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Introduction: Few data exist on long-term growth hormone (GH) treatment in patients with Noonan syndrome (NS). Objective: To evaluate the effectiveness and safety of GH treatment in NS in clinical practice. Methods: Height gain, near-adult height (NAH), and safety were assessed in 2 complementary non-interventional studies: NordiNet® IOS and ANSWER. The safety analysis included 412 patients, and the effectiveness analysis included 84 GH-treated patients (male, n = 67) with ≥4 years’ height standard deviation score (HSDS) data. HSDS was determined using national reference (NR) and NS-specific (NSS) data. Results: The mean (SD) baseline age was 8.38 (3.57) years; HSDS, −2.76 (1.03); GH dose, 41.6 (11.1) µg/kg/day. The mean (SD) HSDS increase from baseline (ΔHSDS) was 0.49 (0.37) (first year), 0.79 (0.58) (second year), and 1.01 (0.60) (third year) (NR). The mean (SD) HSDS at year 3 was −1.66 (1.00) (NR; 1.06 [1.12] [NSS]). Twenty-four patients achieved NAH. The mean (SD) NAH SDS (NR) was −1.51 (0.60) (154.90 [3.21] cm) in females and −1.79 (1.09) (165.61 [7.19] cm) in males; 70.8% (17/24) had NAH SDS ≥ −2. Adverse drug reactions and GH-unrelated serious adverse events (n = 34) were reported in 22/412 (5.3%) patients. Four neoplasms and 3 cases of scoliosis were reported; no cardiovascular adverse events occurred. Conclusions: GH-treated children with NS achieved substantial height gain during the first 3 years of follow-up. Overall, 24 patients achieved NAH, with 70.8% having NAH SDS ≥ –2. There was no evidence to support a higher prevalence of neoplasm, or cardiac or other comorbidities.

It is accepted that usage of antimicrobials (AMs) in food animals causes the emergence and spread of antimicrobial resistance (AMR) in this sector, while also contributing to the burden of AMR in humans. Curbing the increasing occurrence of AMR in food animals requires in-depth knowledge of the quantitative relationship between antimicrobial usage (AMU) and AMR to achieve desired resistance reductions from interventions targeting AMU. In the observational study, the relationships between lifetime AMU in 83 finisher batches from Danish farms and the AMR gene abundances of seven antimicrobial classes in their gut microbiomes were quantified using multi-variable linear regression models. These relationships and the national lifetime AMU in pigs were included in the predictive modelling that allowed for testing of scenarios with changed lifetime AMU for finishers produced in Denmark in 2014. A total of 50 farms from the observational study were included in validating the observational study and the predictive modelling. The results from the observational study showed that the relationship was linear, and that the parenteral usage of AMs had a high effect on specific AM-classes of resistance, whereas the peroral usage had a lower but broader effect on several classes. Three different scenarios of changed lifetime AMU were simulated in the predictive modelling. When all tetracycline usage ceased, the predicted interval reductions of aminoglycoside, lincosamide and tetracycline resistance were 4–42 %, 0–8 % and 9–18 %, respectively. When the peroral tetracycline usage of the 10 % highest users was replaced with peroral macrolide usage, the tetracycline resistance fell by 1–2 % and the macrolide and MLSb resistance increased by 5–8 %. When all extended-spectrum penicillin usage was replaced with parenteral lincosamide usage, the beta-lactam resistance fell by 2–7 %, but the lincosamide usage and resistance increased by 194 % and 10–45 %, respectively. The external validation provided results within the 95 % CI of the predictive modelling outcome at national level, while the external validation at farm level was less accurate. In conclusion, interventions targeting AMU will reduce AMR abundance, though differently depending on the targeted AM-class and provided the reduction of one AM-class usage is not replaced with usage of another AM-class. Predicting several classes of AMR gene abundance simultaneously will support stakeholders when deciding on interventions targeting AMU in the finisher production to avoid adverse and unforeseen effects on the AMR abundance. This study provides a sound predictive modelling framework for further development, including the dynamics of AMU on AMR in finishers at national level.

Bacterial antimicrobial resistance (AMR) in pigs is an important public health concern due to its possible transfer to humans. We aimed at quantifying the relationship between the lifetime exposure of antimicrobials and seven antimicrobial resistance genes in Danish slaughter pig farms. AMR gene levels were quantified by qPCR of total-community DNA in faecal samples obtained from 681 batches of slaughter pigs. The lifetime exposure to antimicrobials was estimated at batch level for the piglet, weaner, and finisher periods individually for the sampled batches. We showed that the effect of antimicrobial exposure on the levels of AMR genes was complex and unique for each individual gene. Several antimicrobial classes had both negative and positive correlations with the AMR genes. From 10–42% of the variation in AMR gene levels could be explained in the final regression models, indicating that antimicrobial exposure is not the only important determinant of the AMR gene levels.

Vancomycin-resistant Enterococcus spp. is a major health problem worldwide and livestock have been implicated in constituting a reservoir for the transmission of vancomycin resistance to zoonotic pathogens. Vancomycin resistance determinants can be situated on mobile genetic elements and transferred between bacterial species The livestock reservoir must therefore be included in a risk assessment of the vancomycin resistance burden. Avoparcin, a vancomycin analogue, has not been used in Danish pig production for over 20 years and vancomycin has never been used. The objective of this study was to screen faecal samples from Danish pig farms for nine selected vancomycin resistance determinants. We found at least four different vancomycin resistance determinants in all screened Danish pig farms (665 finisher farms and 78 sow farms). The vancomycin resistance determinants present in vanB or vanG clusters were found at significantly different levels in sow and finisher farms. However, vanA was not detected in any of the farms. In conclusion, vancomycin resistance determinants are still present in Danish pig production 25 years after the ban on avoparcin use.

Background The majority of antimicrobials given during the production of pigs are given to nursery pigs. The influence of antimicrobial use on the levels of antimicrobial resistant (AMR) genes is important to quantify to be able to assess the impact of resistance on the food chain and risk to human and animal health. Results This study investigated the response on the levels of nine AMR genes to five different treatment strategies with oxytetracycline, and the dynamics of gene abundance over time by following 1167 pigs from five different farms in Denmark. The results showed no significant difference between treatments and an increase in abundance for the efflux pump encoding tet(A) gene and the genes encoding the ribosomal protection proteins tet(O) and tet(W) tetracycline resistant genes following treatment, while tet(M) showed no response to treatment. However, it was also observed that the levels of tet(O), tet(W), and ermB in some farms would drift more over time compared to a single treatment-course with antibiotic. Conclusion This study underlines the large variation in AMR levels under natural conditions and the need for increased investigation of the complex interactions of antimicrobial treatment and other environmental and managerial practices in swine production on AMR gene abundance.

SUMMARYAntimicrobial resistance (AMR) in pig populations is a public health concern. There is a lack of information of spatial distributions of AMR genes in pig populations at large scales. The objective of the study was to describe the spatial pattern of AMR genes in faecal samples from pig farms and to test if the AMR genes were spatially randomly distributed with respect to the geographic distribution of the pig farm population at risk. Faecal samples from 687 Danish pig farms were collected in February and March 2015. DNA was extracted and the levels of seven AMR genes (ermB, ermF, sulI, sulII, tet(M), tet(O) and tet(W)) were quantified on a high-throughput real-time PCR array. Spatial differences for the levels of the AMR genes measured as relative quantities were evaluated by spatial cluster analysis and creating of risk maps using kriging analysis and kernel density estimation. Significant spatial clusters were identified for ermB, ermF, sulII and tet(W). The broad spatial trends in AMR resistance evident in the risk maps were in agreement with the results of the cluster analysis. However, they also showed that there were only small scale spatial differences in the gene levels. We conclude that the geographical location of a pig farm is not a major determinant of the presence or high levels of AMR genes assessed in this study.

A cross-sectional study design is relatively inexpensive, fast and easy to conduct when compared to other study designs. Careful planning is essential to obtaining a representative sample of the population, and the recommended approach is to use simple random sampling from an exhaustive list of units in the target population. This approach is rarely feasible in practice, and other sampling procedures must often be adopted. For example, when slaughter pigs are the target population, sampling the pigs on the slaughter line may be an alternative to on-site sampling at a list of farms. However, it is difficult to sample a large number of farms from an exact predefined list, due to the logistics and workflow of an abattoir. Therefore, it is necessary to have a systematic sampling procedure and to evaluate the obtained sample with respect to the study objective. We propose a method for 1) planning, 2) conducting, and 3) evaluating the representativeness and reproducibility of a cross-sectional study when simple random sampling is not possible. We used an example of a cross-sectional study with the aim of quantifying the association of antimicrobial resistance and antimicrobial consumption in Danish slaughter pigs. It was not possible to visit farms within the designated timeframe. Therefore, it was decided to use convenience sampling at the abattoir. Our approach was carried out in three steps: 1) planning: using data from meat inspection to plan at which abattoirs and how many farms to sample; 2) conducting: sampling was carried out at five abattoirs; 3) evaluation: representativeness was evaluated by comparing sampled and non-sampled farms, and the reproducibility of the study was assessed through simulated sampling based on meat inspection data from the period where the actual data collection was carried out. In the cross-sectional study samples were taken from 681 Danish pig farms, during five weeks from February to March 2015. The evaluation showed that the sampling procedure was reproducible with results comparable to the collected sample. However, the sampling procedure favoured sampling of large farms. Furthermore, both under-sampled and over-sampled areas were found using scan statistics. In conclusion, sampling conducted at abattoirs can provide a spatially representative sample. Hence it is a possible cost-effective alternative to simple random sampling. However, it is important to assess the properties of the resulting sample so that any potential selection bias can be addressed when reporting the findings.

Background: Cavalier King Charles Spaniels (CKCS) are predisposed to myxomatous mitral valve disease (MMVD). Studies have indicated a strong genetic background. Objective: The aim of this study was to evaluate the effect of a breeding scheme involving auscultation and echocardiography. Animals: In the Danish Kennel Club mandatory breeding scheme, 997 purebred CKCS were examined during the period 2002-2011. Each dog was evaluated 1-4 times with a total of 1,380 examinations. Methods: Auscultation and echocardiography were performed to evaluate mitral regurgitation murmur severity and degree of mitral valve prolapse (MVP). The odds of having mitral regurgitation murmur or MVP > grade 1 in 2010-2011 compared to 2002-2003 were estimated using logistic regression analysis including age and sex as covariates. Odds were estimated for dogs that were products of the breeding scheme (defined as dogs with both parents approved by the breeding scheme before breeding) and non-products of the breeding scheme (defined as dogs with at least 1 parent with unknown cardiac status). Results: In 2010-2011, the odds of having mitral regurgitation murmur were 0.27 if dogs were a product of the breeding scheme compared with dogs in 2002-2003, reflecting a 73% decreased risk (P < .0001). If non-products of the breeding scheme examined in 2010-2011 were compared with dogs in 2002-2003, no difference in odds was found (P = .49). Conclusion and Clinical Importance: A mandatory breeding scheme based on auscultation and echocardiography findings significantly decreased the prevalence of MMVD over the 8- to 10-year period. Such a breeding scheme therefore is recommended for CKCS.Background: Cavalier King Charles Spaniels (CKCS) are predisposed to myxomatous mitral valve disease (MMVD). Studies have indicated a strong genetic background. Objective: The aim of this study was to evaluate the effect of a breeding scheme involving auscultation and echocardiography. Animals: In the Danish Kennel Club mandatory breeding scheme, 997 purebred CKCS were examined during the period 2002-2011. Each dog was evaluated 1-4 times with a total of 1,380 examinations. Methods: Auscultation and echocardiography were performed to evaluate mitral regurgitation murmur severity and degree of mitral valve prolapse (MVP). The odds of having mitral regurgitation murmur or MVP > grade 1 in 2010-2011 compared to 2002-2003 were estimated using logistic regression analysis including age and sex as covariates. Odds were estimated for dogs that were products of the breeding scheme (defined as dogs with both parents approved by the breeding scheme before breeding) and non-products of the breeding scheme (defined as dogs with at least 1 parent with unknown cardiac status). Results: In 2010-2011, the odds of having mitral regurgitation murmur were 0.27 if dogs were a product of the breeding scheme compared with dogs in 2002-2003, reflecting a 73% decreased risk (P < .0001). If non-products of the breeding scheme examined in 2010-2011 were compared with dogs in 2002-2003, no difference in odds was found (P = .49). Conclusion and Clinical Importance: A mandatory breeding scheme based on auscultation and echocardiography findings significantly decreased the prevalence of MMVD over the 8- to 10-year period. Such a breeding scheme therefore is recommended for CKCS. Background: Cavalier King Charles Spaniels (CKCS) are predisposed to myxomatous mitral valve disease (MMVD). Studies have indicated a strong genetic background. Objective: The aim of this study was to evaluate the effect of a breeding scheme involving auscultation and echocardiography. Animals: In the Danish Kennel Club mandatory breeding scheme, 997 purebred CKCS were examined during the period 2002-2011. Each dog was evaluated 1-4 times with a total of 1,380 examinations. Methods: Auscultation and echocardiography were performed to evaluate mitral regurgitation murmur severity and degree of mitral valve prolapse (MVP). The odds of having mitral regurgitation murmur or MVP > grade 1 in 2010-2011 compared to 2002-2003 were estimated using logistic regression analysis including age and sex as covariates. Odds were estimated for dogs that were products of the breeding scheme (defined as dogs with both parents approved by the breeding scheme before breeding) and non-products of the breeding scheme (defined as dogs with at least 1 parent with unknown cardiac status). Results: In 2010-2011, the odds of having mitral regurgitation murmur were 0.27 if dogs were a product of the breeding scheme compared with dogs in 2002-2003, reflecting a 73% decreased risk (P < .0001). If non-products of the breeding scheme examined in 2010-2011 were compared with dogs in 2002-2003, no difference in odds was found (P = .49). Conclusion and Clinical Importance: A mandatory breeding scheme based on auscultation and echocardiography findings significantly decreased the prevalence of MMVD over the 8- to 10-year period. Such a breeding scheme therefore is recommended for CKCS.