Uterine Tube Resection by Vaginotomy as an Alternative to Ovariectomy in Mature Cattle.

The prevention of pregnancy is desirable for female cattle destined for sale in the northern Australian rangelands for both economic and welfare reasons. Controlled access to bulls is often not feasible, nor are any non-surgical methods currently available. Many females are therefore surgically spayed. This study describes a technique for uterine tube resection (UTR), which leaves the ovaries intact and is performed using a vaginal approach, and compares the outcomes from 70 Brahman cows subjected to the procedure with 60 heifers spayed using the dropped ovary technique. The animals were monitored for 10 days following the surgery. There were no mortalities, and two animals were treated for illnesses after the UTRs and recovered. The animals subjected to both surgical procedures showed signs of pelvic discomfort and mild inflammation during recovery. The cows gained an average of 9.3 kg (SD 14.5 kg) of weight over the 10 days of the study compared to the spayed heifers, which lost 3.5 kg (SD 13.3 kg), with 19 and 63% of the animals in each of the groups losing weight, respectively. Uterine tube resection can be considered as a viable alternative to surgical spaying.

A novel cardiovascular systems model to quantify drugs effects on the inter-relationship between contractility and other hemodynamic variables.

The use of systems-based pharmacological modeling approaches to characterize mode-of-action and concentration-effect relationships for drugs on specific hemodynamic variables has been demonstrated. Here, we (i) expand a previously developed hemodynamic system model through integration of cardiac output (CO) with contractility (CTR) using pressure-volume loop theory, and (ii) evaluate the contribution of CO data for identification of system-specific parameters, using atenolol as proof-of-concept drug. Previously collected experimental data was used to develop the systems model, and included measurements for heart rate (HR), CO, mean arterial pressure (MAP), and CTR after administration of atenolol (0.3-30 mg/kg) from three in vivo telemetry studies in conscious Beagle dogs. The developed cardiovascular (CVS)-contractility systems model adequately described the effect of atenolol on HR, CO, dP/dtmax, and MAP dynamics and allowed identification of both system- and drug-specific parameters with good precision. Model parameters were structurally identifiable, and the true mode of action can be identified properly. Omission of CO data did not lead to a significant change in parameter estimates compared to a model that included CO data. The newly developed CVS-contractility systems model characterizes short-term drug effects on CTR, CO, and other hemodynamic variables in an integrated and quantitative manner. When the baseline value of total peripheral resistance is predefined, CO data was not required to identify drug- and system-specific parameters. Confirmation of the consistency of system-specific parameters via inclusion of data for additional drugs and species is warranted. Ultimately, the developed model has the potential to be of relevance to support translational CVS safety studies.

Australian Livestock Export Industry Workers' Attitudes toward Animal Welfare.

Understanding live export industry workers' attitudes and beliefs toward animal welfare can provide insight into their decision-making processes and likely behavior. Industry workers (n = 265) with various roles within the supply chain were surveyed from different global regions. Participants were divided into ten categories according to their industry roles and compared using ordinal regression. Respondents were highly likely to have a positive attitude toward animal welfare; the majority of workers enjoyed working with livestock (95.8%) and agreed that livestock should be treated with respect (97.7%). Workers demonstrated a strong understanding of animal welfare concepts, 168 respondents (63.4%) provided examples of ways they had improved animal welfare in their workplace, and 164 workers (61.9%) suggested ways that animal welfare could be improved further. Most workers (95.8%) agreed that animal welfare was satisfactory in their workplace. Five out of the 24 multiple-choice responses differed significantly by the participant's industry role, but no particular group displayed consistently divergent beliefs or attitudes. Given the community concern regarding animals in the livestock export supply chain, it is imperative to understand the attitudes of industry personnel who are responsible for the daily management of the animals. This knowledge assists in the development of animal welfare policy and can inform strategies to manage public perception.

Systems Modeling to Quantify Safety Risks in Early Drug Development: Using Bifurcation Analysis and Agent-Based Modeling as Examples.

Quantitative Systems Toxicology (QST) models, recapitulating pharmacokinetics and mechanism of action together with the organic response at multiple levels of biological organization, can provide predictions on the magnitude of injury and recovery dynamics to support study design and decision-making during drug development. Here, we highlight the application of QST models to predict toxicities of cancer treatments, such as cytopenia(s) and gastrointestinal adverse effects, where narrow therapeutic indexes need to be actively managed. The importance of bifurcation analysis is demonstrated in QST models of hematologic toxicity to understand how different regions of the parameter space generate different behaviors following cancer treatment, which results in asymptotically stable predictions, yet highly irregular for specific schedules, or oscillating predictions of blood cell levels. In addition, an agent-based model of the intestinal crypt was used to simulate how the spatial location of the injury within the crypt affects the villus disruption severity. We discuss the value of QST modeling approaches to support drug development and how they align with technological advances impacting trial design including patient selection, dose/regimen selection, and ultimately patient safety.

Suppressor of cytokine signaling-1 mimetic peptides attenuate lymphocyte activation in the MRL/lpr mouse autoimmune model.

Autoimmune diseases are driven largely by a pathogenic cytokine milieu produced by aberrantly activated lymphocytes. Many cytokines, including interferon gamma (IFN-γ), utilize the JAK/STAT pathway for signal propagation. Suppressor of Cytokine Signaling-1 (SOCS1) is an inducible, intracellular protein that regulates IFN-γ signaling by dampening JAK/STAT signaling. Using Fas deficient, MRL/MpJ-Faslpr/J (MRL/lpr) mice, which develop lupus-like disease spontaneously, we tested the hypothesis that a peptide mimic of the SOCS1 kinase inhibitory region (SOCS1-KIR) would inhibit lymphocyte activation and modulate lupus-associated pathologies. Consistent with in vitro studies, SOCS1-KIR intraperitoneal administration reduced the frequency, activation, and cytokine production of memory CD8+ and CD4+ T lymphocytes within the peripheral blood, spleen, and lymph nodes. In addition, SOCS1-KIR administration reduced lymphadenopathy, severity of skin lesions, autoantibody production, and modestly reduced kidney pathology. On a cellular level, peritoneal SOCS1-KIR administration enhanced Foxp3 expression in total splenic and follicular regulatory T cells, reduced the effector memory/naïve T lymphocyte ratio for both CD4+ and CD8+ cells, and reduced the frequency of GL7+ germinal center enriched B cells. Together, these data show that SOCS1-KIR treatment reduced auto-reactive lymphocyte effector functions and suggest that therapeutic targeting of the SOCS1 pathway through peptide administration may have efficacy in mitigating autoimmune pathologies.

Varying Opinions about Animal Welfare in the Australian Live Export Industry: A Survey.

There is significant public interest in the Australian live animal export industry and a need to develop a program that can measure and monitor animal welfare throughout the supply chain. An online survey of stakeholder opinions of this industry and animal welfare measures was carried out in 2015 with 921 respondents: 30% from the public who identified as animal welfare advocates (AWAs); 44% from the public who did not identify as AWAs (general public; GP); 26% live export industry (LEI) workers. AWA and GP respondents expressed greater concern than LEI respondents for animal welfare throughout the supply chain but had less concern for animals at Australian feedlots than in other parts of the supply chain. The majority of AWA and GP respondents believed data collected on animal welfare should be made public and should be collected by independent welfare officers and used to regulate the industry and impose penalties for poor welfare. LEI workers believed that data should be confidential, collected by LEI workers and used by the industry to self-regulate. AWA and GP respondents rated the importance and practicality of a number of welfare indicators greater than LEI workers, while respondents shared an analogous view of the importance and practicality of these indicators. Results can be used to develop welfare assessments that ensure a better understanding between industry members and those not in the industry, while facilitating welfare improvements and promoting greater transparency for the live export industry.

Review of the Online One Welfare Portal: Shared Curriculum Resources for Veterinary Undergraduate Learning and Teaching in Animal Welfare and Ethics.

This article introduces the online One Welfare learning and teaching portal (OWP) and describes its development, use, importance and relevance to animal welfare and ethics (AWE) stakeholders. As animal welfare issues increase in importance, veterinarians must be trained to lead the science that underpins AWE discourses. The OWP is a collection of resources designed to engage and challenge veterinary science students as they become advocates for animals. It was developed collaboratively by all eight veterinary schools in Australia and New Zealand, and funded by the Australian Government Office for Learning and Teaching. Surveys to investigate the attitudes of students and educators to AWE issues in six context-specific themes based on the Australian Animal Welfare Strategy (AAWS) (companion animals; animals used in research and teaching; livestock/production animals; animals used for sport, recreation or display; animals in the wild and aquatic animals) were administered through all participating schools. Students assigned more importance to Day One competence in knowledge of welfare concepts than did educators for the following groups: production animals, companion animals, animals in the wild, aquatic animals, animals used in research and teaching, and animals used for sport, recreation or display (all p < 0.01). Agreement between educators and students was closer regarding the importance of Day One competence for euthanasia for all six context-specific themes (p < 0.01 - 0.03). Students assigned more importance than educators to social, economic and cultural drivers of welfare outcomes in production animals (p < 0.01); slaughter and preslaughter inspections in production animals (p < 0.01); animal abuse and hoarding in companion animals (p < 0.01); shelter medicine in companion animals (p < 0.01); disaster preparedness in wildlife animals (p < 0.01); pain and distress caused by fishing in aquatic animals (p < 0.01); conscientious objection related to animals held for research and teaching (p < 0.01); behaviour, selection and training of animals used for sport, recreation and display (p = 0.046) and educating the public around sporting animal welfare (p < 0.01). Agreement between educators and students was closer for strategies to address painful husbandry procedures in production animals (p = 0.03); behaviour and training of companion animals (p = 0.03); veterinarians' duties to wild animals in wildlife (p = 0.02); the 3Rs in animals held for research and teaching (p = 0.03) and ownership responsibility in sporting animals (p = 0.01). This report discusses the reasons for differences among students and educators as they approach these issues. The portal is expected to gather more content as veterinary schools in other countries use its resources and users submit scenarios and discussion topics that reflect local needs.

Review of Livestock Welfare Indicators Relevant for the Australian Live Export Industry.

Animal welfare is an important issue for the live export industry (LEI), in terms of economic returns, community attitudes and international socio-political relations. Mortality has traditionally been the main welfare measure recorded within the LEI; however, high mortality incidents are usually acted upon after adverse events occur, reducing the scope for proactive welfare enhancement. We reviewed 71 potential animal welfare measures, identifying those measures that would be appropriate for use throughout the LEI for feeder and slaughter livestock species, and categorised these as animal-, environment- and resource-based. We divided the live export supply chain into three sectors: (1) Australian facilities, (2) vessel and (3) destination country facilities. After reviewing the relevant regulations for each sector of the industry, we identified 38 (sector 1), 35 (sector 2) and 26 (sector 3) measures already being collected under current practice. These could be used to form a 'welfare information dashboard': a LEI-specific online interface for collecting data that could contribute towards standardised industry reporting. We identified another 20, 25 and 28 measures that are relevant to each LEI sector (sectors 1, 2, 3, respectively), and that could be developed and integrated into a benchmarking system in the future.

Discovery and pharmacological characterization of AZD3229, a potent KIT/PDGFRα inhibitor for treatment of gastrointestinal stromal tumors.

Gastrointestinal stromal tumor (GIST) is the most common human sarcoma driven by mutations in KIT or platelet-derived growth factor α (PDGFRα). Although first-line treatment, imatinib, has revolutionized GIST treatment, drug resistance due to acquisition of secondary KIT/PDGFRα mutations develops in a majority of patients. Second- and third-line treatments, sunitinib and regorafenib, lack activity against a plethora of mutations in KIT/PDGFRα in GIST, with median time to disease progression of 4 to 6 months and inhibition of vascular endothelial growth factor receptor 2 (VEGFR2) causing high-grade hypertension. Patients with GIST have an unmet need for a well-tolerated drug that robustly inhibits a range of KIT/PDGFRα mutations. Here, we report the discovery and pharmacological characterization of AZD3229, a potent and selective small-molecule inhibitor of KIT and PDGFRα designed to inhibit a broad range of primary and imatinib-resistant secondary mutations seen in GIST. In engineered and GIST-derived cell lines, AZD3229 is 15 to 60 times more potent than imatinib in inhibiting KIT primary mutations and has low nanomolar activity against a wide spectrum of secondary mutations. AZD3229 causes durable inhibition of KIT signaling in patient-derived xenograft (PDX) models of GIST, leading to tumor regressions at doses that showed no changes in arterial blood pressure (BP) in rat telemetry studies. AZD3229 has a superior potency and selectivity profile to standard of care (SoC) agents-imatinib, sunitinib, and regorafenib, as well as investigational agents, avapritinib (BLU-285) and ripretinib (DCC-2618). AZD3229 has the potential to be a best-in-class inhibitor for clinically relevant KIT/PDGFRα mutations in GIST.

Importance of Stability Analysis When Using Nonlinear Semimechanistic Models to Describe Drug-Induced Hematotoxicity.

Stability analysis, often overlooked in pharmacometrics, is essential to explore dynamical systems. The model developed by Friberg et al.1 to describe drug-induced hematotoxicity is widely used to support decisions across drug development, and parameter values are often identified from observed blood counts. We use stability analysis to study the parametric dependence of stable and unstable solutions of several Friberg-type models and highlight the risks associated with system instability in the context of nonlinear mixed effects modeling. We emphasize the consequences of unstable solutions on prediction performance by demonstrating nonbiological system behaviors in a real case study of drug-induced thrombocytopenia. Ultimately, we provide simple criteria for identifying parameters associated with stable solutions of Friberg-type models. For instance, in the original Friberg model, we find that stability depends only on the parameter that governs the feedback from peripheral cells to progenitors and provide the exact range of values that results in stable solutions.

Semi-mechanistic modelling platform to assess cardiac contractility and haemodynamics in preclinical cardiovascular safety profiling of new molecular entities.

BACKGROUND AND PURPOSE: Cardiovascular safety is one of the most frequent causes of safety-related attrition both preclinically and clinically. Preclinical cardiovascular safety is routinely assessed using dog telemetry monitoring key cardiovascular functions. The present research was to develop a semi-mechanistic modelling platform to simultaneously assess changes in contractility (dPdtmax ), heart rate (HR) and mean arterial pressure (MAP) in preclinical studies. EXPERIMENTAL APPROACH: Data from dPdtmax , HR, preload (left ventricular end-diastolic pressure [LVEDP]) and MAP were available from dog telemetry studies after dosing with atenolol (n = 27), salbutamol (n = 5), L-NG -nitroarginine methyl ester (L-NAME; n = 4), milrinone (n = 4), verapamil (n = 12), dofetilide (n = 8), flecainide (n = 4) and AZ001 (n = 14). Literature model for rat CV function was used for the structural population pharmacodynamic model development. LVEDP was evaluated as covariate to account for the effect of preload on dPdtmax . KEY RESULTS: The model was able to describe drug-induced changes in dPdtmax , HR and MAP for all drugs included in the developed framework adequately, by incorporating appropriate drug effects on dPdtmax , HR and/or total peripheral resistance. Consistent with the Starling's law, incorporation of LVEDP as a covariate on dPdtmax to correct for the preload effect was found to be statistically significant. CONCLUSIONS AND IMPLICATIONS: The contractility and haemodynamics semi-mechanistic modelling platform accounts for diurnal variation, drug-induced changes and inter-animal variation. It can be used to hypothesize and evaluate pharmacological effects and provide a holistic cardiovascular safety profile for new drugs.

Developing an Animal Welfare Assessment Protocol for Livestock Transported by Sea.

Australian livestock industries face increased scrutiny from animal welfare groups and society, and the long-distance transport of livestock by sea has recently gained particular attention. Other than non-compliance with broad regulatory standards and voyage mortality rates, there is minimal information to ascertain the welfare of exported livestock. There is currently no standardised, validated animal welfare assessment protocol for livestock on-farm prior to live export or when undergoing transport. This study describes a novel assessment protocol suitable for use on live feeder and slaughter animals exported by sea from Australia. Health and welfare indicators for use in the livestock export supply chain were identified by reviewing three internationally recognised animal welfare assessment protocols for livestock; Welfare Quality®, AWIN and AssureWel, as well as consulting with industry compliance standards and guidelines. This paper proposes a welfare protocol designed to assess sheep and beef cattle exported by sea from Australia, and incorporates environmental-, resource-, management- and animal-based measures. In collaboration with industry, this welfare protocol can be tested on commercial livestock consignments, and be used for ongoing management, for increased transparency and to provide feedback to operators for continuous improvement.

Current and future approaches to nonclinical cardiovascular safety assessment.

Our goal is to accurately predict all types of cardiovascular events in patients utilising nonclinical cardiovascular safety data. In the past two decades, cardiovascular safety science has primarily focused on events associated with the electrocardiogram. Broadening out to other cardiovascular parameters, we share real-life case studies that highlight our progress towards improved and better-informed project progression based upon use of disease models, mechanism-based translation and structure-function relationships. To fulfil this goal, further advances in patient-relevant humanised models will be required to enable cardiovascular safety science to keep pace with the ever-changing landscape of novel therapeutic paradigms.

Quantifying Drug-Induced Bone Marrow Toxicity Using a Novel Haematopoiesis Systems Pharmacology Model.

Haematological toxicity associated with cancer therapeutics is monitored by changes in blood cell count, and their primary effect is on proliferative progenitors in the bone marrow. Using observations in rat bone marrow and blood, we characterize a mathematical model that comprises cell proliferation and differentiation of the full haematopoietic phylogeny, with interacting feedback loops between lineages in homeostasis as well as following carboplatin exposure. We accurately predicted the temporal dynamics of several mature cell types related to carboplatin-induced bone marrow toxicity and identified novel insights into haematopoiesis. Our model confirms a significant degree of plasticity within bone marrow cells, with the number and type of both early progenitors and circulating cells affecting cell balance, via feedback mechanisms, through fate decisions of the multipotent progenitors. We also demonstrated cross-species translation of our predictions to patients, applying the same core model structure and considering differences in drug-dependent and physiology-dependent parameters.

A Pilot Welfare Assessment of Working Ponies on Gili Trawangan, Indonesia.

Many working equids in developing countries experience poor health and welfare due to environmental and management factors. Collecting baseline data on these populations is essential to inform education projects to improve equid health and welfare. Gili Trawangan is an island in Indonesia that has no motor vehicles and a working pony population of approximately 200. This pilot study sought to determine baseline data on their health, welfare, and husbandry to inform future health and welfare strategies. A cross-sectional study was performed in May 2017 consisting of a pony cart driver questionnaire (n = 33) and a basic pony health examination (n = 38). The body condition scores of ponies were 3/5 (60.5%), 2/5 (31.6%), and 1/5 (7.9%), while 38% and 92% of ponies had lameness and foot pathology, respectively, and 31 ponies (86.1%) had at least one wound. Thirty percent of cart drivers stated they would work their ponies despite evidence of injury or illness. Limited education, poor access to veterinary services, and remoteness pose barriers to improving pony health and welfare. Our results indicate a need for, and can help inform, targeted education programmes to improve the lives of working ponies and protect livelihoods and tourism on Gili Trawangan.

VETERINARY STUDENTS' OPINIONS ON THEIR REQUIRED COMPETENCE IN DEALING WITH WELFARE AND ETHICS ISSUES PERTAINING TO WILDLIFE.

The aim of this research was to determine what veterinary students in Australia and New Zealand consider important for animal welfare and ethics (AWE) competence when dealing with wildlife, and to determine how these priorities correlate with gender and stage of study. These students were asked to state their gender and stage of veterinary education and to rank the importance of six AWE topics: (1) "disaster preparedness," (2) "veterinarians' duties to wild animals," (3) "methods and justification for wild animal use" (e.g., harvesting/ hunting, wildlife parks), (4) "tensions between animal-welfare concerns and environmental concerns," (5) "the nature and status of semiowned animals," and (6) "euthanasia," pertaining to wildlife for competence on the first day after their graduation. Data were then analyzed. Of 3,320 students invited to participate, 556 responded to questions about animals in the wild. The AWE topic ranked as the most important was "veterinarians' duties to wild animals," followed by "euthanasia." Senior students ranked "euthanasia" as the most important topic. The rankings of "methods and justification for wild animal use" and "tension between animal welfare and environmental concerns" were significantly less important for students in the later years of study than for those in early years. Male respondents ranked "euthanasia" as more important than female respondents did, especially in later years of study. Senior veterinary students ranked "euthanasia" as the most important AWE topic for day one competency.

Australian and New Zealand Veterinary Students' Opinions on Animal Welfare and Ethical Issues Concerning Animal Use within Sport, Recreation, and Display.

Animals used for sport, recreation and display are highly visible and can divide community attitudes. The study of animal welfare and ethics (AWE) as part of veterinary education is important because it is the responsibility of veterinarians to use their scientific knowledge and skills to promote animal welfare in the context of community expectations. To explore the attitudes of veterinary students in Australia and New Zealand to AWE, a survey of the current cohort was undertaken. The survey aimed to reveal how veterinary students in Australia and New Zealand rate the importance of five selected AWE topics for Day One Competences in animals used in sport, recreation and display and to establish how veterinary students' priorities were associated with gender and stage of study. The response rate (n = 851) across the seven schools was just over 25%. Results indicated little variation on ratings for topics. The topics were ranked in the following order (most to least important): Pushing of animals to their physiologic/behavioral limits; ownership/responsibility; euthanasia; educating the public; and behavior, selection, and training for sport and recreation displays. In contrast to related studies, ratings were not associated with stage of study and there were few differences associated with gender. More females rated the pushing of animals to physiologic/behavioral limits as extremely important than did males ( p < .001). The role of veterinarians in advocating for and educating the public about the welfare of animals used in sport, recreation and display merits further discussion.

Exploring how end-of-life management is taught to Australasian veterinary students. Part 1: technical euthanasia.

This descriptive study explored how end-of-life management was taught to students in all eight Australasian veterinary schools. A questionnaire-style interview guide was used by a representative at each university to conduct structured interviews with educators in a snowball sampling approach. Four categories of animals were addressed: livestock, equine, companion and avian/wildlife. This article focuses on the first part of the questionnaire: teaching the technical aspects of euthanasia. Euthanasia techniques were taught at more universities in clinical years than preclinical years. Clinical teaching relied on opportunities presenting, for example, euthanasia consultations. Few universities gave students a chance to practise euthanasia during a consultation and those that did were all with livestock. Competency in euthanasia techniques is an important aspect of clinical practice and these findings can be used to inform curriculum reviews of veterinary training.

Qualitative Behavioural Assessment as a Method to Identify Potential Stressors during Commercial Sheep Transport.

Land transport is an unavoidable experience for most livestock, yet there is limited research comparing animal welfare under different conditions. We video recorded sheep responses during short (2 h) commercial road transport journeys. Using Qualitative Behavioural Assessment, observers (blinded to the treatments) scored the behavioural expression of sheep and reached significant consensus in their scoring patterns (p < 0.001). There were also significant effects of vehicle crate design (sheep transported in a 'standard' crate were more calm/relaxed than those transported in a 'convertible' crate), deck position (sheep on upper decks were more curious/alert than those on lower decks), and sheep breed (fat-tail sheep were more agitated/distressed than merino sheep) on observer scores. We only found marginal differences for sheep originating from feedlot or saleyard. Significant effects of vehicle driver (included as a random factor in all but one of our analyses) suggest driving patterns contributed to demeanour of the sheep. Finally, the fourteen drivers who participated in the study were asked their opinions on livestock transport; none of the factors we tested were identified by drivers as important for sheep welfare during transport. This study supports the use of qualitative measures in transport and revealed differences that could inform truck design.

A Systematic Review of Heat Load in Australian Livestock Transported by Sea.

The transport of animals by sea ('live export') is one of the most important current animal welfare issues in Australian society. Recent media attention has highlighted concerns regarding the effects of high environmental temperature and humidity on the welfare and mortality of sheep being shipped live from Australia to the Middle East, especially during the Northern Hemisphere summer. To improve understanding of how and why harmful heat load occurs, we systematically reviewed Australian research into heat load and sea transport. High thermal load occurs during the sea transport of sheep and cattle from Australia when animals are subject to hot and humid environmental conditions and cannot remove heat generated by metabolic processes in the body, potentially also gaining heat from the environment. Several approaches have been proposed to mitigate these risks, including avoidance of voyages in hot seasons, selection of heat-resistant livestock breeds, reducing stocking density, and improved ventilation. We identified a lack of scientific literature relating to heat load in animals transported by sea and considerable potential for bias in the literature that was found. We identified the following priority research areas: (i) experimental manipulation of variables thought to influence the incidence and severity of harmful heat load, including sheep density; (ii) further assessment of the Heat Stress Risk Assessment (HSRA) model used to predict heat load events, and (iii) development of a suite of animal welfare indicators that may allow identification of 'at risk' sheep before they reach debilitating heat load condition. Addressing these knowledge gaps will assist efforts to reduce the frequency and intensity of harmful heat load events.