Simulation of dual-purpose chicken breeding programs implementing gene editing.

BACKGROUND: In spite of being controversial and raising ethical concerns, the application of gene editing is more likely to be accepted when it contributes to improving animal welfare. One of the animal welfare and ethical issues in chicken breeding is chick culling, the killing of the male layer chicks after hatching due to the poor fattening performance. Although establishing dual-purpose chicken lines could solve this problem, unfavorable genetic correlations between egg and meat production traits hindered their competitiveness. Although it is also controversial in ethical terms, gene editing may accelerate genetic progress in dual-purpose chicken and alleviate the ethical concerns from chick culling. RESULTS: The simulation compared the utility improvement in dual-purpose use under two breeding schemes: one consisting in the improvement of the laying hens, and the second in the improvement of a synthetic line obtained from a layer broiler cross. In each breeding scheme, the breeding programs were simulated with and without gene editing. Polygenic breeding values and 500 simulated quantitative trait loci (QTL) with different levels of pleiotropy caused negative correlations between egg production, meat production, and overall health. The results of the simulation demonstrated that genetic gain could be accelerated by at most 81% for several generations if gene editing was used. The actual increase in genetic gain depended on the number of single nucleotide polymorphisms (SNPs) being edited per animal. The rate of genetic improvement became equal in scenarios with and without gene editing after 20 generations. This is because the remaining segregating QTL had small effects and their edition would have negative overall health effects from potential off-target edits. Although gene editing can improve genetic gain in quantitative traits, it can only be recommended as long as QTL with reasonable effect sizes are segregating and detectable. CONCLUSIONS: This simulation demonstrates the potential of gene editing to accelerate the simultaneous improvement of negatively correlated traits. When the risk of negative consequences from gene editing persists, the number of SNPs to be edited should be chosen carefully to obtain the optimal genetic gain.

Methodical advances in reproducibility research: A proof of concept qualitative comparative analysis of reproducing animal data in humans.

BACKGROUND: While the term reproducibility crisis mainly reflects reproducibility of experiments between laboratories, reproducibility between species also remains problematic. We previously summarised the published reproducibility between animal and human studies; i.e. the translational success rates, which varied from 0% to 100%. Based on analyses of individual factors, we could not predict reproducibility. Several potential analyses can assess effect of combinations of predictors on an outcome. Regression analysis (RGA) is common, but not ideal to analyse multiple interactions and specific configurations (≈ combinations) of variables, which could be highly relevant to reproducibility. Qualitative comparative analysis (QCA) is based on set theory and Boolean algebra, and was successfully used in other fields. We reanalysed the data from our preceding review with QCA. RESULTS: This QCA resulted in the following preliminary formula for successful translation: ∼Old*∼Intervention*∼Large*MultSpec*Quantitative Which means that within the analysed dataset, the combination of relative recency (∼ means not; >1999), analyses at event or study level (not at intervention level), n < 75, inclusion of more than one species and quantitative (instead of binary) analyses always resulted in successful translation (>85%). Other combinations of factors showed less consistent or negative results. An RGA on the same data did not identify any of the included variables as significant contributors. CONCLUSIONS: While these data were not collected with the QCA in mind, they illustrate that the approach is viable and relevant for this research field. The QCA seems a highly promising approach to furthering our knowledge on between-species reproducibility.

Experiences and recommendations of veterinarians for the Dutch disciplinary system-a survey-based study.

Introduction: In the Netherlands, the veterinary disciplinary system is governmentally executed and was originally designed to provide an educational effect on veterinarians as part of maintaining quality standards. Methods: Over 900 veterinarians were questioned (20% of the total number of veterinarians working in veterinary medicine in the Netherlands). It was ascertained whether or not they were aware of the disciplinary system, if it affected their way of working and what impact it had on their way of working after having faced a disciplinary case. Respondents were given the opportunity to express their opinions about the system and possible improvements. Results: The risk of complaints was found to be significantly greater when a veterinarian owned a practice compared to veterinarians who were employees. Veterinarians with their own practice were generally older (male) veterinarians. Whether this was a direct effect or just the effect of having a longer career could not be answered. Multiple disciplinary procedures appeared to have no influence. In 13%, veterinarians indicated that the disciplinary system had led to a more defensive way of practicing medicine to avoid complaints. Discussion and conclusions: Most veterinarians supported a disciplinary system as a tool for maintaining and improving the integrity and reputation of the profession as a whole. Recommendations to improve were (1) shortening the length of the procedure, (2) screening for validity, (3) using online systems for communication with the disciplinary council, (4) the option of mediation before getting involved in a full procedure and (5) instituting a complaint fee.

As if you were hiring a new employee: on pig veterinarians' perceptions of professional roles and relationships in the context of smart sensing technologies in pig husbandry in the Netherlands and Germany.

Veterinarians are increasingly confronted with new technologies, such as Precision Livestock Farming (PLF), which allows for automated animal monitoring on commercial farms. At the same time, we lack information on how veterinarians, as stakeholders who may play a mediating role in the public debate on livestock farming, perceive the use and the impact of such technologies. This study explores the meaning veterinarians attribute to the application of PLF in the context of public concerns related to pig production. Semi-structured interviews were carried out with pig veterinarians located in the Netherlands and Germany. By using an inductive and semantic approach to reflexive thematic analysis, we developed four main themes from the interview data: (1) the advisory role of the veterinarian, which is characterized by a diverse scope, including advice on PLF, generally positive evaluations and financial dependencies; (2) the delineation of PLF technologies as supporting tools, which are seen as an addition to human animal care; (3) the relationship between veterinarian and farmer, which is context-related, ranging from taking sides with to distancing oneself from farmers; and (4) the distance between agriculture and society, in the context of which PLF has both a mitigating and reinforcing potential. The present findings indicate that veterinarians play an active role in the emerging field of PLF in livestock farming. They are aware of and reflect on competing interests of different groups in society and share positions with different stakeholders. However, the extent to which they are able to mediate between stakeholder groups in practice seems to be constrained by external factors, such as financial dependencies. Supplementary Information: The online version contains supplementary material available at 10.1007/s10460-023-10450-6.

Challenging Future Generations: A Qualitative Study of Students' Attitudes toward the Transition to Animal-Free Innovations in Education and Research.

In 2016, the Dutch government declared its commitment to phasing out animal experiments by 2025. Although a high number of animal experiments are still performed and the 2025 target will not be met, the commitment remains. Efforts are being made to identify levers that might foster the transition to animal-free science. Education has been found to play a key role in the future of animal-free science and young generations are increasingly seen as key stakeholders. However, their attitudes toward the transition to animal-free innovations have not been investigated. The present article focuses on the values and beliefs held by students, who in 2022, participated in the course 'Replacing Animal Testing' (RAT) Challenge, organized by a consortium of Dutch universities. Contextually, students' motivations to follow the course were investigated. The research was based on a qualitative study, including semi-structured interviews and a literature review. Our analysis of the findings revealed that students feel aligned with the social, ethical, and scientific reasons that support the transition to animal-free innovations. Moreover, the participants identified a series of regulatory, educational, cultural, and political obstacles to the transition that align with those identified in recent literature. From the discussion of these findings, we extrapolated six fundamental challenges that need to be addressed to foster the transition to animal-free science in an acceptable and responsible way.

15 years of facts and figures on veterinary disciplinary measures in the Netherlands.

In most countries, a veterinary disciplinary system is in force to ensure the quality of the veterinary profession and to offer an objective platform for complaints. We present an analysis of 15 years of veterinary disciplinary verdicts (2001-2016) to compare facts and figures and identify which factors are of major influence on the outcome of the verdicts. Rulings were collected from both paper files and the digital database of the veterinary disciplinary council (VDC), categorized, and used to create a database that enabled a statistical analysis. The results showed that complaints pertaining to companion animals are filed predominantly by owners, whereas complaints about livestock are mostly filed by the governmental civil servant (CS). CS complaints mostly address compliance issues. For the complaints made by owners (client complaints, CCs), reporting, communication, and veterinary mistakes appeared to be of statistical significance. Further studies are needed to investigate the impact of the complaints on veterinarians in general and how we can improve the veterinary disciplinary system.

Caught on Camera: On the Need of Responsible Use of Video Observation for Animal Behavior and Welfare Research.

Video analysis is a popular and frequently used tool in animal behavior and welfare research. In addition to the actual object of research, video recordings often provide unforeseen information about the progress of the study, the animals or the people involved. Conflicts can arise when this information is weighed against the original intention of the recordings and broader social expectations. Uncertainty may prevent the video observers, often less experienced researchers, to properly address these conflicts, which can pose a threat to animal welfare and research quality and integrity. In this article, we aim to raise awareness of the interrelationship of variables characteristic for video-based animal studies and the potential conflicts emerging from this. We propose stepping stones for a framework which enables a culture of openness in dealing with unexpected and unintended events observed during video analysis. As a basis, a frame of reference regarding privacy and duty of care toward animals should be created and shared with all persons involved. At this stage, expectations and responsibilities need to be made explicit. During running and reporting of the study, the risk of animal welfare and research integrity issues can be mitigated by making conflicts discussible and offering realistic opportunities on how to deal with them. A practice which is outlined and guided by conversation will prevent a mere compliance-based approach centered on checklists and decision trees. Based on these stepping stones, educational material can be produced to foster reflection, co-creation and application of ethical practice.

Multiphoton intravital microscopy of rodents.

Tissues are heterogeneous with respect to cellular and non-cellular components and in the dynamic interactions between these elements. To study the behaviour and fate of individual cells in these complex tissues, intravital microscopy (IVM) techniques such as multiphoton microscopy have been developed to visualize intact and live tissues at cellular and subcellular resolution. IVM experiments have revealed unique insights into the dynamic interplay between different cell types and their local environment, and how this drives morphogenesis and homeostasis of tissues, inflammation and immune responses, and the development of various diseases. This Primer introduces researchers to IVM technologies, with a focus on multiphoton microscopy of rodents, and discusses challenges, solutions and practical tips on how to perform IVM. To illustrate the unique potential of IVM, several examples of results are highlighted. Finally, we discuss data reproducibility and how to handle big imaging data sets.

Eligibility criteria for ambulatory colectomy.

PURPOSE OF THE STUDY: To determine the statistical indicators aimed at identifying patients for whom ambulatory colectomy could be proposed without additional risk. PATIENTS AND METHODS: The medical charts of patients who benefited from scheduled colonic or rectal resection during conventional hospitalization stays between 2018 and 2019 were reviewed. Eligibility for ambulatory colectomy was defined by hospital stay≤4 days and absence of any postoperative complication. Patient characteristics were compared, and the results were modeled in the form of a decision-making tree. The effect of an enhanced recovery after surgery (ERAS) protocol for each sub-group was calculated. RESULTS: One hundred and ten (110) patients were selected (41 "eligible" and 69 "non-eligible"). Median age was 73 years (27-95). Nearly 80% of the patients were operated for cancer. In multivariate analysis, age (≥65 years, OR=3.15, CI95%=1.22-8.12), diabetes (OR=3.91, CI95%=1.03-14.8) and indication (sigmoidectomy for diverticulosis, OR=0.21, CI=95%=0.05-0.9) were the only identified independent variables. Likelihood for ambulatory eligibility was 83.3% (<65 years, sigmoidectomy pour diverticulosis, +ERAS=92%-96.9%), 58.3% (<65 years, other indication, +ERAS=63.4%-89.9%), 35.7% (≥65 years without diabetes, +ERAS=40.0%-55.9%) and 8.3% (≥65 years with diabetes, +ERAS=10.0%-20.1%). CONCLUSION: Sigmoidectomy for diverticulosis in a patient under 65 years age represents the best indication for ambulatory colectomy, a procedure that must not be proposed to diabetic patients over 65 years of age. In the other cases (<65 years operated in another indication and non-diabetic≥65 years), ambulatory surgery is possible, pending satisfactory application of the ERAS protocol.

Risk-Based Decision Making: A Systematic Scoping Review of Animal Models and a Pilot Study on the Effects of Sleep Deprivation in Rats.

Animals, including humans, frequently make decisions involving risk or uncertainty. Different strategies in these decisions can be advantageous depending the circumstances. Short sleep duration seems to be associated with more risky decisions in humans. Animal models for risk-based decision making can increase mechanistic understanding, but very little data is available concerning the effects of sleep. We combined primary- and meta-research to explore the relationship between sleep and risk-based decision making in animals. Our first objective was to create an overview of the available animal models for risky decision making. We performed a systematic scoping review. Our searches in Pubmed and Psychinfo retrieved 712 references, of which 235 were included. Animal models for risk-based decision making have been described for rodents, non-human primates, birds, pigs and honey-bees. We discuss task designs and model validity. Our second objective was to apply this knowledge and perform a pilot study on the effect of sleep deprivation. We trained and tested male Wistar rats on a probability discounting task; a "safe" lever always resulted in 1 reward, a "risky" lever resulted in 4 or no rewards. Rats adapted their preferences to variations in reward probabilities (p < 0.001), but 12 h of sleep deprivation during the light phase did not clearly alter risk preference (p = 0.21).

Dilemmas in the Management of Liminal Rodents-Attitudes of Dutch Pest Controllers.

When non-human animals are labeled as 'pests', their moral status and welfare seem relatively unimportant. In a multi-stakeholder project, we develop an assessment frame for a more responsible rodent management that includes animal welfare. An online survey among 129 Dutch pest controllers was carried out in order to find out more about pest controllers' attitudes about animal welfare. Respondents indicate to consider animal welfare in their job. They see differences in the welfare impact of different rodent control methods. A dilemma may occur when methods with a high impact, such as rodenticides, are ofttimes used in practice. Respondents also indicate that in different real-life scenarios (the hospital kitchen vs. the private backyard), a different weight may be attributed to the importance of animal welfare. Almost half of the respondents encounter difficulties when weighing animals against human interests. The problems are mainly related to clients who are not willing to invest sufficient money in preventive methods, where respondents do believe in. Some differences were found between respondents depending on membership of a professional association for pest controllers. The results of this study are relevant input for focus groups with pest controllers and their clients and for the development of the aforementioned assessment frame.

Improving Translation by Identifying Evidence for More Human-Relevant Preclinical Strategies.

Preclinical animal studies are performed to analyse the safety and efficacy of new treatments, with the aim to protect humans. However, there are questions and concerns about the quality and usefulness of preclinical animal research. Translational success rates vary between 0 and 100%, and no clear relationship has been found with possible predictive factors such as animal species or field of research. Therefore, it is not yet possible to indicate what factors predict successful translation. Translational strategies were therefore discussed at an international conference held in the Netherlands in November 2019, aiming to develop practical guidelines for more robust animal-to-human translation. The conference was organised during the course of a research project funded by the Dutch Research Council (313-99-310), addressing possible solutions for the low translational values that had been published for a multitude of animal studies in human health care. This article provides an overview of the project and the conference discussions. Based on the conference results and the findings from the research project, we define four points of attention that are crucial in the search for improved translational success rates: (a) optimising the methods and design of studies; (b) incorporation of the complexity of the human patient in research; (c) start with the patient rather than existing animal models as the gold standard; and (d) more and better collaboration within the chain from funding to pharmacy. We conclude that this requires improved organization and use of procedures, as well as a change of attitude and culture in research, including a consideration of the translational value of animal-free innovations and human-relevant science.

Joining forces: the need to combine science and ethics to address problems of validity and translation in neuropsychiatry research using animal models.

BACKGROUND: Current policies regulating the use of animals for scientific purposes are based on balancing between potential gain of knowledge and suffering of animals used in experimentation. The balancing process is complicated, on the one hand by plurality of views on our duties towards animals, and on the other hand by more recent discussions on uncertainty in the probability of reaching the final aim of the research and problems of translational failure. METHODS: The study combines ethical analysis based on a literature review with neuropsychiatry-related preclinical research as a case study. RESULTS: Based on the analysis and the case study we show that neuropsychiatry-related preclinical research is an especially interesting case from an ethical perspective. The 3R principles (Replacement, Reduction and Refinement) are used to minimize the negative consequences for the animals used in research. However, neuropsychiatric research is characterized by specific challenges in assessing the probability of success of reaching the final aim, due to our limited mechanistic knowledge of human neuropsychiatric illness. Consequently, the translational value of the currently used animal models may be difficult to prove, which undermines the validity of these models and complicated the ethical assessment. CONCLUSIONS: We conclude that a combined approach that deals with both science and the ethical dimensions is necessary to address the problems of validity and translation in neuropsychiatry-related preclinical research. We suggest this approach to comprise first, improved experimental methods, e.g. by using systematic reviews, second, a more patients-based approach that leads to models that reflect interindividual variation better, and third, more interdisciplinary cooperation.

Smart Technologies Lead to Smart Answers? On the Claim of Smart Sensing Technologies to Tackle Animal Related Societal Concerns in Europe Over Current Pig Husbandry Systems.

Current pig production systems in Europe are subject to public criticism. At the same time, Precision Livestock Farming (PLF) technologies, which allow for automated animal monitoring are entering commercial pig farms. With their claim of improving animal health and welfare, these innovations may respond to public concerns. However, they may raise problems of societal acceptance themselves. In this review, we investigate whether the available literature allows for an analysis to which extent PLF can mitigate or reinforce societal concerns related to pig production. We first analyze papers on pig husbandry systems in general, and then those on PLF as an innovation in animal production. In general, there is a tension between citizens and farmers. Citizens hold rather negative attitudes whereas farmers evaluate pig production more positively. Literature on attitudes of other actors, such as veterinarians, is missing. Information on the attitudes toward PLF of stakeholders other than farmers is lacking. Possible challenges of societal acceptance of PLF and chances to overcome these are only discussed in theoretical approaches. We conclude that to analyze the role of PLF in addressing societal concerns over pig production, there is a need for further empirical research including attention to underlying values of all stakeholders. This should focus on the attitudes of the currently missing stakeholders toward pig husbandry in general, and on those of the wider society toward PLF. Only by means of additional data, it will be possible to evaluate whether PLF has the potential to address societal concerns related to pig production.

One Health: How Interdependence Enriches Veterinary Ethics Education.

What does One Health imply for veterinary ethics education? In order to answer this question, we will first have to establish what One Health itself involves. The meaning and scope of One Health, however, cannot be established without reference to its values-whose health matters? Veterinary ethics education is well equipped to facilitate such an open-ended inquiry into multispecies health. One Health also widens the scope of veterinary ethics by making salient, among other fields, environmental ethics, global health justice, and non-Western approaches to ethics. Finally, One Health requires students to engage with interdependence. Discussing three levels of interdependence, we argue that veterinary ethics stands to benefit from a more contemplative pedagogy.

Animal to human translation: a systematic scoping review of reported concordance rates.

BACKGROUND: Drug development is currently hampered by high attrition rates; many developed treatments fail during clinical testing. Part of the attrition may be due to low animal-to-human translational success rates; so-called "translational failure". As far as we know, no systematic overview of published translational success rates exists. SYSTEMATIC SCOPING REVIEW: The following research question was examined: "What is the observed range of the animal-to-human translational success (and failure) rates within the currently available empirical evidence?". We searched PubMed and Embase on 16 October 2017. We included reviews and all other types of "umbrella"-studies of meta-data quantitatively comparing the translational results of studies including at least two species with one being human. We supplemented our database searches with additional strategies. All abstracts and full-text papers were screened by two independent reviewers. Our scoping review comprises 121 references, with various units of measurement: compound or intervention (k = 104), study/experiment (k = 10), and symptom or event (k = 7). Diagnostic statistics corresponded with binary and continuous definitions of successful translation. Binary definitions comprise percentages below twofold error, percentages accurately predicted, and predictive values. Quantitative definitions comprise correlation/regression (r2) and meta-analyses (percentage overlap of 95% confidence intervals). Translational success rates ranged from 0 to 100%. CONCLUSION: The wide range of translational success rates observed in our study might indicate that translational success is unpredictable; i.e. it might be unclear upfront if the results of primary animal studies will contribute to translational knowledge. However, the risk of bias of the included studies was high, and much of the included evidence is old, while newer models have become available. Therefore, the reliability of the cumulative evidence from current papers on this topic is insufficient. Further in-depth "umbrella"-studies of translational success rates are still warranted. These are needed to evaluate the probabilistic evidence for predictivity of animal studies for the human situation more reliably, and to determine which factors affect this process.

Systematic review of the impact of osteoarthritis on health outcomes for comorbid disease in older people.

OBJECTIVE: A systematic review was undertaken examining the impact of comorbid osteoarthritis on health outcomes for people aged 50 years or older with cardiovascular disease, diabetes or obesity. DESIGN: The protocol is registered in PROSPERO (CRD42015023417). Relevant electronic databases and grey literature were systematically searched for studies published in English between January 2005 and December 2016. Two reviewers independently screened studies for selection using predetermined inclusion and exclusion criteria, and independently completed methodological quality review. Data was extracted at study level by one reviewer and independently checked by a second reviewer, using a standardized form. The results across studies were qualitatively synthesized with outcomes described and summarized. RESULTS: Of 1456 articles, we identified 15 relevant studies, with nine good to high quality studies describing significant negative impact of osteoarthritis on outcomes for cardiovascular diseases. There were too few studies focussing on diabetes and obesity to make conclusions in regard to these diseases. CONCLUSIONS: This review provides evidence that osteoarthritis should not be overlooked when impacts of chronic disease on health outcomes and related health service use are considered. There is a clear need for more studies that consider the impacts of osteoarthritis on comorbid disease, especially those that consider the impact of osteoarthritis beyond the morbidity impacts. The management of comorbid osteoarthritis should be addressed for those with cardiovascular disease, and treatment choices considered given this association.

Dynamic outcome prediction in a socio-demographically diverse population-based cohort of extremely preterm neonates.

OBJECTIVE: Accurate outcome prediction is crucial for counseling parents and providing individualized treatment to extremely premature infants. We sought to improve upon existing prediction model by using a diverse population-based cohort of extremely premature live births (⩽28 weeks' gestation) for survival and survival without severe neonatal morbidity at different times throughout the first week of life and to evaluate potential differences by race/ethnicity and maternal education. STUDY DESIGN: Retrospective cohort study of all California live births from 2007 through 2011 with linked birth, death and hospital discharge records. RESULTS: A total of 6009 infants were included. In the validation data set at time of delivery, the area under the receiver-operating characteristic curve for the model containing all predictors was 0.863 for survival and 0.789 for survival without severe morbidity. The marginal probability of survival without severe neonatal morbidity of an Asian infant born to a mother with <12 years of education compared with the reference (Caucasian infant, mother with ⩾12 years of education) was -0.23 (95% confidence interval (CI) -0.31 to -0.15) for all infants at time of birth and -0.28 (95% CI -0.39 to -0.18) for infants with attempted resuscitation. Notably, no other differences by racial/ethnic category and maternal education emerged. CONCLUSIONS: Probabilities of survival and survival without major morbidity change rapidly throughout the first week of life. Extremely premature infants born to Asian mothers with less than a high school education appear to have a lower probability to survive without significant morbidity compared with their Caucasian peers.