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Topic:Anthelmintic Resistance

Anthelmintic resistance in horses refers to the reduced effectiveness of deworming agents, known as anthelmintics, in controlling parasitic worm populations. This phenomenon arises when parasites develop the ability to survive treatments that previously were effective at standard doses. Anthelmintic resistance is a growing concern in equine management, as it can lead to increased parasite burdens and associated health issues in horses. Common parasites affected by resistance include small strongyles (cyathostomins) and ascarids (Parascaris spp.). This page compiles peer-reviewed research studies and scholarly articles that explore the mechanisms, prevalence, and management strategies related to anthelmintic resistance in equine populations.
Salivary Cortisol, Equine Characteristics, and Management Factors Associated With Strongyle-Type Egg Shedding of Ohio Horses.
Journal of equine veterinary science    February 24, 2021   Volume 101 103431 doi: 10.1016/j.jevs.2021.103431
Keating DL, Lehman JS, Burk SV.Identification of factors associated with parasite infestation in horses could reduce frequency of anthelmintic administration and slow development of anthelmintic resistance. The study aim was to evaluate management factors, equine characteristics, and equine salivary cortisol concentrations for association with strongyle-type egg shedding levels. As immunocompromised horses appear to be more susceptible to parasite infestation, it was hypothesized that salivary cortisol concentration could be associated with parasite egg shedding. Saliva and fecal samples were collected from 200 horses acros...
Helminth infections in Italian donkeys: Strongylus vulgaris more common than Dictyocaulus arnfieldi.
Journal of helminthology    February 4, 2021   Volume 95 e4 doi: 10.1017/S0022149X20001017
Buono F, Veronesi F, Pacifico L, Roncoroni C, Napoli E, Zanzani SA, Mariani U, Neola B, Sgroi G, Piantedosi D, Nielsen MK, Veneziano V.Donkeys have been used as working animals for transport and farm activities worldwide. Recently, in European countries, there has been an increasing interest in donkeys due to their use as pets, onotherapy or milk production. During 2014-2016, a countrywide survey was conducted to determine prevalence and risk factors of principal helminth infections in 1775 donkeys in 77 Italian farms. A questionnaire on management and parasite control practices was filled out for each farm. Faecal samples were examined using a modified McMaster technique, a centrifugation/flotation method and a sedimentation...
Anthelmintic resistance of horse strongyle nematodes to ivermectin and pyrantel in Lithuania.
Acta veterinaria Scandinavica    January 25, 2021   Volume 63, Issue 1 5 doi: 10.1186/s13028-021-00569-z
Dauparaitė E, Kupčinskas T, von Samson-Himmelstjerna G, Petkevičius S.With intensive use of anthelmintic drugs in recent decades, anthelmintic resistance (AR) in horse nematodes is becoming a growing issue in many countries. However, there is little available information about the parasites, treatment practices or AR in the horse population in Lithuania. The aim of this study was to assess the current situation of AR on horse farms in Lithuania. The study was conducted in 25 stables on horses with a strongyle faecal egg count (FEC) of ≥ 200 eggs per gram. A faecal egg count reduction test (FECRT) was performed on each farm after administration of ivermectin ...
Gastrointestinal Strongyles Egg Excretion in Relation to Age, Gender, and Management of Horses in Italy.
Animals : an open access journal from MDPI    December 3, 2020   Volume 10, Issue 12 2283 doi: 10.3390/ani10122283
Scala A, Tamponi C, Sanna G, Predieri G, Dessì G, Sedda G, Buono F, Cappai MG, Veneziano V, Varcasia A.Current equine helminth control strategies play a key role in strongyle epidemiology and anthelmintic resistance and have led to the recommendation for new treatment plans, which include diagnostic and efficacy surveillance. Assessing the equine strongyle distribution patterns would thus be useful and this study describes the strongyle prevalence in the equine population in Italy through coprological analysis and coproculture. In addition, individual data on each animal were collected in order to identify risk factors associated with strongyle egg shedding. Of the total number of stables inves...
Monitoring equine ascarid and cyathostomin parasites: Evaluating health parameters under different treatment regimens.
Equine veterinary journal    November 23, 2020   Volume 53, Issue 5 902-910 doi: 10.1111/evj.13374
Nielsen MK, Gee EK, Hansen A, Waghorn T, Bell J, Leathwick DM.Strongylid and ascarid parasites are omnipresent in equine stud farms, and ever-increasing levels of anthelmintic resistance are challenging the industry with finding more sustainable and yet effective parasite control programs. Objective: To evaluate egg count levels, bodyweight and equine health under defined parasite control protocols in foals and mares at two Standardbred and two Thoroughbred stud farms. Methods: Longitudinal randomised field trial. Methods: A total of 93 foals were enrolled and split into two treatment groups, and 99 mares were enrolled and assigned to three treatment gro...
Nutritional Supplements Containing Cardus mariano, Eucalyptus globulus, Gentiana lutea, Urtica urens, and Mallotus philippinensis Extracts Are Effective in Reducing Egg Shedding in Dairy Jennies (Equus asinus) Naturally Infected by Cyathostomins.
Frontiers in veterinary science    November 5, 2020   Volume 7 556270 doi: 10.3389/fvets.2020.556270
Arfuso F, Bazzano M, Brianti E, Gaglio G, Passantino A, Tesei B, Laus F.The increasing levels of anthelmintic resistance together with the restrictions in the use of drugs in food producing animals have enforced the search for sustainable alternative approaches for parasite control. The current study aimed to investigate the safety and the efficacy of a commercially available phytotherapic formulation against gastrointestinal strongyles in donkeys. Twenty-two Ragusana jennies (2.6 ± 0.5 years old) were assigned to two equal groups. One group was treated with two doses of a phytotherapic supplement Paraxitebio® containing , and , 14 days apart (Group A). One grou...
Meta-analysis of cyathostomin species-specific prevalence and relative abundance in domestic horses from 1975-2020: emphasis on geographical region and specimen collection method.
Parasites & vectors    October 12, 2020   Volume 13, Issue 1 509 doi: 10.1186/s13071-020-04396-5
Bellaw JL, Nielsen MK.Cyathostomins infect virtually all horses, and concomitant infections with 10 or more species per horse is standard. Species-specific knowledge is limited, despite potential species bias in development of disease and anthelmintic resistance. This is the first meta-analysis to examine effects of geographical region and cyathostomin collection method on reported composition of cyathostomin communities. Methods: Thirty-seven articles published in English in 1975 or later, in which adults of individual species were systematically enumerated, were included. Seven regions; North America, South Ameri...
Importation of macrocyclic lactone resistant cyathostomins on a US thoroughbred farm.
International journal for parasitology. Drugs and drug resistance    September 30, 2020   Volume 14 99-104 doi: 10.1016/j.ijpddr.2020.09.004
Nielsen MK, Banahan M, Kaplan RM.Anthelmintic resistance in equine cyathostomins is both widespread and highly prevalent in the benzimidazole and tetrahydropyrimidine classes; however, reports of resistance to macrocyclic lactone (ML) drugs are sparse and sporadic. This study reports a case of clear ML resistance in a group of Thoroughbred yearlings imported from Ireland to the US in 2019. Fecal egg count reduction (FECR) following ivermectin administered in February 2020 demonstrated 100% reduction in the US bred yearlings, but 93.5%, 70.5%, and 74.5% reduction in three groups of the imported yearlings. The two former groups...
Anthelmintic Efficacy of Strongyle Nematodes to Ivermectin and Fenbendazole on Working Donkeys (Equus asinus) in and around Hosaena Town, Southern Ethiopia.
Veterinary medicine international    September 24, 2020   Volume 2020 4868797 doi: 10.1155/2020/4868797
Fesseha H, Mathewos M, Kidanemariam F.Gastrointestinal helminth parasite infection is a major influencing factor against profitability of working equines all over the world. Objective: A study was conducted from October 2016 to May 2017 in and around Hosaena to determine the efficacy of benzimidazole (BZ) and avermectin (AVM) chemical groups against strongyle nematodes in working donkeys. Methods: A total of 230 donkeys from Hosaena, Soro, Anlemo, and Gombora were randomly allocated into 5 groups of 46 donkeys in each group. All groups, except group 1 (control), were treated with ivermectin 1%, ivertong 10%, fenbendazole, and Fena...
Climate change is likely to increase the development rate of anthelmintic resistance in equine cyathostomins in New Zealand.
International journal for parasitology. Drugs and drug resistance    September 17, 2020   Volume 14 73-79 doi: 10.1016/j.ijpddr.2020.09.001
Sauermann CW, Leathwick DM, Lieffering M, Nielsen MK.Climate change is likely to influence livestock production by increasing the prevalence of diseases, including parasites. The traditional practice of controlling nematodes in livestock by the application of anthelmintics is, however, increasingly compromised by the development of resistance to these drugs in parasite populations. This study used a previously developed simulation model of the entire equine cyathostomin lifecycle to investigate the effect a changing climate would have on the development of anthelmintic resistance. Climate data from six General Circulation Models based on four di...
The P-glycoprotein repertoire of the equine parasitic nematode Parascaris univalens.
Scientific reports    August 12, 2020   Volume 10, Issue 1 13586 doi: 10.1038/s41598-020-70529-6
Gerhard AP, Krücken J, Heitlinger E, Janssen IJI, Basiaga M, Kornaś S, Beier C, Nielsen MK, Davis RE, Wang J, von Samson-Himmelstjerna G.P-glycoproteins (Pgp) have been proposed as contributors to the widespread macrocyclic lactone (ML) resistance in several nematode species including a major pathogen of foals, Parascaris univalens. Using new and available RNA-seq data, ten different genomic loci encoding Pgps were identified and characterized by transcriptome-guided RT-PCRs and Sanger sequencing. Phylogenetic analysis revealed an ascarid-specific Pgp lineage, Pgp-18, as well as two paralogues of Pgp-11 and Pgp-16. Comparative gene expression analyses in P. univalens and Caenorhabditis elegans show that the intestine is the maj...
Prevalence of gastrointestinal nematodes, parasite control practices and anthelmintic resistance patterns in a working horse population in Egypt.
Equine veterinary journal    August 11, 2020   Volume 53, Issue 2 339-348 doi: 10.1111/evj.13325
Salem SE, Abd El-Ghany AM, Hamad MH, Abdelaal AM, Elsheikh HA, Hamid AA, Saud MA, Daniels SP, Ras R.Anthelmintic resistance is commonly reported in horse populations in developed countries, but evidence in some working horse populations is either lacking or inconclusive. Objective: To estimate prevalence of GI nematode infections in working horses in Egypt and to evaluate strongyle resistance to ivermectin, doramectin and fenbendazole. Methods: Cross-sectional study. Methods: Faecal egg count was performed on 644 working horses from 2 provinces in Egypt. A short questionnaire about horse signalment and worming history was completed for each horse. Horses identified with ≥50 strongyle type ...
Novel Equine Faecal Egg Diagnostics: Validation of the FECPAKG2.
Animals : an open access journal from MDPI    July 23, 2020   Volume 10, Issue 8 1254 doi: 10.3390/ani10081254
Tyson F, Dalesman S, Brophy PM, Morphew RM.Faecal egg counts (FECs) are the standard method of diagnosing the level of parasitic helminth egg shedding in horses and other grazing animals. Testing before treatment is an important factor in slowing the appearance of anthelmintic resistance in nematode parasites. The FECPAK, optimised for livestock, is reported to allow owners to perform FECs on their own animals without the need for a separate microscope or any specialist knowledge by tapping into remote expertise. However, the performance of the FECPAK has yet to be assessed for equids. Therefore, a comparison of the FECPAK (G2) method ...
Transcriptional responses in Parascaris univalens after in vitro exposure to ivermectin, pyrantel citrate and thiabendazole.
Parasites & vectors    July 9, 2020   Volume 13, Issue 1 342 doi: 10.1186/s13071-020-04212-0
Martin F, Dube F, Karlsson Lindsjö O, Eydal M, Höglund J, Bergström TF, Tydén E.Parascaris univalens is a pathogenic parasite of foals and yearlings worldwide. In recent years, Parascaris spp. worms have developed resistance to several of the commonly used anthelmintics, though currently the mechanisms behind this development are unknown. The aim of this study was to investigate the transcriptional responses in adult P. univalens worms after in vitro exposure to different concentrations of three anthelmintic drugs, focusing on drug targets and drug metabolising pathways. Methods: Adult worms were collected from the intestines of two foals at slaughter. The foals were natu...
Habronematidosis in Equids: Current Status, Advances, Future Challenges.
Frontiers in veterinary science    July 3, 2020   Volume 7 358 doi: 10.3389/fvets.2020.00358
Barlaam A, Traversa D, Papini R, Giangaspero A.Over the past few decades, among equine parasitoses caused by gastrointestinal nematodes, habronematidosis has been discontinuously studied worldwide. Habronematidosis is a parasitic disease distributed all over the world. It is caused by Habronema microstoma, Habronema muscae, and Draschia megastoma (Spirurida, Habronematidae), and it is maintained in the environment by muscid flies which act as intermediate hosts. At larval and adult stages these species live in the stomach of domestic and wild equids. However, the larvae can also be found on the skin, causing lesions known as "summer sores"...
A survey of ivermectin resistance in Parascaris species infected foals in south-eastern Poland.
Acta veterinaria Scandinavica    June 5, 2020   Volume 62, Issue 1 28 doi: 10.1186/s13028-020-00526-2
Studzińska MB, Sallé G, Roczeń-Karczmarz M, Szczepaniak K, Demkowska-Kutrzepa M, Tomczuk K.Parascaris spp. are major gastro-intestinal nematodes that infect foals and can lead to respiratory symptoms, poor growth, and in some cases obstruction of the small intestine and death. Ivermectin resistance has been reported for Parascaris spp. in many countries. In Poland, the knowledge of the level of resistance against ivermectin in Parascaris spp. is limited. The aim of this study was to examine the efficacy of ivermectin against Parascaris spp. in foals from south-eastern Poland. Foals (n = 225 = reared in 7 stud farms) were treated orally with ivermectin paste. Faecal samples w...
Time to ‘think smart’ on anthelmintic use.
The Veterinary record    March 22, 2020   Volume 186, Issue 11 338 doi: 10.1136/vr.m1125
No abstract available
Anthelmintic resistance in strongylids (Nematoda: Strongylidae) parasitizing wild and domestic equids in the Askania Nova Biosphere Reserve, Ukraine.
Annals of parasitology    March 22, 2020   Volume 66, Issue 1 49–60 doi: 10.17420/ap6601.237
Kuzmina ТА, Zvegintsova NS, Yasynetska NI, Kharchenko VA.Resistance of strongylids in domestic horses to benzimidazole anthelmintics (BZ) has been detected worldwide; however, information on the presence of BZ-resistance in wild equids has not been published to date. The purpose of this study was to analyze the manifestations of the BZ resistance in strongylids in domestic and wild equids kept in the Askania Nova Biosphere Reserve, Ukraine. Four species of equids: domestic horses and Shetland ponies (Equus caballus), donkeys (E. asinus), plains zebras (E. burchelli) and Grévy’s zebras (E. grevyi) kept under semi-free conditions were examined usin...
Reduced efficacy of ivermectin and moxidectin against Parascaris spp. in foals from Argentina.
Veterinary parasitology, regional studies and reports    February 20, 2020   Volume 20 100388 doi: 10.1016/j.vprsr.2020.100388
Cooper LG, Caffe G, Cerutti J, Nielsen MK, Anziani OS.Macrocyclic lactones are the most widely used drugs for the control of gastrointestinal nematodes of horses in Argentina. Ivermectin and moxidectin are used as broad spectrum anthelmintics and although there are several international reports on the resistance of Parascaris spp., the resistance status of the local nematode population is largely unknow. This report informs a case of suboptimal efficacy to both drugs to control Parascaris spp in foals in central Argentina. In February 2018, routine fecal parasite egg counts showed a moderate-high number of Parascaris spp eggs (mean = 680 eggs p...
Eficacy of ivermectin, moxidectin and febendazole in equine in Brazil.
Veterinary parasitology, regional studies and reports    February 19, 2020   Volume 20 100374 doi: 10.1016/j.vprsr.2020.100374
Vera JHS, Fachiolli DF, Ramires LM, de Lima Saes I, Yamada PH, Gonçalves JA, de Oliveira K, do Amarante AFT, de Soutello RVG.The objectives of the present study were to evaluate the efficacy of three anthelmintic drugs, i.e. fenbendazole, ivermectin and moxidectin; to determine the genera and species of the most abundant strongyles; and to investigate parasite control measures used in herds of horses in the western region of the state of São Paulo, Brazil. This study was onducted between February and December 2013 on 10 farms in this region. Coprological evaluations were conducted for counting the numbers of eggs per gram of feces (EPG) and coprocultures were made in order to identify third-stage larvae (L3) of str...
Ascarids exposed: a method for in vitro drug exposure and gene expression analysis of anthelmintic naïve Parascaris spp.
Parasitology    February 12, 2020   Volume 147, Issue 6 659-666 doi: 10.1017/S0031182020000189
Scare JA, Dini P, Norris JK, Steuer AE, Scoggin K, Gravatte HS, Howe DK, Slusarewicz P, Nielsen MK.Ascarid parasites infect a variety of hosts and regular anthelmintic treatment is recommended for all species. Parascaris spp. is the only ascarid species with widespread anthelmintic resistance, which allows for the study of resistance mechanisms. The purpose of this study was to establish an in vitro drug exposure protocol for adult anthelmintic-naïve Parascaris spp. and report a preliminary transcriptomic analysis in response to drug exposure. Live worms were harvested from foal necropsies and maintained in RPMI-1640 at 37 °C. Serial dilutions of oxibendazole (OBZ) and ivermectin (IVM) we...
A questionnaire study of parasite control in Thoroughbred and Standardbred horses in Australia.
Equine veterinary journal    February 7, 2020   Volume 52, Issue 4 547-555 doi: 10.1111/evj.13207
Wilkes EJA, Heller J, Raidal SL, Woodgate RG, Hughes KJ.Information regarding parasite control practices currently used on Thoroughbred and Standardbred studs in Australia is lacking. Anthelmintic resistance (AR) is a global problem which has implications for equine health and welfare. Objective: To identify parasite control practices currently used on horse studs in Australia and investigate the frequency of use of management factors that have been associated with the likelihood of promoting or delaying AR. Methods: Questionnaire study of equine parasite control on Thoroughbred and Standardbred studs in Australia. Methods: An online questionnaire ...
Not playing by the rules: Unusual patterns in the epidemiology of parasites in a natural population of feral horses (Equus caballus) on Sable Island, Canada.
International journal for parasitology. Parasites and wildlife    February 5, 2020   Volume 11 183-190 doi: 10.1016/j.ijppaw.2020.02.002
Jenkins E, Backwell AL, Bellaw J, Colpitts J, Liboiron A, McRuer D, Medill S, Parker S, Shury T, Smith M, Tschritter C, Wagner B, Poissant J....Sable Island, Nova Scotia, Canada hosts one of few natural populations of feral horses (Equus caballus) never exposed to anthelmintics. Coproculture revealed cyathostomes, Strongylus equinus, S. edentatus, and S. vulgaris, with S. equinus (unusually) dominating in adult horses and cyathostomes dominating in young horses (<3 years of age). We examined 35 horses found dead in the springs of 2017 and 2018, as well as fecal samples from live horses in spring (n = 45) and summer 2018 (n = 236) using McMaster fecal flotation and Baermann larval sedimentation on fresh samples, and modified Wiscon...
Drug Efficacy of Ivermectin Against Primary Nematodes Parasitizing Captive Przewalski’s Horse (Equus Ferus Przewalskii) after Ten Years of Annually Treatment.
Helminthologia    January 25, 2020   Volume 57, Issue 1 57-62 doi: 10.2478/helm-2020-0004
Tang L, Xiu Y, Yan L, Cui Y, Ma X, Ente M, Zhang Y, Li K, Zhang D.Reintroduction of endangered species to natural habitat is considered as an important tool for conservation. The effect of drug management on captive population of reintroduced species is largely neglected. Decreased drug efficacy could pose a substantial threat to health of animals. More importantly, captive population without proper drug administration could act as transmission medium of resistance nematodes to wild population, making it important to delay the occurrence of drug resistance in captive population. Ivermectin have been used in captive Przewalski's horse () to eradicate intestin...
Evaluation of a Marketed Polyherbal Dewormer Against Intestinal Strongyles in Naturally Infected Donkeys.
Helminthologia    January 25, 2020   Volume 57, Issue 1 78-82 doi: 10.2478/helm-2020-0003
The study evaluated the effectiveness of a commercially available polyherbal dewormer to control intestinal strongyles in naturally infected donkeys. The animals were allotted to two groups: treated with the herbal dewormer (n=8) according to manufacturer recommendations and untreated control group (n=6). Fecal samples were taken from each animal on days 0 (day of treatment), 14, 21 (day of second additional treatment), 35, and 42. Faecal egg count reduction tests showed very negligible or no reduction in number of strongyle eggs for donkeys in the phytotherapeutic treatment group compared to ...
Dealing with double trouble: Combination deworming against double-drug resistant cyathostomins.
International journal for parasitology. Drugs and drug resistance    December 16, 2019   Volume 12 28-34 doi: 10.1016/j.ijpddr.2019.12.002
Scare JA, Leathwick DM, Sauermann CW, Lyons ET, Steuer AE, Jones BA, Clark M, Nielsen MK.An alternative control regimen for drug-resistant parasites is combination deworming, where two drugs with different modes of action are administered simultaneously to target the same parasite. Few studies have investigated this in equine cyathostomins. We previously reported that an oxibendazole (OBZ) and pyrantel pamoate (PYR) combination was not sustainable against a cyathostomin population with high levels of OBZ and PYR resistance. This study consisted of a field study and two computer simulations to evaluate the efficacy of a moxidectin-oxibendazole (MOX-OBZ) combination against the same...
Horses grazing with cattle have reduced strongyle egg count due to the dilution effect and increased reliance on macrocyclic lactones in mixed farms.
Animal : an international journal of animal bioscience    November 4, 2019   Volume 14, Issue 5 1076-1082 doi: 10.1017/S1751731119002738
Forteau L, Dumont B, Sallé G, Bigot G, Fleurance G.Strongyle infection is an important issue in horse breeding. It impairs horse health and performance, with young horses being the most sensitive. Strongyle control has long relied on the systematic use of chemical treatments. However, expanding anthelmintic resistance among strongyles calls for alternative options. Mixed grazing is assumed to reduce strongyle load on the pasture as the result of a dilution effect. This has been shown in small ruminants grazing with cattle, but the putative benefits of co-grazing between horses and cattle have not yet been evaluated. Here, we conducted field su...
Fatal Peritoneal Migration of Strongylus edentatus in a Foal.
Journal of comparative pathology    October 18, 2019   Volume 172 88-92 doi: 10.1016/j.jcpa.2019.09.004
Gonzales-Viera O, Fritz H, Mete A.A 7-month-old female mixed breed foal with a 2-day history of recumbency and inability to open its mouth convulsed acutely and died and was submitted for necropsy examination. The foal was thin and large patches of haemorrhage were present throughout the peritoneal wall, the diaphragmatic surfaces and the retroperitoneum. Numerous nematode larvae were visible on the serosal surfaces and penetrated and embedded into the subserosa associated with the haemorrhages. The dorsal portion of the abdominal diaphragm had a partial tear and large numbers of nematodes were within the muscle fibres. Histol...
Pixel by pixel: real-time observation and quantification of passive flotation speeds of three common equine endoparasite egg types.
International journal for parasitology    September 20, 2019   Volume 49, Issue 11 885-892 doi: 10.1016/j.ijpara.2019.06.004
Norris JK, Slusarewicz P, Nielsen MK.The efficacy of anthelmintic treatments against populations of endoparasites infecting livestock throughout the world is decreasing. To mitigate this, the use of fecal egg counts is recommended to determine both the necessity, and to ensure the appropriate choice, of anthelmintic treatment. Traditionally, and in order to facilitate easier identification and/or enumeration, samples are analysed after separating eggs from other fecal particulates by exposing them to a solution with a density higher than that of the eggs, but lower than the remaining fecal contents. While many parasite egg flotat...
A survey of the level of horse owner uptake of evidence-based anthelmintic treatment protocols for equine helminth control in the UK.
Veterinary parasitology    September 19, 2019   Volume 274 108926 doi: 10.1016/j.vetpar.2019.108926
Tzelos T, Morgan ER, Easton S, Hodgkinson JE, Matthews JB.Interval treatment control programmes used widely in equine helminth control have favoured the development of anthelmintic resistance worldwide. Best practice guidelines have been designed to address resistance and include the requirement for improved pasture hygiene to break helminth transmission cycles, along with anthelmintic application informed by the results of diagnostic tests to reduce selection pressure for resistance. Using an online questionnaire, this study examined uptake of measures recommended in these guidelines by UK horse owners. The survey comprised 58 questions spanning gra...
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