Analysis of canine cardiovascular therapeutic agent prescriptions using electronic health records in primary care veterinary practices in the United Kingdom.

INTRODUCTION/OBJECTIVES: Canine cardiovascular (CV) diseases are often managed in primary care settings. The objectives were to describe CV therapeutic agent (CVTA) prescribing patterns in primary care practices in the United Kingdom (UK) and to evaluate recorded clinical signs, diagnostic tests and justifications for use of torasemide, a recently marketed and authorised loop-diuretic in the UK. ANIMALS, MATERIALS AND METHODS: Electronic health records (EHRs) describing 3,579,420 consultations (1,043,042 unique dogs) were collated (1 April 2014 and 31 December 2018) by the Small Animal Veterinary Surveillance Network from 270 veterinary practices. Consultations prescribing at least one CVTA were identified. Annual variation in individual CVTA prescriptions was analysed using mixed-effects binomial regression models. Free-text clinical narratives were manually read to determine the first-prescribing event for torasemide. RESULTS: Twenty-nine thousand and seven consultations (0.81% of all consultations, 95% confidence interval [CI], 0.76-0.86) prescribed CVTA in 14,148 (1.36%) dogs. Furosemide (52.8% of CV-prescribing consultations, 95% CI 50.7-54.9) and pimobendan (51.9%, 95% CI 50.1-53.7) were most prescribed. Longitudinal analysis (2014-2018) showed a significant negative temporal trend for angiotensin-converting enzyme inhibitors (p < 0.001), and furosemide (p = 0.003) and a positive temporal trend for pimobendan (p = 0.020) and torasemide (p < 0.001). First prescriptions of torasemide were identified in 16.5% of torasemide-prescribing consultations. Where justification for prescription of torasemide was identified (32.5%), furosemide resistance was the most common (92.0%). CONCLUSIONS: EHRs can be used to temporally monitor prescribing habits, including responses to market authorisations. Despite authorisation in the UK for torasemide use as a first-line diuretic, it was most commonly prescribed after furosemide resistance.

New approaches to pharmacosurveillance for monitoring prescription frequency, diversity, and co-prescription in a large sentinel network of companion animal veterinary practices in the United Kingdom, 2014-2016.

Pharmaceutical agents (PAs) are commonly prescribed in companion animal practice in the United Kingdom. However, little is known about PA prescription on a population-level, particularly with respect to PAs authorised for human use alone prescribed via the veterinary cascade; this raises important questions regarding the efficacy and safety of PAs prescribed to companion animals. This study explored new approaches for describing PA prescription, diversity and co-prescription in dogs, cats and rabbits utilising electronic health records (EHRs) from a sentinel network of 457 companion animal-treating veterinary sites throughout the UK over a 2-year period (2014-2016). A novel text mining-based identification and classification methodology was utilised to semi-automatically map practitioner-defined product descriptions recorded in 918,333 EHRs from 413,870 dogs encompassing 1,242,270 prescriptions; 352,730 EHRs from 200,541 cats encompassing 491,554 prescriptions, and 22,526 EHRS from 13,398 rabbits encompassing 18,490 prescriptions respectively. PA prescription as a percentage of booked consultations was 65.4% (95% confidence interval, CI, 64.6-66.3) in dogs; in cats it was 69.1% (95% CI, 67.9-70.2) and in rabbits, 56.3% (95% CI, 54.7-57.8). Vaccines were the most commonly prescribed PAs in all three species, with antibiotics, antimycotics, and parasiticides also commonly prescribed. PA prescription utilising products authorised for human use only (hence, 'human-authorised') comprised 5.1% (95% CI, 4.7-5.5) of total canine prescription events; in cats it was 2.8% (95% CI, 2.6-3.0), and in rabbits, 7.8% (95% CI, 6.5-9.0). The most commonly prescribed human-authorised PA in dogs was metronidazole (antibiotic); in cats and rabbits it was ranitidine (H2 histamine receptor antagonist). Using a new approach utilising the Simpson's Diversity Index (an ecological measure of relative animal, plant etc. species abundance), we identified differences in prescription based on presenting complaint and species, with rabbits generally exposed to a less diverse range of PAs than dogs or cats, potentially reflecting the paucity of authorised PAs for use in rabbits. Finally, through a novel application of network analysis, we demonstrated the existence of three major co-prescription groups (preventive health; treatment of disease, and euthanasia); a trend commonly observed in practice. This study represents the first time PA prescription has been described across all pharmaceutical families in a large population of companion animals, encompassing PAs authorised for both veterinary and human-only use. These data form a baseline against which future studies could be compared, and provides some useful tools for understanding PA comparative efficacy and risks when prescribed in the varied setting of clinical practice.

Use of vaccines and factors associated with their uptake variability in dogs, cats and rabbits attending a large sentinel network of veterinary practices across Great Britain.

Vaccination remains a mainstay of companion animal population health. However, how vaccine use at a population level complies with existing guidelines is unknown. Here we use electronic health records to describe vaccination in dogs, cats and rabbits attending a large sentinel network of UK veterinary practices. In total, 77.9% (95% CI: 77.6-78.1) of animals had recorded vaccinations. The percentage of animals with recorded vaccinations was higher in dogs, neutered animals, in insured dogs and cats and in purebred dogs. Vaccination rates varied in different regions of Great Britain in all species. Dogs and cats belonging to owners living in less deprived areas of England and Scotland were more likely to be recorded as vaccinated. In the vaccinated population, cats received more core vaccines per year of life (0.86) than dogs (0.75), with feline leukaemia vaccines almost as frequent as core vaccines. In dogs, leptospira vaccines were more frequent than core vaccines. This descriptive study suggests a substantial proportion of animals are not benefiting from vaccine protection. For the first time, we identify potential factors associated with variations in recorded vaccination frequency, providing a critical baseline against which to monitor future changes in companion animal vaccination and evidence to inform future targeted health interventions.

Patterns of antimicrobial agent prescription in a sentinel population of canine and feline veterinary practices in the United Kingdom.

Antimicrobial resistance is an increasingly important global health threat and the use of antimicrobial agents is a key risk factor in its development. This study describes antimicrobial agent prescription (AAP) patterns over a 2year period using electronic health records (EHRs) from booked consultations in a network of 457 sentinel veterinary premises in the United Kingdom. A semi-automated classification methodology was used to map practitioner defined product codes in 918,333 EHRs from 413,870 dogs and 352,730 EHRs from 200,541 cats, including 289,789 AAPs. AAP as a proportion of total booked consultations was more frequent in dogs (18.8%, 95% confidence interval, CI, 18.2-19.4) than cats (17.5%, 95% CI 16.9-18.1). Prescription of topical antimicrobial agents was more frequent in dogs (7.4%, 95% CI 7.2-7.7) than cats (3.2%, 95% CI 3.1-3.3), whilst prescription of systemic antimicrobial agents was more frequent in cats (14.8%, 95% CI 14.2-15.4) than dogs (12.2%, 95% CI 11.7-12.7). A decreasing temporal pattern was identified for prescription of systemic antimicrobial agents in dogs and cats. Premises which prescribed antimicrobial agents frequently for dogs also prescribed frequently for cats. AAP was most frequent during pruritus consultations in dogs and trauma consultations in cats. Clavulanic acid potentiated amoxicillin was the most frequently prescribed antimicrobial agent in dogs (28.6% of prescriptions, 95% CI 27.4-29.8), whereas cefovecin, a third generation cephalosporin, was the most frequently prescribed antimicrobial agent in cats (36.2%, 95% CI 33.9-38.5). This study demonstrated patterns in AAP over time and for different conditions in a population of companion animals in the United Kingdom.

Canine babesiosis and tick activity monitored using companion animal electronic health records in the UK.

Recent publications highlighting autochthonous Babesia canis infection in dogs from Essex that have not travelled outside the UK are a powerful reminder of the potential for pathogen emergence in new populations. Here the authors use electronic health data collected from two diagnostic laboratories and a network of 392 veterinary premises to describe canine Babesia cases and levels of Babesia concern from January 2015 to March 2016, and the activity of ticks during December 2015-March 2016. In most areas of the UK, Babesia diagnosis in this population was rare and sporadic. In addition, there was a clear focus of Babesia cases in the affected area in Essex. Until February 2016, analysis of health records indicated only sporadic interest in Babesia largely in animals coming from overseas. Following media coverage in March 2016, there was a spike in owner concern that was geographically dispersed beyond the at-risk area. Tick activity (identified as ticks being removed from animals in veterinary consultations) was consistent but low during the period preceding the infections (<5 ticks/10,000 consultations), but increased in March. This highlights the use of electronic health data to describe rapidly evolving risk and concern that follows the emergence of a pathogen.

Minimum energy structure of hydridotris(pyrazolyl)borato iridium(V) tetrahydride is not a C(3upsilon) capped octahedron.

Recent synthesis and NMR spectroscopy of neutral Ir(V) complexes hydridotris(3,5-dimethylpyrazol-1-yl)borato tetrahydride (Tp*IrH(4)) and hydridotris(pyrazol-1-yl)borato tetrahydride (TpIrH(4)) have been interpreted as supporting face-capped octahedral structures (C(3upsilon)) with each of three Ir-H bonds trans to an Ir-N bond and the fourth hydride capping the IrH(3) face. Here, density functional geometry optimizations and coupled cluster calculations on hydridotris(pyrazol-1-yl)borato iridium tetrahydrogen find that a C(s) edge-bridged octahedral tetrahydride structure and a C(1) eta(2)-dihydrogen, dihydride structure are local minima and find that the C(3upsilon) structure is a local maximum (second-order saddle point). Several low energy transition states connecting the local minima have been located, and these minima can be used to simulate the experimental NMR spectra. A comparison of the experimental infrared spectrum of Tp*IrH(4) and the harmonic frequency calculations on the C(s), C(1), and C(3upsilon) structures also supports the assignment of the C(s)and C(1) structures as the observed ones.

Isotope effects and the mechanism of allylic hydroxylation of alkenes with selenium dioxide.

The mechanism of the allylic oxidation of 2-methyl-2-butene with selenium dioxide was explored by a combination of experimental and theoretical studies. A comparison of the experimental (13)C and (2)H kinetic isotope effects with predicted values shows that the observed isotope effects are consistent with an initial concerted ene step mediated by SeO(2). However, this comparison also does not rule out the involvement of a selenous ester in the ene reaction or a stepwise reaction involving reversible electrophilic addition of HSeO(2)(+) followed by rate-limiting proton abstraction. Becke3LYP calculations strongly favor SeO(2) over a selenous ester as the active oxidant, with the predicted barrier for reaction of 2-methyl-2-butene with SeO(2) being 21-24 kcal/mol lower than that for reaction with H(2)SeO(3). The possibility of a selenous ester being the active oxidant is also disfavored by the observation of oxidations in non-hydroxylic solvents. The involvement of HSeO(2)(+) does not appear consistent with a lack of dependence of the reaction on the basicity of the reaction mixture. A concerted ene reaction with SeO(2) as the active oxidant appears to be the major mechanistic pathway operative in these reactions.

13C and (2)H kinetic isotope effects and the mechanism of Lewis acid-catalyzed ene reactions of formaldehyde.

13C and (2)H kinetic isotope effects were determined for the ene reaction of formaldehyde with 2-methyl-2-butene at natural abundance catalyzed by diethylaluminum chloride. The reactive methyl group exhibits a k(12)(C)/k(13)(C) of 1.006-1.009 and a k(H)/k(D) of approximately 1.22-1.23. The latter represents a combination of primary and secondary effects and is consistent with a significant primary deuterium isotope effect. A very close correspondence of the other isotope effects with the equilibrium isotope effects predicted for formation of a model intermediate cation is observed. An intermolecular deuterium isotope effect of 2.0-2.5 was observed under several reaction conditions in the Lewis acid-catalyzed reaction of formaldehyde with d(0)/d(12)-tetramethylethylene. The results are interpreted as supporting the reversible formation of an essentially classical open cation followed by rate-limiting proton transfer.

13C and 2H kinetic isotope effects and the mechanism of bromination of 1-pentene under synthetic conditions.

[formula: see text] The 13C and 2H kinetic isotope effects for the bromination of 1-pentene with Br2 in CCl4 were determined and interpreted with the aid of calculationally predicted isotope effects. The isotope effects observed are consistent with rate-limiting bromonium ion formation and do not fit with either rate-limiting production of a pi complex or reaction of a reversibly formed bromonium ion. This rules out some of the mechanistic complexities suggested for other brominations, though the identity of the brominating reagent(s) under these synthetic conditions remains uncertain.

Carbometalations of simple alkenes with allyldibromoborane.

[formula: see text] The allylboration of alkenes with allyldibromoborane is described. Utilizing an improved methodology for the synthesis of allyldibromoborane, 1,3-dienes, styrene, and even isolated alkenes could be carbometalated in high yield regio- and stereospecifically at 0 degree C. This high reactivity of allyldibromoborane significantly expands the scope of carbometalations of alkenes.

Deuterium kinetic isotope effects and the mechanism of the bacterial luciferase reaction.

A combined experimental and theoretical investigation of the deuterium isotope effects on the bacterial luciferase reaction is described. The experimental studies focus on determining if the unusual aldehydic deuterium isotope effect of approximately 1.5 observed in these reactions is an intrinsic isotope effect resulting from a single rate-limiting step or is a composite of multiple rate-limiting steps. The isotope effect observed is not significantly affected by variation in the aldehyde chain length, changes in the pH over a range of 6-9, use of alphaC106A and alphaC106S site-directed mutants, or chloride substitution at the 8-position of the reduced flavin, though the isotope effect is decreased when the 8-methoxy-substituted flavin is used as a substrate. From these observations it is concluded that the aldehydic isotope effect arises from the change in rate of a single kinetic step. A stopped-flow kinetic analysis of the microscopic rate constants for the reactions of 1-[1H]decanal and 1-[2H]decanal in the bacterial luciferase reaction was carried out, and aldehyde hydration isotope effects were determined. From the results it is estimated that the aldehydic deuterium isotope effect is approximately 1.9 after formation of an intermediate flavin C4a-hydroperoxy hemiacetal. Ab initio calculations were used to examine the transformation of the aldehyde into a carboxylic acid and to predict isotope effects for possible mechanisms. These calculations indicate that the mechanism involving rate-limiting electron transfer from the flavin C4a-hydroxide to an intermediate dioxirane is consistent with the enigmatic aldehydic isotope effect and that the intermediacy of a dioxirane is energetically plausible.