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Refined handling improves laboratory mouse welfare and research outcomes when compared to traditional tail handling, yet implementation does not seem to be widespread. Refined handling includes picking up a mouse using a tunnel or cupped hands. The aim of this study was to determine the current prevalence of and beliefs towards refined handling using the theory of planned behavior. It was predicted that refined handling prevalence is low compared to traditional handling methods, and its implementation is determined by individual and institutional beliefs. Research personnel were recruited via online convenience sampling through email listservs and social media. A total of 261 participants in diverse roles (e.g. veterinarians, managers, caretakers, researchers, etc.) responded primarily from the USA (79%) and academic institutions (61%) Participants were surveyed about their current use, knowledge, and beliefs about refined handling. Quantitative data were analyzed via descriptive statistics and generalised regression. Qualitative data were analyzed by theme. Research personnel reported low levels of refined handling implementation, with only 10% of participants using it exclusively and a median estimate of only 10% of institutional mice being handled with refined methods. Individually, participants had positive attitudes, neutral norms, and positive control beliefs about refined handling. Participants' intention to provide refined handling in the future was strongly associated with their attitudes, norms, and control beliefs (p<0.01). Participants believed barriers included jumpy mice, perceived incompatibility with restraint, lack of time, and other personnel. However, participants also believed refined handling was advantageous to mouse welfare, handling ease, personnel, and research. Although results from this survey indicate that current refined handling prevalence is low in this sample, personnel believe it has important benefits, and future use is associated with their beliefs about the practice. People who believed refined handling was good, felt pressure to use it, and were confident in their use reported higher implementation. Increased refined handling could be encouraged through education on misconceptions, highlighting advantages, and addressing important barriers. [ABSTRACT FROM AUTHOR]

The laboratory mouse is a key player in preclinical oncology research. However, emphasis of techniques reporting at the expense of critical animal-related detail compromises research integrity, animal welfare, and, ultimately, the translation potential of mouse-based oncology models. To evaluate current reporting practices, we performed a cross-sectional survey of 400 preclinical oncology studies using mouse solid-tumour models. Articles published in 2020 were selected from 20 journals that specifically endorsed the ARRIVE (Animal Research: Reporting of In Vivo Experiments) preclinical reporting guidelines. We assessed reporting compliance for 22 items in five domains: ethical oversight assurance, animal signalment, husbandry, welfare, and euthanasia. Data were analysed using hierarchical generalised random-intercept models, clustered on journal. Overall, reporting of animal-related items was poor. Median compliance over all categories was 23%. There was little or no association between extent of reporting compliance and journal or journal impact factor. Age, sex, and source were reported most frequently, but verifiable strain information was reported for <10% of studies. Animal husbandry, housing environment, and welfare items were reported by <5% of studies. Fewer than one in four studies reported analgesia use, humane endpoints, or an identifiable method of euthanasia. Of concern was the poor documentation of ethical oversight information. Fewer than one in four provided verifiable approval information, and almost one in ten reported no information, or information that was demonstrably false. Mice are the "invisible actors" in preclinical oncology research. In spite of widespread endorsement of reporting guidelines, adherence to reporting guidelines on the part of authors is poor and journals fail to enforce guideline reporting standards. In particular, the inadequate reporting of key animal-related items severely restricts the utility and translation potential of mouse models, and results in research waste. Both investigators and journals have the ethical responsibility to ensure animals are not wasted in uninformative research. [ABSTRACT FROM AUTHOR]

Based on queries received during our 2021 LASA 3Rs' presentation, we describe operational highlights and concerns that came up during the rollout of nonaversive handling as standard of care at our mouse breeding facility. We describe the development of the square handling tunnel (or 'squnnel'), some of the pros and cons of its introduction and use, general concerns about increased work burden associated with non-aversive handling and, key items to be included during planning and implementation when non-aversive handling is to be introduced as a new standard of care. [ABSTRACT FROM AUTHOR]

Translation of animal-based preclinical research is hampered by poor validity and reproducibility issues. Unfortunately, preclinical research has 'fallen between the stools' of competing study design traditions. Preclinical studies are often characterised by small sample sizes, large variability, and 'problem' data. Although Fisher-type designs with randomisation and blocking are appropriate and have been vigorously promoted, structured statistically-based designs are almost unknown. Traditional analysis methods are commonly misapplied, and basic terminology and principles of inference testing misinterpreted. Problems are compounded by the lack of adequate statistical training for researchers, and failure of statistical educators to account for the unique demands of preclinical research. The solution is a return to the basics: statistical education tailored to non-statistician investigators, with clear communication of statistical concepts, and curricula that address design and data issues specific to preclinical research. Statistics curricula should focus on statistics as process: data sampling and study design before analysis and inference. Properly-designed and analysed experiments are a matter of ethics as much as procedure. Shifting the focus of statistical education from rote hypothesis testing to sound methodology will reduce the numbers of animals wasted in noninformative experiments and increase overall scientific quality and value of published research. [ABSTRACT FROM AUTHOR]

Non-aversive handling is a well-documented refinement measure for improving rodent welfare. Because maternal stress is related to reduced productivity, we hypothesized that welfare benefits associated with non-aversive handling would translate to higher production and fewer litters lost in a laboratory mouse breeding colony. We performed a randomized controlled trial to examine the effects of a standard method of handling (tail-lift with forceps) versus non-aversive handling with transfer tunnels ('tunnel-handled') on breeding performance in 59 C57BL/6J mouse pairs. Intervention assignments could not be concealed from technicians, but were concealed from assessors and data analyst. An operationally significant effect of tunnel-handling (large enough differences to warrant programmatic change) was defined before study initiation as a 5% increase in productivity, or one extra pup over the reproductive lifetime of each pair. Pairs were randomly allocated to handling intervention and cage rack location, and monitored over an entire 6-month breeding cycle. For each group, we measured number of pups born and weaned, and number of entire litters lost prior to weaning. Differences between transfer methods were estimated by two-level hierarchical mixed models adjusted for parental effects and parity. Compared to tail-lift mice, tunnel-handled mice averaged one extra pup per pair born (+1.0; 95% CI 0.9, 1.1; P = 0.41) and weaned (+1.1, 95% CI 0.9, 1.2; P = 0.33). More tunnel-handled pairs successfully weaned all litters produced (13/29 pairs, 45% vs 4/30 pairs, 13%; P = 0.015), averaged fewer litter losses prior to weaning (11/29 pairs [38%] vs 26/30 pairs [87%]; P <0.001), and had a 20% lower risk of recurrent litter loss. The increase in numbers of pups produced and weaned with tunnel handling met threshold requirement for operational significance. These data and projected cost savings persuaded management to incorporate tunnel handling as standard of care across the institution. These data also suggest that overlooked husbandry practices such as cage transfer may be major confounders in studies of mouse models. [ABSTRACT FROM AUTHOR]

Best-practice clinical decision-making for patient blood management (PBM) and transfusion in cardiac surgery requires high-quality, timely information. However, evidence will be misleading if published information lags too far behind evolving practice, or if trial results are biased, incomplete, or unreported. The result is that providers are deprived of accurate data, and patients will not receive best possible care. Publicly accessible trial registries provide information for structured audits of reporting compliance, and appraisal of evidence attrition and distortion. Trials related to blood management and transfusion in cardiac surgery and those registered in Clinical-Trials.gov were evaluated for relevance, reliability, transparency, timeliness, and prevalence of unreported trial results. Evidence was considered to have "disappeared" if no results were posted to the registry and no related PUBMED publications were available by July 2019. Data were summarized by descriptive statistics. A total of 181 registered trials were surveyed; 52% were prospectively registered. Most commonly reported primary outcomes were laboratory surrogate measures (34%). Patient- and practice-relevant outcomes--mortality/major morbidity (7%), transfusion (27%), and major bleeding (28%)--were less common. Only seven studies posted results to the registry within the mandated 12 months from study completion; median time to posting was 17 (interquartile range [IQR] 13, 37) months. Trial results for 58%were unreported 3-9 years after trial completion. A staggering amount of clinical trial evidence for PBM in cardiac surgery is missing from publicly accessible records and the literature. Investigators must be incentivized to promptly and completely report all results. Penalties for noncompliance are already in place and should be enforced. Simplified information linkage, centralized and routine audit cycles, and prioritization of robust "living" reviews may be more positive motivators. Implementation will require a sea change in the prevailing culture of research reporting, plus coordinated efforts of clinicians, applied statisticians, information technology specialists, and research librarians. [ABSTRACT FROM AUTHOR]

Poor quality data in preclinical trials can result from inconsistent and unstandardized experimental processes. Unpredictable pre-intervention variability generates unreliable data, biases outcomes and results in needless waste of animals and resources. We applied Define-Measure-Analyse-Improve-Control (DMAIC) quality improvement processes to pilot development of a swine model of trauma, haemorrhagic shock and coagulopathy. The goal was to reduce variability through protocol standardization and error reduction. Six male Sinclair swine were sequentially anesthetized, intubated, mechanically ventilated and instrumented, then subjected to multiple-hit injury, followed by fluid resuscitation monitoring and coagulation testing. Experimental tasks were defined and mapped. Performance measures were task performance times, subject stabilization time and number of task execution errors. Process improvement was assessed by reduced times and errors, and subject stability at target physiological values. Previously-overlooked performance errors and deficiencies were identified. 'Mistake-proofing' actions included personnel retraining, revisions of standard operating procedures and use of checklists. The quality improvement pilot trial produced a stable model with reduced protocol deviations. Data quality can be improved and animal waste minimized, if experimental planning incorporates strategies to ensure protocol adherence and reduced operator performance variation and errors. Properly designed pilot trials can be essential components of refinement and reduction strategies in animal-based research. [ABSTRACT FROM AUTHOR]

Purpose: Vasoplegia is a clinical syndrome marked by severe arteriolar vasodilatation, hypotension, and low systemic vascular resistance refractory to multiple vasopressor treatment. We report our experience with hydroxocobalamin (B12) infusion as a potential rescue adjunct for refractory vasoplegia during cardiopulmonary bypass (CPB).Methods: We performed a retrospective chart review of 33 patients undergoing cardiac surgery between 1 January 2013 and 31 December 2015, who were given intravenous B12 for refractory hypotension during, or immediately following, CPB. We assessed mean arterial pressure (MAP) responses using semi-parametric group-based models (trajectory analysis). Vasopressor use was evaluated by norepinephrine-equivalent rates calculated five minutes prior, and up to 60 min following, B12 administration.Results: Patients were mostly male (82%), had a mean (SD) age of 53 (13) yr, and median (IQR) EuroSCORE mortality index of 9 [4-40]. Four patterns of MAP responses to B12 were identified. In Group 1 ("poor responders") nine of 33 patients (27%) had the highest median [IQR] mortality risk (EuroSCORE 40 [4-52]), lowest mean pre-B12 MAP (50 mmHg), and minimal hemodynamic response in spite of continued vasopressor support. In contrast, Group 2 "responders" (8/33, 24%) showed a brisk MAP response (> 15 mmHg) to B12, sustained for > 60 min post-infusion, with 50% vasopressor reduction. Groups 3 and 4 had the lowest median mortality risk (EuroSCORE 8) and highest pre-B12 MAP (72 mmHg). Although Group 3 patients ("sustainers"; 9/33, 27%) showed a sustained MAP improvement, those in Group 4 ("rebounders"; 7/33, 21%) were characterized by hypertensive overshoot followed by a decrease in MAP.Conclusion: These data indicate considerable heterogeneity in patient response to B12, potentially dependent on both patient preoperative condition and non-standardized time of administration. B12 may provide a useful alternative therapy for refractory hypotension and vasoplegia, but controlled clinical trials to assess efficacy are needed. [ABSTRACT FROM AUTHOR]

Background: Clinical trial success depends on appropriate management, but practical guidance to trial organisation and planning is lacking. The Incident Command System (ICS) is the 'gold standard' management system developed for managing diverse operations in major incident and public health arenas. It enables effective and flexible management through integration of personnel, procedures, resources, and communications within a common hierarchical organisational structure. Conventional ICS organisation consists of five function modules: Command, Planning, Operations, Logistics, and Finance/Administration. Large clinical trials will require a separate Regulatory Administrative arm, and an Information arm, consisting of dedicated data management and information technology staff. We applied ICS principles to organisation and management of the Prehospital Use of Plasma in Traumatic Haemorrhage (PUPTH) trial. This trial was a multidepartmental, multiagency, randomised clinical trial investigating prehospital administration of thawed plasma on mortality and coagulation response in severely injured trauma patients. We describe the ICS system as it would apply to large clinical trials in general, and the benefits, barriers, and lessons learned in utilising ICS principles to reorganise and coordinate the PUPTH trial.Results: Without a formal trial management structure, early stages of the trial were characterised by inertia and organisational confusion. Implementing ICS improved organisation, coordination, and communication between multiple agencies and service groups, and greatly streamlined regulatory compliance administration. However, unfamiliarity of clinicians with ICS culture, conflicting resource allocation priorities, and communication bottlenecks were significant barriers.Conclusions: ICS is a flexible and powerful organisational tool for managing large complex clinical trials. However, for successful implementation the cultural, psychological, and social environment of trial participants must be accounted for, and personnel need to be educated in the basics of ICS.Trial Registration: ClinicalTrials.gov, NCT02303964 . Registered on 28 November 2014. [ABSTRACT FROM AUTHOR]

Background: Severe traumatic injury and haemorrhagic shock are frequently associated with disruptions of coagulation function (such as trauma-induced coagulopathy TIC) and activation of inflammatory cascades. These pathologies may be exacerbated by current standard of care resuscitation protocols. Observational studies suggest early administration of plasma to severely-injured haemorrhaging patients may correct TIC, minimise inflammation, and improve survival. The proposed randomised clinical trial will evaluate the clinical effectiveness of pre-hospital plasma administration compared with standard- of-care crystalloid resuscitation in severely-injured patients with major traumatic haemorrhage. Methods/design: This is a prospective, randomized, open-label, non-blinded trial to determine the effect of pre-hospital administration of thawed plasma (TP) on mortality, morbidity, transfusion requirements, coagulation, and inflammatory response in severely-injured bleeding trauma patients. Two hundred and ten eligible adult trauma patients will be randomised to receive either two units of plasma, to be administered in-field, vs standard of care normal saline (NS). Main analyses will compare subjects allocated to TP to those allocated to NS, on an intention-to-treat basis. Primary outcome measure is all-cause 30-day mortality. Secondary outcome measures include coagulation and lipidomic/pro-inflammatory marker responses, volume of resuscitation fluids (crystalloid, colloid) and blood products administered, and major hospital outcomes (e.g. incidence of MSOF, length of ICU stay, length of hospital stay). Discussion: This study is part of a US Department of Defense (DoD)-funded multi-institutional investigation, conducted independently of, but in parallel with, the University of Pittsburgh and University of Denver. Demonstration of significant reductions in mortality and coagulopathic/inflammatory-related morbidities as a result of pre-hospital plasma administration would be of considerable clinical importance for the management of haemorrhagic shock in both civilian and military populations. [ABSTRACT FROM AUTHOR]

Background: Severe traumatic injury and haemorrhagic shock are frequently associated with disruptions of coagulation function (such as trauma-induced coagulopathy TIC) and activation of inflammatory cascades. These pathologies may be exacerbated by current standard of care resuscitation protocols. Observational studies suggest early administration of plasma to severely-injured haemorrhaging patients may correct TIC, minimise inflammation, and improve survival. The proposed randomised clinical trial will evaluate the clinical effectiveness of pre-hospital plasma administration compared with standard- of-care crystalloid resuscitation in severely-injured patients with major traumatic haemorrhage. Methods/design: This is a prospective, randomized, open-label, non-blinded trial to determine the effect of pre-hospital administration of thawed plasma (TP) on mortality, morbidity, transfusion requirements, coagulation, and inflammatory response in severely-injured bleeding trauma patients. Two hundred and ten eligible adult trauma patients will be randomised to receive either two units of plasma, to be administered in-field, vs standard of care normal saline (NS). Main analyses will compare subjects allocated to TP to those allocated to NS, on an intentionto- treat basis. Primary outcome measure is all-cause 30-day mortality. Secondary outcome measures include coagulation and lipidomic/pro-inflammatory marker responses, volume of resuscitation fluids (crystalloid, colloid) and blood products administered, and major hospital outcomes (e.g. incidence of MSOF, length of ICU stay, length of hospital stay). Discussion: This study is part of a US Department of Defense (DoD)-funded multi-institutional investigation, conducted independently of, but in parallel with, the University of Pittsburgh and University of Denver. Demonstration of significant reductions in mortality and coagulopathic/inflammatory-related morbidities as a result of pre-hospital plasma administration would be of considerable clinical importance for the management of haemorrhagic shock in both civilian and military populations. [ABSTRACT FROM AUTHOR]

Clinicians have limited experience with assessment and treatment of overdose from newer anticonvulsant medications. The aim of this investigation was to evaluate clinical effects of newer anticonvulsant overdose, determine if a relationship exists between dose and clinical effect, and if a particular agent appears more toxic in overdose. This was a retrospective study using electronic poison center data, evaluating clinical outcomes from newer anticonvulsant overdose. The Toxicall™ database from January 1, 2002 to December 31, 2011 was queried using key words: 'gabapentin,' 'lamotrigine,' 'levetiracetam,' 'tiagabine,' 'topiramate,' 'zonisamide,' 'pregabalin,' and 'oxcarbazine.' Polypharmacy overdose and children less than 15 years of age were excluded. Charts were reviewed by two abstractors for pharmaceutical, self-reported dose, clinical effect score, and clinical signs, symptoms, and vital signs recorded in the chart. Ordinal logistic regression was used to evaluate the relationship between drug type, dose, age, and sex to clinical effect score. Out of 501 cases identified, 347 met the final inclusion criteria. There were 116 gabapentin, 67 lamotrigine, 15 levetiracetam, 15 tiagabine, 56 topiramate, 23 pregabalin, and 55 oxcarbazepine cases. Overdose of newer anticonvulsants frequently results in altered mental status. Seizures may be more common with tiagabine, lamotrigine, and oxcarbazepine. There was one death reported from intentional overdose of topiramate. An information index was created to rank drug toxicity based on reported signs and symptoms for each overdose. There was no significant effect of dose on severity of outcome ( β = 0.12, p = 0.23). However, the risk of a more severe outcome score was significantly increased with tiagabine relative to other drugs ( β = 2.8, p = 0.001). Lamotrigine ranked highest in terms of toxicity (HT = 1.66) and number of interventions performed (HI = 1.17), and levetiracetam the lowest (HT = 0.98; HI = 0.88). We could not identify a dose-effect in these data which likely reflects the limitations of self-reported doses. Despite limitations of these data, the risk of more severe outcome scores appear to be higher with tiagabine overdose while lamotrigine overdose appears to result in more reported signs, symptoms, and interventions. [ABSTRACT FROM AUTHOR]

Moles are the only fertile true hermaphrodites described up to now among mammals. This paper investigates the development and growth of the mole Talpa occidentalis. Fifteen developmental stages (8 prenatal and 7 postnatal) were established and 12 of them, ranging from early gestation to weaning, are described in detail. The growth of moles was shown to fit triphasic curves for both males and females. The coefficient of reproductive effort of females, defined as mass of the litter at weaning relative to maternal body mass, is inversely proportional to mass of the female, according to an exponential function. Compared with other insectivores with lower body mass (shrews), this coefficient in female moles (2.69) is significantly higher than expected (1.91), which implies that reproductive effort of moles is 36% greater. This study provides the chronological criteria (based on body mass, crown-rump length, and major external morphological features) needed for age determination of individual developing moles and thus represents a useful tool for further studies in these mammals. [ABSTRACT FROM AUTHOR]

We studied dispersal and breeding patterns in a solitary gerbil, Meriones tamariscinus, from 1995 to 1999 in Kalmykia, southern Russia. The females of this species delay breeding far beyond the age of maturation. We suggest that delayed breeding in young females is associated with delayed emigration from the natal site. Most young female M. tamariscinus showed strong natal philopatry that resulted in female kin clustering. Proximity to adult females suppressed their maturation and restricted breeding opportunities. Breeding rate of young females correlated negatively with the survival rate of adult females. Therefore, dispersal and breeding patterns in this solitary species appear similar to those in social (group living) species of gerbils. Results are discussed in terms of ecological, demographic, and life-history traits of this species that set constraints on dispersal and breeding in young females. [ABSTRACT FROM AUTHOR]

We radiotracked 23 Japanese dormice (Glirulus japonicus) in a natural oak forest and a larch plantation to locate their daily rest sites. In 363 tracking days, 123 rest sites were used, 72% in trees and 28% in shallow underground sites or a rock crevice. Nest boxes and tree cavities were the most frequently used rest sites in trees. Natural arboreal rest sites and nest boxes were used regularly by individual dormice, whereas most underground rest sites were used for only 1 day. Nest boxes and underground rest sites were used more frequently in the larch plantation than in the oak forest. Males used nest boxes more than underground rest siedtes, whereas females regularly used the same natural arboreal rest sites. Dormice had large home ranges relative to their body mass. Males had larger home ranges and moved for longer distances at night than did females. A close relationship between rest-site use and daily torpor was apparent; nesting material was not found in natural rest sites used only once, and dormice frequently changed their rest sites. [ABSTRACT FROM AUTHOR]

Examines the standardized measurement of operative temperature for mallard ducklings using heated taxidermic mounts. Method used in calibrating the mounts; Details of the mathematical computation used in the calibration of mounts.

Most duckling mortality occurs during the week following hatching and is often associated with cold, windy, wet weather and scattering of the brood. We estimated the thermoregulatory demands imposed by cold, windy weather on isolated 1-d-old mallard (Anas platyrhynchos) ducklings resting in cover. We measured O2 consumption and evaporative water loss at air temperatures from 5° to 25°C and wind speeds of 0.1, 0.2, 0.5, and 1.0 m/s. Metabolic heat production increased as wind increased or temperature decreased but was less sensitive to wind than that of either adult passerines or small mammals. Evaporative heat loss ranged from 5% to 17% of heat production. Evaporative heat loss and the ratio of evaporative heat loss to metabolic heat production was significantly lower in rest phase. These data were used to define a standard operative temperature (T[subes] ) scale for night or heavy overcast conditions. An increase of wind speed from 0.1 to 1 m/s decreased T[subes] by 3°--5°C. [ABSTRACT FROM AUTHOR]

Investigates the thermoregulatory effects of radiotelemetry transmitters on mallard ducks. Possibility of attachments disrupting downy insulation and biasing survival rates during cold weather; Comparison of surface temperatures; Rates of net heat production; Body mass loss.

Background: Severe traumatic injury and haemorrhagic shock are frequently associated with disruptions of coagulation function (such as trauma-induced coagulopathy TIC) and activation of inflammatory cascades. These pathologies may be exacerbated by current standard of care resuscitation protocols. Observational studies suggest early administration of plasma to severely-injured haemorrhaging patients may correct TIC, minimise inflammation, and improve survival. The proposed randomised clinical trial will evaluate the clinical effectiveness of pre-hospital plasma administration compared with standard- of-care crystalloid resuscitation in severely-injured patients with major traumatic haemorrhage.Methods/design: This is a prospective, randomized, open-label, non-blinded trial to determine the effect of pre-hospital administration of thawed plasma (TP) on mortality, morbidity, transfusion requirements, coagulation, and inflammatory response in severely-injured bleeding trauma patients. Two hundred and ten eligible adult trauma patients will be randomised to receive either two units of plasma, to be administered in-field, vs standard of care normal saline (NS). Main analyses will compare subjects allocated to TP to those allocated to NS, on an intention-to-treat basis. Primary outcome measure is all-cause 30-day mortality. Secondary outcome measures include coagulation and lipidomic/pro-inflammatory marker responses, volume of resuscitation fluids (crystalloid, colloid) and blood products administered, and major hospital outcomes (e.g. incidence of MSOF, length of ICU stay, length of hospital stay).Discussion: This study is part of a US Department of Defense (DoD)-funded multi-institutional investigation, conducted independently of, but in parallel with, the University of Pittsburgh and University of Denver. Demonstration of significant reductions in mortality and coagulopathic/inflammatory-related morbidities as a result of pre-hospital plasma administration would be of considerable clinical importance for the management of haemorrhagic shock in both civilian and military populations.Trial Registration: ClinicalTrials.gov: NCT02303964 on 28 November 2014. [ABSTRACT FROM AUTHOR]