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Background: Anatomical location-dependent differences in transdermal opioid penetration are well described in human patients. Although this has been investigated in horses with fentanyl, there is no literature available on location-dependent plasma buprenorphine concentrations when administered as a transdermal matrix-type patch., Objective: This study aims to compare the plasma concentrations achieved from the matrix-type transdermal buprenorphine patches placed at different anatomical sites (metacarpus, gaskin, and ventral tail base) in healthy adult horses., Study Design: This is a randomized experimental study with a Latin square design., Methods: Six adult horses were given each of three treatments with a minimum 10-day washout period. For each treatment, two 20 μg h -1 matrix-type buprenorphine patches were applied to the ventral aspect of the tail base (Tail TDP ), metacarpus region (Metacarpus TDP ), or gaskin region (Gaskin TDP ). Whole blood samples (for determination of buprenorphine concentration) and physiological variables were collected before (0 h) and at 0.5, 2, 4, 6, 8, 10, 12, 16, 24, 32, 48, 56, 72, 96 and 120 h after patches were applied. The patches were removed 96 h following placement and were analyzed for residual buprenorphine content. Buprenorphine concentrations were measured in plasma by LC-MS/MS. A mixed-effects model was used to analyze the physiological variables., Results: Between the three treatment groups, there was no change in physiological variables across timepoints as compared to baseline and when compared to each other in a single horse and between horses ( p  > 0.3). When comparing all three locations, the buprenorphine uptake was observed to be more consistent with respect to measurable plasma concentrations >0.1 ng ml -1 when applied to the ventral aspect of the tail base. In the Tail TDP group, the mean plasma buprenorphine concentrations were >0.1 ng ml -1 from 2 to 32 h. The highest group mean was 0.25 ng ml -1 noted at 4 h., Conclusions: The metacarpal and gaskin regions presented more erratic and inconsistent buprenorphine uptake and plasma concentrations as compared to the ventral aspect of the tail base. Further research must be directed at investigating the optimal dose, achievable duration of analgesia, change in measurable plasma concentrations, and behavioral and systemic effects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Paranjape, Knych, Berghaus, Giancola, Cathcart and Reed.)

Objective: To evaluate the accuracy, precision, and observer agreement of three pressure measurement devices., Study Design: In vitro model study., Sample Population: Water manometer with built-in gauge (WMg), arterial pressure transducer (APT), and Compass CT (CCT)., Methods: The model was set to five predetermined pressures (4, 8, 13, 17, and 24 cm H 2 O) using a water manometer with a ruler (WMr) as the gold standard. Each device was tested at each pressure in a randomized order by three investigators. Bland-Altman plots were used to assess agreement between devices. Intraclass correlation coefficients (ICC) were calculated for interobserver and intraobserver agreements., Results: The mean differences (cm H 2 O) ± SEM in comparison with the set pressure were -0.020 ± 0.010 (WMg), -0.390 ± 0.077 (APT), and -1.267 ± 0.213 (CCT). Pressures measured by WMg did not differ from those measured by WMr. Pressures measured by all devices did not differ from each other (p > .062 for all comparisons). Interobserver agreement was excellent (1.000), and intraobserver agreement was excellent (0.985, 0.990, 0.998 for each observer)., Conclusion: Compared to the WMr, the WMg was the most accurate and precise, followed by the APT; the CCT was the least accurate and precise. Interobserver and intraobserver agreements for all three devices were excellent., Clinical Significance: The largest mean difference of all devices was within 1.3 cm H 2 O of the set pressure, indicating possible clinical utility of any of the devices. However, WMr or WMg should be considered first due to their high precision and accuracy., (© 2023 The Authors. Veterinary Surgery published by Wiley Periodicals LLC on behalf of American College of Veterinary Surgeons.)

Introduction: Understanding the pharmacokinetics and pharmacodynamics of fentanyl in horses is crucial for optimizing pain management strategies in veterinary medicine., Methods: Six adult horses were enrolled in a randomized crossover design. Treatments included: placebo, two 100 mcg/h patches (LDF), four 100 mcg/h patches (MDF), and six 100 mcg/h patches (HDF). Patches were in place for 72 h. Blood was obtained for fentanyl plasma concentration determination, thermal threshold, mechanical threshold, heart rate, respiratory rate, and rectal temperature were obtained prior patch placement and at multiple time points following patch placement for the following 96 h. Fentanyl plasma concentration was determined using LC-MS/MS. Data were analyzed using a generalized mixed effects model., Results: Mean (range) maximum plasma concentration (Cmax), time to Cmax, and area under the curve extrapolated to infinity were 1.39 (0.82-1.82), 2.64 (1.21-4.42), 4.11 (2.78-7.12) ng/ml, 12.7 (8.0-16.0), 12.7 (8.0-16.0), 12 (8.0-16.0) h, 42.37 (27.59-55.56), 77.24 (45.62-115.06), 120.34 (100.66-150.55) h ng/ml for LDF, MDF, and HDF, respectively. There was no significant effect of treatment or time on thermal threshold, mechanical threshold, respiratory rate, or temperature ( p  > 0.063). There was no significant effect of treatment on heart rate ( p  = 0.364). There was a significant effect of time ( p  = 0.003) on heart rate with overall heart rates being less than baseline at 64 h., Conclusions: Fentanyl administered via transdermal patch is well absorbed and well tolerated but does not result in an anti-nociceptive effect as measured by thermal and mechanical threshold at the doses studied., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Reed, Berghaus, Reynolds, Holmes, Krikorian, Sakai, Ishikawa and Knych.)

Background: Matrix type transdermal buprenorphine patches have not been investigated in horses and may provide an effective means of providing continuous pain control for extended period and eliminating venous catheterization., Objective: Assessment of the physiological variables (heart rate, respiratory rate, body temperature) and thermal nociceptive threshold testing, and describing the pharmacokinetic profile of transdermal buprenorphine matrix-type patch (20 μg h -1 and 40 μg h -1 dosing) in healthy adult horses., Study Design: Randomised experimental study with a Latin-square design., Methods: Six adult healthy horses received each of the three treatments with a minimum 10 day washout period. BUP0 horses did not receive a patch (control). BUP20 horses received one patch (20 μg h -1 ) applied on the ventral aspect of the tail base resulting in a dose of 0.03-0.04 μg kg -1 h -1 . BUP40 horses received two patches placed alongside each other (40 μg h -1 ) on the tail base resulting in a dose of 0.07-0.09 μg kg -1 h -1 . Whole blood samples (for determination of buprenorphine concentration), physiological variables and thermal threshold testing were performed before (0 h) and at 2, 4, 8, 12, 16, 24, 32, 40, 48, 56, 64, 72, and 96 h after patch application. The patches were removed 72 h following placement and were analyzed for residual buprenorphine content., Results: Between the three groups, there was no change in physiological variables across timepoints as compared to baseline ( p  > 0.1). With the higher dose, there was a significant increase in thermal thresholds from baseline values from 2 h until 48 h and these values were significantly higher than the group receiving the lower patch dose for multiple timepoints up to 40 h. 40 μg h -1 patch led to consistent measurable plasma concentrations starting at 2 h up to 96 h, with the mean plasma concentrations of > 0.1 ng/ml from 4 h to 40 h., Conclusions: 20 μg h -1 and 40 μg h -1 patch doses were well tolerated by all horses. At higher dose, plasma buprenorphine concentrations were more consistently measurable and blunted thermal thresholds for 48 h vs. 32 h with 20 μg h -1 dosing as compared to control., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Paranjape, Knych, Berghaus, Cathcart, Giancola, Craig, James, Saksena and Reed.)

Objective: To determine, using a rapid sequence induction (RSI) technique, whether rocuronium improves the quality and speed of endotracheal intubation in healthy dogs., Study Design: Randomized, crossover, experimental study., Animals: Six adult intact male Beagles (12.3 ± 0.4 kg)., Methods: Dogs were premedicated with intravenous acepromazine (0.03 mg kg -1 ) and hydromorphone (0.1 mg kg -1 ). Ten minutes later, anesthesia was induced with intravenous propofol (2 mg kg -1 over 5 seconds), followed by saline (0.06 mL kg -1 , CT group) or rocuronium (0.6 mg kg -1 , RT group), with orotracheal intubation attempted after 45 seconds. Intubation time (IT) and conditions (IC) were assessed. PaO 2 , PaCO 2 , arterial blood pH and serum cortisol were obtained before and after RSI. After endotracheal intubation, saline (0.04 mL kg -1 ) or sugammadex (4 mg kg -1 ) were administered intravenously in CT or RT groups, respectively. Spontaneous ventilation restoration was noted., Results: The IT was 54.3 ± 6.9 (mean ± SD) and 57.8 ± 5.2 seconds for CT and RT, respectively (p = 0.385). All laryngoscopies indicated good IC in both treatment groups. Heart rate was lower in CT group than in RT group (66 ± 16 versus 103 ± 39 beats minute -1 , p = 0.016). PaCO 2 , pH, PaO 2 and cortisol did not differ between treatments. Compared with baseline, PaCO 2 increased from 47.7 ± 6.2 to 58.8 ± 5.8 (p < 0.001) and pH decreased from 7.35 ± 0.04 to 7.28 ± 0.04 (p = 0.003), independent of treatment. Dogs in both treatment groups returned to spontaneous ventilation within 30 seconds of RSI., Conclusions and Clinical Relevance: RSI resulted in respiratory acidosis without hypoxemia or increased cortisol. Rocuronium did not improve IT or IC. Spontaneous ventilation was observed immediately after administering saline or sugammadex. The co-administration of rocuronium showed no clinical benefits over propofol alone in RSI in healthy dogs., (Copyright © 2023 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Objective: To determine if transdermally delivered fentanyl can achieve greater concentrations of fentanyl in synovial fluid when applied over a synovial structure., Study Design: Randomized, experimental study., Animals: Six healthy adult horses., Methods: Each horse had two 100 μg/h fentanyl matrix patches applied on the dorsal aspect of one, randomly assigned, carpometacarpal joint (CMCJ) for 48 h. Whole blood and bilateral synovial samples from the intercarpal joint were obtained at 0, 2, 6, 12, 24, 36 and 48 h. Fentanyl concentrations were measured with liquid chromatography-mass spectrometry., Results: All subjects achieved detectable concentrations of fentanyl in both plasma and synovial fluid. Time to peak synovial and plasma concentration was 12 h. At 6 h, the synovial concentration in the untreated carpus (0.104 ng/mL ± 0.106) was lower than plasma fentanyl concentrations 0.31 ± 0.27 (p = .036). At 12 h, both treated (0.55 ng/mL ± 0.3) and untreated (0.53 ng/mL ± 0.28) synovial fluid fentanyl concentrations were lower than plasma (0.87 ng/mL ± 0.48) concentrations (p < .001 and p = .001, respectively). Synovial concentrations of fentanyl did not differ between treated and untreated joints (p > 0.608 for all time points)., Conclusion: Application of fentanyl matrix patches directly over the CMCJ did not result in increased fentanyl concentrations in the synovial fluid of the treated intercarpal joint in normal horses., Clinical Significance: There is likely no analgesic advantage to placing fentanyl patches directly over the affected joint, as it did not result in increased synovial concentrations at the tested site., (© 2023 The Authors. Veterinary Surgery published by Wiley Periodicals LLC on behalf of American College of Veterinary Surgeons.)

Background: Equine pain scoring may be affected by the residual effect of anesthetic drugs., Objectives: To compare pain scores in the hours immediately following anesthetic recovery to baseline pre-anesthetic scores in equine patients undergoing surgical and non-surgical procedures., Study Design: Clinical observational study., Methods: Fifty adult horses undergoing anesthesia for surgical or non-surgical procedures were enrolled. Horses underwent pain scoring using the Composite Pain Score (CPS) and Equine Utrecht University Scale for Facial Assessment of Pain (EQUUS-FAP) prior to anesthesia (T0) and following anesthetic recovery to standing, every hour for 5 h (T1-T5). Data were analyzed using a generalized linear mixed effects model. A post-hoc Dunnett's test for multiple comparisons was performed for variables where an effect was detected., Results: Mean (95% confidence interval) CPS scores for T0-T5 were 1.6 (1.2-2.0), 6.8 (6.0-7.6), 5.1 (4.3-5.9), 4.3 (3.4-5.2), 3.7 (2.8-4.6), and 2.8 (2.0-3.6) and EQUUS-FAP scores were 0.6 (0.3-0.9), 3.0 (2.5-3.5), 1.9 (1.6-2.2), 1.1 (0.8-1.4), 0.6 (0.4-0.8), and 0.7 (0.4-1.0), respectively. For the CPS, scores greater than 5, and for the EQUUS-FAP scores greater than 3, are consistent with minor pain. There was no effect of type of procedure (surgical vs non-surgical) on CPS or EQUUS-FAP scores. There was an effect of time with CPS scores significantly greater than baseline at T1-T5 and EQUUS-FAP scores significantly greater than baseline at T1 and T2., Main Limitations: Discomfort caused by hoisting was not quantified and it was difficult to ascertain if this affected the results., Conclusions: Post-anesthetic pain scores may be influenced by the residual effect of anesthetic agents for as long as 5 h and 2 h for the CPS and EQUUS-FAP, respectively., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Reed, Krikorian, Reynolds, Holmes, Branning, Lemons, Barletta, Quandt, Burns, Dantino and Sakai.)

Sedation and anesthesia alter the raw electroencephalogram (EEG). Interpretation of the EEG is facilitated by measuring the patient state index (PSI), visual inspection of density spectral arrays (DSA), and power density analysis of the delta (0.1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), and beta plus gamma (12-40 Hz) frequency bands. Baseline data were recorded in six male intact Beagles before sedation with intravenous acepromazine (0.03 mg/kg) and hydromorphone (0.1 mg/kg). Anesthesia was induced and maintained for five minutes with intravenous propofol (1.5 mg/kg over five seconds followed by 12 mg/kg/h). Additional propofol (0.5-1.0 mg/kg and up to 16.7 mg/kg/h) was administered within this time frame if the PSI was above 50. The effects of sedation and anesthesia were evaluated with a mixed-effect model followed by Dunnett's test (alpha = 0.05). The average baseline PSI (95% confidence interval) was 93.0 (91.4-94.6) and decreased on sedation [88.7 (86.0-91.3); p = 0.039] and anesthesia [44.5 (40.8-48.2); p < 0.001]. The awake DSA showed dense power in all bands. The power density decreased with sedation. During anesthesia, the power density was reduced in frequencies above 12 Hz. The baseline power density on the delta, theta, alpha, and beta plus gamma bands was higher than sedation (p < 0.007). Compared to baseline, anesthesia had lower power on delta, and beta plus gamma bands (p < 0.002). The interpretation in awake, sedated, and anesthetized dogs of the EEG can be facilitated by processing and generating PSI and DSA., Competing Interests: Declaration of Competing Interest The authors declare no competing interests related to this manuscript., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: To evaluate the effects of rocuronium and sugammadex on the patient state index (PSI) in dogs anesthetized with propofol., Animals: 6 intact healthy male Beagles., Procedures: Anesthesia was induced with and maintained on a propofol infusion. The estimated plasma propofol concentration (ePC) was recorded. Baseline PSI and train-of-four ratio (TOFR) readings were collected for 2 minutes in stable general anesthesia. Neuromuscular blockade (NMB) was induced with 0.6 mg/kg, IV, rocuronium, and full NMB was confirmed with a TOFR of 0. After 5 minutes, the neuromuscular function was restored with 4 mg/kg sugammadex, IV (reversal), and monitored for 5 minutes. Throughout the data collection, ePC, PSI, and TOFR were recorded every 15 seconds and compared with mixed-effect ANOVA., Results: Baseline ePC, PSI, and TOFR were 3.63 ± 0.38, 41 ± 6, and 0.97 ± 0.08 µg/mL, respectively. There was no difference between the baseline of ePC and PSI from NMB or reversal. Compared to the baseline, the TOFR decreased to 0 with NMB (P < .001) and returned to 0.96 ± 0.08 (P = .721) on reversal. After 5 minutes, sugammadex fully reversed 5 out of 6 dogs to TOFR > 0.90 and partially reversed 1 animal to TOFR = 0.80., Clinical Relevance: There was no evidence that NMB with rocuronium and sugammadex-induced reversal interfered with PSI readings under steady-state total intravenous anesthesia with propofol. Further evaluation of PSI is warranted to assess its utility in a clinical population to detect changes in levels of consciousness during NMB.

Objective: To evaluate a regional anesthetic technique for blocking the abdominal midline in horses., Study Design: Anatomical description and prospective, crossover, placebo-controlled, blinded study., Animals: Adult horses; two cadavers, six healthy animals., Methods: In stage 1, 0.5% methylene blue with 0.25% bupivacaine (0.5 mL kg -1 ) was injected using ultrasonography into the internal rectus abdominis sheath (RAS) of two cadavers with a one-point or two-point technique. The dye spread was described after the dissection of the abdomens. In stage 2, each horse was injected with 1 mL kg -1 of 0.9% NaCl (treatment PT) or 0.2% bupivacaine (treatment BT) using a two-point technique. The abdominal midline mechanical nociceptive threshold (MNT) was measured with a 1 mm blunted probe tip and results analyzed with mixed-effect anova. Signs of pelvic limb weakness were recorded., Results: The cadaver dissections showed staining of the ventral branches from the eleventh thoracic (T11) to the second lumbar (L2) nerve with the one-point technique and T9-L2 with the two-point technique. Baseline MNTs were, mean ± standard deviation, 12.6 ± 1.6 N and 12.4 ± 2.4 N in treatments PT and BT, respectively. MNT increased to 18.9 ± 5.8 N (p = 0.010) at 30 minutes, and MNT was between 9.4 ± 2.0 and 15.3 ± 3.4 N from 1 to 8 hours (p > 0.521) in treatment PT. MNTs in treatment BT were 21.1 ± 5.9 to 25.0 ± 0.1 N from 30 minutes to 8 hours (p < 0.001). MNTs after the RAS injections were higher in treatment BT than PT (p = 0.007). No pelvic limb weakness was observed., Conclusions and Clinical Relevance: Antinociception of at least 8 hours without pelvic limb weakness was observed in the abdominal midline in standing horses after the RAS block. Further investigations are necessary to evaluate suitability for ventral celiotomies., (Copyright © 2023 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Objective: To compare the effect of a circulating warm water blanket (WWB) in combination with a heated humidified breathing circuit (HHBC) heated to 45 °C on rectal temperature (RT) in dogs undergoing general anesthesia for elective ovariohysterectomies., Animals: 29 healthy dogs., Procedures: Dogs in the experimental group (n = 8) and dogs in the control group (21) were connected to an HHBC and a conventional rebreathing circuit, respectively. All dogs were placed on a WWB in the operating room (OR). The RT was recorded at baseline, premedication, induction, transfer to OR, every 15 minutes during maintenance of anesthesia, and extubation. Incidence of hypothermia (RT < 37 °C) at extubation was recorded. Data were analyzed using unpaired t tests, the Fisher exact test, and mixed-effect ANOVA. Statistical significance was defined as P < .05., Results: There was no difference in RT during baseline, premedication, induction, and transfer to OR. The overall RT was higher for the HHBC group during anesthesia (P = .005) and at extubation (37.7 ± 0.6 °C) compared with the control group (36.6 ± 1.0 °C; P = .006). The incidence of hypothermia at extubation was 12.5% for the HHBC group and 66.7% for the control group (P = .014)., Clinical Relevance: The combination of HHBC and WWB can reduce the incidence of postanesthetic hypothermia in dogs. Use of an HHBC should be considered in veterinary patients.

Objective: Ovariohysterectomy (OVH) is frequently recommended at the time of c-section in canines, yet prior literature suggests poor mothering ability and increased morbidity to the bitch with c-section with concurrent OVH (CSOVH). The study objective was to compare maternal survival, complications, and mothering ability between bitches that underwent c-section alone (CS) or CSOVH., Animals: 125 bitches., Procedures: Medical records from 2014 through 2021 were retrospectively reviewed; owners were surveyed for information up to weaning., Results: 80 bitches undergoing CS and 45 bitches undergoing CSOVH were identified. There was no difference in anesthesia duration, intraoperative complications, postoperative complications, mothering ability, puppy survival to weaning, or other variables compared between groups. CSOVH bitches had longer surgery times (P = .045; 54.4 ± 20.7 min vs 46.9 ± 16.6 min) and longer time from delivery to nursing (P = .028; 75.4 ± 22.3 min vs 65.2 ± 19.5 min). Ninety (72%) owners responded to the survey. All 90 bitches survived until puppy weaning. CSOVH bitches were more frequently perceived as painful postoperatively (P = .015)., Clinical Relevance: Performing an OVH at the time of c-section does not pose a significant increase in risk of mortality, intraoperative complications, postoperative complications, or decreased mothering ability of the bitch. The increased duration of surgery and increased time from delivery to nursing in the CSOVH group were clinically insignificant. Appropriate postoperative pain management should be emphasized post-CSOVH. Based on these results, OVH should be performed concurrently with c-section if indicated.

The administration, uptake, and elimination of inhalant anesthetics is a challenging topic in the veterinary curriculum, and lecture-based learning is often insufficient to ensure that students understand these concepts. We hypothesized that the use of an interactive electronic book (e-book) would enhance student comprehension of the material. Two sequential Doctorate of Veterinary Medicine student cohorts participated in a prospective controlled study. The first cohort received traditional lecture-based learning while the second cohort was taught the topic using an interactive e-book. Student comprehension of the material was assessed twice during the course via multiple-choice questions: five questions in a midcourse quiz and seven within the final exam. At the end of the course, students also completed a Likert survey assessing their confidence regarding the topic. Averaged across assessment types, students taught using the interactive e-book scored higher than those taught via the traditional method (p < .001). Final exam scores were significantly higher in the e-book cohort compared with the lecture-based cohort (p < .001). However, there was no difference in quiz scores between groups (p = .109). No significant difference was found between groups in responses to the Likert survey. In conclusion, students using the interactive e-book had better comprehension of the material than students in the traditional lecture group as measured by their scores on multiple-choice question assessments. Future studies are needed to determine whether this advantage persists later in the curriculum when students apply these concepts in the clinical year.

Background: Innovative treatments are urgently needed for metastatic cancer. DeltaRex-G, a tumor-targeted retrovector encoding a dominant-negative/cytocidal cyclin G1 (CCNG1 gene) inhibitor construct-has been tested in over 280 cancer patients worldwide in phase 1, phase 2 studies and compassionate use studies, demonstrating long term (>10 years) survivorship in patients with advanced cancers, including pancreatic cancer, osteosarcoma, malignant peripheral nerve sheath tumor, breast cancer, and B-cell lymphoma. Patient and Methods: Endpoints: Survival, response, treatment-related adverse events. Study one is entitled "Blessed: Expanded Access for DeltaRex-G for Advanced Pancreatic Cancer and Sarcoma (NCT04091295)". Study two is entitled "Individual Patient Use of DeltaRex-G for Solid Malignancies (Investigational New Drug#19130). In both studies, patients will receive DeltaRex-G at 1-3 x 10e11 cfu i.v. over 30-45 min, three x a week until significant disease progression or unacceptable toxicity or death occurs. Results: Seventeen patients were enrolled, nine sarcoma, two pancreatic adenocarcinoma, one non-small cell lung cancer, two breast carcinoma, one prostate cancer, one cholangiocarcinoma and one basal cell carcinoma and actinic keratosis. Three patients were enrolled in Study 1 and 14 patients were enrolled in Study 2. Twelve of 17 enrolled patients were treated with DeltaRex-G monotherapy or in combination with United States Food and Drug Administration-approved cancer therapies. Five patients died before receiving DeltaRex-G. Efficacy Analysis: Of the 12 treated patients, 5 (42%) are alive 15-36 months from DeltaRex-G treatment initiation. Two patients with early-stage HR + HER2+ positive or triple receptor negative invasive breast cancer who received DeltaRex-G as adjuvant/first line therapy are alive in complete remission 23 and 16 months after DeltaRex-G treatment initiation respectively; three patients with metastatic chordoma, chondrosarcoma and advanced basal cell carcinoma are alive 36, 31, and 15 months after DeltaRex-G treatment initiation respectively. Safety Analysis: There were no treatment-related adverse events reported. Conclusion: Taken together, the data suggest that 1) DeltaRex-G may evoke tumor growth stabilization after failing standard chemotherapy, 2) DeltaRex-G may act synergistically with standard chemotherapy/targeted therapies, and 3) Adjuvant/first line therapy with DeltaRex-G for early-stage invasive carcinoma of breast may be authorized by the USFDA when patients refuse to receive toxic chemotherapy., Competing Interests: Authors were DB, RR, FH, and EG employed by the company Aveni Foundation, Author WS was employed by the company Expression Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chawla, Wong, Quon, Moradkhani, Chua, Brigham, Reed, Swaney, Hall and Gordon.)

Abstract: Cutaneous T-cell lymphoma (CTCL) is a rare cancer of skin-homing T cells. A subgroup of patients develops large cell transformation with rapid progression to an aggressive lymphoma. Here, we investigated the transformed CTCL (tCTCL) tumor ecosystem using integrative multiomics spanning whole-exome sequencing (WES), single-cell RNA sequencing, and immune profiling in a unique cohort of 56 patients. WES of 70 skin biopsies showed high tumor mutation burden, UV signatures that are prognostic for survival, exome-based driver events, and most recurrently mutated pathways in tCTCL. Single-cell profiling of 16 tCTCL skin biopsies identified a core oncogenic program with metabolic reprogramming toward oxidative phosphorylation (OXPHOS), cellular plasticity, upregulation of MYC and E2F activities, and downregulation of MHC I suggestive of immune escape. Pharmacologic perturbation using OXPHOS and MYC inhibitors demonstrated potent antitumor activities, whereas immune profiling provided in situ evidence of intercellular communications between malignant T cells expressing macrophage migration inhibitory factor and macrophages and B cells expressing CD74., Significance: Our study contributes a key resource to the community with the largest collection of tCTCL biopsies that are difficult to obtain. The multiomics data herein provide the first comprehensive compendium of genomic alterations in tCTCL and identify potential prognostic signatures and novel therapeutic targets for an incurable T-cell lymphoma. This article is highlighted in the In This Issue feature, p. 1171., (©2022 American Association for Cancer Research.)

Objective: To evaluate the effect of a constant rate infusion of ketamine on cardiac index (CI) in sheep, as estimated using noninvasive cardiac output (NICO) monitoring by partial carbon dioxide rebreathing, when anesthetized with sevoflurane at the previously determined minimum alveolar concentration that blunts adrenergic responses (MACBAR)., Animals: 12 healthy Dorset-crossbred adult sheep., Procedures: Sheep were anesthetized 2 times in a balanced placebo-controlled crossover design. Anesthesia was induced with sevoflurane delivered via a tight-fitting face mask and maintained at MACBAR. Following induction, sheep received either ketamine (1.5 mg/kg IV, followed by a constant rate infusion of 1.5 mg/kg/h) or an equivalent volume of saline (0.9% NaCl) solution (placebo). After an 8-day washout period, each sheep received the alternate treatment. NICO measurements were performed in triplicate 20 minutes after treatment administration and were converted to CI. Blood samples were collected prior to the start of NICO measurements for analysis of ketamine plasma concentrations. The paired t test was used to compare CI values between groups and the ketamine plasma concentrations with those achieved during the previous study., Results: Mean ± SD CI of the ketamine and placebo treatments were 2.69 ± 0.65 and 2.57 ± 0.53 L/min/m2, respectively. No significant difference was found between the 2 treatments. Mean ketamine plasma concentration achieved prior to the NICO measurement was 1.37 ± 0.58 µg/mL, with no significant difference observed between the current and prior study., Clinical Relevance: Ketamine, at the dose administered, did not significantly increase the CI in sheep when determined by partial carbon dioxide rebreathing.

Objective: To compare the effects of two doses of doxapram intravenous injection and carbon dioxide inhalation on the cardiovascular and laryngeal functions of anesthetized hounds., Study Design: Experimental study., Animals: Six healthy adult dogs., Methods: In a Latin-square design, the mean arterial blood pressure (MABP) and heart rate (HR) were recorded continuously. The inspiratory normalized glottic gap areas (iNGGA) were measured before and after each stimulation with 0.55 mg/kg of doxapram (L-DOX), 2.2 mg/kg of doxapram (H-DOX), or 90 s of inhalation of 10% carbon dioxide in oxygen (I-CO 2 ). The stimulations were tested in duplicate or triplicate. Video clips of the laryngeal movement were scored by board-certified surgeons masked to the treatment., Results: The MABP increased with L-DOX and H-DOX up to 81% (both p < .001 compared to I-CO 2 ), and persisted during the other stimulations (both p < .001). An intermittent tachycardic effect of up to 79% increase in HR was observed with doxapram. The HR following H-DOX was higher than L-DOX and I-CO 2 (both p < .016). Neither hypertension nor tachycardia was observed with I-CO 2 . The iNGGA increased with all treatments (p < .001). The iNGGA was greater with H-DOX than L-DOX and I-CO 2 (both p < .007). All treatments received higher scores (all p < .001) with acceptable inter- and intra-observers Krippendorff's alphas., Conclusion: All treatments were effective respiratory stimulants in anesthetized dogs; however, doxapram caused hypertension and tachycardia., Clinical Significance: Carbon dioxide inhalation might improve arytenoid motion without cardiovascular effects in dogs during clinical airway examinations., (© 2021 American College of Veterinary Surgeons.)

Sentinel lymph node (SLN) evaluation is important for accurate cancer staging. Computed tomography (CT) lymphangiography with aqueous contrast is a feasible technique for SLN identification in dogs. Although most studies report success rates around 90%, success rates as low as 60% have been reported. One reason for low success rates may be the difference in viscosity of the various agents used in comparison to normal lymph viscosity. The objective of this study was to evaluate contrast agents of differing viscosities for use in CT lymphangiography for SLN identification and to determine the influence of massage on contrast flow rates. The hypothesis was that lower viscosity agents would have a higher success rate and faster time to identification of the SLN than higher viscosity agents and that massage would increase contrast flow rates. Dogs were anaesthetised and CT lymphangiography was performed with four contrast agents of differing viscosities in a randomized crossover design. Injections were made on the dorsal pes bilaterally on two study days and the popliteal lymph nodes were evaluated for contrast uptake. There was no significant difference in success of SLN identification or time to SLN identification among the four agents. Massage of the injection site increased rate of contrast flow through the lymphatics. No specific recommendation for one contrast agent over another can be made with these results. Massage is recommended to improve lymphatic flow when performing CT lymphangiography with aqueous contrast in dogs., (© 2021 John Wiley & Sons Ltd.)

Objective: To determine the effect of xylazine on intracranial pressure (ICP) in standing compared to isoflurane-anesthetized horses., Design: Prospective, crossover study design., Setting: University Teaching Hospital., Animals: Six adult horses donated to the University. Horses were determined to be healthy via physical examination, complete blood count, and neurological evaluation., Interventions: Horses were anesthetized, maintained on isoflurane in oxygen in left lateral recumbency, and ventilated to normocapnia. Horses were instrumented for intraparenchymal measurement of ICP, invasive blood pressure, pulse oximetry, and end tidal gas analyzer. Xylazine 1 mg/kg was administered IV and ICP, systolic arterial pressure, mean arterial pressure (MAP), diastolic arterial pressure, and heart rate were recorded and cerebral perfusion pressure (CPP) was calculated for the following 15 minutes. Twenty-four to 36 hours following anesthetic recovery, xylazine 1 mg/kg was administered IV and ICP, heart rate, and Doppler blood pressure (BPdop) on the tail were monitored for 15 minutes., Measurements and Main Results: There was a decrease in ICP following administration of xylazine in anesthetized horses (P < 0.003) but not standing horses (P = 0.227). There was an increase in systolic arterial pressure, MAP, diastolic arterial pressure (P < 0.001), and BPdop (P = 0.001) following administration of xylazine. As a result, CPP increased in anesthetized horses (P < 0.03). There was a negative association between ICP and MAP in anesthetized horses (P = 0.007) but not ICP and BPdop conscious horses (P = 0.379)., Conclusions: Administration of xylazine to anesthetized horses resulted in an increased CPP due to decreased ICP with concurrent increased MAP. Administration of xylazine to standing horses did not result in a change in ICP. However, with the increase in BPdop found in awake horses, it is likely that CPP would also increase in awake horses following xylazine administration., (© Veterinary Emergency and Critical Care Society 2021.)

Objective: To determine whether an association exists between direct intracranial pressure (ICP) measurement and ultrasonographic measurement of optic nerve sheath diameter (ONSD) in anesthetized and standing horses., Design: Cross-sectional study performed on a convenience sample of healthy adult horses., Setting: University teaching hospital., Animals: Eight adult horses donated to the University. Enrolled horses were free of abnormalities on physical examination, CBC, neurological evaluation, and ophthalmological examination., Measurements and Main Results: Horses were anesthetized in lateral recumbency for placement of an ICP transducer. Three head positions (neutral, elevated, and lowered) were used to alter ICP. ICP and ONSD in 2 directions (D1 and D2) were recorded at 5 and 10 minutes after position change to elevated and lowered. ICP and ONSD measurements were repeated in standing sedated horses 24-36 hours after recovery from anesthesia. Linear regressions were performed with ICP as the dependent variable and ONSD as the independent variable by head position and times. Linear regressions were also performed for change from neutral under anesthesia, with ONSD as the independent variable and ICP as the dependent variable, by head position and times. Significance was set at P < 0.05. There was a moderate association between ICP and ONSD in horses with head lowered at 5 and 10 minutes (R 2 values = 63%-78%) and weak association in head elevated at 10 minutes (R 2 values = 56%-63%). There was a weak association between change from neutral ICP and change from neutral ONSD in the elevated anesthetized position at 10 minutes for summed D1 + D2 (R 2  = 33%)., Conclusions: Consistent associations between direct ICP and ONSD in anesthetized or standing horses were not observed. This inconsistency limits the clinically utility of transpalpebral ultrasonographic ONSD measurement for ICP monitoring in horses., (© Veterinary Emergency and Critical Care Society 2021.)

Low arterial oxygen is a common complication in anesthetized horses and placing the animal in reverse Trendelenburg (RT) position may treat hypoxemia. The objective of this study was to assess the arterial partial pressure of oxygen (PaO 2 ) in horses placed in a 5-degree RT compared to horizontal (H) position. Client-owned healthy horses (n = 60) undergoing elective surgeries were enrolled in a randomized controlled clinical study. Horses were sedated with butorphanol, an α 2 -adrenoceptor agonist, ± acepromazine and induced with ketamine combined with a benzodiazepine, propofol, or guaifenesin. Anesthesia was maintained with isoflurane in oxygen with mechanical ventilation. Each group (RT and H) included 30 horses, 10 in each recumbency (dorsal, right and left lateral). Arterial blood gas analyses (aBG) were performed following arterial catheter placement then hourly. Time first-to-last aBG, changes in PaO 2 , dynamic compliance (C dyn ), estimated pulmonary shunt fraction (F-shunt), and alveolar dead space to tidal volume ratio (V D /V T ) were evaluated with a 2-way analysis of variance. Statistical significance was set at p < .05. Overall, PaO 2 increased in all groups; however no significant difference was found between recumbencies (dorsal, right and left lateral) and RT versus H in changes over time for PaO 2 (p = .064 and p = .070, respectively), C dyn (p = .721 and p = .672, respectively), F-shunt (p = .055 and p = .054, respectively), or V D /V T (p = .616 and p = .064, respectively). In healthy anesthetized horses, 5-degree RT did not affect changes in PaO 2 as compared to H position., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Preterm babies are a vulnerable population that experience significant short and long-term morbidity. Rehospitalisations constitute an important, potentially modifiable adverse event in this population. Improving the ability of clinicians to identify those patients at the greatest risk of rehospitalisation has the potential to improve outcomes and reduce costs. Machine-learning algorithms can provide potentially advantageous methods of prediction compared to conventional approaches like logistic regression. Objective: To compare two machine-learning methods (least absolute shrinkage and selection operator (LASSO) and random forest) to expert-opinion driven logistic regression modelling for predicting unplanned rehospitalisation within 30 days in a large French cohort of preterm babies. Design, Setting and Participants: This study used data derived exclusively from the population-based prospective cohort study of French preterm babies, EPIPAGE 2. Only those babies discharged home alive and whose parents completed the 1-year survey were eligible for inclusion in our study. All predictive models used a binary outcome, denoting a baby's status for an unplanned rehospitalisation within 30 days of discharge. Predictors included those quantifying clinical, treatment, maternal and socio-demographic factors. The predictive abilities of models constructed using LASSO and random forest algorithms were compared with a traditional logistic regression model. The logistic regression model comprised 10 predictors, selected by expert clinicians, while the LASSO and random forest included 75 predictors. Performance measures were derived using 10-fold cross-validation. Performance was quantified using area under the receiver operator characteristic curve, sensitivity, specificity, Tjur's coefficient of determination and calibration measures. Results: The rate of 30-day unplanned rehospitalisation in the eligible population used to construct the models was 9.1% (95% CI 8.2-10.1) (350/3,841). The random forest model demonstrated both an improved AUROC (0.65; 95% CI 0.59-0.7; p = 0.03) and specificity vs. logistic regression (AUROC 0.57; 95% CI 0.51-0.62, p = 0.04). The LASSO performed similarly (AUROC 0.59; 95% CI 0.53-0.65; p = 0.68) to logistic regression. Conclusions: Compared to an expert-specified logistic regression model, random forest offered improved prediction of 30-day unplanned rehospitalisation in preterm babies. However, all models offered relatively low levels of predictive ability, regardless of modelling method., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Reed, Morgan, Zeitlin, Jarreau, Torchin, Pierrat, Ancel and Khoshnood.)

Objective: To describe the pharmacokinetics and pharmacodynamics of meperidine after IM and subcutaneous administration in horses., Study Design: prospective, randomized, blinded, crossover trial., Animals: Six adult horses weighing 494 ± 33 kg., Methods: Treatments included meperidine 1 mg/kg IM with saline 6 mL subcutaneously, meperidine 1 mg/kg subcutaneously with saline 6 mL IM, and saline 6 mL subcutaneously and 6 mL IM, with a 7-day washout between treatments. Plasma meperidine concentrations and pharmacodynamic values (thermal and mechanical thresholds, physiological variables, fecal production) were collected at various time points for 24 hours. Accelerometry data were obtained for 8 hours to measure locomotor activity. Data were analyzed with a mixed effects model, and α was set at .05., Results: Meperidine terminal half-life (T 1/2 ), maximal plasma concentrations, and time to maximal concentration were 186 ± 59 and 164 ± 56 minutes, 265.7 ± 47.2 and 243.1 ± 80.1 ng/mL at 17 ± 6, and 24 ± 13 minutes for IM at subcutaneous administration, respectively. No effect of treatment or time was observed on thermal or mechanical thresholds, heart rate, respiratory rate, locomotor activity, frequency of defecations, or fecal weight (P > .2 for all)., Conclusion: Maximum meperidine concentrations were achieved quickly with a short T 1/2 in both treatment groups. Neither IM nor subcutaneous meperidine influenced thermal or mechanical threshold or physiological variables., Clinical Significance: The short half-life and lack of detectable antinociceptive effect do not support IM or subcutaneous administration meperidine at 1 mg/kg for analgesia in horses., (© 2020 American College of Veterinary Surgeons.)

Obesity negatively affects lower extremity physical function (LEPF) in older adults. Exercise and a higher protein diet are both known to positively and independently affect body composition, muscle strength, and LEPF during weight loss; however, their potential interactive effects have not been well characterized in older women., Purpose: The aim of this study was to determine the relative efficacy of a higher protein diet with or without exercise to improve body composition, muscle strength, and LEPF in older inactive overweight/obese women after weight loss., Methods: Postmenopausal women (body mass index = 31.1 ± 5.1 kg·m, 69.2 ± 3.6 yr) completed a 6-month weight loss program after randomization to three groups (n = 72 randomized; 15% dropout): 1) higher protein diet (PRO, ~30% energy from protein; n = 20), 2) PRO plus exercise (PRO + EX; n = 19), or 3) a conventional protein control diet plus EX (CON + EX, ~18% energy from protein; n = 22). EX was supervised, multicomponent (aerobic, muscle strengthening, balance, and flexibility), and three sessions per week. Body composition was measured via dual-energy x-ray absorptiometry, leg strength by isokinetic dynamometry, and LEPF via 6-min walk, 8-ft up and go, and 30-s chair stand tests., Results: Changes in weight (-7.5 ± 4.1 kg; -9.2% ± 4.8%), fat mass, and leg lean mass did not differ among groups (all P > 0.50). Despite weight loss, muscle strength improved in the exercise groups (PRO + EX and CON + EX) but it declined in the PRO group (P = 0.008). For all LEPF measures, the PRO group had attenuated improvements compared with both PRO + EX and CON + EX (all P < 0.01)., Conclusion: Exercise during weight loss is critical to preserve strength and enhance LEPF; however, a higher protein diet does not appear to influence body composition, muscle strength, or LEPF changes when combined with multicomponent exercise.

Objectives: To evaluate changes in immunological parameters following subcutaneous (SC) and intramuscular (IM) administration of meperidine in horses through quantitative analysis of plasma tryptase, histamine, and IgE levels. Methods: Six adult horses were enrolled in a prospective randomized crossover design. Horses were administered one treatment per day, with a seven day washout period: (a) meperidine 1 mg/kg IM, saline 6 mL SC; (b) saline 6 mL IM, meperidine 1 mg/kg SC; (c) saline 6 mL SC, saline 6 mL IM. Blood samples were obtained for plasmatic histamine (baseline, 5, 10, 15, 30, and 60 min) via LC-MS/MS and plasmatic tryptase (baseline, 15, 30, 60, 120, and 240 min) quantification with enzyme-linked immunoabsorbent assays. Serum immunoglobulin E (IgE) concentrations prior to any meperidine treatment and 7-14 days following the first meperidine treatment were evaluated with enzyme-linked immunoabsorbent assays. Histamine and tryptase concentrations were evaluated with a mixed-effect analysis of variance. The levels of IgE at baseline (before the administration of the first dose of meperidine) were compared with the IgE values at 60 min following the second meperidine administration with the Paired t test. Biopsies of localized injection site reactions from subcutaneous meperidine administration were collected from two horses. Results: No statistically significant elevations from baseline in histamine ( p = 0.595), tryptase ( p = 0.836), or IgE ( p = 0.844) were found in any of the horses in this study. There were no differences between treatment groups. Administration of SC meperidine caused a localized vasculitis and thrombosis with regional edema and hemorrhage. Conclusion: No evidence of anaphylactoid or anaphylactic type reactions occurred following IM or SC meperidine administration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Trenholme, Sakai, Berghaus, Hanafi, Knych, Ryan, McHale, Banovic, Quandt, Barletta and Reed.)

Objective: To compare the pharmacokinetics and pharmacodynamics of hydromorphone in horses after intravenous (IV) and intramuscular (IM) administration., Study Design: Randomized, masked, crossover design., Animals: A total of six adult horses weighing [mean ± standard deviation (SD))] 447 ± 61 kg., Methods: Horses were administered three treatments with a 7 day washout. Treatments were hydromorphone 0.04 mg kg ⁻1 IV with saline administered IM (H-IV), hydromorphone 0.04 mg kg ⁻1 IM with saline IV (H-IM), or saline IV and IM (P). Blood was collected for hydromorphone plasma concentration at multiple time points for 24 hours after treatments. Pharmacodynamic data were collected for 24 hours after treatments. Variables included thermal nociceptive threshold, heart rate (HR), respiratory frequency (f R ), rectal temperature, and fecal weight. Data were analyzed using mixed-effects linear models. A p value of less than 0.05 was considered statistically significant., Results: The mean ± SD hydromorphone terminal half-life (t 1/2 ), clearance and volume of distribution of H-IV were 19 ± 8 minutes, 79 ± 12.9 mL minute ⁻1 kg ⁻1 and 1125 ± 309 mL kg ⁻1 . The t 1/2 was 26.7 ± 9.25 minutes for H-IM. Area under the curve was 518 ± 87.5 and 1128 ± 810 minute ng mL ⁻1 for H-IV and H-IM, respectively. The IM bioavailability was 217%. The overall thermal thresholds for both H-IV and H-IM were significantly greater than P (p < 0.0001 for both) and baseline (p = 0.006). There was no difference in thermal threshold between H-IV and H-IM. No difference was found in physical examination variables among groups or in comparison to baseline. Fecal weight was significantly less than P for H-IV and H-IM (p = 0.02)., Conclusions and Clinical Relevance: IM hydromorphone has high bioavailability and provides a similar degree of antinociception to IV administration. IM hydromorphone in horses provides a similar degree and duration of antinociception to IV administration., (Published by Elsevier Ltd.)

Minimizing sympathetic stimulation under anesthesia prevents activation of the neuroendocrine stress response. The minimum alveolar concentration blunting adrenergic responses in 50% of the population when exposed to a noxious stimulus is defined as MAC-BAR. The purpose of this study was to determine the MAC-BAR of sevoflurane (MAC-BAR sevo ) in sheep and the MAC-BAR sparing effects of ketamine. Thirteen healthy Dorset-cross adult ewes, 4 ± 1 year old and weighing 74 ± 9 kg, were enrolled in a randomized blinded crossover study design. Ewes were anesthetized twice for MAC-BAR sevo determination. After face mask induction with sevoflurane, sheep received intravenous ketamine at 1.5 mg/kg and a constant rate infusion of 1.5 mg/kg/h or an equivalent volume of saline (placebo). After 8 day washout, the other treatment was administered. A bracketing technique was used for MAC-BAR sevo determination and values were collected in duplicate. The mechanical stimulus (sponge forceps) was applied at the coronary band for 1 min and blood was collected for ketamine plasma concentrations. The MAC-BAR sevo values of each treatment were compared using a paired t-test. Mean MAC-BAR sevo of the ketamine and placebo were 2.73 ± 0.23% and 2.77 ± 0.31%, respectively and no significant difference was found (p = .638). Average ketamine plasma concentrations was 1.54 ± 0.18 μg/mL maintained through the study. Ketamine at 1.5 mg/kg, followed by 1.5 mg/kg/h, did not decrease the MAC-BAR sevo in sheep. Further studies to determine the effect of higher doses of ketamine on inhalational anesthetic agents and their potential adverse effects are warranted., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Gaining a better understanding of the probability, timing and prediction of rehospitalisation amongst preterm babies could help improve outcomes. There is limited research addressing these topics amongst extremely and very preterm babies. In this context, unplanned rehospitalisations constitute an important, potentially modifiable adverse event. We aimed to establish the probability, time-distribution and predictability of unplanned rehospitalisation within 30 days of discharge in a population of French preterm babies., Methods: This study used data from EPIPAGE 2, a population-based prospective study of French preterm babies. Only those babies discharged home alive and whose parents responded to the one-year survey were eligible for inclusion in our study. For Kaplan-Meier analysis, the outcome was unplanned rehospitalisation censored at 30 days. For predictive modelling, the outcome was binary, recording unplanned rehospitalisation within 30 days of discharge. Predictors included routine clinical variables selected based on expert opinion., Results: Of 3841 eligible babies, 350 (9.1, 95% CI 8.2-10.1) experienced an unplanned rehospitalisation within 30 days. The probability of rehospitalisation progressed at a consistent rate over the 30 days. There were significant differences in rehospitalisation probability by gestational age. The cross-validated performance of a ten predictor model demonstrated low discrimination and calibration. The area under the receiver operating characteristic curve was 0.62 (95% CI 0.59-0.65)., Conclusions: Unplanned rehospitalisation within 30 days of discharge was infrequent and the probability of rehospitalisation progressed at a consistent rate. Lower gestational age increased the probability of rehospitalisation. Predictive models comprised of clinically important variables had limited predictive ability.

Objective: To evaluate the quality of recovery in dogs undergoing elective orthopaedic surgery induced with either propofol or a combination of ketamine and diazepam., Materials and Methods: Sixty client-owned dogs undergoing single-limb elective orthopaedic procedures were enrolled. Dogs were randomly assigned to receive induction with propofol (4 mg/kg) (group P) or ketamine (5 mg/kg) with diazepam (0.25 mg/kg) (group KD) to which all scorers were blinded. The recovery monitoring period lasted for 1 hour following extubation. The recovery period was video-recorded for blinded scoring at a later time. Scoring for quality of recovery was carried out using three different systems (lower numbers=better quality): a simple descriptive scale (1 to 5), a visual analogue scale (0 to 10 cm) and a numeric rating scale (0 to 10). Videos were reviewed by three ACVAA board-certified anaesthesiologist raters., Results: Five dogs were deemed to be ineligible. The mean (±SD) duration of anaesthesia was 260.4 ±57.84 minutes in group KD and 261.1 ±51.83 minutes in group P. There was no difference between groups for time to extubation, head lift or sternal recumbency. The number of dogs having a recovery that was scored overall as bad (mean simple descriptive scale > 4, mean visual analogue scale or numeric rating scale > 5) was not different between groups. Dogs in group KD had significantly lower scores than group P dogs (simple descriptive scale P=0.01, numeric rating scale P=0.03, visual analogue scale P=0.03)., Clinical Significance: Induction with ketamine and diazepam resulted in a smoother recovery from anaesthesia than induction with propofol., (© 2019 British Small Animal Veterinary Association.)

The purpose of this study was to examine the relative contributions of changes in muscle quality and body composition to changes in lower-extremity physical function (LEPF) following a 6-month exercise and weight loss intervention in overweight and obese older women. Thirty-eight overweight and obese (BMI = 30.0 ± 4.4 kg/m 2 ) older (age = 69.3 ± 4.1 y) women completed 6 months of multicomponent exercise (cardiorespiratory, resistance, balance and flexibility training) and weight loss (hypocaloric diet that reduced energy intake by ~500 kcal/d). Body composition was measured via dual-energy X-ray absorptiometry and muscle quality (N-m/kg) was defined as maximal concentric isokinetic knee torque divided by upper-leg lean mass. The standardized scores of four objective measures of physical function were summed to yield a composite LEPF Z-score. At 6 months, there were significant reductions in body weight (-9.6 ± 3.5%, p < 0.01), absolute fat mass (-6.8 ± 2.4 kg, p < 0.01) and relative adiposity (-4.9 ± 2.1%, p < 0.01). There were also improvements in both muscle quality (+1.6 ± 1.8 N-m/kg, p < 0.01) and individual measures of LEPF (11-57%, p < 0.01). Multivariate linear regression indicated that increased muscle quality was the strongest independent predictor of an improvement in LEPF Z-score (standardized β = 0.64, p < 0.01) and explained 34% of the variance. A reduction in body weight also predicted an improvement in LEPF, independent of the change in muscle quality. In conclusion, muscle quality can be increased in the presence of clinically meaningful weight loss, and is the primary determinant of improved physical function in overweight/obese older women., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To apply the critical incident technique (CIT) methodology to a series of perianesthetic cardiac arrest events at a university teaching hospital to describe the factors that contributed to cardiac arrest., Study Design: CIT qualitative analysis of a case series., Animals: A group of 16 dogs and cats that suffered a perioperative cardiac arrest between November 2013 and November 2016., Methods: If an arrest occurred, the event was discussed among the anesthesiologists. The discussion included a description of the case, a description of the sequence of events leading up to the arrest and a discussion of what could have been done to affect the outcome. A written description of the case and the event including animal signalment and a timeline of events was provided by the supervising anesthesiologist following discussion among the anesthesiologists. Only dogs or cats were included. After the data collection period, information from the medical record was collected. A qualitative document analysis was performed on the summaries provided about each case by the supervising anesthesiologist, the medical record and any supporting documents. Each case was then classified into one or more of the following: animal, human, equipment, drug and procedural factors for cardiac arrest., Results: The most common factor was animal (n=14), followed by human (n=12), procedural (n=4), drugs (n=1) and equipment (n=1). The majority (n=11) of animals had multiple factors identified., Conclusions and Clinical Relevance: Cardiac arrests during anesthesia at a referral teaching hospital were primarily a result of animal and human factors. Arrests because of procedural, drug and equipment factors were uncommon. Most animals experienced more than one factor and two animals arrested after a change in recumbency. Future work should focus on root cause analysis and interventions designed to minimize all factors, particularly human ones., (Copyright © 2018 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Eating behaviors (cognitive restraint, flexible and rigid restraint, disinhibition, hunger) have been associated with obesity and weight loss success in middle-aged individuals, but little is known about these relationships in older adults. This study examined relationships between eating behaviors and weight loss in overweight/obese older women (n = 61; 69 ± 3.6 years; body mass index = 31.1 ± 5.0 kg/m 2 ) completed a 6-month behavioral weight loss intervention. Baseline, postintervention, and change measures of eating behaviors (51-items Three-Factor Eating Questionnaire) were assessed for relationships with weight loss. In the final regression model, an increase in flexible restraint accompanied by a decrease in rigid restraint predicted greater weight loss (adjusted R 2  = 0.21, Model F (4, 56) = 4.97, P < 0.01). No associations were found with disinhibition or hunger and degree of weight loss (all P > 0.05). Results suggest encouraging a flexible approach to eating behavior and discouraging rigid adherence to a diet may lead to better intentional weight loss for overweight and obese older women.

The ICH Q1B guidance and additional clarifying manuscripts provide the essential information needed to conduct photostability testing for pharmaceutical drug products in the context of manufacturing, packaging, and storage. As the previous 2 papers in this series highlight for drug products administered by injection (part 1) and drug products administered via topical application (part 2), there remains a paucity of guidance and methodological approaches to conducting photostability testing to ensure effective product administration. Part 3 in the series is presented here to provide a similar approach and commentary for photostability testing for oral drug products. The approach taken, as was done previously, is to examine "worst case" photoexposure scenarios in combination with ICH-defined light sources to derive a set of practical experimental approaches to support the safe and effective administration of photosensitive oral drug products., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

We investigate the influence of high energy photons and thiol ligands on the photophysical properties of sub-monolayer CdTe/CdS quantum dots (QDs) immobilized in porous silica (PSiO2) scaffolds. The highly disperse, uniform distributions of QDs in a three-dimensional PSiO2 framework ensure uniform interaction of not only radiation but also subsequent surface repassivation solutions to all immobilized QDs. The high optical densities of QDs achieved using PSiO2 enable straightforward monitoring of the QD photoluminescence intensities and carrier lifetimes. Irradiation of QDs in PSiO2 by high energy photons, X-rays, and γ-rays leads to dose-dependent QD photodarkening, which is accompanied by accelerated photooxidative effects in ambient environments that give rise to blue-shifts in the peak QD emission wavelength. Irradiation in an oxygen-free environment also leads to QD photodarkening but with no accompanying blue-shift of the QD emission. Significant reversal of QD photodarkening is demonstrated following QD surface repassivation with a solution containing free-thiols, suggesting reformation of a CdS shell, etching of surface oxidized species, and possible reduction of photoionized dark QDs to a neutral, bright state. Permanent lattice displacement damage effects may contribute toward some irreversible γ radiation damage. This work contributes to an improved understanding of the influence of surface ligands on the optical properties of QDs and opens up the possibilities of engineering large area, low-cost, reuseable, and flexible QD-based optical radiation sensors.

The role of cutaneous human papillomavirus (HPV) infection in the development of subsequent cutaneous squamous cell carcinoma (SCC) is unknown. Pathologically confirmed cases of SCC ( n = 150) enrolled in a previously conducted case-control study were included in a retrospective cohort study to examine the association of cutaneous HPV at the time of SCC diagnosis with the risk of subsequent SCC development. Data on HPV seropositivity, HPV DNA in eyebrow hairs (EB) and SCC tumors were available from the parent study. Incidence of subsequent SCC was estimated using person-years of follow up. Cox Proportional Hazards ratios were estimated to evaluate the associations of both, HPV seropositivity and HPV DNA positivity with subsequent SCC. The five year cumulative incidence of subsequent SCC was 72%. Seropositivity to cutaneous HPV was not associated with the risk of subsequent SCC (HR = 0.83, 95% CI = 0.41-1.67). Any beta HPV infection in EB was associated with reduced risk (HR = 0.30, 95% CI = 0.11-0.78) of subsequent SCC among cases who were positive for beta HPV DNA in tumor tissue. Infection with beta HPV type 2 (HR = 0.32, 95% CI = 0.12-0.86) in EB was associated with reduced risk of subsequent SCC among HPV DNA positive SCCs. In conclusion, beta HPV infection was inversely associated with the risk of subsequent SCC., Competing Interests: The authors declare that there is no conflict of interests regarding the publication of this paper.

Objective: To determine the minimum infusion rate (MIR) of propofol required to prevent movement in response to a noxious stimulus in dogs anesthetized with propofol alone or propofol in combination with a constant rate infusion (CRI) of ketamine., Animals: 6 male Beagles., Procedures: Dogs were anesthetized on 3 occasions, at weekly intervals, with propofol alone (loading dose, 6 mg/kg; initial CRI, 0.45 mg/kg/min), propofol (loading dose, 5 mg/kg; initial CRI, 0.35 mg/kg/min) and a low dose of ketamine (loading dose, 2 mg/kg; CRI, 0.025 mg/kg/min), or propofol (loading dose, 4 mg/kg; initial CRI, 0.3 mg/kg/min) and a high dose of ketamine (loading dose, 3 mg/kg; CRI, 0.05 mg/kg/min). After 60 minutes, the propofol MIR required to prevent movement in response to a noxious electrical stimulus was determined in duplicate., Results: Least squares mean ± SEM propofol MIRs required to prevent movement in response to the noxious stimulus were 0.76 ± 0.1 mg/kg/min, 0.60 ± 0.1 mg/kg/min, and 0.41 ± 0.1 mg/kg/min when dogs were anesthetized with propofol alone, propofol and low-dose ketamine, and propofol and high-dose ketamine, respectively. There were significant decreases in the propofol MIR required to prevent movement in response to the noxious stimulus when dogs were anesthetized with propofol and low-dose ketamine (27 ± 10%) or with propofol and high-dose ketamine (30 ± 10%)., Conclusions and Clinical Relevance: Ketamine, at the doses studied, significantly decreased the propofol MIR required to prevent movement in response to a noxious stimulus in dogs.

Introduction: Radiofrequency ablation (RFA) is used for the local treatment of liver cancer. RFA is effective for small (<3 cm) tumors, but for tumors > 3 cm, there is a tendency to leave viable tumor cells in the margins or clefts of overlapping ablation zones. This increases the possibility of incomplete ablation or local recurrence. Lyso-Thermosensitive Liposomal Doxorubicin (LTLD), is a thermally sensitive liposomal doxorubicin formulation for intravenous administration, that rapidly releases its drug content when exposed to temperatures >40°C. When used with RFA, LTLD releases its doxorubicin in the vasculature around the zone of ablation-induced tumor cell necrosis, killing micrometastases in the ablation margin. This may reduce recurrence and be more effective than thermal ablation alone., Purpose: The purpose of this study was to optimize the RFA procedure used in combination with LTLD to maximize the local deposition of doxorubicin in a swine liver model. Pigs were anaesthetized and the liver was surgically exposed. Each pig received a single, 50 mg/m2 dose of the clinical LTLD formulation (ThermoDox®). Subsequently, ablations were performed with either 1, 3 or 6 sequential, overlapping needle insertions in the left medial lobe with total ablation time of 15, 45 or 90 minutes respectively. Two different RFA generators and probes were evaluated. After the final ablation, the ablation zone (plus 3 cm margin) was dissected out and examined for doxorubicin concentration by LC/MS and fluorescence., Conclusion: The mean Cmax of plasma total doxorubicin was 26.5 μg/ml at the end of the infusion. Overall, increased heat time from 15 to 45 to 90 minutes shows an increase in both the amount of doxorubicin deposited (up to ~100 μg/g) and the width of the ablation target margin to which doxorubicin is delivered as determined by tissue homogenization and LC/MS detection of doxorubicin and by fluorescent imaging of tissues.

Although essential guidance to cover the photostability testing of pharmaceuticals for manufacturing and storage is well-established, there continues to be a significant gap in guidance regarding testing to support the effective administration of photosensitive drug products. Continuing from Part 1, (Baertschi SW, Clapham D, Foti C, Jansen PJ, Kristensen S, Reed RA, Templeton AC, Tønnesen HH. 2013. J Pharm Sci 102:3888-3899) where the focus was drug products administered by injection, this commentary proposes guidance for testing topical drug products in order to support administration. As with the previous commentary, the approach taken is to examine "worst case" photoexposure scenarios in comparison with ICH testing conditions to provide practical guidance for the safe and effective administration of photosensitive topical drug products., (© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Purpose: Plaster casts can cause burns. Synthetic casts do not. Composite plaster-synthetic casts have not been thoroughly evaluated. This study analyzed the temperature from plaster casts compared with composite casts in a variety of in vitro conditions that would simulate clinical practice., Methods: A Pyrex cylinder filled with constant body temperature circulating water simulated a human extremity. Circumferential casts, of either plaster or composite construction (plaster inner layer with outer synthetic layer), were applied to the model. Peak temperatures generated by the exothermic reactions were studied relative to the following variables: dip water temperature (24 °C versus 40 °C), cast thickness (16, 30, and 34 ply), and delayed (5-min) versus immediate application of the synthetic outer layers. Peak temperatures from the all-plaster casts were compared with the composite casts of the same thickness. Finally, the relative cast strength was determined., Results: Potentially dangerous high temperatures were measured only when 40 °C dip water was used or when thick (30- or 34-ply) casts were made. Cast strength increased with increasing cast thickness. However, the presence of synthetics in the composite casts layers did not increase cast strength in every case., Conclusion: When applying composite casts, the outer synthetic layers should be applied several minutes after the plaster to minimize temperature rise. Composite casts do not routinely generate peak temperatures higher than plaster casts of similar thickness. Because the skin of children and the elderly is more temperature-sensitive than average adult skin, extra care should be taken to limit the exothermic reaction when casting children and the elderly: clean, room temperature dip water, minimal required cast thickness, avoidance of insulating pillows/blankets while the cast is drying.

Protein phosphatase 5 (PP5) is auto-inhibited by intramolecular interactions with its tetratricopeptide repeat (TPR) domain. Hsp90 has been shown to bind PP5 to activate its phosphatase activity. However, the functional implications of binding Hsp70 to PP5 are not yet clear. In this study, we find that both Hsp90 and Hsp70 bind to PP5 using a luciferase fragment complementation assay. A fluorescence polarization assay shows that Hsp90 (MEEVD motif) binds to the TPR domain of PP5 almost 3-fold higher affinity than Hsp70 (IEEVD motif). However, Hsp70 binding to PP5 stimulates higher phosphatase activity of PP5 than the binding of Hsp90. We find that PP5 forms a stable 1:1 complex with Hsp70, but the interaction appears asymmetric with Hsp90, with one PP5 binding the dimer. Solution NMR studies reveal that Hsc70 and PP5 proteins are dynamically independent in complex, tethered by a disordered region that connects the Hsc70 core and the IEEVD-TPR contact area. This tethered binding is expected to allow PP5 to carry out multi-site dephosphorylation of Hsp70-bound clients with a range of sizes and shapes. Together, these results demonstrate that Hsp70 recruits PP5 and activates its phosphatase activity which suggests dual roles for PP5 that might link chaperone systems with signaling pathways in cancer and development.

Basic guidance on the photostability testing of pharmaceuticals, designed to cover manufacturing and storage over shelf life, has long been established within ICH Q1(ICH,B(10) , but the guideline does not cover the photostability of drugs during or after administration (i.e., under conditions of use). To date, there has been a paucity of guidance covering the additional testing that would be of value during the clinical preparation and use of products. This commentary suggests a systematic approach, based on realistic "worst case" photoexposure scenarios and the existing ICH Option 1 and 2 light sources, to provide valuable data to pharmaceutical manufacturers and compounding pharmacists for the safe and effective use of photosensitive injection products., (© 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Alzheimer's disease (AD) is a complex neurological disorder with multiple inter-connected factors playing roles in the onset and progression of the disease. One strategy currently being explored for the development of new therapeutics for AD involves linking tacrine, a known acetylcholinesterase (AChE) inhibitor, to another drug to create bifunctional hybrids. The role and influence on activity of the linker moiety in these hybrids remains ill-defined. In this study, three series of 6-chlorotacrine with linkers varying in terminal functional group and length were synthesized, evaluated for AChE inhibition, and compared to tacrine and 6-chlorotacrine-mefenamic acid hybrids. Out of the compounds with terminal amine, methyl, and hydroxyl moieties tested, several highly potent molecules (low nanomolar IC50 values) comprised of linkers with terminal amines were identified. These 6-chlorotacrine with linkers were significantly more potent than tacrine alone and were often more potent than similar 6-chlorotacrine-mefenamic acid hybrids., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The advent of pathotropic (disease-seeking) targeting has transported genetic medicine across the threshold of history with the progressive clinical validation of Rexin-G, a tumor-targeted nanosized anti-cancer agent. Achieving noteworthy single-agent efficacy and survival benefits in otherwise intractable cancers, the molecular biotechnology platform has stimulated intense interest in the underlying mechanisms-of-action. This report exhibits the effective localization of Rexin-G nanoparticles within a metastatic liver lesion, as observed upon its surgical excision.

During digestive organogenesis, the primitive gut tube (PGT) undergoes dramatic elongation and forms a lumen lined by a single-layer of epithelium. In Xenopus, endoderm cells in the core of the PGT rearrange during gut elongation, but the morphogenetic mechanisms controlling their reorganization are undetermined. Here, we define the dynamic changes in endoderm cell shape, polarity, and tissue architecture that underlie Xenopus gut morphogenesis. Gut endoderm cells intercalate radially, between their anterior and posterior neighbors, transforming the nearly solid endoderm core into a single layer of epithelium while concomitantly eliciting "radially convergent" extension within the gut walls. Inhibition of Rho/ROCK/Myosin II activity prevents endoderm rearrangements and consequently perturbs both gut elongation and digestive epithelial morphogenesis. Our results suggest that the cellular and molecular events driving tissue elongation in the PGT are mechanistically analogous to those that function during gastrulation, but occur within a novel cylindrical geometry to generate an epithelial-lined tube., ((c) 2009 Wiley-Liss, Inc.)