THE VALUE OF N-OF-1 DATA IN ZOOLOGICAL MEDICINE: A METHODOLOGICAL REVIEW.

N-of-1 data are unavoidable in zoological medicine. Accordingly, zoological medicine clinicians and investigators need research techniques that can make use of these data. This article reviews two methodologies for using both observational and experimental N-of-1 data: 1) systematic reviews and meta-analyses of case reports and 2) prospective N-of-1 trials. Systematic reviews of case reports and other observational evidence are formal, unbiased summaries of the clinical characteristics of a particular disease-taxon combination. They offer advantages to narrative reviews by minimizing omission of relevant articles, thereby reducing the potential for mischaracterization of the literature. Meta-analyses are extensions of systematic reviews that quantitatively synthesize the data from the included articles. Although valuable, systematic reviews and meta-analyses of case reports can have limited interpretations due to publication bias and confounding present in their source materials. In contrast to case reports, N-of-1 trials are prospective study designs that allow clinicians to make strong inferences about the effect of an intervention in a particular patient. They are double-blinded, single-patient, multicrossover studies that are of particular value in fields where it is difficult to recruit sufficient patients for conventional randomized control trials (RCTs), such as zoological medicine. Because they require multiple crossover periods, N-of-1 trials are ideal for evaluating short-acting interventions in patients with somewhat stable chronic diseases, such as osteoarthritis. More complex than conventional therapeutic trials, N-of-1 trials require prior consideration of how to achieve blinding, appropriate placebo controls, quantitative primary outcomes, analysis methods, and ethical approval. Aggregation of N-of-1 trials allows estimation of the average treatment effect across the population with fewer participants than a conventional RCT. Although systematic reviews and meta-analyses of case reports can be used to synthesize the observational N-of-1 data already in existence, N-of-1 trials offer an exciting way to prospectively generate strong evidence that will be useful for evidence-based decision-making.

Adult-onset epilepsy and hippocampal pathology in a California sea lion (Zalophus californianus): A case study of suspected in utero exposure to domoic acid.

Domoic acid (DA) is a naturally occurring marine neurotoxin produced by Pseudo-nitzschia diatoms. Adult California sea lions (Zalophus californianus) can experience multiple post-exposure syndromes, including acute toxicosis and chronic epilepsy. Additionally, a delayed-onset epileptic syndrome is proposed for California sea lions (CSL) exposed in utero. This brief report explores a case of a CSL developing adult-onset epilepsy with progressive hippocampal neuropathology. Initial brain magnetic resonance imaging (MRI) and hippocampal volumetric analyses relative to brain size were normal. Approximately 7 years later, MRI studies to evaluate a newly developed epileptic syndrome demonstrated unilateral hippocampal atrophy. While other causes of unilateral hippocampal atrophy cannot be completely excluded, this case may represent in vivo evidence of adult-onset epileptiform DA toxicosis in a CSL. By estimating in utero DA exposure time period, and extrapolating from studies conducted on laboratory species, this case provides circumstantial evidence for a neurodevelopmental explanation correlating in utero exposure to adult-onset disease. Evidence of delayed disease development secondary to gestational exposure to naturally occurring DA has broad implications for marine mammal medicine and public health.

Clinical predictive models in equine medicine: A systematic review.

Clinical predictive models use a patient's baseline demographic and clinical data to make predictions about patient outcomes and have the potential to aid clinical decision making. The extent of equine clinical predictive models is unknown in the literature. Using PubMed and Google Scholar, we systematically reviewed the predictive models currently described for use in equine patients. Models were eligible for inclusion if they were published in a peer-reviewed article as a multivariable model used to predict a clinical/laboratory/imaging outcome in an individual horse or herd. The agreement of at least two authors was required for model inclusion. We summarised the patient populations, model development methods, performance metric reporting, validation efforts, and, using the Predictive model Risk of Bias Assessment Tool (PROBAST), assessed the risk of bias and applicability concerns for these models. In addition, we summarised the index conditions for which models were developed and provided detailed information on included models. A total of 90 predictive models and 9 external validation studies were included in the final systematic review. A plurality of models (41%) was developed to predict outcomes associated with colic, for example, need for surgery or survival to discharge. All included models were at high risk of bias, defined as failing one or more PROBAST signalling questions, primarily for analysis-related reasons. Importantly, a high risk of bias does not necessarily mean that models are unusable, but that they require more careful consideration prior to clinical use. Concerns about applicability were low for the majority of models. Systematic reviews such as this can serve to increase veterinarians' awareness of predictive models, including evaluation of their performance and their use in different patient populations.

SERUM BIOCHEMICAL AND HEMATOLOGIC REFERENCE INTERVALS FOR WEANLING NORTHWEST ATLANTIC GRAY SEALS (HALICHOERUS GRYPUS).

Baseline health parameters are limited in the primary literature for gray seals (Halichoerus grypus) in the northwest Atlantic. Accurate normal physiologic reference ranges for both species and specific geographic populations are vital tools for assessing the health of individuals and understanding the health of the entire population. This study developed comprehensive reference intervals for biochemical and hematologic parameters of recently weaned gray seal pups on Cape Cod, Massachusetts from samples collected in 2013, 2016, and 2017. Reference ranges were developed using methodology outlined by the American Society of Clinical Veterinary Pathology. By establishing more comprehensive biochemical and hematologic reference ranges for this population based on a robust sample size, this study provides a new tool for clinicians, researchers, and rehabilitation organizations to improve individual patient care and population research.

ASSOCIATION BETWEEN POSITIVE CANINE HEARTWORM (DIROFILARIA IMMITIS) ANTIGEN RESULTS AND PRESENCE OF ACANTHOCHEILONEMA ODENDHALI MICROFILARIA IN CALIFORNIA SEA LIONS (ZALOPHUS CALIFORNIANUS).

This study establishes a relationship between positive canine heartworm (Dirofilaria immitis) test results frequently observed in California sea lions (Zalophus californianus) and infection with the filarid nematode Acanthocheilonema odendhali. Four commercially available canine heartworm antigen tests were evaluated for cross-reaction with A. odendhali in California sea lions. Sera were tested from fifteen California sea lions with A. odendhali-associated microfilaremia, confirmed by blood smear, and with no evidence of D. immitis infection at necropsy. Ninety-five percent of tests were falsely positive for D. immitis. This study also determined that the prevalence of A. odendhali infection in stranded California sea lions from central California is approximately 23% by comparing the number of findings of mircofilaremia to the total number of California sea lions sampled at The Marine Mammal Center between 2005 and 2011, inclusive. Acanthocheilonema odenhali microfilaremia in California sea lions is likely to cross-react with canine heartworm antigen tests, and clinicians should interpret results with caution.