A multinational survey of companion animal veterinary clinicians: How can antimicrobial stewardship guidelines be optimised for the target stakeholder?

Antimicrobial stewardship initiatives are widely regarded as a cornerstone for ameliorating the global health impact of antimicrobial resistance. Within companion animal health, such efforts have largely focused on development and dissemination of antimicrobial stewardship guidelines (ASGs). However, there have been few attempts to understand veterinarian attitudes towards and knowledge of ASGs or to determine how awareness regarding ASGs might best be increased. An online survey regarding ASGs was formulated for veterinarians who treat companion animals. The survey was distributed across 46 European and associated countries between 12 January and 30 June, 2022. In total, 2271 surveys were completed, with 64.9% of respondents (n = 1474) reporting awareness and usage of at least one ASG. Respondents from countries with greater awareness of ASGs tended to report more appropriate use of antimicrobials (Spearman's rank coefficient = 0.6084, P ≤ 0.001), with respondents from countries with country-specific ASGs tending to score highest across both awareness and appropriate use domains. Respondents prioritised guidance around antimicrobial choice (82.0%, n = 1863), duration of treatment (66.0%, n = 1499), and dosage (51.9%, n = 1179) for inclusion in future ASGs, with 78.0% (n = 1776) of respondents preferring ASGs to be integrated into their patient management system. Awareness of ASGs and their use in companion animal veterinary practice appears to be greater than previously reported, with respondents tending to report antimicrobial prescription decision making broadly in line with current clinical recommendations. However, further initiatives aimed at maximising accessibility to ASGs both within countries and individual veterinary practices are recommended.

The effect of antibiotic versus no treatment at dry-off on udder health and milk yield in subsequent lactation: A retrospective analysis of Austrian health recording data from dairy herds.

Bovine mastitis is the most commonly diagnosed disease of dairy cows worldwide and causes extensive economic losses to milk producers. Intramammary infection status before dry-off plays a decisive role with respect to udder health and milk yield in the subsequent lactation. The aim of this study was to compare the effect of antibiotic dry cow therapy (DCT) versus no treatment at dry-off on milk yield, somatic cell count (SCC), inflammation of the mammary gland (IMG), and the incidence of clinical mastitis in the subsequent lactation. Dairy herd data from 251 Austrian dairy farms were recorded over an observation period of 12 mo and subsequently analyzed. The data set included 5,018 dairy cows: 2,078 were treated with antibiotics (abDCT group) and 2,940 were not treated (noDCT group) at dry-off. The abDCT group was subdivided, based on the antimicrobial active substances used for drying off, into 4 different groups (penicillins, cloxacillin, cephalosporins, and rifaximin). Based on bacteriological culture results, infections were grouped into those caused by major, minor, and other pathogens. Additionally, the IMG was defined via SCC from milk recording data using a cutoff of 200,000 cells/mL before drying off and after calving. The incidence of clinical mastitis cases within 30 and 90 d in milk was calculated using veterinary diagnosis data. To investigate the effect of different dry cow therapies on the following parameters: milk yield, SCC, and diagnosed clinical mastitis cases, different linear mixed models were constructed. Overall, the abDCT group was determined to have a significantly higher milk yield over 305 d in milk in the subsequent lactation (increase of 6.18%), compared with the noDCT group (increase of 4.29%). Both groups (abDCT and noDCT) demonstrated a decrease in the first SCC after calving compared with the SCC before dry-off, although the treated cows had a significantly higher reduction. Regarding the different antibiotic groups, with exception of the rifaximin treated cows, all antibiotic groups showed a significant difference from not treated cows with respect to SCC. Additionally, we were able to demonstrate that cows with IMG before dry-off had a 2.073 times higher chance of an increased SCC (>200,000 cells/mL) after calving. With respect to the veterinary diagnosis data, neither the IMG before drying off nor the type of DCT had a significant influence on the probability of developing clinical mastitis within 30 or 90 d in milk. Only a small number of treatments was accompanied with a bacteriological examination before drying off. However, the existing data in this study indicates that the intramammary infection status before dry-off in combination with different dry cow treatments influences udder health and milk yield after calving. Nevertheless, further studies with larger data sets of bacteriological examinations are necessary to enable a more in-depth investigation into the effects of different antibiotic substances used for DCT.

Usability of bacteriological milk analyses for genetic improvement of udder health in Austrian Fleckvieh cows.

In addition to somatic cell count records and clinical mastitis diagnoses, results of bacteriological milk analyses provide valuable information regarding udder health. The pathogen causing an udder infection is currently not considered in Austria as part of the information used for estimation of routine breeding values for mastitis resistance. Therefore the objective of this study was to estimate heritabilities for, and genetic correlations between, udder traits of bacterial infection (bacterial infection, gram-positive and gram-negative bacterial infection) and routinely recorded udder health traits [acute mastitis, chronic mastitis, culling due to udder health problems, and somatic cell score (SCS)] in Austrian Fleckvieh cows. The basis for the genetic analyses was a data set with results from bacteriological milk analyses collected from 237 dairy farms and 6,822 cows over a period of 1 yr. Traits were defined as binary, apart from SCS, for which measures were available continuously. Multivariate analyses using a linear animal model were applied for estimating genetic parameters. The heritabilities for the occurrence of bacterial udder infection traits were 0.01. Heritabilities were 0.04 for acute mastitis, 0.02 for chronic mastitis, 0.02 for culling due to udder health problems, and 0.20 for SCS. Genetic correlations between bacteriological infection and the routinely recorded udder health traits were positive and ranged from 0.62 to 0.96. The genetic correlation between gram-positive and gram-negative bacterial infection was -0.20. The genetic correlation between acute and chronic mastitis was also close to zero. These results show that mastitis caused by different pathogens may be seen as different traits. As analyses were based on a relatively small data set and results were associated with rather high standard errors, further research with a larger data set should be carried out to confirm these results.

Varlitinib plus capecitabine in second-line advanced biliary tract cancer: a randomized, phase II study (TreeTopp).

BACKGROUND: Patients with advanced biliary tract cancer who progress on first-line therapy have limited treatment options. The TreeTopp study assessed varlitinib, a reversible small molecule pan-human epidermal growth factor receptor inhibitor, plus capecitabine in previously treated advanced biliary tract cancer. PATIENTS AND METHODS: This global, double-blind, randomized, placebo-controlled phase II study enrolled patients with confirmed unresectable or metastatic biliary tract cancer and disease progression after one prior line of gemcitabine-containing chemotherapy. Patients received oral varlitinib 300 mg or placebo twice daily (b.i.d.) for 21 days, plus oral capecitabine 1000 mg/m2 b.i.d. on days 1-14, in 21-day treatment cycles. Co-primary endpoints were objective response rate and progression-free survival (PFS) according to RECIST v1.1 by Independent Central Review. RESULTS: In total, 127 patients received varlitinib plus capecitabine (n = 64) or placebo plus capecitabine (n = 63). The objective response rate was 9.4% with varlitinib plus capecitabine versus 4.8% with capecitabine alone (odds ratio 2.28; P = 0.42). Median PFS was 2.83 versus 2.79 months [hazard ratio (HR), 0.90; 95% confidence interval (CI), 0.60-1.37; P = 0.63] and overall survival was 7.8 versus 7.5 months (HR, 1.11; 95% CI, 0.69-1.79; P = 0.66), respectively. In a subgroup analysis, the addition of varlitinib appeared to provide a PFS benefit in female patients (median, 4.1 versus 2.8 months; HR, 0.59; 95% CI, 0.28-1.23) and those with gallbladder cancer (median, 2.9 versus 1.6 months; HR, 0.55; 95% CI, 0.26-1.19). Grade ≥3 treatment-emergent adverse events were reported in 65.6% of patients receiving varlitinib plus capecitabine versus 58.7% of those receiving capecitabine alone. CONCLUSIONS: In patients with advanced biliary tract cancer, second-line treatment with varlitinib plus capecitabine was well tolerated but did not improve efficacy versus capecitabine alone. A PFS benefit was suggested in female patients and those with gallbladder cancer.

Spatial variation in the parasite communities and genomic structure of urban rats in New York City.

Brown rats (Rattus norvegicus) are a globally distributed pest. Urban habitats can support large infestations of rats, posing a potential risk to public health from the parasites and pathogens they carry. Despite the potential influence of rodent-borne zoonotic diseases on human health, it is unclear how urban habitats affect the structure and transmission dynamics of ectoparasite and microbial communities (all referred to as "parasites" hereafter) among rat colonies. In this study, we use ecological data on parasites and genomic sequencing of their rat hosts to examine associations between spatial proximity, genetic relatedness and the parasite communities associated with 133 rats at five sites in sections of New York City with persistent rat infestations. We build on previous work showing that rats in New York carry a wide variety of parasites and report that these communities differ significantly among sites, even across small geographical distances. Ectoparasite community similarity was positively associated with geographical proximity; however, there was no general association between distance and microbial communities of rats. Sites with greater overall parasite diversity also had rats with greater infection levels and parasite species richness. Parasite community similarity among sites was not linked to genetic relatedness of rats, suggesting that these communities are not associated with genetic similarity among host individuals or host dispersal among sites. Discriminant analysis identified site-specific associations of several parasite species, suggesting that the presence of some species within parasite communities may allow researchers to determine the sites of origin for newly sampled rats. The results of our study help clarify the roles that colony structure and geographical proximity play in determining the ecology of R. norvegicus as a significant urban reservoir of zoonotic diseases. Our study also highlights the spatial variation present in urban rat parasite communities, indicating that rats across New York City are not reservoirs for a homogenous set of parasites and pathogens. As a result, the epidemiological risks may be similarly heterogeneous for people in urban habitats.

Cytomegalovirus infection is associated with an increase in systolic blood pressure in older individuals.

BACKGROUND: Cytomegalovirus (CMV) is a chronic infection that is widely distributed in the population. CMV infects a range of tissues, including endothelium, and viral replication is suppressed by the host immune system. Infection is associated with increased risk of mortality from vascular disease in older people, but the mechanisms behind this have not been determined. AIM: We investigated the association between CMV infection and cardiovascular phenotype in a cohort of healthy elderly donors. DESIGN: CMV serostatus and cardiovascular parameters were determined in the Lothian Birth cohort, which comprises 1091 individuals aged 70 years in whom many environmental, biochemical and radiological correlates of vascular function have been determined. METHODS: CMV serostatus was determined by enzyme-linked immunosorbant assay and correlated with a range of biochemical and phenotypic measures. RESULTS: Sixty-five percent of participants were CMV seropositive, which indicates chronic infection. The mean sitting systolic blood pressure (SBP) was 149.2 mmHg in CMV seropositive individuals compared with 146.2 mmHg in CMV seronegative subjects (SD 18.7 vs. 19.7; P < 0.017). This association between CMV infection and SBP was not attenuated after adjustment for a wide range of biological and socio-economic factors. CONCLUSIONS: These data show that CMV infection is associated with an increase in SBP in individuals at age 70 years. The magnitude is comparable to environmental variables such as obesity, diabetes or high salt intake. This is the first evidence to show that a chronic infection may be an important determinant of blood pressure and could have significant implications for the future management of hypertension.

Influence of porcine circovirus type 2 vaccination on the level of antimicrobial consumption on 65 Austrian pig farms.

The administration of antibiotics to farm animals is an important contemporary topic. Veterinarians, pig producers, politicians, retailers and consumers all have a vested interest in reducing antimicrobial use on farm, while ensuring adequate health and welfare of food-producing animals. Vaccination programmes may be used to reduce the overall level of clinical disease in a population, subsequently leading to a decline in antimicrobial use. In 2008, a vaccination programme against porcine circovirus type 2 (PCV-2) was initiated in Austria. In the retrospective observational study presented here, farm medication records (2008-2011) from 65 conventional pig farms were evaluated. As PCV-2 has been shown to lead to generalised immunosuppression, enabling secondary bacterial infections to occur, the authors hypothesised that PCV-2 vaccination would decrease antimicrobial consumption at farm level. Firstly, we focused on the annual antimicrobial consumption expressed as the number of administered animal daily doses per kg liveweight (nADDkg/kg/year). Secondly, a linear mixed effects model was applied to evaluate the influence of PCV-2 vaccination on the antimicrobial consumption at farm level. The interaction between farm type and PCV-2 vaccination was found to be a highly significant factor (P=0.0002) influencing antimicrobial use at farm level. The estimated impact of PCV-2 vaccination revealed a highly significant (P<0.001) decline in total antimicrobial drug use from 1.72 ADDkg/kg/year to 0.56 ADDkg/kg/year on finishing farms, whereas only a negligible decline was detectable on farrow-to-finish farms.

Preliminary Survey of Ectoparasites and Associated Pathogens from Norway Rats in New York City.

The Norway rat (Rattus norvegicus) is a reservoir of many zoonotic pathogens and lives in close proximity to humans in urban environments. Human infection with rodent-borne disease occurs either directly through contact with a rat or its excreta, or indirectly via arthropod vectors such as fleas and ticks. Here, we report on the diversity and abundance of ectoparasitic arthropod species and associated pathogenic bacteria from 133 Norway rats trapped over a 10-mo period in Manhattan, New York, NY. Norway rats were host to the tropical rat mite [Ornithonyssus bacoti (Hirst)], the spiny rat mite (Laelaps echidnina Berlese), Laelaps nuttalli Hirst, the spined rat louse [Polyplax spinulosa (Burmeister)], and the Oriental rat flea [(Xenopsylla cheopis) (Rothschild)], with an average of 1.7 species per individual. A flea index of 4.1 X. cheopis was determined, whereas previous studies in New York City reported 0.22 fleas per rat. Multiple species of pathogenic Bartonella were identified from Oriental rat fleas that were related to Bartonella tribocorum, Bartonella rochalimae, and Bartonella elizabethae. However, no evidence of Yersinia pestis or Rickettsia spp. infection was detected in fleas. The identification of multiple medically important ectoparasite species in New York City underscores the need for future efforts to fully characterize the diversity and distribution of ectoparasites on Norway rats, and assess the risk to humans of vector-borne disease transmission.

Novel one-stop multidisciplinary follow-up clinic significantly improves cancer risk management in BRCA1/2 carriers.

The purpose of this study is to measure the impact of a multidisciplinary one-stop follow-up clinic (MDOSC) on breast and ovarian surveillance, risk reducing surgery and enrolment in clinical trials in BRCA1/2 carriers. All BRCA1/2 carriers in our region were invited and chose which specialists to see in our MDOSC offering best practice using clinical protocols based on national guidelines and published data. Uptake was evaluated over 24 months recording numbers of individuals undergoing breast and ovarian surveillance, risk reducing surgery, newly diagnosed cancers, their method of detection and participation in clinical trials. 172 (60%) of invited BRCA1/2 carriers chose to attend the MDOSC. Breast surveillance was initiated in 88% and screening frequency altered in 14% of women to comply with national guidelines. Risk reducing salpingo-oophorectomy was chosen by 47% of women and an additional 39% were considering it. The rate of failure to remove fallopian tubes fell from 15 to 3% of procedures (P < 0.01) and peritoneal washings and serial sectioning of tubes and ovaries rose from 25% and 14% before, to 67% (P < 0.001) and 63% (P < 0.001) procedures, respectively, after initiation of our MDOSC. 24% of women considered and 18% decided to undergo risk reducing mastectomy during the follow-up period. Participation in clinical trials increased significantly from 51 to 229 enrolments (P < 0.001). Our novel MDOSC designed to devise an individually tailored cancer risk management strategy had a high uptake amongst our BRCA1/2 carriers. Attendance resulted in improved breast and ovarian cancer risk management.

Psychometric evaluation of the outcome based performance measures.

The Outcome Based Performance Measures are widely used to evaluate and accredit organizations providing services to persons with disabilities. This study evaluated the interrater reliability, levels of difficulty for items, and factor groupings of this measure with 448 Nevadans with mental retardation. Results supported the measure's reliability and most of the items' levels of difficulty. Factor analysis yielded seven factors with item loadings that varied moderately from prior reports, tending to coincide with the original measure's logically-based groupings. Revisions to the measure are suggested.

A free-energy-based stochastic simulation of the Tar receptor complex.

We recently developed a stochastic-based program that allows individual molecules in a cell signalling pathway to be simulated. This program has now been used to model the Tar complex, a multimeric signalling complex employed by coliform bacteria. This complex acts as a solid-state computational cassette, integrating and disseminating information on the presence of attractants and repellents in the environment of the bacterium. In our model, the Tar complex exists in one of two conformations which differ in the rate at which they generate labile phosphate groups and hence signal to the flagellar motor. Individual inputs to the complex (aspartate binding, methylation at different sites, binding of CheB, CheR and CheY) are represented as binary flags, and each combination of flags confers a different free energy to the two conformations. Binding and catalysis by the complex are performed stochastically according to the complete set of known reactions allowing the swimming performance of the bacterium to be predicted. The assumption of two conformational states together with the use of free energy values allows us to bring together seemingly unrelated experimental parameters. Because of thermodynamic constraints, we find that the binding affinity for aspartate is linked to changes in phosphorylation activity. We estimate the pattern of Tar methylation and effective affinity constant of receptors over a range of aspartate levels. We also obtain evidence that both the methylating and demethylating enzymes must operate exclusively on one or other of the two conformations, and that sites of methylation of the complex are occupied in sequential order rather than independently. Detailed analysis of the response to aspartate reveals several quantitative discrepancies between simulated and experimental data which indicate areas for future research.

Predicting temporal fluctuations in an intracellular signalling pathway.

We used a newly developed stochastic-based program to predict the fluctuations in numbers of molecules in a chemotactic signalling pathway of coliform bacteria. Specifically, we examined temporal changes in molecules of CheYp, a cytoplasmic protein known to influence the direction of rotation of the flagellar motor. Signalling molecules in the vicinity of a flagellar motor were represented as individual software objects interacting according to probabilities derived from experimentally-observed concentrations rate constants. The simulated CheYp molecules were found to undergo random fluctuations in number about an average corresponding to the deterministically calculated concentration. Both the relative amplitude of the fluctuations, as a proportion of the total number of molecules, and their average duration, increased as the simulated volume was reduced. In a simulation corresponding to 10% of the volume of a bacterium, the average duration of fluctuations was found to be 80.7 ms, which is much shorter than the observed alternations between clockwise and counter clockwise rotations of tethered bacteria (typically 2.6 s). Our results are therefore not in agreement with a simple threshold-crossing model for motor switching. However, it is possible to filter the CheYp fluctuations to produce temporal distributions closer to the observed swimming behaviour and we discuss the possible implications for the control of motor rotation.

Receptor clustering as a cellular mechanism to control sensitivity.

Chemotactic bacteria such as Escherichia coli can detect and respond to extremely low concentrations of attractants, concentrations of less than 5 nM in the case of aspartate. They also sense gradients of attractants extending over five orders of magnitude in concentration (up to 1 mM aspartate). Here we consider the possibility that this combination of sensitivity and range of response depends on the clustering of chemotactic receptors on the surface of the bacterium. We examine what will happen if ligand binding changes the activity of a receptor, propagating this change in activity to neighbouring receptors in a cluster. Calculations based on these assumptions show that sensitivity to extracellular ligands increases with the extent of spread of activity through an array of receptors, but that the range of concentrations over which the array works is severely diminished. However, a combination of low threshold of response and wide dynamic range can be attained if the cell has both clusters and single receptors on its surface, particularly if the extent of activity spread can adapt to external conditions. A mechanism of this kind can account quantitatively for the sensitivity and response range of E. coli to aspartate.

Origins of individual swimming behavior in bacteria.

Cells in a cloned population of coliform bacteria exhibit a wide range of swimming behaviors--a form of non-genetic individuality. We used computer models to examine the proposition that these variations are due to differences in the number of chemotaxis signaling molecules from one cell to the next. Simulations were run in which the concentrations of seven gene products in the chemotaxis pathway were changed either deterministically or stochastically, with the changes derived from independent normal distributions. Computer models with two adaptation mechanisms were compared with experimental results from observations on individuals drawn from genetically identical populations. The range of swimming behavior predicted for cells with a standard deviation of protein copy number per cell of 10% of the mean was found to match closely the experimental range of the wild-type population. We also make predictions for the swimming behaviors of mutant strains lacking the adaptational mechanism that can be tested experimentally.

Myocardial infarction in a child with Salmonella enterocolitis.

The case history and findings of a seven-month-old North American Indian girl with myocardial infarction following a prolonged febrile seizure associated with Salmonella typhimurium enterocolitis are presented and discussed. This appears to be a unique observation not previously described in the literature.