Inpatient management of epidermolysis bullosa: Consensus-based hands-on instructions for neonates and postneonates.

BACKGROUND: Epidermolysis bullosa (EB), characterized by skin fragility and blistering, often requires hospitalization. Training for inpatient management of EB is limited, with no unified recommendations available in North America. OBJECTIVE: To develop consensus-derived best practices for hands-on inpatient management of EB in both the neonatal and postneonatal period. METHODS: A modified Delphi method (expert-based input via 2 surveys and a final review) was implemented. Available guidelines from EB Clinical Research Consortium centers were analyzed to determine areas of focus and formulate statements to be voted on by EB Clinical Research Consortium members, experienced EB nurses, and select family members. Study participants evaluated statements using a Likert scale: statements with at least 70% agreement were accepted; statements with 30% or more disagreement were rejected. RESULTS: Ten areas of focus were identified. Delphi participants included 15 dermatologists, 8 nurses, and 6 nonhealth care caregivers. Consensus was established on 103/119 neonatal statements and 105/122 postneonatal statements; no statements were rejected. Most recommendations applied to both age groups. LIMITATIONS: Recommendations may require adjustment based on individual patient's clinical context. CONCLUSION: Using the Delphi method, a consensus-derived resource for hospital-based health care professionals who manage patients with EB has been developed to improve the quality of inpatient care.

Pilot Study on the Efficacy and Safety of Long-Term Oral Imepitoin Treatment for Control of (Thunder)Storm-Associated Noise Phobia/Noise Aversion in Dogs Using an Individualized-Dose Titration Approach.

Imepitoin is a low-affinity partial agonist for benzodiazepine binding sites of gamma-aminobutyric acid receptors with anxiolytic effects. It has been shown to reduce anxiety during noise-related events in dogs when given at 30 mg/kg PO BID, although this dose was associated with ataxia and increased appetite in some cases. The objective of this study was to assess its safety and efficacy for storm anxiety when started at 10 mg/kg PO BID and titrated to effect up to 30 mg/kg PO BID during storm season. Significant decreases in anxiety scores were seen in weekly surveys and storm logs (SLs) at 10, 20 and 30 mg/kg PO BID. Serious adverse events (AEs) were not reported in any subject. Ataxia was the most commonly reported non-serious AE (14/33), followed by increased hunger (13/33). The frequency of AEs was higher in the 20 mg/kg PO BID group than in the 10 mg/kg group PO BID. No clinically significant changes were seen in lab work pre- and post-study. In conclusion, Imepitoin given during storm season at doses ranging from 10 to 30 mg/kg PO BID reduced clinical signs of fear and anxiety during storms for the dogs in this study. These findings support the use of an individually titrated dose.

Bare parts in the Galliformes: the evolution of a multifunctional structure.

A morphological trait can have multiple functions shaped by varying selective forces. Bare parts in birds, such as wattles, casques and combs, are known to function in both signalling and thermoregulation. Studies have demonstrated such structures are targets of sexual selection via female choice in several species of Galliformes (junglefowl, turkeys and grouse), though other studies have shown some role in thermoregulation (guineafowl). Here, we tested fundamental hypotheses regarding the evolution and maintenance of bare parts in Galliformes. Using a phylogeny that included nearly 90% of species in the order, we evaluated the role of both sexual and natural selection in shaping the function of bare parts across different clades. We found a combination of both environmental and putative sexually selected traits strongly predicted the variation of bare parts for both males and females across Galliformes. When the analysis is restricted to the largest family, Phasianidae (pheasants, junglefowl and allies), sexually selected traits were the primary predictors of bare parts. Our results suggest that bare parts are important for both thermoregulation and sexual signalling across Galliformes but are primarily under strong sexual selection within the Phasianidae.

Neo-Natal Castration Leads to Subtle Differences in Porcine Anterior Cruciate Ligament Morphology and Function in Adolescence.

Female adolescent athletes are at a higher risk of tearing their anterior cruciate ligament (ACL) than male counterparts. While most work related to hormones has focused on the effects of estrogen to understand the increased risk of ACL injury, there are other understudied factors, including testosterone. The purpose of this study was to determine how surgical castration in the male porcine model influences ACL size and function across skeletal growth. Thirty-six male Yorkshire crossbreed pigs were raised to 3 (juvenile), 4.5 (early adolescent), and 6 months (adolescent) of age. Animals were either castrated (barrows) within 2 weeks after birth or were left intact (boars). Posteuthanasia, joint and ACL size were assessed via MRI, and biomechanics were assessed via a robotic testing system. Joint size increased throughout age, yet barrows had smaller joints than boars. ACL cross-sectional area (CSA), length, volume, and in situ stiffness increased with age, as did the percent contribution of the ACL anteromedial (AM) bundle to resisting loads. Boar ACL, AM bundle, and PL bundle volumes were 19%, 25%, and 15% larger than barrows across ages. However, ACL CSA, in situ stiffness, and bundle contribution were similar between boars and barrows. The barrows had smaller temporal increases in AM bundle function than boars, but these data were highly variable. Early and sustained loss in testosterone leads to subtle differences in ACL morphology but may not influence measures associated with increased injury risk, such as CSA or bundle forces in response to applied loads.

Neo-natal castration leads to subtle differences in porcine anterior cruciate ligament morphology and function in adolescence.

Female adolescent athletes are at a higher risk of tearing their anterior cruciate ligament (ACL) than male counterparts. While most work related to hormones has focused on the effects of estrogen to understand the increased risk of ACL injury, there are other understudied factors, including testosterone. The purpose of this study was to determine how surgical castration in the male porcine model influences ACL size and function across skeletal growth. Thirty-six male Yorkshire crossbreed pigs were raised to 3 (juvenile), 4.5 (early adolescent), and 6 months (adolescent) of age. Animals were either castrated (barrows) within 1-2 weeks after birth or were left intact (boars). Post-euthanasia, joint and ACL size were assessed via MRI, and biomechanics were assessed via a robotic testing system. Joint size increased throughout age, yet barrows had smaller joints than boars (p<0.001 for all measures). ACL cross-sectional area (CSA), length, volume, and stiffness increased with age (p<0.0001), as did ACL anteromedial (AM) bundle percent contribution to resisting loads (p=0.012). Boar ACL, AM bundle, and PL bundle volumes were 19% (p=0.002), 25% (p=0.003), and 15% (p=0.04) larger than barrows across ages. However, CSA, stiffness, and bundle contribution were similar between boars and barrows (p>0.05). The barrows had smaller temporal increases in AM bundle percent function than boars, but these data were highly variable. Thus, early and sustained loss in testosterone leads to subtle differences in ACL morphology, but may not influence measures associated with increased injury risk, such as CSA or bundle forces in response to applied loads.

Estimating ancient biogeographic patterns with statistical model discrimination.

The geographic ranges in which species live is a function of many factors underlying ecological and evolutionary contingencies. Observing the geographic range of an individual species provides valuable information about these historical contingencies for a lineage, determining the distribution of many distantly related species in tandem provides information about large-scale constraints on evolutionary and ecological processes generally. We present a linear regression method that allows for the discrimination of various hypothetical biogeographical models for determining which landscape distributional pattern best matches data from the fossil record. The linear regression models used in the discrimination rely on geodesic distances between sampling sites (typically geologic formations) as the independent variable and three possible dependent variables: Dice/Sorensen similarity; Euclidean distance; and phylogenetic community dissimilarity. Both the similarity and distance measures are useful for full-community analyses without evolutionary information, whereas the phylogenetic community dissimilarity requires phylogenetic data. Importantly, the discrimination method uses linear regression residual error to provide relative measures of support for each biogeographical model tested, not absolute answers or p-values. When applied to a recently published dataset of Campanian pollen, we find evidence that supports two plant communities separated by a transitional zone of unknown size. A similar case study of ceratopsid dinosaurs using phylogenetic community dissimilarity provided no evidence of a biogeographical pattern, but this case study suffers from a lack of data to accurately discriminate and/or too much temporal mixing. Future research aiming to reconstruct the distribution of organisms across a landscape has a statistical-based method for determining what biogeographic distributional model best matches the available data.

Static posturography as a novel measure of the effects of aging on postural control in dogs.

Aging is associated with impairment in postural control in humans. While dogs are a powerful model for the study of aging, the associations between age and postural control in this species have not yet been elucidated. The aims of this work were to establish a reliable protocol to measure center of pressure excursions in standing dogs and to determine age-related changes in postural sway. Data were obtained from 40 healthy adult dogs (Group A) and 28 senior dogs (Group B) during seven trials (within one session of data collection) of quiet standing on a pressure sensitive walkway system. Velocity, acceleration, root mean square, 95% ellipse area, range and frequency revolve were recorded as measures of postural sway. In Group A, reliability was assessed with intraclass correlation, and the effect of morphometric variables was evaluated using linear regression. By means of stepwise linear regression we determined that root mean square overall and acceleration in the craniocaudal direction were the best variables able to discriminate between Group A and Group B. The relationship between these two center-of-pressure (COP) measures and the dogs' fractional lifespan was examined in both groups and the role of pain and proprioceptive deficits was evaluated in Group B. All measures except for frequency revolve showed good to excellent reliability. Weight, height and length were correlated with most of the measures. Fractional lifespan impacted postural control in Group B but not Group A. Joint pain and its interaction with proprioceptive deficits influence postural sway especially in the acceleration in the craniocaudal direction, while fractional lifespan was most important in the overall COP displacement. In conclusion, our study found that pressure sensitive walkway systems are a reliable tool to evaluate postural sway in dogs; and that postural sway is affected by morphometric parameters and increases with age and joint pain.

A lateral surgical approach to the larynx may impair cervical esophageal function in dogs.

OBJECTIVE: To determine whether muscle-sparing laryngoplasty results in fewer changes in swallowing function compared to standard surgical treatment for laryngeal paralysis. ANIMALS: 12 clinically normal sexually intact male Beagles. PROCEDURES: Group A dogs (n = 4) had a standard approach to the larynx, with left arytenoid cartilage lateralization. Group B dogs (n = 4) had a muscle-sparing laryngoplasty performed with the thyropharyngeus muscle fibers bluntly separated, and the cricoarytenoideus dorsalis muscle spared. Pre- and 24-hour postoperative fluoroscopic swallowing studies were performed and graded. Larynges were harvested after humane euthanasia, and glottic area was measured. Group C dogs (n = 4) acted as controls, with surgical dissection ending lateral to the thyropharyngeus muscle, arytenoid lateralization not performed, and the dogs not euthanized. The study was performed between October 15, 2011 and May 15, 2021. RESULTS: Changes in pharyngeal and upper esophageal sphincter function were not detected in any group. There was no difference in glottic area between treatment groups. Aspiration of liquid was not a consistent finding. Two dogs in each treatment group developed moderate to severe cervical esophageal paresis. This did not occur in control dogs. CLINICAL RELEVANCE: We found no evidence to support our hypothesis that muscle-sparing laryngoplasty results in less severe changes in swallowing function compared to a standard technique. The cervical esophageal paresis identified in both treatment groups could increase the risk of postoperative aspiration pneumonia in dogs treated for laryngeal paralysis via a lateral approach to the larynx. Further study to determine the frequency, cause, and duration of esophageal dysfunction is warranted.

The impact of undernutrition on KNDy (kisspeptin/neurokinin B/dynorphin) neurons in female lambs.

Undernutrition limits reproduction through inhibition of gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) secretion. Because KNDy neurons coexpress neuropeptides that play stimulatory (kisspeptin and neurokinin B [NKB]) and inhibitory (dynorphin) roles in pulsatile GnRH/LH release, we hypothesized that undernutrition would inhibit kisspeptin and NKB expression at the same time as increasing dynorphin expression. Fifteen ovariectomized lambs were either fed to maintain pre-study body weight (controls) or feed-restricted to lose 20% of pre-study body weight (FR) over 13 weeks. Blood samples were collected and plasma from weeks 0 and 13 were assessed for LH by radioimmunoassay. At week 13, animals were killed, and brain tissue was processed for assessment of KNDy peptide mRNA or protein expression. Mean LH and LH pulse amplitude were lower in FR lambs compared to controls. We observed lower mRNA abundance for kisspeptin within KNDy neurons of FR lambs compared to controls with no significant change in mRNA for NKB or dynorphin. We also observed that FR lambs had fewer numbers of arcuate nucleus kisspeptin and NKB perikarya compared to controls. These findings support the idea that KNDy neurons are important for regulating reproduction during undernutrition in female sheep.

Development and validation of a high resolving power absolute quantitative per- and polyfluoroalkyl substances method incorporating Skyline data processing.

RATIONALE: The ability to perform absolute quantitation and non-targeted analysis on a single mass spectrometry instrument would be advantageous to many researchers studying per- and polyfluoroalkyl substances (PFAS). High-resolution accurate mass (HRAM) instrumentation (typically deployed for non-targeted work) carries several advantages over traditional triple quadrupole workflows when performing absolute quantitation. Processing this data using a vendor-neutral software would promote collaboration for these environmental studies. METHODS: LC-MS (Orbitrap Exploris 240) was used for absolute quantitation of 45 PFAS using precursor (MS1) peak areas for quantitation, whereas isotope pattern matching and fragmentation (MS2) pattern matching were used for qualitative identification. In addition, a fluorinated chromatographic column achieved superior separation compared to the typical C18 columns typically used in PFAS analyses. This method was validated across eight different chemical classes using recommended guidelines found in EPA Method 537.1 and Skyline data processing software. RESULTS: The validated limits of all 45 compounds, as well as metrics or accuracy and reproducibility, are reported. Most compounds achieved limits of quantitation in the range of 2-50 ng/L. Four newly released Chemours-specific compounds (PEPA, PFO3OA, PFO4DA, and PFO5DoA) were also validated. Aspects of data analysis specific to high resolving power absolute quantitation are reviewed as are the details of processing these data via Skyline. CONCLUSIONS: This method shows the feasibility of performing reproducible absolute quantitation of PFAS on an HRAM platform and does so using an open-source vendor-neutral data processing software to facilitate sharing of data across labs and institutions.

Impact of Classical Counterconditioning (Quiet Kennel Exercise) on Barking in Kenneled Dogs-A Pilot Study.

Excessive barking is a major source of noise pollution in dog kennels and negatively impacts welfare. Because resources are often limited, minimizing barking in the simplest and most easily implementable way is imperative. This pilot study implemented a Quiet Kennel Exercise (QKE) that utilized classical counterconditioning to change the dogs' negative emotional state (which can lead to barking) to a more positive emotional state. Therefore, barking motivation is reduced, so barking should decrease. This study aims to show proof of concept that decreasing barking through classical counterconditioning is effective. It was conducted in one ward of day-time boarding kennels at North Carolina State University College of Veterinary Medicine. Data was collected three times per day and included decibel readings, number of dogs present, and number of dogs barking during a 5-day initial baseline and 10-day intervention period. During baseline, people passing through the ward acted as they normally would. During intervention, passersby were asked to simply toss each dog a treat regardless of the dogs' behaviors in the kennel. Descriptive results show improvement in maximum level of barking after QKE, fewer dogs barking over time, dogs barking less each time, and the most improvement noted in the afternoon.

Sex-specific biomechanics and morphology of the anterior cruciate ligament during skeletal growth in a porcine model.

Pediatric anterior cruciate ligament (ACL) injuries are on the rise, and females experience higher ACL injury risk than males during adolescence. Studies in skeletally immature patients indicate differences in ACL size and joint laxity between males and females after the onset of adolescence. However, functional data regarding the ACL and its anteromedial and posterolateral bundles in the pediatric population remain rare. Therefore, this study uses a porcine model to investigate the sex-specific morphology and biomechanics of the ACL and its bundles throughout skeletal growth. Hind limbs from male and female Yorkshire pigs aged early youth to late adolescence were imaged using magnetic resonance imaging to measure the size and orientation of the ACL and its bundles, then biomechanically tested under anterior-posterior drawer using a robotic testing system. Joint laxity decreased (p < 0.001) while joint stiffness increased (p < 0.001) throughout skeletal growth in both sexes. The ACL was the primary stabilizer against anterior tibial loading, while the functional role of the anteromedial bundle increased with age (p < 0.001), with an earlier increase in males. ACL and posterolateral bundle cross-sectional area and ACL and anteromedial bundle length were larger in males than females during adolescence (p < 0.01 for all), while ACL and bundle sagittal angle remained similar between sexes. Additionally, in situ ACL stiffness versus cross-sectional area regressions were significant across skeletal growth (r2 = 0.75, p < 0.001 in males and r2 = 0.64, p < 0.001 in females), but not within age groups. This study has implications for age and sex-specific surgical intervention strategies and suggests the need for human studies.

Influence of long-stay jugular catheters on hemostatic variables in healthy dogs.

OBJECTIVE: To compare hemostatic variables performed on blood samples obtained from indwelling jugular catheters or direct venipuncture over a 72-hour period. DESIGN: Prospective experimental study. SETTING: University research laboratory. ANIMALS: Five healthy neutered male purpose-bred Beagle dogs. INTERVENTIONS: Each dog was sedated to facilitate placement of a long-stay 20-Ga polyurethane IV catheter into the jugular vein. Blood samples were obtained from the preplaced catheters at 4 time points corresponding to 0, 24, 48, and 72 hours relative to placement. Blood samples were also obtained by direct venipuncture of a peripheral vein using a 21-Ga butterfly catheter and evacuated blood tubes at the same time points. Platelet count, platelet closure time, prothrombin time, activated partial thromboplastin time, fibrinogen, and kaolin-activated thromboelastography were performed on these paired samples at each time point. The patency of the indwelling catheters was maintained by flushing every 6 hours with heparinized saline. MEASUREMENTS AND MAIN RESULTS: No significant differences were identified in any of the hemostatic variables obtained by either blood collection technique at any time point during the study (P > 0.05). There was also no significant day-to-day variation in any catheter-derived hemostatic variable obtained from individual dogs identified over the course of the study. CONCLUSIONS: These data suggest that accurate hemostatic variables may be obtained using blood collected from indwelling jugular catheters, maintained with heparinized saline for at least 72 hours, in healthy dogs.

Computer vision for detecting field-evolved lepidopteran resistance to Bt maize.

BACKGROUND: Resistance evolution of lepidopteran pests to Bacillus thuringiensis (Bt) toxins produced in maize and cotton is a significant issue worldwide. Effective toxin stewardship requires reliable detection of field-evolved resistance to enable the implementation of mitigation strategies. Currently, visual estimates of maize injury are used to document changing susceptibility. In this study, we evaluated an existing maize injury monitoring protocol used to estimate Bt resistance levels in Helicoverpa zea (Lepidoptera: Noctuidae). RESULTS: We detected high interobserver variability across multiple injury metrics, suggesting that the precision and accuracy of maize injury detection could be improved. To do this, we developed a computer vision-based algorithm to measure H. zea injury. Algorithm estimates were more accurate and precise than a sample of human observers. Moreover, observer estimates tended to overpredict H. zea injury, which may increase the false-positive rate, leading to prophylactic insecticide application and unnecessary regulatory action. CONCLUSIONS: Automated detection and tracking of lepidopteran resistance evolution to Bt toxins are critical for genetically engineered crop stewardship to prevent the use of additional insecticides to combat resistant pests. Advantages of this computerized screening are: (i) standardized Bt injury metrics in space and time, (ii) preservation of digital data for cross-referencing when thresholds are reached, and (iii) the ability to increase sample sizes significantly. This technological solution represents a significant step toward improving confidence in resistance monitoring efforts among researchers, regulators and the agricultural biotechnology industry.

A conditional female lethal system for genetic suppression of the global fruit crop pest Drosophila suzukii.

BACKGROUND: Drosophila suzukii (Matsumura, 1931, Diptera: Drosophilidae) is a global pest of soft-skinned fruits such as blueberries, cherries and raspberries. Also known as spotted-wing drosophila, D. suzukii is native to Asia but is now widely distributed in the Americas and Europe, and presents a serious challenge for growers. Genetic control strategies offer an environmentally friendly approach for the control of D. suzukii. RESULTS: In this study, we developed transgenic strains of D. suzukii that carry dominant conditional female lethal transgenes. When raised in the absence of tetracycline, female D. suzukii die. We show that repeated releases of an excess of transgenic males can suppress D. suzukii populations in laboratory cage trials. CONCLUSION: Our data suggest that the transgenic strain could provide an effective approach for control of this invasive pest of soft-skinned fruits.

Evaluation of Pexion® (imepitoin) for treatment of storm anxiety in dogs: A randomised, double-blind, placebo-controlled trial.

BACKGROUND: While often grouped with other noise aversions, fearful behaviour during storms is considered more complex than noise aversion alone. The objective here was to assess the effect of imepitoin for the treatment of storm anxiety in dogs. METHODS: In this double-blind, placebo-controlled randomised study, eligible dogs completed a baseline then were randomised to receive either imepitoin (n = 30; 30 mg/kg BID) or placebo (n = 15) for 28 days. During storms, owners rated their dog's intensity for 16 behaviours using a Likert scale. Weekly, owners rated intensity and frequency of these behaviours. Summary scores were compared to baseline and between groups. RESULTS AND CONCLUSIONS: Imepitoin was significantly superior to placebo in storm logs and weekly surveys for weeks 2 and 4, and in the end-of-study survey. Mild/moderate adverse events were reported in 26 patients (24 active: two placebo); the most frequent adverse event was ataxia. Owners of dogs in the imepitoin group, compared to placebo, were significantly more likely to report that treatment reduced their dogs fear and anxiety during storms (p < 0.001) and other noise events (p < 0.001). Twice daily administration of imepitoin decreased anxiety scores in dogs with storm anxiety. Future work may evaluate optimal dosage regimens.

Randomized, Placebo-Controlled Prospective Clinical Trial Evaluating the Efficacy of the Assisi Anti-anxiety Device (Calmer Canine) for the Treatment of Canine Separation Anxiety.

Introduction: Separation anxiety (SA) is among the most common canine behavior disorders and affects quality-of-life for dogs and their owners. Dogs with SA show signs of anxiety during absence or perceived absence of their owners. While psychoactive medications are often helpful for treating SA, dog and human factors may limit their utility. This study explored the efficacy of a pulsed electromagnetic field (PEMF) device for treatment of canine SA. Materials and Methods: In this double-blind randomized placebo-controlled study, a screening questionnaire and baseline video confirmed the diagnosis of SA. Owners treated their dog with the device twice daily for 6 weeks, completed weekly questionnaires, and noted adverse events. Videos were taken of the dog while alone at weeks 4 and 6. Behaviors were coded and categorized as negative and positive. Questionnaire and video data at weeks 4 and 6 were compared to baseline. Results: Forty client-owned dogs with moderate to severe SA completed the study. There were no differences between groups for age, weight, or sex. In owner questionnaires, no difference in behavior or overall score was found between the active and sham groups (p > 0.05). Videos of the active group compared to the sham group showed significant reduction in negative behaviors by week 6 (p = 0.036) and higher percentage of success at week 4 (Z = 2.83, p = 0.005), at week 6 (Z = 1.65, p = 0.098), and across the full study (Z = 1.99, p = 0.047). Adverse events were reported in eight dogs (6 active, 2 sham); all resolved and were unlikely to be related to treatment. Discussion: This study supports the efficacy and safety of this PEMF device for treatment of SA in dogs. Questionnaire results may not be sensitive enough to detect subtle negative behavioral states compared to video, and may not capture other owner observed behavioral changes. A caregiver placebo effect may account for some improvement seen in both groups. Video data appear better for diagnosis and monitoring dog's behavior when left alone. Future studies should assess PEMF's impact on other anxieties or combination of anxiety disorders in dogs.

The influence of feeding and gastroprotectant medications on the Factor Xa inhibitory activity of orally administered rivaroxaban in normal dogs.

OBJECTIVE: Rivaroxaban is a new anticoagulant option for dogs, yet its reported oral bioavailability is as low as 60%. The objective of this study was to examine the influence of feeding and gastroprotectant medications on the bioactivity (anti-Xa activity) of rivaroxaban in healthy dogs. DESIGN: Prospective experimental study. SETTING: University research laboratory. ANIMALS: Five healthy neutered male purpose-bred Beagles. INTERVENTIONS: Dogs were administered a median dose of 1.8 mg/kg rivaroxaban (range, 1.6-1.8 mg/kg) orally once daily for 2 consecutive days with either (1) no food, (2) food, (3) sucralfate 30 minutes before rivaroxaban, or (4) omeprazole at the same time as rivaroxaban. Blood was collected from preplaced jugular catheters immediately before and at 6 time points after rivaroxaban administration (2, 4, 8, 24, 36, and 48 hours). A rivaroxaban calibrated anti-Xa activity assay (RIVA) was used to monitor anticoagulant effect. MEASUREMENTS AND MAIN RESULTS: Rivaroxaban administration resulted in significant increases in RIVA (P = 0.02), with peak activities occurring 2 to 4 hours after dosingduring each study arm. No feeding was associated with significantly higher RIVA at the 36-hour time point compared to all other treatment arms (P < 0.0001), and feeding resulted in high RIVA at the 48-hour time point compared with sucralfate administration (P = 0.003). No significant changes in RIVA were otherwise identified with respect to feeding or gastroprotectant administration (P = 0.2). CONCLUSIONS AND CLINICAL IMPORTANCE: Although administration without food demonstrated an apparent increase in RIVA 36 hours after drug administration, clinically relevant differences among treatment groups were not identified in combined analyses of time points. Based on these results, dogs treated with rivaroxaban do not require special modification of feeding practices or gastroprotectant drug administration.

Evaluation of point-of-care coagulation tests as alternatives to anti-Xa activity for monitoring the anticoagulant effects of rivaroxaban in healthy dogs.

OBJECTIVE: To evaluate a panel of coagulation assays for their potential utility in rivaroxaban monitoring as alternatives to the rivaroxaban-specific anti-Xa activity (RIVA). DESIGN: Prospective experimental study. SETTING: University research laboratory. ANIMALS: Five healthy neutered male Beagles. INTERVENTIONS: Dogs were administered a median dose of 1.8 mg/kg rivaroxaban (range, 1.6-1.8 mg/kg) orally once daily for 2 consecutive days as part of a pharmacodynamic study. Blood was collected from a preplaced jugular catheter at time points relative to their rivaroxaban administration (0, 2, 4, 8, 24, 36, and 48 h) for measurement of RIVA, prothrombin time (PT), activated partial thromboplastin time, RapidTEG, and thrombin generation variables. MEASUREMENTS AND MAIN RESULTS: One hundred forty data points were available for analysis. There was poor correlation between RIVA and RapidTEG variables: R time (R) (min) (r = 0.554, P < 0.0001), K time (K) (min) (r = -0.204, P = 0.016), alpha angle (degrees) (r = 0.152, P = 0.073), Maximum amplitude (MA) (mm) (r = 0.106, P = 0.215), and G value (G) (dynes/s) (r = 0.108, P = 0.205). A good correlation was noted between thrombin generation variables and RIVA: lag time (min) (r = 0.827, P < 0.0001), peak (nM) (r = -0.752, P < 0.0001), and endogenous thrombin potential (nM·min) (r = -0.762, P < 0.0001). There was an excellent correlation between PT and RIVA (r = 0.915, P < 0.0001) and a good correlation between activated partial thromboplastin time and RIVA (r = 0.772, P < 0 .0001). CONCLUSIONS: Of all the coagulation tests investigated, the PT correlated best with RIVA. There is potential for PT being a convenient second-line monitoring option in dogs receiving rivaroxaban, but further work is necessary to validate other PT assays. Thromboelastography performed with strong activators correlated poorly with anti-Xa activity.

Peptide variability and signatures associated with disease progression in CSF collected longitudinally from ALS patients.

We employ shotgun proteomics and data-independent acquisition (DIA) mass spectrometry to analyze cerebrospinal fluid longitudinally collected from 14 amyotrophic lateral sclerosis (ALS) patients (8 males and 6 females). We perform three main analyses of these data: (1) examine the intra- and inter-patient protein variability in CSF; (2) explore the association of inflammation with rate of disease progression; and (3) develop a mixed-effects model to best explain the decrease in ALS-Functional Rating Scale (ALS-FRS) score. Overall, the CSF protein abundances are tightly regulated with the intra-individual variability contributing just 4% to the overall variance. In four patients, a moderately significant correlation (p < 0.1) was observed between inflammation and rate of disease progression. Using a least absolute shrinkage and selection operator (LASSO) variable selection, we selected 55 viable peptides for mathematical modeling via a linear mixed-effects regression. We then employed forward selection to generate a final model by minimizing Akaike's information criterion (AIC). The final model utilized changes in abundance from 28 peptides as fixed effects to model progression of the disease in these patients. These peptides were from proteins involved in stress response and innate immunity. Graphical abstract.