an age of 56 years old with data scatter of 14 years; finally, Level 4 exhibited the largest area fraction of dark areas associated with p-tau accumulation indicating that these players had incurred the greatest amount of damage. The age associated with Level 4 was 77 years old with data scatter of 12 years. The definition of each level was qualitatively assessed by the Boston University Team.et al.https://imagej.nih.gov/) was then used to create global thresholding restrictions to determine the damage area and the total area of each brain slice image, which were both approximately converted from pixel density to cm2. Additionally, the nucleation (#/cm2) of each brain slice were calculated usingATotal is the total area of each slice. The nearest neighbor distances (NNDs) between each tau protein damage area were then calculated using ImageJ and the “Nearest Neighbor Distances Calculation with ImageJ” plugin.ADamage is the previously determined damage area and ATotal is the total area of each brain slice image. As McKee et al.NND data set was arranged in descending order and assigned approximate ages (years). For Figs. NND, and damage (%) data sets were then fit to the ISV models in Figs. To quantify the p-tau protein damage throughout the various levels of CTE, the 76 full brain slice images documented in McKee Figure As Fig. Figure et al.As Garrison and MoodyCcoeff is the coefficient to the equation, and M is a complicated term that includes the microstructure and stress-state dependence. Because of the lack of knowledge of the subscale information associated with the regions of p-tau protein accumulations, the M parameter is yet to be related to microstructural features. Furthermore, a hydrostatic tension for the stress-state dependence locally is assumed; hence, even when compression occurs as a boundary condition, locally there is tension because of the Poisson ratio.Instead of coarse coding into four stages that the Boston University Team employed for the progressive damage states, we reorganize the data as one continuous stream of data by sorting all points by the general trend seen in the four stages. This allows for easier correlations to the ISV damage variables. The ISV nucleation model of Horstemeyer and GokhaleZ includes the microstructure and stress-state dependence similar to the nucleation equation.The equation used for damage growth is similar to the nucleation equation and is given by the following:NND and coalescence are given by the following:Q includes the microstructure and stress-state dependence similar to the nucleation equation, Ccoeff is the coefficient to the coalescence equation, and d is the square root of the area damaged by p-tau accumulation.The equations for the et al.The multiplication of the ISV nucleation, ISV growth, and ISV coalescence together gives rise to the total damage, which is the area fraction curve as shown in the following equation from Horstemeyer We correlate the physics-based ISV model with the sorted data of the Boston University data regarding CTE p-tau pathology and we relate the data and damage mechanisms to football player positions.2)] as a function of approximate time of death for the 76 specimens with pictures examined in the Boston University study.ηcoeff equals 0.01, and M equals 5.338, a close correlation of the damage ISV nucleation model to the tau protein pathology garnered by the Boston University Team exists  damaged by p-tau protein deposition signifying the damage growth of tau protein spots as measured on the brains of the deceased NFL players in the Boston University studyet al.Z equals 0.105, an excellent correlation of the damage growth model to the tau protein pathology garnered by the Boston University Team is found.Figure NND needs to be quantified. Horstemeyer et al.et al.NNDs (cm) within the region damaged by p-tau deposition signifying the damage interaction of tau protein measured on the brains of the deceased NFL players analyzed in the Boston University studyNND  incurred by the players. Nevertheless, the differences between the skill player positions and linemen resides in the fact that LCF and HCF regimes are being exhibited, respectively, as illustrated in the fatigue-life curve shown in Fig. The Boston University studieset al.,et al.,et al.,et al.,While a player at any position can experience an LCF monotonic overload (i.e. concussion), a couple of trends correlating player position to the abnormal accumulation of p-tau can be discerned. Based upon the data of Pellman Although greater magnitude loads could occur in a blast or a car crash, where brain tissue tearing or arterial tearing could arise from very large mechanical loads, the football related damage events are more related to a CTE threshold as denoted by the black line in Fig. Also of note, the LCF regime transitions to the HCF regime at the point where the plastic deformation asymptote intersects the elastic deformation asymptote (which are both designated by the dashed lines). Given this information, the high amplitude impacts experienced at the positions of QB/WR/DB/TE occur within the LCF regime, while repetitive cycles of low amplitude impacts result in HCF failure, like those experienced by linemen.et al.,et al.et al.et al.et al.,et al.et al.et al.,et al.et al.et al.et al.Figure et al.et al.et al.et al.Additional data was required to plot the strain-life curve in Fig. et al.et al.et al.et al.As mentioned previously, Funk et al.et al.et al.et al.et al.et al.,et al.et al.et al.et al.et al.et al.As aforementioned, offensive linemen incur HCF regime related damage but a skill position such as a QB incurs LCF regime related damage. Figure et al.et al.The fatigue curve Fig.  for the et al.et al.et al.et al.In Figs. et al.The brain consists of at least two networks of recursively branching structures: the blood vessels and the neural processes of axons and dendrites. In addition, the brain contains tubes within tubes: microtubules within the fluid-filled neurites that transport chemicals out and back to synaptic terminals. The mechanical properties at a subcellular scale are very nonuniform and like the neurons themselves are likely to be highly anisotropic and heterogeneous. Therefore, a detailed, multiscale model of brain mechanics will necessarily explore the points of particular vulnerability and respond to experimental data from animal studies that do not yet exist. Despite our present paucity of knowledge there exist intriguing data from other related areas of investigation. For example, Da Mesquita neurofilament light can be detected in the blood and spinal CSF of a particular group of Alzheimer’s patients many years before there is behavioral impairment.neurofilament light is also likely to be associated with brain damage in TBI, and if so, should be investigated in football players and in animal studies.Although p-tau accumulation is associated with microtubule damage repair, agglomeration of misfolded p-tau into fibrils is pathological, and its precise effects are not understood. We speculate that these fibrils may disrupt the cytoskeleton and possibly extracellular matrix. One recent study has found that There are a number of pathologies collectively amyloidosis in which plaques of accumulated proteins accumulate and change the properties of the tissue. The lens of the eye is an interesting model in that the progressive stiffening of the lens with age is due to the agglomeration of proteins that easily stick together to form fibrils. A recent paper has found that a particular steroid molecule, lanosterol, can dissolve these protein plaques and reverse the course of lens stiffening. While it is unknown what the mechanical effects of tau fibrils is in CTE, the studies in the lens are suggestive of work that needs to be undertaken.At a greater length scale, the axons of projection neurons are organized into a number of nerve tracts that traverse the brain both anteroposteriorly, radially from cortex to subcortical nuclei and back, and laterally between the two cerebral hemispheres. Large, long distance axons may be particularly vulnerable to mechanical insult and it would be interesting to examine how tau concentration is related to nerve tract terminations. All of these, and many other molecular neurobiological issues that we do not have space to discuss here, are suggestive of what a next-generation multiscale model might contain to examine detailed mediating mechanisms in CTE.et al.et al.NND) has been correlated to the damage progression found in the brains of deceased NFL players donated to Boston University. The strong correlation indicates that the different mechanics notions of nucleation, growth, and coalescence are key deformation mechanisms in brain damage progression.An ISV model with three physically motivated ISV rate equations  contributed to the p-tau accumulation and damage nucleation, growth, and coalescence in the brains of the deceased NFL players.Different football player positions were identified with various mechanical loading conditions. Skill position players, like QBs, incurred mainly LCF damage; whereas, linemen incurred mostly HCF damage.Given the unknown multiscale mechanisms, this study introduces a “first order” mechanical damage framework