Assessment of a methodology for determination of H[2]O[2] concentration and pH in exhaled breath condensate in horses with and without lower airway inflammation

Measurement of hydrogen peroxide (H2O2) concentration and pH in exhaled breath condensate (EBC) is useful for detection and monitoring of diseases of the lower respiratory tract in humans, including asthma and chronic obstructive pulmonary disease. In contrast, limited information on the use of these parameters for the investigation of lower airway inflammation (LAI) is available for horses. Aims of the current study were to develop a device to collect EBC from non-sedated horses, assess inter-day and intra-day variability of EBC H2O2 concentration and pH and determine if there was an association between these parameters and the presence and severity of LAI. The methodology used for collection of EBC was adapted from that used in a previous study (Wyse et al. 2005) and was evaluated for its repeatability. Hydrogen peroxide was measured using previously reported analytic methods (Wyse et al. 2005). During studies for the determination of a methodology for measurement of pH in EBC, samples of EBC were divided into 3 aliquots. One aliquot was left non-deaerated, one aliquot was deaerated with argon and one aliquot underwent standardisation with CO2. The pH of each aliquot was measured using a bench pH meter. The most repeatable measurement of EBC pH was obtained from plain samples (i.e. non-dearated). Intra-day and inter-day variability of H2O2 concentration and pH were assessed by collecting and analysing EBC three times a day for 3 consecutive days. For H2O2 the variability in concentrations was large (60-103%), while the pH of EBC had little variability (3-7%). No significant difference in the intra-day or inter-day H2O2 concentrations or pH measurements were found in control or LAI horses, except for inter-day H2O2 concentration in horses with LAI (p=0.019). There was no significant difference in EBC H2O2 concentration between control horses (Mean +/- SD) and horses with LAI (mean +/- SD). There was no significant difference in EBC pH between control horses (Mean +/- SD) and horses with LAI (mean +/- SD), however a trend for a reduced pH in horses with LAI was observed (p= 0.079). The results of this study suggest that EBC H2O2 concentration is not suitable for detecting mild LAI or monitoring horses with LAI due to the high variability. The pH of EBC is more stable overtime and the measurements are more repeatable than H2O2 concentration and further studies are required to improve the stability of its measurement and to assess its sensitivity in a population of horses with more severe LAI against healthy controls. Further studies are also required to determine whether determination of H2O2 concentration in EBC is useful for detection of marked LAI in horses

Biochemical and epidemiological investigations of non-steroidal anti-inflammatory drug usage and related side effects in equids

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in equine veterinary practice. These drugs exert their effect by inhibiting cyclooxygenase (COX) enzymes, which control prostaglandin production, a major regulator of tissue perfusion. Two isoforms of COX enzymes exist: COX-1 is physiologically present in tissues, while COX-2 is up-regulated during inflammation and has been indicated as responsible for the negative effects of an inflammatory response. Evidence suggests that NSAIDs that inhibit only COX-2, preserving the physiological function of COX-1 might have a safer profile. Studies that evaluate the effect of NSAIDs on COX enzymes are all performed under experimental conditions and none uses actual clinical patients. The biochemical investigations in this work focus on describing the effect on COX enzymes activity of flunixin meglumine and phenylbutazone, two non-selective COX inhibitors and firocoxib, a COX-2 selective inhibitor, in clinical patients undergoing elective surgery. A separate epidemiological investigation was aimed at describing the impact that the findings of biochemical data have on a large population of equids. Electronic medical records (EMRs) from 454,153 equids were obtained from practices in the United Kingdom, United States of America and Canada. Information on prevalence and indications for NSAIDs use was extracted from the EMRs via a text mining technique, improved from the literature and described and validated within this Thesis. Further the prevalence of a clinical sign compatible with NSAID toxicity, such as diarrhoea, is reported along with analysis evaluating NSAID administration in light of concurrent administration of other drugs and comorbidities. This work confirms findings from experimental settings that NSAIDs firocoxib is COX-2 selective and that flunixin meglumine and phenylbutazone are non-selective COX inhibitors and therefore their administration carries a greater risk of toxicity. However the impact of this finding needs to be interpreted with caution as epidemiological data suggest that the prevalence of toxicity is in fact small and the use of these drugs at the labelled dose is quite safe

Proportion of nonsteroidal anti-inflammatory drug prescription in equine practice

BACKGROUND: There is little knowledge of the prescription of nonsteroidal anti-inflammatory drugs (NSAIDs) and whether their prescription varies between countries. OBJECTIVE: To describe prescription practices of NSAIDs in equids in the United Kingdom (UK), United States of America (USA) and Canada. STUDY DESIGN: Descriptive observational study. METHODS: Free-text electronic medical records from 141,543 equids from 10 equine practices in the UK, 255,777 equids from 7 equine practices with 20 branches from the USA and 2 practices with 7 branches from Canada were evaluated. A validated text-mining technique was used to describe the proportion of equids prescribed NSAIDs at least once in these countries. The choice of NSAIDs in orthopaedic and colic cases was evaluated. RESULTS: The prescription of NSAIDs is more common in the USA (42.4%) and Canada (34.2%) than in the UK (28.6%). Phenylbutazone and flunixin meglumine were the drugs mostly prescribed in all countries. While flunixi meglumine was most prescribed with colic cases in all countries, a proportion received phenylbutazone despite this drug being licensed for use only with musculoskeletal disease. Phenylbutazone was the most commonly prescribed drug in cases with orthopaedic disease followed by flunixin meglumine in all countries. Only a small proportion of cases received meloxicam, ketoprofen or firocoxib. MAIN LIMITATIONS: The retrospective design might have resulted in an unknown number of incomplete records, particularly in the reporting of colic and orthopaedic disease. Although the data set is large, the relatively small number of practices recruited from each country may introduce bias. CONCLUSIONS: Clinical practice can differ between countries although the influence of individual practitioners and practice-specific policy on apparent intercountry differences requires further research. Despite several other NSAIDs being available and a substantial effort being made to evaluate their efficacy, the prescription of NSAIDs other than phenylbutazone and flunixin meglumine remains rather limited

Validation of an improved computer-assisted technique for mining free-text electronic medical records

Background: The use of electronic medical records (EMRs) offers opportunity for clinical epidemiological research. With large EMR databases, automated analysis processes are necessary but require thorough validation before they can be routinely used.Objective: The aim of this study was to validate a computer-assisted technique using commercially available content analysis software (SimStat-WordStat v.6 (SS/WS), Provalis Research) for mining free-text EMRs.Methods: The dataset used for the validation process included life-long EMRs from 335 patients (17,563 rows of data), selected at random from a larger dataset (141,543 patients, ~2.6 million rows of data) and obtained from 10 equine veterinary practices in the United Kingdom. The ability of the computer-assisted technique to detect rows of data (cases) of colic, renal failure, right dorsal colitis, and non-steroidal anti-inflammatory drug (NSAID) use in the population was compared with manual classification. The first step of the computer-assisted analysis process was the definition of inclusion dictionaries to identify cases, including terms identifying a condition of interest. Words in inclusion dictionaries were selected from the list of all words in the dataset obtained in SS/WS. The second step consisted of defining an exclusion dictionary, including combinations of words to remove cases erroneously classified by the inclusion dictionary alone. The third step was the definition of a reinclusion dictionary to reinclude cases that had been erroneously classified by the exclusion dictionary. Finally, cases obtained by the exclusion dictionary were removed from cases obtained by the inclusion dictionary, and cases from the reinclusion dictionary were subsequently reincluded using Rv3.0.2 (R Foundation for Statistical Computing, Vienna, Austria). Manual analysis was performed as a separate process by a single experienced clinician reading through the dataset once and classifying each row of data based on the interpretation of the free-text notes. Validation was performed by comparison of the computer-assisted method with manual analysis, which was used as the gold standard. Sensitivity, specificity, negative predictive values (NPVs), positive predictive values (PPVs), and F values of the computer-assisted process were calculated by comparing them with the manual classification.Results: Lowest sensitivity, specificity, PPVs, NPVs, and F values were 99.82% (1128/1130), 99.88% (16410/16429), 94.6% (223/239), 100.00% (16410/16412), and 99.0% (100×2×0.983×0.998/[0.983+0.998]), respectively. The computer-assisted process required few seconds to run, although an estimated 30 h were required for dictionary creation. Manual classification required approximately 80 man-hours.Conclusions: The critical step in this work is the creation of accurate and inclusive dictionaries to ensure that no potential cases are missed. It is significantly easier to remove false positive terms from a SS/WS selected subset of a large database than search that original database for potential false negatives. The benefits of using this method are proportional to the size of the dataset to be analyzed

Disease and pharmacologic risk factors for first and subsequent episodes of equine laminitis: a cohort study of free-text electronic medical records

Electronic medical records from first opinion equine veterinary practice may represent a unique resource for epidemiologic research. The appropriateness of this resource for risk factor analyses was explored as part of an investigation into clinical and pharmacologic risk factors for laminitis. Amalgamated medical records from seven UK practices were subjected to text mining to identify laminitis episodes, systemic or intra-synovial corticosteroid prescription, diseases known to affect laminitis risk and clinical signs or syndromes likely to lead to corticosteroid use. Cox proportional hazard models and Prentice, Williams, Peterson models for repeated events were used to estimate associations with time to first, or subsequent laminitis episodes, respectively. Over seventy percent of horses that were diagnosed with laminitis suf- fered at least one recurrence. Risk factors for first and subsequent laminitis episodes were found to vary. Corticosteroid use (prednisolone only) was only significantly associated with subsequent, and not ini- tial laminitis episodes. Electronic medical record use for such analyses is plausible and offers important advantages over more traditional data sources. It does, however, pose challenges and limitations that must be taken into account, and requires a conceptual change to disease diagnosis which should be considered carefully

Prevalence, survival analysis and multimorbidity of chronic diseases in the general veterinarian-attended horse population of the UK

he average age of the global human population is increasing, leading to increased interest in the effects of chronic disease and multimorbidity on health resources and patient welfare. It has been posited that the average age of the general veterinarian-attended horse population of the UK is also increasing, and therefore it could be assumed that chronic diseases and multimorbidity would pose an increasing risk here also. However, evidence for this trend in ageing is very limited, and the current prevalence of many chronic diseases, and of multimorbidity, is unknown. Using text mining of first-opinion electronic medical records from seven veterinary practices around the UK, Kaplan-Meier and Cox proportional hazard modelling, we were able to estimate the apparent prevalence among veterinarian-attended horses of nine chronic diseases, and to assess their relative effects on median life expectancy following diagnosis. With these methods we found evidence of increasing population age. Multimorbidity affected 1.2% of the study population, and had a significant effect upon survival times, with co-occurrence of two diseases, and three or more diseases, leading to 6.6 and 21.3 times the hazard ratio compared to no chronic disease, respectively. Laminitis was involved in 74% of cases of multimorbidity. The population of horses attended by UK veterinarians appears to be aging, and chronic diseases and their co-occurrence are common features, and as such warrant further investigation

Effect of flunixin meglumine and firocoxib on ex vivo cyclooxygenase activity in horses undergoing surgery

OBJECTIVE: To evaluate ex vivo cyclooxygenase (COX) inhibition and compare in vitro and ex vivo COX-1 inhibition by flunixin meglumine and firocoxib in horses.<p></p> ANIMALS: 4 healthy horses for in vitro experiments and 12 healthy horses (6 males and 6 females; 5 Thoroughbreds, 5 Warmbloods, and 2 ponies) undergoing elective surgery for ex vivo experiments.<p></p> PROCEDURES: 12 horses received flunixin meglumine (1.1 mg/kg, IV, q 12 h) or firocoxib (0.09 mg/kg, IV, q 24 h). Blood samples were collected before (baseline) and 2 and 24 hours after NSAID administration. Prostanoids (thromboxane B2, prostaglandin E2, and prostaglandin E metabolites) served as indicators of COX activity, and serum drug concentrations were measured by use of high-performance liquid chromatography. An in vitro coagulation-induced thromboxane B2 assay was used to calculate drug concentration-COX-1 inhibition curves. Effect of time and treatment on COX activity was determined. Agreement between in vitro and ex vivo measurement of COX activity was assessed with Bland-Altman analysis.<p></p> RESULTS: At 2 and 24 hours after NSAID administration, COX-1 activity was reduced, compared with baseline activity, for the flunixin meglumine group only and relative COX-1 activity was significantly greater for the firocoxib group, compared with that for the flunixin meglumine group. There was no significant change in COX-2 activity after surgery for either group. Bland-Altman analysis revealed poor agreement between in vitro and ex vivo measurement of COX-1 activity.<p></p> CONCLUSIONS AND CLINICAL RELEVANCE: Compared with flunixin meglumine, firocoxib had COX-1-sparing effects ex vivo in equine patients that underwent elective surgery