The Monarch Initiative in 2024: an analytic platform integrating phenotypes, genes and diseases across species.

Bridging the gap between genetic variations, environmental determinants, and phenotypic outcomes is critical for supporting clinical diagnosis and understanding mechanisms of diseases. It requires integrating open data at a global scale. The Monarch Initiative advances these goals by developing open ontologies, semantic data models, and knowledge graphs for translational research. The Monarch App is an integrated platform combining data about genes, phenotypes, and diseases across species. Monarch's APIs enable access to carefully curated datasets and advanced analysis tools that support the understanding and diagnosis of disease for diverse applications such as variant prioritization, deep phenotyping, and patient profile-matching. We have migrated our system into a scalable, cloud-based infrastructure; simplified Monarch's data ingestion and knowledge graph integration systems; enhanced data mapping and integration standards; and developed a new user interface with novel search and graph navigation features. Furthermore, we advanced Monarch's analytic tools by developing a customized plugin for OpenAI's ChatGPT to increase the reliability of its responses about phenotypic data, allowing us to interrogate the knowledge in the Monarch graph using state-of-the-art Large Language Models. The resources of the Monarch Initiative can be found at monarchinitiative.org and its corresponding code repository at github.com/monarch-initiative/monarch-app.

Metabolic Disorders Associated with Renal Disease in Horses.

This article overviews metabolic disorders associated with renal disease. Included is a discussion of the pathophysiology, clinical signs, and treatment of hyperchloremic metabolic acidosis associated with renal tubular acidosis. Conditions affecting the central nervous system including uremic encephalopathy and hyponatremic encephalopathy secondary to renal disease are presented. Finally, a discussion of the unique features of calcium and phosphorus homeostasis in horses is provided with special emphasis on a recently described syndrome of calcinosis and calciphylaxis of unknown etiology.

The Vertebrate Breed Ontology: Towards Effective Breed Data Standardization.

Background ­: Limited universally adopted data standards in veterinary science hinders data interoperability and therefore integration and comparison; this ultimately impedes application of existing information-based tools to support advancement in veterinary diagnostics, treatments, and precision medicine. Hypothesis/Objectives ­: Creation of a Vertebrate Breed Ontology (VBO) as a single, coherent logic-based standard for documenting breed names in animal health, production and research-related records will improve data use capabilities in veterinary and comparative medicine. Animals ­: No live animals were used in this study. Methods ­: A list of breed names and related information was compiled from relevant sources, organizations, communities, and experts using manual and computational approaches to create VBO. Each breed is represented by a VBO term that includes all provenance and the breed's related information as metadata. VBO terms are classified using description logic to allow computational applications and Artificial Intelligence-readiness. Results ­: VBO is an open, community-driven ontology representing over 19,000 livestock and companion animal breeds covering 41 species. Breeds are classified based on community and expert conventions (e.g., horse breed, cattle breed). This classification is supported by relations to the breeds' genus and species indicated by NCBI Taxonomy terms. Relationships between VBO terms, e.g. relating breeds to their foundation stock, provide additional context to support advanced data analytics. VBO term metadata includes common names and synonyms, breed identifiers/codes, and attributed cross-references to other databases. Conclusion and clinical importance ­: Veterinary data interoperability and computability can be enhanced by the adoption of VBO as a source of standard breed names in databases and veterinary electronic health records.

Complex central nervous system malformations in a Dutch Warmblood foal.

A neonatal Dutch Warmblood colt was evaluated for inability to stand, incoordination and intention tremor. Despite partial improvement in clinical signs during the first 4 days of hospitalization, neurological deficits remained. Magnetic resonance imaging identified a unilateral infratentorial arachnoid cyst-like lesion with ipsilateral compression and displacement of the cerebellar hemisphere, absent corpus collosum, polymicrogyria, suspect leukoencephalopathy, and noncompressive occipitoatlantal malformation. Improvement in clinical signs during the first 6 months of life suggests that horses can survive with complex congenital neurological malformations, but prognosis for athletic performance is poor. The accessibility of magnetic resonance imaging should improve the diagnostic accuracy of central nervous system disorders in neonatal foals in which congenital malformations are suspected. Euthanasia often is elected in foals with suspected congenital central nervous system disorders because of poor prognosis for athletic performance, limiting understanding of clinical progression in these cases.

The effect of neonatal dysphagia on subsequent racing performance in Standardbred horses.

BACKGROUND: Previously we described a clustering of dysphagic foal cases on a Pennsylvania (PA) Standardbred farm which was associated with exposure of pregnant mares to high concentrations of polycyclic aromatic hydrocarbons (PAHs) in the well water. The effect of dysphagia on future athleticism was uncertain. OBJECTIVES: To determine if, as adults, dysphagic foals were less likely to race and if athleticism (age of first race, Speed Index and Earnings Per Start Index) differed from that of healthy foals that raced as adults. STUDY DESIGN: Prospective cohort study. METHODS: All foals born during the study period (2014-2017) on the affected PA or an unaffected New York (NY) farm with the same proprietor were eligible for inclusion in the study. Foals with dysphagia attributed to causes other than PAH environmental exposure were excluded. The proportion of foals from both farms that raced, their age of first race, Earnings Per Start Index and Speed Index were compared between the dysphagic and normal foals using Chi-Square and Wilcoxon Rank Sum Tests. Significance level was P < .05. RESULTS: A total of 116 foals met the inclusion criteria. No significant difference was found in the percentages of foals that raced from each farm: On the PA farm, 54% of healthy and 72% of dysphagic foals raced; 70% of healthy NY farm foals raced. Median (interquartile range) age of first race, Earnings Per Start Index or Speed Index for dysphagic foals (2 years (2, 2); 57 (49, 60); 60 (45, 66) was not different from those of healthy foals from both farms (2 years (2, 3); 55 (39, 78)) or the PA farm (2 years (2, 2); 61(24, 73); 68 (57, 85)). All P > .05. MAIN LIMITATIONS: Small sample size and unique type of dysphagia. CONCLUSIONS: The athleticism of formerly dysphagic foals does not appear to be negatively impacted compared with normal foals as measured by age of first race, Earnings Per Start Index and Speed Index.

Environmental surveillance and adverse neonatal health outcomes in foals born near unconventional natural gas development activity.

Studies of neonatal health risks of unconventional natural gas development (UNGD) have not included comprehensive assessments of environmental chemical exposures. We investigated a clustering of dysphagic cases in neonatal foals born between 2014 and 2016 in an area of active UNGD in Pennsylvania (PA),USA. We evaluated equine biological data and environmental exposures on the affected PA farm and an unaffected New York (NY) farm owned by the same proprietor. Dams either spent their entire gestation on one farm or moved to the other farm in late gestation. Over the 21-month study period, physical examinations and blood/tissue samples were obtained from mares and foals on each farm. Grab samples of water, pasture soil and feed were collected; continuous passive sampling of air and water for polycyclic aromatic hydrocarbons was performed. Dysphagia was evaluated as a binary variable; logistic regression was used to identify risk factors. Sixty-five foals were born, 17 (all from PA farm) were dysphagic. Odds of dysphagia increased with the dam residing on the PA farm for each additional month of gestation (OR = 1.4, 95% CI 1.2, 1.7, p = 6.0E-04). Males were more likely to be born dysphagic (OR = 5.5, 95% CI 1.2, 24.5, p = 0.03) than females. Prior to installation of a water filtration/treatment system, PA water concentrations of 3,6-dimethylphenanthrene (p = 6.0E-03), fluoranthene (p = 0.03), pyrene (p = 0.02) and triphenylene (p = 0.01) exceeded those in NY water. Compared to NY farm water, no concentrations of PAHs were higher in PA following installation of the water filtration/treatment system. We provide evidence of an uncommon adverse health outcome (dysphagia) in foals born near UNGD that was eliminated in subsequent years (2017-2019) following environmental management changes. Notably, this study demonstrates that domestic large animals such as horses can serve as important sentinels for human health risks associated with UNGD activities.

Pharmacokinetics of single-dose intragastric and intravenous pregabalin administration in clinically normal horses.

OBJECTIVE: To assess pharmacokinetics of pregabalin in horses after a single intragastric or IV dose. ANIMALS: 5 healthy adult mares. PROCEDURES: Horses received 1 dose of pregabalin (approx 4 mg/kg) via nasogastric tube in a crossover-design study; after a 3-week washout period, the same dose was administered IV. Food was not withheld. Plasma pregabalin concentrations in samples obtained 0 to 36 hours after administration were measured by use of ultra-performance liquid chromatography with triple quadrupole tandem mass spectrometry. Pharmacokinetic variables were estimated by means of noncompartmental analysis. RESULTS: Mild sedation was observed in 2 horses following intragastric and IV pregabalin administration. Signs of mild, transient colic or behavioral abnormalities were observed in all horses following IV administration. After intragastric administration, median (range) maximal plasma concentration was 5.0 µg/mL (4.4 to 6.7 µg/mL), time to maximal plasma concentration was 1. 0 hour (0.5 to 2.0 hours), elimination half-life was 8.0 hours (6.2 to 9.4 hours), and area under the curve from time 0 to infinity (AUC0-∞) was 47.2 µg·h/mL (36.4 to 58.4 µg·h/mL). After IV administration, initial concentration was 22.2 µg/mL (19.8 to 27.7 µg/mL), elimination half-life was 7.74 hours (6.94 to 8.17 hours), and AUC0-∞ was 48.3 µg·h/mL (44.8 to 57.2 µg·h/mL). Bioavailability was 97.7% (80.7% to 109.8%). Median predicted values for minimal, mean, and maximal steady-state plasma concentrations after intragastric administration assuming an 8-hour dosing interval were 3.9, 5.3, and 6.3 µg/mL, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: At a simulated intragastric dosage of approximately 4 mg/kg every 8 hours, median pregabalin steady-state plasma concentration in healthy horses was within the therapeutic range reported for humans. Therapeutic concentrations and safety of this dosage have not been established in horses.