Molnupiravir versus placebo in unvaccinated and vaccinated patients with early SARS-CoV-2 infection in the UK (AGILE CST-2): a randomised, placebo-controlled, double-blind, phase 2 trial.

BACKGROUND: The antiviral drug molnupiravir was licensed for treating at-risk patients with COVID-19 on the basis of data from unvaccinated adults. We aimed to evaluate the safety and virological efficacy of molnupiravir in vaccinated and unvaccinated individuals with COVID-19. METHODS: This randomised, placebo-controlled, double-blind, phase 2 trial (AGILE CST-2) was done at five National Institute for Health and Care Research sites in the UK. Eligible participants were adult (aged ≥18 years) outpatients with PCR-confirmed, mild-to-moderate SARS-CoV-2 infection who were within 5 days of symptom onset. Using permuted blocks (block size 2 or 4) and stratifying by site, participants were randomly assigned (1:1) to receive either molnupiravir (orally; 800 mg twice daily for 5 days) plus standard of care or matching placebo plus standard of care. The primary outcome was the time from randomisation to SARS-CoV-2 PCR negativity on nasopharyngeal swabs and was analysed by use of a Bayesian Cox proportional hazards model for estimating the probability of a superior virological response (hazard ratio [HR]>1) for molnupiravir versus placebo. Our primary model used a two-point prior based on equal prior probabilities (50%) that the HR was 1·0 or 1·5. We defined a priori that if the probability of a HR of more than 1 was more than 80% molnupiravir would be recommended for further testing. The primary outcome was analysed in the intention-to-treat population and safety was analysed in the safety population, comprising participants who had received at least one dose of allocated treatment. This trial is registered in ClinicalTrials.gov, NCT04746183, and the ISRCTN registry, ISRCTN27106947, and is ongoing. FINDINGS: Between Nov 18, 2020, and March 16, 2022, 1723 patients were assessed for eligibility, of whom 180 were randomly assigned to receive either molnupiravir (n=90) or placebo (n=90) and were included in the intention-to-treat analysis. 103 (57%) of 180 participants were female and 77 (43%) were male and 90 (50%) participants had received at least one dose of a COVID-19 vaccine. SARS-CoV-2 infections with the delta (B.1.617.2; 72 [40%] of 180), alpha (B.1.1.7; 37 [21%]), omicron (B.1.1.529; 38 [21%]), and EU1 (B.1.177; 28 [16%]) variants were represented. All 180 participants received at least one dose of treatment and four participants discontinued the study (one in the molnupiravir group and three in the placebo group). Participants in the molnupiravir group had a faster median time from randomisation to negative PCR (8 days [95% CI 8-9]) than participants in the placebo group (11 days [10-11]; HR 1·30, 95% credible interval 0·92-1·71; log-rank p=0·074). The probability of molnupiravir being superior to placebo (HR>1) was 75·4%, which was less than our threshold of 80%. 73 (81%) of 90 participants in the molnupiravir group and 68 (76%) of 90 participants in the placebo group had at least one adverse event by day 29. One participant in the molnupiravir group and three participants in the placebo group had an adverse event of a Common Terminology Criteria for Adverse Events grade 3 or higher severity. No participants died (due to any cause) during the trial. INTERPRETATION: We found molnupiravir to be well tolerated and, although our predefined threshold was not reached, we observed some evidence that molnupiravir has antiviral activity in vaccinated and unvaccinated individuals infected with a broad range of SARS-CoV-2 variants, although this evidence is not conclusive. FUNDING: Ridgeback Biotherapeutics, the UK National Institute for Health and Care Research, the Medical Research Council, and the Wellcome Trust.

Characterisation of SARS-CoV-2 genomic variation in response to molnupiravir treatment in the AGILE Phase IIa clinical trial.

Molnupiravir is an antiviral, currently approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for treating at-risk COVID-19 patients, that induces lethal error catastrophe in SARS-CoV-2. How this drug-induced mechanism of action might impact the emergence of resistance mutations is unclear. To investigate this, we used samples from the AGILE Candidate Specific Trial (CST)-2 (clinical trial number NCT04746183). The primary outcomes of AGILE CST-2 were to measure the drug safety and antiviral efficacy of molnupiravir in humans (180 participants randomised 1:1 with placebo). Here, we describe the pre-specified exploratory virological endpoint of CST-2, which was to determine the possible genomic changes in SARS-CoV-2 induced by molnupiravir treatment. We use high-throughput amplicon sequencing and minor variant analysis to characterise viral genomics in each participant whose longitudinal samples (days 1, 3 and 5 post-randomisation) pass the viral genomic quality criteria (n = 59 for molnupiravir and n = 65 for placebo). Over the course of treatment, no specific mutations were associated with molnupiravir treatment. We find that molnupiravir significantly increased the transition:transversion mutation ratio in SARS-CoV-2, consistent with the model of lethal error catastrophe. This study highlights the utility of examining intra-host virus populations to strengthen the prediction, and surveillance, of potential treatment-emergent adaptations.

An Open Label, Adaptive, Phase 1 Trial of High-Dose Oral Nitazoxanide in Healthy Volunteers: An Antiviral Candidate for SARS-CoV-2.

Repurposing approved drugs may rapidly establish effective interventions during a public health crisis. This has yielded immunomodulatory treatments for severe coronavirus disease 2019 (COVID-19), but repurposed antivirals have not been successful to date because of redundancy of the target in vivo or suboptimal exposures at studied doses. Nitazoxanide is a US Food and Drug Administration (FDA) approved antiparasitic medicine, that physiologically-based pharmacokinetic (PBPK) modeling has indicated may provide antiviral concentrations across the dosing interval, when repurposed at higher than approved doses. Within the AGILE trial platform (NCT04746183) an open label, adaptive, phase I trial in healthy adult participants was undertaken with high-dose nitazoxanide. Participants received 1,500 mg nitazoxanide orally twice-daily with food for 7 days. Primary outcomes were safety, tolerability, optimum dose, and schedule. Intensive pharmacokinetic (PK) sampling was undertaken day 1 and 5 with minimum concentration (Cmin ) sampling on days 3 and 7. Fourteen healthy participants were enrolled between February 18 and May 11, 2021. All 14 doses were completed by 10 of 14 participants. Nitazoxanide was safe and with no significant adverse events. Moderate gastrointestinal disturbance (loose stools or diarrhea) occurred in 8 participants (57.1%), with urine and sclera discoloration in 12 (85.7%) and 9 (64.3%) participants, respectively, without clinically significant bilirubin elevation. This was self-limiting and resolved upon drug discontinuation. PBPK predictions were confirmed on day 1 but with underprediction at day 5. Median Cmin was above the in vitro target concentration on the first dose and maintained throughout. Nitazoxanide administered at 1,500 mg b.i.d. with food was safe with acceptable tolerability a phase Ib/IIa study is now being initiated in patients with COVID-19.

Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study.

OBJECTIVES: AGILE is a Phase Ib/IIa platform for rapidly evaluating COVID-19 treatments. In this trial (NCT04746183) we evaluated the safety and optimal dose of molnupiravir in participants with early symptomatic infection. METHODS: We undertook a dose-escalating, open-label, randomized-controlled (standard-of-care) Bayesian adaptive Phase I trial at the Royal Liverpool and Broadgreen Clinical Research Facility. Participants (adult outpatients with PCR-confirmed SARS-CoV-2 infection within 5 days of symptom onset) were randomized 2:1 in groups of 6 participants to 300, 600 and 800 mg doses of molnupiravir orally, twice daily for 5 days or control. A dose was judged unsafe if the probability of 30% or greater dose-limiting toxicity (the primary outcome) over controls was 25% or greater. Secondary outcomes included safety, clinical progression, pharmacokinetics and virological responses. RESULTS: Of 103 participants screened, 18 participants were enrolled between 17 July and 30 October 2020. Molnupiravir was well tolerated at 300, 600 and 800 mg doses with no serious or severe adverse events. Overall, 4 of 4 (100%), 4 of 4 (100%) and 1 of 4 (25%) of the participants receiving 300, 600 and 800 mg molnupiravir, respectively, and 5 of 6 (83%) controls, had at least one adverse event, all of which were mild (≤grade 2). The probability of ≥30% excess toxicity over controls at 800 mg was estimated at 0.9%. CONCLUSIONS: Molnupiravir was safe and well tolerated; a dose of 800 mg twice daily for 5 days was recommended for Phase II evaluation.

AGILE: a seamless phase I/IIa platform for the rapid evaluation of candidates for COVID-19 treatment: an update to the structured summary of a study protocol for a randomised platform trial letter.

BACKGROUND: There is an urgent unmet clinical need for the identification of novel therapeutics for the treatment of COVID-19. A number of COVID-19 late phase trial platforms have been developed to investigate (often repurposed) drugs both in the UK and globally (e.g. RECOVERY led by the University of Oxford and SOLIDARITY led by WHO). There is a pressing need to investigate novel candidates within early phase trial platforms, from which promising candidates can feed into established later phase platforms. AGILE grew from a UK-wide collaboration to undertake early stage clinical evaluation of candidates for SARS-CoV-2 infection to accelerate national and global healthcare interventions. METHODS/DESIGN: AGILE is a seamless phase I/IIa platform study to establish the optimum dose, determine the activity and safety of each candidate and recommend whether it should be evaluated further. Each candidate is evaluated in its own trial, either as an open label single arm healthy volunteer study or in patients, randomising between candidate and control usually in a 2:1 allocation in favour of the candidate. Each dose is assessed sequentially for safety usually in cohorts of 6 patients. Once a phase II dose has been identified, efficacy is assessed by seamlessly expanding into a larger cohort. AGILE is completely flexible in that the core design in the master protocol can be adapted for each candidate based on prior knowledge of the candidate (i.e. population, primary endpoint and sample size can be amended). This information is detailed in each candidate specific trial protocol of the master protocol. DISCUSSION: Few approved treatments for COVID-19 are available such as dexamethasone, remdesivir and tocilizumab in hospitalised patients. The AGILE platform aims to rapidly identify new efficacious and safe treatments to help end the current global COVID-19 pandemic. We currently have three candidate specific trials within this platform study that are open to recruitment. TRIAL REGISTRATION: EudraCT Number: 2020-001860-27 14 March 2020 ClinicalTrials.gov Identifier: NCT04746183  19 February 2021 ISRCTN reference: 27106947.

A Case of Ovarian Dysplasia and a Vaginal Fibroleiomyoma in a Young Golden Retriever.

This case demonstrates a unique ovarian congenital anomaly that likely contributed to the development of a rare fibroleiomyoma in the cranial vagina of a young bitch. A 13 month old intact female Golden Retriever presented to the veterinary teaching hospital for urinary incontinence, hematuria, and persistent vaginal discharge. Physical examination revealed a mucopurulent serosanguinous malodorous vulvar discharge, and after further diagnostics was reclassified as persistent estrus. Abdominal palpation and ultrasound revealed uterine thickening and poorly visualized ovaries. The reproductive tract was removed during an ovariohysterectomy, revealing small ovaries and a white anterior vaginal mass. Histopathology revealed dysplastic ovaries with hyperplastic granulosa cells and a benign vaginal fibroleiomyoma. These morphologic changes are consistent with elevated estrogen levels. It was thus concluded that her persistent estrus and the fibroleiomyoma were both secondary to persistent estrogen production by the hyperplastic granulosa cells.

Histopathological and immunohistochemical findings of primary and metastatic medullary thyroid carcinoma in a young dog.

This report describes the gross, histological, and immunohistochemical features of medullary thyroid carcinoma (MTC) with pulmonary metastases in a young dog. Sheets of pleomorphic cells supported by fibrous stroma characterized the primary mass, while metastatic nodules had a neuroendocrine pattern. Despite differing histologic features, all masses showed marked immunoreactivity against calcitonin and multiple neuroendocrine markers consistent with MTC. Although MTC is a well-recognized entity, it may be difficult to distinguish this mass from other thyroid neoplasms, necessitating immunohistochemical characterization.

Bovine leukemia virus infection in a juvenile alpaca with multicentric lymphoma.

A 13-month-old alpaca (Vicugna pacos) was presented for mandibular masses and weight loss. Histopathology of biopsy tissue was consistent with lymphoma. The alpaca was euthanized and necropsy revealed lymphoma masses in multiple organs. Immunohistochemistry for T- and B-cell typing was inconclusive. Serology and in-situ polymerase chain reaction hybridization were positive for bovine leukemia virus.

Sensitivity of low-field T2 images for detecting the presence and severity of histopathologic meniscal lesions in dogs.

The sensitivity of low-field magnetic resonance (MR) T2 images for predicting the presence of meniscal lesions was determined in 12 dogs with naturally-occurring cranial cruciate ligament rupture and three control dogs, using histopathology as the reference standard. Previously published grading systems were used to grade the severity of meniscal lesions on MR images, gross inspection and histopathology. Focal areas of increased signal intensity were detected in 11/12 symptomatic dogs and 3/3 control dogs. Lesions mimicking meniscal tears (pseudotears) were identified at junctions between meniscal margins and adjacent connective tissue in control dogs and dogs with naturally occurring disease. Histopathologic lesions were present in all menisci of both symptomatic and control dogs, including the menisci from two affected dogs that appeared grossly normal but were removed and submitted based on MR imaging findings. Histopathologic lesions identified included hyaline cartilage metaplasia and changes in the amount of ground substance and cellularity. The sensitivity of MR imaging for detecting the presence of meniscal histopathologic lesions was 90% in symptomatic dogs and 91% in control dogs. However, agreement between severity scores for the different tests was poor. Low-field MR imaging is a sensitive test for predicting the presence but not severity of meniscal histopathologic lesions in dogs with naturally-occurring cranial cruciate ligament rupture. Findings also supported previous studies indicating that histopathologic lesions can be present in dogs with grossly normal menisci. An improved grading system for comparing MR images and histopathologic severity of meniscal lesions in dogs is needed.

Imaging diagnosis--Dorsal mediastinal T-cell lymphoma in an alpaca.

A 14-year-old male alpaca had refractory pleural effusion. The cause of the effusion was not apparent either radiographically or sonographically, or following a pleural fluid cytologic examination. Using computed tomographic (CT) examination, a dorsal paravertebral mass was identified and similar masses were found in the cranial mediastinum, retroperitoneal space, and adjacent to the hepatic entry of the portal vein. The histopathologic diagnosis was multicentric T-cell lymphoma. CT examination may prove to be a valuable imaging modality in the localization and staging of neoplasia in new world camelids.

Concurrent nasal adenocarcinoma and rhinosporidiosis in a cat.

A 10-year-old, neutered, male Domestic Shorthair cat was presented to the teaching hospital for labored breathing, anorexia, and weight loss of several months duration. External examination revealed distortion of the bridge of the nose and pink fleshy polyps protruding from each nostril. The cat was euthanized and submitted for postmortem examination. In addition to the external findings, the nasal cavity had extensive bone and cartilage loss and contained a tan firm mass in the caudal region of the nasal cavity near the cribriform plate. On histologic examination, the mass was a nasal adenocarcinoma, and the polyps were composed of hyperplastic nasal epithelium and submucosal stroma that contained sporangia consistent with Rhinosporidium seeberi.

What is your diagnosis? Shoulder mass in a dog with lameness.

An adult castrated male Golden Retriever of unknown age was presented with a history of weight loss and progressive left thoracic limb lameness. On physical examination, a solid mass was palpated on the left scapula that had areas of lysis on radiographs and an area of cortical bone loss on ultrasound. Hepatomegaly, abdominal distension, and numerous intra-abdominal soft tissue masses were also found. Fine-needle aspirates of the scapula and several abdominal masses contained numerous free nuclei mixed with fewer individualized, intact cells that were round in shape and rarely formed small sheets. The cells had high nuclear to cytoplasmic ratios, central nuclei, coarsely stippled chromatin, 1-2 prominent nucleoli, and basophilic cytoplasm with indistinct cell borders. The cytopathologic interpretation was neuroendocrine neoplasia, either metastatic or multicentric. The dog was subsequently euthanized and based on gross and histologic findings at necropsy, a diagnosis of pheochromocytoma with multiple metastases was made. The neoplastic cells stained positive with Grimelius stain and were immunoreactive for synaptophysin and chromogranin A. Pheochromocytomas are rare tumors in dogs and uncommonly undergo distant metastasis, especially to bone.

Histophilus somni biofilm formation in cardiopulmonary tissue of the bovine host following respiratory challenge.

Biofilms form in a variety of host sites following infection with many bacterial species. However, the study of biofilms in a host is hindered due to the lack of protocols for the proper experimental investigation of biofilms in vivo. Histophilus somni is an agent of respiratory and systemic diseases in bovines, and readily forms biofilms in vitro. In the present study the capability of H. somni to form biofilms in cardiopulmonary tissue following experimental respiratory infection in the bovine host was examined by light microscopy, transmission electron microscopy, immunoelectron microscopy of ultrathin cryosections, scanning electron microscopy of freeze-fractured samples, and fluorescent in situ hybridization. Biofilms were evident and most prominent in the myocardium, and were associated with a large amount of amorphous extracellular material. Furthermore, Pasteurella multocida was often cultured with H. somni from heart and lung samples. Transposon mutagenesis of H. somni strain 2336 resulted in the generation of mutants that expressed more or less biofilm than the parent strain. Six mutants deficient in biofilm formation had an insertion in the gene encoding for a homolog of filamentous haemagglutinin (FHA), predicted to be involved in attachment. Thus, this investigation demonstrated that H. somni is capable of forming a biofilm in its natural host, that such a biofilm may be capable of harboring other bovine respiratory disease pathogens, and that the genes responsible for biofilm formation can be identified by transposon mutagenesis.

Inability to induce tympanic squamous metaplasia using organochlorine compounds in vitamin A-deficient red-eared sliders (Trachemys scripta elegans).

Previously, we reported that wild eastern box turtles (Terrapene carolina carolina) with aural abscesses contained higher body burdens of organochlorine (OC) compounds than those without the lesion. This lesion in captive chelonians is associated with turtles that are fed diets deficient in vitamin A. To examine the pathophysiology of this lesion and evaluate the relationship between OC burdens and vitamin A metabolism, we maintained red-eared sliders (Trachemys scripta elegans) under different conditions of OC exposure and dietary vitamin A concentrations from August 2005 to February 2006. Dietary vitamin A concentration (0 or 5 international units/g in the diet) and OC exposure (no OC compound or the mixture of 2 mg/kg chlordane, 0.25 mg/kg aroclor, and 1 mg/kg lindane) did not affect histologic score based on degree of squamous metaplasia of the tympanic epithelium or levels of plasma or liver vitamin A among the study groups. The results of this study suggest that 6 mo of exposure to the selected OC compounds, or similar duration of reduced dietary vitamin A concentrations do not influence the formation of squamous metaplasia and aural abscesses in red-eared sliders. Further studies are required to determine whether the duration of the experiment was insufficient, the OC compounds selected were inappropriate, the dosing was incorrect, and whether there are other unknown mechanisms causing the reported association between OC exposure and aural abscesses seen in eastern box turtles.

Effect of nephrotomy on renal function and morphology in normal cats.

OBJECTIVE: To assess effects over 12 weeks of bisection nephrotomy on renal function, size, and morphology in cats. STUDY DESIGN: Controlled, randomized, blinded experiment. SAMPLE POPULATION: Ten adult female cats. METHODS: Glomerular filtration rate (GFR), determined by quantitative renal scintigraphy using (99m)Technetium-diethylenetriamine-pentaacetic acid, urinalysis, urine culture, and ultrasonographic measurement of renal size were performed preoperatively. Left or right nephrotomy (5 cats/group) was performed. Total and individual kidney GFRs were determined at 2, 28, and 84 days, ultrasonographic measurements at 28 and 86 days, and ultrasound-guided biopsy at 86 days. RESULTS: No significant differences in mean GFR and kidney size of operated versus unoperated kidneys were observed. Individual GFR and renal size of all except 1 cat remained within normal limits. Two cats had evidence of transient ureteral obstruction in the immediate postoperative period. No significant, generalized histologic abnormalities were observed. CONCLUSIONS: Bisection nephrotomy in normal cats does not adversely affect renal function or morphology during the initial 12 weeks. CLINICAL RELEVANCE: Bisection nephrotomy can be safely performed in normal feline kidneys without causing a significant deleterious effect on renal function. Studies in cats with pre-existing renal insufficiency are needed to ensure adverse effects would not occur in clinical cases where this surgical procedure is warranted.

Lymphoma and Mycobacterium avium infection in a ferret (Mustela putorius furo).

A 6-year-old, neutered male ferret presented with weight loss. Radiography revealed an enlarged liver and other abdominal masses. The ferret was euthanized, and at necropsy, the stomach wall was thickened, mesenteric lymph nodes were enlarged, and the liver contained multifocal tan nodules. Histopathology confirmed lymphoma and granulomatous inflammation in all affected organs. Acid-fast bacilli were present in the lesions and were confirmed to be Mycobacterium avium by PCR.

Placental improvement and reduced distal limb defects by maternal interferon-gamma injection in methylnitrosourea-exposed mice.

BACKGROUND: Methylnitrosourea (MNU), an alkylating agent derived from creatinine metabolism, is cytotoxic, genotoxic, and mutagenic. Mid-gestational exposure to MNU leads to distal limb defects in mice. Previous studies have shown that nonspecific maternal immune stimulation protects against MNU-induced teratogenesis. A role for immune-mediated placental improvement in this effect remains uncertain. METHODS: The immune system of timed-pregnant C57BL/6N and CD-1 mice was stimulated by GD 7 intraperitoneal (IP) injection with the cytokine interferon-gamma (IFN-gamma). A teratogenic dose of MNU was then administered by IP injection on the morning of GD 9 to disrupt distal limb formation. Fetal limb length, body length, digital deformities, and placental integrity were evaluated on GD 14. RESULTS: The incidence of syndactyly, polydactyly, and interdigital webbing in MNU-exposed mice was decreased by maternal IFN-gamma treatment. In C57BL/6N mice, these defects were reduced by 47, 100, and 63%, respectively, as compared to previous reports on CD-1 mice, by 39, 71, and 20%, respectively. Administration of IFN-gamma significantly diminished MNU-induced endothelial and trophoblast placental damage in both strains of mice. CONCLUSIONS: These findings support a possible link between maternal immunity, placental integrity, and fetal distal limb development. Further, these results suggest that IFN-gamma might act through placental improvement to indirectly protect against MNU-induced fetal limb malformations.

Altered splenocyte function in aged C57BL/6 mice prenatally exposed to diethylstilbestrol.

The linkage between in utero exposure to diethylstilbestrol (DES) and the manifestation of a variety of reproductive disorders and possibly immune alterations in adults (i.e., human and mice) is suggestive of a fetal basis of adult disease. While the long-term adverse consequences of prenatal DES-exposure on reproductive disorders are well known, there is a paucity of data with regard to immune outcome. We hypothesize that prenatal DES-exposure "imprints" the immune system, altering the response to subsequent exposure to DES in adult mice. In this pilot study, C57BL/6 mice were prenatally exposed to DES or vehicle only (oil) and then exposed to DES at 1 year of age. Potential alterations in the spleen were then examined. Female DES-exposed mice (DES(prenatal)/DES(adult)) or female(DES) had higher serum levels of interferon-gamma (IFNgamma) in response to administration of an IFNgamma -inducer (soluble proteins-derived from Toxoplasma gondii), compared to female controls, which received oil during prenatal life (Oil(prenatal)/DES(adult)). Splenic lymphocytes from female DES(prenatal)/DES(adult) mice, when activated with Concanavalin A (ConA), also secreted higher levels of IFNgamma compared to female controls (Oil(prenatal)/DES(adult)) when examined at 14-months of age. This increase in IFNgamma in prenatal DES-exposed mice is not due to enhanced numbers of splenocytes or increased relative percentages of CD4(+) or CD8(+) cells. ConA-activated T-cells from female DES(prenatal)/DES(adult) had increased expression of the co-stimulatory molecule, CD28. These above immune changes were not evident in the males prenatally exposed to DES. Prenatal DES exposure also did not induce autoimmunity in non-autoimmune C57BL/6 mice. Overall, results from these prefatory studies suggest that prenatal DES exposure may have long-term immune alterations, which become evident following a secondary exposure to DES in adult life.

Fibrocartilaginous embolic myelopathy in a calf.

A 5-month-old Angus heifer with a history of acute hindlimb paresis that quickly progressed to lateral recumbency was necropsied. Gross lesions included a 6-cm segment of gray to brown discoloration and softening of the right ventrolateral spinal cord between T2 and T3. Microscopically, there was liquefactive necrosis of ventrolateral white and gray matter, and multiple intravascular emboli partially or completely occluded many intralesional and adjacent spinal and meningeal arteries and veins. Emboli were alcian blue positive, consistent with fibrocartilage of the nucleus pulposus of the intervertebral disk. No gross abnormalities were detected in the vertebrae or intervertebral disks. Fibrocartilaginous embolic myelopathy appears to be very rare in cattle; however, it should be considered in cases of acute, nonprogressive spinal cord dysfunction.