Validation, visibility, vagueness and variation: A qualitative assessment of existing veterinary guidelines for antimicrobial use in cattle and sheep in the UK.

Antimicrobials are essential in veterinary medicine to treat and control bacterial disease in animals. Their prudent use in food-producing animals has been encouraged to reduce the development and spread of antimicrobial resistance. National and international guidelines for responsible antimicrobial use have been developed as tools to guide and rationalise antimicrobial prescribing decisions by veterinarians and usage decisions by farmers. Yet, there is little understanding of whether these existing guidelines are fit for purpose. Accordingly, this study rigorously assessed 128 veterinary guidelines for antimicrobial use in ruminants in the UK, following established qualitative methodologies. Findings revealed four pertinent themes: validation of the veterinarian as the prescriber, visibility of responsible use realities, vagueness in interpretation and variation in directing behaviour. These themes encompassed the roles and responsibilities of the veterinarian and the realities of prescribing scenarios, alongside concerns relating to the specificity within and variation between guidelines. Resultant recommendations to inform and support the future development of guidelines include establishing species-specific and disease-specific guidelines, expanding guidelines to include disease prevention measures, including definitions to resolve vagueness and promoting congruence in interpretation, encouraging the development of practice-level guidelines to endorse collaboration and ownership, and fostering active working between stakeholders to align priorities and messaging.

Designing a National Veterinary Prescribing Champion Programme for Welsh Veterinary Practices: The Arwain Vet Cymru Project.

Antimicrobial use in agriculture has been identified as an area of focus for reducing overall antimicrobial use and improving stewardship. In this paper, we outline the design of a complex antimicrobial stewardship (AMS) intervention aimed at developing a national Veterinary Prescribing Champion programme for Welsh farm animal veterinary practices. We describe the process by which participants were encouraged to design and deliver bespoke individualised AMS activities at practice level by forging participant "champion" identities and communities of practice through participatory and educational online activities. We describe the key phases identified as important when designing this complex intervention, namely (i) involving key collaborators in government and industry to stimulate project engagement; (ii) grounding the design in the literature, the results of stakeholder engagement, expert panel input, and veterinary clinician feedback to promote contextual relevance and appropriateness; and (iii) taking a theoretical approach to implementing intervention design to foster critical psychological needs for participant motivation and scheme involvement. With recruitment of over 80% of all farm animal practices in Wales to the programme, we also describe demographic data of the participating Welsh Veterinary Prescribing Champions in order to inform recruitment and design of future AMS programmes.

Reduced Antibacterial Drug Resistance and blaCTX-M ß-Lactamase Gene Carriage in Cattle-Associated Escherichia coli at Low Temperatures, at Sites Dominated by Older Animals, and on Pastureland: Implications for Surveillance.

Little is known about the drivers of critically important antibacterial resistance in species with zoonotic potential present on farms (e.g., CTX-M ß-lactamase-positive Escherichia coli). We collected samples monthly between January 2017 and December 2018 on 53 dairy farms in South West England, along with data for 610 variables concerning antibacterial usage, management practices, and meteorological factors. We detected E. coli resistant to amoxicillin, ciprofloxacin, streptomycin, and tetracycline in 2,754/4,145 (66%), 263/4,145 (6%), 1,475/4,145 (36%), and 2,874/4,145 (69%), respectively, of samples from fecally contaminated on-farm and near-farm sites. E. coli positive for blaCTX-M were detected in 224/4,145 (5.4%) of samples. Multilevel, multivariable logistic regression showed antibacterial dry cow therapeutic choice (including use of cefquinome or framycetin) to be associated with higher odds of blaCTX-M positivity. Low average monthly ambient temperature was associated with lower odds of blaCTX-ME. coli positivity in samples and with lower odds of finding E. coli resistant to each of the four test antibacterials. This was in addition to the effect of temperature on total E. coli density. Furthermore, samples collected close to calves had higher odds of having E. coli resistant to each antibacterial, as well as E. coli positive for blaCTX-M Samples collected on pastureland had lower odds of having E. coli resistant to amoxicillin or tetracycline, as well as lower odds of being positive for blaCTX-MIMPORTANCE Antibacterial resistance poses a significant threat to human and animal health and global food security. Surveillance for resistance on farms is important for many reasons, including tracking impacts of interventions aimed at reducing the prevalence of resistance. In this longitudinal survey of dairy farm antibacterial resistance, we showed that local temperature-as it changes over the course of a year-was associated with the prevalence of antibacterial-resistant E. coli We also showed that prevalence of resistant E. coli was lower on pastureland and higher in environments inhabited by young animals. These findings have profound implications for routine surveillance and for surveys carried out for research. They provide important evidence that sampling at a single time point and/or single location on a farm is unlikely to be adequate to accurately determine the status of the farm regarding the presence of samples containing resistant E. coli.

Veterinary Diagnostic Practice and the Use of Rapid Tests in Antimicrobial Stewardship on UK Livestock Farms.

In this paper we consider the shifting role, practice and context of veterinary diagnosis in addressing concerns over what is, in the context of the growing threat of antimicrobial resistance, considered unnecessary or excessive antimicrobial medicine use in UK livestock farms. With increasing policy and regulatory interest in diagnostic practices and technologies, coupled with an expanding focus on the development and deployment of new rapid and point-of-care on-farm diagnostic testing, this paper investigates current diagnostic practices amongst veterinarians working on dairy, pig and poultry farms in Great Britain (England, Wales, and Scotland) and, more specifically, veterinarians' use and perceptions of new and emerging rapid and point-of-care diagnostic tests. Drawing on a series of 30 semi-structured interviews with farm animal veterinary professionals across the three sectors, this paper examines the manner in which such tests are both used and anticipated in clinical farm animal veterinary practice and the possible impact rapid test technologies might have on broader farm animal health management and disease control. Analysis of the transcribed interviews reveals a number of complexities around the use of rapid and point-of-care diagnostic tests. The relative rapidity and simplification of such tests, facilitating immediate treatment responses, is held in balance against both the accuracy and the more detailed and documented procedures of established laboratory testing routes. In situations of multifaceted on-farm etiologies, respondents maintained that rapid tests may offer restricted diagnostic capabilities, though in other situations they were found to offer ready confirmation of disease presence. A third complexity arising from the growth of rapid and point-of-care testing and revealed in this study relates to the shifting distribution of responsibilities in animal health care within contemporary food chains. The growing availability of rapid and point-of-care tests effectively diversifies the range of diagnostic actors with consequences for the flow of diagnostic and disease information. The veterinarians in this study identified areas where new rapid and point-of-care tests would be of particular value to them in their clinical practice particularly in addressing concerns over inappropriate antimicrobial use in animal treatment. However, despite the considerable policy advocacy on rapid and point-of-care tests as key tools in shifting diagnostic practice and reducing unnecessary antimicrobial use, veterinarians in this study, while recognizing the potential future role of such tools and technologies, nonetheless viewed diagnostic practice as a far more complex process for which rapid tests might constitute only a part.

Diagnostics and the challenge of antimicrobial resistance: a survey of UK livestock veterinarians' perceptions and practices.

BACKGROUND: This paper explores the current role and place of diagnostic tests in the treatment of farm animal disease. With the growing focus on reduced reliance on antibiotic medicines in both animal and human patient care, attention is increasingly being focused on the practice, the technology and the function of diagnostic tests and how these can support responsible antimicrobial use. Emerging diagnostic technologies offer the possibility of more rapid testing for bacterial disease, while food chain actors and others are increasingly seeking to make diagnostic tests mandatory before the use of critically important antibiotics. METHOD: This paper reports the findings of a recent large-scale online survey of UK farm animal veterinarians (n=153) which investigated current veterinary diagnostic practice with particular attention to the relationship between diagnostic test use and antibiotic treatment. RESULTS: Results revealed a range of factors that influence veterinary diagnostic practice and demonstrate the continuing importance of clinical observation and animal/herd knowledge in the selection of antibiotic treatment. CONCLUSION: The findings identify a considerable ambivalence on the part of farm animal veterinarians regarding the current and future uses of rapid and point-of-care diagnostic tests as a means of improving clinical diagnosis and addressing inappropriate antibiotic medicine use.

Storage of prescription veterinary medicines on UK dairy farms: a cross-sectional study.

Prescription veterinary medicine (PVM) use in the UK is an area of increasing focus for the veterinary profession. While many studies measure antimicrobial use on dairy farms, none report the quantity of antimicrobials stored on farms, nor the ways in which they are stored. The majority of PVM treatments occur in the absence of the prescribing veterinarian, yet there is an identifiable knowledge gap surrounding PVM use and farmer decision making. To provide an evidence base for future work on PVM use, data were collected from 27 dairy farms in England and Wales in Autumn 2016. The number of different PVMs stored on farms ranged from 9 to 35, with antimicrobials being the most common therapeutic group stored. Injectable antimicrobials comprised the greatest weight of active ingredient found, while intramammary antimicrobials were the most frequent unit of medicine stored. Antimicrobials classed by the European Medicines Agency as critically important to human health were present on most farms, and the presence of expired medicines and medicines not licensed for use in dairy cattle was also common. The medicine resources available to farmers are likely to influence their treatment decisions; therefore, evidence of the PVM stored on farms can help inform understanding of medicine use.

Evaluation of metrics for benchmarking antimicrobial use in the UK dairy industry.

The issue of antimicrobial resistance is of global concern across human and animal health. In 2016, the UK government committed to new targets for reducing antimicrobial use (AMU) in livestock. Although a number of metrics for quantifying AMU are defined in the literature, all give slightly different interpretations. This paper evaluates a selection of metrics for AMU in the dairy industry: total mg, total mg/kg, daily dose and daily course metrics. Although the focus is on their application to the dairy industry, the metrics and issues discussed are relevant across livestock sectors. In order to be used widely, a metric should be understandable and relevant to the veterinarians and farmers who are prescribing and using antimicrobials. This means that clear methods, assumptions (and possible biases), standardised values and exceptions should be published for all metrics. Particularly relevant are assumptions around the number and weight of cattle at risk of treatment and definitions of dose rates and course lengths; incorrect assumptions can mean metrics over-represent or under-represent AMU. The authors recommend that the UK dairy industry work towards the UK-specific metrics using the UK-specific medicine dose and course regimens as well as cattle weights in order to monitor trends nationally.

Does inclusion of glutamine in oral rehydration solutions improve recovery from mild to moderate diarrhoea in preweaned calves?

Critically Appraised Topics (CATs) are a standardised, succinct summary of research evidence organised around a clinical question, and a form of evidence synthesis used in the practice of evidence-based medicine (EBM) and evidence-based veterinary medicine (EBVM). Access to CATs enables clinicians to incorporate evidence from the scientific literature into clinical practice and they have been used to teach EBVM at the University of Bristol's School of Veterinary Sciences since 2011. Veterinary Record is including CATs from Bristol university in its Clinical Decision Making section. The first of these, along with an explanation of how they can be used, was published in VR, January 30, 2016, vol 178, pp 118-119.

Germline minisatellite mutations in workers occupationally exposed to radiation at the Sellafield nuclear facility.

Germline minisatellite mutation rates were investigated in male workers occupationally exposed to radiation at the Sellafield nuclear facility. DNA samples from 160 families with 255 offspring were analysed for mutations at eight hypervariable minisatellite loci (B6.7, CEB1, CEB15, CEB25, CEB36, MS1, MS31, MS32) by Southern hybridisation. No significant difference was observed between the paternal mutation rate of 5.0% (37 mutations in 736 alleles) for control fathers with a mean preconceptional testicular dose of 9 mSv and that of 5.8% (66 in 1137 alleles) for exposed fathers with a mean preconceptional testicular dose of 194 mSv. Subgrouping the exposed fathers into two dose groups with means of 111 mSv and 274 mSv revealed paternal mutation rates of 6.0% (32 mutations in 536 alleles) and 5.7% (34 mutations in 601 alleles), respectively, neither of which was significantly different in comparisons with the rate for the control fathers. Maternal mutation rates of 1.6% (12 mutations in 742 alleles) for the partners of control fathers and 1.7% (19 mutations in 1133 alleles) for partners of exposed fathers were not significantly different. This study provides evidence that paternal preconceptional occupational radiation exposure does not increase the germline minisatellite mutation rate and therefore refutes suggestions that such exposure could result in a destabilisation of the germline that can be passed on to future generations.

Germline minisatellite mutations in survivors of childhood and young adult cancer treated with radiation.

PURPOSE: To investigate minisatellite germline mutation rates in survivors of childhood and young adult cancer who received radiotherapy. MATERIALS AND METHODS: DNA samples from 100 families, where one parent was a cancer survivor, were analysed for mutations at eight hypervariable minisatellite loci (B6.7, CEB1, CEB15, CEB25, CEB36, MS1, MS31, MS32) by Southern hybridisation. RESULTS: No significant difference was observed between the paternal mutation rate of 5.6% in exposed fathers with a mean preconceptional testicular dose of 1.23 Gy (56 mutations in 998 informative alleles) and that of 5.8% in unexposed fathers (17 in 295 informative alleles). Subgrouping the exposed fathers into dose groups of < 0.10 Gy, 0.10-0.99 Gy, 1.00-1.99 Gy, ≥ 2.00 Gy revealed no significant differences in paternal mutation rate in comparison with the unexposed fathers. Maternal mutation rates of 1.6% in cancer survivor mothers with a mean preconceptional ovarian dose of 0.58 Gy (five mutations in 304 informative alleles) and 2.1% in unexposed mothers (21 in 987 informative alleles) were not significantly different. There were no differences in minisatellite mutation rates associated with treatment with chemotherapeutic agents. CONCLUSIONS: This study provides evidence that preconception radiotherapy for childhood or early adulthood cancer does not increase the germline minisatellite mutation rate.

The heritability of G2 chromosomal radiosensitivity and its association with cancer in Danish cancer survivors and their offspring.

PURPOSE: To investigate the relationship between chromosomal radiosensitivity and early-onset cancer under the age of 35 years and to examine the heritability of chromosomal radiosensitivity. MATERIALS AND METHODS: Peripheral blood lymphocytes were cultured for 72 hours prior to being irradiated with 0.5 Gy, 300 kV X-rays. Colcemid was added to cultures 30 min post-irradiation. Cultures were harvested 90 min post-irradiation and analysed for chromatid gaps and breaks. Heritability was estimated using Sequential Oligogenic Linkage Analysis Routines (SOLAR) software and by segregation analysis. RESULTS: Elevated radiosensitivity was seen for seven out of 29 (24.1%) cancer survivors, three out of 29 (10.3%) partners and 10 out of 53 (20.8%) offspring. Although the proportion of individuals displaying enhanced radiosensitivity was twice as high in both the cancer survivor and offspring groups than the partner controls, neither reached statistical significance. Heritability analysis of the radiosensitive phenotype suggested 57.9-78.0% of the variance could be attributed to genetic factors. CONCLUSION: An association between G(2) chromosomal radiosensitivity and childhood and young adult cancer is suggested but was not statistically significant. In contrast, there is strong evidence for heritability of the radiosensitive phenotype. The cancer survivors included a broad range of malignancies and future studies should focus on specific cancers with known or likely faults in deoxyribonucleic acid (DNA) damage recognition and repair mechanisms.

Comparison of germ line minisatellite mutation detection at the CEB1 locus by Southern blotting and PCR amplification.

Identification of de novo minisatellite mutations in the offspring of parents exposed to mutagenic agents offers a potentially sensitive measure of germ line genetic events induced by ionizing radiation and genotoxic chemicals. Germ line minisatellite mutations (GMM) are usually detected by hybridizing Southern blots of unamplified size-fractionated genomic DNA with minisatellite probes. However, this consumes a relatively large amount of DNA, requires several steps and may lack sensitivity. We have developed a polymerase chain reaction (PCR)-based GMM assay, which we applied to the hypermutable minisatellite, CEB1. Here, we compare the sensitivity and specificity of this assay with the conventional Southern hybridization method using DNA from 10 spouse pairs, one parent of each pair being a survivor of cancer in childhood, and their 20 offspring. We report that both methods have similar specificity but that the PCR method uses 250 times less DNA, has fewer steps and is better at detecting GMM with single repeats provided that specific guidelines for allele sizing are followed. The PCR GMM method is easier to apply to families where the amount of offspring DNA sample is limited.

Can clinicians use the PHQ-9 to assess depression in people with vision loss?

PURPOSE: To investigate whether the Patient Health Questionnaire-9 (PHQ-9) possesses the essential psychometric characteristics to measure depressive symptoms in people with visual impairment. METHODS: The PHQ-9 scale was completed by 103 participants with low vision. These data were then assessed for fit to the Rasch model. RESULTS: The participants' mean +/- standard deviation (SD) age was 74.7 +/- 12.2 years. Almost one half of them (n = 46; 44.7%) were considered to have severe vision impairment (presenting visual acuity <6/60 in the better eye). Disordered thresholds were evident initially. Collapsing the two middle categories produced ordered thresholds and fit to the Rasch model (chi = 10.1; degrees of freedom = 9; p = 0.34). The mean (SD) items and persons Fit Residual values were -0.31 (1.12) and -0.25 (0.78), respectively, where optimal fit of data to the Rasch model would have a mean = 0 and SD = 1. Unidimensionality was demonstrated confirming the construct validity of the PHQ-9 and there was no evidence of differential item functioning on a number of factors including visual disability. The person separation reliability value was 0.80 indicating that the PHQ-9 has satisfactory precision. There was a degree of mistargeting as expected in this largely non-clinically depressed sample. CONCLUSIONS: Our findings demonstrate that the PHQ-9, when scaled with Rasch analysis, forms a linear interval measurement of depressive symptoms suitable for use in a vision impaired population.

A pilot study examining germline minisatellite mutations in the offspring of Danish childhood and adolescent cancer survivors treated with radiotherapy.

PURPOSE: To investigate germline mutation rate at eight minisatellite loci in 24 Danish families, where one parent is the survivor of childhood or adolescent cancer treated with radiotherapy. MATERIALS AND METHODS: Parents and offspring were profiled for eight hypervariable minisatellite loci (B6.7, CEB1, CEB15, CEB25, CEB36, MS1, MS31, MS32) by Southern blotting. RESULTS: Seven paternal mutations were observed for 130 informative alleles in 18 offspring from 11 radiation-exposed fathers (mean preconceptional dose for offspring 0.29 Gy, range<0.01-1.2 Gy), compared to six mutations for 146 informative alleles in 21 offspring from 13 unexposed fathers. No statistically significant difference between the total paternal mutation rates was observed (5.4% for exposed fathers and 4.1% for unexposed fathers). Three maternal mutations were observed for 148 informative alleles in 21 offspring from 13 radiation-exposed mothers (mean preconceptional dose for offspring 0.71 Gy, range <0.01-9.2 Gy), compared to one mutation for 130 informative alleles in 18 offspring from 11 unexposed mothers. Again, no statistically significant difference was observed between the total maternal mutation rates (2.0% for exposed mothers and 0.8% for unexposed mothers). CONCLUSIONS: The data from this pilot study demonstrate no statistically significant increase in germline minisatellite mutation rate associated with radiotherapy for childhood and adolescent cancer.

Chromosome analysis in childhood cancer survivors and their offspring--no evidence for radiotherapy-induced persistent genomic instability.

Suggestions that the induction of genomic instability could play a role in radiation-induced carcinogenesis and heritable disease prompted the investigation of chromosome instability in relation to radiotherapy for childhood cancer. Chromosome analysis of peripheral blood lymphocytes at their first in vitro division was undertaken on 25 adult survivors of childhood cancer treated with radiation, 26 partners who acted as the non-irradiated control group and 43 offspring. A statistically significant increase in the frequency of dicentrics in the cancer survivor group compared with the partner control group was attributed to the residual effect of past radiation therapy. However, chromatid aberrations plus chromosome gaps, the aberrations most associated with persistent instability, were not increased. Therefore, there was no evidence that irradiation of the bone marrow had resulted in instability being transmitted to descendant cells. Frequencies of all aberration categories were significantly lower in the offspring group, compared to the partner group, apart from dicentrics for which the decrease did not reach statistical significance. The lower frequencies in the offspring provide no indication of transmissible instability being passed through the germline to the somatic cells of the offspring. Thus, in this study, genomic instability was not associated with radiotherapy in those who had received such treatment, nor was it found to be a transgenerational radiation effect.

DNA repair gene polymorphisms in relation to chromosome aberration frequencies in retired radiation workers.

Polymorphic variation in DNA repair genes was examined in a group of retired workers from the British Nuclear Fuels plc facility at Sellafield in relation to previously determined translocation frequencies in peripheral blood lymphocytes. Variation at seven polymorphisms in four genes involved in the base excision repair (XRCC1 R194W, R399Q and a [AC]n microsatellite in the 3' UTR) and double strand break repair (XRCC3 T241M and a [AC]n microsatellite in intron 3 of XRCC3, XRCC4 I134T, and a GACTAn microsatellite located 120 kb 5' of XRCC5) pathways was determined for 291 retired radiation workers who had received cumulative occupational external radiation doses of between 0 and 1873 mSv. When the interaction between radiation dose and each DNA repair gene polymorphism was examined in relation to translocation frequency there was no evidence for any of the polymorphisms studied influencing the response to occupational exposure. A positive interaction observed between genotype (individuals with at least one allele > or =20 repeat units) at a microsatellite locus in the XRCC3 gene and smoking status should be interpreted cautiously because interactions were investigated for seven polymorphisms and two exposures. Nonetheless, further research is warranted to examine whether this DNA repair gene variant might be associated with a sub-optimal repair response to smoking-induced DNA damage and hence an increased frequency of translocations.